Cystic fibrosis transmembrane conductance regulator ion channel function testing in recurrent acute pancreatitis.

GOALS: To understand the relationship between acute recurrent pancreatitis and cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. BACKGROUND: An emerging number of patients present with a nonclassic phenotype of cystic fibrosis (CF) with partial features or single-organ disease only. The association between the phenotype of recurrent pancreatitis CFTR dysfunction is unclear. METHODS: Patients with idiopathic recurrent pancreatitis were referred for electrophysiologic investigation. RESULTS: Thirty-three patients (18 males) aged 20+/-12 years with recurrent pancreatitis were studied. Three patients had mild asthma and 1 patient had mild ulcerative colitis. There was no family history of CF. All patients had normal imaging of the pancreatic duct by endoscopic retrograde cholangiopancreatography or magnetic resonance cholangiopancreatography. No patient was pancreatic insufficient. Mean sweat chloride values were 41+/-14 meq/L (range: 18 to 64). Nasal potential difference (NPD) measurement was pathologic in 7 patients. Mean basal potential difference in these 7 patients was -33+/-13 mV and there was an abnormal response to chloride-free and isoproterenol solutions. There was no difference in sweat chloride concentration between the 2 groups. Mutation analysis revealed W1282X/5T, D1152H/5T, and W1282X/- in 3 patients with abnormal NPD and 1 W1282X allele was found in 1 patient with normal NPD. CONCLUSIONS: In this series, 21% of patients with recurrent pancreatitis have abnormalities of CFTR function. Patients presenting with recurrent, "idiopathic" pancreatitis require CFTR function testing.

Reproducibility of nasal potential difference measurements in cystic fibrosis.

BACKGROUND: Nasal potential difference (NPD) measurement has been advocated as a diagnostic tool for cystic fibrosis (CF) patients and as a method for assessing the response to new therapies. The purpose of this study was to examine the reproducibility of NPD measurements performed in a single center. METHODS: A total of 68 CF patients with a mean (+/- SD) age of 16 +/- 8 years (age range, 6 to 52 years) underwent NPD measurements on at least two occasions. RESULTS: A total of 25 patients with classic CF (mean age, 21 +/- 8 years) and 43 patients with nonclassic CF (mean age, 14 +/- 8 years) underwent sweat tests and NPD measurements. The mean sweat chloride values were 102 +/- 18 and 54 +/- 14 mEq/L, respectively, for classic CF and nonclassic CF groups. All patients underwent repeat NPD measurements. The basal NPD and the response to amiloride (DeltaAmil) and response to Cl(-) free and isoproterenol (DeltaCl(-) free + iso) were very similar in both measurements. In the classic CF group, the basal potential difference values were -40 +/- 12 vs -39 +/- 11 mV (p = 0.57), respectively, for the first and second measurements; 27 +/- 9 vs 26 +/- 10 mV (p = 0.55), respectively, for DeltaAmil; and 2.1 +/- 3.8 vs 0.4 +/- 2.9 mV (p = 0.07), respectively, for DeltaCl(-) free + iso. In the nonclassic CF group, the values were -32 +/- 13 vs -28 +/- 10 mV (p = 0.008), respectively; 19 +/- 10 vs 17 +/- 8 mV (p = 0.388), respectively; and -3.2 +/- 4.6 vs -3.3 +/- 4.4 mV (p = 0.876), respectively. CONCLUSION: When performed in a single center, NPD is a reproducible test for CF patients and thus may be a useful outcome measurement for assessment of the efficacy of new treatments.

Familial concordance of phenotype and microbial variation among siblings with CF.

The clinical spectrum of cystic fibrosis (CF) is influenced by the cystic fibrosis transmembrane conductance regulator (CFTR) genotype. However, variable courses of the disease were demonstrated among patients with identical genotypes. Since siblings share identical CFTR mutations and environmental factors, they can serve as a model to assess the effect of modifier genes on disease expression, and also to evaluate cross-infection. The aim of this study was to compare disease expression among siblings with CF. All sibling pairs treated at 7 CF centers in Israel were included in the study. Data were collected from patients' medical charts. Fifty families with at least 2 siblings were identified. As expected, the second-born sibling was diagnosed at an earlier age compared to the first-born. The mode of CF presentation at diagnosis showed significant familial concordance. In the families where the first sibling presented with gastrointestinal manifestations, 79% of the second siblings also presented with gastrointestinal manifestations. When gastrointestinal manifestations were absent in the first sibling, only 12% of the second siblings presented with gastrointestinal manifestations (P < 0.0001). Likewise, when the first sibling presented with respiratory symptoms, 60% of the second siblings presented with the similar symptoms. However, when the first sibling presented without respiratory symptoms, only 12% of the second siblings presented with respiratory symptoms (P < 0.001). Meconium ileus (MI) was present in 20 patients (21%). In 10 families where the first-born sibling had MI, 8 (80%) of the subsequent siblings had MI. On the other hand, in the 39 families where the first-born sibling did not have MI, only 2 (5%) subsequent siblings had MI (P < 0.001). Pancreatic insufficiency (PI) also had high familial concordance (P < 0.0001). Percentile growth for weights and heights and lung function (FVC, FEV(1), and FEF(25-75)) at ages 7 and 10 years were similar between siblings. P. aeruginosa grew from sputum in 89% of our study patients. When P. aeruginosa was isolated from the first-born patient, 91% of the second siblings were also positive for P. aeruginosa, whereas when the initial sibling was not a carrier of P. aeruginosa, only 50% of subsequent siblings were positive (P < 0.0001). This familial concordance was not observed for S. aureus. By contrast, the age of first isolation of P. aeruginosa and S. aureus was significantly earlier in the second sibling than in the first for the two bacteria: 10.3 +/- 5.1 vs. 7.3 +/- 5.2 years (P < 0.05) for P. aeruginosa, and 11.5 +/- 5.4 years vs. 6.8 +/- 5.1 years (P < 0.05) for S. aureus. CF siblings tend to share similar phenotypes that are not mutation-dependent. The lack of variability between siblings in mode of initial CF presentation, rates of MI, pulmonary function, and nutritional status supports the role of modifier genes in the determination of these factors.

Oligohydrosis and hyperthermia: pilot study of a novel topiramate adverse effect.

A 6-year-old boy with partial complex seizures developed recurrent episodes of hyperthermia 2 months after topiramate was introduced into his antiepilepsy drug regimen. Further investigation revealed that the febrile episodes were related to environmental temperature and physical activity. A pilocarpine iontophoresis sweat test showed that the amount of sweat produced by the child was 5% that of age-matched controls. Topiramate discontinuation resulted in the disappearance of febrile episodes and normalization of sweat quantity in repeat sweat testing. Based on this observation and the previous data on zonisamide and isolated case reports on topiramate-related hyperthermia and the effect on sweat production, topiramate was suspected of causing oligohydrosis. A pilot study was carried out involving 13 additional children and young adults (age range 1-37 years) receiving topiramate. All patients were directly questioned regarding symptoms of decreased sweating and heat intolerance, went through a pilocarpine iontophoresis sweat test, and were compared with 14 age-matched controls who went through the sweat test for unrelated reasons. Nine of the patients were found to have reduced sweat quantity on the pilocarpine iontophoresis sweat test (including index case) (mean 0.089 g/30 minutes, SD 0.082; age-matched control: mean 0.21 g/30 minutes, SD 0.06). Eight of them were children (below 16 years). However, only three patients revealed symptoms related to heat intolerance. Topiramate is most likely responsible for decreased sweat production as detected by a pilocarpine iontophoresis sweat test. The effect seems to be more significant in children than in adults. There is a discrepancy between test results and clinical symptoms. Interestingly, oligohydrosis was found to be a relatively common side effect of zonisamide. Both zonisamide and topiramate share a carbonic anhydrase inhibitor activity. The significance of oligohydrosis in hot climates should not be underestimated. Its extent, the role of sweat test prediction, and clinical significance during topiramate treatment should be further estimated.

13C-urea breath test to validate eradication of Helicobacter pylori in an Israeli population.

BACKGROUND: The 13C-urea breath test is the best non-invasive test to validate Helicobacter pylori eradication. Serology is unreliable for this purpose due to the slow and unpredictable decline in the antibody titer. OBJECTIVES: To characterize a specific group of patients who were treated for H. pylori and tested for successful eradication by 13C-UBT in our central laboratory, to correlate the eradication success rate with specific drug combinations, and to evaluate other factors that may influence eradication success. METHODS: 13C-UBT for H. pylori was performed in the central laboratory of Clalit Health Services. The breath test was performed by dedicated nurses in 25 regional laboratories and the samples were analyzed by a mass spectrometer (Analytical Precision 2003, UK). The physician who ordered the test completed a questionnaire computing demographic data (age, gender, origin), indication, use of non-steroidal anti-inflammatory drugs or proton pump inhibitor, and combination of eradication therapy. RESULTS: Of the 1,986 patients tested to validate successful H. pylori eradication, 539 (27%) had a positive test (treatment failure group) and 1,447 (73%) had a negative test (successful treatment group). Male gender, older age and European-American origin predicted better eradication rates. Dyspeptic symptoms and chronic PPI therapy predicted treatment failure. Combination therapy that included clarithromycin had a higher eradication rate than a combination containing metronidazole. The combination of omeprazole, amoxicillin and clarithromycin achieved an eradication rate of 81.3%, which was better than the combination of omeprazole, metronidazole and clarithromycin (77.2%) (not significant), or of omeprazole, amoxicillin and metronidazole (66.1%) (P < 0.01). CONCLUSION: Gender, age, origin, dyspepsia and PPI therapy may predict H. pylori eradication results. Our findings also support an increase in metronidazole resistance of H. pylori strains in Israel, as reported in other countries. We recommend combination therapy with omeprazole, amoxicillin and clarithromycin and avoidance of metronidazole as one of the first-line eradication drugs.

Probiotic supplementation affects pulmonary exacerbations in patients with cystic fibrosis: a pilot study.

OBJECTIVE: Probiotics reduce intestinal inflammation in, and Lactobacillus GG (LGG) reduces pulmonary exacerbation rate cystic fibrosis (CF) patients. We intended to determine the effect of a mixed probiotic preparation on pulmonary exacerbations and inflammatory characteristics of the sputum in CF patients. STUDY DESIGN: A prospective pilot study of 10 CF patients with mild-moderate lung disease and Pseudomonas aeruginosa colonization, treated with probiotics for 6 months. Pulmonary function tests (PFT's), sputum cultures with semi-quantitative bacterial analysis, and sputum neutrophil count and interleukin-8 (IL-8) levels were compared to pre-treatment and post-treatment values. The rate of pulmonary exacerbations was compared to 2 years prior to the study. RESULTS: The exacerbation rate was significantly reduced in comparison to the previous 2 years and to 6 months post-treatment (P = 0.002). PFT's have not changed at the end of treatment and during 6 months post-treatment. No change in sputum bacteria, neutrophil count, and IL-8 levels was observed. CONCLUSION: Probiotics reduce pulmonary exacerbations rate in patients with CF. Probiotics may have a preventive potential for pulmonary deterioration in CF patients.

The changing face of the exocrine pancreas in cystic fibrosis: the correlation between pancreatic status, pancreatitis and cystic fibrosis genotype.

OBJECTIVES: The aims of this study were to determine the current pancreatic status of the entire cystic fibrosis (CF) population of Israel, to analyze the clinical characteristics of the pancreatic sufficient (PS) patients, and to characterize the correlation between pancreatic status, pancreatitis, and CF genotype. METHODS: The Israeli CF database includes 505 patients. These patients were defined as being PS or insufficient according to their fecal pancreatic elastase level or by coefficient fat absorption findings. Mutations were categorized as severe (DeltaF508, W1282X, G542X, S549R, N1303K, Q359K/T360K, 405+1G, and 1717) or mild/variable (3849+10 kb, D1152H, G85E, I1234V, R334W, and 5T) based on disease severity in patients carrying these mutations. Age at diagnosis, presenting symptoms, sweat-chloride concentrations, occurrence of pancreatitis, presence of diabetes, and liver disease were recorded. RESULTS: One hundred and thirty-nine (27.5%) of the CF patients were PS. None carried two mutations associated with severe disease. Over one third (34%) had normal or borderline sweat tests; 20 of these 139 patients had pancreatitis (14.3%) but none of the 366 pancreatic insufficient patients had it. Four initially PS patients became pancreatic insufficient: conversion followed several events of pancreatitis in three of them. Nasal potential differences were all pathological in 35 tested PS patients. None had either diabetes or liver disease. CONCLUSIONS: A substantial number of CF patients are PS. All of them carry at least one mild mutation enabling production of a sufficient amount of normal mRNA to maintain exocrine pancreatic function. Pancreatitis occurs only in CF patients who are PS. These patients are at risk of progressing to pancreatic insufficiency.