Hemolytic Uremic Syndrome (HUS)

A 5 year old child presents with bloody diarrhea, pallor, decreased urine output, and fatigue several days after eating undercooked beef. Laboratory evaluation reveals anemia, thrombocytopenia, elevated creatinine, elevated LDH, low haptoglobin, and schistocytes on peripheral smear. Coombs test is negative. Diagnosis?

Diagnosis is Hemolytic Uremic Syndrome (HUS).

1. Definition

Hemolytic uremic syndrome is a thrombotic microangiopathy characterized by the triad of:

1. Microangiopathic hemolytic anemia (MAHA)
2. Thrombocytopenia
3. Acute kidney injury

2. Types

2.1 Typical HUS (Shiga Toxin–Associated HUS)

1. Most commonly caused by Shiga toxin–producing enterohemorrhagic E. coli (EHEC O157:H7)
2. May also occur with Shigella dysenteriae
3. Usually preceded by bloody diarrhea
4. Commonly associated with ingestion of:
• Undercooked beef
• Unpasteurized milk or juice
• Contaminated food/water

2.2 Atypical HUS (aHUS)

1. Caused by complement pathway dysregulation
2. May be hereditary or acquired
3. Common abnormalities involve:
• Factor H
• Factor I
• MCP/CD46
• C3
• Factor B
• Anti–factor H antibodies
4. Associated laboratory pattern:
• Low C3
• Normal C4
5. Often recurrent and more severe

3. Pathophysiology

3.1 Typical HUS

1. Shiga toxin damages endothelial cells
2. Endothelial injury activates platelets and coagulation
3. Formation of microthrombi in small vessels
4. RBC fragmentation causes schistocyte formation
5. Renal microvascular injury leads to acute kidney injury

3.2 Atypical HUS

1. Uncontrolled activation of the alternative complement pathway
2. Complement-mediated endothelial injury
3. Persistent thrombotic microangiopathy

4. Clinical Features

4.1 Classic Triad

HUS

• H – Hemolysis (MAHA)
• U – Uremia (Acute kidney injury)
• S – Scarce platelets (Thrombocytopenia)

4.2 Common Features

1. Pallor
2. Fatigue
3. Oliguria or anuria
4. Hematuria
5. Edema
6. Hypertension
7. Petechiae or purpura

4.3 Gastrointestinal Features

1. Bloody diarrhea
2. Abdominal pain
3. Vomiting

4.4 Neurologic Features

1. Seizures
2. Altered mental status
3. Stroke-like symptoms

Prominent neurologic manifestations in adults should raise concern for TTP.

5. Diagnosis

5.1 CBC

1. Anemia
2. Thrombocytopenia

5.2 Peripheral Blood Smear

1. Schistocytes
2. Helmet cells

5.3 Hemolysis Markers

1. Elevated LDH
2. Elevated indirect bilirubin
3. Low haptoglobin
4. Increased reticulocyte count

5.4 Coagulation Studies

1. PT normal
2. aPTT normal
3. Fibrinogen normal

5.5 Renal Function Tests

1. Elevated serum creatinine
2. Elevated BUN
3. Proteinuria and hematuria may occur

5.6 Stool Testing

1. Stool culture or PCR for:
• EHEC O157:H7
• Shiga toxin

5.7 Complement Studies (Atypical HUS)

1. Low C3
2. Normal C4

5.8 ADAMTS13 Testing

1. Helps differentiate HUS from TTP
2. Severe ADAMTS13 deficiency strongly suggests TTP

6. Differential Diagnosis

1. Thrombotic thrombocytopenic purpura (TTP)
2. Disseminated intravascular coagulation (DIC)
3. Severe malignant hypertension
4. HELLP syndrome
5. Autoimmune hemolytic anemia
6. Sepsis-associated DIC

7. Distinguishing HUS from TTP

Feature	HUS	TTP
Predominant involvement	Renal	Neurologic
Age group	More common in children	More common in adults
Diarrheal illness	Common	Rare
ADAMTS13 deficiency	Absent/mild	Severe
Neurologic symptoms	Variable	Prominent
Plasma exchange	Usually not required	Urgent treatment

8. Management

8.1 Supportive Care

1. Intravenous fluids
2. Electrolyte correction
3. Blood transfusion if severe anemia
4. Dialysis if indicated for acute kidney injury

8.2 Important Precautions

1. Avoid antibiotics and antimotility agents in suspected EHEC/STEC-associated HUS because toxin release may worsen disease
2. Platelet transfusion generally avoided unless:
• Life-threatening bleeding
• Urgent invasive procedure required

8.3 Atypical HUS Treatment

1. Eculizumab (C5 complement inhibitor)
2. Ravulizumab may also be used
3. Plasma exchange in selected cases

9. Complications

1. Acute kidney injury
2. Chronic kidney disease
3. Hypertension
4. Neurologic complications
5. Seizures
6. Heart failure
7. Death (rare with prompt treatment)

10. Prognosis

Typical HUS

1. Usually self-limited
2. Most children recover completely
3. Mortality is low with supportive care

Atypical HUS

1. More severe and recurrent
2. Higher risk of chronic kidney disease
3. Worse long-term prognosis without complement inhibition

11. Key Clinical Insight

Child with bloody diarrhea followed by MAHA + thrombocytopenia + acute kidney injury strongly suggests typical HUS

12. Exam-Level Pearls

1. Most common cause of HUS:
• EHEC O157:H7
2. Classic association:
• Undercooked beef
3. Peripheral smear shows:
• Schistocytes
4. Coombs test is:
• Negative
5. PT and aPTT are:
• Normal
6. Typical HUS is primarily treated with:
• Supportive care
7. Avoid antibiotics in suspected STEC/EHEC infection
8. Atypical HUS is associated with:
• Complement dysregulation
9. Eculizumab is the treatment of choice for atypical HUS