A 38-year-old man is evaluated in the emergency department for a 2-day history of severe, … — USMLE Step 3

A 38-year-old man is evaluated in the emergency department for a 2-day history of severe, diffuse abdominal pain. Over the last six months, he has had recurrent episodes of profound fatigue, intermittent difficulty swallowing, and noting that his urine is occasionally unusually dark, particularly with his first morning void. He also mentions a recent onset of erectile dysfunction, which he attributed to stress. He takes no medications and does not use tobacco, alcohol, or illicit drugs. Vital signs show a temperature of 37.1°C (98.8°F), blood pressure 138/86 mm Hg, heart rate 108/min, and respiratory rate 18/min. Physical examination reveals marked pallor and scleral icterus. The abdomen is diffusely tender without rebound or guarding. Bowel sounds are hypoactive.

Laboratory findings are as follows:

Laboratory Test	Result	Reference Range
Hemoglobin	8.2 g/dL	13.5-17.5 g/dL
Mean corpuscular volume	98 fL	80-100 fL
Reticulocyte count	9%	0.5-1.5%
Leukocyte count	$3,100/\mu L$	$4,500-11,000/\mu L$
Platelet count	$88,000/\mu L$	$150,000-400,000/\mu L$
Total bilirubin	3.2 mg/dL	0.1-1.2 mg/dL
Direct bilirubin	0.4 mg/dL	0.0-0.3 mg/dL
Lactate dehydrogenase	1,850 U/L	100-250 U/L
Haptoglobin	<10 mg/dL	41-165 mg/dL

Direct antiglobulin (Coombs) test is negative.
Urinalysis reveals 4+ blood with 0-2 red blood cells/hpf.

A contrast-enhanced CT scan of the abdomen reveals superior mesenteric vein thrombosis without bowel infarction.

Which of the following is the most likely underlying condition causing this patient's presentation?

Paroxysmal nocturnal hemoglobinuriaAnswer
B
Antiphospholipid syndrome
C
Autoimmune hemolytic anemia
D
Acute intermittent porphyria
E
Polycythemia vera

Answer

The most likely underlying condition is Paroxysmal nocturnal hemoglobinuria.

The correct answer identifies Paroxysmal Nocturnal Hemoglobinuria (PNH). This patient presents with the classic triad of PNH: Coombs-negative intravascular hemolysis (anemia, elevated LDH/indirect bilirubin, low haptoglobin, hemoglobinuria), pancytopenia (leukopenia, thrombocytopenia), and unprovoked atypical venous thrombosis (superior mesenteric vein). The mutation in the PIGA gene leads to a lack of GPI-anchored proteins (CD55 and CD59) on cell surfaces, making red blood cells highly susceptible to complement-mediated lysis. The episodic dysphagia and erectile dysfunction are highly specific clinical clues representing smooth muscle dystonia, which occurs because free plasma hemoglobin (from intravascular hemolysis) irreversibly binds and depletes circulating nitric oxide.

Step-by-Step Solution

Analyze the hematological and urinalysis data to determine the type of anemia.

The patient has a normocytic anemia with a high reticulocyte count, elevated LDH, elevated indirect bilirubin, and low haptoglobin, indicating hemolysis. The negative Coombs test and the presence of 4+ blood on urine dipstick with no RBCs on microscopy confirm Coombs-negative intravascular hemolysis resulting in hemoglobinuria.

Establishing the mechanism of anemia is the first step in narrowing the differential diagnosis for fatigue and dark urine.

Synthesize the hematological findings with the complete blood count and imaging results.

The patient has concurrent pancytopenia (leukopenia, thrombocytopenia) and an unprovoked atypical venous thrombosis (superior mesenteric vein).

Identifying the classic triad of Coombs-negative intravascular hemolysis, pancytopenia, and atypical venous thrombosis is highly specific for an acquired stem cell disorder.

Correlate the atypical systemic symptoms (dysphagia, erectile dysfunction) with the pathophysiological process.

These are symptoms of smooth muscle dystonia, which occurs because free plasma hemoglobin scavenges circulating nitric oxide, further supporting the diagnosis of massive intravascular hemolysis.

Connecting seemingly unrelated symptoms to the core pathophysiological mechanism confirms the unified diagnosis and avoids premature closure.

Key Concept

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell mutation characterized by the classic triad of Coombs-negative intravascular hemolysis, pancytopenia, and venous thrombosis (often in atypical sites). Free hemoglobin scavenging nitric oxide also causes characteristic smooth muscle dystonia.

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