F. Scaglioni

Epidemiology of Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is rapidly becoming the most common liver disease worldwide. The prevalence of NAFLD in the general population of Western countries is 20–30%. About 2–3% of the general population is estimated to have non-alcoholic steatohepatitis (NASH), which may progress to liver cirrhosis and hepatocarcinoma. As a rule, the prevalence of NAFLD is higher in males and increases with increasing age, and it is influenced by the diagnostic method and the characteristics of the population, especially lifestyle habits. Population-based studies provide better estimates of the prevalence of NAFLD as compared to autoptic and clinical studies, but few such studies have been performed to date. The diagnosis of NAFLD in population studies is usually obtained by ultrasonography, which is known to underestimate the prevalence of fatty liver. The Dallas Heart Study and the Dionysos Study reported that 30% of the adults in the USA and 25% in Italy have NAFLD. In these studies, 79% and 55% of patients with NAFLD had normal aminotransferase levels, showing that liver enzymes are not surrogate markers of NAFLD in the general population. Noninvasive markers such as the fatty liver index obtained from the Dionysos Study may be useful to screen for NAFLD in the general population. The most important risk factors for NAFLD are male gender, age, obesity, insulin resistance and the cardiometabolic alterations that define the metabolic syndrome. The prevalence of NAFLD is 80–90% in obese adults, 30–50% in patients with diabetes and up to 90% in patients with hyperlipidemia. The prevalence of NAFLD among children is 3–10%, rising up to 40–70% among obese children. Moreover, pediatric NAFLD increased from about 3% a decade ago to 5% today, with a male-to-female ratio of 2:1. The incidence and natural history of NAFLD are still not well defined, but it is recognized that the majority of individuals with NAFLD do not develop NASH. The incidence of NAFLD is probably increasing in Western countries, strictly linked to lifestyle habits.

ASH and NASH

Non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) have a similar pathogenesis and histopathology but a different etiology and epidemiology. NASH and ASH are advanced stages of non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD). NAFLD is characterized by excessive fat accumulation in the liver (steatosis), without any other evident causes of chronic liver diseases (viral, autoimmune, genetic, etc.), and with an alcohol consumption ≤20–30 g/day. On the contrary, AFLD is defined as the presence of steatosis and alcohol consumption >20–30 g/day. The most common phenotypic manifestations of primary NAFLD/NASH are overweight/obesity, visceral adiposity, type 2 diabetes, hypertriglyceridemia and hypertension. The prevalence of NAFLD in the general population in Western countries is estimated to be 25–30%. The prevalence and incidence of NASH and ASH are not known because of the impossibility of performing liver biopsy in the general population. Up to 90% of alcoholics have fatty liver, and 5–15% of these subjects will develop cirrhosis over 20 years. The risk of cirrhosis increases to 30–40% in those who continue to drink alcohol. About 10–35% of alcoholics exhibit changes on liver biopsy consistent with alcoholic hepatitis. Natural histories of NASH and ASH are not completely defined, even if patients with NASH have a reduced life expectancy due to liver-related death and cardiovascular diseases. The best treatment of AFLD/ASH is to stop drinking, and the most effective first-line therapeutic option for NAFLD/NASH is non-pharmacologic lifestyle interventions through a multidisciplinary approach including weight loss, dietary changes, physical exercise, and cognitive-behavior therapy.

Is nonalcoholic steatohepatitis associated with a high-though-normal thyroid stimulating hormone level and lower cholesterol levels?

Hypothyroidism is associated with the risk of development of the metabolic syndrome (MS) and hypercholesterolemia. Direct evidence that hypothyroidism might be associated with advanced chronic liver disease via nonalcoholic steatohepatitis (NASH) is limited. We studied the relationship between thyroid hormones, thyroid stimulating hormone (TSH), cholesterol, and NASH. In consecutive euthyroid patients with biopsy-proven nonalcoholic fatty liver disease, TSH and thyroid hormone (FT3 and FT4) concentrations were compared in 25 patients with steatosis and 44 non-cirrhotic NASH patients featuring concurrent ballooning, lobular inflammation and steatosis. The MS was diagnosed according to ATP III criteria. A meta-analysis of previously published studies was performed to evaluate whether NASH, compared to simple steatosis, is associated with lower cholesterol levels. At univariate analysis, compared to those with steatosis, patients with NASH have a wider waist, elevated levels of BMI, ALT, AST, fasting insulin, HOMA-IR, ferritin, TSH and a lower serum cholesterol. At stepwise multivariable logistic regression analysis, the independent predictors of NASH are high HOMA and TSH and lower total cholesterol (Model 1); MS and high TSH (Model 2). At meta-analysis, serum total cholesterol levels are significantly lower in predominantly non-cirrhotic NASH than in simple steatosis. This study provides cross-sectional and meta-analytic evidence that, in euthyroid patients, high-though-normal TSH values are independently associated with NASH. Further work is needed to ascertain the role, if any, of lower cholesterol serum levels in assisting in the diagnosis of NASH.

Short-term multidisciplinary non-pharmacological intervention is effective in reducing liver fat content assessed non-invasively in patients with nonalcoholic fatty liver disease (NAFLD)

BACKGROUND Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to steatohepatitis, and cirrhosis in patients with alcohol intake less than 20 g/day, and is usually associated with insulin resistance (IR). AIM Given that no drugs are specifically approved for NAFLD, we tested the efficacy of a non-pharmacological multidisciplinary intervention based on a personalized diet, physical activity and behavior therapy. METHODS In this open non-randomized study, personalized diet, physical exercise and behaviour therapy for 3 months were prescribed in 12 consecutive patients with NAFLD. Lifestyle, including total caloric intake, physical activity and resting energy expenditure was monitored by a SenseWear Armband. Insulin Resistance (IR) was measured by HOMA and oral glucose insulin sensitivity tests (OGIS); fat liver content was estimated by two different semi-quantitative scores and by the Doppler Power Index (DPI). RESULTS Data show that the multidisciplinary intervention produced a significant reduction of total caloric intake, a 8% reduction in body weight, a modest increase in daily physical activity, a significant (P<0.001) reduction of aminotransferases and a decrease of total hepatic fat content. CONCLUSIONS A 3-month multidisciplinary intervention inducing at least 8% of weight loss, improves liver tests and decreases liver fat content.

HCV, HBV and alcohol - the Dionysos study.

Population-based studies on the natural history of chronic viral liver disease that consider co-morbidity factors, such as alcohol or metabolic diseases, are lacking. We report here the contribution of ethanol intake and non-organ-specific autoantibodies (NOSA) to the course of chronic viral disease in the Dionysos cohort. As reported elsewhere, the Dionysos study was performed in two towns of Northern Italy, started in 1992 with 10 years of follow-up in 2002, and allowed us to quantify the burden of chronic liver disease in Northern Italy. We followed 139 subjects with chronic hepatitis C virus (HCV) infection and 61 with chronic hepatitis B virus (HBV) infection for a median (IQR) time of 8.4 (1.0) and 8.3 (0.9) years, respectively. The incidence and remission rates of steatosis were 9.0 and 29.7 per 1,000 person-years in the HCV cohort and 4.0 and 30.4 per 1,000 person-years in the HBV cohort. Progression to cirrhosis and hepatocarcinoma was more common in the HCV than in the HBV cohort. In the HCV cohort, ethanol intake was an independent predictor of liver cirrhosis and of death rate in both cohorts. We found no association between baseline NOSA and 8.4-year mortality. We conclude that morbidity and mortality rate of HBV and HCV infection in the general population is lower than that reported in secondary care populations, blood donors, or clinical series, and that ethanol intake >30 g/day is the most important and evitable risk factor for cirrhosis and death in patients with chronic HCV or HBV infection.