Mini Review

Effects of Endocrine on the Breakthrough of Immune-tolerant in Chronic Hepatitis B Virus Infected Children

Jia-Feng Wu1

1Departments of Pediatrics, National Taiwan University Children’s Hospital, Taipei, Taiwan.

Corresponding Author:Jia-Feng Wu, MD. PhD, Departments of Pediatrics, National Taiwan University Children’s Hospital, No.8, Chung-Shan S.Rd, Taipei, Taiwan,Tel: (886-2)-23123456;

  • Received Date: 18 Dec 2016   Accepted Date: 27 Dec 2016   Published Date: 29 Dec 2016
  • Copyright © 2016 Jia-Feng Wu

Citation: Jia-Feng Wu. (2016). Effects of Endocrine on the Breakthrough of Immune-tolerant in Chronic Hepatitis B Virus Infected Children. M J Pedi. 1(1): 006.


The hepatitis B virus (HBV) infection in endemic areas usually starts since infancy and early childhood and persists lifelong chronic infected status. The clinical course and severity varies among different chronic infected subjects, especially between different genders. Majority of chronic HBV infected children present with immune-tolerant status initially with normal liver profile, hepatitis Be antigen (HBeAg)-positive and high HBV viral load. They will then experience the immune clearance phase with various degree of liver injury at various age, and majority during or beyond puberty, and then enter the inactive phase after HBeAg seroconversion.
The adrenarche and puberty onset modulate the start of immune clearance and the severity of liver inflammation in chronic HBV infected children. The sex steroid then acts differently on the host immune system, viral replication and even tumor suppressive genes. The difference between males and females are associated with different risk of HBeAg-negative hepatitis, liver cirrhosis, and even the occurrence of hepatocellular carcinoma in later life. Early events in childhood during chronic HBV infection may serve as important predictors for the later outcoms in adulthood. Understanding the mechanisms triggering liver inflammation and their long-term impacts may enhance the development of better and earlier therapeutic strategies for patients with chronic HBV infection.


Adrenarche; Hepatitis B Virus; Immune-Tolerant; Immune Clearance; Menarche; Puberty; Endocrine System.


Alanine aminotransferase, ALT; deoxyribonucleic acid, DNA; dehydroepiandrosterone sulphate, DHEAS; hepatitis B virus, HBV; hepatitis B surface antigen, HBsAg; hepatitis B e antigen, HBeAg; hepatitis B core antigen, HBcAg; hepatitis B X protein, HBx; hepatocellular carcinoma, HCC


Human hepatitis B virus (HBV) remains the leading cause of liver insufficiency, liver cirrhosis, and even hepatocellular carcinoma in the world [1]. HBV belong to hepadna virus, which is a small enveloped virus with partially double stranded circular deoxyribonucleic acid (DNA) that replicate by reverse transcription in human hepatocytes [2] The partial double stranded circular viral DNA is then converted to a covalently closed circular DNA (cccDNA) that serve as the transcriptional template for pre-genomic ribonucleic acid (RNA) and messenger RNA (mRNA) for hepatitis B surface antigen (HBsAg), hepatitis B e antigen / core antigen (HBeAg / HBcAg), polymerase, and X protein (HBx) [3].
The clinical course of chronic HBV infection is diverse among individuals with different host genetic background, viral strains, and host-viral interactions. The HBV acquisition age is known to associate with the chronicity of viral infection [4-6]. In endemic areas, such as Taiwan, perinatal infection account for 90% of the cases of chronic HBV infection after the universal HBV vaccination program [7]. The natural course of chronic HBV infection was generally sub-divided into immune-tolerant, immune clearance/inflammatory, post HBeAg seroconversion inactive phases. Up to 10-25% of the infected subjects were expected to suffer from HBeAg-negative hepatitis reactivation phase, and even develop liver cirrhosis or hepatocellalar carcinoma (HCC) [8, 9]. Very minority of chronic HBV infected subjects may develop HBsAg seroconversion, and get rid off chronic infected status. The immune-tolerant phase is indicated by normal alanine aminotransferase (ALT) levels, high HBV viral load, and HBeAg-positivity. In majority of the patients during or after the adolescent stage, the flare of ALT and the HBeAg seroconversion to its antibody (Anti-HBe) indicate the immune clearance phase. HBeAg seroconversion generally indicates the decrement of active viral replication and hepatitis activity, while delayed HBeAg seroconversion with persistently high viremia after the 3rd decade of life indicates a higher risk of developing liver cirrhosis, and hepatocellular carcinoma (HCC) [10-14].


The triggering host factors to terminate the immune-tolerant phase, shortening of the period of high viremia, modulating the course of immune-clearance are the key determinants to the life-long risk of liver injuries, liver cirrhosis and HCC. This article aimed to review the roles of human endocrine system on the breakthrough of immune-tolerant phase in chronic HBV infected children

Nature course of the breakthrough of immune-tolerant

From a long-term chronic HBV cohort study, the spontaneous HBeAg seroconversion rate was low before 10 years of age, and accelerated since the second decade of life [15]. The annual spontaneous HBeAg seroconversion rate was 1.70% (95% CI = 0.43%–2.97%) in the first decade of life, 3.78% (95% CI = 2.61%–4.94%) in the second decade of life, and 4.02% (95% CI = 1.61%–6.23%) in the third decade of life in genotype B and C chronic HBV infected patients [15]. The serum alanine transaminase (ALT) level elevated to above 30 IU/L, predict the occurrence of HBeAg seroconversion, indicating the breakthrough of immune tolerant. The annual spontaneous HBeAg seroconversion rate in the first decade of life is significantly lower than that in the second and third decade of life in the study. These data indicated that the breakthrough of immune tolerance in chronic HBV infected children is around the peripuberty period.

Effect of Puberty and androgen

In chronic HBV infected males, earlier puberty onset and increased steroid 5-alpha reductase type II (SRD5A2) enzyme activity are reported to associate with earlier HBeAg seroconversion [16]. Testosterone secretion in men increases beginning at the onset of puberty with the peak serum level occurring during their 20s, and then declines gradually after the 3rd decade of life with decreases of roughly 10% per decade thereafter.
In a chronic genotypes B and C HBV infected Taiwanese male cohort (mean enrollment age at 6.8±1.6 years and the mean follow-up duration of 16.8±3.4 years), earlier-onset puberty had higher serum testosterone levels than subjects with later- onset puberty in Taiwanese males at the age of 15 and 20 years [16]. In the survival analysis to assess the difference in spontaneous HBeAg seroconversion age, subjects with earlier- onset puberty had a younger spontaneous HBeAg seroconversion age than those with later-onset puberty (median age, 13.2 vs. 22.5 years, HR, 3.0; P, 0.005) [16]. The decrement in the HBV viral load from puberty to young adulthood was significantly higher in the subjects with earlier-onset puberty than those with later-onset puberty males (earlier vs. lateronset puberty: 1.6±0.3 vs. 0.2±0.4 log10copies/mL HBV viral load decrement from 15 to 20 years of age, P=0.01) [16].

Effect of Puberty and Menarche

From a chronically genotypes B and C HBV-infected Taiwanese young female cohort (mean enrollment was 4.6 ± 3.1 years and the mean follow-up duration was 24.0 ± 3.8 years), earlier menarche in females, also indicating earlier puberty-onset, is also associated with earlier HBeAg seroconversion in Taiwanese female subjects with chronic HBV infection [17].
The annual decrease in HBsAg titer from 15 to 20 years of age also was greater in the early menarche group compared with the late menarche group. The baseline HBV viral load was also borderline low in female subjects with earlier menarche as compared with others (6.10 ± 2.29 vs. 7.02 ± 1.89 log10 copies/ mL; 95% CI = 5.06 - 7.15 vs. 6.60-7.44 log10 copies/mL; P = 0.06). Earlier menarche onset was associated with higher spontaneous HBeAg seroconversion, HBsAg seroclearance, and HBsAg seroconversion rate before 15 years of age in females with chronic HBV infection [17].

Roles and Adrenarche and Dehydroepiandrosterone sulphate (DHEAS)

The clinical courses of infection with various pathogens differ greatly between males and females; the difference is thought to result from cross-talk between different sex steroids and immune effectors [18, 19]. The main sex steroids at puberty are testosterone and estradiol in male and female subjects, respectively. Animal studies showed the androgen pathway can increase HBV transcription, while the estrogen pathway may repress the efficacy of HBV genes transcription [20-22]. Hence, the association of puberty onset in both genders with the breakthrough of immune tolerance may not be answered by the sex steroids alone.19,20 Other hormone factors other than sex steroids and common to both genders, acting during or even before the peri-puberty period, may contribute to the termination of immune tolerant phase [23].
DHEAS, a adrenarche marker, generally elevated 2 years before puberty is significantly associated with the age of HBeAg seroconversion in both genders [23]. The elevation of serum DHEAS is generally between 6-8 years of age in both genders, and peaks at the third decade of life [24, 25]. The pattern is quite similar to the immune breakthrough age in chronic HBV infected patients. The DHEAS, itself, is regarded as a potent immune modulator in human immune responses to various infectious pathogens [26-29]. Hence, the DHEAS may serve as a cross-talk window between human endocrine and immune systems. Higher serum DHEAS levels at mid-puberty was further showed to predict higher decay rate of HBV viral load and HBsAg titer from mid-puberty to young adulthood [23].
Although the immune factors play the key roles during the long-term host-viral interaction, inflammatory intensity, and immune escape HBV mutant strains selection [30-37]. The endocrine factors, particularly the DHEAS, change with the onset of adrenarche may be partially responsible for the breakthrough of immune tolerant, initiation of immune clearance in chronic HBV infection patients.

Effect of endocrine systems and early events on late clinical courses

HBeAg seroconverters in a pediatric cohort showed persist low HBV viral loads, normal ALT, and uneventful courses after HBeAg seroconversion [38]. However, HBeAg seroconversion beyond the 3rd to 4th decade of life in adults is associated with increased risk of increased HBV viral load, HBeAg-negative hepatitis flare, liver cirrhosis and even HCC [13, 14]. Hence, different endocrine trigger, immune mechanism and possible different HBV mutants selected during the immune clearance phase between young and old HBeAg seroconverters may results in different clinical courses and life-long outcomes.
From our cohort constitute 434 subjects [spontaneous HBeAg-seroconversion occurred in 359 subjects, and 75 subjects developed HBeAg-seroconversion after antiviral therapy followed for a median of 14.40 years (IRQ: 6.14–22.02 years) after HBeAg-seroconversion], gender was demonstrated to be a key determinant of the HBeAg-negarive hepatitis risk after HBeAg seroconversion (Hazard ratio = 3.15; 95% CI = 1.06- 9.32; P = 0.04) [39]. The relative risk of HBV-related HCC and liver disease related death are consistently several fold (1.5- 7.6 times) higher in males than females [40-42]. Our previous study also demonstrated the severity of liver inflammation is closely associated with the serum testosterone levels in chronic HBV infected males [16]. The different outcomes between chronic HBV infected males and females are closely related to the effect of sex steroids on HBV biosynthesis [20-22].
The HBeAg seroconversion age and the severity of liver damage during the immune clearance phase are both important outcome determine factors during the natural course of chronic HBV infection. Extremely early HBeAg seroconversion before 3 years of age with severe liver damage was noted to increase the risk of childhood HCC [43,44]. While the HBeAg seroconversion during childhood without severe liver damage have been demonstrated to associate with a relatively uneventful course with low viremia profile, lower incidence of hepatitis reactivation after HBeAg seroconversion, and higher chance of spontaneous HBsAg seroconversion.38,39 Recently, we demonstrated earlier breakthrough of immune-tolerance and earlier HBeAg seroconversion in children indicating lower risk of HBeAg negative hepatitis and higher chance of spontaneous HBsAg seroconversion in later life [39,45].


The HBV infection in endemic area mostly occurred in infant, and resulted in chronic HBV infected status. The viral factors, host factors, and host-virus interactions performed as an orchestra, and acting together to modulate the natural course of chronic HBV infection. The early events of chronic HBV infection occurring during childhood, reflecting the complex interactions between the host and virus, are key earlier predictors of the life-long outcomes of chronic HBV infection. Realizing the relevant host and viral factors, and providing early and effective intervention may improve the long-term outcome of chronic HBV infected patients.


  1. Beasley RP, Hwang LY, Lin CC, Chien al. (1981). Hepatocellular carcinoma and hepatitis B virus: a prospective study of 22,707 men in Taiwan. Lancet. 2, 1129-33.
  2. Ganem D and Varmus HE. (1987). The molecular biology of the hepatitis B virus. Annual Review of Biochemistry. 56, 651-693.
  3. Tuttleman JS, Pugh JC and Summers JW. (1986). In vitro experimental infection of primary duck hepatocyte cultures with duck hepatitis B virus. J Virol. 58, 17-25.
  4. Stevens CE, Beasley RP, Tsui J and Lee WC. (1975). Vertical transmission of hepatitis B antigen in Taiwan. N Engl J Med. 292(15), 771-774.
  5. Lok AS and McMahon BJ. (2007). Chronic hepatitis B. Hepatology. 45(6), 507-539.
  6. Beasley RP. (2009). Rocks along the road to the control of HBV and HCC. Ann Epidemiol. 19(4), 231-234.
  7. Ni YH, Huang LM, Chang MH, Yen CJ, et al. (2007). Two decades of universal hepatitis B vaccination in Taiwan: impact and implication for future strategies. Gastroenterology. 132(4), 1287-1293.
  8. Chen DS. (1993). From hepatitis to hepatoma: lessons from type B viral hepatitis. Science. 262(5132), 369-370.
  9. Kao JH and Chen DS. (2002). Global control of hepatitis B virus infection. Lancet Infect Dis. 2(7), 395-403.
  10. Chu CM, Hung SJ, Lin J, Tai DI, et al. (2004). Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels. Am J Med. 116(12), 829-834.
  11. Chu CM and Liaw YF. (2007). Chronic hepatitis B virus infection acquired in childhood: special emphasis on prognostic and therapeutic implication of delayed HBeAg seroconversion. J Viral Hepat. 14(3), 147-152.
  12. Yang HI, Lu SN, Liaw YF, You SL, et al. (2002). Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med. 347(3), 168-174.
  13. Chang ML and Liaw YF. (2014). Hepatitis B flares in chronic hepatitis B: Pathogenesis, natural course, and management. J Hepatol. 61(6), 1407-1417.
  14. Chen YC, Chu CM and Liaw YF. (2010). Age-specific prognosis following spontaneous hepatitis B e antigen seroconversion in chronic hepatitis B. Hepatology. 51(2), 435-444.
  15. Wu JF, Su YR, Chen CH, Chen HL, et al. (2012). Predictive effect of serial serum alanine aminotransferase levels on spontaneous HBeAg seroconversion in chronic genotypes B and C HBVinfected children. J Pediatr Gastroenterol Nutr. 54(1), 97-100.
  16. Wu JF, Tsai WY, Hsu HY, Ni YH, et al. (2010). The effect of puberty onset on spontaneous hepatitis B virus e antigen seroconversion in men. Gastroenterology. 138(3), 942-948.
  17. Wu JF, Tsai WY, Tung YC, Chen HL, et al. (2014). Effect of menarche onset on the clinical course in females with chronic hepatitis B virus infection. J Pediatr. 165(3), 534-538.
  18. Schuurs AH and Verheul HA. (1990). Effects of gender and sex steroids on the immune response. J Steroid Biochem Mol Biol. 35(2), 157-172.
  19. Guerra-Silveira F and Abad-Franch F. (2013). Sex bias in infectious disease epidemiology: patterns and processes. PLoS One. 8, e62390.
  20. Wang SH, Yeh SH, Lin WH, Wang HY, Chen DS, Chen PJ. (2009). Identification of androgen response elements in the enhancer I of hepatitis B virus: a mechanism for sex disparity in chronic hepatitis B. Hepatology. 50(5), 1392-1402.
  21. Chen PJ, Yeh SH, Liu WH, Lin CC, et al. (2012). Androgen pathway stimulates microRNA-216a transcription to suppress the tumor suppressor in lung cancer-1 gene in early hepatocarcinogenesis. Hepatology. 56(2), 632-643.
  22. Wang SH, Yeh SH, Lin WH, Yeh KH, et al. (2012). Estrogen receptor a represses transcription of HBV genes via interaction with hepatocyte nuclear factor 4a. Gastroenterology. 142(4), 989-998.
  23. Wu JF, Tsai WY, Tung YC, Chen HL, et al. (2014). Role of serum dehydroepiandrosterone sulfate level on the clearance of chronic hepatitis B virus infection. J Gastroenterol. 49(5), 900-906.
  24. Nawata H, Yanase T, Goto K, Okabe T, et al. (2004). Andropause. Horm Res. 62(3), 110-114.
  25. Hazeldine J, Arlt W and Lord JM. (2010). Dehydroepiandrosterone as a regulator of immune cell function. J Steroid Biochem Mol Biol. 120(2-3), 127-136.
  26. de la Torre B, vonKrogh G, Svensson M, and HolmbergV. (1997). Blood cortisol and dehydroepiandrosterone sulfate (DHEAS) levels and CD4 T cell counts in HIV infection. Clin Exp Rheumatol.15(1), 87-90.
  27. Chittiprol S, Kumar AM, Shetty KT, Kumar HR, et al. (2009). HIV-1 clade C infection and progressive disruption in the relationship between cortisol, DHEAS and CD4 cell numbers: a two-year follow-up study. Clin Chim Acta. 409(1-2), 4-10.
  28. Bertoni R, Sidney J, Fowler P, Chesnut RW, et al. (1997). Human histocompatibility leukocyte antigen-binding supermotifs predict broadly cross-reactive cytotoxic T lymphocyte responses in patients with acute hepatitis. J Clin Invest. 100(3), 503-513.
  29. Kutlu NO, Akinci A, So¨nmezgo¨z E, Temel I, et al. (2003). The effects of androstenediol and dehydroepiandrosterone on the immune response to BCG at puberty. J Trop Pediatr. 49(3), 181-185.
  30. Thursz MR, Kwiatkowski D, Allsopp CE, Greenwood BM, et al. (1995). Association between an MHC class II allele and clearance of hepatitis B virus in the Gambia. N Engl J Med. 332(16), 1065-1069.
  31. Nishida N, Sawai H, Matsuura K, Sugiyama M, et al. (2012). Genome-wide association study confirming association of HLA-DP with protection against chronic hepatitis B and viral clearance in Japanese and Korean. PLoS One. 7(6), e39175.
  32. Wu JF, Chen CH, Hsieh RP, Shih HH, et al. (2006). HLA typing associated with hepatitis B e antigen seroconversion in children with chronic hepatitis B virus infection: a prospective sibling cohort study in Taiwan. J Pediatr. 148(5), 647-651.
  33. Kao PC, Wu JF, Ni YH, Lin YT, et al. (2010). Tumour necrosis factor-a promoter region polymorphisms affect the course of spontaneous HBsAg clearance. Liver Int. 30(10), 1448-1453.
  34. Wu JF, Wu TC, Chen CH, Ni YH, et al. (2010). Serum levels of interleukin 10 and 12 predict early, spontaneous hepatitis B virus e antigen seroconversion. Gastroenterology. 138(1), 165-172.
  35. Wu JF, Chen CH, Ni YH, Lin YT, et al. (2012). Toll-like receptor and hepatitis B virus clearance in chronic infected patients: a long-term prospective cohort study in Taiwan. J Infect Dis. 206(5), 662-668.
  36. Wu JF, Hsu HY, Ni YH, Chen HL, et al. (2012). Suppression of furin by interferon-? and the impact on hepatitis B virus antigen biosynthesis in human hepatocytes. Am J Pathol. 181(1), 19-25.
  37. Wu JF, and Chang MH. (2015). Natural history of chronic hepatitis B virus infection from infancy to adult life -the mechanism of inflammation triggering and long-term impacts. J Biomed Sci. 22:92.
  38. Ni YH, Chang MH, Wang KJ, Hsu HY, et al. (2004). Clinical relevance of hepatitis B virus genotype in children with chronic infection and hepatocellular carcinoma. Gastroenterology. 127(6), 1733-1738.
  39. Wu JF, Chiu YC, Chang KC, Chen HL, et al. (2016). Predictors of hepatitis B e antigen-negative hepatitis in chronic hepatitis B virus infected patients from childhood to adulthood. Hepatology. 63(1), 74-82.
  40. Lee CM, Lu SN, Changchien CS, Yeh CT, et al. (1999). Age, gender, and local geographic variations of viral etiology of hepatocellular carcinoma in a hyperendemic area for hepatitis B virus infection. Cancer. 86(7), 1143-1150.
  41. Evans AA, Chen G, Ross EA, Shen FM, et al. (2002). Eightyear follow-up of the 90000-person Haimen city cohort: I. hepatocellular carcinoma mortality, risk factors, and gender differences. Cancer Epidemiol Biomarkers Prev . 11(4), 369-376.
  42. Chang MH, Shau WY, Chen CJ, Wu TC, et al. (2000). Hepatitis B vaccination and hepatocellular carcinoma rates in boys and girls. JAMA . 284(23), 3040-3042.
  43. Tseng YR, Wu JF, Kong MS, Hu FC, et al. (2014). Infantile hepatitis B in immunized children: risk for fulminant hepatitis and long-term outcomes. PLoS One. 9(11), e111825.
  44. Chang MH, Hsu HY, Hsu HC, Ni YH, et al. (1995). The significance of spontaneous hepatitis B e antigen seroconversion in childhood: with special emphasis on the clearance of hepatitis B e antigen before 3 years of age. Hepatology. 22(5), 1387-1392.
  45. Wu JF, Hsu HY, Chiu YC, Chen HL,et al. (2015). The effects of cytokines on spontaneous hepatitis B surface antigen seroconversion in chronic hepatitis B virus infection. J Immunol. 194(2), 690-696.

Jia-Feng Wu. (2016). Effects of Endocrine on the Breakthrough of Immune-tolerant in Chronic Hepatitis B Virus Infected Children. M J Pedi. 1(1): 006.