PMC

 Nasal potential difference measurement in (A) a healthy person and (B) a person with classic CF. In a healthy person the basal PD is negative (−20 to −30 mV), rises moderately (towards zero) after application of amiloride, and decreases after application of chloride free solution and isoproterenol. In a patient with typical CF the baseline PD is more negative and the rise after application of amiloride is greater. There is no change in PD after application of chloride free solution and isoproterenol.

 Intestinal current measurement in (A) a healthy person and (B) in a patient with classic CF. The responses to carbachol and histamine consist of two components: a lumen positive current that is most likely caused by the apical potassium efflux and a lumen negative current caused by apical chloride secretion. In ICM measurements of non‐CF individuals the apical potassium efflux component in reaction to carbachol and histamine is masked by the much larger chloride efflux. In CF the response is reversed due to the apical potassium efflux in the absence of a chloride efflux.

 Algorithm for the diagnosis of CF starting with the sweat test. When entering the algorithm it is advised to continue the diagnostic work up if symptoms in a patient persist, as well as when symptoms have resolved but are highly suspicious for CF such as pancreatitis or Pseudomonas aeruginosa lung disease. Wherever the algorithm ends with “CF unlikely” it is advised to investigate for alternative diagnoses such as primary ciliary dyskinesia, humoral immunodeficiency, Shwachman syndrome. For patients with CFTR dysfunction, the physician needs to decide the most appropriate diagnostic label (non‐classic CF or an item from the WHO diagnostic list shown in table 1 in patients with very limited symptoms). Patients with a borderline sweat test (30–60 mmol/l), only one CFTR mutation identified, and an inconclusive nasal potential difference (PD) cannot at present be classified correctly. They are at least CF carriers. In the presence of persistent symptoms they need structured follow up at an appropriate facility (for some patients this may be the CF centre) and symptomatic treatment. Genetic counselling is important in these patients and their families. CFTR DNA test: screening test to search for the most frequent mutations in the population from which the patient originates. Mutation scanning of CFTR gene: this test is only necessary in some patients in whom the diagnosis cannot be supported by other means. The tests in the grey area are optional because two clearly positive sweat tests are sufficient to support the diagnosis of CF in a compatible clinical setting. However, in most CF centres the CFTR DNA test will be performed to confirm the diagnosis, to allow for further cascade screening if necessary, and at times for research purposes. Consult genetic lab: in patients with an elevated sweat chloride level it would be unusual but not impossible not to find any mutation. In case of doubt about the diagnosis, a mutation scanning of the complete gene can be done. A falsely positive sweat test and the possibility of CF heterogeneity also need to be considered.

 Algorithm for the diagnosis of CF starting with the CFTR DNA test. When entering the algorithm it is advised to continue the diagnostic work up if symptoms in a patient persist as well as when symptoms have resolved but are highly suspicious for CF such as pancreatitis or Pseudomonas aeruginosa lung disease. Wherever the algorithm ends with “CF unlikely” it is advised to investigate for alternative diagnoses such as primary ciliary dyskinesia, humoral immunodeficiency, Shwachman syndrome. For patients with CFTR dysfunction, the physician needs to decide the most appropriate diagnostic label (non‐classic CF or an item from the WHO diagnostic list shown in table 1 in patients with very limited symptoms). Patients with a borderline sweat test, only one CFTR mutation identified, and an inconclusive nasal potential difference (PD) can not at present be classified correctly. They are at least CF carriers. In the presence of persistent symptoms they need structured follow up at an appropriate facility (for some patients this may be the CF centre) and symptomatic treatment. Genetic counselling is important in these patients and their families. CFTR DNA test: screening test to search for the most frequent mutations in the population from which the patient originates. Mutation scanning of CFTR gene: this test is only necessary in some patients in whom the diagnosis cannot be supported by other means. The tests in the grey area are optional because detection of two disease causing mutations is sufficient to support the diagnosis of CF in a compatible clinical setting. However, in many CF centres a sweat test will also be performed to further confirm this lifelong diagnosis. Consult genetic lab: in patients with two mutations detected it would be unusual to have a sweat chloride value below 60 mmol/l unless one or both mutations are classified as mild. One should not, however, forget the possibility of mislabelling a sample or errors in sweat test or DNA test; in patients with an elevated sweat chloride level it would be unusual but not impossible not to find any mutation. In case of doubt about the diagnosis, a mutation scanning of the complete gene can be done. A falsely positive sweat test and the possibility of CF heterogeneity also need to be considered.