Cystic fibrosis is frequently complicated by endocrine disorders. Diabetes can be expected to affect most with CF and pancreatic insufficiency and varies widely in age of onset, but early identification and treatment improve morbidity and mortality. Short stature can be exacerbated by relative delay of puberty and by use of inhaled corticosteroids. Bone disease in CF causes fragility fractures and should be assessed by monitoring bone mineral density and optimizing vitamin D status. Detecting and managing endocrine complications in CF can reduce morbidity and mortality in CF. These complications can be expected to become more common as the CF population ages.
Key points
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Endocrine complications of cystic fibrosis (CF) tend to occur more frequently in older individuals and thus can be expected to become more common as CF medical care improves and the population grows older.
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It is unknown to what degree that these complications may be affected by treatment with CF transmembrane conductance regulator (CFTR) modulator medications.
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It is essential to detect and treat endocrine complications as part of high-quality medical care for people with CF.
Introduction
CF is caused by defects in the CF transmembrane conductance regulator ( CFTR ) gene, an epithelial chloride channel that is widely expressed. The most common complications of CF are exocrine pancreatic insufficiency (PI) and progressive lung disease, which is the most common cause of death from CF. In addition, people with CF have several important endocrine abnormalities, which are the focus of this review, including diabetes (CF-related diabetes [CFRD]), bone disease, poor linear growth, and hypogonadism.
Introduction
CF is caused by defects in the CF transmembrane conductance regulator ( CFTR ) gene, an epithelial chloride channel that is widely expressed. The most common complications of CF are exocrine pancreatic insufficiency (PI) and progressive lung disease, which is the most common cause of death from CF. In addition, people with CF have several important endocrine abnormalities, which are the focus of this review, including diabetes (CF-related diabetes [CFRD]), bone disease, poor linear growth, and hypogonadism.
The relationship of cystic fibrosis transmembrane conductance regulator genetics and complications of cystic fibrosis
The risks of developing complications of CF depend in part on the level and function of the CFTR protein. Most people (approximately 85%) with CF have 2 mutations resulting in essentially no CFTR function; these individuals almost always develop exocrine PI within the first year of life, and they are at risk of developing all of the endocrine complications of CF, including diabetes and bone disease, as well as the nonendocrine complications, such as lung disease, meconium ileus, and liver disease. The remaining approximately 15% of people with CF have 1 or 2 copies of CFTR with partial function, which confer delayed-onset exocrine PI or pancreatic sufficiency (PS). People with CFTR mutations in this category can have lower risk of some endocrine and nonendocrine complications (diabetes, meconium ileus, and liver disease) but not others (bone disease) and still develop CF lung disease at a high rate.
Cystic fibrosis–related diabetes
Individuals with CF are at high risk of developing a form of diabetes over time, which is called CFRD. CFRD is distinct from type 1 diabetes mellitus and type 2 diabetes mellitus but has similarities to both. As is the case for all forms of diabetes, people with CFRD have elevated blood glucose (hyperglycemia). In type 1 diabetes mellitus, hyperglycemia is due to complete or near-complete absence of insulin-producing β-cells in the pancreatic islets. In type 2 diabetes mellitus, hyperglycemia is due to a combination of reduced sensitivity to insulin and insufficient production of insulin. People with CFRD tend to have normal insulin sensitivity but have reduced and abnormal production of insulin. In contrast to type 1A diabetes mellitus, in which insulin production declines rapidly and has an abrupt and symptomatic onset, in CFRD, insulin production declines gradually, and diabetes can be asymptomatic.
The main complications of CFRD are worse lung disease, poorer nutritional status, and increased mortality. In addition, CFRD can cause some of the same complications seen for other forms of diabetes, including retinopathy, nephropathy, and neuropathy. All of the CF-specific complications have been shown to improve with treatment of CFRD. Therefore, detection and appropriate treatment of CFRD are key components of the medical care for persons with CF.
Epidemiology
As of 2014, in the US CF Foundation Patient Registry, the prevalence of CFRD among all living patients was 22%, with few prepubertal children with CFRD, approximately 10% to 15% adolescents, and 30% to 40% adults. These prevalence statistics may, however, under-represent the actual risk of CFRD to most people with CF. The risk of CFRD is approximately 5 times higher in people with CFTR genotypes that cause exocrine PI than in those with residual-function mutations that cause PS. The risk of developing CFRD for people with PI CFTR genotypes begins to rise in adolescence and reaches greater than 80% by age 40. Individuals with PS CFTR genotypes do develop CFRD over time at a rate that is still substantially higher than that of type 2 diabetes mellitus in the general population.
Apart from age and CFTR genotype, several other risk factors have been identified. Genes other than CFTR (genetic modifiers) strongly influence the risk of CFRD, and the 5 such risk variants identified so far are responsible for approximately 4-fold variation in CFRD risk. Two other potent risk factors are a family history of type 2 diabetes mellitus and CF-related liver disease, both varying the risk by approximately 3-fold.
Pathophysiology
CFRD is characterized by reduced or delayed insulin secretion with generally normal sensitivity to insulin action. In the fasted state, insulin and C-peptide levels tend to be normal. Reduced early-phase insulin release, prolonged hyperglycemia, and reactive hypoglycemia are all seen in both CFRD and in type 2 diabetes mellitus.
The strong correlation of CFRD with exocrine PI suggests that preexisting PI contributes to causing CFRD, initially thought primarily by a reduction in endocrine pancreatic mass. In CF with PI, lack of CFTR causes abnormally viscous secretions, plugging of pancreatic ducts, and a chronic pancreatitis-like picture with fatty infiltration and fibrosis of the pancreas. Pancreatic islets are relatively spared in autopsy studies, but the number and mass of islets are reduced in all patients with CF regardless of whether CFRD was present. Therefore, CFRD did not correlate with islet number or mass. CFRD has been reported, however, to correlate with presence in islets of amyloid, a peptide cosecreted with insulin, also deposited in the setting of type 2 diabetes mellitus and which may be detrimental to islet cells. This finding suggests that factors intrinsic to the islet cell or β-cell also contribute to the development of CFRD.
Other studies have demonstrated defects beyond islet cell mass in development of CFRD. Mice with CF do not have pancreatic insufficiency but are more prone to developing diabetes after a mild β-cell injury, suggesting that the β-cells have an intrinsic defect. In humans, the risk of CFRD is increased in people with a family history of type 2 diabetes mellitus or who have susceptibility gene variants for type 2 diabetes mellitus, indicating that some of the same glucose metabolic pathways play a role in both CFRD and in type 2 diabetes mellitus. Insulin production can be both increased and decreased in CF animal models, further supporting qualitative rather than quantitative defects in insulin production. Finally, there are recent reports that CFTR is present in islets and affects insulin secretion, which could help explain the qualitative alterations in insulin secretion in CF.
With the development of CFTR modulator medications, such as ivacaftor and lumacaftor, the extent to which CFRD is reversible has become a clinically relevant question. So far, 3 small studies have reported improvement of insulin secretion and hyperglycemia after treatment with ivacaftor. Anecdotal reports of hypoglycemia in people treated with CFTR modulators suggest the need for caution and perhaps increased blood glucose monitoring after beginning treatment with a CFTR modulator medication.
Diagnosis of Cystic Fibrosis–Related Diabetes
The Cystic Fibrosis Foundation and the American Diabetes Association issued guidelines in 2010, which have been endorsed by the Pediatric Endocrine Society and the International Society for Pediatric and Adolescent Diabetes. CFRD may be diagnosed in individuals with classic symptoms of diabetes (polydipsia and polyuria) with plasma glucose greater than or equal to 200 mg/dL (7.0 mmol/L). In asymptomatic individuals, CFRD is diagnosed by elevated glucose on an oral glucose tolerance test or after sufficiently abnormal random glucose measurements or sufficiently elevated hemoglobin A 1c . Because CFRD has an impact on the course of CF but may be asymptomatic, the Cystic Fibrosis Foundation and the European Cystic Fibrosis Society guidelines recommend annual screening by 2-hour oral glucose tolerance test starting at age 10 years. Alternative screening and diagnosis strategies using different provocation, identifying high-risk or low-risk groups or continuous glucose monitoring are under investigation.
Treatment of Cystic Fibrosis–Related Diabetes
CFRD is a disease of insulin insufficiency, and the only treatment that has been shown to improve outcomes is insulin. A typical insulin regimen used is basal-bolus, consisting of once-daily or twice-daily long-acting insulin injections plus extra short-acting insulin with a meal or snacks. Use of basal-only regimen has been shown effective in some studies, perhaps in early CFRD. Insulin pumps are effective in CFRD and can simplify the intensive insulin regimen resulting in increased adherence. Tube feedings can be covered by premixed insulin of intermediate duration or with appropriate programming of an insulin pump. Use of continuous subcutaneous insulin infusion (ie, insulin pump) is an effective option for insulin delivery, which can be particularly advantageous if a person with CF is requiring multiple boluses for frequent extra meals; in addition, because of the minimal risk of diabetic ketoacidosis to people with CFRD, continuous subcutaneous insulin infusion is associated with lower risk in CFRD compared with type 1 diabetes mellitus. Continuous glucose sensors have been recommended as a tool to help guide insulin therapy.
There are no general restrictions on quantity of dietary carbohydrates in CFRD, in contrast to the general recommendations for type 2 diabetes mellitus. Pure sugar, such as sweet sodas, are not recommended, but otherwise, the same dietary recommendations for people with CF without CFRD (eg, high-calorie, high-fat, and high-protein diet) stand for those with CFRD. It is recommended to avoid large quantities of simple carbohydrate and to spread the daily intake of complex carbohydrate over all meals.
Insulin secretagogues, such as repaglinide, may increase insulin secretion in early CFRD. Studies have failed to demonstrate, however, efficacy of repaglinide in improving body mass index (BMI) or lung function, so this class of oral agents is thought inferior to insulin and recommended only as adjunct to insulin or in cases where insulin cannot be used. Insulin sensitizing agents, such as metformin or thiazolidinediones, are not generally recommended for CFRD, because insulin sensitivity is generally normal, and these medications carry associated side effects and risks as well. Glucagon-like peptide-1 (GLP-1) agonists (eg, sitagliptin) or dipeptidyl peptidase 4 inhibitors, which indirectly increase GLP-1 levels (eg, exenatide), are under investigation in CFRD but are not currently recommended outside of the context of a research study. Acarbose, which prevents absorption of carbohydrate, is not generally recommended for use in CFRD, because carbohydrates plus insulin are necessary for adequate nutrition.
Hypoglycemia
People with CF may experience hypoglycemia even in the absence of CFRD or insulin treatment, occurring either postprandially or otherwise. There are no consistent data relating hypoglycemia to later CFRD or to other CF outcomes. It is recommended that CF practitioners become familiar with symptoms of hypoglycemia and alert people with CF to the possibility of hypoglycemia. Individuals with symptoms that might be due to hypoglycemia may benefit from point-of-care (glucometer) testing at the time of symptoms.
Linear growth abnormalities in cystic fibrosis
Reduced linear growth has been reported in several studies in CF (reviewed by Wong and colleagus ) with a prevalence of short stature (defined by height z score <−2 SDs below the Centers for Disease Control mean) found in approximately 20% of all people with CF in 1993. A clear likely contributor to poor growth is fat and micronutrient malabsorption, which may not always be completely treated using pancreatic enzyme replacement therapy. Other factors include chronic inflammation, chronic infection, and treatment with inhaled and systemic glucocorticoid medications. Inhaled glucocorticoids even at moderate doses (eg, budesonide, 400 μg/d, in 5–13 year olds), when given consistently and daily, can suppress growth. It has been proposed that chronic insufficiency of insulin, which itself is an anabolic hormone, may also contribute to poor linear growth in CF. Growth can seem poorer when parents’ heights are below average or puberty is late to normal or delayed in CF. On the other hand, at birth, average length (with or without adjustment for gestational age) and levels of insulin-like growth factor 1 (IGF-1) levels in CF are reduced in humans and animal models, suggesting that intrauterine growth abnormalities may occur before many of these factors likely play a role.
The extent to which abnormalities in the growth hormone (GH)/IGF-1 axis play a role is unclear. Like insulin, GH and IGF-1 have anabolic effects and could theoretically have beneficial effects in people with CF. Many studies have associated IGF-1 levels with reduced nutrition in CF and reduced lean body mass, with 1 study also finding IGF-1 to predict worse nutrition in 1 year. A possible confounder is that fasting and malnutrition cause both GH resistance and reduced IGF-1 levels (reviewed by Wong and colleagues ). Studies of recombinant human GH (rhGH) in CF have been summarized in 2 recent meta-analyses and a recent review. In meta-analysis, rhGH was found to increase height by approximately 0.2 to 0.6 SDs and to increase lean body mass in people with CF with short stature. Also, GH has been reported to increase bone mineral content, increase forced vital capacity, and reduce hospitalization rate (see Thaker and colleagues and Phung and colleagues ), but outcomes were not consistent across studies, and other key outcomes, such as forced expiratory volume in 1 second and rate of pulmonary exacerbation, were not affected. More research is needed to determine whether treatment with rhGH might have clinical benefit in some people with CF and growth failure, who do not have GH deficiency.
Recommendations
At each clinic visit, height, weight, and BMI percentiles should be calculated using World Health Organization (for age <2 y) and Centers for Disease Control (for age 2–20 y) growth charts. Assessment of growth should be made considering the context of parental heights and of pubertal stage (because delayed puberty can mimic growth failure). Poor linear growth can manifest either as low absolute height or as abnormal height trajectory (eg, low growth velocity causing downward crossing of height percentiles on a growth chart). When growth failure is identified, treatable causes should be considered. CF disease treatments should be optimized. Inhaled and systemic glucocorticoid medications should be reduced to the lowest dose necessary to achieve therapeutic goals. Adherence and effectiveness of pancreatic enzyme replacement therapy should be monitored. Screening for CFRD should be performed. Non–CF-related diagnoses may also be considered, such as thyroid dysfunction, GH deficiency, or celiac or inflammatory bowel disease. Treatment should be directed to the cause identified.
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