Patients with nonalcoholic fatty liver disease (NAFLD) had a significantly higher risk of developing hepatocellular carcinoma (HCC) based on elevated biomarker levels of serum iron or transferrin saturation, a researcher reported.

In an analysis of over 18,000 NAFLD patients, elevated serum iron levels over 175 μg/dL were associated with a more than two-fold higher risk of developing HCC (HR 2.44, 95% CI 1.06-5.62), while lower iron levels (less than 75 μg/dL) were associated with a 33% reduction in HCC risk (HR 0.67, 95% CI 0.48-0.93, P<0.001) versus patients with normal serum iron levels (75 to 175 μg/dL range), reported Yi-Chuan Yu, MD, of the University of Pittsburgh Medical Center Hillman Cancer Center.

Transferrin saturation levels greater than 35% were also associated with a two-fold greater risk for these patients to develop HCC (HR 2.18, 95% CI 1.27-3.74) versus those with normal transferrin saturation levels (25% to 35% range), he said in a presentation at the American Association for the Study of Liver Diseases (AASLD) virtual meeting.

Over the course of 4.35 years of follow-up, 192 patients with NAFLD developed HCC, and the majority were white, men, older in age, smokers or prior smokers, and had hypertension, hyperlipidemia, or type 2 diabetes (T2D) compared with patients with NAFLD who did not develop HCC (P<0.001 for all), according to the researchers.

Douglas T. Dieterich, MD, of the Icahn School of Medicine at Mount Sinai in New York City, called the findings interesting, stating that “We know that iron is a proinflammatory compound so that part makes sense. The real question to ask is: Are those patients with elevated iron heterozygous for hemochromatosis?”

No significant association with HCC risk was observed for the other iron biomarkers, serum ferritin or total iron binding capacity.

“The fact that ferritin is not associated would argue against this hemochromatosis, another good marker to look into as a prognostic predictor for NASH [nonalcoholic steatohepatitis],” Dieterich added, who was not involved in this study.

“Nonalcoholic fatty liver disease has become a major contributor to rising incidence of hepatocellular carcinoma here in the U.S.,” Yu said. “Iron, an essential metal, is primarily stored in hepatocytes and this metal played a role in the development of NAFLD related to HCC,” describing limited epidemiological data available for NAFLD patients without hemochromatosis or other major underlying causes of chronic liver disease.

Iron overload has been caused by hereditary hemochromatosis, a metabolic risk factor associated with the development of HCC, the researchers noted. Excess iron deposits have also been associated with microvascular complications of poorly controlled T2D.

Yu and colleagues evaluated electronic health records data on 47,970 patients (ages 40-89) with NAFLD who did not have hemochromatosis. They were enrolled in a large healthcare system from January 2004 to December 2018. For the current analysis, 18,569 patients were included after being tested for at least one of four iron biomarkers — serum ferritin, serum iron, transferrin saturation, or total iron binding capacity. The NAFLD cohort had compensated cirrhosis, decompensated cirrhosis, and NASH.

Primary outcome assessed the association of the serum biomarkers of iron with HCC incidence among patients with NAFLD. Proportional regression analysis for calculating HCC incidence associated with an elevation in an iron biomarker adjusted for demographics, BMI, smoking, and T2D.

Patients were mostly white (93%) and female (51%) with a mean age of 66 and a mean BMI of 32.5.

“We conclude that this clinical surveillance of serum iron levels, especially the serum iron in transferrin saturation tests, may be a potential strategy in identifying patients with NAFLD who are at higher risk for hepatocellular carcinoma,” Yu said.

Study limitations included a lack of diversity in participants, limiting the generalizability of the results.

“Further research is warranted to study the association of iron indices on risk of developing HCC in NAFLD,” the researchers wrote.