Current Pharmaceutical Design - Volume 19, Issue 29, 2013

Non-alcoholic fatty liver disease (NAFLD) currently represents the most common liver disease in Western countries, being found in 25-30% of the general population. NAFLD embraces a wide range of metabolic hepatic damage characterised by steatosis and, in some cases, associated non-alcoholic steatohepatitis (NASH). The long-term hepatic prognosis of NAFLD patients depends on the histological stage at diagnosis: simple steatosis has a favourable outcome, whereas patients with NASH can develop cirrhosis and other liver-related complications, including hepatocellular carcinoma. Progression of fibrosis is thought to develop in up to one third of NASH patients, including the development of cirrhosis, but regression is also possible in pre-cirrhotic stages. Independent predictors of fibrosis are older age, diabetes, obesity, hypertension, and the degree of insulin resistance. Patients with NAFLD, particularly those with NASH, have a higher prevalence and incidence of clinically manifested cardiovascular disease, independently of classical cardiometabolic risk factors. Hepatocellular carcinoma (HCC) is usually diagnosed at a late stage, but it may also occur in non-cirrhotic NASH, as obesity and diabetes both independently increases the risk of developing HCC. Liver-related mortality is increased up to ten-fold in patients with NASH.

Non-alcoholic fatty liver disease (NAFLD) encompasses pure steatosis through nonalcoholic steatohepatitis (NASH) and is the most common cause of chronic liver disease in Western countries. NASH is a progressive liver disease that increases the risk of cirrhosis and end-stage liver disease. Interestingly, the global health risk of NAFLD is not confined to the liver. Compared with those without NAFLD, patients with NAFLD exhibit not only increased liver-related complications and liver-related mortality but also increased risk of developing type 2 diabetes, cardiovascular disease (CVD) and chronic kidney disease, increased risk of post-operative complications after major liver surgery, and increased risk of developing certain malignancies, including primary liver cancer and colorectal cancer. In this review, we discuss the current evidence linking NAFLD with the risk of CVD in the setting of the more complex scenario of other hepatic and extra-hepatic complications that may occur during the natural course of NAFLD. Moreover, we provide a brief description of the putative biological mechanisms underlying such complications, particular emphasis being given to CVD. We conclude that NAFLD is a complex health problem with implications far beyond the liver. Hence, it may cause a significant global health burden and the assistance of patients with NAFLD impacts on the work of physicians from many different medical specialties.

Nonalcoholic fatty liver disease (NAFLD) affects about 20%-30% of the general population, and its clinical relevance arises from the fact that 20%-30% of these subjects develop non-alcoholic steatohepatitis (NASH), a condition at risk of cirrhosis progression. In addition NAFLD, and in particular NASH patients, are also at high risk of cardiovascular alterations, suffering overall from an increased liver and no liver-related events of risk and death. At the moment liver biopsy is the gold standard for a correct evaluation of NASH and fibrosis among NAFLD patients. However, the high and increasing prevalence of NAFLD has triggered an intensive search for alternative and non-invasive methods for evaluating disease severity. Specifically we can distinguish two main groups of non-invasive methodologies, namely ‘serum markers’ that use clinical and/or biochemical variables, and methodologies derived from elaboration of parameters arising from liver imaging techniques. All these tools showed encouraging results, even though their utility in clinical practice in the individual patients is still under debate. Therefore further efforts are needed in order to generate non-invasive algorithms that correctly assess liver damage in NAFLD patients. In particular, it should be interesting to perform gender-specific analysis, by combining old and new tools, with the aim to generate more accurate scores. Finally we think that non-invasive scores should not only be able to correctly classify the severity of liver disease in NAFLD patients, but also predict liver and non-liver related morbidity and mortality, further acting as time-dependent markers of liver and systemic disease activity. This review summarizes the present knowledge on noninvasive diagnosis in NAFLD patients, and suggest future directions for this complex research area.

Liver fat deposition related to systemic insulin resistance defines non-alcoholic fatty liver disease (NAFLD) which, when associated with oxidative hepatocellular damage, inflammation, and activation of fibrogenesis, i.e. non-alcoholic steatohepatitis (NASH), can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease and the leading cause of altered liver enzymes in Western countries. Epidemiological, familial, and twin studies provide evidence for an element of heritability of NAFLD. Genetic modifiers of disease severity and progression have been identified through genome-wide association studies. These include the Patatin-like phosholipase domain-containing 3 (PNPLA3) gene variant I148M as a major determinant of inter-individual and ethnicity-related differences in hepatic fat content independent of insulin resistance and serum lipid concentration. Association studies confirm that the I148M polymorphism is also a strong modifier of NASH and progressive hepatic injury. Furthermore, a few large multicentre case-control studies have demonstrated a role for genetic variants implicated in insulin signalling, oxidative stress, and fibrogenesis in the progression of NAFLD towards fibrosing NASH, and confirm that hepatocellular fat accumulation and insulin resistance are key operative mechanisms closely involved in the progression of liver damage. It is now important to explore the molecular mechanisms underlying these associations between gene variants and progressive liver disease, and to evaluate their impact on the response to available therapies. It is hoped that this knowledge will offer further insights into pathogenesis, suggest novel therapeutic targets, and could help guide physicians towards individualised therapy that improves clinical outcome.

NAFLD is the most common liver disease worldwide but it is the potential evolution to cirrhosis and hepatocellular carcinoma (HCC) that makes NAFLD of such clinical importance. The current work provides an overview of the main mechanims and potential therapeutical insights involved in NAFLD, NASH, fibrosis and HCC progression.

Non alcoholic steatohepatitis (NASH) is the more severe form of nonalcoholic fatty liver disease. In NASH, fatty liver, hepatic inflammation, hepatocyte injury and fibrogenesis are associated, and this condition may eventually lead to cirrhosis. Current treatment of NASH relies on the reduction of body weight and increase in physical activity, but there is no pharmacologic treatment approved as yet. Emerging data indicate that NASH progression results from parallel events originating from the liver as well as from the adipose tissue, the gut and the gastrointestinal tract. Thus, dysfunction of the adipose tissue through enhanced flow of free fatty acids and release of adipocytokines, and alterations in the gut microbiome generate proinflammatory signals that underlie NASH progression. Additional ‘extrahepatic hits’ include dietary factors and gastrointestinal hormones. Within the liver, hepatocyte apoptosis, ER stress and oxidative stress are key contributors to hepatocellular injury. In addition, lipotoxic mediators and danger signals activate Kupffer cells which initiate and perpetuate the inflammatory response by releasing inflammatory mediators that contribute to inflammatory cell recruitment and development of fibrosis. Inflammatory and fibrogenic mediators include chemokines, the cannabinoid system, the inflammasome and activation of pattern-recognition receptors. Here we review the major mechanisms leading to appearance and progression of NASH, focusing on both extrahepatic signals and local inflammatory mechanisms, in an effort to identify the most promising molecular targets for the treatment of this condition.

Healthy habits in terms of food intake and physical activity are first-line approach to prevention and treatment of nonalcoholic fatty liver disease, but difficulties arise in turning attempts into practice. Independently of the specific role of individual nutrients, not universally proven, overweight, obesity and diabetes are the specific conditions most frequently associated with hepatic fat accumulation. Accordingly, weight loss is mandatory in the majority of patients; this can be achieved by dietary restriction, but is rarely maintained in the long-term. Physical activity programs, both aerobic and resistance exercise may improve cardiorespiratory fitness, reduce the multiple conditions associated with the metabolic syndrome and help weight loss maintenance. However, motivating sedentary individuals to move is difficult and is favored by structured programs carried out along the lines of cognitive-behavior therapy. The role of behavior therapy is now supported by pilot studies, observational studies and finally by a randomized controlled study with histological outcomes. In the future, behavior interventions might be supported by important technological advances, such as smart phone technology and webbased platforms to facilitate interactive engagement amongst patients and with their health care providers. Lifestyle programs must also incorporate methods of overcoming barriers to accessing health service, engaging with workplace health programs and linking with community attempts to improve public health.

Background. Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, comprises a spectrum of conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH is associated with an increased risk of hepatocellular carcinoma (HCC) and cardiometabolic disease. Insulin resistance (IR) is the underlying pathogenic mechanism for NAFLD, the presence of which in turn, is a strong predictor for the development of metabolic disorders. Hence, therapy of NAFLD with insulin-sensitizing drugs (ISDs) should ideally improve the key hepatic histological changes (steatosis, inflammation and fibrosis), but should also reduce cardiometabolic and cancer risk. Objectives. In this review, the rationale for the use of ISDs and the evidence for their efficacy are detailed. In particular, the mechanism of action, potential for use, limitations and untoward effects of metformin and thiazolidinediones are systematically reviewed. Further, we discuss novel ISDs that may have potential clinical utility in NAFLD. Results and Conclusion. Despite the theoretical prediction that ISDs might have beneficial effects on disease outcomes, evidence that ISDs are able to alter the natural history of NAFLD are presently not available. The exploration of novel strategies exploiting “nonconventional” ISDs is encouraged.

This review is part of a special issue dealing with various aspects of non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). We will focus on promising treatments of NASH with antioxidants and drugs that interfere with lipid metabolism.The other therapies of interest, such as diet, behavioral changes, and insulin sensitizers are presented elsewhere. Oxidative stress is believed to play a key role in the pathogenesis of NASH and other liver diseases. Antioxidants aimed at improving chronic alcoholic or viral liver diseases have been an object of study for some time. However, only a few high quality, randomized, versus placebo-controlled, double-blinded trials have been carried out to assess these drugs. Vitamin E is currently the most widely assessed antioxidant. Several questions need to be answered, including long-term tolerance and efficacy of vitamin E in particular subsets, such as diabetes and NASH-related cirrhosis. Other antioxidants are promising, and should be assessed using the standards of evidence-based medicine. NAFLD frequently coexists with hyperlipidemia and carries an increased risk of cardiovascular disease (CVD). Furthermore, altered lipid metabolism is thought to be central to the pathogenesis of liver injury in NASH. Therefore, lipid-lowering drugs are attractive therapeutic tools in the treatment of NAFLD. Statins have ameliorated surrogate markers of steatosis in several randomized controlled trials, but their impact on liver histology is unknown. They have, however, been found to be the only class of lipid-lowering drugs that reduces cardiovascular risk in NAFLD. Preliminary evidence suggests that ezetimibe, an inhibitor of intestinal and hepatic cholesterol absorption, may improve liver histology, but its impact on the risk of CVD and on clinical outcome remains to be determined. Despite strong experimental evidence supporting the use of omega-3 polyunsaturated fatty acids in NAFLD, the studies published on humans have consisted of small sample sizes and had a number of methodological flaws, including the absence of post-treatment histology. Association of antioxidants and/or lipid-lowering drugs plus other drugs of interest in NASH, such as insulin sensitizers, warrant investigation. However, as promising as these drug treatments may continue to be, they should be associated with diet and modifications in lifestyle.

There is increasing evidence for a correlation between intestinal microbiota, bacterial translocation and hepatic steatosis. Intestinal microbiota affects nutrient absorption and energy homeostasis. Altered intestinal permeability may favor the passage of bacteriaderived compounds into systemic circulation, causing a systemic inflammatory state, characteristic of the metabolic syndrome. The interaction between intestinal permeability and luminal bacteria is involved in the pathogenesis and evolution of non-alcoholic liver disease. Microbiota pharmacological modulation could be a promising tool for a new therapeutical approach to non-alcoholic fatty liver disease.