How is necroinflammation managed in liver diseases, particularly in terms of reducing the necroinflammation activity score?

Management of Necroinflammation in Liver Diseases

Immunosuppressive therapy with corticosteroids and azathioprine is the cornerstone of treatment for reducing necroinflammatory activity in autoimmune hepatitis, while antiviral therapy is essential for viral hepatitis-related necroinflammation. 1

Assessment of Necroinflammation

Necroinflammation refers to the inflammatory activity in the liver that causes hepatocyte death and is a key driver of disease progression in various liver conditions. Assessment of necroinflammation is crucial for treatment decisions:

• Liver biopsy remains the gold standard for assessing necroinflammatory activity, with the Hepatitis Activity Index (HAI) score providing quantitative evaluation of the inflammatory process 1
• Histological features of necroinflammation include:
  • Interface hepatitis (inflammation at the boundary between portal tracts and parenchyma)
  • Portal lymphoplasmacytic infiltration
  • Lobular necroinflammation
  • Perivenular pattern of injury (may be an early manifestation in autoimmune hepatitis) 1
• Non-invasive methods for assessing necroinflammation are being explored but currently have limitations in autoimmune hepatitis due to interference of inflammatory activity 1

Management Based on Etiology

1. Autoimmune Hepatitis (AIH)

AIH is characterized by immune-mediated necroinflammation that responds well to immunosuppression:

• First-line therapy: Combination of corticosteroids and azathioprine is effective in approximately 80% of patients 2

  • Prednisone/prednisolone (starting at 0.5-1 mg/kg/day) with gradual tapering
  • Azathioprine (1-2 mg/kg/day) as a steroid-sparing agent 1

• Alternative for patients with comorbidities: Budesonide (9 mg/day) plus azathioprine (1-2 mg/kg/day) may be appropriate for non-cirrhotic patients with conditions that might be exacerbated by conventional steroids (diabetes, osteoporosis, psychosis) 1

• Treatment decisions based on necroinflammatory activity:

  • Moderate to severe AIH (HAI ≥4/18): Treatment strongly recommended 1
  • Mild disease (HAI <4/18) without advanced fibrosis: Treatment may be optional, requiring individualized decision based on age, comorbidities, and patient preference 1
  • Untreated mild AIH should be closely monitored as activation and relapse can occur at any time 1

• Treatment endpoints:

  • Normalization of liver enzymes
  • Reduction in necroinflammatory activity on follow-up biopsy
  • Improvement in IgG levels 1

2. Viral Hepatitis

Hepatitis B

• Treatment indications: Patients with active viral replication and significant necroinflammation 1

  • Nucleos(t)ide analogs (NAs) are the mainstay of treatment for reducing necroinflammation in chronic hepatitis B 1
  • Entecavir has demonstrated superior histologic improvement (reduction in Knodell Necroinflammatory Score) compared to lamivudine in both HBeAg-positive (72% vs 62%) and HBeAg-negative (70% vs 61%) patients 3

• Special considerations:

  • Even patients with undetectable HBV DNA and normal ALT may have moderate necroinflammation and severe fibrosis, suggesting that these markers alone may not always reflect the true extent of liver damage 4
  • Serum S100A9 has shown potential as a biomarker for discriminating grades of liver necroinflammation in chronic hepatitis B patients, particularly those with normal or mildly increased ALT levels 5

Hepatitis D (HDV)

• Peginterferon alfa is the standard treatment for HDV for 48 weeks, which improves necroinflammation on liver biopsy 1
• Newer agents:
  • Bulevirtide (BLV), an entry inhibitor for HDV, has shown promising results in reducing HDV RNA and ALT levels 1

3. Non-alcoholic Steatohepatitis (NASH)

• Weight loss through diet and exercise is the primary intervention for reducing necroinflammation in NASH
• Vitamin E and pioglitazone have shown some benefit in reducing necroinflammation in non-diabetic NASH patients

Monitoring Treatment Response

• Regular assessment of liver biochemistry (ALT, AST)
• Monitoring of IgG levels in autoimmune hepatitis
• Follow-up liver biopsy may be considered to evaluate histological response, particularly in cases with discordance between biochemical and clinical response 1
• The histological features of necroinflammatory activity and severity of AIH are often not parallel with the biochemical activity of the disease, emphasizing the importance of histological assessment 1

Special Populations

Elderly Patients

• Older patients with AIH are often less symptomatic at presentation but may have more advanced fibrosis 1
• In elderly patients with mild interface activity and low necroinflammatory scores, treatment decisions should be individualized, considering:
  • Comorbidities
  • Risk of progression (10-year survival without treatment: 67% vs. 98% with treatment) 1
  • Potential for steroid-related side effects

Patients with Osteoporosis

• Consider budesonide-based regimens to minimize systemic steroid effects 1
• Early steroid withdrawal should be attempted when possible 1

Common Pitfalls and Caveats

• Relying solely on ALT levels to assess disease activity can be misleading, as histological necroinflammation may not correlate with biochemical markers 1, 4
• Untreated mild AIH can progress to symptomatic disease and should be closely monitored 1
• Non-invasive methods for assessing fibrosis and inflammation have limitations in AIH due to interference from active inflammation 1
• Necroinflammation in the acute phase of AIH may present with pericentral necrosis that can be histologically indistinguishable from drug-induced liver injury 1

By targeting the underlying cause of necroinflammation and implementing appropriate therapy, the necroinflammatory activity score can be reduced, leading to improved outcomes and prevention of disease progression to cirrhosis and end-stage liver disease.