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Journal of Peking University (Health Sciences) ›› 2022, Vol. 54 ›› Issue (5): 920-926. doi: 10.19723/j.issn.1671-167X.2022.05.019

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Natural history and disease progression of chronic hepatitis B virus infection

Lei-jie WANG1,Ming-wei LI2,Yan-na LIU1,Xiang-mei CHEN1,Jing-min ZHAO3,Shu-hong LIU3,*(),Feng-min LU1,4,*()   

  1. 1. Department of Microbiology & Infectious Disease Center, Peking University School of Basic Medical Sciences, Beijing 100191, China
    2. Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, China
    3. Department of Pathology and Hepatology, Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing 100039, China
    4. Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Disease, Peking University People's Hospital, Beijing 100044, China
  • Received:2022-07-04 Online:2022-10-18 Published:2022-10-14
  • Contact: Shu-hong LIU,Feng-min LU E-mail:18511862409@163.com;lu.fengmin@hsc.pku.edu.cn
  • Supported by:
    the Beijing Natural Science Foundation(7212063)

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Abstract:

Objective: To better understand and revise the natural history and disease progression of chronic hepatitis B virus (HBV) infection through analysis of a single-center large-scale cohort of indivi-duals with chronic HBV infection. Methods: Patients with chronic HBV infection who had undergone liver biopsy in the Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital from January 2014 to October 2020 were retrospectively recruited. Based on patient's hepatitis B e antigen (HBeAg) states and pathologic diagnosis, they were categorized into four disease progression statuses (or phases according to the old-terminology in the updated guidelines of chronic hepatitis B (CHB), such as European Association for the Study of the Liver (EASL) 2017, Clinical Practice Guidelines on the Management of Hepatitis B Virus Infection: HBeAg-positive chronic HBV infection (immune tolerance), HBeAg-positive CHB (immune active HBeAg positive), HBeAg-negative chronic HBV infection (inactive carrier), and HBeAg-negative CHB (immune reactive HBeAg negative). Then the demographic, laboratory tests and liver histological results of the patients in different disease progression stages were compared. Age differences between the two groups were evaluated using Mann-Whitney U test. Results: A total of 760 eligible patients with a median age of 29 (interquartile range: 16-39) years were enrolled. Among them, 197 were underage individuals (age < 18 years) and 563 were adults; and 456 were males and 304 females. According to the pathological diagnosis, the patients were classified, and in each of the above four natural disease phases there were 173, 329, 95, and 163 individuals, respectively. Further comparison of the ages of the patients of the four disease progression statuses revealed that patients of HBeAg-negative CHB had a median age at 37 years, which was reasonably higher than those with HBeAg-positive CHB in immune active phase (37 vs. 24 years, P < 0.001), but was relatively younger than those with HBeAg-negative chronic HBV infection (37 vs. 39 years, P= 0.240). Conclusion: According to this study, it could be speculated that HBeAg-negative CHB patients probably not all reactivate from individuals of HBeAg-negative chronic HBV infection. Instead, certain HBeAg-negative CHB patients may also come from HBeAg-positive CHB patients who have undergone HBeAg clearance or seroconversion and still remain in the immune active state.

Key words: Chronic hepatitis B, Natural history, Hepatitis B e antigen

CLC Number: 

  • R373.2

Table 1

Clinical characteristics of HBeAg-positive and HBeAg-negative patients"

Items HBeAg positive(n=502) HBeAg negative(n=258) P value
Age/yearsa 25 (11, 33) 39 (30, 46) < 0.001
Gender，n(%)
  Male, 307 (61.2) 149 (57.8)
  Female 195 (38.8) 109 (42.2) 0.364
Serum indicators of virological
  HBV DNA/(lg IU/mL)a 7.95 (7.16, 8.34) 3.50 (2.57, 4.68) < 0.001
  HBsAg/(lg IU/mL)a 4.26 (3.79, 4.68) 3.32 (2.76, 3.68) < 0.001
Serum biochemical indicators
  ALT/(U/L)a 72 (37, 170) 27 (17, 52) < 0.001
  AST/(U/L)a 53 (31, 105) 26 (20, 41) < 0.001
  ALP/(U/L)a 100 (73, 228) 77 (63, 98) < 0.001
  GGT/(U/L)a 20 (14, 38) 20 (14, 29) 0.121
Serum indicators of liver function
  ALB/(g/L)a 41 (38, 43) 42 (40, 44) < 0.001
  PA/(mg/L)b 166±50 197±52 < 0.001
  PT/sa 11 (11, 12) 11 (11, 12) 0.025
  PLT/(×109/L)a 210 (177, 254) 186 (154, 224) < 0.001
Histological assessment
  Inflammation Grade, n (%)c
    G0-G1 228 (45.4) 182 (70.5)
    G2-G4 274 (54.6) 76 (29.5) < 0.001
  Fibrosis stage, n (%)c
    S0-1 260 (51.8) 107 (41.5)
    S2-4 242 (48.2) 151 (58.5) 0.007

Table 2

Information and clinical characteristics of patients at different stages of chronic hepatitis B virus infection disease progression"

Stages HBeAg positive HBeAg negative P value
Chronic HBV carrier statusa(n=173) Chronic hepatitisb(n=329) Inactive HBsAg carrier statusc(n=95) Chronic hepatitisd(n=163)
Age/yearse 25 (11, 34)△▲ 24 (12, 33)△▲ 39 (32, 47)*# 37 (29, 46)*# < 0.001
Gender, n(%)f
  Male, 106 (61.3) 201 (61.1) 53 (55.8) 96 (58.9) 0.785
  Female 67 (38.7) 128 (38.9) 42 (44.2) 67 (41.1)
Serum indicators of virological
  HBV DNA/(lg IU/mL)e 8.00 (7.56, 8.54)#△▲ 7.77 (6.89, 8.24)*△▲ 3.12 (2.40, 4.00)*# 3.97 (2.72, 5.32)*# < 0.001
  HBsAg/(lg IU/mL)e 4.61 (4.06, 4.85)#△▲ 4.09 (3.66, 4.52)*△▲ 3.21 (2.60, 3.60)*# 3.39 (2.95, 3.72)*# < 0.001
Serum biochemical indicators
  ALT/(U/L)e 41 (25, 65)#△ 112 (50, 263)*△▲ 22 (16, 38)*▲ 31 (20, 71)#△ < 0.001
  AST/(U/L)e 32 (24, 49)#△ 77 (40, 149)*△▲ 23 (19, 30)* #▲ 30 (21, 52)#△ < 0.001
  ALP/(U/L)e 89 (66, 211)#△▲ 108 (78, 235)*△▲ 75 (61, 91)* # 79 (64, 103)*# < 0.001
  GGT/(U/L)e 15 (12, 20)#▲ 29 (16, 51)*△▲ 17 (13, 24)#▲ 21 (15, 38)*#△ < 0.001
Serum indicators of liver function
  ALB/(g/L)e 41 (38, 44) 40 (38, 43)△▲ 43 (40, 45)# 42 (39, 44)# < 0.001
  PA/(mg/L)g 195±46#△ 151±46*△▲ 215±48*#▲ 187±52#△
  PT/se 11.1 (10.6, 11.7)# 11.4 (10.8, 11.9)*△ 10.8 (10.3, 11.4)#▲ 11.3 (10.7, 11.9)△ < 0.001
  PLT/(×109/L)e 218 (190, 260)△▲ 206 (172, 252)▲ 196 (164, 234)* 180 (145, 220)*#
Histological assessment
  Inflammation grade, n (%)f
    G0-G1 173 (100.0) 55 (16.7) 95 (100.0) 87 (53.4)
    G2-G4 0 (0.0) 274 (83.3) 0 (0.0) 76 (46.6)
  Fibrosis Stage, n (%)f
    S0-1 173 (100.0) 87 (26.4) 95 (100.0) 12 (7.4)
    S2-4 0 (0.0) 242 (73.6) 0 (0.0) 151 (92.6)

Figure 1

Schematic diagram of modified natural history of chronic hepatitis B virus infection in Guidelines for the Prevention and Treatment of Chronic Hepatitis B (version 2019) HBeAg, hepatitis B e antigen; HBV DNA, hepatitis B virus deoxyribonucleic acid; ALT, alanine aminotransferase; ULN, upper limit of normal."

Table 3

Characteristics of modified natural history of chronic hepatitis B virus infection in Guidelines for the Prevention and Treatment of Chronic Hepatitis B (version 2019)"

Clinical characteristics/immune status Immune tolerant phase Immune clearance phase Immune control phase Reactivation phase
Modified corresponding staging HBeAg positive chronic HBV carrier status a HBeAg positivechronic hepatitis HBeAg negativechronic hepatitis Inactive HBsAg carrier status b HBeAg negative or positive chronic hepatitisc
HBeAg + + - - +/-
ALT Normal Intermittently or persistently elevated Intermittently or persistently elevated Normal Intermittently or persistently elevated
Histological assessment None/minimal inflammation and fibrosis Moderate to severe inflammationc/fibrosis or cirrhosis Moderate to severe inflammation/fibrosis or cirrhosisc None/minimal inflammation and fibrosis Moderate to severe inflammation/fibrosis or cirrhosisc
HBV DNA High Moderate to high Low Low or undetectable Elevated
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