In a patient with thalassemia and elevated transaminases, what are the most likely causes and how should the work‑up and management be approached?

Transaminitis in Thalassemia: Causes and Management

Primary Causes

In thalassemia patients with elevated transaminases, the two dominant causes are transfusion-transmitted viral hepatitis (particularly hepatitis C) and iron overload, which act synergistically to cause liver injury. 1

Viral Hepatitis

• Chronic hepatitis C is the most common form of transfusion-transmitted hepatitis worldwide, while hepatitis B predominates in Asia 1
• The prevalence of chronic hepatitis C remains high in patients born before 1990, despite screening programs that reduced transmission risk to <2 per million after the 1990s 1
• Anti-HCV positivity shows statistically significant association with ALT ≥40 U/L, with mean ALT of 60.91 U/L in anti-HCV positive versus 39.29 U/L in negative patients 2

Iron Overload

• Both viral hepatitis and iron overload independently cause liver fibrosis, cirrhosis, and hepatocellular carcinoma; when both are present, the effect is synergistic 1
• Mean serum ferritin is significantly higher in patients with ALT ≥40 (2553 μg/L versus 1784 μg/L, p=0.012) 2
• Mean ALT is significantly higher when transferrin saturation ≥60% (41.26 U/L versus 28.82 U/L, p=0.021) 2
• Grade 3-4 hemosiderosis occurs in 44% of patients and correlates with higher liver enzymes 3

Chelator-Related Hepatotoxicity

• Deferasirox has documented renal side effects and can affect liver function 1
• Irregular use of iron chelators predicts higher liver iron load regardless of chelator type 4

Diagnostic Work-Up

Initial Laboratory Assessment

• Check anti-HCV antibody, HBsAg, serum ferritin, transferrin saturation, and complete liver enzyme panel 2
• Measure serum iron and calculate transfusion index (frequency × units of transfusion), as both are significantly higher in anti-HCV positive patients 2
• Serum ferritin level is the single most significant predictor of liver iron load in multiple regression models 4

Advanced Imaging

• T2 MRI is the gold standard for quantifying liver iron concentration* and should be performed to assess iron burden 4
• Liver biopsy provides definitive information on fibrosis stage and liver iron content that cannot be accurately predicted from peripheral blood markers alone 3
• Hepatic fibrosis occurs in 30% of patients and is significantly associated with higher serum ferritin, liver enzymes, and liver iron content 3

Hepatitis C Genotyping

• Obtain HCV genotype and viral load, as genotype 1 is associated with poorer treatment response 5
• Lower serum HCV RNA levels predict better treatment response 5

Management Approach

Iron Chelation Optimization

• Iron chelation therapy with deferoxamine or deferasirox is the treatment of choice for secondary iron overload associated with ineffective erythropoiesis 1
• Multiple studies document efficacy of deferoxamine in preventing complications of iron overload in β-thalassemia 1
• Ensure regular, not irregular, use of chelators—irregular use is associated with higher risk of cardiac and liver iron load regardless of chelator type 4
• Monitor liver iron concentration as it provides accurate, quantitative means for monitoring iron balance 1

Antiviral Therapy Considerations

• Hepatic iron overload does not prevent sustained virological response to interferon-based therapy—28% of patients with massive iron overload (median HIC 2583 μg/g) achieved durable sustained response after mean 66 months follow-up 5
• Liver iron concentration does not differ between responders and nonresponders to interferon therapy 5
• Do not delay antiviral treatment based solely on elevated iron stores 5

Surveillance for Complications

• The prevalence of cirrhosis in adult thalassemia major patients ranges from 10-20%, which predisposes to end-stage liver failure and hepatocellular carcinoma 1
• Hepatocellular carcinoma, once rare, now has rising prevalence in thalassemia major 1
• Patients with cirrhosis require regular screening for hepatocellular carcinoma, following protocols similar to other causes of cirrhosis 1

Critical Pitfalls to Avoid

• Do not assume normal serum ferritin excludes significant liver iron overload—severe hemosiderosis and hepatic fibrosis occur despite chelation therapy, and liver biopsy may reveal very high liver iron content (>15 mg/g) in 16.3% of patients 3
• Do not withhold antiviral therapy based on iron overload alone, as hepatic iron concentration does not reliably predict interferon response 5
• Re-evaluate transfusion protocols and chelation doses when transaminitis develops, particularly in older patients with higher transfusion indices 2
• Recognize that in individual patients with both viral hepatitis and iron overload, it may be impossible to distinguish the relative contribution of each factor 1