Pearl of the Month

Case: Older patient with T2D has recurrent flushing


A 64 year-old man with type 2 diabetes complains of recurrent flushing for the past 6 months. He has had no other symptoms. His only abnormalities on physical exam are a blood pressure of 160/100 and mild peripheral edema.

Dr. Douglas S. Paauw, University of Washington, Seattle

Dr. Douglas S. Paauw

His current medications include: Famotidine 20 mg b.i.d., Pseudoephedrine/guaifenesin SR b.i.d., Metformin 1,000 mg twice a day, Nifedipine 60 mg XL once a day, and Atorvastatin 20 mg once a day.

His laboratory work up includes: blood urea nitrogen: 20, creatinine: 1.3, sodium: 140, Chloride: 104, potassium: 3.9, glucose: 205, white blood cell count: 6,000, hematocrit: 41, 24-hour urine 5-hydroxyindoleacetic acid (5HIAA) test: 12 mg/day (normal 2-8 mg/day), free catecholamines: 80 mg/24 hours (normal less than 100 mg/24 hours).

What is the most likely diagnosis?

A. Drug effect

B. Pheochromocytoma

C. Carcinoid syndrome

D. Mastocytosis

E. Medullary thyroid cancer

The most likely diagnosis is a drug effect. His flushing is likely caused by nifedipine.

Flushing is one of the most common side effects of this drug.1 This patient had lab testing done for carcinoid (urine 5HIAA), presumably because he had flushing. This lab test result was a false positive, likely because of guaifenesin ingestion, which can cause false-positive 5HIAA results.2

Carcinoid syndrome is very rare (estimates from less than 1 patient/100,000), and the vast majority of patients who have it present with metastatic disease at presentation. Drug side effects are common, and usually are much more likely than rare diseases.

Four principles for assisting with making a diagnosis

This case points out the following four principles that I will touch on to help us make diagnoses in challenging cases.

1. Trigger symptoms: These are symptoms that make us think of a rare disease. In this case, the symptom is flushing, which may make you think of carcinoid syndrome.

Another good example of a trigger symptom is night sweats, where you may think of tuberculosis or lymphoma. These symptoms almost always have a much more common and likely cause, which in this case is a common drug side effect.

Trigger symptoms are great to pay attention to, but do not jump to working up the rare diagnosis without more evidence that it is a plausible diagnosis. Working up rare diseases without a reasonable pretest probability will lead to significant false-positive results.

2. Distinguishing features: These are findings, or combinations of findings, that make rarer diseases more likely. For example, flushing, although seen in many patients with carcinoid syndrome, is much more commonly caused by rosacea, medications, or estrogen/testosterone deficiency.

If a patient presents with flushing plus diarrhea, carcinoid syndrome becomes more likely in differentials. An example of a specific distinguishing feature is transient visual obstructions in patients with idiopathic intracranial hypertension (IIH or pseudotumor cerebri).

Sudden transient visual loss is not a symptom we see often, but headaches and obesity are problems we see every day. A patient with headaches and obesity is very likely to have IIH if they have transient visual obstructions along with headaches and obesity.

3. Intentional physical exams: Do the physical exam focusing on what findings will change your diagnostic probabilities. For example, in this case, if you are considering carcinoid, do a careful abdominal exam, with close attention to the liver, as 75% of patients with carcinoid syndrome have liver metastases.

If you are thinking about IIH, a fundoscopic exam is mandatory, as papilledema is a key feature of this diagnosis.

Read about the rare diagnosis you are considering, this will help with targeting your exam.

4. Remember the unusual presentation of a common disease is more common than the common presentation of a rare disease: Good examples of this are sleep apnea and gastroesophageal reflux disease causing night sweats more commonly than finding lymphomas or active tuberculosis (in the United States) as the cause.3

Pearl: Trigger symptoms help us think of rare diseases, but distinguishing features are most helpful in including or excluding the diagnosis.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at


1. Gueret P et al. Drugs. 1990;39 Suppl 2:67-72.

2. Corcuff J et al. Endocr Connect. 2017;6:R87.

3. Smith CS and Paauw DS. J Am Board Fam Pract. 2000;13:424-9.

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