Diagnostic performance of FibroTest, SteatoTest and ActiTest in patients with NAFLD using the SAF score as histological reference.

BACKGROUND: Blood tests of liver injury are less well validated in non-alcoholic fatty liver disease (NAFLD) than in patients with chronic viral hepatitis. AIMS: To improve the validation of three blood tests used in NAFLD patients, FibroTest for fibrosis staging, SteatoTest for steatosis grading and ActiTest for inflammation activity grading. METHODS: We pre-included new NAFLD patients with biopsy and blood tests from a single-centre cohort (FibroFrance) and from the multicentre FLIP consortium. Contemporaneous biopsies were blindly assessed using the new steatosis, activity and fibrosis (SAF) score, which provides a reliable and reproducible diagnosis and grading/staging of the three elementary features of NAFLD (steatosis, inflammatory activity) and fibrosis with reduced interobserver variability. We used nonbinary-ROC (NonBinAUROC) as the main endpoint to prevent spectrum effect and multiple testing. RESULTS: A total of 600 patients with reliable tests and biopsies were included. The mean NonBinAUROCs (95% CI) of tests were all significant (P < 0.0001): 0.878 (0.864-0.892) for FibroTest and fibrosis stages, 0.846 (0.830-0.862) for ActiTest and activity grades, and 0.822 (0.804-0.840) for SteatoTest and steatosis grades. FibroTest had a higher NonBinAUROC than BARD (0.836; 0.820-0.852; P = 0.0001), FIB4 (0.845; 0.829-0.861; P = 0.007) but not significantly different than the NAFLD score (0.866; 0.850-0.882; P = 0.26). FibroTest had a significant difference in median values between adjacent stage F2 and stage F1 contrarily to BARD, FIB4 and NAFLD scores (Bonferroni test P < 0.05). CONCLUSIONS: In patients with NAFLD, SteatoTest, ActiTest and FibroTest are non-invasive tests that offer an alternative to biopsy, and they correlate with the simple grading/staging of the SAF scoring system across the three elementary features of NAFLD: steatosis, inflammatory activity and fibrosis.

HCV genotype 3 and squamous cell carcinoma antigen (SCCA)-IgM are independently associated with histological features of NASH in HCV-infected patients.

Nonalcoholic steatohepatitis (NASH) enhances the risk of progressive liver disease. In chronic hepatitis C (CHC), liver steatosis is frequent, especially in genotype 3, but its clinical significance is debated. As squamous cell carcinoma antigen (SCCA)-IgM has been associated with advanced liver disease and risk of tumour development, we evaluated its occurrence in CHC and the possible relation with NASH at liver biopsy. Using a validated ELISA, serum SCCA-IgM was measured in 91 patients with CHC at the time of liver biopsy performed before antiviral treatment, at the end of treatment and 6 months thereafter, and in 93 HCV-negative patients with histological diagnosis of nonalcoholic fatty liver disease, as controls. SCCA-IgM was detected in 33% of CHC patients and in 4% of controls. This biomarker was found more elevated in CHC patients with histological NASH, and at multivariate analysis, SCCA-IgM and HCV genotype 3 were independently associated with NASH [OR (95% CI): 6.94 (1.21-40) and 27.02 (4.44-166.6)]. As predictors of NASH, HCV genotype 3 and SCCA-IgM had a specificity and a sensitivity of 97% and 44%, and of 95% and 27%, respectively. PPV and NPV were 80% and 86% for HCV genotype 3 vs 73% and 72% for SCCA-IgM. In patients with sustained virologic response to therapy, SCCA-IgM levels decreased significantly, while these remained unchanged in nonresponders. In conclusion, SCCA-IgM is detectable in one-third of patients with CHC and significantly correlates with histological NASH.

Non-alcoholic steatohepatitis (NASH) and oral lichen planus: a rare occurrence.

Oral lichen planus (OLP) is frequently associated with hepatitis C virus infection but uncommonly with other causes of liver disorder. The authors report the case of a 41-year-old male patient with a clinical and histological diagnosis of OLP who presented with a marked alteration of the transaminase values, with no signs of past or present HBV, HCV, HGV or TTV infection. The patient did not consume alcohol and no exposure to hepatotoxic substances was reported. All autoantibodies were negative. Hepatic fine needle biopsy showed macrovesicular steatosis with a slight chronic portal inflammatory infiltrate and signs of siderosis. Iron metabolism was slightly altered. Genetic tests showed a heterozygotic mutation for hereditary haemochromatosis gene (HLA-H C282Y) but not for HLA-H63D. The patient presented slight insulin resistance but had normal glycaemic values. The results are consistent with a diagnosis of non-alcoholic steatohepatitis (NASH). This is the first reported case of NASH associated with OLP.

Venesection for non-alcoholic fatty liver disease unresponsive to lifestyle counselling--a propensity score-adjusted observational study.

BACKGROUND/AIM: To test the short-term clinical usefulness of venesection associated with lifestyle counselling as against counselling alone on insulin resistance and liver enzymes in subjects with non-alcoholic fatty liver disease (NAFLD), using a propensity score approach. METHODS: We carried out a 6- to 8-month observational analysis of 198 NAFLD patients in three Italian referral centres (79 venesection and 119 counselling alone). Insulin resistance was measured by the homeostasis model assessment (HOMA) method. Logistic regression was used to identify factors associated with normal HOMA and normal alanine aminotransferase (ALT) at the end of observation. The results were adjusted for the propensity score to be enrolled in the venesection programme, based on clinical and laboratory data, including common HFE polymorphisms and liver biopsy (available in 161 cases). RESULTS: After adjustment for propensity and changes in BMI, venesection was significantly associated with normal HOMA [all cases: odds ratio (OR) 3.00; 95% confidence interval (CI) 1.51-5.97; cases with histology: OR 2.29; 95% CI 1.08-4.87] and ALT within normal limits (all cases: OR 2.56; 95% CI 1.29-5.10; cases with histology: OR 2.81; 95% CI 1.20-5.24). The results were confirmed in an analysis of 57 pairs matched for propensity, where venesection similarly increased the probability of normal HOMA (OR 3.27; 95% CI 1.16-7.84) and normal ALT (OR 5.60; 95% CI 2.09-15.00). Similar data were obtained in the subset of cases with normal basal ferritin (<350 ng/ml). CONCLUSION: Iron depletion by venesection favours the normalization of insulin resistance and raised liver enzymes in non-haemochromatosis patients with NAFLD.

Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee.

We report the evidence-based Italian Association for the Study of Liver guidelines for the appropriate diagnosis and management of patients with nonalcoholic fatty liver disease in clinical practice and its related research agenda. The prevalence of nonalcoholic fatty liver disease varies according to age, gender and ethnicity. In the general population, the prevalence of nonalcoholic fatty liver disease is about 25% and the incidence is of two new cases/100 people/year. 2-3% of individuals in the general population will suffer from nonalcoholic steatohepatitis. Uncomplicated steatosis will usually follow a benign course. Individuals with nonalcoholic steatohepatitis, however, have a reduced life expectancy, mainly owing to vascular diseases and liver-related causes. Moreover, steatosis has deleterious effects on the natural history of HCV infection. Nonalcoholic fatty liver disease is usually diagnosed in asymptomatic patients prompted by the occasional discovery of increased liver enzymes and/or of ultrasonographic steatosis. Medical history, complete physical examination, etiologic screening of liver injury, liver biochemistry tests, serum lipids and insulin sensitivity tests should be performed in every patient. Occult alcohol abuse should be ruled out. Ultrasonography is the first-line imaging technique. Liver biopsy, the gold standard in diagnosis and prognosis of nonalcoholic fatty liver disease, is an invasive procedure and its results will not influence treatment in most cases but will provide prognostic information. Assessment of fibrosis by composite scores, specific laboratory parameters and transient elastography might reduce the number of nonalcoholic fatty liver disease patients requiring liver biopsy. Dieting and physical training reinforced by behavioural therapy are associated with improved nonalcoholic fatty liver disease. Diabetes and the metabolic syndrome should be ruled out at timed intervals in nonalcoholic fatty liver disease. Nonalcoholic steatohepatitis patients should undergo periodic evaluation of cardiovascular risk and of advancement of their liver disease; those with nonalcoholic steatohepatitis-cirrhosis should be evaluated for early diagnosis of hepatocellular carcinoma.

Use of corticosteroids, immunomodulators, and infliximab at a third-level Day-Hospital Service of Gastro-Hepatology.

AIM: Third-level Day-Hospital Services of Gastro-Hepatology are likely to recruit patients with an increased disease severity. The burden of request for immunomodulation drugs is presently unclear. METHODS: The charts of 1 012 consecutive patients who underwent day-hospital admission were reviewed. Among them, 975 were admitted for several reasons (percutaneous liver biopsies, abdominal fluid aspirations, infiltrations of hepatic nodules, gastrointestinal endoscopies with specific treatments). Data of the remaining 37 patients were elaborated. RESULTS: Of them, 31 (83%) suffered from ulcerative colitis (UC) or Crohn's disease (CD) (17 and 14, respectively) and 6 from autoimmune type 1 hepatitis (AIH). Of the 14 non-operated UC patients, 12 were taking azathioprine (AZA) and 2 infliximab (IFX). Among CD patients, the majority received AZA (N=6) or IFX (N=6). Of the AIH patients, 5 were treated with AZA and 2 had also cyclosporine. Overall, corticosteroids (32%) and IFX (21%) ranked first and second among the induction drugs, and AZA ranked first (62%) as maintenance option. Of the 4 CD patients under IFX treatment, 2 were switched to leukapheresis for incomplete response, the third one developed thrombotic complications, and the last one achieved disease remission after 12 months. Of the 2 cases of UC, one lost response soon and was colectomized, the other is maintaining moderately active disease, requiring scheduled injections every 8 weeks. CONCLUSION: Despite the caution imposed by the very small numbers, this analysis confirms that the potent available options are difficult to be correctly positioned in the therapeutic algorithm of inflammatory bowel disease.

Histological progression of non-alcoholic fatty liver disease: a critical reassessment based on liver sampling variability.

BACKGROUND: In non-alcoholic fatty liver disease, histological lesions display a significant sampling variability that is ignored when interpreting histological progression during natural history or therapeutic interventions. AIM: To provide a method taking into account sampling variability when interpreting crude histological data, and to investigate how this alters the conclusions of available studies. METHODS: Natural history studies detailing histological progression and therapeutic trials were compared with the results of a previously published sampling variability study. RESULTS: Natural history studies showed an improvement in steatosis, which was significantly higher than expected from sampling variability (47% vs. 8%, P < 0.0001). In contrast, no study showed a change in activity grade or ballooning higher than that of sampling variability. There was only a marginal effect on fibrosis with no convincing demonstration of a worsening of fibrosis, a conclusion contrary to what individual studies have claimed. Some insulin sensitizing drugs and anti-obesity surgery significantly improved steatosis, while most did not significantly impact on fibrosis or activity. CONCLUSIONS: Sampling variability of liver biopsy is an overlooked confounding factor that should be considered systematically when interpreting histological progression in patients with non-alcoholic fatty liver disease.

Non-alcoholic steatohepatitis and cancer.

Hepatocellular carcinoma (HCC) is part of the natural history of non-alcoholic steatohepatitis (NASH). A significant proportion of people who have cryptogenic cirrhosis develop HCC. NASH-related cirrhosis carries a substantial risk for early HCC development. Diagnosis of HCC often is made at first referral; the tumor usually is large with multiple localizations. Patients who have obesity or diabetes are at risk for HCC and a variety of cancers. Given the epidemic of obesity and diabetes, the incidence of NASH-related HCC is expected to increase. In addition to developing new diagnostic tools and pharmacologic therapies, efforts should be directed at preventing non-alcoholic fatty liver disease.

Steatosis and hepatocellular carcinoma risk.

The natural history of Non Alcoholic Fatty Liver Disease (NAFLD) is difficult to assess, but there is mounting evidence that patients with NAFLD may eventually develop cirrhosis and hepatocellular carcinoma (HCC). Retrospective, case-control studies have shown that features suggestive of Non Alcoholic SteatoHepatitis (NASH) are more frequent in HepatoCellular Carcinoma (HCC) complicating cryptogenic cirrhosis than in matched HCC patients with known etiology. In the only available prospective cohort study, there is the absence of HCC as a complication of NASH-associated cirrhosis after a mean follow up of 7 years (median 5 years). However prospective NASH studies are too short to exclude late complications. In fact the average lenght of cirrhosis before the diagnosis of HCC was 16 years. The prevalence of risk factors associated with NASH can account for the increasing incidence of cryptogenic cirrhosis and subsequent HCC. Obesity and diabetes per se are significantly associated with the development of HCC. In particular diabetes was found to be a risk factor for HCC independent of age, gender, and race. Chronic hyperinsulinaemia and insulin-like growth factor 1 (IGF-1) might be involved in hepato-carcinogenesis. Exposure to physiological insulin concentrations stimulate proliferation of human and rat hepatoma cell line. Changes in the expression pattern of IGF-system components has been observed in patients with HCC, in human hepatoma cell lines and in their conditioned culture medium.

Review article: steatosis, the metabolic syndrome and cancer.

The incidence of hepatocellular carcinoma is increasing, but the temporal changes of risk factors remain unclear. A significant proportion of hepatocellular carcinoma (7-30%) develops in cryptogenic cirrhosis, and may represent the most worrisome complication of non-alcoholic steatohepatitis. Non-alcoholic steatohepatitis is tightly related to insulin resistance and several features of the metabolic syndrome, i.e obesity, type 2 diabetes and dyslipidaemia. Nearly two-thirds of adults in the United States and an increasing percentage of the population worldwide are overweight or obese. Diabetes prevalence is increasing as well. The rising prevalence of risk factors associated with non-alcoholic steatohepatitis can partially account for the increasing incidence of cryptogenic cirrhosis and subsequent hepatocellular carcinoma. Moreover, recent evidence demonstrates that both obesity and diabetes are per se associated with an increased cancer risk. Large prospective studies show a significant association with obesity for several cancers, including cancers of the colon, female breast, endometrium, kidney, oesophagus and liver (hepatocellular carcinoma). Type 2 diabetes is also related with increased risks of colon, endometrial, kidney, pancreatic cancer and hepatocellular carcinoma. In western countries, the insulin resistance syndrome is emerging as a risk factor for a wide variety of cancers, including hepatocellular carcinoma.

Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms.

AIMS/HYPOTHESIS: Non-alcoholic fatty liver disease (NAFLD) has been associated with the metabolic syndrome. However, it is not clear whether insulin resistance is an independent feature of NAFLD, and it remains to be determined which of the in vivo actions of insulin are impaired in this condition. METHODS: We performed a two-step (1.5 and 6 pmol min(-1) kg(-1)) euglycaemic insulin clamp coupled with tracer infusion ([6,6-2H2]glucose and [2H5]glycerol) and indirect calorimetry in 12 non-obese, normolipidaemic, normotensive, non-diabetic patients with biopsy-proven NAFLD and six control subjects. RESULTS: In NAFLD patients, endogenous glucose production (basal and during the clamp) was normal; however, peripheral glucose disposal was markedly decreased (by 30% and 45% at the low and high insulin doses, respectively, p<0.0001) at higher plasma insulin levels (p=0.05), due to impaired glucose oxidation (p=0.003) and glycogen synthesis (p<0.001). Compared with control subjects, glycerol appearance and lipid oxidation were significantly increased in NAFLD patients in the basal state, and were suppressed by insulin to a lesser extent (p<0.05-0.001). The lag phase of the in vitro copper-catalysed peroxidation of LDL particles was significantly shorter in the patients than in the control subjects (48+/-12 vs 63+/-13 min, p<0.04). Lipid oxidation was significantly related to endogenous glucose production, glucose disposal, the degree of hepatic steatosis, and LDL oxidisability. CONCLUSIONS/INTERPRETATION: Insulin resistance appears to be an intrinsic defect in NAFLD, with the metabolic pattern observed indicating that adipose tissue is an important site.

Non-alcoholic fatty liver and insulin resistance: a cause-effect relationship?

The role of insulin resistance in non-alcoholic fatty liver disease is suggested by laboratory data (hyperinsulinemia and decreased sensitivity to endogenous and exogenous insulin). The clinical association with features of the metabolic syndrome, particularly in the most aggressive stages of the disease, further confirms a causative role. Fat accumulation in the liver may stem either from genetic defects, primarily responsible for insulin resistance, or excessive calorie intake and visceral obesity, and is mediated by adipocytokines (leptin, adiponectin, tumour necrosis factor-alpha). Progression of fatty liver to steatohepatitis may be the result of an imbalance between pro-inflammatory and anti-inflammatory cytokines, triggering the formation of reactive oxygen species and intrahepatic lipid peroxidation. This process may also be promoted or accelerated by pro-oxidant xenobiotics or environmental factors. Insulin resistance provides a target for specific treatment of non-alcoholic fatty liver, and insulin-sensitising agents (metformin or thiazolidinediones) as well as lifestyle changes to reduce visceral adiposity are the most promising therapeutic options. Future trials need to be performed in order to test the long-term effectiveness of these treatments on the basis of clinically relevant histological outcomes.

Low ghrelin concentrations in nonalcoholic fatty liver disease are related to insulin resistance.

Several physiological and pathophysiological conditions, including changes in body fat, food intake, and insulin resistance, are known to be associated with variations in plasma ghrelin concentrations. We tested the hypothesis that insulin resistance exerts a primary role by measuring ghrelin in 86 patients with nonalcoholic fatty liver disease (NAFLD), a condition in which insulin resistance is relatively independent of obesity. Compared with 40 matched healthy subjects, patients with NAFLD had similar glucose levels and higher plasma insulin and insulin resistance [homeostasis model assessment (HOMA)-R index] by over 60%. Ghrelin was reduced (mean +/- SD, 226 +/- 72 pmol/liter in NAFLD vs. 303 +/- 123 in controls; P < 0.0001). In relation to quartiles of body mass index, ghrelin progressively decreased in controls (P = 0.003), but not in patients (P = 0.926). In relation to quartiles of HOMA-R, ghrelin decreased in both groups, and significantly correlated with HOMA-R. After adjustment for age and sex, HOMA-R was the sole factor significantly associated with low ghrelin in the whole group (odds ratio, 5.79; 95% confidence interval, 2.62-12.81; P < 0.0001) and specifically in NAFLD (2.96; 1.12-7.79; P = 0.028). The study suggests that insulin resistance is a major factor controlling ghrelin levels in subjects with and without NAFLD.

Nonalcoholic fatty liver disease: a feature of the metabolic syndrome.

Insulin sensitivity (euglycemic clamp, insulin infusion rate: 40 mU. m(-2). 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 insulin-mediated 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.

Cardiovascular disease in cirrhosis--a point-prevalence study in relation to glucose tolerance.

OBJECTIVE: Impaired glucose tolerance or diabetes are frequently observed in cirrhosis. Overt diabetes was reported to affect long term survival of cirrhotic patients by increasing the risk of hepatocellular failure, without increasing the risk of diabetes-associated cardiovascular events. METHODS: We evaluated the prevalence of cardiovascular disease in 122 patients with cirrhosis, subdivided according to their glucose tolerance. The following parameters were considered: arterial pressure, peripheral vascular disease (ankle to brachial pressure ratio), ischemic heart disease, microalbuminuria, retinopathy. The prevalence of abnormal findings was compared with that observed in 60 randomly selected patients with noninsulin-dependent diabetes and in 40 controls. RESULTS: Noninsulin-dependent diabetic patients and patients with cirrhosis and diabetes were comparable for age, metabolic control, and smoking habits; the duration of diabetes was 5 yr longer for noninsulin-dependent diabetes. In cirrhosis, the prevalence of micro- and peripheral macroangiopathy, as well as coronary heart disease, was not different in relation to glucose tolerance, it was comparable to that of controls, and significantly lower than that observed in non-insulin-dependent diabetes. CONCLUSIONS: Cirrhotic patients, even in the presence of overt diabetes, are at low risk of cardiovascular disease. The low prevalence may be related to shorter duration of diabetic disease, also in relation to reduced life expectancy, as well as to liver disease-induced abnormalities protecting the cardiovascular system from atherosclerosis.

Gender-dependent alterations in serum leptin in alcoholic cirrhosis.

BACKGROUND & AIMS: Leptin is a peptide that decreases food intake and increases energy expenditure. It is produced in fat cells, is stimulated by cytokines, and its levels in serum are higher in females. Because anorexia, hypermetabolism, and elevated cytokine levels are frequently observed in cirrhosis, we hypothesized that the serum leptin level would be elevated in cirrhosis. The aim of this study was to investigate the relationship of serum leptin to gender, body composition, and tumor necrosis factor (TNF). METHODS: Male (n = 18) and female (n = 10) abstinent alcoholic cirrhotic patients were studied and compared with control subjects (15 male and 8 female). Fat mass, fat-free body mass, and body cell mass were calculated by using H2[18O] and bromide dilution methodology. Serum leptin and TNF concentrations were measured by immunoassays. RESULTS: Fat mass was decreased only in male cirrhotics (P < 0.05), whereas body cell mass was decreased in both male and female cirrhotics (P < 0.01). Leptin levels were elevated in female (P < 0. 001) but not male cirrhotics compared with controls. When expressed per kilogram of fat mass, leptin was elevated in both male (P < 0. 01) and female (P < 0.01) cirrhotics. Women in both cirrhotic and control groups had higher leptin levels than men. TNF was elevated in both male and female cirrhotics and did not correlate with leptin levels. CONCLUSIONS: Cirrhotics have elevated serum leptin levels, which are related to both gender- and gender-dependent alterations in body composition.

Glutathione kinetics in normal man and in patients with liver cirrhosis.

BACKGROUND/AIMS: The dynamics of glutathione in plasma has always been studied by bolus injections. Data are available suggesting that the low plasma levels of cirrhosis are due to decreased production in glutathione-producing tissues, mainly the liver. We aimed to measure the kinetics of glutathione during controlled steady-state conditions, and to determine the reasons for its reduced plasma levels in advanced cirrhosis. METHODS: The plasma clearance of glutathione was measured in six control subjects and in ten patients with cirrhosis during a 2-step infusion study, producing steady-state levels approximately 5 and 10 times basal values. The plasma disappearance curve after infusion stop was used to determine the apparent volume of distribution and half-life of glutathione, and the estimated basal appearance rate. RESULTS: The clearance of glutathione did not reject 1st-order kinetics, i.e., it was concentration-independent, and was nearly doubled in cirrhosis. The half-life of exogenous glutathione was not different, whereas the volume of distribution was larger in cirrhosis, in the same range as extracellular water. The endogenous basal appearance rate of glutathione was reduced by 50%, and correlated with liver function, measured by routine and dynamic tests. CONCLUSIONS: The data confirm that the primary defect responsible for reduced glutathione in liver disease is a reduced production, possibly related to hepatocyte dysfunction and a block along the pathway of methionine metabolism.

Sulphur amino acid pattern in chronic liver disease.

The metabolism of sulphur-containing amino acids is impaired in patients with advanced liver disease, but very few data are available in less severe chronic liver disease. We measured fasting plasma levels of methionine, cystine and taurine in 10 healthy subjects and 50 patients with biopsy proven liver disease: chronic persistent/active hepatitis (30 cases), compensated cirrhosis (10 cases) and decompensated cirrhosis (10 cases). Hypermethioninemia (up to 10 times control values) was present only in decompensated cirrhosis. Cystine was markedly reduced in patients with compensated chronic liver disease, while in advanced cirrhosis its concentration was within the normal range. No differences in taurine plasma levels were observed between the various groups. This study suggests that a derangement in sulphur amino acid metabolism, possibly located at various steps along the trans-sulphuration pathway, is also present in mild forms of chronic liver disease.