Anatomic Pathology

The pathophysiology of CF leads to clinical, gross, and his-tologic changes in organs and organ systems expressing abnormal CFTR, including respiratory, pancreas, hepatobiliary, gastrointestinal, and reproductive (14). With the current age of individuals affected with CF ranging from 0 to 74 yr, and the predicted survival age for a newly diagnosed child as 33.4 yr, pulmonary and extrapulmonary disorders (gastrointestinal, hepatobiliary, vascular, and musculoskeletal) will become increasingly manifest (15). The degree of disease correlates with the degree of CFTR function.

Microsatellite Instability Pancreatic

Nitrocellulose strip Fig. 2. Schematic representation of a reverse line probe assay.

5.1. RESPIRATORY SYSTEM Lung infection remains the leading cause of morbidity and mortality in CF patients (16). It is currently recognized that CF lung disease is the consequence of recurrent chronic pulmonary infection by the well-known opportunistic pathogens Pseudomonas aeruginosa (mucoid and nonmucoid), Burkholderia cepacia, Staphylococcus aureus, and Haemophilus influenza (17). Recurrent infection and the inflammatory response result in progressive irreversible lung damage, of which bronchiectasis is the landmark change. Bronchial mucous plugging as a result of tenacious mucus facilitates colonization by micro-organisms (18). Often, subpleural bronchiectatic cavities develop and communicate with the subpleural space with resultant spontaneous secondary pneumothorax, the incidence of which increases later in life (15).

5.2. PANCREAS Exocrine pancreas insufficiency is present in the majority of patients with CF. This clinically manifests by failure to thrive and fatty bulky stools because of deficiency of pancreatic enzymes. The pancreatic lesions, however, vary greatly in severity and might be absent in some patients who die in infancy (19). Early in the postnatal development of the pancreas, patients with CF have a deficiency of normal acinar development. Increased secretion of tenaceous and viscous mucus within the ducts and increased duct volume contribute to progressive degradation and atrophy of pancreatic acini. These factors result in duct obstruction and progressive pancreatic pathologic changes (20,21). Exocrine pancreatic disease appears to develop as a result of ductal mucus accumulation resulting from decreased anion secretion. Coupled to normal protein load derived from acinar cell secretion, this leads to pancreatic protein hyperconcentration within the pancreatic ducts. The protein hyperconcentration increases susceptibility to precipitation and duct luminal obstruction (22-24). Hence, the characteristic lesion is cystic ductal dilation, atrophy of pancreatic acini, and severe parenchymal fibrosis.

5.3. HEPATOBILIARY SYSTEM The manifestation of CF in the hepatobiliary system is directly related to CFTR expression. This results in the only inherited liver disease resulting form impaired secretory function of the biliary epithelium (25). Males are more likely to be affected than females and the risk for developing liver disease is beween 4% and 17% as assessed by yearly exams and biochemical testing (26,27). Although a variety of liver manifestations exist (28,29), including fatty infiltration (steatosis), common bile duct stenosis, sclerosing cholangitis (25,30), and gallbladder disease (31-33), the rare but characteristic liver lesion in CF is focal biliary cirrhosis (34). The latter develops in a minority of patients, usually older children and adults, and results from abnormal bile composition, reduced flow, and intrahepatic bile duct obstruction (35).

5.4. GASTROINTESTINAL SYSTEM The gastrointestinal manifestations of cystic fibrosis, seen mainly in the neonatal period, include meconium ileus, distal intestinal obstruction syndrome (DIOS), fibrosing colonopathy, strictures, gastroe-sophageal reflux, rectal prolapse, and constipation in later childhood (26,36-40). Throughout the intestines, CFTR is the determinant of chloride concentration and secondary water loss into the intestinal lumen. Decreased water content results in viscous intestinal contents, with a 10-15% risk of meconium ileus in babies born with cystic fibrosis and accounting for DIOS and constipation in older children (41). DIOS (formerly meconium ileus equivalent) is a recurrent partial or complete obstruction of the intestine in patients with CF and pancreatic insufficiency (40).

5.5. BONES AND JOINTS Arthritis is a rare but recognized complication of cystic fibrosis that generally occurs in

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