Nonalcoholic steatohepatitis: a brief review on its concept

Since the first report by Ludwig, considerable progress has been made in the understanding of NASH and it is not currently considered as a merely benign clinical entity, but is rather thought as a common disease with a variety of clinical sequelae including liver cirrhosis and even hepatocellular carcinoma. Thus, NASH is considered as a type of a larger spectrum of nonalcoholic fatty liver disease (NAFLD) that is a consequence of insulin resistance and other underlining factors with histological findings ranging from fatty change alone to fat plus inflammation, to fat plus ballooning degeneration, and to fat plus alcoholic hepatitis-like lesions including Mallory body and fibrosis, the latter two categories being considered as NASH. In this brief review article, particular emphasis has been paid to the clinical entity, namely cryptogenic cirrhosis in relation to the pathogenesis of NASH.     

Approach to the pathogenesis and treatment of nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) represents an advanced stage of fatty liver disease developed in the absence of alcohol abuse. Its increasing prevalence in western countries, the diagnostic difficulties by noninvasive tests, and the possibility of progression to advanced fibrosis and even cirrhosis make NASH a challenge for hepatologists. NASH is frequently associated with type 2 diabetes and the metabolic syndrome, and several genetic and acquired factors are involved in its pathogenesis. Insulin resistance plays a central role in the development of a steatotic liver, which becomes vulnerable to additional injuries. Several cyclic mechanisms leading to self-enhancement of insulin resistance and hepatic accumulation of fat have been recently identified. Excess intracellular fatty acids, oxidant stress, tumor necrosis factor-alpha, and mitochondrial dysfunction are causes of hepatocellular injury, thereby leading to disease progression and to the establishment of NASH. Intestinal bacterial overgrowth also plays a role, by increasing production of endogenous ethanol and proinflammatory cytokines. Therapeutic strategies aimed at modulating insulin resistance, normalizing lipoprotein metabolism, and downregulating inflammatory mediators with probiotics have promising potential.     

Exercise as a therapeutic tool to prevent mitochondrial degeneration in nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease, encompassing hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, is a significant health problem associated with modern lifestyle, based on caloric overconsumption and physical inactivity. Although the mechanisms associated with progression from the ‘benign’ steatosis to NASH are still elusive, mitochondrial dysfunction seems to play an important role in this degenerative process. Degeneration of mitochondrial function during NASH has been associated with impaired β‐oxidation, oxidative phosphorylation and increased reactive oxygen species production, contributing to hepatocyte death and inflammatory response. Despite the fact that several therapeutic approaches can be used in the context of NASH, including insulin‐sensitizing agents, anti‐obesity drugs, lipid‐lowering drugs or mitochondrial‐targeted drugs, dietary and physical activity are still the most effective strategies. In fact, active lifestyles decrease insulin resistance and body weight and result in decreased histological signs of liver injury. In fatty liver, physical activity prevents the disease progression through mitochondrial adaptations, namely by increasing cytochrome c content, enzyme activities and fatty acid oxidation, which are lost after some days of physical inactivity. However, less is known about the effect of physical activity on NASH‐associated mitochondrial dysfunction. After a brief characterization of NASH and its association with liver mitochondrial (dys)function, the present review addresses the impact of physical (in)activity on NASH and, particularly, the possible contribution of active lifestyles to the modulation of liver mitochondrial dysfunction.     

Role of oxidative stress in non-alcoholic steatohepatitis

Oxidative stress plays an important role in the pathogenesis of non-alcoholic steatohepatitis (NASH). Reactive oxygen species (ROS) would derive from mitochondria, cytochrome P-450 2E1, peroxisome, and iron overload in the liver with steatosis. These excessive ROS is considered to cause simple steatosis to progress to NASH. On the other hand, oxidative stress exacerbates insulin sensitivity in hepatocytes, while hepatic steatosis causes oxidative stress. Thus, oxidative stress and insulin resistance might be interactive in NASH. Actually, we have found that the grade of steatosis correlates with serum thioredoxin level, a marker of oxidative stress, in NASH patients. Therefore, we propose that the feedback loop of oxidative stress, insulin resistance, and steatosis would play a significant role in the development of NASH.     

Non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) refers to the accumulation of hepatic steatosis not due to excess alcohol consumption. The prevalence of NAFLD is up to 30% in developed countries and nearly 10% in developing nations, making NAFLD the most common liver condition in the world. The pathogenesis of NAFLD is related to insulin resistance and, thus, it is frequently found in individuals who have central obesity or diabetes. Insulin resistance and excess adiposity are associated with increased lipid influx into the liver and increased de novo hepatic lipogenesis, promoting hepatic triglyceride accumulation. Defects in lipid utilization via mitochondrial oxidation and lipid export may also contribute to hepatic lipid build-up. Adipocytokine alterations, lipotoxicity from saturated fatty acids and fructose have been all been implicated in causing hepatocyte injury in NAFLD through pathways involving oxidative and endoplasmic reticulum stress. Clinically, NAFLD is commonly asymptomatic and frequently detected incidentally by blood liver function tests or imaging performed for other reasons. Subjects with NAFLD have a higher mortality rate than the general population and are at increased risk of developing cardiovascular disease and diabetes in the future. Histologically, NAFLD occurs as a spectrum from mild hepatic steatosis only, to non-alcoholic steatohepatitis (NASH) characterized by hepatocellular injury and inflammation, to cirrhosis. A diagnosis of NASH with associated fibrosis heralds a more significant prognosis as it is more likely to progressive to cirrhosis with complications of hepatic failure and hepatocellular carcinoma. Currently, the diagnosis of NASH requires a liver biopsy, however, serum based markers of hepatocyte apoptosis such as cytokeratin-18 fragments offer promise as accurate non-invasive diagnostic tests. Treatment of NAFLD revolves around addressing concomitant metabolic risk factors and improving insulin resistance through weight loss measures and exercise. Insulin sensitizing agents such as pioglitazone and anti-oxidant agents such as vitamin E show some promise in improving liver histology in patients with NASH, however, the long-term benefit of these medications has not been demonstrated.     

New diagnostic and treatment approaches in non-alcoholic fatty liver disease (NAFLD)

Non-alcoholic fatty liver disease or NAFLD is a chronic liver condition characterized by hepatic steatosis and associated with insulin resistance and type 2 diabetes mellitus (T2DM). In many patients fat accumulation leads to steatohepatitis (NASH) with chronic necrosis, inflammation, and fibrosis, and eventually to the development of cirrhosis. Obese and T2DM patients are at the greatest risk for NASH and progressive disease. New diagnostic techniques, such as magnetic resonance imaging and spectroscopy (MRS), have enhanced our way to non-invasively quantify liver fat and suggest that the epidemic of NAFLD is much larger than previously believed. However, the diagnosis of NAFLD for clinicians remains difficult due to a number of factors: limited awareness, non-specific symptoms, few laboratory findings, and the need for a liver biopsy to confirm the diagnosis. Traditional treatment approaches have centered on weight loss, but data are limited on its long-term efficacy, and the overall compliance is poor. Recently, pioglitazone has been shown to be safe and effective in patients with NASH and may radically change our approach to the disease. Still, many aspects remain poorly understood. Taken together, wider use of new diagnostic methods and treatment approaches appears to signal the dawn of a new era in the management of NAFLD.     

A Mouse Model of Metabolic Syndrome: Insulin Resistance,Fatty Liver and Non-Alcoholic Fatty Pancreas Disease (NAFPD) in C57BL/6 Mice Fed a High Fat Diet

Diet-induced obesity in C57BL/6 mice triggers common features of human metabolic syndrome (MetS). The purpose is to assess the suitability of a diet-induced obesity model for investigating non-alcoholic fatty pancreatic disease (NAFPD), fatty liver and insulin resistance. Adult C57BL/6 mice were fed either high-fat chow (HFC, 60% fat) or standard chow (SC, 10% fat) during a 16-week period. We evaluated in both groups: hepatopancreatic injuries, pancreatic islets size, alpha and beta-cell immunodensities, intraperitoneal insulin tolerance test (IPITT) and oral glucose tolerance test (OGTT). The HFC mice displayed greater mass gain (p<0.0001) and total visceral fat pads (p<0.001). OGTT showed impairment of glucose clearance in HFC mice (p<0.0001). IPITT revealed insulin resistance in HFC mice (p<0.0001). The HFC mice showed larger pancreatic islet size and significantly greater alpha and beta-cell immunodensities than SC mice. Pancreas and liver from HFC were heavier and contained higher fat concentration. In conclusion, C57BL/6 mice fed a high-fat diet develop features of NAFPD. Insulin resistance and ectopic accumulation of hepatic fat are well known to occur in MetS. Additionally, the importance of fat accumulation in the pancreas has been recently highlighted. Therefore, this model could help to elucidate target organ alterations associated with metabolic syndrome.     

Different susceptibility to insulin resistance and fatty liver depending on the combination of TNF-α C-857T and adiponectin G+276T gene polymorphisms in Japanese subjects with type 2 diabetes

The C-857T promoter polymorphism of TNF-α gene is associated with obese type 2 diabetes, while the adiponectin G+276T gene polymorphism in intron 2 may influence the fat accumulation in the liver. In this study, we examined effects of these polymorphisms on clinical markers of insulin resistance and fatty liver (a liver/spleen CT ratio < 0.9). These polymorphisms were determined in 342 Japanese subjects with type 2 diabetes. The liver/spleen CT ratio was lower in the subjects with the adiponectin +276G/G genotype than that in the subjects with the +276T allele (P < 0.05), indicating that fat accumulation in the liver is associated with the +276G/G genotype. Multiple comparisons among the 4 combinations of each polymorphism of the TNF-α and adiponectin genes revealed a significant difference in the liver/spleen CT ratio (P < 0.05) among the 4 groups, indicating that the gene combinations influence the degree of fat accumulation in the liver. The subjects carrying the TNF-α -857T allele (C/T or T/T genotype) and the adiponectin +276G/G genotype had greater risks for fatty liver and insulin resistance that was evaluated by higher levels of fasting insulin and homeostasis model assessment of insulin resistance, as compared with the other groups. Therefore, Japanese subjects with the TNF-α -857T allele and the adiponectin +276G/G genotype may be more susceptible to insulin resistance and fatty liver. The present study provides the evidence for the interaction between TNF-α and adiponectin genes in the insulin resistance and fatty liver in Japanese subjects with type 2 diabetes.     

Treatment of NASH: nutritional counseling and physical exercise

Nonalcoholic fatty liver disease(NAFLD) is recognized as a cause of potentially progressive liver damage. NAFLD is often associated with metabolic syndrome that comprises central obesity, insulin resistance, and hyperlipidemia. Among these, severer forms with histopathological features of increasing ballooned hepatocytes and fibrosis are defined as nonalcoholic steatohepatitis (NASH). The natural history of NASH is only partly known, the disease is slowly progressive and therapeutic outcomes are difficult to define. Since central obesity and insulin resistance are most likely involved in the pathogenesis, justification of life style including physical exercise and nutritional counseling is essential for the treatment of NASH.     

Alpha2-Heremans-Schmid glycoprotein/fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans

OBJECTIVE: The alpha(2)-Heremans-Schmid glycoprotein (AHSG; fetuin-A in animals) impairs insulin signaling in vitro and in rodents. Whether AHSG is associated with insulin resistance in humans is under investigation. In an animal model of diet-induced obesity that is commonly associated with hepatic steatosis, an increase in Ahsg mRNA expression was observed in the liver. Therefore, we hypothesized that the AHSG plasma protein, which is exclusively secreted by the liver in humans, may not only be associated with insulin resistance but also with fat accumulation in the liver. RESEARCH DESIGN AND METHODS: Data from 106 healthy Caucasians without type 2 diabetes were included in cross-sectional analyses. A subgroup of 47 individuals had data from a longitudinal study. Insulin sensitivity was measured by a euglycemic-hyperinsulinemic clamp, and liver fat was determined by (1)H magnetic resonance spectroscopy. RESULTS: AHSG plasma levels, adjusted for age, sex, and percentage of body fat, were higher in subjects with impaired glucose tolerance compared with subjects with normal glucose tolerance (P = 0.006). AHSG plasma levels were negatively associated with insulin sensitivity (r = -0.22, P = 0.03) in cross-sectional analyses. Moreover, they were positively associated with liver fat (r = 0.27, P = 0.01). In longitudinal analyses, under weight loss, a decrease in liver fat was accompanied by a decrease in AHSG plasma concentrations. Furthermore, high AHSG levels at baseline predicted less increase in insulin sensitivity (P = 0.02). CONCLUSIONS: We found that high AHSG plasma levels are associated with insulin resistance in humans. Moreover, AHSG plasma levels are elevated in subjects with fat accumulation in the liver. This is consistent with a potential role of AHSG as a link between fatty liver and insulin resistance.     

Central Role of Fatty Liver in the Pathogenesis of Insulin Resistance in Obese Adolescents

OBJECTIVE

We evaluated the role of fatty liver in the alteration of insulin sensitivity and β-cell function in two groups of obese adolescents, differing in hepatic fat content (hepatic fat fraction [HFF]) but with similar intrabdominal intramyocellular lipid content (IMCL) and overall degree of obesity.

RESEARCH DESIGN AND METHODS

We studied 23 obese adolescents with high HFF (HFF >5.5%) and 20 obese adolescents with low HFF (HFF <5.5%), matched for age, Tanner stage, BMI z score, and percentages of body fat, visceral fat, and IMCL. All subjects underwent an oral glucose tolerance test and a two-step hyperinsulinemic-euglycemic clamp, magnetic resonance imaging and ¹H nuclear magnetic resonance to assess abdominal fat distribution, HFF, and IMCL, respectively.

RESULTS

The high HFF group showed significantly lower whole-body insulin sensitivity index (P = 0.001) and estimates of insulin secretion (P = 0.03). The baseline hepatic glucose production (EGP) rate was not different between the two groups. Suppression of EGP was significantly lower (P = 0.04) in the high HFF group during low-dose insulin; no differences were observed during the second step. Baseline fatty acids, glycerol concentrations, and clamp suppression of glycerol turnover did not differ between the groups. During the second step, the glucose disposal rate was significantly lower (P = 0.01) in the high HFF group.

CONCLUSIONS

Fatty liver, independent of visceral fat and IMCL, plays a central role in the insulin-resistant state in obese adolescents.Fat accumulation in the liver is becoming a common complication in pediatric obesity and is strongly associated with alterations in glucose and lipid metabolism, possibly because of the presence of insulin resistance (1). The mechanisms responsible for the interrelationships between fatty liver disease and insulin resistance are not clearly understood; in fact, it remains unclear whether hepatic steatosis is a consequence or a cause of derangements in insulin sensitivity. As recently shown by our group, the severity of fatty liver, independent of obesity, is associated with the presence of pre-diabetes (2). Of note is the fact that in those studies, fatty liver accumulation rose in parallel with increasing visceral fat as well as intramyocellular fat (intramyocellular lipid content [IMCL]) (2,3). Therefore, from those earlier studies it was virtually impossible to assess the independent contribution of the liver to the development of insulin resistance, because both visceral fat and intramyocellular fat are also known to modulate insulin sensitivity (4,5).Thus, herein we examined the exclusive role of fatty liver in the alteration of insulin sensitivity and β-cell function in two groups of obese adolescents, differing in the amount of hepatic fat content (hepatic fat fraction [HFF]), but characterized by similar distribution of abdominal and muscle fat and overall degree of obesity. We hypothesized that, independent of visceral fat and IMCL, liver fat content would be a key determinant of global insulin resistance, involving liver, muscle, and adipose tissue.     

Insulin sensitizers in nonalcoholic fatty liver disease and steatohepatitis: Current status

Nonalcoholic fatty liver disease (NAFLD), first described in 1980, is now recognized as one of the most common causes of elevated liver enzymes and chronic liver disease in Western countries. The incidence of NAFLD in both adults and children is rising, in conjunction with the burgeoning epidemics of obesity and type 2 diabetes mellitus. NAFLD often coexists with other sequelae of the metabolic syndrome: central obesity, type 2 diabetes, hypertension, and hyperlipidemia. NAFLD encompasses a spectrum of pathologic liver diseases ranging from simple hepatic steatosis to a predominant lobular necro-inflammation, with or without centrilobular fibrosis (called nonalcoholic steatohepatitis or NASH). NASH can progress to cirrhosis, decompensated liver disease, and hepatocellular carcinoma. Though the natural history of NASH is still not clearly defined, it has been observed to progress to cirrhosis in 15%–220% of those affected. Insulin resistance is nearly universal in NASH and is thought to play an important role in its pathogenesis leading to dysregulated lipid metabolism. The prevalence of insulin resistance is reported in the general population to be approaching 45%, suggesting that NAFLD and NASH will contin nue to be an important public health concern. To date, NASH has proven to be a difficult disease to treat. Front-line therapy with lifestyle modifications resulting in weight loss through decreased caloric intake and moderate exercise is generally believed to be beneficial in patients with NASH, but is often difficult to maintain long term. Given that insulin resistance plays a dominant role in the pathogenesis, many studies have examined the use of insulin sensitizers: the biguanides (metformin), thiazolidinediones (pioglitazone, troglitazone, and rosiglitazone), glucagon-like peptide-1-receptor agonists, or incretins (exenatide)in NASH. This review will provide an overview of insulin resistance in NAFLD and provide a detailed summary on the clinical data regarding the use of insulin sensitizers in NASH.     

Metabolic implications of body fat distribution.

Insulin resistance is the cornerstone for the development of non-insulin-dependent diabetes mellitus (NIDDM). Free fatty acids (FFAs) cause insulin resistance in muscle and liver and increase hepatic gluconeogenesis and lipoprotein production and perhaps decrease hepatic clearance of insulin. It is suggested that the depressing effect of insulin on circulating FFA concentration is dependent on the fraction derived from visceral adipocytes, which have a low responsiveness to the antilipolytic effect of insulin. Elevated secretion of cortisol and/or testosterone induces insulin resistance in muscle. This also seems to be the case for low testosterone concentrations in men. In addition, cortisol increases hepatic gluconeogenesis. Cortisol and testosterone have "permissive" effect on adipose lipolysis and therefore amplify lipolytic stimulation; FFA, cortisol, and testosterone thus have powerful combined effects, resulting in insulin resistance and increased hepatic gluconeogenesis. All these factors promoting insulin resistance are active in abdominal visceral obesity, which is closely associated with insulin resistance, NIDDM, and the "metabolic syndrome." In addition, the endocrine aberrations may provide a cause for visceral fat accumulation, probably due to regional differences in steroid-hormone-receptor density. In addition to the increased activity along the adrenocorticosteroid axis, there also seem to be signs of increased activity from the central sympathetic nervous system. These are the established endocrine consequences of hypothalamic arousal in the defeat and defense reactions. There is some evidence that suggests an increased prevalence of psychosocial stress factors is associated with visceral distribution of body fat. Therefore, it is hypothesized that such factors might provide a background not only to a defense reaction and primary hypertension, suggested previously, but also to a defeat reaction, which contributes to an endocrine aberration leading to metabolic aberrations and visceral fat accumulation, which in turn leads to disease.     

Central role of the adipocyte in the metabolic syndrome.

Insulin resistance is associated with a plethora of chronic illnesses, including Type 2 diabetes, dyslipidemia, clotting dysfunction, and colon cancer. The relationship between obesity and insulin resistance is well established, and an increase in obesity in Western countries is implicated in increased incidence of diabetes and other diseases. Central, or visceral, adiposity has been particularly associated with insulin resistance; however, the mechanisms responsible for this association are unclear. Our laboratory has been studying the physiological mechanisms relating visceral adiposity and insulin resistance. Moderate fat feeding of the dog yields a model reminiscent of the metabolic syndrome, including visceral adiposity, hyperinsulinemia, and insulin resistance. We propose that insulin resistance of the liver derives from a relative increase in the delivery of free fatty acids (FFA) from the omental fat depot to the liver (via the portal vein). Increased delivery results from 1) more stored lipids in omental depot, 2) severe insulin resistance of the central fat depot, and 3) possible regulation of visceral lipolysis by the central nervous system. The significance of portal FFA delivery results from the importance of FFA in the control of liver glucose production. Insulin regulates liver glucose output primarily via control of adipocyte lipolysis. Thus, because FFA regulate the liver, it is expected that visceral adiposity will enhance delivery of FFA to the liver and make the liver relatively insulin resistant. It is of interest how the intact organism compensates for insulin resistance secondary to visceral fat deposition. While part of the compensation is enhanced B-cell sensitivity to glucose, an equally important component is reduced liver insulin clearance, which allows for a greater fraction of B-cell insulin secretion to bypass liver degradation, to enter the systemic circulation, and to result in hyperinsulinemic compensation. The signal(s) resulting in B-cell up-regulation and reduced liver insulin clearance with visceral adiposity is (are) unknown, but it appears that the glucagon-like peptide (GLP-1) hormone plays an important role. The integrated response of the organism to central adiposity is complex, involving several organs and tissue beds. An investigation into the integrated response may help to explain the features of the metabolic syndrome.     

Nonalcoholic Fatty Liver Disease: Evidence-Based Management and Early Recognition of Nonalcoholic Steatohepatitis

Nonalcoholic fatty liver disease is the most prevalent liver disease in the world. Metabolic syndrome and obesity are associated risk factors. The inflammatory subtype, nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis, is predicted to become the primary indication for liver transplantation within the next decade. Although there are no approved medications for NASH, there are ongoing multicenter trials aimed at targeting aspects of fat accumulation, inflammation, and fibrosis throughout the disease process. Nurse practitioners should focus on identifying patients at risk for NASH, while using guidelines for the management of nonalcoholic fatty liver disease and the comorbidities contributing to disease progression.     

Angiotensin receptor blockers in the treatment of NASH/NAFLD: Could they be a first-class option?

Nonalcoholic fatty liver disease (NAFLD) is a condition pathogenically linked to metabolic syndrome (MS) by insulin resistance (IR), and characterized by hepatic steatosis in the absence of significant alcohol use, hepatotoxicity, and/or other known liver diseases. The principles of NAFLD therapy target IR: the key point of MS. As the renin-angiotensin system (RAS) plays a central role in IR, and subsequently in NAFLD and nonalcoholic steatohepatitis (NASH), an attempt to block the deleterious effects of RAS overexpression seems a logical target. While many potential therapies tested in NASH target only the consequences of this condition, or try to “get rid” of excessive fat, angiotensin receptor blockers (ARBs) could act as an elegant tool for adequate correction of the various imbalances that act in harmony in NASH/NAFLD. Indeed, by inhibiting RAS we can improve the intracellular insulin signaling pathway, better control adipose tissue proliferation and adipokine production, and produce more balanced local and systemic levels of various cytokines. At the same time, by controlling the local RAS in the liver we might be able to prevent at least fibrosis and also slow down the vicious cycle that links steatosis to necroinflammation. By targeting the pancreatic effects of angiotensin we should be able to preserve an adequate insulin secretion and acquire a better metabolic balance. In our opinion there are two major advantages of ARBs that make them a possible therapeutic option for treating NASH and MS: their specific antihypertensive effect, and their impact on liver fibrosis. In light of this, and based on the current evidence (including existent human studies), we can speculate that some ARBs like telmisartan, candesartan, and losartan can be beneficial in treating NASH/NAFLD and its consequences, and further larger controlled clinical trials will bring consistent data into this field.     

Therapy for Nonalcoholic Fatty Liver Disease: Current Options and Future Directions

PurposeNonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease that is driven by the metabolic syndrome. NAFLD encompasses nonalcoholic fatty liver, >5% fat in the liver without inflammation of fibrosis, nonalcoholic steatohepatitis (NASH), fat plus varying degrees of inflammation and fibrosis, and cirrhosis of the liver from NASH. As facets of the metabolic syndrome, particularly diabetes and obesity, become more common worldwide, the incidence of new NAFLD is increasing.MethodsA qualitative systematic review was performed via searches of PubMed and ClinicalTrials.gov for therapeutic interventions for NAFLD.FindingsCurrent therapies rely on metabolic syndrome risk factor control and lifestyle changes to achieve weight loss. Because sustained weight loss is difficult for many patients, there is a critical unmet need for pharmacotherapy to treat NAFLD, especially the progressive form, NASH, to prevent cirrhosis of the liver. New therapies for NAFLD focus on the subset of patients with NASH and some degree of fibrosis. Novel mechanisms of action, including farnesoid X nuclear receptor agonism, C–C motif chemokine receptor 2 and receptor 5 antagonism, stearoyl-CoA desaturase-1, and thyroid hormone receptor β agonism, are currently under investigation as monotherapy. The products also hold potential for use in combination with and without insulin sensitizers and other established drugs in the future.ImplicationsThis review of NASH treatments details the interventions that are currently available as well as those in late-stage clinical trials that may represent the future of NASH therapy.     

Molecular mechanism in the development of the complications associated with obesity--the physiological and pathological role of adipocytokines

Visceral fat accumulation often accompanies various complications, such as insulin resistance, hypertension, dyslipidemia and atherosclerosis. Adipose tissue has been found to secrete various biologically active adipocytokines including free fatty acids. Accumulation of visceral fat increases the portal free fatty acids concentration to cause insulin resistance and dyslipidemia. Tumor necrosis alpha (TNF alpha) deteriorates insulin resistance in obesity. The levels of plasminogen activator inhibitor(PAI)-1 increase and plasma adiponectin concentration decreases in obesity leading to the development of vascular disease. The finding of genes specifically expressed in visceral fat and new adipocytokines should facilitate clarification of the mechanism for the development and complications of visceral fat accumulation.     

Pediatric nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease related to excessive accumulation of hepatic fat, and represents a spectrum of liver disease ranging from fat accumulation alone (steatosis) to the more significant histologic finding of steatohepatitis. Nonalcoholic steatohepatitis is a progressive liver disease associated with increased risk of liver cirrhosis and cancer. NAFLD is becoming increasingly prevalent in the pediatric population in direct correlation with the emergence of childhood obesity as a significant pediatric health problem. The exact pathophysiology of NAFLD remains unclear, although the interplay of insulin resistance, oxidative stress, and release of proinflammatory cytokines are implicated in the process. The diagnostic workup and treatment for NAFLD and nonalcoholic steatohepatitis remains controversial. This review discusses current concepts regarding the natural history, pathophysiology, and management of pediatric patients with NAFLD.