What is the pathogenesis of childhood Hemolytic Uremic Syndrome (HUS)?

Pathogenesis of Childhood Hemolytic Uremic Syndrome

Childhood HUS develops through two distinct pathogenic mechanisms: typical HUS results from Shiga toxin-mediated endothelial injury following STEC infection (90% of cases), while atypical HUS arises from dysregulated complement activation due to genetic mutations or autoantibodies (5-10% of cases). 1, 2

Typical (STEC-Associated) HUS Pathogenesis

Initial Infection and Toxin Production

• Shiga toxin-producing Escherichia coli (STEC), particularly O157:H7 and non-O157 strains (O26, O45, O103, O111, O121, O145), colonize the gastrointestinal tract after ingestion of contaminated food, water, or through person-to-person transmission 1, 3
• The infectious dose is remarkably low, requiring fewer than 100 organisms for O157 and O111 strains 1
• After a median incubation period of three days, patients develop diarrhea (bloody in approximately 60% of cases), which typically precedes HUS by 4-5 days 4, 3

Toxin-Mediated Endothelial Damage

• Shiga toxin binds to globotriosyl ceramide (Gb3) receptors on endothelial cells, particularly abundant in renal glomerular and tubular cells 5
• Once internalized, the toxin interferes with protein synthesis by cleaving ribosomal RNA, leading to endothelial cell death 5
• The kidney is the primary target organ, though nearly every organ system can be involved, with central nervous system damage occurring in 10-20% of cases 4, 5

Thrombogenic Cascade

• Endothelial injury causes loss of antithrombogenic properties and triggers a cascade of prothrombotic events 5
• Multiple mediators participate in this cascade: von Willebrand factor release, platelet activation via platelet-activating factor, inflammatory cytokines (interleukins 1,6,8), activated polymorphonuclear neutrophils, and altered arachidonic acid metabolites (particularly reduced prostacyclin I2) 5
• Nitric oxide depletion and lipopolysaccharide effects further contribute to microvascular thrombosis 5
• This results in the characteristic triad: microangiopathic hemolytic anemia (from red cell fragmentation in damaged microvasculature), thrombocytopenia (from platelet consumption), and acute renal injury 1, 3

Atypical HUS Pathogenesis

Complement Dysregulation

• Atypical HUS results from uncontrolled activation of the alternative complement pathway on endothelial cell surfaces 6, 2
• Genetic mutations in complement regulatory proteins occur in approximately 60% of atypical HUS cases, affecting genes including CFH, CFI, CD46, C3, CFB, THBD, and CFHR1-5 4, 6, 2
• These mutations lead to excessive complement activation and formation of the membrane attack complex (C5b-9) on endothelial cells 6

Autoantibody-Mediated Disease

• Some patients develop autoantibodies against complement regulatory proteins (particularly anti-factor H antibodies) that impair normal complement regulation 6
• This mechanism is more common in adults than children with atypical HUS 7

Age-Specific Considerations in Infants

• When atypical HUS presents in the first year of life, mutations in complement-unrelated genes should be considered, particularly DGKE and WT1 4
• Methylmalonic acidemia with homocystinuria cblC type (MMACHC) represents an ultra-rare metabolism-associated HUS caused by cobalamin deficiency 4

Secondary HUS-Like Mechanisms

Other Thrombotic Microangiopathies

• Systemic lupus erythematosus can produce HUS-like syndromes through monoclonal immunoglobulins acting as autoantibodies against complement regulatory proteins 1
• Antiphospholipid syndrome causes similar pathology by inhibiting prostacyclin formation and protein C activation 4, 1
• Chronic hemolytic anemias (sickle cell disease, thalassemia, hereditary spherocytosis) can trigger thrombotic microangiopathy through high nitric oxide consumption 1

Clinical Implications of Pathogenesis

• The pathogenic distinction between typical and atypical HUS has critical prognostic implications: typical HUS rarely relapses and has favorable immediate outcomes with supportive care, while atypical HUS follows a relapsing course with more than 50% progressing to chronic renal dysfunction and 10% mortality 6, 8, 2
• Children under 5 years have the highest incidence of STEC infection and greatest risk for HUS progression, making this the most common cause of acute renal failure requiring dialysis in this age group 1
• The timing of diarrhea onset helps distinguish etiologies: STEC-HUS typically appears 4-5 days after diarrhea onset, while simultaneous onset of diarrhea and HUS suggests atypical HUS 4