Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ONGOING

without end-stage liver disease

1st line – diet and exercise

Back
ONGOING
|
without end-stage liver disease
1st line – 

diet and exercise

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. 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 5% to 7% of total body weight.[75]​[76]​​​ Moreover, ≥10% weight loss has been associated with improvement in all histological features of metabolic dysfunction-associated steatohepatitis (MASH) including portal inflammation and fibrosis.[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]

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]

Consider – pioglitazone

Back
ONGOING
|
without end-stage liver disease
Consider – 

pioglitazone

Additional treatment recommended for SOME patients in selected patient group

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]

Pioglitazone may be given in combination with vitamin E (see below).[41]

Primary options

pioglitazone: 15-45 mg orally once daily

Consider – vitamin E

Back
ONGOING
|
without end-stage liver disease
Consider – 

vitamin E

Additional treatment recommended for SOME patients in selected patient group

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 randomised controlled trial 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 may be given in combination with pioglitazone (see above).[41]

Primary options

alpha tocopherol: 800 units orally once daily

Consider – weight loss pharmacotherapy

Back
ONGOING
|
without end-stage liver disease
Consider – 

weight loss pharmacotherapy

Additional treatment recommended for SOME patients in selected patient group

For obese and overweight patients, treatment with these agents should be according to obesity guidelines.

Orlistat 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]

Consider – roux-en-Y gastric bypass

Back
ONGOING
|
without end-stage liver disease
Consider – 

roux-en-Y gastric bypass

Additional treatment recommended for SOME patients in selected patient group

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.

In patients with MASLD, roux-en-Y gastric bypass has 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 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.

Plus – optimise diabetic control

Back
ONGOING
|
without end-stage liver disease
|
with diabetes
Plus – 

optimise diabetic control

Treatment recommended for ALL patients in selected patient group

Drug selection is based on treatment of diabetes. Careful consideration must be given to the risks and benefits for each patient.

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]

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]

Plus – lipid-lowering therapy

Back
ONGOING
|
without end-stage liver disease
|
with dyslipidaemia
Plus – 

lipid-lowering therapy

Treatment recommended for ALL patients in selected patient group

Treatment with these agents should follow the guidelines for treatment of the specific dyslipidaemia.

​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] 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] 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]

end-stage liver disease

1st line – liver transplantation

Back
ONGOING
|
end-stage liver disease
1st line – 

liver transplantation

End-stage liver disease secondary to MASH is projected to become the primary indication for liver transplant in the near future.[115] 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]

2nd line – transjugular intrahepatic portosystemic shunt

Back
ONGOING
|
end-stage liver disease
2nd line – 

transjugular intrahepatic portosystemic shunt

Transjugular intrahepatic portosystemic shunt 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]

back arrow

Choose a patient group to see our recommendations

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

Use of this content is subject to our disclaimer