Background: Hepatocellular carcinoma (HCC) is the 6th most commonly diagnosed cancer and the 3rd leading cause of cancer death in the US. Around 85-90% of primary liver cancer is HCC. Besides identified risk factors for HCC including chronic infection with hepatitis B and C virus (HBV and HCV), alcohol abuse, dietary aflatoxin exposure and hereditary hemochromatosis, nonalcoholic fatty liver disease (NAFLD) is as another important risk factor for HCC. NAFLD is a spectrum of liver disease that ranges from hepatic steatosis through non-alcoholic steatohepatitis (NASH) with or without fibrosis and may progress to cirrhosis or HCC. Iron is an essential metal and hepatocytes are its main storage site. Increased body iron from the intestine due to high dietary iron or hereditary or acquired hemochromatosis may result in hepatic iron overload. NAFLD is frequently associated with elevated serum iron indices when hepatic iron in the absence of hemochromatosis. Epidemiologic data on the association between serum iron markers and risk of HCC are sparse. The aim of the study was to examine the association of iron related serum markers with risk of HCC in NAFLD patients. We hypothesized that elevated serum iron levels, which reflects hepatic iron, are associated with increased risk of HCC among NAFLD patients.

Methods: 48,328 patients with NAFLD were identified in the electronic health records (EHR) of the University of Pittsburgh Medical Center (UPMC) between 1/1/2004 to 12/31/2018. Among them, 19,908 had at least one measurement of serum iron, transferrin saturation, total iron binding capacity (TIBC) and serum ferritin. After an average 4.47 years of follow-up, 363 patients with NAFLD were diagnosed with HCC at least 30 days after measurement of iron markers. Cox proportional hazard regression was used to calculate hazard ratios (HRs) and the 95% confidence intervals (CIs) for HCC incidence associated with elevated levels of the four iron markers adjusted for age, sex, race, body mass index, history of diabetes and tobacco smoking.

Results: Serum iron and transferrin saturation were significantly elevated in NAFLD patients who developed HCC compared to others who remained free of HCC during the study. The HR of HCC for elevated serum iron >175 mcg/dl was 3.41 (95% CI 1.48 - 7.85) compared to its normal range at 75-175 mcg/dl. Similarly, the HR for HCC associated with elevated transferrin saturation >35% was 2.56 (95% CI 1.49-4.39) relative to the normal range at 25-35%. The associations were not statistically significant for TIBC and serum ferritin with HCC risk.

Conclusions: Elevated serum iron and transferrin saturation levels, but not TIBC or serum ferritin, were significantly associated with increased risk of developing HCC in NAFLD patients. These findings support future studies evaluating serum iron level in risk stratification of NAFLD patients at risk of HCC and potential links to pathogenesis of HCC.

Citation Format: Yi-Chuan Yu, Renwei Wang, Jaideep Behari, Ada Youk, Nancy W. Glynn, Jian-Min Yuan. Serum iron markers in relation to hepatocellular carcinoma risk among patients with non-alcoholic fatty liver disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 754.