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Introduction and objectives Surrogate biomarkers of liver fibrosis developed in tertiary care are increasingly used in general populations. We evaluated the association between liver stiffness (LS) and five continuous (AST/ALT, APRI, Forns Index, FIB-4, GGT) and two discrete biomarkers (BARD, BAAT) in a general population. Patients and methods 636 (29%) of the 2159 citizens of the Bagnacavallo Study had LS measured by transient elastography. Using linear regression with univariate multiple imputation, we evaluated the association of LS with the above biomarkers in the total sample of 2159 citizens. Results The mean change of LS between the 5th and 95th internal percentile of any continuous biomarker was ≤1 kPa. The mean change of LS between scores 0 and 3 of BARD and scores 0 and ≥3 of BAAT was >1 kPa but of doubtful clinical relevance. Conclusion We found a modest association between LS and seven biomarkers of liver fibrosis in a general population.

We externally validated the fatty liver index (FLI), the lipid accumulation product (LAP), the hepatic steatosis index (HSI), and the Zhejiang University index (ZJU) for the diagnosis of fatty liver (FL) and non-alcoholic fatty liver disease (NAFLD) in the general population. The validation was performed on 2159 citizens of the town of Bagnacavallo (Ravenna, Italy). Calibration was evaluated by calculating the calibration slope and intercept and by inspecting calibration plots, discrimination was evaluated using the c-statistic. The average calibration slope was 1 and the average intercept was 0 for all combinations of outcomes and indices. For the diagnosis of FL, the c-statistic was 0.85 for FLI, 0.83 for ZJU, 0.82 for HSI, and 0.80 for LAP, for the diagnosis of NAFLD, the c-statistic was 0.77 for FLI, 0.76 for ZJU, 0.75 for HSI, and 0.74 for LAP. All indices were strongly correlated with each other. In conclusion, FLI, LAP, HSI, and ZJU perform similarly well to diagnose FL and NAFLD in the Bagnacavallo population, even if FLI has a small advantage as discrimination is concerned.

the FLIP Consortium and the FibroFrance Group; International audience; BackgroundBlood tests of liver injury are less well validated in non-alcoholic fatty liver disease (NAFLD) than in patients with chronic viral hepatitis.AimsTo 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.MethodsWe 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.ResultsA 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).ConclusionsIn 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.

OBJECTIVE: Evaluation of the interaction between alcohol intake and cofactors [hepatitis B virus (HBV), hepatitis C virus (HCV), body mass index] and coffee consumption on the risk of cirrhosis. DESIGN: Seven hundred and forty-nine consecutive patients with chronic liver disease referring to units for liver or alcohol diseases in Italy during a 6-months period. Teetotalers were excluded. The odds ratios (OR) for cirrhosis were evaluated using chronic hepatitis cases as the control group. RESULTS: An alcohol intake of more than 3 units/day resulted associated with the likelihood of cirrhosis both in males (OR 4.3; 95% CI=2.5-7.3) and in females (OR 5.7; 95% CI=2.3-14.5). A multiplicative interaction on the risk of cirrhosis between risky alcohol intake and HBsAg or HCV-Ab/HCV-RNA positivity was observed. A reduction of cirrhosis risk was observed in subjects consuming more than 3 alcohol units/day with increasing coffee intake. The OR for the association with cirrhosis decreased from 2.3 (95% CI=1.2-4.4) in subjects drinking 0-2 cups of coffee/day to 1.4 (95% CI=0.6-3.6) in those drinking more than 2 cups/day. CONCLUSIONS: In subjects with an alcohol intake >3 units/day the coexistence of HBV or HCV multiplies the risk of cirrhosis. Coffee represents a modulator of alcoholic cirrhosis risk.

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. © 2016 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd

AIMS: The aim of this consensus paper is to review the available evidence on the association between moderate alcohol use, health and disease and to provide a working document to the scientific and health professional communities. DATA SYNTHESIS: In healthy adults and in the elderly, spontaneous consumption of alcoholic beverages within 30 g ethanol/d for men and 15 g/d for women is to be considered acceptable and do not deserve intervention by the primary care physician or the health professional in charge. Patients with increased risk for specific diseases, for example, women with familiar history of breast cancer, or subjects with familiar history of early cardiovascular disease, or cardiovascular patients should discuss with their physician their drinking habits. No abstainer should be advised to drink for health reasons. Alcohol use must be discouraged in specific physiological or personal situations or in selected age classes (children and adolescents, pregnant and lactating women and recovering alcoholics). Moreover, the possible interactions between alcohol and acute or chronic drug use must be discussed with the primary care physician. CONCLUSIONS: The choice to consume alcohol should be based on individual considerations, taking into account the influence on health and diet, the risk of alcoholism and abuse, the effect on behaviour and other factors that may vary with age and lifestyle. Moderation in drinking and development of an associated lifestyle culture should be fostered.

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.

a b s t r a c t Background: Data on the efficacy of Peg-interferon/ribavirin therapy for chronic hepatitis C are mostly derived from treatment of selected patients enrolled in clinical trials. This study aimed to assess the effectiveness of Peg-interferon/ribavirin therapy in “real world” chronic hepatitis C patients in Italy. Methods: Independent observational multicentre study including consecutive patients receiving Peginterferon/ribavirin in the 18 months before (retrospective phase) and after (prospective phase) the start of the study. Results: 4176 patients were eligible. The final study population consisted of 2051 patients in the retrospective and 2073 in the prospective phase. Sustained virological response was achieved by 1036 patients (50.5%) during the retrospective phase: 325 were genotypes 1/4 (34.1%) and 684 were genotypes 2/3 (67.2%) and by 800 patients (38.6%) during the prospective phase: 300 were genotypes 1/4 (28.4%) and 473 were genotypes 2/3 (51.5%). During multivariate analysis genotypes 2/3 were significantly associated with higher sustained virological response rates; cirrhosis and -glutamil-transpeptidase >2 times the normal limit were associated with poorer response. Conclusions: The response to Peg-interferon/ribavirin therapy in “real world” clinical practice is distinctly lower than in registration trials. The difference in response rates was more pronounced among easy-totreat than among difficult-to-treat hepatitis C virus genotypes.

Nonalcoholic fatty liver disease (NAFLD) is systematically associated with insulin resistance and the metabolic syndrome, where behavior therapy remains the primary treatment, simultaneously addressing all the clinical and biochemical defects. However, very few studies have tested the effectiveness of intensive behavior therapy in NAFLD, aimed at lifestyle modifications to produce stable weight loss by reduced calorie intake and increased physical activity. Searching the literature for studies testing weight loss and lifestyle modifications for the treatment of NAFLD, only 14 reports were traced where the entry assessment satisfied well-defined criteria. The final effectiveness was based on hard histological outcomes in 5 cases. All but 1 were pilot, uncontrolled studies or limited case series, and in general the details of treatment were scanty. In only 3 cases treatment was carried out along the guidelines of behavior treatment to reduce excess nutrition and increase exercise; in these cases, a remarkable effect on weight loss and an improvement in liver histology were reported. The principles of behavior therapy are presented in detail, to help physicians change their prescriptive attitude into a more empowerment-based approach. A brief section is also included on the practical aspects and public policies to be implemented at societal level to obtain the maximum effects in lifestyle changes. There is a need for multidisciplinary teams including dietitians, psychologists, and physical activity supervisors caring for patients with NAFLD. Alternatively, general practitioners and physicians working in gastrointestinal units should limit their intervention to engage patients with NAFLD before referral to specialized teams set up for the treatment of diabetes and obesity. Copyright © 2008 by the American Association for the Study of Liver Diseases

Although a lot of novel information and data on the epidemiology of hepatitis C virus (HCV) infection are available worldwide, the majority of these information are often fragmentary and sometimes contradictory. This review tries to highlight all the data available on the prevalence (i.e. the number of cases present in a known population), the risk factors, the natural history and the incidence (i.e. the number of new cases that occur every year) of HCV infection in the world, and particularly in Italy.

Background: Although hepatic steatosis is seen with increasing frequency in clinical practice, its prevalence and risk factors are unknown. Objective: To investigate the prevalence of and risk factors for hepatic steatosis, such as alcohol consumption and obesity. Design: Cross-sectional, observational study. Setting: Participants in the Dionysos Study. Patients: 257 participants assigned to one of four categories (67 controls, 66 obese persons, 69 heavy drinkers, and 55 obese heavy drinkers). Measurements: Ethanol intake, assessed by a validated questionnaire and expressed as daily (g/d) and lifetime (kg) consumption, and body mass, expressed as body mass index. Biochemical tests of liver and metabolic function and hepatic ultrasonography were done. Results: The prevalence of steatosis was increased in heavy drinkers (46.4% [95% CI, 34% to 59%]) and obese persons (75.8% [CI, 63% to 85%]) compared with controls (16.4% [CI, 8% to 25%]). Steatosis was found in 94.5% (CI, 85% to 99%) of obese heavy drinkers. Compared with controls, the risk for steatosis was higher by 2.8-fold (CI, 1.4-fold to 7.1 -fold) in heavy drinkers, 4.6-fold (CI, 2.5-fold to 11.0-fold) in obese persons, and 5.8-fold (Cl, 3.2-fold to 12.3-fold) in persons who were obese and drank heavily. In heavy drinkers, obesity increased the risk for steatosis by twofold (CI, 1.5-fold to 3.0-fold) (P< 0.001), but heavy drinking was associated with only a 1.3-fold (Cl, 1.02-fold to 1.6-fold) increase in risk in obese persons (P = 0.0053). Elevated alanine aminotransferase and triglyceride levels are the most reliable markers of steatosis. Conclusions: Steatosis is frequently encountered in healthy persons and is almost always present in obese persons who drink more than 60 g of alcohol per day. Steatosis is more strongly associated with obesity than with heavy drinking, suggesting a greater role of overweight than alcohol consumption in accumulation of fat in the liver.

Background - The severity, clinical course, and risk of hepatitis C virus (HCV) related chronic liver disease are still rather poorly defined. Aims - To investigate the prevalence, risk factors, and severity of HCV related liver disease in the general population, and investigate whether infection with a specific genotype is associated with an increased risk of cirrhosis or hepatocellular carcinoma. Methods - HCV RNA determination by polymerase chain reaction (PCR) and HCV genotyping were performed in all anti-HCV positive subjects belonging to the Dionysos study (6917 subjects). Diagnosis of cirrhosis and hepatocellular carcinoma was established by liver biopsy in all cases. All the data were analysed by univariate and multivariate statistics in all the cohort. To investigate the natural history of HCV infection, anti-HCV positive subjects were followed up every six months for three years with liver function tests and ultrasonograms. Results - The overall prevalence of HCV RNA positivity was 2.3%. Positivity increased progressively with age, and was higher in women (ratio of men to women = 0.7). Genotypes 1b and 2a were the most frequent (42 and 24% of HCV RNA positive patients), with a prevalence of 1 and 0.6% respectively. Intravenous drug use, blood transfusions received before 1990, history of previous hepatitis among the cohabiting, and history of animal (mainly dogs) bites were significantly (p

Data on the prevalence of chronic liver disease, derived from selected series of hospitalized patients or from mortality registers, underestimate the prevalence of chronic liver disease. The Dionysos Study is a cohort study that investigated for the first time the prevalence of chronic liver disease in a general population. All the citizens of two towns in northern Italy, Campogalliano and Cormons, aged 12 to 65 yr were contacted by letter. From March 1991 through March 1993, 6,917 of a total of 10,150 citizens were enrolled (compliance, 69%). The standardized protocol for each enrollee included (a) a color-illustrated food questionnaire on dietary habits and alcohol intake; (b) a detailed medical history, including questions on risk factors for chronic liver disease; (c) a physical examination; and (d) blood tests for AST, ALT, γ-glutamyl-transpeptidase, mean cell volume, platelet count and hepatitis B virus and hepatitis C virus markers. Signs suggestive of chronic liver disease were seen in 21.3% of the subjects, and who then underwent further liver function tests, upper abdominal ultrasonography and, when necessary, liver biopsy. Persistent signs of chronic liver disease were present in 17.5% of the subjects, including 1.1% with cirrhosis and 0.07% with hepatocellular carcinoma. The prevalence rates of hepatitis B virus and hepatitis C virus positivity (second-generation enzyme-linked immunosorbent assay) were 1.3% and 3.2%, respectively. Alcohol abuse was the etiological agent in 23%. Other factors which predisposed subjects to chronic liver disease were age older than 35 yr, male sex, body mass index higher than 27, history of blood transfusion, drug addiction and presence of chronic liver disease in the subject's family. Cirrhosis was due to hepatitis B virus or hepatitis C virus in 37%, and alcohol was the cause in 26%. In those subjects with alcohol abuse, viral infection, especially hepatitis C virus, played an important role in the deterioration of chronic liver disease and its progression to hepatocellular carcinoma. We conclude that the Dionysos study, the first study of the prevalence of chronic liver disease in a general population of northern Italy, found a much higher prevalence of chronic liver disease than reported previously in selected populations from Western countries. Hepatitis viral infections and alcoholism were the most important causative agents.

The ability of ursodeoxycholic acid (UDCA, 600 mg/day) to lower alanine aminotransferase (ALT) blood levels in blood donors rejected for donation because of fluctuating hypertransaminasemia was evaluated in a randomized, controlled, double-blind clinical trial vs. placebo. All subjects with ALT values at least twice the normal upper limit in at least two out of three previous checks (the last one not more than 1 month previously) were admitted to the study. Checks were carried out 1, 2 and 3 months after the admission. 59 out of 65 patients completed the study. Although all patients were asked to abstain from alcohol, more than 50% of them in both groups had basal gamma-glutamyltransferase (gamma-GT) values higher than normal. After 1 month of treatment and throughout its duration, UDCA was effective in lowering ALT in all patients (30% decrease with respect to the basal value) and, especially, in lowering gamma-GT in those patients with elevated levels (50% decrease with respect to the basal value). This decrease was significantly different from the spontaneous 10% decrease of the ALT and gamma-GT levels observed in the placebo group. 3 months after suspension of therapy a rebound of both ALT and gamma-GT to values comparable to the basal ones or even higher was found only in UDCA-treated patients. We conclude that the short-term administration of UDCA is free of hepatotoxic effects and could be useful in lowering ALT and gamma-GT serum levels. The real significance of UDCA treatment in the natural history of chronic liver diseases deserves further investigation.

a b s t r a c t The prevalence of fatty liver (steatosis) in the general population is rapidly increasing worldwide. The progress of knowledge in the physiopathology of fatty liver is based on the systems biology approach to studying the complex interactions among different physiological systems. Similarly, translational and clinical research should address the complex interplay between these systems impacting on fatty liver. The clinical needs drive the applications of systems medicine to re-define clinical phenotypes, assessing the multiple nature of disease susceptibility and progression (e.g. the definition of risk, prognosis, diag- nosis criteria, and new endpoints of clinical trials). Based on this premise and in light of recent findings, the complex mechanisms involved in the pathology of fatty liver and their impact on the short- and long- term clinical outcomes of cardiovascular, metabolic liver diseases associated with steatosis are presented in this review using a new "systems medicine" approach. A new data set is proposed for studying the impairments of different physiological systems that have an impact on fatty liver in different subsets of subjects and patients.