Epidemiology of cystic fibrosis-related diabetes

doi:10.1016/j.jpeds.2004.12.039

The Journal of Pediatrics

Volume 146, Issue 5, May 2005, Pages 681-687

https://doi.org/10.1016/j.jpeds.2004.12.039 Get rights and content

Objectives

Cystic fibrosis-related diabetes (CFRD) has emerged as an important complication of CF. To better understand who is at risk of developing CFRD, to gain insight into the impact of CFRD on pulmonary and nutritional status, and to assess the association of CFRD with various practice patterns and comorbid conditions, we characterized the Epidemiologic Study of Cystic Fibrosis (ESCF) patient population.

Study design

Analyses were performed on the 8247 adolescents and adults who were evaluated at one of 204 participating sites during 1998. CFRD was defined as the use of insulin or an oral hypoglycemic agent at any time during the year.

Results

Previously reported risk factors for CFRD including age, gender (female), and pancreatic insufficiency were confirmed in this study. Patients with CFRD had more severe pulmonary disease, more frequent pulmonary exacerbations, and poorer nutritional status as compared with those without diabetes. CFRD also was associated with liver disease.

Conclusions

CFRD is a common complication in adolescents and adults that is associated with more severe disease.

Section snippets

Methods

The ESCF is a longitudinal, encounter-based patient registry that has been used to characterize demographics, practice patterns, and risk factors for decline in pulmonary function of the patient population in the United States.14, 15, 16 Institutional review board approval and written informed consent were obtained at institutions where required. There were 10,695 patients ≥13 years of age who were in ESCF throughout 1998 (definition: enrolled in ESCF before 1/1/98, ≥13 years of age on 1/1/98,

Gender and Age Distribution of CFRD

The gender distribution of the entire adolescent and adult population was 54.4% males and 45.6% females. However females were disproportionately affected by CFRD with a prevalence of 17.1% as compared with 12.0% in males. The mean (SD) age of the CFRD population was 25.9 (8.9) years as compared with 22.5 (8.5) years for the non-CFRD group.

Pancreatic Status and Genotype

Previous reports suggested that pancreatic exocrine insufficiency is a risk factor for the development of CFRD. We defined pancreatic insufficiency as the use

Discussion

This is the largest analysis to date of the epidemiology of CFRD. We confirm previous reports that CFRD is associated with increased age, female gender, pancreatic insufficiency,1, 8 and the δ F508 homozygous genotype.7, 21 In addition, these new data show a striking correlation between CFRD and worsened clinical status as indicated by poorer pulmonary function, increased frequency of acute pulmonary exacerbations, increased prevalence of important sputum pathogens, poorer nutritional status,

References (30)

A. Moran et al.
Abnormal glucose metabolism in cystic fibrosis
J Pediatr
(1998)
A. Moran et al.
Diagnosis, screening and management of cystic fibrosis related diabetes mellitus: a consensus conference report
Diabetes Res Clin Pract
(1999)
D.S. Hardin et al.
Insulin resistance is associated with decreased clinical status in cystic fibrosis
J Pediatr
(1997)
J. Rosenecker et al.
Genetic determination of diabetes mellitus in patients with cystic fibrosis
J Pediatr
(1995)
S.M. Finkelstein et al.
Diabetes mellitus associated with cystic fibrosis
J Pediatr
(1988)
P.V. Hamill et al.
Physical growth: National Center for Health Statistics percentiles
Am J Clin Nutr
(1979)
H. Eigen et al.
A multicenter study of alternate-day prednisone therapy in patients with cystic fibrosis. Cystic Fibrosis Foundation Prednisone Trial Group
J Pediatr
(1995)
N.N. Huang et al.
Clinical features, survival rate, and prognostic factors in young adults with cystic fibrosis
Am J Med
(1987)
S. Lanng et al.
Glucose tolerance in patients with cystic fibrosis: five year prospective study
BMJ
(1995)
B. Yung et al.
Cystic fibrosis-related diabetes: the role of peripheral insulin resistance and beta-cell dysfunction
Diabet Med
(2002)

Cystic Fibrosis Foundation Patient Registry 2003 Annual Data Report to the Center Directors

(2004)

Koch C, Rainisio M, Madessani U, Harms HK, Hodson ME, Mastella G, S, et al. 2001. Presence of cystic fibrosis-related...

S. Lanng et al.

Influence of the development of diabetes mellitus on clinical status in patients with cystic fibrosis

Eur J Pediatr

(1992)

C.E. Milla et al.

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

Am J Respir Crit Care Med

(2000)

T.G. Liou et al.

Predictive 5-year survivorship model of cystic fibrosis

Am J Epidemiol

(2001)

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Airway inflammation underlies cystic fibrosis (CF) pulmonary exacerbations. In a prospective multicenter study of randomly selected, clinically stable adolescents and adults, we assessed relationships between 24 inflammation-associated molecules and the future occurrence of CF pulmonary exacerbation using proportional hazards models. We explored relationships for potential confounding or mediation by clinical factors and assessed sensitivities to treatments including CF transmembrane regulator (CFTR) protein synthesis modulators. Results from 114 participants, including seven on ivacaftor or lumacaftor-ivacaftor, representative of the US CF population during the study period, identified 10 biomarkers associated with future exacerbations mediated by percent predicted forced expiratory volume in 1 s. The findings were not sensitive to anti-inflammatory, antibiotic, and CFTR modulator treatments. The analyses suggest that combination treatments addressing RAGE-axis inflammation, protease-mediated injury, and oxidative stress might prevent pulmonary exacerbations. Our work may apply to other airway inflammatory diseases such as bronchiectasis and the acute respiratory distress syndrome.
Screening strategies for glucose tolerance abnormalities and diabetes in people with cystic fibrosis
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The increase in life expectancy of patients with cystic fibrosis has come with new comorbidities, particularly diabetes. The gradual development of glucose tolerance abnormalities means that 30 to 40% of adults will be diabetic. Cystic fibrosis–related diabetes is a major challenge in the care of these patients because it is a morbidity and mortality factor at all stages of the disease. Early glucose tolerance abnormalities observed from childhood, before the stage of diabetes, are also associated with a poor pulmonary and nutritional outcome. The long asymptomatic period justifies systematic screening with an annual oral glucose tolerance test from the age of 10 years. However, this strategy does not take into account the new clinical profiles of patients with cystic fibrosis, recent pathophysiological knowledge of glucose tolerance abnormalities, and the emergence of new diagnostic tools in diabetology. In this paper, we summarise the challenges of screening in the current context of new patient profiles – patients who are pregnant, have transplants, or are being treated with fibrosis conductance transmembrane regulator modulators – and put forward an inventory of the various screening methods for cystic fibrosis–related diabetes, including their applications, limitations and practical implications.
Screening of glucose tolerance abnormalities and diabetes in people with cystic fibrosis: A French position
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Long-term follow-up and liver outcomes in children with cystic fibrosis and nodular liver on ultrasound in a multi-center study
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Citation Excerpt :
Liver disease, defined as portal hypertension, abnormal liver enzymes, or the use of a bile acid (ursodeoxycholic acid or taurine) was previously reported as a risk factor for the development of CFRD in population-based studies [8,25]. In another study, cirrhosis, but not elevation of liver biochemistries, was found to be more common in people with CF who had CFRD [24]. In one recent international study, CFRD was not identified as a clinical feature of severe CFLD with portal hypertension and in another, participants with severe CFLD showed a tendency toward impaired glucose homeostasis with larger studies like this one recommended [26,27].
Nodular liver (NOD) in cystic fibrosis (CF) suggests advanced CF liver disease (aCFLD); little is known about progression of liver disease (LD) after detection of sonographic NOD.
Clinical, laboratory, and ultrasound (US) data from Prediction by Ultrasound of the Risk of Hepatic Cirrhosis in CFLD Study participants with NOD at screening or follow-up were compared with normal (NL). Linear mixed effects models were used for risk factors for LD progression and Kaplan-Meier estimator for time-to-event.
54 children with NOD (22 screening, 32 follow-up) and 112 NL were evaluated. Baseline (BL) and trajectory of forced expiratory volume, forced vital capacity, height/BMI z-scores were similar in NOD vs NL. Platelets were lower in NOD at BL (250 vs 331×10³/microL; p < 0.001) and decreased by 8600/year vs 2500 in NL. Mean AST to Platelet Ratio Index (1.1 vs 0.4; p < 0.001), Fibrosis-4 Index (0.4 vs 0.2, p < 0.001), and spleen size z-score (SSZ) [1.5 vs 0.02; p < 0.001] were higher in NOD at BL; SSZ increased by 0.5 unit/year in NOD vs 0.1 unit/year in NL. Median liver stiffness (LSM) by transient elastography was higher in NOD (8.2 kPa, IQR 6–11.8) vs NL (5.3, 4.2–7, p < 0.0001). Over 6.3 years follow-up (1.3–10.3), 6 NOD had esophageal varices (cumulative incidence in 10 years: 20%; 95% CI: 0.0%, 40.0%), 2 had variceal bleeding, and 2 underwent liver transplantation; none had ascites or hepatic encephalopathy. No NL experienced liver-related events.
NOD developed clinically evident portal hypertension faster than NL without worse growth or lung disease.
Glycemia and β-cell function before and after elexacaftor/tezacaftor/ivacaftor in youth and adults with cystic fibrosis
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Diabetes is prevalent among people with CF (PwCF) and associated with worse clinical outcomes. CFTR modulators are highly effective in improving the disease course of CF. However, the effects of elexacaftor/tezacaftor/ivacaftor (ETI) on glucose metabolism in PwCF are unclear.
Twenty youth and adults with CF underwent frequently sampled oral glucose tolerance tests (fsOGTT) before and after ETI initiation. Glucose, insulin, and C-peptide were collected at 0, 10, 30, 60, 90, and 120 min after 1.75 g/kg (max 75 g) of dextrose. HbA1c and continuous glucose monitoring (CGM) were collected in a subset. Estimates of insulin secretion (C-peptide index), insulin resistance (HOMA2 IR and IS(OGTT Cpep)), and β-cell function (C-peptide oral disposition index, oDI_coeo), were compared before and after ETI.
Participants were a median (IQR) of 20.4 (14.1, 28.6) years old, 75 % male. Follow-up occurred 10.5 (10.0, 12.3) months after ETI initiation. BMI z-score increased from 0.3 (-0.3, 0.8) to 0.8 (0.4, 1.5), p = 0.013 between visits. No significant differences were observed in glucose tolerance, glucose area under the curve, nor fsOGTT glucose concentrations before and after ETI. Median (IQR) C-peptide index increased from 5.7 (4.1, 8.3) to 8.8 (5.5, 10.8) p = 0.013 and HOMA2 IR increased (p < 0.001), while oDI_coeo was unchanged (p = 0.67). HbA1c decreased from 5.5 % (5.5, 5.8) to 5.4 % (5.2, 5.6) (p = 0.003) while CGM variables did not change.
BMI z-score and measures of both insulin resistance and insulin secretion increased within the first year of ETI initiation. β-cell function adjusted for insulin sensitivity (oDI_coeo) did not change.
2D Shear Wave Elastography, a promising screening tool for Cystic Fibrosis liver disease, shows a correlation between vitamin D and liver stiffness
2022, Journal of Cystic Fibrosis
Liver disease in Cystic Fibrosis (CFLD) is an early complication of CF. Evidence of CFLD is often subclinical and screening is recommended. Screening includes a biochemical work-up and an ultrasound investigation. Non-invasive methods measuring liver stiffness such as shear wave elastography could be beneficial. This study describes the use of 2D Shear Wave Elastography (2D SWE) in screening for CFLD in a clinical setting and explores its correlation to other indicators of CFLD. Furthermore, a relationship between liver stiffness and nutritional status, lung function and glucose tolerance was explored.
A retrospective cohort study was performed at a pediatric CF center. Information was gathered from the patients’ charts and the Swedish national CF registry. The patients included had been evaluated for the presence of CFLD by ultrasound and 2D SWE during 2018-2020. Demographic data as well as data concerning nutritional status, lung function and glucose tolerance were collected.
Fifty-one subjects were included with a median age of 11 years. Four children who had biopsy confirmed liver cirrhosis had significantly increased liver stiffness. There was a statistically significant negative correlation between liver stiffness and vitamin D levels and FEV1% predicted respectively. Children with abnormal glucose tolerance had increased liver stiffness compared to their normal glucose tolerant counterparts.
Measuring liver stiffness by 2D SWE is a reliable addition to CFLD screening with data comparable to the more conventional ultrasound investigation. Increased liver stiffness is associated with lower vitamin D levels, lower FEV1% predicted and abnormal glucose tolerance.

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Genentech, Inc. funds the Epidemiologic Study of Cystic Fibrosis. Dr Marshall was a member of the advisory board for the study at the time of these analyses and received grant support from Genentech, Inc. in the past. Dr Morgan is a member of the advisory board for the study, and has received grants and other support from Genentech, Inc.

^∗Reprint requests: Seema Asthana, Genentech, Inc. E-mail: [email protected].

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Original ArticleEpidemiology of cystic fibrosis-related diabetes

Objectives

Study design

Results

Conclusions

Section snippets

Methods

Gender and Age Distribution of CFRD

Pancreatic Status and Genotype

Discussion

J Pediatr

Diabetes Res Clin Pract

J Pediatr

J Pediatr

J Pediatr

Am J Clin Nutr

J Pediatr

Am J Med

Glucose tolerance in patients with cystic fibrosis: five year prospective study

BMJ

Cystic fibrosis-related diabetes: the role of peripheral insulin resistance and beta-cell dysfunction

Diabet Med

Cystic Fibrosis Foundation Patient Registry 2003 Annual Data Report to the Center Directors

Influence of the development of diabetes mellitus on clinical status in patients with cystic fibrosis

Eur J Pediatr

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

Am J Respir Crit Care Med

Predictive 5-year survivorship model of cystic fibrosis

Am J Epidemiol

Original Article
Epidemiology of cystic fibrosis-related diabetes