Celiac Disease, Thyrotoxicosis, and Autoimmune Hepatitis in a Child

Abstract

Autoimmune diseases such as celiac disease (CD), juvenile diabetes mellitus, and thyroid dysfunction tend to cluster in one patient (1–5). This may occur because of a common association with HLA-class II molecules DR3, DQ2, and DR4, DQ8 (6). The role of gluten in predisposing a patient to other autoimmune diseases has been suggested. Usually autoimmune disorders precede mucosal inflammation, and it has been suggested that a gluten-free diet may protect against the development of other autoimmunopathies, although this is not always the case (7). Autoimmune hepatitis is one of the rare disorders occasionally reported in association with CD (8), although transiently increased serum aminotransferase levels is more commonly observed (9). Here we describe a child in whom two additional autoimmune diseases developed after the diagnosis of CD and who had a strong family history of autoimmunopathies. CASE REPORT An 11-year-old girl was admitted to our hospital in November 1995 after a 4-month history of weight loss, fatigue, abdominal pain, and diarrhea. Blood tests showed a markedly increased titer of reticulin antibodies to 1:2,000 (normal <1:5) and slightly increased immunoglobulin A gliadin antibodies. Small bowel biopsy specimen demonstrated villous atrophy and crypt hyperplasia, confirming the diagnosis of CD. In addition, an increased density of intraepithelial γ/δ T-cells was observed. The CD-related symptoms disappeared during the gluten-free diet and the antireticulin antibodies decreased to 1:50 within 6 months. In May 1996, 6 months after the initial diagnosis of CD, symptoms typical of thyroid hyperfunction appeared and thyrotoxicosis was diagnosed on the basis of abnormally decreased serum thyroid stimulating hormone concentration and increased thyroxin levels. Increased autoantibody titers and thyroid microsomal antibodies (1:25,600) and increased thyroid-stimulating antibody concentrations (22 U/L) were observed, confirming the diagnosis of an autoimmune thyroiditis. Treatment with propranolol and carbimazole was administered. Levothyroxine sodium was added after the thyroxin value had normalized. By July 1998, hypothyroidism had developed and the medication was altered accordingly. The alanine aminotransferase levels, checked regularly during the disease course, became abnormal (63 U/L) in December 1997, and remained so at control 1 month later. By April 1999, it became evident that despite a strict gluten-free diet, the patient had lost 14 kg during the past year and felt abnormally tired. Testing showed markedly increased serum values of alanine aminotransferase (251 U/L) and immunoglobulin G (44.50 g/L), and increased sedimentation rate (100 mm/h). The glutamyl transferase activity was initially normal but increased to 140 U/L. Increased autoantibody titers were also observed: antinuclear antibodies were 1:1280, antineutrophil cytoplasmic antibodies with perinuclear staining were 1:2560, smooth muscle antibodies were 1:200, and liver–kidney microsomal antibodies were 1:50. Serologic test results for hepatitis A, B, and C were negative. Immunoglobulin A antigliadin antibodies increased to greater than 10 ELISA U/mL despite normal endomysial antibody concentrations. Histologic examination of a liver biopsy specimen showed chronic inflammation in the portal area and proliferation of the small hepatic ductules. Patchy degeneration of the liver cells was also observed. The findings were considered typical of autoimmune hepatitis. Prednisolone was administered at 60 mg daily. Because of a favorable response to therapy, the dosage was gradually tapered during the next 3 months. However, a relapse occurred and the dosage of prednisolone was increased and, azathioprine and ursodeoxycholic acid therapies were added. Apart from a notable weight gain because of the prednisolone treatment, the patient has remained well during the follow-up until February 2002. Hyperglycemia has been observed, but other tests that measure glucose metabolism have excluded a diabetes diagnosis. Tests for antinuclear cytoplasmic antibodies have remained positive, but serologic markers for CD have finally become negative. The family on the father's side does not carry any burden of autoimmune diseases. However, on the mothers side of the family, several cases of autoimmune diseases exist: the patient's mother has celiac disease, thyrotoxicosis, and sarcoidosis and a few additional relatives have been diagnosed with juvenile diabetes mellitus, CD, or diseases of the thyroid gland, which were suspected on the basis of clinical symptoms (Fig. 1). Therefore, first-degree relatives of the patient underwent HLA typing. The patient and her mother tested positive for the HLA haplotype known to be associated with autoimmune diseases (DR3, DQ2). The twin brother and older sister of the patient do not carry the HLA haplotype consistent with CD. The older sister has a fatty liver with fluctuating aminotransferase activity, the cause of which remains unknown.FIG. 1.: Family tree of the described patient. Closed symbols denote patients affected by autoimmune diseases. Arrow shows the described patient. CD, celiac disease; hyperthyr, hyperthyreosis; AIH, autoimmune hepatitis.The patient and her mother gave informed consent before preparation of the manuscript for this article. DISCUSSION Many authors have described a connection between CD and other autoimmune diseases (1–5,10). Yet, only a few reports have been published about the clustering of autoimmune diseases in families, and these mainly concern CD and diabetes (11). The family of the patient we describe gives an excellent example of CD and other autoimmune diseases occurring in the same family: 6 of 33 relatives had been diagnosed with CD, 4 have hyperthyreosis, and 2 have juvenile diabetes mellitus. The autoimmune background described here and the fact that the patient carries HLA-DR3, DQ2 confirms earlier findings supporting the hypothesis that CD is one form of autoimmune disease, in which a putative autoantigen also has recently been found (12). However, healthy persons in the family did not have the haplotype HLA-DR3 or DR4, suggesting that HLA typing of the healthy family members may be a way to target screening of autoimmune diseases to individuals who really are at risk. The development of autoimmune diseases has been associated with duration of gluten exposure. If CD is diagnosed in adolescence, the prevalence of autoimmune disorders increases sevenfold compared with healthy controls. Therefore, an early diagnosis of CD may protect against the development of other autoimmune diseases (7). In our patient with CD, two autoimmune diseases, thyrotoxicosis and hepatitis, developed during a strict gluten-free diet. Our findings support two previously published pediatric case reports: one of which described a patient with treated CD complicated afterward by type 1 diabetes, hypothyroidism, selective IgA deficiency, and chronic liver disorder of unknown origin (13), and the other described a patient with autoimmune hepatitis and erythroblastopenia before CD diagnosis (14). In our case, the familial background of autoimmunity seemed obvious. Autoimmune hepatitis has been shown to be a risk factor for CD development (9) and, as shown here, vice versa. Liver involvement most often precedes CD, although CD-specific antibodies also have been found in these patients by the time liver disease was diagnosed (15). Because clinical signs of liver involvement often are lacking, regularly testing liver values is advisable, at least in children with CD associated with poor growth and weight loss during the diet. This case reminds us of the occurrence of multiple autoimmune diseases in some patients and families, which may be caused by an extraordinary genetic predisposition, as shown here, in which the patient carries a heavy family burden for these disorders. Therefore, it may be advisable to serologically screen family members not only for CD but also for other autoimmune diseases.