Lack of association of coeliac disease with idiopathic and ischaemic dilated cardiomyopathies

Objective. A prevalence of coeliac disease higher than in the general population has been reported not only in patients with idiopathic dilated cardiomyopathy, a presumable autoimmune disease, but also in patients with ischaemic or valvular cardiomyopathy. The evidence is controversial, however, and the concept itself of an association unrelated to aetiology is intriguing and warrants further testing. The aim of our study was to assess the prevalence of coeliac disease in a cohort of patients with dilated cardiomyopathy screened for the presence of serum anti‐transglutaminase antibodies. We provisionally assessed the sensitivity and specificity of two commercially available kits for tissue transglutaminase antibodies detection. Material and methods. We screened for anti‐transglutaminase antibodies in 350 consecutive patients with idiopathic (n = 182) and with ischaemic (n = 168) dilated cardiomyopathy using the previously validated method for anti‐transglutaminase antibody assay. Coeliac disease diagnosis has been confirmed by duodenal histopathology in patients testing positive at serological screening. Results. Two coeliac patients (0.6% prevalence) have been identified, one with idiopathic and one with ischaemic dilated cardiomyopathy. They presented with iron deficiency anaemia and with recurrent abdominal pain and diarrhoea, respectively, and both had villous atrophy at histopathology. After 1 year on a gluten‐free diet, the echocardiographic parameters did not improve in either patient. Conclusions. Our results indicate that the prevalence of coeliac disease in patients with dilated cardiomyopathies is similar to that reported for the Italian general population. The confounding factor of conditions associated with both coeliac disease and dilated cardiomyopathies may explain the association unrelated to aetiology reported in previous studies mostly based on small sample size.     

Addisonian crisis precipitated by thyroxine therapy: a complication of type 2 autoimmune polyglandular syndrome

Hypothyroidism is a common condition. Rarely, it may occur in combination with autoimmune failure of other endocrine glands (autoimmune polyendocrinopathy syndrome type 2, previously known as Schmidt's syndrome). In such cases, restoring normal thyroid function may precipitate adrenal failure. Clinicians should have a high index of suspicion for this condition in patients with Addison's disease, those with a family history of autoimmune endocrine gland failure, patients with one autoimmune endocrine disease who develop nonspecific or serious illness, and patients with type 1 diabetes mellitus whose insulin requirements drop without obvious explanation.     

Coeliac disease and epilepsy

Whether there is an association between coeliac disease and epilepsy is uncertain. Recently, a syndrome of coeliac disease, occipital lobe epilepsy and cerebral calcification has been described, mostly in Italy. We measured the prevalence of coeliac disease in patients attending a seizure clinic, and investigated whether cerebral calcification occurred in patients with both coeliac disease and epilepsy. Screening for coeliac disease was by IgA endomysial antibody, measured by indirect immunofluorescence using sections of human umbilical cord. Of 177 patients screened, four patients were positive. All had small-bowel histology typical of coeliac disease. The overall frequency of coeliac disease in this mixed patient sample was 1 in 44. In a control group of 488 pregnant patients, two serum samples were positive (1 in 244). Sixteen patients with both coeliac disease and epilepsy, who had previously attended this hospital, were identified. No patient had cerebral calcification on CT scanning. Coeliac disease appears to occur with increased frequency in patients with epilepsy, and a high index of suspicion should be maintained. Cerebral calcification is not a feature of our patients with epilepsy and coeliac disease, and may be an ethnically-or geographically-restricted finding.      

The hunt for coeliac disease in primary care

BACKGROUND: Serological screening suggests that most coeliac disease goes undetected. AIM: To determine how often coeliac disease is found in patients referred for gastroscopy by general practitioners. DESIGN: Testing of 9971 consecutive patients referred to a single health centre for their first open-access gastroscopy over a 10-year period, without previously-diagnosed coeliac disease or dermatitis herpetiformis. METHODS: Endoscopy and routine duodenal biopsy were in use throughout the study period. The occurrence of coeliac disease was evaluated in patients with dyspepsia, in those with regurgitation, and in those with symptoms suggestive of coeliac disease. RESULTS: Altogether, 147 (1.47%) patients had coeliac disease: 18/2974 (0.61%) with regurgitation, 41/5347 (0.77%) with dyspepsia, and 88/1650 (5.33%) with suspected coeliac disease. Increasing age reduced the risk very slightly (OR 0.98; 95%CI 0.97-0.99). Risk was significantly increased when there was a suspicion of coeliac disease (OR 9.085; 95%CI 5.371-15.369), while no difference was found between patients with dyspepsia and those with reflux disease (OR 1.33; 95%CI 0.75-2.34). The risk in women was not increased (OR 0.97; 95%CI 0.69-1.38). DISCUSSION: In this primary-care setting, <1% of patients with upper abdominal symptoms suffered from coeliac disease; population-based serological screening is expected to yield a corresponding prevalence. When physicians had suspected coeliac disease, the condition was nine times more common.     

Polyglandular autoimmune syndrome, type 2

We have described two patients with Addison's disease and associated endocrinopathies, a condition termed polyglandular autoimmune (PGA) syndrome, type 2. One of our patients also had autoimmune hypothyroid disease, and the other had premature gonadal failure and Hashimoto's thyroiditis. This syndrome shows that glandular disorders tend to occur together. It has been suggested that an HLA-associated genetic predisposition coupled with environmental factors triggers an autoimmune process resulting in glandular hypofunction or hyperfunction. We stress the necessity for evaluation of every individual with idiopathic Addison's disease for associated endocrinopathies.     

Absence of high-affinity calreticulin autoantibodies in patients with systemic rheumatic diseases and coeliac disease

Calreticulin has been reported to be an autoantigen in various autoimmune connective tissue diseases and in coeliac disease. Previous studies have used incubation buffers with low salt and low detergent concentrations (low stringency conditions) with serum albumin or other proteins as a blocking agent. Using these conditions we found a relatively high level of non-specific binding in many sera. Antibodies to proteins that are used as blocking reagents in ELISA (bovine serum albumin (BSA), ovalbumin, skimmed milk powder) are frequently present in sera, and these may cause false-positive results. Moreover, the low isoelectric point of calreticulin and its chaperone properties may give rise to false-positive results under low stringency conditions. We report that the use of a simple buffer without protein (50 mM Tris, pH 7.5, 1% Tween 20, 0.3 M NaCl) removes most of the problems with unwanted binding (high stringency conditions). Using the high stringency conditions, we screened sera from 107 patients with systemic lupus erythematosus, sera from patients with other systemic autoimmune diseases and from children with coeliac disease for the presence of high-affinity calreticulin autoantibodies by immunoblotting and ELISA. None of the sera contained high-affinity calreticulin antibodies. It is concluded that calreticulin is not a common autoantigen in patients with autoimmune connective tissue diseases or coeliac disease.     

Addison's disease

Addison's disease is an uncommon endocrine condition manifested by a variety of nonspecific symptoms, such as malaise, anorexia and nausea. Symptoms usually do not occur until most of the adrenal gland has been destroyed. Autoimmune disease has surpassed tuberculosis as the primary cause of Addison's disease. Nevertheless, tuberculosis still accounts for a significant proportion of cases. The rapid adrenocorticotropic hormone (ACTH) stimulation test is useful for identifying adrenal insufficiency. Maintenance therapy consists of hydrocortisone and fludrocortisone.     

Celiac disease occurring in a patient with hypoparathyroidism and autoimmune thyroid disease

Patients with an underlying autoimmune endocrine disorder are at an increased risk of developing other autoimmune diseases. We describe a patient with idiopathic autoimmune hypoparathyroidism who developed hyperthyroidism due to Graves disease and subsequently was diagnosed with celiac disease. Malabsorption of L-thyroxine was the only clue regarding the presence of celiac disease. This particular association of these three autoimmune disorders occurring in the same patient has not, to our knowledge, been previously reported. The presentation, investigations performed, and treatment provided are discussed and the literature pertaining to similar cases is reviewed.     

A novel visual immunoassay for coeliac disease screening

BACKGROUND: To date, the most commonly accepted techniques for the screening of coeliac disease are indirect immunofluorescence and enzyme-linked immunosorbent assay (ELISA), which reveal antiendomysium and antigliadin antibodies respectively. We report the use of a simple visual system for coeliac disease screening based on the use of Staphylococcus aureus protein A, which binds to both IgG and IgA, thus avoiding the need for two parallel immunoassays. MATERIALS AND METHODS: Opaque polystyrene microwell strips coated with a wheat gliadin extract were incubated with sera followed by incubation with protein A-colloidal gold conjugate. The resulting colour was compared with that of positive and negative control sera. The procedure took less than an hour. RESULTS: One hundred and forty-five biopsy-proven sera, 94 from active coeliac patients and 51 from non-coeliac patients with diverse gastrointestinal pathologies or diabetes mellitus, were assayed. Ninety of the 94 sera from the active coeliac patients were positive, whereas only 3 of the 51 non-coeliac control subjects were positive. The technique has a sensitivity of 95.7% and a specificity of 94.1%. CONCLUSIONS: The sensitivity and specificity of the visual system are greater than those of most ELISA systems and are similar to those observed with IgA antiendomysium antibodies when tested in the same population. Moreover, it is inexpensive, quick, simple to perform and easy to interpret, i.e. it requires no qualified personnel. It is for these features, together with the outstanding sensitivity and specificity, that we propose this immunoassay as a new test for reliable coeliac disease screening.     

Epidemiological survey of coeliac disease and inflammatory bowel disease in first-degree relatives of coeliac patients

One hundred and sixty-two of 182 patients with coeliac disease provided satisfactory details of family size and the prevalence of coeliac disease and inflammatory bowel disease among their first-degree relatives. Patients ranged in age from 11 months to 79 years with a mean age of 41 (+/- 23) years. Twenty patients had at least one first-degree relative with coeliac disease: a total of 25 of 861 relatives were affected (prevalence = 2904/100,000) compared with an expected 0.9 cases (prevalence = 100/100,000; p less than 0.001). Six relatives had inflammatory bowel disease (prevalence = 697/100,000) compared with an expected 1.3 cases (prevalence = 150/100,000; p less than 0.001). Five of these had ulcerative colitis, and one had Crohn's disease. The relative risk of ulcerative colitis is, therefore, five times greater for first-degree relatives of people with coeliac disease than for the general population (95 per cent confidence interval, 4.7-7.2). There is a clear association between coeliac disease and ulcerative colitis, which may point to factors involved in the aetiology of colitis.     

The association of autoimmune disorders with inflammatory bowel disease

Medical records of patients with ulcerative colitis (n = 858), Crohn's disease (n = 378) and coeliac disease (n = 148) were examined to determine the prevalence of associated autoimmune disorders. Of outpatient controls (n = 300), 2 per cent had at least one autoimmune disorder, compared to 7 per cent with ulcerative colitis, 2 per cent with Crohn's disease and 6 per cent with coeliac disease. Inclusion of primary sclerosing cholangitis with the autoimmune disorders increased the overall prevalence in ulcerative colitis to over 9 per cent. The results provide further indirect evidence of involvement of autoimmune mechanisms in the pathogenesis of ulcerative colitis.     

Hyposplenism and T lymphocyte subpopulations in coeliac disease and after splenectomy

An imbalance in immunoregulatory cells might explain the increase in autoimmune phenomena associated with hyposplenism. Using the monoclonal antibodies OKT3, OKT4 and OKT8 to identify T-lymphocyte subsets, we have studied 19 patients with treated coeliac disease, 9 of whom had hyposplenism, 10 splenectomized subjects, 10 gastrointestinal control patients and 10 normal subjects. There was no significant difference in the proportion of lymphocytes, OKT3+, OKT4+ or OKT8+ cells, nor in the OKT4+/OKT8+ ratio, between any of the patient groups and normal or control subjects. Splenectomized subjects had higher total lymphocyte counts than normals (p less than 0.01). Hyposplenic coeliac patients had higher total lymphocyte counts than other coeliacs (p less than 0.05). Hyposplenic coeliac patients and splenectomized subjects tended to have an increase in the absolute number of OKT8+ cells, which in the latter group was statistically significant (p less than 0.05). We conclude that the increased frequency of autoimmune phenomena associated with hyposplenism due to coeliac disease or after splenectomy is not the result of an altered ratio of OKT4+/OKT8+ cells or a deficiency of OKT8+ cells.     

Increased luminal nitric oxide concentrations in the small intestine of patients with coeliac disease

BACKGROUND: Inflammation is known to be associated with enhanced nitric oxide production. A role for nitric oxide in coeliac disease has been suggested because of increased expression of the inducible isoform of nitric oxide synthase in the small intestine of patients with untreated coeliac disease. DESIGN: During small bowel endoscopy in 11 control subjects, 10 patients with untreated coeliac disease and seven patients with treated coeliac disease, gas was aspirated from different parts of the upper gastrointestinal tract and immediately analysed using a chemiluminescence technique. Luminal nitric oxide concentrations were also quantified in 13 control subjects who had undergone colonoscopy. RESULTS: Jejunal luminal nitric oxide concentrations were more than 20 times higher in patients with coeliac disease than in normal control subjects (mean 755 +/- 173 ppb, range 215-1690 ppb, vs. mean 31 +/- 9 ppb, range 1-83 ppb, P < 0.001). Jejunal luminal nitric oxide levels in patients with treated coeliac disease (mean 54 +/- 18 ppb, range 3-126 ppb) did not differ from those of control subjects. CONCLUSIONS: This study shows that intraluminal jejunal nitric oxide concentrations are significantly increased in patients with untreated active coeliac disease.     

Two different cytochrome P450 enzymes are the adrenal antigens in autoimmune polyendocrine syndrome type I and Addison's disease.

Autoimmune polyendocrine syndrome type I (APS I) and idiopathic Addison's disease are both disorders with adrenal insufficiency but with differences in genetic background, clinical presentation, and extent of extraadrenal manifestations. In this study the major adrenal autoantigen identified with sera from patients with APS I was characterized by analyses using indirect immunofluorescence, Western blots of adrenal subcellular fractions and of recombinant proteins, immunoprecipitations of [35S]methionine-labeled lysates of a human steroid-producing cell line, and studies of enzymatic activity. Sera from patients with APS I, identifying cells in adrenal glands and testes involved in steroid synthesis, reacted in Western blots with a 53-kD antigen, which comigrated with the cytochrome P450 cholesterol side chain cleavage enzyme (SCC). The sera also immunoprecipitated this protein from lysates of radiolabeled adrenal cells. The enzymatic activity of SCC was inhibited by the APS I sera but not by control sera. Sera from patients with idiopathic Addison's disease did not react with the SCC. The results show that the autoimmune responses towards adrenal tissue in patients suffering from APS I and Addison's disease are remarkably selective and suggest that a determination of the antigen involved in a patient with autoimmune adrenal insufficiency will have diagnostic as well as prognostic implications.     

Coeliac disease, anaemia and pregnancy

We have investigated the prevalence of positive serology for coeliac disease in pregnant women, using the IgA anti-endomysium antibody test. Five of 216 pregnant women with a haemoglobin less than 11 g/dl were positive, compared to 0/350 with haemoglobin > or = 11 g/dl. Four of these five had low plasma ferritin levels, indicative of iron deficiency anaemia; the fifth was borderline normal. We found no association between positive coeliac disease serology and folate deficiency. None of thirty mothers of children born with neural tube defects were IgA anti-endomysium antibody positive. This study has identified a very high prevalence of occult coeliac disease in pregnancy and a strong association with anaemia. We advise that in cases with a haemoglobin of less than 11 g/dl in pregnancy, coeliac disease should be excluded.     

Gliadin IgA antibodies in diagnosis of celiac disease in childhood]

An enzyme immunoassay kit for the determination of anti-gliadin-IgA antibodies in serum has been evaluated in the diagnosis of coeliac disease in childhood. 84 patients, 22 of them with coeliac disease according to ESPGAN's criteria were tested between 1978 and 1989 and the results have been correlated with the findings on small intestine biopsy and the clinical features. The sensitivity of the test was 95.5% and the specificity was 87.0% on initial diagnosis. On a gluten-free diet reduced antibody levels were seen in all patients. During gluten challenge 11 of 13 children showed an increase in anti-gliadin-IgA concentration. Of the remaining 2 without antibody elevation IgA deficiency became manifest in one patient, the other had a nearly normal mucosa on small intestine biopsy. Provided that IgA deficiency is ruled out and the gluten intake is sufficient the test seems to be useful for screening and might replace biopsy after gluten challenge in cases of increasing antibody levels.     

Receptors, antibodies, and disease

Abnormal antibody production is now recognized as the basis of specific endocrine and neurological diseases and their complications. Among the autoimmune diseases, the best understood from a mechanistic point of view are myasthenia gravis, Graves' disease, several variants of insulin resistance, and a variant of bronchial asthma. In each of these human disorders, the clinical symptoms can be traced to the actions of antireceptor antibodies produced by a deranged immune system. The autoantibodies produced in these diseases are functionally heterogeneous. They may produce the clinical symptoms of hormone or neurotransmitter insufficiency either by blocking the binding of these agents to target cell surface receptors or by accelerating the internalization and degradation of these receptors. In other cases, the autoantibodies may produce the clinical signs of hormone excess by mimicking the actions of the hormone, in an uncontrollable fashion. In some cases, functionally different types of autoantibodies will appear in the same patient at different stages of the disease. For all of these autoantibodies, of whatever function, assays for their presence in serum are available, in forms suitable for clinical chemists, as well as for researchers; these will be described in this review. In addition to the known anti-receptor autoimmune diseases, there are a large number of other autoimmune diseases for which there is fragmentary evidence that their clinical symptoms have an anti-receptor autoantibody etiology. Several examples of this group will be discussed, and assays suitable for establishing the presence of anti-receptor antibodies in the sera of such patients will be provided. The disorders to be considered are: type I diabetes mellitus, chronic atrophic gastritis, autoimmune Addison's disease, autoimmune hypoparathyroidism, type II pseudohypoparathyroidism, resistant ovary syndrome, connective tissue diseases, and the HLA-B8/DR3 antigen haplotype as a potential marker for autoimmune diseases of the anti-receptor type.     

High prevalence of celiac disease in autoimmune hepatitis detected by anti-tissue tranglutaminase autoantibodies

Celiac disease (CD) may be found in association with other autoimmune diseases. We investigated the relation between autoimmune hepatitis (AIH) and CD by assessing the prevalence of IgA and IgG anti-tissue transglutaminase (tTG) antibodies in AIH, and by verifying whether the findings were associated with clinical and histological features of CD. Forty-seven consecutive patients with AIH (type I: n = 39; type II: n = 8) were studied. One hundred patients with chronic hepatitis C, and 120 healthy blood donors were also studied as controls. We analyzed sera for the presence of IgA and IgG anti-tTG antibodies using a specific human recombinant tTG immunoenzymatic assay. Anti-tTG positive patients and controls were further tested for anti-endomysium antibodies (EMA) and HLA typing, and those found positive by either of these tests underwent duodenal biopsy to confirm a possible diagnosis of CD. Three of the 47 AIH patients (6.4%) were positive for IgA anti-tTG and EMA antibodies, and were subsequently confirmed to be affected with CD by small-bowel biopsy findings. No IgG anti-tTG positivity was found in the AIH patients. None of the controls were positive for IgA anti-tTG, and only one with chronic hepatitis C had a low positive reaction for IgG anti-tTG, which resulted as a false positive. The crude prevalence rate of CD in AIH was 63.8 per 1,000 (95% CI, 13.2-186.1), and it was significantly higher than that found in the general population in Italy (4.9 per 1,000; 95% CI, 2.8-7.8). The results of this study showed a high prevalence of CD in patients with AIH. For this reason, early serological screening testing for CD is strongly recommended for all AIH patients.     

Thyrotoxicosis in a patient with Addison's disease

We report the case of a patient who suffered recurrent episodes of hypoadrenal crisis, despite conventional replacement therapy for Addison's disease. She was found to have hyperthyroidism and after this was treated, she had no further relapse. Thyrotoxicosis should be considered when patients taking replacement therapy for Addison's disease present in hypoadrenal crisis.     

The prevalence of coeliac disease in adult diabetes mellitus

Coeliac disease occurs more commonly in children with insulin-dependentdiabetes mellitus (IDDM) than in the general population, butthe prevalence of coeliac disease in adults with diabetes isunknown. We therefore screened an adult hospital-based diabeticpopulation using IgA antigliadin antibody (IgA-AGA) to identifythose patients requiring intestinal biopsy. In 1 year, 1789patients (43% IDDM, 57% NIDDM) were screened, and 73 had raisedIgA-AGA. Of these patients, 49 agreed to duodenal biopsy and13 (10 IDDM) had coeliac disease. Selective IgA deficiency wasfound in eight patients, one of whom had coeliac disease. Ofthese 14 patients with newly diagnosed coeliac disease, fourhad microcytic anaemia, nine a low serum ferritin, and foura low albumin-corrected calcium. Eight patients had symptomswhich improved on gluten withdrawal. Dietary compliance wasmaintained in 6/8 symptomatic patients, but only in 1/6 withoutsymptoms. Included in the 1789 patients were four (all IDDM)with known coeliac disease. The overall prevalence of coeliacdisease in adult patients with IDDM was 1:50 compared with 1:340in NIDDM. Coeliac disease is common in adults with IDDM andmay cause malabsorption and ill health. It should be suspectedin any IDDM patient with gastrointestinal symptoms or unexplainedanaemia.