Phenotypic and Genotypic Differences Between a Child With Vertically Acquired Severe Hepatitis C Liver Disease and His Mother

This is the authors' abstract. We don't add key points for this paper.

Liver transplantation for end-stage liver disease secondary to chronic hepatitis C (CHC) in children is rare. According to the United Network for Organ Sharing, 133 subjects younger than 22 years have undergone liver transplantation for CHC in the United States from January 1988 to November 2009 (1); survival rates are lower than rates for other conditions, primarily because of recurrent CHC (2). Host and viral factors responsible for recurrent CHC after orthotopic liver transplant are not well studied in children. We report a case of a pediatric patient with vertically transmitted CHC who presented with end-stage liver disease and underwent a living-related liver transplant from his hepatitis C virus (HCV)–infected mother with mild disease. The present case offered a unique opportunity to characterize phenotypic and genotypic differences in HCV between the mother and her child. A 5½-year-old white boy presented to the clinic with liver failure and portal hypertension secondary to CHC, having failed antiviral therapy with α-interferon. Extensive workup failed to reveal any comorbid conditions. The mother was a 40-year-old white woman with bipolar affective disorder who was in stable condition under psychiatric care. The mother had lost her only other child from causes unrelated to HCV (severe congenital heart disease) and was greatly motivated to donate her liver. At approximately age 14 years, she had acquired HCV (genotype 1) from injection drug use, but drug testing had been repeatedly negative for 17 years. She had no clinical or biochemical signs of liver disease, despite having been infected with HCV for approximately 26 years. Given the unusual nature of the request, the case was extensively reviewed by both our adult and pediatric liver transplant teams and the ethics committee of the hospital. Our consensus was that the mother's HCV virus had been tolerated by her for 26 years without clinical evidence of liver disease. We presumed that the child (like almost all of the recipients undergoing liver transplantation for HCV) would experience universal recurrence of the infection that he had acquired from his mother (whether he received her liver or a cadaveric HCV-negative liver); therefore, there was no precedent for believing that his course would have been any worse with use of the mother's liver. The child underwent living-related liver transplantation from his mother at age 5 years. A biopsy of her liver at the time of donation was consistent with mild CHC (Fig. 1A and B). The child's liver explant showed established cirrhosis (Fig. 1C). HCV RNA was detected in the child's plasma 15 months postoperation, and he was then treated with α-interferon and acyclovir because it was a common practice at that time (3). Liver biopsy at 10 and 13 months posttransplant showed mild chronic hepatitis consistent with CHC (Fig. 1D and E). The child was admitted for acute hepatic decompensation secondary to recurrent CHC at 7 years of age, 1.5 years after his first transplant, and received a second liver transplant (cadaveric, orthotopic). The liver explant showed established cirrhosis with mild to moderate ongoing portal and septal chronic inflammation. The posttransplant period was complicated by recurrent CHC and liver failure, necessitating a third orthotopic liver transplant at 8 years of age. The liver explant showed early cirrhosis (Fig. 1F). The child died of hemorrhagic shock secondary to gastrointestinal bleeding 2 months after his third transplant, <3 years after his initial transplant.FIGURE 1: A, The donor liver from the mother showed mild to moderate portal chronic inflammation at frozen section. A portal tract with moderate portal chronic inflammation is shown (hematoxylin and eosin, original magnification ×64). B, The donor liver from the mother showed mild lobular chronic inflammation (hematoxylin and eosin, original magnification ×64). C, The native liver of the child showed established cirrhosis with mild ongoing portal and septal chronic inflammation (hematoxylin and eosin, original magnification ×40). D, A liver biopsy at 13 months posttransplant showed generally mild to focally moderate portal chronic inflammation (hematoxylin and eosin, original magnification ×100). E, The 13-month posttransplant liver biopsy also showed mild diffuse lobular hepatitis (hematoxylin and eosin, original magnification ×100). F, The second explanted liver showed early cirrhosis. An area with marked bridging fibrosis and developing nodularity is shown (Masson Trichrome stain, original magnification ×20).SERUM SAMPLES Serum samples were obtained from the child 18 months after the initial liver transplant, when he was experiencing severe recurrent CHC, and from the mother 15 months after the initial liver transplant, after she provided written informed consent for serum samples to be obtained via a protocol approved by the Johns Hopkins institutional review board. Samples were analyzed by reverse transcriptase-polymerase chain reaction, sequencing, and quasispecies in the hypervariable region 1 (HVR1), as previously described (4). Analyses of Quasispecies No nucleotide or amino acid variations were found in the 18 clones of the HVR1 region of HCV present in the serum of the child (online-only supplemental Figures 1 [https://links.lww.com/MPG/A62] and 2 [https://links.lww.com/MPG/A63] and Table 1). On the contrary, 3 quasispecies at the nucleotide level were found in the 19 clones of the HVR1 region of HCV in the mother's serum (Table 1); however, these 3 variants represented synonymous nucleotide mutations that did not change the amino acid sequence of HVR1. In HVR1, there were no identical clones at the nucleotide or amino acid level observed between child and mother (supplemental Figures 1 and 2).TABLE 1: Quasispecies in the hypervariable region of E2There are 3 basic residues, H, R, and K, in the consensus sequence of HVR1. Based on the reference patterns of basic residues in HVR1 previously reported for HCV genotypes (5), the sequence for the child had an “f” pattern (basic residues in position 3, 11, 14, 25) (supplemental Figure 1). Interestingly, the sequence of HVR1 in the circulating virus of the mother had basic residues in position 3, 14, 25, which is different from the most commonly reported pattern of HVR1. The quasispecies analysis suggests a divergence of the child's virus from that of the mother. Although evolution of quasispecies is known to progress in children who acquire HCV from their mother, the few studies that address this question suggest that usually some sequences remain identical between mother and child. For example, in the report of 2 HCV-infected mother–infant pairs by Ishii et al (6), the sequence identity at 7 to 10 years of age with the mothers was 69.3% to 90.7% for nucleotides. The significance of the divergence of our patient's HVR1 sequence from that of his mother is unknown, but it is possible that the child's quasispecies was more virulent, possibly because of the basic amino acids (5) and/or that the innate immunologic systems in mother and child were strikingly different. Because of the relatively small number of clones sequenced, the use of a pair of samples from a single time point, and the relatively low viral loads detected in these samples, it is highly likely that minor quasispecies have been missed in our analysis; however, the low HCV genetic diversity in our patient seems to be consistent with observations of others reporting much less viral diversity in immunosuppressed liver transplant recipients compared with patients with CHC (7–11). We present this report hoping that it will stimulate further investigations of the role of viral evolution in the severity of vertically transmitted HCV. For example, the application of more sensitive sequencing strategies such as 454 deep sequencing may be required to shed further light on the evolution of HCV in the setting of vertical transmission (12).