Metabolic dysfunction–associated steatotic liver disease
Metabolic dysfunction–associated steatotic liver disease, previously known as non-alcoholic fatty liver disease, is a type of chronic liver disease.
This condition is diagnosed when there is excessive fat build-up in the liver, and at least one metabolic risk factor. When there is also increased alcohol intake, the term MetALD, or metabolic dysfunction and alcohol associated/related liver disease is used, and differentiated from alcohol-related liver disease where alcohol is the predominant cause of the steatotic liver disease. The terms non-alcoholic fatty liver and non-alcoholic steatohepatitis have been used to describe different severities, the latter indicating the presence of further liver inflammation. MASLD may progress to MASH, with the risk of progression estimated as 7–35% per year. MASH may also regress to MASLD, especially with healthy diet, exercise and medications. Both MASLD and MASH have liver related complications such as cirrhosis, liver cancer, liver failure, as well as liver independent complications such as cardiovascular disease. These complications are much more common with MASH.
Obesity and type 2 diabetes are strong risk factors for MASLD. Other risks include being overweight, metabolic syndrome, a diet high in fructose, and older age. Obtaining a sample of the liver after excluding other potential causes of fatty liver can confirm the diagnosis.
Treatment for MASLD is weight loss by dietary changes and exercise; bariatric surgery can improve or resolve severe cases. There is some evidence for SGLT-2 inhibitors, GLP-1 agonists, pioglitazone, vitamin E and milk thistle in the treatment of MASLD. In March 2024, resmetirom was the first drug approved by the FDA for MASH. Approval in the EU followed in August 2025. Those with MASH have a 2.6% increased risk of dying per year.
MASLD is the most common liver disorder in the world; about 25–38% of people have it and the prevalence is rising. It is very common in developed nations, such as the United States, and affected about 75 to 100 million Americans in 2017. Over 90% of obese, 60% of diabetic, and up to 20% of normal-weight people develop MASLD. MASLD was the leading cause of chronic liver disease and the second most common reason for liver transplantation in the United States and Europe in 2017. MASLD affects about 20 to 25% of people in Europe. In the United States, estimates suggest that 30% to 40% of adults have MASLD, and about 3% to 12% of adults have MASH. The annual economic burden was about US$103 billion in the United States in 2016.
Classification
As of 2023, steatotic liver disease has been chosen as an umbrella term encompassing different disease subcategories that begin with fatty accumulation in more than 5% of hepatocytes. When at least one metabolic risk factor is present, the condition is termed metabolic dysfunction–associated steatotic liver disease. If there is also increased alcohol intake, the term MetALD is used. This is differentiated from alcohol-related liver disease, in which alcohol is the predominant cause of the steatotic liver disease. MASLD is thus distinguished from other causes such as cryptogenic SLD, drug-induced liver injury, and monogenic diseases.By various mechanisms and possible insults to the liver, SLD may progress to steatohepatitis, a state in which steatosis is combined with inflammation and sometimes fibrosis. MASH can then lead to complications such as cirrhosis and hepatocellular carcinoma.
For formally known NASLD and NASH see History
Signs and symptoms
People with MASLD often have no noticeable symptoms, and it is often only detected during routine blood tests or unrelated abdominal imaging or liver biopsy. In some cases, it can cause symptoms related to liver dysfunction such as fatigue, malaise, and dull right-upper-quadrant abdominal discomfort. Mild yellow discoloration of the skin may occur, although this is rare. MASH can severely impair liver function, leading to cirrhosis, liver failure, and liver cancer.Comorbidities
The condition is strongly associated with or caused by type 2 diabetes, insulin resistance, and metabolic syndrome. It is also associated with hormonal disorders, persistently elevated transaminases, increasing age, and hypoxia caused by obstructive sleep apnea; some of these conditions predict disease progression.Most normal-weight people with MASLD have impaired insulin sensitivity, are sedentary, and have increased cardiovascular disease risk and increased liver lipid levels. These are the consequences of a decreased capacity for storing fat and reduced mitochondrial function in fat and increased hepatic de novo lipogenesis. A recent systematic review reported an increased risk of severe COVID-19 infection in MASLD patients, but no difference in mortality was observed between MASLD and non-MASLD patients.
Risk factors
Genetics
Two-thirds of families with a history of diabetes type 2 report more than one family member having MASLD. There is a higher risk of fibrosis for family members where someone was diagnosed with MASH. Asian populations are more susceptible to metabolic syndrome and MASLD than their western counterparts. Hispanic persons have a higher prevalence of MASLD than white individuals, whereas the lowest prevalence is observed in black individuals. MASLD is twice as prevalent in men as in women, which might be explained by lower levels of estrogen in men.Genetic variations in two genes are associated with MASLD: non-synonymous single-nucleotide polymorphisms in PNPLA3 and TM6SF2. Both correlate with MASLD presence and severity, but their roles for diagnosis remain unclear. Although MASLD has a genetic component, the American Association for the Study of Liver Diseases does not recommend screening family members as there is not enough confirmation of heritability, although there is some evidence from familial aggregation and twin studies.
From diet
According to the Asia-Pacific Working Group on MASLD, overnutrition is a major factor of MASLD and MASH, particularly for lean MASLD. Diet composition and quantity, in particular omega-6 fatty acid and fructose, have important roles in disease progression from MASL to MASH and fibrosis. Choline deficiency can lead to the development of MASLD.Higher consumption of processed, red, and organ meats have been associated with higher risk of developing MASLD. Some research also suggests eggs are also associated with developing MASLD. On the other hand, studies have found healthful plant foods such as legumes and nuts, to be associated with a lower risk of developing MASLD. Two different studies have found healthy plant-based diets rich in healthy plant foods and low in animal foods to be associated with a lower risk of developing MASLD, even after adjusting for BMI.
From lifestyle
Habitual snoring may be a risk factor for MASLD. Severe snoring often signals the presence of obstructive sleep apnea, a much more serious breathing condition. Blockage or narrowing of the airways, even temporarily, can cause the body to experience lowered oxygen levels in the blood. This in turn may cause a variety of changes within the body such as tissue inflammation, increased insulin resistance, and liver injury. A prospective cohort study found the association between habitual snoring and MASLD development to be significant, and the trend was noted to be most prominent in lean individuals.Estrogen and menopause
The liver is responsive to estrogen. Animal models of estrogen deficiency accumulate liver fat as well as inflammation and fibrosis. The protective effect of estrogen is the usual explanation to why women have a much lower incidence of MASLD than men, prior to menopause. On the other hand, women with an earlier age at menopause are at increased risk for MASLD, and post-menopausal women with MASLD are at greater risk to develop severe fibrosis. Studies of various forms of menopausal hormone replacement therapy as potential treatment for MASLD, have yielded conflicting results.Pathophysiology
The primary characteristic of MASLD is the accumulation of lipids in the liver, largely in the form of triglycerides. However, the mechanisms by which triglycerides accumulate and the reasons that accumulation can lead to liver dysfunction are complex and incompletely understood. MASLD can include steatosis along with varied signs of liver injury: either lobular or portal inflammation or ballooning degeneration. Similarly, MASH can include histological features such as portal inflammation, polymorphonuclear cell infiltrates, Mallory bodies, apoptotic bodies, clear vacuolated nuclei, microvesicular steatosis, megamitochondria, and perisinusoidal fibrosis. Hepatocyte death via apoptosis or necroptosis is increased in MASH compared with simple steatosis, and inflammation is a hallmark of MASH. The degree of inflammation can be correlated to the number of inflammatory foci. Various definitions exist for an inflammatory focus, but one defines it as the presence of more than four mononuclear cells in close proximity inside the hepatic parenchyma.One debated mechanism proposes that hepatic steatosis progresses to steatosis with inflammation following some further injury, or second hit. Oxidative stress, hormonal imbalances, and mitochondrial abnormalities are potential causes of this "second hit" phenomenon. A further nutrigenomics model named multiple hit extends the second hit model, suggesting that multiple disease biomarkers and factors such as genes and nutrition influence MASLD and MASH progression. This model attempts to use these factors to predict the impact of lifestyle changes and genetics for the evolution of the MASLD pathology. Many researchers describe MASLD as a multisystem disease, as it impacts and is influenced by organs and regulatory pathways other than the liver.
The accumulation of senescent cells in the liver is seen in persons with MASLD. In mice, liver senescent hepatocytes result in increased liver fat deposition. Treatment of MASLD mice with senolytic agents has been shown to reduce hepatic steatosis.
Based on gene knockout studies in murine models, it has been suggested that, among many other pathogenic factors, TGF beta signals may be crucially involved in promoting the progression of MASH.