Natural history of chronic hepatitis B: Phases in a complex relationship

Table 2 Phases of disease in chronic hepatitis B

	Phase 1	Phase 2	Phase 3	Phase 4
	Immune tolerance	Immune clearance	Immune control	Immune escape
Serology	HBeAg positive	HBeAg positive	HBeAg negative	HBeAg negative
	HBeAb negative	HBeAb negative	HBeAb positive	HBeAb positive
ALT (IU/mL)	Persistently normal	Persistently or intermittently abnormal	Persistently normal	Persistently or intermittently abnormal
HBV DNA (IU/mL)	Very high (usually > 2 × 106-2 × 107)	High but less so than in Immune tolerant phase	< 2000 IU/mL (but up to 20000 IU/mL)	> 2000 IU/mL (fluctuating)
Liver histology	Normal or mild hepatitis	Moderate or severe necroinflammation and fibrosis	Normal or mild inflammation	Moderate to severe inflammation and fibrosis ± cirrhosis
Specific features	Age usually young (< 20-30 yr). Phase absent or very short in Mediterranean CHB	Intermittent flares or ongoing mild elevation of ALT. Ends with seroconversion to HBeAb positive state	May have serum HBsAg levels < 1000 IU/mL	Predominance of HBV with precore/basal core promotor mutations
Alternative nomenclature	Immunotolerant	HBeAg positive immune active (AASLD)/immune reactive HBeAg positive phase (EASL)	Inactive HBsAg carrier state (EASL and AASLD)/residual or inactive chronic HBV infection (APASL)	HBeAg negative CHB (EASL)/reactivation or relapse (APASL)

Adapted from Ref [33]. CHB: Chronic hepatitis B; AASLD: American Association of the study of liver diseases; EASL: European Association for the study of the liver; APASL: Asian Pacific Association for the study of the liver; ALT: Alanine aminotransferase; HBV: Hepatitis B virus; HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B e antigen.