Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver

Abstract

The mechanism(s) determining the progression from fatty liver to steatohepatitis is currently unknown. Our goal was to define the relative impact of iron overload, genetic mutations of HFE, and insulin resistance on the severity of liver fibrosis in a population of subjects with nonalcoholic fatty liver disease (NAFLD) who had low prevalence of obesity and no overt symptoms of diabetes. In a cohort of 263 prospectively enrolled patients with NAFLD, 7.4% of patients had signs of peripheral iron overload and 9% had signs of hepatic iron overload, but 21.1% had hyperferritinemia. The prevalence of C282Y and H63D HFE mutations was similar to the general population and mutations were not associated with iron overload. Although subjects were on average only moderately overweight, insulin sensitivity, measured both in the fasting state and in response to oral glucose, was lower. Univariate analysis demonstrated that the presence of severe fibrosis was independently associated with older age, female sex, overweight, aspartate/alanine aminotransferase ratio, serum ferritin level, fasting glucose and insulin levels, decreased insulin sensitivity, and with histologic features (degree of necroinflammation and steatosis). After adjustment for body mass index (BMI), age, sex, and degree of steatosis, ferritin levels (odds ratio [OR] ‫؍‬ 1.77; 95% CI ‫؍‬ 1.21-2.58; P ‫؍‬ .0032) and the oral glucose insulin sensitivity (OR ‫؍‬ 0.53; CI ‫؍‬ 0.33-0.87; P ‫؍‬ .0113) were independent predictors of severe fibrosis. In conclusion, the current study indicates that insulin resistance is a major, independent risk factor for advanced fibrosis in patients with NAFLD. Increased ferritin levels are markers of severe histologic damage, but not of iron overload. Iron burden and HFE mutations do not contribute significantly to hepatic fibrosis in the majority of patients with NAFLD. (HEPATOLOGY 2004;39:179 -187.) N onalcoholic fatty liver disease (NAFLD) is growing in importance, causing in a wide spectrum of hepatic injury, ranging from fatty liver to steatohepatitis and cirrhosis. 1 Whereas pure fatty liver has a benign clinical course, nonalcoholic steatohepatitis (NASH) is a recognized cause of progressive liver fibrosis that eventually leads to cirrhosis, liver failure, and hepatocellular carcinoma. 2-4 NAFLD and NASH are the two most common chronic liver diseases in Western countries, with an estimated prevalence in the general population of 10% to 20% and 2% to 3%, respectively. 2,5-7 A two-hit theory 8 has been proposed to explain the progression from simple steatosis to NASH, fibrosis, or cirrhosis. The first hit is represented by excessive hepatic fat accumulation primarily owing to insulin resistance and is supported by the close relation observed between NAFLD and several features of the metabolic syndrome (visceral obesity, type II diabetes mellitus, and dyslipidemia). 9 -11 The second hit is related mainly to increased intrahepatic oxidative stress, which promotes hepatic fibrosis through the production of reactive oxygen sp...

Hepatic iron concentration correlates with insulin sensitivity in nonalcoholic fatty liver disease

“…Notably, in keeping with our findings, a cross‐sectional study of 80 Italian patients with biopsy‐proven NAFLD found that the oral glucose sensitivity index increased with increasing HIC 28. Furthermore, a recently published, randomized, controlled study by Laine et al16 of 274 participants with dysmetabolic iron overload and significantly elevated HIC (>50 mmol/kg) found that venesection was associated with significantly increased serum insulin and HOMA‐IR scores over time.…”

Role of free radicals in liver diseases

“…However, most studies do not [134][135][136][137][138]. On the contrary, 30% of the patients with NAFLD have elevated ferritin levels [139][140][141], and there is an association between insulin resistance and liver iron [142,143].…”

High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis

“…The overall prevalence of abnormal fasting glucose values in this group were: IFG 13% (95% CI [8][9][10][11][12][13][14][15][16][17][18][19][20]; diabetes 26% (95% CI 20-34). Thirty-two of the males (31%) and four of the females (12%) had diabetes.…”

“…Some of these studies are difficult to interpret, because subjects with established diabetes were studied, in which case the attendant hyperglycaemia may itself have resulted in insulin resistance and insulin secretory abnormalities [13]. Furthermore, the studies most clearly demonstrating iron effects on insulin sensitivity (Si) in patients without diabetes are those of subjects with transfusional or idiopathic iron overload, and not of subjects with haemochromatosis [11,14].…”