As previously discussed, cystic fibrosis is a genetic disease caused by improper coding of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This protein (among other things) provides a channel for the chloride ion to pass into and out of the cell, especially accomodating the passage of chloride through epithelial cells. It is mainly the impairment of this action that provides the most basic causes for the major clinical symptoms of cystic fibrosis. In the most problematic clinical symptoms, the failure of chloride to pass through the epithelia lining the inner mucous membranes of the body keeps the mucus at a low osmolality; since chloride does not pass through the epithelia, there is no concentration gradient to help sodium into the lumen, and the resulting lack of an osmolality gradient does not help water into the lumen. The result is a mucus that is much thicker than normal; this thick mucous is the secondary cause of the most serious clinical symptoms.
Typical presentation of CF is quite varied between individuals, and even varies with age. Its major clinical problems are manifested in the respiratory and gastrointestinal systems; we consider each of these separately.
The pathophysiology of the gastrointestinal disorders of CF patients is of two varieties. As mentioned above, both are caused by a thick mucus resulting from the failure of the CFTR protein. In the first case, a thicker mucus lining the intestines causes a more likely intestinal blockage. In approximately 10% of CF patients, this is the first sign of CF, as this blockage (meconium ileus) keeps them from passing their first stool (a tarry, greenish-black stool called the meconium and normally passed within 24-48 hours after birth) within the typical time period. Especially among younger patients, this thicker intestinal mucus may lead to intestinal problems from inflammation to twists in the intestine itself.
Later gastrointestinal problems are mainly of the second variety, caused by thick mucus blocking the ducts of the pancreas into the intestines. This blockage leads to a failure of pancreatic enzymes to enter the digestive tract. These enzymes normally digest fats and proteins; the lack of them therefore leads to chronic malnutrition and failure to thrive, while also causing excess fat to be expelled in the stool, leading to characteristic diarrhea or foul-smelling, bulky, pale, greasy stools that float (steatorrhea). Patients may also experience abdominal pain relating to overactive bowels and excess gas, and often experience other consequences of overactive bowels, such as hemorrhoids, inflammation of the intestines, dehydration, and occasional rectal prolapse. Failure to digest fats also means failure to intake fat-soluble vitamins (A, D, E, and K), and therefore leads to associated vitamin deficiency disorders. Because the pancreas is blocked, about 7% also develop type I diabetes.
Thick mucus or sputum in the lungs leads, as expected, to decreased air intake and shortness of breath, which leads to chronic cyanosis (dark bluish coloring of lips and nail beds). Furthermore, the thicker mucus is not expelled from the lungs as easily as normal mucus, hence a higher level of mucus at any time, forming an ideal breeding ground for microorganisms. The most common infection is by Pseudomonas aeruginosa, causing typical pneumonia and a chronic, phlegm-producing cough. Frequent wheezing is often noted, and permanent lung damage may be seen on x-ray. Lung disease is the most common cause of death of CF patients.
Irritation of the respiratory tract may be seen on clinical exam, most commonly rhinosinusitis, nasal polyps, and coughing up blood.
Diagnosis is most often made on the basis of a sweat chloride concentration test. Chloride is normally present in perspiration, and the CFTR typically reclaims chloride back into the body. Note that this is the opposite of the typical problems of CF above. In CF, of course, the CFTR does not work properly, causing an abnormally high level of chloride (and, due to the electrochemical gradient, sodium) in the sweat. In the sweat test, a small area of skin, usually the forearm, has a chemical and a small electrical stimulation supplied to force sweat for 30-40 minutes onto a piece of gauze or filter paper wrapped in plastic. The result is analyzed for salt concentration; above 60 mmol/L is considered consistent with CF (below 40 is normal). The sweat salt concentration does not change with age or with temporary illnesses such as cold, and is positive in the vast majority of CF patients.
In some symptomatic CF patients with normal sweat tests, and in young infants who do not produce enough sweat to measure, an immunoreactive trypsinogen test can test for pancreatic insufficiency. This test, however, gives a large number of false positives and even a real positive may have causes unrelated to CF.
The only failsafe diagnostic testing is, of course, gene mutation testing.
Some cystic fibrosis patients also suffer from cirrhosis of the liver, due to the blockage of ducts from the liver similar to that of the pancreas, choleocystitis and gallstones from the same effect on the gall bladder, infertility (in men) due to blockage of the vas deferens, and abnormal heart rhythms due to deyhydration and hyponatremia (lack of sodium).