Section 4. Lung and Airway Disorders

Chapter 53. Cystic Fibrosis

Topic: Cystic Fibrosis

Cystic Fibrosis

Cystic fibrosis is a hereditary disease that causes certain glands to produce abnormal secretions, resulting in tissue and organ damage, especially in the lungs and the digestive tract.

Cystic fibrosis is the most common inherited disease leading to a shortened life span among white people in the United States. It occurs in about 1 of 3,300 white infants and in 1 of 15,300 black infants. It is rare in Asians. Cystic fibrosis is equally common in boys and girls.

See the figure Cystic Fibrosis: Not Just a Lung Disease.

Cystic fibrosis results when a person inherits two defective copies (mutations) of a particular gene. This gene controls the production of a protein that regulates the transport of chloride and sodium (salt) across cell membranes. Worldwide, about 3 of 100 white people carry one defective copy of the gene; thus, they are carriers but they themselves do not get sick. About 3 of 10,000 white people inherit two defective copies of the gene; thus, they develop cystic fibrosis. In these people, chloride and sodium transport is disrupted and dehydration and increased stickiness of secretions occur.

Cystic fibrosis affects many organs throughout the body and nearly all the glands that secrete fluids into a duct (exocrine glands). The secretions are abnormal in different ways, and they affect gland function differently. In some glands, such as the pancreas, the secretions are thick or solid and may block the gland completely. Eventually, the pancreas can become scarred. The mucus-producing glands in the airways of the lungs produce abnormal secretions that clog the airways and allow bacteria to multiply. The sweat glands and small salivary glands in the cheek (parotid glands) secrete fluids containing more salt than normal.

Symptoms

The lungs are normal at birth, but breathing problems can develop at any time afterward. Thick secretions eventually block the small airways, which leads to inflammation and thickening of their walls. As larger airways fill with secretions, areas of the lung collapse and contract (a condition called atelectasis (see Section 4, Chapter 48)), and the lymph nodes enlarge. All these changes make breathing increasingly difficult and reduce the lungs' ability to transfer oxygen to the blood. Respiratory tract infections occur because of bacterial growth in the bronchial secretions and walls of the airways.

The blockage of pancreatic ducts and intestinal glands leads to digestive problems, including poor absorption of fats, proteins, and vitamins. This, in turn, can lead to nutritional deficiencies, and slower than expected growth. Some people may have episodes of intestinal obstruction when abnormal stool contents block the bowel.

About 15 to 20% of newborns who have cystic fibrosis have meconium ileus, a serious obstruction of the small intestine (see Section 23, Chapter 265). Meconium ileus is sometimes complicated by a twisting of the intestine on itself (volvulus) or incomplete development of the intestine. Newborns who have meconium ileus almost always develop other symptoms of cystic fibrosis later. Meconium can also temporarily obstruct the large intestine in some newborns with cystic fibrosis, so that a bowel movement may not occur in these newborns until 1 to 2 days after birth.

The first symptom of cystic fibrosis in an infant who does not have meconium ileus is often a delay in regaining birth weight or poor weight gain at 4 to 6 weeks of age. Inadequate amounts of pancreatic enzymes, which are essential for proper digestion of fats and proteins, lead to poor digestion in most infants with cystic fibrosis. The infant has frequent, bulky, foul-smelling, oily stools and may have a distended abdomen and small muscles. Weight gain is slow despite a normal or large appetite.

About half the children with cystic fibrosis are first taken to the doctor because of frequent coughing, wheezing, and respiratory tract infections. Coughing, the most noticeable symptom, is often accompanied by gagging, vomiting, and disturbed sleep. As the disease progresses, the chest becomes barrel-shaped, and insufficient oxygen may make the fingers clubbed (see Section 4, Chapter 39) and the nail beds bluish. Polyps may form in the nose. The sinuses may fill with thick secretions, leading to chronic or recurrent sinus infections.

When a child or adult with cystic fibrosis sweats excessively in hot weather or because of a fever, dehydration may result because of the increased loss of salt and water. A parent may notice the formation of salt crystals or even a salty taste on the child's skin.

Adolescents often have slowed growth, delayed puberty, and declining physical endurance. As the disease progresses, lung infection becomes a major problem. Recurrent bronchitis and pneumonia gradually destroy the lungs.

Complications

Inadequate absorption of the fat-soluble vitamins--A, D, E, and K--may lead to night blindness, rickets, anemia, and bleeding disorders. In about 20% of untreated infants and toddlers, the lining of the rectum protrudes through the anus, a condition called rectal prolapse. Infants with cystic fibrosis who have been fed soy protein formula or breast milk may develop anemia and swelling of the extremities, because they are not absorbing enough protein.

Complications in adolescents and adults with cystic fibrosis include a rupture of the small air sacs of the lung (alveoli) into the pleural space (the space between the lung and chest wall). This rupture can allow air to enter into this space (pneumothorax), which collapses the lung (see Section 4, Chapter 52). Other complications include heart failure and massive or recurrent bleeding in the lungs.

About 15% of adults with cystic fibrosis develop insulin-dependent diabetes because the scarred pancreas can no longer produce enough insulin. The blockage of bile ducts by thick secretions can lead to inflammation of the liver and eventually to scarring of the liver (cirrhosis) in about 5% of adults with cystic fibrosis (see Section 10, Chapter 136). Cirrhosis may increase the pressure in the veins entering the liver (portal hypertension (see Section 10, Chapter 135)), leading to enlarged, fragile veins at the lower end of the esophagus (esophageal varices), which can rupture and bleed profusely. In almost all people with cystic fibrosis, the gallbladder is small and filled with thick bile and does not function well. About 10% of people develop gallstones, but only a small percentage develop symptoms. Surgical removal of the gallbladder is rarely needed.

People with cystic fibrosis often have impaired reproductive function. Almost all men have a low sperm count (which makes them sterile) because one of the ducts of the testis (the vas deferens) has developed abnormally and blocks the passage of sperm. In women, cervical secretions are too thick, causing decreased fertility. Otherwise, sexual function is not affected. Women with cystic fibrosis have a higher likelihood of complications during pregnancy (such as developing a lung infection or diabetes), but many women with cystic fibrosis have given birth.

Other complications may include arthritis, kidney stones, and inflammation of the blood vessels (vasculitis).

Diagnosis

The diagnosis of cystic fibrosis is usually confirmed in infancy or early childhood, but cystic fibrosis goes undetected until adolescence or early adulthood in about 10% of people with the disease.

The diagnosis is suggested by one or more of the typical symptoms and is confirmed by a sweat test. This test measures the amount of salt in sweat. The drug pilocarpine is placed on the skin to stimulate sweating, and filter paper or thin tubing is placed against the skin to collect the sweat. The concentration of salt in the sweat is then measured. A salt concentration higher than normal confirms the diagnosis in people who have symptoms of cystic fibrosis or who have a sibling with cystic fibrosis. Although the results of this test are valid any time after a newborn is 48 hours old, collecting a large enough sweat sample from a newborn younger than 3 or 4 weeks old may be difficult. The sweat test, which can be performed on an outpatient basis, can also confirm the diagnosis in older children and young adults.

In newborns with cystic fibrosis, the level of the digestive enzyme, trypsin, in the blood is high. This enzyme level can be measured in a small drop of blood collected on a piece of filter paper. Measurement of this enzyme in addition to sweat testing and genetic testing is the basis of cystic fibrosis newborn screening programs performed in many parts of the world. However, this test is not yet routinely performed in the United States.

The diagnosis of cystic fibrosis can also be confirmed by genetic testing in a person who exhibits one or more typical symptoms or has a history of cystic fibrosis in a sibling. Finding two abnormal cystic fibrosis genes (mutations) confirms the diagnosis. However, because genetic testing can confirm only a small percentage of the more than 1000 different kinds of cystic fibrosis mutations, failure to detect two mutations does not exclude a diagnosis of cystic fibrosis. The disease can be diagnosed prenatally by performing genetic testing on the fetus using chorionic villus sampling or amniocentesis (see Section 22, Chapter 256).

Because cystic fibrosis can affect several organs, other tests may be helpful. If pancreatic enzyme levels are reduced, an analysis of the person's stool may reveal low or undetectable levels of the digestive enzymes trypsin and chymotrypsin (both secreted by the pancreas) or high levels of fat. If insulin secretion is reduced, blood sugar levels are high. Pulmonary function tests (see Section 4, Chapter 39) may show that breathing is compromised and are good indicators of how well the lungs are functioning. Also, chest x-rays and computed tomography may be helpful to document lung infection and the extent of lung damage.

Carrier testing can be performed for prospective parents. In particular, relatives of a child with cystic fibrosis may want to know if they are likely to have children with the disease, and they should be offered genetic testing and counseling. A small blood sample is taken to help determine if a person has a defective cystic fibrosis gene. Unless both prospective parents have at least one such gene, their children will not have cystic fibrosis. If both parents carry a defective cystic fibrosis gene, each pregnancy has a 25% chance of producing a child with cystic fibrosis.

Treatment

A person with cystic fibrosis should have a comprehensive program of therapy directed by an experienced doctor--usually a pediatrician or an internist--along with a team of other doctors, nurses, a dietitian, social worker, genetics counselor, psychologist, and physical and respiratory therapists. The goals of therapy include long-term prevention and treatment of lung and digestive problems and other complications, maintenance of good nutrition, and encouragement of physical activity.

Children with cystic fibrosis need psychologic and social support because they may be unable to participate in normal childhood activities and may feel isolated. Much of the burden of treating a child with cystic fibrosis falls on the parents, who should receive adequate information and training so they can understand the condition and the reasons for the treatments.

The treatment of lung problems focuses on preventing airway blockage and controlling infection. The person should receive all routine immunizations (see Section 17, Chapter 189) and the influenza vaccine, because viral infections can further damage the lungs. Infants and toddlers should receive pneumococcal immunization as part of their routine care.

Respiratory therapy--consisting of postural drainage, percussion, hand vibration over the chest wall, and encouragement of coughing--is started at the first sign of lung problems (see Section 4, Chapter 40). Parents of a young child can learn these techniques and carry them out at home every day. Older children and adults can carry out respiratory therapy independently, using special breathing devices or a compression vest.

Often, people are given drugs that help prevent their airways from narrowing (bronchodilators). People with severe lung problems and a low level of oxygen in the blood may need supplemental oxygen therapy. In general, people with respiratory failure do not benefit from using a ventilator; however, occasional, short periods of mechanical ventilation in the hospital may help during an acute infection, after a surgical procedure, or while waiting for a lung transplant.

An aerosol drug, such as dornase alfa (recombinant human deoxyribonuclease I) is widely used to help thin the pus-filled mucus; such a drug makes it easier to cough up sputum, improves lung function, and may also decrease the frequency of serious respiratory tract infections. Mist tents have no proven benefit. Corticosteroids can relieve symptoms in infants with severe bronchial inflammation and in people who have narrowed airways that cannot be opened with bronchodilators. Sometimes, a nonsteroidal anti-inflammatory drug (NSAID) (see Section 6, Chapter 78) is used to slow the deterioration of lung function.

Respiratory tract infections must be treated as early as possible with antibiotics. At the first sign of a respiratory tract infection, a sample of coughed-up sputum or a throat culture is collected and tested, so that the infecting organism can be identified and the doctor can choose the drugs most likely to control it. Staphylococcus aureus and Pseudomonas species are commonly found. An antibiotic often can be given by mouth, or an antibiotic such as tobramycin can be given in an aerosol mist. However, if the infection is severe, intravenous antibiotics may be needed. This treatment often requires hospitalization but may be given at home. Taking oral or aerosol antibiotics intermittently or continuously may help prevent recurrences of infection and slow the decline in lung function.

People who have pancreatic problems must take pancreatic enzyme replacements with each meal; a powder (for infants) and capsules are available. Special milk formulas containing protein and fats that are easy to digest may help infants who have pancreatic problems and poor growth.

The diet should provide enough calories and protein for normal growth. The proportion of fat should be normal to high. Because people with cystic fibrosis need more calories, they need to consume higher than normal amounts of fat to ensure adequate growth. People with cystic fibrosis should take double the usual recommended daily amount of fat-soluble vitamins (A, D, E, and K) in a special formulation that is more easily absorbed. When they exercise, have a fever, or are exposed to hot weather, people who have cystic fibrosis should increase their salt intake. Children who cannot absorb enough nutrients from food may need supplementary feedings through a tube inserted into the stomach or small intestine.

At some time, surgery may be needed to treat a pneumothorax, chronic sinus infection, severe chronic infection restricted to one area of the lung, bleeding from blood vessels in the esophagus, gallbladder disease, or obstruction of the intestine. Massive or recurrent bleeding in the lung can be treated by a procedure called embolization, which blocks off the bleeding artery.

Liver transplantation has been successful for severe liver damage. Double lung transplantation for severe lung disease is becoming more routine and more successful with experience and improved techniques. One year after transplantation of both the right and the left lungs, about 75% of people are alive, and their condition is much improved.

Gene therapy, in which normal cystic fibrosis genes are delivered directly to the airways, holds great promise for treating cystic fibrosis. However, this therapy is only available in research trials. A number of new drugs, delivered by mouth or aerosol, are under investigation.

Prognosis

The severity of cystic fibrosis varies greatly from person to person regardless of age; the severity is determined largely by how much the lungs are affected. In the United States, half of the people with cystic fibrosis live about 33 years or longer. The outlook for longer survival has improved steadily over the past 50 years, mainly because treatments can now postpone some of the changes that occur in the lungs. Long-term survival is somewhat better in males and in people whose initial symptoms were restricted to the digestive tract; however, long-term survival is also significantly better in people who do not develop pancreatic problems.

However, deterioration is inevitable, leading to loss of lung function and eventually death. People with cystic fibrosis usually die of respiratory failure after many years of deteriorating lung function. A small number, however, die of heart failure, liver disease, bleeding into the airways, or complications of surgery. Despite their many problems, people with cystic fibrosis usually attend school or work until shortly before death.