Immune Tolerant Chronic Hepatitis B: The Unrecognized Risks

Abstract

Chronic infection with hepatitis B virus (HBV) progresses through multiple phases, including immune tolerant, immune active, immune control, and, in a subset of patients who achieve immune control, reactivation. The first, the immune tolerant phase, is considered to be prolonged in duration but essentially benign in nature, lacking long-term consequences, and thus not recommended for antiviral therapy. This review challenges the notion that the immune tolerant phase is truly benign and considers the possibility that events during this phase may contribute significantly to cirrhosis, hepatocellular carcinoma (HCC), and the premature death of 25% of HBV carriers worldwide. Thus, earlier treatment than recommended by current guidelines should be considered. Low therapeutic coverage exacerbated by restrictive treatment guidelines may facilitate disease progression in many patients but also increase the risk of neonatal and horizontal transmission from untreated mothers to their children. While a prophylactic vaccine exists, there are many areas worldwide where the treatment of adults and the delivery of an effective vaccination course to newborns present difficult challenges.

Keywords: cirrhosis; hepatitis B; hepatocellular carcinoma; immune tolerant; inflammation; vaccine.

Figure 1

Age specific hepatocellular carcinoma (HCC) mortality in Taiwan. Adapted from Figure 2 of a paper by R.P. Beasley [31].

Figure 2

Incidence of HBeAg(−) patients among various age groups of HBsAg(+) Taiwanese males. Adapted from Table 2 of a paper by You et al. [32].

Figure 3

Predictions of hepatocyte clone size based on liver growth and hepatocyte turnover. Two models are compared, one assuming that all hepatocytes contribute to liver growth and hepatocyte turnover (consensus model) [80], the other assuming that proliferation is an exclusive property of hepatocytes surrounding the central vein [70]. In these simulations, hepatocyte clones develop beginning from birth. The liver linearly expands 10-fold in size over a period of 14 years. In both simulations, 0.15% of hepatocytes were replaced daily due to random cell death. Hepatocytes are uniquely marked at time zero to follow their loss and/or clonal expansion. Two FORTRAN computer models of the liver were compared; in the first (csize8), all hepatocytes participate in growth and replacement. In the second (ran-rep-c5), only central vein hepatocytes, considered to represent 1% of total hepatocytes, are able to divide. (Interestingly, if liver growth is not included, then the stem cell model, with 0.15% daily turnover, predicts 42% replacement of the liver with stem cell (central vein hepatocyte) daughters after a year, similar to experimental observations [70]). These FORTRAN models are available upon request from W.S.M. (ws_mason@fccc.edu) or S.L. (S_Litwin@fccc.edu). The right pointing arrow illustrates the average maximum clone size for IT patients ranging from 15 to 39 years of age; no age dependence was observed [63].