CF-related Diabetes Mellitus Research Articles

Cystic fibrosis lung transplant recipients 10 years of age or younger: Predisposing factors for end-stage disease.

The largest age group among children and adolescents referred for lung transplantation for cystic fibrosis (CF) have been those in the pubertal or postpubertal age range. However, over 100 younger patients with CF have undergone lung transplantation over the last three decades in the United States. We performed a retrospective review of our experience with 18 children with CF who underwent lung transplantation in our center before the age of 11 years and compared them to our older CF lung transplant recipients and our larger CF Center population. The transplant population was demographically distinct from our CF center in terms of ethnicity, country of origin, and insurance status. Other notable findings were a high prevalence of methicillin-resistant Staphylococcus aureus, a high prevalence of CF-related diabetes mellitus, and a high prevalence of consolidated lobar or whole lung disease. Posttransplant outcomes were comparable to those older than 10 years of age in our center until 5 years after transplant after which the younger cohort showed a superior enduring survival. In an era of increasingly effective medications modifying the natural history of CF, identification of risk factors for early severe lung disease in CF remains relevant to permit interventions to prevent or postpone the time of future lung transplantation.

Endocrine Complications of Cystic Fibrosis: A Multisystem Disease of the Endocrine Organs.

Cystic fibrosis (CF) is one of the most common life-limiting genetic disorders. Although CF is typically considered primarily as a pulmonary disease, the CF conductance transmembrane regulator is present throughout the body. From an endocrine perspective, this multisystem disease manifests primarily in the pancreas as a unique form of diabetes (CF-related diabetes mellitus), as bone disease, and as reproductive health issues in people with CF. These complications have become ever more concerning to people with CF as treatment for pulmonary disease improves and lifespans lengthen, increasing the impact of nonpulmonary complications. Our understanding of the management of these concerns continues to evolve, and, although there are some effective treatments, there is great opportunity for continued investigation into the pathophysiology of the endocrine complications of CF and their treatment.

Cystic Fibrosis: Advancing Along the Continuum

Cystic fibrosis (CF) is an autosomal recessive genetic disorder resulting from a mutation in the gene which encodes a cellular transmembrane protein channel known as the CF transmembrane conductance regulator. Located systemically on the surface of numerous cells, these altered channels yield multisystem dysfunction. Typical manifestations seen are chronic, progressive, obstructive lung disease, pancreatic insufficiency, CF-related diabetes mellitus, malabsorption and malnutrition, liver disease, and infertility.Once considered a pediatric disorder, through developments in innovative care and therapeutic modalities, CF now spans the life continuum and has established itself as an ageless disease. Facing management of maturing-life issues, advanced practice nurses (APNs) in pediatrics now find themselves needing to collaborate with or facilitate transition of care to other APNs, such as nurse midwives and adult APNs, as well as their counterpart specialists in medicine, all while maintaining open communication with the patient, family and managing CF center.

Pulmonary function patterns and their association with genotype and phenotype in adult cystic fibrosis patients

ABSTRACTBackground: While cystic fibrosis (CF) lung disease is generally considered to be an obstructive disorder, other pulmonary function patterns (PFP) may occur. Furthermore, little is known about possible associations between PFP and genotype or phenotypical characteristics.Methods: Cross-sectional study including CF patients aged 16 years or more, identifying different PFP and exploring associations between PFP and genotype or phenotypical characteristics.Results: Obstructive PFP was most prevalent in our population (n = 80), comprising obstructive lung disease (62.5%), small airway (obstructive) disease (11.2%), and mixed obstructive-restrictive disorder (1.3%). However, one in four adult CF patients did not show any obstruction at all: normal (13.7%) or restrictive (8.8%) lung disease and isolated diffusion disorder (2.5%). Obstructive PFP was associated with a greater proportion of CF-related diabetes mellitus (CFRD) (P = 0.04), Pseudomonas aeruginosa colonization (P = 0.02) and frequent exacerbators (P = 0.04). We observed no association between PFP and genotype.Conclusions: Obstructive PFP remains the most common pulmonary function pattern in adult CF and is associated with CFRD, Pseudomonas aeruginosa colonization and frequent exacerbators.

Severe disease in Cystic Fibrosis and fecal calprotectin levels

Fecal calprotectin (FC) is used to asses the presence of intestinal inflammation also in patients with Cystic Fibrosis (CF) and recent studies showed a correlation between bowel and lung disease in these patients. The aim of this study was to analyze the levels of FC in CF and correlate them with different phenotypes of disease.We enrolled a cohort of 54 CF patients and 50 healthy controls. In these patients, calprotectin has been assayed on a stools sample using an ELISA kit.In all patients we analyzed, FC levels were elevated above the cut-off value and significantly higher than in healthy controls. Among CF patients, FC was significantly higher in patients older than 18 years, with pancreatic insufficiency, underweight status, Pseudomonas Aeruginosa airways colonization, CF-related diabetes mellitus, reduced lung function, or high number of pulmonary exacerbations.These results suggest that in patients with CF, FC levels are not only influenced by the CF enteropathy but also by the severity of the genetic disease. Since we found higher FC levels in patients with a severe phenotype (P. Aeruginosa airways colonization, FEV1<50% of predicted, pancreatic insufficiency, underweight status,) we suggest that this marker could be useful to monitor longitudinally a clinical worsening.

178 Glucose tolerance in cystic fibrosis patients over a 3-year period (DIAMUCO study)

Objectives The aim of DIAMUCO study is to describe the natural history of the glucose tolerance (GT) and to identify predictive factors of the changes in GT in cystic fibrosis (CF) patients for a three-year period. Methods We used a cross-sectional study design and included a total of 228 patients, 111 children (between 10 and 18 years) and 117 adults between 2009 and 2011. All patients had an annual screening. Patients were classified as having normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or CF-related diabetes mellitus (CFRD) using the 2-h oral glucose tolerance test (OGTT). Results At baseline, 67.1% (n = 153) patients were classified as NGT, 25.4% (n = 58) as IGT and 7.4% (n = 17) as CFRD. Over half of patients changed at least once of glucose tolerance status during follow-up. The mean decline of FEV1 was 1.54 per year without difference between female and male. A decrease in FEV1 (p TableClinical characteristicsTotalCFRDIGTNTpAge20.1±8.124.3±9.319.3±7.420.0±8.20.1FEV172.4±24.165.0±22.173.8±23.972.6±24.50.4Weight z-score0.5±1.5−0.70±1.24−0.79±1.18−0.37±1.50.1 Conclusion We confirm the variability of glucose tolerance status over time. The impact of glucose tolerance status on respiratory deterioration seems to concern only patients with permanently CFRD status. The early treatment decision must therefore be careful.

NOVOSTI V OBRAVNAVI BOLEZNI PREBAVIL IN ZAPLETOV PRI CISTIČNI FIBROZI TER ORGANIZACIJA PREHODA IZ PEDIATRIČNEGA CENTRA V CENTER ZA CISTIČNO FIBROZO ZA ODRASLE

Cystic fibrosis (CF) is the most common autosomal recessive lethal hereditary disorder among whites. Survival of patients with CF has progressively improved over the last four decades.As life expectancy has been greatly extended, complications like osteopenia and CF-related diabetes mellitus (CFRDM) occur. In our article, a new management of these two complications is described.Gastrointestinal tract, exocrine pancreas and liver are also affected in CF.Maintaining good nutrition while treating pancreatic insufficiency, treating gastroesophageal reflux disease and treating liver disease are very important issues in the treatment gastrointestinal tract disease in CF.As the CF patient population median survival increases, a growing number of adolescents require care in the adult health care system which must be capable of responding appropriately to their needs.We present a model of transition from paediatric to adult medical care in our CF center.

A ROLE OF MODIFIER GENE TCF7L2 FOR DEVELOPMENT OF DIABETES IN ADULT PATIENTS WITH CYSTIC FIBROSIS

Introduction. Patients with cystic fibrosis (CF) are in a high risk of a particular type of diabetes mellitus. The aim of this study was to investigate predictive factors for development of CF-related diabetes mellitus. Methods. Allele and genotype frequencies of 3 gene transcription factor 7-like 2 (TCF7L2) polymorphisms (rs12255372, rs7903146, rs11196205) were investigated in adult patients with СF with or without carbohydrate metabolism disorders, in patients with diabetes mellitus and in controls. Results. Russian population of rs12255372 polymorphism carriers is in a higher risk of diabetes development. Investigations of rs7903146 polimorphism of TCF7L2 showed that C allele frequency was higher than T allele frequency in all the patients' groups. Conclusion. C allele and C/C + C/G genotypes seemed to play a protective role and were related to lower risk of carbohydrate metabolism disorders in CF patients. On the contrary, G allele and G/G homozygous genotype were related to 2.0 – 2.5-fold increase in the risk of carbohydrate metabolism disorders.

Effect of Maternal Cystic Fibrosis Genotype on Diabetes in Pregnancy

To evaluate the association between the cystic fibrosis (CF) genotype and the rate of diabetes complicating pregnancy. We conducted a retrospective cohort analysis of all pregnant patients with CF from 1972-2011 at a single institution. Patients who were homozygous for the ΔF508 mutation were compared with patients who were heterozygous for the ΔF508 mutation. Primary outcomes measured were incidence of CF-related diabetes and gestational diabetes mellitus (GDM) stratified by CF genotype. Secondary outcomes measured included pancreatic insufficiency, preterm premature rupture of membranes, preterm delivery, mode of delivery, gestational age at delivery, and maternal mortality. We identified 54 pregnancies among 36 women who met inclusion criteria. Of these pregnancies, 28 (51.9%) were carried by women who were homozygous for the ΔF508 mutation. Homozygous women had a significantly greater incidence of pancreatic insufficiency (89.3% compared with 61.5%, P=.03) and diabetes complicating pregnancy (60.7% compared with 23.1%, P<.01) compared with heterozygous women. In addition, there was some evidence of an increased incidence of GDM specifically among homozygous women (35.7% compared with 15.4%, P=.12). Regarding neonatal outcome, there was a lower mean birthweight (2,881 g compared with 3,203 g, P=.04) among the women who were homozygous for the ΔF508 mutation. There was no statistical difference in preterm deliveries, mode of delivery, gestational age at delivery, rate of preterm premature rupture of membranes, or incidence of maternal mortality between the two groups. Women with CF who are homozygous for the ΔF508 mutation have an increased risk of having a pregnancy complicated by diabetes.

Metabolic abnormalities in adults with cystic fibrosis

Survival of patients with cystic fibrosis (CF) has improved, resulting in increased exposure of patients to cardiovascular risk factors. Diabetes mellitus is common in patients with CF; however, less is known about lipid abnormalities in this population. In this study, the prevalence of lipid abnormalities was investigated in a contemporary population of adults with CF. Clinical and laboratory data on 221 adult patients with CF were collected retrospectively. Fasting serum glucose levels and lipid profiles were recorded. The age-specific values for healthy individuals, as reported by the National Health and Nutrition Examination Surveys, were used for comparison. The mean age of the patients was 30 +/- 10 years, 55.1% were men and the mean FEV(1)% was 68 +/- 25%. Sixty-nine patients (31.2%) had CF-related diabetes mellitus and 52 (23.5%) were receiving insulin therapy. In addition, 36 patients (16.3%) had impaired glucose tolerance. Triglyceride levels were similar to those of historical control subjects (mean +/- SEM, 1.37 +/- 0.05 and 1.39 +/- 0.02 mmol/L, respectively, P = 0.75). However, in the 30-39 years age group of CF patients, triglyceride levels were increased relative to those of their control counterparts (1.79 +/- 0.14 vs 1.38 +/- 0.04 mmol/L, P = 0.006). Total cholesterol levels were lower in the CF patients compared with control subjects, across all age groups. Abnormalities of glucose metabolism are highly prevalent in CF patients, and are accompanied by hypertriglyceridaemia in the 30-39 years age group. Prospective studies are required to confirm lipid abnormalities and investigate possible cardiovascular complications in patients with CF.

Persistence of Essential Fatty Acid Deficiency in Cystic Fibrosis Despite Nutritional Therapy

To study the evolution of plasma fatty acid composition of patients with cystic fibrosis (CF) in relation to nutritional status, pancreatic function, and development of CF-related liver disease (CFRLD) and diabetes mellitus, 24 CF pediatric patients with stable pulmonary disease were studied before and after an approximate period of 8 y. Nutritional status, pulmonary function, pancreatic function, and presence of CFRLD or diabetes mellitus were recorded. Results were compared with data obtained in 83 healthy children. Patients with CF have significantly lower linoleic acid (LA), docosahexaenoic acid (DHA), lignoceric acid, and LA x DHA product and higher oleic acid, mead acid, dihomo-gamma-linoleic acid, and docosapentaenoic acid (DPA). Comparison of samples taken at first and second studies revealed a significant decrease in LA levels and lignoceric acid associated with a significant increase in dihomo-gamma-linoleic acid levels. Patients with CFRLD showed significantly higher mead acid/arachidonic acid ratio and lower total omega6 polyunsaturated fatty acids content. There was no relation of plasma fatty acids composition with pancreatic function, pulmonary function, or diabetes mellitus. Follow-up of patients with CF shows that essential fatty acids deficiency, particularly in LA and DHA content, persisted unmodified along time despite an adequate nutritional therapy. Future studies after supplementation with omega3 polyunsaturated fatty acids should be undertaken.

Health related quality of life in cystic fibrosis: To work or not to work?

Background The present study investigated whether patients with CF who are studying or working report a better HRQoL in comparison to non-working/studying patients. Methods 57 adult CF patients completed the Cystic Fibrosis Questionnaire—Revised, a CF-specific measure of HRQoL. Medical condition was quantified in terms of FEV1 % predicted, BMI, Pseudomonas aer. status, pancreatic status (PS), having an indwelling catheter device (PAC), CF Related Diabetes Mellitus and nutritional status. Results Mean age was 26.7 years (SD 8.1), mean FEV1 % predicted was 65.09 (SD 22.18), mean BMI was 21.23 (SD 3.45). FEV1 % predicted was related to HRQoL domains Physical Functioning and General Health ( r = 0.27 and 0.38 respectively, p < 0.05). A higher BMI was associated with better scores on Eating Disturbances (= fewer problems; r = 0.44, p < 0.01) and a better perception of Weight ( r = 0.43, p < 0.01) and Body Image ( r = 0.28, p < 0.05). Analysis of variance showed that specific domains of HRQoL were related to diabetes (Weight), taking caloric supplements (Body Image and Weight) and/or PAC (Physical Functioning, Treatment Burden, Role, Weight). Twenty-four patients worked/studied, these patients had a higher FEV1, and fewer had Pseudomonas aer. or a PAC or took high caloric supplements, compared to non-working/studying patients. After controlling for medical parameters, patients who were working/studying scored higher than non-working/studying patients on Physical Functioning, Role Functioning and Social Functioning. Conclusions CF patients' HRQoL is related to medical status. The non-working/studying CF patients in this sample had greater disease severity and reported a lower quality of life than their working/studying peers, even after controlling for relevant medical parameters. The decision to stop work/study for CF patients is difficult and affects patients' personal, social and financial well-being.

Investigating suspected CF-related diabetes mellitus utilising serial capillary blood glucose profiling

Investigating suspected CF-related diabetes mellitus utilising serial capillary blood glucose profiling

Risk factors for increased need for intravenous antibiotics for pulmonary exacerbations in adult patients with cystic fibrosis

Pulmonary exacerbations (P Exs) are important in cystic fibrosis (CF). They are very common, and are associated with poor quality of life. P Exs are regarded as an important end point in clinical trials. Risk factors associated with increase in P Exs have not been examined at a large scale. This study investigates factors associated with P Exs in a large cohort of adolescent and adult patients. This is a cross-sectional study on data collected in the South and West Regions in England in 2002. Patients aged 16 years and over were included. Data on age, gender, FEV(1), body mass index (BMI), infection with Pseudomonas aeruginosa (Pa) and on CF-related diabetes were included in the analysis. P Ex was defined as an episode treated with IV antibiotics. Forward stepwise multiple regression analysis was performed with the number of P Exs being the independent variable. The rest of the variables were considered to be the dependent variables. Data from 341 patients (194 female), mean age (SD), 24.9 (8.9) years were available. In 2002, a total of 599 P Exs were reported, median 1.00 range 0-16 P Exs. Using stepwise multiple regression analysis factors associated with increased number of P Exs were: infection with Pa (t-value -5.0, P < 0.0001), FEV(1), (t-value -4.9, P < 0.0001) and diabetes mellitus, (t-value -2.1, P = 0.04). Age, gender and BMI did not influence the annual number of exacerbations. In this study, risk factors for P Exs were found to be as follows: growth of Pa in the sputum, reduced FEV1 and CF-related diabetes mellitus.

NUTRITIONAL STATUS IN CYSTIC FIBROSIS

OBJECTIVE: We aimed to investigate the nutritional status of patients with cystic fibrosis (CF) in relation to their clinical manifestations. METHODS: In 68 patients with CF (aged 2–38 years), body weight, height, and composition (bioelectrical impedance analysis), respiratory function, Pseudomonas colonization, pancreatic function, CF-related diabetes mellitus (CF-DM), and genotype were measured. RESULTS: BMI was &amp;lt;5th percentile in 12 patients (18%), between the 5th and 10th percentiles in 6 (7%), between the 10th and 85th percentiles in 41 (60%), between the 85th and 95th percentiles (overweight) in 4 (6%), and &amp;gt;95th percentile (obese) in 5 (7%). Among 18 patients with a BMI at &amp;lt;10th percentile, 18 (100%) had pancreatic insufficiency, 16 (89%) had Pseudomonas, and 7 (38%) had CF-DM. Among 41 patients with a BMI in the 10th to 85th percentile, 37 (90%) had pancreatic insufficiency, 28 (82%) had Pseudomonas, and 9 (22%) had CF-DM. Among 9 patients with a BMI at &amp;gt;85th percentile, 3 (33%) had pancreatic insufficiency, 1 (11%) had Pseudomonas, and none had CF-DM. Forced expiratory volume in 1 second was significantly better among overweight patients than among patients with a low or normal BMI (P &amp;lt; .05). In addition, forced expiratory volume in 1 second correlated with BMI (P = .014), age (P = .029), and percent free fat mass (P = .039). Overweight/obese patients were homozygotes for mild mutations. CONCLUSIONS: Most patients with CF had an optimal nutritional status. A small percentage were overweight or obese, especially those with pancreatic sufficiency and carriers of mild mutations. These patients had mild-to-moderate lung disease and were less likely to be colonized with Pseudomonas or have liver disease.

Incidence and Risk Factors for Multiple Antibiotic-Resistant Pseudomonas aeruginosa in Cystic Fibrosis

Infection with multiple antibiotic-resistant Pseudomonas aeruginosa (MARPA) in individuals with cystic fibrosis (CF) has caused much concern among caregivers, yet little is known about the risks associated with acquiring resistance. The main objective of the study was to estimate the incidence and identify risk factors for the acquisition of MARPA among individuals with CF. Five-year cohort study of individuals followed in the Cystic Fibrosis Foundation Registry from 1998 through 2002. Demographics, anthropometrics, spirometry, respiratory culture results, comorbidities, antibiotic usage, and hospitalizations were collected. Of the 4,293 patients with P aeruginosa infection during the study period, MARPA developed in 341. The overall incidence of MARPA was 1.8%/yr. Independent risk factors for MARPA included CF-related diabetes mellitus (hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.11 to 2.43), long-term inhaled tobramycin usage (HR, 2.08; 95% CI, 1.56 to 2.77), and care at a CF center with a baseline MARPA prevalence in the top quartile (HR, 2.00; 95% CI, 1.31 to 3.04). Frequent courses of IV antibiotics and repeated hospitalizations were also found to independently increase the risk for MARPA. Infection with MARPA is common among patients with CF. Diabetes, long-term inhaled tobramycin usage, and frequent acute pulmonary exacerbations requiring hospitalization or IV antibiotics increase the risk for MARPA. Receiving CF care at a center with a high prevalence of resistant Pseudomonas also increases the risk for MARPA in patients with CF. Further study is needed to investigate the mechanisms of acquiring resistant strains and the clinical impact of MARPA on CF outcomes.

How Can We Prevent Multisystem Complications of Cystic Fibrosis?

Cystic fibrosis (CF) is a multisystem disease. Some of this is accounted for by CF transmembrane regulator (CFTR) dysfunction in individual organs but in some cases this is compounded by the effects of systemic inflammation. The inflammation is in response to the chronic infection in the airways and is particularly important as a contributor to CF-related bone disease, CF-related diabetes mellitus, CF-related arthropathy, and vasculitis. Preventing these multisystem complications is difficult. Aggressive specific therapies to treat complications is critically important to maintain nutrition, stop the damaging effects of diabetes, and improve bone mineral density. Aggressive treatment of lung disease to reduce systemic inflammation is likely to be of benefit in preventing the development of CF-related bone disease and may be beneficial in at least delaying the onset of CF-related diabetes. Aggressive treatment of pulmonary infection and inflammation in conjunction with holistic management plans to treat specific organ diseases is an important strategy in improving morbidity and reducing mortality in people with CF.

Cystic fibrosis; een vergrijzend ziektebeeld?

Cystic fibrosis (cf) is the most frequent occurring hereditary lethal disease in Western countries. Improvement of treatment strategies in cf have resulted in major improvements of life expectancy. Several decades ago cf was treated exclusively by paediatricians, nowadays the median life expectancy is between 30 and 35 years. Many patients are treated by pulmonologists and other medical specialists for adults. The improved survival has led to the emergence of new complications of the disease, like allergic bronchopulmonary aspergillosis (abpa), cf-related liver diseases, cf-related diabetes mellitus, and osteoporosis. Additionally, patients wish to become parents themselves. Each of these aspects ask attention of both paediatricians (information and prevention) and medical specialists for adults (treatment). Intensive collaboration between these specialists in cf centers and structured transition of care is of urgent importance.

Hyperglycaemia and insulinopenia in a neonate with cystic fibrosis

Abnormal glucose tolerance is a frequent late complication of cystic fibrosis (CF), but the prevalence of CF-related diabetes mellitus (CFRD) in children less than 10 y old is less than 2%. The youngest child with CFRD reported to date was 6 mo of age. Insulinopenia is the primary cause of abnormal glucose tolerance/CFRD, but it is unknown whether it may begin in the neonatal period. We describe a case of a neonate with CF who presented with hyperglycaemia in the diabetic range and marked insulinopenia. Insulinopenia and impaired glucose tolerance were permanent findings at 6 and 15 mo of age. This case suggests that abnormal glucose tolerance/diabetes may occur much earlier in the course of CF, even during neonatal age. Careful follow-up and further studies in CF infants could reveal that the real incidence of glucose intolerance and diabetes in this age group has been underestimated.

Trends in pulmonary function in patients with cystic fibrosis correlate with the degree of glucose intolerance at baseline.

In patients with cystic fibrosis, CF-related diabetes mellitus (CFRD) has been associated with increased morbidity and mortality. Whether glucose intolerance is also associated with poor outcomes is unclear. To better define these relationships we prospectively followed a group of 152 patients with CF without diabetes for 4 yr. Patients were classified as having normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or CFRD without fasting hyperglycemia (CFRD-No FH). FEV(1), FVC, and body mass index (BMI) were measured at baseline and quarterly. At baseline 45% of the patients had NGT, 38.8% had IGT, and 15.8% had CFRD-No FH. FEV(1), FVC, and BMI at baseline were comparable among these groups (all p > 0.1). After 4 yr an overall decline in FEV(1) and FVC occurred, with no change in BMI. The rates of decline for FEV(1) and FVC correlated with the glucose tolerance groups, with the highest rates of decline occurring among the CFRD-No FH group. In addition, patients in the lowest quartile for insulin production at baseline experienced the highest rates of pulmonary function decline over time, suggesting a relationship between insulin deficiency and clinical deterioration. We conclude that the degree of glucose intolerance is a strong determinant of future lung function decline in patients with CF.