What is the treatment for a patient with Hemophagocytic Lymphohistiocytosis (HLH) and acute hepatic failure?

Treatment of HLH with Acute Hepatic Failure

Immediate HLH-directed immunosuppression with dexamethasone (10 mg/m² daily) combined with etoposide is the cornerstone of treatment, alongside aggressive supportive care and identification/treatment of underlying triggers, though prognosis remains guarded and liver transplantation is generally contraindicated. 1

Initial Assessment and Diagnostic Confirmation

• Confirm HLH diagnosis using HLH-2004 criteria (≥5 of 8 criteria including fever, splenomegaly, cytopenias, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia >500 µg/L, low/absent NK cell activity, elevated sCD25, and hemophagocytosis on bone marrow) 1
• Investigate underlying triggers aggressively: viral infections (EBV, CMV, VZV, HSV, HIV), malignancies (particularly T-cell lymphomas), and autoimmune conditions 1, 2
• Bone marrow biopsy should be performed to document hemophagocytosis, though absence does not exclude HLH 1, 3
• Monitor ferritin, sCD25, complete blood counts, and liver function tests to assess disease severity and treatment response 1

HLH-Directed Immunosuppressive Therapy

Severe Presentation with Organ Failure (Most Cases with ALF)

Immediate etoposide-based therapy is indicated for severe HLH with imminent organ failure: 1

• Dexamethasone 10 mg/m² daily (divided doses) 1, 2
• Etoposide at modified HLH-94 dosing, though dose reduction is NOT required for isolated hyperbilirubinemia or elevated transaminases (only reduce for renal impairment) 1
• Weekly reevaluation of need for continued etoposide therapy, with most patients requiring 8 weeks of treatment 1
• Cumulative etoposide dose should stay below 2-3 g/m², particularly in non-malignant HLH 1

Adjunctive Therapies

• Intravenous immunoglobulin (IVIG) up to 1.6 g/kg in split doses over 2-3 days may be added for anti-inflammatory effects 1, 2
• Cyclosporine A (2-7 mg/kg/day) can be added for insufficient response, with careful drug level monitoring 1
• Anakinra (2-10 mg/kg/day subcutaneously in divided doses) is emerging as an alternative, particularly for refractory cases, though efficacy data in adults with ALF are limited 1, 4

Trigger-Specific Treatment

Concurrent treatment of underlying triggers is essential and may be lifesaving: 1

• EBV-HLH: Consider adding rituximab (375 mg/m² weekly for 2-4 doses) to target B-cell reservoir, though this cannot replace anti-T-cell therapy with corticosteroids/etoposide 1
• VZV/HSV: High-dose acyclovir with immunosuppression has shown success in case reports 2
• HIV-HLH: Short-course corticosteroids ± IVIG; etoposide used in approximately half of cases 1
• Bacterial/fungal infections: Broad-spectrum antimicrobials with prophylaxis against Pneumocystis jirovecii and fungi during immunosuppressive therapy 1

Critical Care Management

ICU-level supportive care is mandatory: 1

• Frequent reassessment (at least every 12 hours) to determine need for escalation of HLH-directed therapy 1
• Broad antimicrobial prophylaxis given profound immunosuppression from both disease and treatment 1
• Standard ALF supportive measures including coagulopathy management, metabolic monitoring, and infection surveillance 1
• Consider HEPA-filtered air in hospitalization units 1

Role of Liver Transplantation

Liver transplantation is generally CONTRAINDICATED in HLH-associated ALF: 1

• Primary (familial) HLH: LT does not address the underlying immune dysregulation and carries high risk of HLH relapse in the transplanted organ 1
• Secondary HLH: The 2014 AASLD/AST/NASPGHAN guideline states that "chemotherapy and bone marrow transplantation may reverse an otherwise unfavorable prognosis" and that "LT is considered contraindicated given the relapse risk" 1
• Exception: A 2025 case report suggests LT may be considered in highly selected secondary HLH-ALF cases when medical management fails, though post-transplant complications are significant 5

Prognosis and Outcomes

Survival remains poor despite aggressive treatment: 3, 6

• Adult HLH-ALF has high mortality, with most patients dying or requiring transplantation in historical series 2, 3
• Biochemical response to etoposide-based therapy is high (>75% ferritin reduction in 21/23 adults), but one-year survival was only 33% in one series 6
• Successful medical rescue without transplantation has been reported in isolated cases using combination of trigger-specific therapy (acyclovir), dexamethasone, and etoposide 2

Critical Pitfalls to Avoid

• Do not delay etoposide in severe HLH with organ failure due to concerns about hepatotoxicity—dose reduction is not required for liver dysfunction alone 1
• Do not miss underlying triggers, particularly treatable viral infections that require specific antiviral therapy 1, 2
• Do not pursue liver transplantation as first-line therapy—medical management with HLH-directed immunosuppression and bone marrow transplantation (for primary HLH) is the appropriate approach 1
• Do not withhold antimicrobial prophylaxis—secondary infections are a major cause of mortality during immunosuppressive therapy 1