Autoimmune hepatitis in Down syndrome
Kim-Doan Nguyen, Scott Duong, Farrah Lazare, Rajeev Nagpal, J Decker Butzner, Maria Triantafyllopoulou, William Treem and Ian Leibowitz
We sought to determine the clinical features of autoimmune hepatitis in children with Down syndrome. After an inquiry on the PEDS GI Board, a questionnaire was sent to interested colleagues. Seven patients with autoimmune hepatitis and Down syndrome were reported. The median age at diagnosis was 10 yrs, range 3-15 yrs. All seven were ANA+ and SMA+; none were anti-LKM1+. Initially, three were treated with corticosteroids alone, three with corticosteroids and azathioprine (AZA), and one with cyclosporine alone. Three are currently on AZA alone; two remain on corticosteroids. No patients underwent liver transplant. There were two deaths. We concluded that autoimmune hepatitis is another autoimmune disease to consider in the evaluation of children with Down syndrome.
Autoimmune diseases such as autoimmune thyroid disease, type 1 diabetes
mellitus, and coeliac disease are more common in patients with Down
syndrome. Previous reports of adolescents with Down syndrome show a high
prevalence of autoimmune thyroiditis and anti-thyroid antibodies in
patients with Down syndrome compared to non Down syndrome patients with
thyroiditis. Type 1 diabetes has an earlier age of onset and occurs in
1.4%-10.6% of patients with Down syndrome compared to 0.1% in the general
population. A high percentage of Down syndrome patients with newly
diagnosed type 1 diabetes mellitus have anti-islet cell antibodies. Coeliac disease is also associated with Down syndrome, affecting 3%-16% of
patients with Down syndrome, which is significantly higher than the
incidence of 0.7-1.0% in the general population[2-5]. Anti-gliadin
antibodies are present in 10%-40% of patients with Down syndrome[1-4].
Although other autoimmune diseases are associated with Down syndrome, a
literature search identified only three case reports of autoimmune hepatitis
in patients with Down syndrome, with only one reported in a paediatric
patient[6-8]. We sought to determine the clinical features of autoimmune
hepatitis in children with Down syndrome.
After an inquiry on the PEDS GI Internet Bulletin Board, a
questionnaire was sent to colleagues who indicated that they cared for
children with Down syndrome and autoimmune hepatitis. One case of primary
sclerosing cholangitis/autoimmune hepatitis overlap syndrome was eliminated.
Except for age, gender, and ethnicity, other patient identifiers were
removed from data collection documents. For laboratory data, median and
range were calculated.
Seven patients with autoimmune hepatitis and Down syndrome were included
in this case series. The clinical presentations are summarised in
The median age at diagnosis was 10 years with a range of 3-15 years. There
were four males; two Caucasians, two African-Americans, one Filipino, one
Hispanic, and one Turkish patient. Two patients had other autoimmune
diseases including type 1 diabetes, thyroiditis, and alopaecia areata. Three
patients had a family history of autoimmune diseases including Graves’
disease, rheumatoid arthritis, and hypothyroidism. The most common
presenting symptoms were jaundice, fatigue, and weight loss. Hepatomegaly
was present in four patients and three had splenomegaly.
|Initial signs and symptoms
||# of patients (n = 7)
Table 1 | Clinical presentation
parameters at the time of presentation are summarised in Table 2. All
patients were hypergammaglobulinaemic and had elevated ESR and serum
aminotransferases. All seven patients had type 1 autoimmune hepatitis with
both positive ANA and SMA, but none were anti-LKM1 positive. One patient
also had other autoantibodies, including anti-thyroglobulin, anti-thyroid
peroxidase, and anti-cardiolipin antibodies. This patient had type 1
diabetes and thyroiditis.
|Alk phos (u/L)
|T/D bilirubin (mg/dL)
Table 2 | Laboratory presentation
Liver biopsy specimens were reviewed by one
pathologist at each contributing author’s institution. Histological data and Knodell scores
were assigned by the pathologist. The lowest Knodell score
reported was 5 but two patients had a Knodell score of 13. The median score
was seven. Three patients had evidence of bridging fibrosis.
One patient was
initially treated with cyclosporine alone, but was subsequently treated with
prednisone and azathioprine to maintain remission. Three patients were
initially treated with corticosteroids alone and three with corticosteroids
and azathioprine (AZA). Two patients currently remain on corticosteroids,
including the patient who was on cyclosporine. This patient is now five
years post diagnosis. Three patients are currently taking AZA alone, but two
of them have required corticosteroids intermittently due to relapses. Three
are in remission, one has chronic active hepatitis, and one has portal
hypertension and coagulopathy. No patients underwent liver transplant. There
were two deaths. The cause of death in one patient was reported as
respiratory failure/end-stage liver disease, and the other patient died from
complications of a seizure disorder and lobar pneumonia.
Down syndrome is a chromosomal disorder associated with several
autoimmune diseases, including thyroiditis, coeliac disease, and type 1
diabetes mellitus. The reason for this association is unclear, but various
hypotheses have been proposed. The thymus of patients with Down syndrome has
increased numbers of CD8+ T cells and depletion of CD4+ T cells. T cell
function is defective in patients with Down syndrome. Lymphoid cells from
Down syndrome patients show over-expression of lymphocyte-function
associated antigen-1 (LFA-1), which plays an important role in the
trafficking and activation of leukocytes. Increased expression of LFA-1
increases sensitivity to interferons, which in turn may augment MHC II and
ICAM-1 expression. This process could contribute to enhanced autoantigen
presentation in patients with Down syndrome.
There have been many reports
of the association of thyroid disease, coeliac disease, and type 1 diabetes
mellitus with Down syndrome. However, our literature search revealed only
three cases of autoimmune hepatitis in Down syndrome[6-8] and only one
report in a child. In a retrospective case control study by Goldacre et al.,
a review of hospital admissions and death records was performed to study the
association of cancers and immune-related disorders in patients with Down
syndrome. The authors included patients who had Down syndrome listed as
a diagnosis at the time of admission or as a cause of death. This study
found that patients with Down syndrome were 47 times more likely to have
autoimmune hepatitis than a reference cohort of non Down syndrome patients.
Although paediatric patients were included in the analysis, the number of
children with Down syndrome who had autoimmune hepatitis was not clearly
reported. A recently compiled series of autoimmune hepatitis from 1993-2005
at one U.S. children’s hospital consisted of 65 children less than 20 years
of age with documented autoimmune hepatitis, two of whom also had Down
syndrome [Triantafyllopoulou et al., unpublished data]. Compared with the
general population where Down syndrome birth prevalence is estimated to be
about 0.1%, the observation that 3% of patients with autoimmune hepatitis in
this series also have Down syndrome suggests a significant increased
association between these two conditions.
To our knowledge, this case series
is the first attempt to describe the clinical features of autoimmune
hepatitis in children with Down syndrome. In many ways, the clinical
features of autoimmune hepatitis in patients with Down syndrome mimic those
of non Down syndrome patients. However, previous series of autoimmune
hepatitis in non Down syndrome children reported between 15%-40% type II
autoimmune hepatitis patients[11-14]. In our small series of Down
syndrome/autoimmune hepatitis, all patients had type I autoimmune hepatitis.
The finding that there is no type II autoimmune hepatitis in our case series
may reflect a small sample bias and precludes any conclusion about whether
there is a predominance of type I autoimmune hepatitis in Down syndrome.
Further study will reveal whether this finding is significant.
requirement for medical therapy may be a feature of autoimmune hepatitis in
patients with Down syndrome. In our series of Down syndrome/autoimmune
hepatitis, we note that two patients were finally weaned off corticosteroids
at 8 and 23 months after initiation of treatment. Two patients remain on
corticosteroids, one of whom is now five years post-diagnosis. None of the
patients in our series have been successfully weaned off all medications.
Although three patients are currently receiving AZA alone, they have
required intermittent courses of corticosteroids due to relapses. Gregorio
et al. reported on fifty-two non Down syndrome paediatric patients with
autoimmune hepatitis, thirty-two of whom had type I autoimmune
hepatitis. Six of the thirty-two ND type I autoimmune hepatitis (19%)
patients in their series successfully weaned off all immunosuppressive
treatment, and they have remained in remission for a period of 9 to 13
years. Saadah et al. also reported six non Down syndrome autoimmune
hepatitis patients who remained off all medications after a median eight
year follow up. Banerjee et al. reported successfully weaning off
corticosteroid therapy on five non Down syndrome paediatric patients with
autoimmune hepatitis after a mean of 378 days. These patients were
maintained on AZA alone for median of 37 months. Only one of the patients
had a relapse after 75 months of AZA monotherapy but responded to the
addition of corticosteroids.
Autoimmune hepatitis should be included in the
list of autoimmune diseases to consider in children with Down syndrome. We
report a series of seven patients with Down syndrome and type I autoimmune
hepatitis, none of whom are off treatment. Further study with a larger
number of patients and a case-control design are needed to validate whether
there are significant differences between Down syndrome autoimmune hepatitis
and non Down syndrome autoimmune hepatitis.
Glossary of Terms
- PEDS GI Board: internet bulletin for
communication between members of the North American
Society of Pediatric Gastroenterology, Hepatology,
- ANA+: anti-nuclear antibody
smooth muscle antibody
- Corticosteroids: synthetic drug used to reduce inflammation, control
allergic disorders, and prevent graft rejection
- Azathioprine: synthetic drug that suppresses the
body’s immune responses, widely used during and
after transplant surgery to prevent rejection of the
- Type I diabetes mellitus: disorder in which there is no control of
blood sugar, due to inadequate insulin production
disease: a disorder caused by sensitivity to gluten
that causes malabsorption
- Autoimmune thyroiditis: inflammation of the thyroid gland due to an
overactive immune response to the body’s own tissues
- Anti-thyroid: antibodies directed against
the thyroid gland
- Primary sclerosing cholangitis:
chronic cholestatic liver disease of unknown origin,
which can lead to inflammation and destruction of
bile ducts and fibrosis, and progress to biliary
cirrhosis and liver failure
- Alopaecia areata:
autoimmune disorder due to antibodies against hair
follicles resulting in patchy and progressive hair
- Hypothyroidism: deficiency in the production of
- Hepatomegaly: enlargement of the
- Splenomegaly: abnormal enlargement of the
- Hypergammaglobulinaemic: excess levels of certain immunoglobulin in
the blood serum
- Aminotransferases: best known are aspartate
aminotransferase (AST) and alanine aminotransferase
(ALT), normally found in cells of the liver, heart, and muscle released
into the bloodstream as a result of tissue injury
- Anti-thyroglobulin: antibody against molecule used by thyroid gland
to produce thyroid hormones, T4 and T3
- Anti-thyroid peroxidase:
antibody against an enzyme expressed in thyroid that
liberates iodine for addition onto tyrosine residues
- Anti-cardiolipin: antibody to
- Knodell score: Numerical scoring of liver biopsy specimens which
describes the degree of inflammation and fibrosis
- Cyclosporine: drug obtained from soil fungus and used to suppress the
body’s immune system in order to prevent tissue rejection in transplant
- Coagulopathy: disorder in the natural clotting cascade
- Lobar pneumonia: inflammation of a lobe of the lungs due to bacterial
or viral infection
- CD4+ T cells: helper T cells, which collaborate with antigen
presenting cells in the initiation of an immune response
- CD8+ T cells: cytotoxic T cells, which are
directly responsible for killing cells that present
peptides through major histocompatibility complex I
- Leukocytes: white blood cells
- MHC II: major histocompatibility complex II, expressed on antigen
presenting cells; primarily presents peptides which have been derived
from extracellular proteins
- ICAM-1: inter-cellular adhesion molecule-1; trans-membrane protein
that stabilises cell-cell interactions and activates
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No financial support was obtained for this study.
Received: 22 August
2008; Accepted: 5 May 2009; Published online: 17 December 2009