1426 EDITORIALS
GASTROENTEROLOGY Vol. 102, No. 4
recent study suggested that there are only minor differences in the absolute rate of production of H, by different individuals.‘” Thus, the great individual variability observed in H, excretion after ingestion of similar doses of nonabsorbable carbohydrates appears to reflect differences in H, consumption, At present, therapy for flatulence is limited to dietary alterations that attempt to reduce the quantity of fermentable substrate reaching the colonic bacteria, a treatment that usually fails because of the wide variety of carbohydrates that are incompletely absorbed by the normal small intestine. Future approaches to this problem may take the form of manipulations designed to enhance H, consumption via either reduction of fecal stirring or implantation of Hz-consuming bacteria into the right colon. ALESSANDRA STROCCHI, M.D. MICHAEL D. LEVITT, M.D. Research Service
Veterans Administration Medical Center Minneapolis,
Minnesota
References 1. Weaver
2.
3. 4.
5. 6.
GA, Krause JA, Miller TL, Wolin MJ. Constancy of glucose and starch fermentations by two different human faecal microbial communities. Gut 1989;30:19-25. Stephen AM, Haddad AC, Phillips SF. Passage of carbohydrate into the colon. Direct measurements in humans. Gastroenterology 1983;85:589-595. Sanders T. Man shoots sparks when he passes gas. Weekly Word News 199l;October 15:37. Christ1 SU, MurgatroydPR, Gibson GR, Cummings JH. Production, metabolism, and excretion of hydrogen in the large intestine. Gastroenterology 1992;102:1269-1277. Kirk E. The quantity and composition of human colonic flatus. Gastroenterology 1949;19:782-794. Calloway DH, Murphy EL. The use of expired air to measure intestinal gas formation. Ann NY Acad Sci 1968;150:82-95.
Community-Acquired Infection Hepatitis C virus (HCV), which contains a singlestranded RNA encoding a number of proteins, has been identified as the principal cause of non-A, nonB (NANB) hepatitis in transfusion recipients, hemophilics, and injection drug abusers. Its presence can be detected by host antibodies to a few of its proteins’,’ and by polymerase chain reaction (PCR) assays that make use of specific sequences within the viral genome.3
7. Tomlin J, Lowis C, Read NW. Investigation of normal flatus production in healthy volunteers. Gut 1991;32:665-669, 8. Levitt MD. Production and excretion of hydrogen gas in man. N Engl J Med 1969;281:122-127. 9. Levitt MD, Berggren T, Hastings J, Bond JH. Hydrogen (H,) catabolism in the colon of the rat. J Lab Clin Med 1974;84:163167.
10. Wolin MJ. Fermentation in the rumen and human large intestine. Science 1981;213:1463-1468. 11. Gibson GR. A review. Physiology and ecology of sulphate-reducing bacteria. J Appl Bacterial 1990;69:769-767. 12. Lajoie SF, Bank S, Miller TL, Wolin MJ. Acetate production from hydrogen and [‘%]carbon dioxide by the microflora of human feces. Appl Environ Microbial 1988;54:2723-2727. 13. Gibson GR, Cummings JH, Macfarlane GT. Competition for hydrogen between sulphate-reducing bacteria and methanogenie bacteria from the human large intestine. J Appl Bacteriol 1988;65:241-247. 14. Gibson GR, Macfarlane GT, Cummings JH. Occurrence of sulphate-reducing bacteria in human faeces and the relationship of dissimilatory sulphate reduction to methanogenesis in the large gut. J Appl Bacterial 1988;65:103-111. 15. Strocchi A, Furne JK, Ellis JC, Levitt MD. Competition for hydrogen by human faecal bacteria: evidence for the predominance of methane producing bacteria. Gut 1991;32:14981501. 16. Strocchi A, Levitt MD. Factors affecting hydrogen
production and consumption by human fecal flora: The critical role of hydrogen tension and methanogenesis. J Clin Invest (in press). 17. Levitt MD, Ingelfinger FJ. Hydrogen and methane production in man. Ann NY Acad Sci 1965;150:65-81. 18. Flourie BF, Etanchaud F, Florent C, Pellier P, Bouhnik Y, Rambaud JC. Comparative study of hydrogen and methane production in the human colon using caecal and faecal homogenates. Gut 1990;31:684-685.
Address requests for reprints to: Michael Levitt, M.D., ACOS Research, Veterans Administration Medical Center, 1 Veteran’s Drive, Minneapolis, Minnesota 55417. This is a U.S. government work. There are no restrictions on its use.
Hepatitis
C Virus
The ability to serologically identify and treat hepatitis C has raised the consciousness of affected individuals concerning the mechanisms by which their disease may be transmitted to others. Although percutaneous or parenteral transmission is readily accepted by these patients as the principal mode of spread of HCV, their concern is invariably focused on the potential for contact-associated transmission. Patients wish to know whether oral transmission of
April 1992
HCV by saliva, e.g., by kissing, or by objects contaminated with saliva may occur or if transmission by sexual intercourse is possible. In a study of community-acquired acute NANB hepatitis conducted by the Centers for Disease Control (CDC) between 1986 and 1988 in four counties located in Washington, Colorado, Alabama, and Florida, no source of infection was identified in 40% of the subjects.* Of the cases tested, 70% were found to be anti-HCV positive when serial samples of blood were examined. Another study from Italy also found no evidence of overt parenteral exposure in about 40% of patients with community-acquired acute NANB hepatitis.5 Nine percent of the subjects in the CDC study reported that they were exposed to a household contact or sexual partner who had hepatitis or to multiple sexual partners in the 6 months preceding the onset of their acute hepatitis. This rate is similar to reports originating in Japan and Italy in which 8% of 122 family members exposed to chronic hepatitis cases had serologic evidence of HCV.6,7 Unfortunately, validation of these results with supplemental assays have not been performed. In contrast to these reports, additional studies in the United States evaluating the risk of acquiring HCV among 80 household or sexual contacts of 60 patients with chronic hepatitis C showed no evidence of infection detectable by the PCR assay8 or by an anti-HCV test.‘*’ In contradistinction to these studies, ~5% of our patients with chronic hepatitis C (verified by a PCR assay for HCV RNA) failed to provide a history of exposure to blood or blood components. In some of them, the possibility of dental exposure cannot be excluded. This suggests that contact-associated transmission leading to acute disease in a community setting either infrequently contributes to chronicity or that surveillance techniques fail to extract critical details pertaining to the mode of transmission. Subjects are understandably reluctant to confide in casual acquaintances connected with a study (or even to hepatology fellows for that matter) concerning their use of illicit injections and may be uninformed as to whether they received any blood transfusions during a prior surgical procedure. Similarly, clinicians often may not appreciate the fact that low-birth-weight infants or those with neonatal hemolysis may have received small volume transfusions during their stay in the hospital, which may have resulted in hepatitis C infection, A careful review of previous hospital records and the nurses’ notes sometimes discloses this information, Are isolated instances of surreptitious injection drug abuse, inapparent percutaneous exposure, or overlooked transfusions received in infancy sufficient to account for community-acquired HCV
EDITORIALS
1427
infection? Possibly, but other potential modes of transmission should not be excluded. Vertical transmission of HCV is difficult to show unequivocally using only serologic tests, because anti-HCV may be transferred passively from mother to child.‘O~” Initial studies have purported to show that perinatal transmission of HCV to infants is low (~4%) based on seroconversion to anti-HCV.‘2,‘3 However, dual infection of the mother with HCV and human immunodeficiency virus (HIV) appears to predispose the infant to HCV infection provided that the infant also becomes infected with H1V.l’ Recently, HCV RNA was found at birth and during follow-up in infants born to antiHIV negative, HCV-infected mothers, suggesting that HCV infection can occur in the absence of HIV.14 The more powerful technique of nucleic acid sequencing has provided supporting evidence for vertical transmission of HCV. In a study on a Japanese family, the grandmother, mother, and infant were found to have similar or identical HCV RNA sequences in their blood, proving that HCV transmission from generation to generation was possible.15 The importance of this mode of HCV transmission is unclear, and the pathogenetic consequences of these infections remain to be elucidated. In two studies,“‘l” the prevalence of anti-HCV was significantly increased in homosexual men who also were positive for anti-HIV (9.8% of 400 men) when compared with those who were negative for anti-HIV (0.9% of 584 men). Because it is usually not possible to determine the specific sequence of these infections or whether they were acquired at the same time, modes of transmission cannot be elucidated. Regardless, the relatively low rate of HCV infection in this highly promiscuous population and unreliability of other exposure history suggest that sexual practices play a minor role in the eventual development of chronic hepatitis C even in the presence of HIV infection, In the absence of persuasive data from prospective trials on the transmission patterns of community-acquired HCV, experimental methods using animal models and molecular technology may provide the best means for assessing risk. Abe et a1.17presumably transmitted HCV to a chimpanzee which had been inoculated with saliva from another chimpanzee infected with HCV (strain F). Although the animal failed to develop any biochemical or histological evidence of hepatitis, characteristic ultrastructural changes were seen in a liver biopsy specimen obtained 21 weeks after inoculation. In a subsequent study, Abe and Inchauspe” detected HCV RNA in saliva from two of four chimpanzees infected with hepatitis C. A chimpanzee inoculated with HCV RNA-positive saliva apparently became infected. Other investigators also have reported the detection
1428
EDITORIALS
of HCV RNA in the saliva of patients C 1920
GASTROENTEROLOGY Vol. 102, No. 4
with hepatitis
These positive results seem to be at variance with other reports in which HCV RNA was not detected in samples of saliva, semen, and other body fluids.21J2 The study by Fried et al.” in this issue of GASTROENTEROLOGY failed to find HCV RNA in saliva and semen from nine patients with chronic hepatitis C whose titer of HCV RNA in serum ranged from 10-l to 10p3.Samples from either saliva or semen were available from an additional five patients with hepatitis C and also were negative. It is important to note that these investigators clarified the semen and saliva, e.g. removed cells, before RNA extraction, whereas all but one” of the other studies obtaining positive results extracted RNA from whole saliva. The other study that failed to detect the HCV genome in saliva, semen, and other body fluids froze the samples without clarification.16 Whether this process may have had a detrimental effect on recovery of viral genomic material was not experimentally determined. As in hepatitis B,23*24 a rather steep gradient probably exists between the concentrations of HCV found in serum and saliva. Whether HCV resides in lymphocytes present in the crevicular fluid that originates at the root-capillary interface of teeth has yet to be determined. Regardless, the presence of HCV in body secretions probably reflects the degree of viremia present in each patient. The development of HCV after a human bitez5 and after inoculation of saliva into chimpanzees17*18 provides evidence that saliva is infectious but does not incriminate transmission by the oral route. In this regard it should be recalled that primates were found to be susceptible to HBV-positive saliva only by parenteral routes (SC and IV) and not after ingestion of the samples.26 We conclude that unless the inoculum is large or the concentration of virus in the blood is unusually high, oral transmission by saliva or with objects contaminated by saliva is unlikely. Whereas the risk may be slightly greater after sexual activities, sufficient evidence is not available to change current recommendations to refrain from any alterations of a patient’s sexual practices if a stable relationship exists. In this regard, we receive considerable comfort from the careful studies of Fried et al.” and will continue to advise our patients that whereas the risk of oral or sexual transmission of HCV in a monogamous relationship is not zero, it does not warrant any behavioral modification at this time. Conversely, patients should always be apprised of the possibility of intrafamilial spread of the disease by inapparent percutaneous exposure through shared razors or toothbrushes. From our perspective, it appears that the major factors in community-acquired HCV infec-
tions are but variations on the known risk factors, i.e., injection drug abuse, inapparent percutaneous exposure, and blood transfusion. F. BLAINE HOLLINGER, M.D. HSIANG JU LIN, D.Sc.
Division of Molecular Virology and Department of Medicine Baylor College of Medicine and Veterans Affairs Medical Center Houston, Texas References 1 Alter HJ, Purcell
RH, Shih JW, Melpoder JC, Houghton M, Choo QL, Kou G. Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N Engl J Med 1989;321:1494-
1500. 2. Aach RD, Stevens CE, Hollinger FB, Mosley JW, Peterson
DA, Taylor PE, Johnson RG, Barbosa LH, Nemo GJ. Hepatitis C virus infection in post-transfusion hepatitis: an analysis with first- and second-generation assays. N Engl J Med 1991;
325:1325-1329. 3 Simmonds P, Zhang LQ, Watson HG, Rebus S, Ferguson
ED, Balfe P, Leadbetter GH, Yap PL, Peutherer JF, Ludlam CA. Hepatitis C quantification and sequencing in blood products, hemophiliacs and drug users. Lancet 1990;336:1469-1472. 4. Alter MJ. Epidemiology of community-acquired hepatitis C. In: Hollinger FB, Lemon SM, Margolis H, eds. Viral hepatitis and liver disease. Baltimore: Williams & Wilkins: 1991:410413. 5. Bortolotti F, Tagger A, Cadrobbi P, Crivellaro C, Pregliasco F, Ribero ML, Alberti A. Antibodies to hepatitis C virus in community-acquired acute non-A, non-B hepatitis. J Hepatol 1991;12:176-180. 6. Kamitsukasa H, Harada H, Yakura M, Fukuda A, Ohbayashi A, Saito I, Miyamura T, Choo QL, Houghton M, Huo G. Intrafamilial transmission of hepatitis C virus (letter]. Lancet 1989;2:987. 7. Ideo G, Bellati G, Pedraglio G, Botelli R, Donzelli T, Putignano G. Intrafamilial transmission of hepatitis C virus (letter). Lancet 1990;335:353. a. Luba D, Hsu H, Martin MC, Gregory PB, Greenberg HB, Garcia G. Failure of transmission of hepatitis C through household or sexual contact (abstr). Hepatology 1991;14:77A. 9. Everhart JE, Di Bisceglie AM, Murray LM, Alter HJ, Melpolder JJ, Kuo G, Hoofnagle JH. Risk for non-A, non-B (type C) hepatitis through sexual or household contact with chronic carriers. Ann Intern Med 1990;112:544-545. 10. Giovanninni M, Tagger A, Ribero ML, Zuccotti G, Pogliani L, Grossi A, Ferroni P, Fiocchi A. Maternal-infant transmission of hepatitic C virus and HIV infections: a possible interaction. Lancet 1990;335:1166. 11. Reesink HW, Wong VCW, Ip HMH, van der Poe1 CL, van ExelOehlers PJ, Lelie PN. Mother-to-infant transmission and hepatitis C virus. Lancet 1990;335:1216-1217. of 12. Stevens CE, Taylor PE. Perinatal and sexual transmission hepatitis C virus: a preliminary report. In: Hollinger FB, Lemon SM, Margolis H, eds. Viral hepatitis and liver disease. Baltimore: Williams & Wilkins: 1991:407-410. 13. Wejstal R, Hermodsson S, Iwarson R, Norkrans G. Mother to infant transmission of hepatitis C virus infection. J Med Virol 1990;30:178-180. 14. Thaler MM, Park CK, Landers DV, Wara DW, Houghton M, Veereman-Wauters G, Sweet RL, Han JH. Vertical transmission of hepatitis C virus. Lancet 1991;338:17-18.
EDITORIALS
April 1992
15. Inoue Y, Miyamura T, Unayama T, Takahashi K, Saito I. Maternal transfer of HCV. Nature 1991;353:609. 16. Papaevangelou G, Roumeliotou A, Kotsianopoulou M, Kallinikos G, Papoutsakis G. Sexual transmission of HCV. In: Hollinger FB, Lemon SM, Margolis H, eds. Viral hepatitis and liver disease. Baltimore: Williams & Wilkins; 1991:420-421. 17. Abe K, Kurata T, Shikata T, Sugitani M, Oda T. Experimental transmission of non-A, non-B hepatitis by saliva. J Infect Dis 1987;155:1078-1079. 18. Abe K, Inchauspe G. Transmission of hepatitis C by saliva (letter]. Lancet 1991;337:248. 19. Wang JT, Wang TH, Lin JT, Sheu JC, Lin SM, Chen DS. Hepatitis C virus RNA in saliva of patients with post-transfusion hepatitis C infection (letter). Lancet 1991;337:48. 20. Takamatsu K, Koyanagi Y, Okita K, Yamamoto N. Hepatitis C virus RNA in saliva (letter). Lancet 1990;336:1515. 21. Hsu HH, Wright TL, Luba D, Marton M, Feinstone SM, Garcia G, Greenberg HB. Failure to detect hepatitis C virus genome in human secretions with the polymerase chain reaction. Hepatology 1991;14:763-767. 22. Fried MW, Shindo M, Fong TL, Fox PC, Hoofnagle JH, Di Biscegli AM. Absence of hepatitis C viral RNA from saliva and
23.
24.
25. 26.
1429
semen of patients with chronic hepatitis C. Gastroenterology 1992;102:1306-1308. Davison F, Alexander GJM, Trowbridge R, Fagan EA, Williams R. Detection of hepatitis B virus DNA in spermatozoa, urine, saliva, and leucocytes of chronic HBsAg carriers. J Hepatol 1987;4:37-44. Jenison SA, Lemon SM, Baker LN, Newbold JE. Quantitative analysis of hepatitis B virus DNA in saliva and semen of chronically infected homosexual men. J Infect Dis 1987;156:299-307. Dusheiko GM, Smith M, Scheuer PJ. Hepatitis C virus transmitted by human bite (letter). Lancet 1990;336:503-504. Hollinger FB, Robinson WS, Purcell RH, Gerin JL, Ticehurst J, eds. Viral hepatitis: biological and clinical features, specific diagnosis, and prophylaxis. 2nd ed. New York: Raven, 1991:97-98.
Address requests for reprints to: F. Blaine Hollinger, M.D., Division of Molecular Virology, One Baylor Plaza, Texas Medical Center, Houston, Texas 77030-3498. 0 1992 by the American Gastroenterological Association
What Is the Role of Major Histocompatibility Complex Expression in Cholestasis? Major histocompatibility complex (MHC) antigens, termed HLA antigens in humans, are required for the interaction of T lymphocytes with antigen presenting cells (APC). APCs expressing class I MHC antigens interact with CD8 cells while APCs expressing class II MHC antigens are restricted in their interactions to CD4 cells. Both CD4 and CD8 cells have been found in areas of portal inflammation and piecemeal necrosis of patients with cholestatic liver disease.le3 In 1984, Ballardini published a seminal paper that described the abberent expression of class II antigens by biliary epithelial cells in patients with primary biliary cirrhosis (PBC).4 Since that time, much attention has been focused on MHC antigen expression by liver tissue in various disease states. Ordinarily, class I antigens are expressed by hepatic sinusoidal cells and biliary epithelial cells but not hepatocytes, whereas class II antigens are expressed by hepatic sinusoidal and dendritic cells but not hepatocytes or biliary epithelial cells. In patients with PBC, class I MHC antigens are expressed by periportal hepatocytes in areas of piecemeal necrosis, and, as previously noted, class II MHC antigens are found on biliary epithelial cells. However, these findings are not specific for PBC in that other inflammatory liver conditions such as chronic active hepatitis are associated with class I expression on hepatocytes; and cholestasis, whether associated with primary
sclerosing cholangitis or extrahepatic obstruction, has been associated with biliary expression of class II MHC antigens (5). In this issue of GASTROENTEROLOGY, Calmus, et al. conclude that cholestasis in patients with extrahepatic obstruction is associated with expression of MHC antigens and extends these observations in a rat mode1.6 Further observations show that immunosuppressive treatment does not alter the expression of class I MHC antigens by hepatocytes in the rat model. Calmus et al. raise a number of interesting questions regarding the mechanisms leading to the observed effects, about the larger issue of the importance of MHC antigen expression associated with chronic cholestatic conditions, and lastly about the relationship of changes in MHC antigen expression with respect to treatment response. The authors have observed that cholestasis in the form of PBC was associated with class I but not class II MHC expression on hepatocytes, which was also observed with cholestasis from extrahepatic obstruction. Furthermore, they found that there was a less pronounced expression of class II MHC antigens by bile duct cells in the presence of cholestasis in which only half of the patients showed aberrent class II expression. It was of note that all the bile duct cells in controls as well as patients, as expected, expressed
GASTROENTEROLOGY Vol. 102, No. 4
recent study suggested that there are only minor differences in the absolute rate of production of H, by different individuals.‘” Thus, the great individual variability observed in H, excretion after ingestion of similar doses of nonabsorbable carbohydrates appears to reflect differences in H, consumption, At present, therapy for flatulence is limited to dietary alterations that attempt to reduce the quantity of fermentable substrate reaching the colonic bacteria, a treatment that usually fails because of the wide variety of carbohydrates that are incompletely absorbed by the normal small intestine. Future approaches to this problem may take the form of manipulations designed to enhance H, consumption via either reduction of fecal stirring or implantation of Hz-consuming bacteria into the right colon. ALESSANDRA STROCCHI, M.D. MICHAEL D. LEVITT, M.D. Research Service
Veterans Administration Medical Center Minneapolis,
Minnesota
References 1. Weaver
2.
3. 4.
5. 6.
GA, Krause JA, Miller TL, Wolin MJ. Constancy of glucose and starch fermentations by two different human faecal microbial communities. Gut 1989;30:19-25. Stephen AM, Haddad AC, Phillips SF. Passage of carbohydrate into the colon. Direct measurements in humans. Gastroenterology 1983;85:589-595. Sanders T. Man shoots sparks when he passes gas. Weekly Word News 199l;October 15:37. Christ1 SU, MurgatroydPR, Gibson GR, Cummings JH. Production, metabolism, and excretion of hydrogen in the large intestine. Gastroenterology 1992;102:1269-1277. Kirk E. The quantity and composition of human colonic flatus. Gastroenterology 1949;19:782-794. Calloway DH, Murphy EL. The use of expired air to measure intestinal gas formation. Ann NY Acad Sci 1968;150:82-95.
Community-Acquired Infection Hepatitis C virus (HCV), which contains a singlestranded RNA encoding a number of proteins, has been identified as the principal cause of non-A, nonB (NANB) hepatitis in transfusion recipients, hemophilics, and injection drug abusers. Its presence can be detected by host antibodies to a few of its proteins’,’ and by polymerase chain reaction (PCR) assays that make use of specific sequences within the viral genome.3
7. Tomlin J, Lowis C, Read NW. Investigation of normal flatus production in healthy volunteers. Gut 1991;32:665-669, 8. Levitt MD. Production and excretion of hydrogen gas in man. N Engl J Med 1969;281:122-127. 9. Levitt MD, Berggren T, Hastings J, Bond JH. Hydrogen (H,) catabolism in the colon of the rat. J Lab Clin Med 1974;84:163167.
10. Wolin MJ. Fermentation in the rumen and human large intestine. Science 1981;213:1463-1468. 11. Gibson GR. A review. Physiology and ecology of sulphate-reducing bacteria. J Appl Bacterial 1990;69:769-767. 12. Lajoie SF, Bank S, Miller TL, Wolin MJ. Acetate production from hydrogen and [‘%]carbon dioxide by the microflora of human feces. Appl Environ Microbial 1988;54:2723-2727. 13. Gibson GR, Cummings JH, Macfarlane GT. Competition for hydrogen between sulphate-reducing bacteria and methanogenie bacteria from the human large intestine. J Appl Bacteriol 1988;65:241-247. 14. Gibson GR, Macfarlane GT, Cummings JH. Occurrence of sulphate-reducing bacteria in human faeces and the relationship of dissimilatory sulphate reduction to methanogenesis in the large gut. J Appl Bacterial 1988;65:103-111. 15. Strocchi A, Furne JK, Ellis JC, Levitt MD. Competition for hydrogen by human faecal bacteria: evidence for the predominance of methane producing bacteria. Gut 1991;32:14981501. 16. Strocchi A, Levitt MD. Factors affecting hydrogen
production and consumption by human fecal flora: The critical role of hydrogen tension and methanogenesis. J Clin Invest (in press). 17. Levitt MD, Ingelfinger FJ. Hydrogen and methane production in man. Ann NY Acad Sci 1965;150:65-81. 18. Flourie BF, Etanchaud F, Florent C, Pellier P, Bouhnik Y, Rambaud JC. Comparative study of hydrogen and methane production in the human colon using caecal and faecal homogenates. Gut 1990;31:684-685.
Address requests for reprints to: Michael Levitt, M.D., ACOS Research, Veterans Administration Medical Center, 1 Veteran’s Drive, Minneapolis, Minnesota 55417. This is a U.S. government work. There are no restrictions on its use.
Hepatitis
C Virus
The ability to serologically identify and treat hepatitis C has raised the consciousness of affected individuals concerning the mechanisms by which their disease may be transmitted to others. Although percutaneous or parenteral transmission is readily accepted by these patients as the principal mode of spread of HCV, their concern is invariably focused on the potential for contact-associated transmission. Patients wish to know whether oral transmission of
April 1992
HCV by saliva, e.g., by kissing, or by objects contaminated with saliva may occur or if transmission by sexual intercourse is possible. In a study of community-acquired acute NANB hepatitis conducted by the Centers for Disease Control (CDC) between 1986 and 1988 in four counties located in Washington, Colorado, Alabama, and Florida, no source of infection was identified in 40% of the subjects.* Of the cases tested, 70% were found to be anti-HCV positive when serial samples of blood were examined. Another study from Italy also found no evidence of overt parenteral exposure in about 40% of patients with community-acquired acute NANB hepatitis.5 Nine percent of the subjects in the CDC study reported that they were exposed to a household contact or sexual partner who had hepatitis or to multiple sexual partners in the 6 months preceding the onset of their acute hepatitis. This rate is similar to reports originating in Japan and Italy in which 8% of 122 family members exposed to chronic hepatitis cases had serologic evidence of HCV.6,7 Unfortunately, validation of these results with supplemental assays have not been performed. In contrast to these reports, additional studies in the United States evaluating the risk of acquiring HCV among 80 household or sexual contacts of 60 patients with chronic hepatitis C showed no evidence of infection detectable by the PCR assay8 or by an anti-HCV test.‘*’ In contradistinction to these studies, ~5% of our patients with chronic hepatitis C (verified by a PCR assay for HCV RNA) failed to provide a history of exposure to blood or blood components. In some of them, the possibility of dental exposure cannot be excluded. This suggests that contact-associated transmission leading to acute disease in a community setting either infrequently contributes to chronicity or that surveillance techniques fail to extract critical details pertaining to the mode of transmission. Subjects are understandably reluctant to confide in casual acquaintances connected with a study (or even to hepatology fellows for that matter) concerning their use of illicit injections and may be uninformed as to whether they received any blood transfusions during a prior surgical procedure. Similarly, clinicians often may not appreciate the fact that low-birth-weight infants or those with neonatal hemolysis may have received small volume transfusions during their stay in the hospital, which may have resulted in hepatitis C infection, A careful review of previous hospital records and the nurses’ notes sometimes discloses this information, Are isolated instances of surreptitious injection drug abuse, inapparent percutaneous exposure, or overlooked transfusions received in infancy sufficient to account for community-acquired HCV
EDITORIALS
1427
infection? Possibly, but other potential modes of transmission should not be excluded. Vertical transmission of HCV is difficult to show unequivocally using only serologic tests, because anti-HCV may be transferred passively from mother to child.‘O~” Initial studies have purported to show that perinatal transmission of HCV to infants is low (~4%) based on seroconversion to anti-HCV.‘2,‘3 However, dual infection of the mother with HCV and human immunodeficiency virus (HIV) appears to predispose the infant to HCV infection provided that the infant also becomes infected with H1V.l’ Recently, HCV RNA was found at birth and during follow-up in infants born to antiHIV negative, HCV-infected mothers, suggesting that HCV infection can occur in the absence of HIV.14 The more powerful technique of nucleic acid sequencing has provided supporting evidence for vertical transmission of HCV. In a study on a Japanese family, the grandmother, mother, and infant were found to have similar or identical HCV RNA sequences in their blood, proving that HCV transmission from generation to generation was possible.15 The importance of this mode of HCV transmission is unclear, and the pathogenetic consequences of these infections remain to be elucidated. In two studies,“‘l” the prevalence of anti-HCV was significantly increased in homosexual men who also were positive for anti-HIV (9.8% of 400 men) when compared with those who were negative for anti-HIV (0.9% of 584 men). Because it is usually not possible to determine the specific sequence of these infections or whether they were acquired at the same time, modes of transmission cannot be elucidated. Regardless, the relatively low rate of HCV infection in this highly promiscuous population and unreliability of other exposure history suggest that sexual practices play a minor role in the eventual development of chronic hepatitis C even in the presence of HIV infection, In the absence of persuasive data from prospective trials on the transmission patterns of community-acquired HCV, experimental methods using animal models and molecular technology may provide the best means for assessing risk. Abe et a1.17presumably transmitted HCV to a chimpanzee which had been inoculated with saliva from another chimpanzee infected with HCV (strain F). Although the animal failed to develop any biochemical or histological evidence of hepatitis, characteristic ultrastructural changes were seen in a liver biopsy specimen obtained 21 weeks after inoculation. In a subsequent study, Abe and Inchauspe” detected HCV RNA in saliva from two of four chimpanzees infected with hepatitis C. A chimpanzee inoculated with HCV RNA-positive saliva apparently became infected. Other investigators also have reported the detection
1428
EDITORIALS
of HCV RNA in the saliva of patients C 1920
GASTROENTEROLOGY Vol. 102, No. 4
with hepatitis
These positive results seem to be at variance with other reports in which HCV RNA was not detected in samples of saliva, semen, and other body fluids.21J2 The study by Fried et al.” in this issue of GASTROENTEROLOGY failed to find HCV RNA in saliva and semen from nine patients with chronic hepatitis C whose titer of HCV RNA in serum ranged from 10-l to 10p3.Samples from either saliva or semen were available from an additional five patients with hepatitis C and also were negative. It is important to note that these investigators clarified the semen and saliva, e.g. removed cells, before RNA extraction, whereas all but one” of the other studies obtaining positive results extracted RNA from whole saliva. The other study that failed to detect the HCV genome in saliva, semen, and other body fluids froze the samples without clarification.16 Whether this process may have had a detrimental effect on recovery of viral genomic material was not experimentally determined. As in hepatitis B,23*24 a rather steep gradient probably exists between the concentrations of HCV found in serum and saliva. Whether HCV resides in lymphocytes present in the crevicular fluid that originates at the root-capillary interface of teeth has yet to be determined. Regardless, the presence of HCV in body secretions probably reflects the degree of viremia present in each patient. The development of HCV after a human bitez5 and after inoculation of saliva into chimpanzees17*18 provides evidence that saliva is infectious but does not incriminate transmission by the oral route. In this regard it should be recalled that primates were found to be susceptible to HBV-positive saliva only by parenteral routes (SC and IV) and not after ingestion of the samples.26 We conclude that unless the inoculum is large or the concentration of virus in the blood is unusually high, oral transmission by saliva or with objects contaminated by saliva is unlikely. Whereas the risk may be slightly greater after sexual activities, sufficient evidence is not available to change current recommendations to refrain from any alterations of a patient’s sexual practices if a stable relationship exists. In this regard, we receive considerable comfort from the careful studies of Fried et al.” and will continue to advise our patients that whereas the risk of oral or sexual transmission of HCV in a monogamous relationship is not zero, it does not warrant any behavioral modification at this time. Conversely, patients should always be apprised of the possibility of intrafamilial spread of the disease by inapparent percutaneous exposure through shared razors or toothbrushes. From our perspective, it appears that the major factors in community-acquired HCV infec-
tions are but variations on the known risk factors, i.e., injection drug abuse, inapparent percutaneous exposure, and blood transfusion. F. BLAINE HOLLINGER, M.D. HSIANG JU LIN, D.Sc.
Division of Molecular Virology and Department of Medicine Baylor College of Medicine and Veterans Affairs Medical Center Houston, Texas References 1 Alter HJ, Purcell
RH, Shih JW, Melpoder JC, Houghton M, Choo QL, Kou G. Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N Engl J Med 1989;321:1494-
1500. 2. Aach RD, Stevens CE, Hollinger FB, Mosley JW, Peterson
DA, Taylor PE, Johnson RG, Barbosa LH, Nemo GJ. Hepatitis C virus infection in post-transfusion hepatitis: an analysis with first- and second-generation assays. N Engl J Med 1991;
325:1325-1329. 3 Simmonds P, Zhang LQ, Watson HG, Rebus S, Ferguson
ED, Balfe P, Leadbetter GH, Yap PL, Peutherer JF, Ludlam CA. Hepatitis C quantification and sequencing in blood products, hemophiliacs and drug users. Lancet 1990;336:1469-1472. 4. Alter MJ. Epidemiology of community-acquired hepatitis C. In: Hollinger FB, Lemon SM, Margolis H, eds. Viral hepatitis and liver disease. Baltimore: Williams & Wilkins: 1991:410413. 5. Bortolotti F, Tagger A, Cadrobbi P, Crivellaro C, Pregliasco F, Ribero ML, Alberti A. Antibodies to hepatitis C virus in community-acquired acute non-A, non-B hepatitis. J Hepatol 1991;12:176-180. 6. Kamitsukasa H, Harada H, Yakura M, Fukuda A, Ohbayashi A, Saito I, Miyamura T, Choo QL, Houghton M, Huo G. Intrafamilial transmission of hepatitis C virus (letter]. Lancet 1989;2:987. 7. Ideo G, Bellati G, Pedraglio G, Botelli R, Donzelli T, Putignano G. Intrafamilial transmission of hepatitis C virus (letter). Lancet 1990;335:353. a. Luba D, Hsu H, Martin MC, Gregory PB, Greenberg HB, Garcia G. Failure of transmission of hepatitis C through household or sexual contact (abstr). Hepatology 1991;14:77A. 9. Everhart JE, Di Bisceglie AM, Murray LM, Alter HJ, Melpolder JJ, Kuo G, Hoofnagle JH. Risk for non-A, non-B (type C) hepatitis through sexual or household contact with chronic carriers. Ann Intern Med 1990;112:544-545. 10. Giovanninni M, Tagger A, Ribero ML, Zuccotti G, Pogliani L, Grossi A, Ferroni P, Fiocchi A. Maternal-infant transmission of hepatitic C virus and HIV infections: a possible interaction. Lancet 1990;335:1166. 11. Reesink HW, Wong VCW, Ip HMH, van der Poe1 CL, van ExelOehlers PJ, Lelie PN. Mother-to-infant transmission and hepatitis C virus. Lancet 1990;335:1216-1217. of 12. Stevens CE, Taylor PE. Perinatal and sexual transmission hepatitis C virus: a preliminary report. In: Hollinger FB, Lemon SM, Margolis H, eds. Viral hepatitis and liver disease. Baltimore: Williams & Wilkins: 1991:407-410. 13. Wejstal R, Hermodsson S, Iwarson R, Norkrans G. Mother to infant transmission of hepatitis C virus infection. J Med Virol 1990;30:178-180. 14. Thaler MM, Park CK, Landers DV, Wara DW, Houghton M, Veereman-Wauters G, Sweet RL, Han JH. Vertical transmission of hepatitis C virus. Lancet 1991;338:17-18.
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April 1992
15. Inoue Y, Miyamura T, Unayama T, Takahashi K, Saito I. Maternal transfer of HCV. Nature 1991;353:609. 16. Papaevangelou G, Roumeliotou A, Kotsianopoulou M, Kallinikos G, Papoutsakis G. Sexual transmission of HCV. In: Hollinger FB, Lemon SM, Margolis H, eds. Viral hepatitis and liver disease. Baltimore: Williams & Wilkins; 1991:420-421. 17. Abe K, Kurata T, Shikata T, Sugitani M, Oda T. Experimental transmission of non-A, non-B hepatitis by saliva. J Infect Dis 1987;155:1078-1079. 18. Abe K, Inchauspe G. Transmission of hepatitis C by saliva (letter]. Lancet 1991;337:248. 19. Wang JT, Wang TH, Lin JT, Sheu JC, Lin SM, Chen DS. Hepatitis C virus RNA in saliva of patients with post-transfusion hepatitis C infection (letter). Lancet 1991;337:48. 20. Takamatsu K, Koyanagi Y, Okita K, Yamamoto N. Hepatitis C virus RNA in saliva (letter). Lancet 1990;336:1515. 21. Hsu HH, Wright TL, Luba D, Marton M, Feinstone SM, Garcia G, Greenberg HB. Failure to detect hepatitis C virus genome in human secretions with the polymerase chain reaction. Hepatology 1991;14:763-767. 22. Fried MW, Shindo M, Fong TL, Fox PC, Hoofnagle JH, Di Biscegli AM. Absence of hepatitis C viral RNA from saliva and
23.
24.
25. 26.
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semen of patients with chronic hepatitis C. Gastroenterology 1992;102:1306-1308. Davison F, Alexander GJM, Trowbridge R, Fagan EA, Williams R. Detection of hepatitis B virus DNA in spermatozoa, urine, saliva, and leucocytes of chronic HBsAg carriers. J Hepatol 1987;4:37-44. Jenison SA, Lemon SM, Baker LN, Newbold JE. Quantitative analysis of hepatitis B virus DNA in saliva and semen of chronically infected homosexual men. J Infect Dis 1987;156:299-307. Dusheiko GM, Smith M, Scheuer PJ. Hepatitis C virus transmitted by human bite (letter). Lancet 1990;336:503-504. Hollinger FB, Robinson WS, Purcell RH, Gerin JL, Ticehurst J, eds. Viral hepatitis: biological and clinical features, specific diagnosis, and prophylaxis. 2nd ed. New York: Raven, 1991:97-98.
Address requests for reprints to: F. Blaine Hollinger, M.D., Division of Molecular Virology, One Baylor Plaza, Texas Medical Center, Houston, Texas 77030-3498. 0 1992 by the American Gastroenterological Association
What Is the Role of Major Histocompatibility Complex Expression in Cholestasis? Major histocompatibility complex (MHC) antigens, termed HLA antigens in humans, are required for the interaction of T lymphocytes with antigen presenting cells (APC). APCs expressing class I MHC antigens interact with CD8 cells while APCs expressing class II MHC antigens are restricted in their interactions to CD4 cells. Both CD4 and CD8 cells have been found in areas of portal inflammation and piecemeal necrosis of patients with cholestatic liver disease.le3 In 1984, Ballardini published a seminal paper that described the abberent expression of class II antigens by biliary epithelial cells in patients with primary biliary cirrhosis (PBC).4 Since that time, much attention has been focused on MHC antigen expression by liver tissue in various disease states. Ordinarily, class I antigens are expressed by hepatic sinusoidal cells and biliary epithelial cells but not hepatocytes, whereas class II antigens are expressed by hepatic sinusoidal and dendritic cells but not hepatocytes or biliary epithelial cells. In patients with PBC, class I MHC antigens are expressed by periportal hepatocytes in areas of piecemeal necrosis, and, as previously noted, class II MHC antigens are found on biliary epithelial cells. However, these findings are not specific for PBC in that other inflammatory liver conditions such as chronic active hepatitis are associated with class I expression on hepatocytes; and cholestasis, whether associated with primary
sclerosing cholangitis or extrahepatic obstruction, has been associated with biliary expression of class II MHC antigens (5). In this issue of GASTROENTEROLOGY, Calmus, et al. conclude that cholestasis in patients with extrahepatic obstruction is associated with expression of MHC antigens and extends these observations in a rat mode1.6 Further observations show that immunosuppressive treatment does not alter the expression of class I MHC antigens by hepatocytes in the rat model. Calmus et al. raise a number of interesting questions regarding the mechanisms leading to the observed effects, about the larger issue of the importance of MHC antigen expression associated with chronic cholestatic conditions, and lastly about the relationship of changes in MHC antigen expression with respect to treatment response. The authors have observed that cholestasis in the form of PBC was associated with class I but not class II MHC expression on hepatocytes, which was also observed with cholestasis from extrahepatic obstruction. Furthermore, they found that there was a less pronounced expression of class II MHC antigens by bile duct cells in the presence of cholestasis in which only half of the patients showed aberrent class II expression. It was of note that all the bile duct cells in controls as well as patients, as expected, expressed
