MASH Cirrhosis: Overview, Stages, and Management

MASH cirrhosis, previously known as NASH cirrhosis, is an advanced liver disease linked to metabolic dysfunction. It develops due to chronic inflammation and fibrosis, often in individuals with obesity, type 2 diabetes, or other metabolic conditions. As the disease progresses, it can lead to liver failure and an increased risk of liver cancer.

Early detection and proper management are crucial for slowing progression and preventing life-threatening outcomes. Understanding its stages and treatment options can improve prognosis and quality of life.

Pathogenesis

MASH cirrhosis results from metabolic dysfunction, chronic hepatic inflammation, and progressive fibrosis. Insulin resistance promotes lipid accumulation in hepatocytes, leading to steatosis, oxidative stress, and mitochondrial dysfunction. Reactive oxygen species (ROS) generated in this process trigger lipid peroxidation and hepatocyte injury.

Inflammatory pathways activate immune cells such as Kupffer cells and macrophages, which release cytokines like TNF-α, IL-6, and TGF-β. These cytokines drive hepatic inflammation and stimulate fibrogenesis. Hepatic stellate cells (HSCs), normally quiescent, become activated and deposit extracellular matrix proteins, particularly collagen, disrupting liver architecture.

Persistent fibrosis leads to cirrhotic changes, including regenerative nodules and sinusoidal capillarization, which impair hepatic blood flow and increase portal hypertension. These alterations exacerbate liver dysfunction and raise the risk of hepatocellular carcinoma.

Clinical Indicators

MASH cirrhosis is often asymptomatic in early stages. Fatigue and mild right upper quadrant discomfort may be early signs but are frequently overlooked. Laboratory tests may show mild elevations in ALT and AST, though these markers lack specificity. A decreasing platelet count, an early indicator of portal hypertension, can precede overt symptoms.

As cirrhosis progresses, jaundice, ascites, and lower extremity edema emerge, signaling hepatic decompensation. Spontaneous bacterial peritonitis (SBP) can complicate ascites, presenting with fever and worsening abdominal pain.

Neurological symptoms such as confusion, asterixis, and cognitive impairment indicate hepatic encephalopathy, a result of impaired ammonia metabolism. Clotting abnormalities increase the risk of spontaneous bruising and gastrointestinal bleeding. Esophageal varices, which develop due to elevated portal pressure, pose a significant risk for life-threatening hemorrhage.

Diagnostic Approaches

Diagnosis combines clinical evaluation, laboratory tests, and imaging. Liver function tests (ALT, AST, ALP, and GGT) suggest hepatic injury but lack specificity. Noninvasive fibrosis assessments, such as the AST-to-platelet ratio index (APRI) and Fibrosis-4 (FIB-4) score, help stratify risk.

Ultrasound is a first-line imaging tool that detects nodular liver contour, splenomegaly, and ascites. Transient elastography (FibroScan) measures liver stiffness as a fibrosis marker, while magnetic resonance elastography (MRE) offers greater accuracy. Cross-sectional imaging with contrast-enhanced CT or MRI helps assess cirrhotic morphology and screen for hepatocellular carcinoma.

Liver biopsy remains the gold standard for definitive diagnosis but is reserved for inconclusive cases due to its invasive nature. Emerging serum biomarkers, such as cytokeratin-18 fragments and microRNA panels, may improve diagnostic accuracy without requiring biopsy.

Cirrhosis Stages

MASH cirrhosis progresses from compensated to decompensated stages. In compensated cirrhosis, the liver maintains function despite fibrosis. Many individuals remain asymptomatic, though imaging may reveal increased liver stiffness.

As fibrosis advances, portal hypertension develops, leading to early decompensated cirrhosis. Signs such as splenomegaly, thrombocytopenia, and fluid retention signal worsening liver function. This stage increases the risk for varices and mild hepatic encephalopathy.

Pharmacological Management

Medications focus on slowing fibrosis, managing complications, and addressing metabolic dysfunction. While no FDA-approved drugs specifically target MASH cirrhosis, several therapies show promise.

Obeticholic acid, an FXR agonist, reduces fibrosis by modulating bile acid metabolism and inhibiting stellate cell activation, though side effects such as pruritus and lipid profile changes limit its use. Resmetirom, a thyroid hormone receptor-beta agonist, enhances hepatic lipid metabolism and reduces steatosis.

To manage complications, non-selective beta-blockers like propranolol lower portal pressure and reduce variceal bleeding risk. Aldosterone antagonists such as spironolactone, often combined with loop diuretics like furosemide, help control ascites. Lactulose and rifaximin are used to treat hepatic encephalopathy by reducing ammonia levels.

Lifestyle Factors

Lifestyle modifications play a critical role in managing MASH cirrhosis. Nutrition, exercise, and weight control can improve liver health and slow disease progression.

Balanced Nutrition

A diet rich in whole foods, including vegetables, lean proteins, and healthy fats, supports liver function. Reducing fructose and refined carbohydrates helps mitigate insulin resistance and hepatic lipogenesis. The Mediterranean diet, which emphasizes monounsaturated fats from olive oil, nuts, and fish, has been associated with reduced hepatic steatosis.

Protein intake should be maintained to prevent sarcopenia, while excessive sodium should be avoided to minimize fluid retention. Nutritional counseling tailored to individual needs can further optimize dietary habits.

Physical Activity

Regular exercise improves insulin sensitivity, reduces hepatic fat, and enhances cardiovascular health. Both aerobic and resistance training benefit individuals with MASH cirrhosis.

Moderate-intensity aerobic exercise, such as brisk walking or cycling, for at least 150 minutes per week reduces liver fat. Resistance training helps maintain muscle mass and metabolic efficiency, particularly important for those at risk of sarcopenia.

Weight Control

Sustained weight loss significantly improves liver histology. A 7–10% reduction in body weight has been shown to reduce fibrosis and hepatic inflammation. Gradual weight loss through diet and exercise is preferred over rapid fluctuations, which can lead to muscle loss.

For severe obesity, bariatric surgery may be considered, as procedures like sleeve gastrectomy have demonstrated benefits in reducing fibrosis. However, surgical risks must be carefully weighed against potential gains.

Cardio-Metabolic Conditions

MASH cirrhosis is closely linked to metabolic disorders such as insulin resistance and cardiovascular disease. Managing glycemic control through medications like GLP-1 receptor agonists can help reduce hepatic inflammation and fibrosis progression.

Cardiovascular disease is a leading cause of mortality in MASH cirrhosis. Dyslipidemia, hypertension, and systemic inflammation increase the risk of atherosclerosis. Statins provide cardiovascular protection and may have antifibrotic effects. Blood pressure control with ACE inhibitors or angiotensin receptor blockers benefits both hepatic and cardiovascular health.

Given the overlap between MASH cirrhosis and metabolic syndrome, a multidisciplinary approach involving hepatologists, endocrinologists, and cardiologists is essential for optimizing long-term outcomes.