Severe Hypertriglyceridemia: A Review

The patient with a markedly high serum triglyceride (TG) level poses an interesting challenge for hospitalists. Hypertriglyceridemia (HTG) is defined as a fasting plasma TG level that is above the 95^th percentile for age and sex.1 TG levels are commonly classified into categories according to Adult Treatment Panel III guidelines with desirable levels <150 mg/dL (1.7 mmol/L), borderline levels 150199, high levels 200499 mg/dL, and very high levels >500 mg/dL (5.6 mmol/L).2 A TG level exceeding an arbitrary threshold of >1000 mg/dL (11.3 mmol/L) is referred to as severe HTG. The Lipid Research Clinics Program Prevalence Study found that 1.79 per 10,000 outpatients (<0.02%) had TG levels > 2000 mg/dL.3 Chylomicronemia syndrome occurs when severe HTG is accompanied by 1 or more of the following: symptoms of abdominal pain or acute pancreatitis or physical examination findings such as eruptive xanthomas or lipemia retinalis. There is no TG level above which pancreatitis invariably occurs, making the decision to hospitalize difficult. The goal of this review is to discuss the causes of severe HTG; the clinical assessment, including criteria for hospitalization; and the available treatment options for this infrequent but serious condition. We begin with a clinical case of severe HTG.

CASE PRESENTATION

A 47‐year‐old woman with a history of chronic myelogenous leukemia was admitted to the hospital with a serum triglyceride level of 17,393 mg/dL. Two years prior to admission, she underwent allogenic stem cell transplantation for chronic myelogenous leukemia and has since remained in remission. Six months prior to admission, severe diarrhea from intestinal graft‐versus‐host disease required the use of total parenteral nutrition (TPN) and immunosuppressive therapy consisting of prednisone 20 mg/day, mycophenolate mofetil 250 mg thrice daily, and sirolimus 0.3 mg/day. During treatment with steroids, she developed diabetes mellitus requiring insulin, with a subsequent hemoglobin A1c level of 7.7% (normal, <7%). The serum TG level prior to transplantation was unknown but was 343 mg/dL prior to TPN initiation. One month prior to admission, the diarrhea resolved and TPN was stopped. The TG level was 7463 mg/dL 1 week prior to admission, and despite use of fenofibrate, it rose to 17,393 mg/dL. The patient denied abdominal pain, and did not have abdominal tenderness or eruptive xanthomas. She denied a family history of dyslipidemia or recent medication changes. Given the extreme TG elevation, the lack of response to outpatient treatment and the concern for developing acute pancreatitis, the patient was admitted to the hospital for inpatient TG‐lowering treatment.

Upon admission, serum lipase and amylase were within normal limits, but the blood glucose level was 243 mg/dL. Insulin infusion and oral fenofibrate 145 mg/day was started, and the patient was kept non per os (NPO). Six hours later, despite insulin infusion, the TG level rose to 26,250 mg/dL. Therapeutic plasma exchange (TPE) was performed on 2 consecutive days with a resultant decrease in TG level to 530 mg/dL. The patient was later discharged home on fenofibrate and omega‐3 ethyl esters, her same immunosuppressive and insulin regimen, and instructions for a very low‐fat diet. In the next 3 months, her serum TG level did not rise above 530 mg/dL. The cause of our patient's extreme TG elevation was likely a combination of genetic factors exacerbated by immunosuppressive and glucocorticoid therapy.

This case featured dramatic elevations in serum TG levels that the managing doctors believed merited a hospital admission. Management of patients with severe HTG first requires an understanding of TG metabolism.

ETIOLOGY

Serum TGs produced by the liver are carried by very low‐density lipoproteins (VLDLs), whereas TGs derived from dietary fat are carried by chylomicrons. Both chylomicrons and VLDLs are hydrolyzed by the same enzymelipoprotein lipase (LPL). TGs are hydrolyzed into fatty acids for uptake by muscle and adipose tissue, whereas remnants of VLDL and chylomicrons are removed by the liver. More details on TG pathophysiology may be found in a recent review.4 When LPL is saturated with VLDL, ingestion of a fatty meal may cause chylomicrons to linger in circulation for days instead of hours. Asking the laboratory to spin down the blood of a patient with severe HTG and keep the test tube upright at 4C may reveal a large creamy supernatant layer demonstrating chylomicronemia.

A fasting TG level drawn 12 hours after the last meal reflects hepatic TG production. Although a nonfasting TG level may reflect postprandial chylomicrons, values above 1000 mg/dL strongly suggest true HTG, particularly in the setting of acute pancreatitis. Treatment should not be delayed to obtain a fasting TG level.

HTG may result from increased VLDL production, reduced VLDL/chylomicron clearance, or more likely a combination of the two. The causes of these metabolic derangements are classified as primary (genetic) or secondary (acquired) (Table 1). In adult patients, HTG is usually the result of a combination of primary and secondary causes. A study of 123 patients with TG levels >2000 mg/dL found that all patients had a primary metabolic defect and 110/123 had a coexistent secondary cause.3 An underlying genetic lipoprotein metabolism derangement is often clinically silent until coupled with a secondary cause of HTG that together raise TG levels high enough to cause the chylomicronemia syndrome.

The most common primary cause of HTG in adults is familial HTG, an autosomal dominant condition with a population prevalence ranging from 1%2% to 5%10% and age‐dependent penetrance.5, 6 Other genetic causes are much rarer, such as LPL deficiency (1 in 1 million patients), apolipoprotein‐CII, and other mutations resulting in impaired binding to LPL.79 Primary causes of HTG are often listed as Fredrickson phenotypes (Table 1). Recent genome‐wide association studies reveal a complex polygenic basis to the Fredrickson categories and suggest additional undefined genes or nongenetic factors may significantly contribute to the final phenotype.10 Diagnosis of familial lipid disorders requires an accurate family history that may be difficult to obtain.

Secondary causes of HTG can be categorized using a four‐D mnemonic: Diseases, Diet, Disorder of Metabolism, and Drugs.11 The most common condition associated with HTG is obesity.6 The mechanism between obesity and HTG is complex and likely involves an increase in fatty acid flux from adipose tissue to other tissues and insulin resistance.12 Asking whether a patient's current weight is close to the heaviest lifetime weight is a clue to diagnosing obesity‐driven HTG. One case series of hypertriglyceridemic pancreatitis found that diabetes or excessive alcohol intake account for the majority of secondary causes of HTG.13 The cause of HTG among patients with diabetes is multifactorial: insulin deficiency reduces LPL levels (insulin is required for synthesis of LPL), whereas insulin resistance attenuates the ability of insulin to decrease hepatic cholesterol synthesis and thus increases hepatic secretion of VLDL.14 Alcohol impairs lipolysis and increases VLDL production that can lead to severe HTG, particularly in those patients with an underlying functional deficiency in LPL. Other secondary etiologies of severe HTG may be elicited through careful attention to medical and medication history.

CLINICAL ASSESSMENT

Table 2 proposes a reasonable initial assessment of the history and physical and laboratory tests in patients with severe HTG.

Distinguishing physical examination findings may arise when serum TG levels exceed 1000 mg/dL. Eruptive xanthoma form when large amounts of TG are sequestered in cutaneous histiocytes, resulting in small yellow‐orange papules with an erythematous base. This finding is seen in a minority of HTG patients and may be missed altogether without a careful examination of the extensor surfaces of arms, legs, back, and buttocks.15 Effective TG‐lowering treatment will result in resolution of these xanthomas. An ophthalmologic examination may reveal lipemia retinalis, a condition that occurs when retinal vessels appear white from lipemic serum and contrast against a pale salmon‐colored retina. Although a dramatic finding, these changes do not result in vision impairment. Hepatomegaly from fatty infiltration of the liver occurs frequently,16 and diffuse lymphadenopathy may also be found.17

Laboratory tests are also essential in the clinical assessment of severe HTG. Important tests include thyroid‐stimulating hormone, creatinine, serum urea nitrogen, and a urinalysis. A hemoglobin A1c test provides information on the level of glycemic control and is now recognized by the American Diabetes Association to diagnose diabetes mellitus.18 Liver function tests commonly reveal a transaminase elevation from underlying steatohepatitis and also provide a baseline value prior to initiating any lipid‐lowering medications. Additional diagnostic tests may be useful in selected patients: HIV testing, serum protein electrophoresis, and urine protein electrophoresis to help diagnose paraproteinemias such as multiple myeloma, and an antinuclear antibody and double‐stranded DNA for systemic lupus erythematosus.

Severe HTG may interfere with the result of 2 commonly obtained laboratory tests. The sodium concentration can be falsely low (pseudohyponatremia) due to the high levels of TG displacing sodium containing water from the plasma.19 Due to interference by plasma lipids, amylase levels may be near normal in up to 50% of patients with hypertriglyceridemic pancreatitis at the time of admission.20 Thus, if the suspicion for pancreatitis is high, it is reasonable to proceed to imaging if amylase or lipase levels are not confirmatory. Abdominal imaging with computed tomography or magnetic resonance imaging may be used to diagnose acute pancreatitis.

Behind excessive alcohol consumption and gallstone disease, HTG is the third leading cause of pancreatitis, accounting for up to 10% of cases in the general population.21 The exact mechanism by which HTG causes pancreatitis is unclear. One theory is that elevated plasma TG levels are hydrolyzed in the pancreas to cause an increase in local free fatty acids, which in turn may cause inflammation and overt pancreatitis.22 Another theory proposes that elevated levels of chylomicrons lead to plasma hyperviscosity, which causes ischemia and local acidosis in pancreatic capillaries.23 Whatever the cause, it is unclear why only some patients with severe HTG develop acute pancreatitis. One study of 129 patients with severe HTG found mean serum TG levels to be higher in patients with acute pancreatitis than in those without (4470 versus 2450 mg/dL), suggesting the threshold to develop acute pancreatitis is higher than previously thought.24 Without a firm TG threshold above which patients develop pancreatitis, the decision to hospitalize can be difficult.

WHEN TO HOSPITALIZE?

The choice of whether to hospitalize a patient with severe HTG is first based on the presence or absence of abdominal pain and/or acute pancreatitis. Figure 1 diagrams a suggested admission and treatment algorithm. If abdominal pain is present, the patient should be hospitalized and assessed for possible triggers with prompt initiation of pharmacologic treatment. In the absence of abdominal pain, the decision to admit the patient with severe HTG requires clinical judgment. In these cases, prompt consultation with a physician experienced in the management of lipid disorders is recommended. In our experience, admission is usually driven by factors such as (1) severe hyperglycemia requiring inpatient insulin therapy; (2) severe HTG at or near a level where pancreatitis has occurred in the past in a patient for whom adherence is suspect (mindful of the great variability at the levels where patients develop pancreatitis); (3) unremitting triggers of severe HTG such as ongoing use of essential medications also known to exacerbate HTG (such as some forms of chemotherapy) or pregnancy in the third trimester. TG levels rise continuously throughout pregnancy and peak during the third trimester, when hypertriglyceridemic pancreatitis most often occurs. Asymptomatic patients with severe HTG not requiring hospitalization need close outpatient follow‐up to prevent the onset of chylomicronemia syndrome.

Figure 1

INPATIENT MANAGEMENT

No professional recommendations exist regarding a standardized treatment plan for severe HTG. The treatment regimen is first based on the presence or absence of symptoms. Treatment of hypertriglyceridemic pancreatitis should target a serum TG level <1000 mg/dL and resolution of abdominal pain. The initial goal for asymptomatic patients is a TG level <1000 mg/dL, as this level represents a significant reduction in the risk of developing chylomicronemia syndrome. In either case, the first 2 components of the treatment regimen are dietary changes and oral medications.

CONCLUSIONS

As the prevalence of obesity and diabetes continues to rise, so too does the clinical importance of proper management of severe HTG. Recognizing chylomicronemia syndromeone of the most dramatic consequences of lipid disordersand the underlying primary and secondary causes of HTG is required before starting treatment. Patients with severe HTG may require hospitalization for immediate reduction in TG levels and relief of abdominal pain, if present. Treatment involves modifying secondary causes, if possible, and eliminating dietary fat intake. Although use of medications such as an oral fibrate, omega‐3 fatty acids, and insulin are routine, the use of a more invasive procedure such as TPE should be considered on a case‐by‐case basis and may be limited by availability. Upon hospital discharge, careful follow‐up should promote lifestyle changes and medication adherence to prevent recurrence of severe HTG.

The patient with a markedly high serum triglyceride (TG) level poses an interesting challenge for hospitalists. Hypertriglyceridemia (HTG) is defined as a fasting plasma TG level that is above the 95^th percentile for age and sex.1 TG levels are commonly classified into categories according to Adult Treatment Panel III guidelines with desirable levels <150 mg/dL (1.7 mmol/L), borderline levels 150199, high levels 200499 mg/dL, and very high levels >500 mg/dL (5.6 mmol/L).2 A TG level exceeding an arbitrary threshold of >1000 mg/dL (11.3 mmol/L) is referred to as severe HTG. The Lipid Research Clinics Program Prevalence Study found that 1.79 per 10,000 outpatients (<0.02%) had TG levels > 2000 mg/dL.3 Chylomicronemia syndrome occurs when severe HTG is accompanied by 1 or more of the following: symptoms of abdominal pain or acute pancreatitis or physical examination findings such as eruptive xanthomas or lipemia retinalis. There is no TG level above which pancreatitis invariably occurs, making the decision to hospitalize difficult. The goal of this review is to discuss the causes of severe HTG; the clinical assessment, including criteria for hospitalization; and the available treatment options for this infrequent but serious condition. We begin with a clinical case of severe HTG.

CASE PRESENTATION

A 47‐year‐old woman with a history of chronic myelogenous leukemia was admitted to the hospital with a serum triglyceride level of 17,393 mg/dL. Two years prior to admission, she underwent allogenic stem cell transplantation for chronic myelogenous leukemia and has since remained in remission. Six months prior to admission, severe diarrhea from intestinal graft‐versus‐host disease required the use of total parenteral nutrition (TPN) and immunosuppressive therapy consisting of prednisone 20 mg/day, mycophenolate mofetil 250 mg thrice daily, and sirolimus 0.3 mg/day. During treatment with steroids, she developed diabetes mellitus requiring insulin, with a subsequent hemoglobin A1c level of 7.7% (normal, <7%). The serum TG level prior to transplantation was unknown but was 343 mg/dL prior to TPN initiation. One month prior to admission, the diarrhea resolved and TPN was stopped. The TG level was 7463 mg/dL 1 week prior to admission, and despite use of fenofibrate, it rose to 17,393 mg/dL. The patient denied abdominal pain, and did not have abdominal tenderness or eruptive xanthomas. She denied a family history of dyslipidemia or recent medication changes. Given the extreme TG elevation, the lack of response to outpatient treatment and the concern for developing acute pancreatitis, the patient was admitted to the hospital for inpatient TG‐lowering treatment.

Upon admission, serum lipase and amylase were within normal limits, but the blood glucose level was 243 mg/dL. Insulin infusion and oral fenofibrate 145 mg/day was started, and the patient was kept non per os (NPO). Six hours later, despite insulin infusion, the TG level rose to 26,250 mg/dL. Therapeutic plasma exchange (TPE) was performed on 2 consecutive days with a resultant decrease in TG level to 530 mg/dL. The patient was later discharged home on fenofibrate and omega‐3 ethyl esters, her same immunosuppressive and insulin regimen, and instructions for a very low‐fat diet. In the next 3 months, her serum TG level did not rise above 530 mg/dL. The cause of our patient's extreme TG elevation was likely a combination of genetic factors exacerbated by immunosuppressive and glucocorticoid therapy.

This case featured dramatic elevations in serum TG levels that the managing doctors believed merited a hospital admission. Management of patients with severe HTG first requires an understanding of TG metabolism.

ETIOLOGY

Serum TGs produced by the liver are carried by very low‐density lipoproteins (VLDLs), whereas TGs derived from dietary fat are carried by chylomicrons. Both chylomicrons and VLDLs are hydrolyzed by the same enzymelipoprotein lipase (LPL). TGs are hydrolyzed into fatty acids for uptake by muscle and adipose tissue, whereas remnants of VLDL and chylomicrons are removed by the liver. More details on TG pathophysiology may be found in a recent review.4 When LPL is saturated with VLDL, ingestion of a fatty meal may cause chylomicrons to linger in circulation for days instead of hours. Asking the laboratory to spin down the blood of a patient with severe HTG and keep the test tube upright at 4C may reveal a large creamy supernatant layer demonstrating chylomicronemia.

A fasting TG level drawn 12 hours after the last meal reflects hepatic TG production. Although a nonfasting TG level may reflect postprandial chylomicrons, values above 1000 mg/dL strongly suggest true HTG, particularly in the setting of acute pancreatitis. Treatment should not be delayed to obtain a fasting TG level.

HTG may result from increased VLDL production, reduced VLDL/chylomicron clearance, or more likely a combination of the two. The causes of these metabolic derangements are classified as primary (genetic) or secondary (acquired) (Table 1). In adult patients, HTG is usually the result of a combination of primary and secondary causes. A study of 123 patients with TG levels >2000 mg/dL found that all patients had a primary metabolic defect and 110/123 had a coexistent secondary cause.3 An underlying genetic lipoprotein metabolism derangement is often clinically silent until coupled with a secondary cause of HTG that together raise TG levels high enough to cause the chylomicronemia syndrome.

The most common primary cause of HTG in adults is familial HTG, an autosomal dominant condition with a population prevalence ranging from 1%2% to 5%10% and age‐dependent penetrance.5, 6 Other genetic causes are much rarer, such as LPL deficiency (1 in 1 million patients), apolipoprotein‐CII, and other mutations resulting in impaired binding to LPL.79 Primary causes of HTG are often listed as Fredrickson phenotypes (Table 1). Recent genome‐wide association studies reveal a complex polygenic basis to the Fredrickson categories and suggest additional undefined genes or nongenetic factors may significantly contribute to the final phenotype.10 Diagnosis of familial lipid disorders requires an accurate family history that may be difficult to obtain.

Secondary causes of HTG can be categorized using a four‐D mnemonic: Diseases, Diet, Disorder of Metabolism, and Drugs.11 The most common condition associated with HTG is obesity.6 The mechanism between obesity and HTG is complex and likely involves an increase in fatty acid flux from adipose tissue to other tissues and insulin resistance.12 Asking whether a patient's current weight is close to the heaviest lifetime weight is a clue to diagnosing obesity‐driven HTG. One case series of hypertriglyceridemic pancreatitis found that diabetes or excessive alcohol intake account for the majority of secondary causes of HTG.13 The cause of HTG among patients with diabetes is multifactorial: insulin deficiency reduces LPL levels (insulin is required for synthesis of LPL), whereas insulin resistance attenuates the ability of insulin to decrease hepatic cholesterol synthesis and thus increases hepatic secretion of VLDL.14 Alcohol impairs lipolysis and increases VLDL production that can lead to severe HTG, particularly in those patients with an underlying functional deficiency in LPL. Other secondary etiologies of severe HTG may be elicited through careful attention to medical and medication history.

CLINICAL ASSESSMENT

Table 2 proposes a reasonable initial assessment of the history and physical and laboratory tests in patients with severe HTG.

Distinguishing physical examination findings may arise when serum TG levels exceed 1000 mg/dL. Eruptive xanthoma form when large amounts of TG are sequestered in cutaneous histiocytes, resulting in small yellow‐orange papules with an erythematous base. This finding is seen in a minority of HTG patients and may be missed altogether without a careful examination of the extensor surfaces of arms, legs, back, and buttocks.15 Effective TG‐lowering treatment will result in resolution of these xanthomas. An ophthalmologic examination may reveal lipemia retinalis, a condition that occurs when retinal vessels appear white from lipemic serum and contrast against a pale salmon‐colored retina. Although a dramatic finding, these changes do not result in vision impairment. Hepatomegaly from fatty infiltration of the liver occurs frequently,16 and diffuse lymphadenopathy may also be found.17

Laboratory tests are also essential in the clinical assessment of severe HTG. Important tests include thyroid‐stimulating hormone, creatinine, serum urea nitrogen, and a urinalysis. A hemoglobin A1c test provides information on the level of glycemic control and is now recognized by the American Diabetes Association to diagnose diabetes mellitus.18 Liver function tests commonly reveal a transaminase elevation from underlying steatohepatitis and also provide a baseline value prior to initiating any lipid‐lowering medications. Additional diagnostic tests may be useful in selected patients: HIV testing, serum protein electrophoresis, and urine protein electrophoresis to help diagnose paraproteinemias such as multiple myeloma, and an antinuclear antibody and double‐stranded DNA for systemic lupus erythematosus.

Severe HTG may interfere with the result of 2 commonly obtained laboratory tests. The sodium concentration can be falsely low (pseudohyponatremia) due to the high levels of TG displacing sodium containing water from the plasma.19 Due to interference by plasma lipids, amylase levels may be near normal in up to 50% of patients with hypertriglyceridemic pancreatitis at the time of admission.20 Thus, if the suspicion for pancreatitis is high, it is reasonable to proceed to imaging if amylase or lipase levels are not confirmatory. Abdominal imaging with computed tomography or magnetic resonance imaging may be used to diagnose acute pancreatitis.

Behind excessive alcohol consumption and gallstone disease, HTG is the third leading cause of pancreatitis, accounting for up to 10% of cases in the general population.21 The exact mechanism by which HTG causes pancreatitis is unclear. One theory is that elevated plasma TG levels are hydrolyzed in the pancreas to cause an increase in local free fatty acids, which in turn may cause inflammation and overt pancreatitis.22 Another theory proposes that elevated levels of chylomicrons lead to plasma hyperviscosity, which causes ischemia and local acidosis in pancreatic capillaries.23 Whatever the cause, it is unclear why only some patients with severe HTG develop acute pancreatitis. One study of 129 patients with severe HTG found mean serum TG levels to be higher in patients with acute pancreatitis than in those without (4470 versus 2450 mg/dL), suggesting the threshold to develop acute pancreatitis is higher than previously thought.24 Without a firm TG threshold above which patients develop pancreatitis, the decision to hospitalize can be difficult.

WHEN TO HOSPITALIZE?

The choice of whether to hospitalize a patient with severe HTG is first based on the presence or absence of abdominal pain and/or acute pancreatitis. Figure 1 diagrams a suggested admission and treatment algorithm. If abdominal pain is present, the patient should be hospitalized and assessed for possible triggers with prompt initiation of pharmacologic treatment. In the absence of abdominal pain, the decision to admit the patient with severe HTG requires clinical judgment. In these cases, prompt consultation with a physician experienced in the management of lipid disorders is recommended. In our experience, admission is usually driven by factors such as (1) severe hyperglycemia requiring inpatient insulin therapy; (2) severe HTG at or near a level where pancreatitis has occurred in the past in a patient for whom adherence is suspect (mindful of the great variability at the levels where patients develop pancreatitis); (3) unremitting triggers of severe HTG such as ongoing use of essential medications also known to exacerbate HTG (such as some forms of chemotherapy) or pregnancy in the third trimester. TG levels rise continuously throughout pregnancy and peak during the third trimester, when hypertriglyceridemic pancreatitis most often occurs. Asymptomatic patients with severe HTG not requiring hospitalization need close outpatient follow‐up to prevent the onset of chylomicronemia syndrome.

Figure 1

INPATIENT MANAGEMENT

No professional recommendations exist regarding a standardized treatment plan for severe HTG. The treatment regimen is first based on the presence or absence of symptoms. Treatment of hypertriglyceridemic pancreatitis should target a serum TG level <1000 mg/dL and resolution of abdominal pain. The initial goal for asymptomatic patients is a TG level <1000 mg/dL, as this level represents a significant reduction in the risk of developing chylomicronemia syndrome. In either case, the first 2 components of the treatment regimen are dietary changes and oral medications.

CONCLUSIONS

As the prevalence of obesity and diabetes continues to rise, so too does the clinical importance of proper management of severe HTG. Recognizing chylomicronemia syndromeone of the most dramatic consequences of lipid disordersand the underlying primary and secondary causes of HTG is required before starting treatment. Patients with severe HTG may require hospitalization for immediate reduction in TG levels and relief of abdominal pain, if present. Treatment involves modifying secondary causes, if possible, and eliminating dietary fat intake. Although use of medications such as an oral fibrate, omega‐3 fatty acids, and insulin are routine, the use of a more invasive procedure such as TPE should be considered on a case‐by‐case basis and may be limited by availability. Upon hospital discharge, careful follow‐up should promote lifestyle changes and medication adherence to prevent recurrence of severe HTG.

The patient with a markedly high serum triglyceride (TG) level poses an interesting challenge for hospitalists. Hypertriglyceridemia (HTG) is defined as a fasting plasma TG level that is above the 95^th percentile for age and sex.1 TG levels are commonly classified into categories according to Adult Treatment Panel III guidelines with desirable levels <150 mg/dL (1.7 mmol/L), borderline levels 150199, high levels 200499 mg/dL, and very high levels >500 mg/dL (5.6 mmol/L).2 A TG level exceeding an arbitrary threshold of >1000 mg/dL (11.3 mmol/L) is referred to as severe HTG. The Lipid Research Clinics Program Prevalence Study found that 1.79 per 10,000 outpatients (<0.02%) had TG levels > 2000 mg/dL.3 Chylomicronemia syndrome occurs when severe HTG is accompanied by 1 or more of the following: symptoms of abdominal pain or acute pancreatitis or physical examination findings such as eruptive xanthomas or lipemia retinalis. There is no TG level above which pancreatitis invariably occurs, making the decision to hospitalize difficult. The goal of this review is to discuss the causes of severe HTG; the clinical assessment, including criteria for hospitalization; and the available treatment options for this infrequent but serious condition. We begin with a clinical case of severe HTG.

CASE PRESENTATION

A 47‐year‐old woman with a history of chronic myelogenous leukemia was admitted to the hospital with a serum triglyceride level of 17,393 mg/dL. Two years prior to admission, she underwent allogenic stem cell transplantation for chronic myelogenous leukemia and has since remained in remission. Six months prior to admission, severe diarrhea from intestinal graft‐versus‐host disease required the use of total parenteral nutrition (TPN) and immunosuppressive therapy consisting of prednisone 20 mg/day, mycophenolate mofetil 250 mg thrice daily, and sirolimus 0.3 mg/day. During treatment with steroids, she developed diabetes mellitus requiring insulin, with a subsequent hemoglobin A1c level of 7.7% (normal, <7%). The serum TG level prior to transplantation was unknown but was 343 mg/dL prior to TPN initiation. One month prior to admission, the diarrhea resolved and TPN was stopped. The TG level was 7463 mg/dL 1 week prior to admission, and despite use of fenofibrate, it rose to 17,393 mg/dL. The patient denied abdominal pain, and did not have abdominal tenderness or eruptive xanthomas. She denied a family history of dyslipidemia or recent medication changes. Given the extreme TG elevation, the lack of response to outpatient treatment and the concern for developing acute pancreatitis, the patient was admitted to the hospital for inpatient TG‐lowering treatment.

Upon admission, serum lipase and amylase were within normal limits, but the blood glucose level was 243 mg/dL. Insulin infusion and oral fenofibrate 145 mg/day was started, and the patient was kept non per os (NPO). Six hours later, despite insulin infusion, the TG level rose to 26,250 mg/dL. Therapeutic plasma exchange (TPE) was performed on 2 consecutive days with a resultant decrease in TG level to 530 mg/dL. The patient was later discharged home on fenofibrate and omega‐3 ethyl esters, her same immunosuppressive and insulin regimen, and instructions for a very low‐fat diet. In the next 3 months, her serum TG level did not rise above 530 mg/dL. The cause of our patient's extreme TG elevation was likely a combination of genetic factors exacerbated by immunosuppressive and glucocorticoid therapy.

This case featured dramatic elevations in serum TG levels that the managing doctors believed merited a hospital admission. Management of patients with severe HTG first requires an understanding of TG metabolism.

ETIOLOGY

Serum TGs produced by the liver are carried by very low‐density lipoproteins (VLDLs), whereas TGs derived from dietary fat are carried by chylomicrons. Both chylomicrons and VLDLs are hydrolyzed by the same enzymelipoprotein lipase (LPL). TGs are hydrolyzed into fatty acids for uptake by muscle and adipose tissue, whereas remnants of VLDL and chylomicrons are removed by the liver. More details on TG pathophysiology may be found in a recent review.4 When LPL is saturated with VLDL, ingestion of a fatty meal may cause chylomicrons to linger in circulation for days instead of hours. Asking the laboratory to spin down the blood of a patient with severe HTG and keep the test tube upright at 4C may reveal a large creamy supernatant layer demonstrating chylomicronemia.

A fasting TG level drawn 12 hours after the last meal reflects hepatic TG production. Although a nonfasting TG level may reflect postprandial chylomicrons, values above 1000 mg/dL strongly suggest true HTG, particularly in the setting of acute pancreatitis. Treatment should not be delayed to obtain a fasting TG level.

HTG may result from increased VLDL production, reduced VLDL/chylomicron clearance, or more likely a combination of the two. The causes of these metabolic derangements are classified as primary (genetic) or secondary (acquired) (Table 1). In adult patients, HTG is usually the result of a combination of primary and secondary causes. A study of 123 patients with TG levels >2000 mg/dL found that all patients had a primary metabolic defect and 110/123 had a coexistent secondary cause.3 An underlying genetic lipoprotein metabolism derangement is often clinically silent until coupled with a secondary cause of HTG that together raise TG levels high enough to cause the chylomicronemia syndrome.

The most common primary cause of HTG in adults is familial HTG, an autosomal dominant condition with a population prevalence ranging from 1%2% to 5%10% and age‐dependent penetrance.5, 6 Other genetic causes are much rarer, such as LPL deficiency (1 in 1 million patients), apolipoprotein‐CII, and other mutations resulting in impaired binding to LPL.79 Primary causes of HTG are often listed as Fredrickson phenotypes (Table 1). Recent genome‐wide association studies reveal a complex polygenic basis to the Fredrickson categories and suggest additional undefined genes or nongenetic factors may significantly contribute to the final phenotype.10 Diagnosis of familial lipid disorders requires an accurate family history that may be difficult to obtain.

Secondary causes of HTG can be categorized using a four‐D mnemonic: Diseases, Diet, Disorder of Metabolism, and Drugs.11 The most common condition associated with HTG is obesity.6 The mechanism between obesity and HTG is complex and likely involves an increase in fatty acid flux from adipose tissue to other tissues and insulin resistance.12 Asking whether a patient's current weight is close to the heaviest lifetime weight is a clue to diagnosing obesity‐driven HTG. One case series of hypertriglyceridemic pancreatitis found that diabetes or excessive alcohol intake account for the majority of secondary causes of HTG.13 The cause of HTG among patients with diabetes is multifactorial: insulin deficiency reduces LPL levels (insulin is required for synthesis of LPL), whereas insulin resistance attenuates the ability of insulin to decrease hepatic cholesterol synthesis and thus increases hepatic secretion of VLDL.14 Alcohol impairs lipolysis and increases VLDL production that can lead to severe HTG, particularly in those patients with an underlying functional deficiency in LPL. Other secondary etiologies of severe HTG may be elicited through careful attention to medical and medication history.

CLINICAL ASSESSMENT

Table 2 proposes a reasonable initial assessment of the history and physical and laboratory tests in patients with severe HTG.

Distinguishing physical examination findings may arise when serum TG levels exceed 1000 mg/dL. Eruptive xanthoma form when large amounts of TG are sequestered in cutaneous histiocytes, resulting in small yellow‐orange papules with an erythematous base. This finding is seen in a minority of HTG patients and may be missed altogether without a careful examination of the extensor surfaces of arms, legs, back, and buttocks.15 Effective TG‐lowering treatment will result in resolution of these xanthomas. An ophthalmologic examination may reveal lipemia retinalis, a condition that occurs when retinal vessels appear white from lipemic serum and contrast against a pale salmon‐colored retina. Although a dramatic finding, these changes do not result in vision impairment. Hepatomegaly from fatty infiltration of the liver occurs frequently,16 and diffuse lymphadenopathy may also be found.17

Laboratory tests are also essential in the clinical assessment of severe HTG. Important tests include thyroid‐stimulating hormone, creatinine, serum urea nitrogen, and a urinalysis. A hemoglobin A1c test provides information on the level of glycemic control and is now recognized by the American Diabetes Association to diagnose diabetes mellitus.18 Liver function tests commonly reveal a transaminase elevation from underlying steatohepatitis and also provide a baseline value prior to initiating any lipid‐lowering medications. Additional diagnostic tests may be useful in selected patients: HIV testing, serum protein electrophoresis, and urine protein electrophoresis to help diagnose paraproteinemias such as multiple myeloma, and an antinuclear antibody and double‐stranded DNA for systemic lupus erythematosus.

Severe HTG may interfere with the result of 2 commonly obtained laboratory tests. The sodium concentration can be falsely low (pseudohyponatremia) due to the high levels of TG displacing sodium containing water from the plasma.19 Due to interference by plasma lipids, amylase levels may be near normal in up to 50% of patients with hypertriglyceridemic pancreatitis at the time of admission.20 Thus, if the suspicion for pancreatitis is high, it is reasonable to proceed to imaging if amylase or lipase levels are not confirmatory. Abdominal imaging with computed tomography or magnetic resonance imaging may be used to diagnose acute pancreatitis.

Behind excessive alcohol consumption and gallstone disease, HTG is the third leading cause of pancreatitis, accounting for up to 10% of cases in the general population.21 The exact mechanism by which HTG causes pancreatitis is unclear. One theory is that elevated plasma TG levels are hydrolyzed in the pancreas to cause an increase in local free fatty acids, which in turn may cause inflammation and overt pancreatitis.22 Another theory proposes that elevated levels of chylomicrons lead to plasma hyperviscosity, which causes ischemia and local acidosis in pancreatic capillaries.23 Whatever the cause, it is unclear why only some patients with severe HTG develop acute pancreatitis. One study of 129 patients with severe HTG found mean serum TG levels to be higher in patients with acute pancreatitis than in those without (4470 versus 2450 mg/dL), suggesting the threshold to develop acute pancreatitis is higher than previously thought.24 Without a firm TG threshold above which patients develop pancreatitis, the decision to hospitalize can be difficult.

WHEN TO HOSPITALIZE?

The choice of whether to hospitalize a patient with severe HTG is first based on the presence or absence of abdominal pain and/or acute pancreatitis. Figure 1 diagrams a suggested admission and treatment algorithm. If abdominal pain is present, the patient should be hospitalized and assessed for possible triggers with prompt initiation of pharmacologic treatment. In the absence of abdominal pain, the decision to admit the patient with severe HTG requires clinical judgment. In these cases, prompt consultation with a physician experienced in the management of lipid disorders is recommended. In our experience, admission is usually driven by factors such as (1) severe hyperglycemia requiring inpatient insulin therapy; (2) severe HTG at or near a level where pancreatitis has occurred in the past in a patient for whom adherence is suspect (mindful of the great variability at the levels where patients develop pancreatitis); (3) unremitting triggers of severe HTG such as ongoing use of essential medications also known to exacerbate HTG (such as some forms of chemotherapy) or pregnancy in the third trimester. TG levels rise continuously throughout pregnancy and peak during the third trimester, when hypertriglyceridemic pancreatitis most often occurs. Asymptomatic patients with severe HTG not requiring hospitalization need close outpatient follow‐up to prevent the onset of chylomicronemia syndrome.

Figure 1

INPATIENT MANAGEMENT

No professional recommendations exist regarding a standardized treatment plan for severe HTG. The treatment regimen is first based on the presence or absence of symptoms. Treatment of hypertriglyceridemic pancreatitis should target a serum TG level <1000 mg/dL and resolution of abdominal pain. The initial goal for asymptomatic patients is a TG level <1000 mg/dL, as this level represents a significant reduction in the risk of developing chylomicronemia syndrome. In either case, the first 2 components of the treatment regimen are dietary changes and oral medications.

CONCLUSIONS

As the prevalence of obesity and diabetes continues to rise, so too does the clinical importance of proper management of severe HTG. Recognizing chylomicronemia syndromeone of the most dramatic consequences of lipid disordersand the underlying primary and secondary causes of HTG is required before starting treatment. Patients with severe HTG may require hospitalization for immediate reduction in TG levels and relief of abdominal pain, if present. Treatment involves modifying secondary causes, if possible, and eliminating dietary fat intake. Although use of medications such as an oral fibrate, omega‐3 fatty acids, and insulin are routine, the use of a more invasive procedure such as TPE should be considered on a case‐by‐case basis and may be limited by availability. Upon hospital discharge, careful follow‐up should promote lifestyle changes and medication adherence to prevent recurrence of severe HTG.