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Key Clinical Summary: Identifying Complications in Metabolic Dysfunction-Associated Steatohepatitis

This is a micro-learning module summary of Prof Maya Balakrishnan's MASH Academy session which you can find here.

Before participating please read our CME and disclosure information which can be found here.

The MASH Academy was supported by an independent medical education grant from Novo Nordisk.

Introduction:

This summary focuses on identifying patients at risk for complications of Metabolic Dysfunction-Associated Steatohepatitis (MASH), a severe form of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). It emphasizes the importance of recognizing liver disease progression and the need for appropriate referral pathways.

Definitions and Terminology:

  • MASLD: Chronic, progressive liver disease characterized by steatosis (triglycerides in ≥5% of hepatocytes) driven by obesity and insulin resistance. It replaces the term "non-alcoholic fatty liver disease" (NAFLD).
  • Steatotic Liver Diseases (SLD): A family of liver conditions where liver injury is manifested by hepatic fat accumulation (steatosis).
  • Etiology: The cause of the liver injury leading to steatosis.

Importance of Etiology:

  • Accurately identifying the etiology of steatotic liver disease is crucial for management and anticipating complications.
  • This summary focuses on MASLD (steatosis driven by obesity and insulin resistance).

Clinical Presentation of MASLD:

  • MASLD is often asymptomatic or presents with non-specific symptoms like fatigue or abdominal pain.
  • Signs of insulin resistance may be present.
  • Overt liver disease symptoms (variceal bleeding, jaundice, ascites, spider angiomas, splenomegaly) indicate advanced cirrhosis, a late and irreversible stage.
  • Key Point: Liver enzymes are frequently normal in MASLD, do not correlate with disease severity, and are not reliable indicators of progression.

Identifying Patients at Risk:

  • A high level of suspicion for MASLD is essential in three clinical scenarios:
  • Patients with abnormal liver enzymes (especially hepatocellular pattern).
  • Patients with incidental finding of steatosis on imaging.
  • Patients with MASLD risk factors (diabetes, obesity, ≥2 metabolic syndrome criteria).
  • For patients with suspected or confirmed MASLD, it's crucial to:
  • Confirm the diagnosis.
  • Identify patients at high risk for liver disease complications.
  • Refer high-risk patients to a hepatologist.

Diagnosis of MASLD:

  • In patients with hepatic steatosis, determine if they have any cardiometabolic criteria (features of metabolic syndrome). If yes, and no other causes of steatosis, they have MASLD.
  • Determine if metabolic dysfunction is the sole driver of steatosis or if there are other etiologies (e.g., alcohol).
  • Screen for significant alcohol consumption and test for other liver diseases (viral hepatitis, Wilson disease, etc.) if liver enzymes are abnormal.

Prevalence and Significance of MASLD:

  • MASLD is highly prevalent (estimated 30% in the general population).
  • Prevalence is even higher in specific populations (e.g., 75% in people with type 2 diabetes).
  • MASLD is clinically significant because it increases the risk of systemic complications.
  • Leading causes of death in MASLD: Cardiovascular disease, malignancy, and liver complications.

Major Adverse Cardiovascular and Liver Outcomes:

  • Patients with MASLD face competing risks from:
  • MACE (Major Adverse Cardiovascular Events): Ischemic heart disease, stroke, heart failure, death.
  • MALO (Major Adverse Liver Outcomes): Cirrhosis-related decompensations (variceal bleeding, ascites, hepatic encephalopathy), liver failure, hepatocellular carcinoma, and liver-related death.
  • Risk of MACE is significantly higher than MALO.
  • Cardiovascular risk assessment and management should follow standard guidelines.
  • Risk of MALO is lower than MACE but still significant.
  • Key Point: The degree of hepatic fibrosis is the strongest predictor of developing MALO. Patients with stage 2 fibrosis or more are at the highest risk.

Pathogenesis of MASLD and Fibrosis Progression:

  • Pathogenesis:
  • Increased fatty acid flux to the liver (driven by visceral obesity and insulin resistance) leads to hepatic steatosis.
  • In a subset of patients (30%), excess fatty acids lead to lipotoxic metabolites, activating inflammatory pathways and fibrogenesis (MASH).
  • Approximately 20% of patients with MASH develop progressive fibrosis, ultimately leading to cirrhosis.
  • Cirrhosis increases the risk of liver decompensation and related complications.
  • Fibrosis Progression:
  • Fibrosis progresses in stages (0 to 4, cirrhosis).
  • Average progression between stages is approximately 7 years, but can be faster (2-3 years) in some.
  • Risk factors for fibrosis progression: Type 2 diabetes, higher BMI (>30), older age, concomitant alcohol use, and certain genetic variants.
  • Key Point: The presence of significant fibrosis (stage 2 or more) on liver biopsy is the strongest independent predictor of cirrhosis complications and mortality.

Identifying Severe Fibrosis:

  • Liver biopsy is the historical reference standard but is not practical for routine use.
  • Liver enzymes are not reliable for identifying severe fibrosis.
  • Non-invasive fibrosis tests (NITs) are used to predict the likelihood of severe fibrosis.

Recommended Non-Invasive Tests (NITs):

  • First-Line Test: FIB-4 Score:
  • A simple clinical risk score calculated from age, AST, ALT, and platelet count.
  • FIB-4 < 1.3: Low likelihood of severe fibrosis (reassess in 1-2 years).
  • FIB-4 > 2.67: Increased possibility of severe fibrosis (refer to hepatology).
  • FIB-4 between 1.3 and 2.66: Indeterminate risk (requires second-line test).
  • Second-Line Tests:
  • FibroScan (VCTE): Ultrasound-based elastography measuring liver stiffness.
  • LSM (liver stiffness measurement) < 8 kPa: Low likelihood of severe fibrosis.
  • LSM ≥ 8 kPa: Increased possibility of severe fibrosis (refer to hepatology).
  • ELF (Enhanced Liver Fibrosis) Test: Blood test measuring markers of matrix turnover.
  • ELF < 7.7: Low likelihood of significant fibrosis.
  • ELF ≥ 7.7: Increased possibility of significant fibrosis (refer to hepatology).

Algorithm for Risk Stratification and Referral:

  • Use NITs to assess for significant fibrosis in:
  • Patients with abnormal liver enzymes and diagnosed MASLD.
  • Patients with steatosis on imaging and normal liver enzymes.
  • Patients with risk factors for MASLD.
  • Risk Stratification:
  • FIB-4 < 1.3: Low risk, manage in primary care (focus on obesity and cardiovascular disease prevention), repeat testing in 1-2 years.
  • FIB-4 > 2.67: High risk, refer to hepatology.
  • FIB-4 1.3-2.67 (indeterminate): Perform a second-line test (FibroScan or ELF) to determine risk and need for referral.

Management at the Hepatologist's Office:

  • Hepatologists:
  • Repeat testing to rule out other liver diseases and confirm MASLD.
  • May use liver biopsy or MR elastography to confirm significant fibrosis.
  • Offer MASH-modifying treatments to patients with stage 2 or 3 fibrosis.
  • Screen for hepatocellular carcinoma and manage portal hypertension complications in patients with cirrhosis.

MASH-Modifying Treatments:

  • Four clinically available treatments:
  • Weight loss
  • Pioglitazone
  • GLP-1 agonists
  • Resmetirom
  • These treatments have varying effects on MASH resolution and fibrosis regression.
  • Their long-term impact on adverse liver outcomes is still under investigation.
  • Recommendations are based on data showing effects on MASH resolution and fibrosis regression.

Weight Loss Recommendations:

  • Weight loss is recommended for all patients with MASLD.
  • Degree of weight loss:
  • 5% weight loss: Reduces steatosis.
  • 7% weight loss: Increases the likelihood of MASH resolution.
  • 10% or more weight loss: Increases the likelihood of fibrosis regression.
  • Patients with severe fibrosis should aim for at least 7-10% weight loss.
  • Lifestyle changes (diet and exercise) are crucial but often require intensive support and behavioral programs.
  • Weight loss medications and bariatric surgery are considered for existing indications, but specific recommendations for MASH are limited.
  • GLP-1 agonists (e.g., semaglutide) show promise for weight loss and MASH resolution.

Other MASH-Modifying Treatments:

  • Pioglitazone: Improves MASH resolution but not fibrosis regression.
  • Resmetirom: First FDA-approved medication for MASH, a thyroid hormone receptor-beta agonist that reduces hepatic fat and improves MASH resolution and fibrosis regression.

Conclusion:

  • Identify patients at risk for MASH complications (those with risk factors or diagnosed MASLD and severe fibrosis).
  • Use non-invasive tests (FIB-4, FibroScan, ELF) to assess for severe fibrosis.
  • Refer patients with high-risk findings (FIB-4 > 2.67, liver stiffness ≥ 8 kPa, ELF ≥ 7.7) to a hepatologist.
  • Available treatments for reducing the risk of adverse liver outcomes: weight loss, semaglutide, pioglitazone, and resmetirom.