Metabolic dysfunction-associated steatotic liver disease

Metabolic dysfunction-associated steatotic liver disease (MASLD), is the accumulation of excess fat in hepatocytes in individuals with at least one cardiometabolic risk factor (e.g., hypertension, impaired glucose tolerance) in the absence of an alternative cause (e.g., heavy alcohol use, drug-induced liver injury). MASLD was previously known as nonalcoholic fatty liver disease. It is highly prevalent in patients with type 2 diabetes mellitus (T2DM), obesity, and/or metabolic syndrome. MASLD is usually asymptomatic and is a diagnosis of exclusion. Diagnostic findings may include hepatic steatosis on imaging and elevated transaminases. Patients with MASLD should be assessed for advanced liver fibrosis using a combination of laboratory-based noninvasive testing, such as the FIB-4, and vibration-controlled transient elastography. Metabolic dysfunction-associated steatohepatitis (MASH) is a subtype of MASLD characterized by chronic hepatocyte inflammation and damage due to lipid accumulation and is associated with a higher risk of progression to liver fibrosis and cirrhosis. MASH was previously known as nonalcoholic steatohepatitis (NASH). Biopsy may be indicated if there is diagnostic uncertainty. Management focuses on the prevention and treatment of associated metabolic conditions.

The nomenclature for steatotic liver disease was updated by international liver disease societies in June 2023. ^[1]

• Metabolic dysfunction-associated steatotic liver disease (MASLD) ^[1]
  • A type of steatotic liver disease that occurs in individuals with ≥ 1 criterion for metabolic syndrome in the absence of an alternative cause (e.g., heavy alcohol use)
  • Previously referred to as nonalcoholic fatty liver disease (NAFLD)
• Metabolic dysfunction-associated steatohepatitis (MASH) ^[1]
  • A subtype of MASLD characterized by chronic hepatocellular inflammation and damage
  • Previously referred to as nonalcoholic steatohepatitis (NASH)

• Global prevalence in the general adult population
  • MASLD: 25–30% ^[2][3]
  • MASH: 12–14% ^[2]
• Prevalence in US patients with T2DM
  • MASLD: ∼ 70% ^[2]
  • MASH: 30–40% ^[2]

Epidemiological data refers to the US, unless otherwise specified.

MASLD is a multifactorial disease with metabolic and genetic components. ^[2]

• Cardiometabolic risk factors: any criterion for metabolic syndrome ^[4]
  • Central obesity
  • Prediabetes or T2DM
  • Hypertension ≥ 130/85 mm Hg or taking antihypertensives
  • Hypertriglyceridemia, low HDL cholesterol , or taking lipid-lowering drugs
• Genetic factors: Individuals with a first-degree relative with MASH-related cirrhosis are at increased risk. ^[2]

• MASLD: excess energy supply → insulin resistance →; ↑ circulating dietary sugars and free fatty acids → ↑ hepatic free fatty acids → ↑ triglyceride synthesis → hepatic steatosis ^[2]
• MASH cirrhosis: oxidative stress, endoplasmic reticulum stress, and inflammasome activation → inflammation and hepatocyte stress and/or death → fibrogenesis → cirrhosis ^[2]

• Often asymptomatic
• MASH can manifest with signs of advanced liver disease, e.g.:
  • Hepatomegaly, splenomegaly
  • Clinical features of cirrhosis

Approach ^[2][3][4]

• MASLD is a diagnosis of exclusion.
• Consider MASLD in patients with any cardiometabolic risk factor and either:
  • Incidental finding of hepatic steatosis on imaging or biopsy
  • Persistent idiopathic elevation of transaminases (e.g., for > 6 months) ^[3]
• Rule out alternative causes of hepatic steatosis based on patient history (e.g., current or prior heavy alcohol use), laboratory studies, and imaging.
• Evaluate all patients for liver fibrosis, e.g., by calculating a FIB-4 score.
• Consider referral for liver biopsy if the diagnosis remains uncertain.

It is only possible to distinguish MASLD from alcohol-associated fatty liver disease using patient history.

Initial studies

Laboratory studies ^[4]

• Liver chemistries
  • Transaminases
    • Normal or ↑ AST and/or ALT
    • AST/ALT ratio usually < 1
    • AST/ALT ratio of > 1 may indicate progression to cirrhosis.
  • Normal or ↓ serum albumin
• CBC: normal or ↓ platelet count
• Tests to rule out alternative diagnoses
  • All patients: serology for hepatitis B and hepatitis C
  • Additional studies based on clinical suspicion, e.g.: ^[2]
    • Serology for type 1 autoimmune hepatitis
    • Tissue transglutaminase IgA for celiac disease
    • Serum ferritin and transferrin saturation for iron overload disorders
    • Testing for alpha-1 antitrypsin deficiency
    • Serum ceruloplasmin to screen for Wilson disease

There is often more ALT than AST (AST/ALT ratio < 1) when Lipids infiltrate the Liver.

Abdominal ultrasound ^[5]

• May be used to confirm hepatic steatosis and/or exclude alternative diagnoses ^[2]
• Often nondiagnostic in patients with mild steatosis
• Supportive finding: ↑ liver echogenicity

Transaminase levels and abdominal ultrasound findings can be normal even in patients with advanced MASH and/or liver fibrosis and therefore should not be used to exclude advanced liver disease. ^[2]

Evaluation for advanced liver fibrosis ^[2][4]

All patients with suspected or confirmed MASLD should be evaluated for liver fibrosis.

• Noninvasive tests
  • FIB-4 (preferred) ^[2][4]
    • A low-risk score excludes advanced liver fibrosis; consider retesting in 1–3 years. ^[4]
    • Indeterminate or high-risk score: Perform further testing, e.g., liver stiffness measurement.
  • Other tests include the NAFLD fibrosis score and AST-to-platelet ratio index.
• Liver stiffness measurement ^[4]
  • Vibration-controlled transient elastography (VCTE): best initial test for patients with an indeterminate or high risk on noninvasive testing
  • MR elastography: Consider if there is diagnostic uncertainty after VCTE. ^[3]

Liver biopsy ^[3][4]

• Indication: diagnostic uncertainty after noninvasive testing and imaging
• Supportive findings for MASLD: hepatocellular lipid accumulation, mostly macrovesicular
• Additional findings in MASH
  • Ballooning degeneration ; and necrosis
  • Inflammatory infiltrates with scattered lymphocytes, neutrophils, and Kupffer cells

General principles

• Currently, there are no curative treatments for MASLD.
• Management is focused on the prevention and treatment of associated metabolic conditions.
• Provide multidisciplinary care (e.g., involve the primary care physician, endocrinologist, hepatologist, and dietitian).
• Refer to hepatology for:
  • Further assessment in patients with indeterminate noninvasive test results
  • Pharmacological management to reduce hepatic steatosis
  • Management of advanced liver fibrosis or cirrhosis

Nonpharmacological management ^[2][3][4]

• Lifestyle changes
  • Healthy diet, e.g., Mediterranean diet
  • Regular exercise
  • Avoidance of alcohol
  • Weight loss for patients who are overweight
• Management of associated metabolic conditions
  • Management of diabetes mellitus
  • Management of obesity
  • Management of hypertension
  • Management of ASCVD

Pharmacological management ^[2][3]

Consider the following medications in consultation with a specialist (e.g., hepatologist) to reduce hepatic steatosis and/or steatohepatitis:

• MASLD
  • SGLT-2 inhibitor (e.g., dapagliflozin or empagliflozin) for patients with T2DM ^[6][7]
  • Tirzepatide for patients with T2DM or obesity ^[8]
• MASH
  • Vitamin E for certain patients without T2DM or cirrhosis ^[2][3]
  • GLP-1 receptor agonist (e.g., semaglutide or liraglutide) for patients with T2DM or obesity and no cirrhosis ^[2]
  • Pioglitazone for patients with T2DM ^[2]

There are currently no FDA-approved medications for the treatment of MASLD.

Monitoring for liver fibrosis ^[2][3][4]

Reevaluate all patients with MASLD or cardiometabolic risk factors for MASLD for advanced liver fibrosis using noninvasive testing, e.g., the FIB-4 score.

• Every 1–2 years for patients with either:
  • Prediabetes or T2DM
  • ≥ 2 other cardiometabolic risk factors for MASLD
• Every 2–3 years for patients with only one of the following risk factors:
  • Central obesity
  • Hypertension or taking antihypertensive therapy
  • Dyslipidemia or taking lipid-lowering drugs

• Alcohol-associated liver disease
• Drug-induced liver injury due to:
  • Amiodarone
  • Methotrexate
  • Tamoxifen
  • Valproate
  • Antiretroviral drugs
  • Corticosteroids
• Viral hepatitis
  • Hepatitis C
  • Hepatitis B
• Inherited or autoimmune disorders
  • Hemochromatosis
  • Alpha-1 antitrypsin deficiency
  • Wilson disease
  • Autoimmune hepatitis
• Reye syndrome
• Pregnancy-related conditions
  • HELLP syndrome
  • Acute fatty liver of pregnancy
• Nutrition-related conditions
  • Malnutrition
  • Acute weight loss (e.g., from metabolic surgery or starvation)
  • Celiac disease
  • Parenteral nutrition

The differential diagnoses listed here are not exhaustive.

• Advanced liver fibrosis, cirrhosis
• Hepatocellular carcinoma

We list the most important complications. The selection is not exhaustive.

• MASLD ^[4]
  • Low risk of progression to cirrhosis or hepatocellular carcinoma in patients with only one cardiometabolic risk factor
  • The risk of progression increases with each additional risk factor.
• Approximately 20% of patients with MASH develop liver fibrosis. ^[3]