Nonalcoholic fatty liver disease: relationship to insulin sensitivity and oxidative stress. Treatment spproaches using vitamin E, magnesium, and betaine - Fatty Liver

Alternative Medicine Review, August, 2002 by Lyn Patrick

Although hepatic iron does appear to be a factor increasing risk for fibrosis, (17) elevated ferritin is only found in about 50 percent of patients. Elevated ferritin levels, however, do not always indicate elevated hepatic iron stores. In NASH, hepatic iron levels are usually normal. Elevated ferritin and transferrin levels, when they do occur, may be the result of hepatocyte necrosis. (2)

Several studies have examined signs and symptoms that correlate with presence of fibrosis (Table 1). In a study of 144 patients with NASH, over age 45, the presence of type 2 diabetes and a body mass index (BMI) of 30 or over were predictive of fibrosis, and indicated the need of a liver biopsy to provide both an accurate diagnosis and to serve as a baseline to determine the efficacy of treatment. (2) In a study of 105 obese patients (BMI over 35), independent predictors of fibrosis were hypertension (140/90 or above), an elevated index of insulin resistance, and a serum ALT level over 40. (18) This population is not uncommon; 26 percent of the American population is considered obese (BMI over 30 kg/[m.sup.3]). (19)

Pathogenesis of NAFLD and NASH

Insulin Resistance and its Relationship to Fatty Liver

Multiple authors have proposed that NASH be included as a clinical feature in the metabolic disorder of insulin resistance. (20-22) Insulin resistance, estimated to occur in approximately 25 percent of the general population, has been associated with hyperinsulinemia, abnormal glucose tolerance, type 2 diabetes mellitus, hypertriglyceridemia, decreased high-density lipoprotein levels, hypertension, abnormal fibrinolysis, increased visceral fat accumulation, hyperuricemia, polycystic ovarian syndrome, and other lipid abnormalities. (23) This constellation of signs and symptoms, particularly hypertension, hypertriglyceridemia, and impaired glucose tolerance, has been designated as metabolic syndrome or syndrome X. (24)

NASH has been shown to be strongly associated with the major features of syndrome X: obesity, central fat accumulation, diabetes, dyslipemia (depressed HDL levels, elevated triglycerides), hypertension, and cardiovascular disease. (25) Indications of insulin resistance-type 2 diabetes mellitus or glucose intolerance are present in up to 30 percent of patients with NASH, commonly coexisting with hypertriglyceridemia or hypercholesterolemia. (26) The phenomenon of NASH as simply another manifestation of insulin resistance in type 2 diabetics, who commonly have NAFLD, may be indicated by data that show type 2 diabetics are more likely to die from liver disease than from cardiovascular disease. (27)

The relationship between NASH and obesity also involves insulin resistance. Central (truncal) or visceral obesity is a central feature of syndrome X, (28) and waist-to-hip ratios and BMI are significantly greater in NASH patients than in controls. (21,29) Insulin resistance has also been found to occur in significant numbers of NASH patients. In one population of 66 patients (both lean and obese), 98 percent were insulin resistant, and only 39 percent of those were diabetic. (30) Insulin resistance was determined by fasting levels of serum C-peptide (a measure of insulin production), insulin, and glucose. Insulin resistance was not dependent on increasing body mass index but significantly related to evidence of central obesity; i.e., increased waist-to-hip ratios were present even in lean individuals. This finding has also been seen in other NASH studies. (21)