What disorders are associated with hemolytic anemia and chronic diarrhea?

Disorders Associated with Hemolytic Anemia and Chronic Diarrhea

The most critical disorder to identify when hemolytic anemia and chronic diarrhea coexist is hemolytic uremic syndrome (HUS), particularly atypical HUS (aHUS), which presents with the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal injury, often preceded by diarrhea. 1, 2

Primary Differential Diagnosis

Hemolytic Uremic Syndrome (HUS)

HUS is the leading diagnosis to consider when hemolytic anemia occurs with diarrhea, as it represents a life-threatening thrombotic microangiopathy requiring urgent recognition and treatment.

• Typical (STEC-HUS): Caused by Shiga toxin-producing E. coli O157:H7, this is the most common cause of acute renal failure in children and presents with bloody diarrhea followed by hemolytic anemia, thrombocytopenia, and renal failure approximately 4-5 days after diarrhea onset 1, 3

• Atypical HUS (aHUS): Characterized by complement dysregulation and can occur at any age, though onset is more frequent in childhood 1, 2

  • In pediatric patients, both aHUS and STEC-HUS may present with diarrhea; however, a short period of diarrhea or simultaneous onset of diarrhea and HUS should raise suspicion for aHUS rather than STEC-HUS 1, 2
  • In adults, aHUS should be strongly suspected when hemolytic anemia and diarrhea occur together, particularly in males 4
  • Not all three clinical signs (hemolytic anemia, thrombocytopenia, renal involvement) may be clearly present at disease onset in up to 50% of cases 1, 2

Key Diagnostic Features of HUS

• Laboratory criteria: Microangiopathic hemolytic anemia with schistocytes, burr cells, or helmet cells on peripheral smear; platelet count <150,000/mm³; elevated LDH; reduced haptoglobin; negative direct Coombs test 1, 2
• Renal involvement: Hematuria, proteinuria, or elevated creatinine (≥1.0 mg/dL in children <13 years; ≥1.5 mg/dL in adults ≥13 years) 1, 2
• Timing: Classic STEC-HUS appears within 3 weeks after bloody diarrhea onset, typically at the end of gastrointestinal illness 1, 2

Secondary Considerations

Invasive Bacterial Infections with Hemolytic Complications

Certain bacterial infections causing diarrhea are associated with invasive disease and hemolytic complications, particularly in patients with underlying hemolytic conditions:

• Noncholera Vibrio infections (especially V. vulnificus): Risk factors include chronic liver disease, iron overload states (hemochromatosis, hemolytic anemia, or chronic renal failure), and other immunocompromising conditions 1
• Invasive nontyphoidal Salmonella: Risk factors include hemoglobinopathies, recent malaria, HIV infection, malnutrition, and cirrhosis 1
• Yersiniosis: Higher risk in patients with iron-overload states, chronic liver disease, and diabetes 1

Coeliac Disease

Coeliac disease should be considered in all patients with chronic diarrhea, as it commonly presents with iron deficiency anemia (not typically hemolytic) but can be associated with various hematologic abnormalities:

• Diarrhea is present in 43-85% of newly diagnosed coeliac disease patients 1
• Prevalence in patients with chronic diarrhea ranges from 3-10% 1
• Iron deficiency anemia is a sensitive indicator of small bowel enteropathy 1
• Serological testing for coeliac disease is mandatory in patients presenting with chronic diarrhea 1

Autoimmune Hemolytic Anemia with Inflammatory Bowel Disease

• Autoimmune hemolytic anemia should be considered in patients with inflammatory bowel disease presenting with anemia and chronic diarrhea 5
• The direct antiglobulin test (Coombs test) will be positive in autoimmune hemolytic anemia, distinguishing it from other causes 6, 5

Critical Diagnostic Algorithm

When encountering a patient with hemolytic anemia and chronic diarrhea, follow this systematic approach:

1. Confirm hemolysis: Obtain reticulocyte count, LDH, indirect bilirubin, haptoglobin, and peripheral blood smear 7, 6

2. Assess for HUS/TMA: Check platelet count, renal function (creatinine, urinalysis), and examine peripheral smear for schistocytes 7, 2

3. Determine immune vs. non-immune: Perform direct antiglobulin test (Coombs test) 8, 6

4. If Coombs-negative and thrombocytopenia present: Urgently measure ADAMTS13 activity to distinguish aHUS from thrombotic thrombocytopenic purpura (TTP) 1, 7

5. Obtain stool studies: Culture for E. coli O157:H7 and perform Shiga toxin testing 3

6. Assess complement function: Measure C3, C4, CH50, and AP50 if aHUS is suspected 7

7. Screen for coeliac disease: Obtain tissue transglutaminase antibody (TTG IgA) and endomysial antibody (EMA) with total IgA level 1

Common Pitfalls to Avoid

• Do not wait for all three features of HUS to be present before initiating evaluation—up to 50% of aHUS cases may not have all three signs at onset 1, 2
• Do not assume STEC-HUS in adults with diarrhea and hemolysis—aHUS is more common in adults and requires different management 4
• Do not rely solely on schistocytes—their absence should not exclude early TMA diagnosis due to low sensitivity 7
• Do not overlook IgA deficiency when testing for coeliac disease—selective IgA deficiency occurs in 2.6% of coeliac patients and will cause false-negative IgA-based antibody tests 1
• Consider drug-induced hemolytic anemia—medications can cause hemolysis through multiple mechanisms, and chronic diarrhea may be medication-related 6