Metabolic Dysfunction–Associated Liver Disease (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 MASLD and MASH are complex; however, insulin resistance is a key factor in pathogenesis, leading to increased release of free fatty acids in the liver and hepatic de novo lipogenesis. Other potential mechanisms include reduced synthesis of very low density lipoprotein (VLDL), increased hepatic triglyceride synthesis, genetic factors with lipid handling, and possibly alterations in hepatic uric acid production (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 MASLD and MASH are complex; however, insulin resistance is a key factor in pathogenesis, leading to increased release of free fatty acids in the liver and hepatic de novo lipogenesis. Other potential mechanisms include reduced synthesis of very low density lipoprotein (VLDL), increased hepatic triglyceride synthesis, genetic factors with lipid handling, and possibly alterations in hepatic uric acid production (1). Ongoing inflammation can stimulate hepatic stellate cells, resulting in fibrosis. If advanced, MASH can cause cirrhosis (sometimes with progression to hepatocellular carcinoma) and portal hypertension. MASH can also regress to simple steatosis (2, 3).

Most patients are asymptomatic, especially those with simple steatosis. However, some have fatigue, malaise, or right upper quadrant abdominal discomfort. Hepatomegaly develops in approximately 75% of patients with MASH (1). 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.

• Hepatic steatosis (by imaging, biomarkers, or biopsy)

• At least 1 cardiometabolic risk factors

• Limited history of alcohol intake (no more than 2 drinks per day in women or 3 drinks per day in men)

• Serology to exclude hepatitis B and C

The diagnosis of MASLD should be suspected in patients with metabolic syndrome or metabolic risk factors (typically obesity, type 2 diabetes mellitus or a high fasting plasma glucose level, hypertension, and dyslipidemia), limited history of alcohol intake and in patients with unexplained laboratory abnormalities suggesting liver disease.

The formal diagnosis of MASLD requires evidence of hepatic steatosis, and at least 1 cardiometabolic risk factor (1). Cardiometabolic risk factors significant to meet diagnostic criteria include at least 1 of these 5 factors:

• BMI > 25 kg/m² (BMI > 23 in Asian populations) or waist circumference > 94 cm (men) or 80 cm (women)

• Fasting serum glucose > 100 mg/dL or HgbA1c > 5.7% or type 2 diabetes or current treatment for type 2 diabetes

• Blood Pressure > 130/85 mm/Hg or currently being treated with antihypertensives

• Triglycerides > 150 or currently being treated with lipid lowering therapy

• HDL cholesterol 40 mg/dL (men) or HDL 50mg/dL (women) or currently being treated with lipid lowering medications (2)

Diagnosis of MASH requires evidence of hepatic inflammation as well as steatosis, and requires biopsy showing histologic evidence of hepatocellular injury and inflammation with or without fibrosis (1, 2). Cirrhosis may also be present.

Differentiating MASLD from MASH can be difficult and elevated liver enzymes are not a sensitive predictor for identifying MASH. The presence of metabolic syndrome (especially type 2 diabetes) 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 FibroTest^TM (knowns as FibroSure® in the United States) 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, evidence (such as a history corroborated by friends and relatives) that alcohol intake is not excessive (eg, is < 20 g/day in women and < 30 g/day in men) is needed, and serologic tests showing absence of hepatitis B and C (ie, negative hepatitis B surface antigen and hepatitis C virus antibody) is helpful, although not required. Liver biopsy in MASH reveals large fat droplets (macrovesicular fatty infiltration) in greater than 5% of hepatocytes, damaged ("ballooned") hepatocytes and chronic inflammation with a lymphocyte predominance in the hepatic lobule. Some patients may have fibrosis which is typically in a pericellular or "chicken wire" fibrosis pattern. Indications for biopsy include lack of clarity of discrepancy regarding diagnosis or staging or unexplained signs of portal hypertension (eg, splenomegaly, cytopenia).

Liver imaging tests, including ultrasound, 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 (3, 4). Transient elastography and ultrasound elastography can be limited by body habitus (eg, ultrasound waves may not penetrate adequately in a patient with obesity), 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.

The following English-language resource may be useful. Please note that The Manual is not responsible for the content of this resource.

1. MASHCAN.com. A collection of clinical calculators for the evaluation of MASLD status.

• Elimination of causes and control of risk factors

• Sometimes resmetirom (for patients with moderate to severe fibrosis)Sometimes resmetirom (for patients with moderate to severe fibrosis)

The cornerstone of treatment for most patients remains focused on elimination of potential causes and control of metabolic risk factors (1). Such a goal may include discontinuation of medications or toxins, weight loss, and treatment for dyslipidemia or treatment for hyperglycemia. Weight loss interventions can reduce hepatic inflammation, steatosis, and fibrosis both by laboratory markers and histologically (2, 3, 4). Preliminary evidence suggests that thiazolidinediones and vitamin E can help correct biochemical and histologic abnormalities in MASH, but may not reduce fibrosis (). Preliminary evidence suggests that thiazolidinediones and vitamin E can help correct biochemical and histologic abnormalities in MASH, but may not reduce fibrosis (1). Further, high-dose vitamin E is contraindicated in patients with diabetes, which limits its usefulness. Many other treatments (eg, ursodeoxycholic acid, metronidazole, metformin, betaine anhydrous, glucagon, L-glutamine infusion) have not been proved definitively effective.). Further, high-dose vitamin E is contraindicated in patients with diabetes, which limits its usefulness. Many other treatments (eg, ursodeoxycholic acid, metronidazole, metformin, betaine anhydrous, glucagon, L-glutamine infusion) have not been proved definitively effective.

Resmetirom, a thyroid beta receptor agonist, can be used to treat patients with MASLD and moderate to severe (F2 and F3) fibrosis (Resmetirom, a thyroid beta receptor agonist, can be used to treat patients with MASLD and moderate to severe (F2 and F3) fibrosis (5). In a randomized trial, resmetirom use led to reversal of steatosis and MASH in 30% of patients and improvement in fibrosis by at least one stage in 25% of patients (). In a randomized trial, resmetirom use led to reversal of steatosis and MASH in 30% of patients and improvement in fibrosis by at least one stage in 25% of patients (6). Clinical trials have demonstrated good tolerance and adverse effect profile (most commonly diarrhea and nausea). It is recommended to check a lipid panel, thyroid-stimulating hormone levels and liver tests (including serum aminotransferases) prior to starting therapy; liver test monitoring should be repeated at 3, 6, and 12 months.

Emerging therapies for MASLD that target several different molecular pathways, including peroxisome proliferator-activated receptor-alpha (PPAR-alpha), glucagon-like peptide-1 (GLP-1) modulators, and farnesoid X receptor (FXR) ligands, show promise with respect to both resolution of MASH as well as reversal of preexisting fibrosis. Further study is ongoing. Emerging therapies for MASLD that target several different molecular pathways, including peroxisome proliferator-activated receptor-alpha (PPAR-alpha), glucagon-like peptide-1 (GLP-1) modulators, and farnesoid X receptor (FXR) ligands, show promise with respect to both resolution of MASH as well as reversal of preexisting fibrosis. Further study is ongoing.

Prognosis is driven by degree of fibrosis, the only measure that correlates with liver-related mortality and need for liver transplantation (1, 2). Simple steatosis progresses to MASH in 12 to 40% of patients (3). Prognosis is hard to predict, although patients with MASLD who have MASH on histologic examination with evidence of fibrosis have a higher burden of morbidity and mortality (4). It has been estimated that 10% of patients with MASLD progress to cirrhosis over a 20-year period (5). Alcohol as well as some medications (eg, cytotoxic medications) and metabolic disorders (eg, insulin resistance, hypertension, obesity) 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, ). Alcohol as well as some medications (eg, cytotoxic medications) and metabolic disorders (eg, insulin resistance, hypertension, obesity) 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.