Clinical and Developmental Immunology
Volume 2012 (2012), Article ID 785627, 4 pages
doi:10.1155/2012/785627
http://www.hindawi.com/journals/cdi/2012/785627/
Review Article
Autoimmunity and Extrahepatic Manifestations in Treatment-Naïve Children
with Chronic Hepatitis C Virus Infection
Giuseppe
Indolfi,1 Elisa Bartolini,1 Biagio
Olivito,2 Chiara Azzari,2 and
Massimo
Resti1
1Paediatric and Liver Unit, Meyer Children
University Hospital of Florence, Italy
2Immunology Unit and Immunology Laboratory, Meyer Children
University Hospital of Florence, Department of Sciences for Woman and Child's
Health, University of Florence, Florence, Italy
Received 4 January 2012; Accepted 21 February 2012
Academic Editor: Domenico Sansonno
Copyright © 2012 Giuseppe Indolfi et al. This is an open access article
distributed under the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited.
Abstract
Hepatitis C virus (HCV) infection has been associated with autoimmunity and
extrahepatic manifestations in adults. Few data are available on these topics in
children. Nonorgan specific auto-antibodies development is part of the natural
course of chronic hepatitis C in children. Smooth muscle autoantibody is the
most common autoantibody found, while liver-kidney microsomal type-1 antibody
positivity is the most peculiar autoimmune feature of children with HCV
infection. The clinical significance of non-organ specific autoantibodies in the
course of paediatric chronic hepatitis C is still debated. Autoantibody
positivity can be considered neutral for most patients, while it can be
associated with negative connotations for others, especially those positive for
liver-kidney microsomal type-1 autoantibody. Subclinical hypothyroidism but not
autoimmune thyroiditis has been demonstrated in HCV infection in children, while
only few cases of HCV-associated membranoproliferative glomerulonephritis have
been described. Single reports are available in the literature reporting the
anecdotal association between chronic hepatitis C and other extrahepatic
manifestations such as myopathy and opsoclonus-myoclonus syndrome. Despite the
low incidence of extrahepatic manifestations of chronic hepatitis C in children,
overall, available data suggest a careful monitoring.
1. Introduction
Since its discovery in 1989 [1], hepatitis C virus (HCV) has been associated with
autoimmunity and extrahepatic manifestations [2]. Data on these topics in children are scarce, but
the incidence of extrahepatic manifestations is overall lower in children with
chronic hepatitis C when compared to adults [2–6]. The purpose of the present article is to
summarize the current knowledge on autoimmunity and extrahepatic manifestations
in treatment-naïve children with chronic HCV infection.
2. Nonorgan Specific Autoantibodies
Nonorgan specific autoantibodies (NOSAs) development is considered part of
the natural course of chronic HCV infection in children [3–6]. Different mechanisms have been
implicated in the development of NOSAs during chronic hepatitis C [7]. The high prevalence
of NOSAs in adults is considered the clear evidence of the altered immune system
homeostasis in chronically infected patients.
The characteristic lymphotropism of HCV could be one of the bases of the increased production
of autoantibodies. It has been hypothesized that HCV interacting with B lymphocytes
can lower the B-cell activation threshold favouring autoantibodies production, and that HCV,
such as other hepatitis viruses, triggers autoimmune response via a molecular mimicry
mechanism. Molecular mimicry originates when the target of the immune response
to a microorganism shares similarities with a “self” antigen, and the original
antimicrobial immune response becomes cross-reactive with the “self,” that is,
autoimmune. By a complementary mechanism, HCV can induce cellular injury
determining the release of “self” antigens that are normally protected from the
immune system but when released are able to elicit an autoimmune response [8, 9].
The prevalence of NOSAs in children with chronic HCV infection has been
investigated in few studies, and wide ranges of positive results have been found
(Table 1) [3–6]. The heterogeneity of the prevalence estimations
among different studies is due probably to technical differences in the
laboratory methods used and to the fluctuating behaviour of autoantibodies. For
these reasons studies based on determinations of NOSAs on serial samples [4],
using lower dilution thresholds of positivity [4, 5] and more sensitive laboratory methods [4], had
results higher than those based on single point determinations [3, 5], using higher thresholds
of positivity [3, 6] and less sensitive methods.
Table 1: Studies investigating the prevalence of nonorgan specific auto-antibodies in children with
chronic hepatitis C.
Firstly, in 1996 Bortolotti et al. [3] analyzed the prevalence of NOSAs in forty Italian
children with chronic HCV infection. About one third of the children studied had
circulating NOSAs smooth muscle autoantibody (SMA) being the most common
autoantibody found. Interestingly, in this cohort, patients with liver-kidney
microsomal type-1 (LKM-1) autoantibody were more often infected by HCV genotypes
1 and 2, while no difference was found between autoantibodies positive and
negative cases with respect to clinical features, γ-globulins levels, and
liver histology. Few years later, in 1998 Gregorio et al. [4] in a cohort of fifty-one children
with chronic infection using a lower dilution threshold of positivity (1 : 10) and a homemade
substrate for indirect immunofluorescence found an higher prevalence of
autoantibodies positivity (65%). SMA was again the most common autoantibody
detected being present in 51% of the patients. Twenty-nine percent of the
patients enrolled were positive for antibodies to gastric parietal cells [4]. Muratori et al. in
2003 [5] found NOSAs in 34% of forty-seven children, and they did not find any difference in
clinical, virological, and biochemical parameters between NOSAs-positive and -negative
children. Confirming previous findings in adults, NOSAs negative children in this
cohort had significantly higher HCV viral load than those with NOSAs. As a possible
explanation the authors speculated that the unbalanced immune reaction determining autoimmunity
creates a cytokine environment which hampers viral replication [5].
In all the studies examined NOSAs titres were usually lower, and the antigenic specificity
by indirect immunofluorescence was different than that usually found in children with autoimmune hepatitis (AIH)
[3–5]. Antinuclear antibodies (ANA) presented with a speckled rather than homogeneous pattern
and SMA reacted only with vessels, sparing glomerular and tubular structures which are
additional targets in AIH type 1. Not all the children studied presented LKM-1 positivity reacting with
the cytochrome P45IID6 (CYP2D6) that is the common target of LKM-1 autoantibody in type 2 AIH.
In the studies by Gregorio and Muratori [4, 5] children with chronic hepatitis C were enrolled
together with children with chronic hepatitis B and with other chronic liver
diseases as controls. Overall, NOSAs were more common in children with chronic
hepatitis C than in children with other liver disorders of similar severity [4, 5], suggesting that
the presence of autoantibodies is not just a consequence of the chronic liver damage.
It is noteworthy that LKM-1 reactivity was not found in any of the controls suggesting that LKM-1
positivity, even if not the most common, was the most peculiar autoimmune
feature of children with chronic hepatitis C. Furthermore, LKM-1 prevalence in
HCV-infected children was consistently higher than that found in studies
involving HCV-infected adults [2].
2.1. Clinical Significance of NOSAs
The clinical significance of NOSAs in the course of chronic hepatitis C is
still debated [7]. The real challenge for clinicians and scientists
is to understand whether and to what extent HCV-induced autoimmunity contributes
to liver damage distinguishing two theoretically possible populations of
children: (1) children with HCV infection and histologically silent HCV-induced
autoimmunity and (2) children with HCV infection and HCV-driven autoimmune liver
damage.
As first hypothesis, NOSAs reactivity in children with hepatitis C could be
considered a simple consequence of hepatocellular damage without pathogenic
significance. This hypothesis is supported by the observation that different
children despite NOSAs presence and persistence have normal serum
aminotransferase level, will not develop other features of autoimmunity such as
increased γ-globulins levels, and usually have autoantibodies titres
lower than that observed in AIH and with a different pattern as detected by
indirect immunofluorescence [3–5]. On the other hand autoimmunity could have
pathogenetic implications in liver damage of chronically infected children. Some
data supporting this hypothesis are available. In adults some studies showed
that the presence of autoantibodies was associated with elevated levels of
γ-globulins, immunoglobulins, alkaline phosphatase, and γ-glutamil
transpeptidase [10, 11].
Furthermore, LKM-1 positive HCV-infected children have been demonstrated to have
a more advanced liver disease when compared with LKM-1 negative peers [12].
Positivity for LKM-1 autoantibody in chronically infected children appears to
have important clinical implication in view of the significant biochemical
deterioration observed in LKM-1 positive patients who developed marked increases
in aminotransferase activity when treated with interferon-α [3–5, 12]. This is a hot topic
given the recent approval of the combined treatment with pegylated interferon-α and ribavirin
by FDA and EMA for children older than three years. It has been hypothesized that in
LKM-1 positive children interferon-α may amplify the autoimmune response
targeting CYP2D6 and thereby trigger acute LKM-1 mediated liver damage. It is
important that treatment of LKM-1/HCV positive patients is decided after
thorough investigations to exclude AIH. The issue of immunosuppressive therapy
in these children is debated as it can improve clinical and biochemical
parameters in selected patients, but it favours persistent HCV replication.
3. Thyroid
Few data are available regarding natural history of thyroid dysfunction and
thyroid autoimmune disease in children with chronic HCV infection [4, 6, 13].
Gregorio et al. tested the presence of antithyroglobulin and antithyroperoxidase (TPOA)
in chronic HCV positive children before and after treatment with interferon-α with no positive
result [4]. Ghering et al. investigating thyroid function and prevalence of autoimmune
phenomena in chronic HCV-infected children treated with interferon-α, found a strong
correlation between treatment and emergence of thyroid antibodies [6].
Before treatment all children had normal thyroid function, one child had an isolate TSH elevation
and a further one had borderline TPOA levels [6]. Indolfi et al. in a case-control study enrolling
a cohort of untreated children with vertically acquired chronic HCV infection (𝑛=36), showed
a high prevalence of subclinical hypothyroidism (11%) and of autoimmune thyroiditis (5.6%) [13].
Subclinical hypothyroidism was not related to length of infection, or to different HCV genotypes,
but it was related to the presence of active liver disease. Subclinical hypothyroidism was not found in
children with apparent virus clearance but only in those with chronic infection
and persistent viraemia even though no correlation was found between development
of subclinical hypothyroidism and levels of viraemia. No child with subclinical
hypothyroidism in this study presented antithyroid autoantibodies suggesting
that the mechanism of subclinical hypothyroidism in HCV-infected children is not
antibody mediated [13], although autoimmunity cannot be excluded
absolutely as in adults autoimmune thyroiditis without detectable circulating
anti-thyroid antibody titres has been demonstrated and autoimmunity can be
executed by autoreactive T cells also in the absence of detectable
autoantibodies [14].
The possible role in the genesis of subclinical hypothyroidism during chronic
HCV infection of the impaired hepatic metabolism of thyroid hormones [12] and of the
thyroid infection by HCV [15] remains speculative.
4. Kidney
Membranoproliferative glomerulonephritis is the most common renal disease
associated with HCV infection in adults [2]. To the best of our knowledge only three cases of
HCV-associated membranoproliferative glomerulonephritis in children have been
reported [16–18]. The specific pathogenesis of the glomerular injury caused by HCV infection
is not known, but it is thought to result from the deposition of circulating immune complexes
of HCV and anti-HCV on the glomerular capillary in the mesangium [2].
In one of the three children described, successful antiviral monotherapy with pegylated interferon-α
resulted in HCV RNA clearance and disappearance of proteinuria [16].
5. Anecdotal Observations
Single reports are available in the literature reporting the anecdotal
association between chronic hepatitis C and extrahepatic manifestations. Mohan
et al. described a 15-year-old boy with diabetes, chronic HCV infection, and an
inflammatory myopathy presumed to be associated with HCV infection [19].
The potential association between inflammatory myopathy and HCV infection has been
infrequently reported in adult patients [20], and an autoimmune mechanism has been
hypothesized. Ertekin and Tan reported a 9-year-old boy with progressive cerebellar ataxia,
action myoclonus, palpebral flutter, vomiting, headache, and opsoclonus, diagnosed
with opsoclonus-myoclonus syndrome [21]. This rare neurologic disorder characterized by
multidirectional chaotic eye movements, myoclonus in the limbs, and ataxia may
be associated with viral infections and for the first time with hepatitis C [21].
The exact immunopathogenesis of the disease is undefined [22], but as for other extrahepatic
manifestations of HCV infection, the underlying mechanism was postulated to be immune system
dysregulation.
6. Conclusions
The wide range of extrahepatic manifestations of HCV in adults suggests that
HCV chronic infection should be considered a systemic disease. An important role
in the development of extrahepatic manifestations of HCV is thought to be played
by geographic, genetic, or environmental cofactors as well as by the disease
activity [2]. Chronic hepatitis C is much different in children
when compared to adults with regard to disease activity, response to treatment,
and extrahepatic manifestations. Mixed cryoglobulinaemia, for example, is the
most documented extrahepatic manifestation of HCV infection in adults and has
never been described in children. Although discussed, the association between
mixed cryoglobulinaemia and severe liver damage has been shown by different
epidemiological studies [2, 23]. The natural history of chronic hepatitis in
children is usually of a mild disease [24], and the low incidence of severe liver damage
during childhood could be partly responsible for the absence of mixed
cryoglobulinaemia in children. Despite the low incidence of extrahepatic
manifestations in children, overall, available data suggest a careful monitoring.
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