Obesity and the liver: nonalcoholic fatty liver disease.

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REVIEW ARTICLE Obesity and the liver: nonalcoholic fatty liver disease Q23

SEAN W. P. KOPPE CHICAGO, ILL

The increasing prevalence of nonalcoholic fatty liver disease (NAFLD) parallels the rise of obesity and its complications. NAFLD is a common cause of cirrhosis and a leading indication for liver transplant. Genetic susceptibility, dietary composition, and exercise habits influence the development of NAFLD, and insulin resistance results in widespread metabolic perturbations with a net effect of triglyceride accumulation in the liver. Some patients will develop hepatocyte cellular injury and fibrosis of the liver, which can progress to cirrhosis and require liver transplant. Treatments targeting the pathophysiological mechanisms of NAFLD exist, but carry some potential risk and are not universally effective. Weight loss and lifestyle changes remain the most effective and safest approach, but sustainable change is difficult for most patients to achieve. Future work will continue to focus on developing effective and safe interventions to prevent the development of advanced liver disease, whereas efforts in the public health domain continue to combat obesity. (Translational Research 2014;-:1–11) Abbreviations: ApoC3 ¼ apolipoprotein C III; ChREBP ¼ carbohydrate response–elementbinding protein; CK-18 ¼ cytokeratin-18; DAG ¼ diacylglycerol; ER ¼ endoplasmic reticulum; HCC ¼ hepatocellular carcinoma; IRS-2 ¼ insulin receptor substrate 2; LOXL2 ¼ lysyl oxidaselike 2; LPS ¼ lipopolysaccharide; LXR ¼ liver X receptor; MET ¼ metabolic equivalent of task; MnSOD ¼ manganese-superoxide dismutase 2; NAFLD ¼ nonalcoholic fatty liver disease; NASH ¼ nonalcoholic steatohepatitis; OCA ¼ obeticholic acid; PKCε ¼ protein kinase Cε; PNPLA3 ¼ patatin-like phospholipase domain containing 3; ROS ¼ reactive oxygen species; SREBP-1 ¼ sterol regulatory element-binding protein 1; TLR4 ¼ toll-like receptor 4

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INTRODUCTION

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he exploding rate of obesity in the United States over the past several decades has led to an increased prevalence of diabetes and cardiovascular disease as well as nonalcoholic fatty liver disease (NAFLD). NAFLD is present in 20%–30% of adults in the United

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States and 10% of children.1-3 NAFLD represents a spectrum of disease with most patients having only steatosis; however, a sizable number of patients can also develop inflammation, cellular injury, and fibrosis, termed nonalcoholic steatohepatitis (NASH). The cellular injury in NASH is characterized by ballooned

From the Division of Gastroenterology and Hepatology, Northwestern Medicine, Chicago, Ill.

1931-5244/$ - see front matter

Submitted for publication March 31, 2014; revision submitted June 18, 2014; accepted for publication June 19, 2014.

http://dx.doi.org/10.1016/j.trsl.2014.06.008

Ó 2014 Mosby, Inc. All rights reserved.

Reprint requests: Sean W.P. Koppe, Kovler Organ Transplantation Center, 676 N. St. Clair, Suite 1900, Chicago, IL 60611; e-mail: [email protected].

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Translational Research - 2014

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% Liver Transplants for Alcohol and NASH/Cryptogenic Cirrhosis

18% 16% 14% 12% 10% 8% 6% 4% 2% 0% 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Fig 1. Percentage of liver transplants for alcohol and NASH/cryptogenic cirrhosis. The number of patients transplanted with a primary diagnosis of NASH/cryptogenic cirrhosis (black) has steadily risen and is nearly equal to the number of patients transplanted with primary diagnosis of alcohol (gray). Hepatitis C remains the most common indication for liver transplant. Patients with a primary diagnosis of hepatocellular carcinoma are excluded. http://optn.transplant.hrsa.gov. NASH, nonalcoholic steatohepatitis.

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hepatocytes, which frequently contain Mallory-Denk bodies.4 Patients with NAFLD found to have only steatosis are unlikely to progress to cirrhosis; however, steatosis can accelerate other forms of liver disease.5-7 Patients found to have NASH represent a subset of those with NAFLD at the greatest risk of progressing to cirrhosis, and it is estimated that 3%–5% of the general population has NASH.8 NASH now represents the third most common indication for liver transplantation, although at its current trend it is expected to soon eclipse alcohol as an indication for liver transplantation (Fig 1). In addition to increasing rates of transplantation for NASH, increased prevalence of obesity and diabetes in potential cadaveric donors has led to increased organ discard rate exacerbating the mismatch between supply and demand for liver transplants.9 The rising rate of childhood obesity has also led to the development of NAFLD/NASH in the pediatric population. Estimates based on elevated ALT and an autopsy series suggest a prevalence of pediatric NAFLD of 8%–10%.10 Risk factors for pediatric NAFLD mirror those for adult NAFLD and children with NASH can even progress to cirrhosis and require liver transplantation.11 Similar histologic changes are often noted in pediatric NASH compared with adult NASH; however, some cases of pediatric NASH present with less

hepatocyte ballooning and more portal-based inflammation and fibrosis.4,10 Although NAFLD leads to increased morbidity and mortality from liver disease, the most frequent cause of morbidity and mortality in the NAFLD population remains cardiovascular. Efforts continue to better understand the pathophysiology of NAFLD and develop treatments addressing those patients who develop NASH and have progressive liver disease. However, NAFLD should continue to be viewed as the hepatic manifestation of the metabolic syndrome and treatment of associated diabetes, hyperlipidemia, and hypertension are equally as important as the treatment of the actual liver disease. This review will discuss current understanding of the pathophysiology of NAFLD/ NASH and its management. PATHOGENESIS OF NAFLD/NASH

Fat accumulation in the liver is the culmination of dysregulation of fatty acid influx to the liver, fatty acid efflux, and hepatic de novo lipogenesis. Circulating adipokines and cytokines mediate and result from this process. Insulin resistance is near universally present in NAFLD and diabetes is a very frequent finding in those patients who develop NASH. Lipotoxicity,

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Fig 2. Pathways of liver injury in NAFLD. Insulin resistance is characterized by hyperinsulinemia and elevated levels of circulating FFAs. Elevated insulin activates the lipogenic transcription factor sterol regulatory binding protein-1c and coupled with increased FFA levels results in increased de novo lipogenesis. Elevated FFA leads to increased DAG levels, which further worsens insulin resistance. Elevated FFA also results in increased levels of ceramides, increased fatty acid oxidation leading to generation of ROS, and increased ER stress. Collectively, these processes result in generation of proinflammatory cytokines and reduced adiponectin levels. Increased inflammatory cytokines can also be generated by the interaction of LPS and TLR4. Saturated fatty acids and ceramides also serve as non-LPS agonists of TLR4 leading to generation of proinflammatory cytokines. Genetics and lifestyle factors also influence the development of NAFLD. DAG, diacylglycerol; ER, endoplasmic reticulum; FFA, free fatty acid; IL-6, interleukin 6; IL-10, interleukin 10; LPS, lipopolysaccharide; NAFLD, nonalcoholic fatty liver disease; PNPLA3, patatin-like phospholipase domain containing 3; ROS, reactive oxygen species; TLR4, toll-like receptor 4; TNF a, tumor necrosis factor a.

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mitochondrial dysfunction, oxidative stress, and endoplasmic reticulum (ER) stress are involved in hepatic injury. Adipose tissue distribution and genetic factors influence this process, and gut microbiota may also play a role (Fig 2). Genetics. Certain groups tend to have a higher prevalence of NAFLD/NASH with Mexican-Americans having a particularly high burden (24%) compared with non-Hispanic whites (18%) and non-Hispanic blacks (14%).1 There may be some differences based on alternate dietary patterns; however, genetic factors are a significant contributor to these differences. Patatin-like phospholipase domain containing 3 (PNPLA3) is a gene strongly associated with susceptibility to develop steatosis and progressive liver disease and may explain some of the racial differences. The precise function of PNPLA3 is unclear, but it appears to be involved with acylglycerol synthesis and also hydrolysis. Liver X receptor (LXR) and sterol regulatory element-binding protein 1 (SREBP-1) appear to regulate its expression, and fatty acids synthesized in the liver then delay degradation of PNPLA3.12 A variant of the PNPLA3 gene (rs738409[G]—I148M) has been shown to be significantly associated with hepatic steatosis, independent of body mass index (BMI) and the presence of diabetes, and also shown to

be associated with increased risk of NASH and even hepatocellular carcinoma (HCC).13-15 The initial study that discovered the importance of this particular allele found that it was most frequently found in Hispanics (0.49), followed by European Americans (0.23) and African Americans (0.17) and is therefore likely a strong factor in the racial differences observed with NAFLD.16 A precise understanding of the mechanism by which this polymorphism leads to liver disease is lacking but likely relates to liver-specific PNPLA3 dysfunction rather than adipose tissue PNPLA3 dysfunction.17 However, the finding that PNPLA3 genotype of liver transplant recipients is more important than the PNPLA3 genotype of donors in the development of post-transplant hepatic steatosis suggests that there may be other factors involved.18 Apolipoprotein C III (ApoC3) is found on VLDL and inhibits lipoprotein lipase activity, thereby reducing peripheral fat uptake and increasing serum triglycerides. Two common gene variants resulting in Q8 increased ApoC3 levels were found to place individuals at a higher risk of hypertriglyceridemia and NAFLD in the setting of modest caloric excess.19,20 ApoC3 accentuates steatosis related to caloric excess and its effect can be countered by low calorie, low-fat intake.21 A polymorphism in the SOD2 gene encoding Q9


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manganese-superoxide dismutase 2 may also contribute to the severity of NAFLD by altering sensitivity to oxidative stress. Other genetic polymorphisms enhancing susceptibility to NAFLD/NASH have also been reported.22,23 Insulin resistance and lipotoxicity. Increased adiposity and insulin resistance leads to elevated circulating levels of free fatty acids (FFAs) in patients with NAFLD. Insulin resistance leads to impaired suppression of lipolysis in all adipose tissues, and visceral adipose tissue is felt to be a particularly significant contributor to hepatic FFA exposure given its drainage via the splanchnic circulation.24 Elevated hepatic FFAs result in increased triglyceride synthesis and worsening insulin resistance mediated via lipid intermediates. Hyperinsulinemia also leads to activation of SREBP-1c, a key transcription factor regulating triglyceride synthesis. SREBP-1c activation coupled with increased availability of fatty acids promotes steatosis. Although triglyceride synthesis plays some pathologic role, particularly in insulin resistance, it is also viewed as a potential protective mechanism to lessen the damage produced by FFAs and other lipid intermediates.25,26 Lipid-derived metabolites are a significant contributor to the insulin resistance observed in patients with NAFLD. Elevated FFAs can result in increased diacylglycerol (DAG) formation, and elevated levels of DAG have been documented in patients with NAFLD.27-30 Accumulating DAG interferes with insulin signaling in the liver by activating protein kinase Cε leading to reduced insulin-stimulated tyrosine phosphorylation of the insulin receptor substrate 2.31 Ceramides, sphingolipids important in the lipid bilayer of cellular membranes, are also increased in the setting of increased FFAs in the liver.32-34 Ceramides may contribute to insulin resistance through inactivation of Akt; however, the evidence for ceramides contributing directly to insulin resistance in the liver is conflicting.30,34,35 Ceramides appear to play a role in NAFLD and progression to NASH, but this may be related to ceramideassociated generation of proinflammatory cytokines, apoptosis, and/or ER stress.36,37 FFAs in the liver can be esterified into triglycerides or enter the mitochondria to undergo b-oxidation. During the process of b-oxidation, reactive oxygen species (ROS) are generated via the mitochondrial respiratory chain. Increased fatty acid levels in NAFLD result in increased mitochondrial fatty acid b-oxidation.38-40 Increases in fatty acid b-oxidation in NAFLD are accompanied by mitochondrial structural changes and increased ROS generation compatible with mitochondrial dysfunction.38,41,42 Cytochrome P450 2E1, present in high concentrations in mitochondria, is

increased in NAFLD and also contributes to increased ROS generation.43,44 Increased ROS can result in increased lipid peroxidation, which is well described in patients with NAFLD and NASH.45-47 Elevated ROS also contributes to proinflammatory cytokine production and cellular apoptosis resulting in progression to NASH.48 ER stress is also implicated in the development of NAFLD and progression to NASH. ER stress can result in the unfolded protein response, an adaptive mechanism by cells to deal with threats to homeostasis; however, with prolonged stress stimuli the unfolded protein response can result in apoptosis and cell death.49,50 Elevated levels of FFAs can lead to ER stress in the liver, likely because of unfavorably altering the amount of saturated phospholipid in ER membranes resulting in decreased membrane fluidity with loss of functionality.51-53 Increased markers of ER stress have been noted in patients with NAFLD and NASH, supporting an important role for this pathway.54-56 Activation of the ER stress pathway promotes apoptosis and inflammation and also is noted to worsen insulin resistance.49 Adiponectin, innate immune system, endotoxin and microbiota. Certain cytokines produced by adipose

tissue or immune cells within the liver or circulating in the periphery appear to play an important role in the pathogenesis of NAFLD and progression of liver disease. Tumor necrosis factor a (TNF-a), interleukin 6, interleukin 10, and adiponectin are adipocytokines frequently implicated in NAFLD. Adiponectin is pro- Q12 duced by adipose tissue and has been found to improve insulin sensitivity and decrease inflammation. Adiponectin is generally protective and reduced levels are frequently found in patients with progressive NAFLD, although this association is not universally present.57,58 Adiponectin appears to reduce ceramide levels via induction of a ceramidase in various tissues with resulting improvement in insulin sensitivity and reduced inflammatory cytokines.59 Curiously, patients with NASH cirrhosis have been found to have paradoxically elevated adiponectin levels despite reduced adipose tissue and loss of hepatic steatosis (ie, ‘‘burnt out NASH’’ or cryptogenic cirrhosis). This has been explained by increased levels of bile acids mediating production of adiponectin via farnesoid X receptor (FXR).60 Toll-like receptor 4 (TLR4) is an innate pattern recognition receptor found in greatest abundance on innate immune cells such as macrophages and dendritic cells, but is also found in other cells that are participants in developing NAFLD and its progression to NASH, such as hepatocytes, adipocytes, and the hepatic stellate cell—a critical mediator of liver fibrosis.61-63 Endotoxin


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(lipopolysaccharide) is a potent activator of TLR4 and gut endotoxemia has long been suspected as an important potentiator of various liver diseases, including NAFLD.64 TLR4 activation results in proinflammatory cytokine production and can also contribute to insulin resistance.61,64 Additionally, there is evidence that TLR4 can be activated by nonendotoxin products particularly relevant in NAFLD, such as saturated fatty acids and ceramide.37,65,66 The gut microbiome has become increasingly recognized as an important factor in human health and disease, and work is now beginning to focus on the potential role the microbiome may play in the pathogenesis of obesity and NAFLD. Dietary composition can quickly modify the microbiome and provides an additional pathway by which diet influences obesity and its complications, such as NAFLD.67 Alterations in the microbiome are believed to influence obesity and NAFLD through generation of microbial products, which interact locally with enterocytes and influence signaling involved in obesity and NAFLD, increased permeability of the gut barrier leading to increased exposure to lipopolysaccharide and other TLR activators involved in inflammation, and through changes leading to increased availability of calories or pathologically altered micronutrient composition resulting from microbial metabolism of nutrients.68 Germ-free mice have improved insulin sensitivity and reduced inflammatory cytokines in response to high-fat diet.69 Transfer of microbiota from mice prone to develop insulin resistance also leads to higher rates of insulin resistance and upregulation of lipogenesis resulting in increased fatty liver when placed on a high-fat diet.70 A small study in humans has also suggested influence of microbiota on insulin resistance when transfer of microbiota from lean subjects resulted in improved insulin sensitivity in recipients who were obese with the metabolic syndrome.71 Additionally, work in mouse models suggests that the microbiome may influence the risk of developing HCC in obesity-related liver disease.72,73 MANAGEMENT OF NAFLD/NASH

According to the joint practice guideline from the American Association for the Study of Liver Disease, the American College of Gastroenterology, and the American Gastroenterological Association, the diagnosis of NAFLD requires the presence of steatosis by imaging or histology, the lack of any significant alcohol consumption, and the exclusion of other forms of chronic liver disease as well as no plausible alternative explanation for the development of hepatic steatosis.8 Simple steatosis is generally not felt to represent a significant risk to develop progressive fibrosis; however, it

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is difficult to determine if a patient has simple steatosis or steatohepatitis (NASH) without an invasive liver biopsy. Patient characteristics can be useful in predicting the likelihood of NASH and helping to better determine which patients may be more likely to warrant a liver biopsy. The presence of the metabolic syndrome increases the likelihood of a patient having NASH and might factor in the decision to perform a liver biopsy. Additionally, determination of the NAFLD fibrosis score (http://nafldscore.com), a noninvasive scoring system using readily available clinical characteristics (age, BMI, platelet count, hyperglycemia, albumin, and AST-to-ALT ratio), could also be useful for targeting liver biopsies toward those expected to most likely have advanced fibrosis.8 Findings on biopsy of ballooning degeneration, inflammatory infiltrates, mega mitochondria, and fibrosis/cirrhosis are consistent Q13 with a diagnosis of NASH. Noninvasive biomarkers such as cytokeratin-18 (CK-18) and terminal peptide of procollagen III (PIIINP) hold promise but are not Q14 yet widely accepted. Apoptosis in the liver activates caspase 3 and results in cleaving of CK-18, an intermediate filament protein in the hepatocyte. Elevations in CK-18 fragments have been suggested to be a predictor of NASH; however, a more recent study suggests that it lacks suitable sensitivity to differentiate between NASH and simple steatosis.74,75 PIIINP is a byproduct of type III collagen and was shown in a recent study to differentiate between simple steatosis and NASH or advanced fibrosis, but further studies will be needed to validate its use.76 Noninvasive imaging techniques (ultrasound transient elastography and magnetic resonance imaging elastography) also exist for assessing Q15 patients for fibrosis in NAFLD and emerging data suggest that these may prove to be a useful alternative to liver biopsy; however, at the present time they remain investigational.77,78 The least expensive and most effective treatment for NAFLD/NASH is weight loss. Modest weight loss of 5% can often improve steatosis and liver chemistries, and weight loss of 10% is frequently associated with histologic improvement and lower risk of disease progression.79,80 In a prospective study that followed patients up to 5 years after bariatric surgery, sustained weight loss was associated with a significant reduction in steatosis and a significant reduction in the amount of hepatocyte ballooning, the characteristic lesion of NASH.81 Additionally, although there was a slight overall increase in fibrosis of the cohort, 96% of patients remained at a fibrosis level #F1.81 Weight loss has been shown to reduce markers of ER stress in adipose and liver tissues in a cohort of patients who underwent gastric bypass surgery.54 Adiponectin levels have also been found to favorably increase with weight loss after


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laparoscopic gastric banding surgery.82 Roux-en-Y gastric bypass and weight loss achieved by lifestyle changes have been shown to reduce plasma ceramide levels resulting in a more favorable milieu in the liver as well.83,84 Exercise, independent of weight loss, can also be associated with improved insulin sensitivity and improvement of NASH and should be recommended to all patients. Exercise in patients with NAFLD for just 1 week has been shown to favorably increase the relative amounts of polyunsaturated lipids in the liver, increase serum adiponectin levels, and decrease levels of circulating CK-18.85,86 The intensity of exercise may also play a role in reducing the risk of NASH and fibrosis. An analysis of patients enrolled in the NASH Clinical Research Network database found that patients who reported vigorous exercise ($6 metabolic equivalent of task [MET]) for at least 75 min/wk were less likely to have NASH and advanced fibrosis.87 Light jogging is the equivalent of 6 MET and running at 5 mph is the equivalent of 8.3 MET. A comprehensive list of activities ranging from home repair to exercise to religious activities to hunting have been assigned a ‘‘MET’’ value and a review of the list can be both enlightening and entertaining for patients and clinicians to quantify the intensity and duration of their activities.88 Diet composition can have an influence on NAFLD regardless of overall calorie consumption. Although excess caloric intake clearly plays a role in the development of obesity and NAFLD, diets high in polyunsaturated fat and low in saturated fats and trans-fats are likely beneficial in NAFLD. Trans-fatty acids may be particularly toxic to the liver, but fortunately their consumption has been significantly decreased in recent years, and there has become widespread acceptance regarding their toxicity.89-91 Fructose consumption has more than doubled over the past several decades with much of that consumption in the form of soda, which has been shown to confer an increased risk of NAFLD regardless of BMI.92,93 Fructose consumption stimulates carbohydrate response–element-binding protein and SREBP-1c, which serves to increase de novo lipogenesis and fructose has a more pronounced effect on de novo lipogenesis, dyslipidemia, insulin sensitivity, and visceral adiposity compared with an isocaloric glucose load.94-96 Coffee consumption has been linked to lower rates of obesity, diabetes, cardiovascular disease, and mortality.97-99 Coffee consumption appears to also have a favorable impact on NAFLD with an inverse relationship between coffee consumption and degree of fibrosis.100 Coffee consumption is associated with reduced fibrosis from a variety of liver diseases and also lowers the risk of developing HCC.101,102 The

benefit of coffee is limited to filtered coffee and there are likely several components of coffee contributing to its benefits, but caffeine is likely an important mediator. Caffeine has been shown to reduce levels of the profibrotic cytokine transforming growth factor beta and reduce hepatic fibrosis in animal models.103 Hepatic stellate cells, responsible for coordinating the fibrotic response in the liver, are activated via the A2A adenosine receptor and given that caffeine is an established antagonist of adenosine receptors, it is plausible that this is an important mechanism by which coffee/ caffeine reduces liver fibrosis.103,104 Q16 Pharmacologic treatment may be considered for patients with NASH when efforts at weight loss are unsuccessful. Evidence supports a modest benefit of high-dose vitamin E (800 U) and the peroxisome proliferator–activated receptor gamma (PPAR-g) agonist pioglitazone for reducing steatosis, inflammation, and liver enzymes.8,105,106 Pioglitazone and vitamin E have not been shown to definitively reduce liver fibrosis; however, it is also possible that trials of longer duration would be needed to demonstrate this benefit. Vitamin E functions as an antioxidant and PPAR-g is a member of the nuclear hormone receptor superfamily and has a central role in adipose tissue metabolism and function. PPAR-g influences adipogenesis, adipose differentiation, circulating FFA levels, and adipokine levels.107 PPAR-g activation results in reduced circulating FFA levels, improved insulin sensitivity, and increased adiponectin levels.107 Rare individuals who possess dominant-negative mutations in PPAR-g offer insight into the importance of the role of PPAR-g as these individuals exhibit the metabolic syndrome, central adiposity, low adiponectin levels, and nonalcoholic fatty liver.108 Pioglitazone and vitamin E have shown some benefit in adult patients with NASH; however, adverse effects and concerns about long-term use dampen the enthusiasm of many clinicians. Vitamin E has also been shown to be of potential benefit in children and adolescents with NASH. In the TONIC trial, vitamin E was shown to improve Q17 some histologic endpoints and more frequently led to resolution of NASH compared with placebo.109 PPAR-g agonists are associated with weight gain and pioglitazone was associated with 4.7 kg weight gain in the large trial showing benefit in NASH.105,110 For a population already grappling with obesity, this weight gain can be difficult to rationalize. Additionally, concerns about long-term use of PPAR-g agonists increasing the risk of bladder cancer, causing fluid retention, and reducing bone mineral density also must be factored into the decision to use pioglitazone.107 Vitamin E use is also associated with potential safety concerns, namely the possible increase in overall


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mortality that has been reported in prior meta-analysis and potential increased risk of prostate cancer and hemorrhagic stroke.106 The safety of long-term vitamin E usage in the pediatric population is also unknown. Although pioglitazone and vitamin E offer some benefit for patients with NASH, the concerns mentioned previously raise concern about their widespread use and limit their usefulness for chronic management of NASH. Pentoxifylline may also provide some modest benefit to patients with NASH. Pentoxifylline may produce its effects through reducing oxidative stress, reducing TNF-a production, and possibly via antagonism of the A2A adenosine receptor on hepatic stellate cells, similar to caffeine. Small, randomized controlled trials have suggested a benefit of pentoxifylline in NASH and a recent meta-analysis supports a benefit as well.111-113 Pentoxifylline was shown to decrease oxidized lipid products and likely has some impact on TNF-a as well.111,114 Pentoxifylline is a methylxanthine, similar to caffeine, and can act as an A2A adenosine receptor antagonist.115,116 Blockade of the A2A adenosine receptor has been shown to decrease liver fibrosis and this may be an underappreciated beneficial mechanism of pentoxifylline.104,117 Although there is evidence suggesting a benefit of pentoxifylline for NASH, larger randomized prospective trials are needed to recommend its widespread use. The semisynthetic bile acid derivative obeticholic acid (OCA) functions as an FXR agonist and has shown promising results in early clinical trials in patients with NASH. FXR is a nuclear hormone receptor that is regulated by bile acids and influences a wide array of metabolic pathways, including bile acid metabolism, glucose homeostasis, lipid metabolism, inflammatory responses, and vascular remodeling.118,119 Activation of FXR can result in downregulation of SREBP-1c leading to reduced hepatic triglyceride synthesis and can lead to decreased circulating VLDL levels via FXRmediated increase in VLDL receptor expression.120,121 FXR has also been shown to antagonize nuclear factor kb–mediated inflammatory response in the liver and also to inhibit hepatic stellate cell activation resulting in decreased liver fibrosis.122,123 FXR has also been shown in animal models to favorably reduce gluconeogenesis and improve insulin sensitivity.124,125 Interestingly, FXR signaling has also recently been shown to be an important mediator of improved glucose tolerance and sustained weight loss after bariatric surgery (vertical sleeve gastrectomy).126 This appears to be related to elevated circulating levels of bile acids that are observed after bariatric surgery.127,128 OCA’s potential multifaceted beneficial effects as an FXR agonist have been observed in early clinical trials of patients with NASH. In 1 small trial it was shown to

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improve insulin sensitivity, improve liver biochemistries, and reduce markers of liver fibrosis.129 A phase II clinical trial (‘‘FLINT’’-ClinicalTrials.gov NCT012 65498) was then recently stopped early because OCA showed a significant improvement in liver histology during an interim analysis when compared with placebo. These early findings are encouraging but enthusiasm for OCA is tempered by the unexpected finding of a modest increase in LDL in both trials by unclear Q19 mechanisms.129 Elevating LDL in a population with a high prevalence of CAD will be a major concern unless Q20 it is ultimately shown to not increase the development of atherosclerosis or increase the risk of cardiac events. Another promising therapeutic under investigation is a direct antifibrotic approach with the inhibition of collagen cross-linking. Lysyl oxidase-like 2 promotes cross-linking of type 1 collagen, which results in stabilization of the extracellular matrix. Pharmacologic lysyl oxidase-like 2 inhibitors have been developed and clinical trials in various liver disorders are underway, including a trial examining their use in patients with NASH.130 There remains an unmet need for an effective, safe medication for NASH to prevent progression of liver disease and reduce the need for liver transplant and the risk of developing liver cancer; however, clinicians must continue to address the increased risk of cardiovascular mortality in patients with NAFLD/NASH. Statin use in patients with chronic, stable liver disease is well tolerated, and when indicated, should not be withheld from patients with NAFLD/NASH.131 CONCLUSIONS

The obesity epidemic has led to an increased burden of liver disease with increasing numbers of patients requiring liver transplants for NASH cirrhosis and its complications. The pathogenesis of NAFLD involves insulin resistance, adipose tissue distribution, and dietary and genetic factors that place an individual at risk of NASH. Like many obesity-related complications, addressing NAFLD/NASH is best accomplished with preventive approaches to promote calorie restriction and favorable dietary composition before liver disease develops. Weight loss and exercise remain inexpensive and effective solutions but few are successful at achieving durable lifestyle changes. Promising therapeutic targets are being addressed with modest success and ongoing research to delineate the mechanisms of steatohepatitis and fibrosis will likely lead to even more effective treatments. ACKNOWLEDGMENTS

Conflict of interests: None.


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REFERENCES

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Obesity-associated nonalcoholic fatty liver disease.

Nonalcoholic Fatty liver disease, diabetes, obesity, and hepatocellular carcinoma.

Host genetic variants in obesity-related nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease and cardiovascular disease.

Acetaminophen-induced liver injury in obesity and nonalcoholic fatty liver disease.

Bariatric surgery and nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease and hepatocellular carcinoma.

Nonalcoholic fatty liver disease and hepatocellular carcinoma.

Probiotics and Nonalcoholic Fatty liver Disease.

Micronutrient Antioxidants and Nonalcoholic Fatty Liver Disease.

CKD and nonalcoholic fatty liver disease.

Herbal medicines and nonalcoholic fatty liver disease.

Association of nonalcoholic fatty liver disease and liver cancer.

Histopathology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

Surgical management of obesity in patients with morbid obesity and nonalcoholic fatty liver disease.

Pharmacotherapy for Nonalcoholic Fatty Liver Disease.

Biomarkers in nonalcoholic fatty liver disease.

Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease.

Nonmedicinal interventions in nonalcoholic fatty liver disease.

Endocrine causes of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease: Diagnostic biomarkers.

Nutritional therapy for nonalcoholic fatty liver disease.

Extrahepatic Manifestations of Nonalcoholic Fatty Liver Disease.

Circulating homocysteine in nonalcoholic fatty liver disease.