Sporadic vs. posttransfusion hepatitis C: Why the differences?

October

1991

advanced liver disease usually tolerate interferon alfa poorly, pretransplant administration may not be feasible. Another potential problem with the use of interferon alfa in transplant recipients is that enhancement of HLA expression on hepatocytes by interferon (Hepatology 1986;6:1038-1041) could precipitate graft rejection, although this does not appear to be a problem outside the immediate posttransplant period (Semin Liver Dis 1989;9:267-272). Thus, at present the role of interferon alfa, if any, in transplant recipients with hepatitis B needs to be clarified further. There is more experience with the use of HBIg immunoprophylaxis in transplant recipients with hepatitis B, although no randomized controlled trials have been performed to evaluate this method of preventing HBV reinfection. There is a widespread clinical impression that HBIg in doses sufficient to maintain serum antiHBs concentrations of 2 100 W/L may have some efficacy. Because previous attempts with short-term HBIg immunoprophylaxis had resulted in failure to prevent reinfection (Transplant Proc 1987;19: 2387-2389), Lauchart et al. (Transplant Proc 1987;5:4051-4053) studied the use of long-term prophylaxis with HBIg for up to 6 months after transplantation. Four serum HBV DNA-negative patients who received this longer regimen successfully cleared hepatitis B infection and remained uninfected without HBIg during the subsequent follow-up period of up to 6 months, but in two of three HBV DNA-positive patients, HBV infection recurred despite HBIg. In contrast, Mora et al. (Transplant Proc 1990;22:1549-1550) reported a similar rate of recurrent hepatitis B infection in patients treated and not treated with HBIg after liver transplantation. However, treatment with HBIg appeared to delay histological recurrence of hepatitis; in the patients treated with HBIg, histological recurrence was observed a mean of 313 2 116 days after transplantation, whereas in the untreated patients histological recurrence was observed a mean of 99 + 58 days after transplantation. Davies et al. have divided recurrent hepatitis B into three phases following liver transplantation based on serological findings (Hepatology 1991;13:150-157). The first period is the “incubation phase,” in which serum HBsAg is undetectable or decreasing in titer. The next phase is that of “early infection, “the first 3 months after return of HBsAg seropositivity or an increasing HBsAg titer. The third phase is that of “established infection,” in which there is active HBV replication manifested by the presence in serum of HBeAg or HBV DNA. HBIg may delay the recurrence of significant hepatitis B-related liver injury through the period when the patient is at greatest risk of major perioperative morbidity. In this regard, HBIg may be beneficial despite ultimate recurrence of HBV infection. The results of Samuel et al. appear encouraging; they found an overall recurrence rate of 30% and a l-year survival rate of 84% in a group of 83 patients receiving transplants for hepatitis B-related liver disease and treated with HBIg for up to 58 months [Transplant Proc 1991;23:1492-1494). Nevertheless, in the subgroup of patients with cirrhosis caused by HBV, the recurrence rate of HBV infection as assessed by HBsAg in serum was 59%. Moreover, the recurrence rate of HBV infection was 93% in the 14 patients with cirrhosis who had detectable HBV DNA in serum. Thus, HBIg seems to be most effective in those patients least likely to need it, that is, those with low levels of HBV replication. Delta hepatitis (hepatitis D) also may recur after liver transplantation (Lancet 1987;2:469-471). It has been observed that hepatitis D can pursue a benign clinical course after graft reinfection (Transplant Proc 1989;21:2421-2423). However, Davies et al. (Hepatology 1991;13:150-157) noted that the degree of parenchymal liver damage in recurrent hepatitis D was no less severe than that in patients with recurrent hepatitis B alone. It appears that clinical expression of HDV graft reinfection becomes apparent only when HBV replication comes to full expression with the appearance in serum of HBeAg (J Hepatol 1989:9:S68). Moreover, not infrequently, HBV infection does not recur in these patients, perhaps

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because HDV suppresses HBV replication. The role of HBIg is uncertain (Trans Proc 1989;21:2424-2425). A final method that has been tried to prevent recurrent hepatitis B after transplantation has been the perioperative use of monoclonal anti-HBs produced by a hybridoma. In a preliminary report at last year’s International Symposium on Viral Hepatitis, use of monoclonal anti-HBs was said to prevent recurrence of HBV infection in three of seven HBV carriers who underwent liver transplantation. Application of this new technology requires further study but may be limited by the development of so-called escape mutants, which lose a critical determinant on HBsAg needed for binding to anti-HBs (Gastroenterology 1991;100:578579). A critical factor in the recurrence of hepatitis B after transplantation is the ability of HBV to replicate in extrahepatic sites. A variety of solid organs (Hepatology 1990;12:187-192) as well as circulating peripheral blood cells (Transplantation 1990;49:1155-1158) have been reported to harbor replicating HBV during the course of HBV infection. Thus, any form of prophylaxis against graft reinfection by HBV may be doomed to failure because of extrahepatic reservoirs of replicating HBV. At present, it appears that immunoprophylaxis merely delays and does not prevent recurrence of hepatitis B in liver transplant recipients. It remains to be proven that delaying graft reinfection ultimately affects outcome. Clearly, attempts must continue to devise new approaches to the prevention of recurrent hepatitis B in liver transplant recipients. P. MAKTIN, M.D. 1.. S. FRIEDMAN. M.D.

SPORADIC VS. POS’ITRANSFUSION HEPATITIS C: WHY THE DIFFERENCES? Bortolotti F, TaggerA, Cadrobbi P, et al. [University of Padua, University of Milan, and Padua Hospital, Padua, Italy). Antibodies to hepatitis C virus in community-acquired acute non-A, non-B hepatitis. J Hepatology 1991;12:176180 (March). Antibodies to hepatitis C virus (anti-HCV) were investigated using enzyme-liked immunosorbent assay (ELISA) in a series of 129 adult Italian patients with acute, communityacquired non-A, non-B hepatitis, defined as those with no history of blood transfusions or drug abuse and negative hepatitis B virus, Epstein-Barr virus, and cytomegalovirus serology. Of these 129,39 (30%) had been exposed to health care facilities for hospitalization for other disease, surgery without blood transfusions, dental work, or endoscopy. Nine patients (7%) reported sexual intercourse with drug abusers whose serology was apparently unknown. Similar exposures are not reported for any control group. Sera were obtained during the acute phase, defined as the first 6 weeks after onset of symptoms, in all patients, but in 100 (78%) only one sample was obtained; 29 were tested serially. Anti-HCV was detected in 50 (38%) cases, with a prevalence rate that increased from 19% in sera obtained during the first 2 weeks of illness to 52% in samples obtained 5-6 weeks after onset. Of these 50,46 (92%) were positive in the first 6 weeks of illness. Anti-HCV positivity was independent of risk factors in the clinical history. The outcome of the disease could be evaluated in 85 of the 129 patients. Seventy-one (84%) recovered, including 3 who had protracted courses lasting 6 months and 8 months; 14 (16%) developed chronic disease. No liver biopsies were reported.

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In the 85 patients with sufficient data, anti-HCV positivity correlated with the outcome of the disease. Eighteen of 68 (26%) patients who recovered promptly were anti-HCV positive, but 3 who had a protracted course followed by recovery and 10 of 14 (71%) who progressed to chronicity (P < 0.01) were all positive. Anti-HCV titers were significantly higher (P < 0.05) in 4 of 16 (29%) patients who recovered compared with 8 of 9 (89%) patients who progressed to chronicity. In those 14 with a chronic course, the antibody persisted for more than 12 months after the onset of the illness. Conversely, in 12 of 14 (85%) serially tested patients who recovered, anti-HCV positivity was transient, lasting from a few weeks to a few months. The authors state that these findings indicate that HCV is implicated in a consistent proportion of acute community-acquired non-A, non-B (NANB) hepatitis cases, particularly cases that progress to chronicity. A large proportion of cases (62%) remained unclassified, however, and it will be important to define whether they represent cases of HCV infection with poor serological response or are due instead to other, as yet unidentified, non-A, non-B agents. Comment. The existence of more than one virus causing posttransfusion NANB hepatitis has been known for some time (Lancet 1975;2:221-223; N Engl J Med 1977;296:75-78; N Engl J Med 1983;85:439-462; J Infect Dis 1983;148:254-265). That NANB hepatitis is more likely to result in spontaneous resolution when acquired by means other than transfusion has also been known (Semin Liver Dis 1986;6:67-81). In 1986 it was estimated that 10% of sporadic NANB becomes chronic and, if chronic, is more likely to be chronic persistent than chronic active hepatitis (Semin Liver Dis 1986;6:67-81). Bortolotti et al. suggest that one is more likely to recover promptly from acute NANB hepatitis if the anti-HCV is negative or if it is positive in high titer early on but becomes negative within weeks or a few months. It is difficult to accept their conclusion that 62% of the study group were unclassified and therefore may represent another virus. Seventy-eight percent of their cases underwent only one serological study for anti-HCV within the first 6 weeks of icterus, but many were studied (once) within the first 2 weeks of illness. The rate increased to 52% when samples were obtained between the 4th and 6th weeks of illness. Others have concluded that the most appropriate time to test is 4-12 months after exposure or 2-10 months after the onset of hepatitis [J Gastroenterol Hepatol1990;5(Suppl1):78-941. Nevertheless, most studies have found that about 15%-50% of cases remain unclassified, and the higher numbers are found in studies of non-transfusion-acquired NANB hepatitis. Some of this discrepancy may be attributable to prospective studies that have an easily identified point of possible infection, i.e., blood transfusionacquired as opposed to community-acquired disease. It is unfortunate that the authors did not perform an equally thorough analysis of anti-HCV-negative cases to compare rates of clinical chronicity. Without such controls, rates in anti-HCVpositive cases are hard to interpret. Histological data in both groups would greatly strengthen the presentation. The authors make the important observation that 30% of their patients had been exposed to their health care systems without receiving blood transfusions. In similarly selected patients in Japan, 8.5% of 91 patients with acute NANB hepatitis (exclusion criteria) underwent a surgical procedure without blood transfusions, with a mean incubation of 25 f 9 days (Am J Gastroenterol1985;80:298-302). No control data on such exposures in patients with no evidence of liver disease from the same population are presented in either study, and these exposures are therefore difficult to evaluate. It would be unwise to ignore the implications. Parenthetically, note is made of the recent

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brief report from Wang et al. of the presence of HCV RNA in the saliva of three patients with acute HCV hepatitis after blood transfusions (Lancet 1991;337:48) and the transmission of NANB hepatitis in chimpanzees by saliva (J Infect Dis 1987;155:10781079). The present literature on sporadic NANB and confirmed sporadic HCV hepatitis is sparse. Epidemiological data on NANB (N Engl J Med 1983;85:439-462; N Engl J Med 1983;85:743-768) and the present report of patients with anti-HCV suggests that there are several differences between the hepatitis C disease that occurs after transfusions and that which occurs in the community without such exposure. The posttransfusion disease appears to be more severe morphologically and becomes chronic more than twice as often as the sporadic disease. Further, histological examination of such cases shows cirrhosis in about half of them. In contrast, five histological studies of 38 patients with chronic NANB (largely sporadic cases, but a few with percutaneous exposure) found that only 2 had cirrhosis, 8 had chronic active hepatitis, and 28 had chronic persistent hepatitis (N Engl J Med 1983;85:439-462, table 7, p. 454). Regardless of the mode of infection, most cases of HCV hepatitis are not clinically evident, and the clinical significance of histological cirrhosis in these cases has been questioned (Current perspectives in hepatology; New York: Plenum, 1989, pp. 83-97). The magnitude of the problem is not defined. Fulminant hepatitis appears to be more common after communityacquired NANB hepatitis than after posttransfusion NANB hepatitis (J Gastroenterol Hepatol 1990;5(Suppl 1):78-94; Gut 1983;24: 1194-1198). These apparent differences in the presentation and prognosis based on mode of transmission are difficult to rationalize. However, chimpanzee experiments have shown that NANB hepatitis virus does not “breed true” in that serial passage may see significantly different incubation periods (N Engl J Med 1983;85: 743-768). It seems to follow that the same virus may present in rather different ways; another virus need not necessarily be present to account for differences. It is possible that the means by which a virus gains entry significantly alters its subsequent manifestations, perhaps by stimulation of the host immune system in ways not identical to direct blood inoculation, although animal experiments do not support this concept. Future investigations using polymerase chain reaction amplification, and perhaps other methods of detection, will be needed to define this confusing picture. Although Bortolotti et al. present data that reinforce previously noted differences between community- and transfusion-acquired NANB hepatitis and identify about half as HCV, our current technology does not allow conclusions about the presence of yet another (non-A, -B, -C, -D, or -E) virus (or viruses). The evidence in this report and others is circumstantial and persuasive but by no means conclusive. The differences could well be caused by patient variability in response to infection. The search goes on. J. L. ACHORD, M.D.. F.A.C.P., F.A.C.G.

BIDIRECTIONAL COMMUNICATION BETWEEN MAST CELLS AND NERVES CONTROLS INTESTINAL SECRETION Perdue

MH, Masson S, Wershil BK, Galli SJ (Intestinal Disease Research Unit and Department of Pathology, McMaster University, Hamilton, Ontario, Canada; Department of Pathology, Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts; and The Combined Program in Pediatric Gastroenterology and Nutrition, Harvard Medical School, Boston, Massachusetts). Role of mast cells in ion transport abnormalities associated with intestinal anaphylaxis. Correction of the diminished secretory response in