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Cystic Fibrosis

by Beryl J. Rosenstein, MD

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 caused by inherited genetic mutations that cause thick, sticky secretions to clog the lungs and other organs.

  • Typical symptoms include vomiting and abdominal bloating, loose stools, and poor weight gain in newborns, as well as coughing, wheezing, and frequent respiratory tract infections throughout life.

  • The diagnosis is based on sweat test results and/or genetic testing.

  • Half of the people with this disease live to their early 40s.

  • Treatments include antibiotics, bronchodilators, drugs to thin lung secretions, airway clearance treatments for respiratory problems, supplements of pancreatic enzymes and vitamins for digestive problems, and a drug to improve cystic fibrosis protein activity in people with certain mutations.

  • Some people benefit from lung transplantation.

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. Because improvements in treatment have extended life expectancy for people with cystic fibrosis, about 50% of people in the United States with this disease are adults. Cystic fibrosis is equally common among boys and girls.

Causes

Abnormal genes

Cystic fibrosis results when a person inherits two defective copies (mutations) of a particular gene, one from each parent. 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. People with one defective copy are carriers but they themselves do not get sick. About 3 of 10,000 white people inherit two defective copies of the gene and develop cystic fibrosis. In these people, chloride and sodium transport is disrupted, leading to increased stickiness of secretions throughout the body.

Abnormal secretions

Cystic fibrosis affects many organs throughout the body and nearly all the glands that secrete fluids into a duct (exocrine glands). The organs most commonly affected are the lungs, the pancreas, the intestines, the liver and gallbladder, and the reproductive organs.

The lungs are normal at birth, but problems can develop at any time afterward as thick secretions begin to block the small airways (termed mucus plugging). The plugging leads to chronic bacterial infections and inflammation that cause permanent damage to the airways (termed bronchiectasis). These problems make breathing increasingly difficult and reduce the lungs’ ability to transfer oxygen to the blood. People also have frequent bacterial respiratory tract infections.

Blockage of ducts in the pancreas prevents digestive enzymes from reaching the intestine. A lack of these enzymes leads to poor absorption of fats, proteins, and vitamins. This poor absorption, in turn, can lead to nutritional deficiencies and poor growth. Eventually, the pancreas can become scarred and no longer produce enough insulin , so some people develop diabetes. However, about 5 to 15% of people who have cystic fibrosis do not develop pancreatic problems.

The intestines can become blocked by thick secretions. This blockage is common immediately after birth (called meconium ileus). Older children and adults may also have problems with constipation and blockage of the intestines (called distal intestinal obstruction syndrome).

The sweat glands secrete fluid containing more salt than normal, increasing the risk of dehydration.

Symptoms

About 15 to 20% of newborns who have cystic fibrosis have meconium ileus, which causes vomiting, bloating (distention) of the abdomen, and absence of bowel movements. Meconium ileus is sometimes complicated by perforation of the intestine, a dangerous condition causing peritonitis and, if untreated, shock and death. Some newborns have 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. Meconium can also temporarily block the large intestine in some newborns with cystic fibrosis, so that a bowel movement may not occur 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. This poor weight gain is due to poor absorption of nutrients related to inadequate amounts of pancreatic enzymes. The infant has frequent, bulky, foul-smelling, oily stools and may have a bloated (distended) abdomen. Without treatment, weight gain in infants and older children is slow despite a normal or large appetite.

Unless a diagnosis is made through newborn screening, 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. Children may have difficulty breathing, wheezing, or both. As the disease progresses, symptoms tend to occur more frequently, the chest becomes barrel-shaped, and insufficient oxygen may make the fingers clubbed (see Clubbing) 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.

Older children and adults may have episodes of constipation or develop recurring and sometimes chronic blockage of the intestines. Symptoms include a change in stooling pattern, crampy abdominal pain a decreased appetite, and sometimes vomiting. Gastroesophageal reflux is relatively common among older children and adults.

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, osteoporosis, 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. Infrequently, infants with cystic fibrosis who have been fed soy formula or hypoallergenic formula may develop anemia and swelling of the extremities, because they are not absorbing enough protein.

Complications in adolescents and adults with cystic fibrosis include 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 the pleural space (called pneumothorax—see Pneumothorax), which collapses the lung. Other complications include heart failure and massive or recurrent bleeding in the airways.

About 2% of children, 20% of adolescents, and 40% 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 2 to 3% of people with cystic fibrosis (see Cirrhosis of the Liver). Cirrhosis may increase the pressure in the veins entering the liver (portal hypertension—see Portal Hypertension), 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 develops 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 somewhat decreased fertility. However, many women with cystic fibrosis have carried pregnancies to term. The outcome of the pregnancy for both the mother and the newborn is related to the mother's health status during pregnancy. Otherwise, sexual function is not impaired in men or women.

Other complications may include arthritis, kidney stones, and an increased risk of cancer of the bile ducts and intestines.

Diagnosis

Screening tests for cystic fibrosis are done on all newborns in the United States. A small drop of blood is collected on a piece of filter paper and the level of trypsin (a digestive enzyme) is measured. If the trypsin level in the blood is high, newborns undergo confirmatory testing. Confirmatory tests include sweat testing and/or genetic testing. Over 90% of new cases of cystic fibrosis are now identified by newborn screening tests.

If newborn screening is not done, 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.

A sweat test is done in newborns who have a positive screening test and in infants, children, and older people who have symptoms that suggest cystic fibrosis. This test, which is done on an outpatient basis, 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 about 2 weeks old may be difficult.

Genetic testing can confirm the diagnosis of cystic fibrosis in a person who shows one or more typical symptoms or has a sibling with cystic fibrosis. Finding two abnormal cystic fibrosis genes (mutations) confirms the diagnosis. However, because typical genetic testing does not look for all of the more than 1,900 different cystic fibrosis mutations, failure to detect two mutations does not guarantee the person does not have cystic fibrosis (although the chance of having cystic fibrosis is very low). The disease can be diagnosed prenatally by doing genetic testing on the fetus using chorionic villus sampling or amniocentesis (see Prenatal Diagnostic Testing).

Carrier testing can be done for people who want to become parents in the future or are looking for prenatal care. In particular, relatives of a person with cystic fibrosis may want to know whether they are at increased risk of having children with the disease, and they should be offered genetic testing and counseling. A small blood sample is taken to help determine whether a person has a defective cystic fibrosis gene (mutation). Unless both potential parents have at least one such mutation, 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, a 50% chance of producing a child who is a carrier, and a 25% chance of producing a child with no defective cystic fibrosis genes.

Because cystic fibrosis can affect several organs, other tests may be helpful. Because pancreatic enzyme levels are reduced, an analysis of the person’s stool may reveal low or undetectable levels of the digestive enzymes elastase, trypsin, and chymotrypsin (secreted by the pancreas) or high levels of fat. Blood tests are done to determine whether insulin secretion is reduced and blood sugar levels are high. Pulmonary function tests (see Pulmonary Function Testing (PFT)) may show that breathing is compromised and are good indicators of how well the lungs are functioning. Also, chest x-rays and computed tomography (CT) of the chest may be helpful to document lung infection and the extent of lung damage. CT of the sinuses is done for people who have serious sinus symptoms, particularly if they have nasal polyps.

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 41 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 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.

Treatment

A person with cystic fibrosis should have a comprehensive program of therapy directed by a doctor experienced with cystic fibrosis care—usually a pediatrician or an internist—along with a team of other doctors, nurses, a dietitian, and a respiratory therapist and ideally a social worker, genetics counselor, pharmacist, psychologist, and physical therapist. 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 disorder and the reasons for the treatments.

Treatments for the lungs

The treatment of lung problems focuses on preventing airway blockage and controlling infection. The person should receive all routine immunizations (see Childhood Vaccination Schedule), particularly for those infections that cause respiratory problems, such as Haemophilus influenzae, influenza, measles, pertussis, pneumococcus, and varicella.

Airway clearance techniques, which include postural drainage, chest percussion, hand vibration over the chest wall, and encouragement of coughing, are started when cystic fibrosis is first diagnosed (see Chest Physical Therapy). Parents of a young child can learn these techniques and carry them out at home every day. Older children and adults can carry out airway clearance techniques independently, using special breathing devices or a compression vest. Aerobic exercise, done regularly, can also help keep the airways clear.

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 chronic respiratory failure do not benefit from using a ventilator (breathing machine). 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.

Aerosol (nebulized) drugs, such as dornase alfa (recombinant human deoxyribonuclease I) or a highly concentrated (hypertonic) salt solution (in people older than 6 years of age), are widely used to help thin the thick mucus in the airways. Such drugs make it easier to cough up sputum, improve lung function, and may also decrease the frequency of serious respiratory tract infections. Corticosteroids can relieve symptoms in infants with severe bronchial inflammation and in people who have narrowed airways that cannot be opened with bronchodilators. Sometimes, ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID—see Nonopioid Analgesics : Nonsteroidal Anti-Inflammatory Drugs), 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 , including methicillin-resistant strains, and Pseudomonas species are commonly found. An antibiotic often can be given by mouth (orally), or an antibiotic such as tobramycin or aztreonam can be given in an aerosol mist. However, if the infection is severe, antibiotics given by vein (intravenously) may be needed. This treatment often requires hospitalization but may be given at home. Taking the aerosol form of tobramycin or aztreonam for a long time, usually every other month, and also continuously taking an oral form of the antibiotic azithromycin may help prevent recurrences of infection and slow the decline in lung function.

Ivacaftor is a new drug that improves the function of the protein that regulates the transport of chloride and sodium (salt) across cell membranes. However, ivacaftor is recommended only for people age 6 years and older who have 1 or 2 copies of a specific cystic fibrosis mutation including G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1349D, R117H, or G970R. These mutations are present in only a small proportion of people who have cystic fibrosis. In these people, the drug can improve lung function, increase weight, and decrease lung symptoms. Doctors are working to develop similar drugs that will help people with other mutations that cause cystic fibrosis.

Injections of human growth hormone may improve lung function, increase height and weight, and reduce the rate of hospitalization. However, this drug is costly and inconvenient, so doctors do not commonly prescribe it.

Diet and supplements

The diet should provide enough calories and protein for normal growth. Because digestion and absorption can be abnormal even when pancreatic enzyme supplements are used, most children need to consume 30 to 50% more calories than the usually recommended amount to ensure adequate growth. The proportion of fat should be normal to high. High-calorie oral supplements can provide extra calories for children and adults. People who cannot absorb enough nutrients from food may need supplemental feedings given through a tube inserted into the stomach or small intestine. 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. Drugs that stimulate the appetite may be given to some people. When people exercise, have a fever, or are exposed to hot weather, they should increase their fluid and salt intake.

Pancreatic enzymes

People whose pancreas has been affected by cystic fibrosis must take capsules of pancreatic enzyme supplements with all meals and snacks. For infants, parents open the capsules and mix the contents with food or formula. Special milk formulas containing protein and fats that are easy to digest may help infants who have pancreatic problems and poor growth.

Insulin

People with cystic fibrosis who have diabetes need to take insulin injections. Oral drugs for diabetes are not adequate treatment. In addition to insulin , management includes nutrition counseling, a diabetes self-management program, and monitoring for eye and kidney complications. People also need special nutrition counseling because standard dietary recommendations for people with only diabetes or only cystic fibrosis are not adequate.

Surgery

At times, surgery may be needed to treat a collapsed lung, 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. About 60% of people are alive 5 years after transplantation of both lungs, and their condition is much improved.

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  • ISOPTO CARPINE, PILOPINE HS, SALAGEN
  • TOBI, TOBREX
  • ADVIL, MOTRIN IB
  • ZITHROMAX
  • KALYDECO
  • AZACTAM