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Metabolic Dysfunction–Associated Liver Disease (MASLD)

By

Danielle Tholey

, MD, Sidney Kimmel Medical College at Thomas Jefferson University

Reviewed/Revised Sep 2023
View PATIENT EDUCATION

Steatotic liver disease is due to excessive accumulation of lipid in hepatocytes. Metabolic dysfunction–associated liver disease (MASLD) includes simple fatty infiltration (a benign condition called steatotic liver disease), whereas metabolic dysfunction–associated steatohepatitis (MASH) is defined as the presence of fat leading to lipotoxicity and inflammatory damage to hepatocytes. Histologically, MASH is difficult to distinguish from alcoholic hepatitis. Thus to diagnose MASH, underlying alcohol use must be ruled out. Differentiating simple steatosis from MASH can be difficult without a liver biopsy, and elevated liver enzymes are not a sensitive predictor for identifying MASH. The presence of metabolic syndrome (obesity, dyslipidemia, hypertension, and glucose intolerance) increases the likelihood that a patient has MASH rather than simple steatosis. Pathogenesis is poorly understood but seems to be linked to insulin resistance (eg, as in obesity or metabolic syndrome). Most patients are asymptomatic. Although noninvasive diagnostic tests are usually sufficient, liver biopsy remains the gold standard. Treatment includes elimination of causes and risk factors; new therapies are rapidly emerging but still in the clinical trial phase.

(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 Hepatic Fibrosis Hepatic fibrosis is overly exuberant wound healing in which excessive connective tissue builds up in the liver. The extracellular matrix is overproduced and insufficiently degraded. The trigger... read more . If advanced, MASH can cause cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more and portal hypertension Portal Hypertension Portal hypertension is elevated pressure in the portal vein. It is caused most often by cirrhosis (in North America), schistosomiasis (in endemic areas), or hepatic vascular abnormalities. Consequences... read more .

Symptoms and Signs of MASLD

Diagnosis of MASLD

The diagnosis of MASH should be suspected in patients with metabolic syndrome Metabolic Syndrome Metabolic syndrome is characterized by a large waist circumference (due to excess abdominal adipose tissue), hypertension, abnormal fasting plasma glucose or insulin resistance, and dyslipidemia... read more (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 Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more . When liver enzymes are elevated the most common laboratory abnormalities are elevations in aminotransferase levels. Unlike in alcohol-related liver disease Alcohol-Related Liver Disease Alcohol consumption is high in most Western countries. According to a survey using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition of alcohol... read more 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 Serology Acute viral hepatitis is diffuse liver inflammation caused by specific hepatotropic viruses that have diverse modes of transmission and epidemiologies. A nonspecific viral prodrome is followed... read more 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 Portal Hypertension Portal hypertension is elevated pressure in the portal vein. It is caused most often by cirrhosis (in North America), schistosomiasis (in endemic areas), or hepatic vascular abnormalities. Consequences... read more (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 Imaging Tests of the Liver and Gallbladder Imaging is essential for accurately diagnosing biliary tract disorders and is important for detecting focal liver lesions (eg, abscess, tumor). It is limited in detecting and diagnosing diffuse... read more Imaging Tests of the Liver and Gallbladder , 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 Ultrasonography Ultrasonography , 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 Diagnosis references Steatotic liver disease is due to excessive accumulation of lipid in hepatocytes. Metabolic dysfunction–associated liver disease (MASLD) includes simple fatty infiltration (a benign condition... read more ). 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. 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. 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 Treatment Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol (HDL-C) level that contributes to the development of atherosclerosis... read more Treatment or treatment for hyperglycemia Treatment Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. Early symptoms are related to hyperglycemia and include polydipsia... read more . Preliminary evidence suggests that thiazolidinediones and vitamin E can help correct biochemical and histologic abnormalities in MASH but does not improve fibrosis. Further, vitamin E is contraindicated in patients with diabetes, which limits its usefulness. Many other treatments (eg, ursodeoxycholic acid, metronidazole, metformin, betaine, glucagon, glutamine infusion) have not been proved definitively effective.

There are currently many emerging therapies for MASH targeting 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. These new therapies show promise with respect to both resolution of MASH as well as reversal of preexisting fibrosis. Further study with several phase 3 clinical trials is ongoing.

Prognosis for MASLD

Prognosis is driven by degree of fibrosis Hepatic Fibrosis Hepatic fibrosis is overly exuberant wound healing in which excessive connective tissue builds up in the liver. The extracellular matrix is overproduced and insufficiently degraded. The trigger... read more and is the only measure that correlates with liver-related mortality and need for liver transplantation (1 Prognosis references Steatotic liver disease is due to excessive accumulation of lipid in hepatocytes. Metabolic dysfunction–associated liver disease (MASLD) includes simple fatty infiltration (a benign condition... read more ). Prognosis is hard to predict, although patients with MASLD who have MASH on histology and evidence of fibrosis Hepatic Fibrosis Hepatic fibrosis is overly exuberant wound healing in which excessive connective tissue builds up in the liver. The extracellular matrix is overproduced and insufficiently degraded. The trigger... read more are more likely to develop cirrhosis (2 Prognosis references Steatotic liver disease is due to excessive accumulation of lipid in hepatocytes. Metabolic dysfunction–associated liver disease (MASLD) includes simple fatty infiltration (a benign condition... read more ). It has been estimated that 10% of patients with MASLD progress to cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more over a 20-year period (3 Prognosis references Steatotic liver disease is due to excessive accumulation of lipid in hepatocytes. Metabolic dysfunction–associated liver disease (MASLD) includes simple fatty infiltration (a benign condition... read more ). 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 Varices Varices are dilated veins in the distal esophagus or proximal stomach caused by elevated pressure in the portal venous system, typically from cirrhosis. They may bleed massively but cause no... read more Varices ) develop.

Prognosis references

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.

Drugs Mentioned In This Article

Drug Name Select Trade
Afrezza, Exubera
Alph-E-Mixed , AQUA-E, Aquasol E , Aquavite-E
Actigall, Reltone, Urso 250, Urso Forte
Flagyl, Flagyl ER, Flagyl RTU, LIKMEZ, MetroCream, MetroGel, MetroGel Vaginal, MetroLotion, Noritate, NUVESSA, Nydamax, Rosadan, Rozex, Vandazole, Vitazol
Fortamet, Glucophage, Glucophage XR, Glumetza, Riomet, RIOMET ER
BAQSIMI, GlucaGen, Glucagon, Gvoke, Gvoke HypoPen, Gvoke PFS
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NOTE: This is the Professional Version. CONSUMERS: View Consumer Version
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