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Difficulty: MediumFormulating a Differential Diagnosis

A 27-year-old man visits an ambulatory care clinic complaining of profound fatigue, shortness of breath with minimal exertion, and yellowing of his skin for the past two days. Three weeks ago, he returned from a volunteer assignment in a rural region of Sub-Saharan Africa. He reports having no abdominal pain, nausea, vomiting, or fever. During his trip, he initially took atovaquone-proguanil for malaria prophylaxis but switched to primaquine during his final week abroad because he lost his original medication. He has no prior medical history and takes no other medications. His temperature is 37.0°C (98.6°F), blood pressure is 118/76 mm Hg, and pulse is 108/min. Physical examination reveals marked conjunctival pallor and mild scleral icterus. The abdomen is soft, non-tender, and without hepatosplenomegaly.

Laboratory results are as follows:
Hemoglobin: 7.4 g/dL
Mean corpuscular volume: 92 fL
Platelet count: 240,000/mm³
Leukocyte count: 6,800/mm³
Total bilirubin: 5.8 mg/dL
Direct bilirubin: 0.5 mg/dL
Aspartate aminotransferase: 34 U/L
Alanine aminotransferase: 38 U/L
Alkaline phosphatase: 88 U/L
Lactate dehydrogenase: 950 U/L

Which of the following is the most likely diagnosis?

  1. Glucose-6-phosphate dehydrogenase deficiencyAnswer
  2. B
    Acute viral hepatitis A
  3. C
    Plasmodium falciparum infection
  4. D
    Gilbert syndrome
  5. E
    Drug-induced liver injury

Answer

The most likely diagnosis is Glucose-6-phosphate dehydrogenase deficiency presenting as an acute hemolytic crisis.
The patient presents with an acute onset of fatigue, dyspnea, and jaundice following the initiation of primaquine. Laboratory results show a normocytic anemia, significantly elevated unconjugated (indirect) bilirubin, and markedly elevated lactate dehydrogenase, with entirely normal liver transaminases. This constellation of findings indicates intravascular hemolysis rather than hepatocellular injury. Primaquine is a well-known oxidative stressor that can precipitate acute hemolytic episodes in individuals with Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked recessive disorder. The lack of fever and normal liver enzymes make infectious or primary hepatotoxic causes highly unlikely.

Step-by-Step Solution

1
Analyze the patient's primary symptoms and physical examination findings in the context of his recent history.
The patient exhibits acute onset of fatigue, dyspnea, and jaundice (scleral icterus) without fever, abdominal pain, or hepatosplenomegaly, shortly after returning from Africa and switching to primaquine.
Establishing the core clinical syndrome helps narrow the differential diagnosis from a broad list of travel-related illnesses to specific systemic or hepatobiliary processes.
2
Interpret the laboratory results to determine the specific etiology of the patient's jaundice.
Labs demonstrate severe normocytic anemia, markedly elevated lactate dehydrogenase (LDH), and predominantly unconjugated hyperbilirubinemia, with entirely normal liver transaminases and alkaline phosphatase.
This specific laboratory pattern confirms pre-hepatic jaundice due to active intravascular hemolysis, effectively ruling out primary hepatocellular injury or biliary cholestasis.
3
Correlate the confirmed hemolytic episode with the patient's medication exposure history.
The onset of hemolysis coincides with the recent administration of primaquine, a well-known oxidative stressor.
Identifying an oxidative trigger for acute hemolysis in an otherwise healthy male strongly points to an underlying erythrocyte enzyme defect, leading to the definitive diagnosis of Glucose-6-phosphate dehydrogenase deficiency.

Key Concept

Formulating a differential diagnosis for acute jaundice requires distinguishing pre-hepatic (hemolysis) from hepatic and post-hepatic causes by systematically interpreting the complete blood count, lactate dehydrogenase, bilirubin fractionation, and hepatic transaminases.
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Formulating a Differential Diagnosis

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