The wide spectrum of disease manifestations in Cystic Fibrosis

Our insight into cystic fibrosis (CF) and diseases associated with CF gene mutations has changed. Cystic fibrosis now includes a wide spectrum of phenotypes ranging from patients affected by the historical multi-system disease to patients with single-organ manifestations of CF such as chronic sinopulmonary disease and recurrent acute or chronic pancreatitis. This heterogeneity is largely but not completely explained by the large number of CFTR mutations, which are associated with different functional and clinical consequences on different CF-affected organs. The overarching hypothesis is disease manifestation in CF-affected organs begin to develop when a specific threshold of CFTR ion channel function is lost. This threshold varies considerably between organs that are affected by CF disease and may lead to diagnostic challenges. Furthermore, this threshold can be defined by ion channel measurements and correlating the CF-phenotype and CFTR genotype. The thesis is based on studies of symptomatic individuals who present with single organ manifestations of CF and the genotype-phenotype study of acute pancreatitis. This thesis demonstrated the following: (1) The wide spectrum of CF phenotypes has resulted in difficulties in diagnosing CF and discrepancies in diagnostic terminology and criteria, which in turn has resulted in risk of patients receiving different diagnostic outcomes; (2) Diagnostic uncertainty may remain in a subset of patients who present with single-organ manifestations of CF despite comprehensive evaluation by sweat test, nasal potential difference (NPD) and extensive genotyping – with issues of discordance between sweat test and NPD and extensive genotyping providing the lowest diagnostic yield; (3) A combined ion channel measurement based on more than one CF-affected end-organ epithelia, may improve the diagnostic performance for CF by incorporating the variations in organ specific penetrance of ion channel defects; and (4) The risk of pancreatitis in CF is paradoxically higher among patients ...