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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3460-3464
A Multicenter Prospective Study on the Risk of Acquiring Liver
Disease in Anti-Hepatitis C Virus Negative Patients Affected
From Homozygous  -Thalassemia
By
Daniele Prati,
Alberto Zanella,
Elena Farma,
Claudia De Mattei,
Patrizia Bosoni,
Manuela Zappa,
Alessandra Picone,
Fulvio Mozzi,
Paolo Rebulla,
Maria Domenica Cappellini,
Jean-Pierre Allain, and
Girolamo Sirchia for the Cooleycare Cooperative Group
From the Centro Trasfusionale e di Immunologia dei Trapianti,
Servizio Autonomo per il Prelievo e la Conservazione di Organi e
Tessuti, Divisione di Ematologia, and Centro Anemie Congenite, IRCCS
Ospedale Maggiore di Milano, Milano, Italy; and the Division of
Transfusion Medicine, University of Cambridge, Cambridge, UK.
 |
ABSTRACT |
Although the risk of transfusion-transmitted hepatitis has been
recently reduced, transfusion-dependent  -thalassemia patients may
still develop liver disease due to viral infection or iron overload. We
assessed the frequency and causes of liver dysfunction in a cohort of
anti-hepatitis C virus (HCV) negative thalassemics. Of 1,481 thalassemics enrolled in 31 centers, 219 (14.8%) tested anti-HCV by second-generation assays; 181 completed a
3-year follow-up program consisting of alanine-aminotransferase (ALT)
measurement at each transfusion and anti-HCV determination by
third-generation enzyme-immunoassay (EIA-3) at the end of study. Serum
ferritin levels were determined at baseline and at the end of
follow-up. Ten patients were anti-HCV+ by EIA-3 at the
end of follow-up. Of them, seven were already positive in 1992 to 1993 when the initial sera were retested by EIA-3, one tested indeterminate
by confirmatory assay, and two had true seroconversion (incidence,
4.27/1,000 person years; risk of infection, 1/7,100 blood units, 95%
confidence interval [CI], 1 in 2,000-1 in 71,000 units). At baseline,
67 of 174 thalassemics had abnormal ALT. Of those with normal ALT,
seven subsequently developed at least one episode of moderate ALT
increase (incidence, 24.6/1,000 person-years). All of the 20 patients
with ferritin values  3,000 ng/mL had clinically relevant ALT
abnormalities, as compared with 53 of 151 with <3,000 ng/mL (P
< .005). Hepatic dysfunction is still frequent in thalassemics.
Although it is mainly attributable to siderosis and primary HCV
infection, the role of undiscovered transmissible agents cannot be
excluded.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
PATIENTS AFFECTED FROM homozygous
-thalassemia have a high prevalence of chronic liver disease, mainly
as a consequence of viral infections acquired through blood transfusion
during the past decades.1-3
Although the incidence of posttransfusion hepatitis has been greatly
reduced after the introduction of blood donors' screening for
antibodies to hepatitis C virus (HCV),4-8 multitransfused patients are still at risk of developing liver dysfunction. In fact,
cases of posttransfusion hepatitis have been described that are not
related to known viral agents and cannot be prevented by current
techniques for donor selection.8-10 Hepatitis G virus (HGV), a recently discovered member of the Flaviviridae family, was
initially indicated as a possible causative agent in these cases,11,12 but this was not confirmed in further
studies.9,10,13,14 Thus far, the current epidemiologic
relevance and the possible causes of non A-C hepatitis have not been
extensively evaluated in prospective surveys.
Thalassemic patients may acquire hepatitis C through the administration
of HCV-infected blood collected during the donor window period.7,15 Moreover, they have frequent nosocomial
exposure, which is an additional risk factor for HCV
infection.16,17 Nonetheless, no information is as yet
available on the rate of HCV seroconversion in these patients.
Finally, although iron overload is an independent cause of liver
dysfunction in thalassemics,3 the relationship between liver disease and iron status in anti-HCV patients
has been poorly investigated. In the forthcoming years, this piece of
information will be particularly useful for the management of
thalassemia, as the proportion of patients uninfected with HCV is
progressively increasing.
This report presents the results of a prospective study of a cohort of
anti-HCV thalassemic patients followed during a
period of 3 years. The study was conducted within Cooleycare, a
cooperative group of clinical centers where large numbers of Italian
patients with thalassemia are treated2,14,18-20 and was
aimed at assessing the incidence and the possible causes of hepatic
disease.
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MATERIALS AND METHODS |
Patients.
In 1992, the centers of the Cooleycare program were invited to
participate in a longitudinal study on posttransfusion hepatitis in
-thalassemia as a part of an ongoing survey on transfusion transmitted infections, which started in 1989.2,14,18-20
Thirty-one centers agreed to participate, and all of the 1,481 homozygous -thalassemia patients regularly transfused at these
centers (760 men and 721 women; median age, 17 years; range, 0 to 45)
were enrolled. For each patient, a baseline serum sample collected in
December 1992 to March 1993 was sent to the reference laboratory of the
Cooleycare group in Milan for anti-HCV determination. A total of 219 patients (14.8%) were anti-HCV and 1,262 (85.2%)
were anti-HCV+.
Additional serum samples of the anti-HCV patients
were requested from the participating centers after 3 years, together
with a record reporting the results of alanine-aminotransferase (ALT) measurements determined at each transfusion event and the number of red
blood cell units transfused. Informative records were
obtained from 181 subjects (82.6%; 95 men and 86 women; median age at
enrollment, 7 years; range, 0 to 28 years) of 30 centers. The remaining
38 patients (17.4%; 19 men and 19 women, median age, 9 years; range, 1 to 44 years) were lost to follow-up due to death (n = 4, 1.8%), bone
marrow transplantation (n = 15, 7%), transfer to other care units (n = 6, 2.7%), and unavailability of sample or data (n = 13, 6%). All of
the 219 patients included in the study had received hepatitis B
vaccination and were hepatitis B surface antigen (HBsAg) negative at
study entry. Therapy with deferoxamine was administered according to
current protocols.
Laboratory tests.
All of the assays, except for ALT determination, were performed at the
central laboratory in Milan.
With regard to the anti-HCV determination, we used a second-generation
enzyme-immunoassay (EIA) at the baseline evaluation and a
third-generation EIA for the analysis of the follow-up sample (EIA-2
and EIA-3; both from Ortho Diagnostic Systems, Raritan, NJ). The latter
assay was also used to retest the baseline samples of anti-HCV
seroconverting patients. Anti-HCV reactivity was confirmed by second-
and third-generation recombinant immunoblot assays (RIBA-2 and RIBA-3,
Ortho Diagnostic Systems), which carry four different antigens in
separate bands from some structural and nonstructural regions of the
virus. Samples were considered positive when reactive to at least two
bands, negative when not reactive, and indeterminate when single band
reactivity was detected. Qualitative serum HCV RNA determination was
performed with the Amplicor HCV kit (Roche Molecular Systems, Basel,
Switzerland) in the seroconverting patients.
Serum ferritin was determined on baseline and follow-up samples by EIA
(IMx Ferritina; Abbott Divisione Diagnostici, Rome, Italy). The upper
reference limit (URL) was 280 ng/mL in men and 186 ng/mL in women.
ALT measurements were determined at each transfusion event in the
Cooleycare centers using standard methods. The URL for ALT was 40 U/L
in men and 30 U/L in women.14,16,21 The ALT pattern was
classified as normal when the enzyme levels were persistently below the
URL; it was considered abnormal if ALT values were persistently or
intermittently above the URL. For each patient, we defined a baseline
ALT pattern, considering the values observed during the first 6 months
of the study, and a follow-up pattern, on the basis of the values
reported during the remaining study period. It was decided that to
validly define the ALT pattern, at least 70% of the planned
measurements should be obtained from each patient. At the time of data
analysis, we found that all the patients fulfilled these criteria.
Liver dysfunction was classified as minimal (when the peak value of ALT
was below two times the URL), mild (between two and three times the
URL), or moderate (above three times the URL).
Serum specimens collected at the baseline and at the end of follow-up
from the patients meeting the criteria for the diagnosis of hepatitis
were tested for HBsAg and antibodies to hepatitis B core antigen
(anti-HBc) by EIAs (Murex, Dartford, UK, and Abbott Laboratories,
Chicago, IL), and for HCV RNA; HGV RNA was also determined by reverse
transcriptase-polymerase chain reaction (RT-PCR) using primers derived
from the 5 noncoding region (5NCR); positive results were
confirmed using primers derived from the nonstructural region 5a
(NS5a), as previously described.14,22
Statistical analysis.
The incidence of infection was expressed as the number of new
infections per 1,000 person-years. The risk of acquiring infection was
computed by the ratio between the number of seroconverting patients and
the total number of red blood cell units transfused to the patient
group during the study period. The 95% confidence intervals (CI) of
incidence and risk were derived from the exact confidence limits of the
expected value of Poisson distribution. The  2 test, the
t-test, and the Wilcoxon test were used when appropriate.
| |
RESULTS |
Incidence of HCV infection.
Ten of 181 anti-HCV EIA-2 negative patients (5%) seroconverted to HCV
with EIA-3 during follow-up. The analysis of the baseline samples by
EIA-3 showed that seven patients were already positive in 1992 to 1993. During the period of the study, one patient (9 years old) developed
strong C33 reactivity on RIBA-3, was classified indeterminate, and
remained HCV RNA negative with normal ALT levels. Two patients (6 and 7 years old) became RIBA-3 and HCV RNA positive. Seroconversion occurred
in 1993 and 1994, respectively. Both patients had ALT flare-ups to 183 and 526 U/L, respectively. Thereafter, ALT values remained abnormal,
ranging between 49 to 130 and 92 to 370, respectively. Two of 174 patients (1.2%) were therefore considered HCV infected.
During the period of the study, all patients received anti-HCV EIA-2 or
EIA-3 negative red blood cells. The 174 patients who were
anti-HCV at the baseline evaluation received a total
number of 14,266 red blood cell units (82 ± 31 units per patient),
during 468.5 years of follow up (32 ± 4 months per patient). The
incidence of HCV infection was 4.27 per 1,000 person-years (95% CI,
0.43 to 15.4 per 1,000). The risk of infection was 1 in 7,100 blood units (95% CI, 1 in 2,000-1 in 71,000 units).
Frequency of liver disease.
Of the 171 thalassemics who remained anti-HCV
throughout the study period, 67 (39%) had an abnormal ALT pattern at
the baseline. Elevation was moderate in 51 subjects (76%), mild in 10 (15%), and minimal in 6 (9%). During follow-up, 61 of 67 patients
(91%) maintained altered ALT values. Of the 104 patients (61%) who
had normal liver function at the baseline, 17 (16%) subsequently
showed biochemical signs of liver dysfunction, as suggested by enzyme flare-ups during the period of follow-up. Seven of the 104 patients (6.7%) had at least one episode of moderate ALT increase, accounting for an incidence of 24.6 per 1,000 person-years (95% CI, 9.8 to 51 per
1,000), and a risk of 1 in 1,250 units (95% CI, 1 in 608-1 in 3,125 units). The main clinical and demographic characteristics of these
subjects are reported in Table 1. None had
HCV or HBV infection, as documented by the persistent negativity of
HCV-RNA, HBsAg, and anti-HBc. Patients 1 and 2 were
HGV-RNA+ in 1992 to 1993 and became
HGV-RNA in 1995 to 1996. Patient 3 developed HGV
viremia during follow-up. In patient 6, HGV-RNA was positive both at
the baseline and at the end of follow-up. The other three patients
remained HGV-RNA throughout the study period. Three
of seven patients (43%) developed chronic liver dysfunction, as
suggested by the persistence or recurrence of ALT abnormality during
the remaining period of observation. Their clinical course is
summarized in Fig 1.
View this table:
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Table 1.
Clinical and Demographic Characteristics of the Patients
Who Had Normal ALT at Study Entry and Developed Moderate ALT
Increase During Follow-up
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| Fig 1.
Three patients who developed moderate ALT increase
followed by chronic liver dysfunction. Levels of ALT (U/L, dotted line)
are plotted against the date of determination. The upper reference
limit for ALT was 40 U/L. The results of HGV RNA determination,
performed at the beginning and at the end of follow-up, are also
reported. These patients had a higher increase of serum ferritin levels
than those who maintained normal aminotransferase values (difference of
ferritin concentration between follow-up and baseline sample, 1,850 ± 368 ng/mL v 111 ± 814 ng /mL).
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Relation between serum ferritin levels and ALT pattern.
There was an overall increase in serum ferritin levels during the study
period: median values were 1,680 ng/mL (range, 260 to 8,620) at
baseline, and 1,930 ng/mL (range, 340 to 12,300) at the end of
follow-up (P = .014 by the Wilcoxon test). The mean serum
ferritin levels according to ALT pattern in the 171 anti-HCV patients are reported in
Table 2. A mild to moderate ALT increase was observed in
all of the 20 patients with ferritin values equal to or above 3,000 ng/mL, and in 53 of 151 (35%) with less than 3,000 ng/mL (P < .005 by 2 test). Ferritin concentration was not
associated with age or gender.
| |
DISCUSSION |
Liver disease ranks second as a cause of death among adolescents and
adults with thalassemia.1 Although the incidence of transfusion-transmitted hepatitis has been dramatically reduced after
the introduction of hepatitis B vaccination for chronic transfusion
recipients and the application of reliable procedures for the screening
of blood donors,4-8 thalassemic patients may still develop
liver dysfunction due to infection with blood-borne agents, either
known or undiscovered, and to transfusional iron overload. We conducted
a prospective study on a large cohort of anti-HCV
thalassemics to elucidate the extent of the problem and to identify the
possible causes of hepatic damage.
At the baseline evaluation, more than one third of the patients had an
abnormal aminotransferase pattern. In the majority of the subjects,
liver dysfunction was clinically relevant, the degree of ALT alteration
being comparable to that commonly observed in thalassemics with chronic
hepatitis C.23,24 This indicates that liver disease remains
an open issue in the management of thalassemia. The incidence of HCV
infection was 4.27 per 1,000 person-years, a figure 40-fold higher than
that recently observed among low-risk adults from the same geographic
area.16 Moreover, in the seroconverting subjects, the
presence of HCV viremia was accompanied by chronic liver dysfunction.
Our findings suggest that HCV infection is still a cause
of morbidity among thalassemics, even after the introduction of
reliable procedures for the prevention of transmissible agents to
transfusion recipients. Although this study was not specifically
designed to identify the source of HCV infection, some considerations
on this issue can be made. Because risks due to drug abuse and sexual
activity were reasonably low on the basis of the young age of the
patients, HCV infection was most probably related to patients' medical
treatment. The observed rate of infection reflects a risk per
transfused blood unit similar to that previously measured in United
States blood recipients,6 but substantially higher than
that estimated using a mathematical model based on the incidence of
infection and the duration of the window period in North American
repeat blood donors.7 Considering that the incidence rates
of HCV infection among donors in the two countries are comparable (10.1 v 4.84 per 100,000 person-years),7,16 it seems
possible that a proportion of HCV cases currently occurring among
thalassemics are not related to blood transfusion. Indeed, frequent
nosocomial exposure might favor patient-to-patient transmission, which
appears to be an important route of HCV spread.16,17 Otherwise, thalassemics might be more susceptible to infections because
of impaired immune status consequent to their disease and/or to
repeated antigenic stimulation.25
To our knowledge, this is the first study describing the relations
between liver function and iron status in thalassemics without evidence
of infection with major hepatotropic viruses, thus excluding factors
able to synergize both hepatotoxicity and siderosis.3,26
The analysis of hepatic iron concentration was not possible, mainly due
to the very young age of most patients, which made liver biopsy not
feasible; hence, we used serum ferritin measurement, which is the
indicator of iron load most commonly used in clinical
practice.3 Despite the young age of the subjects, the
administration of deferoxamine therapy and the absence of detectable
hepatotropic infections, iron stores were larger than expected. In
fact, ferritin concentrations equal to or below 1,000 ng/mL, which are
considered the optimal target of iron-chelating treatment,3
were observed in less than 10% of cases, and the degree of iron
overload tended to increase during follow-up. All of the patients with
mean ferritin values exceeding 3,000 ng/mL had clinically relevant
liver damage. Interestingly, this threshold is very close to that used
to identify thalassemic patients at increased risk of cardiac disease
(ie, 2,500 ng /mL).27 Overall, our data indicate that in
the absence of a more rigorous control of the siderosis through
chelation therapy, iron accumulation will soon become the principal
cause of hepatic dysfunction among young thalassemic patients. This
should be taken into account when discussing the indications to
antiviral treatment of thalassemics with chronic hepatitis C, because
underlying iron-induced liver disease may affect the clinical response
to interferon therapy.23
Alanine-aminotransferase abnormalities were observed also in a subset
of patients with lower ferritin concentration, which suggests that even
relatively small increases of the iron burden may cause hepatocellular
damage. Alternatively, ferritin measurement may underestimate body iron
stores in these patients.3,27
However, causes of liver disease other than iron overload should be
considered. In this regard, we found that 6.7% of the patients who at
the beginning of the study had normal ALT levels subsequently had at
least one episode of clinically relevant hepatocellular injury.
Moreover, 2.9% developed permanent hepatic dysfunction, and their
aminotransferase pattern mimicked that commonly observed in
posttransfusion hepatitis.8,28 Many of these patients had a
remarkable increase of ferritin levels during follow-up. Thus, the
possibility that the gradual enlargement of body iron stores secondary
to transfusion therapy was the only factor responsible for hepatic
dysfunction cannot be ruled out. However, this hypothesis is not
completely convincing, given the steep increase of ALT generally
observed. Hence, at least in part, the elevation of serum ferritin may
be the consequence rather than the cause of liver-cell
injury.3,27 None of the cases of liver disease described
here was due to HCV infection not producing detectable seropositivity,
in contrast with a previous report on community-acquired hepatitis.29 A proportion of the patients had detectable
HGV viremia, but there is no convincing evidence that this agent had a
direct pathogenetic role in inducing liver damage. In fact, primary
infection was found only in one of the three patients who developed
chronic hepatic dysfunction. Moreover, we recently observed that HGV
infection, although frequent in blood donors and recipients of our
country,14,22,30 has no effect on the severity of liver
disease and has often a natural progression toward recovery in
patients with thalassemia.14 Therefore, it remains to be
elucidated whether hitherto unidentified infectious agents or
noninfectious causes of hepatocellular damage are involved in the
pathogenesis of these cases of transfusion-associated liver disease.
In conclusion, despite chelation therapy and viral screening for blood
donations, iron overload and primary HCV infection remain important
causes of liver dysfunction among young thalassemic patients of our
country. Undiscovered transmissible agents might also contribute to
induce hepatocellular injury. These factors must be considered in the
definition of protocols for the specific treatment of liver disease in
-thalassemia. Whether hepatic dysfunction will significantly affect
survival and quality of life of thalassemic patients should be assessed
in future studies.
| |
FOOTNOTES |
Submitted March 31, 1998;
accepted June 29, 1998.
Supported in part by a grant from the Italian National Institute of
Health ("Progetto Sangue," Istituto Superiore di Sanità).
Cooleycare members providing samples and data for this study are listed
in the Appendix.
Address reprint requests to Daniele Prati, MD, Centro Trasfusionale e
di Immunologia dei Trapianti, IRCCS Ospedale Maggiore, Via Francesco
Sforza, 35, 20122 Milano, Italy.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank Silvano Milani, PhD, for critical revision of the
manuscript.
| |
APPENDIX |
Cooleycare members providing samples and data for this study:
M. Alessi (Catania); C. Artaz (Aosta); M.G. Batzella (S. Gavino Monreale); P. Bellavita (Bergamo); G. Bertrand (Sassari); F. Betto (Rho); A. Biolchini (Iglesias); C. Borgna (Verona); S. Calò
(Magenta); A. Cambosu, A. Carta (Oristano); E. Cichella (Rovigo); V. Cilla (Matera); E. Corvaglia (Casarano); D. Costantino (Locri); C. De Rosa (Napoli); F. Di Gregorio (Catania); P. Di Paola (Palermo); D. Gallisai (Sassari); G. Girelli (Roma); M. Lendini (Olbia); R. Longhi
(Como); C. Magnano (Catania); L. Luongo (Agrigento); A. Mangiagli
(Siracusa); A. Meo (Messina); S. Strada (Monza); S. Montin (Monselice);
G. Forni (Genova); P. Rizzone Favacchio (Ragusa); F. Schettini (Bari);
and G. Sciorelli (Monza).
| |
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Abstract
Introduction
Abstract