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non-alcoholic steatohepatitis (NASH); metabolic dysfunction-associated steatohepatitis (MASH)

Etiology: 1) generally results from metabolic syndrome 2) risk factors a) obesity b) hyperlipidemia c) diabetes mellitus 3) 40% of biopsy-proven cases with no risk factors Epidemiology: 1) common disorder 2) most common in middle-aged women 3) common in severely obese individuals [3] Pathology: 1) liver histology: a) fatty change b) inflammation c) fibrosis & cirrhosis may be seen d) Mallory bodies may be seen 2) histology may be similar to alcoholic hepatitis [2] 3) 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] 4) generally benign condition Laboratory: 1) elevated serum transaminases (3-fold not uncommon) a) most common cause of elevated serum transaminases b) serum AST, serum ALT - 1/4 patients with NASH or advanced hepatic fibrosis with serum ALT < 40 IU/L [22] c) monitor serum transaminases 2) serum alkaline phosphatase is increased in 1/3 of patients 3) serum GGT 4) platelet count: thrombocytopenia consistent with splenomegaly 5) hepatitis A serology 6) hepatitis B serology (serologic diagnosis) a) hepatitis B surface antigen in serum (HBsAg) - negative in resolved infection b) hepatitis B surface antibody in serum (HBsAb) - positive in persons - immunized with hepatitis B vaccine - persons with resolved hepatitis B infection c) hepatitis B e antigen in serum (HBeAg) - positive in active hepatitis B infection (acute or chronic) - use HBV DNA to monitor infectivity [19] d) 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 7) hepatitis C serology 8) 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: 1) response to treatment of risk factors is variable a) weight reduction of least 3% to 5% of body weight [8] - weight reduction through life-style modification or bariatric surgery of benefit [9] b) control of hyperlipidemia c) control of diabetes mellitus d) Mediterranean diet [11] 2) pharmaceuticals a) 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] b) lanifibranor 1200 mg QD (another peroxisome proliferator) attenuates progression of fibrosis (not yet FDA-approved Oct 2021) [20] c) resmetirom reduces hepatic fibrosis in patients with NASH (FDA-approved) [24] d) 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] e) 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] f) although ursodeoxycholic acid may be helpful in some patients, it is not recommended [8] g) metformin is not recommended [8] h) semaglutide may increase likelihood of NASH resolution, but does not improve fibrosis stage [17] h) orlistat in conjunction with weight loss may be of benefit 4] j) recommendation of omega-3 fatty acids is premature [8] 3) bariatric surgery a) may be effective, but recommendation premature [6] - in patients with nonalcoholic steatohepatitis & obesity, bariatric surgery reduces risk of major adverse liver outcomes & cardiovascular events [21] b) avoid in patients with cirrhosis 4) liver transplantation for end-stage liver disease 5) prognosis: 20-30% progress to cirrhosis - 8% within 13 years [6]

Related

cirrhosis Mallory body; alcoholic hyalin

General

hepatitis steatosis; fatty liver; nonalcoholic fatty liver disease (NAFLD); metabolic dysfunction-associated steatotic liver disease (MASLD)

References

  1. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 321
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015
  3. 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: 11438497
  4. 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: 16630771
  5. Belfort R et al, A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. NEJM 2006, 355:2361 PMID: 17135584
  6. 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: 17006923
  7. 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: 20858492
  8. 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: 22488764 (corresponding NGC guideline withdrawn Dec 2017)
  9. Vilar-Gomez E et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2015 Aug; 149:367. PMID: 25865049 - Lassailly G et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology 2015 Aug; 149:379. PMID: 25917783
  10. 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 PMID: 27322798 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 PMID: 27322890 http://annals.org/article.aspx?articleid=2529687
  11. 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: 28371239
  12. Diehl AM, Day C Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis. N Engl J Med 2017; 377:2063-2072. Nov 23, 2017 PMID: 29166236 http://www.nejm.org/doi/full/10.1056/NEJMra1503519
  13. NEJM Knowledge+ Question of the Week. Jan 23, 2018 https://knowledgeplus.nejm.org/question-of-week/488/
  14. 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: 27062661
  15. 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: 31332029 https://care.diabetesjournals.org/content/42/8/1481
  16. NEJM Knowledge+ Question of the Week. Dec 15, 2020 https://knowledgeplus.nejm.org/question-of-week/1577/
  17. 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: 33185364 https://www.nejm.org/doi/full/10.1056/NEJMoa2028395
  18. 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: 34212895 https://journals.lww.com/ajg/Abstract/9900/Chemopreventive_Effect_of_Statin_on_Hepatocellular.36.aspx
  19. 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: 34670043 https://www.nejm.org/doi/10.1056/NEJMoa2029349
  20. 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: 34670042 https://www.nejm.org/doi/10.1056/NEJMoa2036205
  21. 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: 34762106 https://jamanetwork.com/journals/jama/fullarticle/2786270
  22. 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: 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: 37339349 https://diabetesjournals.org/care/article/46/7/1332/151555/Hunting-for-Progressive-NAFLD-in-Type-2-Diabetes
  23. 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: 38324483 https://www.nejm.org/doi/full/10.1056/NEJMoa2309000
  24. 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: 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: 37356033 PMCID: PMC10718287 (available on 2024-03-14) https://www.nejm.org/doi/10.1056/NEJMoa2304286
  25. 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: 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: 38153279 PMCID: PMC10807722 Free PMC article. Review. https://onlinelibrary.wiley.com/doi/10.1111/apt.17846