Medicine · 7 authors, 3 centres
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This review examines how abnormal hepcidin expression leads to iron overload in various liver diseases, including chronic hepatitis B and C, alcoholic liver disease, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Hepcidin dysregulation disrupts iron homeostasis, promoting oxidative stress and liver damage. Understanding these mechanisms may guide iron-reduction therapies such as phlebotomy, chelation, and interferon to improve patient outcomes.
**Background** Iron is essential for many biochemical processes, but excess iron is toxic. The liver is the primary site of iron storage and the main source of hepcidin, a 25-amino-acid peptide hormone that regulates systemic iron homeostasis by binding to ferroportin (FPN) and inducing its degradation, thereby reducing iron release into the circulation. Iron overload (defined as >5 g of total body iron) leads to reactive oxygen species (ROS) production via the Fenton reaction, causing cellular damage. This review explores the relationship between abnormal hepcidin expression and iron overload in liver diseases.
**Methods** This is a narrative review summarizing published literature on hepcidin regulation and its role in liver diseases. The authors discuss the BMP-SMAD pathway, IL-6/STAT-3 signaling, and the EPO-ERFE axis as key regulators of hepcidin. They then examine evidence linking hepcidin dysregulation to iron overload in chronic hepatitis B (CHB), chronic hepatitis C (CHC), alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), and hepatocellular carcinoma (HCC).
**Key Results** - **CHB:** Up to 27.1% of patients have elevated transferrin saturation, and 48.7% have liver iron deposition. Serum ferritin decreases after anti-HBV therapy. IL-6 levels are higher in CHB patients and stimulate hepcidin via STAT-3. Hepcidin changes are associated with HBV progression. - **CHC:** Up to 40% of patients have elevated total iron reserves. HCV suppresses hepcidin expression, unlike HBV. HCV-induced ROS and histone deacetylase activity reduce hepcidin transcription. Iron overload is linked to more advanced fibrosis and may contribute to diabetes risk. - **ALD:** Alcohol inhibits C/EBPα, reducing hepcidin mRNA expression. In a study of 45 ALD patients, the ratio of hepcidin mRNA to serum ferritin was significantly decreased. Low hepcidin levels in 237 alcoholic cirrhosis patients were independently associated with death and higher liver cancer risk. - **NAFLD:** Approximately 30% of NAFLD patients have iron overload (dysmetabolic hepatic iron overload syndrome). Up to 60% of NASH patients have elevated serum ferritin. Serum hepcidin is higher in NAFLD, leading to decreased FPN and increased hepatocyte iron. Iron overload is associated with higher fibrosis grade. - **HCC:** Hepcidin mRNA is generally suppressed in HCC tissues. In HBV-related HCC, serum iron is negatively correlated with tumor size. Iron overload is present in 50% of HCC patients with noncirrhotic liver. Sorafenib combined with deferasirox enhances HCC cell apoptosis. - **Iron reduction therapy:** Interferon-α upregulates hepcidin via STAT-3. Phlebotomy reduces disease progression and HCC incidence in HCV patients. Chelating agents like deferasirox effectively remove iron but have liver/kidney side effects. Erythrocytapheresis selectively removes red blood cells to increase iron removal.
**Clinical Implications** Hepcidin dysregulation is central to iron overload in multiple liver diseases. Iron overload exacerbates liver injury, fibrosis, and HCC risk. Monitoring serum ferritin and hepcidin levels may help stratify risk and guide therapy. Iron reduction strategies (phlebotomy, chelation, interferon) can improve outcomes, but further research is needed to optimize treatment and understand the mechanisms linking iron to liver disease progression.