What is Non-Alcoholic Steatohepatitis (NASH)?

Non-Alcoholic Steatohepatitis (NASH): Definition, Pathophysiology, and Management

Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) characterized by hepatic steatosis (≥5% fat infiltration), inflammation, and hepatocyte injury (ballooning) with or without fibrosis, which can lead to cirrhosis, liver failure, and hepatocellular carcinoma if left untreated. 1

Definition and Diagnosis

NASH is distinguished from simple non-alcoholic fatty liver (NAFL) by specific histological features:

• NAFL: ≥5% hepatic steatosis without evidence of hepatocellular injury
• NASH: ≥5% hepatic steatosis with inflammation and hepatocyte injury (ballooning) 1

The diagnosis of NASH requires:

1. Evidence of hepatic steatosis (by imaging or histology)
2. Absence of significant alcohol consumption (<210g/week for men, <140g/week for women)
3. Exclusion of other causes of liver disease
4. Liver biopsy showing characteristic features 1

Epidemiology

• Global prevalence of NAFLD is approximately 25% of the general population 1, 2
• NASH affects approximately 3-12% of the US population 1, 3
• NASH prevalence is higher in patients with:
  • Obesity
  • Type 2 diabetes
  • Metabolic syndrome
  • Dyslipidemia 2

Pathophysiology

NASH develops through multiple parallel mechanisms:

1. Lipotoxicity: Excessive free fatty acid accumulation in hepatocytes leading to cellular damage 4
2. Oxidative stress: Production of reactive oxygen species causing hepatocellular injury 1
3. Inflammation: Activation of Kupffer cells and release of pro-inflammatory cytokines 4
4. Insulin resistance: Core metabolic abnormality contributing to fat accumulation 1
5. Gut microbiome dysregulation: Altered intestinal permeability and bacterial endotoxin release 4

Natural History and Progression

NASH represents a more aggressive form of NAFLD with higher risk of progression:

• Approximately 30-40% of patients with NASH develop fibrosis 1
• About 20% of NASH patients progress to cirrhosis 3
• NASH cirrhosis can lead to hepatocellular carcinoma (HCC) 5
• Annual all-cause mortality rate is 25.56 per 1000 person-years 3
• Liver-specific mortality rate is 11.77 per 1000 person-years 3

The concept of NAFL and NASH as separate entities is evolving, with evidence suggesting they may represent points on a disease continuum rather than distinct conditions 1.

Management

Lifestyle Modifications

The cornerstone of NASH treatment is lifestyle modification targeting weight loss:

• Weight loss goal: 7-10% of body weight 2

• Diet recommendations:

  • Daily caloric deficit of 500-1000 calories
  • Target intake: 1500-1800 kcal/day for men, 1200-1500 kcal/day for women
  • Mediterranean diet focusing on vegetables, fruits, whole grains, legumes, and olive oil
  • Avoid processed foods and those high in added fructose 2

• Exercise recommendations:

  • 150-300 minutes of moderate-intensity or 75-150 minutes of vigorous-intensity aerobic exercise weekly
  • Exercise at least 30 minutes, more than 3 times per week 2

Pharmacological Interventions

For patients with biopsy-proven NASH:

• Vitamin E (800 IU daily): Consider for non-diabetic patients with biopsy-proven NASH

  • Caution in patients with prostate cancer risk 1, 2

• Pioglitazone (30 mg daily): Consider for patients with or without diabetes

  • Improves insulin sensitivity and reduces hepatic fat
  • May cause weight gain, edema, and increased fracture risk 1, 2

Monitoring and Follow-up

• Baseline liver evaluation: liver ultrasound, complete blood count, liver panel, INR, and creatinine
• Regular monitoring of liver function tests every 3-6 months
• Repeat imaging in 6-12 months
• Reassessment of fibrosis markers in 1-2 years 2

Special Considerations

• Advanced fibrosis: Patients with bridging fibrosis (F3) or cirrhosis (F4) require closer monitoring for complications
• Cirrhosis: Screening for varices and hepatocellular carcinoma is essential
• Medications to avoid: Corticosteroids, amiodarone, methotrexate, tamoxifen, estrogens, tetracyclines, and valproic acid may worsen steatosis 2

Emerging Concepts

• GLP-1 receptor agonists (semaglutide, liraglutide) show promise for NASH treatment 2
• SGLT2 inhibitors may provide benefit but require further investigation 2
• Bariatric surgery may be considered for patients with obesity who fail lifestyle interventions 3, 6

NASH represents a significant health burden with increasing prevalence. Early identification and aggressive management focusing on weight loss through lifestyle modification are essential to prevent progression to cirrhosis and its complications.