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| '''Editor in Chief''': Elliot Tapper, M.D., Beth Israel Deaconess Medical Center
| | {{Non alcoholic fatty liver disease}} |
| | {{CMG}}; {{AE}} {{VKG}} |
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| {{Editor Help}} | | {{See also|Fatty liver}} |
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| ==Overview and Impact==
| | '''For the patient information page on this topic, click [[non-alcoholic fatty liver disease (patient information)|here]].''' |
| {{DiseaseDisorder infobox |
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| Name = Non-alcoholic steatohepatitis |
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| DiseasesDB = 29786|
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| ICD10 = {{ICD10|K|76|0|k|70}} |
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| ICD9 = {{ICD9|571.8}} |
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| eMedicineSubj = med |
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| eMedicineTopic = 775 |
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| '''Non-alcoholic fatty liver disease''' ('''[[NAFLD]]''') is a spectrum of [[liver]] disease in the absence of excessive [[alcoholism|alcohol]] use that begins as fatty accumulation in the liver (hepatic [[steatosis]]). A fatty liver does not necessarily disturb the function of the liver, but by varying mechanisms and insults, it may progress to [[inflammation]] of the liver. When inflammation occurs in this setting, the condition is then called NASH - '''[[Non-alcoholic steatohepatitis]]'''. NASH, in turn, may progress to fibrosis and, later, cirrhosis. Studies of serial liver biopsies estimate a 26-37% rate of hepatic fibrosis and 2-9% rate of cirrhosis in less than 6 years. <ref>Adams LA, Sanderson S, Lindor KD, et al. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol 2005;42(1):132–8.</ref><ref>Harrison SA, Torgerson S, Hayashi PH. The natural history of nonalcoholic fatty liver disease:a clinical histopathological study. Am J Gastroenterol 2003;98(9):2042–7.</ref> In 2001, NASH represented 2.9% of the indications of liver transplantation.<ref name=Charlton> Charlton M et al. Frequency of Nonalcoholic Steatohepatitis as a Cause of Advanced Liver Disease .Liver Transpl 2001;7:608-614</ref> | |
| NAFLD/NASH was first described in a 1980 series of obese, non-alcoholic patients of the [[Mayo Clinic]].<ref>Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434-438. PMID 7382552.</ref> Since that seminal description, our understanding of NAFLD has progressed minimally. <ref>Day, CP. Non-alcoholic steatohepatitis (NASH): where are we now and where are we going? Gut. 2002 May; 50(5): 585–588.</ref> The disease is most closely associated with the increasing obesity, insulin resistance, type two diabetes mellitus and hyperlipedmia endemic to the developed world. Roughly half of all patients with NAFLD, however, do not meet criteria for metabolic syndrome. <ref>Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43:S99–S112.</ref>
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| ==Epidemiology==
| | {{SK}} NASH, NAFLD, non-alcoholic steatohepatitis, metabolic dysfunction-associated steatotic liver disease (MASLD) |
| Estimates are that between 30- 90 million Americans have some degree of NAFLD and 5-6% have NASH. <ref name=McCullough> McCullough, AJ. Thiazolidinediones for NASH. NEJM 2006;355(22):2361-2363.</ref> A Japanese study estimates the prevalence of NAFLD in that country at 31 per 1000 and found an incidence of approximately 10% - 308 new cases of NAFLD in a group of 3,147 patient followed over 414 days.<ref>Hamaguchi M, Kojima T, Takeda N, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005;143(10):722–8</ref>. In the third National Health and Nutrition Examination Survey (NHANES III), the peak prevalence of NAFLD in men occurred in the fourth decade and in the sixth decade for women.<ref>Ong JP et al. Epidemiology and Natural History of NAFLD and NASH. Clin Liver Dis 11 (2007) 1–16</ref><ref>Ruhl CE, Everhart JE. Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the united states. Gastroenterology 2003;124(1):71–9.</ref>
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| Some have suggested a genetic or sociocultural component to NAFLD spectrum disease.<ref name=Caldwell>Caldwell et al. Has natural selection in human populations produced two types of metabolic syndrome (with and without fatty liver). J of Gastroenterology and Hepatology 2007;22(S1):S11-S19</ref> As a part of the Dallas Heart Study,<ref name=Browning>Browning et al. Prevalence of Hepatic Steatosis in an Urban Population in the United States: Impact of Ethnicity. Hepatology 2004;40:1387-1395.</ref> 2,240 patients - 1,105 african-americans, 401 hispanics and 734 caucasians - received abdominal MRI's from which we can infer the presence of steatosis. Hepatic steatosis was found in 45% of hispanics (both men and women), 33% of caucasians (42% of men, 24% of women) and 24% of african-american (23% of men, 24% of women). This pattern may hold true in children as well. In a San Diego study of 742 consecutive autopsies of children victims of trauma over 10 years, fatty liver was found in 9.6% of all children, 38% of the obese, 12% of hispanics, 10% of asians, 8.6% of caucasians and 1.5% of african-americans.<ref name=Schwimmer>Schwimmer et al. Prevalence of fatty liver in children and adolescents. Pediatrics 2006;118;1388-93.</ref>
| | ==[[Non-alcoholic fatty liver disease overview|Overview]]== |
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| ===Pathophysiology=== | | ==[[Non-alcoholic fatty liver disease historical perspective|Historical Perspective]]== |
| ==Overview==
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| The exact cause is still ''unknown''. However both [[obesity]] and [[insulin resistance]] likely play a strong role in this disease process. The exact reasons and mechanisms by which this disease progresses from one entity to the next is a subject of much research and debate. This is the so-called ‘two-hit hypothesis.’ The first hit is steatosis. The second hit is controversial and is likely numerous. The second hit is likely any injury which causes a change that leads from hepatic steatosis to [[hepatic]] inflammation and fibrosis by way of lipid peroxidation.<ref>Berson A, De Beco V, Lette´ron P, Robin MA, Moreau C, El KahwajiJ, Verthier N, Feldmann G, Fromenty B, Pessayre D. Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes. Gastroenterology 1998;114:764–774.</ref> [[Oxidative stress]], hormonal imbalances, endotoxemia and [[Mitochondrion|mitochondrial]] abnormalities may all be potential causes.
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| ==Insulin Resistance==
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| Clinicopathologic studies in patients with NAFLD have confirmed that insulin resistance is a cause and not a result of liver disease. For example, 75% of NAFLD/NASH patients – lean or obese – having insulin resistance while only 7.5% of patients with Hepatitis C are insulin resistant.<ref name=Chitturi> Chitturi S, Abeygunasekera S, Farrell GC, et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002;35:373–379</ref> In another study, a fasting glucose >110 mg/dL was the most predictive feature of NAFLD.<ref> Marchesini G, Brizi M, Bianchi G, et al.Metformin in nonalcoholic steatohepatitis. Lancet 2001;358:893–894</ref>
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| ==Comorbid Liver Disease== | | ==[[Non-alcoholic fatty liver disease classification|Classification]]== |
| The evidence for oxidative stress as a second-hit comes from many sources. For example, as in hemachromatosis liver disease, any degree of iron overload engenders enhanced free radical production in the liver. As many as 31% of patients with NASH have been discovered to have C282Y mutations (compared to a prevalence of less than 12.5% in the general population).<ref> George DK, Goldwurm S, Macdonald GA, Cowley LL, Walker NI, Ward PJ, Jazwinska EC, Powell LW. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 1998;114:311–318.</ref> Similarly, while 2-3.6% of the population have the profibrotic MZ alpha-1 antitrypsin deficiency phenotype, it is present in as many as 16.7% of NASH patients requiring liver transplantation.<ref name=Charlton>
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| ==Endotoxins==
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| One of the original theories of NASH pathogenesis derived from clinical experience involving obese patients who developed cirrhosis after a jejuno-ileal bypass.<ref>Hocking et al. Jejunoileal bypass for morbid obesity. Late follow-up in 100 cases. NEJM 1983;308(17):995-999</ref> This sort of intestinal deformity may increase the concentration of bacterial endotoxins in the portal circulation, which in turn may cause an elevation of intrahepatic levels of pro-inflammatory cytokines, including tumor necrosis factor-alpha. Some degree of steatohepatitis was even reversed after treatment with metronidazole<ref> Wigg AJ et al. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor α in the pathogenesis of non-alcoholic steatohepatitis. Gut 2001;48:206-211</ref>
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| ==Adiponectin==
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| Other groups have implicated variations in different metabolic pathways. One of the principle pathways under investigation is that which is affected by adiponectin. Adiponectin is an anti-atherogenic, insulin sensitizing cytokine whose secretion is decreased in obesity. One study found an inverse relationship between circulating concentrations of adiponectin and tumor necrosis factor.<ref name=Anania> Anania. Adiponectin and Alcoholic Fatty Liver: Is It, After All, About What You Eat? Hepatology 2005;42(3):530-532</ref>. Another implication of the research on adiponectin is that different dietary fats have variable effects on adiponectin levels, with polyunsaturated fatty acids leading to decreased levels and more hepatic inflammation.<ref> You M, Considine RV, Leone TC, Kelly DP, Crabb DW. Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice. Hepatology 2005;42:568-577.</ref>
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| ==Adenosine== | |
| Another pathway under investigation is purinergic metabolism. CD39 is the dominant vascular (and immune cell) ectonucleotidase in the liver that hydrolyzes extracellular ATP and ADP to AMP which can then be converted to adenosine via ecto-5’-nucleotidase/CD73. Alterations in purinergic signaling induced by altered CD39 expression have major impacts upon hepatic metabolism, repair mechanisms, regeneration and associated immune responses.<ref> Beldi G, et al. The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism. Frontiers Biosci 2008; 13, 2588-2603</ref> Varying levels of CD39 and adenosine have thus been implicated in the spectrum of NAFLD/NASH phenotypes.
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| Based on knockout studies, the experimental evidence is mounting in support of a major role for both CD39 and adenosine in the development of steatosis, inflammation and, later, fibrosis. Firstly, the deletion of CD39 and thus the local reduction of adenosine results in hepatic insulin resistance and increased serum levels of several inflammatory cytokines.<ref> Enjyoji, K et al. Deletion of Cd39/Entpd1 Results in Hepatic Insulin Resistance. Diabetes. 2008; 57:2311–2320</ref>
| | ==[[Non-alcoholic fatty liver disease pathophysiology|Pathophysiology]]== |
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| Secondly, adenosine appears to be a critical supportive link in the cell’s cascade of responses to inflammation ;<ref> Haschemi A, Wagner O, Marculescu R, Wegiel B, Robson SC, Gagliani N, Gallo D, et al. Cross-regulation of carbon monoxide and the adenosine A2A receptor in macrophages. J. Immunol. 2007;178;5921-5929</ref> Adenosine suppresses inflammation and, as inflammation, tissue repair and scarring are closely linked events, it enhances fibrosis by increasing matrix formation in healing insulted tissues and facilitating regeneration.<ref name=Chan> Chan ES, Montesinos MC, Fernandez P, Desai A, Delano DL, Yee H, Reiss AB, et al. Adenosine A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis. Br J Pharmacol 2006;148:1144-1155.</ref><ref>Montesinos MC et al. Wound healing is accelerated by agonists of adenosine A2 (G alpha s-linked) receptors. J. Exp. Med.1997;186:1615–162010-11)</ref> CD39 deletion shifts the local population of cytokines toward the pro-inflammatory and non-fibrinogenic (e.g. interferon gamma).<ref> Kunzli BM et al. Upregulation of CD39/NTPDases and P2 receptors in human pancreatic disease. AJP-Gastrointest Liver Physiol 2007;292:223-230</ref>
| | ==[[Non-alcoholic fatty liver disease causes|Causes]]== |
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| Thirdly, in CD39 knockout models of hepatitis and pancreatitis, there is a marked decrease in fibrogenesis.<ref> Kunzli BM et al. Disordered Pancreatic Inflammatory Responses and Inhibition of Fibrosis in CD39-null mice. Gastroenterology. 2008 January ; 134(1): 292–305. </ref> And adenosine receptor A2A is a major factor in the pathogenesis of cirrhosis.<ref name=Chan>
| | ==[[Non-alcoholic fatty liver disease differential diagnosis|Differentiating Non-Alcoholic Fatty Liver Disease from other Diseases]]== |
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| | ==[[Non-alcoholic fatty liver disease epidemiology and demographics|Epidemiology and Demographics]]== |
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| ===Secondary causes=== | | ==[[Non-alcoholic fatty liver disease risk factors|Risk Factors]]== |
| NAFLD can also be caused by the following medications (termed ''secondary'' NAFLD):
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| * [[Amiodarone]]
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| * [[Antiviral drug]]s ([[nucleoside analogues]])
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| * [[Aspirin]] / [[NSAID]]S
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| * [[Corticosteroid]]s
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| * [[Methotrexate]]
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| * [[Nifedipine]]
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| * [[Perhexiline]]
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| * [[Tamoxifen]]
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| * [[Tetracycline]]
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| * [[Valproic acid]]
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| ===Signs, Symptoms and associations=== | | ==[[Non-alcoholic fatty liver disease screening|Screening]]== |
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| Most patients with NAFLD have no or few symptoms. Infrequently patients may complain of fatigue, [[malaise]] and dull right upper quadrant [[abdominal pain|abdominal discomfort]]. Mild [[jaundice]] can rarely be noticed. More commonly it is diagnosed as a result of abnormal [[liver function tests]] during routine blood tests. Often following an asymptomatic course, the disease may present first with cirrhosis and/or the complication of portal hypertension. In that respect, NASH is becoming an increasingly common indication for liver transplantation. <ref name=Choudhury>Choudhury J, Sanyal A. Clinical Aspects of Fatty Liver Disease. Semin Liver Dis 2004; 24: 349-362.</ref> As awareness of this condition spreads, it has been regarded as a major cause of cryptogenic [[cirrhosis]] of the liver.<ref name=Clark>Clark JM, Diehl AM. Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. ''JAMA'' 2003;289:3000-4. PMID 12799409.</ref> The diagnosis of cryptogenic cirrhosis is usually made in patients with similar clinical characteristics to those with NAFLD spectrum disease. Cryptogenic cirrhotics tend to be women, aged 63 (+/- 11) years who are obese and type 2 diabetics. <ref name=Caldwell>Caldwell SH, Oelsner DH, Iezzoni JC. Cryptogenic Cirrhosis: Clinical Characterization and Risk Factor for Underlying Disease. Hepatology 1999;29(3);664-69</ref>. Moreover, there are case reports of patients with NASH who received serial liver biopsies where there was a progression to cirrhosis with a dissapearance of the histologcal stigmatia of NASH. Without the index biopsy, these patients' cirrhosis would have been classified as cryptogenic.<ref>Yoshioka Y, Hashimoto E, Yatsuji S. “NASH: cirrhosis, hepatocellular carcinoma and burnt-out NASH.” J Gastroenterol 2004;39;1215-1218</ref><ref name=Caldwell>
| | ==[[Non-alcoholic fatty liver disease natural history, complications and prognosis|Natural History, Complications, and Prognosis]]== |
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| ==Diagnosis== | | ==Diagnosis== |
| Disturbed liver enzymes are common. Typically, one finds a 2-4 fold elevation of the ALT above normal limit and an AST/ALT ratio of less than 1. Another blood test that can be elevated is the ferritin. Typically, and except in very advanced disease, the liver's synthetic function is intact with normal albumin and INR. Imaging is often ordered in the workup of suspected NAFLD. Ultrasound and computed tomography have sensitivities between 93-100%, but 62-76% positive predictive values. Problematically, ultrasound of fatty liver reveals a hyperechoic echotexture - a so-called 'bright liver' - that can often be indistinguishable from fibrosis and neither modality may reliable delineate NAFLD from NASH.<ref>MIshra P et al. Abdominal Ultrasound for Diagnosis of Nonalcoholic Fatty Liver Disease (NAFLD). Am J Gastroenterol 2007;102:2716–2717).</ref> Statistics are similar for MRI, however using advanced MR techniques, some groups have been able to both quantify steatosis and differentiate steatohepatitis from steatosis.<ref>Taouli B et al.Advanced MRI Methods for Assessment of Chronic Liver Disease. AJR 2009; 193:14–27.</ref>
| | [[Non-alcoholic fatty liver disease history and symptoms|History and Symptoms]] | [[Non-alcoholic fatty liver disease physical examination|Physical Examination]] | [[Non-alcoholic fatty liver disease laboratory findings|Laboratory Findings]] | [[Non-alcoholic fatty liver disease electrocardiogram|Electrocardiogram]] | [[Non-alcoholic fatty liver disease x ray|X Ray]] | [[Non-alcoholic fatty liver disease CT|CT]] | [[Non-alcoholic fatty liver disease MRI|MRI]] | [[Non-alcoholic fatty liver disease ultrasound|Ultrasound]] | [[Non-alcoholic fatty liver disease other imaging findings|Other Imaging Findings]] | [[Non-alcoholic fatty liver disease other diagnostic studies|Other Diagnostic Studies]] | [[Non-alcoholic fatty liver disease Noninvasive scores| Noninvasive scores]] |
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| A biopsy of the liver is still considered the gold standard in diagnosis. Classically, biopsy reveals macrovesicular steatosis, inflammation, ballooning degeneration, zone 3 perivenular/periportal/perisinusoidal fibrosis and, finally, mallory bodies.<ref name=Chaudhury/> <ref name=Angula>Angula P. Nonalcoholic Fatty Liver Disease. NEJM. 2002 346(16):1221-31</ref><ref name=Brunt>Brunt EM, Janney CG, Di Bisceglie AM et al. Nonalcoholic steatohepatitis: A proposal for grading and staging the histological lesions. Am. J. Gastroenterol. 1999; 94(9):2467-2474</ref> Unfortunately, however, a standard biopsy is only able to sample a volume that is 1/50,000th of the liver, underscoring the substantial room for sampling error.
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| When considering NAFLD, other tests are generally performed, including those for associated conditions (e.g. glucose, hemoglobin A1C) and those to distinguish this disease from viral [[hepatitis]]. Additionally, autoimmune causes are ruled out with serology. [[Thyroid-stimulating hormone|TSH]] is warranted, as [[hypothyroidism]] is more prevalent in NASH patients.<ref>Liangpunsakul S, Chalasani N. Is hypothyroidism a risk factor for non-alcoholic steatohepatitis? ''J Clin Gastroenterol'' 2003;37:340-3. PMID 14506393</ref>
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| ==Treatment== | | ==Treatment== |
| Trials are presently being conducted to optimise treatment of NASH. No standard treatment has yet emerged as the "gold standard". General recommendations include improving metabolic risk factors and reducing alcohol intake.
| | [[Non-alcoholic fatty liver disease medical therapy|Medical Therapy]] | [[Non-alcoholic fatty liver disease surgery|Surgery]] | [[Non-alcoholic fatty liver disease primary prevention|Primary Prevention]] | [[Non-alcoholic fatty liver disease secondary prevention|Secondary Prevention]] | [[Non-alcoholic fatty liver disease cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Non-alcoholic fatty liver disease future or investigational therapies|Future or Investigational Therapies]] |
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| A large number of treatments have been studied for NAFLD. While many may improve biochemical markers, such as [[alanine transaminase]] levels, most have not been shown to reverse the histological abnormalities or reduce clinical endpoints:<ref name=Adams/>
| | ==Case Studies== |
| * Weight loss: gradual weight loss, and possibly [[bariatric surgery]], may improve the process in obese patients.
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| * Insulin sensitisers ([[metformin]] and [[rosiglitazone]] but more markedly [[pioglitazone]]) have shown efficacy in some studies.
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| * [[Antioxidants]] and [[Ursodiol|ursodeoxycholic acid]], as well as lipid-lowering drugs, have little benefit.
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| | [[Non-alcoholic fatty liver disease case study one|Case #1]] |
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| == References == | | ==External Links== |
| <references/>
| | * [http://digestive.niddk.nih.gov/ddiseases/pubs/nash/ NIH] page on Nonalcoholic Steatohepatitis |
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| ==External links==
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| * [http://www.medscape.com/viewarticle/458509_1 Medscape] article on NASH.
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| * [http://www.medicinenet.com/fatty_liver/article.htm MEDICINENET] article on Steatosis.
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| * [http://digestive.niddk.nih.gov/ddiseases/pubs/nash/ NIH] page on Nonalcoholic Steatohepatitis
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| {{SIB}}
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| {{Gastroenterology}} | | {{Gastroenterology}} |
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| [[Category:Gastroenterology]] | | [[Category:Gastroenterology]] |
| [[Category:Hepatitis]] | | [[Category:Hepatology]] |
| | [[Category:Disease]] |
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| [[es:Esteatohepatitis no alcohólica]] | | [[es:Esteatohepatitis no alcohólica]] |
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