Is phlebotomy indicated in Non-Alcoholic Steatohepatitis (NASH) with hyperferritinemia?

From the Guidelines

Phlebotomy is not indicated for patients with non-alcoholic steatohepatitis (NASH) who have hyperferritinemia, as iron overload disorders do not generally cause acute liver injury and evaluation for iron overload is normally not necessary in a NASH patient with acute hepatocellular injury during a clinical trial 1.

Key Considerations

• Elevated ferritin levels in NASH patients typically represent inflammatory changes rather than true iron overload 1.
• Treatment should focus on addressing the underlying NASH through lifestyle modifications, including weight loss, regular exercise, and dietary changes 1.
• Phlebotomy may be considered only in select cases where there is documented hepatic iron overload with evidence of liver injury specifically attributable to iron, which is uncommon in typical NASH.

Evaluation and Management

• Patients with hyperferritinemia should undergo proper evaluation, including genetic testing for hereditary hemochromatosis and possibly liver biopsy to assess iron distribution and quantification.
• Inappropriate phlebotomy in NASH patients can lead to anemia without improving liver outcomes, as the elevated ferritin in these cases is primarily a marker of inflammation and oxidative stress rather than iron toxicity 1.

Clinical Implications

• The presence of hyperferritinemia in NASH patients should not be assumed to indicate iron overload, and phlebotomy should not be initiated without thorough evaluation and documentation of iron overload 1.
• Clinicians should prioritize lifestyle modifications and other evidence-based treatments for NASH, rather than relying on phlebotomy as a primary treatment strategy.

From the Research

Phlebotomy in NASH with Hyperferritinemia

• The use of phlebotomy in patients with nonalcoholic steatohepatitis (NASH) and hyperferritinemia is a topic of debate, with some studies suggesting its potential benefits and others indicating limited efficacy 2, 3, 4, 5, 6.
• A study published in 2001 found that patients with hyperferritinemia and normal transferrin saturation had increased liver iron concentration and were at risk for NASH, suggesting a potential role for iron depletion therapy 2.
• Another study published in 2007 found that iron depletion by phlebotomy improved insulin resistance in patients with nonalcoholic fatty liver disease and hyperferritinemia, although the effect was more pronounced in patients with higher ferritin levels and HFE gene mutations 3.
• However, a systematic review and meta-analysis published in 2018 found that phlebotomy did not significantly improve insulin resistance, liver enzymes, or liver histology in patients with dysmetabolic iron overload syndrome and non-alcoholic fatty liver disease, including those with hyperferritinemia 4.
• Other studies have suggested that hyperferritinemia in patients with NASH may be associated with insulin resistance and fatty liver, rather than iron overload, and that phlebotomy may not be effective in improving liver damage in these patients 5, 6.
• A randomized trial published in 2014 found that iron depletion by phlebotomy was associated with improvement in liver damage and liver enzymes in patients with NASH and hyperferritinemia, although the study had a small sample size and limited follow-up 6.

Key Findings

• Hyperferritinemia is common in patients with NASH and may be associated with insulin resistance and fatty liver, rather than iron overload 2, 5.
• Phlebotomy may improve insulin resistance and liver enzymes in patients with NASH and hyperferritinemia, although the evidence is limited and conflicting 3, 6.
• The use of phlebotomy in patients with NASH and hyperferritinemia should be individualized and based on careful consideration of the potential benefits and risks, as well as the presence of other underlying conditions such as iron overload or HFE gene mutations 2, 3, 4, 5, 6.