Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

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  • A spectrum of fatty liver diseases ranging from metabolic dysfunction-associated steatotic fatty liver disease (MASLD), to metabolic dysfunction-associated steatohepatitis (MASH), to fibrosis and cirrhosis, not due to other causes of fatty infiltration of liver (such as alcohol use).
  • Defined as hepatic steatosis plus at least one cardiometabolic risk factor (obesity, hyperlipidemia, prediabetes, diabetes, hypertension (HTN))
  • Most common chronic liver disease in the United States and worldwide

Description

  • MASLD: previously referred to as NAFLD
    • Reversible condition in which large vacuoles of triglyceride fat accumulate in hepatocytes
    • Liver biopsy: fatty deposits in cells without hepatocellular injury (no hepatocyte ballooning, no necrosis, no fibrosis)
    • ALT and AST normal or <3 to 4 times upper limit of normal (ULN)
    • Possible risk of progressing to cirrhosis or liver failure
    • Synonym: steatosis
  • MASH: progressive form of MASLD
    • Liver biopsy: fatty deposits in cells with hepatocellular injury (ballooning, acute/chronic inflammation, ± fibrosis)
    • ALT and AST elevated, but generally <3 to 4 times ULN
    • 30% with MASH may progress to fibrosis over 5 years, may progress to cirrhosis, liver failure, and rarely hepatocellular cancer
  • MASH cirrhosis: presence of cirrhosis with current or previous histologic evidence of steatosis or steatohepatitis

Epidemiology

  • Most common chronic liver disease in industrialized Western countries
  • Predominant age: 40s to 50s; can occur in children
  • Predominant sex: male > female (40% vs. 26%)
  • Leading indication for liver transplantation in women and those >65 years old (1)

Prevalence

  • United States estimate: 30% but often is undiagnosed (1)
  • Present in 58–74% of obese (BMI ≥30 kg/m2); 90% of morbidly obese (BMI ≥40 kg/m2); 69–87% with type 2 diabetes mellitus (DM); 50% with dyslipidemia

Etiology and Pathophysiology

Primary mechanism is thought to be insulin resistance, leading to increased lipolysis, triglyceride synthesis, increased hepatic uptake of free fatty acids, accumulation of hepatic triglyceride, oxidative stress, inflammation and fibrosis with result.

  • MASLD: excessive triglyceride accumulation in the liver and impaired ability to remove fatty acids
  • MASH: multiple hit theory (insulin resistance, adipose tissue hormones, oxidative stress damage, genetic factors, intestinal bacteria) that causes inflammation and acts on liver parenchymal cells leading to steatohepatitis

Genetics

  • Largely unknown: some familial clustering and increased heritability
  • MASLD: more first-degree relatives with cirrhosis than matched controls
  • MASH: 18% with affected first-degree relative

Risk Factors

  • Type 2 DM, cardiovascular disease (CVD), and chronic kidney disease (CKD)
  • Metabolic risk factors: HTN, hyperlipidemia, obesity, visceral fat
  • Protein–calorie malnutrition; total parenteral nutrition (TPN) >6 weeks
  • Severe weight loss (starvation, bariatric surgery)
  • Organic solvent exposure (e.g., chlorinated hydrocarbons, toluene); vinyl chloride; hypoglycin A
  • Gene for hemochromatosis/other conditions with increased iron stores
  • Smoking
  • Drugs: tetracycline, glucocorticoids, tamoxifen, methotrexate, amiodarone, antiretroviral agents for HIV, valproic acid, fialuridine, many chemotherapy regimens, nucleoside analogues
  • History of cholecystectomy
  • Increasing age associated with increased prevalence, severity, advanced fibrosis, and mortality

Pregnancy Considerations
Acute fatty liver of pregnancy: rare but serious complication in 3rd trimester—50% of cases are associated with preeclampsiaPediatric Considerations

  • Pediatric MASLD
    • Increasing prevalence of MASLD among children parallels rise in pediatric obesity, with prevalence of 9.6%
    • Vitamin E of possible benefit
  • Reye syndrome: fatty liver syndrome with encephalopathy usually following viral illness and aspirin use

General Prevention

  • Avoid excess alcohol: ≤2 units per day (men); ≤1 unit per day (women)
  • Maintain appropriate BMI.
  • Prevention and optimal management of diabetes
  • Avoid hepatotoxic medications.

Commonly Associated Conditions

Central obesity; HTN; type 2 diabetes; insulin resistance; hyperlipidemia; preeclampsia in pregnancy; CVD and arrhythmias; hypothyroidism; hypogonadism; OSA; CKD; growth hormone deficiency; polycystic ovary syndrome (PCOS)

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