The current epidemic of non-alcoholic fatty liver disease (NAFLD) is reshaping the field of hepatology all around the world. The widespread diffusion of metabolic risk factors such as obesity, type2-diabetes mellitus, and dyslipidemia has led to a worldwide diffusion of NAFLD. In parallel to the increased availability of effective anti-viral agents, NAFLD is rapidly becoming the most common cause of chronic liver disease in Western Countries, and a similar trend is expected in Eastern Countries in the next years. This epidemic and its consequences have prompted experts from all over the word in identifying effective strategies for the diagnosis, management, and treatment of NAFLD. Different scientific societies from Europe, America, and Asia-Pacific regions have proposed guidelines based on the most recent evidence about NAFLD. These guidelines are consistent with the key elements in the management of NAFLD, but still, show significant difference about some critical points. We reviewed the current literature in English language to identify the most recent scientific guidelines about NAFLD with the aim to find and critically analyse the main differences. We distinguished guidelines from 5 different scientific societies whose reputation is worldwide recognised and who are representative of the clinical practice in different geographical regions. Differences were noted in: the definition of NAFLD, the opportunity of NAFLD screening in high-risk patients, the non-invasive test proposed for the diagnosis of NAFLD and the identification of NAFLD patients with advanced fibrosis, in the follow-up protocols and, finally, in the treatment strategy (especially in the proposed pharmacological management). These difference have been discussed in the light of the possible evolution of the scenario of NAFLD in the next years.

Based on the assumption that characterizing the history of a disease will help in improving practice while offering a clue to research, this article aims at reviewing the history of nonalcoholic fatty liver disease (NAFLD) in adults and children. To this end, we address the history of NAFLD histopathology, which begins in 1980 with Ludwig’s seminal studies, although previous studies date back to the 19th century. Moreover, the principal milestones in the definition of genetic NAFLD are summarized. Next, a specific account is given of the evolution, over time, of our understanding of the association of NAFLD with metabolic syndrome, spanning from the outdated concept of “NAFLD as a manifestation of the Metabolic Syndrome”, to the more appropriate consideration that NAFLD has, with metabolic syndrome, a mutual and bi-directional relationship. In addition, we also report on the evolution from first intuitions to more recent studies, supporting NAFLD as an independent risk factor for cardiovascular disease. This association probably has deep roots, going back to ancient Middle Eastern cultures, wherein the liver had a significance similar to that which the heart holds in contemporary society. Conversely, the notions that NAFLD is a forerunner of hepatocellular carcinoma and extra-hepatic cancers is definitely more modern. Interestingly, guidelines issued by hepatological societies have lagged behind the identification of NAFLD by decades. A comparative analysis of these documents defines both shared attitudes (e.g., ultrasonography and lifestyle changes as the first approaches) and diverging key points (e.g., the threshold of alcohol consumption, screening methods, optimal non-invasive assessment of liver fibrosis and drug treatment options). Finally, the principal historical steps in the general, cellular and molecular pathogenesis of NAFLD are reviewed. We conclude that an in-depth understanding of the history of the disease permits us to better comprehend the disease itself, as well as to anticipate the lines of development of future NAFLD research.

Combined hepatocellular and cholangiocarcinoma (HCC-CC) is a rare primary liver cancer. It is constituted by neoplastic cells of both hepatocellular and cholangiocellular derivation. Different histology types of HCC-CC have been reported, hinting at heterogeneous carcinogenic pathways leading to the development of this cancer. Due to its rarity and complexity, mixed HCC-CC is a scantly investigated condition with unmet needs and unsatisfactory outcomes. Surgery remains the preferred treatment in resectable patients. The risk of recurrence, however, is high, especially in comparison with other primary liver cancers such as hepatocellular carcinoma. In unresectable or recurring patients, the therapeutic options are challenging due to the dual nature of the neoplastic cells. Consequently, the odds of survival of patients with HCC-CC remains poor. We analysed the literature systematically about the treatment of mixed HCC-CC, reviewing the main therapeutic options and their outcomes and analysing the most interesting developments in this topic with a focus on new potential therapeutic avenues.

Viral hepatitis: Innovations and expectations

In recent decades, following the spread of obesity, metabolic dysfunction has come to represent the leading cause of liver disease. The classical clinical presentation of the cirrhotic patient has, therefore, greatly changed, with a dramatic increase in subjects who appear overweight or obese. Due to an obesogenic lifestyle (lack of physical activity and overall malnutrition, with an excess of caloric intake together with a deficit of proteins and micronutrients), these patients frequently develop a complex clinical condition defined as sarcopenic obesity (SO). The interplay between cirrhosis and SO lies in the sharing of multiple pathogenetic mechanisms, including malnutrition/malabsorption, chronic inflammation, hyperammonemia and insulin resistance. The presence of SO worsens the outcome of cirrhotic patients, affecting overall morbidity and mortality. International nutrition and liver diseases societies strongly agree on recommending the use of food as an integral part of the healing process in the comprehensive management of these patients, including a reduction in caloric intake, protein and micronutrient supplementation and sodium restriction. Based on the pathophysiological paths shared by cirrhosis and SO, this narrative review aims to highlight the nutritional interventions currently advocated by international guidelines, as well as to provide hints on the possible role of micronutrients and nutraceuticals in the treatment of this multifaceted clinical condition.

The role of moderate alcohol consumption in the evolution of NAFLD is still debated. The aim of this study is to evaluate the impact of current and lifelong alcohol consumption in patients with NAFLD. From 2015 to 2020, we enrolled 276 consecutive patients fulfilling criteria of NAFLD (alcohol consumption up to 140 g/week for women and 210 g/week for men). According to their current alcohol intake per week, patients were divided in: abstainers, very low consumers (C1: <70 g/week) and moderate consumers (C2). We created a new tool, called LACU (Lifetime Alcohol Consuming Unit) to estimate the alcohol exposure across lifetime: 1 LACU was defined as 7 alcohol units per week for 1 drinking year. Patients were divided into lifelong abstainers and consumers and the latter furtherly divided into quartiles: Q1-Q4. Stratification according to alcohol intake, both current and cumulative as estimated by LACU, showed that very low consumers (C1 and Q1-Q3) displayed lower frequency of cirrhosis and hepatocellular carcinoma compared to abstainers and moderate consumers (C2 and Q4). We can speculate that up to one glass of wine daily in the context of a Mediterranean diet may be a long-term useful approach in selected NAFLD patients.