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Pathophysiology


worldwide but as yet, a general consensus has not been reached. What is clear is that exact knowledge of the composition of the airway surface liquid will have an enormous impact on future therapeutic regimens.


A less complicated situation is seen in the case of the secretory epithelia. The secretory serous cells of the submucosal glands and the goblet cells do not express eNaC and are believed to be the predominant site of CFTR expression in the airways. Other Cl–


channels than


CFTR might contribute to the overall transport capacity but their molecular identity and importance in the airways is still a matter of debate.24 Secretory epithelia, such as the submucosal glands, secrete mucins, protease inhibitors, antibiotic peptides and enzymes that must be flushed from the glands onto the airway surface epithelium. Recent data obtained from small airway specimens of CF patients have demonstrated no apparent difference in the electrolyte content of the gland secretions but an increased viscosity of the mucus compared control samples.25


At this stage, it is hard to


reconcile these findings with a mere lack of CFTR expression in these glands.


Lung disease


It is generally accepted that defective CFTR leads to an imbalance between fluid absorption and secretion in the lungs of CF patients, resulting in a relatively


Because of the significant implications in making a diagnosis of CF, functional testing and genotype assessment are usually recommended. However, once the diagnosis CF is confirmed the therapeutic regimen might not necessarily need to be changed completely.


The progression of CF lung disease is in many ways similar to that of other chronic airway diseases such as COPD, emphysema and bronchiectasis.2


In


striking contrast, however, is that a variety of bacteria, such as Pseudomonas aeruginosa, Stenotropomonas maltophilia and Burgholderia cepacea, chronically colonise the airways of CF patients. The low susceptibility of these bacteria to antibiotics complicate the treatment and makes eradication challenging. During the recurrent inflammatory episodes that highlight the fight of the body against bacteria, lung tissue is lost and scarred. Clinical parameters such as vital capacity, FEV1 and O2


saturation decline as the disease


takes its course. While the lung function deteriorates, CF patients often develop pulmonary hypertension resulting from loss of lung tissue and the hypoxic constriction of pulmonary blood vessels. Compensatory mechanisms lead to hypertrophy of the right ventricle, generally referred to as Cor pulmonale. During end-stage CF, patients are dependent on supplementary oxygen and mechanical ventilation before they eventually die from respiratory failure or


"Approximately 70–90% of CF patients are born with pancreatic insufficiency, which means that >98% of capacity is already lost in the newborn"


4


dehydrated mucus layer on the airways. The depletion of liquid and the increased viscosity of the mucus impair the function of the cilia and thereby restrict mucociliary clearance. Small particles, bacteria and fungi remain stuck in the airways, which house perfect conditions for growth. The onset of clear symptoms of an impaired lung function remains highly variable. Carriers of CFTR mutations are often referred to clinical centres for the first time when lung problems occur. Persistent coughing, obstruction of the upper airways and recurrent lower respiratory tract infections are often mistaken for symptoms of a general bronchitis, and are therefore treated in a similar fashion.


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cardiopulmonary complications. The only hope for end-stage patients is to receive a lung transplant, which cures the lung disease to an extent but which is also associated with additional problems, such as lifelong immunosuppression and possible graft rejection. The decision to put a patient on the waiting list for a lung transplant should be made before the progression of the disease renders the patient too weak to tolerate the consequences of this intervention.


CFTR in the intestinal tract The GI tract has an astonishing capacity for fluid transport. CFTR is present in almost all epithelia lining the GI tract, from the salivary glands to the distal


colon; therefore, severe consequences of the CFTR mutations for the entire GI tract would be expected. However, the organ most affected in CF is the pancreas. Approximately 70–90% of all CF patients are born with pancreatic insufficiency, which means that more than 98% of the pancreatic capacity is already lost in the newborn. Even in seemingly pancreatic-sufficient patients, the ratio between alkaline fluid and secreted digestive enzymes is decreased significantly. Fluid secretion in the exocrine pancreas is very similar to the mechanisms outlined for the submucosal glands of the airways. Under


physiological conditions pancreatic ducts secrete a HCO3


– - and electrolyte-rich


fluid that serves to flush the digestive enzymes from the acini into the lumen of the small intestine. A lack of fluid secretion leads to an accumulation of lipo- and proteolytic enzymes in the pancreatic ducts, which eventually damage the pancreatic tissue. The tissue damage occurs in utero in pancreatic- insufficient patients; however, in some cases, the process may develop over a period of many years. Pancreatic insufficiency leads to maldigestion and severe steatorrhoea with concominant loss of lipid soluble vitamins and essential fatty acids. The resulting malnutrition renders CF patients more susceptible to infections, and thereby aggravates the lung disease. In contrast to the lung, the symptoms in the GI tract can often be observed shortly after birth. Babies suffering from CF often have bulky, greasy stools that can be initially mistaken for symptoms of coeliac disease. The resulting failure to thrive is often reason enough for the first hospitalisation. Sometimes stool sticks in the gut, causing a so-called meconium ileus that might require surgical intervention. It is not clear whether this symptom is a result of maldigestion in the small intestine or is caused by hyperabsorption in the distal parts of the gut. As more and more patients reach adulthood, clinicians also observe hepatobiliary problems that result from obstructions in the bile duct, presumably as a result of the higher viscosity of the bile in CF. The subsequent destruction of liver tissue sometimes leads to jaundice, and even liver failure, that can only be overcome by transplanting a new organ. Most of the recent drug developments are aimed to cure CF of the lung. One should not forget that a rational drug


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