Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis

OBJECTIVE: The aim of this study was to define in patients with hyperferrit inemia and normal transferrin saturation the relationships among hyperferri tinemia, iron overload, HFE gene mutations, the presence of metabolic alter ations, and nonalcoholic steatohepatitis (NASH). most of the cases associat ed with insulin resistance, is responsible for persistent hyperferritinemia and identifies patients at risk for NASH. METHODS: Forty patients with increased serum ferritin. resistant to dietary restriction and normal transferrin saturation, 90 with ultrasonographic ev idence of hepatic steatosis, and 60 obligate heterozygotes for hemochromato sis, all negative for alcohol abuse, hepatitis virus infections, and inflam mation were studied. Transferrin saturation., serum ferritin, uric acid, li pids, glucose tolerance, insulin resistance, HFE gene mutations. liver hist ology, and hepatic iron concentration were analyzed. RESULTS: Of the 40 patients with hyperferritinemia, 29 (72%) had biochemica l metabolic abnormalities. 18 of the 26 examined (69%) had insulin resistan ce, 26 (65%) had the presence of one of the two HFE gene mutations (normal controls. 33 of 128 [26%], p < 0.0001), and all had increased liver iron co ncentration. Thirty-one patients (77%) had histology compatible with NASH. At univariate analysis, NASH was significantly associated with the presence of metabolic alterations. the C282Y mutation, and severity of fibrosis. At multivariate analysis, NASH was associated with the coexistence of multipl e metabolic alterations (odds ratio = 5.2, 95% CI = 0.95-28.7). The risk of having NASH augmented in the presence of higher values of ferritin and liv er iron concentration. Among the 90 patients with ultrasonographic evidence of hepatic steatosis, 24 (27%) had increased serum ferritin with normal tr ansferrin saturation, but only six remained hyperferritinemic after dietary restriction. CONCLUSION: Increased ferritin with normal transferrin saturation is freque ntly found in patients with hepatic steatosis, but it reflects iron overloa d only in those patients in whom it persists despite an appropriate diet. T he simultaneous disorder of iron and glucose and/or lipid metabolism, in mo st of the cases associated with insulin resistance, is responsible for pers istent hyperferritinemia and identifies patients at risk for NASH.