Cystic fibrosis

Definition

Cystic fibrosis (CF) is an inherited disease that affects the lungs, digestive system, sweat glands, and male fertility. Its name derives from the fibrous scar tissue that develops in the pancreas, one of the principal organs affected by the disease.

Description

Cystic fibrosis affects the body's ability to move salt and water in and out of cells. This defect causes the lungs and pancreas to secrete thick mucus, blocking passageways and preventing proper function.

Many of the symptoms of CF can be treated with drugs or nutritional supplements. Close attention to and prompt treatment of respiratory and digestive complications have dramatically increased the expected life span of a person with CF. While in the 1970s, most children with CF died by age two, in the early 2000s about half of all people with CF live past age 31. That median age is expected to grow as new treatments are developed, and it is estimated that a person born in 1998 with CF has a median expected life span of 40 years.

Demographics

CF affects approximately 30,000 children and young adults in the United States, and about 3,000 babies are born with CF every year. CF primarily affects people of white northern-European descent; rates are much lower in non-white populations.

Causes and symptoms

Causes

Cystic fibrosis is a genetic disease, meaning it is caused by a defect in the person's genes. Genes, found in the nucleus of all the body's cells, control cell function by serving as the blueprint for the production of proteins. Proteins carry out a wide variety of functions within cells. The gene that, when defective, causes CF is called the CFTR gene, which stands for cystic fibrosis transmembrane conductance regulator. A simple defect in this gene leads to all the consequences of CF. There are over 500 known defects in the CFTR gene that can cause CF. However, 70 percent of all people with a defective CFTR gene have the same defect, known as delta-F508.

Much as sentences are composed of long strings of words, each made of letters; genes can be thought of as long strings of chemical words, each made of chemical letters, called nucleotides. Just as a sentence can be changed by rearranging its letters, genes can be mutated, or changed, by changes in the sequence of their nucleotide letters. The gene defects in CF are called point mutations, meaning that the gene is mutated only at one small spot along its length. In other words, the delta-F508 mutation is a loss of one "letter" out of thousands within the CFTR gene. As a result, the CFTR protein made from its blueprint is made incorrectly and cannot perform its function properly.

The CFTR protein helps to produce mucus. Mucus is a complex mixture of salts, water, sugars, and proteins that cleanses, lubricates, and protects many passageways in the body, including those in the lungs and pancreas. The role of the CFTR protein is to allow chloride ions to exit the mucus-producing cells. When the chloride ions leave these cells, water follows, thinning the mucus. In this way, the CFTR protein helps to keep mucus from becoming thick and sluggish, thus allowing the mucus to be moved steadily along the passageways to aid in cleansing.

In CF, the CFTR protein cannot allow chloride ions out of the mucus-producing cells. With less chloride leaving, less water leaves, and the mucus becomes thick and sticky. It can no longer move freely through the passageways, so they become clogged. In the pancreas, clogged passageways prevent secretion of digestive enzymes into the intestine, causing serious impairment of digestion—especially of fat—which may lead to malnutrition . Mucus in the lungs may plug the airways, preventing good air exchange and, ultimately, leading to emphysema. The mucus is also a rich source of nutrients for bacteria, leading to frequent infections.

INHERITANCE OF CYSTIC FIBROSIS Each person actually has two copies of each gene, including the CFTR gene, in each of their body cells. During sperm and egg production, however, these two copies separate, so that each sperm or egg contains only one copy of each gene. When sperm and egg unite, the newly created cell once again has two copies of each gene.

The two gene copies may be the same or they may be slightly different. For the CFTR gene, for instance, a person may have two normal copies, or one normal and one mutated copy, or two mutated copies. A person with two mutated copies will develop cystic fibrosis. A person with one mutated copy is said to be a carrier. A carrier will not have symptoms of CF but can pass on the mutated CFTR gene to his/her children.

When two carriers have children, they have a one-in-four chance of having a child with CF each time they conceive. They have a two-in-four chance of having a child who is a carrier, and a one-in-four chance of having a child with two normal CFTR genes.

Approximately one in every 25 Americans of northern-European descent is a carrier of the mutated CF gene, while only one in 17,000 African Americans and one in 30,000 Asian Americans are carriers. Since carriers are symptom-free, very few people know if they are carriers unless there is a family history of the disease. Two white Americans with no family history of CF have a one in 2,500 chance of having a child with CF.

It may seem puzzling that a mutated gene with such harmful consequences would remain so common; one might guess that the high mortality of CF would quickly lead to loss of the mutated gene from the population. Some researchers in the early 2000s believe the reason for the persistence of the CF gene is that carriers, those with only one copy of the gene, are protected from the full effects of cholera, a microorganism that infects the intestine, causing intense diarrhea and eventual death by dehydration . It is believed that having one copy of the CF gene is enough to prevent the full effects of cholera infection, while not enough to cause the symptoms of CF. This so-called "heterozygote advantage" is seen in some other genetic disorders, including sickle-cell anemia.

Symptoms

The most severe effects of cystic fibrosis are seen in two body systems: the gastrointestinal (digestive) system and the respiratory tract from the nose to the lungs. CF also affects the sweat glands and male fertility. Symptoms develop gradually, with gastrointestinal symptoms often the first to appear.

GASTROINTESTINAL SYSTEM Approximately 10 to 15 percent of babies who inherit CF have meconium ileus at birth. Meconium is the first dark stool that a baby passes after birth; ileus is an obstruction of the digestive tract. The meconium of a newborn with meconium ileus is thickened and sticky, due to the presence of thickened mucus from the intestinal glands. Meconium ileus causes abdominal swelling and vomiting and often requires surgery immediately after birth. Presence of meconium ileus is considered highly indicative of CF. Borderline cases may be misdiagnosed, however, and attributed instead to milk allergy.

Other abdominal symptoms are caused by the inability of the pancreas to supply digestive enzymes to the intestine. During normal digestion, as food passes from the stomach into the small intestine, it is mixed with pancreatic secretions that help to break down the nutrients for absorption. While the intestines themselves also provide some digestive enzymes, the pancreas is the major source of enzymes for the digestion of all types of foods, especially fats and proteins.

In CF, thick mucus blocks the pancreatic duct, which is eventually closed off completely by scar tissue formation, leading to a condition known as pancreatic insufficiency. Without pancreatic enzymes, large amounts of undigested food pass into the large intestine. Bacterial action on this rich food source can cause gas and abdominal swelling. The large amount of fat remaining in the feces makes it bulky, oily, and foul-smelling.

Because nutrients are only poorly digested and absorbed, the person with CF is often ravenously hungry, underweight, and shorter than expected for his age. When CF is not treated for a longer period, a child may develop symptoms of malnutrition, including anemia, bloating, and, paradoxically, appetite loss.

Diabetes becomes increasingly likely as a person with CF ages. Scarring of the pancreas slowly destroys those pancreatic cells which produce insulin, producing type I, or insulin-dependent diabetes.

Gallstones affect approximately 10 percent of adults with CF. Liver problems are less common but can be caused by the buildup of fat within the liver. Complications of liver enlargement may include internal hemorrhaging, accumulation of abdominal fluid (ascites), spleen enlargement, and liver failure.

Other gastrointestinal symptoms can include a prolapsed rectum, in which part of the rectal lining protrudes through the anus; intestinal obstruction; and rarely, intussusception, in which part of the intestinal tube slips over an adjoining part, cutting off blood supply.

Somewhat less than 10 percent of people with CF do not have gastrointestinal symptoms. Most of these people do not have the delta-F508 mutation but a different one, which presumably allows at least some of their CFTR proteins to function normally in the pancreas.

RESPIRATORY TRACT The respiratory tract includes the nose, the throat, the trachea (or windpipe), the bronchi (which branch off from the trachea within each lung), the smaller bronchioles, and the blind sacs called alveoli, in which gas exchange takes place between air and blood.

Swelling of the sinuses within the nose is common in people with CF. This usually shows up on an x ray and may aid the diagnosis of CF. However, this swelling, called pansinusitis, rarely causes problems and does not usually require treatment.

Nasal polyps, or growths, affect about one in five people with CF. These growths are not cancerous and do not require removal unless they become annoying. While nasal polyps appear in older people without CF, especially those with allergies , they are rare in children without CF.

The lungs are the site of the most life-threatening effects of CF. The production of a thick, sticky mucus increases the likelihood of infection, decreases the ability to protect against infection, causes inflammation and swelling, decreases the functional capacity of the lungs, and may lead to emphysema. People with CF live with chronic populations of bacteria in their lungs, and lung infection is the major cause of death for those with CF.

The bronchioles and bronchi normally produce a thin, clear mucus that traps foreign particles including bacteria and viruses. Tiny hair-like projections on the surface of these passageways slowly sweep the mucus along, out of the lungs and up the trachea to the back of the throat, where it may be swallowed or coughed up. This "mucociliary escalator" is one of the principal defenses against lung infection.

The thickened mucus of CF prevents easy movement out of the lungs and increases the irritation and inflammation of lung tissue. This inflammation swells the passageways, partially closing them down, further hampering the movement of mucus. A person with CF is likely to cough more frequently and more vigorously as the lungs attempt to clean themselves out.

At the same time, infection becomes more likely since the mucus is a rich source of nutrients. Bronchitis, bronchiolitis , and pneumonia are frequent in CF. The most common infecting organisms are the bacteria Staphylococcus aureus, Haemophilus influenzae , and Pseudomonas aeruginosa. A small percentage of people with CF have infections caused by Burkholderia cepacia , a bacterium which was resistant to most antibiotics as of 2004. ( Burkholderia cepacia was formerly known as Pseudomonas cepacia .) The fungus Aspergillus fumigatus may infect older children and adults.

The body's response to infection is to increase mucus production; white blood cells fighting the infection thicken the mucus even further as they break down and release their cell contents. These white blood cells also provoke more inflammation, continuing the downward spiral that marks untreated CF.

As mucus accumulates, it can plug up the smaller passageways in the lungs, decreasing functional lung volume. Getting enough air can become difficult; tiredness, shortness of breath, and intolerance of exercise become more common. Because air passes obstructions more easily during inhalation than during exhalation, over time, air becomes trapped in the smallest chambers of the lungs, the alveoli. As millions of alveoli gradually expand, the chest takes on the enlarged, barrel-shaped appearance typical of emphysema.

For unknown reasons, recurrent respiratory infections lead to digital clubbing, in which the last joint of the fingers and toes becomes slightly enlarged.

SWEAT GLANDS The CFTR protein helps to regulate the amount of salt in sweat. People with CF have sweat that is much saltier than normal, and measuring the saltiness of a person's sweat is the most important diagnostic test for CF. Parents may notice that their infants taste salty when they kiss them. Excess salt loss is not usually a problem except during prolonged exercise or heat. While most older children and adults with CF compensate for this extra salt loss by eating more salty foods, infants and young children are in danger of suffering its effects (such as heat prostration), especially during summer. Heat prostration is marked by lethargy, weakness, and loss of appetite and should be treated as an emergency condition.

FERTILITY Some 98 percent of men with CF are sterile, due to complete obstruction or absence of the vas deferens (the tube carrying sperm out of the testes). While boys and men with CF form normal sperm and have normal levels of sex hormones, sperm are unable to leave the testes, and fertilization is not possible. Most women with CF are fertile, though they often have more trouble getting pregnant than women without CF. In both boys and girls, puberty is often delayed, most likely due to the effects of poor nutrition or chronic lung infection. Women with good lung health usually have no problems with pregnancy, while those with ongoing lung infection often do poorly.

Diagnosis

The decision to test a child for cystic fibrosis may be triggered by concerns about recurring gastrointestinal or respiratory symptoms or salty sweat. A child born with meconium ileus will be tested before leaving the hospital. Families with a history of CF may wish to have all children tested, especially if there is a child who already has the disease. Some hospitals require routine screening of newborns for CF.

Sweat test

The sweat test is both the easiest and most accurate test for CF. In this test, a small amount of the drug pilocarpine is placed on the skin. A very small electrical current is then applied to the area, which drives the pilocarpine into the skin. The drug stimulates sweating in the treated area. The sweat is absorbed onto a piece of filter paper and is then analyzed for its salt content. A person with CF will have salt concentrations that are 1.5 to 2 times greater than normal. The test can be done on persons of any age, including newborns, and its results can be determined within an hour. Virtually every person who has CF will test positively on it, and virtually everyone who does not will test negatively.

Genetic testing

The discovery of the CFTR gene in 1989 allowed the development of an accurate genetic test for CF. Genes from a small blood or tissue sample are analyzed for specific mutations; presence of two copies of the mutated gene confirms the diagnosis of CF in all but a very few cases. However, since there are so many different possible mutations and since testing for all of them would be too expensive and time-consuming, a negative gene test cannot rule out the possibility of CF.

Couples planning a family may decide to have themselves tested if one or both have a family history of CF. Prenatal genetic testing is possible through amniocentesis . Many couples who already have one child with CF decide to undergo prenatal screening in subsequent pregnancies and use the results to determine whether to terminate the pregnancy. Siblings in these families are also usually tested, to determine if they will develop CF and to determine if they are carriers, to aid in their own family planning. If the sibling has no symptoms, determining his carrier status is often delayed until his teen years or later, when he is closer to needing the information to make decisions.

Newborn screening

Some states in the early 2000s require screening of newborns for CF, using a test known as the IRT test. This blood test measures the level of immunoreactive trypsinogen, which is generally higher in babies with CF than those without it. This test gives many false positive results immediately after birth and so requires a second test several weeks later. A second positive result is usually followed by a sweat test.

Treatment

As of 2004 there was no cure for CF. However, treatment advanced during the last quarter of the twentieth century, increasing both the life span and the quality of life for most people affected by CF. Early diagnosis is important to prevent malnutrition and infection from weakening the young child. With proper management, many people with CF engage in the full range of school and sports activities.

Nutrition

People with CF usually require high-calorie diets and vitamin supplements. Height, weight, and growth of a person with CF are monitored regularly. Most people with CF need to take pancreatic enzymes to supplement or replace the inadequate secretions of the pancreas. Tablets containing pancreatic enzymes are taken with every meal; depending on the size of the tablet and the meal, as many as 20 tablets may be needed. Because of incomplete absorption even with pancreatic enzymes, a person with CF needs to take in about 30 percent more food than a person without CF. Low-fat diets are not recommended except in special circumstances, since fat is a source of both essential fatty acids and abundant calories.

Some people with CF cannot absorb enough nutrients from the foods they eat, even with specialized diets and enzymes. For these people, tube feeding is an option. Nutrients can be introduced directly into the stomach through a tube inserted either through the nose (a nasogastric tube) or through the abdominal wall (a gastrostomy tube). A jejunostomy tube, inserted into the small intestine, is also an option. Tube feeding can provide nutrition at any time, including at night while the person is sleeping, allowing constant intake of high-quality nutrients. The feeding tube may be removed during the day, allowing normal meals to be taken.

Respiratory health

The key to maintaining respiratory health in a person with CF is regular monitoring and early treatment. Lung function tests are done frequently to track changes in functional lung volume and respiratory effort. Sputum samples are analyzed to determine the types of bacteria present in the lungs. Chest x-rays are usually taken at least once a year. Lung scans, using a radioactive gas, can show closed off areas not seen on the x ray. Circulation in the lungs may be monitored by injection of a radioactive substance into the bloodstream.

People with CF live with chronic bacterial colonization; that is, their lungs are constantly host to several species of bacteria. Good general health, especially good nutrition, can keep the immune system healthy, which decreases the frequency with which these colonies begin an infection or attack on the lung tissue. Exercise is another important way to maintain health, and people with CF are encouraged to maintain a program of regular exercise.

In addition, clearing mucus from the lungs helps to prevent infection, and mucus control is an important aspect of CF management. Postural drainage is used to allow gravity to aid the mucociliary escalator. For this technique, the person with CF lies on a tilted surface with head downward, alternately on the stomach, back, or side, depending on the section of lung to be drained. An assistant thumps the rib cage to help loosen the secretions. A device called a flutter offers another way to loosen secretions: it consists of a stainless steel ball in a tube. When a person exhales through it, the ball vibrates, sending vibrations back through the air in the lungs. Some special breathing techniques may also help clear the lungs.

Several drugs are available to prevent the airways from becoming clogged with mucus. Bronchodilators and theophyllines open up the airways; steroids reduce inflammation; and mucolytics loosen secretions. Acetylcysteine (Mucomyst) has been used as a mucolytic during the 1980s and 1990s but is not prescribe frequently in the early 2000s, while DNase (Pulmozyme) is a newer product gaining in popularity. DNase breaks down the DNA from dead white blood cells and bacteria found in thick mucus.

People with CF may pick up bacteria from other CF patients. This is especially true of Burkholderia cepacia , which is not usually found in people without CF. While the ideal recommendation from a health standpoint might be to avoid contact with others who have CF, this is not usually practical (since CF clinics are a major site of care), nor does it meet the psychological and social needs of many people with CF. At a minimum, CF centers recommend avoiding prolonged close contact between people with CF and scrupulous hygiene, including frequent hand washing. Some CF clinics schedule appointments on different days for those with and without B. cepacia colonies.

Some doctors choose to prescribe antibiotics only during infection, while others prefer long-term antibiotic treatment against S. aureus . The choice of antibiotic depends on the particular organism or organisms found. Some antibiotics are given as aerosols directly into the lungs. Antibiotic treatment may be prolonged and aggressive.

Supplemental oxygen may be needed as lung disease progresses. Respiratory failure may develop, requiring temporary use of a ventilator to perform the work of breathing.

Lung transplantation has become increasingly common for people with CF, although the number of people who receive lungs was as of 2004 much lower than those who want them. Transplantation is not a cure, however, and has been likened to trading one disease for another. Long-term immunosuppression is required, increasing the likelihood of other types of infection. About 50 percent of adults and more than 80 percent of children who receive lung transplants live longer than two years. Liver transplants are also done for CF patients whose livers have been damaged by fibrosis.

Long-term use of ibuprofen has been shown to help some people with CF, presumably by reducing inflammation in the lungs. Close medical supervision is necessary, however, since the effective dose is high and not everyone benefits. Ibuprofen at the required doses interferes with kidney function and, together with aminoglycoside antibiotics, may cause kidney failure.

A number of experimental treatments were as of 2004 the subject of much research. Some evidence indicates that aminoglycoside antibiotics may help overcome the genetic defect in some CF mutations, allowing the protein to be made normally. While promising, these results would apply to only about 5 percent of those with CF.

Gene therapy is the most ambitious approach to curing CF. In this set of techniques, non-defective copies of the CFTR gene are delivered to affected cells, where they are taken up and used to create the CFTR protein. While elegant and simple in theory, gene therapy has met with a large number of difficulties in trials, including immune resistance, very short duration of the introduced gene, and inadequately widespread delivery.

Prognosis

People with CF may lead relatively normal lives, with the control of symptoms. The possible effect of pregnancy on the health of a woman with CF requires careful consideration before she and her partner begin a family; as do issues of longevity, and the children's status as carriers. Although most men with CF are functionally sterile, new procedures for removing sperm from the testes are being tried and may offer more men the chance to become fathers.

Approximately half of people with CF live past the age of 30. Because of better and earlier treatment, a person born in 2004 with CF is expected, on average, to live to age 40.

Prevention

Adults with a family history of cystic fibrosis may obtain a genetic test of their carrier status for purposes of family planning. Prenatal testing is also available. There is no known way to prevent development of CF in a person with two defective gene copies.

Resources

BOOKS

Boat, Thomas F. "Cystic Fibrosis." In Nelson Textbook of Pediatrics. Edited by Richard E. Behrman et al. Philadelphia: Saunders, 2004.

Boucher, R. C., et al "Cystic Fibrosis." In Textbook of Respiratory Medicine , 3rd ed. Edited by John F. Murray and Jay A. Nadel. Philadelphia: Saunders, 2000.

ORGANIZATIONS

Cystic Fibrosis Foundation. 6931 Arlington Road, Bethesda, MD 20814. Web site: http://www.cff.org.

WEB SITES

CysticFibrosis.com. Available online at http://www.cysticfibrosis.com (accessed December 26, 2004).

Richard Robinson Rosalyn Carson-DeWitt, MD