Autoimmune hepatitis in Down syndrome

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.

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Down Syndrome Research and Practice


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 [1] . 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 [1] . A high percentage of Down syndrome patients with newly diagnosed type 1 diabetes mellitus have anti-islet cell antibodies [1] . 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 pediatric 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 summarized in Table 1. 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)
Fatigue 4
Hepatomegaly 4
Weight loss 3
Splenomegaly 3
Jaundice 2
Dark urine 1
Fever 1
Vomiting 1
Ascites 1
Decreased appetite 1
URI/sore throat 1

Table 1 | Clinical presentation

Laboratory parameters at the time of presentation are summarized 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.

Parameter Median Range
AST (u/L) 422 46-2232
ALT (u/L) 389 63-1605
Alk phos (u/L) 242 61-570
GGT (u/L) 156 12-410
T/D bilirubin (mg/dL) 3.0/1.9 0.3-7.0/0.01-3.0
TP/albumin (g/dL) 9.5/3.5 9.1-10.3/2.8-4.2
PT (sec) 14.3 11.8-26
ESR (mm/hr) 59 48-100
IgG (mg/dL) 4535 3020-7390

Table 2 | Laboratory presentation

Liver biopsy specimens were reviewed by one pathologist at each contributing author's institution. Histological data and Knodell scores [9] 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 [1] . 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 [1] .

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 [10] . 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 pediatric 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.

Longer 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 pediatric patients with autoimmune hepatitis, thirty-two of whom had type I autoimmune hepatitis [11] . 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 [14] . Banerjee et al. reported successfully weaning off corticosteroid therapy on five non Down syndrome pediatric patients with autoimmune hepatitis after a mean of 378 days [15] . 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, and Nutrition
  • ANA+: anti-nuclear antibody
  • SMA+: smooth muscle antibody
  • Anti-LKM1+: liver-kidney-microsome-1 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 transplanted organ.
  • Type I diabetes mellitus: disorder in which there is no control of blood sugar, due to inadequate insulin production
  • Coeliac 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 loss
  • Hypothyroidism: deficiency in the production of thyroid hormones
  • Hepatomegaly: enlargement of the liver
  • Splenomegaly: abnormal enlargement of the spleen
  • 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 in thyroglobulin
  • Anti-cardiolipin: antibody to phospholipids
  • 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 surgery
  • 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 leukocyte-endothelial transmigration


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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