Could this be Hemolytic Uremic Syndrome (HUS)?

Can This Be Hemolytic Uremic Syndrome (HUS)?

Yes, HUS should be strongly suspected if the patient presents with the classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal involvement, though critically, up to 50% of cases may not show all three features at initial presentation. 1, 2

Immediate Diagnostic Approach

When evaluating any patient with anemia plus thrombocytopenia, immediately order the following laboratory tests 2, 3:

• Complete blood count with peripheral blood smear (looking for schistocytes >1%, though their absence does not exclude early HUS due to low sensitivity) 2, 3
• Haptoglobin (reduced in HUS) 1, 2
• LDH and indirect bilirubin (elevated in HUS) 1, 2, 3
• Direct Coombs test (negative, confirming non-immune hemolysis) 1, 2, 3
• ADAMTS13 activity (must be <10 IU/dL to diagnose TTP; normal or mildly reduced suggests HUS) 1, 3, 4
• Stool testing for verocytotoxin-producing E. coli (VTEC/STEC) 1, 2, 3
• Creatinine and urinalysis (for hematuria and proteinuria) 1, 2, 3

Core Diagnostic Criteria

The diagnosis requires evidence of 1, 2, 3:

1. Microangiopathic hemolytic anemia: Negative direct Coombs test, elevated LDH, reduced haptoglobin, elevated indirect bilirubin, with or without schistocytes on peripheral smear 1, 2

2. Thrombocytopenia: Platelet count <150,000/mm³ or 25% reduction from baseline 1, 2, 3

3. Renal involvement: Hematuria, proteinuria, and/or elevated creatinine (≥1.0 mg/dL in children <13 years; ≥1.5 mg/dL in individuals ≥13 years; or ≥50% increase over baseline) 1, 2

Critical Diagnostic Pitfalls

Do not exclude HUS if one component of the triad is missing or subtle. In pediatric patients, particularly newborns, up to 50% of aHUS cases may not show all three parameters at disease onset 1, 3. Additionally, following renal transplantation, 13% of patients do not show significant platelet reduction and 38% do not exhibit significant anemia or thrombocytopenia 1.

Do not exclude HUS based on near-normal hemoglobin alone, as dehydration may mask anemia 2.

Distinguishing HUS Subtypes

STEC-HUS (Typical HUS)

• Positive stool VTEC testing 3
• Diarrhea onset 4-5 days before HUS symptoms (this timing is critical) 1, 2, 3
• Most common in children under 4 years of age 5, 6
• Bloody diarrhea is typical 1, 5

Atypical HUS (aHUS)

• Negative VTEC testing OR short diarrhea period OR simultaneous onset of diarrhea and HUS 2, 3
• If diarrhea and HUS appear simultaneously or with shorter interval than 4-5 days, suspect aHUS over STEC-HUS 1, 3
• Consider complement testing (C3, C4, CH50, AP50) and genetic testing for complement pathway mutations 2, 7

Special Pediatric Considerations

• In infants <1 year old: Test for complement-unrelated genes (DGKE, WT1) 1, 3
• Consider methylmalonic acidemia with homocystinuria (MMACHC) causing cobalamin deficiency 1, 3

Distinguishing HUS from TTP

ADAMTS13 activity is the key discriminator 3, 4:

• ADAMTS13 <10 IU/dL = TTP 1, 3, 4
• ADAMTS13 normal or mildly reduced = HUS (if STEC negative) 3, 4

Clinical features favoring HUS over TTP 4:

• More prominent acute renal injury (hematuria, proteinuria, elevated creatinine) 4
• Preceding diarrheal illness (especially bloody diarrhea 4-5 days before symptoms) 4
• Less severe thrombocytopenia and fewer schistocytes 4
• Less prominent neurological involvement (though 10-20% of aHUS cases do have neurological symptoms) 1, 4

Neurological Assessment

If neurological symptoms are present (occurs in 10-20% of aHUS cases), obtain 1, 3:

• Neurology consultation 1
• Electroencephalogram (EEG) 1, 3
• Brain MRI (looking for bilateral symmetric hyperintensities in basal ganglia, cerebral peduncles, caudate nuclei, putamen, thalami, hippocampi, insulae, or brainstem) 3

Common neurological manifestations include motor symptoms, generalized weakness, vision changes, seizures, and encephalopathy 1, 3.

Monitoring Protocol

For patients with diagnosed or suspected STEC infection, perform daily monitoring of hemoglobin, platelet counts, electrolytes, BUN, and creatinine during the at-risk period (days 1-14) 2. Monitoring can stop when platelet count begins to increase or stabilize with resolved/resolving symptoms 2.

Treatment Urgency

Do not delay treatment while awaiting confirmatory testing—aHUS is a medical emergency requiring immediate complement inhibitor therapy, while TTP requires plasma exchange. 3, 4 The distinction is life-saving, as eculizumab has dramatically improved outcomes in aHUS since its approval in 2011 7.