å¡ CASE REPORT å¡

Four Cases with Intra familial Clustering of Hepatitis C Virus Infection Michiko Takahashi, Gotaro Yamada, Toshihiko Doi, Hisashi Endo, Hiroshi Nishimoto, Kouichi Takaguchi, Kazuhiro Matsueda, Shigeatsu Fujiki, Motowo Mizuno, Shingo Kinoyama and Takao Tsuji Four hepatitis C patients with intra familial clustering of hepatitis C virus (HCV) infection are reported. Antibodies to C100-3 antigen, capsid protein of HCV and GOR epitope were tested to detect histories of HCV infection. Transmission of HCV from mother to children, from father to children, and from wife to husband was implicated. Of all family members studied, three were positive for all antibodies, one for only antibody to capsid protein, two for anti bodies to capsid protein and GOR epitope but negative for antibody to C100-3 antigen and one (Internal Medicine 31: 224-226, 1992) vice versa. Key words: household contact, epidemiology, antibody to HCV

Intr oduction Hepatitis C virus (HCV) is a major cause of com munity-acquired as well as transfusion-associated non A, non-B hepatitis (1). Although there are a few reports on intra familial spread of HCV (2-4) , precise evaluation of familial transmission of HCV is dependent on the method of detection of HCV infection. Here, we report four families with intra familial clustering of HCV in fection revealed by detection of serum antibodies to C100-3 antigen (anti-C100-3) (Ortho HCV antibody ELISA test system, Ortho Diagnostic Systems Inc., New Jersey, U.S.A.) (5) or to capsid protein of HCV (anti-CP9 ELISA test) (6) or to GOR epitope (anti GOR ELISA test) (7). Case Report

histological classification) by liver biopsy. Examination of serum HCV markers revealed that the husband had anti-C100-3, anti-CP9 and anti-GOR and the youngest daughter had anti-CP9 and anti-GOR but was negative for anti-C100-3. The other daughters had no HCV markers (Table 1). About 40yr ago, there was an epi demic outbreak in the area where this family lived, however themembers family had movedofthere, ago. None of the hadonly a history blood30yr transfusion or drug addiction. They had no occupational exposures to blood or blood products.

Case2 A 60-year-old woman with liver cirrhosis, type C [anti-C100-3(+), anti-CP9(-), anti-GOR(+)], received a blood transfusion 29yr ago just after she gave birth to her third son. Eight years ago, she felt general fatigue, and laboratory examination revealed abnormal liver Case1 function tests. Liver biopsy done in September 1989 A 49-year-old woman with liver cirrhosis, type C revealed liver cirrhosis. Her second and third sons had [anti-C100-3(+), anti-CP9(+), anti-GOR(+)], had been diagnosed to have chronic hepatitis, type non-A, jaundice 24 yr previously when she was pregnant for her non-B, 3 and 2yr ago, respectively. Liver biopsies taken third child. After this episode, she has had abnormal in April 1988, and in September 1989 disclosed that both liver function tests and developed liver cirrhosis. Her of the sons had chronic active hepatitis. Her husband husband was treated for chronic hepatitis, type non-A, non-B, for 5 yr, and the youngest of her three daughters and three sons were tested for HCV markers. The second and third sons had the three types of antibodies; the was found to have chronic persistent hepatitis (European From The First Department of Internal Medicine, Okayama University Medical Okayama other had none School, (Table 2). The area where the family Received for publication November 13, 1990; Accepted for publication June ll, 1991 Reprints requests should be addressed to Michiko Takahashi, MD, The First Department of Internal Medicine, Okayama University Med School, 2-5-1 Shikata-cho, Okayama 700, Japan 224

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Intra familial

Clustering

of Hepatitis

C

Table 1. Liver Diseases and HCV Markers in Family Members of Table 3. Liver Diseases and HCV Markers in Family Members of Case1 Case3 M em b er

A ge

L iver disease

F ath er M o th er* C hild -1 C h ild -2 C h ild -3

52 49 29 27 24

chro nic hepatitis 1iver cirrhosis h ealth y h ealth y chro nic h epatitis

* Index patient, ( ): optical Cut off values of antibodies

A ntibo dies to H C V C lOO-3 CP9 GO R

M em b er

A ge

L iver disease

A ntib odies to H C V C lOO-3 CP9 G OR

+ (o ver 3) + (1.021)

+ (2 .697) + (2 .629)

+ (2 .000) + (2 .711)

F ather* M other C hild-1 C hild-2

43 19 16

ch ronic hep atitis healthy healthy healthy

+ (2 .837) N D -

-

+ (2 .754)

+ (2 .491)

C hild-3

14

h ealthy

+ (2 .503 )

density value to HCV are 0.450.

+ (2.688 ) ND + (0.979)

+ (1.638) ND + (0 .726)

* Index patient, ( ): optical density value, ND: not done Cut off values of antibodies to HCV are 0.450.

Table 2. Liver Diseases and HCV Markers in Family Members of Table 4. Liver Diseases and HCV Markers in Family Members of Case2 Case4 Antibodies Member Age F M C C C

a th e r o th e r* h ild -! h ild -2 h ild -3

60 60 35 32 29

Liver disease h e a lth y liv e r cirrh o sis h e a lth y ch ro n ic h e p atitis ch ro n ic h e p atitis

C100-3

to HCV CP9

Antibodies GOR

+ (o v e r 3 )

.-

+ (2 .6 8 3 )

+ (o v e r 3 ) + (o v e r 3 )

+ (2 .9 6 3 ) + (1 .3 2 9 )

+ (2 .7 0 5 ) + (2 .7 6 9 )

* Index patient, ( ): optical density value Cut off values of antibodies to HCV are 0.450. lived was not known to be a hepatitis-infected area. The mother continued to breast feed her children after trans fusion. Until the liver diseases were discovered, they all felt healthy and they had never received an injection at the same time. Case3 A 43-year-old man with chronic hepatitis, type C [anti-C100-3(+), anti-CP9(+), anti-GOR(+)], had a blood transfusion 24yr previously because of a traffic accident. He was discovered to have liver disease during health screening 8 yr previously. Liver histology biopsied in October 1989 showed chronic active hepatitis. His three children and divorced wife had no history of liver disease. His eldest daughter was positive for anti-CP9 and anti-GOR but negative for anti-C100-3, whereas his youngest son was positive for anti-C100-3 but negative for anti-CP9 and anti-GOR. Their liver function tests were normal (Table 3). The family had never lived in a hepatitis-infected area. The children with positive HCV markers were healthy, and had no history of blood transfusion. Case4 A 57-year-old woman with chronic hepatitis, type C [anti-C100-3(+), anti-CP9(+), anti-GOR(+)], received a blood transfusion at the time of an operation for myoma of the uterus llyr previously and developed post-transfusion hepatitis. She underwent liver biopsy in September 1989 which showed chronic active hepatitis. Internal

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Vol. 31, No. 2 (February

1992)

Member

Age

Liver disease

C100-3

to HCV CP9

GOR

Husband 60 healthy - +(2.214) Wife* 57 chronichepatitis +(over3) +(2.307) +(2.494) * Index patient, ( ): optical density value Cut off values of antibodies to HCV are 0.450. She was treated with interferon therapy. Her husband was positive for anti-CP9 with a high titer but negative for anti-C100-3 and anti-GOR (Table 4). He was healthy and had no history of blood transfusion or liver disease. They have never lived in a hepatitis-infected area, and have not had occupational exposure to blood or blood products. Discussion We report four family cases with the clustering of HCV infection revealed by the detection of anti-C100-3, anti-CP9 and anti-GOR. Transmission routes of HCV in sporadic hepatitis C are usually obscure, and the transmission through not only ordinary household con tact but also perinatal (8, 9) or sexual (10, ll) contact is still controversial. The husbands of Cases 1 and 4, who were members of the community, were thought to have had many chances for HCV infection. In particular, the husband of Case 1, who lived in a HCV-infected area, But they hadbeen no obvious withinHCV other than could have infectedcontacts with HCV the community. the close contact with their wives. In the other cases, many of whom are young, intra familial spreads of HCV are easy to hypothesize. The mother-to-child transmis sion in Case 1 seemed to happen during the perinatal period. In Case 2, intimate contacts between the mother and her children would play an important role of HCV infection. In Case 3, an ordinary household contact was likely the route of HCV infection. Recently, the transmission of HCV through saliva via a human bite was reported (12). Body fluids including saliva might 225

Takahashi be important in the intra familial spread of HCV. Six family members including the index patients were positive for three types of HCV markers, three members for two of the three types, and two members only for anti-C100-3 or anti-CP9. The antibodies detected in the family members were often not identical to those of the index patient. It has been reported that in the case of post-transfusion hepatitis, anti-C100-3 or anti-GOR was found to have seroconverted after transfusion of seronegative blood (13). And it was shown that anti C100-3 was undetectable although the chimpanzee was infected with HCV after inoculation of anti-C100-3 positive serum (14). Furthermore, in post-transfusion hepatitis, not only the interval between transfusion and anti-C100-3 also the of anti These reportsseroconversion indicate that thebut absence ofduration anti-C100-3 C100-3 response were different in each patient (15). or anti-CP9 or anti-GOR in the present cases might be attributable to an inadequate immune response to HCV or the period from infection. Another possibility is that the family members with normal liver function tests had already lost one or two antibodies after resolution of HCV infection, as these antibodies observed in the healthy men could reflect a past infection with HCV Anti-CP9 (6, 7, 13).is an antibody against the putative capsid protein of HCV. Anti-CP9 and anti-C100-3 overlap in 54% of patients with non-A, non-B liver diseases; 18% are positive only for anti-CP9, while 15% are positive only for anti-C100-3 (6). GOR epitope is not encoded by reported sequences of HCV but instead is coded for by a host cellular sequence, and anti-GOR is closely associated with HCV infection. Among non-A, non-B liver disease patients, 67% are positive for both anti GOR and anti-C100-3, 18% only for anti-GOR, and 11% only for anti-C100-3 (7). Based on the reports that anti-CP9 or anti-GOR appears at a higher rate than anti C100-3 in non-A, non-B hepatitis patients and volunteer blood donors (6, 7), we looked for antibodies to HCV among family members of hepatitis C patients. We also found that detection of HCV infection only by anti C100-3 assay could lead to an underestimation of the intra familial spread of HCV. These findings suggest that tests of HCV markers including anti-CP9 and anti-GOR are more useful for evaluation of intra familial HCV infection. Furthermore, assays employing other epitopes in addition to C100-3, CP9 and GOR, and a polymerase

226

et al chain reaction assay detecting HCV RNA, would be helpful for more precise evaluation. Acknowledgments: We thank Dr. Hiroshi Yoshizawa in the De partment of Hygiene of Hiroshima University Medical School and Dr. Kazuaki Takahashi in the Department of Public Health of Hamamatsu University School of Medicine, for analysis of anti-CP9 and anti-GOR. References 1) Kuo G, Choo QL, Alter HJ, et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 244: 362, 1989. 2) Dienstag JL. Non-A, non-B hepatitis. I. Recognition, epidemi ology, and clinical features. Gastroenterology 85: 439, 1983. 3) Kamitsukasa H, Harada H, Yakura M, et al. Intra familial trans mission of hepatitis C virus. Lancet 2: 987, 1989. 4) Ideo G, Bellati G, Pedraglio E, Bottelli R, Donzelli T, Putignano G. Intra familial transmission of hepatitis C virus. Lancet 335: 353, 1990. 5) Choo QL, Kuo G, WeinerAJ, Overby LR, Bradley DW, Hough ton M. Isolation of a CDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244: 359, 1989. 6) Okamoto H, Gkada S, Sugiyama Y, et al. Enzyme-linked im munosorbent assay for antibodies against the capsid protein of hepatitis C virus with a synthetic oligopeptide. Jpn J Exp Med 60: 223, 1990. 7) Mishiro S, Hoshi Y, Takeda K, et al. Non-A, non-B hepatitis specific antibodies directed at host-derived epitope: Implication for an autoimmune process. Lancet 336: 1400, 1990. 8) Wejstal R, Hermodsson S, Iwarson S, Norkrans G. Mother to infant transmission of hepatitis C virus infection. J Med Virol 30: 178, 1990. 9) Reesink HW, Wong VCW, Ip HMH, van der Poel CL, van Exel Oehlers PJ, Lelie PN. Mother-to-infant transmission and hepatitis C virus. Lancet 335: 1216, 1990. 10) Everhart JE, Di Bisceglie AM, Murray LM, et al. Risk for non A, non-B (type C) hepatitis through sexual or household contact with chronic carriers. Ann Intern Med 112: 544, 1990. ll) Melbye M, Biggar RJ, Wantzin P, Krogsgaard K, Ebbesen P, Becker NG. Sexual transmission of hepatitis C virus: Cohort study (1981-9) among European homosexual men. Br Med J 301: 210, 1990. 12) Dusheiko GM, Smith M, Scheuer PJ. Hepatitis C virus trans mitted by human bite. Lancet 336: 503, 1990. 13) Yoshizawa H, Nojiri N, Takahashi K. Measurement of anti GOR antibodies in prevention of post-transfusion non-A, non B hepatitis. Lancet 337: 47, 1991. 14) Weiner AJ, Kuo G, Bradley DW, et al. Detection of hepatitis C viral sequences in non-A, non-B hepatitis. Lancet 335: 1, 1990. 15) Alter HJ, Purcell RH, Shih JW, et al. Detection of antibody to hepatitis C virus in prospective followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N Engl J Med 321: 1494, 1989.

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1992)