steatosis; fatty liver; nonalcoholic fatty liver disease (NAFLD); metabolic dysfunction-associated steatotic liver disease (MASLD)
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Introduction
New nomenclature: NAFLD will be called
metabolic dysfunction-associated steatotic liver disease (MASLD)[34]
Diagnosis of exclusion in overweight patients with preserved liver function.
Generally a benign condition.
Etiology
- alcoholism
- obesity
- distinct group of patients that are not obese[16]
- visceral abdominal adiposity in nonobese NAFLD
- high dietary intakes of cholesterol & fructose[16]
- distinct group of patients that are not obese[16]
- diabetes mellitus type-2
- low-grade insulin resistance
- hyperlipidemia, hypertriglyceridemia
- hypertension[16]
- fatty liver of pregnancy
- red meat & processed meat consumption may increase risk[18]
- may be 1st sign of metabolic syndrome X
- risk factors:
Epidemiology
- most common cause of liver disease worldwide
- most common cause of elevated LFTs not due to:
- 24% of Americans[5], 52% of Americans[40]
Pathology
- accumulation of excess triglyceride in the hepatocytes
- insulin resistance
- ceramide & diacylglycerol have been proposed in mechanisms of insulin resistance[23]
- dyslipidemia
- 20% have nonalcoholic steatohepatitis (NASH)
- hepatic steatosis, inflammation & often fibrosis
Genetics
- single nucleotide polymorphisms in apolipoprotein C3 APOC3 (C-482T & T-455C) are associated with NAFLD & insulin resistance[7]
- genetic variations in PNPLA3 are a cause of susceptibility to non-alcoholic fatty liver disease type 1
- polymorphisms in PNPLA3, CETP, SREBF-2, & TM6SF2 have been implicated in nonobese NAFLD[16]
Clinical manifestations
- most patients are asymptomatic
- vague right upper quadrant discomfort, fatigue & malaise in some patients
- most patients obese
- in primary care, patients with risk factors for NAFLD should be screened with the fibrosis-4/5 index
Laboratory
- liver function tests
- fasting lipid panel, serum triglycerides
- hepatitis C serology
- hepatitis B surface antigen in serum
- antinuclear antibody[14]
- serum glucose, hemoglobin A1c[11]
- consider oral glucose tolerance test if equivocal
- serum ferritin, transferrin saturation (r/o hemochromatosis)[25]
- platelet count for FIB-4 index score
Diagnostic procedures
- liver biopsy
- diagnosis unclear
- patient at risk for cirrhosis
Radiology
- abnormal abdominal ultrasound (B-mode)
- increased echogenicity consistent with fatty infiltration
- no bile-duct dilation
- sensitivity for detecting steatosis is 89% & specificity is 81%[33]
- standard B-mode ultrasound not recommended (low sensitivity)[32]
- transient elastography to assess hepatic fibrosis
- abdominal CT: low-density hepatic parenchyma
Complications
- steatohepatitis (NASH) (10-20%)
- hepatic cirrhosis (<5%)[6][9]
- 10% of patients with normal serum transaminases have hepatic fibrosis[21]
- patients with normal liver function tests have risks for cirrhosis & hepatocellular carcinoma similar to patients without steatosis[24]
- transient mild hemolysis (Zieve's syndrome)
- not a risk factor for myocardial infarction of stroke[22]
- increased risk for dementia (RR=1.4)[29]
- increased risk of colorectal adenomatous polyps[35]
- mortality is not increased[6][10]
- younger age of NAFLD associated with greater cancer risk[36]
- NAFLD is associated with increased risk of cardiovascular events
- risk is further increased by comorbid diabetes mellitus[39]
- disease interaction(s) of diabetes mellitus type-2 with steatosis (NAFLD, MASLD)
- disease interaction(s) of atherosclerosis with steatosis (NAFLD)
Differential diagnosis
- hemachromatosis
- Wilson's disease
- alpha-1 antitrypsin deficiency
- polycystic ovary syndrome
- autoimmune hepatitis[14]
Management
- prudent objectives
- weight reduction of least 3-5% of body weight[11]
- 5-10%[14]
- hepatic fibrosis may not improve with weight reduction[20]
- alcoholic beverage cessation
- of no cardiovascular benefit[17]
- can exacerbate underlying chronic liver disease[17]
- control of diabetes
- control of hyperlipidemia (hypertriglyceridemia)
- Mediterranean diet recommended[27]
- weight reduction of least 3-5% of body weight[11]
- exercise
- 750 MET-minutes/week (150 minutes/week of brisk walking) reduces liver fat independent of weight loss[30]
- pharmaceutical agents
- only useful for patients who fail diet & exercise[14]
- no FDA-approved drugs[27]
- vitamin E, pioglitazone, & GLP-1 receptor agonists may benefit some patients
- vitamin E 800 IU/day improves liver histology; however, some evidence suggests high-dose vitamin E increases risks for all-cause mortality & prostate cancer[11]
- vitamin E protective against liver fibrosis in NAFLD[37]
- pentoxyfylline may be a useful[14]
- avoidance of statins & thiazolidinediones unnecessary[5]
- pioglitazone can be used; however long-term safety & efficacy is unknown, & weight gain is common
- although statins are safe, controlled trials are necessary to determine if are specifically useful for treatment of NASH
- combination of daily atorvastatin (20 mg), vit E (1000 IU) & vit C (1000 mg) may be of benefit[8]
- GLP-1 receptor agonists (glutides) may improve liver histology,
- evidence supporting reversal of fibrosis is weak[32]
- NAFLD regression more likely with glutides than with other hypoglycemics[38]
- metformin & ursodeoxycholic acid are not recommended
- recommendation of omega-3 fatty acids is premature[11]
- daily aspirin associated with reduced risk for progression of fibrosis[19]
- flavonoid-rich foods are associated with reduced risk of NAFLD among middle-aged adults[11]
- liver biopsy
- persistently elevated serum transaminases
- splenomegaly, thromobocytopenia
- metabolic syndrome
- negative HBsAg, negative hepatitis C Ab, negative autoantibodies[31]
- bariatric surgery
- may be effective, but recommendation premature[11]
- in patients with nonalcoholic steatohepatitis & obesity, bariatric surgery reduces risk of major adverse liver outcomes & cardiovascular events[28]
- avoid in patients with cirrhosis
- may be effective, but recommendation premature[11]
- routine screening not recommended
More general terms
More specific terms
- cardiac steotosis
- fatty liver of pregnancy
- non-alcoholic steatohepatitis (NASH); metabolic dysfunction-associated steatohepatitis (MASH)
Additional terms
References
- ↑ kaiser permanente nothern california, lab tips, sept. 1999
- ↑ journal watch vol 19 #22, pg 173, nov 15, 1999
- ↑ journal watch vol 19 #24, pg 190, dec 15, 1999
- ↑ medical knowledge self assessment program (mksap) 11, 16, 18, 19. american college of physicians, philadelphia 1998, 2012, 2018, 2021.
- ↑ 5.0 5.1 5.2 prescriber's letter 12(6): 2005 use of statins and thiazolidinediones in patients with nonalcoholic fatty liver disease detail-document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=210620&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 6.0 6.1 6.2 ekstedt m et al, long-term follow-up of patients with nafld and elevated liver enzymes hepatology 2006, 44:865 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17006923
- ↑ 7.0 7.1 petersen kf et al apolipoprotein c3 gene variants in nonalcoholic fatty liver disease. n engl j med 2010 mar 25; 362:1082 PMID: https://www.ncbi.nlm.nih.gov/pubmed/20335584
riordan sm and williams r. gut flora and hepatic encephalopathy in patients with cirrhosis. n engl j med 2010 mar 25; 362:1140. PMID: https://www.ncbi.nlm.nih.gov/pubmed/20335591 - ↑ 8.0 8.1 foster t et al. atorvastatin and antioxidants for the treatment of nonalcoholic fattly liver disease: the st francis heart study randomized clinical trial. am j gastroenterol 2011 jan; 106:71 PMID: https://www.ncbi.nlm.nih.gov/pubmed/20842109
- ↑ 9.0 9.1 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
- ↑ 10.0 10.1 lazo m et al. non-alcoholic fatty liver disease and mortality among us adults: prospective cohort study. bmj 2011 nov 18; 343:d6891 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22102439
- ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 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)
- ↑ perlemuter g, bigorgne a, cassard-doulcier am, naveau s. nonalcoholic fatty liver disease: from pathogenesis to patient care. nat clin pract endocrinol metab. 2007 jun;3(6):458-69. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17515890
- ↑ cheung o, sanyal aj. recent advances in nonalcoholic fatty liver disease. curr opin gastroenterol. 2010 may;26(3):202-8 PMID: https://www.ncbi.nlm.nih.gov/pubmed/20168226
- ↑ 14.0 14.1 14.2 14.3 14.4 14.5 anello j, feinberg b, heinegg j, lindsey r, wojdylo c, wong o. medcsape oncology. august 2014 recommendations for nonalcoholic fatty live disease from the world gastroenterology organization (wgo) http://reference.medscape.com/features/slideshow/guidelines-review/august2014
- ↑ chalasani n, younossi z, lavine je et al the diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the american gastroenterological association, american association for the study of liver diseases, and american college of gastroenterology. gastroenterology. 2012 jun;142(7):1592-609 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22656328 (corresponding ngc guideline withdrawn dec 2017)
- ↑ 16.0 16.1 16.2 16.3 16.4 16.5 kim d, kim wr. non-obese fatty liver disease. clin gastroenterol hepatol 2016 aug 28; PMID: https://www.ncbi.nlm.nih.gov/pubmed/27581063
- ↑ 17.0 17.1 17.2 vanwagner lb et al. alcohol use and cardiovascular disease risk in patients with nonalcoholic fatty liver disease. gastroenterology 2017 aug 9 PMID: https://www.ncbi.nlm.nih.gov/pubmed/28802566
- ↑ 18.0 18.1 zelber-sagi s, ivancovsky-wajcman d, fliss isakov n, et al. high red and processed meat consumption is associated with non-alcoholic fatty liver disease and insulin resistance. j hepatol 2018 mar 15; PMID: https://www.ncbi.nlm.nih.gov/pubmed/29571924 https://linkinghub.elsevier.com/retrieve/pii/s0168827818300588
- ↑ 19.0 19.1 simon tg, henson j, osganian s et al. daily aspirin use associated with reduced risk for fibrosis progression in patients with nonalcoholic fatty liver disease. clin gastroenterol hepatol 2019 may 8; PMID: https://www.ncbi.nlm.nih.gov/pubmed/31077838 https://www.cghjournal.org/article/s1542-3565(19)30493-8/pdf
- ↑ 20.0 20.1 koutoukidis da, astbury nm, tudor ke et al. association of weight loss interventions with changes in biomarkers of nonalcoholic fatty liver disease: a systematic review and meta-analysis. jama intern med 2019 jul 1; PMID: https://www.ncbi.nlm.nih.gov/pubmed/31260026 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2737321
adler e, brandman d. treatment of fatty liver disease - time to implement common sense measures. jama intern med 2019 jul 1; PMID: https://www.ncbi.nlm.nih.gov/pubmed/31260055 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2737317 - ↑ 21.0 21.1 gawrieh s, wilson la, cummings ow, et al. histologic findings of advanced fibrosis and cirrhosis in patients with nonalcoholic fatty liver disease who have normal aminotransferase levels. am j gastroenterol 2019 oct; 114:1626 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31517638 https://journals.lww.com/ajg/abstract/2019/10000/histologic_findings_of_advanced_fibrosis_and.13.aspx
- ↑ 22.0 22.1 alexander m, loomis ak, van der lei j et al. non-alcoholic fatty liver disease and risk of incident acute myocardial infarction and stroke: findings from matched cohort study of 18 million european adults. bmj 2019 oct 8; 367:l5367 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31594780 free pmc article
- ↑ 23.0 23.1 samuel vt, shulman gi nonalcoholic fatty liver disease, insulin resistance, and ceramides. n engl j med 2019; 381:1866-1869 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31693811 https://www.nejm.org/doi/full/10.1056/nejmcibr1910023
- ↑ 24.0 24.1 natarajan y, kramer jr, yu x et al. risk of cirrhosis and hepatocellular cancer in patients with non-alcoholic fatty liver disease and normal liver enzymes. hepatology 2020 feb 5; PMID: https://www.ncbi.nlm.nih.gov/pubmed/32022277 https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.31157
- ↑ 25.0 25.1 nejm knowledge+ question of the week. dec 15, 2020 https://knowledgeplus.nejm.org/question-of-week/1577/
chalasani n et al. the diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the american association for the study of liver diseases. hepatology 2018 jan; 67:328 PMID: https://www.ncbi.nlm.nih.gov/pubmed/28714183 - ↑ 26.0 26.1 rodriguez la, shiboski sc, bradshaw pt et al. predicting non-alcoholic fatty liver disease for adults using practical clinical measures: evidence from the multi-ethnic study of atherosclerosis. j gen intern med 2021 sep; 36:2648 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33501527 https://link.springer.com/article/10.1007%2fs11606-020-06426-5
- ↑ 27.0 27.1 27.2 kanwal f, shubrook jh, adams la et al. clinical care pathway for the risk stratification and management of patients with nonalcoholic fatty liver disease. gastroenterology 2021 nov; 161:1657. PMID: https://www.ncbi.nlm.nih.gov/pubmed/34602251 https://www.gastrojournal.org/article/s0016-5085(21)03384-9/fulltext
- ↑ 28.0 28.1 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
- ↑ 29.0 29.1 hamza z nafld tied to higher dementia risk
findings were stronger among patients with comorbid heart disease. medpage today july 13, 2022 https://www.medpagetoday.com/neurology/dementia/99704https://www.medpagetoday.com/neurology/dementia/99704
shang y, widman l, hagstrom h nonalcoholic fatty liver disease and risk of dementia: a population-based cohort study. neurology. 2022. july 13 PMID: https://www.ncbi.nlm.nih.gov/pubmed/35831178 https://n.neurology.org/content/early/2022/07/13/wnl.0000000000200853 - ↑ 30.0 30.1 Crist C Exercise training reduces liver fat in patients with nafld, even without weight loss. Medscape. February 13, 2023
- ↑ 31.0 31.1 nejm knowledge+ gastroenterology
- ↑ 32.0 32.1 32.2 Rinella ME et al. AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology 2023 May; 77:1797. PMID: https://www.ncbi.nlm.nih.gov/pubmed/36727674 https://journals.lww.com/hep/Fulltext/2023/05000/AASLD_Practice_Guidance_on_the_clinical_assessment.31.aspx
- ↑ 33.0 33.1 Lee CM et al. A reappraisal of the diagnostic performance of B-mode ultrasonography for mild liver steatosis. Am J Gastroenterol 2023 May; 118:840. PMID: https://www.ncbi.nlm.nih.gov/pubmed/36305695 https://journals.lww.com/ajg/Abstract/2023/05000/A_Reappraisal_of_the_Diagnostic_Performance_of.20.aspx
- ↑ 34.0 34.1 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 - ↑ 35.0 35.1 Yang, Y, Teng Y, Shi J et al Association of nonalcoholic fatty liver disease with colorectal adenomatous polyps and non-adenomatous polyps: a cross-sectional study. Eur J Gastroenterol Hepatol. 2023. Aug 23 PMID: https://www.ncbi.nlm.nih.gov/pubmed/37642651
- ↑ 36.0 36.1 Liu C, Liu T, Zhang Q et al New-Onset Age of Nonalcoholic Fatty Liver Disease and Cancer Risk. JAMA Netw Open. 2023;6(9):e2335511. PMID: https://www.ncbi.nlm.nih.gov/pubmed/37747732 PMCID: PMC10520743 Free PMC article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2809840
- ↑ 37.0 37.1 Qi X, Guo J, Fang C et al Vitamin E intake is inversely associated with NAFLD measured by liver ultrasound transient elastography. Sci Rep. 2024 Jan 31;14(1):2592. PMID: https://www.ncbi.nlm.nih.gov/pubmed/38296998 PMCID: PMC10831069 Free PMC article https://www.nature.com/articles/s41598-024-52482-w
- ↑ 38.0 38.1 Jang H et al. Outcomes of various classes of oral antidiabetic drugs on nonalcoholic fatty liver disease. JAMA Intern Med 2024 Feb 12; [e-pub] PMID: https://www.ncbi.nlm.nih.gov/pubmed/38345802 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2814646
- ↑ 39.0 39.1 Kim KS et al. Association of non-alcoholic fatty liver disease with cardiovascular disease and all cause death in patients with type 2 diabetes mellitus: Nationwide population based study. BMJ 2024 Feb 13; 384:e076388 PMID: https://www.ncbi.nlm.nih.gov/pubmed/38350680 PMCID: PMC10862140 Free PMC article https://www.bmj.com/content/384/bmj-2023-076388
- ↑ 40.0 40.1 Sharma A, Godina Leiva E, Kalavalapalli S et al Obesity increases the risk of hepatic fibrosis in young adults with type 2 diabetes mellitus: the need to screen. Obesity (Silver Spring). 2024 Oct;32(10):1967-1974. PMID: https://www.ncbi.nlm.nih.gov/pubmed/39315409
- ↑ Bell W, Jennings A, Thompson AS et al A flavonoid-rich diet is associated with lower risk and improved imaging biomarkers of nonalcoholic fatty liver disease: a prospective cohort study. Am J Clin Nutr. 2024 Sep 26:S0002-9165(24)00791-3. PMID: https://www.ncbi.nlm.nih.gov/pubmed/39341459 Free article.
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