non-alcoholic steatohepatitis (NASH); metabolic dysfunction-associated steatohepatitis (MASH)
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Etiology
- generally results from metabolic syndrome
- risk factors
- 40% of biopsy-proven cases with no risk factors
Epidemiology
Pathology
- liver histology:
- fatty change
- inflammation
- fibrosis & cirrhosis may be seen
- Mallory bodies may be seen
- histology may be similar to alcoholic hepatitis[2]
- thyroid hormone receptor beta function in the liver is impaired, leading to a reduction in mitochondrial function & beta-oxidation of fatty acids with an increase in fibrosis[23]
- generally benign condition
Laboratory
- elevated serum transaminases (3-fold not uncommon)
- most common cause of elevated serum transaminases
- serum AST, serum ALT
- 1/4 patients with NASH or advanced hepatic fibrosis with serum ALT < 40 IU/L[22]
- monitor serum transaminases
- serum alkaline phosphatase is increased in 1/3 of patients
- serum GGT
- platelet count:
- thrombocytopenia consistent with splenomegaly
- platelet count needed for FIB-4 index score
- hepatitis A serology
- hepatitis B serology (serologic diagnosis)
- hepatitis B surface antigen in serum (HBsAg)
- negative in resolved infection
- hepatitis B surface antibody in serum (HBsAb)
- positive in persons
- immunized with hepatitis B vaccine
- persons with resolved hepatitis B infection
- positive in persons
- hepatitis B e antigen in serum (HBeAg)
- positive in active hepatitis B infection (acute or chronic)
- use HBV DNA to monitor infectivity[19]
- hepatitis B core antibody in serum (HBcAb)
- hepatitis B core IgM in serum for acute prodrome
- hepatitis B core IgG in serum positive for
- resolved hepatitis B infection
- chronic hepatitis B infection (all forms)
- negative for persons immunized with hepatitis B vaccine
- hepatitis B surface antigen in serum (HBsAg)
- hepatitis C serology
- liver biopsy generally unnecessary unless diagnosis uncertain or cirrhosis suspected[2][13]
Radiology
- ultrasound
- may be helpful, but cannot confirm or exclude diagnosis
- useful for assessment of portal hypertension[2]
- splenomegaly suggests portal hypertension due to cirrhosis
- CT or MRI add little to ultrasound (not useful)
Complications
- hepatic cirrhosis rare[7]
- portal hypertension[2]
- ascites, encephalopathy, variceal bleeding & mortality higher with greater degrees of fibrosis[19]
Management
- response to treatment of risk factors is variable
- weight reduction of least 3% to 5% of body weight[8]
- weight reduction through life-style modification or bariatric surgery of benefit[9]
- control of hyperlipidemia
- control of diabetes mellitus
- Mediterranean diet[11]
- weight reduction of least 3% to 5% of body weight[8]
- pharmaceuticals
- pioglitazone 45 mg QD may be of benefit[5]
- improves serum transaminases
- increases hepatic insulin sensitivity
- diminishes hepatic fat content
- long-term safety & efficacy is unknown
- weight gain is common
- beneficial in patients with prediabetes & type 2 diabetes[10]
- lanifibranor 1200 mg QD (another peroxisome proliferator) attenuates progression of fibrosis (not yet FDA-approved Oct 2021)[20]
- resmetirom reduces hepatic fibrosis in patients with NASH (FDA-approved)[24]
- although statins are safe, controlled trials are necessary to determine if are specifically useful for treatment of NASH
- dose-dependent statin use reduces risk of hepatocellular carcinoma in patients with NASH cirrhosis (RR=0.4)[18]
- vitamin E 800 IU/day improves liver histology
- some evidence suggesst high-dose vitamin E increases risks for all-cause mortality & prostate cancer[8]
- has not been studied in patients with type 2 diabetes[13]
- vitamin E alone ineffective for NASH in patients with type 2 diabetes[15]
- although ursodeoxycholic acid may be helpful in some patients, it is not recommended[8]
- metformin is not recommended[8]
- once-weekly semaglutide 2.4 mg reduces steatohepatitis & liver fibrosis in adults with NASH & moderate or advanced liver fibrosis[27]
- semaglutide may increase likelihood of NASH resolution, but does not improve fibrosis stage[17]
- orlistat in conjunction with weight loss may be of benefit 4]
- recommendation of omega-3 fatty acids is premature[8]
- pioglitazone 45 mg QD may be of benefit[5]
- bariatric surgery
- likely effective[6]
- in patients with nonalcoholic steatohepatitis & obesity, bariatric surgery reduces risk of major adverse liver outcomes & cardiovascular events[21]
- cost-effective in patients with obesity & cirrhosis[26]
- likely effective[6]
- liver transplantation for end-stage liver disease
- prognosis: 20-30% progress to cirrhosis
- 8% within 13 years[6]
More general terms
Additional terms
References
- ↑ Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 321
- ↑ 2.0 2.1 2.2 2.3 2.4 Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015
- ↑ 3.0 3.1 Journal Watch 21(15):123, 2001 Dixon JB et al Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 121:91, 2001 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11438497
- ↑ Zelber-Zagi S et al, A double-blind randomized placebo-controlled trial for orlistat for the treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2006, 4:639 PMID: https://www.ncbi.nlm.nih.gov/pubmed/16630771
- ↑ 5.0 5.1 Belfort R et al, A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. NEJM 2006, 355:2361 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17135584
- ↑ 6.0 6.1 6.2 Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, Kechagias S. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006 Oct;44(4):865-73. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17006923
- ↑ 7.0 7.1 Williams CD et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: A prospective study. Gastroenterology 2011 Jan; 140:124 PMID: https://www.ncbi.nlm.nih.gov/pubmed/20858492
- ↑ 8.0 8.1 8.2 8.3 8.4 8.5 Chalasani N et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012 Jun; 55:2005 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22488764 (corresponding NGC guideline withdrawn Dec 2017)
- ↑ 9.0 9.1 Vilar-Gomez E et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2015 Aug; 149:367. PMID: https://www.ncbi.nlm.nih.gov/pubmed/25865049
Lassailly G et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology 2015 Aug; 149:379. PMID: https://www.ncbi.nlm.nih.gov/pubmed/25917783 - ↑ 10.0 10.1 Cusi K, Orsak B, Bril F et al Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized, Controlled Trial. Ann Intern Med. Published online 21 June 2016 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27322798 <Internet> http://annals.org/article.aspx?articleid=2529686
Vilar-Gomez E, Adams LA Pioglitazone: An Addition to Our Toolbox for Patients With Diabetes and Nonalcoholic Steatohepatitis? Ann Intern Med. Published online 21 June 2016 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27322890 <Internet> http://annals.org/article.aspx?articleid=2529687 - ↑ 11.0 11.1 Zelber-Sagi S, Salomone F;, Mlynarsky L. The Mediterranean Dietary Pattern as the Diet of Choice for Non-alcoholic Fatty Liver Disease: Evidence and Plausible Mechanisms. Liver Int. 2017 Jul;37(7):936-949 PMID: https://www.ncbi.nlm.nih.gov/pubmed/28371239
- ↑ Diehl AM, Day C Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis. N Engl J Med 2017; 377:2063-2072. Nov 23, 2017 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/29166236 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMra1503519
- ↑ 13.0 13.1 13.2 NEJM Knowledge+ Question of the Week. Jan 23, 2018 https://knowledgeplus.nejm.org/question-of-week/488/
- ↑ European Association for the Study of the Liver (EASL);. European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016 Jun;64(6):1388-402 PMID: https://www.ncbi.nlm.nih.gov/pubmed/27062661
- ↑ 15.0 15.1 Bril F et al. Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: A randomized controlled trial. Diabetes Care 2019 Aug; 42:1481 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31332029 https://care.diabetesjournals.org/content/42/8/1481
- ↑ NEJM Knowledge+ Question of the Week. Dec 15, 2020 https://knowledgeplus.nejm.org/question-of-week/1577/
- ↑ 17.0 17.1 Newsome PN, Buchholtz K, CusiK et al A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med 2021; 384:1113-1124. March 25 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33185364 https://www.nejm.org/doi/full/10.1056/NEJMoa2028395
- ↑ 18.0 18.1 Reuters Staff Study Supports Chemopreventive Effect of Statins on Liver Cancer in NASH Cirrhosis. Medscape. July 20, 2021 https://www.medscape.com/viewarticle/954877
Pinyopornpanish K, Al-Yaman W, Butler RS et al Chemopreventive Effect of Statin on Hepatocellular Carcinoma in Patients With Nonalcoholic Steatohepatitis Cirrhosis. Am J Gastroenterol. 2021. July 2 PMID: https://www.ncbi.nlm.nih.gov/pubmed/34212895 https://journals.lww.com/ajg/Abstract/9900/Chemopreventive_Effect_of_Statin_on_Hepatocellular.36.aspx - ↑ 19.0 19.1 19.2 Sanyal AJ, Van Natta ML, Clark J et al. Prospective study of outcomes in adults with nonalcoholic fatty liver disease. N Engl J Med 2021 Oct 21; 385:1559. PMID: https://www.ncbi.nlm.nih.gov/pubmed/34670043 https://www.nejm.org/doi/10.1056/NEJMoa2029349
- ↑ 20.0 20.1 Francque SM, Bedossa P, Ratziu V et al. A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH. N Engl J Med 2021 Oct 21; 385:1547. PMID: https://www.ncbi.nlm.nih.gov/pubmed/34670042 https://www.nejm.org/doi/10.1056/NEJMoa2036205
- ↑ 21.0 21.1 Aminian A, Al-Kurd A, Wilson R et al Association of Bariatric Surgery With Major Adverse Liver and Cardiovascular Outcomes in Patients With Biopsy-Proven Nonalcoholic Steatohepatitis. JAMA. Published online November 11, 2021. PMID: https://www.ncbi.nlm.nih.gov/pubmed/34762106 https://jamanetwork.com/journals/jama/fullarticle/2786270
- ↑ 22.0 22.1 Castera L et al. High prevalence of NASH and advanced fibrosis in type 2 diabetes: A prospective study of 330 outpatients undergoing liver biopsies for elevated ALT, using a low threshold. Diabetes Care 2023 Jul; 46:1354-1362. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37043830 https://diabetesjournals.org/care/article/46/7/1354/148710/High-Prevalence-of-NASH-and-Advanced-Fibrosis-in
Scoditti E et al. Hunting for progressive NAFLD in type 2 diabetes: Do not trust liver enzymes! Diabetes Care 2023 Jul; 46:1332-1334. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37339349 https://diabetesjournals.org/care/article/46/7/1332/151555/Hunting-for-Progressive-NAFLD-in-Type-2-Diabetes - ↑ 23.0 23.1 Harrison SA, Bedossa P, Guy CD et al A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N Engl J Med 2024; 390:497-509. Feb 8 PMID: https://www.ncbi.nlm.nih.gov/pubmed/38324483 https://www.nejm.org/doi/full/10.1056/NEJMoa2309000
- ↑ 24.0 24.1 Harrison SA et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med 2024 Feb 8; 390:497. PMID: https://www.ncbi.nlm.nih.gov/pubmed/38324483 https://www.nejm.org/doi/10.1056/NEJMoa2309000
Loomba R et al. Randomized, controlled trial of the FGF21 analogue pegozafermin in NASH. N Engl J Med 2023 Sep 14; 389:998. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37356033 PMCID: PMC10718287 (available on 2024-03-14) https://www.nejm.org/doi/10.1056/NEJMoa2304286 - ↑ Rinella ME, Lazarus JV, Ratziu V et al A multi-society Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023. June 24. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37364790 Free article. Review. https://journals.lww.com/hep/Fulltext/9900/A_multi_society_Delphi_consensus_statement_on_new.488.aspx
Loomba R, Wong VW. Implications of the new nomenclature of steatotic liver disease and definition of metabolic dysfunction-associated steatotic liver disease. Aliment Pharmacol Ther. 2024 Jan;59(2):150-156. PMID: https://www.ncbi.nlm.nih.gov/pubmed/38153279 PMCID: PMC10807722 Free PMC article. Review. https://onlinelibrary.wiley.com/doi/10.1111/apt.17846 - ↑ 26.0 26.1 Bansal S, Bader A, Mahmud N, Kaplan DE. Survival and Cost-Effectiveness of Bariatric Surgery Among Patients With Obesity and Cirrhosis. JAMA Surg. 2025 Apr 2. PMID: https://www.ncbi.nlm.nih.gov/pubmed/40172871 https://jamanetwork.com/journals/jamasurgery/fullarticle/2832074
- ↑ 27.0 27.1 No authors listed Phase 3 ESSENCE Trial: Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. Gastroenterol Hepatol (N Y). 2024. PMID: https://www.ncbi.nlm.nih.gov/pubmed/39896971 PMCID: PMC11784563 Free PMC article.
Sanyal AJ, et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. N Engl J Med. 2025. PMID: https://www.ncbi.nlm.nih.gov/pubmed/40305708 https://www.nejm.org/doi/10.1056/NEJMoa2413258