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CFTR is involved in the regulation of transepithelial ion transport and water-electrolyte homeostasis in many organ systems.Current guidelines recommend annual screening for cystic fibrosis-related diabetes with oral glucose-tolerance testing.24 Cystic fibrosis-related liver disease ranges from steatosis associated with increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin levels to focal biliary fibrosis or to severe cholestasis and advanced liver cirrhosis with portal hypertension warranting liver transplantation.Noncirrhotic portal hypertension without synthetic liver dysfunction, which is common in persons with cystic fibrosis, may not warrant liver transplantation.In the sweat glands, normal CFTR activity results in chloride ion absorption from primarily isotonic perspiration; CFTR dysfunction in persons with cystic fibrosis causes impaired chloride absorption in the sweat-gland ducts and consequently elevated sweat chloride concentrations.1,2 The absence or dysfunction of CFTR in airway epithelium leads to decreased chloride and bicarbonate secretion at the apical membrane, the inability of alternative chloride channels such as TMEM16A (also called anoctamin 1 and ANO1) to compensate, and persistent sodium absorption through loss of CFTR-mediated inhibition of the epithelial sodium channel, which causes absorption of airway-surface fluid.9 The consequences of this fluid imbalance in the lungs are thickened secretions and reduced mucociliary transport, resulting in mucus retention and plugging of airways.Chronic lung disease with progressive decline in lung function and ultimately respiratory failure continues to be the major cause of death, but cystic fibrosis is a multiorgan disease In classic cystic fibrosis, thickened secretions cause pancreatic autodigestion and fatty replacement of the organ.

CFTR is involved in the regulation of transepithelial ion transport and water–electrolyte homeostasis in many organ systems. In the sweat glands, normal CFTR activity results in chloride ion absorption from primarily isotonic perspiration; CFTR dysfunction in persons with cystic fibrosis causes impaired chloride absorption in the sweat-gland ducts and consequently elevated sweat chloride concentrations.1,2 The absence or dysfunction of CFTR in airway epithelium leads to decreased chloride and bicarbonate secretion at the apical membrane, the inability of alternative chloride channels such as TMEM16A (also called anoctamin 1 and ANO1) to compensate, and persistent sodium absorption through loss of CFTR-mediated inhibition of the epithelial sodium channel, which causes absorption of airway-surface fluid.9 The consequences of this fluid imbalance in the lungs are thickened secretions and reduced mucociliary transport, resulting in mucus retention and plugging of airways. Mucus plugging alone can cause an inflammatory response in the airways even in the absence of pathogens.10,11 Mucus retention also favors recurrent and persistent bacterial infections with consecutively increased mucus production and inflammation, a cycle leading to the development of structural lung damage (bronchiectasis).1,2
Studies involving pigs with cystic fibrosis have shown the importance of bicarbonate secretion for the release and unfolding of mucins from submucosal glands, with the absence of CFTR resulting in mucus bands stuck to the glandular lumen.12,13 Bicarbonate deficiency also affects bacterial killing, and together with impaired mucociliary clearance it promotes bacterial infection of the lower airways. Chronic lung disease with progressive decline in lung function and ultimately respiratory failure continues to be the major cause of death, but cystic fibrosis is a multiorgan disease
In classic cystic fibrosis, thickened secretions cause pancreatic autodigestion and fatty replacement of the organ. Pancreatic insufficiency affects approximately 80% of persons with cystic fibrosis; can cause abdominal gas and bloating, steatorrhea, and weight loss; and is usually defined by reduced fecal elastase-1 content in stool. In some persons with cystic fibrosis — usually those carrying so-called milder variants (class IV through VI) — pancreatic insufficiency may develop later in life or never. Pancreatic function may not be normal in these persons, and pancreatic-sufficient persons with cystic fibrosis have a higher risk of acute pancreatitis than pancreatic-insufficient persons with cystic fibrosis.23
Cystic fibrosis–related diabetes increases in prevalence with age and affects approximately a quarter of persons with cystic fibrosis who are older than 30 years of age. Current guidelines recommend annual screening for cystic fibrosis–related diabetes with oral glucose-tolerance testing.24
Cystic fibrosis–related liver disease ranges from steatosis associated with increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin levels to focal biliary fibrosis or to severe cholestasis and advanced liver cirrhosis with portal hypertension warranting liver transplantation. Cystic fibrosis–related liver disease tends to be focal in nature, and currently there is no well-established biomarker to predict the development of severe liver involvement. In addition, no preventive treatment strategies have been shown to be efficacious. Noncirrhotic portal hypertension without synthetic liver dysfunction, which is common in persons with cystic fibrosis, may not warrant liver transplantation.