Can antithymocyte globulin (ATG) cause an increase in serum transaminases (AST and ALT)?

Can ATG Increase Transaminases?

Yes, ATG can cause transaminase elevations, though the frequency and severity differ between formulations: equine ATG causes uncommonly reported liver toxicity, while rabbit ATG causes transient liver function abnormalities that are rarely observed but can be severe when they occur.

Key Differences Between ATG Formulations

Equine ATG (ATGAM)

According to the American College of Chest Physicians guidelines, liver toxicity with equine ATG is uncommonly reported 1. When it does occur, it typically manifests as part of a broader serum sickness reaction, with nephrotoxicity being more common (occurring in approximately 10% of patients) 1.

Rabbit ATG (Thymoglobulin)

The guidelines state that transient liver function abnormalities are rarely observed with rabbit ATG 1. However, clinical research reveals a more nuanced picture:

• Severe acute hepatotoxicity (SAH) occurs in approximately 26% of patients receiving rabbit ATG before allogeneic stem cell transplantation 2
• Transaminase elevations typically occur within 1-3 days after ATG administration 2, 3
• Peak levels can reach 8.7× ULN for AST and 11.7× ULN for ALT (range up to 100-160× ULN in severe cases) 2
• Elevations are typically self-limiting, resolving below 2× ULN within a median of 9 days 2

Clinical Characteristics of ATG-Induced Transaminitis

Pattern of elevation:

• Rapid onset (hours to 2 days post-infusion) 3
• Predominantly transaminase elevation (AST/ALT) with inconsistent bilirubin elevation 1
• International Normalized Ratio may be elevated in 44% of cases 2
• Resolution typically occurs within 1-2 weeks without intervention 2, 4

Special populations at higher risk:

• Patients with myelofibrosis receiving ATG experience hyperbilirubinemia in 90% of cases (compared to 56% in non-MF patients), likely due to extramedullary hematopoiesis in the liver 5
• Patients with systolic blood pressure <90 mmHg during ATG administration 2
• Patients with prior autologous stem cell transplants 2

Clinical Significance and Management

The transaminase elevation is generally benign:

• No deleterious impact on survival, non-relapse mortality, or GVHD has been demonstrated 2
• Not predictive of hepatic sinusoidal obstruction syndrome (SOS) or liver GVHD 5
• Hepatic dysfunction was reported in 25% of patients in NCCN guidelines but was not associated with poor outcomes 6

Important monitoring considerations: According to FDA labeling and clinical guidelines, hepatic function should be monitored periodically during ATG therapy 7:

• Daily monitoring during initiation of therapy 1
• In clinical trials, mycophenolate mofetil was stopped if AST/ALT remained >3× ULN after 35 days 7

Critical management points:

• Avoid hepatotoxic drugs during the acute elevation period to prevent compounding liver injury 2
• Monitor for hemorrhagic complications if INR is elevated 2
• Attention to biliary-excreted drugs (busulfan, antifungals) is warranted, as altered bile flow may enhance their toxicity 5
• If severe hepatotoxicity occurs with one ATG formulation, switching to an alternative formulation may be successful (e.g., horse to rabbit ATG) 8

Common Pitfalls

1. Mistaking ATG-induced transaminitis for other causes: The rapid onset (within hours to days) and self-limiting nature help distinguish this from viral hepatitis, drug-induced liver injury from other agents, or GVHD-related liver injury

2. Unnecessary discontinuation of ATG: Given the transient and generally benign nature, continuation or completion of ATG therapy is usually appropriate unless transaminases remain severely elevated beyond 2 weeks

3. Inadequate monitoring in high-risk populations: Patients with myelofibrosis or pre-existing liver involvement require closer monitoring for both transaminase and bilirubin elevations