Cystic fibrosis (CF) is no longer solely a pediatric disease. CF is the most common potentially lethal genetic disease affecting Caucasians. Its incidence shows regional variations, but overall incidence in Caucasians is approximately 1 per 2,500 live births; it is inherited as an autosomal recessive trait. CF is also the most common cause of chronic lung disease and pancreatic insufficiency in patients under the age of 20.

Over the past decade the fundamental biochemical defect in CF has been identified. The gene has been cloned and up to 300 alleles have been discovered. The gene product is a protein called the cystic fibrosis transmembrane conductance regulator. This regulator, the main chloride transport system, is defective in individuals with CF. The regulator is synthesized within the epithelial cell, then transported to the apical cell membrane of the epithelial duct cells of the proximal pancreatic duct. Its main function is to act as a chloride channel activated through cAMP-mediated phosphorylation, thus allowing secretion of chloride ions into the pancreatic duct or to the outside of the body. In addition to cystic fibrosis transmembrane conductance regulator, these cells contain "Cl^-/HCO₃^- exchangers," which are responsible for bicarbonate secretion and are dependent on luminal chloride, which is supplied by cAMP-activated chloride channels. Thus, in CF, altered chloride secretion results in decreased bicarbonate production and ultimately failure to adequately hydrate and alkalinize the concentrated protein secretions of the acinar cells. This proteinaceous material becomes inspissated, resulting in ductal obstruction and ultimately acinar cell destruction, fibrosis and mal-absorption. The decrease in bicarbonate secretion also results in failure to neutralize duodenal acid, thus leading to further malabsorption by decreasing lipase activity and altering the bioavailability of enteric-coated enzyme supplement.

The "classic" picture of a chronically malnourished child with a progressive lung disease and pancreatic dysfunction culminating in early death is an oversimplification. CF should now be regarded as a syndrome with a heterogeneous assortment of presentations involving variable degrees of organ dysfunction and damage. Pulmonary disease and its complications still dominate the clinical picture in most patients, and are the primary determinants of overall morbidity and mortality. However, as many as 20% of CF patients are not diagnosed until after the age of 15 because they have atypical presentations (e.g., recurrent sinusitis, nasal polyps, chronic bronchitis, recurrent abdominal pain, loose, foul-smelling stools, cirrhosis and infertility).

The advent of vigorous physiotherapy, more effective antibiotics, improved pancreatic extracts and continuing care in specialized CF clinics has resulted in a median survival of at least 18 years. Indeed, in many CF centers, half the patients survive 26 years, and up to 90% of patients may live more than 18 years after the diagnosis has been made. With such increased survival, gastro-intestinal complications are becoming increasingly common.

Abnormalities have been identified in glycoproteins, mucus secretions, circulating proteases and cell transport mechanisms. Liver and biliary tract disease may occur in individuals with CF. The incidence of biliary cirrhosis reaches 14% during the second decade of life in these who have pancreatic insufficiency. In these individuals subclinical hepatic involvement, manifested as biochemical or ultrasound abnormalities of the liver, are common. High losses of sodium and chloride through sweating during periods of heat in the summer months can lead to sodium depletion, dehydration, cardiovascular collapse and death. The abnormally thick mucus produced obstructs ductules and tubules, and results in distal organ damage, which leads to chronic obstructive lung disease, pancreatic insufficiency, hepatic fibrosis and intestinal obstruction. The mucosal and submucosal glands of the small intestine are dilated, with acidophilic concretions. Steatorrhea and enteral protein loss result from exocrine pancreatic failure, low duodenal pH and perhaps also impaired absorption of fatty acids. These patients require supplementation with fat-soluble vitamins A, D, E and K.

Abdominal pain is common in CF patients. It may be related to steatorrhea, constipation, meconium ileus equivalent, intussusception, cholelithiasis, duodenal ulcer or pancreatitis. In contrast to infants and children, adults are less affected by malabsorption, although close questioning may reveal that they experience cramps, flatulence and frequent, greasy, foul-smelling, bulky stools.

There are a number of nonpulmonary complications of CF in adults (Table 8). Most CF patients have height and weight levels that are less than the mean for their age and sex. Although during adulthood nutritional status declines progressively with advancing age, not all patients are malnourished at the time of diagnosis or in early adulthood. In early adulthood, some 10% of patients are above the 90th percentile, while others are even overweight.

There is no correlation between the patient's nutritional status and the severity of the steatorrhea or gastrointestinal symptoms, or age at diagnosis. The height and weight attained seem to correlate only with the severity of the pulmonary disease; those individuals with the least pancreatic insufficiency tend to have better preservation of pulmonary function.

Pancreatic insufficiency markedly overshadows the other complications of CF. In spite of the clinical impression of a voracious appetite, overall energy intake in the CF patient is usually inadequate. Maldigestion and malabsorption, along with the increased energy requirements associated with pulmonary disease, further compound the energy problem.

CF patients also show biochemical evidence of essential fatty acid deficiency. Improvement may be achieved with oral linoleic acid monoglyceride or with total parenteral nutrition. Essential fatty acid deficiency is associated with impaired intracellular oxygenation, decreased membrane fluidity and impaired transport mechanisms. It has not yet been established, however, what benefit will be derived by treating and preventing essential fatty acid deficiency.

In addition to the problems of essential fatty acid and energy deficiency, there is a third major problem in the nutrition of the CF patient: deficiency of fat-soluble vitamins. Even with a standard supplementation of vitamin A 4,000 IU/day, vitamin A levels, retinol binding protein levels and serum carotene may remain low. Approximately 25% of patients have evidence of vitamin D deficiency.

The management of pancreatic insufficiency in adults with cystic fibrosis is similar to the management of pancreatic insufficiency due to other conditions. About half of the adults with CF show some degree of glucose intolerance. Diabetes mellitus is easy to control with insulin; because glucagon levels are decreased, ketoacidosis is extremely uncommon. The presumed pathogenesis of the pancreatic islet cell dysfunction is fibrosis-induced islet cell disarray and strangulation.

Meconium ileus is seen in approximately 10% of neonates with CF and is primarily related to the secretion of abnormal mucinous (glycoprotein) material by the intestinal glands. Children, adolescents and adults have a counterpart, termed meconium ileus equivalent, that is characterized by recurrent episodes of intestinal obstruction. Typically, there is colicky abdominal pain, a palpable, indentable right lower quadrant mass and evidence of mechanical obstruction. Constipation is considered a milder form of this disorder, and must be differentiated from intussusception, which occurs in a small number of CF patients. There is usually a history of precipitating cause, such as immobilization, use of antidiarrheal agents, dietary indiscretions, or reduction or abrupt discontinuation of oral enzyme therapy.

The diagnosis of meconium ileus equivalent is suggested by the presentation. Plain abdominal radiographs may show an empty colon with bubbly granular material proximally, and ileal distention with air fluid levels. It is necessary to confirm the diagnosis by early Gastrografin® enema studies because of the high mortality of this condition and the need to rule out intussusception. Nasogastric suction and correction of electrolyte imbalance result in resolution of the obstruction in 80% of cases. Decompressive surgery may be necessary if medical management fails.

Pancreatitis is relatively uncommon in CF patients, but tends to occur in those patients (some 15%) whose pancreatic function is initially normal. The pathophysiology of the pancreatitis is presumably related to precipitation of abnormal secretions in the tubules, with subsequent damage. Biliary tract disease and alcohol are other possible causes of pancreatitis in these patients.

An increase in the incidence of duodenal ulcer might be expected in CF patients because of the loss of pancreatic bicarbonate buffer, but in fact duodenal ulcer is uncommon.

Patients with untreated pancreatic insufficiency commonly have profound malabsorption of bile acids in the terminal ileum and fecal losses of bile acids. This interrupts the normal enterohepatic circulation of bile acids. The etiology of bile acid wastage is unknown, but it probably relates to the presence of steatorrhea, with bile acid binding to undigested fat, fiber and other intraluminal contents. As a result of the excessive fecal bile acid loss, there is a decrease in the total bile acid pool; the bile becomes saturated with cholesterol. Up to 60% of adolescents and adults with CF have gallbladder abnormalities (e.g., cholelithiasis, nonvisualization, microgallbladder, and marginal filling defects or septation). There is a high incidence of both gallbladder abnormalities and abdominal pain in these patients, but there is not necessarily a cause-effect relationship between the cholelithiasis or gallbladder abnormalities and the clinical symptoms. The hazards of surgery must be weighed against the hazards of nonoperative intervention. The structure and function of the gallbladder may be evaluated by ultrasonography and oral cholecystography.

Treatment of pancreatic insufficiency with oral enzymes will decrease bile acid loss, thus correcting the lithogenic nature of the bile. However, the abnormal glycine:taurine ratio and the preponderance of cholic and chenodeoxycholic acid persist despite enzyme replacement. Ursodeoxycholic acid therapy remains experimental.

With increased age and survival, liver disease is becoming increasingly prevalent in CF patients. The most common hepatic lesion in CF is steatosis, secondary to decreased circulating lipoprotein levels and decreased hepatic triglyceride clearance. Other hepatic lesions seen include nonspecific portal changes, excessive biliary ductal mucus, mild ductal proliferation and focal biliary cirrhosis. A small number of these patients will develop multilobular biliary cirrhosis, the progression remaining clinically silent until portal hypertension supervenes with classical presentation of ascites, hypersplenism or variceal bleeding. Hepatic decompensation and portal-systemic encephalopathy are extremely uncommon because of the relative hepatic parenchymal integrity and the overall focal nature of the pathology. The only clinical clue is the development of a hard, knobby liver, while liver biochemical tests remain relatively normal. The results of therapeutic portacaval anastomoses are encouraging, with no development of portal-systemic enceph-alopathy.

Classical CF in infants and children is easy to diagnose. However, diagnosis of CF is more difficult in adults and in mild or atypical cases. The cornerstone of diagnosis is the quantitative pilocarpine iontophoresis sweat chloride test. This should be performed on two separate occasions, using a sample of 100 mg of sweat or more. Chloride levels that are continually above 60 mEq/L are virtually diagnostic. Such levels are not found with other chronic pulmonary or gastrointestinal tract diseases. Sweat chlorides may, however, occasionally reach 60 mEq/L or more in a variety of other disorders, including untreated adrenal insufficiency, hereditary nephrogenic diabetes insipidus, hypothyroidism and a variety of genetic mucopolysaccharide disorders.

Sweat chloride testing should be performed in infants and children with chronic pulmonary disease, meconium ileus, steatorrhea, rectal prolapse, failure to thrive, heat prostration or pansinusitis, and in siblings of affected individuals. In addition, children, adolescents and young adults should be screened if they have any type of chronic liver disease, long-standing gastrointestinal complaints, childhood or cryptogenic cirrhosis, aspermia or malabsorption.

Pancreatic enzyme replacement is the mainstay of treatment in patients with CF who suffer from pancreatic insufficiency. Enteric-coated enzymes ideally should be used, since they are not inactivated by gastric acids. Ultimately these enzymes could be used in combination with an H₂ blocker. At least 30,000 USP units of lipase should be administered and taken together with food.

Hyperuricosuria may occur in these patients secondary to the large purine content in the enzyme preparation. This complication can be controlled by decreasing the dose of the enzymes.