Tamarah Katz

Early Glucose Abnormalities in Cystic Fibrosis Are Preceded by Poor Weight Gain

OBJECTIVE Progressive β-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 (BGmax) 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 BGmax (both P = 0.02) and with CGM time >7.8 mmol/l (P = 0.006 and P = 0.02, respectively) but not with BG120 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 ≥4.5% detected declining wtSDS with 89% sensitivity and 86% specificity (area under the ROC curve 0.89, P = 0.003). BGmax ≥8.2 mmol/l gave 87% sensitivity and 70% specificity (0.76, P = 0.02). BG120 min did not detect declining wtSDS (0.59, P = 0.41). After exclusion of two patients with BG120 min ≥11.1 mmol/l, the decline in wtSDS was worse if BGmax was ≥8.2 mmol/l (−0.3 ± 0.4 vs. 0.0 ± 0.4 for BGmax <8.2 mmol/l, P = 0.04) or if CGM time above 7.8 mmol/l was ≥4.5% (−0.3 ± 0.4 vs. 0.1 ± 0.2 for time <4.5%, P = 0.01). CONCLUSIONS BGmax ≥8.2 mmol/l on an OGTT and CGM time above 7.8 mmol/l ≥4.5% are associated with declining wtSDS and lung function in the preceding 12 months.

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%FEV1) 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%FEV1 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.

Intestinal Inflammation and Impact on Growth in Children With Cystic Fibrosis

Objective: The aim of the study was to evaluate and compare faecal markers of intestinal inflammation in children with cystic fibrosis (CF), and determine whether intestinal inflammation adversely affects the nutritional phenotype. Methods: Faecal samples for markers of intestinal inflammation, calprotectin, S100A12, and osteoprotegerin, were collected from children with CF, healthy controls (HCs), and Crohn disease (CD). Associations between inflammatory markers and clinical and nutritional indices were determined in subjects with CF. Results: Twenty-eight children with CF (mean [standard deviation (SD)] 8.4 [3.3] years old, 22 pancreatic insufficient [PI]), 47 HC, and 30 CD were recruited. Mean (SD) faecal calprotectin in CF (94.3 [100.6] mg/kg) was greater than HC (26.7 [15.4] mg/kg, P < 0.0001), but lower than CD (2133 [2781] mg/kg, P = 0.0003). Abnormal faecal calprotectin was found in subjects only with PI (17/22 (77%), P = 0.001). There was no difference in faecal mean (SD) S100A12 (0.8 [0.9] vs 1.5 [2.2] mg/kg, P = 0.14) and osteoprotegerin concentrations (72.7 [52.2] vs 62.5 [0.0] pg/mL, P = 0.2) between CF and HC. Patients with CD had significantly elevated S100A12 and osteoprotegerin compared with CF and HC. Faecal calprotectin inversely correlated with both weight (r = −0.5, P = 0.003) and height z scores (r = −0.6, P = 0.002) in CF. Conclusions: The pattern of intestinal inflammation in CF is unique and distinct from inflammatory bowel disease, with elevated faecal calprotectin but normal faecal S100A12 and osteoprotegerin concentrations. The severity of intestinal inflammation, based on faecal calprotectin, significantly correlates with poor growth.

Update of Faecal Markers of Inflammation in Children with Cystic Fibrosis

There is evidence of intestinal inflammation in patients with CF. Intestinal inflammation may negatively impact the nutritional status of patient with CF, which adversely affects pulmonary function and survival. This paper provides an up-to-date review of intestinal inflammation in CF and an evaluation of utility of two specific faecal inflammatory markers (S100A12 and calprotectin).

Single high-dose oral vitamin D3 (stoss) therapy — A solution to vitamin D deficiency in children with cystic fibrosis?

OBJECTIVES To determine the safety and efficacy of stoss therapy on vitamin D levels over a 12 month period in children with cystic fibrosis and vitamin D deficiency (<75 nmol/L). STUDY DESIGN Retrospective chart review of 142 paediatric CF patients from 2007 till 2011. RESULTS Thirty eight children received stoss therapy and 37 children with vitamin D deficiency were not treated and served as a control group. The stoss treated group had a significant and sustained increase in 25-hydroxyvitamin D levels measured at 1, 3, 6 and 12 months post treatment compared to controls (94.82 ± 41.0 nmol/L, p=0.001; 81.54 ± 24.6 nmol/L, p=0.001; 92.18 ± 36.5 nmol/L, p=0.008 and 64.6 ± 20.0 nmol/L, p=0.006 respectively). At 12 months post intervention, the mean difference in vitamin D levels from baseline between the stoss treated group and controls was significant at 15 nmol/L compared to 5 nmol/L (p=0.038). CONCLUSION Stoss therapy effectively achieves and maintains levels of 25-hydroxyvitamin D greater than 75 nmol/L over 12 months.

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.

Fecal biomarkers of intestinal health and disease in children

The identification of various fecal biomarkers has provided insight into the intestinal milieu. Most of these markers are associated with the innate immune system of the gut, apart from the more novel M2-pyruvate kinase. The innate immunity of the gut plays a role in maintaining a fine balance between tolerance to commensal bacteria and immune response to potential pathogens. It is a complex system, which comprises of multiple elements, including antimicrobial peptides (e.g., defensins, cathelicidins, lactoferrin, and osteoprotegerin), inflammatory proteins (e.g., calprotectin and S100A12), and microbial products (e.g., short-chain fatty acids). Dysfunction of any component can lead to the development of intestinal disease, and different diseases have been associated with different fecal levels of these biomarkers. Each fecal biomarker provides information on specific biological and disease processes. Therefore, stool quantification of these biomarkers provides a non-invasive method to define potential pathways behind the pathogenesis of diseases and can assist in the assessment and diagnosis of various gastrointestinal conditions. The abovementioned fecal biomarkers and their role in intestinal health and disease will be reviewed in this paper with a pediatric focus.

Fat-soluble vitamin deficiency in children and adolescents with cystic fibrosis.

Aims Determine the prevalence of fat-soluble vitamin deficiency in children with cystic fibrosis (CF) aged ≤18 years in New South Wales (NSW), Australia, from 2007 to 2010. Methods A retrospective analysis of fat-soluble vitamin levels in children aged ≤18 years who lived in NSW and attended any of the three paediatric CF centres from 2007 to 2010. An audit of demographic and clinical data during the first vitamin level measurement of the study period was performed. Results Deficiency of one or more fat-soluble vitamins was present in 240/530 children (45%) on their first vitamin level test in the study period. The prevalence of vitamins D and E deficiency fell from 22.11% in 2007 to 15.54% in 2010, and 20.22% to 13.89%, respectively. The prevalence of vitamin A deficiency increased from 11.17% to 13.13%. Low vitamin K was present in 29% in 2007, and prevalence of prolonged prothrombin time increased from 19.21% to 22.62%. Fat-soluble vitamin deficiency is present in 10%–35% of children with pancreatic insufficiency, but only a very small proportion of children who are pancreatic-sufficient. Conclusions This is one of few studies of fat-soluble vitamin deficiency in children with CF in Australia. Fat-soluble vitamin testing is essential to identify deficiency in pancreatic-insufficient children who may be non-compliant to supplementation or require a higher supplement dose, and pancreatic-sufficient children who may be progressing to insufficiency. Testing of vitamin K-dependent factors needs consideration. Further studies are needed to monitor rates of vitamin deficiency in the CF community.

Elevated fecal M2-pyruvate kinase in children with cystic fibrosis: A clue to the increased risk of intestinal malignancy in adulthood?

Adult patients with cystic fibrosis (CF) have an increased risk of gastrointestinal malignancies. We hypothesized that increased intestinal cell turnover beginning in childhood may explain the increased risk of malignancy in early adulthood. Therefore, we aimed to measure fecal M2‐pyruvate kinase (M2‐PK), a biomarker of intestinal cell turnover, in children with CF. To assess whether the increased cell turnover is secondary to intestinal inflammation, the secondary aims were to measure fecal calprotectin and evaluate its association with fecal M2‐PK.

High ambient temperature and risk of intestinal obstruction in cystic fibrosis.

Distal intestinal obstruction syndrome (DIOS) and constipation in cystic fibrosis (CF) are conditions associated with impaction and/or obstruction by abnormally viscid mucofaecal material within the intestinal lumen. Dehydration has been proposed as a risk factor for DIOS and constipation in CF. The study primarily aimed to determine whether warmer ambient temperature and lower rainfall are risk factors for DIOS and constipation in CF.