Cystic fibrosis

Cystic fibrosis (CF) is the most common life-threatening autosomal recessive genetic disease in the Caucasian population, with a worldwide prevalence of 1 in 2500 live births. CF patients are now living well into adulthood and non-pulmonary manifestations of the disease have become prevalent. CF-related diabetes (CFRD) has emerged as the most common comorbidity.


Altered glucose metabolism in CF patients was first described in 1938 when Andersen described several children with evidence of hyperinsulinism. There was no mention of diabetes. It was not until 1955 when Shwachman provided the first description of diabetes associated with CF in three children.[1] CFRD now is the most common complication of CF (50% of CF patients develop diabetes by the age of 30 years) and it is associated with a sixfold increase in morbidity and mortality.[2]

Since the early 1990s the management of CF has come a long way and advances in both nutritional and medical care have resulted in a median age of survival of 30–35 years, compared with a life expectancy of <1 year in the 1950s. As a consequence, the prevalence of complications has increased: cystic fibrosis-related diabetes (CFRD) and glucose intolerance (IGT) have risen dramatically over the past 20 years.[3][4][5]

Clinical features

The median age at CFRD diagnosis is between 18 and 24 years, although it can present at any age. CFRD falls at the end of a spectrum of progressive glucose tolerance abnormalities. Proposed development mechanism of CFRD. It is a multifactorial process.
Proposed development mechanism of CFRD. It is a multifactorial process.
The earliest change is intermittent postprandial hyperglycaemia followed by impaired glucose tolerance, diabetes without fasting hyperglycaemia, and diabetes with fasting hyperglycaemia. Sometimes hyperglycaemia only occurs during periods of stress. Ketoacidosis is uncommon. While CFRD shares features of both type 1 and type 2 diabetes, there are important differences which necessitate a unique approach to diagnosis and management.

In addition to polyuria, polydipsia and weight loss, classic symptoms of type 1 diabetes mellitus, non-specific manifestations such as reduction in the rate of growth, delayed pubertal development and unexplained decline in pulmonary function suggest the diagnosis. Diabetes can occasionally be the first manifestation of CF. The presence of CFRD is associated with worsening lung function, poorer nutritional status and decreased survival compared with CF patients without diabetes. Pulmonary deterioration is correlated with the degree of insulin deficiency at baseline. These patients die from respiratory failure due to chronic lung inflammation and infection.[6]

Diabetic microvascular complications have been described in several case reports, sometimes with significant morbidity such as blindness, glaucoma, hypertension and renal failure. About 27% of patients with CFRD has retinopathy approaching the prevalence level in patients with type 1 diabetes of similar duration of disease. Hypertension and microalbuminuria, but not diabetic nephropathy, are also prevalent.[7] Macrovascular complications have never been reported in CFRD, despite the fact that these patients are living longer.[a]

Diag nosis

CFRD is the most frequent co-morbidity associated with cystic fibrosis. CFRD is often clinically silent, but may also present with the classical symptoms of diabetes mellitus, such as polydipsia, polyuria and weight loss; an early diagnosis is very important to avoid chronic consequences of diabetes and further pulmonary deterioration that actually is associated with insulin deficiency. The oral glucose tolerance test (OGTT) is the screening test of choice for CFRD and it has been introduced as a screening tool since 2008 for children from 10 years old by the International Society for Pediatric and Adolescent Diabetes (ISPAD); the test is repeated annually. CFRD is defined by 2-hour glycaemia≥ 200 mg/dL (PG2) at the OGTT, fasting glycaemia measurements greater than 126 mg/dL, and HbA1c≥ 6.5%. The test should be confirmed by repeat testing except for patients with random glycaemia greater than 200 mg/dL plus polyuria and polydipsia. The OGTT should be performed in the morning during a period of stable baseline health (at least 6 weeks since an acute exacerbation) using the World Health Organization pr otocol. Moreover there are some special situations, which are common in patients with CF, that have began to be considered to determinate CFRD diagnosis: acute illness, pregnancy, healthy outpatients and continuous drip feeding.


Treatment goals of CFRD are to reverse protein catabolism, maintain a healthy weight, and reduce acute and chronic diabetes complications. Insulin, the only medical therapy recommended for CFRD must be accompanied by an high-calorie, high-fat diet to prevent underweight. Insulin therapy regimens should always follow the patient's needs due to the type of CF progression. These regimens go from the utilization of rapid or ultra-rapid-action insulin, to suppress postprandial hyperglycemia, to the use of the basal-bolus regimen in multiple doses, and even to an insulin infusion system for the most insulin-deficient patients. A new surgical treatment has been adopted for patients with advanced pulmonary disease: combined Pancreatic Islet-lung transplantation. The cultured islets are injected via a percutaneous transhepatic approach. Despite several complications (10%) like thrombosis of the portal vein and intra-abdominal hemorrhage, both metabolic and pulmonary functions were satisfactory. Further studies are required to evaluate the long-therm benefits of this kind of intervention.The presence of another diagnosis without obvious symptoms is frequently difficult to accept for CF patients and a multidisciplinary team (pneumologist, physical therapist, nutritionist, endocrinologist,) is essential to promote the understanding of, and the adherence to the treatment and control of CFRD.


Cystic fibrosis related diabetes is present in 2% of children, 19% of adolescents, and 40-50% of adults. Incidence estimated at 2.7 cases per 100 patient-years. There are no sex differences neither in clinical manifestations, nor in mortality rate, but incidence and prevalence are higher in female subjects aged 30-39 years. The OGTT tests demonstrate that fasting hyperglycemia prevalence rises with age. A study called “Genetic Modifiers Play a Substantial Role in Diabetes Complicating Cystic Fibrosis” conducted in 2008 by the Division of Pediatric Endocrinology and McKusick-Nathans Institute of Genetic Medicine, of the Johns Hopkins University School of Medicine of Baltimore, identified key independent risk factors :

  • having a twin or sibling with CF and diabetes,
  • increased age,
  • female sex,
  • pancreatic exocrine insufficiency or two mutations causing severe CFTR dysfunction,homozygosity for the delta F508 mutation
  • decreased lung function or decreased body mass index,
  • presence of Pseudomonas aeruginosa or Bacteroides cepacia complex in the sputum
  • allergic bronchopulmonary aspergillosus
  • impaired nutritional status
  • liver disease
  • longer duration of glucocorticoid treatment.

The concordance rate for diabetes was substantially higher in monozygous twins (0.73) than in dizygous twins and siblings with CF (0.18; P = 0.002). Heritability was estimated as near one (95% confidence interval 0.42–1.0).

When we compare lung function and nutritional status in CFRD patients to those in CF patients without diabetes we can observe that only lung function is still worse in the first group. No evident differences are present in nutritional status and pulmonary status between patients without fasting hyperglycemia and those with fasting hyperglycemia.


The principal mechanisms involved in the pathogenesis of cystic fibrosis related diabetes are:

  • Insulin insufficiency
  • Insulin resistance
  • Genetic predisposition to diabetes

Insulin insufficiency

As we know, cystic fibrosis is caused by mutation of the CF transmembrane conductance regulator (CFTR) gene, coding for a chloride channel that also influences sodium and water transport. The CFTR defect results in viscous secretions causing inflammation, obstruction, and destruction of small ducts in the lungs, pancreas, liver, and reproductive organs. Damage to the pancreas is characterized by a reduced β-cell mass leading to insulin insufficiency. The β-cell destruction is not complete and residual endogenous insulin secretion is present, making that these patients are not prone to ketosis. The α-cell mass is also reduced, making that CF patients are not able to appropriately increase glucagon secretion in response to arginine or hypoglycemia. The lack of ketosis in these patients may be related to low glucagon levels. Glucose excursion (?) is better in response to a mixed meal compared with oral glucose because incretin levels (gastric inhibitory peptide and glucagon-like peptide 1) are normal in CF.

Insulin resistance.

While in nondiabetic CF patients euglycemic clamp studies generally demonstrate normal peripheral muscle insulin sensitivity, insulin resistance has been described related to greater severity of illness and inflammation. Modest peripheral insulin resistance occurs once diabetes develops. It has been hypothesized that, may be for the increased energy needs of CF patients, there is a physiologic balance between elevated hepatic glucose production and high glucose demand, so there is liver insulin resistance with elevated hepatic glucose production (both in the fasting state and in response to insulin infusion) not only in CF patients with diabetes, but also in those with completely normal fasting glucose levels.

Genetic predisposition to diabetes.

Currently the link between CFTR gene mutations and cystic fibrosis, and between HLA DR3/4 and diabetes is well known. The objective of new research is to demonstrate a genetic association between type 2 diabetes and CFRD. A finding of islet amyloid deposition in individuals with CFRD, characteristic for type 2 diabetes but rare in type 1 diabetes or in patients with chronic pancreatitis, suggests that CFRD may also be associated with type 2 diabetes. Variation in transcription factor 7-like 2 (TCF7L2) (a type 2 diabetes susceptibility gene) was shown to be associated with diabetes in CF and decreased the mean age of diabetes diagnosis by 7 years. An association was also found between CFRD and a genetic polymorphism in calpain-10, which has been reported in type 2 diabetes . Calpain-10 is involved in insulin secretion and inflammation, both of which may be relevant in CFRD.


  1. ^ Bernard Yung, et al. Diabetes in cystic fibrosis, J R Soc Med 1999;92(Suppl.37):35-40

  2. ^ Stephen M.P. O'Riordan, et al. Cystic Fibrosis-Related Diabetes in Childhood.Horm Res Paediatr 2010;15-24. Mini Review.

  3. ^ O'Riordan SMP, Robinson PD, Donaghue KC, Moran A. Management of Cystic Fibrosis-related diabetes. Pediatric Diabetes 9 (Part I) 338-334

  4. ^ L. Kessler, M.Greget, A.C. Metivier, F Moreau, M.Armanet, N. Santelmo, G. Massard, T.berney, and R. Kessler

  5. ^ Renata Maria de NoronhaI; Luís Eduardo Procópio CalliariII; Neiva DamacenoIII; Lucia Harumi MuramatuIII; Osmar MonteIV

  6. ^ Moran A,et al. Epidemiology, pathophysiology, and prognostic implications of cystic fibrosis-related a technical review. Diabetes Care 2010 Dec;33(12):2677-83. Review.

  7. ^ Henrik U. Andersen, et al. Cystic Fibrosis-Related Diabetes, the presence of microvascular diabetes complications. Diabetes Care 2006, 2660-2663.


  1. ^ This webpage was created by Nicoletta D'Alessandris, Ruben Manuel Luciano Colunga Biancatelli, and Alessia Cardarola, medical studients at La Sapienza Hospital, Rome.


Nobody has commented on this article

Commenting is only available for registered Diapedia users. Please log in or register first.