Liver disease as risk factor for cystic fibrosis-related diabetes development.

AIM: To evaluate clinical and genetic factors, besides pancreatic insufficiency, associated with increased risk of cystic fibrosis-related diabetes. METHODS: Case-control (1:1) study on 138 cystic fibrosis patients. Data were collected on gender, age at diagnosis, reason for cystic fibrosis diagnosis, family history of type 1 or 2 diabetes mellitus, pre-existing severe liver disease, and class of cystic fibrosis transmembrane regulation mutation. Moreover, information was obtained on lung involvement and degree of exocrine pancreatic insufficiency evaluated 1 year before the diagnosis of cystic fibrosis-related diabetes in patients and age-matched controls. RESULTS: Compared to controls, patients with cystic fibrosis-related diabetes had a higher probability of having already been diagnosed with liver disease (16.7% versus 1.7%, OR = 11.6, 95% CI 1.43-93.0). Moreover, in the year before diabetes onset, cases had slightly worse pulmonary function compared to controls (FEV1 = 58.4 +/- 27% predicted versus 67.4 +/- 21% predicted; p = 0.05). No significant effects related to the other factors considered were found. CONCLUSION: Severe liver disease was found to significantly increase the risk of developing cystic fibrosis-related diabetes. Patients with liver disease should be scheduled for earlier diabetes screening in order to identify and possibly treat glucose intolerance.

Increased soluble CD40 ligand levels in cystic fibrosis.

Chronic inflammation represents a key pathogeneric event in the progression of lung disease in cystic fibrosis (CF). To identify novel mechanisms of the inflammatory reaction in CF and analyze its relation with coagulative activation, we carried-out a cross-sectional study to evaluate circulating levels of the inflammatory mediators soluble (s) CD40L, C-reactive protein (CRP), interleukin (IL)-1beta, the coagulation markers activated factor VII (FVIIa) and prothrombin fragment (F) 1+2, as well as urinary 11-dehydro-thromboxane (TX)B2, an index of in vivo platelet activation, in 34 CF patients and 34 matched healthy subjects. We observed that CF patients displayed significantly increased circulating levels of sCD40L compared to controls [2.8 (0.4-15.6) vs 1.1 (0.2-2.7) ng mL(-1), P = 0.0003]. sCD40L levels inversely correlated with forced expiratory volume at 1 second (FEV1) (rho = -0.788, P = 0.0001), whereas it directly correlated with CRP and IL-1beta levels (rho = 0.621, P = 0.0004; and rho = 0.745, P = 0.0001, respectively), which were also elevated in CF patients. CF patients had also enhanced levels of FVIIa and F1+2 compared to controls [39.2 (22.6-69.8) vs 22.3 (16.2-32.4) mU mL(-1), P = 0.0001; 0.60 (0.30-1.80) vs 0.17 (0.10-0.40) nmol L(-1), P = 0.0001, respectively]. A direct correlation was observed between sCD40L and both plasma FVIIa (rho = 0.691, P = 0.0001) and F1+2 (rho = 0.545, P = 0.0017) as well as between sCD40L and urinary 11-dehydro-TXB2 (rho = 0.433, P = 0.0129). Our findings suggest that in CF patients, sCD40L could represent a biochemical link between the inflammatory state, and endothelial damage and coagulative activation, leading to progressive impairment of pulmonary function.

Phenotype/genotype correlation and cystic fibrosis related diabetes mellitus (Italian Multicenter Study).

BACKGROUND: A genotype/phenotype correlation between early onset cystic fibrosis related diabetes (CFRD) and the N1303K mutation of the CF gene was previously identified in a small series of 28 CFRD patients, out of 313 CF patients. PATIENTS AND METHODS: In order to confirm the observation, data of 141 CFRD patients out of 1,229 CF patients attending 14 Italian CF centers were collected. All patients were older than 10 years and had been genotyped. RESULTS: DeltaF508 was the most frequent mutation (147/282 alleles: 52%) and N1303K the second most frequent mutation (18/282 alleles: 6.3%) in CFRD patients, without significant difference as compared with CF patients without DM (52% vs 48.6% and 6.3% vs 5.1%, respectively). W1282X was the third most frequent mutation in CFRD patients, more frequent than in CF patients without DM (5.3% vs 2%; p<0.001). CONCLUSIONS: Unlike the previous study, we did not find a higher frequency of the N1303K mutation in CFRD patients; moreover, data from this large CF series showed a significant correlation between the W1282X mutation and CFRD.

Comparison of two enteric coated microsphere preparations in the treatment of pancreatic exocrine insufficiency caused by cystic fibrosis.

BACKGROUND: Pancreatic exocrine insufficiency is a common condition in patients with cystic fibrosis. Large amounts of pancreatic enzyme supplements are required to reduce malabsorption but patient compliance is not always optimal. AIMS: To compare patients' preference and the efficacy of two enteric coated microsphere preparations in patients with cystic fibrosis. PATIENTS: Patients with pancreatic exocrine insufficiency due to cystic fibrosis. METHODS: Patients were assigned to the crossover treatment with Creon or Pancrease for 1 week and then to the alternative treatment. Patients had to follow a fixed diet (at least 2 g fat/kg) and had to assume 1000 units lipase/g fat. The evaluation parameters were: patients' preference, acceptance of therapy, stool fat excretion, stool weight, gastrointestinal symptoms, and tolerance. RESULTS AND CONCLUSIONS: Of the 33/60 patients who expressed a preference for one of the two treatments, 30 preferred Creon while only 3 patients preferred Pancrease (p<0.001). No difference between the two treatments was observed regarding stool characteristics, gastrointestinal symptoms and tolerance. The mean number of capsules taken daily was reduced by 35% with Creon. The results of this study showed a preference in favour of Creon probably due to the reduction of daily capsule intake of 35%, supporting digestion as well as Pancrease.

In vivo lipid peroxidation and platelet activation in cystic fibrosis.

F(2)-isoprostanes are bioactive peroxidation products of arachidonic acid whose urinary excretion provides an index of lipid peroxidation in vivo. We tested the hypothesis that formation of F(2)-isoprostanes is altered in patients with cystic fibrosis and contributes to platelet activation and pulmonary dysfunction in this setting. The urinary excretion of immunoreactive 8-iso-prostaglandin F(2alpha) (PGF(2alpha)) was significantly (p = 0.0001) higher in 36 patients with cystic fibrosis than in 36 age-matched healthy subjects: 618 +/- 406 versus 168 +/- 48 pg/mg creatinine. The urinary excretion of immunoreactive 11-dehydro-thromboxane B(2) (TXB(2)), an index of in vivo platelet activation, was also significantly (p = 0.0001) higher in patients than in control subjects: 2,440 +/- 1,453 versus 325 +/- 184 pg/mg creatinine. The excretion rate of 8-iso-PGF(2alpha) was correlated with that of 11-dehydro-TXB(2) (rho = 0.51; p = 0.0026) and inversely related to FEV(1) (rho = -0.40; p = 0.0195). Urinary 8-iso-PGF(2alpha) excretion was largely unaffected during cyclooxygenase inhibition with low-dose aspirin, nimesulide, or ibuprofen, consistent with a noncyclooxygenase mechanism of F(2)-isoprostane formation in cystic fibrosis. Increased vitamin E supplementation (from 200 to 600 mg/d) was associated with statistically significant (p = 0.005) reductions in urinary 8-iso-PGF(2alpha) and 11-dehydro-TXB(2) excretion, by 42% and 29%, respectively. We conclude that enhanced lipid peroxidation is an important feature of cystic fibrosis and may contribute to persistent platelet activation and pulmonary dysfunction via generation of bioactive isoeicosanoids. Our results provide a rationale for reassessing the adequacy of vitamin E supplementation in this setting.

[Anti-Pseudomonas aeruginosa antibodies and lung disease in cystic fibrosis] / Anticorpi anti Psudomonas aeruginosa e malattia polmonare in fibrosi cistica.

The aim of our study was to diagnose and to control three aspects of the evolution of lung disease in CF: the absence of infection, the intermittent colonization and chronic infection by Pseudomonas aeruginosa. Therefore a study of anti-pseudomonas antibodies (Ab) (anti-protease, anti-elastin and antihexo-toxin A) for diagnosis and follow-up of CF patients was considered. Moreover, we related the presence of Ab to the sputum culture, to FEV1, to patient age and to genotype. Tbe Ab were dosed in 121 patients by quantitative ELISA method. Values < 1: 500 were considered negative, values> 1: 500 and < 1:1250 borderline, and > 1:1250 positive. 16.5% of patients did not have Ab, 17% had borderline values and 69.5% had positive values. All the patients with negative Ab had negative sputum culture; 47% of patients with borderline values had at least one positive culture while 53% were negative. 87% of patients with positive values had chronic colonization, 13% intermittent colonization. The increase in the Ab rate is statistically related to a more severe lung disease (p < 0.013). The presence of a severe mutation (?F 508) is related to positive values of Ab. Evaluation of anti-Pseudomonas aeruginosa is an important tool for diagnosis and follow-up of CF lung disease

Simultaneous detection of fourteen Italian cystic fibrosis mutations in seven exons by reverse dot-blot analysis.

The increasing number of cystic fibrosis (CF) mutations is a great obstacle to the use of DNA procedures in the detection of gene defects. We describe a fast, cheap and non-radioactive procedure, Reverse dot-blot analysis (RDB), for the simultaneous detection of CF mutations in the Italian population. We used this approach to study seven exons of the CF gene for 14 CF gene defects and were able to characterize 222 of 272 CF chromosomes (80%). The cost of the procedure was $25 per sample analysed.

Use of famotidine in severe exocrine pancreatic insufficiency with persistent maldigestion on enzymatic replacement therapy. A long-term study in cystic fibrosis.

In patients with pancreatic exocrine insufficiency, the use of pancreatic enzyme does not abolish steatorrhea in some cases. We carried out a long-term prospective study in an attempt to clarify the effectiveness of the associated use of famotidine to enzymatic supplementation on fat absorption and nutritional parameters of patients with pancreatic insufficiency due to cystic fibrosis. We studied 10 patients, mean age 12.5 years, with persistent steatorrhea on enzymatic supplementation. A double-blind crossover design was used and famotidine (1 mg/kg/day) or placebo was given as adjuvant to enzymatic preparations for either of two six-month periods. A statistically significative reduction in fecal wet weight (P less than 0.0001), an improvement in the coefficient of fat absorption (P less than 0.01) and in the steatocrit values (P less than 0.028) were found on famotidine. Moreover, the weight and the height increases were greater after famotidine than after placebo period (respectively, P less than 0.012 and P less than 0.01); also the serum calcium and triglycerides levels were higher after the period on famotidine (respectively, P less than 0.0025 and P less than 0.025). No adverse effects of famotidine were noted. These data suggest that famotidine is a useful adjuvant to pancreatic enzyme therapy in patients with severe pancreatic insufficiency and persistent maldigestion on large doses of pancreatic supplements; in fact, famotidine improves not only fat absorption but the nutritional status of the patients.

Prevalence of diabetes mellitus and impaired glucose tolerance in cystic fibrosis.

The aim of this study was to evaluate the prevalence of impaired glucose tolerance or diabetes mellitus in 99 patients (53 M, 46 F; mean age 10.5 +/- 6.9 years), with cystic fibrosis. Glucose tolerance was evaluated in all patients without overt diabetes using the oral glucose tolerance test (OGTT). Six patients showed a pathological OGTT and 2 patients had insulin-requiring diabetes mellitus. The mean age of the patients with impaired glucose tolerance was significantly higher than that of the subjects with normal glucose metabolism (p less than 0.0001). Patients with overt diabetes mellitus were the oldest subjects in the study group.