- Email: [email protected]
Renal transplantation and hepatitis B
EDITORIALS
January 1988
References 1. Wallace JL. “Cytoprotection’‘-define
2.
3.
4.
5.
6. 7.
8.
9.
10.
11.
12.
13.
14.
it or dipose of it (lett). Dig Dis Sci 1986;31:667-8. Robert A. Prostaglandins and the gastrointestinal tract. In: Johnson LR, ed. Physiology of the gastrointestinal tract. New York: Raven, 1981:1407-34. Miller TA. Protective effects of prostaglandins against gastric mucosal damage: current knowledge and proposed mechanisms. Am J Physiol 1983;245(Gastrointest Liver Physiol 8):G601-23. Hawkey CJ, Rampton DS. Prostaglandins and the gastrointestinal mucosa: are they important in its function, disease, or treatment? Gastroenterology 1985;89:1162-88. Robert A, Nezamis JE, Lancaster C, Janchar AJ. Cytoprotection by prostaglandins in rats. Prevention of gastric necrosis produced by alcohol, HCl, NaOH, hypertonic NaCl, and thermal injury. Gastroenterology 1979;77:43343. Robert A. Cytoprotection by prostaglandins. Gastroenterology 1979;77:761-7. Lacy ER, Ito S. Microscopic analysis of ethanol damage to rat gastric mucosa after treatment with a prostaglandin. Gastroenterology 1982;83:619-25. Wallace JL, Morris GP, Krausse EJ, Greaves SE. Reduction by cytoprotective agents of ethanol-induced damage to the rat gastric mucosa: a correlated morphological and physiological study. Can J Physiol Pharmacol 1982;60:1686-99, Tarnawski A, Hollander D, Stachura J, Krause WJ, Gergely H. Prostaglandin protection of the gastric mucosa against alcohol injury-a dynamic time-related process. Role of the mucosal proliferative zone. Gastroenterology 1958;88:334-52. Svanes K, Critchlow J, Takeuchi K, Magee D, Ito S, Silen W. Factors influencing reconstitution of frog gastric mucosa: role of prostaglandins. In: Allen A, Flemstrom G, Garner A, Silen W, Turnberg LA, eds. Mechanisms of mucosal protection in the upper gastrointestinal tract. New York: Raven, 1984:33-g. Rowe PH, Starlinger MJ, Kasdon E, Marrone G, Silen W. Effect of simulated systemic administration of aspirin, salicylate, and indomethacin on amphibian gastric mucosa. Gastroenterology 1986;90:559-69. Saario I, Carter K, Rosen S, Silen W. Effects of ethanol on the in vitro frog gastric mucosa: electrophysiology and acid secretion (abstr). Gastroenterology 1987;92:1607. Oates PJ, Hakkinen JP. Studies on the mechanism of ethanolinduced gastric damage in rats. Gastroenterology 1988;94:1021. Skillman JJ, Lisbon A, Long PC, Silen W. 15 (R)-15-methyl
235
prostaglandin Ez does not prevent gastrointestinal bleeding in seriously ill patients. Am J Surg 1984;147:451-5. for peptic ulcer: a prom15. Hawkey CJ, Walt RP. Prostaglandins ise unfulfilled. Lancet 1986;ii:1084-7. by mild irritants of 16. Chaudhury TK, Robert A. Prevention gastric necrosis produced in rats by sodium taurocholate. Dig Dis Sci 1980;25:830-6. 17. Robert A, Nezamis JE, Lancaster C, Hanchar AJ. Mild irritants prevent gastric necrosis through “adaptive cytoprotection” mediated by prostaglandins. Am J Physiol 1983;245:G113-21. 18. Lacy ER. Gastric mucosal resistance to a repeated ethanol insult. Stand J Gastroenterol 1985;2O(Suppl 110):63-72. of mucosal recovery 19. Morris GP, Harding PL. Mechanisms from acute gastric damage: the roles of extracellular mucus and cell migration. In: Allen A, Flemstrom G, Garner A, Silen W, Turnberg LA, eds. Mechanisms of mucosal protection in the upper gastrointestinal tract. New York: Raven, 1984:20913. 20. Wallace JL, Whittle BJ. Role of mucus in the repair of gastric
21.
22.
23.
24.
25
26
epithelial damage in the rat. Inhibition of epithelial recovery by mucolytic agents. Gastroenterology 1986;91:603-11. Wallace JL. Increased resistance of the rat gastric mucosa to hemorrhagic damage after exposure to an irritant. Role of the “mucoid cap” and prostaglandin synthesis. Gastroenterology 1988;94:22-32. Hawkey CJ, Kemp RT, Walt RP, Baskar NK, Davies J, Filipowicz B. Adaptive cytoprotection: evidence against mediation by prostaglandins (abstr). Gut 1985;26:A1147. Ligumsky M, Golanska EM, Hansen DG, Kauffman GL Jr. Aspirin can inhibit gastric mucosal cycle-oxygenase without causing lesions in rat. Gastroenterology 1983;84:756-61. Ligumsky M, Grossman MI, Kauffman GL Jr. Endogenous gastric mucosal prostaglandins: their role in mucosal integrity. Am J Physiol 1982;242(Gastrointest Liver Physiol 5):G337-41. Konturek SJ, Piastucki I, Brzozowski T, et al. Role of prostaglandins in the formation of aspirin-induced gastric ulcers. Gastroenterology 1982;80:4-9. Trier JS, Szabo S, Allan CH. Ethanol-induced damage to mucosal capillaries of rat stomach. Ultrastructural features and effects of prostaglandin F,, and cysteamine. Gastroenterology 1987;92:13-22.
Address requests for reprints to: William Silen, M.D., Beth Israel Hospital, Department of Surgery, 330 Brookline Avenue, Boston, Massachusetts 02215. 0 1988 by the American Gastroenterological Association
Renal Transplantation and Hepatitis B Exposure to hepatitis B virus (HBV) is common in renal transplant recipients. Hemodialysis and intentional blood transfusions before transplantation and additional blood exposure in the peritransplant period all contribute to the potential for HBV infection. In addition to the natural immunosuppression of the chronic renal failure that antedates transplantation, renal transplant recipients are subjected to pharmacologic immunosuppression to prevent allograft re-
jection. Like other immunosuppressed patients, once infected with HBV, transplant recipients are less likely to experience a recognizable acute icteric illness but more likely to remain chronically infected, to retain high levels of virus replication, and to be very infectious for their contacts (1). Reactivation of hepatitis B (reexpression of hepatitis B surface antigen, HBsAg) after renal transplantation has been observed in patients with antibody to hepatitis
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EDITORIALS
B core antigen before transplantation (23). Similarly, reemergence of viral replication in those with nonreplicative HBV infection (i.e., HBsAg positive, HBV DNA negative, hepatitis B e antigen negative) at the time of transplantation (3) occurs as well. Also observed in oncology patients receiving cytotoxic chemotherapy (4,5), these serologic patterns are consistent with the possibility that some apparent de novo cases of hepatitis B after transplantation actually represent reactivation. Differences in allograft survival have been observed that are influenced by the recipient’s response to HBV. London et al. (6,7)found that patients with HBsAg positivity before transplantation had a higher rate of allograft survival, whereas transplant patients, primarily women, with pretransplantation antibody to HBsAg (anti-HBs) and who received male donor kidneys had an increased rate of allograft rejection. Presumably, this is a result of increased immunologic tolerance to the transplanted organ in those who are immunologically tolerant of HBsAg. Although slight decreases in graft survival in anti-HBs-positive renal transplant recipients have been observed by others, the differences have not always been significant, and others have detected no difference (8) or even an increase in graft survival among anti-HBS-positive patients; most investigators have not been able to detect any difference in graft survival (i.e., no increase in graft tolerance) in HBsAg-positive recipients, Also controversial is the effect of HBV infection on patient survival after renal transplantation. Pirson et al. (9) reported that mortality resulting from progressive liver disease was fivefold higher between 6 mo and 4 yr after transplantation in HBsAg-positive compared to HBsAg-negative renal allograft recipients. Hillis et al. (10)also found that HBsAg-positive renal transplant recipients had a higher mortality rate, related not to liver disease but to infections and cerebrovascular accidents, Many other investigators, however, have been unable to detect any increase in patient mortality in HBsAg-positive renal transplant recipients (11-13). Theoretically, the conflicting experiences could be attributed to the confounding effect of differences in immunosuppressive protocols, superimposed non-A, non-B hepatitis, and/or cytomegalovirus infection, or HLA types; however, these variables have not been found to account for the conflicting observations. Generating the most concern were observations reported by Parfrey et al. (14). Among 22 HBsAgpositive renal transplant recipients, two-thirds of whom acquired their HBV infections after transplantation, progression of liver disease was quite common. Despite the fact that most patients remained asymptomatic, insidious progression occurred. Even
GASTROENTEROLOGY Vol. 94,
No. 1
in patients with normal histology or chronic persistent hepatitis on early liver biopsies, a 25%40% progression to chronic active hepatitis and cirrhosis has been reported (14,15). By the end of the l-8-yr observation period in the study by Parfrey et al. (14), 13 patients (59%) had chronic active hepatitis or cirrhosis, and, in 8 of the 13, jaundice, portal hypertension, or liver failure, or a combination thereof developed; 3 died of liver failure and 2 died of hepatocellular carcinoma. The rate of liver-related deaths in the HBsAg-positive renal transplant group was 5% per patient-year. In contrast, 10 patients with chronic renal failure managed with maintenance hemodialysis instead of transplantation experienced no liver-related deaths, and 4 ultimately lost their HBsAg. These ominous findings have led some transplant centers to avoid renal (as well as other organ) transplantation in HBsAg-positive patients. As hepatitis B has been reduced in hemodialysis populations by control measures, however, so too has the role of HBV in posttransplantation hepatic disease appeared to decline. In this issue of GASTROENTEROLOGY, however, Degos and colleagues (16) resurrect the specter of hepatitis B even in recipients of renal transplants who lack HBsAg in serum. Ninety patients (34 HBsAg positive and 56 HBsAg negative) are described, a proportion of whom were tested at the time of renal transplantation for serum and liver HBV DNA and serially thereafter for serum HBV DNA. The addition of testing both serum and liver for HBV DNA revealed the following: (a) In HBsAgpositive patients, 62% had serum HBV DNA on early determinations, but, of those who lacked serum HBV DNA initially, 92% became positive within 3-12 mo after transplantation. This means that the likelihood of “replicative” infection is high to begin with but becomes almost universal once immunosuppression is introduced. In 13 of the 15 HBsAg-positive patients, nonintegrated HBV DNA was detected in liver, including patients whose initial serum lacked, but later serum samples contained, HBV DNA. (b) In initially HBsAg-positive patients, chronic hepatitis detected histologically was just as likely in the absence of as in the presence of replicative (HBV DNA positive in serum or liver) infection. (c) Among initially HBsAg-negative patients, 71% of whom had detectable antibodies to HBV antigens, none had HBV DNA in serum on initial determination, but in 20% of those tested subsequently, serum HBV DNA was detected during follow-up. In 44% of 27 HBsAgnegative patients tested, HBV DNA was detected in initial liver specimens, and the DNA tended to be integrated into the host genome. Although HBsAg did not become detectable, these HBsAg-negative patients with HBV DNA in liver initially or in serum
January 1988
eventually appear to have experienced reactivation of HBV replication after immunosuppression. (d) Although indicators of HBV replication appeared with equal frequency in HBsAg-positive patients with normal liver and with chronic hepatitis, in HBsAg-negative patients, the presence of HBV DNA in liver was associated with chronic hepatitis. This difference between HBsAg-positive and HBsAgnegative HBV infections remains unexplained. In brief, then, the principal message is that HBV replication is very common in the French renal transplant patients studied, whether they express expected serologic markers of HBV or not. A hint of what accounts for the distinction between those who are HBsAg-positive and HBsAg-negative derives from the study of liver HBV DNA. The HBsAgpositive patients had free HBV DNA, which tends to be associated with a relatively early phase of infection, whereas the HBsAg-negative patients tended to have integrated HBV DNA, associated with a later phase of infection. In either case, immunosuppression provided a permissive environment for increased levels of HBV replication. Although debate has been generated about the meaningfulness of reports in recent years of intrahepatic HBV DNA in the absence of serum HBsAg, the description of such sub-rosa HBV infections in immunosuppressed transplant patients comes as no surprise. Studies of HBV DNA in serum and liver confirm earlier observations cited above that reaction of HBV replication and HBsAg expression occurs in immunosuppressed patients; therefore, there is no need to invoke the explanation that the HBsAgnegative patients are infected with HBV variants. But how representative are these findings? Can we conclude that HBV infection is so generalized in all transplant recipients ? Does the almost universal presence of HBV infection in these French transplant patients apply to North American and British transplant units? Segregation of HBsAg-negative from HBsAg-positive dialysis and transplant patients, among other measures, has led to a dramatic reduction in the frequency of dialysis-associated and transplant-associated hepatitis B in American and British dialysis units and transplantation programs. Why should this be the case if the data of Degos et al. (16)can be extrapolated and if so many of the HBsAg-negative patients are really HBV DNApositive? In fact, the findings of Degos et al. (16)appear to apply to a dialysis/transplant population heavily contaminated by HBV. The presence of HBsAg in 46% of dialysis patients in France, as mentioned by Degos et al. (16), the presence of antibodies to HBV antigens found by Degos et al. in 71% of HBsAgnegative transplant recipients, and the very high
EDITORIALS
237
l-year hepatitis B attack rate, 45%, observed among patients receiving placebo during a controlled trial of hepatitis B vaccine in French dialysis patients (17) reflect the ubiquity of HBV in these units. In contrast, after the introduction of control measures to prevent hepatitis B in American hemodialysis units, the prevalence of HBsAg was only 2.7% (18),the prevalence of hepatitis B surface antibody in HBsAgnegative patients (before the availability of hepatitis and the annual attack B vaccine) was only 12% (18), rate of new HBV infections in hemodialysis patients receiving placebo during a controlled trial of hepatitis B vaccine was only 5% (19). And yet, although the findings of Degos et al. (16) are not likely to apply to contemporary dialysis/ transplant units in America and Britain (or even France, for that matter, now that control measures have been introduced), the meaningfulness of the HBsAg-negative/HBV DNA-positive pattern remains an important issue. In the studies cited above concerning the natural history of patients and renal allografts in HBsAg-positive patients, patients were always classified based on HBsAg positivity and negativity, and the correlations that emerged in some (not all) studies distinguished the two groups. Could the occurrence of HBsAg-negative/HBV DNApositive persons influence these correlations? Would we expect HBsAg-negative/HBV DNA-positive patients and grafts to behave like HBsAg-positive or HBsAg-negative patients and grafts? Degos and his colleagues (16)did include information on patient and allograft survival. The number of patients followed for a sufficient time was small, as the authors pointed out, and the number of deaths did not permit interpretation. Despite the small numbers, however, a trend was suggested for aliograft survival. During the 2-3-yr observation period, kidney graft survival was 82% in HBsAgpositive patients, 75% in HBsAg-negative/HBV DNA-positive patients, and 61% in the entire group of HBsAg-negative patients (data on HBsAgnegative/HBV DNA-negative patients were not given). These findings may not reach a level of statistical significance, but a correlation emerges between the degree of presumed immunological tolerance to HBsAg and the level of graft survival. This is the pattern that was reported originally by London et al. (6,7). These findings raise the possibility that previously reported conflicting observations concerning the impact of HBV on patient and graft outcome after renal transplantation may have represented differences in the frequency of HBsAg-negative HBV infection among the various centers. Potentially, those centers with a high frequency of HBsAg-negative HBV infec-
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EDITORIALS
tion may have failed to detect a difference between their HBsAg-positive and HBsAg-negative patients, whereas those with few HBsAg-negative HBV cases may have been able to demonstrate a difference between HBsAg-positive and HBsAg-negative patients. This hypothesis certainly can be tested, as I hope it will be, by the investigators who have been involved in the controversy. Still, our understanding of the impact of HBV infection on the outcome of patient and graft survival after renal transplantation remains incomplete. Although the observations of Degos et al. (16)suggest a potential explanation for contradictory experiences in terms of allograft survival, currently, this controversy and the one concerning the effect of HBV infection on patient survival remain unresolved. In addition, as the presence of HBV infection continues to decline in hemodialysis units, its contribution to liver disease after transplantation is likely to change as well. Until contradictory data can be reconciled and changing patterns of infection become established, current observations appear to be insufficient to support a universal policy of denying organ transplants to HBsAg-positive patients. JULES L. DIENSTAG, M.D.
Gastrointestinal Unit Massachusetts General Hospital and Department of Medicine Harvard Medical School Boston, Massachusetts
GASTROENTEROLOGY Vol. 94, No. 1
6.
7.
8.
9.
10.
11.
12.
13. 14.
15.
16.
17.
References 1. Coughlin
2. 3.
4.
5.
GP, Van Deth AG, Disney APS, et al. Liver disease and the e antigen in HBsAg carriers with chronic renal failure. Gut 1980;21:118-22. Nagington J, Cossart YE, Cohen BJ. Reactivation of hepatitis B after transplantation operations. Lancet 1977;i:558-60. Dusheiko G, Song E, Bowyer S, et al. Natural history of hepatitis B virus infection in renal transplant recipients-a fifteen-year follow-up. Hepatology 1983;3:330-6. Wands JR, Chura CM, Roll FJ, et al. Serial studies of hepatitisassociated antigen and antibody in patients receiving antitumor chemotherapy for myeloproliferative and lymphoproliferative disorders. Gastroenterology 1975;68:105-12. Hoofnagle JH, Dusheiko GM, Schafer DF, et al. Reactivation of
18.
19.
chronic hepatitic B virus infection by cancer chemotherapy. Ann Intern Med 1982;96:447-9. London WT, Drew JS, Blumberg BS, et al. Association of graft survival with host response to hepatitis B infection in patients with kidney transplants. N Engl J Med 1977;296:2414. London WT, Jarvinen H, Jasko L, et al. Hepatitis B virus infection in kidney transplant recipients. In: Bianchi L, Gerok W, Sickinger K, Stalder GA, eds. Virus and the liver. Lancaster: MTP Press, 1980:267-76. Szmuness W. Large-scale efficacy trials of hepatitis B vaccines in the USA: baseline data and protocols. J Med Viral 1979;4:327-40. Pirson Y, Alexandre GPJ, van Ypersele de Strihou C. Longterm effect of HBs antigenemia on patient survival after renal transplantation. N Engl J Med 1977;296:194-6. Hillis WD, Hillis A, Walker WG. Hepatitis B surface antigenemia in renal transplant recipients: increased mortality risk. JAMA 1979;242:329-32. Chatterjee SN, Payne JE, Bischell MD, et al. Successful renal transplantation in patients positive for hepatitis B antigen. N Engl J Med 1974;291:62-5. Berne TV, Fitzgibbons TJ, Silberman H. The effect of hepatitis B antigenemia on long-term success and hepatic disease in renal transplantation. Transplantation 1977;24:412-5. Fine RN, Malekzadeh MH, Pennisi AJ, et al. HBs antigenemia in renal allograft recipients. Ann Surg 1977;185:411-6. Parfrey PS, Forbes RDC, Hutchinson TA, et al. The clinical and pathological course of hepatitis B liver disease in renal transplant recipients. Transplantation 1984;37:461-6. Degos F, Degott C, Bedrossian J, et al. Is renal transplantation involved in post-transplantation liver disease? A prospective study. Transplantation 1980;29:100-2. Degos F, Lugassy C, Degott C, et al. Hepatitis B virus and hepatitis B-related viral infection in renal transplant recipients. A prospective study of 90 patients. Gastroenterology 1987;94:151-6. Crosnier J, Jungers P, Courouce AM, et al. Randomized placebo-controlled trial of hepatitis B surface antigen vaccine in French haemodialysis units. II. Haemodialysis patients. Lancet 1981;i:797-800. Alter MJ, Favero MS, Maynard JE. Hemodialysis-associated hepatitis in the United States (abstr]. In: Vyas GN, Dienstag JL, Hoofnagle JH, eds. Viral hepatitis and liver disease. Orlando, Florida: Grune & Stratton, 1984:636. Stevens CE, Alter HJ, Taylor PE, et al. Hepatitis B vaccine in patients receiving hemodialysis: immunogenicity and efficacy. N Engl J Med 1984;311:496-501.
Address requests for reprints to: Dr. J. L. Dienstag, Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts 02114. 0 1988 by the American Gastroenterological Association.
January 1988
References 1. Wallace JL. “Cytoprotection’‘-define
2.
3.
4.
5.
6. 7.
8.
9.
10.
11.
12.
13.
14.
it or dipose of it (lett). Dig Dis Sci 1986;31:667-8. Robert A. Prostaglandins and the gastrointestinal tract. In: Johnson LR, ed. Physiology of the gastrointestinal tract. New York: Raven, 1981:1407-34. Miller TA. Protective effects of prostaglandins against gastric mucosal damage: current knowledge and proposed mechanisms. Am J Physiol 1983;245(Gastrointest Liver Physiol 8):G601-23. Hawkey CJ, Rampton DS. Prostaglandins and the gastrointestinal mucosa: are they important in its function, disease, or treatment? Gastroenterology 1985;89:1162-88. Robert A, Nezamis JE, Lancaster C, Janchar AJ. Cytoprotection by prostaglandins in rats. Prevention of gastric necrosis produced by alcohol, HCl, NaOH, hypertonic NaCl, and thermal injury. Gastroenterology 1979;77:43343. Robert A. Cytoprotection by prostaglandins. Gastroenterology 1979;77:761-7. Lacy ER, Ito S. Microscopic analysis of ethanol damage to rat gastric mucosa after treatment with a prostaglandin. Gastroenterology 1982;83:619-25. Wallace JL, Morris GP, Krausse EJ, Greaves SE. Reduction by cytoprotective agents of ethanol-induced damage to the rat gastric mucosa: a correlated morphological and physiological study. Can J Physiol Pharmacol 1982;60:1686-99, Tarnawski A, Hollander D, Stachura J, Krause WJ, Gergely H. Prostaglandin protection of the gastric mucosa against alcohol injury-a dynamic time-related process. Role of the mucosal proliferative zone. Gastroenterology 1958;88:334-52. Svanes K, Critchlow J, Takeuchi K, Magee D, Ito S, Silen W. Factors influencing reconstitution of frog gastric mucosa: role of prostaglandins. In: Allen A, Flemstrom G, Garner A, Silen W, Turnberg LA, eds. Mechanisms of mucosal protection in the upper gastrointestinal tract. New York: Raven, 1984:33-g. Rowe PH, Starlinger MJ, Kasdon E, Marrone G, Silen W. Effect of simulated systemic administration of aspirin, salicylate, and indomethacin on amphibian gastric mucosa. Gastroenterology 1986;90:559-69. Saario I, Carter K, Rosen S, Silen W. Effects of ethanol on the in vitro frog gastric mucosa: electrophysiology and acid secretion (abstr). Gastroenterology 1987;92:1607. Oates PJ, Hakkinen JP. Studies on the mechanism of ethanolinduced gastric damage in rats. Gastroenterology 1988;94:1021. Skillman JJ, Lisbon A, Long PC, Silen W. 15 (R)-15-methyl
235
prostaglandin Ez does not prevent gastrointestinal bleeding in seriously ill patients. Am J Surg 1984;147:451-5. for peptic ulcer: a prom15. Hawkey CJ, Walt RP. Prostaglandins ise unfulfilled. Lancet 1986;ii:1084-7. by mild irritants of 16. Chaudhury TK, Robert A. Prevention gastric necrosis produced in rats by sodium taurocholate. Dig Dis Sci 1980;25:830-6. 17. Robert A, Nezamis JE, Lancaster C, Hanchar AJ. Mild irritants prevent gastric necrosis through “adaptive cytoprotection” mediated by prostaglandins. Am J Physiol 1983;245:G113-21. 18. Lacy ER. Gastric mucosal resistance to a repeated ethanol insult. Stand J Gastroenterol 1985;2O(Suppl 110):63-72. of mucosal recovery 19. Morris GP, Harding PL. Mechanisms from acute gastric damage: the roles of extracellular mucus and cell migration. In: Allen A, Flemstrom G, Garner A, Silen W, Turnberg LA, eds. Mechanisms of mucosal protection in the upper gastrointestinal tract. New York: Raven, 1984:20913. 20. Wallace JL, Whittle BJ. Role of mucus in the repair of gastric
21.
22.
23.
24.
25
26
epithelial damage in the rat. Inhibition of epithelial recovery by mucolytic agents. Gastroenterology 1986;91:603-11. Wallace JL. Increased resistance of the rat gastric mucosa to hemorrhagic damage after exposure to an irritant. Role of the “mucoid cap” and prostaglandin synthesis. Gastroenterology 1988;94:22-32. Hawkey CJ, Kemp RT, Walt RP, Baskar NK, Davies J, Filipowicz B. Adaptive cytoprotection: evidence against mediation by prostaglandins (abstr). Gut 1985;26:A1147. Ligumsky M, Golanska EM, Hansen DG, Kauffman GL Jr. Aspirin can inhibit gastric mucosal cycle-oxygenase without causing lesions in rat. Gastroenterology 1983;84:756-61. Ligumsky M, Grossman MI, Kauffman GL Jr. Endogenous gastric mucosal prostaglandins: their role in mucosal integrity. Am J Physiol 1982;242(Gastrointest Liver Physiol 5):G337-41. Konturek SJ, Piastucki I, Brzozowski T, et al. Role of prostaglandins in the formation of aspirin-induced gastric ulcers. Gastroenterology 1982;80:4-9. Trier JS, Szabo S, Allan CH. Ethanol-induced damage to mucosal capillaries of rat stomach. Ultrastructural features and effects of prostaglandin F,, and cysteamine. Gastroenterology 1987;92:13-22.
Address requests for reprints to: William Silen, M.D., Beth Israel Hospital, Department of Surgery, 330 Brookline Avenue, Boston, Massachusetts 02215. 0 1988 by the American Gastroenterological Association
Renal Transplantation and Hepatitis B Exposure to hepatitis B virus (HBV) is common in renal transplant recipients. Hemodialysis and intentional blood transfusions before transplantation and additional blood exposure in the peritransplant period all contribute to the potential for HBV infection. In addition to the natural immunosuppression of the chronic renal failure that antedates transplantation, renal transplant recipients are subjected to pharmacologic immunosuppression to prevent allograft re-
jection. Like other immunosuppressed patients, once infected with HBV, transplant recipients are less likely to experience a recognizable acute icteric illness but more likely to remain chronically infected, to retain high levels of virus replication, and to be very infectious for their contacts (1). Reactivation of hepatitis B (reexpression of hepatitis B surface antigen, HBsAg) after renal transplantation has been observed in patients with antibody to hepatitis
236
EDITORIALS
B core antigen before transplantation (23). Similarly, reemergence of viral replication in those with nonreplicative HBV infection (i.e., HBsAg positive, HBV DNA negative, hepatitis B e antigen negative) at the time of transplantation (3) occurs as well. Also observed in oncology patients receiving cytotoxic chemotherapy (4,5), these serologic patterns are consistent with the possibility that some apparent de novo cases of hepatitis B after transplantation actually represent reactivation. Differences in allograft survival have been observed that are influenced by the recipient’s response to HBV. London et al. (6,7)found that patients with HBsAg positivity before transplantation had a higher rate of allograft survival, whereas transplant patients, primarily women, with pretransplantation antibody to HBsAg (anti-HBs) and who received male donor kidneys had an increased rate of allograft rejection. Presumably, this is a result of increased immunologic tolerance to the transplanted organ in those who are immunologically tolerant of HBsAg. Although slight decreases in graft survival in anti-HBs-positive renal transplant recipients have been observed by others, the differences have not always been significant, and others have detected no difference (8) or even an increase in graft survival among anti-HBS-positive patients; most investigators have not been able to detect any difference in graft survival (i.e., no increase in graft tolerance) in HBsAg-positive recipients, Also controversial is the effect of HBV infection on patient survival after renal transplantation. Pirson et al. (9) reported that mortality resulting from progressive liver disease was fivefold higher between 6 mo and 4 yr after transplantation in HBsAg-positive compared to HBsAg-negative renal allograft recipients. Hillis et al. (10)also found that HBsAg-positive renal transplant recipients had a higher mortality rate, related not to liver disease but to infections and cerebrovascular accidents, Many other investigators, however, have been unable to detect any increase in patient mortality in HBsAg-positive renal transplant recipients (11-13). Theoretically, the conflicting experiences could be attributed to the confounding effect of differences in immunosuppressive protocols, superimposed non-A, non-B hepatitis, and/or cytomegalovirus infection, or HLA types; however, these variables have not been found to account for the conflicting observations. Generating the most concern were observations reported by Parfrey et al. (14). Among 22 HBsAgpositive renal transplant recipients, two-thirds of whom acquired their HBV infections after transplantation, progression of liver disease was quite common. Despite the fact that most patients remained asymptomatic, insidious progression occurred. Even
GASTROENTEROLOGY Vol. 94,
No. 1
in patients with normal histology or chronic persistent hepatitis on early liver biopsies, a 25%40% progression to chronic active hepatitis and cirrhosis has been reported (14,15). By the end of the l-8-yr observation period in the study by Parfrey et al. (14), 13 patients (59%) had chronic active hepatitis or cirrhosis, and, in 8 of the 13, jaundice, portal hypertension, or liver failure, or a combination thereof developed; 3 died of liver failure and 2 died of hepatocellular carcinoma. The rate of liver-related deaths in the HBsAg-positive renal transplant group was 5% per patient-year. In contrast, 10 patients with chronic renal failure managed with maintenance hemodialysis instead of transplantation experienced no liver-related deaths, and 4 ultimately lost their HBsAg. These ominous findings have led some transplant centers to avoid renal (as well as other organ) transplantation in HBsAg-positive patients. As hepatitis B has been reduced in hemodialysis populations by control measures, however, so too has the role of HBV in posttransplantation hepatic disease appeared to decline. In this issue of GASTROENTEROLOGY, however, Degos and colleagues (16) resurrect the specter of hepatitis B even in recipients of renal transplants who lack HBsAg in serum. Ninety patients (34 HBsAg positive and 56 HBsAg negative) are described, a proportion of whom were tested at the time of renal transplantation for serum and liver HBV DNA and serially thereafter for serum HBV DNA. The addition of testing both serum and liver for HBV DNA revealed the following: (a) In HBsAgpositive patients, 62% had serum HBV DNA on early determinations, but, of those who lacked serum HBV DNA initially, 92% became positive within 3-12 mo after transplantation. This means that the likelihood of “replicative” infection is high to begin with but becomes almost universal once immunosuppression is introduced. In 13 of the 15 HBsAg-positive patients, nonintegrated HBV DNA was detected in liver, including patients whose initial serum lacked, but later serum samples contained, HBV DNA. (b) In initially HBsAg-positive patients, chronic hepatitis detected histologically was just as likely in the absence of as in the presence of replicative (HBV DNA positive in serum or liver) infection. (c) Among initially HBsAg-negative patients, 71% of whom had detectable antibodies to HBV antigens, none had HBV DNA in serum on initial determination, but in 20% of those tested subsequently, serum HBV DNA was detected during follow-up. In 44% of 27 HBsAgnegative patients tested, HBV DNA was detected in initial liver specimens, and the DNA tended to be integrated into the host genome. Although HBsAg did not become detectable, these HBsAg-negative patients with HBV DNA in liver initially or in serum
January 1988
eventually appear to have experienced reactivation of HBV replication after immunosuppression. (d) Although indicators of HBV replication appeared with equal frequency in HBsAg-positive patients with normal liver and with chronic hepatitis, in HBsAg-negative patients, the presence of HBV DNA in liver was associated with chronic hepatitis. This difference between HBsAg-positive and HBsAgnegative HBV infections remains unexplained. In brief, then, the principal message is that HBV replication is very common in the French renal transplant patients studied, whether they express expected serologic markers of HBV or not. A hint of what accounts for the distinction between those who are HBsAg-positive and HBsAg-negative derives from the study of liver HBV DNA. The HBsAgpositive patients had free HBV DNA, which tends to be associated with a relatively early phase of infection, whereas the HBsAg-negative patients tended to have integrated HBV DNA, associated with a later phase of infection. In either case, immunosuppression provided a permissive environment for increased levels of HBV replication. Although debate has been generated about the meaningfulness of reports in recent years of intrahepatic HBV DNA in the absence of serum HBsAg, the description of such sub-rosa HBV infections in immunosuppressed transplant patients comes as no surprise. Studies of HBV DNA in serum and liver confirm earlier observations cited above that reaction of HBV replication and HBsAg expression occurs in immunosuppressed patients; therefore, there is no need to invoke the explanation that the HBsAgnegative patients are infected with HBV variants. But how representative are these findings? Can we conclude that HBV infection is so generalized in all transplant recipients ? Does the almost universal presence of HBV infection in these French transplant patients apply to North American and British transplant units? Segregation of HBsAg-negative from HBsAg-positive dialysis and transplant patients, among other measures, has led to a dramatic reduction in the frequency of dialysis-associated and transplant-associated hepatitis B in American and British dialysis units and transplantation programs. Why should this be the case if the data of Degos et al. (16)can be extrapolated and if so many of the HBsAg-negative patients are really HBV DNApositive? In fact, the findings of Degos et al. (16)appear to apply to a dialysis/transplant population heavily contaminated by HBV. The presence of HBsAg in 46% of dialysis patients in France, as mentioned by Degos et al. (16), the presence of antibodies to HBV antigens found by Degos et al. in 71% of HBsAgnegative transplant recipients, and the very high
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l-year hepatitis B attack rate, 45%, observed among patients receiving placebo during a controlled trial of hepatitis B vaccine in French dialysis patients (17) reflect the ubiquity of HBV in these units. In contrast, after the introduction of control measures to prevent hepatitis B in American hemodialysis units, the prevalence of HBsAg was only 2.7% (18),the prevalence of hepatitis B surface antibody in HBsAgnegative patients (before the availability of hepatitis and the annual attack B vaccine) was only 12% (18), rate of new HBV infections in hemodialysis patients receiving placebo during a controlled trial of hepatitis B vaccine was only 5% (19). And yet, although the findings of Degos et al. (16) are not likely to apply to contemporary dialysis/ transplant units in America and Britain (or even France, for that matter, now that control measures have been introduced), the meaningfulness of the HBsAg-negative/HBV DNA-positive pattern remains an important issue. In the studies cited above concerning the natural history of patients and renal allografts in HBsAg-positive patients, patients were always classified based on HBsAg positivity and negativity, and the correlations that emerged in some (not all) studies distinguished the two groups. Could the occurrence of HBsAg-negative/HBV DNApositive persons influence these correlations? Would we expect HBsAg-negative/HBV DNA-positive patients and grafts to behave like HBsAg-positive or HBsAg-negative patients and grafts? Degos and his colleagues (16)did include information on patient and allograft survival. The number of patients followed for a sufficient time was small, as the authors pointed out, and the number of deaths did not permit interpretation. Despite the small numbers, however, a trend was suggested for aliograft survival. During the 2-3-yr observation period, kidney graft survival was 82% in HBsAgpositive patients, 75% in HBsAg-negative/HBV DNA-positive patients, and 61% in the entire group of HBsAg-negative patients (data on HBsAgnegative/HBV DNA-negative patients were not given). These findings may not reach a level of statistical significance, but a correlation emerges between the degree of presumed immunological tolerance to HBsAg and the level of graft survival. This is the pattern that was reported originally by London et al. (6,7). These findings raise the possibility that previously reported conflicting observations concerning the impact of HBV on patient and graft outcome after renal transplantation may have represented differences in the frequency of HBsAg-negative HBV infection among the various centers. Potentially, those centers with a high frequency of HBsAg-negative HBV infec-
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tion may have failed to detect a difference between their HBsAg-positive and HBsAg-negative patients, whereas those with few HBsAg-negative HBV cases may have been able to demonstrate a difference between HBsAg-positive and HBsAg-negative patients. This hypothesis certainly can be tested, as I hope it will be, by the investigators who have been involved in the controversy. Still, our understanding of the impact of HBV infection on the outcome of patient and graft survival after renal transplantation remains incomplete. Although the observations of Degos et al. (16)suggest a potential explanation for contradictory experiences in terms of allograft survival, currently, this controversy and the one concerning the effect of HBV infection on patient survival remain unresolved. In addition, as the presence of HBV infection continues to decline in hemodialysis units, its contribution to liver disease after transplantation is likely to change as well. Until contradictory data can be reconciled and changing patterns of infection become established, current observations appear to be insufficient to support a universal policy of denying organ transplants to HBsAg-positive patients. JULES L. DIENSTAG, M.D.
Gastrointestinal Unit Massachusetts General Hospital and Department of Medicine Harvard Medical School Boston, Massachusetts
GASTROENTEROLOGY Vol. 94, No. 1
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Address requests for reprints to: Dr. J. L. Dienstag, Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts 02114. 0 1988 by the American Gastroenterological Association.