Cystic Fibrosis-Related Diabetes: Clinical approach and knowledge gaps.

Cystic Fibrosis-Related Diabetes (CFRD) is a unique type of diabetes mellitus that shares some features with both type 1 and type 2 diabetes. Yet, its distinguishing feature of acute pulmonary complications associated with hyperglycemia and the catabolic metabolism associated with a relative insulin deficiency poses challenges to the application of traditional definitions and treatments for diabetes mellitus. People with CF (pwCF) undergo rigorous annual screening starting at age 10, a process that is challenging for patients and limited by sensitivity, specificity, and reproducibility. As pwCF continue to live longer, over 50% are expected to develop CFRD over their lifetime, including up to 20% of adolescents. Increasing numbers of people with CFRD will make this disease increasingly relevant to diabetes practitioners. Evidence-guided practice in CFRD care is limited by small and short studies. Our current understanding of CFRD may change significantly with the recent introduction of CF Transmembrane Regulator (CFTR) modulator medications. This review will explore current challenges in the diagnosis and management of CFRD, specifically highlighting knowledge gaps in the pathophysiology of CFRD, optimal screening methods, priorities for research and provide guidance with regards to screening, diagnosis, and treatment.

Thyroid nodules in children and adolescents: Investigation and management.

Clinically detectable thyroid nodules are less common in children than adults. However, they are associated with an increased risk of malignancy. Therefore, thorough evaluation of paediatric thyroid nodules is necessary, and an understanding of the features associated with a higher risk of malignancy is important to guide management and referral. Thyroid cancer in children differs significantly from that seen in adults in terms of genetics, presentation, response to treatment and prognosis. Children often present with more advanced disease, but the vast majority have excellent long-term prognosis. Evaluation and management of thyroid nodules and thyroid cancer require a multidisciplinary team approach and involvement of specialists with experience in this field. This review summarises investigative pathways for thyroid nodules in children and outlines current management strategies for paediatric thyroid nodules and cancer.

Cystic fibrosis-related diabetes and lung disease: an update.

The development of cystic fibrosis-related diabetes (CFRD) often leads to poorer outcomes in patients with cystic fibrosis including increases in pulmonary exacerbations, poorer lung function and early mortality. This review highlights the many factors contributing to the clinical decline seen in patients diagnosed with CFRD, highlighting the important role of nutrition, the direct effect of hyperglycaemia on the lungs, the immunomodulatory effects of high glucose levels and the potential role of genetic modifiers in CFRD.

Glucose abnormalities detected by continuous glucose monitoring are common in young children with Cystic Fibrosis.

It is not yet known whether continuous glucose monitoring (CGM) abnormalities persist in young children with CF. We evaluated longitudinal CGM results for children with CF < 10 years of age. We performed 3-day CGM at baseline, 12 months, and 24 months on 11 CF children (1 female) initially aged mean (SD) 3.8 (2.5) years. CGM analysis included (i) mean sensor glucose (SG), (ii) standard deviation (SD) for SG, (iii) peak SG and (iv)% time spent above a threshold of 7.8 mmol/L. Only three (3/11, 27%) had normal CGM at all time-points. Nearly three quarters of the participants (8/11, 73%) spent more than 4.5 percent time > 7.8 mmol/L at one time-point, five of whom had an elevated percent time on a subsequent test. Young children with CF have glucose abnormalities detected by CGM that fluctuate over time.

Peak OGTT glucose is associated with lower lung function in young children with cystic fibrosis.

BACKGROUND: Screening for Cystic Fibrosis-related diabetes is recommended in patients with CF <10 years old when there are concerns about growth and lung function. The Oral Glucose Tolerance Test (OGTT) is recommended but has not been validated in this cohort. We sought to determine whether the 2-h OGTT, the gold standard diagnostic test for CFRD, detects clinical decline in children with CF <10 years old. METHODS: We analysed blood glucose(BG) levels collected every 30 min during OGTT in 27 children with CF < 10 years old, comparing the 2-hour BG (BG120min), peak BG (BGmax) and Area Under the Curve(AUC) for glucose and the association with lung function and nutritional status. We also compared the OGTT results with results from Continuous Glucose Monitoring (CGM) performed in 11 participants. RESULTS: The BGmax was higher than the BG120min in 25/27 (93%) participants. There was a significant inverse correlation between BGmax and weight z-score (rs = -0.56, p = .002) and between BGmax and FEV1 (rs = -0.54, p = .014) that was not present for BG120min. A significant inverse correlation was also identified between fasting insulin level and elevated glucose on CGM, defined as AUC >7.8 mmol/L (rs = - 0.69, p = .027) or as % time > 7.8 (rs = - 0.76, p = .011). CONCLUSIONS: Children with CF < 10 years of age with higher BGmax on OGTT have lower lung function and weight z- scores that may not be identified using the 2 h OGTT BG120min. CGM also identifies glucose excursions in young children with CF.

Continuous glucose monitoring in cystic fibrosis - A practical guide.

Our ability to monitor blood glucose levels has become increasingly accurate over the last few decades. Continuous glucose monitoring (CGM) technology now allows providers and patients the ability to monitor glucose levels retrospectively as well as in real-time for diabetes management. CGM also provides the ability to study glucose patterns and trends for insight into the pathophysiology and natural history of disease. CGM captures a more complete picture of glucose profiles than traditional measures of glycemia such as the hemoglobin A1c or self-monitoring of blood glucose levels. This article provides a review of the history of glucose monitoring, a review of the literature pertaining to CGM with a focus on studies in patients with cystic fibrosis, and discusses practical uses of CGM technology and its application for the evaluation and management of cystic fibrosis related diabetes.

Early glucose abnormalities are associated with pulmonary inflammation in young children with cystic fibrosis.

BACKGROUND: Children with CF are insulin deficient from infancy but very little is known about the impact of glucose abnormalities in early life. We aimed to identify and describe interstitial glucose levels in CF children <6 years and to evaluate the association with pulmonary infection and inflammation. METHODS: We assessed 18 children (5 females) with median age of 3.2 years (range 0·9-5.5) with Continuous Glucose Monitoring for 3 days. Bronchoalveolar lavage (BAL) fluid was cultured for known pathogenic microbial agents and assessed for total white blood cells, percentage of neutrophils and IL-8 level. RESULTS: Peak sensor glucose (SG) was >11.1 mmol/L in 39% of participants. The percentage neutrophil count on BAL was positively correlated with elevated SG (peak SG rs = 0.48, p = .044) and with glucose variability (SG standard deviation r = 0.62, ß = 38.5, p = .006). BAL IL-8 level was significantly correlated with all measures of CGM hyperglycemia including % time > 7.8 mmol/L (p = .008) and standard deviation (p < .001). Participants with a history of Pseudomonas aeruginosa had a higher % time > 7.8 mmol/L glucose (16% versus 3%, p = .015). CONCLUSION: Children with CF frequently demonstrate elevated SG levels before age 6 years, which are associated with increased pulmonary inflammation and Pseudomonas aeruginosa infection. Transient SG elevations into the diabetic range (≥11.1 mmol/L) were identified in children from 1 year of age.

Diagnosing cystic fibrosis-related diabetes: current methods and challenges.

INTRODUCTION: Cystic fibrosis-related diabetes (CFRD) is the end-point of a spectrum of glucose abnormalities in cystic fibrosis that begins with early insulin deficiency and ultimately results in accelerated nutritional decline and loss of lung function. Current diagnostic and management regimens are unable to entirely reverse this clinical decline. AREAS COVERED: This review summarises the current understanding of the pathophysiology of CFRD, the issues associated with using oral glucose tolerance tests in CF and the challenges faced in making the diagnosis of CFRD. Medline database searches were conducted using search terms "Cystic Fibrosis Related Diabetes", "Cystic Fibrosis" AND "glucose", "Cystic Fibrosis" AND "insulin", "Cystic Fibrosis" AND "Diabetes". Additionally, reference lists were studied. Expert commentary: Increasing evidence points to early glucose abnormalities being clinically relevant in cystic fibrosis and as such novel diagnostic methods such as continuous glucose monitoring or 30 minute sampled oral glucose tolerance test (OGTT) may play a key role in the future in the screening and diagnosis of early glucose abnormalities in CF.

Advances in the detection and management of cystic fibrosis related diabetes.

PURPOSE OF REVIEW: This review will outline the screening, diagnosis and management of cystic fibrosis related diabetes (CFRD). It will also discuss advances in the detection of early glucose abnormalities, their clinical significance and the emerging role for early insulin therapy. RECENT FINDINGS: Before the onset of diabetes (as currently defined), patients with cystic fibrosis (CF) display glucose abnormalities, detectable either by 30-minutely sampled oral glucose tolerance testing (OGTT), or by continuous ambulatory interstitial glucose monitoring (CGM). These early glucose abnormalities are associated with the presence of glucose in airway fluid, potentially promoting the growth of airway pathogens and contributing to the progression of respiratory disease. Progressive insulin deficiency underlies these glucose abnormalities, and insulin deficiency also causes catabolism. Pilot studies of once-daily insulin therapy in the early stages of insulin deficiency show improved lung function and weight gain (important predictors of survival in CF). SUMMARY: Early stages of insulin deficiency may be contributing to catabolism and deteriorating lung function in CF. It is plausible that early insulin therapy may prevent this deterioration, a view supported by pilot studies. Randomized controlled trials of early insulin therapy will now determine whether insulin therapy should be commenced earlier than current practice in CF.

Cystic fibrosis related diabetes: potential pitfalls in the transition from paediatric to adult care.

One of the major complications of Cystic Fibrosis (CF) is CF-Related Diabetes (CFRD), which increases in incidence with age, from 1-2% below the age of 10 years to ∼20% of adolescents and 40-50% of adults. Multiple guidelines have been published over the last few years for the diagnosis and management of CFRD, from the American Diabetes Association (ADA) / US Cystic Fibrosis Foundation, International Society for Pediatric and Adolescent Diabetes (ISPAD) and the Thoracic Society of Australia and New Zealand-Australian Diabetes Society. However, little is published about the particular issues involved in transition of patients with CFRD from paediatric to adult care, nor the issues concerning the development of CFRD during the transition period. This document seeks to provide assistance to physicians, dieticians, nurses, diabetes educators, CF patients and their families by outlining the issues surrounding CFRD during transition from paediatric to adult care.

Australian standards of care for cystic fibrosis-related diabetes.

Multiple guidelines have been published over the last few years for the diagnosis and management of cystic fibrosis (CF) and cystic fibrosis related diabetes (CFRD), although some of the recommendations are based on extrapolation from other forms of diabetes and/or expert opinions. This document seeks to combine the guidelines to provide an Australian approach to the management of CFRD and establish the guidelines within the Australian CF Standards of Care. It is intended that this document will provide assistance to doctors, nurses, dietitians, physiotherapists, diabetes educators and CF patients concerning the issues surrounding CFRD, and will be reviewed and updated in 2016.

Home blood sodium monitoring, sliding-scale fluid prescription and subcutaneous DDAVP for infantile diabetes insipidus with impaired thirst mechanism.

BACKGROUND/AIMS: Infants with diabetes insipidus (DI), especially those with impaired thirst mechanism or hypothalamic hyperphagia, are prone to severe sodium fluctuations, often requiring hospitalization. We aimed to avoid dangerous fluctuations in serum sodium and improve parental independence. METHODS: A 16-month old girl with central DI, absent thirst mechanism and hyperphagia following surgery for hypothalamic astrocytoma had erratic absorption of oral DDAVP during chemotherapy cycles. She required prolonged hospitalizations for hypernatremia and hyponatremic seizure. Intensive monitoring of fluid balance, weight and clinical assessment of hydration were not helpful in predicting serum sodium. Discharge home was deemed unsafe. Oral DDAVP was switched to subcutaneous (twice-daily injections, starting with 0.01mcg/dose, increasing to 0.024mcg/dose). The parents adjusted daily fluid allocation by sliding-scale, according to the blood sodium level (measured by handheld i-STAT analyser, Abbott). We adjusted the DDAVP dose if fluid allocation differed from maintenance requirements for 3 consecutive days. RESULTS: After 2.5 months, sodium was better controlled, with 84% of levels within reference range (135-145 mmol/L) vs. only 51% on the old regimen (p = 0.0001). The sodium ranged from 132-154 mmol/L, compared to 120-156 on the old regimen. She was discharged home. CONCLUSION: This practical regimen improved sodium control, parental independence, and allowed discharge home.

Once daily insulin detemir in cystic fibrosis with insulin deficiency.

The aim of this study was to determine if once daily insulin detemir reverses decline in weight and lung function in patients with cystic fibrosis (CF). 12 patients with early insulin deficiency and six with CF related diabetes (aged 7.2-18.1 years) were treated for a median of 0.8 years. Changes in weight and lung function following treatment were compared to pretreatment changes. Before treatment, the change in weight SD score (ΔWtSDS), percentage of predicted forced expiratory volume in 1 s (Δ%FEV(1)) and percentage of predicted forced vital capacity (Δ%FVC) declined in the whole study population (-0.45±0.38, -7.9±12.8%, -5.8±14.3%) and in the subgroup with early insulin deficiency (-0.41±0.43, -9.8±9.3%, -6.8±10.3%). Following treatment with insulin ΔWtSDS, Δ%FEV(1) and Δ%FVC significantly improved in the whole study population (+0.18±0.29 SDS, p=0.0001; +3.7±10.6%, p=0.007; +5.2±12.7%, p=0.013) and in patients with early insulin deficiency (+0.22±0.31 SDS, p=0.003; +5.3±11.5%, p=0.004; +5.8±13.4%, p=0.024). Randomised controlled trials are now needed.

Cystic fibrosis related diabetes (CFRD)--the end stage of progressive insulin deficiency.

In cystic fibrosis, gradual pancreatic destruction causes progressive insulin deficiency, culminating in cystic fibrosis related diabetes (CFRD). As a consequence of insulin deficiency, elevated glucose levels can be detected (well before the diagnosis of CFRD), by continuous ambulatory subcutaneous interstitial fluid glucose monitoring or 30-min sampled oral glucose tolerance test (OGTT). Current diagnostic criteria for CFRD (based on 0 and 120-min OGTT blood glucose levels) were originally designed to forecast microvascular disease in type 2 diabetes, rather than CF-specific outcomes such as declining weight or lung function. In CF, decline in either weight or lung function predicts early mortality. Both may precede the diagnosis of CFRD by several years. Insulin, a potent anabolic hormone, is recommended treatment for CFRD, but use in earlier stages of insulin deficiency is not established. Conventional dosing (with four or more insulin injections per day) is burdensome and carries substantial risk of hypoglycemia. However, recent uncontrolled trials suggest that once-daily injection of intermediate or long-acting insulin improves weight and lung function, with minimal hypoglycemia risk, in CFRD and also in early insulin deficiency. It is plausible that insulin may be of greater benefit to respiratory function when given prior to the diagnosis of CFRD, after which structural lung disease may be irreversible. It is also plausible that early insulin treatment may prolong the lifespan of the remaining insulin-secreting ß-cells. Randomized controlled trials are now needed to determine whether or not current clinical practice should be altered toward the earlier commencement of insulin in CF.

Increased detection of cystic-fibrosis-related diabetes in Australia.

OBJECTIVES: To estimate the incidence of cystic-fibrosis-related diabetes (CFRD) in youth from New South Wales (NSW) and the Australian Capital Territory (ACT), Australia and to examine demographic/clinical features at diagnosis. METHODS: Incident cases of CFRD in young people aged ≤ 18 years diagnosed during 2000 to 2008 were identified from four paediatric cystic fibrosis (CF) clinics and the NSW/ACT Australasian Paediatric Endocrine Group Diabetes Register. RESULTS: CFRD was diagnosed in 41 cases (59% girls). The estimated mean annual incidence of CFRD among patients with CF was 9.4 per 1000 person years (95% CI 6.8 to 12.8). Incidence increased from 2.0 per 1000 person years in 2000 to 22.1 per 1000 in 2008 (incidence RR 1.3, 95% CI 1.1 to 1.4). Haemoglobin A1c (HbA1c) was abnormal in the majority at diagnosis: median HbA1c was 6.9% (6.2-8.1%). More cases were diagnosed using an oral glucose tolerance test in 2007-2008 compared with previous years (61% vs 6%, p<0.001). CONCLUSIONS: CFRD is increasingly recognised and now affects approximately one in five young people with CF. The rising incidence is likely to be due to increased detection, resulting from greater awareness and changes in screening practices. Widespread uptake of consensus guidelines for screening will ensure accurate case detection, but will also impact on patient care and resource allocation.

Early glucose abnormalities in cystic fibrosis are preceded by poor weight gain.

OBJECTIVE: Progressive beta-cell loss causes catabolism in cystic fibrosis. Existing diagnostic criteria for diabetes were based on microvascular complications rather than on cystic fibrosis-specific outcomes. We aimed to relate glycemic status in cystic fibrosis to weight and lung function changes. RESEARCH DESIGN AND METHODS: We determined peak blood glucose (BG(max)) during oral glucose tolerance tests (OGTTs) with samples every 30 min for 33 consecutive children (aged 10.2-18 years). Twenty-five also agreed to undergo continuous glucose monitoring (CGM) (Medtronic). Outcome measures were change in weight standard deviation score (wtSDS), percent forced expiratory volume in 1 s (%FEV1), and percent forced vital capacity (%FVC) in the year preceding the OGTT. RESULTS: Declining wtSDS and %FVC were associated with higher BG(max) (both P = 0.02) and with CGM time >7.8 mmol/l (P = 0.006 and P = 0.02, respectively) but not with BG(120 min). A decline in %FEV1 was related to CGM time >7.8 mmol/l (P = 0.02). Using receiver operating characteristic (ROC) analysis to determine optimal glycemic cutoffs, CGM time above 7.8 mmol/l > or =4.5% detected declining wtSDS with 89% sensitivity and 86% specificity (area under the ROC curve 0.89, P = 0.003). BG(max) > or =8.2 mmol/l gave 87% sensitivity and 70% specificity (0.76, P = 0.02). BG(120 min) did not detect declining wtSDS (0.59, P = 0.41). After exclusion of two patients with BG(120 min) > or =11.1 mmol/l, the decline in wtSDS was worse if BG(max) was > or =8.2 mmol/l (-0.3 +/- 0.4 vs. 0.0 +/- 0.4 for BG(max) <8.2 mmol/l, P = 0.04) or if CGM time above 7.8 mmol/l was > or =4.5% (-0.3 +/- 0.4 vs. 0.1 +/- 0.2 for time <4.5%, P = 0.01). CONCLUSIONS: BG(max) > or =8.2 mmol/l on an OGTT and CGM time above 7.8 mmol/l > or =4.5% are associated with declining wtSDS and lung function in the preceding 12 months.