Management of MASH: Best Practices

Overview

This lecture by Prof. Arun Sanyal covers the pathophysiology, disease burden, and evolving management framework for metabolic dysfunction-associated steatohepatitis (MASH), emphasizing the shift from organ-based to systemic metabolic medicine as a foundation for best practices.

Key Clinical Topics

• Nomenclature evolution from NAFLD/NASH to MASLD/MASH
• Global burden of non-communicable diseases and MASLD
• Pathophysiological link between hepatic steatosis and cardiorenal metabolic outcomes
• Disease progression from steatosis to cirrhosis and its clinical consequences
• Bidirectional relationship between metabolic syndrome and liver outcomes
• Transition toward a metabolic medicine framework for patient management

Key Learning Points

• MASLD vs. MASL: MASLD encompasses two phenotypes — simple steatosis (MASL) and the more aggressive MASH, defined by steatosis plus lobular inflammation and ballooning degeneration
• Ballooning degeneration: hallmark histological lesion of steatohepatitis, distinguishing it from bland steatosis and indicating active disease with fibrogenic potential
• Metabolic comorbidities as connected conditions: obesity, type 2 diabetes, hypertension, cardiovascular disease, and chronic kidney disease are not merely risk factors but true comorbidities sharing the root biology of metabolic stress, systemic inflammation, and fibrosis
• Lean MASLD: patients in Asia may fall within normal BMI ranges yet harbour increased visceral adipose tissue and metabolic dysfunction, representing a physiologically unhealthy metabolic state
• Fibrosis stage as primary outcome driver: liver-related morbidity and mortality rise sharply at F3–F4 fibrosis, with cirrhosis placing patients on an accelerated trajectory toward decompensation and death
• Hepatic lipid export and cardiovascular risk: dysregulated HMG-CoA reductase and SREBP-2 upregulation in steatotic livers drives excess VLDL production, ultimately enriching LDL that promotes coronary atherosclerosis
• Sequence of disease onset: population-level data suggest hepatic steatosis precedes type 2 diabetes, as beta-cell loss is a later event — positioning the liver as an early and central target for intervention
• Pre-cirrhotic mortality: before cirrhosis, leading causes of excess mortality are cardiometabolic disease and cancer; after cirrhosis, liver-related outcomes become the dominant driver
• Four-step hepatic injury model: excess fatty acid and sugar delivery → hepatic metabolic overdrive → organelle stress and cell death → sterile inflammation → progressive fibrosis → cirrhosis

Clinical Data & Study Results

• Non-communicable diseases globally: responsible for approximately 71% of deaths worldwide, equating to roughly 41 million deaths annually, with prevalence increasing across all age groups
• Advanced fibrosis burden projection: by 2030, over 40 million people in the USA, Western Europe, China, and Japan are expected to be living with F3–F4 fibrosis or cirrhosis from MASLD
• MASLD and cardiorenal metabolic outcomes (>1 million patients): after adjustment for confounders, MASLD is associated with a 40% increased hazard ratio for MACE, 160% increased risk for type 2 diabetes (HR 2.6), 40% increased risk for CKD (HR 1.4), and elevated risk for Alzheimer's disease
• Metabolic syndrome features and liver outcomes: hazard ratio for liver-related outcomes rises from 1.5 with two metabolic syndrome components to 4.0 with six components, confirming a dose-dependent relationship
• Long-term fibrosis outcome cohort (~18,070 patients, median follow-up 5 years, up to 10 years): Kaplan–Meier analysis demonstrated that cirrhosis conferred dramatically higher cumulative probability of decompensation and mortality compared to earlier fibrosis stages, with **