Increased serum iron may hint at HCC risk in NAFLD patients

Increased serum iron or transferrin saturation levels in individuals with non-alcoholic fatty liver disease (NAFLD) may point to an increased risk of hepatocellular carcinoma (HCC), according to a study presented at The Liver Meeting Digital Experience™.

“Since HCC develops in only a small percentage of NAFLD patients, our findings – if confirmed in larger, prospective studies – may help identify patients at increased risk of developing HCC. Those patients could then be targeted for more intensive surveillance,” said senior author Professor Jian-Min Yuan, Arnold Palmer Endowed Chair in Cancer Prevention, UPMC Hillman Cancer Center, and professor of epidemiology at the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, US.

Based on electronic health records from the University of Pittsburgh Medical Center Health Plan in 2004–2018, the researchers identified 47,165 patients who were aged 40–89 years (mean age 66.1 years, 51.2 percent female, 92.6 percent White) when diagnosed with NAFLD*. Of these, 18,569 had available data (≥1 measurement) on serum iron, transferrin saturation, total iron binding capacity (TIBC), and serum ferritin. A total of 224 patients developed HCC over an average 4.34-year follow-up period.

The mean BMI of the patients was 32.5 kg/m². About 88 percent had a history of hypertension, 61.5 percent had a history of type 2 diabetes (T2D), and 65.2 percent had a history of dyslipidaemia. Forty-seven and 38.5 percent were ever- and never-smokers, respectively.

After adjusting for age, sex, race, BMI, history of T2D, and smoking, patients with NAFLD who developed HCC were more likely to be older and male compared with those who did not develop HCC. They were also more likely to be ever-smokers and have a history of T2D or hypertension, but have lower lipid levels, compared with those who did not develop HCC.

Individuals with elevated serum iron levels (>175 μg/dL) had a more than twofold risk of developing HCC compared with those with normal serum iron levels (75–175 μg/dL; hazard ratio [HR], 2.91, 95 percent confidence interval [CI], 1.34–6.30). [The Liver Meeting Digital Experience™, abstract 1048]

Transferrin saturation >35 percent was also associated with a significantly increased risk of HCC compared with normal transferrin saturation levels (25–35 percent; HR, 2.02, 95 percent CI, 1.22–3.32).

TIBC and elevated serum ferritin levels did not appear to have any bearing on HCC risk in patients with NAFLD.

“NAFLD may contribute to the rising incidence of HCC in the US. However, only a small fraction of NAFLD patients eventually develop HCC,” Yuan said. With the liver being the main reservoir for iron in the body, an overload of iron could contribute to liver damage, he continued.

“Elevated levels of serum iron and transferrin saturation were significantly associated with increased risk of HCC among patients with NAFLD without haemochromatosis or other major underlying causes of chronic liver diseases,” Yuan noted. “A direct link between serum iron level and HCC risk would support a harmful role of iron elevation on HCC development in NAFLD patients.”

However, Yuan highlighted the need for further research into the potential effects of these findings. “[S]ince serum iron levels change constantly in response to physiologic needs, more research is needed to understand the clinical implications of persistence and magnitude of serum iron elevation, as well as the lack of association of ferritin levels with HCC risk in NAFLD patients,” he concluded.