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Metabolic Dysfunction-Associated Steatotic Liver Disease (Masld) and Steatohepatitis (Mash)

Essentials

  • Metabolic syndrome is a very important (and in some countries the most important) predictor of severe liver events.
  • Metabolic dysfunction-associated steatotic liver disease (MASLD) covers a spectrum of diseases from pure (i.e. isolated) metabolic fatty liver to metabolic dysfunction-associated steatohepatitis (MASH), advanced fibrosis (MASLD and F3 or F4 fibrosis), and liver cirrhosis (MASLD and F4 fibrosis). MASLD also increases the risk of hepatocellular carcinoma.
  • The probability of MASLD is higher the more components of metabolic syndrome a patient has.
  • A person may have several risk factors for steatotic liver disease, such as metabolic syndrome and alcohol consumption.
  • Pure fatty liver should not be looked for by imaging studies. Outpatient care should focus on identifying people with advanced fibrosis.
  • Lifestyle guidance is of key importance in the treatment of MASLD.
  • See also the articles on Assessing patients with abnormal liver function test results Assessing a Patient with an Abnormal Liver Function Test Result and Metabolic syndrome Metabolic Syndrome.

Examination and diagnosis

Diagnostic principles

  • Fatty liver is a common incidental finding on imaging.
  • Slightly elevated ALAT is suggestive of MASLD, especially if the patient has features of metabolic syndrome. However, ALAT is normal in 50% of patients with fatty liver.
  • Since MASLD is common in the general population (about 25%) and fatty liver without fibrosis has no prognostic significance, fatty liver should not be sought by imaging studies.
  • If fatty liver is detected, the aetiological factors should be assessed and a diagnosis made on the basis of the factors.
  • The risk of advanced fibrosis should be assessed using a risk calculator whenever MASLD is detected (see Detection of advanced steatotic liver disease here below). It is also recommended to assess the risk of fibrosis in individuals with metabolic syndrome or repeatedly elevated ALAT during follow-up.

Diagnosis of MASLD

  • The liver is found to be fatty on the basis of an imaging study or liver biopsy.
    • Causes and classification of steatotic liver disease: see table T1 and picture 2.
    • Aetiological investigations on a case-by-case basis: see table T2
  • In addition to fatty liver, the diagnosis of MASLD requires that the patient has one or more components of metabolic syndrome. The more components a patient has, the higher the risk of severe liver disease.
  • A diagnosis of MASLD requires that alcohol consumption does not exceed 20 g/day in women or 30 g/day in men.
    • If MASLD criteria are otherwise met and alcohol consumption is between 20-50 g/day for women and 30-60 g/day for men, the patient has both MASLD and alcohol-related liver disease (ALD), i.e. MetALD, see picture 2.
    • The diagnosis of MASLD is coded as K76.0 (Fatty liver, not elsewhere classified).

Causes of fatty liver (steatosis)

Metabolic syndrome Metabolic Syndrome (at least 3 of the following: obesity, hyperglycaemia, hypertriglyceridaemia, low HDL level, elevated blood pressure)
Alcohol consumption
Hepatitis C (genotype 3), hepatitis B
Drugs (methotrexate, glucocorticoids, tamoxifen, amiodarone, oestrogens, anti-retroviral medication)
Rare causes: autoimmune diseases, haemochromatosis, psoriasis, Wilson's disease, apoprotein B deficiency, hypothyroidism, starvation, parenteral nutrition, excessive intake of medium-chain triglycerides (MCT; coconut fat and oil), HIV
Causes of microvesicular steatosis, such as drugs (valproate, tetracycline), pregnancy

Detection of advanced steatotic liver disease

  • Among patients, the individuals with advanced fibrosis (F3 fibrosis or F4 fibrosis, i.e. cirrhosis) or hepatocellular carcinoma should be identified.
  • Advanced steatotic liver disease cannot be diagnosed or ruled out on the basis of liver enzymes or ultrasonography.
  • MASH can only be diagnosed by liver biopsy.
  • Indications of advanced fibrosis are looked for clinically (see table T2) and by risk scores.
  • A recommended means of detecting advanced fibrosis is determining the FIB-4 index http://www.mdcalc.com/fibrosis-4-fib-4-index-liver-fibrosis based on the patient's age, AST, ALT and platelet levels.
  • The FIB-4 index should be used to assess the risk of fibrosis if
    • fatty liver is found incidentally, or
    • criteria of metabolic syndrome are met, or
    • ALAT is repeatedly elevated.
  • Elastography is a non-invasive, ultrasound-based examination for quite reliable detection of advanced fibrosis. The ELF (enhanced liver fibrosis) test is a laboratory test that measures fibrosis markers in the blood and can be used as an alternative to elastography. Its relatively high price, however, should be taken into account.
  • For workup, see table T2.

Aetiological investigations in patients with fatty liver disease

Detection of metabolic syndrome (BMI, lipids, blood pressure, fasting glucose, HbA1c, and depending on diabetes risk score, glucose tolerance test)
Detection of high-risk alcohol consumption (see Detecting substance abuse Recognition of Alcohol and Drug Abuse)
History: family history of cirrhosis, use of alcohol (AUDIT calculator Audit), drugs, hormonal or natural products
Clinical examination to exclude advanced liver disease: spider naevi, palmar erythema, yellow skin and sclerae, ascites, muscular wasting
Elastography, if available
Laboratory tests, as far as applicable:
  • To define the functional capacity of the liver, albumin, bilirubin levels, thromboplastin time (PT or INR, if PT is not available)
  • To exclude viral hepatitis, HCVAb, HBsAg

Treatment

  • For people with MASLD alone, the treatment plan is done in primary health care.
  • Patients with MASLD should undergo medical assessment of the risk of fibrosis by a physician every 1-3 years, as considered appropriate, even though pure fatty liver disease probably progresses slowly. Follow-up is mainly performed within primary health care.
  • For overweight or obese patients, the primary treatment is weight loss Conservative (Non-Surgical) Treatment of Obesity, the target being 10% per year.
    • Weight loss will improve all histological changes in the liver, including fibrosis, in direct proportion to the weight loss (see e.g. Table 2 and Figure 3 in http://www.gastrojournal.org/article/S0016-5085(15)00496-5/fulltext).
    • In MASLD, reducing weight is particularly important because it can reduce both cardiovascular risk and the progression of MASLD to advanced liver disease.
  • The GLP-1 receptor agonist semaglutide (2.4 mg once a week) reduces the development of MASH and fibrosis (phase III study 7).
  • Suitable patients can be referred for locally available healthy weight loss coaching or to a weight control group. Relevant services may also be available online.
  • Persistently obese, motivated patients should be referred to an outpatient obesity clinic in specialized care for consideration of e.g. bariatric surgery if the BMI is HASH(0x2fb5b98) 35 kg/m2 (see also Bariatric Surgery (Obesity Surgery))
  • Dietary intake of saturated fats (such as butter, coconut fat, sausages and cheeses high in fat) and energy dense fast sugars, such as soft drinks with sugar, energy drinks and sweets, should be avoided, in particular. Provide the patient with adequate guidance.
  • Both aerobic exercise and exercise increasing muscle strength and endurance (strength training) reduce liver fat content. The average recommendation is to take moderately intense exercise (aerobic or gym exercise) 3-5 times a week for a total of 150-200 min.
  • Alcohol consumption should be stopped.
  • Drugs (see table T1) and natural products contributing to the accumulation of fat in the liver should be avoided.
  • Statins should be used actively in the treatment of dyslipidemia. Statins are not hepatotoxic and an elevated ALAT due to fatty liver is not a contraindication to starting a statin.

Consulting specialized care

  • If a FIB-4 calculator http://www.mdcalc.com/calc/2200/fibrosis-4-fib-4-index-liver-fibrosis shows a high risk of advanced fibrosis (>2.67), the patient should be referred to specialized care.
  • If elastography is available in primary health care, it can be used to screen for patients needing referral to specialized care.
  • Before referral to specialized care, the examinations listed in table T2 should be performed.
  • For the workup in specialized care, see table T3.

The tasks of specialized care in MASLD

Confirmation of the aetiology of fatty liver by additional workup, as necessary
  • For rare causes of steatosis, see table T1.
  • Elastography, if not already performed, and a decision on liver biopsy
If liver biopsy shows MASH and fibrosis F2-F3
  • Exclusion of hepatocellular carcinoma
  • Close cooperation with a unit specialized in treating obesity. Semaglutide (maintenance dose of 2.4 mg once weekly) has been shown to beneficial in the treatment of both obesity and MASH, and of F2-F3 fibrosis.
  • Cooperation with a bariatric surgery team; consider bariatric surgery if the BMI exceeds 35 kg/m2 despite conservative treatment and pharmacotherapy of obesity
  • Planning and follow-up of pharmacotherapy
MASLD with cirrhosis
  • Determining the severity of liver disease based on the Child-Pugh score http://www.mdcalc.com/child-pugh-score-cirrhosis-mortality
  • Gastroscopy to exclude oesophageal varices
  • Exclusion of hepatocellular carcinoma
  • Consultation of a bariatric surgeon particularly if there are signs of liver fibrosis while conservative treatment and pharmacotherapy have been used for several years with no success and there are no contraindications for surgery (these include decompensated liver cirrhosis, jaundice, ascites, bleeding oesophageal varices)
  • Planning of follow-up and treatment
The PNPLA3 gene http://medlineplus.gov/genetics/gene/pnpla3/ test can be considered in specialized care for patients whose fatty liver is not explained by metabolic syndrome.

    References

    • Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. N Engl J Med 2025; online ahead of print [PubMed]
    • Drake I, Giontella A, Miari M, et al. Lifestyle and genetic risk of chronic liver disease in metabolically healthy and unhealthy individuals from the general population. JHEP Rep 2024;6(8):101105 [PubMed]
    • European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol 2024;81(3):492-542 [PubMed]
    • Shang Y, Grip ET, Modica A, et al. Metabolic Syndrome Traits Increase the Risk of Major Adverse Liver Outcomes in Type 2 Diabetes. Diabetes Care 2024;47(6):978-985 [PubMed]
    • Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol 2023;79(6):1542-1556 [PubMed]

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