Insulin sensitivity (euglycemic clamp, insulin infusion rate: 40 mU ⅐ m ؊2 ⅐ min ؊1) was studied in 30 subjects with biopsy-proven nonalcoholic fatty liver disease (NAFLD), normal glucose tolerance, and a BMI <30 kg/m 2 . Of those 30 subjects, 9 had pure fatty liver and 21 had evidence of steatohepatitis. In addition, 10 patients with type 2 diabetes under good metabolic control and 10 healthy subjects were studied. Most NAFLD patients had central fat accumulation, increased triglycerides and uric acid, and low HDL cholesterol, irrespective of BMI. Glucose disposal during the clamp was reduced by nearly 50% in NAFLD patients, as well as in patients with normal body weight, to an extent similar to that of the type 2 diabetic patients. Basal free fatty acids were increased, whereas insulin-mediated suppression of lipolysis was less effective (؊69% in NAFLD vs. ؊84% in control subjects; P ‫؍‬ 0.003). Postabsorptive hepatic glucose production (HGP), measured by [6,6-2 H 2 ]glucose, was normal. In response to insulin infusion, HGP decreased by only 63% of basal in NAFLD vs. 84% in control subjects (P ‫؍‬ 0.002). Compared with type 2 diabetic patients, NAFLD patients were characterized by lower basal HGP, but with similarly reduced insulinmediated suppression of HGP. There was laboratory evidence of iron overload in many NAFLD patients, but clinical, histological, and biochemical data (including insulin sensitivity) were not correlated with iron status. Four subjects were heterozygous for mutation His63Asp of the HFE gene of familiar hemochromatosis. We concluded that NAFLD, in the presence of normoglycemia and normal or moderately increased body weight, is characterized by clinical and laboratory data similar to those found in diabetes and obesity. NAFLD may be considered an additional feature of the metabolic syndrome, with specific hepatic insulin resistance. Diabetes

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Zinc deficiency is common in cirrhosis and has been tent is common in patients with advanced cirrhosis, involved in the altered nitrogen metabolism. In this particularly of alcohol origin, 2 but the biochemical basis study, we measured the effects of zinc supplementation for zinc deficiency is still unknown. Several factors, on the dynamics of amino acid-derived urea synthesis such as poor dietary intake, impaired intestinal absorpin cirrhosis with mild or latent encephalopathy. The he-tion, and excessive urinary losses may be responsible patic conversion of amino acids into urea was studied in for reduced whole-body zinc content. rent hepatic encephalopathy, zinc levels after zinc for hepatocellular failure and encephalopathy, served as controls. Plasma zinc levels were reduced in all pa-supplementation and artificially induced zinc defitients and returned to normal after oral zinc. The ala-ciency correlated closely with mental state and electronine-stimulated urea nitrogen synthesis rate in relation encephalography tracings. 4 In a randomized doubleto a-amino-N concentration-the functional hepatic ni-blind trial, zinc sulfate oral supplements increased to trogen clearance-increased by 25% after zinc supple-normal plasma zinc levels of cirrhotic patients and sigmentation, i.e., more urea was produced at any a-amino-nificantly improved mild encephalopathy of the chronic N concentration. Basal and alanine-induced glucagon type.5 During treatment, ammonia levels decreased, decreased by 50%, and the ammonia response to alanine and plasma urea concentration increased. The results decreased by 30%. Psychometric tests improved, as did routine and dynamic liver function tests and the Child-were not confirmed in a short-term crossover study Pugh score. Also, the plasma concentration of lipid per-with zinc acetate supplements, which failed to normaloxides was reduced by zinc. No significant changes were ize plasma zinc levels. 6 Also episodes of acute encephaobserved in the control group. Our data indicate that lopathy after gastrointestinal hemorrhage have been long-term oral zinc speeds up the kinetics of urea forma-successfully treated with zinc. 7 In cirrhotic rats, zinc tion from amino acids and ammonia. Changes in the hor-supplementation was shown to increase the hepatic ac- be the biochemical basis for the beneficial effects of zinc on mental state in humans. Zinc is considered an essential trace element for sevThe liver plays a pivotal role in amino acid/protein eral metabolic processes, exerting a protective action disposition. Most of the amino acid nitrogen that is not on liver cell activity and possibly preventing cellular used for protein synthesis is converted by hepatocytes damage caused by oxidative stress.1 Reduced zinc con-into urea, which is irreversibly lost in the urine. The process may be quantified, after standardization for to study the effects of disease, hormone, drugs, and Received March 2, 1995; accepted December 11, 1995. dietary manipulations on the dynamics of amino acidSupported by a gr...

Zinc deficiency is common in cirrhosis and has been tent is common in patients with advanced cirrhosis, involved in the altered nitrogen metabolism. In this particularly of alcohol origin, 2 but the biochemical basis study, we measured the effects of zinc supplementation for zinc deficiency is still unknown. Several factors, on the dynamics of amino acid-derived urea synthesis such as poor dietary intake, impaired intestinal absorp-in cirrhosis with mild or latent encephalopathy. The he-tion, and excessive urinary losses may be responsible patic conversion of amino acids into urea was studied in for reduced whole-body zinc content. 3 eight patients with advanced cirrhosis under controled The importance of zinc deficiency in precipitating ep-conditions of substrate availability (continuous alanine isodes of hepatic encephalopathy is a matter of discus-infusion), before and after 3-month oral zinc sulfate sup-sion. In a single patient with cirrhosis and severe recur-plementation (600 mg/d). Eight more patients, matched rent hepatic encephalopathy, zinc levels after zinc for hepatocellular failure and encephalopathy, served as controls. Plasma zinc levels were reduced in all pa-supplementation and artificially induced zinc defi-tients and returned to normal after oral zinc. The ala-ciency correlated closely with mental state and electro-nine-stimulated urea nitrogen synthesis rate in relation encephalography tracings. 4 In a randomized double-to a-amino-N concentration-the functional hepatic ni-blind trial, zinc sulfate oral supplements increased to trogen clearance-increased by 25% after zinc supple-normal plasma zinc levels of cirrhotic patients and sig-mentation, i.e., more urea was produced at any a-amino-nificantly improved mild encephalopathy of the chronic N concentration. Basal and alanine-induced glucagon type. 5 During treatment, ammonia levels decreased, decreased by 50%, and the ammonia response to alanine and plasma urea concentration increased. The results decreased by 30%. Psychometric tests improved, as did routine and dynamic liver function tests and the Child-were not confirmed in a short-term crossover study Pugh score. Also, the plasma concentration of lipid per-with zinc acetate supplements, which failed to normal-oxides was reduced by zinc. No significant changes were ize plasma zinc levels. 6 Also episodes of acute encepha-observed in the control group. Our data indicate that lopathy after gastrointestinal hemorrhage have been long-term oral zinc speeds up the kinetics of urea forma-successfully treated with zinc. 7 In cirrhotic rats, zinc tion from amino acids and ammonia. Changes in the hor-supplementation was shown to increase the hepatic ac-monal drive and/or the antioxidant activity of zinc might tivity of ornithine transcarbamoylase, a key-enzyme of be involved in the general improvement in liver func-urea cycle. 8 This was accompanied by increased urea tion, whereas the beneficial effects on encephalopathy might stem from decreased ammonia. (HEPATOLOGY formation and decreased ammonia l...