Metabolic Dysfunction–Associated Liver Disease (MASLD)

ByDanielle Tholey, MD, Sidney Kimmel Medical College at Thomas Jefferson University
Reviewed/Revised Sept 2023
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(See also the American Association for the Study of Liver Diseases [AASLD] 2018 practice guidance on the diagnosis and management of MASLD.)

MASLD includes simple fatty infiltration (a benign condition called steatotic liver disease) and metabolic dysfunction–associated steatohepatitis (MASH), a less common but more important variant. MASH (sometimes called steatonecrosis) is diagnosed most often in patients between 40 and 60 years but can occur in all age groups. Many affected patients have obesity, type 2 diabetes mellitus (or glucose intolerance), dyslipidemia, and/or metabolic syndrome.

Pathophysiology of MASLD

Steatotic liver disease develops for many reasons, involves many different biochemical mechanisms, and causes different types of liver damage. Pathophysiology involves fat accumulation (steatosis), inflammation, and, variably, fibrosis. Steatosis results from hepatic triglyceride accumulation. Possible mechanisms for steatosis include reduced synthesis of very low density lipoprotein (VLDL) and increased hepatic triglyceride synthesis (possibly due to decreased oxidation of fatty acids or increased free fatty acids being delivered to the liver). Inflammation may result from lipid peroxidative damage to cell membranes. These changes can stimulate hepatic stellate cells, resulting in fibrosis. If advanced, MASH can cause cirrhosis and portal hypertension.

Symptoms and Signs of MASLD

Most patients are asymptomatic. However, some have fatigue, malaise, or right upper quadrant abdominal discomfort. Hepatomegaly develops in about 75% of patients. Splenomegaly may develop if advanced hepatic fibrosis is present and is usually the first indication that portal hypertension has developed. Patients with cirrhosis due to MASH can be asymptomatic and may lack the usual signs of chronic liver disease.

Diagnosis of MASLD

  • History (presence of risk factors, absence of excessive alcohol intake)

  • Serologic tests that rule out hepatitis B and C

  • Ultrasound evidence of steatosis or MR elastography with fat fraction

  • Liver biopsy

The diagnosis of MASH should be suspected in patients with metabolic syndrome (typically obesity, type 2 diabetes mellitus or a high fasting plasma glucose level, hypertension, and dyslipidemia) and in patients with unexplained laboratory abnormalities suggesting liver disease. Differentiating simple steatosis from MASH can be difficult and elevated liver enzymes are not a sensitive predictor for identifying MASH. The presence of metabolic syndrome as well as elevated ferritin increases the likelihood that a patient has MASH rather than simple steatosis. Further, clinical scoring systems such as the FIB4 score, MASLD fibrosis score calculator or laboratory MASH FibroSure® can identify patients at risk for fibrosis and thus those more likely to have MASH and be at risk for progression to cirrhosis. When liver enzymes are elevated the most common laboratory abnormalities are elevations in aminotransferase levels. Unlike in alcohol-related liver disease, the ratio of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) in MASH is usually < 1. Alkaline phosphatase and gamma–glutamyl transpeptidase (GGT) occasionally increase. Hyperbilirubinemia, prolongation of prothrombin time (PT), and hypoalbuminemia are uncommon.

For diagnosis, strong evidence (such as a history corroborated by friends and relatives) that alcohol intake is not excessive (eg, is < 20 g/day) is needed, and serologic tests should show absence of hepatitis B and C (ie, hepatitis B surface antigen and hepatitis C virus antibody should be negative). Liver biopsy reveals damage similar to that seen in alcoholic hepatitis, usually including large fat droplets (macrovesicular fatty infiltration) as well as pericellular or "chicken wire" fibrosis. Indications for biopsy include unexplained signs of portal hypertension (eg, splenomegaly, cytopenia) and unexplained elevations in aminotransferase levels that persist for > 6 months in a patient with diabetes, obesity, or dyslipidemia.

Liver imaging tests, including ultrasonography, CT, and particularly MRI, may identify hepatic steatosis. Noninvasive measures of fibrosis such as transient elastography (a test that uses both ultrasound and low-frequency elastic waves), ultrasound elastography, or MR elastography can assess severity of steatosis as well as estimate fibrosis, thereby obviating the need for liver biopsy in many cases (1, 2). Transient elastography and ultrasound elastography can be limited by body habitus (too big/fat for ultrasound waves to penetrate adequately), whereas MR elastography is not. However, these tests cannot identify the inflammation typical of MASH and cannot differentiate MASH from other causes of hepatic steatosis.

Diagnosis references

  1. 1. Cassinotto C, Boursier J, de Ledinghen V, et al: Liver stiffness in nonalcoholic fatty liver disease: A comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy. Hepatology 63(6):1817-1827, 2016. doi: 10.1002/hep.28394

  2. 2. Lee MS, Bae JM, Joo SK, et al: Prospective comparison among transient elastography, supersonic shear imaging and ARFI for predicting fibrosis in nonalcoholic fatty liver disease. PLoS One 12(11)e:0188321, 2017. doi: 10.1371/journal.pone.0188321. eCollection 2017. Erratum in: PLoS One 3(6):e0200055, 2018. doi: 10.1371/journal.pone.0200055. eCollection 2018.

Treatment of MASLD

  • Elimination of causes and control of risk factors

The only widely accepted treatment goal is to eliminate potential causes and risk factors. Such a goal may include discontinuation of drugs or toxins, weight loss, and treatment for dyslipidemia or treatment for hyperglycemia

Prognosis for MASLD

Prognosis is driven by degree of fibrosis and is the only measure that correlates with liver-related mortality and need for liver transplantation (1). Prognosis is hard to predict, although patients with MASLD who have MASH on histology and evidence of fibrosis are more likely to develop cirrhosis (2). It has been estimated that 10% of patients with MASLD progress to cirrhosis over a 20-year period (3). Alcohol as well as some drugs (eg, cytotoxic drugs) and metabolic disorders are associated with acceleration of metabolic dysfunction–associated steatohepatitis (MASH). As a result, even modest alcohol use should be avoided given the risk of accelerated progression to fibrosis. Prognosis is often good unless complications (eg, variceal hemorrhage) develop.

Prognosis references

  1. 1. Angulo P, Kleiner DE, Dam-Larsen S, et al: Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149(2):389-398, 2015. e10. doi: 10.1053/j.gastro.2015.04.043

  2. 2. American Association for the Study of Liver Diseases: 2018 Practice Guidelines.

  3. 3. Nasr P, Ignatova S, Kechagias E, et al: Natural history of nonalcoholic fatty liver disease: A prospective follow-up study with serial biopsies. Hepatol Commun 2(2);199-210, 2017. doi: 10.1002/hep4.1134. eCollection 2018 Feb.

Key Points

  • MASLD includes a benign condition called steatotic liver disease as well as metabolic dysfunction-associated steatohepatitis (MASH).

  • MASH causes histologic liver damage similar to that in alcoholic hepatitis but occurs in patients who are not alcoholics and who often are obese or have type 2 diabetes mellitus or dyslipidemia.

  • Symptoms are usually absent, but some patients have right upper quadrant discomfort, fatigue, and/or malaise.

  • Signs of portal hypertension and cirrhosis can eventually occur and may be the first manifestations.

  • Rule out alcoholism (based on corroborated history) and hepatitis B and C (with serologic tests) and do noninvasive imaging scans to assess fatty infiltration and degree of fibrosis.

  • Eliminate causes and control risk factors when possible.

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