Approach

Metabolic dysfunction-associated steatotic liver (MASL) has a benign course and does not warrant treatment beyond lifestyle modification. Because metabolic dysfunction-associated steatohepatitis (MASH) has the potential to progress to cirrhosis in a significant number of patients, pharmacological treatment may be considered in those with more advanced disease on biopsy. Several treatments improve liver enzyme abnormalities, radiographic findings, and histological disease progression. However, there are no data that demonstrate improvement in morbidity or mortality. Effective treatment options are needed to prevent future disease-related morbidity and mortality.

Management of steatosis should be individualised and should target relevant modifiable risk factors.

Weight loss through lifestyle modification

Dietary modifications, physical activity, and weight loss are first-line therapy in patients with metabolic dysfunction-associated steatotic liver disease (MASLD).[3]​​

A diet rich in fresh fruit and vegetables, fibre, and omega-3 polyunsaturated fatty acids is recommended. A calorie-deficit diet is recommended for patients with MASLD who are overweight or obese.[3]​ Patients should reduce intake of sugar-sweetened beverages and highly processed foods.[69]

Weight loss causes a loss of adipose tissue that leads to reduced insulin resistance and improved muscular insulin sensitivity. Studies have shown variable improvement in liver enzymes with weight loss, with some also showing an improvement in histology.[70][71][72] 

Weight loss should be gradual, approximately 0.5 to 1.0 kg per week through dietary alterations (restriction of carbohydrates and saturated fats with a 500 to 1000 kcal/day caloric deficit) and regular aerobic exercise (30 minutes 3-5 times per week).[73] Patients should be cautioned not to lose too much weight quickly, as the development of portal inflammation and fibrosis may occur in patients who lose >1.5 kg per week.[74]

Improvement in SLD has been demonstrated in patients able to lose 3% to 5% of total body weight.​[3]​​ Moreover, ≥10% weight loss has been associated with improvement in all histological features of MASH including portal inflammation and fibrosis.[3][21][75]​ Weight loss is also associated with improvement in glucose metabolism and plasma lipid profile in patients with MASLD.[76]

Physical activity recommendations should be individualised to the patient.[41] Both aerobic activity and progressive resistance training are associated with a reduction of liver fat, even without weight loss.[71][77] Increasing physical activity to ≥150 minutes per week is associated with greater improvements in liver enzymes.[78]

One meta-analysis examined randomised controlled trials (RCTs) of lifestyle interventions, compared with usual care, for patients with MASLD. Most RCTs identified were at high risk of bias. The follow-up periods ranged from 2 to 24 months, so data on clinical events related to MASLD were sparse, and there was significant uncertainty about the effects of the intervention. High-quality RCTs with adequate follow-up (at least 8 years) are recommended.[79]

Any level of alcohol use may be harmful to liver health in patients with MASLD.[80] Patients should be counselled to abstain or keep alcohol intake below the risk threshold.[3]​​[41][80]

Weight loss through pharmacological agents or surgery

Orlistat is an enteric lipase inhibitor that prevents the absorption of fats from the gastrointestinal tract. Systematic reviews suggest that orlistat may improve biochemical indicators of liver damage, but its effect on liver histology remains unclear.[72][81]

Patients with a BMI >40 kg/m² or patients with a BMI >35 kg/m², and at least one or more obesity-related comorbidity, should be considered for bariatric surgery, which facilitates sustained weight loss. An overwhelming majority of patients undergoing bariatric surgery will have MASLD.[82] The American Association for the Study of Liver Diseases (AASLD) recommends bariatric surgery in patients meeting the criteria for metabolic weight loss surgery.[3]​ In patients with MASLD, roux-en-Y gastric bypass demonstrated significant improvement in both steatosis and fibrosis.[83] One systematic review reported biopsy-confirmed resolution of steatosis in 66% of patients with MASLD following bariatric surgery.[84] Randomised controlled trials (RCTs) comparing bariatric surgery with any intervention in patients with MASLD are, however, rare; most data are derived from observational studies.[83][84][85]

Patients need to be selected cautiously and evaluated thoroughly for obesity-related comorbidities and cirrhosis. Patients with cirrhosis need to be risk stratified by a hepatologist prior to surgery. Patients should also be followed carefully after surgery, as a minority may develop worsening steatohepatitis or mild fibrosis.

Thiazolidinediones

Meta-analyses have found that pioglitazone improves liver histological scores in patients with MASLD.[86][87][88][89][90] Long-term treatment may be required as beneficial effects seem to reverse after discontinuation.[91]

Pioglitazone is generally well tolerated, but adverse effects typical of thiazolidinediones (universal weight gain [2-5 kg], osteoporosis in postmenopausal women on long-term therapy, and lower extremity oedema) can limit its use.[92][93] Congestive heart failure has rarely been reported with thiazolidinediones.[94] 

US and European Guidelines recommend that treatment with pioglitazone may be considered for patients with biopsy-proven MASH with and without type 2 diabetes mellitus. The risks and benefits should be discussed with each patient before starting therapy.[3]​​[41] Use of pioglitazone for this indication is off-label. Data regarding pioglitazone use in Asian patients are lacking. Asia-Pacific guidelines advise it may be used short-term in patients with pre-diabetes or type 2 diabetes, following a careful assessment of comorbid conditions that may influence its suitability for the patient.[69]

Rosiglitazone decreases steatosis and aminotransferase levels in patients with MASH. It has been associated with improvement in histological features of MASH in some trials; however, results are conflicting.[95][96] Rosiglitazone has been associated with serious adverse cardiovascular events in patients with type 2 diabetes.[97] For this reason, rosiglitazone has been withdrawn from the market in Europe. Although it is still available in some other locations, including the US, it is generally not recommended in practice.

Vitamin E

Meta-analyses indicate that vitamin E significantly improves liver function and histological changes in patients with MASLD/MASH.[87][98][99] One subsequent study of 263 patients with biopsy-proven MASH and bridging fibrosis demonstrated that vitamin E was associated with improved clinical outcomes.[100]

Meta-analyses have suggested that vitamin E supplementation may increase risk of mortality and haemorrhagic stroke.[101][102] One RCT reported an increased risk of prostate cancer in healthy men who took vitamin E, compared with placebo (hazard ratio 1.17, absolute risk increase 1.6 per 1000 person-years).[103]

Vitamin E treatment may be considered for adults with biopsy-proven MASH who do not have diabetes or cirrhosis.[3]​​[41] The risks and benefits should be discussed with each patient before starting therapy.

Vitamin E and pioglitazone may be given in combination.[41]

Management of comorbid conditions

Patients with MASLD have an increased risk of fatal and non-fatal cardiovascular events, particularly if they have advanced fibrosis, independent of other cardiovascular risk factors.[104] In patients with MASLD without advanced fibrosis, cardiovascular disease and non-hepatic malignancies are the most common causes of death, whereas in patients with MASLD with advanced fibrosis, liver disease is the most common cause of death.[3]​ Risk factors for cardiovascular disease should be sought and treated.[3]​​[41][51]

Post hoc analysis of a randomised study of patients with coronary heart disease suggests that statin treatment is safe and effective for primary prevention of cardiovascular disease in a group of patients with MASLD with mild to moderately elevated liver function tests.[105] Meta-analysis has shown that statin therapy is safe in patients with MASLD and mild elevations in liver enzymes.[106] The AASLD recommends statins to reduce risk of cardiovascular events in patients with MASLD.[3]​ Lipid-lowering therapy should be offered to patients with MASLD who meet current criteria.[3]​ Statins should be used with caution in patients with acute liver failure or decompensated cirrhosis because of a theoretical risk of rhabdomyolysis.[107]

Statins have been investigated as a treatment for MASLD and MASH. Study results are inconsistent and statin use solely to treat MASLD or MASH is not recommended.[3]​​[108][109]

European guidelines mandate screening all patients diagnosed with MASLD for type 2 diabetes mellitus. Patients who are diagnosed with diabetes should be referred to a diabetes clinic to optimise management.[41]

Metformin may be used as the first-line antidiabetic drug in patients with MASLD and type 2 diabetes. It leads to weight reduction, and reduced glycosylated haemoglobin and fasting plasma glucose, in patients with MASLD.[110] Metformin is not recommended for treating MASH in the absence of diabetes because it does not improve histological scores or fibrosis.[87][111]

Ursodeoxycholic acid

Ursodeoxycholic acid is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria. Enthusiasm for its potential use in patients with MASH was curbed by a large multicentre trial in which patients with MASH were treated with the drug for 2 years. Although safe and well tolerated, it was found to be no better than placebo with regard to changes in steatosis, necro-inflammation, or fibrosis and it is not recommended for the treatment of MASLD or MASH.[3]​​[112][113]

Presence of end-stage liver failure

Transjugular intrahepatic portosystemic shunt (TIPS)

TIPS is an effective means of treating specific complications of end-stage liver disease and has been well studied in patients with refractory ascites and oesophageal variceal bleeding not amenable to endoscopic treatment; it is also commonly used to treat hepatic hydrothorax and gastric variceal bleeding.[114]

Liver transplantation

End-stage liver disease secondary to MASH is projected to become the primary indication for liver transplant. One single-centre study showed that 5-year outcomes were similar when compared with age-, sex-, and model for end-stage liver disease (MELD)-matched controls.[115]​​ [ MELDNa scores (for liver transplantation listing purposes, not appropriate for patients under age 12 years) (SI units) Opens in new window ] ​​​ This study was confirmed by a larger analysis of the Scientific Registry of Transplant Recipients (SRTR) database.[116] A subset of patients with MASH (aged >60 years, BMI >30 kg/m², and pre-liver transplant diabetes and hypertension) were deemed high risk and had a 1-year mortality of 50%.[115][117]

Patients transplanted for MASH may be at an increased risk for postoperative cardiovascular events.[118] Typically, transplant candidates with MASH have concurrent obesity, metabolic, and cardiovascular risks, which directly impact patient evaluation and selection, waitlist morbidity and mortality, and eventually post-transplant outcomes.[119]

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