Role of Total Homocysteine Level and Anti-Factor H Antibody in Pediatric HUS
Total Homocysteine Level
Total homocysteine level is critical for identifying methylmalonic acidemia with homocystinuria (MMACHC) causing cobalamin deficiency, which can present as HUS-like thrombotic microangiopathy, particularly in infants under 1 year of age. 1
When to Measure Homocysteine
Measure total homocysteine level in all pediatric patients with suspected HUS, especially infants <1 year old, to exclude complement-unrelated genetic causes of thrombotic microangiopathy. 1
This test helps differentiate between true complement-mediated aHUS and metabolic disorders that mimic HUS clinically but require entirely different treatment approaches. 1
Clinical Significance
Elevated homocysteine levels combined with methylmalonic acid elevation indicate MMACHC deficiency, which requires cobalamin supplementation rather than complement inhibition. 1
This distinction is crucial because treating MMACHC-related TMA with eculizumab would be inappropriate and delay correct metabolic therapy. 1
Anti-Factor H (Anti-FH) Antibody
Anti-Factor H antibody testing is essential for diagnosing a specific, highly treatable form of aHUS that requires immunosuppression and plasma exchange rather than complement inhibitors alone. 2, 3
Diagnostic Role
Anti-FH antibodies cause 6-10% of aHUS cases and primarily affect children between 9-13 years old, though adults can also be affected. 3
In Indian pediatric cohorts, anti-FH antibody-associated HUS constitutes up to 56% of all HUS cases, making it a common cause in certain populations. 2
The presence of anti-FH antibodies fundamentally changes treatment strategy from complement inhibition to immunosuppression plus plasma exchange. 2, 4
Key Clinical Features of Anti-FH HUS
High frequency of gastrointestinal symptoms at presentation, which can confuse the clinical picture with STEC-HUS. 3
Extrarenal complications occur commonly. 3
Relapsing course is characteristic, requiring long-term immunosuppressive maintenance therapy. 2, 3
Antibody titers are typically very high (mean 7054 AU/ml) and correlate inversely with C3 levels, but not with Factor H levels themselves. 2
Genetic Association
Homozygous deletion of the CFHR1 gene is found in approximately 88% (60 of 68) of patients with anti-FH antibody-associated HUS. 2
This genetic finding supports the autoimmune mechanism and helps confirm the diagnosis. 2
Treatment Implications
Prompt plasma exchanges combined with induction immunosuppression (prednisolone with or without intravenous cyclophosphamide or rituximab) significantly improves outcomes, preventing one adverse outcome for every 2.6 patients treated. 2
Antibody titers fall significantly following plasma exchanges and increase during relapses, making serial anti-FH antibody measurements useful for monitoring disease activity and guiding treatment. 2, 5
Maintenance immunosuppression with prednisolone plus either mycophenolate mofetil or azathioprine significantly reduces relapse risk. 2
Prognostic Factors
Independent risk factors for adverse outcome (stage 4-5 CKD or death) include:
Activation of the alternative complement pathway at disease onset portends poor prognosis. 3
Monitoring Strategy
Serial anti-FH IgG titer measurements serve as sensitive markers of disease activity and should guide treatment decisions regarding plasma exchange frequency and immunosuppression intensity. 5
Rising titers indicate impending relapse and need for treatment intensification. 2, 5
Critical Pitfalls to Avoid
Do not assume all pediatric aHUS requires eculizumab—anti-FH antibody-associated HUS responds better to immunosuppression and plasma exchange. 2, 4
Do not delay testing for anti-FH antibodies while initiating supportive care, as early specific treatment leads to favorable outcomes. 3
Do not stop immunosuppression prematurely in anti-FH HUS, as this leads to relapse with rising antibody titers. 2
In transplant recipients, anti-FH antibodies can emerge decades after initial HUS presentation (up to 30 years later), requiring vigilant monitoring. 5
Practical Testing Algorithm
Order both total homocysteine and anti-FH antibody testing as part of the initial aHUS workup, alongside genetic testing for complement genes. 6, 1
If anti-FH antibodies are positive, also measure C3 levels (expect inverse correlation with antibody titer) and consider CFHR1 gene deletion testing. 2
Continue monitoring anti-FH antibody titers every 3-6 months during maintenance therapy to detect early relapse. 2, 5