Pathophysiology


Pathophysiology of cystic fibrosis: an overview


In the first of two articles, Martin Hug provides an overview of the mechanisms and symptoms of cystic fibrosis, and an insight into some recent advances in its treatment


Martin J Hug PhD Pharmacy, University Medical Center Freiburg, Freiburg, Germany Email: martin.hug@uniklinik-freiburg.de


Cystic fibrosis (CF) is a monogenetic autosomal recessive disease that affects approximately 75,000 people worldwide.1


Patients with CF show


symptoms in the lungs and upper airways but also in the gastrointestinal (GI) tract and reproductive system.2 Fibrotic, scarred tissue and fluid-filled cysts in the exocrine pancreas were the pathological findings that eventually led scientists to name the disease ‘cystic fibrosis of the pancreas’.3


Another


common feature found in all organs affected in CF are highly viscous mucus plugs that impair the function of these systems. The abnormal mucus rheology has prompted some investigators to coin the term ‘mucoviscidosis’.4


Most


patients with CF also lose an increased amount of salt during perspiration, something that bears no immediate danger for the patients but which has, so far, been used as diagnostic test.5


CF is


still a lethal disease but the reports that not only the lifespan but also the quality of life for CF patients has increased dramatically over the past ten years are encouraging. Nowadays, many patients with CF reach adulthood and lead an otherwise seemingly normal life. The development of the median survival time of patients diagnosed with CF against time is shown in Figure 1.


2


It is surprising that this trend cannot be attributed to the introduction of a new drug with groundbreaking effects on


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"Cystic fibrosis is a monogenetic autosomal recessive disease that affects approximately 75,000 people worldwide"


the cause of the disease. Nevertheless, the outcome of CF still remains fatal and imposes a tremendous burden on patients and relatives. But why do mutations in a single protein have such an impact on the physiological functions of the body?


A protein with multiple functions The defect underlying the disease results from mutations in the cystic fibrosis


transmembrane conductance regulator (CFTR) gene. The gene product, CFTR, belongs to the family of the ATP binding cassette (ABC) proteins.6


Similar to other


members of this family, CFTR consists of 12 transmembrane spanning domains that are separated by a nucleotide- binding fold and a regulatory subunit.7


A


second nucleotide-binding fold is located at the C-terminal end.7


The protein is heavily glycosylated and functions as a 40 36.8 32.5 30 29


20 16 10 0.5 0 1940 1950 1960 1970 Year Figure 1: Median survival age of CF patients in the USA. (Modified from Reference 1). 1980 1990 2000 2010 2 10


18


Median survival age (years)


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