Vol. 8 Issue S1
On the cover: Official Journal of the Mexican Association of Hepatology and the Latin-American Association for the Study of the Liver
The authors summarize and update the most recent knowledge in the field of prevalence, natural history and incidence of Non Alcoholic Fatty Liver Disease (NAFLD) and Non Alcoholic Steatohepatitis (NASH). These novel diseases, firstly recognized at the beginning of the second millennium, arose suddenly to the attention of the clinicians, because they are the hepatic expression of the "so-called" metabolic syndrome. Due to the epidemic burden of obesity, diabetes, and metabolic diseases, NAFLD and NASH will become soon probably the most common hepatic disease worldwide, and they surely will keep busy our future young hepatologists.
The consequences of pathologic adipose tissue accumulation have been described for almost all organs. Nonalcoholic fatty liver disease (NAFLD) is considered the most relevant hepatic manifestation of obesity. There is great interest in the study of NAFLD, and new insights into its pathogenic process have been described. Currently, in addition to insulin resistance, which was considered the hallmark of this disease, endocrine, immunologic, and central nervous system factors are attracting interest as explanatory variables. In this review, new factors associated with the main theories on the pathophysiology of NAFLD are analyzed.
The development of nonalcoholic fatty liver disease (NAFLD) is strongly associated with the metabolic syndrome as reflected by the fact that approximately 90% of the patients with NAFLD have more than one feature of metabolic syndrome and about 33% have three or more criteria. The physiopathology, epidemiology and therapeutic considerations of the disease are reviewed here. Lipotoxicity plays a predominant role in the pathophysiology of both entities. It leads to accumulation of triglycerides in the liver as a result of an imbalance among the uptake, synthesis, export, and oxidation of fatty acids. Both conditions are very common in Mexico. Using the Adult Treatment Panel diagnostic criteria, the 1994 prevalence of the metabolic syndrome was 26.6%.Although the prevalence of NAFLD is not known, but it can be estimated from the prevalence of obesity (30%). Since NAFLD is found in over two thirds of the obese subjects, this condition may exist in 20% of the adult population. The treatment of both conditions should be based in an integral approach, including the adoption of a healthy lifestyle, weight loss and may be pharmacotherapy. In summary, NAFLD is the hepatic expression of the metabolic syndrome. The study and treatment of these disorders could not be viewed as separate issues.
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, affecting approximately 30% of Western populations and a frequent indication for liver transplantation. The histologic spectrum of NAFLD includes simple steatosis, which has a benign prognosis, and nonalcoholic steatohepatitis, a more aggressive form of liver injury that may progress to cirrhosis and its complications. At present, the only widely accepted means of differentiating these lesions, including the severity of hepatic fibrosis, is liver biopsy. However, due to the invasiveness of this procedure, the rising prevalence of NAFLD, and the expected availability of effective therapies for this condition, the identification of noninvasive tools for the diagnosis and staging of NAFLD has emerged as a major clinical and research priority. This review summarizes important advances in this field during the past decade, including the development of biomarkers of hepatic fibrosis, apoptosis, and inflammation; novel imaging techniques such as transient elastography; and high-throughput technologies including proteomics and genomics. Future studies must focus on the development of accurate, inexpensive, and reliable tools that can differentiate the major histologic determinants of NAFLD; are responsive to changes in NAFLD severity due to therapeutic intervention and time; and have prognostic significance. Until such tools are developed, liver biopsy remains an important tool in the assessment of patients with NAFLD.
Obesity and related disorders are a common cause of morbidity worldwide. Nonalcoholic fatty liver disease is the most important hepatic consequence of adipose accumulation. There is strong evidence of obesity-related disorders as risk factors for hepatocellular carcinoma and of nonalcoholic fatty liver disease as a cause of hepatocellular carcinoma, but it is apparently less important than other chronic liver diseases. Unfortunately, preventive measures are not well validated in the population of patients with NAFLD. In this review, we analyze the available information supporting the increased risk of hepatocellular carcinoma in obese patients and patients with nonalcoholic fatty liver disease, considering the epidemiological and basic research- derived evidence.
An association between non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) has been recently suggested. Indeed, different studies have demonstrated that NAFLD patients present increased subclinical atherosclerosis compared to non-steatosic individuals, and are supported by the few follow-up studies revealing that CVD is the second most common cause of death in NAFLD patients. However, the nature of the relationship NAFLD/CVD is still under debate.
In the last three decades prevalence of insulin related diseases has been growing worldwide with epidemic obesity, type 2 diabetes mellitus and non alcoholic fatty liver disease. In children such epidemics are particularly worrisome, since metabolic abnormalities track to the adulthood with significant implications for the health care system. Epidemiological studies support a close association between type 2 diabetes and fatty liver disease. We review the most recent epidemiological data on prevalence of both diseases in youth and their association.
With the growing epidemic of obesity and diabetes, more attention has been placed on metabolic syndrome and its associated hepatic manifestation, non-alcoholic fatty liver disease (NAFLD). Within the spectrum of clinico-pathologic conditions known as NAFLD, only a minority of patients has the histological features characteristic of non-alcoholic steatohepatitis (NASH), which has the potential to progress to cirrhosis and hepatocellular carcinoma. Therefore, diagnosis and therapy should target patients with NASH. Current treatment recommendations include weight loss and the reversal of other components of metabolic syndrome, but several other treatment modalities are under investigation. To date, no pharmacologic treatment has been reliably shown to be effective for NASH. This article reviews all available treatment modalities, including lifestyle changes, bariatric surgery, weight loss medications, insulin sensitizers, lipid lowering agents, antioxidants, cytoprotective agents, and other novel treatments.
Non-alcoholic steatohepatitis has emerged as one of the most common causes of chronic liver disease in many regions of the world. Exercise and dietary changes constitute cornerstones of overall therapy aimed at achieving weight loss in hopes of ameliorating lipid-induced hepatocellular injury by mobilizing fat out of the liver. Indeed weight loss is known to be effective as evident in several controlled trials and, in the extreme, with bariatric surgery. However, less is known about exercise in the absence of weight loss especially in terms of altering hepatic fat metabolism. As with steatosis, adipose tissue function and other targets of insulin activity, skeletal muscle physiology is closely integrated with overall energy homeostasis and calorie disposal. Although much remains to be learned, increased physical conditioning appears to be closely linked to improved hepatic metabolism independent of changes in body weight. This is of practical importance to patients attempting lifestyle changes who may become unnecessarily discouraged if there is not evidence of associated weight loss as a result of increased activity. Moreover, the degree of physical conditioning represents an unmeasured and potentially confounding variable in most clinical trials of pharmacological intervention in NASH. Clinical investigation is needed to better understand the effects of exercise on liver fat metabolism and on how best to measure the degree of physical conditioning both as a baseline indicator of overall energy homeostasis and an end-point of treatment.
In chronic hepatitis C, insulin resistance (IR) and type 2 diabetes mellitus (DM) are more prevalent than in healthy controls or in chronic hepatitis B patients. HCV infection promotes IR mainly through increased TNF-α and cytokine suppressor (SOCS-3) production. Both events inhibit insulin receptor and IRS-1 (insulin receptor substrate) tyrosine phosphorylation. Hepatic steatosis is also 2.5 fold more frequent in hepatitis C virus (HCV) infected patients as compared to the general population. Metabolic factors play a crucial role in the etiology of hepatic steatosis genotype non-3 related, which are also the genotypes with a greater association to IR. However, genotype 3, and particularly 3a, has a greater direct steatogenic capacity, and consequently, in those patients, the association with metabolic factors is weaker. Instead, in genotype 3, steatosis associates with viral factors like viral load. Those metabolic factors influence not only the natural history of HCV infection, as well as associate to an accelerated hepatic fibrosis progression, to a worse prognosis when hepatic cirrhosis is present, namely an increased risk of hepatocellular carcinoma, and to a lower sustained viral response rate. On the other hand, in patients who achieve viral eradication, IR and hepatic steatosis may regress, and return if viral infection recurs, which once again indicates an intrinsic steatosis and IR promoter action by HCV.