**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 prognosis.
