Original Paper
Nephron 1992;60:150-153
Department of Virology Fundado Oswaldo Cruz, and Clínica de Doen^s Renais, Rio de Janeiro. Brazil
Key Words Non-A, non-B hepatitis Hepatitis C virus Hemodialysis
Hepatitis C Virus in Chronic Hemodialysis Patients with IMon-A, l\lon-B Hepatitis
Abstract Sixteen o f 110 hemodialysis (HD) patients fulfilling criteria of non-A, non B hepatitis (N A N B H ), i.e. alanine aminotransferase (ALT) > 5 0 U/ml in the absence of both serologic markers for acute H BV and H A V infections and clinical evidence o f another cause o f hepatitis, were tested for the presence of antibodies against hepatitis C virus (anti-HCV) by enzyme immunoassay (Ortho, Diagnostics). All (100%) were anti-HCV-positive. There were 5 patients with a monophasic (M) rise pattern (1 or 2 A L T rises), and 11 cases demonstrated a polyphasic (P) rise elevation pattern (more than 2). The mean A L T value o f the M group was 202.3 ± 209 U/ml and that o f the P group was 116.6 ± 39.1 U/ml. The patients received a mean o f 19.1 ±16.2 units of packed red cells during the follow-up period (69.9 months). Only 1patient received no blood transfusion. Six patients had a past H BV infection and 3 became HIV-infected in the course of this study. The high rate o f infection of hemodialysis patients with hepatitis C virus in our setting points to the need for improved control measures.
Introduction Non-A , non-B-hepatitis (N A N B H ) has become a com mon diagnosis or acute hepatitis, when serologic tests and epidemiologic evidence exclude other hepatotropic viruses (HBV, H A V , H D V , cytomegalovirus and Epstein-Barr vi rus [1]. At least two distinct agents have been associated with N A N B H ; hepatitis C and E viruses, transmitted parenterally and enterally, respectively [2]. N A N B H viruses are im portant causes o f hepatitis among patients and staff mem bers o f hemodialysis (HD) units, especially after hepatitis B has been largely controlled with routine HBsAg screening and adoption o f preventive measures [3]. About 10-15% of the patients undergoing prolonged courses o f H D show
Accepted: Mai 3, 1991
elevated serum alanine aminotransferase (ALT) levels for long periods o f time in the absence of known serologic markers o f hepatotropic viruses [4, 5]. The genome o f one N A N B H virus, named hepatitis C virus (H CV), was recently cloned and identified as a posi tive-strand R N A molecule [6]. An assay for circulating antibodies against the virus was developed using antigens expressed by a plasmid containing a part o f this viral genome. Results obtained with this assay demonstrated that H C V is a major cause of posttransfusion-associated N A N B H . In order to detemine the frequency o f H C V infection in H D patients, we tested a group o f patients in whom N A N B H had been suspected on the basis o f elevated A L T levels. We also correlated the prevalence o f anti-HCV
Clara F.T . Yoshida Departamento de Virología, Fu n dado Oswaldo Cruz Avenida Brasil 4365 C E P 21040. Rio de Janeiro. RJ (Brazil)
© 1992 S. Kargcr A G , Bascl 0028-2766/92/ 0602-0150S2.75/0
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Clara Fumiko Tachibana Yoshida8 Clarina TakahashC Ana Maria Coimbra Gaspara Hermann G . Schatzmayra Frederico Ruzanyb
Anti-HCV testing
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with the duration o f dialysis, number o f blood transfusions and the prevalence o f H BV and H IV markers.
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Fig. 1. M and P A LT pattern and un its of packed red cells received in HD N ANBH patients.
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E L IS A and confirmed with a Western blot test (Fiocruz). In August 1989, blood from these patients was collected for anti-HCV testing, using an Ortho H C V E L IS A (Ortho diagnostics, USA).
Subjects and Methods Results All 16 patients studied were anti-HCV positive (100%). The first elevation o f A L T levels was observed between 1 and 29 months after starting. H D (mean 10, SD 9.7). Eight patients had this change within their first 5 months o f H D . An M A L T rise was observed in 5 patients diagnosed as acute N A N B H , and it resolved in the following few months. Eleven cases had P rises, all diagnosed as chronic N A N B H (fig. 1). In the latter group, up to 25 periods of elevated A L T levels were observed (mean 10, S D 6) during the follow-up period. It was remarkable that these periods o f high A L T levels were intercalated with normal levels in a fluctuating way. Mean A L T values were 202.3 ± 209 and 116.6 ± 39.1 U/ ml in the M and P groups, respectively (table I). All cases were anicteric and asymptomatic, and detected only by the routine screening for A LT . They had received an average o f
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N A N B H diagnosis was established by the occurrence o f at least two rises in serum A L T activity levels of 50 U/ml or greater, 3-7 days apart, in the absence fo serologic markers for acute or chronic H BV or H A V infections and clinic evidence of another cause for hepatitis. We considered the A L T level rise to be monophasic (M) when one or two periods of elevated A L T level were seen and polyphasic (P) when more than two periods occurred. Sixteen o f HO patients fulfilled the above-mentioned crite ria. A L T levels were tested in monthly intervals from the start o f dialysis. These patients had an average age o f 46 ± 15 years, ll were female and the mean duration of dialysis was 66.7 ± 8.4 months (range 35-113 months). The upper normal limit in the A L T assay was 28 U/ml for the uremic popula tion. HBsAg, anti-HBc and anti-HBs were tested with an inhouse E L ISA (Fiocruz). Anti-H AV was tested by HAVAB (Abbott, North Chicago, L). Anti-HIV was tested by
Table 1. Characteristics of A LT level in N AN BH patients during the follow-up period
A LT pattern
Altered A LT level U/ml
Periods of altered ALT'
Time course of altered A LT months
Follow-up months
M P
202.3 ±209 111 .6 ± 39.1
1.4 ±0.5 10.18 ±6.8
4.2 ±2.1 23.4 ±17.4
63.4 ±31.8 75.9 ±24
1 Period is the course since the A LT rise until normality.
Discussion Relatively little information is at present available on the frequency o f H C V infection in H D patients. The prevalence o f antibodies of H C V (anti-HCV) in H D patients ranges from 1% in the U K to 40% in Hungary [8-11]. This large variation has been attributed to varying frequencies of blood transfusions and prevalence of H B V markers in the studied populations. We have recently observed that in Brazil, 50% o f H D patients and 20% o f the continuous ambulatory peritoneal dialysis patients are anti-HCV-positive. We also tested 57 serum samples from H D patients who were anti-HBc-positive and found anti-HCV in 75.4% of this population rein forcing the high prevalence o f H C V infection in our envir onment 1 [unpubl. data]. The high frequency of anti-HCV seropositivity in pa tients who fulfill the criteria for N A N B H suggests that H C V is an important cause of N A N B H in our dialysis center. Although anti-HCV was detected in almost all cases many months after the onset of N A N B H , the anti-HCV response was closely associated with active hepatitis in chronic pa tients (P cases), as demonstrated by the A L T rises (fig. 1).
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Twelve patients probably acquired N A N B H after blood transfusion. Elevated A L T levels were observed on average 2.8 months after receiving packed red cells. Seroconversion seems to occur late after the onset o f the disease since acute posttransfusion N A N B H patients have a lower prevalence o f anti-H CV than chronic cases. Seroconversion occurred at 3^1 months postexposure [9]. The more frequent finding of anti-HCV in chronic N A N B H (cases P 1-11) than in resolved N A N B H (cases M 1-5) may reflect the persistence o f sufficient type C virus antigen to boost the immune response repeatedly [12]. Only 1patient (M 3) had never received any transfusion, which is a very important fact because it suggests other ways o f acquiring this virus during H D . Problems reported with the anti-HCV assay are the long diagnostic window before seroconversion and the specifici ty o f the test. While approximately one third of HCV-infected patients will develop anti-HCV antibody within several weeks, others may take many months, taking as long as 1 year to seroconvert [13]. The application o f sensitive tech niques for H C V genome detection before seroconvertion is important in confirming the diagnosis and establishing the period o f infectivity in H C V patients [14]. Our data reveal that the H C V infection in N A N B H H D patients is frequent in Brazil. Infection is almost always followed after blood transfusion, but can also occur in the absence o f transfusion. The patients frequently develop chonic hepatitis and H C V infection seems to be more common than H BV and H IV infections. More information is needed to establish control and preventive measures in our setting.
Acknowledgements The authors are indebted to Dr. W. H. Gerlich of the University of Gottingen, FR G , for permission to conduct anti-HCV testing in his laboratory. C . F.T. Yoshida wasa trainee at the above institute through the D A A D Program.
Yoshida/Takahashi/Gaspar/Schatzmayr/ Ruzany
H CV in Hemodialysis N AN BH Hepatitis
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19.1 ±16.2 units o f packed red cells during the follow-up period. The elevated A L T levels were observed from 0.5 to 10 months (mean 2.8 ±2.8 months) after blood transfusion. Only 1patient had never received a blood transfusion in the past. Figure 1 and table 1 show the number o f transfusions of packed red cells and periods o f elevated A L T for 11 patients from the beginning of dialysis treatment. The characteris tics o f A L T elevations are also demonstrated. Six patients had past H B V infection and presented antiHBc and anti-HBs markers. Two others were anti-HBs-positive after vaccination. Three patients were anti-HIV-positive.
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