What are the characteristic histologic features of hepatitis B virus infection compared to hepatitis C virus infection?

Histological Patterns of Hepatitis B and C

Hepatitis C demonstrates four characteristic histological features that distinguish it from hepatitis B: bile duct damage, lymphoid follicles/aggregates in portal tracts, large-droplet steatosis, and Mallory body-like material—with the latter being virtually pathognomonic for HCV when present. 1

Key Distinguishing Features

Hepatitis C-Specific Patterns

Bile duct damage is 4.7 times more likely in HCV than HBV infection, manifesting as injury to interlobular bile ducts within portal tracts. 1 This feature, while not exclusive to HCV, represents a critical diagnostic clue when evaluating chronic viral hepatitis. 1

Lymphoid aggregates and follicles appear 2.4 times more frequently in HCV, presenting as well-defined collections of lymphocytes within portal areas. 2, 1 These structures are essentially absent in isolated HBV infection but may appear in coinfection scenarios. 2

Steatosis (large-droplet fat) occurs 2.4 times more commonly in HCV-infected livers compared to HBV. 1 This macrovesicular fat accumulation represents a direct cytopathic effect of the virus on hepatocyte lipid metabolism. 1

Mallory body-like material in hepatocytes is seen exclusively in HCV infection with an odds ratio of 71.6, making it the most specific histological marker when present. 1 However, this feature is not consistently found in all HCV cases. 1

Hepatitis B-Specific Patterns

Ground-glass hepatocytes are the pathognomonic feature of HBV infection, representing cytoplasmic accumulation of HBsAg in hepatocytes. 3, 2 These cells appear with finely granular, eosinophilic cytoplasm and are found in 66.7% of isolated HBV infections. 3 This feature is absent in isolated HCV infection but may be present in coinfection. 2

Sanded nuclei (representing HBcAg accumulation) are characteristic of active HBV replication. 4 These appear as finely granular nuclear material on routine staining. 4

Shared Histological Features

Both HBV and HCV demonstrate similar patterns of:

• Interface hepatitis (periportal necroinflammation extending into the lobule) 5, 4
• Portal lymphoplasmacytic infiltration 5, 4
• Lobular necroinflammation with varying degrees of hepatocyte injury 4, 6
• Progressive fibrosis beginning in portal tracts and advancing to cirrhosis 5, 4

Critical Differences in Disease Progression

Hepatitis C represents a continuous disease process without distinct immunological phases, contrasting sharply with HBV's well-defined immune tolerance, immune clearance, low replication, and reactivation phases. 7, 8 This fundamental difference means HCV histology reflects ongoing chronic inflammation rather than phase-specific patterns seen in HBV. 7

HCV progresses to cirrhosis in 15-30% of patients over 20 years, with fibrosis advancing steadily regardless of aminotransferase levels. 8 In contrast, HBV patients in immune tolerance may show minimal histological changes despite high viral loads. 5

Coinfection Patterns

When HBV and HCV coexist, the histological picture becomes complex:

• More severe fibrosis develops compared to monoinfection (mean fibrosis score 2.1 vs 1.5 in HCV alone). 3
• Suppression of one virus typically occurs, with the dominant virus determining the predominant histological pattern. 3, 2
• Ground-glass hepatocytes appear less frequently (37% vs 66.7% in HBV monoinfection) due to HCV suppression of HBV replication. 3
• Both bile duct lesions and ground-glass hepatocytes may coexist, indicating dual infection. 2

Practical Diagnostic Algorithm

When evaluating liver histology for viral hepatitis:

1. Look for ground-glass hepatocytes first → if present, confirms HBV component 3, 2
2. Assess for bile duct damage → if present, strongly suggests HCV component 1
3. Identify lymphoid follicles → if present, favors HCV over HBV 2, 1
4. Evaluate steatosis pattern → large-droplet fat favors HCV 1
5. Search for Mallory body-like material → if present, virtually diagnostic of HCV 1

Critical Pitfalls to Avoid

Do not rely on necroinflammation severity alone to distinguish HBV from HCV—both can produce identical patterns of interface hepatitis and lobular injury. 2, 4 The specific cytopathic features (ground-glass cells, bile duct damage, lymphoid follicles) provide diagnostic specificity. 2, 1

Adequate tissue sampling is essential: at least 1.5 cm length with sufficient portal tracts (minimum 6-8) to accurately assess fibrosis stage and identify diagnostic features. 5 Inadequate samples may miss focal lesions like ground-glass hepatocytes or lymphoid follicles. 5

Normal aminotransferases do not exclude significant histological disease: 14-24% of HCV patients with persistently normal ALT have more-than-portal fibrosis on biopsy. 8 Similarly, HBV patients in immune tolerance may have normal ALT despite high viral loads and minimal inflammation. 5

Coinfection may mask typical features: when both viruses are present, viral suppression can reduce characteristic findings like ground-glass hepatocytes or detectable HCV RNA, making histological diagnosis more challenging. 3, 2