What is metabolic associated steatohepatitis in middle-aged to older adults with a history of obesity, diabetes mellitus type 2, dyslipidemia, and hypertension?

What is Metabolic-Associated Steatohepatitis (MASH)?

Metabolic-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), is a progressive inflammatory liver disease characterized by fat accumulation, hepatocyte injury, inflammation, and fibrosis that occurs in patients with cardiometabolic risk factors and can lead to cirrhosis, hepatocellular carcinoma, and liver-related death. 1

Disease Definition and Spectrum

MASH represents the severe, progressive form within the broader spectrum of metabolic dysfunction-associated steatotic liver disease (MASLD), which was previously termed non-alcoholic fatty liver disease (NAFLD). 1, 2

The disease spectrum progresses as follows:

• Simple steatosis: Fat accumulation in the liver without inflammation 1
• MASH: Fat accumulation plus hepatocyte injury, inflammation, and ballooning 1
• Fibrosis: Progressive scarring of liver tissue (stages 1-4) 1
• Cirrhosis: Advanced scarring with loss of liver function 1
• Hepatocellular carcinoma: Liver cancer that can develop even before cirrhosis 1

Diagnostic Criteria

MASLD (and therefore MASH) is defined by the presence of hepatic steatosis plus at least one cardiometabolic risk factor from the following: 1

• Abdominal obesity or overweight
• Type 2 diabetes or prediabetes
• Hypertension
• Elevated plasma triglycerides
• Low HDL cholesterol

Critical exclusion criteria include alcohol consumption >20 g/day in women or >30 g/day in men, and absence of other causes of liver disease such as viral hepatitis, drug-induced liver injury, or monogenic diseases. 1

Epidemiology in Your Patient Population

In middle-aged to older adults with obesity, type 2 diabetes, dyslipidemia, and hypertension—the exact profile you're asking about—the prevalence is strikingly high:

• 60-70% of individuals with type 2 diabetes have MASLD 2
• 70-80% of those with obesity have MASLD 2
• More than 90% of obese patients with type 2 diabetes have MASH 3
• The global prevalence of MASLD in adults is 30-40%, with MASH affecting approximately 14% of middle-aged US adults 2, 4
• Men are affected twice as frequently as women, and risk increases significantly after age 50 2

Pathophysiology

The transition from simple steatosis to MASH is driven by toxic lipid accumulation resulting from: 5

• Increased hepatic uptake of fatty acids from insulin-resistant adipose tissue
• Elevated de novo lipogenesis (new fat production in the liver)
• Impaired mitochondrial fatty acid oxidation
• Accumulation of toxic metabolites including saturated fatty acids, free cholesterol, ceramides, lactate, and succinate

These metabolic derangements promote hepatocyte stress and death, activate inflammatory macrophages, and induce fibrogenic transformation of hepatic stellate cells, creating a feed-forward cycle of inflammation and fibrosis. 5

Clinical Significance and Outcomes

The most important prognostic factor is the degree of liver fibrosis, not the presence of inflammation alone. 1 Advanced fibrosis (stage ≥2) predicts liver-related outcomes including cirrhosis, hepatic decompensation (ascites, encephalopathy, variceal bleeding), and hepatocellular carcinoma. 1, 6

However, cardiovascular disease remains the leading cause of death in MASH patients, followed by extrahepatic cancers (primarily gastrointestinal, breast, and gynecologic), and then liver-related complications. 2, 3 In middle-aged individuals aged 45-54, MASLD is an independent risk factor for cardiovascular mortality. 3

MASH is also associated with increased risk for: 3, 4

• De novo type 2 diabetes development
• Chronic kidney disease
• Sarcopenia (muscle loss)
• Decreased health-related quality of life and work productivity

Diagnostic Approach

Case-finding should be performed in all patients with your described risk profile (obesity, type 2 diabetes, dyslipidemia, hypertension) using non-invasive tests rather than routine liver biopsy. 1, 6

The recommended stepwise approach: 1, 6

1. Calculate FIB-4 score (uses age, AST, ALT, platelet count):
   • <1.3 = low risk
   • 1.3-2.67 = intermediate risk

   • 2.67 = high risk

2. For intermediate or high-risk scores, perform transient elastography (vibration-controlled liver stiffness measurement)
3. Refer to hepatology if advanced fibrosis is detected

Liver biopsy is reserved for individual cases requiring definitive diagnosis or when non-invasive tests are inconclusive, not for routine monitoring. 1, 6

Common Pitfalls

• Do not wait for elevated liver enzymes to screen—many patients with significant MASH have normal ALT and AST 1
• Do not assume simple steatosis is benign—even without inflammation, patients remain at increased cardiovascular risk 3
• Do not overlook alcohol intake—carefully quantify consumption, as 20-60 g/day in women or 30-60 g/day in men changes the diagnosis to MetALD (metabolic and alcohol-related liver disease) 1
• Recognize that MASH is a systemic disease—manage it as part of the broader cardiometabolic syndrome, not as an isolated liver condition 1