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Shortness of breath, fever, cough, and more in an elderly woman

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Shortness of breath, fever, cough, and more in an elderly woman

Author(s)

Brody D. Slostad, MD

Megha Prasad, MD

Nandan S. Anavekar, MD

An 87-year-old woman was brought to the intensive care unit with worsening shortness of breath on exertion, fatigue, orthopnea, paroxysmal nocturnal dyspnea, lower extremity swelling, subjective fever, productive cough, and rhinorrhea over the last week. She reported no chest pain, lightheadedness, or palpitations. Her medical history included the following:

Coronary artery disease requiring coronary artery bypass grafting
Ischemic cardiomyopathy
Severe mitral regurgitation
Moderate tricuspid regurgitation
Pulmonary hypertension
Cardiac arrest with recurrent ventricular tachycardia requiring an implanted cardioverter-defibrillator and amiodarone therapy
Hypothyroidism requiring levothyroxine
Asthma with a moderate obstructive pattern: forced expiratory volume in 1 second (FEV₁) 60% of predicted, forced vital capacity (FVC) 2.06 L, FEV₁/FVC 54%, diffusing capacity for carbon monoxide (DLCO) 72% of predicted with positive bronchodilator response
Long-standing essential thrombocythemia treated with hydroxyurea.

Before admission, she had been reliably taking guideline-directed heart failure therapy as well as amiodarone for her recurrent ventricular tachycardia. Her levothyroxine had recently been increased as well.

Physical examination. On admission, her blood pressure was 95/53 mm Hg, heart rate 73 beats per minute, temperature 36.7ºC (98.1ºF), and oxygen saturation 81% requiring supplemental oxygen 15 L/min by nonrebreather face mask. Physical examination revealed elevated jugular venous pressure, bibasilar crackles, lower extremity edema, and a grade 3 of 6 holosystolic murmur both at the left sternal border and at the apex radiating to the axilla. There was no evidence of wheezing or pulsus paradoxus.

Initial laboratory evaluation revealed abnormal values (Table 1).

Electrocardiography showed sinus rhythm and an old left bundle branch block.

Chest radiography showed cardiomegaly, bilateral pleural effusions, and pulmonary edema.

WHAT IS THE CAUSE OF HER SYMPTOMS?

1. Based on the available information, which of the following is the most likely cause of this patient’s clinical presentation?

Acute decompensated heart failure
Pulmonary embolism
Exacerbation of asthma
Exacerbation of chronic obstructive pulmonary disease (COPD)

Heart failure is a clinical diagnosis based on careful history-taking and physical examination. Major criteria include paroxysmal nocturnal dyspnea, orthopnea, elevated jugular venous pressure, pulmonary crackles, a third heart sound, cardiomegaly, pulmonary edema, and weight loss of more than 4.5 kg with diuretic therapy.¹ N-terminal pro-B-type natriuretic peptide (NT-proBNP) is also an effective marker of acute decompensated heart failure in the proper clinical setting.²

Our patient’s elevated jugular venous pressure, bibasilar crackles, lower extremity edema, chest radiography findings consistent with pulmonary edema, markedly elevated NT-proBNP, history of orthopnea, paroxysmal nocturnal dyspnea, and dyspnea on exertion were most consistent with acute decompensated heart failure. Her cough and subjective fevers were thought to be due to an upper respiratory tract viral infection.

Pulmonary embolism causes pleuritic chest pain, dyspnea, and, occasionally, elevated troponin. The most common feature on electrocardiography is sinus tachycardia; nonspecific ST-segment and T-wave changes may also be seen.³

Although pulmonary embolism remained in the differential diagnosis, our patient’s lack of typical features of pulmonary embolism made this less likely.

Asthma is characterized by recurrent airflow obstruction and bronchial hyperresponsiveness.⁴ Asthma exacerbations present with wheezing, tachypnea, tachycardia, and pulsus paradoxus.⁵

Despite her previous asthma diagnosis, our patient’s lack of typical features of asthma exacerbation made this diagnosis unlikely.

COPD exacerbations present with increased dyspnea, cough, sputum production, wheezing, lung resonance to percussion, and distant heart sounds, and are characterized by airflow obstruction.^6,7

Although our patient presented with cough and dyspnea, she had no history of COPD and her other signs and symptoms (elevated jugular venous pressure, elevated NT-proBNP, and peripheral edema) could not be explained by COPD exacerbation.

OUR PATIENT UNDERWENT FURTHER TESTING

Echocardiography revealed severe left ventricular enlargement, an ejection fraction of 20% (which was near her baseline value), diffuse regional wall-motion abnormalities, severe mitral regurgitation, and moderate tricuspid regurgitation consistent with an exacerbation of heart failure.

We considered the possibility that her heart failure symptoms might be due to precipitous up-titration of her levothyroxine dose, given her borderline-elevated free thyroxine (T₄) and increase in cardiac index (currently 4.45 L/min/m², previously 2.20 L/min/m² by the left ventricular outflow tract velocity time integral method). However, given her reduced ejection fraction, this clinical presentation most likely represented an acute exacerbation of her chronic heart failure. Her subjective fevers were thought to be due to a viral infection of the upper respiratory tract. The macrocytic anemia and thrombocytopenia were thought to be a side effect of her long-standing treatment with hydroxyurea for essential thrombocythemia, although amiodarone has also been associated with cytopenia.⁸

Treatment was started with intravenous diuretics and positive pressure ventilation with oxygen supplementation. Her levothyroxine dose was reduced, and her hydroxyurea was stopped.

Figure 1. Chest computed tomography axial views demonstrated increased attenuation in the liver (A, arrow) and left pleural base (B, arrow). Evaluation of the right lung base revealed ground-glass opacities (C, arrow) and honeycombing (D, arrow). These findings were consistent with amiodarone pulmonary toxicity.

After aggressive diuresis, our patient returned to euvolemia. However, she had persistent fine crackles and hypoxia. She had no further fever, and her vital signs were otherwise stable. Her cytopenia improved with cessation of hydroxyurea. Chest computed tomography (CT) showed bibasilar ground-glass infiltrates with areas of interstitial fibrosis, high-attenuation pleural lesions, and increased liver attenuation (Figure 1).

Further testing for connective tissue disease and hypersensitivity pneumonitis was also done, and the results were negative. To exclude an atypical infection, bronchoalveolar lavage was performed; preliminary microbial testing was negative, and the white blood cell count in the lavage fluid was 90% macrophages (pigment-laden), 7% neutrophils, and 3% lymphocytes.

WHAT IS THE CAUSE OF HER PERSISTENT PULMONARY FINDINGS?

2. Given the CT findings and laboratory results, what is the most likely cause of our patient’s persistent crackles and hypoxia?

Heart failure with reduced ejection fraction
Bacterial pneumonia
Idiopathic pulmonary fibrosis
Amiodarone pulmonary toxicity

Heart failure with reduced ejection fraction can cause ground-glass opacities on CT due to increased pulmonary edema. Although our patient initially presented with acute decompensation of heart failure with reduced ejection fraction decompensation, she had returned to euvolemia after aggressive diuresis. Moreover, increased pleural and liver attenuation are not typically seen as a result of heart failure with reduced ejection fraction, making this diagnosis less likely.

Bacterial pneumonia typically presents with cough, fever, and purulent sputum production.⁹ Further evaluation usually reveals decreased breath sounds, dullness to percussion, and leukocytosis.¹⁰ Chest CT in bacterial pneumonia commonly shows a focal area of consolidation, which was not seen in our patient.¹¹

Idiopathic pulmonary fibrosis usually presents with slowly progressive dyspnea and nonproductive cough.¹² Physical examination usually reveals fine crackles and occasionally end-inspiratory “squeaks” if traction bronchiectasis is present.¹² The diagnosis of idiopathic pulmonary fibrosis requires chest CT findings compatible with it (ie, basal fibrosis, reticular abnormalities, and honeycombing). However, it remains a diagnosis of exclusion and requires ruling out conditions known to cause pulmonary fibrosis such as hypersensitivity pneumonitis, connective tissue disease, and certain medications.¹²

Although idiopathic pulmonary fibrosis remained in the differential diagnosis, our patient remained on amiodarone, a known cause of pulmonary fibrosis.¹³ Similarly, the high-attenuation pleural lesions likely represented organizing pneumonia, which is more common in amiodarone pulmonary toxicity. And the ground-glass opacities made idiopathic pulmonary fibrosis unlikely, although they may be seen in an acute exacerbation of this disease.¹⁴ Thus, a diagnosis of idiopathic pulmonary fibrosis could not be made definitively.

Amiodarone pulmonary toxicity most commonly presents with acute to subacute cough and progressive dyspnea.¹³ Physical findings are similar to those in idiopathic pulmonary fibrosis and commonly include bibasilar crackles. Chest CT shows diffuse ground-glass opacities, reticular abnormalities, fibrosis, and increased attenuation of multiple organs, including the lungs, liver, and spleen.¹⁴ Bronchoalveolar lavage findings of lipid-laden macrophages suggest but do not definitively diagnose amiodarone pulmonary toxicity.¹⁵ And patients with acute amiodarone pulmonary toxicity may present with pigment-laden macrophages on bronchoalveolar lavage, as in our patient.¹⁶

Exclusion of hypersensitivity pneumonitis, connective tissue disease, and infection made our patient’s progressive dyspnea and chest CT findings of ground-glass opacities, fibrosis, and increased pulmonary and liver attenuation most consistent with amiodarone pulmonary toxicity.

Amiodarone was therefore discontinued. However, the test result of her lavage fluid for influenza A by polymerase chain reaction came back positive a few hours later.

WHAT IS THE NEXT STEP?

3. Given the positive influenza A polymerase chain reaction test, which of the following is the best next step in this patient’s management?

Surgical lung biopsy
Stop amiodarone and start supportive influenza management
Stop amiodarone and start dronedarone
Start an intravenous corticosteroid

Surgical lung biopsy is typically not required for diagnosis in patients with suspected amiodarone pulmonary toxicity. In addition, acute respiratory distress syndrome has been documented in patients who have undergone surgical biopsy for suspected amiodarone pulmonary toxicity.¹⁷

Thus, surgical biopsy is typically only done in cases of persistent symptoms despite withdrawal of amiodarone and initiation of steroid therapy.

Stopping amiodarone and starting supportive influenza management are the best next steps, as our patient’s fevers, cough, dyspnea, and laboratory test results were consistent with influenza.¹⁸ Moreover, CT findings of ground-glass opacities and reticular abnormalities can be seen in influenza.¹⁹

However, concomitant amiodarone pulmonary toxicity could not be ruled out, as CT showed increased lung and liver attenuation and fibrosis that could not be explained by influenza. And the elevation in aminotransferase levels more than 2 times the upper limit of normal and CT findings of increased liver attenuation suggested amiodarone hepatotoxicity. However, definitive diagnosis would require exclusion of other causes such as congestive hepatopathy, in some cases with liver biopsy.¹³

Our patient’s persistent hypoxia was thought to be due in part to influenza, and thus the best next step in management was to stop amiodarone and provide supportive care for influenza.

Dronedarone is an antiarrhythmic drug structurally and functionally similar to amiodarone. There are far fewer reports of pulmonary toxicity with dronedarone than with amiodarone.²⁰ However, lack of data on dronedarone in amiodarone pulmonary toxicity, increased rates of hospitalization and death associated with dronedarone in patients like ours with advanced heart failure, and our patient’s previously implanted cardioverter-defibrillator for recurrent ventricular tachycardia all made dronedarone an undesirable alternative to amiodarone.²¹

Corticosteroids are useful in the treatment of amiodarone pulmonary toxicity when hypoxia and dyspnea are present at diagnosis.¹³ Our patient’s hypoxia and dyspnea were thought to be due in part to her acute influenza infection, and therefore corticosteroids were not used at the outset.

However, concomitant amiodarone pulmonary toxicity could not be excluded, and the elevation in aminotransferases of more than 2 times the upper limit of normal and CT findings of increased liver attenuation suggested amiodarone hepatotoxicity—though congestive hepatopathy remained in the differential diagnosis. Therefore, supportive therapy for influenza was instituted, and amiodarone was withheld. Her condition subsequently improved, and she was discharged.

FOLLOW-UP 1 MONTH LATER

At a follow-up visit 1 month later, our patient continued to have dyspnea and hypoxia. She did not have signs or symptoms consistent with decompensated heart failure.

Pulmonary function testing revealed the following values:

FEV₁ 0.69 L (56% of predicted)
FVC 1.08 L (64% of predicted)
Figure 2. In A, repeat chest computed tomography demonstrated increased liver attenuation (arrow); in B, it showed persistent ground-glass opacities (white arrow), increased pulmonary attenuation (black arrowhead), and worsening pleural effusions (black arrows). These findings supported the diagnosis of amiodarone pulmonary toxicity.
FEV₁/FVC ratio 64%
DLCO 2.20 mL/min/mm Hg (12% of predicted).

Aminotransferase levels had also normalized. Repeat chest CT showed persistent bibasilar interstitial fibrotic changes, enlarging bilateral pleural effusions, and persistent peripheral ground-glass opacities (Figure 2).

WHAT FURTHER TREATMENT IS APPROPRIATE?

4. Given the chest CT findings, which of the following is the most appropriate treatment strategy for this patient?

No further management, continue to hold amiodarone
Corticosteroids
Repeat bronchoalveolar lavage
Intravenous antibiotics

No further management of amiodarone pulmonary toxicity would be appropriate if our patient did not have a high burden of symptoms. However, when patients with amiodarone pulmonary toxicity present with hypoxia and dyspnea, corticosteroids should be started.¹³ Our patient remained symptomatic after discontinuation of amiodarone and resolution of her influenza infection, and CT showed persistent signs of amiodarone pulmonary toxicity, which required further management.

Corticosteroids are useful in treating amiodarone pulmonary toxicity when hypoxia and dyspnea are present at diagnosis. Our patient’s persistent ground-glass opacities, fibrotic changes, and increased attenuation in multiple organs on CT, coupled with a confirmed reduction in FVC of greater than 15% and reduction in DLCO of greater than 20% after recovery from influenza, were most consistent with persistent amiodarone pulmonary toxicity.¹³

Although our patient’s amiodarone had been discontinued, the long half-life of the drug (45 days) allowed pulmonary toxicity to progress even after the drug was discontinued.²² Because our patient continued to have hypoxia and dyspnea on exertion, the most appropriate next step in management (in addition to managing her pleural effusions) was to start corticosteroids.

For amiodarone pulmonary toxicity, prednisone is typically started at 40 to 60 mg daily and can result in rapid improvement in symptoms.¹³ Tapering should be slow and may take several months.

Bronchoalveolar lavage is typically used in suspected cases of amiodarone pulmonary toxicity only to rule out an alternative diagnosis such as infection. Lipid-laden macrophages may be seen in the fluid. However, lipid-laden macrophages are not diagnostic of amiodarone pulmonary toxicity, as this finding may also be seen in patients taking amiodarone who do not develop pulmonary toxicity.¹⁵ Other findings on bronchoalveolar lavage in amiodarone pulmonary toxicity are nonspecific and are not diagnostically useful.¹³

Intravenous antibiotics are appropriate if bacterial pneumonia is suspected. However, bacterial pneumonia typically presents with cough, fever, purulent sputum production, and focal consolidation on chest imaging.⁹ Our patient’s CT findings of persistent peripheral ground-glass opacities and lack of cough, fever, or purulent sputum production were not consistent with bacterial pneumonia, and therefore intravenous antibiotics were not indicated.

CASE CONCLUSION

Given our patient’s persistent dyspnea, hypoxia, and chest CT findings consistent with amiodarone pulmonary toxicity, it was recommended that she start corticosteroids. However, before starting therapy, she suffered a femoral fracture that required surgical intervention. Around the time of the procedure, she had an ST-segment elevation myocardial infarction requiring vasopressor support and mechanical ventilation. At that time, the patient and family decided to pursue comfort measures, and she died peacefully.

MORE ABOUT AMIODARONE PULMONARY TOXICITY

Pulmonary toxicity is a well-described consequence of amiodarone therapy.²³ Amiodarone carries a 2% risk of pulmonary toxicity.²⁴ Although higher doses are more likely to cause pulmonary toxicity, lower doses also have been implicated.^22,24 Preexisting pulmonary disease may predispose patients taking amiodarone to pulmonary toxicity; however, this is not uniformly seen.²⁵

Mortality rates as high as 10% from amiodarone pulmonary toxicity have been reported. Thus, diligent surveillance for pulmonary toxicity with pulmonary function tests in patients taking amiodarone is mandatory. In particular, a reduction in FVC of greater than 15% or in DLCO of greater than 20% from baseline may be seen in amiodarone pulmonary toxicity.²⁶

Amiodarone pulmonary toxicity can present at any time after the start of therapy, but it occurs most often after 6 to 12 months.¹³ Patients typically experience insidious dyspnea; however, presentation with acute to subacute cough and progressive dyspnea can occur, especially with high concentrations of supplemental oxygen with or without mechanical ventilation.^12,27 Findings on physical examination include bibasilar crackles. CT chest findings include diffuse ground-glass opacities, reticular abnormalities, fibrosis, and increased attenuation in multiple organs, including the lung, liver, and spleen.¹⁴

The diagnosis of amiodarone pulmonary toxicity requires ruling out hypersensitivity pneumonitis, connective tissue disease, heart failure, and infection. Surgical biopsy and bronchoalveolar lavage are not commonly used to establish the diagnosis of amiodarone pulmonary toxicity, as surgical biopsy increases the risk of acute respiratory distress syndrome, and the results of bronchoalveolar lavage are usually nonspecific.^13,15

Initial treatment involves discontinuing the amiodarone once the diagnosis is suspected. If patients have worsening hypoxia or dyspnea at the time of diagnosis, corticosteroids can be used. Prednisone is typically started at 40 to 60 mg daily and can result in rapid improvement in symptoms.¹³ Tapering of corticosteroids should occur slowly and may take several months.

References

McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med 1971; 285(26):1441–1446. doi:10.1056/NEJM197112232852601
Stein PD, Terrin ML, Hales CA, et al. Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest 1991; 100(3):598–603. pmid:1909617
Baggish AL, Siebert U, Lainchbury JG, et al. A validated clinical and biochemical score for the diagnosis of acute heart failure: the ProBNP investigation of dyspnea in the emergency department (PRIDE) acute heart failure score. Am Heart J 2006; 151(1):48–54. doi:10.1016/j.ahj.2005.02.031
National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert panel report 3: Guidelines for the diagnosis and management of asthma. www.nhlbi.nih.gov/sites/default/files/media/docs/asthgdln_1.pdf. Accessed August 3, 2018.
Brenner BE, Abraham E, Simon RR. Position and diaphoresis in acute asthma. Am J Med 1983; 74(6):1005–1009. pmid:6407304
Badgett RG, Tanaka DJ, Hunt DK, et al. Can moderate chronic obstructive pulmonary disease be diagnosed by historical and physical findings alone? Am J Med 1993; 94(2):188–196. pmid:8430714
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. https://goldcopd.org/wp-content/uploads/2017/11/GOLD-2018-v6.0-FINAL-revised-20-Nov_WMS.pdf. Accessed August 17, 2018.
Erie AJ, McClure RF, Wolanskyj AP. Amiodarone-induced bone marrow granulomas: an unusual cause of reversible pancytopenia. Hematol Rep 2010; 2(1):e6. doi:10.4081/hr.2010.e6
Marrie TJ. Community-acquired pneumonia. Clin Infect Dis 1994; 18(4):501–513. pmid:8038304
Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical examination. JAMA 1997; 278(17):1440–1445. pmid:9356004
Walker CM, Abbott GF, Greene RE, Shepard JA, Vummidi D, Digumarthy SR. Imaging pulmonary infection: classic signs and patterns. AJR Am J Roentgenol 2014; 202(3):479–492. doi:10.2214/AJR.13.11463
Raghu G, Collard HR, Egan JJ, et al; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183(6):788–824. doi:10.1164/rccm.2009-040GL
Goldschlager N, Epstein AE, Naccarelli GV, et al; Practice Guidelines Sub-committee, North American Society of Pacing and Electrophysiology (HRS). A practical guide for clinicians who treat patients with amiodarone: 2007. Heart Rhythm 2007; 4(9):1250–1259. doi:10.1016/j.hrthm.2007.07.020
Kuhlman JE, Teigen C, Ren H, Hruban RH, Hutchins GM, Fishman EK. Amiodarone pulmonary toxicity: CT findings in symptomatic patients. Radiology 1990; 177(1):121–125. doi:10.1148/radiology.177.1.2399310
Martin WJ 2nd, Rosenow EC 3rd. Amiodarone pulmonary toxicity: recognition and pathogenesis (Part I). Chest 1988; 93(5):1067–1075. pmid:3282816
Iskandar SB, Abi-Saleh B, Keith RL, Byrd RP Jr, Roy TM. Amiodarone-induced alveolar hemorrhage. South Med J 2006; 99(4):383–387.
Van Mieghem W, Coolen L, Malysse I, Lacquet LM, Deneffe GJ, Demedts MG. Amiodarone and the development of ARDS after lung surgery. Chest 1994; 105(6):1642–1645. pmid:8205854
Nicholson KG. Clinical features of influenza. Semin Respir Infect 1992; 7(1):26–37. pmid:1609165
Muller NL, Franquet T, Lee KS, Silva CIS. Viruses, mycoplasma, and chlamydia. In: Imaging of Pulmonary Infections. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:94–114.
Stack S, Nguyen DV, Casto A, Ahuja N. Diffuse alveolar damage in a patient receiving dronedarone. Chest 2015; 147(4):e131–e133. doi:10.1378/chest.14-1849
De Ferrari GM, Dusi V. Drug safety evaluation of dronedarone in atrial fibrillation. Expert Opin Drug Saf 2012; 11(6):1023–1045. doi:10.1517/14740338.2012.722994
Okayasu K, Takeda Y, Kojima J, et al. Amiodarone pulmonary toxicity: a patient with three recurrences of pulmonary toxicity and consideration of the probable risk for relapse. Intern Med 2006; 45(22):1303–1307. pmid:17170505
Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol 1997; 30(3):791–798. pmid:9283542
Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet 1997; 350(9089):1417–1424. pmid:9371164
Olshansky B, Sami M, Rubin A, et al; NHLBI AFFIRM Investigators. Use of amiodarone for atrial fibrillation in patients with preexisting pulmonary disease in the AFFIRM study. Am J Cardiol 2005; 95(3):404–405. doi:10.1016/j.amjcard.2004.09.044
Camus P. Interstitial lung disease from drugs, biologics, and radiation. In: Schwartz MI, King TE Jr, eds. Interstitial Lung Disease. 5th ed. Shelton, CT: People’s Medical Publishing House; 2011:637–644.
Wolkove N, Baltzan M. Amiodarone pulmonary toxicity. Can Respir J 2009; 16(2):43–48. doi:10.1155/2009/282540

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Brody D. Slostad, MD
Department of Internal Medicine, Mayo Clinic, Rochester, MN

Megha Prasad, MD
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN

Nandan S. Anavekar, MD
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN

Address: Brody D. Slostad, MD, Department of Internal Medicine, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905; slostad.brody@mayo.edu

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Cleveland Clinic Journal of Medicine - 85(9)

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amiodarone, pulmonary toxicity, lung toxicity, shortness of breath, heart failure, ventricular tachycardia, Brody Slostad, Megha Prasad, Nandan Anavekar

Read more about Shortness of breath, fever, cough, and more in an elderly woman

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Symptoms to Diagnosis

Author(s)

Brody D. Slostad, MD

Megha Prasad, MD

Nandan S. Anavekar, MD

Author(s)

Brody D. Slostad, MD

Megha Prasad, MD

Nandan S. Anavekar, MD

Author and Disclosure Information

Brody D. Slostad, MD
Department of Internal Medicine, Mayo Clinic, Rochester, MN

Megha Prasad, MD
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN

Nandan S. Anavekar, MD
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN

Address: Brody D. Slostad, MD, Department of Internal Medicine, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905; slostad.brody@mayo.edu

Author and Disclosure Information

Brody D. Slostad, MD
Department of Internal Medicine, Mayo Clinic, Rochester, MN

Megha Prasad, MD
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN

Nandan S. Anavekar, MD
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN

Address: Brody D. Slostad, MD, Department of Internal Medicine, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905; slostad.brody@mayo.edu

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Article PDF

slostad_shortnessofbreath.pdf

Coronary artery disease requiring coronary artery bypass grafting
Ischemic cardiomyopathy
Severe mitral regurgitation
Moderate tricuspid regurgitation
Pulmonary hypertension
Cardiac arrest with recurrent ventricular tachycardia requiring an implanted cardioverter-defibrillator and amiodarone therapy
Hypothyroidism requiring levothyroxine
Asthma with a moderate obstructive pattern: forced expiratory volume in 1 second (FEV₁) 60% of predicted, forced vital capacity (FVC) 2.06 L, FEV₁/FVC 54%, diffusing capacity for carbon monoxide (DLCO) 72% of predicted with positive bronchodilator response
Long-standing essential thrombocythemia treated with hydroxyurea.

Initial laboratory evaluation revealed abnormal values (Table 1).

Electrocardiography showed sinus rhythm and an old left bundle branch block.

Chest radiography showed cardiomegaly, bilateral pleural effusions, and pulmonary edema.

WHAT IS THE CAUSE OF HER SYMPTOMS?

1. Based on the available information, which of the following is the most likely cause of this patient’s clinical presentation?

Acute decompensated heart failure
Pulmonary embolism
Exacerbation of asthma
Exacerbation of chronic obstructive pulmonary disease (COPD)

Although pulmonary embolism remained in the differential diagnosis, our patient’s lack of typical features of pulmonary embolism made this less likely.

Asthma is characterized by recurrent airflow obstruction and bronchial hyperresponsiveness.⁴ Asthma exacerbations present with wheezing, tachypnea, tachycardia, and pulsus paradoxus.⁵

Despite her previous asthma diagnosis, our patient’s lack of typical features of asthma exacerbation made this diagnosis unlikely.

COPD exacerbations present with increased dyspnea, cough, sputum production, wheezing, lung resonance to percussion, and distant heart sounds, and are characterized by airflow obstruction.^6,7

OUR PATIENT UNDERWENT FURTHER TESTING

Treatment was started with intravenous diuretics and positive pressure ventilation with oxygen supplementation. Her levothyroxine dose was reduced, and her hydroxyurea was stopped.

WHAT IS THE CAUSE OF HER PERSISTENT PULMONARY FINDINGS?

2. Given the CT findings and laboratory results, what is the most likely cause of our patient’s persistent crackles and hypoxia?

Heart failure with reduced ejection fraction
Bacterial pneumonia
Idiopathic pulmonary fibrosis
Amiodarone pulmonary toxicity

Amiodarone was therefore discontinued. However, the test result of her lavage fluid for influenza A by polymerase chain reaction came back positive a few hours later.

WHAT IS THE NEXT STEP?

3. Given the positive influenza A polymerase chain reaction test, which of the following is the best next step in this patient’s management?

Surgical lung biopsy
Stop amiodarone and start supportive influenza management
Stop amiodarone and start dronedarone
Start an intravenous corticosteroid

Thus, surgical biopsy is typically only done in cases of persistent symptoms despite withdrawal of amiodarone and initiation of steroid therapy.

Our patient’s persistent hypoxia was thought to be due in part to influenza, and thus the best next step in management was to stop amiodarone and provide supportive care for influenza.

FOLLOW-UP 1 MONTH LATER

At a follow-up visit 1 month later, our patient continued to have dyspnea and hypoxia. She did not have signs or symptoms consistent with decompensated heart failure.

Pulmonary function testing revealed the following values:

FEV₁ 0.69 L (56% of predicted)
FVC 1.08 L (64% of predicted)
Figure 2. In A, repeat chest computed tomography demonstrated increased liver attenuation (arrow); in B, it showed persistent ground-glass opacities (white arrow), increased pulmonary attenuation (black arrowhead), and worsening pleural effusions (black arrows). These findings supported the diagnosis of amiodarone pulmonary toxicity.
FEV₁/FVC ratio 64%
DLCO 2.20 mL/min/mm Hg (12% of predicted).

WHAT FURTHER TREATMENT IS APPROPRIATE?

4. Given the chest CT findings, which of the following is the most appropriate treatment strategy for this patient?

No further management, continue to hold amiodarone
Corticosteroids
Repeat bronchoalveolar lavage
Intravenous antibiotics

For amiodarone pulmonary toxicity, prednisone is typically started at 40 to 60 mg daily and can result in rapid improvement in symptoms.¹³ Tapering should be slow and may take several months.

CASE CONCLUSION

MORE ABOUT AMIODARONE PULMONARY TOXICITY

Coronary artery disease requiring coronary artery bypass grafting
Ischemic cardiomyopathy
Severe mitral regurgitation
Moderate tricuspid regurgitation
Pulmonary hypertension
Cardiac arrest with recurrent ventricular tachycardia requiring an implanted cardioverter-defibrillator and amiodarone therapy
Hypothyroidism requiring levothyroxine
Asthma with a moderate obstructive pattern: forced expiratory volume in 1 second (FEV₁) 60% of predicted, forced vital capacity (FVC) 2.06 L, FEV₁/FVC 54%, diffusing capacity for carbon monoxide (DLCO) 72% of predicted with positive bronchodilator response
Long-standing essential thrombocythemia treated with hydroxyurea.

Initial laboratory evaluation revealed abnormal values (Table 1).

Electrocardiography showed sinus rhythm and an old left bundle branch block.

Chest radiography showed cardiomegaly, bilateral pleural effusions, and pulmonary edema.

WHAT IS THE CAUSE OF HER SYMPTOMS?

1. Based on the available information, which of the following is the most likely cause of this patient’s clinical presentation?

Acute decompensated heart failure
Pulmonary embolism
Exacerbation of asthma
Exacerbation of chronic obstructive pulmonary disease (COPD)

Although pulmonary embolism remained in the differential diagnosis, our patient’s lack of typical features of pulmonary embolism made this less likely.

Asthma is characterized by recurrent airflow obstruction and bronchial hyperresponsiveness.⁴ Asthma exacerbations present with wheezing, tachypnea, tachycardia, and pulsus paradoxus.⁵

Despite her previous asthma diagnosis, our patient’s lack of typical features of asthma exacerbation made this diagnosis unlikely.

COPD exacerbations present with increased dyspnea, cough, sputum production, wheezing, lung resonance to percussion, and distant heart sounds, and are characterized by airflow obstruction.^6,7

OUR PATIENT UNDERWENT FURTHER TESTING

Treatment was started with intravenous diuretics and positive pressure ventilation with oxygen supplementation. Her levothyroxine dose was reduced, and her hydroxyurea was stopped.

WHAT IS THE CAUSE OF HER PERSISTENT PULMONARY FINDINGS?

2. Given the CT findings and laboratory results, what is the most likely cause of our patient’s persistent crackles and hypoxia?

Heart failure with reduced ejection fraction
Bacterial pneumonia
Idiopathic pulmonary fibrosis
Amiodarone pulmonary toxicity

Amiodarone was therefore discontinued. However, the test result of her lavage fluid for influenza A by polymerase chain reaction came back positive a few hours later.

WHAT IS THE NEXT STEP?

3. Given the positive influenza A polymerase chain reaction test, which of the following is the best next step in this patient’s management?

Surgical lung biopsy
Stop amiodarone and start supportive influenza management
Stop amiodarone and start dronedarone
Start an intravenous corticosteroid

Thus, surgical biopsy is typically only done in cases of persistent symptoms despite withdrawal of amiodarone and initiation of steroid therapy.

Our patient’s persistent hypoxia was thought to be due in part to influenza, and thus the best next step in management was to stop amiodarone and provide supportive care for influenza.

FOLLOW-UP 1 MONTH LATER

At a follow-up visit 1 month later, our patient continued to have dyspnea and hypoxia. She did not have signs or symptoms consistent with decompensated heart failure.

Pulmonary function testing revealed the following values:

FEV₁ 0.69 L (56% of predicted)
FVC 1.08 L (64% of predicted)
Figure 2. In A, repeat chest computed tomography demonstrated increased liver attenuation (arrow); in B, it showed persistent ground-glass opacities (white arrow), increased pulmonary attenuation (black arrowhead), and worsening pleural effusions (black arrows). These findings supported the diagnosis of amiodarone pulmonary toxicity.
FEV₁/FVC ratio 64%
DLCO 2.20 mL/min/mm Hg (12% of predicted).

WHAT FURTHER TREATMENT IS APPROPRIATE?

4. Given the chest CT findings, which of the following is the most appropriate treatment strategy for this patient?

No further management, continue to hold amiodarone
Corticosteroids
Repeat bronchoalveolar lavage
Intravenous antibiotics

For amiodarone pulmonary toxicity, prednisone is typically started at 40 to 60 mg daily and can result in rapid improvement in symptoms.¹³ Tapering should be slow and may take several months.

CASE CONCLUSION

MORE ABOUT AMIODARONE PULMONARY TOXICITY

References

McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med 1971; 285(26):1441–1446. doi:10.1056/NEJM197112232852601
Stein PD, Terrin ML, Hales CA, et al. Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest 1991; 100(3):598–603. pmid:1909617
Baggish AL, Siebert U, Lainchbury JG, et al. A validated clinical and biochemical score for the diagnosis of acute heart failure: the ProBNP investigation of dyspnea in the emergency department (PRIDE) acute heart failure score. Am Heart J 2006; 151(1):48–54. doi:10.1016/j.ahj.2005.02.031
National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert panel report 3: Guidelines for the diagnosis and management of asthma. www.nhlbi.nih.gov/sites/default/files/media/docs/asthgdln_1.pdf. Accessed August 3, 2018.
Brenner BE, Abraham E, Simon RR. Position and diaphoresis in acute asthma. Am J Med 1983; 74(6):1005–1009. pmid:6407304
Badgett RG, Tanaka DJ, Hunt DK, et al. Can moderate chronic obstructive pulmonary disease be diagnosed by historical and physical findings alone? Am J Med 1993; 94(2):188–196. pmid:8430714
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. https://goldcopd.org/wp-content/uploads/2017/11/GOLD-2018-v6.0-FINAL-revised-20-Nov_WMS.pdf. Accessed August 17, 2018.
Erie AJ, McClure RF, Wolanskyj AP. Amiodarone-induced bone marrow granulomas: an unusual cause of reversible pancytopenia. Hematol Rep 2010; 2(1):e6. doi:10.4081/hr.2010.e6
Marrie TJ. Community-acquired pneumonia. Clin Infect Dis 1994; 18(4):501–513. pmid:8038304
Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical examination. JAMA 1997; 278(17):1440–1445. pmid:9356004
Walker CM, Abbott GF, Greene RE, Shepard JA, Vummidi D, Digumarthy SR. Imaging pulmonary infection: classic signs and patterns. AJR Am J Roentgenol 2014; 202(3):479–492. doi:10.2214/AJR.13.11463
Raghu G, Collard HR, Egan JJ, et al; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183(6):788–824. doi:10.1164/rccm.2009-040GL
Goldschlager N, Epstein AE, Naccarelli GV, et al; Practice Guidelines Sub-committee, North American Society of Pacing and Electrophysiology (HRS). A practical guide for clinicians who treat patients with amiodarone: 2007. Heart Rhythm 2007; 4(9):1250–1259. doi:10.1016/j.hrthm.2007.07.020
Kuhlman JE, Teigen C, Ren H, Hruban RH, Hutchins GM, Fishman EK. Amiodarone pulmonary toxicity: CT findings in symptomatic patients. Radiology 1990; 177(1):121–125. doi:10.1148/radiology.177.1.2399310
Martin WJ 2nd, Rosenow EC 3rd. Amiodarone pulmonary toxicity: recognition and pathogenesis (Part I). Chest 1988; 93(5):1067–1075. pmid:3282816
Iskandar SB, Abi-Saleh B, Keith RL, Byrd RP Jr, Roy TM. Amiodarone-induced alveolar hemorrhage. South Med J 2006; 99(4):383–387.
Van Mieghem W, Coolen L, Malysse I, Lacquet LM, Deneffe GJ, Demedts MG. Amiodarone and the development of ARDS after lung surgery. Chest 1994; 105(6):1642–1645. pmid:8205854
Nicholson KG. Clinical features of influenza. Semin Respir Infect 1992; 7(1):26–37. pmid:1609165
Muller NL, Franquet T, Lee KS, Silva CIS. Viruses, mycoplasma, and chlamydia. In: Imaging of Pulmonary Infections. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:94–114.
Stack S, Nguyen DV, Casto A, Ahuja N. Diffuse alveolar damage in a patient receiving dronedarone. Chest 2015; 147(4):e131–e133. doi:10.1378/chest.14-1849
De Ferrari GM, Dusi V. Drug safety evaluation of dronedarone in atrial fibrillation. Expert Opin Drug Saf 2012; 11(6):1023–1045. doi:10.1517/14740338.2012.722994
Okayasu K, Takeda Y, Kojima J, et al. Amiodarone pulmonary toxicity: a patient with three recurrences of pulmonary toxicity and consideration of the probable risk for relapse. Intern Med 2006; 45(22):1303–1307. pmid:17170505
Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol 1997; 30(3):791–798. pmid:9283542
Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet 1997; 350(9089):1417–1424. pmid:9371164
Olshansky B, Sami M, Rubin A, et al; NHLBI AFFIRM Investigators. Use of amiodarone for atrial fibrillation in patients with preexisting pulmonary disease in the AFFIRM study. Am J Cardiol 2005; 95(3):404–405. doi:10.1016/j.amjcard.2004.09.044
Camus P. Interstitial lung disease from drugs, biologics, and radiation. In: Schwartz MI, King TE Jr, eds. Interstitial Lung Disease. 5th ed. Shelton, CT: People’s Medical Publishing House; 2011:637–644.
Wolkove N, Baltzan M. Amiodarone pulmonary toxicity. Can Respir J 2009; 16(2):43–48. doi:10.1155/2009/282540

References

McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med 1971; 285(26):1441–1446. doi:10.1056/NEJM197112232852601
Stein PD, Terrin ML, Hales CA, et al. Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest 1991; 100(3):598–603. pmid:1909617
Baggish AL, Siebert U, Lainchbury JG, et al. A validated clinical and biochemical score for the diagnosis of acute heart failure: the ProBNP investigation of dyspnea in the emergency department (PRIDE) acute heart failure score. Am Heart J 2006; 151(1):48–54. doi:10.1016/j.ahj.2005.02.031
National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert panel report 3: Guidelines for the diagnosis and management of asthma. www.nhlbi.nih.gov/sites/default/files/media/docs/asthgdln_1.pdf. Accessed August 3, 2018.
Brenner BE, Abraham E, Simon RR. Position and diaphoresis in acute asthma. Am J Med 1983; 74(6):1005–1009. pmid:6407304
Badgett RG, Tanaka DJ, Hunt DK, et al. Can moderate chronic obstructive pulmonary disease be diagnosed by historical and physical findings alone? Am J Med 1993; 94(2):188–196. pmid:8430714
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. https://goldcopd.org/wp-content/uploads/2017/11/GOLD-2018-v6.0-FINAL-revised-20-Nov_WMS.pdf. Accessed August 17, 2018.
Erie AJ, McClure RF, Wolanskyj AP. Amiodarone-induced bone marrow granulomas: an unusual cause of reversible pancytopenia. Hematol Rep 2010; 2(1):e6. doi:10.4081/hr.2010.e6
Marrie TJ. Community-acquired pneumonia. Clin Infect Dis 1994; 18(4):501–513. pmid:8038304
Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical examination. JAMA 1997; 278(17):1440–1445. pmid:9356004
Walker CM, Abbott GF, Greene RE, Shepard JA, Vummidi D, Digumarthy SR. Imaging pulmonary infection: classic signs and patterns. AJR Am J Roentgenol 2014; 202(3):479–492. doi:10.2214/AJR.13.11463
Raghu G, Collard HR, Egan JJ, et al; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183(6):788–824. doi:10.1164/rccm.2009-040GL
Goldschlager N, Epstein AE, Naccarelli GV, et al; Practice Guidelines Sub-committee, North American Society of Pacing and Electrophysiology (HRS). A practical guide for clinicians who treat patients with amiodarone: 2007. Heart Rhythm 2007; 4(9):1250–1259. doi:10.1016/j.hrthm.2007.07.020
Kuhlman JE, Teigen C, Ren H, Hruban RH, Hutchins GM, Fishman EK. Amiodarone pulmonary toxicity: CT findings in symptomatic patients. Radiology 1990; 177(1):121–125. doi:10.1148/radiology.177.1.2399310
Martin WJ 2nd, Rosenow EC 3rd. Amiodarone pulmonary toxicity: recognition and pathogenesis (Part I). Chest 1988; 93(5):1067–1075. pmid:3282816
Iskandar SB, Abi-Saleh B, Keith RL, Byrd RP Jr, Roy TM. Amiodarone-induced alveolar hemorrhage. South Med J 2006; 99(4):383–387.
Van Mieghem W, Coolen L, Malysse I, Lacquet LM, Deneffe GJ, Demedts MG. Amiodarone and the development of ARDS after lung surgery. Chest 1994; 105(6):1642–1645. pmid:8205854
Nicholson KG. Clinical features of influenza. Semin Respir Infect 1992; 7(1):26–37. pmid:1609165
Muller NL, Franquet T, Lee KS, Silva CIS. Viruses, mycoplasma, and chlamydia. In: Imaging of Pulmonary Infections. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:94–114.
Stack S, Nguyen DV, Casto A, Ahuja N. Diffuse alveolar damage in a patient receiving dronedarone. Chest 2015; 147(4):e131–e133. doi:10.1378/chest.14-1849
De Ferrari GM, Dusi V. Drug safety evaluation of dronedarone in atrial fibrillation. Expert Opin Drug Saf 2012; 11(6):1023–1045. doi:10.1517/14740338.2012.722994
Okayasu K, Takeda Y, Kojima J, et al. Amiodarone pulmonary toxicity: a patient with three recurrences of pulmonary toxicity and consideration of the probable risk for relapse. Intern Med 2006; 45(22):1303–1307. pmid:17170505
Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol 1997; 30(3):791–798. pmid:9283542
Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet 1997; 350(9089):1417–1424. pmid:9371164
Olshansky B, Sami M, Rubin A, et al; NHLBI AFFIRM Investigators. Use of amiodarone for atrial fibrillation in patients with preexisting pulmonary disease in the AFFIRM study. Am J Cardiol 2005; 95(3):404–405. doi:10.1016/j.amjcard.2004.09.044
Camus P. Interstitial lung disease from drugs, biologics, and radiation. In: Schwartz MI, King TE Jr, eds. Interstitial Lung Disease. 5th ed. Shelton, CT: People’s Medical Publishing House; 2011:637–644.
Wolkove N, Baltzan M. Amiodarone pulmonary toxicity. Can Respir J 2009; 16(2):43–48. doi:10.1155/2009/282540

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Cleveland Clinic Journal of Medicine - 85(9)

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Shortness of breath, fever, cough, and more in an elderly woman

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A 71-year-old woman with shock and a high INR

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A 71-year-old woman with shock and a high INR

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Raja Y. Zaghlol, MD

Michael E. Tierney, MD, BMedSc

Louay Y. Zaghlol

Ayman A. Zayed, MD, MSc, FACE, FACP

A 71-year-old woman is brought to the emergency department by her neighbor after complaining of fatigue and light-headedness for the last 8 hours. The patient lives alone and was feeling well when she woke up this morning, but then began to feel nauseated and vomited twice.

The patient appears drowsy and confused and cannot provide any further history. Her medical records show that she was seen in the cardiology clinic 6 months ago but has not kept her appointments since then.

Her medical history includes atrial fibrillation, hypertension, type 2 diabetes mellitus, and osteoarthritis. Her medications are daily warfarin, atenolol, aspirin, candesartan, and metformin, and she takes acetaminophen as needed. She is neither a smoker nor a drug user, but she drinks alcohol occasionally. Her family history is significant for her mother’s death from breast cancer at age 55.

The neighbor confirms that the patient appeared well this morning and has not had any recent illnesses except for a minor cold last week that improved over 5 days with acetaminophen only.

INITIAL EVALUATION AND MANAGEMENT

Physical examination

On physical examination, her blood pressure is 80/40 mm Hg, respiratory rate 25 breaths per minute, oral temperature 38.3°C (100.9°F), and heart rate 130 beats per minute and irregular.

Her neck veins are flat, and her chest is clear to auscultation with normal heart sounds. Abdominal palpation elicits discomfort in the middle segments, voluntary withdrawal, and abdominal wall rigidity. Her skin feels dry and cool, with decreased turgor.

Initial treatment

The patient is given 1 L of 0.9% saline intravenously over the first hour and then is transferred to the intensive care unit, where a norepinephrine drip is started to treat her ongoing hypotension. Normal saline is continued at a rate of 500 mL per hour for the next 4 hours.

Cardiac monitoring and 12-lead electrocardiography show atrial fibrillation with a rapid ventricular response of 138 beats per minute, but electrical cardioversion is not done.

Initial laboratory tests

Results of basic laboratory tests in the emergency department are shown in Table 1.

Of note, her international normalized ratio (INR) is 6.13, while the therapeutic range for a patient taking warfarin because of atrial fibrillation is 2.0 to 3.0.

Her blood pH is 7.34 (reference range 7.35–7.45), and her bicarbonate level is 18 mmol/L (22–26); a low pH and low bicarbonate together indicate metabolic acidosis. Her sodium level is 128 mmol/L (135–145), her chloride level is 100 mmol/L (97–107), and, as mentioned, her bicarbonate level is 18 mmol/L; therefore, her anion gap is 128 – (100 + 18) = 10 mmol/L, which is normal (≤ 10).¹

Her serum creatinine level is 1.3 mg/dL (0.5–1.1), and her blood urea nitrogen level is 35 mg/dL (7–20).

Her potassium level is 5.8 mmol/L, which is consistent with hyperkalemia (reference range 3.5–5.2).

DIFFERENTIAL DIAGNOSIS

1. Which of the following is the most likely cause of this patient’s symptoms?

Adrenal crisis
Cardiogenic shock due to decreased cardiac contractility
Intracranial hemorrhage
Acute abdomen due to small bowel obstruction
Septic shock due to bacterial toxin-induced loss of vascular tone

Our patient is presenting with shock. Given our inability to obtain a meaningful history, the differential diagnosis is broad and includes all of the above.

Adrenal crisis

The sudden onset and laboratory results that include hyperkalemia, hyponatremia, and normal anion gap metabolic acidosis raise suspicion of adrenal crisis resulting in acute mineralocorticoid and glucocorticoid insufficiency.¹

The patient’s elevated serum creatinine and high blood urea nitrogen-to-creatinine ratio of 26.9 (reference range 10–20) also suggest intravascular volume contraction. Her low hemoglobin level and supratherapeutic INR, possibly due to an interaction between warfarin and acetaminophen combined with poor medical follow-up, raise suspicion of acute bilateral adrenal necrosis due to hemorrhage.

Clinical manifestations of adrenal insufficiency by organ system

Adrenal crisis is a medical emergency that can lead to rapid deterioration and death if not diagnosed and treated promptly. Some of its manifestations (Table 2) are nonspecific and are common to various other conditions.Thus, its diagnosis requires a high index of suspicion.

Bilateral adrenal hemorrhage is one cause of adrenal crisis resulting in bilateral adrenal necrosis. Risk factors for adrenal hemorrhage include anticoagulation therapy, underlying coagulopathy, postoperative states, and certain infections such as meningococcemia and Haemophilus influenzae infection.^2–5 Nevertheless, in most cases the INR is in the therapeutic range and the patient has no bleeding elsewhere.⁴ Other causes of adrenal necrosis include emboli, sepsis, and blunt trauma.^6,7

Other causes of adrenal crisis are listed in Table 3.

Cardiogenic shock

Cardiogenic shock is caused by decreased myocardial contractility, making the heart unable to adequately pump the returning blood. However, the metabolic disturbances in our patient and the finding of flat neck veins make this cause of shock less likely.

Intracranial hemorrhage

Intracranial hemorrhage can present with a decreased level of consciousness, but it is less likely to cause hypotension, as the cranial space is limited. If massive intracranial hemorrhage would occur, the increase in intracranial pressure would more likely cause hypertension by the Cushing reflex than hypotension.

Acute abdomen

Abdominal pain and rigidity along with fever can be presenting symptoms of both adrenal insufficiency and an acute abdomen due to intestinal obstruction.⁴ However, intestinal obstruction typically causes a high anion gap metabolic acidosis due to lactic acidosis, instead of the normal anion gap metabolic acidosis present in this patient.⁸ Moreover, her deranged electrolytes, supratherapeutic INR, and absence of previous gastroenterologic conditions make adrenal crisis a more likely diagnosis.

Septic shock

Septic shock would also cause fever and hypotension as bacterial toxins induce a pyrexic response and vasodilation. However, at such an early stage of sepsis, the patient would be expected to be warm and hyperemic, whereas this patient’s skin is cool and dry due to volume depletion secondary to adrenal insufficiency.⁹ Sepsis would also cause a high anion gap metabolic acidosis due to lactic acidosis, as opposed to this patient’s normal anion gap metabolic acidosis. These findings, along with the metabolic derangements and the absence of a focus of infection, make sepsis a less likely possibility.

CASE CONTINUED: CARDIOMEGALY, PERSISTENT HYPOTENSION

Blood is drawn for cultures and measurement of troponins and lactic acid, and urine samples are taken for culture and biochemical analysis. Chest radiography shows mild cardiomegaly. The patient is started empirically on vancomycin and cefepime, and her warfarin is discontinued.

Five hours after presenting to the emergency department, her blood pressure remains at 80/40 mm Hg even after receiving 3 L of normal saline intravenously.

PROMPT MANAGEMENT OF ADRENAL CRISIS

2. Which of the following is the most appropriate next step in managing this patient?

Draw samples for serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels, then give hydrocortisone 100 mg intravenously
Perform abdominal computed tomography (CT) without contrast
Perform transthoracic echocardiography
Increase the norepinephrine infusion
Immediately give fludrocortisone

First give fluids

The first step in managing a patient with suspected adrenal crisis is liberal intravenous fluid administration to replenish the depleted intravascular space. The amount and choice of fluid is empiric, but a recommendation is 1 L of normal saline or dextrose 5% in normal saline, infused quickly over the first hour and then titrated according to the patient’s fluid status.¹⁰

Measure cortisol and ACTH; start corticosteroids immediately

Immediate therapy with an appropriate stress dose of intravenous corticosteroids (eg, hydrocortisone 100 mg) is essential. However, this should be done after drawing blood for cortisol and ACTH measurements.¹⁰

Do not delay corticosteroid therapy while awaiting the results of the diagnostic tests.

Cortisol and ACTH levels are useful in assessing adrenal function in critically ill patients.¹¹ While inappropriately low serum cortisol usually indicates adrenal insufficiency, measuring plasma ACTH is important to distinguish whether the adrenal insufficiency is primary (ie, due to dysfunction of the adrenal gland itself) or central, ie, either secondary (due to dysfunction of the pituitary gland) or tertiary (due to dysfunction of the hypothalamus). Primary adrenal insufficiency is associated with elevated plasma ACTH, whereas central (secondary or tertiary) adrenal insufficiency is associated with low or inappropriately normal plasma ACTH levels (Figure 1).

In addition, in the early phase of evolving primary adrenal insufficiency, measurement of plasma renin and aldosterone levels may be beneficial, as mineralocorticoid deficiency may predominate.^10,12,13

One of the most important aims of early corticosteroid supplementation is to prevent further hyponatremia by reducing a reactive increase in antidiuretic hormone secretion caused by cortisol deficiency. Corticosteroids also help to restore normal blood pressure by increasing vascular tone, as glucocorticoid receptor activation potentiates the vasoconstrictor actions of norepinephrine, angiotensin II, and other vasoconstrictors.^14,15

Which corticosteroid to use?

Which corticosteroid to use in previously undiagnosed adrenal insufficiency is controversial. The Endocrine Society¹⁰ and Japan Endocrine Society¹⁶ clinical practice guidelines recommend hydrocortisone in a 100-mg intravenous bolus followed by 200 mg over 24 hours.

The choice of hydrocortisone is justified by its superior mineralocorticoid activity.^10,16 Further, hydrocortisone is preferred over dexamethasone if the patient is known to have primary adrenal insufficiency, or if the serum potassium level is higher than 6.0 mmol/L.

Some clinicians, on the other hand, recommend dexamethasone, given as a 4-mg intravenous bolus followed by 4-mg boluses every 12 hours. Their rationale is that dexamethasone, unlike hydrocortisone, does not interfere with subsequent serum cortisol assays if the patient later undergoes ACTH stimulation testing.¹⁷ Dexamethasone may also be preferred to minimize unwanted mineralocorticoid effects, such as in neurosurgical patients at risk of brain edema.

If hydrocortisone is used, ACTH stimulation testing can be done after withholding hydrocortisone for 24 hours once the patient is stable. (It should be restarted after the test if the results are abnormal.)

Other possible steps

Abdominal CT should be done in our patient to address the possibility of bilateral adrenal hemorrhage. However, it is preferable to wait until the patient is stabilized.

Echocardiography. Our patient is likely to have an element of cardiac failure, given her hypertension and cardiomegaly. However, decompensated heart failure is probably not the cause of her presentation. Thus, the first priority is to treat her adrenal crisis, and echocardiography should be deferred.

Increasing the norepinephrine infusion is unlikely to improve her blood pressure very much, as she is significantly volume-depleted. Further, low cortisol decreases the vascular response to norepinephrine.¹⁵

Mineralocorticoids such as fludrocortisone are used to treat primary adrenal insufficiency. However, they are not required during acute management of adrenal crisis, as 40 mg of hydrocortisone offers mineralocorticoid activity equivalent to 100 µg of fludrocortisone. Thus, the high doses of hydrocortisone used to treat adrenal crisis provide adequate mineralocorticoid therapy.^10,18

If dexamethasone is used, its effect along with normal saline supplementation would be sufficient to replete the intravenous space and bring the sodium level back up to normal in the acute setting.

CASE RESUMED: IMPROVEMENT WITH HYDROCORTISONE

The patient’s blood is drawn for serum cortisol and plasma ACTH measurements. A 100-mg intravenous bolus of hydrocortisone is given, followed by a 50-mg bolus every 6 hours until the patient stabilizes.

Twenty-four hours later, the patient states that she has more energy, and her appetite has improved. The norepinephrine infusion is stopped 48 hours after presentation, at which time her blood pressure is 120/70 mm Hg, heart rate 85 beats per minute and irregular, and temperature 36.7°C (98.1°F). Her current laboratory values include the following:

Serum sodium 137 mmolL
Serum potassium 4.3 mmol/L
Hemoglobin 9.3 g/dL
Serum cortisol (random) 7.2 μg/dL
Plasma ACTH 752 pg/mL (10–60 pg/mL).

ESTABLISHING THE DIAGNOSIS OF ADRENAL INSUFFICIENCY

3. Which of the following is the most appropriate test to establish the diagnosis of adrenal insufficiency?

7 am total serum cortisol measurement
Random serum cortisol measurement
7 am salivary cortisol measurement
24-hour urinary free cortisol measurement
ACTH stimulation test for cortisol
Insulin tolerance test for cortisol

Laboratory findings in adrenal insufficiency

Adrenal insufficiency can present acutely with catastrophic outcomes, such as in adrenal crisis. Alternatively, it can present insidiously with multiple vague manifestations and nonspecific laboratory findings (Table 4). But even when the diagnosis of adrenal insufficiency is apparent, laboratory tests are required for confirmation.

These tests also help determine the type of adrenal insufficiency (primary, secondary, or tertiary) and guide further management. Secondary adrenal insufficiency is caused by inadequate pituitary ACTH secretion and subsequent inadequate cortisol production, whereas tertiary adrenal insufficiency is caused by inadequate hypothalamic corticotropin-releasing hormone secretion and subsequent inadequate ACTH and cortisol production. The diagnosis of adrenal insufficiency relies first on demonstrating inappropriately low total serum cortisol production. Subsequently, serum ACTH helps to differentiate between primary (high ACTH) and secondary or tertiary (low or inappropriately normal ACTH) adrenal insufficiency.

Each test listed above may demonstrate a low cortisol level. However, in a nonacute setting, safety concerns (especially regarding insulin tolerance testing), poor diagnostic value, feasibility (ie, the difficulty of 24-hour tests), and poor sensitivity of 7 am cortisol make the ACTH stimulation test the most appropriate test in clinical practice to establish the diagnosis of adrenal insufficiency.

7 am serum cortisol measurement

Measuring the serum cortisol level early in the morning in the nonacute setting could be of diagnostic value, as an extremely low value (< 3–5 μg/dL) is almost 100% specific for adrenal insufficiency in the absence of concurrent exogenous steroid intake. However, the very low cutoff for this test causes poor sensitivity (about 33%), as many patients have partial adrenal insufficiency and hence have higher serum cortisol levels that may even be in the normal physiologic range.^19–22

Random serum cortisol measurements

Random serum cortisol measurements are not very useful in a nonacute setting, since cortisol levels are affected by factors such as stress and hydration status. Moreover, they fluctuate during the day in a circadian rhythm.

On the other hand, random serum cortisol is a very good test to evaluate for adrenal insufficiency in the acute setting. A random value higher than 15 to 18 μg/dL is almost always associated with adequate adrenal function and generally rules out adrenal insufficiency.^11,23,24

7 am salivary cortisol measurement

The same principle applies to early morning salivary cortisol. Only extremely low values (< 2.65 ng/mL) may distinguish patients with adrenal insufficiency from healthy individuals, with 97.1% sensitivity and 93.3% specificity.²⁵

Of note, early morning salivary cortisol is not routinely measured in most clinical practices for evaluation of adrenal function. Hence, morning serum and morning salivary cortisol are useful screening tools and have meaningful results when their values are in the extremes of the spectrum, but they are not reliable as a single test, as they may overlook patients with partial adrenal insufficiency.

Urinary cortisol measurement

Urinary cortisol measurement is not used to diagnose adrenal insufficiency, as values can be normal in patients with partial adrenal insufficiency.

The ACTH stimulation test

The ACTH stimulation test involves an intramuscular or intravenous injection of cosyntropin (a synthetic analogue of ACTH fragment 1–24 that has the full activity of native ACTH) and measuring total serum cortisol at baseline, 30 minutes, and 60 minutes to assess the response of the adrenal glands.

The test can be done using a high or low dose of cosyntropin. The Endocrine Society’s 2016 guidelines recommend the high dose (250 μg) for most patients.¹⁰ The standard high-dose stimulation test can be done at any time during the day.²⁶ If the cosyntropin is injected intravenously, any value higher than 18 to 20 μg/dL indicates normal adrenal function and excludes adrenal insufficiency.^27,28 If intramuscular injection is used, any value higher than 16 to 18 μg/dL at 30 minutes post-consyntropin excludes adrenal insufficiency.²⁹

The ACTH stimulation test may not exclude acute secondary or tertiary adrenal insufficiency.

Insulin tolerance testing

Insulin tolerance testing remains the gold standard for diagnosing adrenal insufficiency and assessing the integrity of the pituitary-adrenal axis. However, given its difficulty to perform, safety concerns, and the availability of other reliable tests, its use in clinical practice is limited. It is nonetheless useful in assessing patients with recent onset of ACTH deficiency.^30,31

CASE RESUMED: PATIENT DISCHARGED, LOST TO FOLLOW-UP

Abdominal CT without contrast is done and demonstrates bilateral adrenal hemorrhage. Thus, the patient is diagnosed with primary acute adrenal insufficiency due to adrenal necrosis.

She is started on oral hydrocortisone and fludrocortisone after intravenous hydrocortisone is discontinued. She is counseled about adhering to medications, wearing a medical alert bracelet, giving herself emergency cortisol injections, taking higher doses of hydrocortisone if she is ill, and monitoring her INR. She is discharged home after her symptoms resolve.

The patient does not keep her scheduled appointment and is lost to follow-up. She returns 2 years later complaining of fatigue and feeling unwell. She admits that she stopped taking hydrocortisone 1 year ago after reading an online article about corticosteroid side effects. She has continued to take fludrocortisone.

MINERALOCORTICOID VS CORTICOSTEROID DEFICIENCY

Clinical features of primary vs central adrenal insufficiency

Our patient has primary adrenal insufficiency. The presentations of primary and central (secondary or tertiary) adrenal insufficiency are similar, but there are critical differences (Table 5). Further, she has been taking her mineralocorticoid (fludrocortisone) replacement but has stopped taking her corticosteroid (hydrocortisone).

4. Which of the following is least likely to be present in this patient at this time?

Intravascular volume depletion
Hyponatremia
Skin hyperpigmentation
Normokalemia
Elevated serum ACTH level

Intravascular volume depletion

Intravascular volume depletion is the least likely to be present. This is because intravascular volume depletion is mainly secondary to mineralocorticoid deficiency rather than corticosteroid deficiency, which is not present in this patient, as she is compliant with her mineralocorticoid replacement therapy.^32,33 However, even with sufficient mineralocorticoid replacement, mild hypotension may be present in this patient due to corticosteroid deficiency-induced loss of vascular tone.

Hyponatremia

Hyponatremia in adrenal insufficiency is not due only to mineralocorticoid deficiency. Patients with secondary or tertiary adrenal insufficiency may also exhibit hyponatremia.³⁴ ACTH deficiency in such patients is not expected to cause mineralocorticoid deficiency, as ACTH has only a minor role in aldosterone production.

It has been proposed that hyponatremia in secondary adrenal insufficiency is due to cortisol deficiency resulting in an increase of antidiuretic hormone secretion.^35,36 The mechanisms for increased antidiuretic hormone include cortisol deficiency resulting in an increased corticotropin-releasing hormone level, which acts as an antidiuretic hormone secretagogue,^37,38 and cortisol directly suppressing antidiuretic hormone secretion.³⁹

In our patient, volume expansion and hyponatremia are expected due to increased antidiuretic hormone secretion as a result of corticosteroid insufficiency.

Hyperpigmentation

Hyperpigmentation of the skin is present only in long-standing primary adrenal insufficiency. This is due to chronic cortisol deficiency causing an increased secretion of pro-opiomelanocortin, a prohormone that is cleaved into ACTH, melanocyte-stimulating hormone, and other hormones. Melanocyte-stimulating hormone causes skin hyperpigmentation due to increased melanin synthesis.⁴⁰ The hyperpigmentation is seen in sun-exposed areas, pressure areas, palmar creases, nipples, and mucous membranes.

This patient has long-standing corticosteroid deficiency due to noncompliance and primary adrenal insufficiency, and as a result she is expected to have elevated serum ACTH and hyperpigmentation.

Normokalemia

Mineralocorticoid deficiency results in hyperkalemia and metabolic acidosis by impairing renal excretion of potassium and acid.⁴¹ This patient is compliant with her mineralocorticoid replacement regimen; thus, potassium levels and pH are expected to be normal.

TAKE-HOME POINTS

Suspect adrenal crisis in any patient who presents with shock.
Acute abdomen or unexplained fever could be among the manifestations.
Initial management requires liberal normal saline intravenous fluid administration to replete the intravascular space.
Draw blood samples for serum chemistry, cortisol, and ACTH, followed immediately by intravenous hydrocortisone supplementation.
In critically ill patients, evaluate adrenal function with random serum cortisol; in a nonacute setting use the ACTH stimulation test.
Chronic management of primary adrenal insufficiency requires corticosteroid and mineralocorticoid therapy.

References

Mani S, Rutecki GW. A patient with altered mental status and an acid-base disturbance. Cleve Clin J Med 2017; 84(1):27–34. doi:10.3949/ccjm.84a.16042
Almiani M, Gorthi J, Subbiah S, Firoz M. Quiz page November 2012: an unusual case of acute hyponatremia and normal anion gap metabolic acidosis. Am J Kidney Dis 2012; 60(5):xxxiii–xxxvi. doi:10.1053/j.ajkd.2012.05.026
Migeon CJ, Kenny FM, Hung W, Voorhess ML. Study of adrenal function in children with meningitis. Pediatrics 1967; 40(2):163–183.
Rao RH, Vagnucci AH, Amico JA. Bilateral massive adrenal hemorrhage: early recognition and treatment. Ann Intern Med 1989; 110(3):227–235.
Shimizu S, Tahara Y, Atsumi T, et al. Waterhouse-Friderichsen syndrome caused by invasive Haemophilus influenzae type B infection in a previously healthy young man. Anaesth Intensive Care 2010; 38(1):214–215.
Castaldo ET, Guillamondegui OD, Greco JA 3rd, Feurer ID, Miller RS, Morris JA Jr. Are adrenal injuries predictive of adrenal insufficiency in patients sustaining blunt trauma? Am Surg 2008; 74(3):262–266.
Xarli VP, Steele AA, Davis PJ, Buescher ES, Rios CN, Garcia-Bunuel R. Adrenal hemorrhage in the adult. Medicine (Baltimore) 1978; 57(3):211–221.
Takeuchi K, Tsuzuki Y, Ando T, et al. Clinical studies of strangulating small bowel obstruction. Am Surg 2004; 70(1):40–44.
MacKenzie IM. The haemodynamics of human septic shock. Anaesthesia 2001; 56(2):130–144.
Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2016; 101(2):364–389. doi:10.1210/jc.2015-1710
Hamrahian AH, Fleseriu M; AACE Adrenal Scientific Committee. Evaluation and management of adrenal insufficiency in critically ill patients: disease state review. Endocr Pract 2017; 23(6):716–725. doi:10.4158/EP161720.RA
Saenger P, Levine LS, Irvine WJ, et al. Progressive adrenal failure in polyglandular autoimmune disease. J Clin Endocrinol Metab 1982; 54(4):863–867.
Coco G, Dal Pra C, Presotto F, et al. Estimated risk for developing autoimmune Addison's disease in patients with adrenal cortex autoantibodies. J Clin Endocrinol Metab 2006; 91(5):1637–1645. doi:10.1210/jc.2005-0860
Ullian ME. The role of corticosteroids in the regulation of vascular tone. Cardiovasc Res 1999; 41(1):55–64.
Yang S, Zhang L. Glucocorticoids and vascular reactivity. Curr Vasc Pharmacol 2004; 2(1):1–12.
Yanase T, Tajima T, Katabami T, et al. Diagnosis and treatment of adrenal insufficiency including adrenal crisis: a Japan Endocrine Society clinical practice guideline [Opinion]. Endocr J 2016; 63(9):765–784. doi:10.1507/endocrj.EJ16-0242
Taylor RL, Grebe SK, Singh RJ. Quantitative, highly sensitive liquid chromatography-tandem mass spectrometry method for detection of synthetic corticosteroids. Clin Chem 2004; 50(10):2345–2352. doi:10.1373/clinchem.2004.033605
Goldfien A, Laidlaw JC, Haydar NA, Renold AE, Thorn GW. Fluorohydrocortisone and chlorohydrocortisone, highly potent derivatives of compound F. N Engl J Med 1955; 252(11):415–421. doi:10.1056/NEJM195503172521101
Jenkins D, Forsham PH, Laidlaw JC, Reddy WJ, Thorn GW. Use of ACTH in the diagnosis of adrenal cortical insufficiency. Am J Med 1955; 18(1):3–14.
Hägg E, Asplund K, Lithner F. Value of basal plasma cortisol assays in the assessment of pituitary-adrenal insufficiency. Clin Endocrinol (Oxf) 1987; 26(2):221–226.
Deutschbein T, Unger N, Mann K, Petersenn S. Diagnosis of secondary adrenal insufficiency: unstimulated early morning cortisol in saliva and serum in comparison with the insulin tolerance test. Horm Metab Res 2009; 41(4):834–839. doi:10.1055/s-0029-1225630
Erturk E, Jaffe CA, Barkan AL. Evaluation of the integrity of the hypothalamic-pituitary-adrenal axis by insulin hypoglycemia test. J Clin Endocrinol Metab 1998; 83(7):2350–2354.
Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med 2003; 348(8):727–734. doi:10.1056/NEJMra020529
Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 2013; 39(2):165–228. doi:10.1007/s00134-012-2769-8
Ceccato F, Barbot M, Zilio M, et al. Performance of salivary cortisol in the diagnosis of Cushing's syndrome, adrenal incidentaloma, and adrenal insufficiency. Eur J Endocrinol 2013; 169(1):31–36. doi:10.1530/EJE-13-0159
Dickstein G, Shechner C, Nicholson WE, et al. Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 1991; 72(4):773–778. doi:10.1210/jcem-72-4-773
May ME, Carey RM. Rapid adrenocorticotropic hormone test in practice. Retrospective review. Am J Med 1985; 79(6):679–884.
Speckart PF, Nicoloff JT, Bethune JE. Screening for adrenocortical insufficiency with cosyntropin (synthetic ACTH). Arch Intern Med 1971; 128(5):761–763.
Peechakara S, Bena J, Clarke NJ, et al. Total and free cortisol levels during 1 μg, 25 μg, and 250 μg cosyntropin stimulation tests compared to insulin tolerance test: results of a randomized, prospective, pilot study. Endocrine 2017; 57(3):388–393. doi:10.1007/s12020-017-1371-9
Finucane FM, Liew A, Thornton E, Rogers B, Tormey W, Agha A. Clinical insights into the safety and utility of the insulin tolerance test (ITT) in the assessment of the hypothalamo-pituitary-adrenal axis. Clin Endocrinol (Oxf) 2008; 69(4):603–607. doi:10.1111/j.1365-2265.2008.03240.x
Lindholm J, Kehlet H. Re-evaluation of the clinical value of the 30 min ACTH test in assessing the hypothalamic-pituitary-adrenocortical function. Clin Endocrinol (Oxf) 1987; 26(1):53–59.
Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet 2014; 383(9935):2152–2167. doi:10.1016/S0140-6736(13)61684-0
Burke CW. Adrenocortical insufficiency. Clin Endocrinol Metab 1985; 14(4):947–976.
Jessani N, Jehangir W, Behman D, Yousif A, Spiler IJ. Secondary adrenal insufficiency: an overlooked cause of hyponatremia. J Clin Med Res 2015; 7(4):286–288. doi:10.14740/jocmr2041w
Oelkers W. Hyponatremia and inappropriate secretion of vasopressin (antidiuretic hormone) in patients with hypopituitarism. N Engl J Med 1989; 321(8):492–496. doi:10.1056/NEJM198908243210802
Ishikawa S, Schrier RW. Effect of arginine vasopressin antagonist on renal water excretion in glucocorticoid and mineralocorticoid deficient rats. Kidney Int 1982; 22(6):587–593.
Wolfson B, Manning RW, Davis LG, Arentzen R, Baldino F Jr. Co-localization of corticotropin releasing factor and vasopressin mRNA in neurones after adrenalectomy. Nature 1985; 315(6014):59–61.
Kalogeras KT, Nieman LK, Friedman TC, et al. Inferior petrosal sinus sampling in healthy subjects reveals a unilateral corticotropin-releasing hormone-induced arginine vasopressin release associated with ipsilateral adrenocorticotropin secretion. J Clin Invest 1996; 97:2045–2050.
Kovacs KJ, Foldes A, Sawchenko PE. Glucocorticoid negative feedback selectively targets vasopressin transcription in parvocellular neurosecretory neurons. J Neurosci 2000; 20:3843–3852.
Sarkar SB, Sarkar S, Ghosh S, Bandyopadhyay S. Addison's disease. Contemp Clin Dent 2012; 3(4):484–486. doi:10.4103/0976-237X.107450
Szylman P, Better OS, Chaimowitz C, Rosler A. Role of hyperkalemia in the metabolic acidosis of isolated hypoaldosteronism. N Engl J Med 1976; 294(7):361–365. doi:10.1056/NEJM197602122940703

Article PDF

zaghlol_shockandhighinr.pdf

Author and Disclosure Information

Raja Y. Zaghlol, MD
Georgetown University/Washington Hospital Center, Department of Internal Medicine, Washington, DC

Michael E. Tierney, MD, BMedSc
Sydney University Orange Health Service, New South Wales, Australia

Louay Y. Zaghlol
School of Medicine, The University of Jordan, Amman, Jordan

Ayman A. Zayed, MD, MSc, FACE, FACP
Chief, Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, School of Medicine, The University of Jordan, Jordan University Hospital, Amman, Jordan

Address: Ayman A. Zayed, MD, MSc, FACE, FACP, PO Box 13046, Amman 11942, Jordan; baraaayman@gmail.com

Issue

Cleveland Clinic Journal of Medicine - 85(4)

Publications

Cleveland Clinic Journal of Medicine

Topics

Page Number

303-312

Legacy Keywords

adrenal crisis, adrenal failure, shock, hypotension, atrial fibrillation, anticoagulation, warfarin, acetaminophen, interaction, prothrombin time, INR, international normalized ratio, adrenal hemorrhage, cortisone, ACTH, adrenocoticotropic hormone, ACTH stimulation test, Raja Zaghlol, Michael Tierney, Louay Zaghlol, Ayman Zayed

Read more about A 71-year-old woman with shock and a high INR

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Symptoms to Diagnosis

Author(s)

Raja Y. Zaghlol, MD

Michael E. Tierney, MD, BMedSc

Louay Y. Zaghlol

Ayman A. Zayed, MD, MSc, FACE, FACP

Author(s)

Raja Y. Zaghlol, MD

Michael E. Tierney, MD, BMedSc

Louay Y. Zaghlol

Ayman A. Zayed, MD, MSc, FACE, FACP

Author and Disclosure Information

Raja Y. Zaghlol, MD
Georgetown University/Washington Hospital Center, Department of Internal Medicine, Washington, DC

Michael E. Tierney, MD, BMedSc
Sydney University Orange Health Service, New South Wales, Australia

Louay Y. Zaghlol
School of Medicine, The University of Jordan, Amman, Jordan

Address: Ayman A. Zayed, MD, MSc, FACE, FACP, PO Box 13046, Amman 11942, Jordan; baraaayman@gmail.com

Author and Disclosure Information

Raja Y. Zaghlol, MD
Georgetown University/Washington Hospital Center, Department of Internal Medicine, Washington, DC

Michael E. Tierney, MD, BMedSc
Sydney University Orange Health Service, New South Wales, Australia

Louay Y. Zaghlol
School of Medicine, The University of Jordan, Amman, Jordan

Address: Ayman A. Zayed, MD, MSc, FACE, FACP, PO Box 13046, Amman 11942, Jordan; baraaayman@gmail.com

Article PDF

zaghlol_shockandhighinr.pdf

Article PDF

zaghlol_shockandhighinr.pdf

The neighbor confirms that the patient appeared well this morning and has not had any recent illnesses except for a minor cold last week that improved over 5 days with acetaminophen only.

INITIAL EVALUATION AND MANAGEMENT

Physical examination

On physical examination, her blood pressure is 80/40 mm Hg, respiratory rate 25 breaths per minute, oral temperature 38.3°C (100.9°F), and heart rate 130 beats per minute and irregular.

Initial treatment

Cardiac monitoring and 12-lead electrocardiography show atrial fibrillation with a rapid ventricular response of 138 beats per minute, but electrical cardioversion is not done.

Initial laboratory tests

Results of basic laboratory tests in the emergency department are shown in Table 1.

Of note, her international normalized ratio (INR) is 6.13, while the therapeutic range for a patient taking warfarin because of atrial fibrillation is 2.0 to 3.0.

Her serum creatinine level is 1.3 mg/dL (0.5–1.1), and her blood urea nitrogen level is 35 mg/dL (7–20).

Her potassium level is 5.8 mmol/L, which is consistent with hyperkalemia (reference range 3.5–5.2).

DIFFERENTIAL DIAGNOSIS

1. Which of the following is the most likely cause of this patient’s symptoms?

Adrenal crisis
Cardiogenic shock due to decreased cardiac contractility
Intracranial hemorrhage
Acute abdomen due to small bowel obstruction
Septic shock due to bacterial toxin-induced loss of vascular tone

Our patient is presenting with shock. Given our inability to obtain a meaningful history, the differential diagnosis is broad and includes all of the above.

Adrenal crisis

Other causes of adrenal crisis are listed in Table 3.

Cardiogenic shock

Intracranial hemorrhage

Acute abdomen

Septic shock

CASE CONTINUED: CARDIOMEGALY, PERSISTENT HYPOTENSION

Five hours after presenting to the emergency department, her blood pressure remains at 80/40 mm Hg even after receiving 3 L of normal saline intravenously.

PROMPT MANAGEMENT OF ADRENAL CRISIS

2. Which of the following is the most appropriate next step in managing this patient?

Draw samples for serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels, then give hydrocortisone 100 mg intravenously
Perform abdominal computed tomography (CT) without contrast
Perform transthoracic echocardiography
Increase the norepinephrine infusion
Immediately give fludrocortisone

First give fluids

Measure cortisol and ACTH; start corticosteroids immediately

Do not delay corticosteroid therapy while awaiting the results of the diagnostic tests.

Which corticosteroid to use?

Other possible steps

Abdominal CT should be done in our patient to address the possibility of bilateral adrenal hemorrhage. However, it is preferable to wait until the patient is stabilized.

If dexamethasone is used, its effect along with normal saline supplementation would be sufficient to replete the intravenous space and bring the sodium level back up to normal in the acute setting.

CASE RESUMED: IMPROVEMENT WITH HYDROCORTISONE

Serum sodium 137 mmolL
Serum potassium 4.3 mmol/L
Hemoglobin 9.3 g/dL
Serum cortisol (random) 7.2 μg/dL
Plasma ACTH 752 pg/mL (10–60 pg/mL).

ESTABLISHING THE DIAGNOSIS OF ADRENAL INSUFFICIENCY

3. Which of the following is the most appropriate test to establish the diagnosis of adrenal insufficiency?

7 am total serum cortisol measurement
Random serum cortisol measurement
7 am salivary cortisol measurement
24-hour urinary free cortisol measurement
ACTH stimulation test for cortisol
Insulin tolerance test for cortisol

7 am serum cortisol measurement

Random serum cortisol measurements

7 am salivary cortisol measurement

Urinary cortisol measurement

Urinary cortisol measurement is not used to diagnose adrenal insufficiency, as values can be normal in patients with partial adrenal insufficiency.

The ACTH stimulation test

The ACTH stimulation test may not exclude acute secondary or tertiary adrenal insufficiency.

Insulin tolerance testing

CASE RESUMED: PATIENT DISCHARGED, LOST TO FOLLOW-UP

Abdominal CT without contrast is done and demonstrates bilateral adrenal hemorrhage. Thus, the patient is diagnosed with primary acute adrenal insufficiency due to adrenal necrosis.

MINERALOCORTICOID VS CORTICOSTEROID DEFICIENCY

4. Which of the following is least likely to be present in this patient at this time?

Intravascular volume depletion
Hyponatremia
Skin hyperpigmentation
Normokalemia
Elevated serum ACTH level

Intravascular volume depletion

Hyponatremia

In our patient, volume expansion and hyponatremia are expected due to increased antidiuretic hormone secretion as a result of corticosteroid insufficiency.

Hyperpigmentation

This patient has long-standing corticosteroid deficiency due to noncompliance and primary adrenal insufficiency, and as a result she is expected to have elevated serum ACTH and hyperpigmentation.

Normokalemia

TAKE-HOME POINTS

Suspect adrenal crisis in any patient who presents with shock.
Acute abdomen or unexplained fever could be among the manifestations.
Initial management requires liberal normal saline intravenous fluid administration to replete the intravascular space.
Draw blood samples for serum chemistry, cortisol, and ACTH, followed immediately by intravenous hydrocortisone supplementation.
In critically ill patients, evaluate adrenal function with random serum cortisol; in a nonacute setting use the ACTH stimulation test.
Chronic management of primary adrenal insufficiency requires corticosteroid and mineralocorticoid therapy.

The neighbor confirms that the patient appeared well this morning and has not had any recent illnesses except for a minor cold last week that improved over 5 days with acetaminophen only.

INITIAL EVALUATION AND MANAGEMENT

Physical examination

On physical examination, her blood pressure is 80/40 mm Hg, respiratory rate 25 breaths per minute, oral temperature 38.3°C (100.9°F), and heart rate 130 beats per minute and irregular.

Initial treatment

Cardiac monitoring and 12-lead electrocardiography show atrial fibrillation with a rapid ventricular response of 138 beats per minute, but electrical cardioversion is not done.

Initial laboratory tests

Results of basic laboratory tests in the emergency department are shown in Table 1.

Of note, her international normalized ratio (INR) is 6.13, while the therapeutic range for a patient taking warfarin because of atrial fibrillation is 2.0 to 3.0.

Her serum creatinine level is 1.3 mg/dL (0.5–1.1), and her blood urea nitrogen level is 35 mg/dL (7–20).

Her potassium level is 5.8 mmol/L, which is consistent with hyperkalemia (reference range 3.5–5.2).

DIFFERENTIAL DIAGNOSIS

1. Which of the following is the most likely cause of this patient’s symptoms?

Adrenal crisis
Cardiogenic shock due to decreased cardiac contractility
Intracranial hemorrhage
Acute abdomen due to small bowel obstruction
Septic shock due to bacterial toxin-induced loss of vascular tone

Our patient is presenting with shock. Given our inability to obtain a meaningful history, the differential diagnosis is broad and includes all of the above.

Adrenal crisis

Other causes of adrenal crisis are listed in Table 3.

Cardiogenic shock

Intracranial hemorrhage

Acute abdomen

Septic shock

CASE CONTINUED: CARDIOMEGALY, PERSISTENT HYPOTENSION

Five hours after presenting to the emergency department, her blood pressure remains at 80/40 mm Hg even after receiving 3 L of normal saline intravenously.

PROMPT MANAGEMENT OF ADRENAL CRISIS

2. Which of the following is the most appropriate next step in managing this patient?

Draw samples for serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels, then give hydrocortisone 100 mg intravenously
Perform abdominal computed tomography (CT) without contrast
Perform transthoracic echocardiography
Increase the norepinephrine infusion
Immediately give fludrocortisone

First give fluids

Measure cortisol and ACTH; start corticosteroids immediately

Do not delay corticosteroid therapy while awaiting the results of the diagnostic tests.

Which corticosteroid to use?

Other possible steps

Abdominal CT should be done in our patient to address the possibility of bilateral adrenal hemorrhage. However, it is preferable to wait until the patient is stabilized.

If dexamethasone is used, its effect along with normal saline supplementation would be sufficient to replete the intravenous space and bring the sodium level back up to normal in the acute setting.

CASE RESUMED: IMPROVEMENT WITH HYDROCORTISONE

Serum sodium 137 mmolL
Serum potassium 4.3 mmol/L
Hemoglobin 9.3 g/dL
Serum cortisol (random) 7.2 μg/dL
Plasma ACTH 752 pg/mL (10–60 pg/mL).

ESTABLISHING THE DIAGNOSIS OF ADRENAL INSUFFICIENCY

3. Which of the following is the most appropriate test to establish the diagnosis of adrenal insufficiency?

7 am total serum cortisol measurement
Random serum cortisol measurement
7 am salivary cortisol measurement
24-hour urinary free cortisol measurement
ACTH stimulation test for cortisol
Insulin tolerance test for cortisol

7 am serum cortisol measurement

Random serum cortisol measurements

7 am salivary cortisol measurement

Urinary cortisol measurement

Urinary cortisol measurement is not used to diagnose adrenal insufficiency, as values can be normal in patients with partial adrenal insufficiency.

The ACTH stimulation test

The ACTH stimulation test may not exclude acute secondary or tertiary adrenal insufficiency.

Insulin tolerance testing

CASE RESUMED: PATIENT DISCHARGED, LOST TO FOLLOW-UP

Abdominal CT without contrast is done and demonstrates bilateral adrenal hemorrhage. Thus, the patient is diagnosed with primary acute adrenal insufficiency due to adrenal necrosis.

MINERALOCORTICOID VS CORTICOSTEROID DEFICIENCY

4. Which of the following is least likely to be present in this patient at this time?

Intravascular volume depletion
Hyponatremia
Skin hyperpigmentation
Normokalemia
Elevated serum ACTH level

Intravascular volume depletion

Hyponatremia

In our patient, volume expansion and hyponatremia are expected due to increased antidiuretic hormone secretion as a result of corticosteroid insufficiency.

Hyperpigmentation

This patient has long-standing corticosteroid deficiency due to noncompliance and primary adrenal insufficiency, and as a result she is expected to have elevated serum ACTH and hyperpigmentation.

Normokalemia

TAKE-HOME POINTS

Suspect adrenal crisis in any patient who presents with shock.
Acute abdomen or unexplained fever could be among the manifestations.
Initial management requires liberal normal saline intravenous fluid administration to replete the intravascular space.
Draw blood samples for serum chemistry, cortisol, and ACTH, followed immediately by intravenous hydrocortisone supplementation.
In critically ill patients, evaluate adrenal function with random serum cortisol; in a nonacute setting use the ACTH stimulation test.
Chronic management of primary adrenal insufficiency requires corticosteroid and mineralocorticoid therapy.

References

Mani S, Rutecki GW. A patient with altered mental status and an acid-base disturbance. Cleve Clin J Med 2017; 84(1):27–34. doi:10.3949/ccjm.84a.16042
Almiani M, Gorthi J, Subbiah S, Firoz M. Quiz page November 2012: an unusual case of acute hyponatremia and normal anion gap metabolic acidosis. Am J Kidney Dis 2012; 60(5):xxxiii–xxxvi. doi:10.1053/j.ajkd.2012.05.026
Migeon CJ, Kenny FM, Hung W, Voorhess ML. Study of adrenal function in children with meningitis. Pediatrics 1967; 40(2):163–183.
Rao RH, Vagnucci AH, Amico JA. Bilateral massive adrenal hemorrhage: early recognition and treatment. Ann Intern Med 1989; 110(3):227–235.
Shimizu S, Tahara Y, Atsumi T, et al. Waterhouse-Friderichsen syndrome caused by invasive Haemophilus influenzae type B infection in a previously healthy young man. Anaesth Intensive Care 2010; 38(1):214–215.
Castaldo ET, Guillamondegui OD, Greco JA 3rd, Feurer ID, Miller RS, Morris JA Jr. Are adrenal injuries predictive of adrenal insufficiency in patients sustaining blunt trauma? Am Surg 2008; 74(3):262–266.
Xarli VP, Steele AA, Davis PJ, Buescher ES, Rios CN, Garcia-Bunuel R. Adrenal hemorrhage in the adult. Medicine (Baltimore) 1978; 57(3):211–221.
Takeuchi K, Tsuzuki Y, Ando T, et al. Clinical studies of strangulating small bowel obstruction. Am Surg 2004; 70(1):40–44.
MacKenzie IM. The haemodynamics of human septic shock. Anaesthesia 2001; 56(2):130–144.
Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2016; 101(2):364–389. doi:10.1210/jc.2015-1710
Hamrahian AH, Fleseriu M; AACE Adrenal Scientific Committee. Evaluation and management of adrenal insufficiency in critically ill patients: disease state review. Endocr Pract 2017; 23(6):716–725. doi:10.4158/EP161720.RA
Saenger P, Levine LS, Irvine WJ, et al. Progressive adrenal failure in polyglandular autoimmune disease. J Clin Endocrinol Metab 1982; 54(4):863–867.
Coco G, Dal Pra C, Presotto F, et al. Estimated risk for developing autoimmune Addison's disease in patients with adrenal cortex autoantibodies. J Clin Endocrinol Metab 2006; 91(5):1637–1645. doi:10.1210/jc.2005-0860
Ullian ME. The role of corticosteroids in the regulation of vascular tone. Cardiovasc Res 1999; 41(1):55–64.
Yang S, Zhang L. Glucocorticoids and vascular reactivity. Curr Vasc Pharmacol 2004; 2(1):1–12.
Yanase T, Tajima T, Katabami T, et al. Diagnosis and treatment of adrenal insufficiency including adrenal crisis: a Japan Endocrine Society clinical practice guideline [Opinion]. Endocr J 2016; 63(9):765–784. doi:10.1507/endocrj.EJ16-0242
Taylor RL, Grebe SK, Singh RJ. Quantitative, highly sensitive liquid chromatography-tandem mass spectrometry method for detection of synthetic corticosteroids. Clin Chem 2004; 50(10):2345–2352. doi:10.1373/clinchem.2004.033605
Goldfien A, Laidlaw JC, Haydar NA, Renold AE, Thorn GW. Fluorohydrocortisone and chlorohydrocortisone, highly potent derivatives of compound F. N Engl J Med 1955; 252(11):415–421. doi:10.1056/NEJM195503172521101
Jenkins D, Forsham PH, Laidlaw JC, Reddy WJ, Thorn GW. Use of ACTH in the diagnosis of adrenal cortical insufficiency. Am J Med 1955; 18(1):3–14.
Hägg E, Asplund K, Lithner F. Value of basal plasma cortisol assays in the assessment of pituitary-adrenal insufficiency. Clin Endocrinol (Oxf) 1987; 26(2):221–226.
Deutschbein T, Unger N, Mann K, Petersenn S. Diagnosis of secondary adrenal insufficiency: unstimulated early morning cortisol in saliva and serum in comparison with the insulin tolerance test. Horm Metab Res 2009; 41(4):834–839. doi:10.1055/s-0029-1225630
Erturk E, Jaffe CA, Barkan AL. Evaluation of the integrity of the hypothalamic-pituitary-adrenal axis by insulin hypoglycemia test. J Clin Endocrinol Metab 1998; 83(7):2350–2354.
Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med 2003; 348(8):727–734. doi:10.1056/NEJMra020529
Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 2013; 39(2):165–228. doi:10.1007/s00134-012-2769-8
Ceccato F, Barbot M, Zilio M, et al. Performance of salivary cortisol in the diagnosis of Cushing's syndrome, adrenal incidentaloma, and adrenal insufficiency. Eur J Endocrinol 2013; 169(1):31–36. doi:10.1530/EJE-13-0159
Dickstein G, Shechner C, Nicholson WE, et al. Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 1991; 72(4):773–778. doi:10.1210/jcem-72-4-773
May ME, Carey RM. Rapid adrenocorticotropic hormone test in practice. Retrospective review. Am J Med 1985; 79(6):679–884.
Speckart PF, Nicoloff JT, Bethune JE. Screening for adrenocortical insufficiency with cosyntropin (synthetic ACTH). Arch Intern Med 1971; 128(5):761–763.
Peechakara S, Bena J, Clarke NJ, et al. Total and free cortisol levels during 1 μg, 25 μg, and 250 μg cosyntropin stimulation tests compared to insulin tolerance test: results of a randomized, prospective, pilot study. Endocrine 2017; 57(3):388–393. doi:10.1007/s12020-017-1371-9
Finucane FM, Liew A, Thornton E, Rogers B, Tormey W, Agha A. Clinical insights into the safety and utility of the insulin tolerance test (ITT) in the assessment of the hypothalamo-pituitary-adrenal axis. Clin Endocrinol (Oxf) 2008; 69(4):603–607. doi:10.1111/j.1365-2265.2008.03240.x
Lindholm J, Kehlet H. Re-evaluation of the clinical value of the 30 min ACTH test in assessing the hypothalamic-pituitary-adrenocortical function. Clin Endocrinol (Oxf) 1987; 26(1):53–59.
Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet 2014; 383(9935):2152–2167. doi:10.1016/S0140-6736(13)61684-0
Burke CW. Adrenocortical insufficiency. Clin Endocrinol Metab 1985; 14(4):947–976.
Jessani N, Jehangir W, Behman D, Yousif A, Spiler IJ. Secondary adrenal insufficiency: an overlooked cause of hyponatremia. J Clin Med Res 2015; 7(4):286–288. doi:10.14740/jocmr2041w
Oelkers W. Hyponatremia and inappropriate secretion of vasopressin (antidiuretic hormone) in patients with hypopituitarism. N Engl J Med 1989; 321(8):492–496. doi:10.1056/NEJM198908243210802
Ishikawa S, Schrier RW. Effect of arginine vasopressin antagonist on renal water excretion in glucocorticoid and mineralocorticoid deficient rats. Kidney Int 1982; 22(6):587–593.
Wolfson B, Manning RW, Davis LG, Arentzen R, Baldino F Jr. Co-localization of corticotropin releasing factor and vasopressin mRNA in neurones after adrenalectomy. Nature 1985; 315(6014):59–61.
Kalogeras KT, Nieman LK, Friedman TC, et al. Inferior petrosal sinus sampling in healthy subjects reveals a unilateral corticotropin-releasing hormone-induced arginine vasopressin release associated with ipsilateral adrenocorticotropin secretion. J Clin Invest 1996; 97:2045–2050.
Kovacs KJ, Foldes A, Sawchenko PE. Glucocorticoid negative feedback selectively targets vasopressin transcription in parvocellular neurosecretory neurons. J Neurosci 2000; 20:3843–3852.
Sarkar SB, Sarkar S, Ghosh S, Bandyopadhyay S. Addison's disease. Contemp Clin Dent 2012; 3(4):484–486. doi:10.4103/0976-237X.107450
Szylman P, Better OS, Chaimowitz C, Rosler A. Role of hyperkalemia in the metabolic acidosis of isolated hypoaldosteronism. N Engl J Med 1976; 294(7):361–365. doi:10.1056/NEJM197602122940703

References

Mani S, Rutecki GW. A patient with altered mental status and an acid-base disturbance. Cleve Clin J Med 2017; 84(1):27–34. doi:10.3949/ccjm.84a.16042
Almiani M, Gorthi J, Subbiah S, Firoz M. Quiz page November 2012: an unusual case of acute hyponatremia and normal anion gap metabolic acidosis. Am J Kidney Dis 2012; 60(5):xxxiii–xxxvi. doi:10.1053/j.ajkd.2012.05.026
Migeon CJ, Kenny FM, Hung W, Voorhess ML. Study of adrenal function in children with meningitis. Pediatrics 1967; 40(2):163–183.
Rao RH, Vagnucci AH, Amico JA. Bilateral massive adrenal hemorrhage: early recognition and treatment. Ann Intern Med 1989; 110(3):227–235.
Shimizu S, Tahara Y, Atsumi T, et al. Waterhouse-Friderichsen syndrome caused by invasive Haemophilus influenzae type B infection in a previously healthy young man. Anaesth Intensive Care 2010; 38(1):214–215.
Castaldo ET, Guillamondegui OD, Greco JA 3rd, Feurer ID, Miller RS, Morris JA Jr. Are adrenal injuries predictive of adrenal insufficiency in patients sustaining blunt trauma? Am Surg 2008; 74(3):262–266.
Xarli VP, Steele AA, Davis PJ, Buescher ES, Rios CN, Garcia-Bunuel R. Adrenal hemorrhage in the adult. Medicine (Baltimore) 1978; 57(3):211–221.
Takeuchi K, Tsuzuki Y, Ando T, et al. Clinical studies of strangulating small bowel obstruction. Am Surg 2004; 70(1):40–44.
MacKenzie IM. The haemodynamics of human septic shock. Anaesthesia 2001; 56(2):130–144.
Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2016; 101(2):364–389. doi:10.1210/jc.2015-1710
Hamrahian AH, Fleseriu M; AACE Adrenal Scientific Committee. Evaluation and management of adrenal insufficiency in critically ill patients: disease state review. Endocr Pract 2017; 23(6):716–725. doi:10.4158/EP161720.RA
Saenger P, Levine LS, Irvine WJ, et al. Progressive adrenal failure in polyglandular autoimmune disease. J Clin Endocrinol Metab 1982; 54(4):863–867.
Coco G, Dal Pra C, Presotto F, et al. Estimated risk for developing autoimmune Addison's disease in patients with adrenal cortex autoantibodies. J Clin Endocrinol Metab 2006; 91(5):1637–1645. doi:10.1210/jc.2005-0860
Ullian ME. The role of corticosteroids in the regulation of vascular tone. Cardiovasc Res 1999; 41(1):55–64.
Yang S, Zhang L. Glucocorticoids and vascular reactivity. Curr Vasc Pharmacol 2004; 2(1):1–12.
Yanase T, Tajima T, Katabami T, et al. Diagnosis and treatment of adrenal insufficiency including adrenal crisis: a Japan Endocrine Society clinical practice guideline [Opinion]. Endocr J 2016; 63(9):765–784. doi:10.1507/endocrj.EJ16-0242
Taylor RL, Grebe SK, Singh RJ. Quantitative, highly sensitive liquid chromatography-tandem mass spectrometry method for detection of synthetic corticosteroids. Clin Chem 2004; 50(10):2345–2352. doi:10.1373/clinchem.2004.033605
Goldfien A, Laidlaw JC, Haydar NA, Renold AE, Thorn GW. Fluorohydrocortisone and chlorohydrocortisone, highly potent derivatives of compound F. N Engl J Med 1955; 252(11):415–421. doi:10.1056/NEJM195503172521101
Jenkins D, Forsham PH, Laidlaw JC, Reddy WJ, Thorn GW. Use of ACTH in the diagnosis of adrenal cortical insufficiency. Am J Med 1955; 18(1):3–14.
Hägg E, Asplund K, Lithner F. Value of basal plasma cortisol assays in the assessment of pituitary-adrenal insufficiency. Clin Endocrinol (Oxf) 1987; 26(2):221–226.
Deutschbein T, Unger N, Mann K, Petersenn S. Diagnosis of secondary adrenal insufficiency: unstimulated early morning cortisol in saliva and serum in comparison with the insulin tolerance test. Horm Metab Res 2009; 41(4):834–839. doi:10.1055/s-0029-1225630
Erturk E, Jaffe CA, Barkan AL. Evaluation of the integrity of the hypothalamic-pituitary-adrenal axis by insulin hypoglycemia test. J Clin Endocrinol Metab 1998; 83(7):2350–2354.
Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med 2003; 348(8):727–734. doi:10.1056/NEJMra020529
Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 2013; 39(2):165–228. doi:10.1007/s00134-012-2769-8
Ceccato F, Barbot M, Zilio M, et al. Performance of salivary cortisol in the diagnosis of Cushing's syndrome, adrenal incidentaloma, and adrenal insufficiency. Eur J Endocrinol 2013; 169(1):31–36. doi:10.1530/EJE-13-0159
Dickstein G, Shechner C, Nicholson WE, et al. Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 1991; 72(4):773–778. doi:10.1210/jcem-72-4-773
May ME, Carey RM. Rapid adrenocorticotropic hormone test in practice. Retrospective review. Am J Med 1985; 79(6):679–884.
Speckart PF, Nicoloff JT, Bethune JE. Screening for adrenocortical insufficiency with cosyntropin (synthetic ACTH). Arch Intern Med 1971; 128(5):761–763.
Peechakara S, Bena J, Clarke NJ, et al. Total and free cortisol levels during 1 μg, 25 μg, and 250 μg cosyntropin stimulation tests compared to insulin tolerance test: results of a randomized, prospective, pilot study. Endocrine 2017; 57(3):388–393. doi:10.1007/s12020-017-1371-9
Finucane FM, Liew A, Thornton E, Rogers B, Tormey W, Agha A. Clinical insights into the safety and utility of the insulin tolerance test (ITT) in the assessment of the hypothalamo-pituitary-adrenal axis. Clin Endocrinol (Oxf) 2008; 69(4):603–607. doi:10.1111/j.1365-2265.2008.03240.x
Lindholm J, Kehlet H. Re-evaluation of the clinical value of the 30 min ACTH test in assessing the hypothalamic-pituitary-adrenocortical function. Clin Endocrinol (Oxf) 1987; 26(1):53–59.
Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet 2014; 383(9935):2152–2167. doi:10.1016/S0140-6736(13)61684-0
Burke CW. Adrenocortical insufficiency. Clin Endocrinol Metab 1985; 14(4):947–976.
Jessani N, Jehangir W, Behman D, Yousif A, Spiler IJ. Secondary adrenal insufficiency: an overlooked cause of hyponatremia. J Clin Med Res 2015; 7(4):286–288. doi:10.14740/jocmr2041w
Oelkers W. Hyponatremia and inappropriate secretion of vasopressin (antidiuretic hormone) in patients with hypopituitarism. N Engl J Med 1989; 321(8):492–496. doi:10.1056/NEJM198908243210802
Ishikawa S, Schrier RW. Effect of arginine vasopressin antagonist on renal water excretion in glucocorticoid and mineralocorticoid deficient rats. Kidney Int 1982; 22(6):587–593.
Wolfson B, Manning RW, Davis LG, Arentzen R, Baldino F Jr. Co-localization of corticotropin releasing factor and vasopressin mRNA in neurones after adrenalectomy. Nature 1985; 315(6014):59–61.
Kalogeras KT, Nieman LK, Friedman TC, et al. Inferior petrosal sinus sampling in healthy subjects reveals a unilateral corticotropin-releasing hormone-induced arginine vasopressin release associated with ipsilateral adrenocorticotropin secretion. J Clin Invest 1996; 97:2045–2050.
Kovacs KJ, Foldes A, Sawchenko PE. Glucocorticoid negative feedback selectively targets vasopressin transcription in parvocellular neurosecretory neurons. J Neurosci 2000; 20:3843–3852.
Sarkar SB, Sarkar S, Ghosh S, Bandyopadhyay S. Addison's disease. Contemp Clin Dent 2012; 3(4):484–486. doi:10.4103/0976-237X.107450
Szylman P, Better OS, Chaimowitz C, Rosler A. Role of hyperkalemia in the metabolic acidosis of isolated hypoaldosteronism. N Engl J Med 1976; 294(7):361–365. doi:10.1056/NEJM197602122940703

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A 67-year-old woman with bilateral hand numbness

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A 67-year-old woman with bilateral hand numbness

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Sohab S. Radwan, MD

Khair M. Hamo

Ayman A. Zayed, MD, MSc, FACE, FACP

A 67-year-old woman presents to the emergency department after 8 weeks of progressive numbness and tingling in both hands, involving all fingers. The numbness has increased in severity in the last 3 days. She also has occasional numbness around her mouth. She reports no numbness in her feet.

She says she underwent thyroid surgery twice for thyroid cancer 10 years ago. Her medical history also includes type 2 diabetes mellitus (diagnosed 1 year ago), hypertension, dyslipidemia, and diastolic heart failure (diagnosed 5 years ago).

Her current medications are:

Metformin 1 g twice a day
Candesartan 16 mg once a day
Atorvastatin 20 mg once a day
Furosemide 40 mg twice a day
Levothyroxine 100 μg per day
Calcium carbonate 1,500 mg twice a day
A vitamin D tablet twice a day, which she has not taken for the last 2 months.

She admits she has not been taking her medications regularly because she has been feeling depressed.

On physical examination, she is alert and oriented but appears anxious. She is not in respiratory distress. Her blood pressure is 150/90 mm Hg and her pulse is 92 beats per minute and regular. There is a thyroidectomy scar on the anterior neck. Her jugular venous pressure is not elevated. Her heart sounds are normal without extra sounds. She has no pulmonary rales and no lower-extremity edema.

The Phalen test and Tinel test for carpal tunnel syndrome are negative in both hands. Using a Katz hand diagram, the patient reports tingling and numbness in all fingers, both palms, and the dorsum of both hands. Tapping the area over the facial nerve does not elicit twitching of the facial muscles (ie, no Chvostek sign), but compression of the upper arm elicits carpal spasm (ie, positive Trousseau sign). There is no evidence of motor weakness in her hands. The rest of the physical examination is unremarkable.

POSSIBLE CAUSES OF NUMBNESS

1. Based on the initial evaluation, which of the following is the most likely cause of our patient’s bilateral hand numbness?

Hypocalcemia due to primary hypoparathyroidism
Carpal tunnel syndrome due to primary hypothyroidism
Diabetic peripheral neuropathy
Vitamin B₁₂ deficiency due to metformin
Hypocalcemia due to low serum calcitonin

All the conditions above except low serum calcitonin can cause bilateral hand paresthesia. Our patient most likely has hypocalcemia due to primary hypoparathyroidism.

Hypocalcemia

In our patient, bilateral hand numbness and perioral numbness after stopping vitamin D and a positive Trousseau sign strongly suggest hypocalcemia. The classic physical findings in patients with hypocalcemia are the Trousseau sign and the Chvostek sign. The Trousseau sign is elicited by inflating a blood pressure cuff above the systolic blood pressure for 3 minutes and observing for ischemia-induced carpopedal spasm, wrist and metacarpophalangeal joint flexion, thumb adduction, and interphalangeal joint extension. The Chvostek sign is elicited by tapping over the area of the facial nerve below the zygoma in front of the tragus, resulting in ipsilateral twitching of facial muscles.

Although the Trousseau sign is more sensitive and specific than the Chvostek sign, neither is pathognomonic for hypocalcemia.¹ The Chvostek sign has been reported to be negative in 30% of patients with hypocalcemia and positive in 10% of normocalcemic individuals.¹ The Trousseau sign, however, is present in 94% of hypocalcemic patients vs 1% of normocalcemic individuals.²

Primary hypoparathyroidism secondary to thyroidectomy. Postsurgical hypoparathyroidism is the most common cause of primary hypoparathyroidism. It results from ischemic injury or accidental removal of the parathyroid glands during anterior neck surgery.^3,4 The consequent hypocalcemia can be transient, intermittent, or permanent. Permanent postsurgical hypoparathyroidism is defined as persistent hypocalcemia with insufficient parathyroid hormone (PTH) for more than 12 months after neck surgery; however, some consider 6 months to be enough to define the condition.^5–7

The incidence of postsurgical hypoparathyroidism varies considerably with the extent of thyroid surgery and the experience of the surgeon.^6,8 In the hands of experienced surgeons, permanent hypoparathyroidism occurs in fewer than 1% of patients after total thyroidectomy, whereas the rate may be higher than 6% with less-experienced surgeons.^5,9 Other risk factors for postsurgical hypoparathyroidism include female sex, autoimmune thyroid disease, pregnancy, and lactation.⁵

Pseudohypoparathyroidism is a group of disorders characterized by renal resistance to PTH, leading to hypocalcemia, hyperphosphatemia, and elevated serum PTH. It is also associated with phenotypic features such as short stature and short fourth metacarpal bones.

Calcitonin deficiency. Calcitonin is a polypeptide hormone secreted from the parafollicular (C) cells of the thyroid gland. After total thyroidectomy, calcitonin levels are expected to be reduced. However, the role of calcitonin in humans is unclear. One study has shown that calcitonin is possibly a vestigial hormone, given that no calcitonin-related disorders (excess or deficiency) have been reported in humans.¹⁰

Carpal tunnel syndrome due to hypothyroidism

Our patient also could have primary hypothyroidism as a result of thyroidectomy. Hypothyroidism can cause bilateral hand numbness due to carpal tunnel syndrome, which is mediated by mucopolysaccharide deposition and synovial membrane swelling.¹¹ One study reported that 29% of patients with hypothyroidism had carpal tunnel syndrome.¹² Symptoms of carpal tunnel syndrome in hypothyroid patients may occur despite thyroid replacement therapy.¹³

Katz hand diagram classification of carpal tunnel syndrome

Carpal tunnel syndrome is a clinical diagnosis. Patients usually experience hand paresthesia in the distribution of the median nerve. Provocative physical tests for carpal tunnel syndrome include the Tinel test, the Phalen test, and the Katz hand diagram, which is considered the best of the 3 tests.^14,15 Based on how the patient marks the location and type of symptoms on the diagram, carpal tunnel syndrome is rated as classic, probable, possible, or unlikely (Table 1).^14,16,17 The sensitivity of a classic or probable diagram ranges from 64% to 80%, while the specificity ranges from 73% to 90%.^14,15

Carpal tunnel syndrome is less likely to be the cause of our patient’s symptoms, as her Katz hand diagram indicates only “possible” carpal tunnel syndrome. Her perioral numbness and positive Trousseau sign make hypocalcemia a more likely cause.

Diabetic peripheral neuropathy

Sensory peripheral neuropathy is a recognized complication of diabetes mellitus. However, neuropathy in diabetic patients most commonly manifests initially as distal symmetrical ascending neuropathy starting in the lower extremities.¹⁸ Therefore, diabetic peripheral neuropathy is less likely in this patient since her symptoms are limited to her hands.

Vitamin B₁₂ deficiency

Metformin-induced vitamin B₁₂deficiency is another possible cause of peripheral neuropathy. It might be secondary to metformin-induced changes in intrinsic factor levels and small-intestine motility with resultant bacterial overgrowth, as well as inhibition of vitamin B₁₂ absorption in the terminal ileum.¹⁹

However, metformin-induced vitamin B₁₂ deficiency is not the most likely cause of our patient’s neuropathy, since she has been taking this drug for only 1 year. Vitamin B₁₂ deficiency with consequent peripheral neuropathy is more likely in patients taking metformin in high doses for 10 or more years.²⁰

Laboratory results and electrocardiography

Table 2 shows the patient’s initial laboratory results. Of note, her serum calcium level is 5.7 mg/dL (reference range 8.9–10.1). Electrocardiography in the emergency department shows:

Prolonged PR interval (23 msec)
Wide QRS complexes (13 msec)
Flat T waves
Prolonged corrected QT interval (475 msec)
Occasional premature ventricular complexes.

CLINICAL MANIFESTATIONS OF HYPOCALCEMIA

2. Which of the following is not a manifestation of hypocalcemia?

Tonic-clonic seizures
Cyanosis
Cardiac ventricular arrhythmias
Acute pancreatitis
Depression

Hypocalcemia can cause a wide range of clinical manifestations (Table 3), the extent and severity of which depend on the severity of hypocalcemia and how quickly it develops. The more acute the hypocalcemia, the more severe the manifestations.²¹

Tetany can cause seizures

Hypocalcemia is characterized by neuromuscular hyperexcitability, manifested clinically by tetany.²² Manifestations of tetany are numerous and include acral paresthesia, perioral numbness, muscle cramps, carpopedal spasm, and seizures. Tetany is the hallmark of hypocalcemia regardless of etiology. However, certain causes are associated with peculiar clinical manifestations. For example, chronic primary hypoparathyroidism may be associated with basal ganglia calcifications that can result in parkinsonism, other extrapyramidal disorders, and dementia (Table 4).⁶

Clinical manifestations of chronic primary hypoparathyroidism

Airway spasm can be fatal

A serious manifestation of acute severe hypocalcemia is spasm of the glottis muscles, which may cause cyanosis and, if untreated, death.²¹

Ventricular arrhythmias

Another potential fatal complication of acute severe hypocalcemia is polymorphic ventricular tachycardia due to prolongation of the QT interval, which is readily identified with electrocardiography.²³

Hypocalcemia does not cause pancreatitis

Hypercalcemia, rather than hypocalcemia, may cause acute pancreatitis.²⁴ Conversely, acute pancreatitis may cause hypocalcemia due to precipitation of calcium in the abdominal cavity.²⁵

Psychiatric manifestations

In addition to depression, hypocalcemia is associated with psychiatric manifestations including anxiety, confusion, and emotional instability.

STEPS TO DIAGNOSIS OF HYPOCALCEMIA

First step: Confirm true hypocalcemia

Calcium circulates in the blood in 3 forms: bound to albumin (40% to 45%), bound to anions (10% to 15%), and free (ionized) (45%). Although ionized calcium is the active form, most laboratories report total serum calcium.

Since changes in serum albumin concentration affect the total serum calcium level, it is imperative to correct the measured serum calcium to the serum albumin concentration. Each 1-g/dL decrease in serum albumin lowers the total serum calcium by 0.8 mg/dL. Thus:

Corrected serum calcium (mg/dL) =
measured total serum calcium (mg/dL) +
0.8 (4 − serum albumin [g/dL]).

If the patient’s serum calcium level remains low when corrected for serum albumin, he or she has true hypocalcemia, which implies a low ionized serum calcium. Conversely, pseudohypocalcemia means that the measured calcium level is low but the corrected serum calcium is normal.

Using this formula, our patient’s corrected calcium level is calculated as 5.7 + 0.8 (4 – 3.2) = 6.3 mg/dL, indicating true hypocalcemia.

PHOSPHATE IS OFTEN HIGH WHEN CALCIUM IS LOW

In addition to hypocalcemia, our patient has an elevated phosphate level (Table 2).

3. Which of the following hypocalcemic disorders is not associated with hyperphosphatemia?

End-stage renal disease
Primary hypoparathyroidism
Pseudohypoparathyroidism
Vitamin D₃ deficiency
Rhabdomyolysis

Vitamin D deficiency is not associated with hyperphosphatemia.

Second step in evaluating hypocalcemia: Check phosphate, magnesium, creatinine

Major causes of hypocalcemia, according to phosphate level

The major causes of hypocalcemia can be categorized according to the serum phosphate level: high vs normal or low (Table 5).

High-phosphate, low-calcium states. In the absence of concurrent end-stage renal disease and an excessive phosphate load, primary hypoparathyroidism is the most likely cause of hypocalcemia associated with hyperphosphatemia.

PTH increases serum ionized calcium by^26,27:

Increasing bone resorption
Increasing reabsorption of calcium from the distal renal tubules
Increasing the activity of 1-alpha-hydroxylase, responsible for conversion of 25-hydroxyvitamin D₃ to 1,25-dihydroxyvitamin D₃ (the most biologically active vitamin D metabolite); 1,25-dihydroxyvitamin D increases the absorption of calcium and phosphate from the intestine.

Conversely, PTH decreases reabsorption of phosphate from proximal renal tubules, resulting in hypophosphatemia. Therefore, low serum PTH (primary hypoparathyroidism) or a PTH-resistant state (pseudohypoparathyroidism) results in hypocalcemia and hyperphosphatemia.^26,27

Both end-stage renal disease and rhabdomyolysis are associated with high serum phosphate levels. The kidney normally excretes excess dietary phosphate to maintain phosphate homeostasis; however, this is impaired in end-stage renal disease, leading to hyperphosphatemia. In rhabdomyolysis, it is mainly the transcellular shift of phosphate into the extracellular space from myocyte injury that raises phosphate levels.

Normal- or low-phosphate, low calcium states. Hypocalcemia can also result from vitamin D deficiency, but this cause is associated with a low or normal serum phosphate level. In such cases, hypocalcemia causes secondary hyperparathyroidism with consequent renal phosphate loss and, thus, hypophosphatemia.²⁷

Third step: Check serum intact PTH and 25-hydroxyvitamin D levels

Hypocalcemia stimulates secretion of PTH. Therefore, hypocalcemia with elevated serum PTH is caused by disorders that do not impair PTH secretion, including chronic renal failure and vitamin D deficiency (Table 5). Conversely, hypocalcemia with low or normal serum PTH levels suggests primary hypoparathyroidism.

Our patient’s serum PTH level is 20 ng/mL, which is within the reference range. This does not discount the diagnosis of primary hypoparathyroidism. Although most patients with primary hypoparathyroidism have low or undetectable serum PTH levels, some have normal PTH levels if some degree of PTH production is preserved.^5,7,28–30 In these patients, the remaining functioning parathyroid tissue is not enough to maintain a normal serum calcium level, resulting in hypocalcemia. As a result, hypocalcemia stimulates the remaining parathyroid tissue to its maximum output, producing PTH levels usually within the lower or middle-normal range.³⁰ In such patients, the terms parathyroid insufficiency and relative primary hypoparathyroidism are more precise than primary hypoparathyroidism.

Postsurgical hypoparathyroidism with an inappropriately normal PTH level is usually seen in patients with disorders that impair intestinal calcium absorption or bone resorption.³¹ In our patient’s case, the “normal” serum PTH level is likely due to maximal stimulation of remaining functioning parathyroid tissue by severe hypocalcemia, which is a result of her discontinuation of calcium and calcitriol therapy and her vitamin D deficiency.

CASE RESUMED: NO RESPONSE TO INTRAVENOUS CALCIUM GLUCONATE

The patient is given 2 10-mL ampules of 10% calcium gluconate diluted in 100 mL of 5% dextrose in water over 20 minutes intravenously. Electrocardiographic monitoring is continued. Two hours later, her measured serum calcium is only 5.8 mg/dL, with no improvement in her symptoms.

A continuous infusion of calcium gluconate is started: 12 ampules of calcium gluconate are added to 380 mL of 5% dextrose in water and infused at 40 mL/hour (infused rate of elemental calcium = 1.3 mg/kg/hour); 3 hours later, her measured serum calcium level is still only 5.8 mg//dL; at 6 hours it is 5.9 mg/dL, and her symptoms have not improved.

4. Which of the following is the most appropriate next step?

Change the calcium gluconate to calcium chloride
Increase the infusion rate to 1.5 mg of elemental calcium/kg/hour
Give a bolus of 2 10-mL ampules of 10% calcium gluconate intravenously over 1 minute
Give additional oral calcium tablets
Check the serum magnesium level

Treatment of hypocalcemia can involve intravenous or oral calcium therapy.

Intravenous calcium is indicated for patients with any of the following^6,32:

Moderate to severe neuromuscular irritability (eg, acral paresthesia, carpopedal spasm, prolonged QT interval, seizures, laryngospasm, bronchospasm)
Acute hypocalcemia with corrected serum calcium level less than 7.6 mg/dL, even if the patient is asymptomatic
Cardiac failure.

One 10-mL ampule of 10% calcium gluconate contains 93 mg of elemental calcium; 1 or 2 ampules are typically diluted in 50 to 100 mL of 5% dextrose in water and infused slowly over 15 to 20 minutes. Rapid administration of intravenous calcium is contraindicated, as it may produce cardiac arrhythmias and possibly cardiac arrest. Therefore, intravenous calcium should be given slowly while continuing electrocardiographic monitoring.³³

Since the effect of 1 ampule of calcium gluconate lasts only 2 to 3 hours, most patients with symptomatic hypocalcemia require continuous intravenous calcium infusion. The recommended dose of infused elemental calcium is 0.5 to 1.5 mg/kg/hour.³⁴ Several ampules are added to 500 to 1,000 mL of 5% dextrose in water or 0.9% normal saline and infused at a rate appropriate for the patient’s corrected calcium and symptoms.

Oral calcium and vitamin D supplements can be given initially to patients with a corrected serum calcium level of 7.6 mg/dL or greater, with or without mild symptoms, if they can tolerate oral intake. However, this is not the treatment of choice for resistant acute hypocalcemia, as in this case.

Calcium chloride has no advantages over calcium gluconate. Further, it can be associated with local irritation and may result in tissue necrosis if extravasation occurs.³⁵

Increasing the infusion rate of calcium gluconate to the maximum recommended dose may improve the patient’s ionized calcium level and symptoms somewhat. However, it is not the best option for this patient, given that she did not respond to 2 ampules of calcium gluconate followed by continuous infusion of 1.3 mg/kg/hour for 6 hours.

Calcium gluconate bolus. Similarly, giving the patient an additional 2 ampules of calcium gluconate over 1 minute would not be recommended, as rapid administration of intravenous calcium gluconate (eg, over 1 minute) is contraindicated.

Check magnesium

If hypocalcemia persists despite intravenous calcium therapy, as in our patient, further investigation or action is required. An important cause of persistent hypocalcemia is severe hypomagnesemia. Severe hypomagnesemia (serum magnesium < 0.8 mg/dL) causes resistant hypocalcemia by several mechanisms:

Inducing PTH resistance^32,36,37
Decreasing PTH secretion^32,36
Decreasing calcitriol production.

The decrease in calcitriol production is a direct effect of hypomagnesemia, but it is also an indirect effect of low PTH secretion, which inhibits the enzyme 1-alpha-hydroxylase. Thus, conversion of 25-hydroxyvitamin D₃ to calcitriol is impaired, leading to low calcitriol production.

Our patient could have hypomagnesemia due to furosemide use and uncontrolled diabetes mellitus. Hypocalcemia resistant to calcium therapy may occasionally respond to magnesium therapy even if the serum magnesium level is normal. This may be due to depleted intracellular magnesium salt levels.^6,38 Rarely, severe hypermagnesemia can also be associated with hypocalcemia due to inhibition of PTH secretion.^37,39

CASE RESUMED

Our patient’s serum magnesium level is 0.6 mg/dL (reference range 1.7–2.4 mg/dL). She is given 2 g of magnesium sulfate in 60 mL of 0.9% normal saline infused over 1 hour, followed by a continuous infusion of magnesium sulfate (12 g diluted in 250 mL of 0.9% normal saline, infused over 24 hours). On repeat testing 4 hours later, her serum magnesium level is 0.7 mg/dL, and at 8 hours later it is 0.9 mg/dL. She is subsequently started on oral magnesium oxide 600 mg per day. The magnesium sulfate infusion is continued for another 24 hours.

PREVENTING HYPERCALCIURIA

Patients with low PTH (primary hypoparathyroidism) may have hypercalciuria due to decreased renal tubular calcium reabsorption. Two important measures can minimize hypercalciuria in such patients:

Keeping the serum calcium level in the low-normal range^4,5,40
Giving a thiazide diuretic (eg, hydrochlorothiazide 12.5–50 mg daily) with a low-salt diet.^41,42

A thiazide diuretic is usually started once the 24-hour urine calcium reaches 250 mg.⁶ Thiazides are thought to enhance both proximal and distal renal tubular calcium reabsorption.^43,44

PRIMARY HYPOPARATHYROIDISM: LONG-TERM MANAGEMENT

Long-term management of primary hypoparathyroidism requires calcium and vitamin D supplementation.

Calcium supplements. The most commonly prescribed calcium preparations are calcium carbonate and calcium citrate (containing 40% and 20% elemental calcium, respectively). Calcium carbonate, which is less expensive than calcium citrate, binds with phosphate intake and requires an acidic environment for absorption, and so it is better absorbed when taken with meals. Because calcium citrate does not require an acidic environment for absorption, it is the calcium preparation of choice for patients on proton pump inhibitors, or patients with achlorhydria or constipation.⁴⁵ Calcium doses vary widely, with most hypoparathyroid patients requiring 1 to 2 g of elemental calcium daily.⁶

Vitamin D supplements. To promote intestinal absorption, calcium is combined with vitamin D in a fixed-dose preparation given in divided doses.⁴⁶ Calcitriol (1,25-dihydroxyvitamin D₃) is the most active metabolite of vitamin D, with rapid onset and offset of action, and it is the preferred form of vitamin D therapy for patients with hypoparathyroidism. If calcitriol is not available or is not affordable, alphacalcidol (1-alpha-hydroxyvitamin D₃) is another option. This is a synthetic analogue of vitamin D that is already hyroxylated at the C1 position. After oral intake, it is hydroxylated in the liver to form calcitriol.

Since renal production of calcitriol is PTH-dependent, in hypoparathyroidism the conversion of 25-hydroxyvitamin D₃ to calcitriol is limited. Therefore, vitamin D₃ (cholecalciferol) and vitamin D₂ (ergocalciferol) are not the preferred forms of vitamin D for such patients. However, either can be added to calcitriol, as they may have extraskeletal benefits.⁷

CASE CONCLUDED

Our patient presented with primary parathyroid insufficiency associated with vitamin D deficiency. Therefore, in addition to calcitriol and calcium combined with vitamin D in a fixed-dose preparation, her management included vitamin D₃ for her vitamin D deficiency.

She was discharged on these medications. At a follow-up visit 3 weeks later, her measured serum calcium level was 8.6 mg/dL. She reported gradual resolution of her symptoms. She was also referred to a psychiatrist for her depression.

TAKE-HOME POINTS

Hypocalcemia causes neuromuscular excitability, manifested clinically by tetany.
Common causes of hypocalcemia include vitamin D deficiency, hypomagnesemia, renal failure, and primary hypoparathyroidism.
The first step in evaluating hypocalcemia is to correct the measured serum calcium to the serum albumin concentration.
Laboratory testing for hypocalcemia should include serum phosphorus, magnesium, creatinine, PTH, and 25-hydroxyvitamin D₃.
Primary hypoparathyroidism is characterized by hypocalcemia, hyperphosphatemia, and low serum PTH.
Moderate to severe manifestations of hypo-
calcemia and acute hypocalcemia (< 7.6 mg/dL), even if asymptomatic, warrant intravenous calcium therapy.
Correction of hypomagnesemia is essential to treat hypocalcemia, especially if resistant to intravenous calcium therapy.
The goal of chronic management of primary hypoparathyroidism includes correcting the serum calcium level to a low-normal range, the serum phosphorus level to an upper-normal range, and prevention of hypercalciuria.

Acknowledgments: The authors wish to thank Mr. Michael Edward Tierney of the School of Medicine, University of Sydney, Australia, for his linguistic editing of the manuscript.

References

Jesus JE, Landry A. Images in clinical medicine. Chvostek’s and Trousseau’s signs. N Engl J Med 2012; 367:e15.
Urbano FL. Signs of hypocalcemia: Chvostek’s and Trousseau’s. Hosp Physician 2000; 36:43–45.
Chisthi MM, Nair RS, Kuttanchettiyar KG, Yadev I. Mechanisms behind post-thyroidectomy hypocalcemia: interplay of calcitonin, parathormone, and albumin—a prospective study. J Invest Surg 2017; 30:217–225.
Shoback DM, Bilezikian JP, Costa AG, et al. Presentation of hypoparathyroidism: etiologies and clinical features. J Clin Endocrinol Metab 2016; 101:2300–2312.
Stack BC Jr, Bimston DN, Bodenner DL, et al. American Association of Clinical Endocrinologists and American College of Endocrinology disease state clinical review: postoperative hypoparathyroidism—definitions and management. Endocr Pract 2015; 21:674–685.
Shoback D. Clinical practice. Hypoparathyroidism. N Engl J Med 2008; 359:391–403.
Abate EG, Clarke BL. Review of hypoparathyroidism. Front Endocrinol (Lausanne) 2017; 7:172.
Coimbra C, Monteiro F, Oliveira P, Ribeiro L, de Almeida MG, Condé A. Hypoparathyroidism following thyroidectomy: predictive factors. Acta Otorrinolaringol Esp 2017; 68:106–111.
Thomusch O, Machens A, Sekulla C, Ukkat J, Brauckhoff M, Dralle H. The impact of surgical technique on postoperative hypoparathyroidism in bilateral thyroid surgery: a multivariate analysis of 5846 consecutive patients. Surgery 2003; 133:180–185.
Hirsch PF, Lester GE, Talmage RV. Calcitonin, an enigmatic hormone: does it have a function? J Musculoskelet Neuronal Interact 2001; 1:299–305.
Karne SS, Bhalerao NS. Carpal tunnel syndrome in hypothyroidism. J Clin Diagn Res 2016; 10:OC36–OC38.
Duyff RF, Van den Bosch J, Laman DM, van Loon BJ, Linssen WH. Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study. J Neurol Neurosurg Psychiatry 2000; 68:750–755.
Palumbo CF, Szabo RM, Olmsted SL. The effects of hypothyroidism and thyroid replacement on the development of carpal tunnel syndrome. J Hand Surg Am 2000; 25:734–739.
Katz JN, Stirrat CR, Larson MG, Fossel AH, Eaton HM, Liang MH. A self-administered hand symptom diagram for the diagnosis and epidemiologic study of carpal tunnel syndrome. J Rheumatol 1990; 17:1495–1498.
Katz JN, Stirrat CR. A self-administered hand diagram for the diagnosis of carpal tunnel syndrome. J Hand Surg Am 1990; 15:360–363.
Calfee RP, Dale AM, Ryan D, Descatha A, Franzblau A, Evanoff B. Performance of simplified scoring systems for hand diagrams in carpal tunnel syndrome screening. J Hand Surg Am 2012; 37:10–17.
D’Arcy CA, McGee S. The rational clinical examination. Does this patient have carpal tunnel syndrome? JAMA 2000; 283:3110–3117.
Marchettini P, Lacerenza M, Mauri E, Marangoni C. Painful peripheral neuropathies. Curr Neuropharmacol 2006; 4:175–181.
Kibirige D, Mwebaze R. Vitamin B12 deficiency among patients with diabetes mellitus: is routine screening and supplementation justified? J Diabetes Metab Disord 2013;12:17.
Akinlade KS, Agbebaku SO, Rahamon SK, Balogun WO. Vitamin B12 levels in patients with type 2 diabetes mellitus on metformin. Ann Ib Postgrad Med 2015; 13:79–83.
Tohme JF, Bilezikian JP. Hypocalcemic emergencies. Endocrinol Metab Clin North Am 1993; 22:363–375.
Macefield G, Burke D. Paraesthesiae and tetany induced by voluntary hyperventilation. Increased excitability of human cutaneous and motor axons. Brain 1991; 114:527–540.
Benoit SR, Mendelsohn AB, Nourjah P, Staffa JA, Graham DJ. Risk factors for prolonged QTc among US adults: Third National Health and Nutrition Examination Survey. Eur J Cardiovasc Prev Rehabil 2005; 12:363–368.
Khoo TK, Vege SS, Abu-Lebdeh HS, Ryu E, Nadeem S, Wermers RA. Acute pancreatitis in primary hyperparathyroidism: a population-based study. J Clin Endocrinol Metab 2009; 94:2115–2118.
McKay C, Beastall GH, Imrie CW, Baxter JN. Circulating intact parathyroid hormone levels in acute pancreatitis. Br J Surg 1994; 81:357–360.
Talmage RV, Mobley HT. Calcium homeostasis: reassessment of the actions of parathyroid hormone. Gen Comp Endocrinol 2008; 156:1–8.
Friedman PA, Gesek FA. Calcium transport in renal epithelial cells. Am J Physiol 1993; 264:F181–F198.
Jensen PV, Jelstrup SM, Homøe P. Long-term outcomes after total thyroidectomy. Dan Med J 2015; 62:A5156.
Ritter K, Elfenbein D, Schneider DF, Chen H, Sippel RS. Hypoparathyroidism after total thyroidectomy: incidence and resolution. J Surg Res 2015; 197:348–353.
Promberger R, Ott J, Kober F, Karik M, Freissmuth M, Hermann M. Normal parathyroid hormone levels do not exclude permanent hypoparathyroidism after thyroidectomy. Thyroid 2011; 21:145–150.
Lorente-Poch L, Sancho JJ, Muñoz-Nova JL, Sánchez-Velázquez P, Sitges-Serra A. Defining the syndromes of parathyroid failure after total thyroidectomy. Gland Surgery 2015; 4:82–90.
Cooper MS, Gittoes NJ. Diagnosis and management of hypocalcaemia. BMJ 2008; 336:1298–1302.
Tohme JF, Bilezikian JP. Diagnosis and treatment of hypocalcemic emergencies. Endocrinologist 1996; 6:10–18.
Carroll R, Matfin G. Endocrine and metabolic emergencies: hypocalcaemia. Ther Adv Endocrinol Metab 2010; 1:29–33.
Kim MP, Raho VJ, Mak J, Kaynar AM. Skin and soft tissue necrosis from calcium chloride in a deicer. J Emerg Med 2007; 32:41–44.
Tong GM, Rude RK. Magnesium deficiency in critical illness. J Intensive Care Med 2005; 20:3–17.
Cholst IN, Steinberg SF, Tropper PJ, Fox HE, Segre GV, Bilezikian JP. The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects. N Engl J Med 1984; 310:1221–1225.
Ryzen E, Nelson TA, Rude RK. Low blood mononuclear cell magnesium content and hypocalcemia in normomagnesemic patients. West J Med 1987; 147:549–553.
Koontz SL, Friedman SA, Schwartz ML. Symptomatic hypocalcemia after tocolytic therapy with magnesium sulfate and nifedipine. Am J Obstet Gynecol 2004; 190:1773–1776.
Brandi ML, Bilezikian JP, Shoback D, et al. Management of hypoparathyroidism: summary statement and guidelines. J Clin Endocrinol Metab 2016; 101:2273–2283.
Porter RH, Cox BG, Heaney D, Hostetter TH, Stinebaugh BJ, Suki WN. Treatment of hypoparathyroid patients with chlorthalidone. N Engl J Med 1978; 298:577–581.
Clarke BL, Brown EM, Collins MT, et al. Epidemiology and diagnosis of hypoparathyroidism. J Clin Endocrinol Metab 2016; 101:2284–2299.
Nijenhuis T, Vallon V, van der Kemp AW, Loffing J, Hoenderop JG, Bindels RJ. Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. J Clin Invest 2005; 115:1651–1658.
Costanzo LS. Localization of diuretic action in microperfused rat distal tubules: Ca and Na transport. Am J Physiol 1985; 248:F527–F535.
Brandi ML, Bilezikian JP, Shoback D, et al. Management of hypoparathyroidism: summary statement and guidelines. J Clin Endocrinol Metab 2016; 101:2273–2283.
Scotti A, Bianchini C, Abbiati G, Marzo A. Absorption of calcium administered alone or in fixed combination with vitamin D to healthy volunteers. Arzneimittelforschung 2001; 51:493–500.

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radwan_bilateralhandnumbness.pdf

Author and Disclosure Information

Sohab S. Radwan, MD
Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, Jordan University Hospital, Amman, Jordan

Khair M. Hamo
School of Medicine, Jordan University Hospital, Amman, Jordan

Ayman A. Zayed, MD, MSc, FACE, FACP
Chief, Division of Endocrinology, Diabetes, and Metabolism Department of Internal Medicine, Jordan University Hospital, Amman, Jordan

Address: Ayman A. Zayed, MD, MSc, FACE, FACP, Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, Jordan University Hospital, The University of Jordan, Queen Rania Street, Amman, Jordan, 11942; baraaayman@gmail.com

Issue

Cleveland Clinic Journal of Medicine - 85(3)

Publications

Cleveland Clinic Journal of Medicine

Type 2 Diabetes ICYMI

Topics

Page Number

200-208

Legacy Keywords

numbness, paresthesia, hypocalcemia, calcium, Trousseau sign, Chvostek sign, hypoparathyroidism, carpal tunnel syndrome, hypothyroidism, diabetic peripheral neuropathy, vitamin B12 deficiency, parathyroid, parathyroid hormone, PTH, thyroid surgery, electrolytes, Sohab Radwan, Khair Hamo, Ayman Zayed

Read more about A 67-year-old woman with bilateral hand numbness

Sections

IM Board Review

Symptoms to Diagnosis

Author(s)

Sohab S. Radwan, MD

Khair M. Hamo

Ayman A. Zayed, MD, MSc, FACE, FACP

Author(s)

Sohab S. Radwan, MD

Khair M. Hamo

Ayman A. Zayed, MD, MSc, FACE, FACP

Author and Disclosure Information

Sohab S. Radwan, MD
Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, Jordan University Hospital, Amman, Jordan

Khair M. Hamo
School of Medicine, Jordan University Hospital, Amman, Jordan

Ayman A. Zayed, MD, MSc, FACE, FACP
Chief, Division of Endocrinology, Diabetes, and Metabolism Department of Internal Medicine, Jordan University Hospital, Amman, Jordan

Author and Disclosure Information

Sohab S. Radwan, MD
Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, Jordan University Hospital, Amman, Jordan

Khair M. Hamo
School of Medicine, Jordan University Hospital, Amman, Jordan

Ayman A. Zayed, MD, MSc, FACE, FACP
Chief, Division of Endocrinology, Diabetes, and Metabolism Department of Internal Medicine, Jordan University Hospital, Amman, Jordan

Article PDF

radwan_bilateralhandnumbness.pdf

Article PDF

radwan_bilateralhandnumbness.pdf

Her current medications are:

Metformin 1 g twice a day
Candesartan 16 mg once a day
Atorvastatin 20 mg once a day
Furosemide 40 mg twice a day
Levothyroxine 100 μg per day
Calcium carbonate 1,500 mg twice a day
A vitamin D tablet twice a day, which she has not taken for the last 2 months.

She admits she has not been taking her medications regularly because she has been feeling depressed.

POSSIBLE CAUSES OF NUMBNESS

1. Based on the initial evaluation, which of the following is the most likely cause of our patient’s bilateral hand numbness?

Hypocalcemia due to primary hypoparathyroidism
Carpal tunnel syndrome due to primary hypothyroidism
Diabetic peripheral neuropathy
Vitamin B₁₂ deficiency due to metformin
Hypocalcemia due to low serum calcitonin

All the conditions above except low serum calcitonin can cause bilateral hand paresthesia. Our patient most likely has hypocalcemia due to primary hypoparathyroidism.

Hypocalcemia

Carpal tunnel syndrome due to hypothyroidism

Diabetic peripheral neuropathy

Vitamin B₁₂ deficiency

Laboratory results and electrocardiography

Table 2 shows the patient’s initial laboratory results. Of note, her serum calcium level is 5.7 mg/dL (reference range 8.9–10.1). Electrocardiography in the emergency department shows:

Prolonged PR interval (23 msec)
Wide QRS complexes (13 msec)
Flat T waves
Prolonged corrected QT interval (475 msec)
Occasional premature ventricular complexes.

CLINICAL MANIFESTATIONS OF HYPOCALCEMIA

2. Which of the following is not a manifestation of hypocalcemia?

Tonic-clonic seizures
Cyanosis
Cardiac ventricular arrhythmias
Acute pancreatitis
Depression

Tetany can cause seizures

Airway spasm can be fatal

A serious manifestation of acute severe hypocalcemia is spasm of the glottis muscles, which may cause cyanosis and, if untreated, death.²¹

Ventricular arrhythmias

Hypocalcemia does not cause pancreatitis

Hypercalcemia, rather than hypocalcemia, may cause acute pancreatitis.²⁴ Conversely, acute pancreatitis may cause hypocalcemia due to precipitation of calcium in the abdominal cavity.²⁵

Psychiatric manifestations

In addition to depression, hypocalcemia is associated with psychiatric manifestations including anxiety, confusion, and emotional instability.

STEPS TO DIAGNOSIS OF HYPOCALCEMIA

First step: Confirm true hypocalcemia

Corrected serum calcium (mg/dL) =
measured total serum calcium (mg/dL) +
0.8 (4 − serum albumin [g/dL]).

Using this formula, our patient’s corrected calcium level is calculated as 5.7 + 0.8 (4 – 3.2) = 6.3 mg/dL, indicating true hypocalcemia.

PHOSPHATE IS OFTEN HIGH WHEN CALCIUM IS LOW

In addition to hypocalcemia, our patient has an elevated phosphate level (Table 2).

3. Which of the following hypocalcemic disorders is not associated with hyperphosphatemia?

End-stage renal disease
Primary hypoparathyroidism
Pseudohypoparathyroidism
Vitamin D₃ deficiency
Rhabdomyolysis

Vitamin D deficiency is not associated with hyperphosphatemia.

Second step in evaluating hypocalcemia: Check phosphate, magnesium, creatinine

The major causes of hypocalcemia can be categorized according to the serum phosphate level: high vs normal or low (Table 5).

PTH increases serum ionized calcium by^26,27:

Increasing bone resorption
Increasing reabsorption of calcium from the distal renal tubules
Increasing the activity of 1-alpha-hydroxylase, responsible for conversion of 25-hydroxyvitamin D₃ to 1,25-dihydroxyvitamin D₃ (the most biologically active vitamin D metabolite); 1,25-dihydroxyvitamin D increases the absorption of calcium and phosphate from the intestine.

Third step: Check serum intact PTH and 25-hydroxyvitamin D levels

CASE RESUMED: NO RESPONSE TO INTRAVENOUS CALCIUM GLUCONATE

4. Which of the following is the most appropriate next step?

Change the calcium gluconate to calcium chloride
Increase the infusion rate to 1.5 mg of elemental calcium/kg/hour
Give a bolus of 2 10-mL ampules of 10% calcium gluconate intravenously over 1 minute
Give additional oral calcium tablets
Check the serum magnesium level

Treatment of hypocalcemia can involve intravenous or oral calcium therapy.

Intravenous calcium is indicated for patients with any of the following^6,32:

Moderate to severe neuromuscular irritability (eg, acral paresthesia, carpopedal spasm, prolonged QT interval, seizures, laryngospasm, bronchospasm)
Acute hypocalcemia with corrected serum calcium level less than 7.6 mg/dL, even if the patient is asymptomatic
Cardiac failure.

Calcium chloride has no advantages over calcium gluconate. Further, it can be associated with local irritation and may result in tissue necrosis if extravasation occurs.³⁵

Check magnesium

Inducing PTH resistance^32,36,37
Decreasing PTH secretion^32,36
Decreasing calcitriol production.

CASE RESUMED

PREVENTING HYPERCALCIURIA

Patients with low PTH (primary hypoparathyroidism) may have hypercalciuria due to decreased renal tubular calcium reabsorption. Two important measures can minimize hypercalciuria in such patients:

Keeping the serum calcium level in the low-normal range^4,5,40
Giving a thiazide diuretic (eg, hydrochlorothiazide 12.5–50 mg daily) with a low-salt diet.^41,42

A thiazide diuretic is usually started once the 24-hour urine calcium reaches 250 mg.⁶ Thiazides are thought to enhance both proximal and distal renal tubular calcium reabsorption.^43,44

PRIMARY HYPOPARATHYROIDISM: LONG-TERM MANAGEMENT

Long-term management of primary hypoparathyroidism requires calcium and vitamin D supplementation.

CASE CONCLUDED

TAKE-HOME POINTS

Hypocalcemia causes neuromuscular excitability, manifested clinically by tetany.
Common causes of hypocalcemia include vitamin D deficiency, hypomagnesemia, renal failure, and primary hypoparathyroidism.
The first step in evaluating hypocalcemia is to correct the measured serum calcium to the serum albumin concentration.
Laboratory testing for hypocalcemia should include serum phosphorus, magnesium, creatinine, PTH, and 25-hydroxyvitamin D₃.
Primary hypoparathyroidism is characterized by hypocalcemia, hyperphosphatemia, and low serum PTH.
Moderate to severe manifestations of hypo-
calcemia and acute hypocalcemia (< 7.6 mg/dL), even if asymptomatic, warrant intravenous calcium therapy.
Correction of hypomagnesemia is essential to treat hypocalcemia, especially if resistant to intravenous calcium therapy.
The goal of chronic management of primary hypoparathyroidism includes correcting the serum calcium level to a low-normal range, the serum phosphorus level to an upper-normal range, and prevention of hypercalciuria.

Acknowledgments: The authors wish to thank Mr. Michael Edward Tierney of the School of Medicine, University of Sydney, Australia, for his linguistic editing of the manuscript.

Her current medications are:

Metformin 1 g twice a day
Candesartan 16 mg once a day
Atorvastatin 20 mg once a day
Furosemide 40 mg twice a day
Levothyroxine 100 μg per day
Calcium carbonate 1,500 mg twice a day
A vitamin D tablet twice a day, which she has not taken for the last 2 months.

She admits she has not been taking her medications regularly because she has been feeling depressed.

POSSIBLE CAUSES OF NUMBNESS

1. Based on the initial evaluation, which of the following is the most likely cause of our patient’s bilateral hand numbness?

Hypocalcemia due to primary hypoparathyroidism
Carpal tunnel syndrome due to primary hypothyroidism
Diabetic peripheral neuropathy
Vitamin B₁₂ deficiency due to metformin
Hypocalcemia due to low serum calcitonin

All the conditions above except low serum calcitonin can cause bilateral hand paresthesia. Our patient most likely has hypocalcemia due to primary hypoparathyroidism.

Hypocalcemia

Carpal tunnel syndrome due to hypothyroidism

Diabetic peripheral neuropathy

Vitamin B₁₂ deficiency

Laboratory results and electrocardiography

Table 2 shows the patient’s initial laboratory results. Of note, her serum calcium level is 5.7 mg/dL (reference range 8.9–10.1). Electrocardiography in the emergency department shows:

Prolonged PR interval (23 msec)
Wide QRS complexes (13 msec)
Flat T waves
Prolonged corrected QT interval (475 msec)
Occasional premature ventricular complexes.

CLINICAL MANIFESTATIONS OF HYPOCALCEMIA

2. Which of the following is not a manifestation of hypocalcemia?

Tonic-clonic seizures
Cyanosis
Cardiac ventricular arrhythmias
Acute pancreatitis
Depression

Tetany can cause seizures

Airway spasm can be fatal

A serious manifestation of acute severe hypocalcemia is spasm of the glottis muscles, which may cause cyanosis and, if untreated, death.²¹

Ventricular arrhythmias

Hypocalcemia does not cause pancreatitis

Hypercalcemia, rather than hypocalcemia, may cause acute pancreatitis.²⁴ Conversely, acute pancreatitis may cause hypocalcemia due to precipitation of calcium in the abdominal cavity.²⁵

Psychiatric manifestations

In addition to depression, hypocalcemia is associated with psychiatric manifestations including anxiety, confusion, and emotional instability.

STEPS TO DIAGNOSIS OF HYPOCALCEMIA

First step: Confirm true hypocalcemia

Corrected serum calcium (mg/dL) =
measured total serum calcium (mg/dL) +
0.8 (4 − serum albumin [g/dL]).

Using this formula, our patient’s corrected calcium level is calculated as 5.7 + 0.8 (4 – 3.2) = 6.3 mg/dL, indicating true hypocalcemia.

PHOSPHATE IS OFTEN HIGH WHEN CALCIUM IS LOW

In addition to hypocalcemia, our patient has an elevated phosphate level (Table 2).

3. Which of the following hypocalcemic disorders is not associated with hyperphosphatemia?

End-stage renal disease
Primary hypoparathyroidism
Pseudohypoparathyroidism
Vitamin D₃ deficiency
Rhabdomyolysis

Vitamin D deficiency is not associated with hyperphosphatemia.

Second step in evaluating hypocalcemia: Check phosphate, magnesium, creatinine

The major causes of hypocalcemia can be categorized according to the serum phosphate level: high vs normal or low (Table 5).

PTH increases serum ionized calcium by^26,27:

Increasing bone resorption
Increasing reabsorption of calcium from the distal renal tubules
Increasing the activity of 1-alpha-hydroxylase, responsible for conversion of 25-hydroxyvitamin D₃ to 1,25-dihydroxyvitamin D₃ (the most biologically active vitamin D metabolite); 1,25-dihydroxyvitamin D increases the absorption of calcium and phosphate from the intestine.

Third step: Check serum intact PTH and 25-hydroxyvitamin D levels

CASE RESUMED: NO RESPONSE TO INTRAVENOUS CALCIUM GLUCONATE

4. Which of the following is the most appropriate next step?

Change the calcium gluconate to calcium chloride
Increase the infusion rate to 1.5 mg of elemental calcium/kg/hour
Give a bolus of 2 10-mL ampules of 10% calcium gluconate intravenously over 1 minute
Give additional oral calcium tablets
Check the serum magnesium level

Treatment of hypocalcemia can involve intravenous or oral calcium therapy.

Intravenous calcium is indicated for patients with any of the following^6,32:

Moderate to severe neuromuscular irritability (eg, acral paresthesia, carpopedal spasm, prolonged QT interval, seizures, laryngospasm, bronchospasm)
Acute hypocalcemia with corrected serum calcium level less than 7.6 mg/dL, even if the patient is asymptomatic
Cardiac failure.

Calcium chloride has no advantages over calcium gluconate. Further, it can be associated with local irritation and may result in tissue necrosis if extravasation occurs.³⁵

Check magnesium

Inducing PTH resistance^32,36,37
Decreasing PTH secretion^32,36
Decreasing calcitriol production.

CASE RESUMED

PREVENTING HYPERCALCIURIA

Patients with low PTH (primary hypoparathyroidism) may have hypercalciuria due to decreased renal tubular calcium reabsorption. Two important measures can minimize hypercalciuria in such patients:

Keeping the serum calcium level in the low-normal range^4,5,40
Giving a thiazide diuretic (eg, hydrochlorothiazide 12.5–50 mg daily) with a low-salt diet.^41,42

A thiazide diuretic is usually started once the 24-hour urine calcium reaches 250 mg.⁶ Thiazides are thought to enhance both proximal and distal renal tubular calcium reabsorption.^43,44

PRIMARY HYPOPARATHYROIDISM: LONG-TERM MANAGEMENT

Long-term management of primary hypoparathyroidism requires calcium and vitamin D supplementation.

CASE CONCLUDED

TAKE-HOME POINTS

Hypocalcemia causes neuromuscular excitability, manifested clinically by tetany.
Common causes of hypocalcemia include vitamin D deficiency, hypomagnesemia, renal failure, and primary hypoparathyroidism.
The first step in evaluating hypocalcemia is to correct the measured serum calcium to the serum albumin concentration.
Laboratory testing for hypocalcemia should include serum phosphorus, magnesium, creatinine, PTH, and 25-hydroxyvitamin D₃.
Primary hypoparathyroidism is characterized by hypocalcemia, hyperphosphatemia, and low serum PTH.
Moderate to severe manifestations of hypo-
calcemia and acute hypocalcemia (< 7.6 mg/dL), even if asymptomatic, warrant intravenous calcium therapy.
Correction of hypomagnesemia is essential to treat hypocalcemia, especially if resistant to intravenous calcium therapy.
The goal of chronic management of primary hypoparathyroidism includes correcting the serum calcium level to a low-normal range, the serum phosphorus level to an upper-normal range, and prevention of hypercalciuria.

Acknowledgments: The authors wish to thank Mr. Michael Edward Tierney of the School of Medicine, University of Sydney, Australia, for his linguistic editing of the manuscript.

References

Jesus JE, Landry A. Images in clinical medicine. Chvostek’s and Trousseau’s signs. N Engl J Med 2012; 367:e15.
Urbano FL. Signs of hypocalcemia: Chvostek’s and Trousseau’s. Hosp Physician 2000; 36:43–45.
Chisthi MM, Nair RS, Kuttanchettiyar KG, Yadev I. Mechanisms behind post-thyroidectomy hypocalcemia: interplay of calcitonin, parathormone, and albumin—a prospective study. J Invest Surg 2017; 30:217–225.
Shoback DM, Bilezikian JP, Costa AG, et al. Presentation of hypoparathyroidism: etiologies and clinical features. J Clin Endocrinol Metab 2016; 101:2300–2312.
Stack BC Jr, Bimston DN, Bodenner DL, et al. American Association of Clinical Endocrinologists and American College of Endocrinology disease state clinical review: postoperative hypoparathyroidism—definitions and management. Endocr Pract 2015; 21:674–685.
Shoback D. Clinical practice. Hypoparathyroidism. N Engl J Med 2008; 359:391–403.
Abate EG, Clarke BL. Review of hypoparathyroidism. Front Endocrinol (Lausanne) 2017; 7:172.
Coimbra C, Monteiro F, Oliveira P, Ribeiro L, de Almeida MG, Condé A. Hypoparathyroidism following thyroidectomy: predictive factors. Acta Otorrinolaringol Esp 2017; 68:106–111.
Thomusch O, Machens A, Sekulla C, Ukkat J, Brauckhoff M, Dralle H. The impact of surgical technique on postoperative hypoparathyroidism in bilateral thyroid surgery: a multivariate analysis of 5846 consecutive patients. Surgery 2003; 133:180–185.
Hirsch PF, Lester GE, Talmage RV. Calcitonin, an enigmatic hormone: does it have a function? J Musculoskelet Neuronal Interact 2001; 1:299–305.
Karne SS, Bhalerao NS. Carpal tunnel syndrome in hypothyroidism. J Clin Diagn Res 2016; 10:OC36–OC38.
Duyff RF, Van den Bosch J, Laman DM, van Loon BJ, Linssen WH. Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study. J Neurol Neurosurg Psychiatry 2000; 68:750–755.
Palumbo CF, Szabo RM, Olmsted SL. The effects of hypothyroidism and thyroid replacement on the development of carpal tunnel syndrome. J Hand Surg Am 2000; 25:734–739.
Katz JN, Stirrat CR, Larson MG, Fossel AH, Eaton HM, Liang MH. A self-administered hand symptom diagram for the diagnosis and epidemiologic study of carpal tunnel syndrome. J Rheumatol 1990; 17:1495–1498.
Katz JN, Stirrat CR. A self-administered hand diagram for the diagnosis of carpal tunnel syndrome. J Hand Surg Am 1990; 15:360–363.
Calfee RP, Dale AM, Ryan D, Descatha A, Franzblau A, Evanoff B. Performance of simplified scoring systems for hand diagrams in carpal tunnel syndrome screening. J Hand Surg Am 2012; 37:10–17.
D’Arcy CA, McGee S. The rational clinical examination. Does this patient have carpal tunnel syndrome? JAMA 2000; 283:3110–3117.
Marchettini P, Lacerenza M, Mauri E, Marangoni C. Painful peripheral neuropathies. Curr Neuropharmacol 2006; 4:175–181.
Kibirige D, Mwebaze R. Vitamin B12 deficiency among patients with diabetes mellitus: is routine screening and supplementation justified? J Diabetes Metab Disord 2013;12:17.
Akinlade KS, Agbebaku SO, Rahamon SK, Balogun WO. Vitamin B12 levels in patients with type 2 diabetes mellitus on metformin. Ann Ib Postgrad Med 2015; 13:79–83.
Tohme JF, Bilezikian JP. Hypocalcemic emergencies. Endocrinol Metab Clin North Am 1993; 22:363–375.
Macefield G, Burke D. Paraesthesiae and tetany induced by voluntary hyperventilation. Increased excitability of human cutaneous and motor axons. Brain 1991; 114:527–540.
Benoit SR, Mendelsohn AB, Nourjah P, Staffa JA, Graham DJ. Risk factors for prolonged QTc among US adults: Third National Health and Nutrition Examination Survey. Eur J Cardiovasc Prev Rehabil 2005; 12:363–368.
Khoo TK, Vege SS, Abu-Lebdeh HS, Ryu E, Nadeem S, Wermers RA. Acute pancreatitis in primary hyperparathyroidism: a population-based study. J Clin Endocrinol Metab 2009; 94:2115–2118.
McKay C, Beastall GH, Imrie CW, Baxter JN. Circulating intact parathyroid hormone levels in acute pancreatitis. Br J Surg 1994; 81:357–360.
Talmage RV, Mobley HT. Calcium homeostasis: reassessment of the actions of parathyroid hormone. Gen Comp Endocrinol 2008; 156:1–8.
Friedman PA, Gesek FA. Calcium transport in renal epithelial cells. Am J Physiol 1993; 264:F181–F198.
Jensen PV, Jelstrup SM, Homøe P. Long-term outcomes after total thyroidectomy. Dan Med J 2015; 62:A5156.
Ritter K, Elfenbein D, Schneider DF, Chen H, Sippel RS. Hypoparathyroidism after total thyroidectomy: incidence and resolution. J Surg Res 2015; 197:348–353.
Promberger R, Ott J, Kober F, Karik M, Freissmuth M, Hermann M. Normal parathyroid hormone levels do not exclude permanent hypoparathyroidism after thyroidectomy. Thyroid 2011; 21:145–150.
Lorente-Poch L, Sancho JJ, Muñoz-Nova JL, Sánchez-Velázquez P, Sitges-Serra A. Defining the syndromes of parathyroid failure after total thyroidectomy. Gland Surgery 2015; 4:82–90.
Cooper MS, Gittoes NJ. Diagnosis and management of hypocalcaemia. BMJ 2008; 336:1298–1302.
Tohme JF, Bilezikian JP. Diagnosis and treatment of hypocalcemic emergencies. Endocrinologist 1996; 6:10–18.
Carroll R, Matfin G. Endocrine and metabolic emergencies: hypocalcaemia. Ther Adv Endocrinol Metab 2010; 1:29–33.
Kim MP, Raho VJ, Mak J, Kaynar AM. Skin and soft tissue necrosis from calcium chloride in a deicer. J Emerg Med 2007; 32:41–44.
Tong GM, Rude RK. Magnesium deficiency in critical illness. J Intensive Care Med 2005; 20:3–17.
Cholst IN, Steinberg SF, Tropper PJ, Fox HE, Segre GV, Bilezikian JP. The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects. N Engl J Med 1984; 310:1221–1225.
Ryzen E, Nelson TA, Rude RK. Low blood mononuclear cell magnesium content and hypocalcemia in normomagnesemic patients. West J Med 1987; 147:549–553.
Koontz SL, Friedman SA, Schwartz ML. Symptomatic hypocalcemia after tocolytic therapy with magnesium sulfate and nifedipine. Am J Obstet Gynecol 2004; 190:1773–1776.
Brandi ML, Bilezikian JP, Shoback D, et al. Management of hypoparathyroidism: summary statement and guidelines. J Clin Endocrinol Metab 2016; 101:2273–2283.
Porter RH, Cox BG, Heaney D, Hostetter TH, Stinebaugh BJ, Suki WN. Treatment of hypoparathyroid patients with chlorthalidone. N Engl J Med 1978; 298:577–581.
Clarke BL, Brown EM, Collins MT, et al. Epidemiology and diagnosis of hypoparathyroidism. J Clin Endocrinol Metab 2016; 101:2284–2299.
Nijenhuis T, Vallon V, van der Kemp AW, Loffing J, Hoenderop JG, Bindels RJ. Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. J Clin Invest 2005; 115:1651–1658.
Costanzo LS. Localization of diuretic action in microperfused rat distal tubules: Ca and Na transport. Am J Physiol 1985; 248:F527–F535.
Brandi ML, Bilezikian JP, Shoback D, et al. Management of hypoparathyroidism: summary statement and guidelines. J Clin Endocrinol Metab 2016; 101:2273–2283.
Scotti A, Bianchini C, Abbiati G, Marzo A. Absorption of calcium administered alone or in fixed combination with vitamin D to healthy volunteers. Arzneimittelforschung 2001; 51:493–500.

References

Jesus JE, Landry A. Images in clinical medicine. Chvostek’s and Trousseau’s signs. N Engl J Med 2012; 367:e15.
Urbano FL. Signs of hypocalcemia: Chvostek’s and Trousseau’s. Hosp Physician 2000; 36:43–45.
Chisthi MM, Nair RS, Kuttanchettiyar KG, Yadev I. Mechanisms behind post-thyroidectomy hypocalcemia: interplay of calcitonin, parathormone, and albumin—a prospective study. J Invest Surg 2017; 30:217–225.
Shoback DM, Bilezikian JP, Costa AG, et al. Presentation of hypoparathyroidism: etiologies and clinical features. J Clin Endocrinol Metab 2016; 101:2300–2312.
Stack BC Jr, Bimston DN, Bodenner DL, et al. American Association of Clinical Endocrinologists and American College of Endocrinology disease state clinical review: postoperative hypoparathyroidism—definitions and management. Endocr Pract 2015; 21:674–685.
Shoback D. Clinical practice. Hypoparathyroidism. N Engl J Med 2008; 359:391–403.
Abate EG, Clarke BL. Review of hypoparathyroidism. Front Endocrinol (Lausanne) 2017; 7:172.
Coimbra C, Monteiro F, Oliveira P, Ribeiro L, de Almeida MG, Condé A. Hypoparathyroidism following thyroidectomy: predictive factors. Acta Otorrinolaringol Esp 2017; 68:106–111.
Thomusch O, Machens A, Sekulla C, Ukkat J, Brauckhoff M, Dralle H. The impact of surgical technique on postoperative hypoparathyroidism in bilateral thyroid surgery: a multivariate analysis of 5846 consecutive patients. Surgery 2003; 133:180–185.
Hirsch PF, Lester GE, Talmage RV. Calcitonin, an enigmatic hormone: does it have a function? J Musculoskelet Neuronal Interact 2001; 1:299–305.
Karne SS, Bhalerao NS. Carpal tunnel syndrome in hypothyroidism. J Clin Diagn Res 2016; 10:OC36–OC38.
Duyff RF, Van den Bosch J, Laman DM, van Loon BJ, Linssen WH. Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study. J Neurol Neurosurg Psychiatry 2000; 68:750–755.
Palumbo CF, Szabo RM, Olmsted SL. The effects of hypothyroidism and thyroid replacement on the development of carpal tunnel syndrome. J Hand Surg Am 2000; 25:734–739.
Katz JN, Stirrat CR, Larson MG, Fossel AH, Eaton HM, Liang MH. A self-administered hand symptom diagram for the diagnosis and epidemiologic study of carpal tunnel syndrome. J Rheumatol 1990; 17:1495–1498.
Katz JN, Stirrat CR. A self-administered hand diagram for the diagnosis of carpal tunnel syndrome. J Hand Surg Am 1990; 15:360–363.
Calfee RP, Dale AM, Ryan D, Descatha A, Franzblau A, Evanoff B. Performance of simplified scoring systems for hand diagrams in carpal tunnel syndrome screening. J Hand Surg Am 2012; 37:10–17.
D’Arcy CA, McGee S. The rational clinical examination. Does this patient have carpal tunnel syndrome? JAMA 2000; 283:3110–3117.
Marchettini P, Lacerenza M, Mauri E, Marangoni C. Painful peripheral neuropathies. Curr Neuropharmacol 2006; 4:175–181.
Kibirige D, Mwebaze R. Vitamin B12 deficiency among patients with diabetes mellitus: is routine screening and supplementation justified? J Diabetes Metab Disord 2013;12:17.
Akinlade KS, Agbebaku SO, Rahamon SK, Balogun WO. Vitamin B12 levels in patients with type 2 diabetes mellitus on metformin. Ann Ib Postgrad Med 2015; 13:79–83.
Tohme JF, Bilezikian JP. Hypocalcemic emergencies. Endocrinol Metab Clin North Am 1993; 22:363–375.
Macefield G, Burke D. Paraesthesiae and tetany induced by voluntary hyperventilation. Increased excitability of human cutaneous and motor axons. Brain 1991; 114:527–540.
Benoit SR, Mendelsohn AB, Nourjah P, Staffa JA, Graham DJ. Risk factors for prolonged QTc among US adults: Third National Health and Nutrition Examination Survey. Eur J Cardiovasc Prev Rehabil 2005; 12:363–368.
Khoo TK, Vege SS, Abu-Lebdeh HS, Ryu E, Nadeem S, Wermers RA. Acute pancreatitis in primary hyperparathyroidism: a population-based study. J Clin Endocrinol Metab 2009; 94:2115–2118.
McKay C, Beastall GH, Imrie CW, Baxter JN. Circulating intact parathyroid hormone levels in acute pancreatitis. Br J Surg 1994; 81:357–360.
Talmage RV, Mobley HT. Calcium homeostasis: reassessment of the actions of parathyroid hormone. Gen Comp Endocrinol 2008; 156:1–8.
Friedman PA, Gesek FA. Calcium transport in renal epithelial cells. Am J Physiol 1993; 264:F181–F198.
Jensen PV, Jelstrup SM, Homøe P. Long-term outcomes after total thyroidectomy. Dan Med J 2015; 62:A5156.
Ritter K, Elfenbein D, Schneider DF, Chen H, Sippel RS. Hypoparathyroidism after total thyroidectomy: incidence and resolution. J Surg Res 2015; 197:348–353.
Promberger R, Ott J, Kober F, Karik M, Freissmuth M, Hermann M. Normal parathyroid hormone levels do not exclude permanent hypoparathyroidism after thyroidectomy. Thyroid 2011; 21:145–150.
Lorente-Poch L, Sancho JJ, Muñoz-Nova JL, Sánchez-Velázquez P, Sitges-Serra A. Defining the syndromes of parathyroid failure after total thyroidectomy. Gland Surgery 2015; 4:82–90.
Cooper MS, Gittoes NJ. Diagnosis and management of hypocalcaemia. BMJ 2008; 336:1298–1302.
Tohme JF, Bilezikian JP. Diagnosis and treatment of hypocalcemic emergencies. Endocrinologist 1996; 6:10–18.
Carroll R, Matfin G. Endocrine and metabolic emergencies: hypocalcaemia. Ther Adv Endocrinol Metab 2010; 1:29–33.
Kim MP, Raho VJ, Mak J, Kaynar AM. Skin and soft tissue necrosis from calcium chloride in a deicer. J Emerg Med 2007; 32:41–44.
Tong GM, Rude RK. Magnesium deficiency in critical illness. J Intensive Care Med 2005; 20:3–17.
Cholst IN, Steinberg SF, Tropper PJ, Fox HE, Segre GV, Bilezikian JP. The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects. N Engl J Med 1984; 310:1221–1225.
Ryzen E, Nelson TA, Rude RK. Low blood mononuclear cell magnesium content and hypocalcemia in normomagnesemic patients. West J Med 1987; 147:549–553.
Koontz SL, Friedman SA, Schwartz ML. Symptomatic hypocalcemia after tocolytic therapy with magnesium sulfate and nifedipine. Am J Obstet Gynecol 2004; 190:1773–1776.
Brandi ML, Bilezikian JP, Shoback D, et al. Management of hypoparathyroidism: summary statement and guidelines. J Clin Endocrinol Metab 2016; 101:2273–2283.
Porter RH, Cox BG, Heaney D, Hostetter TH, Stinebaugh BJ, Suki WN. Treatment of hypoparathyroid patients with chlorthalidone. N Engl J Med 1978; 298:577–581.
Clarke BL, Brown EM, Collins MT, et al. Epidemiology and diagnosis of hypoparathyroidism. J Clin Endocrinol Metab 2016; 101:2284–2299.
Nijenhuis T, Vallon V, van der Kemp AW, Loffing J, Hoenderop JG, Bindels RJ. Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. J Clin Invest 2005; 115:1651–1658.
Costanzo LS. Localization of diuretic action in microperfused rat distal tubules: Ca and Na transport. Am J Physiol 1985; 248:F527–F535.
Brandi ML, Bilezikian JP, Shoback D, et al. Management of hypoparathyroidism: summary statement and guidelines. J Clin Endocrinol Metab 2016; 101:2273–2283.
Scotti A, Bianchini C, Abbiati G, Marzo A. Absorption of calcium administered alone or in fixed combination with vitamin D to healthy volunteers. Arzneimittelforschung 2001; 51:493–500.

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A 75-year-old with abdominal pain, hypoxia, and weak pulses in the left leg

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A 75-year-old with abdominal pain, hypoxia, and weak pulses in the left leg

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Maya Serhal, MD

Natalie Evans, MD, RPVI

Heather L. Gornik, MD, RVT, RPVI

A 75-year-old man presented to the emergency department for evaluation of abdominal pain. He had stage 3 chronic obstructive pulmonary disease (COPD), with a forced expiratory volume in 1 second of 33%.

PREVIOUS HOSPITALIZATION

Aside from his COPD, he had been healthy until 1 month earlier, when he had been hospitalized because of shortness of breath and chest pressure with exertion. His troponin T level had been elevated, peaking at 0.117 ng/mL (reference range 0–0.029).

Left heart catheterization had shown no significant coronary artery disease. A myocardial bridge of the distal left anterior descending coronary artery had been seen, so that the artery appeared to be narrowed by 50% to 60% with ventricular contraction. But this was not thought to have been the cause of his presentation.

On discharge, he required oxygen 4 L/min by nasal cannula. Previously, he had not needed supplemental oxygen.

CURRENT PRESENTATION

The patient described persistent and severe periumbilical abdominal pain during the previous day. It was not associated with eating, and he denied diarrhea, constipation, hematemesis, hematochezia, bright red blood per rectum, or melena. He continued to describe persistent shortness of breath and pleuritic chest pain. His vital signs were as follows:

Heart rate 104 beats per minute
Respiratory rate 16 to 20 breaths per minute
Blood pressure 101–142/62–84 mm Hg
Oxygen saturation 78% on room air.

The patient's laboratory data on presentation

He was placed on oxygen by a Venturi mask, and his oxygen saturation improved to 93%.

Figure 1. The patient’s electrocardiogram on presentation. Arrows point to notable features (see text).

On examination, his lungs were clear bilaterally. His abdomen was diffusely tender but without peritoneal signs. His left lower leg was cool to touch, and his left dorsalis pedal and posterior tibial pulses were only weakly palpable. His right leg pulses were normal. He denied pain in the lower extremities. No jugular venous distention was noted, and cardiac examination was most notable for tachycardia.

His laboratory findings on presentation are shown in Table 1, and his electrocardiogram is shown in Figure 1.

WHAT DOES HIS ELECTROCARDIOGRAM SHOW?

1. Which of the following is the most accurate description of this patient’s electrocardiogram?

Sinus tachycardia, peaked P waves (P pulmonale) in lead II, and T-wave inversions in the right precordial leads
Sinus tachycardia and left bundle branch block
Sinus tachycardia and poor R-wave progression
Sinus tachycardia and ST elevation in the precordial leads

Our patient’s electrocardiogram shows sinus tachycardia, P pulmonale, T-wave inversion in the right precordial leads (V₁–V₃), and biphasic T waves in lead V_4,, which suggest right ventricular strain.

The rhythm most commonly seen in patients with pulmonary embolism is sinus tachycardia, followed by nonspecific ST-segment or T-wave abnormalities. In one series of patients with acute pulmonary embolism, the classic findings of P pulmonale, right ventricular hypertrophy, right axis deviation, and right bundle branch block were rare (< 6%).¹ Thus, these classic findings are not sensitive for the diagnosis of pulmonary embolism, and their absence does not rule it out.

Further studies for our patient

Computed tomography (CT) with a chest pulmonary embolism protocol showed filling defects. — Figure 2. Computed tomography (CT) with a chest pulmonary embolism protocol (top) showed filling defects (arrows). CT of the abdomen and pelvis showed renal artery thrombosis (arrow).

Computed tomography of the chest, abdomen, and pelvis with contrast was performed (Figure 2) to evaluate the patient’s chest pain, shortness of breath, and abdominal pain. It revealed bilateral pulmonary emboli, with filling defects in the distal right and left main pulmonary arteries extending into the lobar branches of the right upper, middle, and lower lobes and left upper and lower lobes; multiple subsegmental pulmonary emboli were also seen. The patient was also found to have evidence of a left renal infarction, with an extensive filling defect in the left renal artery, consistent with renal artery thrombosis.

Transthoracic echocardiography was performed to look for evidence of right ventricular strain secondary to the pulmonary embolism.

ECHOCARDIOGRAPHIC SIGNS OF PULMONARY EMBOLISM

2. Which of the following findings on transthoracic echocardiography would not suggest acute pulmonary embolism?

Midright ventricular wall hypokinesis with apical sparing
Severe tricuspid regurgitation
Left ventricular dilation
Lack of respiratory variation of the inferior vena cava
Septal wall motion toward the left ventricle

Left ventricular dilation does not suggest acute pulmonary embolism. Echocardiograms of patients with acute submassive pulmonary embolism typically show evidence of right ventricular strain, such as the other entities listed above (midright ventricular hypokinesis with apical sparing, severe tricuspid regurgitation, lack of respiratory variation of the inferior vena cava, and septal wall motion toward the left ventricle).

The degree of right ventricular dysfunction is related to the extent of acute pulmonary vascular occlusion and aids in risk-stratification of patients with acute pulmonary embolism. Midright ventricular wall hypokinesis with apical sparing has been termed the McConnell sign.²

In our patient, transthoracic echocardiography showed:

Normal left ventricular ejection fraction
Mild diastolic dysfunction
Right ventricular dilation with moderately decreased right ventricular systolic function and apical sparing
Right ventricular systolic pressure 54 mm Hg, consistent with moderate pulmonary hypertension
Right atrial pressure 10 mm Hg
No inspiratory collapse of a dilated inferior vena cava
Mild tricuspid valve regurgitation.

CLASSIFICATION OF ACUTE PULMONARY EMBOLISM

3. Given the above information, how would you classify the patient’s pulmonary embolism?

Massive
Submassive
Low-risk
Clinically stable

The patient’s pulmonary embolism is submassive.

Many classification schemes exist for acute pulmonary embolism. That of the American Heart Association is shown in Table 2.³

Historically, the classification of pulmonary embolism was determined by the angiographic thrombus burden. However, this has limited utility because clinical factors (eg, hypotension on initial presentation) have been shown to be better predictors of short-term mortality risk.³

Our patient is characterized as having a submassive pulmonary embolism based on elevated biomarkers (troponin T, N-terminal pro-B-type natriuretic peptide) and right ventricular dysfunction in the absence of hypotension.

ULTRASONOGRAPHY FOR DIAGNOSIS OF DEEP VEIN THROMBOSIS

Figure 3. Example of lower-extremity duplex ultrasonography. Arteries and veins are labeled. Veins without deep vein thrombosis are compressible, as seen on the left. A vein is shown that is not compressible, suggesting deep vein thrombosis.

Duplex ultrasonography can show evidence of deep vein thrombosis if a venous segment is not compressible (Figure 3). Of note, approximately 70% of patients with pulmonary embolism have evidence of deep vein thrombosis on imaging studies.⁴

Venous duplex ultrasonography has become the standard for diagnosis of lower extremity deep vein thrombosis. However, its quality and diagnostic accuracy depend on the skill of the person performing the examination. It is further limited by certain patient characteristics, including severe obesity, edema, and wounds and dressings at the site being examined.⁵

Our patient underwent duplex ultrasonography of the lower extremities, which demonstrated acute proximal and calf deep vein thrombosis in the right femoral, popliteal, and peroneal veins and no deep vein thrombosis in the left leg.

RISK STRATIFICATION IN ACUTE PULMONARY EMBOLISM

Multiple models exist to estimate the risk of complications in patients with acute pulmonary embolism.

The Bova score⁶ is based on the following factors:

Systolic blood pressure 90–100 mm Hg (2 points) (patients with systolic blood pressure lower than 90 mm Hg were excluded from the study from which this score was derived)
Cardiac troponin elevation (2 points)
Right ventricular dysfunction on echocardiography or computed tomography (2 points)
Heart rate 100 beats/min or greater (1 point).

A total score of 0, 1, or 2 (stage I) denotes low risk, 3 or 4 points (stage II) intermediate risk, and more than 4 points (stage III) high risk.

The PESI score (Pulmonary Embolism Severity Index)⁷ is based on:

Age (1 point per year)
Sex (10 points for being male)
Heart rate 110 per minute or greater (20 points)
Cancer (30 points)
Heart failure (10 points)
Chronic lung disease (10 points)
Systolic blood pressure less than 100 mm Hg (30 points)
Respiratory rate at least 30 per minute (20 points)
Temperature less than 36ºC (20 points)
Altered mental status (60 points)
Arterial oxygen saturation less than 90% (20 points).

The total score is broken down into 5 classes: I (< 65 points), II (65–85), III (86–105), IV (106–125), and V (> 126). Classes I and II are low risk, and the higher ones are high risk.

The simplified PESI score⁸ was developed to more rapidly risk-stratify patients and has been found to be similar to the PESI score in prognostic accuracy. Patients get 1 point for each of the following:

Age over 80
Cancer
Chronic cardiopulmonary disease (heart failure or chronic lung disease)
Heart rate 110 per minute or greater
Systolic blood pressure less than 100 mm Hg
Arterial oxygen saturation less than 90%.

A total score of 0 is low risk; anything higher is high risk.

Back to our patient

Our patient had proximal and calf deep vein thrombosis of the right leg, bilateral submassive pulmonary emboli with associated biomarker elevation and right ventricular dysfunction, and left renal artery thrombosis with infarction. Using the PESI score, his risk of death in the next 30 days was 13.7% and his 30-day risk of a complicated course was 27%. Using the Bova score, his 30-day risk of death was 15.5% and his 30-day risk of a complicated course was 29.2%.^6,7

Notably, the patient’s right ventricular function had also been impaired on the echocardiogram performed during his admission 1 month previously. On transthoracic echocardiography during the current admission, the patient was found to have a similar degree of right ventricular dysfunction. This finding, along with the oxygen requirement that developed during the earlier admission, suggested that his pulmonary embolism may have been subacute and that the diagnosis may have been missed during the earlier hospital stay.

The patient was treated with unfractionated heparin. After the hospital’s multidisciplinary pulmonary embolism response team discussed and weighed the above factors, they recommended to not pursue thrombolytic therapy or inferior vena cava filter placement.

Of note, the patient’s pulses in the left lower extremity continued to be weak but palpable, and the left leg was cooler to touch than the right leg.

ASSESSING PERIPHERAL ARTERY DISEASE

4. How should the finding of weak pulses in this patient’s left leg be initially investigated?

Computed tomographic angiography with runoff
Ankle-brachial indices with pulse-volume recordings
Arterial duplex ultrasonography
Magnetic resonance angiography of the lower extremities

The ankle-brachial index is the initial diagnostic test for assessment of pulse abnormalities and for diagnosis of lower-extremity peripheral artery disease. It is calculated by dividing the higher of the ankle systolic pressures (posterior tibial or dorsalis pedis) by the higher of the 2 brachial pressures (left or right).⁹Normal values are between 1.00 and 1.40.

Ankle-brachial indices in our patient

Our patient underwent measurement of his brachial, dorsalis pedis, and posterior tibial artery systolic pressures using blood pressure cuffs and continuous-wave Doppler. Ankle pulse-volume recordings were also obtained.

Figure 4. The patient’s ankle-brachial index and pulse-volume recordings. Right side 1.24, left side 0.68. This suggests moderate disease on the left and normal vessels on the right.

The right leg ankle-brachial index was normal at rest with a normal pulse-volume recording waveform. The left leg ankle-brachial index was moderately reduced (0.68), and the pulse-volume recording waveform was also dampened (Figure 4). These findings confirmed that he had arterial disease in the left leg, correlating with the physical findings.

Given the patient’s poor renal function and concern for acute renal infarction, we thought it best to avoid iodinated or gadolinium contrast, such as with magnetic resonance or computed tomographic angiography.

Segmental leg pressures and pulse-volume recordings can be performed to help localize the level of arterial disease in the extremities, but were not done in this case because of the extensive deep vein thrombosis in the right leg.^10,11

Arterial ultrasonography in our patient

Arterial duplex ultrasonography was performed to help determine the location of arterial disease. It showed patent arteries in the right leg. In the left lower extremity there was slow, monophasic blood flow in the distal superficial femoral artery. The popliteal artery was occluded. The posterior tibial artery was occluded at the origin, with reconstitution distally. The peroneal artery was occluded throughout. The anterior tibial artery was patent throughout. The ultrasonographic findings were thought to be suspicious for arterial thromboembolism.

WHAT CAN CAUSE BOTH ARTERIAL AND VENOUS THROMBOSIS?

5. Given that the patient had both arterial thrombosis (renal artery, lower-extremity arteries) and venous thromboembolism (deep vein thrombosis and pulmonary embolism), which of the following would be included in the differential diagnosis?

Antiphospholipid antibody syndrome
Protein C or protein S deficiency
Malignancy
Paradoxical embolization
Factor V Leiden mutation

Correct answers include antiphospholipid antibody syndrome, malignancy, and paradoxical embolization.

The differential diagnosis for concomitant venous and arterial thrombosis is broad,¹² and includes the following:

Structural factors: patent foramen ovale, popliteal artery aneurysm
Malignancy
Inflammatory diseases: Behçet disease, Buerger disease, inflammatory bowel disease, antiphospholipid antibody syndrome, elevated lipoprotein(a), elevated homocysteine
Hematologic diseases: myelodysplastic syndrome, disseminated intravascular coagulation, paroxysmal nocturnal hemoglobinuria, heparin-induced thrombocytopenia.

Traditional risk factors for venous thromboembolism include protein C deficiency, protein S deficiency, factor V Leiden mutation, the prothrombin G20210A gene mutation, and others. These are relatively minor risk factors for venous thrombosis and do not pose a risk for arterial thrombosis.¹² In contrast, antiphospholipid antibody syndrome and malignancy pose a risk for both venous and arterial thrombosis. Paradoxical embolism is a mechanism by which arterial thrombosis (emboli) can develop in the setting of existing venous thrombosis.¹²

Our patient underwent testing for antiphospholipid antibodies and lupus anticoagulant, and he was encouraged to undergo age-appropriate cancer screening as an outpatient.¹²

ANTIPHOSPHOLIPID ANTIBODY SYNDROME

Antiphospholipid antibody syndrome is defined by both clinical and laboratory criteria. Clinical symptoms include vascular thrombosis (arterial, venous, or both) and pregnancy-related complications.¹³

Laboratory criteria require the presence of antiphospholipid antibodies or lupus anticoagulant. These must be confirmed with repeat testing in 12 weeks. Antiphospholipid antibodies are detected by an enzyme-linked immunosorbent assay; laboratory assessment for the presence of lupus anticoagulant is a stepwise process and relies on 4 criteria:

There should be prolongation of a phospholipid-dependent clotting test (eg, activated partial thromboplastin time, dilute Russell viper venom time test).
There must be evidence of an inhibitory activity with mixing study.
The inhibitor must exhibit phospholipid dependence; that is, with more phospholipid there is shortening of clotting time.
Specific inhibitors must be excluded, including factor VIII and anticoagulant drugs such as heparin.^14–17

Figure 5. Antiphospholipid antibody tests and terminology.

Diagnostic criteria for antiphospholipid antibody syndrome were updated in 2006. In the past, repeat testing at 6 weeks was sufficient, but this period has been lengthened to 12 weeks.¹⁵ Antiphospholipid antibodies include lupus anticoagulant, anticardiolipin antibody immunoglobulin G (IgG), anticardiolipin antibody IgM, anti-beta-2-glycoprotein I IgG, and anti-beta-2-glycoprotein I IgM, as well as other less common antibodies (Figure 5).^15,18

Clinically, one should consider antiphospholipid antibody syndrome in patients who have arterial thrombosis, a history of pregnancy morbidity, or unexplained prolongation of activated partial thromboplastin time.¹³

Antiphospholipid antibodies may be present in up to a quarter of patients with venous thromboembolism, but it is persistent positivity of antibody assays that is associated with increased future risk of venous thromboembolism.¹⁹ Of note, the risk of venous thromboembolism in patients with confirmed antiphospholipid antibody syndrome is 10 times higher than in the general population.²⁰

ANTIPHOSPHOLIPID ANTIBODIES ARE NOT ALL THE SAME

6. Which of the following antiphospholipid antibodies have not been associated with an increased thrombotic risk?

Anti-beta-2-glycoprotein I IgG
Lupus anticoagulant
Antiphosphatidylserine
Anticardiolipin IgM
Anticardiolipin IgG

The correct answer is antiphosphatidylserine.¹⁵

Antiphospholipid antibodies are directed against a portion of select plasma proteins that are uncovered upon phospholipid binding. While lupus anticoagulant, anti-beta-2-glycoprotein I, and anticardiolipin antibodies are associated with thrombosis, antiprothrombin antibodies (including antiprothrombin and antiphosphatidylserine antibodies) are not.^15,21

PARADOXICAL EMBOLISM

Patent foramen ovale, a communication between the right and left atrium in the interatrial septum, is associated with an increased risk of paradoxical embolization. The prevalence of patent foramen ovale is estimated to be 27% to 29% in the general population.²² Noncerebral systemic paradoxical embolism occurs less frequently than cerebral embolism, accounting for approximately 5% to 10% of paradoxical emboli.²²

To evaluate for patent foramen ovale, transthoracic echocardiography is performed with a bubble (agitated saline contrast) study to assess for interatrial shunting. Transesophageal echocardiography or transcranial Doppler bubble studies may also be performed.

Although patent foramen ovale is most commonly associated with cerebral embolism, peripheral emboli can occur. Some research suggests that this may be a more common cause of arterial thromboembolism in younger patients. There have also been reports of other sites of systemic embolization, including the renal artery.¹²

Back to our patient

Initial antiphospholipid antibody testing was positive for lupus anticoagulant. Anticardiolipin and anti-beta-2-glycoprotein I antibodies were not detected.

Transesophageal echocardiography revealed a patent foramen ovale with a highly mobile atrial septum (atrial septal aneurysm).

The patient was treated with intravenous unfractionated heparin with bridging to warfarin with a target international normalized ratio (INR) of 2 to 3. His renal artery infarction and his lower-extremity arterial thromboembolic event were conservatively managed. His respiratory status improved, and he no longer required supplemental oxygen. His creatinine peaked at 1.7 mg/dL during his admission and improved to 1.2 mg/dL before he was discharged.

At follow-up, repeat echocardiography showed that his right ventricular systolic pressure had improved (decreased) to 37 mm Hg from 54 mm Hg. Repeat confirmatory testing was positive for lupus anticoagulant 12 weeks later. He has been maintained on warfarin with an INR goal of 2 to 3 as well as low-dose aspirin with plans for long-term anticoagulation. We decided to keep the patient on anticoagulation indefinitely with warfarin; he was not a candidate for a direct oral anticoagulant, given limited data on the use of these agents in the setting of lupus anticoagulant and antiphospholipid antibody syndrome.

SUMMARY OF CASE

In summary, this patient was a 75-year-old man with COPD who presented with abdominal pain. He was noted to have a left renal infarction, extensive unprovoked lower-extremity deep vein thrombosis with pulmonary emboli, and lower limb arterial thromboembolism.

He also had an underlying hypercoagulable state—antiphospholipid antibody syndrome—that predisposed him to both arterial and venous thrombosis. He was ultimately found to have a patent foramen ovale, which further increased the risk of arterial thrombosis by facilitating paradoxical embolization of venous thrombi. It is not certain whether the renal infarction and leg artery thrombi were due to paradoxical embolism or to in situ thrombosis, but we believe that it was most likely paradoxical embolization. 

References

Stein PD, Terrin ML, Hales CA, et al. Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest 1991; 100:598–603.
Alsoos F, Khaddam A. Echocardiographic evaluation methods for right ventricular function. J Echocardiogr 2015; 13:43–51.
Jaff MR, McMurtry MS, Archer SL, et al; American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; American Heart Association Council on Peripheral Vascular Disease; American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011; 123:1788–1830.
Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ 3rd. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000; 160:809–815.
Gornik HL, Sharma AM. Duplex ultrasound in the diagnosis of lower-extremity deep venous thrombosis. Circulation 2014; 129:917–921.
Fernández C, Bova C, Sanchez O, et al. Validation of a model for identification of patients at intermediate to high risk for complications associated with acute symptomatic pulmonary embolism. Chest 2015; 148:211–218.
Aujesky D, Perrier A, Roy PM, et al. Validation of a clinical prognostic model to identify low-risk patients with pulmonary embolism. J Intern Med 2007; 261:597–604.
Jiménez D, Aujesky D, Moores L, et al; RIETE Investigators. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med 2010; 170:1383–1389.
Kim ES, Wattanakit K, Gornik HL. Using the ankle-brachial index to diagnose peripheral artery disease and assess cardiovascular risk. Cleve Clin J Med 2012; 79:651–661.
Jaff MR. Lower extremity arterial disease. Diagnostic aspects. Cardiol Clin 2002; 20:491–500.
Rooke TW, Hirsch AT, Misra S, et al; American College of Cardiology Foundation Task Force; American Heart Association Task Force. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA Guideline Recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 61:1555–1570.
Lichtin A, Bartholomew J. The coagulation consult: a case-based guide. New York, NY: Springer; 2014.
Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002; 346:752–763.
Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH. Thromb Haemost 1995; 74:1185–1190.
Miyakis S, Lockshin M, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4:295–306.
Pengo V, Tripodi A, Reber G, et al; Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2009; 7:1737–1740.
Nichols WL, Kottke-Marchant K, Ledford-Kraemer MR, Homburger HA, Cardel LK. Lupus anticoagulants, antiphospholipid antibodies, and antiphospholipid syndrome. In: Kottke-Marchant K, Davis BH, editors. Laboratory Hematology Practice. Hoboken, New Jersey: Blackwell Publishing, Ltd.; 2012:509–525.
Houghton DE, Moll S. Antiphospholipid antibodies. Vasc Med 2017; 22:545–550.
Roldan V, Lecumberri R, Muñoz-Torrero JFS, et al; RIETE Investigators. Thrombophilia testing in patients with venous thromboembolism. Findings from the RIETE registry. Thromb Res 2009; 124:174–177.
Wahl DG, Guillemin F, de Maistre E, Perret-Guillaume C, Lecompte T, Thibaut G. Meta-analysis of the risk of venous thrombosis in individuals with antiphospholipid antibodies without underlying autoimmune disease or previous thrombosis. Lupus 1998; 7:15–22.
Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. Ann Intern Med 1990; 112:682–698.
Thompson T, Evans W. Paradoxical embolism. QJM 1930; os-23:135–150.

Article PDF

serhal_abdominalpain.pdf

Author and Disclosure Information

Maya Serhal, MD
Vascular Medicine Section, Department of Cardiovascular Medicine, Cleveland Clinic

Natalie Evans, MD, RPVI
Vascular Medicine Section, Department of Cardiovascular Medicine, Cleveland Clinic; Clinical Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Heather L. Gornik, MD, RVT, RPVI
Medical Director, Non-Invasive Vascular Laboratory, Vascular Medicine Section, Department of Cardiovascular Medicine, Cleveland Clinic; Associate Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Maya Serhal, MD, Department of Vascular Medicine, J3-5, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195; Serhalm@ccf.org

Dr. Gornik has disclosed she was a site principal investigator in the Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial, funded by AstraZeneca.

Issue

Cleveland Clinic Journal of Medicine - 85(2)

Publications

Cleveland Clinic Journal of Medicine

Topics

Page Number

145-154

Legacy Keywords

venous thromboembolism, VTE, deep vein thrombosis, DVT, pulmonary embolism, PE, arterial thromboembolism, renal artery thrombosis, antiphospholipid antibody syndrome, Maya Seral, Natalie Evans, Heather Gornik

Read more about A 75-year-old with abdominal pain, hypoxia, and weak pulses in the left leg

Sections

IM Board Review

Symptoms to Diagnosis

Author(s)

Maya Serhal, MD

Natalie Evans, MD, RPVI

Heather L. Gornik, MD, RVT, RPVI

Author(s)

Maya Serhal, MD

Natalie Evans, MD, RPVI

Heather L. Gornik, MD, RVT, RPVI

Author and Disclosure Information

Maya Serhal, MD
Vascular Medicine Section, Department of Cardiovascular Medicine, Cleveland Clinic

Address: Maya Serhal, MD, Department of Vascular Medicine, J3-5, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195; Serhalm@ccf.org

Dr. Gornik has disclosed she was a site principal investigator in the Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial, funded by AstraZeneca.

Author and Disclosure Information

Maya Serhal, MD
Vascular Medicine Section, Department of Cardiovascular Medicine, Cleveland Clinic

Address: Maya Serhal, MD, Department of Vascular Medicine, J3-5, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195; Serhalm@ccf.org

Dr. Gornik has disclosed she was a site principal investigator in the Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial, funded by AstraZeneca.

Article PDF

serhal_abdominalpain.pdf

Article PDF

serhal_abdominalpain.pdf

PREVIOUS HOSPITALIZATION

On discharge, he required oxygen 4 L/min by nasal cannula. Previously, he had not needed supplemental oxygen.

CURRENT PRESENTATION

Heart rate 104 beats per minute
Respiratory rate 16 to 20 breaths per minute
Blood pressure 101–142/62–84 mm Hg
Oxygen saturation 78% on room air.

He was placed on oxygen by a Venturi mask, and his oxygen saturation improved to 93%.

His laboratory findings on presentation are shown in Table 1, and his electrocardiogram is shown in Figure 1.

WHAT DOES HIS ELECTROCARDIOGRAM SHOW?

1. Which of the following is the most accurate description of this patient’s electrocardiogram?

Sinus tachycardia, peaked P waves (P pulmonale) in lead II, and T-wave inversions in the right precordial leads
Sinus tachycardia and left bundle branch block
Sinus tachycardia and poor R-wave progression
Sinus tachycardia and ST elevation in the precordial leads

Further studies for our patient

Transthoracic echocardiography was performed to look for evidence of right ventricular strain secondary to the pulmonary embolism.

ECHOCARDIOGRAPHIC SIGNS OF PULMONARY EMBOLISM

2. Which of the following findings on transthoracic echocardiography would not suggest acute pulmonary embolism?

Midright ventricular wall hypokinesis with apical sparing
Severe tricuspid regurgitation
Left ventricular dilation
Lack of respiratory variation of the inferior vena cava
Septal wall motion toward the left ventricle

In our patient, transthoracic echocardiography showed:

Normal left ventricular ejection fraction
Mild diastolic dysfunction
Right ventricular dilation with moderately decreased right ventricular systolic function and apical sparing
Right ventricular systolic pressure 54 mm Hg, consistent with moderate pulmonary hypertension
Right atrial pressure 10 mm Hg
No inspiratory collapse of a dilated inferior vena cava
Mild tricuspid valve regurgitation.

CLASSIFICATION OF ACUTE PULMONARY EMBOLISM

3. Given the above information, how would you classify the patient’s pulmonary embolism?

Massive
Submassive
Low-risk
Clinically stable

The patient’s pulmonary embolism is submassive.

Many classification schemes exist for acute pulmonary embolism. That of the American Heart Association is shown in Table 2.³

ULTRASONOGRAPHY FOR DIAGNOSIS OF DEEP VEIN THROMBOSIS

RISK STRATIFICATION IN ACUTE PULMONARY EMBOLISM

Multiple models exist to estimate the risk of complications in patients with acute pulmonary embolism.

The Bova score⁶ is based on the following factors:

Systolic blood pressure 90–100 mm Hg (2 points) (patients with systolic blood pressure lower than 90 mm Hg were excluded from the study from which this score was derived)
Cardiac troponin elevation (2 points)
Right ventricular dysfunction on echocardiography or computed tomography (2 points)
Heart rate 100 beats/min or greater (1 point).

A total score of 0, 1, or 2 (stage I) denotes low risk, 3 or 4 points (stage II) intermediate risk, and more than 4 points (stage III) high risk.

The PESI score (Pulmonary Embolism Severity Index)⁷ is based on:

Age (1 point per year)
Sex (10 points for being male)
Heart rate 110 per minute or greater (20 points)
Cancer (30 points)
Heart failure (10 points)
Chronic lung disease (10 points)
Systolic blood pressure less than 100 mm Hg (30 points)
Respiratory rate at least 30 per minute (20 points)
Temperature less than 36ºC (20 points)
Altered mental status (60 points)
Arterial oxygen saturation less than 90% (20 points).

The total score is broken down into 5 classes: I (< 65 points), II (65–85), III (86–105), IV (106–125), and V (> 126). Classes I and II are low risk, and the higher ones are high risk.

Age over 80
Cancer
Chronic cardiopulmonary disease (heart failure or chronic lung disease)
Heart rate 110 per minute or greater
Systolic blood pressure less than 100 mm Hg
Arterial oxygen saturation less than 90%.

A total score of 0 is low risk; anything higher is high risk.

Back to our patient

Of note, the patient’s pulses in the left lower extremity continued to be weak but palpable, and the left leg was cooler to touch than the right leg.

ASSESSING PERIPHERAL ARTERY DISEASE

4. How should the finding of weak pulses in this patient’s left leg be initially investigated?

Computed tomographic angiography with runoff
Ankle-brachial indices with pulse-volume recordings
Arterial duplex ultrasonography
Magnetic resonance angiography of the lower extremities

Ankle-brachial indices in our patient

Arterial ultrasonography in our patient

WHAT CAN CAUSE BOTH ARTERIAL AND VENOUS THROMBOSIS?

Antiphospholipid antibody syndrome
Protein C or protein S deficiency
Malignancy
Paradoxical embolization
Factor V Leiden mutation

Correct answers include antiphospholipid antibody syndrome, malignancy, and paradoxical embolization.

The differential diagnosis for concomitant venous and arterial thrombosis is broad,¹² and includes the following:

Structural factors: patent foramen ovale, popliteal artery aneurysm
Malignancy
Inflammatory diseases: Behçet disease, Buerger disease, inflammatory bowel disease, antiphospholipid antibody syndrome, elevated lipoprotein(a), elevated homocysteine
Hematologic diseases: myelodysplastic syndrome, disseminated intravascular coagulation, paroxysmal nocturnal hemoglobinuria, heparin-induced thrombocytopenia.

Our patient underwent testing for antiphospholipid antibodies and lupus anticoagulant, and he was encouraged to undergo age-appropriate cancer screening as an outpatient.¹²

ANTIPHOSPHOLIPID ANTIBODY SYNDROME

There should be prolongation of a phospholipid-dependent clotting test (eg, activated partial thromboplastin time, dilute Russell viper venom time test).
There must be evidence of an inhibitory activity with mixing study.
The inhibitor must exhibit phospholipid dependence; that is, with more phospholipid there is shortening of clotting time.
Specific inhibitors must be excluded, including factor VIII and anticoagulant drugs such as heparin.^14–17

ANTIPHOSPHOLIPID ANTIBODIES ARE NOT ALL THE SAME

6. Which of the following antiphospholipid antibodies have not been associated with an increased thrombotic risk?

Anti-beta-2-glycoprotein I IgG
Lupus anticoagulant
Antiphosphatidylserine
Anticardiolipin IgM
Anticardiolipin IgG

The correct answer is antiphosphatidylserine.¹⁵

PARADOXICAL EMBOLISM

Back to our patient

Initial antiphospholipid antibody testing was positive for lupus anticoagulant. Anticardiolipin and anti-beta-2-glycoprotein I antibodies were not detected.

Transesophageal echocardiography revealed a patent foramen ovale with a highly mobile atrial septum (atrial septal aneurysm).

SUMMARY OF CASE

PREVIOUS HOSPITALIZATION

On discharge, he required oxygen 4 L/min by nasal cannula. Previously, he had not needed supplemental oxygen.

CURRENT PRESENTATION

Heart rate 104 beats per minute
Respiratory rate 16 to 20 breaths per minute
Blood pressure 101–142/62–84 mm Hg
Oxygen saturation 78% on room air.

He was placed on oxygen by a Venturi mask, and his oxygen saturation improved to 93%.

His laboratory findings on presentation are shown in Table 1, and his electrocardiogram is shown in Figure 1.

WHAT DOES HIS ELECTROCARDIOGRAM SHOW?

1. Which of the following is the most accurate description of this patient’s electrocardiogram?

Sinus tachycardia, peaked P waves (P pulmonale) in lead II, and T-wave inversions in the right precordial leads
Sinus tachycardia and left bundle branch block
Sinus tachycardia and poor R-wave progression
Sinus tachycardia and ST elevation in the precordial leads

Further studies for our patient

Transthoracic echocardiography was performed to look for evidence of right ventricular strain secondary to the pulmonary embolism.

ECHOCARDIOGRAPHIC SIGNS OF PULMONARY EMBOLISM

2. Which of the following findings on transthoracic echocardiography would not suggest acute pulmonary embolism?

Midright ventricular wall hypokinesis with apical sparing
Severe tricuspid regurgitation
Left ventricular dilation
Lack of respiratory variation of the inferior vena cava
Septal wall motion toward the left ventricle

In our patient, transthoracic echocardiography showed:

Normal left ventricular ejection fraction
Mild diastolic dysfunction
Right ventricular dilation with moderately decreased right ventricular systolic function and apical sparing
Right ventricular systolic pressure 54 mm Hg, consistent with moderate pulmonary hypertension
Right atrial pressure 10 mm Hg
No inspiratory collapse of a dilated inferior vena cava
Mild tricuspid valve regurgitation.

CLASSIFICATION OF ACUTE PULMONARY EMBOLISM

3. Given the above information, how would you classify the patient’s pulmonary embolism?

Massive
Submassive
Low-risk
Clinically stable

The patient’s pulmonary embolism is submassive.

Many classification schemes exist for acute pulmonary embolism. That of the American Heart Association is shown in Table 2.³

ULTRASONOGRAPHY FOR DIAGNOSIS OF DEEP VEIN THROMBOSIS

RISK STRATIFICATION IN ACUTE PULMONARY EMBOLISM

Multiple models exist to estimate the risk of complications in patients with acute pulmonary embolism.

The Bova score⁶ is based on the following factors:

Systolic blood pressure 90–100 mm Hg (2 points) (patients with systolic blood pressure lower than 90 mm Hg were excluded from the study from which this score was derived)
Cardiac troponin elevation (2 points)
Right ventricular dysfunction on echocardiography or computed tomography (2 points)
Heart rate 100 beats/min or greater (1 point).

A total score of 0, 1, or 2 (stage I) denotes low risk, 3 or 4 points (stage II) intermediate risk, and more than 4 points (stage III) high risk.

The PESI score (Pulmonary Embolism Severity Index)⁷ is based on:

Age (1 point per year)
Sex (10 points for being male)
Heart rate 110 per minute or greater (20 points)
Cancer (30 points)
Heart failure (10 points)
Chronic lung disease (10 points)
Systolic blood pressure less than 100 mm Hg (30 points)
Respiratory rate at least 30 per minute (20 points)
Temperature less than 36ºC (20 points)
Altered mental status (60 points)
Arterial oxygen saturation less than 90% (20 points).

The total score is broken down into 5 classes: I (< 65 points), II (65–85), III (86–105), IV (106–125), and V (> 126). Classes I and II are low risk, and the higher ones are high risk.

Age over 80
Cancer
Chronic cardiopulmonary disease (heart failure or chronic lung disease)
Heart rate 110 per minute or greater
Systolic blood pressure less than 100 mm Hg
Arterial oxygen saturation less than 90%.

A total score of 0 is low risk; anything higher is high risk.

Back to our patient

Of note, the patient’s pulses in the left lower extremity continued to be weak but palpable, and the left leg was cooler to touch than the right leg.

ASSESSING PERIPHERAL ARTERY DISEASE

4. How should the finding of weak pulses in this patient’s left leg be initially investigated?

Computed tomographic angiography with runoff
Ankle-brachial indices with pulse-volume recordings
Arterial duplex ultrasonography
Magnetic resonance angiography of the lower extremities

Ankle-brachial indices in our patient

Arterial ultrasonography in our patient

WHAT CAN CAUSE BOTH ARTERIAL AND VENOUS THROMBOSIS?

Antiphospholipid antibody syndrome
Protein C or protein S deficiency
Malignancy
Paradoxical embolization
Factor V Leiden mutation

Correct answers include antiphospholipid antibody syndrome, malignancy, and paradoxical embolization.

The differential diagnosis for concomitant venous and arterial thrombosis is broad,¹² and includes the following:

Structural factors: patent foramen ovale, popliteal artery aneurysm
Malignancy
Inflammatory diseases: Behçet disease, Buerger disease, inflammatory bowel disease, antiphospholipid antibody syndrome, elevated lipoprotein(a), elevated homocysteine
Hematologic diseases: myelodysplastic syndrome, disseminated intravascular coagulation, paroxysmal nocturnal hemoglobinuria, heparin-induced thrombocytopenia.

Our patient underwent testing for antiphospholipid antibodies and lupus anticoagulant, and he was encouraged to undergo age-appropriate cancer screening as an outpatient.¹²

ANTIPHOSPHOLIPID ANTIBODY SYNDROME

There should be prolongation of a phospholipid-dependent clotting test (eg, activated partial thromboplastin time, dilute Russell viper venom time test).
There must be evidence of an inhibitory activity with mixing study.
The inhibitor must exhibit phospholipid dependence; that is, with more phospholipid there is shortening of clotting time.
Specific inhibitors must be excluded, including factor VIII and anticoagulant drugs such as heparin.^14–17

ANTIPHOSPHOLIPID ANTIBODIES ARE NOT ALL THE SAME

6. Which of the following antiphospholipid antibodies have not been associated with an increased thrombotic risk?

Anti-beta-2-glycoprotein I IgG
Lupus anticoagulant
Antiphosphatidylserine
Anticardiolipin IgM
Anticardiolipin IgG

The correct answer is antiphosphatidylserine.¹⁵

PARADOXICAL EMBOLISM

Back to our patient

Initial antiphospholipid antibody testing was positive for lupus anticoagulant. Anticardiolipin and anti-beta-2-glycoprotein I antibodies were not detected.

Transesophageal echocardiography revealed a patent foramen ovale with a highly mobile atrial septum (atrial septal aneurysm).

SUMMARY OF CASE

References

Stein PD, Terrin ML, Hales CA, et al. Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest 1991; 100:598–603.
Alsoos F, Khaddam A. Echocardiographic evaluation methods for right ventricular function. J Echocardiogr 2015; 13:43–51.
Jaff MR, McMurtry MS, Archer SL, et al; American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; American Heart Association Council on Peripheral Vascular Disease; American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011; 123:1788–1830.
Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ 3rd. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000; 160:809–815.
Gornik HL, Sharma AM. Duplex ultrasound in the diagnosis of lower-extremity deep venous thrombosis. Circulation 2014; 129:917–921.
Fernández C, Bova C, Sanchez O, et al. Validation of a model for identification of patients at intermediate to high risk for complications associated with acute symptomatic pulmonary embolism. Chest 2015; 148:211–218.
Aujesky D, Perrier A, Roy PM, et al. Validation of a clinical prognostic model to identify low-risk patients with pulmonary embolism. J Intern Med 2007; 261:597–604.
Jiménez D, Aujesky D, Moores L, et al; RIETE Investigators. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med 2010; 170:1383–1389.
Kim ES, Wattanakit K, Gornik HL. Using the ankle-brachial index to diagnose peripheral artery disease and assess cardiovascular risk. Cleve Clin J Med 2012; 79:651–661.
Jaff MR. Lower extremity arterial disease. Diagnostic aspects. Cardiol Clin 2002; 20:491–500.
Rooke TW, Hirsch AT, Misra S, et al; American College of Cardiology Foundation Task Force; American Heart Association Task Force. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA Guideline Recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 61:1555–1570.
Lichtin A, Bartholomew J. The coagulation consult: a case-based guide. New York, NY: Springer; 2014.
Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002; 346:752–763.
Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH. Thromb Haemost 1995; 74:1185–1190.
Miyakis S, Lockshin M, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4:295–306.
Pengo V, Tripodi A, Reber G, et al; Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2009; 7:1737–1740.
Nichols WL, Kottke-Marchant K, Ledford-Kraemer MR, Homburger HA, Cardel LK. Lupus anticoagulants, antiphospholipid antibodies, and antiphospholipid syndrome. In: Kottke-Marchant K, Davis BH, editors. Laboratory Hematology Practice. Hoboken, New Jersey: Blackwell Publishing, Ltd.; 2012:509–525.
Houghton DE, Moll S. Antiphospholipid antibodies. Vasc Med 2017; 22:545–550.
Roldan V, Lecumberri R, Muñoz-Torrero JFS, et al; RIETE Investigators. Thrombophilia testing in patients with venous thromboembolism. Findings from the RIETE registry. Thromb Res 2009; 124:174–177.
Wahl DG, Guillemin F, de Maistre E, Perret-Guillaume C, Lecompte T, Thibaut G. Meta-analysis of the risk of venous thrombosis in individuals with antiphospholipid antibodies without underlying autoimmune disease or previous thrombosis. Lupus 1998; 7:15–22.
Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. Ann Intern Med 1990; 112:682–698.
Thompson T, Evans W. Paradoxical embolism. QJM 1930; os-23:135–150.

References

Stein PD, Terrin ML, Hales CA, et al. Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest 1991; 100:598–603.
Alsoos F, Khaddam A. Echocardiographic evaluation methods for right ventricular function. J Echocardiogr 2015; 13:43–51.
Jaff MR, McMurtry MS, Archer SL, et al; American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; American Heart Association Council on Peripheral Vascular Disease; American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011; 123:1788–1830.
Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ 3rd. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000; 160:809–815.
Gornik HL, Sharma AM. Duplex ultrasound in the diagnosis of lower-extremity deep venous thrombosis. Circulation 2014; 129:917–921.
Fernández C, Bova C, Sanchez O, et al. Validation of a model for identification of patients at intermediate to high risk for complications associated with acute symptomatic pulmonary embolism. Chest 2015; 148:211–218.
Aujesky D, Perrier A, Roy PM, et al. Validation of a clinical prognostic model to identify low-risk patients with pulmonary embolism. J Intern Med 2007; 261:597–604.
Jiménez D, Aujesky D, Moores L, et al; RIETE Investigators. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med 2010; 170:1383–1389.
Kim ES, Wattanakit K, Gornik HL. Using the ankle-brachial index to diagnose peripheral artery disease and assess cardiovascular risk. Cleve Clin J Med 2012; 79:651–661.
Jaff MR. Lower extremity arterial disease. Diagnostic aspects. Cardiol Clin 2002; 20:491–500.
Rooke TW, Hirsch AT, Misra S, et al; American College of Cardiology Foundation Task Force; American Heart Association Task Force. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA Guideline Recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 61:1555–1570.
Lichtin A, Bartholomew J. The coagulation consult: a case-based guide. New York, NY: Springer; 2014.
Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002; 346:752–763.
Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH. Thromb Haemost 1995; 74:1185–1190.
Miyakis S, Lockshin M, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4:295–306.
Pengo V, Tripodi A, Reber G, et al; Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2009; 7:1737–1740.
Nichols WL, Kottke-Marchant K, Ledford-Kraemer MR, Homburger HA, Cardel LK. Lupus anticoagulants, antiphospholipid antibodies, and antiphospholipid syndrome. In: Kottke-Marchant K, Davis BH, editors. Laboratory Hematology Practice. Hoboken, New Jersey: Blackwell Publishing, Ltd.; 2012:509–525.
Houghton DE, Moll S. Antiphospholipid antibodies. Vasc Med 2017; 22:545–550.
Roldan V, Lecumberri R, Muñoz-Torrero JFS, et al; RIETE Investigators. Thrombophilia testing in patients with venous thromboembolism. Findings from the RIETE registry. Thromb Res 2009; 124:174–177.
Wahl DG, Guillemin F, de Maistre E, Perret-Guillaume C, Lecompte T, Thibaut G. Meta-analysis of the risk of venous thrombosis in individuals with antiphospholipid antibodies without underlying autoimmune disease or previous thrombosis. Lupus 1998; 7:15–22.
Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. Ann Intern Med 1990; 112:682–698.
Thompson T, Evans W. Paradoxical embolism. QJM 1930; os-23:135–150.

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A 50-year-old woman with new-onset seizure

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A 50-year-old woman with new-onset seizure

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John R. Queen, MD

Samantha Bogner, CNP, RN

A 50-year-old woman presented to the emergency department after a witnessed loss of consciousness and seizurelike activity. She reported that she had been sitting outside her home, drinking coffee in the morning, but became very lightheaded when she went back into her house. At that time she felt could not focus and had a sense of impending doom. She sat down in a chair and her symptoms worsened.

According to her family, her eyes rolled back and she became rigid. The family helped her to the floor. Her body then made jerking movements that lasted for about 1 minute. She regained consciousness but was very confused for about 10 minutes until emergency medical services personnel arrived. She had no recollection of passing out. She said nothing like this had ever happened to her before.

On arrival in the emergency department, she complained of generalized headache and muscle soreness. She said the headache had been present for 1 week and was constant and dull. There were no aggravating or alleviating factors associated with the headache, and she denied fever, chills, nausea, numbness, tingling, incontinence, tongue biting, tremor, poor balance, ringing in ears, speech difficulty, or weakness.

Medical history: Multiple problems, medications

The patient’s medical history included depression, hypertension, anxiety, osteoarthritis, and asthma. She was allergic to penicillin. She had undergone carpal tunnel surgery on her right hand 5 years previously. She was perimenopausal with no children.

She denied using illicit drugs. She said she had smoked a half pack of cigarettes per day for more than 10 years and was a current smoker but was actively trying to quit. She said she occasionally used alcohol but had not consumed any alcohol in the last 2 weeks.

She had no history of central nervous system infection. She did report an episode of head trauma in grade school when a portable basketball hoop fell, striking her on the top of the head and causing her to briefly lose consciousness, but she did not seek medical attention.

She had no family history of seizure or neurologic disease.

Her current medications included atenolol, naproxen, gabapentin, venlafaxine, zolpidem, lorazepam, bupropion, and meloxicam. The bupropion and lorazepam had been prescribed recently for her anxiety. She reported that she had been given only 10 tablets of lorazepam and had taken the last tablet 48 hours previously. She had been taking the bupropion for 7 days. She reported an increase in stress lately and had been taking zolpidem due to an altered sleep pattern.

PHYSICAL EXAMINATION, INITIAL TESTS

On examination, the patient did not appear to be in acute distress. Her blood pressure was 107/22 mm Hg, pulse 100 beats per minute, respiratory rate 16 breaths per minute, temperature 37.1°C (98.8°F), and oxygen saturation 98% on room air.

Examination of her head, eyes, mouth, and neck were unremarkable. Cardiovascular, pulmonary, and abdominal examinations were normal. She had no neurologic deficits and was fully alert and oriented. She had no visible injuries.

Blood and urine samples were obtained about 15 minutes after her arrival to the emergency department. Results showed:

Glucose 73 mg/dL (reference range 74–99)
Sodium 142 mmol/L (136–144)
Blood urea nitrogen 12 mg/dL (7–21)
Creatinine 0.95 mg/dL (0.58–0.96)
Chloride 97 mmol/L (97–105)
Carbon dioxide (bicarbonate) 16 mmol/L (22–30)
Prolactin 50.9 ng/mL (4.5–26.8)
Anion gap 29 mmol/L (9–18)
Ethanol undetectable
White blood cell count 11.03 × 10⁹/L (3.70–11.00)
Creatine kinase 89 U/L (30–220)
Urinalysis normal, specific gravity 1.010 (1.005–1.030), no detectable ketones, and no crystals seen on microscopic evaluation.

Electrocardiography showed normal sinus rhythm with no ectopy and no ST-segment changes. Chest radiography was negative for any acute process.

The patient was transferred to the 23-hour observation unit in stable condition for further evaluation, monitoring, and management.

SIGNS AND SYMPTOMS OF SEIZURE

1. What findings are consistent with seizure?

Jerking movements
Confusion following the event
Tongue-biting
Focal motor weakness
Urinary incontinence
Aura before the event

All of the above findings are consistent with seizure.

The first consideration in evaluating a patient who presents with a possible seizure is whether the patient’s recollections of the event—and those of the witnesses—are consistent with the symptoms of seizure.¹

In generalized tonic-clonic or grand mal seizure, the patient may experience an aura or subjective sensations before the onset. These vary greatly among patients.² There may be an initial vocalization at the onset of the seizure, such as crying out or unintelligible speech. The patient’s eyes may roll back in the head. This is followed by loss of muscle tone, and if the patient is standing, he or she may fall to the ground. The patient becomes unresponsive and may go into respiratory arrest. There is tonic stiffening of the limbs and body, followed by clonic movements typically lasting 1 to 2 minutes, or sometimes longer.^1,3,4 The patient will then relax and experience a period of unconsciousness or confusion (postictal state).

Urinary incontinence and tongue-biting strongly suggest seizure activity, and turning the head to one side and posturing may also be seen.^3,5 After the event, the patient may report headache, generalized muscle soreness, exhaustion, or periods of transient focal weakness, also known as Todd paralysis.^2,5

Our patient had aura-like symptoms at the outset. She felt very lightheaded, had difficulty focusing, and felt a sense of impending doom. She did not make any vocalizations at the onset, but her eyes did roll backward and she became rigid (tonic). She then lost muscle tone and became unresponsive. Her family had to help her to the floor. Jerking (clonic) movements were witnessed.

She regained consciousness but was described as being confused (postictal) for 10 minutes. Additionally, she denied ever having had symptoms like this previously. On arrival in the emergency department, she reported generalized headache and muscle soreness, but no tongue-biting or urinary incontinence. Her event did not last for more than 1 to 2 minutes according to her family.

Her symptoms strongly suggest new-onset tonic-clonic or grand mal seizure, though this is not completely certain.

LABORATORY FINDINGS IN SEIZURES

2. What laboratory results are consistent with seizure?

Prolactin elevation
Anion gap acidosis
Leukocytosis

As noted above, the patient had an elevated prolactin level and elevated anion gap. Both of these findings can be used, with caution, in evaluating seizure activity.

Prolactin testing is controversial

Prolactin testing in diagnosing seizure activity is controversial. The exact mechanism of prolactin release in seizures is not fully understood. Generalized tonic-clonic seizures and complex partial seizures have both been shown to elevate prolactin. Prolactin levels after these types of seizures should rise within 30 minutes of the event and normalize 1 hour later.⁶

However, other events and conditions that mimic seizure have been shown to cause a rise in prolactin; these include syncope, transient ischemic attack, cardiac dysrhythmia, migraine, and other epilepsy-like variants. This effect has not been adequately studied. Therefore, an elevated prolactin level alone cannot diagnose or exclude seizure.⁷

For the prolactin level to be helpful, the blood sample must be drawn within 10 to 20 minutes after a possible seizure. Even if the prolactin level remains normal, it does not rule out seizure. Prolactin levels should therefore be used in combination with other testing to make a definitive diagnosis or exclusion of seizure.⁸

Anion gap and Denver Seizure Score

The anion gap has also been shown to rise after generalized seizure due to the metabolic acidosis that occurs. With a bicarbonate level of 16 mmol/L, an elevated anion gap, and normal breathing, our patient very likely had metabolic acidosis.

It is sometimes difficult to differentiate syncope from seizure, as they share several features.

The Denver Seizure Score can help differentiate these two conditions. It is based on the patient’s anion gap and bicarbonate level and is calculated as follows:

(24 – bicarbonate) + [2 × (anion gap – 12)]

A score above 20 strongly indicates seizure activity. However, this is not a definitive tool for diagnosis. Like an elevated prolactin level, the Denver Seizure Score should be used in combination with other testing to move toward a definitive diagnosis.⁹

Our patient’s anion gap was 29 mmol/L and her bicarbonate level was 16 mmol/L. Her Denver Seizure Score was therefore 42, which supports this being an episode of generalized seizure activity.

Leukocytosis

The patient had a white blood cell count of 11.03 × 10⁹/L, which was mildly elevated. She had no history of fever and no source of infection by history.

Leukocytosis is common following generalized tonic-clonic seizure. A fever may lower the seizure threshold; however, our patient was not febrile and clinically had no factors that raised concern for an underlying infection.

ANION GAP ACIDOSIS AND SEIZURE

3. Which of the following can cause both anion gap acidosis and seizure?

Ethylene glycol
Salicylate overdose
Ethanol withdrawal without ketosis
Alcoholic ketoacidosis
Methanol

All of the above except for ethanol withdrawal without ketosis can cause both anion gap acidosis and seizure.

Ethylene glycol can cause seizure and an elevated anion gap acidosis. However, this patient had no history of ingesting antifreeze (the most common source of ethylene glycol in the home) and no evidence of calcium oxalate crystals in the urine, which would be a sign of ethylene glycol toxicity. Additional testing for ethylene glycol may include serum ethylene glycol levels and ultraviolet light testing of the urine to detect fluorescein, which is commonly added to automotive antifreeze to help mechanics find fluid leaks in engines.

Salicylate overdose can cause seizure and an elevated anion gap acidosis. However, this patient has no history of aspirin ingestion, and a serum aspirin level was later ordered and found to be negative. In addition, the acid-base disorder in salicylate overdose may be respiratory alkalosis from direct stimulation of respiratory centers in conjunction with metabolic acidosis.

Ethanol withdrawal can cause seizure and may result in ketoacidosis, which would appear as anion gap acidosis. The undetectable ethanol level in this patient would be consistent with withdrawal from ethanol, which may also lead to ketoacidosis.

Alcoholic ketoacidosis is a late finding in patients who have been drinking ethanol and is thus a possible cause of an elevated anion gap in this patient. However, the absence of ketones in her urine speaks against this diagnosis.

Methanol can cause seizure and acidosis, but laboratory testing would reveal a normal anion gap and an elevated osmolar gap. This was not likely in this patient.

The presence of anion gap acidosis is important in forming a differential diagnosis. Several causes of anion gap acidosis may also cause seizure. These include salicylates, ethanol withdrawal with ketosis, methanol, and isoniazid. None of these appears to be a factor in this patient’s case.

DIFFERENTIAL DIAGNOSIS IN OUR PATIENT

4. What is the most likely cause of this patient’s seizure?

Bupropion side effect
Benzodiazepine withdrawal
Ethanol withdrawal
Brain lesion
Central nervous system infection
Unprovoked seizure (new-onset epilepsy)

Bupropion, an inhibitor of neuronal reuptake of norepinephrine and dopamine, has been used in the United States since 1989 to treat major depression.¹⁰ At therapeutic doses, it lowers the seizure threshold; in cases of acute overdose, seizures typically occur within hours of the dose, or up to 24 hours in patients taking extended-release formulations.¹¹

Bupropion should be used with caution or avoided in patients taking other medications that also lower the seizure threshold, or during withdrawal from alcohol, benzodiazepines, or barbiturates.¹⁰

Benzodiazepine withdrawal. Abrupt cessation of benzodiazepines also lowers the seizure threshold, and seizures are commonly seen in benzodiazepine withdrawal syndrome. The use of benzodiazepines is controversial in many situations, and discontinuing them may prove problematic for both the patient and physician, as the potential for abuse and addiction is significant.

Seizures have occurred during withdrawal from even short-term benzodiazepine use. Other factors, such as concomitant use of other medications that lower the seizure threshold, may play a more significant role in causing withdrawal seizures than the duration of benzodiazepine therapy.¹²

Medications shown to be useful in managing withdrawal from benzodiazepines include carbamazepine, imipramine, valproate, and trazodone. Paroxetine has also been shown to be helpful in patients with major depression who are being taken off a benzodiazepine.¹³

Ethanol withdrawal is common in patients presenting to emergency departments, and seizures are frequently seen in these patients. This patient reported social drinking but not drinking ethanol daily, although many patients are not forthcoming about alcohol or drug use when talking with a physician or other healthcare provider.

Alcohol withdrawal seizures may accompany delirium tremens or major withdrawal syndrome, but they are seen more often in the absence of major withdrawal or delirium tremens. Seizures are typically single or occur in a short grouping over a brief period of time and mostly occur in chronic alcoholism. The role of anticonvulsants in patients with alcohol withdrawal seizure has not been established.¹⁴

Brain lesion. A previously undiagnosed brain tumor is not a common cause of new-onset seizure, although it is not unusual for a brain tumor to cause new-onset seizure. In 1 study, 6% of patients with new-onset seizure had a clinically significant lesion on brain imaging.¹⁵ In addition, 15% to 30% of patients with a previously undiagnosed brain tumor present with seizure as the first symptom.¹⁶ Patients with abnormal findings on neurologic examination after the seizure activity are more likely to have a structural lesion that may be identified by computed tomography (CT) or magnetic resonance imaging. (MRI)¹⁵

Unprovoked seizure occurs without an identifiable precipitating factor, or from a central nervous system insult that occurred more than 7 days earlier. Patients who may have recurrent unprovoked seizure will likely be diagnosed with epilepsy.¹⁵ Patients with a first-time unprovoked seizure have a 30% or higher likelihood of having another unprovoked seizure within 5 years.¹⁷

It is most likely that bupropion is the key factor in lowering the seizure threshold in this patient. However, patients sometimes underreport the amount of alcohol they consume, and though less likely, our patient’s report of not drinking for 2 weeks may also be unreliable. Ethanol withdrawal, though unlikely, may also be a consideration with this case.

FURTHER TESTING FOR OUR PATIENT

5. Which tests may be helpful in this patient’s workup?

CT of the brain
Lumbar puncture for spinal fluid analysis
MRI of the brain
Electroencephalography (EEG)

This patient had had a headache for 1 week before presenting to the emergency department. Indications for neuroimaging in a patient with headache include sudden onset of severe headache, neurologic deficits, human immunodeficiency virus infection, loss of consciousness, immunosuppression, pregnancy, malignancy, and age over 50 with a new type of headache.^18,19 Therefore, she should undergo some form of neuroimaging, either CT or MRI.

CT is the most readily available and fastest imaging study for the central nervous system available to emergency physicians. CT is limited, however, due to its decreased sensitivity in detecting some brain lesions. Therefore, many patients with first-time seizure may eventually require MRI.¹⁵ Furthermore, patients with focal onset of the seizure activity are more likely to have a structural lesion precipitating the seizure. MRI may have a higher yield than CT in these cases.^15,20

Lumbar puncture for spinal fluid analysis is helpful in evaluating a patient with a suspected central nervous system infection such as meningitis or encephalitis, or subarachnoid hemorrhage.

This patient had a normal neurologic examination, no fever, and no meningeal signs, and central nervous system infection was very unlikely. Also, because she had had a headache for 1 week before the presentation with seizurelike activity, subarachnoid hemorrhage was very unlikely, and emergency lumbar puncture was not indicated.

MRI is less readily available than CT in a timely fashion in most emergency departments in the United States. It offers a higher yield than CT in diagnosing pathology such as acute stroke, brain tumor, and plaques seen in multiple sclerosis. CT is superior to MRI in diagnosing bony abnormalities and is very sensitive for detecting acute bleeding.

If MRI is performed, it should follow a specific protocol that includes high-resolution images for epilepsy evaluation rather than the more commonly ordered stroke protocol. The stroke protocol is more likely to be ordered in the emergency department.

EEG is well established in evaluating new-onset seizure in pediatric patients. Studies also demonstrate its utility in evaluating first-time seizure in adults, providing evidence that both epileptiform and nonepileptiform abnormalities seen on EEG are associated with a higher risk of recurrent seizure activity than in patients with normal findings on EEG.¹

EEG may be difficult to interpret in adults. According to Benbadis,⁵ as many as one-third of adult patients diagnosed with epilepsy on EEG did not have epilepsy. This is because of normal variants, simple fluctuations of background rhythms, or fragmented alpha activity that can have a similar appearance to epileptiform patterns. EEG must always be interpreted in the context of the patient’s history and symptoms.⁵

Though EEG has limitations, it remains a crucial tool for identifying epilepsy. Following a single seizure, the decision to prescribe antiepileptic drugs is highly influenced by patterns on EEG associated with a risk of recurrence. In fact, a patient experiencing a single, idiopathic seizure and exhibiting an EEG pattern of spike wave discharges is likely to have recurrent seizure activity.²¹ Also, the appropriate use of EEG after even a single unprovoked seizure can identify patients with epilepsy and a risk of recurrent seizure greater than 60%.^21,22

NO FURTHER SEIZURES

The patient was admitted to the observation unit from the emergency department after undergoing CT without intravenous contrast. While in observation, she had no additional episodes, and her vital signs remained within normal limits.

She underwent MRI and EEG as well as repeat laboratory studies and consultation by a neurologist. CT showed no structural abnormality, MRI results were read as normal, and EEG showed no epileptiform spikes or abnormal slow waves or other abnormality consistent with seizure. The repeat laboratory studies revealed normalization of the prolactin level at 11.3 ng/mL (reference range 2.0–17.4).

The final impression of the neurology consultant was that the patient had had a seizure that was most likely due to recently starting bupropion in combination with the withdrawal of the benzodiazepine, which lowered the seizure threshold. The neurologist also believed that our patient had no findings or symptoms other than the seizure that would suggest benzodiazepine withdrawal syndrome. According to the patient’s social history, it was unlikely that she had the pattern of alcohol consumption that would result in ethanol withdrawal seizure.

Seizures are common. In fact, every year, 180,000 US adults have their first seizure, and 10% of Americans will experience at least 1 seizure during their lifetime. However, only 20% to 25% of seizures are generalized tonic-clonic seizures as in our patient.²³

As this patient had an identifiable cause for the seizure, there was no need to initiate anticonvulsant therapy at the time of discharge. She was discharged to home without any anticonvulsant, the bupropion was discontinued, and the lorazepam was not restarted. When contacted by telephone at 1 month and 18 months after discharge, she reported she had not experienced any additional seizures and has not needed antiepileptic medications.

References

Seneviratne U. Management of the first seizure: an evidence based approach. Postgrad Med J 2009; 85:667–673.
Krumholz A, Wiebe S, Gronseth G, et al; Quality Standards Subcommittee of the American Academy of Neurology; American Epilepsy Society. Practice parameter: evaluating an apparent unprovoked first seizure in adults (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2007; 67:1996–2007.
Gram L. Epileptic seizures and syndromes. Lancet 1990; 336:161–163.
Smith PE, Cossburn MD. Seizures: assessment and management in the emergency unit. Clin Med (Lond) 2004; 4:118–122.
Benbadis S. The differential diagnosis of epilepsy: a critical review. Epilepsy Behav 2009; 15:15–21.
Lusic I, Pintaric I, Hozo I, Boic L, Capkun V. Serum prolactin levels after seizure and syncopal attacks. Seizure 1999; 8:218–222.
Chen DK, So YT, Fisher RS; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Use of serum prolactin in diagnosing epileptic seizures: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2005; 65:668–675.
Ben-Menachem E. Is prolactin a clinically useful measure of epilepsy? Epilepsy Curr 2006; 6:78–79.
Bakes KM, Faragher J, Markovchick VJ, Donahoe K, Haukoos JS. The Denver Seizure Score: anion gap metabolic acidosis predicts generalized seizure. Am J Emerg Med 2011; 29:1097–1102.
Jefferson JW, Pradok JF, Muir KT. Bupropion for major depressive disorder: pharmacokinetic and formulation considerations. Clin Ther 2005; 27:1685–1695.
Stall N, Godwin J, Juurlink D. Bupropion abuse and overdose. CMAJ 2014; 186:1015.
Fialip J, Aumaitre O, Eschalier A, Maradeix B, Dordain G, Lavarenne J. Benzodiazepine withdrawal seizures: analysis of 48 case reports. Clin Neuropharmacol 1987; 10:538–544.
Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs 2009; 23:19–34.
Chance JF. Emergency department treatment of alcohol withdrawal seizures with phenytoin. Ann Emerg Med 1991; 20:520–522.
ACEP Clinical Policies Committee; Clinical Policies Subcommittee on Seizures. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with seizures. Ann Emerg Med 2004; 43:605–625.
Sperling MR, Ko J. Seizures and brain tumors. Semin Oncol 2006; 33:333–341.
Musicco M, Beghi E, Solari A, Viani F. Treatment of first tonic-clonic seizure does not improve the prognosis of epilepsy. First Seizure Trial Group (FIRST Group). Neurology 1997; 49:991–998.
Edlow JA, Panagos PD, Godwin SA, Thomas TL, Decker WW; American College of Emergency Physicians. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with acute headache. Ann Emerg Med 2008; 52:407–436.
Kaniecki R. Headache assessment and management. JAMA 2003; 289:1430–1433.
Harden CL, Huff JS, Schwartz TH, et al; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Reassessment: neuroimaging in the emergency patient presenting with seizure (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2007; 69:1772–1780.
Bergey GK. Management of a first seizure. Continuum (Minneap Minn) 2016; 22:38–50.
Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014; 55:475–482.
Ko DY. Generalized tonic-clonic seizures. Medscape. http://emedicine.medscape.com/article/1184608-overview. Accessed December 5, 2017.

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Samantha Bogner, CNP, RN
Center for Emergency Medicine, Cleveland Clinic

Address: John R. Queen, MD, Center for Emergency Medicine, E19, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; queenj@ccf.org

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Center for Emergency Medicine, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Samantha Bogner, CNP, RN
Center for Emergency Medicine, Cleveland Clinic

Address: John R. Queen, MD, Center for Emergency Medicine, E19, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; queenj@ccf.org

Author and Disclosure Information

John R. Queen, MD
Center for Emergency Medicine, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Samantha Bogner, CNP, RN
Center for Emergency Medicine, Cleveland Clinic

Address: John R. Queen, MD, Center for Emergency Medicine, E19, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; queenj@ccf.org

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queen_new-onsetseizure.pdf

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queen_new-onsetseizure.pdf

Medical history: Multiple problems, medications

She had no family history of seizure or neurologic disease.

PHYSICAL EXAMINATION, INITIAL TESTS

Blood and urine samples were obtained about 15 minutes after her arrival to the emergency department. Results showed:

Glucose 73 mg/dL (reference range 74–99)
Sodium 142 mmol/L (136–144)
Blood urea nitrogen 12 mg/dL (7–21)
Creatinine 0.95 mg/dL (0.58–0.96)
Chloride 97 mmol/L (97–105)
Carbon dioxide (bicarbonate) 16 mmol/L (22–30)
Prolactin 50.9 ng/mL (4.5–26.8)
Anion gap 29 mmol/L (9–18)
Ethanol undetectable
White blood cell count 11.03 × 10⁹/L (3.70–11.00)
Creatine kinase 89 U/L (30–220)
Urinalysis normal, specific gravity 1.010 (1.005–1.030), no detectable ketones, and no crystals seen on microscopic evaluation.

Electrocardiography showed normal sinus rhythm with no ectopy and no ST-segment changes. Chest radiography was negative for any acute process.

The patient was transferred to the 23-hour observation unit in stable condition for further evaluation, monitoring, and management.

SIGNS AND SYMPTOMS OF SEIZURE

1. What findings are consistent with seizure?

Jerking movements
Confusion following the event
Tongue-biting
Focal motor weakness
Urinary incontinence
Aura before the event

All of the above findings are consistent with seizure.

Her symptoms strongly suggest new-onset tonic-clonic or grand mal seizure, though this is not completely certain.

LABORATORY FINDINGS IN SEIZURES

2. What laboratory results are consistent with seizure?

Prolactin elevation
Anion gap acidosis
Leukocytosis

As noted above, the patient had an elevated prolactin level and elevated anion gap. Both of these findings can be used, with caution, in evaluating seizure activity.

Prolactin testing is controversial

Anion gap and Denver Seizure Score

It is sometimes difficult to differentiate syncope from seizure, as they share several features.

The Denver Seizure Score can help differentiate these two conditions. It is based on the patient’s anion gap and bicarbonate level and is calculated as follows:

(24 – bicarbonate) + [2 × (anion gap – 12)]

Our patient’s anion gap was 29 mmol/L and her bicarbonate level was 16 mmol/L. Her Denver Seizure Score was therefore 42, which supports this being an episode of generalized seizure activity.

Leukocytosis

The patient had a white blood cell count of 11.03 × 10⁹/L, which was mildly elevated. She had no history of fever and no source of infection by history.

ANION GAP ACIDOSIS AND SEIZURE

3. Which of the following can cause both anion gap acidosis and seizure?

Ethylene glycol
Salicylate overdose
Ethanol withdrawal without ketosis
Alcoholic ketoacidosis
Methanol

All of the above except for ethanol withdrawal without ketosis can cause both anion gap acidosis and seizure.

Methanol can cause seizure and acidosis, but laboratory testing would reveal a normal anion gap and an elevated osmolar gap. This was not likely in this patient.

DIFFERENTIAL DIAGNOSIS IN OUR PATIENT

4. What is the most likely cause of this patient’s seizure?

Bupropion side effect
Benzodiazepine withdrawal
Ethanol withdrawal
Brain lesion
Central nervous system infection
Unprovoked seizure (new-onset epilepsy)

Bupropion should be used with caution or avoided in patients taking other medications that also lower the seizure threshold, or during withdrawal from alcohol, benzodiazepines, or barbiturates.¹⁰

FURTHER TESTING FOR OUR PATIENT

5. Which tests may be helpful in this patient’s workup?

CT of the brain
Lumbar puncture for spinal fluid analysis
MRI of the brain
Electroencephalography (EEG)

Lumbar puncture for spinal fluid analysis is helpful in evaluating a patient with a suspected central nervous system infection such as meningitis or encephalitis, or subarachnoid hemorrhage.

NO FURTHER SEIZURES

Medical history: Multiple problems, medications

She had no family history of seizure or neurologic disease.

PHYSICAL EXAMINATION, INITIAL TESTS

Blood and urine samples were obtained about 15 minutes after her arrival to the emergency department. Results showed:

Glucose 73 mg/dL (reference range 74–99)
Sodium 142 mmol/L (136–144)
Blood urea nitrogen 12 mg/dL (7–21)
Creatinine 0.95 mg/dL (0.58–0.96)
Chloride 97 mmol/L (97–105)
Carbon dioxide (bicarbonate) 16 mmol/L (22–30)
Prolactin 50.9 ng/mL (4.5–26.8)
Anion gap 29 mmol/L (9–18)
Ethanol undetectable
White blood cell count 11.03 × 10⁹/L (3.70–11.00)
Creatine kinase 89 U/L (30–220)
Urinalysis normal, specific gravity 1.010 (1.005–1.030), no detectable ketones, and no crystals seen on microscopic evaluation.

Electrocardiography showed normal sinus rhythm with no ectopy and no ST-segment changes. Chest radiography was negative for any acute process.

The patient was transferred to the 23-hour observation unit in stable condition for further evaluation, monitoring, and management.

SIGNS AND SYMPTOMS OF SEIZURE

1. What findings are consistent with seizure?

Jerking movements
Confusion following the event
Tongue-biting
Focal motor weakness
Urinary incontinence
Aura before the event

All of the above findings are consistent with seizure.

Her symptoms strongly suggest new-onset tonic-clonic or grand mal seizure, though this is not completely certain.

LABORATORY FINDINGS IN SEIZURES

2. What laboratory results are consistent with seizure?

Prolactin elevation
Anion gap acidosis
Leukocytosis

As noted above, the patient had an elevated prolactin level and elevated anion gap. Both of these findings can be used, with caution, in evaluating seizure activity.

Prolactin testing is controversial

Anion gap and Denver Seizure Score

It is sometimes difficult to differentiate syncope from seizure, as they share several features.

The Denver Seizure Score can help differentiate these two conditions. It is based on the patient’s anion gap and bicarbonate level and is calculated as follows:

(24 – bicarbonate) + [2 × (anion gap – 12)]

Our patient’s anion gap was 29 mmol/L and her bicarbonate level was 16 mmol/L. Her Denver Seizure Score was therefore 42, which supports this being an episode of generalized seizure activity.

Leukocytosis

The patient had a white blood cell count of 11.03 × 10⁹/L, which was mildly elevated. She had no history of fever and no source of infection by history.

ANION GAP ACIDOSIS AND SEIZURE

3. Which of the following can cause both anion gap acidosis and seizure?

Ethylene glycol
Salicylate overdose
Ethanol withdrawal without ketosis
Alcoholic ketoacidosis
Methanol

All of the above except for ethanol withdrawal without ketosis can cause both anion gap acidosis and seizure.

Methanol can cause seizure and acidosis, but laboratory testing would reveal a normal anion gap and an elevated osmolar gap. This was not likely in this patient.

DIFFERENTIAL DIAGNOSIS IN OUR PATIENT

4. What is the most likely cause of this patient’s seizure?

Bupropion side effect
Benzodiazepine withdrawal
Ethanol withdrawal
Brain lesion
Central nervous system infection
Unprovoked seizure (new-onset epilepsy)

Bupropion should be used with caution or avoided in patients taking other medications that also lower the seizure threshold, or during withdrawal from alcohol, benzodiazepines, or barbiturates.¹⁰

FURTHER TESTING FOR OUR PATIENT

5. Which tests may be helpful in this patient’s workup?

CT of the brain
Lumbar puncture for spinal fluid analysis
MRI of the brain
Electroencephalography (EEG)

Lumbar puncture for spinal fluid analysis is helpful in evaluating a patient with a suspected central nervous system infection such as meningitis or encephalitis, or subarachnoid hemorrhage.

NO FURTHER SEIZURES

References

Seneviratne U. Management of the first seizure: an evidence based approach. Postgrad Med J 2009; 85:667–673.
Krumholz A, Wiebe S, Gronseth G, et al; Quality Standards Subcommittee of the American Academy of Neurology; American Epilepsy Society. Practice parameter: evaluating an apparent unprovoked first seizure in adults (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2007; 67:1996–2007.
Gram L. Epileptic seizures and syndromes. Lancet 1990; 336:161–163.
Smith PE, Cossburn MD. Seizures: assessment and management in the emergency unit. Clin Med (Lond) 2004; 4:118–122.
Benbadis S. The differential diagnosis of epilepsy: a critical review. Epilepsy Behav 2009; 15:15–21.
Lusic I, Pintaric I, Hozo I, Boic L, Capkun V. Serum prolactin levels after seizure and syncopal attacks. Seizure 1999; 8:218–222.
Chen DK, So YT, Fisher RS; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Use of serum prolactin in diagnosing epileptic seizures: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2005; 65:668–675.
Ben-Menachem E. Is prolactin a clinically useful measure of epilepsy? Epilepsy Curr 2006; 6:78–79.
Bakes KM, Faragher J, Markovchick VJ, Donahoe K, Haukoos JS. The Denver Seizure Score: anion gap metabolic acidosis predicts generalized seizure. Am J Emerg Med 2011; 29:1097–1102.
Jefferson JW, Pradok JF, Muir KT. Bupropion for major depressive disorder: pharmacokinetic and formulation considerations. Clin Ther 2005; 27:1685–1695.
Stall N, Godwin J, Juurlink D. Bupropion abuse and overdose. CMAJ 2014; 186:1015.
Fialip J, Aumaitre O, Eschalier A, Maradeix B, Dordain G, Lavarenne J. Benzodiazepine withdrawal seizures: analysis of 48 case reports. Clin Neuropharmacol 1987; 10:538–544.
Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs 2009; 23:19–34.
Chance JF. Emergency department treatment of alcohol withdrawal seizures with phenytoin. Ann Emerg Med 1991; 20:520–522.
ACEP Clinical Policies Committee; Clinical Policies Subcommittee on Seizures. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with seizures. Ann Emerg Med 2004; 43:605–625.
Sperling MR, Ko J. Seizures and brain tumors. Semin Oncol 2006; 33:333–341.
Musicco M, Beghi E, Solari A, Viani F. Treatment of first tonic-clonic seizure does not improve the prognosis of epilepsy. First Seizure Trial Group (FIRST Group). Neurology 1997; 49:991–998.
Edlow JA, Panagos PD, Godwin SA, Thomas TL, Decker WW; American College of Emergency Physicians. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with acute headache. Ann Emerg Med 2008; 52:407–436.
Kaniecki R. Headache assessment and management. JAMA 2003; 289:1430–1433.
Harden CL, Huff JS, Schwartz TH, et al; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Reassessment: neuroimaging in the emergency patient presenting with seizure (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2007; 69:1772–1780.
Bergey GK. Management of a first seizure. Continuum (Minneap Minn) 2016; 22:38–50.
Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014; 55:475–482.
Ko DY. Generalized tonic-clonic seizures. Medscape. http://emedicine.medscape.com/article/1184608-overview. Accessed December 5, 2017.

References

Seneviratne U. Management of the first seizure: an evidence based approach. Postgrad Med J 2009; 85:667–673.
Krumholz A, Wiebe S, Gronseth G, et al; Quality Standards Subcommittee of the American Academy of Neurology; American Epilepsy Society. Practice parameter: evaluating an apparent unprovoked first seizure in adults (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2007; 67:1996–2007.
Gram L. Epileptic seizures and syndromes. Lancet 1990; 336:161–163.
Smith PE, Cossburn MD. Seizures: assessment and management in the emergency unit. Clin Med (Lond) 2004; 4:118–122.
Benbadis S. The differential diagnosis of epilepsy: a critical review. Epilepsy Behav 2009; 15:15–21.
Lusic I, Pintaric I, Hozo I, Boic L, Capkun V. Serum prolactin levels after seizure and syncopal attacks. Seizure 1999; 8:218–222.
Chen DK, So YT, Fisher RS; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Use of serum prolactin in diagnosing epileptic seizures: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2005; 65:668–675.
Ben-Menachem E. Is prolactin a clinically useful measure of epilepsy? Epilepsy Curr 2006; 6:78–79.
Bakes KM, Faragher J, Markovchick VJ, Donahoe K, Haukoos JS. The Denver Seizure Score: anion gap metabolic acidosis predicts generalized seizure. Am J Emerg Med 2011; 29:1097–1102.
Jefferson JW, Pradok JF, Muir KT. Bupropion for major depressive disorder: pharmacokinetic and formulation considerations. Clin Ther 2005; 27:1685–1695.
Stall N, Godwin J, Juurlink D. Bupropion abuse and overdose. CMAJ 2014; 186:1015.
Fialip J, Aumaitre O, Eschalier A, Maradeix B, Dordain G, Lavarenne J. Benzodiazepine withdrawal seizures: analysis of 48 case reports. Clin Neuropharmacol 1987; 10:538–544.
Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs 2009; 23:19–34.
Chance JF. Emergency department treatment of alcohol withdrawal seizures with phenytoin. Ann Emerg Med 1991; 20:520–522.
ACEP Clinical Policies Committee; Clinical Policies Subcommittee on Seizures. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with seizures. Ann Emerg Med 2004; 43:605–625.
Sperling MR, Ko J. Seizures and brain tumors. Semin Oncol 2006; 33:333–341.
Musicco M, Beghi E, Solari A, Viani F. Treatment of first tonic-clonic seizure does not improve the prognosis of epilepsy. First Seizure Trial Group (FIRST Group). Neurology 1997; 49:991–998.
Edlow JA, Panagos PD, Godwin SA, Thomas TL, Decker WW; American College of Emergency Physicians. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with acute headache. Ann Emerg Med 2008; 52:407–436.
Kaniecki R. Headache assessment and management. JAMA 2003; 289:1430–1433.
Harden CL, Huff JS, Schwartz TH, et al; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Reassessment: neuroimaging in the emergency patient presenting with seizure (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2007; 69:1772–1780.
Bergey GK. Management of a first seizure. Continuum (Minneap Minn) 2016; 22:38–50.
Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014; 55:475–482.
Ko DY. Generalized tonic-clonic seizures. Medscape. http://emedicine.medscape.com/article/1184608-overview. Accessed December 5, 2017.

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A 50-year-old woman with new-onset seizure

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A 50-year-old woman with new-onset seizure

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seizure, epilepsy, aura, prodrome, buproprion, lorazepam, prolactin, anion gap, leukocytosis, alcohol, ethanol, John Queen, Samantha Bogner

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Big heart, small ring

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Big heart, small ring

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Igor Kravets, MD, FACE

A 58-year-old man presents with a 1-year history of chronic daytime fatigue, low libido, and difficulty achieving erections. He is upset: his wife suspects him of having an extramarital affair because, in addition to problems with his sexual performance, he has not been wearing his wedding ring. The patient explains that the ring has become too small for his finger and that he has never cheated on his wife. His wife has also been complaining that he snores loudly at night.

The patient works as an accountant. He has no known allergies to medications and takes no medications or supplements. He has no surgical history. He has never smoked tobacco or abused illicit drugs. He drinks a glass of wine once a week.

His father died at age 78 of a myocardial infarction; his 86-year-old mother has hypertension. He has no siblings. His 28-year-old biological son is healthy.

Physical examination

His temperature is 97.9°F (36.6°C), blood pressure 150/90 mm Hg, heart rate 80 per minute, respiratory rate 12 per minute, and oxygen saturation 98% on room air. His height is 5 feet 11 inches (180 cm), weight 250 lb (113 kg), and body mass index 35 kg/m².

His forehead is wide with deep creases, his jaw, nose, and lower lip are prominent, and his tongue, hands, and feet are large. He has mild thyromegaly with no palpable nodules.

On cardiac examination, his point of maximal impulse is 3 cm lateral to the left midclavicular line in the fifth intercostal space; he has normal S1 and S2 with no murmurs, rubs, or gallops. The lungs are clear on auscultation. His abdomen is soft, nontender, and nondistended; the liver is palpated 2 cm below the costal margin. His extremities are not edematous.

LABORATORY TESTING

1. In addition to a complete blood cell count and comprehensive metabolic panel, which is the most appropriate test to order?

Growth hormone (GH) level
Insulin-like growth factor 1 (IGF-1) level
GH and IGF-1 levels
IGF-2 level

Acromegaly, an overview

The patient’s history of snoring and daytime fatigue suggests obstructive sleep apnea, which together with his enlarging ring finger size, wide forehead with deep creases, prominent jaw, nose, and lower lip, and enlarged thyroid, heart, and liver suggests acromegaly.

This chronic progressive disease is characterized by excessive secretion of GH leading to increased synthesis of IGF-1, the main mediator of GH’s effects. The end result is disproportionate growth of skeletal, soft, and organ tissue.¹ A list of acromegaly’s clinical manifestations is shown in Table 1.^2,3 The disease is often associated with insulin resistance.⁴

In most cases, acromegaly is caused by a GH-secreting pituitary adenoma. Rare causes include hypothalamic tumors that secrete GH-releasing hormone (GHRH) and ectopic secretion of GHRH or GH.¹ Pseudoacromegaly, a mimic, is characterized by acromegalic features without hypersecretion of GH and with normal IGF-1 levels.⁴

The prevalence of acromegaly is 36 to 60 cases per million, and its annual incidence is 3 to 4 per million.⁵

With this patient’s presentation, the most appropriate next step is to order an IGF-1 level to screen for acromegaly.

GH secretion is pulsatile, IGF-1 secretion is not

GH is synthesized and stored in somatotroph cells, which account for more than 50% of pituitary hormone-secreting cells.⁶ Three hormones regulate synthesis and secretion of GH: GHRH, ghrelin, and somatostatin.⁷ GH secretion is pulsatile, with minimal basal secretion dependent on sex, age, neurotransmitters, exercise, and stress.⁷ It exerts its physiologic effects through an interaction with the GH receptor, a single-chain transmembrane glycoprotein.^8,9

A GH-secreting adenoma develops when pituitary somatotroph cells undergo a monoclonal expansion. Mutations of various genes such as GNAS, PRKAR1A, and AIP are suspected of triggering such expansion. Disruption of the MENIN gene leads to multiple endocrine neoplasia syndrome 1, a combination of pituitary adenoma, pancreatic tumor, and primary hyperparathyroidism.⁹ The pattern of cytoplasmic keratin in somatotroph cells defines 2 histologic subtypes: densely granulated and sparsely granulated. The latter subtype is associated with more-invasive lesions that are seen more often in younger patients and are less responsive to somatostatin ligand therapy.¹⁰

GH induces transcription of IGF-1, mostly in the liver. In contrast to GH, IGF-1 secretion is not pulsatile, and therefore IGF-1 can be measured more reliably in serum, and the results can be interpreted according to age- and sex-adjusted reference ranges.

The IGF-1 level is a very sensitive test, but it is not very specific. It can be falsely elevated in pregnancy, in patients on estrogen replacement therapy, and in late adolescence.¹¹ In addition, it may be difficult to interpret the IGF-1 level in the setting of malnutrition, severe hyperglycemia, renal or hepatic failure, and hypothyroidism.^11,12

Nonpulsatile secretion and high sensitivity make the IGF-1 level the screening test of choice for acromegaly.^9,12 In contrast, because of the pulsatile nature of GH synthesis, one cannot rely on a random GH level alone to detect the hormone’s hypersecretion.

IGF-2 has no role in acromegaly

IGF-2, produced mainly by the liver, plays an important role in promoting fetal growth. IGF-2 may induce hypoglycemia when secreted by some mesenchymal tumors.¹³ This hormone has no role in the pathogenesis of acromegaly and should not be measured in this patient.

CASE CONTINUED: FURTHER TESTING

The patient’s IGF-1 level is 590 ng/mL; the reference range for his age and sex is 68 to 245 ng/mL.

A sleep study confirms obstructive sleep apnea, and the patient is started on continuous positive airway pressure at night, with some reduction of his fatigue.

2. What is the most appropriate next step?

Order magnetic resonance imaging (MRI) of the pituitary with gadolinium contrast
Perform a GH suppression test with a 75-g oral glucose load
Perform a GH stimulation test
Refer the patient to a neurosurgeon for a consultation

The most appropriate next step is a GH suppression test, performed by measuring the plasma GH level 2 hours after giving 75 g of glucose by mouth. This confirmatory test is necessary because the IGF-1 level can be falsely elevated. The normal response to an oral glucose challenge is suppression of the GH level to below 1 μg/L. Failure to suppress GH confirms the diagnosis of acromegaly.¹⁴

A GH stimulation test with insulin-induced hypoglycemia or with GHRH-arginine would be appropriate if GH deficiency were suspected rather than hypersecretion.

Imaging of the pituitary with MRI before obtaining biochemical confirmation of the diagnosis of acromegaly may mislead the physician because MRI does not determine the functional status of a pituitary tumor. Correct treatment of a pituitary tumor depends on whether the tumor causes hypersecretion or deficiency of any pituitary hormones.

Referral to a neurosurgeon for a consultation is premature until a biochemical diagnosis of acromegaly is made and a pituitary adenoma is subsequently demonstrated by imaging.

3. The patient’s GH level is 10 μg/L 2 hours after oral administration of 75 g of glucose. What is the most appropriate next step?

Radiography of the skull to image the pituitary at a low cost
MRI of the pituitary with contrast after making sure the patient’s renal function is normal
MRI of the pituitary without contrast
Computed tomography of the head

The next step is MRI of the pituitary with contrast (gadolinium) after obtaining blood urea nitrogen and creatinine measurements to make sure the patient’s renal function is normal.¹⁴

Gadolinium contrast is contraindicated in patients with severely reduced renal function (glomerular filtration rate < 30 mL/min/1.73 m²) because of the risk of nephrogenic systemic fibrosis. In such a case, MRI without contrast would be appropriate.

MRI is the most sensitive imaging test for detecting a pituitary adenoma, as it can detect tumors as small as 2 mm. A pituitary macroadenoma (> 10 mm in diameter) is detected in more than 75% of patients with acromegaly at diagnosis. The tumor often invades one or both cavernous sinuses or extends to the suprasellar region, possibly impinging on the optic chiasm.¹⁵

If MRI is contraindicated, computed tomography of the head should be performed.

CASE CONTINUED: IMAGING

The patient’s comprehensive metabolic panel is normal, but his fasting plasma glucose is 135 mg/dL (reference range 74–99). Pituitary MRI with contrast shows a 3-cm pituitary adenoma with suprasellar extension, impinging on the optic chiasm and invading the right cavernous sinus.

4. In addition to repeating the fasting plasma glucose and measuring hemoglobin A_1c, what is the most appropriate next step in managing this patient?

Measure the prolactin, morning serum cortisol, total testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and free thyroxine (T4) levels; refer the patient to an ophthalmologist for a formal evaluation of visual fields
Measure these hormone levels; perform a gross evaluation of the visual fields and refer the patient to an ophthalmologist only if visual field deficits are found on the gross examination
Measure these hormone levels; refer the patient to an ophthalmologist only if he complains of vision changes
Do not order any additional tests; instruct the patient to call the office if he develops any vision changes

This patient should have all of these hormones measured. In addition, given that his macroadenoma is impinging on the optic chiasm, he should be referred to an ophthalmologist for a formal evaluation of visual fields even if the latter are intact on gross examination and even if the patient does not complain of any visual changes.

Abnormalities of hormones other than GH and IGF-1 in acromegaly

Secretion of pituitary hormones other than GH and IGF-1 must be assessed.

Prolactin. GH-secreting tumors also secrete prolactin in up to one-third of patients, with the resulting hyperprolactinemia contributing to hypogonadism.¹¹ Prolactin hypersecretion should be distinguished from hyperprolactinemia caused by pituitary stalk compression, which may be evident on MRI.

Measuring the serum prolactin level with 1:100 dilution to counteract the “hook effect” may unmask severe hyperprolactinemia due to a large macroprolactinoma. (The hook effect occurs when the prolactin level is so high that there is not enough antibody in the assay to bind both ends of all the prolactin molecules present, causing the reading to be falsely low.).

Cortisol, T4, testosterone. Patients with acromegaly may develop central adrenal insufficiency, central hypothyroidism, and central hypogonadism; these hormonal deficits may occur in isolation or in combination.

Also, patients should be assessed for comorbidities such as colon cancer (all patients with acromegaly require a colonoscopy, as acromegaly raises the risk of colon cancer), diabetes mellitus, hypertension, cardiomyopathy, and sleep apnea.¹⁶

Visual field loss may be insidious

All patients with a pituitary macroadenoma that abuts the optic chiasm should be referred to an ophthalmologist for a formal evaluation of visual fields. If there is a clear space between the tumor and the chiasm, such an evaluation is not necessary. Because these tumors develop insidiously, patients may not be aware of any changes in their vision.

The diagnostic and treatment algorithm for acromegaly is summarized in Figure 1.

CASE CONTINUED: LABORATORY VALUES, TREATMENT OPTIONS

Our patient’s repeat fasting plasma glucose is 137 mg/dL; his hemoglobin A_1c is 7.3%, consistent with diabetes mellitus secondary to acromegaly. Other laboratory values:

Morning cortisol level 15 μg/dL (reference range 5.3–22.5),
Prolactin 23 ng/mL, confirmed with 1:100 dilution (4.0–15.2)
Total testosterone 59 ng/dL (193–824)
LH 2.1 mIU/mL (1.8–10.8)
FSH 3.0 mIU/mL (1.5–12.4)
TSH 2.5 mIU/L (0.5–4.5)
Free T4 1.3 ng/dL (0.9–1.7).

The patient is started on metformin 500 mg by mouth twice a day, counseled on a healthy diet, and informed that his diabetes may be a complication of his acromegaly. He is anxious to learn how his acromegaly can be treated.

5. What treatment would you recommend for the patient’s acromegaly?

Medical treatment first, then transsphenoidal resection of the pituitary macroadenoma if medical treatment fails
Medical treatment first, radiotherapy if medical treatment fails, and transsphenoidal resection of the pituitary macroadenoma as a last resort
Transsphenoidal resection of the pituitary macroadenoma first, medical treatment if surgery fails, and radiotherapy if both surgery and medical treatment fail
Taking a safe, conservative approach, monitoring IGF-1 levels frequently; starting medical treatment if acromegaly does not go into remission in 1 year

The initial treatment of choice for most patients with acromegaly is resection of the pituitary tumor.

A transsphenoidal approach is used for most patients; only rarely is craniotomy necessary. Endoscopic and microsurgical techniques reduce postoperative morbidity.¹⁷ Postoperative complications include symptoms related to the transsphenoidal approach (nasal congestion, sinusitis, epistaxis), cerebrospinal fluid leak, hemorrhage, meningitis, stroke, visual impairment, vascular damage, transient or permanent diabetes insipidus, and hypopituitarism. The surgical mortality rate is less than 0.5%.^18,19

Successful resection of a pituitary tumor would lead to normalization of the IGF-1 level, a drop of the GH level to below 1 μg/L, and relief of the effect of the tumor pressing against other structures. An IGF-1 level and a random GH level should be obtained 12 weeks after the surgery.¹⁴ If the GH level is higher than 1 μg/L, a GH suppression test with a 75-g oral glucose load should be performed.¹⁴ MRI of the sella turcica should be done 12 weeks after surgery to visualize residual tumor and adjacent structures.¹⁴

A large tumor size, suprasellar extension, and high preoperative levels of IGF-1 and GH are associated with a lack of surgical success; however, surgical debulking should still be considered in patients with a low chance for surgical cure to improve the probability of achieving biochemical remission with postoperative medical and radiologic therapy.²⁰

Medical therapy can be the initial treatment if the patient refuses surgery or if surgery is contraindicated because of severe comorbidities or because structural features of the tumor confer a high surgical risk (eg, if the adenoma encases the cavernous portion of a carotid artery).¹³ Medical therapy may shrink the tumor in some patients and may thereby make surgical resection easier and more likely to be successful.

Radiotherapy is usually reserved for patients whose tumors recur or persist postoperatively and who are resistant to or intolerant of medical therapy.¹⁴ The soft tissue changes caused by acromegaly may regress with treatment to some degree, but they are not likely to resolve completely; the bone changes do not regress.

CASE CONTINUED: MEDICAL TREATMENT

Three months after transsphenoidal resection of his pituitary macroadenoma, our patient’s laboratory values are as follows:

IGF-1 400 ng/mL
Morning cortisol 20 μg/dL
Testosterone 95 ng/dL
LH 2.1 mU/mL
FSH 3.7 mU/mL
Prolactin 12 ng/mL
TSH 2.3 mIU/L
Free T4 1.2 ng/dL
Basic metabolic panel normal.

The patient denies frequent urination or increased thirst. Repeat MRI of the pituitary with contrast shows a residual 1.3-cm adenoma with no suprasellar extension.

6. What is the best next treatment choice for the patient?

A GH receptor antagonist (pegvisomant)
A somatostatin receptor ligand (SRL) such as octreotide
Cabergoline (a dopamine agonist)
A combination of an SRL and pegvisomant

An SRL such as octreotide would be the best choice for this patient.

The medical options for acromegaly are SRLs, pegvisomant, and cabergoline.^21–23 The Endocrine Society guidelines recommend either an SRL or pegvisomant as the initial adjuvant medical therapy in patients with persistent disease after surgery.¹⁴ However, pegvisomant is much more expensive than any SRL, so an SRL would be a better choice in this patient. Also, pegvisomant does not suppress tumor growth, in contrast to SRLs, so SRLs are preferred in patients with large tumors abutting the optic chiasm.¹⁴

SRLs are used as primary therapy in patients who cannot be cured by surgery, have extensive cavernous sinus invasion, have no chiasmal compression, or are poor surgical candidates.

Cabergoline, a dopamine agonist, should be tried as the initial adjuvant medical therapy in patients with only modest elevations of serum IGF-1 and mild signs and symptoms of acromegaly.¹⁴

Side effects of drug therapy for acromegaly

Pegvisomant or cabergoline can be added to an SRL in patients who have an inadequate response to an SRL.¹⁴ Combination therapy would be premature in this patient.

The medical treatment of acromegaly is summarized in Table 2.^14,15 Side effects of the medications used to treat acromegaly are summarized in Table 3.¹⁴

CASE CONTINUED: RADIOTHERAPY

The patient is treated with octreotide, and the dose is subsequently titrated upward. His central hypogonadism is treated with testosterone gel. After 3 months, his IGF-1 level decreases to 190 ng/mL, the total testosterone increases to 450 ng/dL, and the hemoglobin A_1c decreases to 5.9%.

The patient asks if stereotactic radiotherapy, which he read about on the Internet, can cure his acromegaly so that he can avoid the monthly octreotide injections.

7. Which statement best describes radiotherapy’s therapeutic effect in acromegaly?

Stereotactic radiotherapy is more effective than medical therapy and should be used as a second-line treatment after surgery
Stereotactic radiotherapy is less effective than conventional radiotherapy
Stereotactic radiotherapy leads to stability or a decrease in the size of the GH-secreting tumor in 93% to 100% of patients in 5 to 10 years and to biochemical remission in 40% to 60% of patients at 5 years
Stereotactic radiotherapy causes hypopituitarism in no more than 1% of patients

Stereotactic radiotherapy leads to stability or a decrease in the size of the GH-secreting tumor in 93% to 100% of patients in 5 to 10 years and biochemical remission in 40% to 60% of patients at 5 years.^24,25

Hypopituitarism develops in up to 50% of patients at 5 years, and its incidence increases with the duration of follow-up.²⁴ The risk of other complications is low (0% to 5% for new visual deficits, cranial nerve damage, or brain radionecrosis, and 0% to 1% for secondary brain tumors).²⁴

Conventional radiotherapy has fallen out of favor because it is associated with an increased risk of death (mainly from stroke) independent of IGF-1 and GH levels, and a higher rate of complications than stereotactic radiotherapy.^14,16 Radiotherapy is reserved for postsurgical treatment of patients with recurrent or persistent tumors who are resistant to or cannot tolerate medical therapy; it is the third-line treatment.²⁴

Given that our patient responded to the medical therapy and tolerated it well and given the high risk of hypopituitarism associated with stereotactic radiotherapy, the latter would not be appropriate for the patient.

His fatigue has diminished further and his sexual performance has improved. He is still married and his wife no longer suspects him of infidelity.

KEY POINTS

IGF-1 is the screening test of choice in a patient with signs and symptoms of acromegaly.
A growth hormone suppression test with a 75-g oral glucose load is the gold standard test for confirmation of the diagnosis of acromegaly in patients with an elevated IGF-1 level.
Transsphenoidal resection of the growth hormone-secreting pituitary macroadenoma is the initial treatment of choice for acromegaly.
Patients with residual or recurrent growth hormone-secreting pituitary macroadenoma can be treated with somatostatin receptor ligands, a growth hormone receptor antagonist (pegvisomant), and a dopamine agonist cabergoline.
Radiotherapy is reserved for postsurgical treatment of patients with recurrent or persistent tumors who are resistant to or intolerant of medical therapy. Stereotactic radiotherapy has largely replaced conventional radiotherapy.

References

Melmed S. Acromegaly pathogenesis and treatment. J Clin Invest 2009; 119:3189–3202.
Molitch ME. Clinical manifestations of acromegaly. Endocrinol Metab Clin North Am 1992; 21:597–614.
Dineen R, Stewart PM, Sherlock M. Acromegaly. QJM 2017; 110:411–420.
Yacub A, Yaqub N. Insulin-mediated pseudoacromegaly: a case report and review of the literature. W V Med J 2008; 104:12–15.
Mestron A, Webb SM, Astorga R, et al. Epidemiology, clinical characteristics, outcome, morbidity and mortality in acromegaly based on the Spanish Acromegaly Registry (Registro Espanol de Acromegalia, REA). Eur J Endocrinol 2004; 151:439–446.
Zhu X, Lin CR, Prefontaine CG, Tollkuhn J, Rosenfeld MG. Genetic control of pituitary development and hypopituitarism. Curr Opin Genet Dev 2005; 15:332–340.
Tannenbaum GS, Epelbaum J, Bowers CY. Interrelationship between the novel peptide ghrelin and somatostatin/growth hormone-releasing hormone in regulation of pulsatile growth hormone secretion. Endocrinology 2003; 144:967–974.
Lanning NJ, Carter-Su C. Recent advances in growth hormone signaling. Rev Endocr Metab Disord 2006; 7:225–235.
Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev 2004; 25:102–152.
Larkin S, Reddy R, Karavitaki N, Cudlip S, Wass J, Ansorge O. Granulation pattern, but not GSP or GHR mutation, is associated with clinical characteristics in somatostatin-naive patients with somatotroph adenomas. Eur J Endocrinol 2013; 168:491–499.
Dineen R, Stewart PM, Sherlock M. Acromegaly. QJM 2017; 110:411–420.
Peacey SR, Toogood AA, Veldhuis JD, Thorner MO, Shalet SM. The relationship between 24-hour growth hormone secretion and insulin-like growth factor I in patients with successfully treated acromegaly: impact of surgery or radiotherapy. J Clin Endocrinol Metab 2001; 86:259–266.
Livingstone C. IGF2 and cancer. Endocr Relat Cancer 2013; 20:R321–R339.
Katznelson L, Laws ER Jr, Melmed S, et al. Acromegaly: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2014; 99:3933–3951.
Melmed S. Acromegaly. N Engl J Med 2006; 355:2558–2573.
Melmed S, Casanueva FF, Klibanski A, et al. A consensus on the diagnosis and treatment of acromegaly complications. Pituitary 2013; 16:294–302.
Marquez Y, Tuchman A, Zada G. Surgery and radiosurgery for acromegaly: a review of indications, operative techniques, outcomes, and complications. Int J Endocrinol 2012; 2012: 386401.
Jane JA Jr, Starke RM, Elzoghby MA, et al. Endoscopic transsphenoidal surgery for acromegaly: remission using modern criteria, complications, and predictors of outcome. J Clin Endocrinol Metab 2011; 96:2732–2740.
Cappabianca P, Cavallo LM, Colao A, de Divitiis E. Surgical complications associated with the endoscopic endonasal transsphenoidal approach for pituitary adenomas. J Neurosurg 2002; 97:293–298.
Nomikos P, Buchfelder M, Fahlbusch R. The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical “cure.” Eur J Endocrinol 2005; 152:379–387.
Howlett TA, Willis D, Walker G, Wass JA, Trainer PJ; UK Acromegaly Register Study Group (UKAR-3). Control of growth hormone and IGF1 in patients with acromegaly in the UK: responses to medical treatment with somatostatin analogues and dopamine agonists. Clin Endocrinol (Oxf) 2013; 79:689–699.
Katznelson L. Pegvisomant for the treatment of acromegaly-translation of clinical trials into clinical practice. Nat Clin Pract Endocrinol Metab 2007; 3:514–515.
Freda PU, Reyes CM, Nuruzzaman AT, Sundeen RE, Khandji AG, Post KD. Cabergoline therapy of growth hormone & growth hormone/prolactin secreting pituitary tumors. Pituitary 2004; 7:21–30.
Castinetti F, Morange I, Dufour H, Regis J, Brue T. Radiotherapy and radiosurgery in acromegaly. Pituitary 2009; 12:3–10.
Gheorghiu ML. Updates in outcomes of stereotactic radiation therapy in acromegaly. Pituitary 2017; 20:154–168.

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Igor Kravets, MD, FACE
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Address: Igor Kravets, MD, Division of Endocrinology, Stony Brook University School of Medicine, 101 Nicolls Road, HSC T-16, Stony Brook, NY 11794; igor.kravets@stonybrookmedicine.edu

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acromegaly, obstructive sleep apnea, wedding ring, pituitary, growth hormone, visual fields, GH, insulin-like growth factor 1, IGF-1, cortisol, prolactin, hormone, somatostatin receptor ligands, SRLs, pegvisomant, dopamine, carbergoline, octreotide, lanreotide, pasireotide, Igor Kravets

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Igor Kravets, MD, FACE

Author(s)

Igor Kravets, MD, FACE

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Igor Kravets, MD, FACE
Assistant Professor of Medicine, Division of Endocrinology, Stony Brook University School of Medicine, Stony Brook, NY

Address: Igor Kravets, MD, Division of Endocrinology, Stony Brook University School of Medicine, 101 Nicolls Road, HSC T-16, Stony Brook, NY 11794; igor.kravets@stonybrookmedicine.edu

Author and Disclosure Information

Igor Kravets, MD, FACE
Assistant Professor of Medicine, Division of Endocrinology, Stony Brook University School of Medicine, Stony Brook, NY

Address: Igor Kravets, MD, Division of Endocrinology, Stony Brook University School of Medicine, 101 Nicolls Road, HSC T-16, Stony Brook, NY 11794; igor.kravets@stonybrookmedicine.edu

Article PDF

kravets_acromegaly.pdf

Article PDF

kravets_acromegaly.pdf

His father died at age 78 of a myocardial infarction; his 86-year-old mother has hypertension. He has no siblings. His 28-year-old biological son is healthy.

Physical examination

His forehead is wide with deep creases, his jaw, nose, and lower lip are prominent, and his tongue, hands, and feet are large. He has mild thyromegaly with no palpable nodules.

LABORATORY TESTING

1. In addition to a complete blood cell count and comprehensive metabolic panel, which is the most appropriate test to order?

Growth hormone (GH) level
Insulin-like growth factor 1 (IGF-1) level
GH and IGF-1 levels
IGF-2 level

Acromegaly, an overview

The prevalence of acromegaly is 36 to 60 cases per million, and its annual incidence is 3 to 4 per million.⁵

With this patient’s presentation, the most appropriate next step is to order an IGF-1 level to screen for acromegaly.

GH secretion is pulsatile, IGF-1 secretion is not

IGF-2 has no role in acromegaly

CASE CONTINUED: FURTHER TESTING

The patient’s IGF-1 level is 590 ng/mL; the reference range for his age and sex is 68 to 245 ng/mL.

A sleep study confirms obstructive sleep apnea, and the patient is started on continuous positive airway pressure at night, with some reduction of his fatigue.

2. What is the most appropriate next step?

Order magnetic resonance imaging (MRI) of the pituitary with gadolinium contrast
Perform a GH suppression test with a 75-g oral glucose load
Perform a GH stimulation test
Refer the patient to a neurosurgeon for a consultation

A GH stimulation test with insulin-induced hypoglycemia or with GHRH-arginine would be appropriate if GH deficiency were suspected rather than hypersecretion.

Referral to a neurosurgeon for a consultation is premature until a biochemical diagnosis of acromegaly is made and a pituitary adenoma is subsequently demonstrated by imaging.

3. The patient’s GH level is 10 μg/L 2 hours after oral administration of 75 g of glucose. What is the most appropriate next step?

Radiography of the skull to image the pituitary at a low cost
MRI of the pituitary with contrast after making sure the patient’s renal function is normal
MRI of the pituitary without contrast
Computed tomography of the head

The next step is MRI of the pituitary with contrast (gadolinium) after obtaining blood urea nitrogen and creatinine measurements to make sure the patient’s renal function is normal.¹⁴

If MRI is contraindicated, computed tomography of the head should be performed.

CASE CONTINUED: IMAGING

4. In addition to repeating the fasting plasma glucose and measuring hemoglobin A_1c, what is the most appropriate next step in managing this patient?

Measure the prolactin, morning serum cortisol, total testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and free thyroxine (T4) levels; refer the patient to an ophthalmologist for a formal evaluation of visual fields
Measure these hormone levels; perform a gross evaluation of the visual fields and refer the patient to an ophthalmologist only if visual field deficits are found on the gross examination
Measure these hormone levels; refer the patient to an ophthalmologist only if he complains of vision changes
Do not order any additional tests; instruct the patient to call the office if he develops any vision changes

Abnormalities of hormones other than GH and IGF-1 in acromegaly

Secretion of pituitary hormones other than GH and IGF-1 must be assessed.

Visual field loss may be insidious

The diagnostic and treatment algorithm for acromegaly is summarized in Figure 1.

CASE CONTINUED: LABORATORY VALUES, TREATMENT OPTIONS

Our patient’s repeat fasting plasma glucose is 137 mg/dL; his hemoglobin A_1c is 7.3%, consistent with diabetes mellitus secondary to acromegaly. Other laboratory values:

Morning cortisol level 15 μg/dL (reference range 5.3–22.5),
Prolactin 23 ng/mL, confirmed with 1:100 dilution (4.0–15.2)
Total testosterone 59 ng/dL (193–824)
LH 2.1 mIU/mL (1.8–10.8)
FSH 3.0 mIU/mL (1.5–12.4)
TSH 2.5 mIU/L (0.5–4.5)
Free T4 1.3 ng/dL (0.9–1.7).

5. What treatment would you recommend for the patient’s acromegaly?

Medical treatment first, then transsphenoidal resection of the pituitary macroadenoma if medical treatment fails
Medical treatment first, radiotherapy if medical treatment fails, and transsphenoidal resection of the pituitary macroadenoma as a last resort
Transsphenoidal resection of the pituitary macroadenoma first, medical treatment if surgery fails, and radiotherapy if both surgery and medical treatment fail
Taking a safe, conservative approach, monitoring IGF-1 levels frequently; starting medical treatment if acromegaly does not go into remission in 1 year

The initial treatment of choice for most patients with acromegaly is resection of the pituitary tumor.

CASE CONTINUED: MEDICAL TREATMENT

Three months after transsphenoidal resection of his pituitary macroadenoma, our patient’s laboratory values are as follows:

IGF-1 400 ng/mL
Morning cortisol 20 μg/dL
Testosterone 95 ng/dL
LH 2.1 mU/mL
FSH 3.7 mU/mL
Prolactin 12 ng/mL
TSH 2.3 mIU/L
Free T4 1.2 ng/dL
Basic metabolic panel normal.

The patient denies frequent urination or increased thirst. Repeat MRI of the pituitary with contrast shows a residual 1.3-cm adenoma with no suprasellar extension.

6. What is the best next treatment choice for the patient?

A GH receptor antagonist (pegvisomant)
A somatostatin receptor ligand (SRL) such as octreotide
Cabergoline (a dopamine agonist)
A combination of an SRL and pegvisomant

An SRL such as octreotide would be the best choice for this patient.

SRLs are used as primary therapy in patients who cannot be cured by surgery, have extensive cavernous sinus invasion, have no chiasmal compression, or are poor surgical candidates.

Cabergoline, a dopamine agonist, should be tried as the initial adjuvant medical therapy in patients with only modest elevations of serum IGF-1 and mild signs and symptoms of acromegaly.¹⁴

Pegvisomant or cabergoline can be added to an SRL in patients who have an inadequate response to an SRL.¹⁴ Combination therapy would be premature in this patient.

The medical treatment of acromegaly is summarized in Table 2.^14,15 Side effects of the medications used to treat acromegaly are summarized in Table 3.¹⁴

CASE CONTINUED: RADIOTHERAPY

The patient asks if stereotactic radiotherapy, which he read about on the Internet, can cure his acromegaly so that he can avoid the monthly octreotide injections.

7. Which statement best describes radiotherapy’s therapeutic effect in acromegaly?

Stereotactic radiotherapy is more effective than medical therapy and should be used as a second-line treatment after surgery
Stereotactic radiotherapy is less effective than conventional radiotherapy
Stereotactic radiotherapy leads to stability or a decrease in the size of the GH-secreting tumor in 93% to 100% of patients in 5 to 10 years and to biochemical remission in 40% to 60% of patients at 5 years
Stereotactic radiotherapy causes hypopituitarism in no more than 1% of patients

His fatigue has diminished further and his sexual performance has improved. He is still married and his wife no longer suspects him of infidelity.

KEY POINTS

IGF-1 is the screening test of choice in a patient with signs and symptoms of acromegaly.
A growth hormone suppression test with a 75-g oral glucose load is the gold standard test for confirmation of the diagnosis of acromegaly in patients with an elevated IGF-1 level.
Transsphenoidal resection of the growth hormone-secreting pituitary macroadenoma is the initial treatment of choice for acromegaly.
Patients with residual or recurrent growth hormone-secreting pituitary macroadenoma can be treated with somatostatin receptor ligands, a growth hormone receptor antagonist (pegvisomant), and a dopamine agonist cabergoline.
Radiotherapy is reserved for postsurgical treatment of patients with recurrent or persistent tumors who are resistant to or intolerant of medical therapy. Stereotactic radiotherapy has largely replaced conventional radiotherapy.

His father died at age 78 of a myocardial infarction; his 86-year-old mother has hypertension. He has no siblings. His 28-year-old biological son is healthy.

Physical examination

His forehead is wide with deep creases, his jaw, nose, and lower lip are prominent, and his tongue, hands, and feet are large. He has mild thyromegaly with no palpable nodules.

LABORATORY TESTING

1. In addition to a complete blood cell count and comprehensive metabolic panel, which is the most appropriate test to order?

Growth hormone (GH) level
Insulin-like growth factor 1 (IGF-1) level
GH and IGF-1 levels
IGF-2 level

Acromegaly, an overview

The prevalence of acromegaly is 36 to 60 cases per million, and its annual incidence is 3 to 4 per million.⁵

With this patient’s presentation, the most appropriate next step is to order an IGF-1 level to screen for acromegaly.

GH secretion is pulsatile, IGF-1 secretion is not

IGF-2 has no role in acromegaly

CASE CONTINUED: FURTHER TESTING

The patient’s IGF-1 level is 590 ng/mL; the reference range for his age and sex is 68 to 245 ng/mL.

A sleep study confirms obstructive sleep apnea, and the patient is started on continuous positive airway pressure at night, with some reduction of his fatigue.

2. What is the most appropriate next step?

Order magnetic resonance imaging (MRI) of the pituitary with gadolinium contrast
Perform a GH suppression test with a 75-g oral glucose load
Perform a GH stimulation test
Refer the patient to a neurosurgeon for a consultation

A GH stimulation test with insulin-induced hypoglycemia or with GHRH-arginine would be appropriate if GH deficiency were suspected rather than hypersecretion.

Referral to a neurosurgeon for a consultation is premature until a biochemical diagnosis of acromegaly is made and a pituitary adenoma is subsequently demonstrated by imaging.

3. The patient’s GH level is 10 μg/L 2 hours after oral administration of 75 g of glucose. What is the most appropriate next step?

Radiography of the skull to image the pituitary at a low cost
MRI of the pituitary with contrast after making sure the patient’s renal function is normal
MRI of the pituitary without contrast
Computed tomography of the head

The next step is MRI of the pituitary with contrast (gadolinium) after obtaining blood urea nitrogen and creatinine measurements to make sure the patient’s renal function is normal.¹⁴

If MRI is contraindicated, computed tomography of the head should be performed.

CASE CONTINUED: IMAGING

4. In addition to repeating the fasting plasma glucose and measuring hemoglobin A_1c, what is the most appropriate next step in managing this patient?

Measure the prolactin, morning serum cortisol, total testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and free thyroxine (T4) levels; refer the patient to an ophthalmologist for a formal evaluation of visual fields
Measure these hormone levels; perform a gross evaluation of the visual fields and refer the patient to an ophthalmologist only if visual field deficits are found on the gross examination
Measure these hormone levels; refer the patient to an ophthalmologist only if he complains of vision changes
Do not order any additional tests; instruct the patient to call the office if he develops any vision changes

Abnormalities of hormones other than GH and IGF-1 in acromegaly

Secretion of pituitary hormones other than GH and IGF-1 must be assessed.

Visual field loss may be insidious

The diagnostic and treatment algorithm for acromegaly is summarized in Figure 1.

CASE CONTINUED: LABORATORY VALUES, TREATMENT OPTIONS

Our patient’s repeat fasting plasma glucose is 137 mg/dL; his hemoglobin A_1c is 7.3%, consistent with diabetes mellitus secondary to acromegaly. Other laboratory values:

Morning cortisol level 15 μg/dL (reference range 5.3–22.5),
Prolactin 23 ng/mL, confirmed with 1:100 dilution (4.0–15.2)
Total testosterone 59 ng/dL (193–824)
LH 2.1 mIU/mL (1.8–10.8)
FSH 3.0 mIU/mL (1.5–12.4)
TSH 2.5 mIU/L (0.5–4.5)
Free T4 1.3 ng/dL (0.9–1.7).

5. What treatment would you recommend for the patient’s acromegaly?

Medical treatment first, then transsphenoidal resection of the pituitary macroadenoma if medical treatment fails
Medical treatment first, radiotherapy if medical treatment fails, and transsphenoidal resection of the pituitary macroadenoma as a last resort
Transsphenoidal resection of the pituitary macroadenoma first, medical treatment if surgery fails, and radiotherapy if both surgery and medical treatment fail
Taking a safe, conservative approach, monitoring IGF-1 levels frequently; starting medical treatment if acromegaly does not go into remission in 1 year

The initial treatment of choice for most patients with acromegaly is resection of the pituitary tumor.

CASE CONTINUED: MEDICAL TREATMENT

Three months after transsphenoidal resection of his pituitary macroadenoma, our patient’s laboratory values are as follows:

IGF-1 400 ng/mL
Morning cortisol 20 μg/dL
Testosterone 95 ng/dL
LH 2.1 mU/mL
FSH 3.7 mU/mL
Prolactin 12 ng/mL
TSH 2.3 mIU/L
Free T4 1.2 ng/dL
Basic metabolic panel normal.

The patient denies frequent urination or increased thirst. Repeat MRI of the pituitary with contrast shows a residual 1.3-cm adenoma with no suprasellar extension.

6. What is the best next treatment choice for the patient?

A GH receptor antagonist (pegvisomant)
A somatostatin receptor ligand (SRL) such as octreotide
Cabergoline (a dopamine agonist)
A combination of an SRL and pegvisomant

An SRL such as octreotide would be the best choice for this patient.

SRLs are used as primary therapy in patients who cannot be cured by surgery, have extensive cavernous sinus invasion, have no chiasmal compression, or are poor surgical candidates.

Cabergoline, a dopamine agonist, should be tried as the initial adjuvant medical therapy in patients with only modest elevations of serum IGF-1 and mild signs and symptoms of acromegaly.¹⁴

Pegvisomant or cabergoline can be added to an SRL in patients who have an inadequate response to an SRL.¹⁴ Combination therapy would be premature in this patient.

The medical treatment of acromegaly is summarized in Table 2.^14,15 Side effects of the medications used to treat acromegaly are summarized in Table 3.¹⁴

CASE CONTINUED: RADIOTHERAPY

The patient asks if stereotactic radiotherapy, which he read about on the Internet, can cure his acromegaly so that he can avoid the monthly octreotide injections.

7. Which statement best describes radiotherapy’s therapeutic effect in acromegaly?

Stereotactic radiotherapy is more effective than medical therapy and should be used as a second-line treatment after surgery
Stereotactic radiotherapy is less effective than conventional radiotherapy
Stereotactic radiotherapy leads to stability or a decrease in the size of the GH-secreting tumor in 93% to 100% of patients in 5 to 10 years and to biochemical remission in 40% to 60% of patients at 5 years
Stereotactic radiotherapy causes hypopituitarism in no more than 1% of patients

His fatigue has diminished further and his sexual performance has improved. He is still married and his wife no longer suspects him of infidelity.

KEY POINTS

IGF-1 is the screening test of choice in a patient with signs and symptoms of acromegaly.
A growth hormone suppression test with a 75-g oral glucose load is the gold standard test for confirmation of the diagnosis of acromegaly in patients with an elevated IGF-1 level.
Transsphenoidal resection of the growth hormone-secreting pituitary macroadenoma is the initial treatment of choice for acromegaly.
Patients with residual or recurrent growth hormone-secreting pituitary macroadenoma can be treated with somatostatin receptor ligands, a growth hormone receptor antagonist (pegvisomant), and a dopamine agonist cabergoline.
Radiotherapy is reserved for postsurgical treatment of patients with recurrent or persistent tumors who are resistant to or intolerant of medical therapy. Stereotactic radiotherapy has largely replaced conventional radiotherapy.

References

Melmed S. Acromegaly pathogenesis and treatment. J Clin Invest 2009; 119:3189–3202.
Molitch ME. Clinical manifestations of acromegaly. Endocrinol Metab Clin North Am 1992; 21:597–614.
Dineen R, Stewart PM, Sherlock M. Acromegaly. QJM 2017; 110:411–420.
Yacub A, Yaqub N. Insulin-mediated pseudoacromegaly: a case report and review of the literature. W V Med J 2008; 104:12–15.
Mestron A, Webb SM, Astorga R, et al. Epidemiology, clinical characteristics, outcome, morbidity and mortality in acromegaly based on the Spanish Acromegaly Registry (Registro Espanol de Acromegalia, REA). Eur J Endocrinol 2004; 151:439–446.
Zhu X, Lin CR, Prefontaine CG, Tollkuhn J, Rosenfeld MG. Genetic control of pituitary development and hypopituitarism. Curr Opin Genet Dev 2005; 15:332–340.
Tannenbaum GS, Epelbaum J, Bowers CY. Interrelationship between the novel peptide ghrelin and somatostatin/growth hormone-releasing hormone in regulation of pulsatile growth hormone secretion. Endocrinology 2003; 144:967–974.
Lanning NJ, Carter-Su C. Recent advances in growth hormone signaling. Rev Endocr Metab Disord 2006; 7:225–235.
Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev 2004; 25:102–152.
Larkin S, Reddy R, Karavitaki N, Cudlip S, Wass J, Ansorge O. Granulation pattern, but not GSP or GHR mutation, is associated with clinical characteristics in somatostatin-naive patients with somatotroph adenomas. Eur J Endocrinol 2013; 168:491–499.
Dineen R, Stewart PM, Sherlock M. Acromegaly. QJM 2017; 110:411–420.
Peacey SR, Toogood AA, Veldhuis JD, Thorner MO, Shalet SM. The relationship between 24-hour growth hormone secretion and insulin-like growth factor I in patients with successfully treated acromegaly: impact of surgery or radiotherapy. J Clin Endocrinol Metab 2001; 86:259–266.
Livingstone C. IGF2 and cancer. Endocr Relat Cancer 2013; 20:R321–R339.
Katznelson L, Laws ER Jr, Melmed S, et al. Acromegaly: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2014; 99:3933–3951.
Melmed S. Acromegaly. N Engl J Med 2006; 355:2558–2573.
Melmed S, Casanueva FF, Klibanski A, et al. A consensus on the diagnosis and treatment of acromegaly complications. Pituitary 2013; 16:294–302.
Marquez Y, Tuchman A, Zada G. Surgery and radiosurgery for acromegaly: a review of indications, operative techniques, outcomes, and complications. Int J Endocrinol 2012; 2012: 386401.
Jane JA Jr, Starke RM, Elzoghby MA, et al. Endoscopic transsphenoidal surgery for acromegaly: remission using modern criteria, complications, and predictors of outcome. J Clin Endocrinol Metab 2011; 96:2732–2740.
Cappabianca P, Cavallo LM, Colao A, de Divitiis E. Surgical complications associated with the endoscopic endonasal transsphenoidal approach for pituitary adenomas. J Neurosurg 2002; 97:293–298.
Nomikos P, Buchfelder M, Fahlbusch R. The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical “cure.” Eur J Endocrinol 2005; 152:379–387.
Howlett TA, Willis D, Walker G, Wass JA, Trainer PJ; UK Acromegaly Register Study Group (UKAR-3). Control of growth hormone and IGF1 in patients with acromegaly in the UK: responses to medical treatment with somatostatin analogues and dopamine agonists. Clin Endocrinol (Oxf) 2013; 79:689–699.
Katznelson L. Pegvisomant for the treatment of acromegaly-translation of clinical trials into clinical practice. Nat Clin Pract Endocrinol Metab 2007; 3:514–515.
Freda PU, Reyes CM, Nuruzzaman AT, Sundeen RE, Khandji AG, Post KD. Cabergoline therapy of growth hormone & growth hormone/prolactin secreting pituitary tumors. Pituitary 2004; 7:21–30.
Castinetti F, Morange I, Dufour H, Regis J, Brue T. Radiotherapy and radiosurgery in acromegaly. Pituitary 2009; 12:3–10.
Gheorghiu ML. Updates in outcomes of stereotactic radiation therapy in acromegaly. Pituitary 2017; 20:154–168.

References

Melmed S. Acromegaly pathogenesis and treatment. J Clin Invest 2009; 119:3189–3202.
Molitch ME. Clinical manifestations of acromegaly. Endocrinol Metab Clin North Am 1992; 21:597–614.
Dineen R, Stewart PM, Sherlock M. Acromegaly. QJM 2017; 110:411–420.
Yacub A, Yaqub N. Insulin-mediated pseudoacromegaly: a case report and review of the literature. W V Med J 2008; 104:12–15.
Mestron A, Webb SM, Astorga R, et al. Epidemiology, clinical characteristics, outcome, morbidity and mortality in acromegaly based on the Spanish Acromegaly Registry (Registro Espanol de Acromegalia, REA). Eur J Endocrinol 2004; 151:439–446.
Zhu X, Lin CR, Prefontaine CG, Tollkuhn J, Rosenfeld MG. Genetic control of pituitary development and hypopituitarism. Curr Opin Genet Dev 2005; 15:332–340.
Tannenbaum GS, Epelbaum J, Bowers CY. Interrelationship between the novel peptide ghrelin and somatostatin/growth hormone-releasing hormone in regulation of pulsatile growth hormone secretion. Endocrinology 2003; 144:967–974.
Lanning NJ, Carter-Su C. Recent advances in growth hormone signaling. Rev Endocr Metab Disord 2006; 7:225–235.
Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev 2004; 25:102–152.
Larkin S, Reddy R, Karavitaki N, Cudlip S, Wass J, Ansorge O. Granulation pattern, but not GSP or GHR mutation, is associated with clinical characteristics in somatostatin-naive patients with somatotroph adenomas. Eur J Endocrinol 2013; 168:491–499.
Dineen R, Stewart PM, Sherlock M. Acromegaly. QJM 2017; 110:411–420.
Peacey SR, Toogood AA, Veldhuis JD, Thorner MO, Shalet SM. The relationship between 24-hour growth hormone secretion and insulin-like growth factor I in patients with successfully treated acromegaly: impact of surgery or radiotherapy. J Clin Endocrinol Metab 2001; 86:259–266.
Livingstone C. IGF2 and cancer. Endocr Relat Cancer 2013; 20:R321–R339.
Katznelson L, Laws ER Jr, Melmed S, et al. Acromegaly: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2014; 99:3933–3951.
Melmed S. Acromegaly. N Engl J Med 2006; 355:2558–2573.
Melmed S, Casanueva FF, Klibanski A, et al. A consensus on the diagnosis and treatment of acromegaly complications. Pituitary 2013; 16:294–302.
Marquez Y, Tuchman A, Zada G. Surgery and radiosurgery for acromegaly: a review of indications, operative techniques, outcomes, and complications. Int J Endocrinol 2012; 2012: 386401.
Jane JA Jr, Starke RM, Elzoghby MA, et al. Endoscopic transsphenoidal surgery for acromegaly: remission using modern criteria, complications, and predictors of outcome. J Clin Endocrinol Metab 2011; 96:2732–2740.
Cappabianca P, Cavallo LM, Colao A, de Divitiis E. Surgical complications associated with the endoscopic endonasal transsphenoidal approach for pituitary adenomas. J Neurosurg 2002; 97:293–298.
Nomikos P, Buchfelder M, Fahlbusch R. The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical “cure.” Eur J Endocrinol 2005; 152:379–387.
Howlett TA, Willis D, Walker G, Wass JA, Trainer PJ; UK Acromegaly Register Study Group (UKAR-3). Control of growth hormone and IGF1 in patients with acromegaly in the UK: responses to medical treatment with somatostatin analogues and dopamine agonists. Clin Endocrinol (Oxf) 2013; 79:689–699.
Katznelson L. Pegvisomant for the treatment of acromegaly-translation of clinical trials into clinical practice. Nat Clin Pract Endocrinol Metab 2007; 3:514–515.
Freda PU, Reyes CM, Nuruzzaman AT, Sundeen RE, Khandji AG, Post KD. Cabergoline therapy of growth hormone & growth hormone/prolactin secreting pituitary tumors. Pituitary 2004; 7:21–30.
Castinetti F, Morange I, Dufour H, Regis J, Brue T. Radiotherapy and radiosurgery in acromegaly. Pituitary 2009; 12:3–10.
Gheorghiu ML. Updates in outcomes of stereotactic radiation therapy in acromegaly. Pituitary 2017; 20:154–168.

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Fever after recent travel

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Fever after recent travel

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Habib Rehman, MBBS, FRCPC, FRCPI, FRCP (Glas), FACP

A 28-year-old man developed fever, night sweats, nausea, headache, reduced appetite, skin rash, and hemoptysis 2 weeks after returning to the United States from Mexico.

The patient had fistulizing Crohn disease and had been taking the tumor necrosis factor alpha (TNF-alpha) blocker adalimumab for the past 3 months. He had no risk factors for human immunodeficiency virus infection, and he had stopped smoking 1 year previously. Chest radiography and a tuberculin skin test before he started adalimumab therapy were negative. While in Mexico, he did not drink more than 1 alcoholic beverage a day.

He had presented recently to his local hospital with the same symptoms and had been prescribed ciprofloxacin, metronidazole, ceftriaxone, vancomycin, and ampicillin, which he was still taking but with no improvement of symptoms. Blood cultures drawn before the start of antibiotic therapy had been negative. Urinalysis, a screen for infectious mononucleosis, and lumbar puncture were also negative. Results of renal function testing were normal except for the anion gap, which was 20.8 mmol/L (reference range 10–20).

INITIAL EVALUATION

On presentation to this hospital, the patient was afebrile but continued to have temperature spikes up to 39.0°C (102.2°F). His heart rate was 90 per minute, blood pressure 104/61 mm Hg, respiratory rate 18 per minute, and oxygen saturation 95% on 2 L of oxygen via nasal cannula.

Figure 1. At presentation, the patient had a sparse, erythematous, macular, nonblanching rash on the lower and upper limbs.

Respiratory examination revealed decreased air entry bilaterally, with fine bibasilar crepitations. The abdomen was tender without guarding or rigidity, and splenomegaly was noted. A sparse erythematous macular nonblanching rash was noted on the lower and upper limbs (Figure 1). The rest of the physical examination was unremarkable.

Table 1 shows the results of initial laboratory testing at our facility, as well as those from a recent presentation at his local hospital. Results of a complete blood cell count were:

White blood cell count 10.0 × 10⁹/L (reference range 4.0–10.0 × 10⁹/L)
Lymphocyte count 6.1 × 10⁹/L (1.2–3.4)
Hemoglobin level 13.6 g/dL (14.0–18.0)
Platelet count 87 × 10^9/L (150–400), reaching a nadir of 62 on hospital day 23
Albumin 47 g/L (35–50)
Total bilirubin 48 µmol/L (2–20)
Alkaline phosphatase 137 U/L (40–135)
Alanine aminotransferase 22 U/L (9–69)
Aspartate aminotransferase 72 U/L (5–45).

He continued to have temperature spikes. His alkaline phosphatase level plateaued at 1,015 U/L on day 30, while his alanine aminotransferase and aspartate aminotransferase levels remained stable.

The patient’s ceftriaxone was continued, and the other antibiotics were replaced with doxycycline. Fluconazole was added when sputum culture grew Candida albicans. However, these drugs were later discontinued in view of worsening results on liver enzyme testing.

The evaluation continues

Sputum cultures were negative for acid-fast bacilli on 3 occasions.

Serologic testing was negative for:

Hepatitis B surface antigen (but hepatitis B surface antibody was positive at > 1,000 IU/L)

Hepatitis C virus antibody
Cytomegalovirus immunoglobulin (Ig) G
Toxoplasma gondii IgG
Epstein-Barr virus viral capsid antigen IgM
Rickettsia antibodies
Antinuclear antibody
Antineutrophil cytoplasmic antibody
Antiglomerular basement membrane antibody.

Chest radiography showed blunting of both costophrenic angles and mild prominence of right perihilar interstitial markings and the right hilum.

Computed tomography of the chest, abdomen, and pelvis showed a subpleural density in the lower lobe of the right lung, small bilateral pleural effusions, right hilar lymphadenopathy, and splenomegaly with no specific hepatobiliary abnormality.

A white blood cell nuclear scan found no occult infection.

Abdominal ultrasonography showed a prominent liver and spleen. The liver parenchyma showed diffuse decreased echogenicity, suggestive of hepatitis.

Transesophageal echocardiography showed no vegetations or valvular abnormalities.

Bronchoscopy showed normal airways without evidence of pulmonary hemorrhage. No foci of infection were obtained. A focus of granuloma consisting of epithelioid histiocytes in tight clusters was seen on washings from the right lower lobe, but no malignant cells were seen.

Sections of pathologically enlarged right hilar and subcarinal lymph nodes obtained with transbronchial needle aspiration were sent for cytologic analysis and flow cytometry.

Cultures for tuberculous and fungal organisms were negative.

Figure 2. Repeat chest radiography showed a new right basilar consolidation with a small effusion (arrow).

Repeat chest radiography showed a new right basilar consolidation with a small effusion (Figure 2).

A clue. On further inquiry, the patient said he had gone swimming in the natural pool, or cenote, under a rock formation at Cenote Maya Park in Mexico.

DIFFERENTIAL DIAGNOSIS

1. Which of the following is not in the differential diagnosis?

Disseminated tuberculosis
Coccidioidomycosis
Subacute infective endocarditis
Disseminated histoplasmosis
Blastomycosis

Although the patient has a systemic disease, subacute infective endocarditis is not likely because of a lack of predisposing factors such as a history of endocarditis, abnormal or artificial heart valve, or intravenous drug abuse. Moreover, negative blood cultures and the absence of vegetations on echocardiography make endocarditis very unlikely.

Given that the patient is immunosuppressed, opportunistic infection must be at the top of the differential diagnosis. Histoplasmosis, coccidioidomycosis, and blastomycosis are endemic in Mexico. Disseminated histoplasmosis is the most likely diagnosis; coccidioidomycosis and blastomycosis are less likely, based on the history, signs, and symptoms. Disseminated tuberculosis must be excluded before other diagnostic possibilities are considered.

TUBERCULOSIS IN PATIENTS ON TNF-ALPHA ANTAGONISTS

Tuberculosis has been reported in patients taking TNF-alpha antagonists.¹ The frequency of tuberculosis is much higher than that of other opportunistic infections, and over 50% of reported cases involve extrapulmonary tissues in patients treated with TNF-alpha antagonists.²

British Thoracic Society guidelines recommend screening for latent tuberculosis before starting treatment with a TNF-alpha antagonist; the screening should include a history of tuberculosis treatment, a clinical examination, chest radiography, and a tuberculin skin test.³ Patients found to have active tuberculosis should receive a minimum of 2 months of standard treatment before starting a TNF-alpha antagonist. Patients with evidence of past tuberculosis or a history of tuberculosis who received adequate treatment should be monitored regularly. Patients with prior tuberculosis not adequately treated should receive chemoprophylaxis before starting a TNF-alpha antagonist.

Fever, night sweats, and intrathoracic and intra-abdominal lymphadenopathy are common features of disseminated tuberculosis. Upper-lobe cavitary disease or miliary lesions may be seen on chest radiography, but atypical presentations with lower-lobe infiltrate are not uncommon in immunosuppressed patients.⁴

A negative tuberculin skin test and a normal chest radiograph 3 months ago, along with negative sputum and bronchial lavage fluid cultures and no history of tuberculosis contact, make tuberculosis unlikely in our patient.

COCCIDIOIDOMYCOSIS

Coccidioidomycosis (valley fever) is caused by the fungus Coccidioides immitis, which lives in the soil and is acquired by inhalation of airborne microscopic spores.

Fatigue, cough, fever, shortness of breath, headache, night sweats, muscle or joint pain, and a rash on the upper body or legs are common symptoms. It may cause a self-limiting flulike illness. From 5% to 10% of patients may develop serious long-term lung problems. In a small number of patients, the disease may progress beyond the lungs to involve the central nervous system, spinal cord, skin, bones, and joints.⁵

Serologic testing is highly useful for the diagnosis. Antigen testing has a sensitivity of 71% and a specificity of 98% for the diagnosis, but cross-reactivity occurs in 10% of patients with other types of mycosis. Respiratory secretions and tissue samples should undergo microscopic study and culture.

BLASTOMYCOSIS

Blastomycosis is caused by the fungus Blastomyces dermatitidis, which lives in soil and in association with decomposing organic matter such as wood and leaves. Inhalation of spores may cause a flulike illness or pneumonia. In serious cases, the disease can spread to skin and bone.

The diagnosis is established with fungal cultures of tissue samples or body fluids (bone marrow, liver tissue, skin, sputum, blood). Rapid diagnosis may be obtained by examination of the secretions under a microscope, where typical broad-based budding yeast can be seen in almost 90% of cases.⁶ Antigen may also be detected in urine and serum⁷; the sensitivity of antigen testing is 93% and the specificity is 98%. Serologic testing is not recommended for diagnosis of blastomycosis because of poor sensitivity and specificity.⁸

NARROWING THE DIFFERENTIAL

Both coccidioidomycosis and blastomycosis should be included in the differential diagnosis of a systemic disease with subacute onset and prominent lung involvement in a patient returning from travel to Mexico. The lack of involvement of the central nervous system, spinal cord, bones, or joints makes these infections less likely in our patient.

However, swimming in a cenote under a rock formation is an important clue to the diagnosis in our patient, as it puts him at risk of inhaling microconidia or hyphal elements of histoplasmosis. This, along with his immunocompromised status, fever, hemoptysis, night sweats, skin and lung features, and the generally subacute course of his illness, make disseminated histoplasmosis the most likely diagnosis.

Radiologic findings of pulmonary infiltrate with effusion and elevated lactate dehydrogenase, aminotransferases, and alkaline phosphatase increase the likelihood of disseminated histoplasmosis.

HISTOPLASMOSIS

Histoplasma capsulatum is a dimorphic fungus that thrives in the soil and caves of regions with moderate climate, especially in soil containing large amounts of bird excreta or bat guano.⁹ Bats are natural hosts of this organism, and it is endemic in North and Central America, including parts of Mexico. Air currents can carry the microconidia for miles, thus exposing people without direct contact with contaminated sites.

The infection is usually acquired by inhalation of microconidia or small hyphal elements or by reactivation of previously quiescent foci of infection in an immunosuppressed patient. Most patients exposed to H capsulatum remain asymptomatic or develop mild symptoms, which are self-limiting. A small number develop acute pulmonary histoplasmosis or chronic cavitary histoplasmosis. Disseminated disease usually occurs only in an immunosuppressed host.

Acute pulmonary histoplasmosis presents with fever, malaise, headache, weakness, substernal chest pain, and dry cough and may be associated with erythema nodosum, erythema multiforme, and arthralgias. It may be mistaken for sarcoidosis since enlarged hilar and mediastinal lymph nodes are often seen on chest radiography.¹⁰

Progressive disseminated histoplasmosis is defined as a clinical illness that does not improve after at least 3 weeks of observation and is associated with physical or radiographic findings with or without laboratory evidence of extrapulmonary involvement.¹¹

Fever, malaise, anorexia, weight loss, night sweats, hepatosplenomegaly, and lymphadenopathy are features of progressive disseminated histoplasmosis.

Cutaneous manifestations of disseminated histoplasmosis occur in 10% to 25% of patients with acquired immunodeficiency syndrome and include papules, plaques with or without crust, pustules, nodules, lesions resembling molluscum contagiosum virus infection, acneiform eruptions, erythematous macules, and keratotic plaques.¹²

TESTING FOR HISTOPLASMOSIS

2. What investigation is least likely to help confirm the diagnosis of disseminated histoplasmosis?

Polymerase chain reaction (PCR) testing of serum, cerebrospinal fluid, and bronchoalveolar lavage specimens
Urinary Histoplasma antigen testing
Serologic testing
Blood and bronchoalveolar lavage cultures

PCR is least likely to confirm the diagnosis of disseminated histoplasmosis. In one report,¹³ although PCR results were positive in 80% of urine specimens containing high levels of Histoplasma antigen, results were negative for serum and cerebrospinal fluid samples containing high concentrations of Histoplasma antigen and positive in only 22% of bronchoalveolar lavage specimens.¹³ The yield of diagnostic tests in endemic mycosis is given in Table 2.^14–17

Urinary Histoplasma antigen has a sensitivity of 90% for the diagnosis of disseminated histoplasmosis in patients with acquired immunodeficiency syndrome.¹⁸ It is less useful for pulmonary forms of histoplasmosis: the sensitivity is 75% and may even be less in milder or chronic forms of pneumonia.¹⁹ False-positive reactions may occur in patients with other fungal infections such as coccidioidomycosis, blastomycosis, paracoccidioidomycosis and penicilliosis.²⁰ Urine antigen levels can also be used to monitor therapy, since levels decrease during therapy and increase in 90% of those who have a relapse.²¹

Our patient’s urinary Histoplasma antigen level was greater than 23.0 ng/mL (positive is > 0.50).

Serologic testing. Immunodiffusion immunoglobulin G (IgG) testing for Histoplasma and Blastomyces was negative, as was an enzyme immunoassay for Coccidioides IgG and IgM. However, antibody tests are less useful in immunosuppressed patients,²² and thus a negative result does not rule out histoplasmosis. A fourfold rise in complement fixation antibody titer is diagnostic of acute histoplasmosis. A single complement fixation titer of 1:32 is suggestive but not diagnostic of histoplasmosis. Cross-reactions may occur with other fungal infections like blastomycosis. The immunodiffusion assay has a greater specificity but slightly less sensitivity than the complement fixation assay.¹⁹

Culture of H capsulatum is the definitive test to establish a diagnosis of histoplasmosis. Culture can be performed on samples taken from blood, bone marrow, sputum, and bronchoalveolar lavage fluid, or from lung, liver, or lymph node tissue. Cultures are positive in 74% to 82% of cases of progressive disseminated histoplasmosis.¹³ However, treatment should not await culture results since the fungus may take several weeks to grow.

Back to our patient

Although Histoplasma serologic studies and cultures were negative, the diagnosis of disseminated histoplasmosis was made on the basis of the patient’s immunosuppressed status, travel history, clinical features, and positivity for urine Histoplasma antigen. Though urine histoplama antigen may be falsely positive in other fungal infections such as coccidioidomycosis, paracoccidioidomycosis, and blastomycosis, clinical features and the absence of central nervous system, joint, and bone involvement suggested disseminated histoplasmosis.

TREATMENT

3. What is the appropriate treatment for this patient?

Amphotericin B followed by oral itraconozole
Oral fluconazole
Oral itraconazole

Liposomal amphotericin B or amphotericin B deoxycholate is recommended as initial therapy for moderately severe to severe and progressive disseminated histoplasmosis. It should be continued for 1 to 2 weeks, followed by oral itraconazole (200 mg 3 times daily for 3 days, then 200 mg 2 times daily for at least 12 months).

Monitoring itraconazole therapy through random serum levels is strongly recommended, and a random concentration of at least 1.0 mg/mL is recommended.²³

Urine antigen levels should be measured before treatment is started, at 2 weeks, at 1 month, then every 3 months during therapy, continuing for 12 months after treatment is stopped.¹¹

Lifelong suppressive therapy with itraconazole 200 mg daily may be required in immunosuppressed patients and patients who have a relapse despite appropriate therapy.¹¹

While oral itraconazole is used as a sole agent for the treatment of mild to moderate acute pulmonary histoplasmosis and chronic cavitary pulmonary histoplasmosis, oral treatment alone with either fluconazole or itraconazole is not recommended for the treatment of progressive disseminated histoplasmosis.¹¹

COMPLICATIONS OF HISTOPLASMOSIS

4. Which of the following is not a possible complication of histoplasmosis?

Chronic cavitary pulmonary histoplasmosis
Fibrosing mediastinitis
Hypoadrenalism
Hypothyroidism

Chronic cavitary pulmonary histoplasmosis usually develops in patients with underlying emphysema. Fatigue, night sweats, fever, anorexia, and weight loss are features of chronic cavitary pulmonary histoplasmosis. Progression of necrosis may lead to “marching cavity,” in which necrosis increases the size of the cavity and may consume an entire lobe.¹⁰

Fibrosing mediastinitis is an uncommon but often lethal complication of disseminated histoplasmosis. Increasing dyspnea, cough, hemoptysis, and signs of superior vena cava syndrome and right heart failure may develop. However, fibrosing mediastinitis is thought to be due to an exuberant immune response to past Histoplasma infection and would not be expected in an immunocompromised patient.¹⁷

Hypoadrenalism. Extensive destruction of the adrenal glands may lead to hypoadrenalism, manifesting as orthostatic hypotension, hyperkalemia, hyponatremia, and evidence of markedly enlarged adrenal glands with central necrosis on computed tomography.²⁴

Hypothyroidism. Acute or disseminated histoplasmosis has not been reported to cause thyroid dysfunction.

CASE CONCLUSION

Our patient was treated with itraconazole 200 mg twice daily for 24 months. Although the literature supports lifelong itraconazole therapy in immunosuppressed patients, our patient was reluctant to do so. He agreed to close monitoring. If symptoms recur, itraconazole will be reinstituted and continued lifelong.

References

Vergidis P, Avery RK, Wheat LJ, et al. Histoplasmosis complicating tumor necrosis factor-a blocker therapy: a retrospective analysis of 98 cases. Clin Infect Dis 2015; 61:409–417.
Gardam MA, Keystone EC, Menzies R, et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanism of action and clinical management. Lancet Infect Dis 2003; 3:148–155.
British Thoracic Society Standards of Care Committee. BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNF-alpha treatment. Thorax 2005; 60:800–805.
Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 38-1998. A 19-year-old man with the acquired immunodeficiency syndrome and persistent fever. N Engl J Med 1998; 339:1835–1843.
Galgiani JN, Ampel NM, Blair JE, et al; Infectious Diseases Society of America. Coccidioidomycosis. Clin Infect Dis 2005; 41:1217–1223.
Lemos LB, Guo M, Baliga M. Blastomycosis: organ involvement and etiologic diagnosis. A review of 123 patients from Mississippi. Ann Diagn Pathol 2000; 4:391–406.
Durkin M, Witt J, Lemonte A, Wheat B, Connolly P. Antigen assay with the potential to aid in diagnosis of blastomycosis. J Clin Micribiol 2004; 42:4873–4875.
Wheat LJ. Approach to the diagnosis of the endemic mycoses. Clin Chest Med 2009; 30:379–389.
Colombo AL, Tobón A, Restrepo A, Queiroz-Telles F, Nucci M. Epidemiology of endemic systemic fungal infections in Latin America. Med Mycol 2011; 49:785–798.
Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev 2007; 20:115–132.
Wheat LJ, Freifeld AG, Kleiman MB, et al; Infectious Diseases Society of America. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007; 45:807–825.
Chang P, Rodas C. Skin lesions in histoplasmosis. Clinics Dermatol 2012; 30:592–598.
Wheat LJ. Improvements in diagnosis of histoplasmosis. Expert Opin Biol Ther 2006; 6:1207–1221.
Connolly P, Hage CA, Bariola JR, et al. Blastomyces dermatitidis antigen detection by quantitative enzyme immunoassay. Clin Vaccine Immunol 2012; 19:53–56.
Castillo CG, Kauffman CA, Miceli MH. Blastomycosis. Infect Dis Clin North Am 2016; 30:247–264.
Stockamp NW, Thompson GR 3rd. Coccidioidomycosis. Infect Dis Clin North Am 2016; 30:229–246.
Wheat LJ, Azar MM, Bahr NC, Spec A, Relich RF, Hage C. Histoplasmosis. Infect Dis Clin North Am 2016; 30:207–227.
Wheat LJ, Garringer T, Drizendine E, Connolly P. Diagnosis of histoplasmosis by antigen detection based upon experience at the histoplasmosis reference laboratory. Diagn Microbiol Infect Dis 2002; 14:1389–1391.
Kauffman CA. Diagnosis of histoplasmosis in immunosuppressed patients. Curr Opin Infect Dis 2008; 21:421–425.
Wheat LJ. Improvements in diagnosis of histoplasmosis. Expert Opin Biol Ther 2006; 6:1207–1221.
Wheat LJ, Connolly P, Haddad N, Le Monte A, Brizendine E, Hafner R. Antigen clearance during treatment of disseminated histoplasmosis with itraconazole versus fluconazole in patients with AIDS. Antimicrob Agents Chemother 2002; 46:248–250.
Wheat LJ. Current diagnosis of histoplasmosis. Trends Microbiol 2003; 11:488–494.
Poirier JM, Cheymol G. Optimisation of itraconazole therapy using target drug concentrations. Clin Pharmacokinet 1998; 35:461–473.
Sarosi GA, Voth DW, Dahl BA, Doto IL, Tosh FE. Disseminated histoplasmosis: results of long-term follow-up. Ann Intern Med 1971; 75:511–516.

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Address: Habib Rehman, MBBS, Department of Medicine, Regina Qu’Appelle Health Region, Regina General Hospital, 1440 – 14th Avenue, Regina, SK, S4P 0W5, Canada; habib31@sasktel.net

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A 28-year-old man developed fever, night sweats, nausea, headache, reduced appetite, skin rash, and hemoptysis 2 weeks after returning to the United States from Mexico.

INITIAL EVALUATION

Table 1 shows the results of initial laboratory testing at our facility, as well as those from a recent presentation at his local hospital. Results of a complete blood cell count were:

White blood cell count 10.0 × 10⁹/L (reference range 4.0–10.0 × 10⁹/L)
Lymphocyte count 6.1 × 10⁹/L (1.2–3.4)
Hemoglobin level 13.6 g/dL (14.0–18.0)
Platelet count 87 × 10^9/L (150–400), reaching a nadir of 62 on hospital day 23
Albumin 47 g/L (35–50)
Total bilirubin 48 µmol/L (2–20)
Alkaline phosphatase 137 U/L (40–135)
Alanine aminotransferase 22 U/L (9–69)
Aspartate aminotransferase 72 U/L (5–45).

He continued to have temperature spikes. His alkaline phosphatase level plateaued at 1,015 U/L on day 30, while his alanine aminotransferase and aspartate aminotransferase levels remained stable.

The evaluation continues

Sputum cultures were negative for acid-fast bacilli on 3 occasions.

Serologic testing was negative for:

Hepatitis B surface antigen (but hepatitis B surface antibody was positive at > 1,000 IU/L)

Hepatitis C virus antibody
Cytomegalovirus immunoglobulin (Ig) G
Toxoplasma gondii IgG
Epstein-Barr virus viral capsid antigen IgM
Rickettsia antibodies
Antinuclear antibody
Antineutrophil cytoplasmic antibody
Antiglomerular basement membrane antibody.