Figure 6.

Computer modeling of the predicted emergence of hepatocyte clones in chronically HBV-infected human liver if all hepatocytes are able to proliferate (Model 4): Calculations were made using the program csize8, which was previously described [75]. This program calculates clone size assuming that all hepatocytes are able to proliferate, at random, to maintain liver mass, and that cells are killed at random, with the daily death rates as shown at the right (e.g., Kd = 0.001 means that 0.1% of hepatocytes die per day, and are replaced by compensatory proliferation of surviving hepatocytes). Liver size is assumed to increase 10-fold between birth and maturity at age 14. All hepatocytes (initially 800,000) are assigned unique identifies at birth. In one calculation, the hepatocyte death rate was assumed to be 10-fold lower (0.3% per day; Kd = 0.003) during the first 14 years than after age 14 (3.0% per day; Kd = 0.03). All curves are averages of 10 simulations, with output collected at yearly intervals. The horizontal bars show the geometric mean of maximum hepatocyte clone sizes observed using inverse-nested PCR assays for integrated HBV DNA in a study of three different groups of patients with chronic infection: immune tolerant (IT), immune active, HBeAg-positive (e(+)), and immune active, HBeAg-negative (e(-)) [75]. The bars span the ages covered by each group of patients. (A) Predicted maximum clone sizes, assuming 100% of hepatocytes had unique lineage-specific markers at birth. (B) Predicted maximum clone sizes if only 1.0% of hepatocytes had detectable lineage-specific markers (e.g., randomly integrated HBV DNA) at birth.