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GASTROENTEROLOGY 2008;134:1900 –1907
Long-Term Course of Chronic Hepatitis C in Children: From Viral
Clearance to End-Stage Liver Disease
FLAVIA BORTOLOTTI,* GABRIELLA VERUCCHI,‡ CALOGERO CAMMÀ,§ GIUSEPPE CABIBBO,§ LUCIA ZANCAN,储
GIUSEPPE INDOLFI,¶ RAFFAELLA GIACCHINO,# MATILDE MARCELLINI,** MARIA GRAZIA MARAZZI,#
CRISTIANA BARBERA,‡‡ GIUSEPPE MAGGIORE,§§ PIETRO VAJRO,储 储 SAMUELA BARTOLACCI,* FIORELLA BALLI,¶¶
ANNA MACCABRUNI,## MARIA GUIDO,*** and the Italian Observatory for HCV Infection and Hepatitis C in Children
CLINICAL ADVANCES
IN LIVER, PANCREAS,
AND BILIARY TRACT
*Clinica Medica 5, University of Padua, Padua; ‡Clinic of Infectious Diseases, Policlinico S. Orsola, Bologna; §Cattedra di Gastroenterologia, University of Palermo,
Paleremo; 储Department of Pediatrics, University of Padua, Padua; ¶Third Pediatric Clinic, Mayer Hospital, Florence; #Department of Infectious Diseases, Gaslini
Institute, Genoa; **Hepatology Service, Hospital Bambin Gesù, Rome; ‡‡Pediatric Clinic, University of Turin, Turin; §§Department of Pediatrics, University of Pisa, Pisa;
储储
Pediatric Clinic, University Federico II Naples, Naples; ¶¶First Pediatric Clinic, University of Modena, Modena; ##Clinic of Infectious Diseases, Policlinico S. Mattia,
Pavia, Pavia; and ***Department of Pathology, University of Padua, Padua, Italy
See Bain VG et al on page 701 in CGH.
Background & Aims: The natural course of chronic
hepatitis C (CHC) in children is not well understood.
The aim of this study was to assess the long-term course
of CHC in a large sample of otherwise healthy children.
Methods: From 1990 to 2005, 504 consecutive antihepatitis C virus (HCV)-positive children were enrolled at 12
centers of a national observatory and were followed up
retrospectively/prospectively. Results: Putative exposure was perinatal in 283 (56.2%) cases, parenteral in 158
(31.3%), and unknown in 63 (12.5%). At baseline, 477
(94.6%) cases were HCV RNA seropositive, 118
(24.7%) of which were treated with standard interferon ␣. Ten years after putative exposure, the outcome in 359 HCV RNA-positive, untreated patients
was (1) undetectable viremia in 27 (7.5%) (by Cox
regression analysis, spontaneous viral clearance was
independently predicted by genotype 3 [hazard ratio
6.44; 95% confidence interval: 2.7–15.5]) and (2) persistent viremia in 332 (92%) cases. Six of these 332
cases (1.8%) progressed to decompensated cirrhosis
(mean age, 9.6 years). This latter group included 5
Italian children perinatally infected with genotype
1a (4 of the mothers were drug users). Thirty-three
(27.9%) treated patients achieved a sustained virologic response. Conclusions: Over the course of a
decade, few children with chronic HCV infection
cleared viremia spontaneously, and those who did were
more likely to have genotype 3. Persistent viral replication led to end-stage liver disease in a small subgroup
characterized by perinatal exposure, maternal drug use,
and infection with HCV genotype 1a. Children with
such features should be considered for early treatment.
H
epatitis C virus (HCV) infection is a major cause of
liver disease worldwide.1 Children constitute a
small proportion of the HCV-infected population.2,3 The
prevalence of circulating anti-HCV in the pediatric population averaged 0.3% in Italy in the early 1990s,4 but the
recent findings of a national observatory study suggest
that the number of “new” pediatric infections dropped
approximately 40% in 2000 –2004 compared with the
previous 5 years.5 The low prevalence of HCV in children
reflects the disappearance of transfusion-related hepatitis6 and the reduced efficiency of mother-to-child (vertical or perinatal) transmission, although this form of
transmission is currently responsible for most “new” infections in the developed world.7–10 This favorable epidemiologic trend is balanced, however, by the strong tendency of HCV infection acquired early in life (either
perinatally or following blood transfusions) to become
chronic.11–16
In the past decade, few children have been treated
successfully with interferon (IFN); thus, an undefined,
but far from negligible proportion of infected children,
can be expected to develop chronic liver disease in adulthood.17 To date, the clinical features and prognosis of
chronic hepatitis C acquired in childhood have been only
partially investigated. Hepatitis C is, and has been, usually described as a mild disease in children and adolescents,18 –21 regardless of the source of infection, but severe
cases have been reported occasionally in the recent literature.22–24
In this multicenter, retrospective/prospective observational study, we investigated the clinical features and
outcomes of chronic HCV infection and related disease in
a large sample of anti-HCV-positive children consecutively observed at 12 pediatric and infectious disease
clinics in Italy between 1990 and 2005. The aims of the
present study were to assess the natural course of chronic
hepatitis C (CHC) and to evaluate the rate and predictors
Abbreviations used in this paper: HIV, human immunodeficiency
virus; LKM1, liver-kidney microsomal autoantibody type 1.
© 2008 by the AGA Institute
0016-5085/08/$34.00
doi:10.1053/j.gastro.2008.02.082
June 2008
Patients and Methods
Study Design
This study was designed and conducted within
the framework of the “Observatory for HCV Infection
and Hepatitis C in Italian Children,” established in 1998
by the Hepatology Group of the Italian Society of Pediatric Gastroenterology and Hepatology, with a view to
taking a census of children with HCV infection and
investigating the clinical aspects and outcomes of liver
disease in this inadequately studied population.25 Twelve
pediatric and infectious diseases centers in Italy were
involved. These centers retrospectively collected all antiHCV-positive cases seen as outpatients from 1990 to
1998 and prospectively observed them from 1999 onwards. None of the centers was managing selected liver
disease populations. Baseline and follow-up clinical information was obtained from patient records. Some of
the patients involved had been included in previous studies.5,18,26
Patients
The inclusion criteria were (1) age between 1 and
16 years, (2) anti-HCV positivity in serum (concomitant
HCV RNA positivity was required for the diagnosis of
infection in children up to 18 months old), (3) at least 1
serum sample tested for HCV RNA at enrollment or
during the first year of follow-up, and (4) a follow-up of
at least 1 year after the infection was diagnosed at the
Observatory center.
The exclusion criteria were (1) coinfection with human
immunodeficiency virus (HIV) or hepatitis B virus (all
children were tested for anti-HIV and hepatitis B surface
antigen [HBsAg]) and (2) concomitant metabolic or autoimmune disorders and underlying systemic diseases,
including previous malignancy, uremia, thalassemia, and
hemophilia.
Based on the clinical records, the putative time of
exposure to HCV infection was conventionally defined as
follows: (1) time of first transfusion or of surgery (in a
few children, most from foreign countries, injections of
medications with nondisposable syringes and hospitalization for intercurrent disease were the single putative
types of exposure emerging from the clinical history); (2)
time of birth for children with mothers known to be
anti-HCV positive at delivery; (3) time of first diagnostic
screening in children whose mothers’ infection was discovered after delivery; and (4) time of first diagnosis of
infection or liver disease in children whose source of
infection is unknown.
The duration of follow-up was calculated from the
putative time of exposure and from the time of enroll-
1901
ment in the study up to the last visit. The children were
regularly seen at the outpatient clinic for physical examination, and serologic tests were administered every 4 – 6
months until they were 5 years old then every 6 –12
months. Liver ultrasonography was added to the baseline
serologic investigation as soon as it became available and
was repeated when clinically required.
In untreated HCV RNA-positive patients, a sustained
viral clearance was defined as the disappearance of HCV
RNA from serum documented in at least 2 consecutive
serum samples taken 6 months apart.
Methods
Routine biochemical tests were performed, including alanine aminotransferase (ALT), bilirubin, albumin, and prothrombin time. Anti-HCV and anti-HIV
were determined by second- and third-generation commercial enzyme-linked immunosorbent assays (ELISA).
HBsAg was determined by a commercial ELISA kit (Abbott Laboratories, North Chicago, IL). HCV RNA was
investigated in fresh, and well-preserved, stored sera by
PCR using initially in house tests (sensitivity limit approximately 103 copies/mL) then replaced by a commercial qualitative test (COBAS Amplicor, version 2; Roche
Diagnostics, Branchburg, NJ; sensitivity limit, 50 IU/mL).
A quantitative test was used for candidates for treatment
(COBAS Amplicor HCV Monitor Test, version 2; Roche
Diagnostics; sensitivity limit, 600 IU/L). Genotyping was
done with a line probe hybridization assay (LIPA HCV;
Innogenetics, Zwijndrecht, Belgium). Antinuclear, smooth
muscle, and liver kidney microsomal (LKM1) autoantibodies were assayed by immunofluorescence, as described elsewhere.27 No attempt was made to collect all sera at the same
laboratory, although, for investigations such as genotyping,
the same commercial assay was used.
Liver biopsy was performed using the Menghini technique, after obtaining the informed consensus of parents
or guardians. Liver biopsy samples were classified according to the Ishak scoring system.28
A file was completed for each patient, recording demographic, epidemiologic, and clinical findings. Privacy was
assured by replacing patient names with codes and dates
of birth in the database. Data were collected by the
coordinating center in Padua, where they were checked
for completeness and internal consistency and amended
by correspondence with the investigators. Finally, the
present report was circulated to all members of the group
and revised in light of their comments. The study was
approved by the Ethics Committee of the Padua University Hospital.
Statistical Analysis
Continuous variables are expressed as mean ⫾ SD
and categorical variables as frequency and percentage.
The ␹2 and ANOVA tests were used as appropriate. We
used the Kaplan–Meier method for the univariate analy-
CLINICAL ADVANCES
IN LIVER, PANCREAS,
AND BILIARY TRACT
of spontaneous HCV RNA clearance during a long-term
follow-up in a cohort of untreated children with different
epidemiologic backgrounds.
HEPATITIS C IN CHILDREN
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BORTOLOTTI ET AL
GASTROENTEROLOGY Vol. 134, No. 7
sis to identify factors predictive of spontaneous viral
clearance and the log-rank test for comparisons. The
following baseline variables were considered for univariate analysis: gender, age at first observation, geographic
origin, type of exposure, HCV genotype, and ALT serum
levels. Variables with a P value ⬍ .10 at univariate analysis
were included in the final multivariate model. The Cox
proportional hazards model was used to identify the
predictors of spontaneous viral clearance. All analyses were
conducted with the Statistical Analysis System, version 6.08,
subroutine PROC PHREG (SAS Institute, Inc, Cary, NC).
delivery or screened later (a remarkable 44% of these
mothers were drug users and 17% were human immunodeficiency virus (HIV) coinfected); group 2 (parenteral)
with 158 children who had been given blood transfusions
or unsafe injections of medication, had undergone surgery, or had been repeatedly hospitalized for other diseases; and group 3 (household/unknown) with 63 children who had either an infected household member (7
cases) or an unknown source of infection; this group
included 25 of the 27 children from foreign countries.
CLINICAL ADVANCES
IN LIVER, PANCREAS,
AND BILIARY TRACT
Patients Features at Baseline
Results
During the survey, 633 consecutive anti-HCV-positive children were recruited by the Observatory, and 504
met the entry criteria. The remaining 129 (21%) subjects
were lost to follow-up for various reasons: the family
moved to another city or country; the child was well, and
regular visits were considered unnecessary; or the compliance of parents was impaired by sociosanitary problems. The clinical features of the 129 children did not
differ significantly from the cohort as a whole (data
available from [email protected]).
Epidemiologic Features
Based on the putative exposure, the 504 patients
were divided as follows: group 1 (maternal) with 283
patients, including 189 born between 1992 and 2004, had
an infected mother either known to be seropositive at
At initial assessment, most children were asymptomatic and had been recruited after serologic screening
prompted by maternal infection, surgery or transfusion,
or adoption. Table 1 compares the baseline clinical, biochemical, virologic, and histologic features of infection in
the 3 groups. Children in group 1 were younger at first
observation, mainly female and more frequently infected
with genotypes 3 and 4. Children in group 2 were prevalently male, recruited at an older age, and more often
symptomatic and infected with genotypes 1 and 2. Children with an unknown source of infection (group 3) had
intermediate features. Most children came from northern
and central Italy; a minority had been adopted or had
emigrated from foreign countries, especially from Eastern Europe and India. It is worth noting that 27 children,
13 of them vertically infected, were HCV RNA negative at
presentation and had normal or near normal ALT levels.
Table 1. Baseline Features in Relation to the Putative Mode of Transmission in 504 anti-HCV-Positive Children Enrolled in
This Study
Type of exposure
Variables at baseline
Male, n (%)
Age, mo, mean ⫾ SDa
Geographic origins, n (%)
Northern Italy
Central Italy
Southern Italy
Foreign countries
Symptomatic children, n (%)
ALT levels, n (%)
ⱕ1⫻ ULN
ⱖ5⫻ ULN
Serum HCV RNA negative, n (%)
HCV genotype
Total cases tested, n (%)
1ab
1b
2
3
4
Group 1,
maternal (n ⫽ 283)
Group 2
parenteral (n ⫽ 158)
Group 3,
household/unknown (n ⫽ 63)
117 (41.3)
40.5 ⫾ 42.5
89 (56.3)
110.6 ⫾ 49.3
31 (49.2)
81.4 ⫾ 47.7
.009
.0001
143 (50)
107 (38)
30 (11)
3 (1)
16 (6)
60 (38)
49 (31)
44 (28)
5 (3)
40 (25)
16 (25)
20 (32)
8 (13)
19 (30)
9 (14)
.0003
.3042
.0001
⬍ .0001
.0001
94 (33)
24 (7)
13 (4)
51 (32)
13 (5)
9 (6)
24 (38)
6 (8)
5 (9)
.70
.95
.55
223 (78.8)
59 (26)
67 (30)
26 (12)
46 (21)
25 (11)
119 (75.3)
19 (15)
65 (55)
30 (25)
5 (4)
0 (0)
47 (74.6)
9 (19)
24 (51)
7 (15)
6 (13)
1 (2)
.07
.0001
.005
.0002
.0002
ALT, alanineaminotransferase; HAI, histologic activity index; IU, international units; ULN, upper limit of normal.
first visit in the referral center.
bFive cases were mixed with genotype 1b.
aAt
P value
HEPATITIS C IN CHILDREN
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CLINICAL ADVANCES
IN LIVER, PANCREAS,
AND BILIARY TRACT
June 2008
Figure 1. Cumulative probability of clearing HCV RNA during childhood and adolescence in 332 untreated children; the probability was
also calculated separately in children with HCV genotype 3 and in those
with genotype other than 3.
LKM1 autoantibodies were detected in 19 of 301 cases
tested (6.3%) and were evenly distributed among children
infected perinatally and postnatally. Liver biopsy was
obtained in a minority of patients not for a uniform
reason and histology was not included in this study.
Events During Follow-Up
The mean follow-up was 5.9 ⫾ 3.8 years after
recruitment by the Observatory and 10.6 ⫾ 6.0 years
from the putative time of exposure. All children were
alive at the time of this study. Figure 1 shows the distribution of the study patients from entry to the end of
their follow-up. Of the 504 children, 118 (23.4%), the
majority with biopsy-proven chronic hepatitis (44 infected perinatally, 64 parenterally, and 10 by unknown
means), had been treated with standard IFN-␣ and were
not included for evaluation.
Table 2 shows the baseline features in the 386 untreated children in relation to outcome. All 27 children
(7%) who were HCV RNA negative at first observation
Figure 2. Flowchart of the distribution of patients in groups and subgroups according to virologic and therapeutic patterns at baseline and
during a mean 10-year follow-up after putative exposure.
remained so, and their ALT levels returned to, or remained, normal. The following patterns were observed
in the other 359 untreated children with viremia at
baseline.
Spontaneous viral clearance. During follow-up,
27 of 359 (8%) patients (26 of them vertically infected),
became HCV RNA negative. Figure 2 shows the cumulative probability of HCV RNA clearance over the years.
Table 2. Baseline Features in Relation to the Virologic Outcomes in 386 Untreated Children
Final HCV RNA status
Baseline features
Male, n (%)
Age at first visit (mo), means ⫾ SD
ALT IU/L (times [⫻] normal), means ⫾ SD
Exposure:
Maternal infection, n (%)
Other, n (%)
HCV genotype
Total cases tested, n (%)
1
2
3
4
HCV RNA always
negative (n ⫽ 27)
HCV RNA
clearance (n ⫽ 27)
HCV RNA
persistence (n ⫽ 332)
12 (44)
80.7 ⫾ 49.9
1.38 ⫾ 1.13
13 (48)
24.1 ⫾ 31.7
2.68 ⫾ 2.66
150 (45)
64.2 ⫾ 56.6
2.15 ⫾ 1.94
13 (48)
14 (52)
26 (96)
1 (4)
201 (61)
131 (39)
.0003
.0003
0
0
0
0
0
20 (74)
7 (35)
2 (10)
10 (50)
1 (5)
262 (79)
164 (63)
44 (17)
33 (12)
21 (8)
.014
.042
.0001
.62
ALT, alanineaminotransferase; IU, international units.
among the 3 groups by ␹2 or ANOVA tests.
aComparison
P valuea
.952
.001
.026
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BORTOLOTTI ET AL
GASTROENTEROLOGY Vol. 134, No. 7
Table 3. Epidemiologic, Clinical, and Histologic Features in 6 Children With Symptoms and Signs of Cirrhosis During the
Survey
Histology
Case no. Sex Age (y)a
Source
ALT
Genotype
CLINICAL ADVANCES
IN LIVER, PANCREAS,
AND BILIARY TRACT
1
M
15
Mother
Increased
1a
2
F
11
Mother DU/HIV
Increasedb
3
F
11
Mother DU
4
F
5
5
6
M
F
14
2
First biopsy
Time between
biopsies (y)
—
1a
Cirrhosis, mild activity,
moderate steatosis
Moderate hepatitis
Increased
1a
Moderate hepatitis
5
Mother DU
Increased
1a
Moderate hepatitis
2
Mother DU
Unknownc
Increased
Increased
1a/1b
3
Moderate hepatitis
Cirrhosis, moderate activity
9
—
3
Second biopsy
Cirrhosis, moderate
activity, mild steatosis
Cirrhosis, mild activity,
moderate steatosis
Cirrhosis, mild activity,
moderate steatosis
Cirrhosis, moderate activity
ALT, alanineaminotransferase; DU, drug user; F, female; HIV, human immunodeficiency virus; LKM1, liver-kidney microsomal autoantibody type
1; M, male.
aAt diagnosis of cirrhosis.
bLKM1 positive.
cAdopted from India.
The majority of cases became HCV RNA seronegative
during the second or third year of life. Univariate Cox
analysis of the variables considered as predictors of clearance showed that age (P ⫽ .0009) at first observation and
genotype 3 (P ⬍ .0001) correlated significantly with viral
clearance. Multivariate Cox analysis revealed that genotype 3 was the only independent predictor of spontaneous viral clearance in children (hazard ratio, 4.71; 95%
confidence interval: 1.94 –11.45), whereas age at first observation was no longer significant.
Persistent viremia. During the follow-up, 332 of
the 359 untreated children (92%) remained HCV RNA
positive. ALT levels were persistently abnormal in 139
of the 332 (42%) patients, constantly normal in 77
(23%), and occasionally abnormal in 116 (35%). Fiftyone of the 332 (15.4%) children had nonspecific, mild,
and transient symptoms, generally at the time of diagnosis. Two girls, with episodes of asthenia and pruritus, and persistently high ALT levels, had high LKM1
autoantibody titers in their serum and histologic features of severe activity.
Disease progression. Among the 332 persistently viremic children, 6 (1.8%) with constantly high
ALT levels developed signs and symptoms of advanced
liver disease (asthenia, epistaxis, pruritus, ascites, gastrointestinal bleeding). The mean duration of HCV
infection from the putative time of exposure to the
diagnosis of cirrhosis (9.87 ⫾ 5.90 years) was similar to
the duration of infection from the putative exposure to
last visit in noncirrhotic children (9.41 ⫾ 5.58 years; P
⫽ .84). The main demographic, serologic, and histologic features of the 6 cirrhotic patients are summarized in Table 3. Case 1, with cirrhosis at first biopsy,
deteriorated during the follow-up despite standard
IFN-␣ and ribavirin treatment and subsequently un-
derwent liver transplantation. An adopted Indian girl
(case 6) infected with HCV genotype 3, whose source of
infection was unknown, had a sharp ALT flare after 6
months of standard IFN treatment but later improved
and remained with near normal ALT levels and mild
intermittent viremia over the next 4 years of follow-up.
The other 4 children, whose first liver biopsy was
consistent with moderate hepatitis, had histologic features of cirrhosis 2 to 9 years later. One of these
children has undergone transplantation. All 5 Italian
children with cirrhosis had been infected vertically
with HCV genotype 1a or 1a/1b. Four mothers were
drug users, and one of them was also coinfected with
HIV. Overall, in the course of a decade following exposure, 2% of the babies of infected mothers and 6.5%
of those with HCV genotype 1a developed symptomatic cirrhosis. None of these children had a history of
drug or alcohol abuse nor were they obese.
Discussion
Children with vertically acquired infection or
transfused early in life afford a good model for studying the natural course of hepatitis C from the early
stages and in the absence of cofactors such as alcohol
or drug abuse. To our knowledge, this is the largest
pediatric observational study including both babies
with perinatal infection and children with parenteral
sources of contagion, most of whom remained untreated. These 2 groups had different epidemiologic
and virologic features, which may have influenced the
outcome of their liver disease and their response to
treatment. There were significantly more females
among the babies of infected mothers than among the
parenterally infected cases; this intriguing finding sup-
ports the results of a recent European study29 showing
that, among the children infected perinatally, females
were twice as likely as males to be infected and suggesting that hormonal or genetic factors may influence
the susceptibility or response to infection. As expected,
the parenterally infected children were older at the first
observation and often identified on screening for HCV
infection years after the clinical diagnosis of chronic
hepatitis. As in our recent epidemiologic survey,5,25
genotypes 3 and 4 were significantly more frequent
among vertically infected children, whereas genotypes
1 and 2 prevailed in transfused children. All these
differences were assessed in relation to the outcome of
infection and liver disease. A mean of 10 years after
putative exposure, 3 major patterns were observed in
the untreated children: (1) undetectable viremia and
normal ALT levels; (2) persistent uncomplicated, mild
liver disease; and (3) progression to end-stage liver
disease.
The rates of HCV RNA clearance reported in the literature for vertically infected children vary considerably. In
a recent large, prospective European study of perinatally
infected children, the rate of viremia clearance was 20%
by the age of 5 years. In the present study, the proportion
of perinatally infected children clearing HCV RNA over a
10-year period was lower (11%), possibly because of the
retrospective data collection, which may have overlooked
cases with early transient viremia. Indeed, if we add the
12 cases with a history of maternal exposure who were
HCV RNA negative since their first observation, the cumulative clearance rate reaches 16%. As in our previous
findings, viremia clearance correlated significantly with
HCV genotype 3 infection; whether HCV RNA clearance
depends on a direct and efficient cytotoxic activity of the
HCV genotype 3 remains to be confirmed. A recent paper
by Lehmann et al30 supports this hypothesis. The authors
investigated a large series of young prisoners with a
history of drug abuse and recent HCV infection, finding
that clearance of the virus was significantly more frequent among patients infected with HCV genotype 3
than in those with HCV genotype 1. For practical purposes, our findings suggest that treatment for perinatally
infected children with HCV genotype 3 could be postponed for up to 5 years.
Retrospective/prospective studies in transfused children indicate that a considerable proportion clear viremia before adulthood. In our cohort, 14 postnatally infected children were already HCV RNA negative at first
observation, and only 1 patient cleared viremia during
the follow-up (overall clearance rate, 11%), suggesting
that viral clearance tends to occur early in the history of
the infection and was probably underestimated in our
study.
Once established, chronic HCV infection tends to persist into adult life. The associated liver disease is usually
asymptomatic, and the pattern of ALT varies, but almost
HEPATITIS C IN CHILDREN
1905
half the patients have sustained cytolysis at follow-up
visits.
In this study, we also found that progression from
chronic hepatitis to cirrhosis takes only a few years
(range, 29 years) in some patients. The reasons for this
accelerated progression remain unclear, but the epidemiologic and clinical features shared by cirrhotic children
could constitute grounds for speculation. All 5 Italian
children with cirrhosis in our series had been infected
perinatally with HCV genotype 1a (mixed with 1b in 1
case). Interestingly, 4 of those children had steatosis on
liver biopsy (none was obese), suggesting that steatosis
could be a risk factor for advanced fibrosis, even in
children. Four children were born of mothers admitting
to drug use, 1 of them HIV coinfected, and all had
persistent ALT abnormalities.
Reports on cirrhosis in HCV-infected children are still
scant and limited to single cases or small series with
different epidemiologic backgrounds. Birnbaum et al22
described 3 cases of cirrhosis in children aged 4 –11 years,
2 born of mothers coinfected with HCV genotype 1a and
HIV. In a quaternary referral center, Rumbo et al24 recorded 7 cases of cirrhosis (including Birnbaum et al’s)
among 91 children with chronic hepatitis C recruited
over 6 years. The available data suggest that at least 4
cases had been vertically infected. Mohan et al20 investigated liver histology in 40 children enrolled by referral
and found that all 3 cases with cirrhosis at final evaluation had been perinatally infected. None of our children
with posttransfusion hepatitis developed cirrhosis, and
Vogt et al11 and Casiraghi et al14 found cirrhosis a rare
long-term outcome of chronic hepatitis C acquired after
occasional blood transfusions early in life. This may seem
to suggest that vertically infected children develop cirrhosis earlier, or more frequently, than transfused children with no underlying systemic diseases. Whether maternal drug use influences host immune response to
hepatocytes infected with HCV genotype 1 remains an
open question.
Another particular aspect of host-virus interaction in
children with chronic hepatitis C concerns the production of LKM1 autoantibodies, which were detectable in
6.3% of our patients. In a previous study,27 we found liver
histology significantly more severe in LKM1-positive
cases, and, in the present series, 1 child with cirrhosis and
both girls with symptomatic hepatitis were LKM1 seropositive. However, the lack of the LKM tests in approximately 40% of the included patients—because of partially
retrospective enrollment—hampers firm conclusions.
The main limitation of the current study, as well as of
other observational studies, is the retrospective recruitment of a consistent proportion of cases. However, it
must be pointed out that all children were consecutively
enrolled, thus limiting the risk of a selection bias. A
further methodologic issue arises in the potential limitation of the generalizability of results to new populations
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IN LIVER, PANCREAS,
AND BILIARY TRACT
June 2008
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CLINICAL ADVANCES
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AND BILIARY TRACT
and settings. Our study included a cohort of European
children who were enrolled in tertiary care centers as
referral institutions, limiting the broad application of the
results. Nevertheless, the majority of our patients was
asymptomatic at presentation, irrespective of the type of
exposure, and had been enrolled after a serologic screening. As a means of gauging the consistency of our sample,
we resorted to the observation that more than 90% of
HCV-infected children born in Italy after 1991 had a
history of maternal infection.5 We calculated that approximately 7 million children were born between 1992
and 2004 and that approximately 2% of the mothers were
anti-HCV positive,10,31 of whom 5% could transmit HCV
to the offspring.10 On this basis, we could hypothesize
that approximately 7000 children with HCV infection
were born between 1992 and 2004. Thus, the 189 children born of infected mothers and enrolled in our study
between 1992 and 2004 would account for approximately
2.7% (189/7000) of the entire population. Therefore, the
relatively homogeneous method of recruitment and the
considerable size of our sample make us confident that
our cohort may be representative of the population of
HCV-infected children in Italy.
In conclusion, in the decade following putative exposure, 3 main patterns emerged in our untreated, otherwise healthy children with chronic hepatitis C: stable
clearance of viremia, usually early in life and in children
with genotype 3 infection; ongoing viral replication, in
asymptomatic children with or without abnormal ALT
levels; and early progression to decompensated cirrhosis
in a small minority (1.8%) of viremic children with persistently abnormal ALT levels, vertically acquired infection with HCV genotype 1a, and a mother with a history
of drug use. Children with this last epidemiologic, biochemical, and virologic pattern should be monitored
carefully and considered for early treatment with interferon and ribavirin.
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HEPATITIS C IN CHILDREN
1907
Received November 11, 2007. Accepted February 28, 2008.
Address requests for reprints to: Flavia Bortolotti, MD, Clinica Medica 5, Policlinico Universitario, Via Giustiniani 2, 35128 Padova, Italy.
e-mail: fl[email protected]; fax: (39) 049 875 4179.
The authors thank Warren Blumberg for his help in editing this
paper and to the following for contributing to the Observatory: Nadia
Gussetti, MD, Padova; Giovanna Zuin, MD, Milan; Loredana Lepore,
MD, Trieste; Paolo Fortunati, MD, Verona, for the survey of patients;
and Alessandra Buja, MD, Padova, for data collection.
Conflicts of interest: No conflicts of interest exist.
CLINICAL ADVANCES
IN LIVER, PANCREAS,
AND BILIARY TRACT
June 2008