Drugs and steatohepatitis

In addition to the usual associations with insulin resistance, type 2 diabetes, central obesity, and hypertriglyceridemia, nonalcoholic steatohepatitis (NASH) has been associated with several drugs and toxins. However, drug-induced liver disease is a relatively uncommon cause of steatohepatitis. The term drug-induced steatohepatitis is preferred when the association appears to result from a direct toxic effect of the drug on the liver. For some agents implicated as causing cirrhosis or fatty liver disorders, the association may be coincidental because NASH is a common component of the insulin resistance (or metabolic) syndrome. In other instances, corticosteroids, tamoxifen, and estrogens may precipitate NASH in predisposed persons by exacerbating insulin resistance, central obesity, diabetes, and hypertriglyceridemia, and methotrexate may worsen hepatic fibrosis in NASH. Drug-induced steatohepatitis is associated with prolonged therapy (more than 6 months) and possibly drug accumulation, which in the case of perhexiline maleate is favored by a genetic polymorphism of CYP2D6 that leads to slow perhexiline oxidation. The toxic mechanism appears to involve mitochondrial injury, which causes steatosis because of impaired beta-oxidation of fatty acids, and leads to generation of reactive oxygen species and ATP depletion. Thus, drug-induced steatohepatitis may provide clues to injurious events in the more common metabolic forms of NASH. A clinical feature of some types of drug-induced steatohepatitis is progression after discontinuation of the causative agent. It follows that early recognition of hepatotoxicity is crucial to prevent the development of severer forms of liver disease and improve the clinical outcome.     

Black raspberries may become part of the armamentarium against esophageal cancer

Autophagy is a critical pathway for the degradation of intracellular components by lysosomes. Established functions for both macroautophagy and chaperone-mediated autophagy in hepatic lipid metabolism, insulin sensitivity and cellular injury suggest a number of potential mechanistic roles for autophagy in nonalcoholic steatohepatitis (NASH). Decreased autophagic function in particular may promote the initial development of hepatic steatosis and progression of steatosis to liver injury. Additional functions of autophagy in immune responses and carcinogenesis may also contribute to the development of NASH and its complications. The impairment in autophagy that occurs with cellular lipid accumulation, obesity and aging may therefore have an important impact on this disease, and agents to augment hepatic autophagy have therapeutic potential in NASH.     

A fresh look at NASH pathogenesis. Part 1: The metabolic movers

The strong relationship between over‐nutrition, central obesity, insulin resistance/metabolic syndrome and non‐alcoholic fatty liver disease (NAFLD) suggest pathogenic interactions, but key questions remain. NAFLD starts with over‐nutrition, imbalance between energy input and output for which the roles of genetic predisposition and environmental factors (diet, physical activity) are being redefined. Regulation of energy balance operates at both central nervous system and peripheral sites, including adipose and liver. For example, the endocannabinoid system could potentially be modulated to provide effective pharmacotherapy of NAFLD. The more profound the metabolic abnormalities complicating over‐nutrition (glucose intolerance, hypoadiponectinemia, metabolic syndrome), the more likely is NAFLD to take on its progressive guise of non‐alcoholic steatohepatitis (NASH). Interactions between steatosis and insulin resistance, visceral adipose expansion and subcutaneous adipose failure (with insulin resistance, inflammation and hypoadiponectinemia) trigger amplifying mechanisms for liver disease. Thus, transition from simple steatosis to NASH could be explained by unmitigated hepatic lipid partitioning with failure of local adaptive mechanisms leading to lipotoxicity. In part one of this review, we discuss newer concepts of appetite and metabolic regulation, bodily lipid distribution, hepatic lipid turnover, insulin resistance and adipose failure affecting adiponectin secretion. We review evidence that NASH only occurs when over‐nutrition is complicated by insulin resistance and a highly disordered metabolic milieu, the same ‘metabolic movers’ that promote type 2 diabetes and atheromatous cardiovascular disease. The net effect is accumulation of lipid molecules in the liver. Which lipids and how they cause injury, inflammation and fibrosis will be discussed in part two.     

Is there a role of lipid-lowering therapies in the management of fatty liver disease?

Atherogenic dyslipidemia is characterized by increased triglyceride-rich lipoproteins and low high-density lipoprotein cholesterol concentrations. It is highly prevalent in non-alcoholic fatty liver disease (NAFLD) and contributes to the increased cardiovascular risk associated with this condition. Alongside insulin resistance it plays an important pathogenetic role in NAFLD/non-alcoholic steatohepatitis (NASH) development and progression. It has been shown that cholesterol-lowering reduces cardiovascular risk more in NAFLD vs non-NAFLD high-risk individuals. This evidence highlights the importance of effective lipid modulation in NAFLD. In this narrative review the effects of the most commonly used lipid-lowering therapies on liver outcomes alongside their therapeutic implications in NAFLD/NASH are critically discussed. Preclinical and clinical evidence suggests that statins reduce hepatic steatosis, inflammation and fibrosis in patients with NAFLD/NASH. Most data are derived from observational and small prospective clinical studies using changes in liver enzyme activities, steatosis/fibrosis scores, and imaging evidence of steatosis as surrogates. Also, relevant histologic benefits were noted in small biopsy studies. Atorvastatin and rosuvastatin showed greater benefits, whereas data for other statins are scarce and sometimes conflicting. Similar studies to those of statins showed efficacy of ezetimibe against hepatic steatosis. However, no significant anti-inflammatory and anti-fibrotic actions of ezetimibe have been shown. Preclinical studies showed that fibrates through peroxisome proliferator-activated receptor (PPAR)α activation may have a role in NAFLD prevention and management. Nevertheless, no relevant benefits have been noted in human studies. Species-related differences in PPARα expression and its activation responsiveness may help explain this discrepancy. Omega-3 fatty acids reduced hepatic steatosis in numerous heterogeneous studies, but their benefits on hepatic inflammation and fibrosis have not been established. Promising preliminary data for the highly purified eicosapentaenoic acid require further confirmation. Observational studies suggest that proprotein convertase subtilisin/kexin9 inhibitors may also have a role in the management of NAFLD, though this needs to be established by future prospective studies.     

Steatosis and steatohepatitis in diabetic patient

Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized condition of excess fat deposition within the liver. NAFLD includes a spectrum of liver pathology ranging from bland hepatic steatosis to steatohepatitis and cirrhosis. Nonalcoholic steatohepatitis (NASH) is an inflammatory and fibrosing condition of the liver thought to be an intermediate stage of NAFLD that may progress to endstage liver disease, liver-related death and hepatocellular carcinoma. Nonalcoholic steatohepatitis (NASH) is a common liver disease that is characterized histologically by hepatic steatosis, lobular inflammation, and hepatocellular ballooning, it can progress to cirrhosis in up to 15% of patients. There is currently no therapy that is of proven benefit for nonalcoholic steatohepatitis. The disease is closely associated with insulin resistance and features of the metabolic syndrome such as obesity (increased waist circumference), hypertriglyceridemia, and type 2 diabetes. The pathologic criteria are now well established and the diagnosis can only be made once the absence or limited use of alcohol is confirmed. In addition to insulin resistance, oxidative stress has been implicated as a key factor contributing to hepatic injury in patients with nonalcoholic steatohepatitis. Thus, both insulin resistance and oxidative stress are attractive targets for therapy in patients with this disease. Several pilot studies have provided evidence that insulin sensitizers such as thiazolidinediones and antioxidants such as vitamin E improve clinical and histologic features of nonalcoholic steatohepatitis. The medical evidence of a benefit, however, is limited, because these studies had small samples and were performed at single centers. Moreover, a recent multicenter trial showed a reduction in hepatic steatosis but no improvement in markers of cell injury after a year of rosiglitazone therapy. The value of these remains uncertain. Until now the best trial was done by Sanyal, who studied 240 patients divided into 3 groups (pioglitazone versus vitamin E versus placebo)--multicenter, randomized, double-blind clinical trial in non-diabetics.     

Potential role of chitotriosidase gene in nonalcoholic fatty liver disease evolution

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by steatosis and periportal and lobular inflammation. The molecular mechanisms involved in the anomalous behavior of liver cells have only partially been disclosed. Human Chitotriosidase (Chit) is a member of the chitinase family that it is mainly synthesized by activated macrophages. We investigated chitotriosidase gene expression in Kupffer cells to determine the potential implication of this enzyme in the inflammation and in the progression from uncomplicated steatosis to steatohepatitis with progressive fibrosis. METHODS: Seventy-five liver biopsies from 40 subjects with NASH, 20 with simple steatosis, and 15 controls were used to detect CHIT expression, tumor necrosis factor-alpha (TNF-alpha), alpha-smooth muscle actin (alpha-SMA), and lipid peroxidation. RESULTS: CHIT was expressed exclusively by Kupffer cells. The levels of CHIT expression were significantly higher in NASH patients than in simple steatosis patients and in the control group. In addition, we found that CHIT over-expression influenced hepatic stellate cells activation, as demonstrated by the significant correlation between CHIT and alpha-SMA expression in NASH patients. A significant correlation was observed also between CHIT, TNF-alpha and lipid peroxidation in both NASH and simple steatosis. CONCLUSION: These results suggest that CHIT over-produced by Kupffer cells may contribute to the progression of hepatic fibrosis.     

Sitagliptin attenuates methionine/choline-deficient diet-induced steatohepatitis

Aims

Accumulating evidence suggests that inhibitors of dipeptidyl peptidase-4 (DPP-4), such as sitagliptin, may play an important role in the prevention of non-alcoholic steatohepatitis (NASH). This study was conducted to elucidate whether sitagliptin could prevent steatohepatitis by inhibiting pathways involved in hepatic steatosis, inflammation, and fibrosis.

Methods

C57BL/6 mice were fed a methionine/choline-deficient (MCD) diet with or without supplement with sitagliptin for 5 weeks. Liver and adipose tissue from mice were examined histologically and immunohistochemically to estimate the effect of sitagliptin on the development of NASH.

Results

Supplementation with sitagliptin resulted in significant improvement of MCD diet-induced fat accumulation in the liver. In addition, sitagliptin treatment lowered fatty acid uptake, expression of VLDL receptor and hepatic triglyceride content. Sitagliptin also effectively attenuated MCD diet-induced hepatic inflammation, endoplasmic reticulum (ER) stress, and liver injury, as evidenced by reduced proinflammatory cytokine levels, ER stress markers, and TUNEL staining. Expression of CYP2E1 and 4NHE were strongly increased by the MCD diet, but this effect was successfully prevented by sitagliptin treatment. Furthermore, sitagliptin significantly decreased levels of MCD diet-induced fibrosis-associated proteins such as fibronectin and α-SMA in the liver. Inflammatory and atrophic changes of adipose tissue by MCD diet were restored by sitagliptin treatment.

Conclusions

Sitagliptin attenuated MCD diet-induced hepatic steatosis, inflammation, and fibrosis in mice through amelioration of mechanisms responsible for the development of NASH, including CD36 expression, NF-κB activation, ER stress, CYP2E1 expression, and lipid peroxidation. Treatment with sitagliptin may represent an effective approach for the prevention and treatment of NASH.     

Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice

Background and Aims: We previously reported that steatohepatitis develops in obese, hypercholesterolemic, diabetic foz/foz mice fed a high‐fat (HF) diet for 12 months. We now report earlier onset of steatohepatitis in relation to metabolic abnormalities, and clarify the roles of dietary fat and bodily lipid partitioning on steatosis severity, liver injury and inflammatory recruitment in this novel non‐alcoholic steatohepatitis (NASH) model. Methods: Foz/foz (Alms1 mutant) and wild‐type (WT) mice were fed a HF diet or chow, and metabolic characteristics and liver histology were studied at 2, 6, 12 and 24 weeks. Results: After 12 weeks HF‐feeding, foz/foz mice were obese and diabetic with approximately 70% reduction in serum adiponectin. Hepatomegaly developed at this time, corresponding to a plateau in adipose expansion and increased adipose inflammation. Liver histology showed mild inflammation and hepatocyte ballooning as well as steatosis. By 24 weeks, HF‐fed foz/foz mice developed severe steatohepatitis (marked steatosis, alanine aminotransferase elevation, ballooning, inflammation, fibrosis), whereas dietary and genetic controls showed only simple steatosis. While steatosis was associated with hepatic lipogenesis, indicated by increased fatty acid synthase activity, steatohepatitis was associated with significantly higher levels of CD36, indicating active fatty acid uptake, possibly under the influence of peroxisome proliferator‐activated receptor‐γ. Conclusion: In mice genetically predisposed to obesity and diabetes, HF feeding leads to restriction of adipose tissue for accommodation of excess energy, causing lipid partitioning into liver, and transformation of simple steatosis to fibrosing steatohepatitis. The way in which HF feeding ‘saturates’ adipose stores, decreases serum adiponectin and causes hepatic inflammation in steatohepatitis may provide clues to pathogenesis of NASH in metabolic syndrome.     

健脾疏肝方对非酒精性脂肪性肝炎大鼠肝脂代谢分子网络的影响

目的:观察健脾疏肝方对非酒精性脂肪性肝炎(non-alcoholic steatohepatitis,NASH)的疗效以及对NASH大鼠肝脂代谢分子网络的影响.方法:将40只♂SD大鼠随机分成空白组、模型组、健脾疏肝方组、易善复组4组,采用高脂饲料造模连续8wk.模型成立后,改用普通饲料饲喂,同时健脾疏肝方组及易善复组分别予健脾疏肝方浸膏和易善复混悬液灌胃,模型组和空白组予去离子水灌胃,连续4wk;实验结束后处死全部大鼠,观察大鼠肝组织病理改变,测定大鼠肝功、血脂、肝脂以及抗氧化指标水平,观察大鼠肝组织SREBP-1c、SCAP、PPAR、PGC-1、LXR mRNA表达.结果:健脾疏肝方可有效改善大鼠肝组织脂肪变性及炎症损伤,降低肝功、血脂、肝脂水平,提高抗氧化物质,并可同时上调PPAR及PGC-1,下调SREBP-1c及SCAP mRNA表达(P<0.05,P<0.01),且在改善大鼠肝指数、体质量,降低谷丙转氨酶(ALT)水平、肝甘油三酯(TG)、MDA含量,提高GSH-PX含量,上调PPAR、PGC-1mRNA表达等方面优于易善复(P<0.05,P<0.01).结论:健脾疏肝方可通过网络调控NASH肝脂代谢而防治NASH,在今后研究中,可将健脾疏肝方作为基础,结合其他治法,辨证施治.     

Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation

BACKGROUND & AIMS: Nonalcoholic steatohepatitis is morphologically identical to alcoholic hepatitis and has multiple etiologic associations and an unknown pathogenesis. The present study used a rat nutritional model of hepatic steatosis with inflammation to test the hypothesis that induction of the alcohol-inducible hepatic cytochrome P450 (CYP) 2E1 is associated with production of steatohepatitis. METHODS: Rats received a diet devoid of methionine-choline. CYP2E1 protein was detected in liver sections by immunohistochemistry and in hepatic microsomal fractions by immunoblotting; CYP2E1 activity was detected by N-demethylation of N,N-dimethylnltrosamine (NDMA). CYP2E1 messenger RNA was analyzed by Northern blotting and slot blot hybridization. RESULTS: After 4 weeks of methionine-choline devoid diet, macrovesicular steatosis and an inflammatory infiltrate were prominent in hepatic acinar zone 3. CYP2E1 immunostaining was increased and had a more extensive acinar distribution corresponding to that of the steatosis. Microsomal CYP2E1 protein, NDMA activity, and hepatic CYP2E1 messenger RNA levels were all correspondingly increased. CONCLUSIONS: CYP2E1 is induced, partly at a pretranslational level, in this experimental form of steatohepatitis. The finding of biochemical and histological similarities between this nutritional model of hepatic steatosis with inflammation and alcoholic hepatitis indicates possible clues to common pathogenetic mechanisms. The relevance of this finding to human nonalcoholic steatohepatitis remains uncertain and requires further investigation of human liver specimens. (Gastroenterology 1996 Dec;111(6):1645-53)     

Nonalcoholic fatty liver disease: from lipid profile to treatment

Nonalcoholic fatty liver disease (NAFLD) is characterized by excess lipid accumulation in the liver. Although the majority of NAFLD is benign simple steatosis, a subset of NAFLD includes nonalcoholic steatohepatitis (NASH), which can progress to liver cirrhosis and liver cancer. In both simple steatosis and steatohepatitis, triglyceride is well known as the major lipid that accumulates in the liver. However, we have little information on the other lipids that deposit in the liver. Thus, lipid profiling is necessary to understand the pathogenesis of NAFLD. In addition, these data provide further information on early detection of NASH and optimal treatment for NAFLD. Although plasma and hepatic lipid profiles are similar between simple steatosis and steatohepatitis, recent intensive researches demonstrate that free cholesterol, polyunsaturated fatty acid (PUFA), and phospholipid levels are altered in human NAFLD. In experimental models, liver injury is induced by free cholesterol accumulation and compositional changes of n-6/n-3 PUFAs and phospholipids. Therefore, these lipid levels are candidates to predict the progression to NASH. Lipid-lowering agents have potential to normalize these lipid levels. Currently, favorable results are obtained using statins, ezetimibe, and n-3 PUFAs in simple steatosis. But the effects of these agents for NASH are limited. These unsatisfactory results may partially depend on the study design because most studies are relatively short-term and small number of patients. Larger studies are necessary to determine the promising effects of lipid-lowering agents for NASH and its comorbidities.     

NASH is an Inflammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications

While non-alcoholic fatty liver disease (NAFLD) is highly prevalent (15% to 45%) in modern societies, only 10% to 25% of cases develop hepatic fibrosis leading to cirrhosis, end-stage liver disease or hepatocellular carcinoma. Apart from pre-existing fibrosis, the strongest predictor of fibrotic progression in NAFLD is steatohepatitis or non-alcoholic steatohepatitis (NASH). The critical features other than steatosis are hepatocellular degeneration (ballooning, Mallory hyaline) and mixed inflammatory cell infiltration. While much is understood about the relationship of steatosis to metabolic factors (over-nutrition, insulin resistance, hyperglycemia, metabolic syndrome, hypoadiponectinemia), less is known about inflammatory recruitment, despite its importance for the perpetuation of liver injury and fibrogenesis. In this review, we present evidence that liver inflammation has prognostic significance in NAFLD. We then consider the origins and components of liver inflammation in NASH. Hepatocytes injured by toxic lipid molecules (lipotoxicity) play a central role in the recruitment of innate immunity involving Toll-like receptors (TLRs), Kupffer cells (KCs), lymphocytes and neutrophils and possibly inflammasome. The key pro-inflammatory signaling pathways in NASH are nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK). The downstream effectors include adhesion molecules, chemokines, cytokines and the activation of cell death pathways leading to apoptosis. The upstream activators of NF-κB and JNK are more contentious and may depend on the experimental model used. TLRs are strong contenders. It remains possible that inflammation in NASH originates outside the liver and in the gut microbiota that prime KC/TLR responses, inflamed adipose tissue and circulating inflammatory cells. We briefly review these mechanistic considerations and project their implications for the effective treatment of NASH.     

Palmitic acid induces production of proinflammatory cytokine interleukin-8 from hepatocytes

Obesity and the metabolic syndrome are closely correlated with hepatic steatosis. Simple hepatic steatosis in nonalcoholic fatty liver disease can progress to nonalcoholic steatohepatitis (NASH), which can be a precursor to more serious liver diseases, such as cirrhosis and hepatocellular carcinoma. The pathogenic mechanisms underlying progression of steatosis to NASH remain unclear; however, inflammation, proinflammatory cytokines, and oxidative stress have been postulated to play key roles. We previously reported that patients with NASH have elevated serum levels of proinflammatory cytokines, such as interleukin-8 (IL-8), which are likely to contribute to hepatic injury. This study specifically examines the effect of hepatic steatosis on IL-8 production. We induced lipid accumulation in hepatocytes (HepG2, rat primary hepatocytes, and human primary hepatocytes) by exposing them to pathophysiologically relevant concentrations of palmitic acid to simulate the excessive influx of fatty acids into hepatocytes. Significant fat accumulation was documented morphologically by Oil Red O staining in cells exposed to palmitic acid, and it was accompanied by an increase in intracellular triglyceride levels. Importantly, palmitic acid was found to induce significantly elevated levels of biologically active neutrophil chemoattractant, IL-8, from steatotic hepatocytes. Incubation of the cells with palmitate led to increased IL-8 gene expression and secretion (both mRNA and protein) through mechanisms involving activation of nuclear factor kappaB (NF-kappaB) and c-Jun N-terminal kinase/activator protein-1. CONCLUSION: These data demonstrate for the first time that lipid accumulation in hepatocytes can stimulate IL-8 production, thereby potentially contributing to hepatic inflammation and consequent liver injury.     

The pathogenesis of nonalcoholic steatohepatitis and other fatty liver diseases: a four-step model including the role of lipid release and hepatic venular obstruction in the progression to cirrhosis

Fatty liver disease involves the accumulation of triglycerides in hepatocytes, necrosis of hepatocytes, inflammation, and often fibrosis with progression to cirrhosis. The two-hit model summarizes the important early metabolic events leading to hepatocellular necrosis in nonalcoholic steatohepatitis (NASH). In this article, we provide evidence of lipid release from hepatocytes in posttransplant fat necrosis and in NASH and quantify vascular obliteration in a series of biopsies with NASH. Obliteration of small hepatic veins (<30 microm) in small numbers is compensated by collateral flow. Obliteration of larger hepatic veins (>30 microm) is associated with fibrotic collapse lesions that are not easily resorbed. Based on these observations, we propose a new four-step model that includes the later events that lead to cirrhosis after necrosis has occurred. This model is applicable to nonalcoholic fatty liver disease (NAFLD), alcoholic disease, postjejunoileal bypass disease, and posttransplant fat necrosis. The first step is steatosis facilitated by insulin, and the second is necrosis induced by intracellular lipid toxicity or lipid peroxidation, or both, modified by alcohol, drugs, and ischemia. The third step is release of bulk lipid from hepatocytes into the interstitium leading to direct and inflammatory injury to hepatic veins. The fourth step is venous obstruction with secondary collapse and ultimately fibrous septation and cirrhosis.     

Rosiglitazone attenuates age- and diet-associated nonalcoholic steatohepatitis in male low-density lipoprotein receptor knockout mice

Nonalcoholic fatty liver disease (NAFLD) is a common complication of obesity that can progress to nonalcoholic steatohepatitis (NASH), a serious liver pathology that can advance to cirrhosis. The mechanisms responsible for NAFLD progression to NASH remain unclear. Lack of a suitable animal model that faithfully recapitulates the pathophysiology of human NASH is a major obstacle in delineating mechanisms responsible for progression of NAFLD to NASH and, thus, development of better treatment strategies. We identified and characterized a novel mouse model, middle-aged male low-density lipoprotein receptor (LDLR)(-/-) mice fed a high-fat diet (HFD), which developed NASH associated with four of five metabolic syndrome (MS) components. In these mice, as observed in humans, liver steatosis and oxidative stress promoted NASH development. Aging exacerbated the HFD-induced NASH such that liver steatosis, inflammation, fibrosis, oxidative stress, and liver injury markers were greatly enhanced in middle-aged versus young LDLR(-/-) mice. Although expression of genes mediating fatty acid oxidation and antioxidant responses were up-regulated in young LDLR(-/-) mice fed HFD, they were drastically reduced in MS mice. However, similar to recent human trials, NASH was partially attenuated by an insulin-sensitizing peroxisome proliferator-activated receptor-gamma (PPARγ) ligand, rosiglitazone. In addition to expected improvements in MS, newly identified mechanisms of PPARγ ligand effects included stimulation of antioxidant gene expression and mitochondrial β-oxidation, and suppression of inflammation and fibrosis. LDLR-deficiency promoted NASH, because middle-aged C57BL/6 mice fed HFD did not develop severe inflammation and fibrosis, despite increased steatosis. Conclusion: MS mice represent an ideal model to investigate NASH in the context of MS, as commonly occurs in human disease, and NASH development can be substantially attenuated by PPARγ activation, which enhances β-oxidation.     

Nonalcoholic steatohepatitis in children

Nonalcoholic steatohepatitis (NASH) is one entity in a spectrum of chronic liver disease related to obesity, hyperinsulinemia, insulin resistance, and liver cell injury from free fatty acid toxicity or other oxidant stress. The more inclusive term ‘nonalcoholic fatty liver disease’ (NAFLD) is increasingly being used to encompass the entire spectrum, which includes simple hepatic steatosis without inflammation (which may not lead to progressive liver injury), NASH itself, and the resulting cirrhosis (which may be devoid of steatosis). Children get NAFLD, and the incidence of this pediatric liver disease is rising as childhood obesity becomes increasingly prevalent. Although much remains to be learned about pediatric NAFLD, it is already evident that children with NASH risk progressive liver damage, including cirrhosis. Liver biopsy is required for definitive diagnosis, and other causes of fatty liver in childhood must be excluded. Gradual weight loss through increased regular exercise and a low-fat, low-refined carbohydrate diet appears to be effective. Drug treatments are being developed. Pediatric NASH is a serious complication of childhood obesity.