Metabolic Dysfunction Associated Steatohepatitis

MASH is the progressive form of MASLD, defined histologically by steatosis, lobular inflammation and hepatocyte ballooning, with or without fibrosis.

• Affects 5 to 7% of the general population, and up to 30% of those with type 2 diabetes and obesity.
• Fibrosis stage drives prognosis. About 20% of F3 patients develop cirrhosis within 5 years.
• Mechanisms are lipotoxicity, oxidative stress, innate immune activation and stellate cell activation.
• Cirrhosis related events and HCC occur at 1 to 2% per year once cirrhotic.
• MASH is now a leading indication for liver transplantation.

• Usually asymptomatic, with raised ALT (often under 100 U/L) in many but normal enzymes in a substantial minority.
• Metabolic syndrome features, central obesity, hepatomegaly.
• Splenomegaly, thrombocytopenia and low albumin suggest advanced fibrosis.
• Decompensation: ascites, variceal bleeding, encephalopathy, jaundice.

• Biopsy is the reference standard: NAFLD activity score (steatosis 0 to 3, inflammation 0 to 3, ballooning 0 to 2) and fibrosis stage F0 to F4.
• Noninvasive pathway: FIB-4, elastography (above 8 kPa), ELF test, MRI proton density fat fraction, MR elastography.
• Biopsy for patients at risk of fibrosis with uncertain results or before trial enrolment.
• Exclude coexisting liver disease (autoimmune, viral, iron overload, alpha 1 antitrypsin).
• Assess cardiovascular risk, diabetes and sleep apnoea.

• Lifestyle intervention with 10% weight loss is first line.
• Resmetirom 80 to 100 mg daily improves resolution of MASH and fibrosis in F2 to F3.
• Semaglutide 2.4 mg SC weekly is approved for MASH with F2 to F3 fibrosis. Tirzepatide 5 to 15 mg weekly also helps.
• Pioglitazone 30 mg daily (diabetes or biopsy proven MASH), vitamin E 800 IU daily (nondiabetic). Monitor for weight gain and fractures with pioglitazone, and prostate cancer concern with vitamin E.
• Metformin has no histological benefit but is used for diabetes. Obeticholic acid is not recommended.
• Statins for cardiovascular risk (atorvastatin 20 to 40 mg), blood pressure control, no alcohol.
• Bariatric surgery for suitable patients.
• Cirrhosis: manage portal hypertension (carvedilol 6.25 to 12.5 mg daily), HCC surveillance every 6 months.
• Reassess fibrosis every 1 to 2 years.