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Prepublished online as a Blood First Edition Paper on April 17, 2002; DOI 10.1182/blood-2001-12-0192.
TRANSFUSION MEDICINE
From the Infectious Diseases Unit, Ospedali Riuniti,
Bergamo, Italy; and Blood Transfusion and Transplantation Immunology
Center and Postgraduate School of Gastroenterology, both of IRCCS
Ospedale Maggiore, Milan, Italy.
Before the introduction of hepatitis C virus (HCV) screening for
blood donors, the risk of acquiring HCV infection as a result of a
transfusion was about 10%. The aim of this study was to assess the
frequency and rate of progression to cirrhosis in patients with
transfusion-associated chronic HCV infection and identify possibly
negative prognostic factors. Of 2477 consecutive patients with clinical
or laboratory evidence of liver disease, 392 (16%) were anti-HCV- and
HCV-RNA-positive, had anamnestic evidence of a single and precisely
dated transfusion event, and showed no other causes of chronic liver
disease; 268 (68%) underwent ultrasound-guided liver biopsy and
were enrolled in the study. After a mean interval of 18.4 years, 54 patients (20.1%) had cirrhosis, which multivariate analysis showed to
be independently associated with the duration of follow-up, age at
infection and at the time of liver biopsy, and serum alanine
aminotransferase levels at biopsy. The time necessary to have a 50%
probability of developing cirrhosis in patients aged 21-30, 31-40, and
more than 40 years was 33, 23, and 16 years, respectively. In
comparison with those aged 20 years or less at infection, the risk
ratio of developing cirrhosis over a period of 30 years for patients
aged 21-30 and at least 31 years at infection was, respectively, 4.51 (95% confidence interval, 1.03-19.76) and 12.29 (95% confidence
interval, 3.06-49.40). In patients with transfusion-associated chronic
hepatitis C, the risk of cirrhosis is related to age at infection and
disease activity. Our findings suggest that an aggressive therapeutic
approach should be adopted in patients infected by HCV at an older age
to prevent the progression to end-stage liver disease.
(Blood. 2002;99:4588-4591) Chronic hepatitis C virus (HCV) infection is the
main cause of end-stage liver disease in developed
countries.1 Until the introduction of anti-HCV screening
for blood donors, the administration of infected blood components
significantly contributed to the spread of the virus. In Italy, more
than 10% of the patients receiving blood transfusion during the 1980s
developed clinically evident posttransfusion hepatitis,2,3
and the prevalence of anti-HCV reactivity among transfusion-dependent
patients starting their transfusion regimens in the same period
approached 90%, with 70% of these patients developing chronic HCV
infection.4,5
The current risk of acquiring HCV infection through blood transfusion
is negligible in comparison with other routes of viral transmission4,6 and can be expected to decrease further
following the adoption of nucleic acid testing technology for blood
screening. However, specialists in various fields of medicine,
including hematologists and hepatologists, are now facing the clinical
effects of the past epidemic of transfusion-associated HCV. Current
recommendations require that individuals receiving blood transfusions
before the initiation of second-generation anti-HCV tests undergo
anti-HCV screening.1 Furthermore, an increasing number of
patients with transfusion-associated infection are now seeking
treatment and counseling.
As detailed in a recent review,7 most studies of the rate
of progression of chronic hepatitis C have so far concentrated on
community-acquired infections, and only scattered data are available
concerning transfusion-associated disease. However, estimates of the
real proportion of patients experiencing a more severe clinical course
and the definition of the risk factors for disease progression are
highly important in order to identify the patients deserving a more
aggressive and targeted clinical approach.
The aim of this study was to assess the frequency of liver disease and
estimate the rate of progression to cirrhosis in a cohort of patients
who acquired HCV infection after a single and precisely dated
transfusion event and to identify the factors associated with a
possibly negative prognosis.
Patients
Of these 392 cases, 39 (9.9%) had evidence of a single
transfusion event between 1948 and 1964 in their medical history and/or personal copies of medical records; the remaining 353 cases were treated in 1965 or later, and the pertinent medical records were fully
accessible on microfilm at Ospedali Riuniti.
Of the enrolled patients, 309 were referred by their family physicians
or a primary or secondary care center because of a persistent
abnormality in liver enzymes or anti-HCV reactivity, whereas the
anti-HCV reactivity in 83 was first recognized during serologic
screenings for blood donations after 1992. Liver biopsy was not
indicated in 100 patients because of persistently normal alanine
aminotransferase (ALT) levels (n = 56), age more than 65 years
(n = 13), chronic ischemic heart disease (n = 7), severe cardiomiopathy (n = 3), obstructive lung disease (n = 4),
concomitant mental disorder (n = 2), or platelet counts of less than
80 × 109/L (80 000/µL) (n = 15). In this last
group, 1 patient had chronic autoimmune thrombocytopenic purpura, 2 had
connective disorder, and 1 had ethylenediaminetetraacetic
acid-dependent pseudothrombocytopenia contraindicating liver biopsy
because of medicolegal concerns; of the remaining 11 patients, 8 had
clinical, biochemical, and/or ultrasound findings consistent with
underlying liver cirrhosis.
At the end of the selection process, a liver biopsy was proposed to the
remaining 292 patients, 268 of whom (91.8%) gave their written
informed consent to the procedure.
Methods
Statistical analysis Conventional descriptive statistics were used to analyze the data. The 2 test and one-way analysis of variance were
respectively used to compare the nonparametric and parametric data.
Univariate and multivariate analyses (multivariate regression model)
were used to assess the independent associations between a histologic
diagnosis of liver cirrhosis and sex, follow-up duration, age at liver
biopsy, age at HCV infection, HCV genotype, and ALT levels at biopsy. The relative risk of developing cirrhosis was estimated, and 95% confidence intervals (CIs) were obtained by means of log
transformation. Survival analysis was made using the Kaplan-Meier
(product limit) method,11 with the duration of follow-up
being defined as the time between the single transfusion event and the
time of the liver biopsy. The statistical analysis was stopped when
fewer than 20% of the patients remained under observation. The
survival inferences were based on the 2 test for
multigroup comparison and the Cox-Mantel test for 2-sample comparisons.12,13 All of the tests were 2-sided, and
P < .05 was considered statistically significant. The
statistical analyses were made using a personal computer and the SPSS
statistical software package (SPSS, Chicago, IL).
The single transfusion events for the 392 eligible patients were
precisely dated between 1948 and 1992 (median 1977). A total of 336 (86%) patients had increased serum ALT levels at the time of liver
biopsy. The demographic and baseline characteristics of the 268 patients included in the study did not differ from those of the 124 patients who did not undergo liver biopsy (Table 1). Of the biopsied patients, 54 (20.1%)
were found to have definite cirrhosis a median of 18.4 years (range,
4.2-43.1 years) after blood transfusion.
Univariate analysis showed that all of the examined variables (sex, follow-up duration, age at liver biopsy, age at HCV infection, HCV genotype, and ALT levels at biopsy) were associated with the presence of cirrhosis. At multivariate analysis, age at infection (P = .001), age at liver biopsy (P = .011), serum ALT levels at biopsy (P = .003), and the duration of follow-up (the time from tranfusion) (P = .002) were independent predictors of the presence of cirrhosis, which was not significantly associated with sex or HCV genotype. However, when analyzed as a function of time using the Cox-Mantel regression test, only age at infection retained its negative statistical prognostic significance (R = 0.6, P < .0001) and significantly correlated with both the staging and grading of liver disease (P < .005 for both). To investigate this aspect further, the patients were divided into 5 10-year age classes (1-10, 11-20, 21-30, 31-40, and > 40 years) on
the basis of their age at infection. The number of patients in each age
class was comparable (30, 47, 89, 59, and 43, respectively), and the
duration of follow-up was adequate (at least 41 years unless all of the
patients had reached the end point). The course of chronic HCV
infection was negatively influenced by age at infection (Figure
1), as indicated by the finding of 3 cases of cirrhosis among the 77 patients aged 20 years or less at
infection as against 51 among the 191 older patients (
Our series included patients with chronic HCV infection due to a single transfusion event between 1948 and 1992. In accordance with the aim of the study, other possible cofactors for chronic liver disease (eg, alcohol abuse, hepatitis B virus and/or human immunodeficiency virus coinfection, iron overload) were carefully excluded, thus minimizing biases in patient recruitment. The 16% of the total cohort of 2477 consecutive patients attending the tertiary care liver unit in Bergamo who fulfilled the enrollment criteria represent a valid population for studying the natural history of transfusion-associated chronic hepatitis C. We are reasonably confident in attributing most of these cases to blood transfusion because, until the end of the 1980s, approximately 10% of the patients receiving blood transfusions in Italy developed posttransfusion hepatitis2 and most were subsequently diagnosed as having HCV infection. Conversely, the incidence of community-acquired HCV infection calculated in the same area in the 1990s was 1 per 10 000 person-years.14 Even if we hypothesize a 10 times higher incidence of nontransfusional sources in the preceding decades, the cumulative frequency after a mean follow-up of 18.4 years would be 1 per 54.3. This would lead to no more than 5 cases (1.84%) being inappropriately classified as "posttransfusional." The overall proportion of viremic patients who developed cirrhosis was 20.1%. However, it is notable that the patients with resolved infection (HCV-RNA-negative) were not included in this computation. Because these patients usually have a normal histologic pattern on liver biopsy,15,16 the actual proportion of cirrhosis among the initially infected patients could be slightly lower. On the other hand, we excluded from the histologic evaluation 8 patients with clinical evidence of cirrhosis because of the presence of thrombocytopenia: this leads to an underestimate in the frequency of liver cirrhosis that, however, was not statistically significant. At multivariate regression analysis, age at infection and biopsy, disease activity at biopsy, and the duration of clinical follow-up were all independently associated with the risk of developing end-stage liver disease. However, in the older age groups (Figure 1d,e) few patients were available for analysis after 25 years of follow-up, and so the data after this period should be cautiously interpreted. The relevance of age at infection is further supported by the finding of a progressively decreasing median time to end-stage liver disease from 33 years to the 16 years observed in the patients aged more than 40 years at infection, who developed cirrhosis at a median age of 62 years. In this regard, it is worth mentioning some recent data relating to children and women. In the first prospective series of 67 patients with chronic HCV infection due to infected blood supply at a mean age of 2.8 years, the infection resolved in 30 (45%) after a mean follow-up of 20 years; of the remaining 37 patients, only 1 had abnormal liver enzymes, and only 3 showed signs of histologic damage although they also had additional risk factors for liver damage.17 The second series included a highly selected cohort of Irish women who had received HCV-infected anti-D immune globulin at a mean age of 28 years: after a median of 17 years, most of the 376 viremic subjects showed minimal changes at liver biopsy; of the 7 with cirrhosis (2%), 2 reported concomitant chronic alcohol abuse.18 Importantly, however, an unexpectedly high proportion (45%) of the infected women recovered and were no longer viremic 20 years after the infection, which may suggest that low viral titers or attenuated strains were present in the infected immunoglobulins due to manufacturing procedures. The data provided by Poynard et al,19 who studied a large cohort of patients who acquired chronic hepatitis C from different sources, are also consistent with the hypothesis of an inverse correlation between age at infection and progression to cirrhosis. The same 3 studies indicate a rate of progression to cirrhosis ranging from nil to 18% 12 to 20 years after infection.17-19 The noticeably higher frequencies in other series (up to 46%)20-22 may be due to the heterogeneity of the sources of infection, the concomitance of relevant comorbidity, and/or the lack of age stratification. Various factors may be responsible for the age-related differences in the clinical course of chronic HCV infection. First, structural, biochemical, and/or immunologic differences have been described in the livers of children and adults, mainly concerning fibrogenic mechanisms; eg, the reduced availability of antioxidizing systems could be responsible for the age-related sensitivity of the liver to the oxygen-reactive compounds and organic aldehyde radicals formed during lipid peroxidation, which can induce the expression of profibrotic and proinflammatory cytokines and increase collagen synthesis by hepatic stellate cells.23-25 Second, a number of reports have described the key role of alcohol intake in both the severity and course of HCV-related chronic infections; eg, in the series studied by Poynard et al19 the liver biopsy findings were significantly worse in the patients consuming at least 50 g/d of alcohol than in those drinking smaller amounts and in teetotalers. An increase in lipid peroxidation and free-radical formation, or a promoting effect on HCV replication, may account for the synergistic effect of alcohol on HCV-related liver damage.26,27 In our series, alcohol intake may have influenced the results in different ways: we excluded patients with a daily alcohol intake of at least 100 g, but alcohol-related toxicity has been reported for much lower doses, and a dose-dependent effect has been repeatedly observed in both HCV- and hepatitis B virus-related liver damage.28 In this context, the less favorable course of chronic HCV infection in older individuals may be attributable to the increasing duration of alcohol consumption. Third, a further factor that may be responsible for the age-related worsening of the clinical course of chronic HCV infection is hepatic steatosis. Hourigan et al have recently demonstrated that fibrosis in chronic hepatitis C correlates with body mass index and steatosis,29 and another study by Adinolfi et al30 found steatosis in about 50% of 221 patients with chronic HCV infection. The degree of liver fat infiltration significantly correlated with liver biopsy staging (fibrosis score) and grading (histologic activity index), and a further interesting finding was the relationship between the degree of fibrosis and age. Our data suggest that HCV genotypes are not related to the degree of histopathological damage and are in line with data previously published by our group31 and confirmed by a recent meta-analysis by Pagliaro et al32; however, a relationship has been found in other series.33-35 The prevalence of cirrhosis calculated in the present study among patients with transfusion-associated infection (20.1%) was similar to that observed in our series of 334 patients with the community-acquired form who underwent liver biopsy (19.3%, 64 cases; data not shown). However, the date of infection could not be precisely identified in this group. Importantly, it needs to be pointed out that our study focused on patients who acquired HCV infection through the transfusional route, and that such patients have a number of particular characteristics that may influence their clinical outcome. These include a high titer of viral particles in the original inoculum and, possibly, deranged clinical conditions and/or immune status at the time of transfusion. Furthermore, transfused individuals have a higher rate of mortality due to the disease for which the transfusion was administered. Our conclusions, therefore, do not necessarily apply to patients with the community-acquired form of the disease. Our data on the outcome of transfusion-associated hepatitis C suggest that the risks and benefits of antiviral treatment should be weighed on the basis of the accelerated course of liver damage with increasing age at infection. Thus, patients who acquired HCV infection at an older age would require a more aggressive and timely therapeutic approach to prevent disease progression.
Submitted December 6, 2001; accepted February 14, 2002.
Prepublished online as Blood First Edition Paper, April 17, 2002; DOI 10.1182/blood-2001-12-0192.
Supported by a Research Competition Award 2000 from IRCCS Ospedale Maggiore, Milan, Italy.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Dario Conte, Postgraduate School of Gastroenterology, IRCCS Ospedale Maggiore, Via F.Sforza 35, 20122 Milano, Italy; e-mail: dario.conte{at}unimi.it.
1. EASL International Consensus Conference on Hepatitis C. Paris, 26-28, February 1999, Consensus Statement. European Association for the Study of the Liver. J Hepatol. 1999;30:956-961[CrossRef][Medline] [Order article via Infotrieve]. 2. Colombo M, Oldani S, Donato MF, et al. A multicenter, prospective study of posttransfusion hepatitis in Milan. Hepatology. 1987;7:709-712[Medline] [Order article via Infotrieve]. 3. Tremolada F, Chiappetta F, Noventa F, Valfre C, Ongaro G, Realdi G. Prospective study of posttransfusion hepatitis in cardiac surgery patients receiving only blood or also blood products. Vox Sang. 1983;44:25-30[Medline] [Order article via Infotrieve].
4.
Prati D, Zanella A, Farma E, et al.
A multicenter prospective study on the risk of acquiring liver disease in anti-HCV negative patients affected from homozygous
5.
Prati D.
Benefits and complications of regular blood transfusion in patients with
6.
Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ.
The risk of transfusion-transmitted viral infections. The Retrovirus Epidemiology Donor Study.
N Engl J Med.
1996;334:1685-1690 7. Freeman AJ, Dore GJ, Law MG, et al. Estimating progression to cirrhosis in chronic hepatitis C virus infection. Hepatology. 2001;34:809-816[CrossRef][Medline] [Order article via Infotrieve]. 8. Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology. 1981;1:431-435[Medline] [Order article via Infotrieve]. 9. Ishak KG, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol. 1995;22:696-699[CrossRef][Medline] [Order article via Infotrieve]. 10. Mac Sween RNM, Burt AD, Portmann BC, Ishak KG, Scheuer PJ, Anthony PP. Pathology of the Liver. 4th ed. Edinburgh, United Kingdom: Churchill Livingstone; 2001. 11. Kaplan EL, Meier P. Non parametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481[CrossRef]. 12. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966;50:163-170[Medline] [Order article via Infotrieve]. 13. Cox DR. Regression models and life tables. J Royal Stat Soc. 1972;34:187-220. 14. Prati D, Capelli C, Silvani C, et al. The incidence and risk factors of community-acquired hepatitis C in a cohort of Italian blood donors. Hepatology. 1997;25:702-704[Medline] [Order article via Infotrieve]. 15. Zanella A, Conte D, Prati D, et al. Hepatitis C virus and liver histology in blood donors reactive to a single antigen by second generation recombinant immunoblot assay. Hepatology. 1995;21:913-917[Medline] [Order article via Infotrieve]. 16. Alberti A, Morsica G, Chemello L, et al. Hepatitis C viraemia and liver disease in symptom-free individuals with anti-HCV. Lancet. 1992;340:697-698[CrossRef][Medline] [Order article via Infotrieve].
17.
Vogt M, Lang T, Frösner G, et al.
Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening.
N Engl J Med.
1999;341:866-870
18.
Kenny-Walsh E.
Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group.
N Engl J Med.
1999;340:1228-1233 19. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349:825-832[CrossRef][Medline] [Order article via Infotrieve].
20.
Tong MJ, el-Farra NS, Reikes AR, Co RL.
Clinical outcomes after transfusion-associated hepatitis C.
N Engl J Med.
1995;332:1463-1466 21. Takahashi M, Yamada G, Miyamoto R, Doi T, Endo H, Tsuji T. Natural course of chronic hepatitis C. Am J Gastroenterol. 1993;88:240-243[Medline] [Order article via Infotrieve]. 22. Yano M, Yatsuhashi H, Inoue O, Inokuchi K, Koga M. Epidemiology and long-term prognosis of hepatitis C virus in Japan. Gut. 1993;34:S13-S16[Medline] [Order article via Infotrieve]. 23. Poli G, Parola M. Oxidative damage and fibrogenesis. Free Radic Biol Med. 1997;22:287-305[CrossRef][Medline] [Order article via Infotrieve]. 24. Johnson FB, Sinclair DA, Guarente L. Molecular biology of aging. Cell. 1999;96:291-302[CrossRef][Medline] [Order article via Infotrieve].
25.
Parola M, Pinzani M, Casini A, et al.
Stimulation of lipid peroxidation or 4-hydroxynonenal treatment increases procollagen 26. Sawada M, Takada A, Takase S, Takada N. Effects of alcohol on the replication of hepatitis C virus. Alcohol Alcohol Suppl. 1993;1B:85-90[Medline] [Order article via Infotrieve]. 27. Oshita M, Hayashi N, Kasahara A, et al. Increased serum hepatitis C virus RNA levels among alcoholic patients with chronic hepatitis C. Hepatology. 1994;20:1115-1120[Medline] [Order article via Infotrieve].
28.
Bellentani S, Pozzato G, Saccoccio G, et al.
Clinical course and risk factors of hepatitis C virus related liver disease in the general population: report from the Dionysos study.
Gut.
1999;44:874-880 29. Hourigan LF, MacDonald GA, Purdie D, et al. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology. 1999;29:1215-1219[CrossRef][Medline] [Order article via Infotrieve]. 30. Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C and correlates with specific HCV genotype and visceral obesity. Hepatology. 2001;33:1358-1364[CrossRef][Medline] [Order article via Infotrieve]. 31. Prati D, Capelli C, Zanella A, et al. Influence of different hepatitis C virus genotypes on the course of asymptomatic hepatitis C virus infection. Gastroenterology. 1996;110:178-183[CrossRef][Medline] [Order article via Infotrieve]. 32. Pagliaro L, Peri V, Linea C, Cammà C, Giunta M, Magrin S. Natural history of chronic hepatitis C. Ital J Gastroenterol Hepatol. 1999;31:28-44[Medline] [Order article via Infotrieve]. 33. Kobayashi M, Tanaka E, Sodeyama T, Urushihara A, Matsumoto A, Kiyosawa K. The natural course of chronic hepatitis C: a comparison between patients with genotypes 1 and 2 hepatitis C viruses. Hepatology. 1996;23:695-699[CrossRef][Medline] [Order article via Infotrieve]. 34. Mihm S, Fayyazi A, Hartmann H, Ramadori G. Analysis of histopathological manifestation of chronic hepatitis C virus infection with respect to virus genotype. Hepatology. 1997;25:735-739[CrossRef][Medline] [Order article via Infotrieve]. 35. Lopez-Labrador FX, Ampurdanès S, Forns X, et al. Hepatitis C virus (HCV) genotypes in Spanish patients with HCV infection: relationship between HCV genotype 1b, cirrhosis and hepatocellular carcinoma. J Hepatol. 1997;27:959-965[CrossRef][Medline] [Order article via Infotrieve].
© 2002 by The American Society of Hematology.
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  D. Posthouwer, M. Makris, T. T. Yee, K. Fischer, J. J. van Veen, A. Griffioen, K. J. van Erpecum, and E. P. Mauser-Bunschoten Progression to end-stage liver disease in patients with inherited bleeding disorders and hepatitis C: an international, multicenter cohort study Blood, May 1, 2007; 109(9): 3667 - 3671. [Abstract] [Full Text] [PDF]
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 I Bakr, C Rekacewicz, M El Hosseiny, S Ismail, M El Daly, S El-Kafrawy, G Esmat, M A Hamid, M K Mohamed, and A Fontanet Higher clearance of hepatitis C virus infection in females compared with males Gut, August 1, 2006; 55(8): 1183 - 1187. [Abstract] [Full Text] [PDF]
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S. Castellino, S. Lensing, C. Riely, S. N. Rai, R. Davila, R. T. Hayden, J. Fleckenstein, M. Levstik, S. Taylor, P. J. Dean, et al. The epidemiology of chronic hepatitis C infection in survivors of childhood cancer: an update of the St Jude Children's Research Hospital hepatitis C seropositive cohort Blood, April 1, 2004; 103(7): 2460 - 2466. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
-thalassemia.
Blood.
1998;92:3460-3464
1 (I) gene expression in human liver fat-storing cells.
Biochem Biophys Res Commun.
1993;194:1044-1050