**6. Cystic fibrosis-related diabetes is associated with poor prognosis**

Cystic fibrosis-related diabetes (CFRD) is a common comorbidity with an estimated prevalence of 20% in adolescents and 40%–50% in adults [31]. As with other disease-related comorbidities, incidence of CFRD continues to increase as life expectancy improves. It encompasses a spectrum of disease from impaired glucose tolerance to CFRD with fasting hyperglycaemia. Impaired chloride channel function leads to thick pancreatic secretions that cause obstructive damage to the exocrine pancreas and subsequent architectural disturbance in islet cells with loss of endocrine function. Insulin deficiency is compounded by insulin resistance that occurs during pulmonary exacerbations as a consequence of increased levels of growth hormone, cortisol, catecholamines, and inflammatory cytokines [32]. Not all patients with CF go on to develop CFRD, and it has been demonstrated that multiple extrinsic factors contribute to disease pathogenesis such as malabsorption, immunosuppressant therapy following lung transplantation, use of glucocorticosteroids, and the presence of liver disease.

Though the relationship between gender and adverse outcomes has been described in a multitude of studies over a vast period of time, a full explanation of this dichotomy remains elusive. Much current research now centres on the role of estrogen in female CF patients. The primary female sex hormone is 17β-estradiol (E2) and circulates in the body bound to sex hormone binding globulin, interacting with target tissues through a range of estrogen receptors (ERs) expressed on the cell surface. E2 levels naturally vary over the course of the normal menstrual cycle and E2 further dehydrates the already compromised airway surface liquid seen in CF and peak levels of E2 lead to an increased risk of infection and subsequent exacerbation [25]. Furthermore, high levels of E2 have been shown to promote TLR hypores‐ ponsiveness to a range of bacteria driven by an inhibition of interleukin-8 (IL-8) release [26]. In a study targeted to investigate the effects of E2 on *Pseudomonas Aeruginosa* (PA). it was found that high levels of E2 promotes mucoid conversion, alginate synthesis, and genetic mutations in mucins lending increased infectivity and virulence to PA in those exposed to E2 [15]. An interesting addendum to this study was the observation that the individuals studied had lower rates of exacerbation and required a lower number of antibiotic courses if they were using the combined oral contraceptive pill [15]. As exacerbation rate is commonly quoted as a predictor for mortality, there is scope here to assess the role of targeted estrogen therapies on mortality

**5. Relationship between exocrine disease and prognosis in cystic fibrosis**

Pancreatic insufficiency is an extremely common complication of CF and affects over 85% of patients at some point during the course of their disease [27]. Loss of pancreatic exocrine function leads to malabsorption of fat, protein, and micronutrients, which in turn causes failure to thrive, steatorrhoea symptoms, and fat-soluble vitamin deficiencies. This arises as a consequence of obstruction of proximal intralobular ducts in the pancreas due to inspissated mucus plugs and tends to arise early in the disease. Chronic pancreatitis is another less common manifestation generally associated with milder (IV-VI) CF genotypes [28, 29], as residual pancreatic acinar tissue is a prerequisite for pancreatitis to develop. Pancreatitis affects over 10% of CF patients and tends to occur in a chronic relapsing and remitting fashion. It is thought to be due to a combination of obstructive tubulopathy and acidification of the acinar lumen due to reduced ductal bicarbonate secretion. Those with symptomatic pancreatitis can often become pancreatic insufficient as their disease progresses. A recent review of the European Cystic Fibrosis registry demonstrated that pancreatic insufficiency was associated with a statistically significant decreases in FEV1%, with pancreatic insufficient patients twice as likely as sufficient patients to experience severe lung disease, defined as FEV < 40% predicted [30]. This indicates that lack of pancreatic exocrine function is associated with worsening

**6. Cystic fibrosis-related diabetes is associated with poor prognosis**

Cystic fibrosis-related diabetes (CFRD) is a common comorbidity with an estimated prevalence of 20% in adolescents and 40%–50% in adults [31]. As with other disease-related comorbidities,

and the gender dichotomy in CF.

8 Cystic Fibrosis in the Light of New Research

prognosis.

CFRD has a significant impact upon clinical parameters of disease and thus impacts upon prognosis. Insulin deficiency and hyperglycaemia negatively affects pulmonary function with the rate of decline in FEV1% over a 4 year period found to be related to the severity of insulin deficiency [33]. Moreover, insulin replacement therapy can improve both nutritional status and pulmonary function in patients with CFRD [34]. Hyperglycaemia also impacts clinically, with moderately elevated blood glucose levels leading to increased airway glucose concen‐ trations, which in turn promotes the growth of various respiratory pathogens and can increase exacerbation rate [35]. CFRD also impacts, predictably, on nutritional status with both insulin deficiency and hyperglycaemia exerting effects. The classical complications of diabetes mellitus also contribute to morbidity in patients with CFRD. Macrovascular complications have not been documented, despite the increasing life expectancy of these patients. However, microvascular complications are common and include mild neuropathy as the most common manifestation with prevalence rates similar to those for non-CF diabetics [36]. Furthermore in one study, retinopathy occurred in 16% of CFRD patients and microalbuminaemia in 14% in a cohort of patients who had diabetes for more than 10 years [36].

In terms of direct mortality, CFRD has been shown to have a negative prognostic effect, with increased mortality seen in association with poorer nutritional status and greater severity of lung disease [37, 38]. In addition, CFRD mortality has been shown to be increased in female cohorts when compared to males [39]. However, over time there have been sustained im‐ provements in CFRD-associated mortality with both female and male mortality decreasing in the period between 1992 and 2003 [31], this effect is presumably a reflection of increased awareness of the importance of CFRD and improvements in diagnosis and treatment strat‐ egies. CFRD is a common and complex co-morbidity in CF which negatively impacts on clinical outcomes and mortality. There is evidence to show that early treatment of CFRD can promote improved nutritional status, pulmonary function, and ultimately improve outcome.
