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

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: 1) alcoholism 2) obesity - distinct group of patients that are not obese [16] - visceral abdominal adiposity in nonobese NAFLD - high dietary intakes of cholesterol & fructose [16] 3) diabetes mellitus type-2 - low-grade insulin resistance 4) hyperlipidemia, hypertriglyceridemia 5) hypertension [16] 5) fatty liver of pregnancy 6) red meat & processed meat consumption may increase risk [18] 7) may be 1st sign of metabolic syndrome X 8) risk factors: - smoking - gender, age, ethnicity [26] Epidemiology: 1) most common cause of liver disease worldwide 2) most common cause of elevated LFTs not due to: a) alcoholic liver disease b) chronic hepatitis B or hepatitis C c) hemochromatosis d) hepatotoxicity e) autoimmune hepatitis f) Epstein-Barr virus (EBV) 3) 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 - 3-27% of patients with BMI < 30 kg/m2 [16] - in primary care, patients with risk factors for NAFLD should be screened with the fibrosis-4/5 index Laboratory: 1) liver function tests - serum biliribin, serum AST, serum ALT, serum GGT, serum albumin - typically serum ALT is 1.5-4 x upper limit of normal - minimal if any abnormalities in serum AST & serum ALP - serum ALT may return to normal is patient can lose 10% of weight 2) fasting lipid panel, serum triglycerides 3) hepatitis C serology 4) hepatitis B surface antigen in serum 5) antinuclear antibody [14] 6) serum glucose, hemoglobin A1c [11] - consider oral glucose tolerance test if equivocal 7) serum ferritin, transferrin saturation (r/o hemochromatosis) [25] 8) platelet count for FIB-4 index score Special laboratory: - 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: 1) steatohepatitis (NASH) (10-20%) 2) 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] 3) transient mild hemolysis (Zieve's syndrome) 4) not a risk factor for myocardial infarction of stroke [22] 5) increased risk for dementia (RR=1.4) [29] 6) increased risk of colorectal adenomatous polyps [35] 7) mortality is not increased [6,10] 8) younger age of NAFLD associated with greater cancer risk [36] 9) NAFLD is associated with increased risk of cardiovascular events - risk is further increased by comorbid diabetes mellitus [39] Differential diagnosis: - hemachromatosis - Wilson's disease - alpha-1 antitrypsin deficiency - polycystic ovary syndrome - autoimmune hepatitis [14] Management: 1) prudent objectives a) weight reduction of least 3-5% of body weight [11] - 5-10% [14] - hepatic fibrosis may not improve with weight reduction [20] b) alcoholic beverage cessation - of no cardiovascular benefit [17] - can exacerbate underlying chronic liver disease [17] c) control of diabetes d) control of hyperlipidemia (hypertriglyceridemia) e) Mediterranean diet recommended [27] 2) exercise - 750 MET-minutes/week (150 minutes/week of brisk walking) reduces liver fat independent of weight loss [30] 3) pharmaceutical agents a) only useful for patients who fail diet & exercise [14] b) no FDA-approved drugs [27] - vitamin E, pioglitazone, & GLP-1 receptor agonists may benefit some patients c) 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] d) pentoxyfylline may be a useful [14] e) 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] f) 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] g) metformin & ursodeoxycholic acid are not recommended h) recommendation of omega-3 fatty acids is premature [11] i) daily aspirin associated with reduced risk for progression of fibrosis [19] 4) liver biopsy - persistently elevated serum transaminases - splenomegaly, thromobocytopenia - metabolic syndrome - negative HBsAg, negative hepatitis C Ab, negative autoantibodies [31] 5) bariatric surgery a) 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] b) avoid in patients with cirrhosis 6) routine screening not recommended

Interactions

disease interactions

Related

obesity

Specific

cardiac steotosis fatty liver of pregnancy non-alcoholic steatohepatitis (NASH); metabolic dysfunction-associated steatohepatitis (MASH)

General

chronic liver disease lipid disorder (dyslipidemia)

Database Correlations

OMIM 613282

References

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