Prevalence of celiac disease and follow-up of EMA in children and adolescents with type 1 diabetes mellitus.

BACKGROUND: The prevalence of celiac disease (CD) in children with diabetes mellitus type 1 (DM) is significantly higher than in the nondiabetic population. Most patients with DM and associated CD do not experience typical gastrointestinal symptoms of CD. There is no agreement on the necessity of screening and management of silent CD for patients with DM or on the time scale for screening. Only few data on follow-up evaluation of children with DM and CD-related antibodies are available. METHODS: One hundred fifty-seven patients with DM (mean age, 14.8 years; range, 4-21 years; male, 83) were screened with endomysial antibodies (EMA) between 1993 and 2001. A follow-up period of at least 3 years, with at least 2 EMA measurements, was possible. Group 1 comprised 37 patients whose first measurement was at the onset of DM. Group 2 comprised 120 patients whose first measurement was during the course of the disease. In patients with positive EMA, small bowel biopsy was performed. Thyroid peroxidase (TPO), thyroglobulin (TgA), glutamate decarboxylase (GAD), antiinsulin (IAA), and islet cell antibodies (IA2) were measured in all patients. RESULTS: EMA was positive in 16 patients, in 5 at onset of DM and in 11 during the course of DM (mean duration, 33.6 months; range, 11-105 months). Biopsy results showed normal mucosa in seven patients, increased intraepithelial lymphocyte counts in one, and flat mucosa in eight. There was no significant difference between EMA-positive and EMA-negative patients regarding height, weight, HbA1c level, frequency of hypoglycemia or hyperglycemia, TPO, TgA, GAD, IAA, or IA2. CONCLUSION: This study emphasizes the high prevalence of CD in patients with DM. Although several patients already had positive EMA titers at the onset of DM, seroconversion may also occur during the course of the disease. Screening for CD with EMA or tissue transglutaminase should be included in the initial investigation of DM, but should also be repeated over time to detect late seroconversion.

Helicobacter pylori in children and adolescents: increase of primary clarithromycin resistance, 1997-2000.

BACKGROUND: The authors evaluate the prevalence of Helicobacter pylori resistance in 117 children and demonstrate the changes over a 4-year period. METHODS: In 117 children and adolescents, H. pylori-positive gastritis was revealed by diagnostic upper endoscopy. Biopsies from the antrum and body of the stomach were tested by histology, urease test, and culture. H. pylori was isolated using standard culture techniques, and susceptibility to amoxicillin, clarithromycin, and metronidazole was tested using the E-test (AB-Biodisk, Sweden). RESULTS: Endoscopy revealed gastric ulcers in 2 of 117 subjects, duodenal ulcers in 6 of 117, and erosive gastritis or duodenitis in 23 of 117. Almost all patients showed antral nodularity. Histology always showed chronic gastritis with different degrees of activity. During the 4-year study period, the authors noticed an increase of primary clarithromycin-resistant H. pylori strains, from 14.3% to 27.6% (mean, 20.3%). Metronidazole resistance varied between 5% and 25%. No resistance to amoxicillin was found. CONCLUSION: Eradication of H. pylori should take place only after testing of susceptibility. The general use of clarithromycin in children should be restricted to better-defined indications. Resistance to clarithromycin of H. pylori may also become a future problem for the treatment of adults.

[Diagnosis and therapy of celiac disease in adolescence and adulthood]. / Diagnostik und Therapie der Zöliakie im Adoleszenz- und Erwachsenenalter - Ein Konsensus der Arbeitsgruppe für chronisch entzündliche Darmerkrankungen der OGGH.

The incidence of celiac disease has increased considerably during the last two decades. Celiac Disease is now diagnosed in adults at least as frequently as in children. A prevalence of about 1:200 seems reasonable in central Europe. Besides the typical symptomatic presentation, silent, latent and potential celiac disease are found. Oligo- to asymptomatic courses (silent celiac disease) are increasingly found in all age groups. Endomysial antibodies and tissue-transglutaminase antibodies are sensitive and specific for about 95% of celiac patients. However, the final diagnosis is only done by a - mostly endoscopical - biopsy from the distal part of the duodenum, demonstrating hyperplastic villous atrophy of the mucosa with increased numbers of intraepithelial lymphocytes. The biopsies should be classified histologically according to the modified Marsh criteria. Increased prevalence in family members (10 to 15%) and in associated diseases (e.g. diabetes mellitus) lead to the recommendation of active screening in populations at risk. Although the clinical symptoms are rather variable and different, the response to a lifelong strict gluten free diet is nearly 100%. So-called refractory celiac disease is very rare. There are numerous associated diseases as dermatitis herpetiformis, diabetes mellitus type I, thyroid and neurologic diseases. The most frequent complications are retardation of growth in childhood, early onset osteoporosis, and an increased risk of abortions. The most severe complication is intestinal lymphoma. Especially patients with late diagnosis and bad dietary adherence are at risk. A regular follow-up of patients, rather with antibody tests than with duodenal biopsies is recommended to test and secure dietary compliance.

IgA cross-reactivity between a nuclear autoantigen and wheat proteins suggests molecular mimicry as a possible pathomechanism in celiac disease.

Celiac disease patients display IgA antibody reactivity to wheat as well as to human proteins. We used serum IgA from celiac patients and, for control purposes, from patients with Crohn's disease, ulcerative colitis and from healthy individuals to identify celiac disease-specific IgA autoantigens in nitrocellulose-blotted extracts from various human cell types (epithelial, endothelial, intestinal cells, fibroblasts). The pattern, recognition intensity and time course of IgA autoreactivity was monitored using serial serum samples obtained from celiac children before and under gluten-free diet. By immunoblot inhibition and subcellular (cytosolic, nuclear) cell fractionation we identified a 55 kDa nuclear autoantigen expressed in intestinal, endothelial cells and in fibroblasts which was recognized by IgA antibodies of approximately half of the celiac disease patients and cross-reacted with wheat proteins. IgA reactivity to the 55 kDa autoantigen disappeared during gluten-free diet and was inhibited after pre-absorption of sera with wheat proteins but not with tissue transglutaminase, previously reported as the unique celiac disease-specific autoantigen. In conclusion, we defined a novel 55 kDa celiac disease-specific nuclear IgA autoantigen which shares epitopes with wheat proteins and which is different from tissue transglutaminase and calreticulin. Although the newly defined autoantigen was recognized much less frequently than tissue transglutaminase, our data suggest molecular mimicry between wheat and human proteins as a possible pathomechanism for the induction and/or maintenance of mucosal tissue damage in celiac disease.

[Consensus of the Chronic Inflammatory Bowl Disease Study Group of the Austrian Society of Gastroenterology and Hepatology on the topic of "diagnosis and therapy of chronic inflammatory bowel diseases in adolescence"]. / Konsensus der Arbeitsgruppe für chronisch-entzündliche Darmerkrankungen der OGGH zum Thema "Diagnostik und Therapie von chronisch-entzündlichen Darmerkrankungen im Adoleszenzalter".

Although up to 20% of patients with Crohn's disease have their first flare during childhood or adolescence, there are no or only a few randomized, controlled studies. However, big differences and uncertainty may be observed between the diagnosis and therapy of pediatricians and gastroenterologists specialized for adults. In addition, special problems result from the enormous somatic and psychological evolution during adolescence. The diagnosis is done as in adult patients by enteroclysm and ileocolonoscopy (including multiple biopsies) whereas a deep sedoanalgesia or anesthesia should be performed routinely. Corticosteroids are the gold standard for therapy of Crohn's disease in the adolescence (especially in cases with high inflammatory activity), but also enteral nutrition over 4-12 weeks--or a combination of both. A recent randomized controlled study demonstrates the positive effect of 6-mercaptopurine in newly diagnosed patients with Crohn's disease in the adolescence. 5-aminosalicylates or the probably more effective azathioprine/6-mercaptopurine could be used for prevention of recurrence in Crohn's disease. The therapy of ulcerative colitis is performed as in adults including the very effective local rectal applications. An accompanying psychosomatic therapy is recommended especially in young patients with disturbed separation from the parents and inadequate coping. The indication for surgery is similar to adults. However, a specific indication for earlier surgery is given, if severe malabsorption and delay of growth takes place in spite of adequate therapy, because this delay of growth could be only caught up before puberty. A conservative therapeutic regimen is recommended in young patients with perianal Crohn's disease.

Screening by anti-endomysium antibody for celiac disease in diabetic children and adolescents in Austria.

BACKGROUND: Unrecognized celiac disease (CD) may be found in a substantial proportion of patients with type I diabetes mellitus. METHODS: A cohort of 403 Austrian children and adolescents with type I diabetes mellitus (210 males and 193 females; age range, 1-22 years) was screened for celiac disease using the IgA anti-endomysium antibody test (EMA) and the immunoglobulin (Ig)G anti-gliadin (AGA-IgG) and IgA anti-gliadin (AGA-IgA) antibody test. RESULTS: Twelve patients' sera (2.98%) yielded positive EMA results and two patients' sera (0.49%) with IgA deficiency had high AGA-IgG values. All but one of these patients underwent intestinal biopsy. Six (1.49%) had clear histologic evidence of CD (flat mucosa), whereas three (0.74%) showed minor histologic changes (increase in intraepithelial lymphocytes) and four (0.99%), including the EMA-negative patients with IgA deficiency, had a normal mucosa. When the cases with silent and potential CD were combined, the overall prevalence in the current cohort was 2.98%. There was no difference in the hemoglobin (Hb)A1c level between antibody-positive and -negative patients, and subsequent gluten-free diet did not change this metabolic parameter. CONCLUSION: The prevalence of clinically unrecognized CD, found by EMA screening, is much higher in Austrian children with diabetes than in a comparable population without diabetes. The prevalence of CD in diabetic children in Austria is distinctly lower, however, than in several other countries.

The histopathology of coeliac disease: time for a standardized report scheme for pathologists.

In this paper, we review the histological features of coeliac disease and propose a standardized report scheme based on the Marsh classification. Furthermore, terms used by pathologists are defined. The most important histological differential diagnoses are given, as well as a definition of the different clinical forms of coeliac disease such as symptomatic, silent, latent, potential, treated and refractory coeliac disease.

In vitro production of endomysial antibodies in cultured duodenal mucosa from patients with celiac disease.

OBJECTIVE: Endomysial antibodies (EMAs) had been found recently after in vitro gluten challenge of duodenal mucosa from treated celiac patients. This was a promising result for diagnosis of potential/latent celiac disease. Therefore, we tested the usefulness of the production of EMAs of in vitro-challenged mucosa for diagnosis of celiac disease and determined the location of EMA production. METHODS: We investigated EMAs in the serum, in the supernatants of in vitro gliadin-challenged duodenal mucosa specimens in 68 patients, and in homogenized native duodenal and gastric specimens in seven patients. Twenty-one of the 68 patients served as nonceliac controls, 11 as candidates for potential celiac disease, 23 celiac patients were on glutenfree diet, and 13 were newly diagnosed. RESULTS: EMAs were just found in the supernatants of duodenal biopsies of those celiac patients who had demonstrable EMAs in serum, independent of gliadin challenge. In these patients EMAs were also found in homogenized native duodenal biopsies, but not in gastric biopsies. CONCLUSIONS: EMAs seem to be produced in the small bowel mucosa of celiac patients, but not in other tissues such as gastric mucosa. The production of EMAs could not be initiated under standard in vitro conditions and therefore, such as in vitro challenge cannot be used for diagnostic purposes.

Wilson's disease in patients presenting with liver disease: a diagnostic challenge.

BACKGROUND & AIMS: In patients with Wilson's disease presenting with liver involvement, the correct diagnosis is often missed or delayed. The aim of this study was to find an algorithm for diagnosis of this difficult patient group. METHODS: Clinical and laboratory findings of 55 patients with Wilson's disease were evaluated at diagnosis before treatment. Presenting symptom was chronic liver disease in 17 patients, fulminant hepatic failure in 5 patients, hemolysis in 3 patients, and neurological disease in 20 patients, and 10 patients were detected by family screening (siblings). Evaluation included neurological and ophthalmologic examination, routine laboratory tests, and parameters of copper metabolism including liver copper content in 43 liver biopsy specimens. RESULTS: In the whole group, serum ceruloplasmin level was <20 mg/dL in 73%, urinary copper excretion was increased in 88%, and liver copper content was elevated in 91% at diagnosis. Kayser-Fleischer rings were detected in 55%. In contrast to patients with neurological disease (90% Kayser-Fleischer rings, 85% low ceruloplasmin), only 65% of patients presenting with liver disease were diagnosed by these typical findings. Ceruloplasmin levels were lower in patients with Kayser-Fleischer rings or with neurological disturbances than in patients without these symptoms. CONCLUSIONS: The commonly used clinical and laboratory parameters are not sufficient to exclude the diagnosis of Wilson's disease in patients with liver disease of unknown origin.

Diagnosis of Wilson's disease in an asymptomatic sibling by DNA linkage analysis.

The molecular genetic diagnosis of Wilson's disease in the 5-year-old sister of a patient with Wilson's disease is reported. The girl was clinically free of disease and had no conventional biochemical markers of Wilson's disease (i.e., normal ceruloplasmin, normal copper in the serum, normal 24-hour urinary copper excretion). Diagnosis with restriction fragment length polymorphisms and a nonradioactive polymerase chain reaction-based analysis with microsatellite markers showed her to be homozygous for the disease-associated markers. A liver biopsy was performed, and a 20-fold increased liver copper content confirmed the diagnosis. The child was treated with chelation therapy with D-penicillamine. The report of this study clearly shows the advantage of DNA linkage analysis (especially polymerase chain reaction) over conventional laboratory methods for presymptomatic diagnosis of Wilson's disease before irreparable liver and neurological damage occurs. The only limitation of this DNA-based diagnosis is the fact that it is only applicable in siblings of an index patient whose diagnosis was made by phenotypic criteria.

Early sensitization to airborne allergens.

We report the case of a 7-month-old child with failure to thrive. Celiac disease was suspected because of highly raised antigliadin IgA and IgG antibodies and subtotal villous atrophy. In peripheral blood mononuclear-cells cellular proliferation was found in response to birch pollen, rye pollen and hazelnut extract. Born in June 1992 the infant had not yet experienced a birch pollen season. He had been fed with birch pollen allergy-associated carrot, apple and potato beginning at 6 weeks of life. In the serum, specific IgG, IgM and IgA to birch pollen and profilin, rye pollen and hazelnut antigens were detectable, indicating possible in utero sensitization or T cell cross-reactivity due to early sensitization with related food antigens.

Screening for celiac disease: a prospective study on the value of noninvasive tests.

OBJECTIVE: Celiac disease is frequently diagnosed in patients with nonspecific abdominal symptoms. Therefore, highly sensitive, specific, and simple noninvasive screening tests are needed. METHODS: This study compared the usefulness of IgG- and IgA-antigliadin antibodies, IgA-endomysial antibodies, and intestinal permeability in diagnosing celiac disease in 102 adult patients with nonspecific abdominal symptoms. In addition, all patients underwent small bowel biopsy as a gold standard for the diagnosis of celiac disease. RESULTS: Forty-nine patients were ultimately diagnosed as having celiac disease because of flat mucosa. Flatulence and signs and symptoms dating back to childhood were more frequent and abdominal pain less frequent (p < 0.05) in celiac disease but were not helpful for screening. IgA-endomysial antibodies showed a sensitivity and specificity of 100%; an altered intestinal permeability had also a 100% sensitivity, but only 55% specificity. IgG- and IgA-antigliadin antibodies' sensitivity (73% and 82%, respectively) and specificity (74% and 83%, respectively) were much lower. Combining the two antigliadin antibodies did not significantly improve the sensitivity and specificity. CONCLUSIONS: Our data show the advantage of IgA-endomysial antibodies for screening of celiac disease except in the case of patients with IgA-deficiency or dermatitis herpetiformis. In these patients, the permeability test could improve noninvasive differential diagnosis.

[Color Doppler ultrasound of gallbladder varicose veins in children. A rare sign of portal hypertension]. / Farbdopplersonographie von Gallenblasenvarizen bei Kindern. Ein seltenes Zeichen der portalen Hypertension.

In a retrospective study of 21 children with portal hypertension (P. H.) four patients (19.2%) presented with gallbladder varices as documented by colour-coded Doppler sonography (CCDS) gallbladder varices (GV). Three of four patients with GV had portal vein thrombosis, one patient had cholestatic cirrhosis. Thickening of the gallbladder wall with serpentine anechoic structures was visible in all cases. Blood flow could be documented within the widened veins of the gallbladder wall in 3 of the 4 patients with duplex Doppler US, but in all patients with CCDS. US follow-up studies within 3-5 years were done on 2 patients and showed that GV appeared 2 years after the clinical diagnosis of P. H. With CCDS, varices of the gallbladder wall may be diagnosed readily and differentiated from other diseases associated with thickening of the gallbladder wall.

Growth failure and insulin-like growth factor (IGF-I) in childhood celiac disease.

The prevalence of underweight, short stature, and abnormal laboratory tests was assessed in a retrospective study of 335 patients with biopsy-verified childhood celiac disease (CCD). Of the patients younger than 2 years old, 67.4% were underweight (body weight: less than - 2SD) and 33.9% were short (height: less than - 2SD). In children older than 2 years, underweight was present in 36.0% of patients; the prevalence of short stature was 50.0%. Therefore, diagnostic procedures related to CCD appear justified in all children with short stature of unknown etiology. However, because 50% of patients were neither short nor underweight, normal height and weight should not preclude workup of a patient with symptoms suggestive of CCD. Of the laboratory tests evaluated, antigliadin antibodies were the most sensitive for CCD. Insulin-like growth factor (IGF-I) serum levels were prospectively studied in 62 patients (32 CCD patients, 30 controls) referred for jejunal biopsy. IGF-I levels were significantly lower in female CCD patients than in control patients. There was a significant negative association between the duration of gluten exposure and IGF-I levels. Results indicate that significant reduction in IGF-I levels in CCD patients occurs only after prolonged gluten exposure but before growth failure. Reevaluation of IGF-I levels on a glutenfree diet showed rapid reversal of reduced IGF-I values.

[Celiac disease (gluten sensitive enteropathy)]. / Zöliakie (glutensensitive Enteropathie).

The frequency in the Austrian population of coeliac disease is approximately 1 in 1000 live births. The diagnosis is easy in most cases, if not obscured by an inconsiderate and inconsequent approach. The most frequent mistake is prescribing gluten free diet on trial before proving the diagnosis by small bowel biopsy. Failure to thrive, deficiency states and abnormal stools are the leading symptoms of coeliac disease. Careful inquiries and drawing of curves for length and weight usually give more information than expensive laboratory tests. Symptoms are frequently equivocal in relapses, in older children, and especially in adults. The basic prerequisite for the diagnosis of coeliac disease is the finding of subtotal villous atrophy in the small bowel mucosa. The only absolute contraindication against small bowel suction biopsy is a blood clotting defect. The small inconvenience from this procedure can be further reduced by experience and discipline of the examiner. Small bowel biopsies are performed in many paediatric hospitals. Thus, there is no excuse for omitting or delaying this procedure. Antigliadin antibodies and antiendomysial antibodies are of high diagnostic significance. The respective IgA antibodies show a high specificity, IgG antibodies a very high sensitivity. Thus, the decision for or against small bowel biopsy is made easier in doubtful cases, the evidence by villous atrophy for coeliac disease is approaching absolute proof. Gluten loading tests and multiple biopsies are therefore necessary only in rare cases. The very high frequency of certain HLA alleles in coeliac patients may also be used for diagnostic purposes. The pathogenesis of coeliac disease appears to involve genetic, immunologic, and environmental factors. The contribution of each of these factors may vary considerably in various patients.

[Failure to thrive as a main symptom of intracranial tumors in early childhood]. / Gedeihstörung als Hauptsymptom intrakranieller Tumoren im frühen Kindesalter.

In the course of only three years we studied three children, who presented for a long time with failure to thrive as the only symptom of an intracranial tumour. Up to 24 months elapsed from the first manifestation at the age of four, ten and eleven months to the final diagnosis. A suprasellar tumour was discovered once, an infratentorial one twice. In spite of lower caloric intake a more rapid weight gain was documented after neurosurgery. The intracranial tumour is an important part of differential diagnosis in infants and young children not thriving satisfactorily.

Toxic epidermal necrolysis due to antiepileptic therapy in an 8-year-old boy.

Toxic epidermal necrolysis (TEN) has rarely been documented in children. We treated an 8-year-old boy who developed generalized blistering dermatosis after anticonvulsive therapy with diphenylhydantoin. The diagnosis was proved by exfoliative cytology, histology, and electron microscopy. The disease entity and its differentiation from staphylococcal scalded-skin syndrome and toxic shock syndrome are reviewed.