NASH in Lean Individuals Younes, Ramy; Bugianesi, Elisabetta
Seminars in liver disease,
02/2019, Letnik:
39, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Nonalcoholic fatty liver disease (NAFLD) is generally associated with obesity and the related comorbidities but it can also develop in subjects with a body mass index (BMI) within the ethnic-specific ...cutoff of 25 kg/m
BMI in Caucasian and 23 kg/m
in Asian subjects, the so-called "lean" NAFLD. This sub-phenotype of NAFLD patients has been described across populations of different ethnicity, particularly in Asia, but it can be diagnosed in 10 to 20% of nonobese Americans and Caucasians. Pathophysiological mechanisms underpinning the "lean" phenotype are not completely understood, but they may include a more dysfunctional fat (visceral obesity, differences in adipocyte differentiation and altered lipid turnover), altered body composition (decreased muscle mass), a genetic background, not limited to patatin-like phospholipase domain-containing protein 3 (PNPLA3) C > G polymorphisms, epigenetic changes occurring early in life and a different pattern of gut microbiota. Lean subjects with NAFLD have milder features of the metabolic syndrome when compared with obese patients. Nonetheless they have a higher prevalence of metabolic alterations (e.g., dyslipidemia, arterial hypertension, insulin resistance, and diabetes) compared with healthy controls. Data on histological severity are controversial, but they can develop the full spectrum of liver disease associated with nonalcoholic steatohepatitis NASH. Since lean NAFLD usually present with less obesity-related comorbidities, it is commonly believed that this group would follow a relatively benign clinical course but recent data challenge this concept. Here, the authors describe the current knowledge about NAFLD in lean individuals and highlight the unanswered questions and gaps in the field.
Growing epidemiological evidence suggests that nonalcoholic fatty liver disease (NAFLD) is an early predictor of and determinant for the development of type 2 diabetes and other features of the ...metabolic syndrome. This finding may have important clinical implications for the diagnosis, prevention and treatment of type 2 diabetes and its chronic complications. However, given the complex and bi‐directional relationships between NAFLD, insulin resistance and chronic hyperglycaemia, it is extremely difficult to distinguish whether NAFLD is a cause or a consequence of insulin resistance and type 2 diabetes. Indeed, at the molecular level, hepatic lipogenesis and hepatic glucose production depend on differentially regulated branches of the insulin signalling pathway. Furthermore, genetic studies suggest that excess hepatic fat is associated with progressive liver disease, but does not always increase the risk of incident type 2 diabetes. Here, we will briefly review the epidemiological, pathophysiological and molecular evidence linking NAFLD to the development of type 2 diabetes. We will also discuss some recent genetic and therapeutic advances that seem to challenge a causal role of NAFLD in the pathogenesis type 2 diabetes, and propose a working hypothesis to explain this apparent conundrum. In conclusion, progressive liver disease and type 2 diabetes are divergent though inter‐related consequences of insulin resistance and the metabolic syndrome.
Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease but the second cause of death among NAFLD patients are attributed to malignancies at both gastrointestinal ...(liver, colon, esophagus, stomach, and pancreas) and extra-intestinal sites (kidney in men, and breast in women). Obesity and related metabolic abnormalities are associated with increased incidence or mortality for a number of cancers. NAFLD has an intertwined relationship with metabolic syndrome and significantly contributes to the risk of hepatocellular carcinoma (HCC), but recent evidence have fuelled concerns that NAFLD may be a new, and added, risk factor for extra-hepatic cancers, particularly in the gastrointestinal tract. In this review we critically appraise key studies on NAFLD-associated extra-hepatic cancers and speculate on how NAFLD may influence carcinogenesis at these sites.
Natural history of NASH Armandi, Angelo; Bugianesi, Elisabetta; Valenti, Luca
Liver international,
June 2021, 2021-06-00, 20210601, Letnik:
41, Številka:
S1
Journal Article
Recenzirano
Odprti dostop
Non‐alcoholic fatty liver disease (NAFLD) is the fastest growing cause of chronic liver disease worldwide. Although only a small proportion of NAFLD patients will progress to end‐stage liver disease ...and death, the clinical burden of NAFLD is substantial due the sheer number of individuals affected worldwide. In fact, recent estimates suggest that 25% of the world have NAFLD, which is now one of the leading causes of cirrhosis and indications for liver transplantation. Although liver‐related mortality is common, the most common cause of death in patients with NAFLD is related to cardiovascular diseases, followed by extra‐hepatic cancers. There is a significant interindividual variability in the susceptibility to liver disease. The severity of metabolic alterations is the main risk factor for progressive NAFLD, but the qualitative components of diet, physical activity and genetic factors also play an important role. In particular, common variants in patatin‐like phospholipase domain‐containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane bound O‐acyl transferase 7 (MBOAT7) and glucokinase regulator (GCKR) have been shown to contribute to the full spectrum of NAFLD. In those at risk of a potentially progressive form of NAFLD or non‐alcoholic steatohepatitis or in those with hepatic fibrosis, additional assessment must be made.
Over the past 2 decades, nonalcoholic fatty liver disease (NAFLD) has grown from a relatively unknown disease to the most common cause of chronic liver disease in the world. In fact, 25% of the ...world’s population is currently thought to have NAFLD. Nonalcoholic steatohepatitis (NASH) is the subtype of NAFLD that can progress to cirrhosis, hepatocellular carcinoma (HCC), and death. NAFLD and NASH are not only found in adults—there is also a high prevalence of these diseases in children and adolescents. Because of the close association of NAFLD with type 2 diabetes (T2DM) and obesity, the latest models predict that the prevalence of NAFLD and NASH will increase, causing a tremendous clinical and economic burden and poor patient‐reported outcomes. Nonetheless, there is no accurate noninvasive method to detect NASH, and treatment of this disease is limited to lifestyle modifications. To examine the state of NAFLD among different regions and understand the global trajectory of this disease, an international group of experts came together during the 2017 American Association for the Study of Liver Diseases Global NAFLD Forum. We provide a summary of this forum and an assessment of the current state of NAFLD and NASH worldwide.
Plasma concentrations of amino acids (AAs), in particular, branched chain AAs (BCAAs), are often found increased in nonalcoholic fatty liver disease (NAFLD); however, if this is due to increased ...muscular protein catabolism, obesity, and/or increased insulin resistance (IR) or impaired tissue metabolism is unknown. Thus, we evaluated a) if subjects with NAFLD without obesity (NAFLD‐NO) compared to those with obesity (NAFLD‐Ob) display altered plasma AAs compared to controls (CTs); and b) if AA concentrations are associated with IR and liver histology. Glutamic acid, serine, and glycine concentrations are known to be altered in NAFLD. Because these AAs are involved in glutathione synthesis, we hypothesized they might be related to the severity of NAFLD. We therefore measured the AA profile of 44 subjects with NAFLD without diabetes and who had a liver biopsy (29 NAFLD‐NO and 15 NAFLD‐Ob) and 20 CTs without obesity, by gas chromatography–mass spectrometry, homeostasis model assessment of insulin resistance, hepatic IR (Hep‐IR; Hep‐IR = endogenous glucose production × insulin), and the new glutamate–serine–glycine (GSG) index (glutamate/serine + glycine) and tested for an association with liver histology. Most AAs were increased only in NAFLD‐Ob subjects. Only alanine, glutamate, isoleucine, and valine, but not leucine, were increased in NAFLD‐NO subjects compared to CTs. Glutamate, tyrosine, and the GSG‐index were correlated with Hep‐IR. The GSG‐index correlated with liver enzymes, in particular, gamma‐glutamyltransferase (R = 0.70), independent of body mass index. Ballooning and/or inflammation at liver biopsy were associated with increased plasma BCAAs and aromatic AAs and were mildly associated with the GSG‐index, while only the new GSG‐index was able to discriminate fibrosis F3‐4 from F0‐2 in this cohort. Conclusion: Increased plasma AA concentrations were observed mainly in subjects with obesity and NAFLD, likely as a consequence of increased IR and protein catabolism. The GSG‐index is a possible marker of severity of liver disease independent of body mass index. (Hepatology 2018;67:145‐158).
Liver-related mortality is the third cause of death in patients with nonalcoholic fatty liver disease, but the long-term prognosis basically depends on the presence and severity of liver damage. ...Thus, life expectancy in patients with simple steatosis is not different from the general population, but liver-related mortality is significantly higher in patients with nonalcoholic steatohepatitis (NASH), particularly in those with advanced fibrosis. Progression of liver disease is observed in up to one-third of patients with NASH. The long-term hepatic prognosis mostly depends on the histologic stage at initial liver biopsy, but multiple risk factors may concur.
Non-alcoholic steatohepatitis is becoming the most important aetiology for advanced liver disease. There has been important progress in the field in recent years and the complexity of the ...pathophysiology of NASH is better understood. Multiple non-invasive circulating and imaging biomarkers have been tested. The importance of lifestyle has been recognised and several drugs are being tested in clinical trials. This review addresses the challenges that healthcare professionals face in the management of NASH patients.
PDF
