Biomedical subjects

E Kerem

Publications and source records attributed to E Kerem.

At least 19 recordsLinked to original sources

PubMed2005

Trampoline use as physiotherapy for cystic fibrosis patients.

Physicians and physiotherapists who care for CF patients have recommended the use of trampolines as a physiotherapeutic tool for enhancing cardiopulmonary performance, encouraging sputum production, and improving general well-being. Despite some therapeutic and recreational benefits associated with trampoline use, papers in the general pediatric population mostly document an increased incidence of injuries, ranging from minor trauma to spinal cord injuries and even death. The aim of this review is to examine the accumulated published data regarding the use of trampolines, to assess their potential contributions and disadvantages for CF patients, and to define whether trampoline use should be recommended. An extensive search in the published medical literature retrieved approximately 60 articles that primarily dealt with trampolines, out of which only two dealt with CF. The preponderance of these articles are reports pertaining to injuries related to the use of trampolines, with only a few describing the medical, physiologic, and/or psychological benefits of trampolines. Based on the accumulated data, the presumed benefits of trampoline use for CF patients are not proven. Furthermore, the suggested benefits could be acquired using other types of exercise. Weighing the known risks of trampolines against the potential benefits that are not unique to this modality suggests that the use of trampolines for CF should not be recommended.

Adolescent↗

PubMed2005

WNK4 regulates airway Na+ transport: study of familial hyperkalaemia and hypertension.

BACKGROUND: WNK [With No K (lysine)] kinases are essential for regulation of blood pressure and potassium homeostasis. WNK4 expression was recently found not only in the distal nephron but also in chloride-transporting epithelia. To establish a physiological role for this distribution we studied patients with familial hyperkalaemia and hypertension (FHH), [pseudohypoaldosteronism type II (PHAII)], which is caused by mutations in WNK4. DESIGN: Measurement of nasal potential difference (NPD) and sweat electrolytes were performed in controls, in six subjects with FHH and ten subjects with cystic fibrosis (CF). RESULTS: Basal NPD was higher in FHH compared with controls (n = 20): 22.8 +/- 5.7 vs. 16.2 +/- 5.3 mV, respectively (P = 0.014). Maximal response to amiloride was also higher in FHH compared with controls: 14.8 +/- 3.5 vs. 10.0 +/- 4.8 mV, respectively (P = 0.03). In CF these values were 42.9 +/- 9.3 and 29.9 +/- 7.4 mV, respectively. The kinetics of the amiloride effect were faster in FHH, and as first reported here also in CF, compared with controls. At 30 s, amiloride-inhibitable residual PD in FHH was 50 +/- 30 vs. 81 +/- 9% in controls (P = 0.0003) and 56 +/- 7% in CF. The response to chloride-free and isoproterenol solutions, which determines chloride transport activity, was similar in FHH compared with controls [16.0 +/- 8.6 vs. 10.4 +/- 5.9 mV (P = 0.08)]. Sweat conductivity in FHH was 49.7 +/- 7.3 vs. 38.2 +/- 8.1 mmol (NaCl eq) L-1 in 16 controls (P = 0.007) and 94.0 +/- 19.3 in CF. CONCLUSIONS: Mutant WNK4 increases Na+ transport in airways, and therefore it is regulated by wild-type WNK4. This may be caused by a regulation of ENaC or a K+ channel.

Cystic Fibrosis↗

PubMed2004

Systemic inflammatory mediators and cystic fibrosis genotype.

Morbidity and mortality in cystic fibrosis patients is mainly attributed to pulmonary infection and inflammation. Chemokines play a pivotal role in the inflammatory process. Although genotype-phenotype correlation in cystic fibrosis patients has been defined, a clear relationship between the defect in the cystic fibrosis transmembrane regulator (CFTR) gene and pulmonary inflammation has not been established. The aim of this study was to assess whether serum chemokines levels in cystic fibrosis patients correlate with genotype and pulmonary function tests, as well as with other clinical characteristics. Serum levels of interleukin-8, RANTES, and monocyte chemoattractant protein-1 were measured in 36 cystic fibrosis patients grouped according to their genotype. Group A included 25 patients who carried two mutations associated with a pathological sweat test and pancreatic insufficiency (deltaF508, W1282X, G542X, N1303K, S549R). Group B included 11 compound heterozygote patients who carried one mutation known to cause mild disease with borderline or normal sweat test and pancreatic sufficiency (3849+10kb C to T, 5T). Associations between chemokine levels, genotype, pulmonary function, Pseudomonas aeruginosa colonization, age, sweat chloride level, and pancreatic and nutritional status were examined. Mean interleukin-8 and monocyte chemoattractant protein-1 levels were significantly higher in group A than group B (11.4 +/- 2.1 pg/ml vs. 5 +/- 0.9 pg/ml and 157 +/- 16 pg/ml vs. 88.8 +/- 16.4 pg/ml, respectively) (P < 0.01). No difference in RANTES levels were found between groups. interleukin-8 levels were inversely related to forced expiratory volume in 1 s (r = -0.37, P < 0.02), while there was no association between the latter and RANTES and monocyte chemoattractant protein-1 levels. The Pseudomonas colonization rate was higher among group A patients than group B (88% vs. 40%, P < 0.01). No relationship was found between measured chemokines and age, sweat chloride levels, and pancreatic and nutritional status. Our study demonstrates an association between interleukin-8, forced expiratory volume, and cystic fibrosis genotype. Hence, elevated interleukin-8 serum levels could serve as an indicator of an early inflammatory process and encourage the initiation of anti-inflammatory treatment.

Adolescent↗

PubMed2003

Serum CA 19-9 levels as a diagnostic marker in cystic fibrosis patients with borderline sweat tests.

Patients with normal or borderline sweat tests present a diagnostic challenge. In spite of the availability of genetic analysis and measurement of nasal potential difference, there is still uncertainty in diagnosing cystic fibrosis in some patients. CA 19-9 is a tumor-associated antigen whose levels were previously found to be elevated in some cystic fibrosis patients. We investigated whether serum CA 19-9 levels can contribute to establishing the diagnosis of cystic fibrosis in patients with a borderline sweat test, and evaluated the influence of different clinical variables on CA 19-9 levels. Serum CA 19-9 levels were measured in 82 cystic fibrosis patients grouped according to their genotype and in 38 healthy individuals. Group A included 50 patients who carried two mutations previously found to be associated with a pathological sweat test and pancreatic insufficiency (DeltaF508, W1282X, G542X, N1303K, and S549R). Group B included 13 compound heterozygote cystic fibrosis patients who carried one mutation known to cause mild disease with a borderline or normal sweat test and pancreatic sufficiency (3849+10kb C-->T, 5T). Group C included 38 normal controls. Nineteen cystic fibrosis patients carried at least one unidentified mutation. An association between CA 19-9 levels and age, pulmonary function, pancreatic status, sweat chloride, previous pancreatitis, serum lipase, meconium ileus, distal intestinal obstruction, liver disease, and diabetes was investigated. The distribution of CA 19-9 levels was significantly different between the three groups ( p<0.01); high CA 19-9 levels were found in 60% (30/50) of group Apatients and in 46.6% (6/13) of group B patients, but in only 5.2% (2/38) of the controls. CA 19-9 levels were inversely related to forced expiratory volume in 1 s, while no association was found with the other clinical parameters examined. Our findings suggest that the serum CA 19-9 in cystic fibrosis patients originates in the respiratory system, and has a useful ancillary role, particularly when diagnostic uncertainty exists. Hence, the diagnosis of cystic fibrosis should be considered in patients with borderline sweat tests and high CA 19-9 levels, but normal levels do not exclude cystic fibrosis.

Adolescent↗

PubMed2001

Lung involvement and enzyme replacement therapy in Gaucher's disease.

Symptomatic lung involvement in Gaucher's disease is relatively rare, being restricted to patients with other severe manifestations. We describe our experience in eight of 411 patients in our referral clinic, who presented with prominent pulmonary signs or symptoms. There were four adults and four children; all have been successfully treated with enzyme replacement therapy. Routine means of monitoring pulmonary status including clinical assessment, chest X-ray, pulmonary function tests, and high-resolution CT (HRCT) were used. Enzyme treatment resulted in decreased hepatosplenomegaly, improved haematological parameters, and increased well-being; There was decreased clubbing and decreased dyspnoea in some of the patients, although on radiology, lung pathology had not normalized. All four children showed improved respiratory compliance, with significant improvement of the radiological findings in one and unchanged disease in the others. Two adults showed improvement in oxygen saturation but worsening of pulmonary hypertension. On chest X-ray, both had increased interstitial markings; one had gradual progression of pulmonary artery accentuation and fine interstitial stable pattern on HRCT. The other two adults had no change in lung function or on chest X-ray, but on HRCT there was apparent improvement in one patient. There is great heterogeneity in presentation and response to enzyme therapy in patients with Gaucher's disease and symptomatic lung involvement. Clinically, some benefited significantly from enzyme therapy, but in contrast to the dramatic reduction in organomegaly, there was no normalization in pulmonary function or lung architecture.

Adolescent↗

PubMed2001

Nasal potential difference measurements in patients with atypical cystic fibrosis.

The diagnosis of cystic fibrosis (CF) is based on characteristic clinical and laboratory findings. However, a subgroup of patients present with an atypical phenotype that comprises partial CF phenotype, borderline sweat tests and one or even no common cystic fibrosis transmembrane conductance regulator (CFTR) mutations. The aim of this study was to evaluate the role of nasal potential difference (PD) measurements in the diagnosis of CF patients with an atypical presentation and in a population of patients suspected to have CF. Nasal PD was measured in 162 patients from four different groups: patients with classical CF (n = 31), atypical phenotype (n = 11), controls (n = 50), and patients with questionable CF (n = 70). The parameter, or combination of nasal PD parameters was calculated in order to best discriminate all CF patients (including atypical CF) from the non-CF group. The patients with atypical CF disease had intermediate values of PD measurements between the CF and non-CF groups. The best discriminate model that assigned all atypical CF patients as CF used: e(response to chloride-free and isoproterenol/response to amiloride) with a cut-off >0.70 to predict a CF diagnosis. When this model was applied to the group of 70 patients with questionable CF, 24 patients had abnormal PD similar to the atypical CF group. These patients had higher levels of sweat chloride concentration and increased rate of CFTR mutations. Nasal potential difference is useful in diagnosis of patients with atypical cystic fibrosis. Taking into account both the sodium and chloride transport elements of the potential difference allows for better differentiation between atypical cystic fibrosis and noncystic fibrosis patients. This calculation may assist in the diagnostic work-up of patients whose diagnosis is questionable.

Adolescent↗

PubMed2001

Vocal cord paralysis secondary to impacted esophageal foreign bodies in young children.

Impacted foreign bodies in the esophagus can result in respiratory symptoms including stridor and aphonia. Several mechanisms have been proposed to explain these symptoms, but the possibility of vocal cord paralysis and its cause has not been adequately emphasized. Two cases of young children with esophageal foreign body are described; both presented with respiratory symptoms, 1 with aphonia and the other with stridor. In both cases, the symptoms were secondary to vocal cord paralysis. A possible mechanism of recurrent nerve injury is proposed.

Aphonia↗

PubMed2001

Ethnic differences in cigarette smoking among adolescents: a comparison of Jews and Arabs in Jerusalem.

BACKGROUND: Prevention of cigarette smoking is an important issue in public health policy. Since most adult smokers began smoking in childhood, understanding behavorial factors associated with smoking initiation would contribute to smoking initiation programs. Health-related behavior may vary between different ethnic groups. OBJECTIVES: To determine the prevalence of smoking among Jewish and Arab adolescents in Jerusalem, and whether there are differences in smoking initiation between the two ethnic groups. METHODS: We carried out a cross-sectional survey of all students in the 6th to 11th grades (age range 11-17 years) of a Jewish school and an Arab school in the Jerusalem area, using an anonymous self-completion questionnaire. A total of 791 questionnaires was analyzed, 479 from the Jewish students and 312 from the Arab students. RESULTS: The lowest prevalence of smoking was found among Arab female students and the highest among Jewish female students (9% vs. 41%, P < 0.001). The prevalence of smoking among Jewish and Arab males was similar. More Arab female students smoked than their mothers. Peer pressure seemed to be a more important factor among Jewish students. CONCLUSIONS: This study demonstrated the presence of ethnic differences in smoking prevalence and the reasons for smoking among adolescents in Israel. These results suggest the need for specific smoking prevention policies for different ethnic groups.

Adolescent↗

PubMed2000

Serum lipase levels as a diagnostic marker in cystic fibrosis patients with normal or borderline sweat tests.

Patients with normal or borderline sweat test present a diagnostic challenge. In spite of the availability of different methods such as genetic analysis and measurements of nasal potential difference, uncertainty in diagnosing cystic fibrosis (CF) in some patients still exists. Neonates with CF have high serum lipase levels, which decline over time in pancreatic-insufficient patients, whereas pancreatic-sufficient patients demonstrate high serum lipase levels beyond infancy. Because patients with borderline or normal sweat test are almost always pancreatic sufficient, this study was aimed to assess whether serum lipase levels may be of help in establishing the diagnosis of CF in these patients. Serum lipase levels were measured in 100 CF patients and in 17 healthy individuals. Patients were grouped according to their genotype. Group A patients (n = 70) carried two mutations previously found to be associated with a pathologic sweat test and pancreatic insufficiency (delta F508, W1282X, G542X, N1303K, S549R). Group B (n = 30) were compound heterozygote patients who carried one mutation known to cause mild disease with borderline or normal sweat tests and pancreatic sufficiency (3849+10kb C-->T, 5T). Group C included 17 healthy controls. Serum lipase levels ranged between 2 and 104.4 U/L (mean +/- SD 16.9 +/- 14.7), 6.1-200 U/L (mean +/- SD 53.9 +/- 47.9), and 8.5-27.8 U/L (mean +/- SD 16.9 +/- 5.1) in Groups A, B, and C, respectively, with some overlapping between groups. The distribution of lipase levels was significantly different in Group B vs Groups A and C (P < 0.01). High lipase levels were found in 63.3% (19/30) of Group B patients, but in only 4.3% (3/70) and 0% (0/17) of Group A and C, respectively. Lipase levels were found to be inversely related to sweat chloride concentrations (r = -0.19, P < 0.05). Patients with borderline or normal sweat tests had high lipase levels, whereas low lipase levels were associated with pathologic sweat tests. Our findings indicate that the serum lipase level is genetically determined and that it has a useful role in the diagnosis of CF. Thus, in patients with borderline sweat tests and high lipase levels, the diagnosis of CF should be considered.

Adult↗

PubMed2000

A pilot study of the effect of gentamicin on nasal potential difference measurements in cystic fibrosis patients carrying stop mutations.

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene containing a premature termination signal are expected to produce little or no CFTR chloride channels. It has been shown in vitro, that aminoglycoside antibiotics can increase the frequency of erroneous insertion of nonsense codons hence permitting the translation of CFTR alleles carrying missense mutations to continue reading to the end of the gene. This led to the appearance of functional CFTR channels at the apical plasma membrane. The aim of this research was to determine if topical application of gentamicin to the nasal epithelium of patients with cystic fibrosis (CF) carrying stop mutations can express, in vivo, functional CFTR channels. Nine CF patients carrying stop mutations (mean age 23 +/- 11 yr, range 12 to 46 yr) received gentamicin drops (0.3%, 3 mg/ml) three times daily intranasally for a total of 14 d. Nasal potential difference (PD) was measured before and after the treatment. Before gentamicin application all the patients had abnormal nasal PD typical of CF. After gentamicin treatment, significant repolarization of the nasal epithelium representing chloride transport was increased from -1 +/- 1 mV to -10 +/- 11 mV (p < 0. 001). In conclusion, gentamicin may influence the underlying chloride transport abnormality in patients with CF carrying stop mutations.

Administration, Intranasal↗

PubMed2000

A prospective study of fever and bacteremia after flexible fiberoptic bronchoscopy in children.

STUDY OBJECTIVES: To assess the incidence of fever and bacteremia after fiberoptic bronchoscopy in immunocompetent children. DESIGN: Prospective study. PATIENTS: Immunocompetent children undergoing fiberoptic bronchoscopy between January 1997 and June 1998. MEASUREMENTS AND RESULTS: Ninety-one children were included in the study. Forty-four children (48%) developed fever within 24 h following bronchoscopy. Bacteremia was not detected in any of the cases at the time of the fever. Children who developed fever were younger than those who remained afebrile (mean age, 2.4 +/- 3.6 years vs 4.2 +/- 3.7 years; p = 0.025). In the fever group, 66% of the bronchoscopies were considered abnormal, compared to 45% in the nonfever group (p = 0.04). Of the fever group, 40.5% of BAL fluid cultures had significant bacterial growth, significantly higher compared to the nonfever group (13.2%; p = 0.006). Of the 80 patients in whom BAL was performed, fever occurred in 52.5% compared to only 18.2% in those who did not have BAL (p = 0.03). BAL fluid content of cell count, lipid-laden macrophages, and interleukin-8 were not significantly different in both groups. In a logistic regression analysis, the significant predictors for developing fever were positive bacterial culture (relative risk, 5.1; 95% confidence interval, 1.6 to 16.4; p = 0.007) and abnormal bronchoscopic findings (relative risk, 3.1, 95% confidence interval, 1.2 to 8.3; p = 0.02). When age < 2 years was included in the model, this factor became highly significant (relative risk, 5.01; 95% confidence interval, 1.83 to 13.75; p < 0.002). CONCLUSIONS: Fever following fiberoptic bronchoscopy is a common event in immunocompetent children and is not associated with bacteremia. Risks to develop this complication are age < 2 years, positive bacterial cultures in BAL fluid, and abnormal bronchoscopic findings.

Bacteremia↗

PubMed1999

Pulmonary epithelial sodium-channel dysfunction and excess airway liquid in pseudohypoaldosteronism.

BACKGROUND: Active sodium absorption is the dominant mechanism of ion transport in airway epithelium, but its role in pulmonary physiology and airway host defense is unknown. To address this question, we studied the function of airway epithelial cells and determined the frequency of pulmonary symptoms in patients with systemic pseudohypoaldosteronism, a salt-losing disorder caused by loss-of-function mutations in the genes for the epithelial sodium channel. METHODS: In nine patients 1.5 to 22 years of age who had systemic pseudohypoaldosteronism, we tested for mutations in the genes for the epithelial sodium channel, estimated the rate of sodium transport in the airway, determined the volume and ion composition of airway surface liquid, reviewed clinical features, collected laboratory data pertinent to pulmonary function, and, in three adults, measured mucociliary clearance. RESULTS: The patients with systemic pseudohypoaldosteronism had loss-of-function mutations in the genes for the epithelial sodium-channel subunits, no sodium absorption from airway surfaces, and a volume of airway surface liquid that was more than twice the normal value. The mean (+/-SE) mucociliary transport rate was higher in the 3 adult patients than in 12 normal subjects (2.0+/-0.7 vs. 0.5+/-0.3 percent per minute, P=0.009). Young patients (those five years of age or less) all had recurrent episodes of chest congestion, coughing, and wheezing, but no airway infections with Staphylococcus aureus or Pseudomonas aeruginosa. Older patients (those more than five years of age) had less frequent respiratory symptoms. CONCLUSIONS: Patients with systemic pseudohypoaldosteronism fail to absorb liquid from airway surfaces; the result is an increased volume of liquid in the airways. These results demonstrate that sodium transport has a role in regulating the volume of liquid on airway surfaces.

Absorption↗

PubMed1999

Pulmonary fibrosarcoma in childhood: fiber-optic bronchoscopic diagnosis and review of the literature.

Primary pulmonary fibrosarcoma is a rare malignant tumor in childhood. In the absence of metastases, complete resection is curative. An 8-year-old boy suffered from unresolving pneumonia due to an obstructing lesion in the left main bronchus. Cytology of the bronchoalveolar lavage fluid and histology of bronchial biopsy revealed the diagnosis of pulmonary fibrosarcoma. The tumor did not respond to chemotherapy, and a total lobectomy with sleeve resection was performed with complete removal of the neoplasm. Two years after the operation the child has no evidence of disease.

Biopsy↗

PubMed1999

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.

Abdomen↗

PubMed1999

Variable levels of normal RNA in different fetal organs carrying a cystic fibrosis transmembrane conductance regulator splicing mutation.

Disease severity varies among cystic fibrosis (CF) patients carrying the same cystic fibrosis transmembrane conductance regulator (CFTR) genotype and among organs of the same individual. It has been shown that the class V splicing mutation 3849 + 10 kb C--> T produces both normal and aberrantly spliced CFTR transcripts. We analyzed the levels of normal CFTR messenger RNA (mRNA) in different organs of an aborted fetus carrying the 3849 + 10 kb C--> T mutation, and found that they correlated with the histopathologic changes observed in these organs. We performed semiquantitative nondifferential reverse transcription-polymerase chain reaction on several organs from a 22-wk aborted CF fetus carrying the 3849 + 10 kb C--> T mutation. A very low level (1%) of normal CFTR mRNA was detected in the severely affected ileum of this fetus. Higher levels were found in the histopathologically unaffected trachea (17%), colon (19%), and lung (26%). Thus, as early as in utero, the regulation of alternative splice-site selection is an important mechanism underlying variable CF severity. Understanding of the mechanisms regulating alternative splicing in different tissues will contribute to potential therapy for patients carrying splicing mutations in CF and other human disease genes.

Alternative Splicing↗

PubMed1999

Clinical manifestations of Bordetella pertussis infection in immunized children and young adults.

STUDY OBJECTIVES: The incidence and prevalence of pertussis in adults have increased in recent years. It has been shown that previously immunized adults and adolescents are the main sources of transmission of Bordetella pertussis. The aim of this study was to describe the clinical presentation and the clinical course of pertussis in children and young adults who were immunized previously against B pertussis. DESIGN: Retrospective study. SUBJECTS: Children and young adults who were reported by local physicians to the Department of Epidemiology in the Israeli Ministry of Health with serologically confirmed pertussis and who were immunized previously were included. Information sought included personal data, epidemiologic data, signs and symptoms, laboratory results, initial diagnosis, and treatment. RESULTS: In the 95 previously immunized patients with serologically confirmed pertussis (mean age [+/- SD], 8.9 +/- 4.4 years old; range, 5 to 30 years old), the mean duration from onset of symptoms until the final diagnosis of pertussis was 23 +/- 15 days. The disease was usually atypical and generally mild. All the described patients had cough, usually prolonged, lasting 4 +/- 3.6 weeks. Only 6% had the classic whoop. The mean WBC count was 8.7 +/- 2.6 cells/mm6, and the lymphocyte count was 40 +/- 12%. Two patients were admitted to the hospital for severe pneumonia. Among the reported cases, the proportion of patients between the ages of 10 and 45 years increased from 6.5% during the period from 1971 to 1980, to 26% during the period from 1980 to 1990, and to 38% during a 1989 outbreak. CONCLUSIONS: Pertussis in previously immunized individuals is usually characterized by an atypical and relatively mild clinical course. Patients suffer mainly from a prolonged and persistent cough. Early diagnosis may lead to prompt administration of therapy. Prophylaxis of exposed persons might be effective in decreasing both severity and transmission of the disease.

Adolescent↗

PubMed1999

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.

Adolescent↗

PubMed1998

The molecular basis of disease variability among cystic fibrosis patients carrying the 3849+10 kb C-->T mutation.

Disease severity varies among cystic fibrosis (CF) patients carrying the same CFTR genotype. Here we studied the mechanism underlying disease variability in individuals carrying a splicing CFTR mutation, 3849+10 kb C-->T. This mutation was shown to produce both correctly and aberrantly spliced CFTR transcripts containing an additional cryptic exon. Semiquantitative nondifferential RT-PCR showed considerable variability in the level (0-28%) of aberrantly spliced RNA transcribed from the 3849+10 kb C-->T mutation in nasal epithelium from 10 patients. A significant inverse correlation was found between the level of the aberrantly spliced CFTR transcripts and pulmonary function, expressed as FEV1 (r = 0.92, P < 0.0001). Patients with normal pulmonary function (FEV1 > 80% predicted) had lower levels of aberrantly spliced CFTR RNA (0 to 3%) than those with FEV1 < 80%, (9 to 28% aberrantly spliced RNA). Only aberrantly spliced CFTR RNA was detected in the lung of a patient with severe lung disease who underwent lung transplantation. Our results show that the severity of CF lung disease correlates with insufficiency of normal CFTR RNA. Thus, the regulation of alternative splice site selection may be an important mechanism underlying partial penetrance in CF. Further understanding of this regulation will contribute to potential therapy for patients carrying splicing mutations in human disease genes.

Adolescent↗