David Branski

Clinical and Genetic Risk Factors for Cystic Fibrosis-related Liver Disease

Objective. The aim of this study was to define the role of possible risk factors for the development of cystic fibrosis (CF)-related liver disease and to analyze the association between liver disease and the different genotypes present in the Israeli CF patient population. Patients and Methods. All patients followed at the seven CF centers in Israel were included in this study. Liver disease was determined by persistently elevated serum liver enzymes and/or bilirubin, and/or significant ultrasonographic changes suggestive of chronic liver disease. The following clinical parameters were evaluated: ethnic origin, age at assessment of liver function, sex, history of meconium ileus, pancreatic function, history of distal intestinal obstruction syndrome, pulmonary function, and cystic fibrosis transmembrane conductance regulator mutation analysis. Results. Of the 288 patients screened, 80 (28%) had liver disease. Of the 256 patients with pancreatic insufficiency, 80 (31%) had liver disease compared with none of the 32 patients with pancreatic sufficiency. Genotype-phenotype correlation was performed on 207 patients carrying identified mutations that were previously classified according to phenotype severity. Liver disease was found in 56 (32%) of 173 patients carrying mutations associated with a severe phenotype and in 6 (38%) of 16 patients carrying at least one mutation associated with a variable genotype (G85E and/or 5T allele). None of the 18 patients carrying the 3849+10kb C->T mutation had liver disease. Prevalence of liver disease increased with age. No correlation was found between liver disease and severity of lung disease, nutritional status, history of meconium ileus, or distal intestinal obstruction syndrome. Conclusion. CF patients who have pancreatic insufficiency and carry mutations associated with a severe or a variable genotype are at increased risk to develop liver disease.

PANCREATIC DISEASES IN CHILDREN

The main congenital anomalies of the exocrine pancreas are reviewed, and several generalized and isolated hereditary pancreatic diseases are discussed. In contrast with adults, the most frequent causes of acute pancreatitis are viral infection, drug induction, and trauma. The dissimilarities between pediatric and acute and chronic pancreatitis are emphasized.

Bloody diarrhea--a possible complication of sulfasalazine transferred through human breast milk.

Sulfasalazine very rarely causes bloody diarrhea. A 3-month-old infant had bloody diarrhea that could be related to sulfasalazine that had been taken by his mother and was transferred through his mothers breast milk. The patient was exclusively breast fed, and no other known etiological factors could be detected for the infants bloody diarrhea.

Pulmonary function abnormalities in type I Gaucher disease

The purpose of this study was to determine the prevalence of pulmonary function and radiographic abnormalities among patients with type I Gauchers disease, and to analyse the relationship between the pulmonary involvement and genotype and clinical severity score. All patients attending the Gaucher clinic at the Shaare Zedek Medical Center, Jerusalem, Israel, during the years 1992-1993 were prospectively evaluated. Each patient had pulmonary function tests, chest radiography, clinical assessment in terms of degree of organ involvement, and genotype analysis. Of the 95 patients included in the study (mean +/- SD age 29 +/- 15 yrs), 68% had some pulmonary function abnormalities, most commonly a reduced FRC and transfer coefficient for carbon monoxide (Kco), found in 45% and in 42% of the patients respectively. Total lung capacity (TLC) was reduced in 22% of the patients and forced expiratory flows in approximately one third of the patients. Signs of airtrapping (elevated residual volume (RV) or RV/TLC) were seen in 18% of the patients. Males had a higher incidence of reduced expiratory flow than females, (forced expiratory volume in one second (FEV1) was reduced in 36% of males vs 5% of females). Chest radiographic abnormalities were found in 17% of the patients, although only 4% had severe changes. Patients with abnormal pulmonary function had a significantly higher severity score index than those with normal pulmonary function tests. There was no association between abnormal pulmonary function and genotype or age. In conclusion, abnormal pulmonary function is common among type I Gaucher patients. Pulmonary function tests show airways obstruction, with reduced expiratory flows, reduction in lung volumes and alveolar-capillary diffusion abnormality. The rate of progression and the clinical significance need to be determined.

INHIBITION OF IL-1BETA AND TNF-ALPHA SECRETION FROM RESTING AND ACTIVATED HUMAN IMMUNOCYTES BY THE HOMEOPATHIC MEDICATION TRAUMEEL S

Abstract Traumeel® S (Traumeel), a mixture of highly diluted (10-1-10-9) extracts from medicinal plants and minerals is widely used in humans to relieve trauma, inflammation and degenerative processes. However, little is known about its possible effects on the behavior of immune cells. The effects of Traumeel were examined in vitro on the ability of resting and PHA-, PMA- or TNF-α-activated human T cells, monocytes, and gut epithelial cells to secrete the prototypic pro-inflammatory mediators IL-1β, TNF-α and IL-8 over a period of 24-72 h. Traumeel inhibited the secretion of all three agents in resting, as well as activated immune cells. IL-β secretion was reduced by up to 70% in both resting and activated cells; TNF-α secretion was reduced by up to 65 and 54%, respectively, and IL-8 secretion was reduced by 50% in both resting and activated cells (P<0.01 for all cells). Interestingly, the effect appeared to be inversely dose-related; maximal inhibition (usually 30-60% inhibition; P<0.01) was seen with dilutions of 10-3-10-6 of the Traumeel stock material. This finding suggests that Traumeel does not inhibit immune cells functions by exerting a toxic effect. Indeed, Traumeel did not affect T cell and monocyte proliferation. Although additional studies are needed to clarify the mode of action of Traumeel and to demonstrate causative relationship between the inhibition of cytokine/chemokine secretion in cell culture and the reported clinical effects of the preparation, our in vitro results offer a mechanism for the anti-inflammatory effects of Traumeel observed in clinical use.

Histologic evaluation of endoscopic versus suction biopsies of small intestinal mucosae in children with and without celiac disease.

BACKGROUND Concern over the adequacy of histologic diagnosis of endoscopic duodenal biopsies in children prompted this comparative study on the histologic quality of endoscopic versus capsule biopsies. We found this problem addressed in only six previous reports. METHODS Blind examinations of the histologic sections of 48 duodenal biopsies obtained by gastrointestinal endoscopy in children aged 2-18 years were compared to 52 biopsies obtained by the small bowel suction method (from children aged 1-16 years). RESULTS Although 87.5% of endoscopic biopsies and 94.2% of capsule biopsies were adequate for histologic diagnosis, fragmentation or squashing was seen in 83.3% of endoscopic biopsies and only in 25% of capsule biopsies. CONCLUSIONS Biopsies obtained by suction are of better quality than those obtained by endoscopy. If endoscopy is preferred for technical reasons, the following conditions should be observed: the patients should be aged over 2 years, and a minimum of four biopsies should be obtained with forceps of a diameter greater than 2 mm. Adequate histologic criteria for diagnosis should include at least one full-thickness mucosal specimen more than 3 mm in length, vertically oriented, and not fragmented. In children under age 2, duodenal or jejunal capsule biopsies are preferred, since the specimens are usually larger and less fragmented. Endoscopy is technically more difficult in the very young patient.

Adrenal Suppression Among Asthmatic Children Receiving Chronic Therapy with Inhaled Corticosteroid with and Without Spacer Device

BACKGROUND Inhaled corticosteroids have become a first-line treatment for chronic asthma. It has been shown that inhaled corticosteroids can have a measurable effect on the hypothalamic-pituitary-adrenal axis in asthmatic children. OBJECTIVE To investigate the prevalence of adrenal suppression among asthmatic children receiving chronic therapy with low to moderate doses (up to 1000 micrograms) of inhaled beclomethasone dipropionate via a metered dose inhaler (MDI) and via MDI attached to a spacer device (MDI-spacer). METHODS The study included 39 asthmatic children currently undergoing therapy; 24 received beclomethasone dipropionate by MDI attached to a spacer, and 15 directly by MDI. All the patients had been treated for at least 4 months. Another 21 children were normal controls. The 24-hour urinary free cortisol excretion was measured to evaluate hypothalamic-pituitary-adrenal axis function. RESULTS Seven of 15 (47%) patients from the MDI group had reduced 24 hour-urinary free cortisol excretion and 2 of 24 (8%) in the MDI-spacer group (P = .006). The mean 24-hour urinary free cortisol excretion of the MDI group was 0.0185 +/- 0.0089 microgram/gram creatinine, and the MDI-spacer and the control groups were, 0.0290 +/- 0.0138 microgram/gram creatinine and 0.0270 +/- 0.0118 microgram/gram creatinine, respectively, (P = 0.37, f = 3.51 ANOVA). CONCLUSION Chronic inhalation of low to moderate doses of corticosteroids is associated with adrenal suppression in some asthmatic children. This side effect is more common among patients inhaling directly from the MDI and is less frequent when a large volume spacer is attached to the MDI.

helicobacter pylori Genotypes in Israeli Children: The Significance of Geography

Background There is substantial genetic variation among different isolates of Helicobacter pylori, which may affect the clinical outcome. The aims of this study were to find the common H. pylori genotypes in Israeli children and to look for a possible genotype–phenotype correlation. Methods Ninety-eight H. pylori cultures were isolated from antral biopsy specimens of symptomatic Israeli children and were analyzed for vacA and iceA genotype and cagA and cagE status by polymerase chain reaction. Results cagA and cagE genes were present in only 25.5% and 24.5%, respectively. The common vacA genotype was s2m2, which was found in 65%. Eleven specimens (11%) contained multiple vacA genotypes. iceA1 was found in 37% and iceA2 in 52% of cases. Both iceA alleles were found in 11%. Increased prevalence of iceA1 and cagE were observed in children with duodenal disease, although it did not reach significance. Conclusions The low prevalence of cagA and the high prevalence of vacA genotype s2m2 in Israeli pediatric patients are different from the genotype prevalence reported globally. However, similar findings have been reported in Egypt, indicating a possible geographic influence. There is a possible correlation between duodenal ulcer and cag E and ice A1 genotype, but the power of the study was too low to prove it.

Celiac disease: an emerging global problem.

Celiac Disease (CD) was considered primarily a disorder of the European and Western populations and those countries to which Europeans have immigrated (1,2). Currently there are more and more reports indicating that CD is relatively common in both Europe and North America. It is estimated that CD affects 1 of every 85 to 300 persons in populations of European descent (1–5). There were suggestions that CD occurs in other populations (3,4); however, loose criteria were used for diagnosis of CD. To answer these discrepancies we need strict criteria for diagnosis and elucidation of genetic components associated with CD in non-European populations worldwide. CD has been reported from the wheat-eating areas of Bengal and the Punjab (6), as well as in children who immigrate from India and Pakistan to England (7). CD was found to occur in Blacks (8), Arabs, and Sudanese of mixed Arab-Black stock (9), Cuban, Mexicans, and Brazilians (10). Furthermore, it has been suggested that the incidence of CD in Asian children is as high as that in Caucasian children (11). Anecdotal evidence claims that CD can be seen in Chinese children (11). A significant concern with the above studies is the possibility that other disorders may simulate clinical presentation of CD and even mimic the histopathologic findings in the small intestine. Such conditions include infectious enteritis, post-infectious diarrhea and protein malnutrition (12). Moreover, in some of the abovementioned studies, the criteria used for the diagnosis of CD were possibly not strict enough. The revised diagnostic criteria of the European Society for Pediatric Gastroenterology and Nutrition (11) should be more workable for developing countries and could be used in future studies. The two requirements mandatory for the diagnosis of CD are characteristic small intestinal mucosal changes while eating an adequate amount of gluten and a full clinical remission following gluten-free diet. In addition, the determination of antibodies to gliadin, endomysium, and tissue transglutaminase at the time of the diagnosis and disappearance after a gluten-free diet should be added to the diagnostic workup for CD (13,14). In this issue, Poddar et al. (15) suggest that by evaluating IgA Antigliadin (AGA) antibodies determination they can determine whether Indian children with small intestinal mucosal injury are true cases of CD. They showed that IgA AGA antibodies are detected in 88% of the children and report no false positively at a cutoff values of 10 units/ml. Poddar et al. (15) suggest that a cutoff value of 5 units/ml of AGA antibodies has 94% sensitivity and can be used as a screening test to select suspected cases for further workup. In addition to AGA antibodies of isotypes IgA and IgG, Antiendomysial (EmA) antibodies of isotype IgA and anti tissue transglutaminase (tTG) antibodies of isotype IgA, were used as screening tests for CD (16,17). While the sensitivity of EmA and tTG antibodies was close to 100%, the sensitivity of AGA IgA and IgG was 89%. The specificity of EmA was 100%, anti tTG was 97%, while AGA IgA was 96% and AGA IgG was 78% (15). The most important predictive value was obtained using EmA antibodies—97%, and it was considerably lower for anti tTG and AGA IgA and IgG antibodies (16). It was demonstrated (17) that tTG enzyme-linked immunoabsorbent assay has a high frequency of false negative and false positive results (17). However, because the test is both simple and fast, it has been suggested that it should be used for large-scale CD screening programs (16). It is suggested that after an initial positive tTG, EmA antibodies should be performed provided that IgA deficiency was excluded (17). The quest for improvement of the current tests for determination of EmA antibodies and tTG antibodies Correspondence to Emanuel Lebenthal, International Institute of Infant Nutrition and Gastrointestinal Disease, Hadassah-Hebrew University, Mount Scopus Medical Center, POB 24035, Mount Scopus, Jerusalem, Israel 91240 (e-mail: elebenthal@yahoo.com). This editorial accompanies an article. Please see Celiac Disease in India: Are They True Cases of Celiac Disease? U Poddar, B Ram Thapa, C Kanwal Nain, A Prasad, and K Singh. J Pediatr Gastroenterol Nutr 2002;35:508–512. Journal of Pediatric Gastroenterology and Nutrition 35:472–474

Findings on Routine Abdominal Ultrasonography in Cystic Fibrosis Patients

BACKGROUND Right lower quadrant abdominal pain may pose a diagnostic problem in patients with cystic fibrosis. Abdominal ultrasound examination, used commonly in the diagnostic work-up, may reveal abnormalities of the appendix. However, interpretation of such findings is problematic, because the appearance of the gastrointestinal system during routine examination has not been documented in patients with cystic fibrosis. The purpose of this study was to investigate the findings during routine abdominal ultrasound scans in our cohort of patients with cystic fibrosis and in control subjects. METHODS Abdominal ultrasound scans were performed prospectively during routine clinic visits in a cohort of patients with cystic fibrosis. RESULTS Fifty patients aged 10+/-6 years, (range, 0.5-28 years) were examined; 45 had pancreatic insufficiency. Four patients (3 with pancreatic insufficiency) reported right lower quadrant pain at the time of the scan. According to standard ultrasound criteria, the appearance of the appendix was abnormal in 8 patients (16%), 6 had a mucoid appendix, and 2 had a pathologically thickened appendiceal wall. Only 1 of these 8 patients mentioned abdominal pain at the time of the study. Other incidental findings included gallstones (3 patients), intussusception (2 patients), and pancreatic cyst (1 patient). CONCLUSIONS Abnormalities can be observed during routine abdominal ultrasonographic studies in cystic fibrosis. These findings may not be associated with abdominal pain; their clinical relevance needs further investigation.