What are the possible diagnoses for a patient with diabetes who develops severe jaundice and hemolytic anemia after gastroenteritis?

Differential Diagnosis of Severe Jaundice with Hemolytic Anemia Following Gastroenteritis in a Diabetic Patient

In a diabetic patient in their sixties presenting with severe jaundice and hemolytic anemia after gastroenteritis, the primary diagnostic considerations are glucose-6-phosphate dehydrogenase (G6PD) deficiency triggered by infection or diabetic ketoacidosis, Wilson disease with acute hemolytic crisis, and drug-induced hemolytic anemia. 1, 2, 3

Primary Diagnostic Considerations

G6PD Deficiency with Oxidative Stress Trigger

• G6PD deficiency is the most common enzymopathy in humans and represents a critical consideration in this clinical scenario. 3
• The combination of diabetes and acute infection (gastroenteritis) creates a perfect storm for hemolytic crisis in G6PD-deficient patients, as both infection and diabetic ketoacidosis are well-established precipitators of oxidative stress. 2, 3
• Severe hemolytic anemia can develop during correction of hyperglycemia in newly diagnosed or poorly controlled diabetes in G6PD-deficient patients. 2
• Clinical presentation includes acute anemia, severe jaundice, back or abdominal pain, fatigue, and hemoglobinuria. 3
• Diagnosis requires G6PD enzyme activity testing (spectrophotometric, fluorescence, or formazan-based spot testing) or molecular analysis. 3

Wilson Disease with Acute Hemolytic Crisis

• Wilson disease can present as acute liver failure with associated Coombs-negative hemolytic anemia, making it a critical diagnosis not to miss in this age group. 1
• The combination of severe jaundice and hemolytic anemia is characteristic of Wilson disease presenting as acute hepatic decompensation. 1
• Patients may have transient or recurrent episodes of jaundice due to hemolysis, and low-grade chronic hemolysis may occur even when liver disease is not clinically evident. 1
• Wilson disease should be considered in any individual between ages 3 and 55 years with liver abnormalities of uncertain cause. 1
• Diagnostic workup includes serum ceruloplasmin (<20 mg/dL), 24-hour urinary copper (>40 μg/day), slit-lamp examination for Kayser-Fleischer rings, and molecular testing for ATP7B mutations. 1

Drug-Induced Hemolytic Anemia

• Metformin, commonly prescribed for diabetes, has been implicated in causing hemolytic anemia, particularly in G6PD-deficient patients. 4
• Other medications that can precipitate hemolysis in diabetic patients include antibiotics used to treat gastroenteritis (particularly quinolones and sulfonamides). 3
• When clinically feasible, oxidative medications should not be used until G6PD diagnostic testing has been performed. 3

Secondary Diagnostic Considerations

Hereditary Hemolytic Anemias

• Pyruvate kinase (PK) deficiency is the second most common hereditary enzymopathy and can present with chronic hemolysis, jaundice, and splenomegaly. 1, 5
• The critical distinguishing feature is that red cell morphology is usually unremarkable with only mild anisocytosis and poikilocytosis. 1, 5
• Reticulocytosis may not be proportional to hemolysis severity before splenectomy because younger defective cells are preferentially sequestered in the spleen. 1, 6
• Diagnosis requires PK enzyme activity assay and PKLR gene sequencing, but recent transfusions can mask deficiency for up to 120 days. 1, 5, 7

Hemoglobin M Variants

• Hemoglobin M variants can present with hemolytic anemia and jaundice, particularly HbM Saskatoon and HbM Hyde Park. 1
• These variants develop cyanosis and may have associated hemolytic anemia due to iron-phenolate complexes that resist reduction. 1
• Diagnosis is made by hemoglobin electrophoresis at pH 7.1 and molecular analysis of globin genes. 1

Autoimmune Hemolytic Anemia

• The direct antiglobulin test (DAT) must be performed before initiating any treatment to differentiate immune from non-immune hemolysis. 7, 8
• Secondary causes include infections (which could be related to the gastroenteritis), lymphoproliferative disorders, and drug-induced hemolysis. 7

Essential Diagnostic Workup

Immediate Laboratory Testing

• Complete blood count with reticulocyte count, peripheral blood smear, elevated LDH, reduced or absent haptoglobin, and elevated indirect (unconjugated) bilirubin confirm hemolysis. 6, 7, 8
• Haptoglobin is the most sensitive indicator of hemolysis and becomes reduced early in hemolytic processes. 6
• Direct antiglobulin test (DAT) to exclude immune-mediated hemolysis. 7, 8

Specific Enzyme and Metabolic Testing

• G6PD enzyme activity testing (spectrophotometric method preferred). 7, 3
• Serum ceruloplasmin, 24-hour urinary copper, and slit-lamp examination if Wilson disease is suspected. 1
• PK enzyme activity if other tests are unrevealing and red cell morphology is normal. 1, 7

Advanced Molecular Testing

• Next-generation sequencing (NGS) gene panels analyzing 68+ hemolytic anemia-related genes represent the gold standard for hereditary hemolytic anemias when initial testing is equivocal. 7

Critical Clinical Pitfalls to Avoid

• Do not interpret PK activity without considering reticulocytosis, recent transfusions, or leukocyte contamination, as these cause falsely normal results. 7
• Obtain timing of last blood transfusion before enzyme testing, as donor red cells can mask enzyme deficiencies for up to 120 days. 5, 7
• Do not dismiss Wilson disease based on age alone; it can present up to age 55 years. 1
• Consider that iron overload can occur even without transfusions in hereditary hemolytic anemias due to ineffective erythropoiesis. 5
• Review all medications, including metformin and antibiotics used for gastroenteritis, as potential hemolytic triggers. 3, 4