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Cystic Fibrosis

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.

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.

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 several decades ago most children with CF died by age two, today 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.

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% 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 digestionespecially of fatwhich 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. To understand the inheritance pattern of CF, it is important to realize that genes actually have two functions. First, as noted above, they serve as the blueprint for the production of proteins. Second, they are the material of inheritance: parents pass on characteristics to their children by combining the genes in egg and sperm to make a new individual.

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 will know whether or not 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.

DOROTHY ANDERSEN (19011963)

Dorothy Andersen was born on May 15, 1901, in Asheville, North Carolina. She was the only child of Hans Peter Andersen and the former Mary Louise Mason. Orphaned as a young adult, Andersen put herself through Saint Johnsbury Academy and Mount Holyoke College before enrolling in the Johns Hopkins School of Medicine, from which she received her M.D. in 1926.

Andersen turned instead to medical research as a pathologist at Babies Hospital of the Columbia-Presbyterian Medical Center in New York City, where she stayed for more than 20 years, eventually becoming chief of pathology in 1952. Andersen is probably best known for her discovery of cystic fibrosis in 1935. That discovery came about during the postmortem examination of a child who had supposedly died of celiac disease, a nutritional disorder. She searched for similar cases in the autopsy files and in medical literature, eventually realizing that she had found a disease that had never been described and to which she gave the name cystic fibrosis.

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 now 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. Ten to fifteen 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 which 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.

Gall stones affect approximately 10% 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, 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% of people with CF do not have gastrointestinal symptoms. Most of these people do not have the delta-F508 mutation, but rather 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 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 will 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 is resistant to most current antibiotics (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. Ninety-eight 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 now 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 one-and-one-half to two 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, both 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 now require screening of newborns for CF, using a test known as the IRT test. This is a blood test which 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

There is no cure for CF. Treatment has advanced considerably in the past several decades, 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% 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 for many years but is not prescribe frequently now, 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 them is still 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% of adults and more than 80% 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 are currently 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% of those with CF.

Gene therapy is currently 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 so far, including immune resistance, very short duration of the introduced gene, and inadequately widespread delivery.

KEY TERMS

Carrier A person with one copy of a defective gene, who does not have the disease it causes, but can pass along the defective gene to offspring.

CFTR Cystic fibrosis transmembrane conductance regulator, the protein responsible for regulating chloride movement across cells in some tissues. When a person has two defective copies of the CFTR gene, cystic fibrosis is the result.

Emphysema A pathological accumulation of air in organs or tissues; term especially applied to the condition when in the lungs.

Mucociliary escalator The coordinated action of tiny projections on the surfaces of cells lining the respiratory tract, which moves mucus up and out of the lungs.

Mucolytic An agent that dissolves or destroys mucin, the chief component of mucus.

Pancreatic insufficiency Reduction or absence of pancreatic secretions into the digestive system due to scarring and blockage of the pancreatic duct.

Alternative treatment

In homeopathic medicine, the symptoms of the disease would be addressed to enhance the quality of life for the person with cystic fibrosis. Treating the cause of CF, because of the genetic basis for the disease, is not possible. Naturopathic medicine seeks to treat the whole person, however, and in this approach might include:

  • mucolytics to help thin mucus
  • supplementation of pancreatic enzymes to assist in digestion
  • respiratory symptoms can be addressed to open lung passages
  • hydrotherapy techniques to help ease the respiratory symptoms and help the body eliminate
  • immune enhancements can help revent the development of secondary infections
  • dietary enhancements and adjustments are used to treat digestive and nutritional problems

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 beginning a family; as do issues of longevity, and their 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 today 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 currently no known way to prevent development of CF in a person with two defective gene copies.

Resources

ORGANIZATIONS

Cystic Fibrosis Foundation. 6931 Arlington Road, Bethesda, MD 20814. (800) 344-4823. http://www.cff.org.

OTHER

CysticFibrosis.com. http://www.cysticfibrosis.com.

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Cystic Fibrosis

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 digestionespecially of fatwhich 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.

KEY TERMS

Carrier A person who possesses a gene for an abnormal trait without showing signs of the disorder. The person may pass the abnormal gene on to offspring. Also refers to a person who has a particular disease agent present within his/her body, and can pass this agent on to others, but who displays no symptoms of infection.

Cystic fibrosis transmembrane conductance regulator (CFTR) The protein responsible for regulating chloride movement across cells in some tissues. Cystic fibrosis results when a person has two defective copies of the CFTR gene.

Emphysema A chronic respiratory disease that involves the destruction of air sac walls to form abnormally large air sacs that have reduced gas exchange ability and that tend to retain air within the lungs. Symptoms include labored breathing, the inability to forcefully blow air out of the lungs, and an increased susceptibility to respiratory tract infections. Emphysema is usually caused by smoking.

Mucociliary escalator The coordinated action of tiny projections on the surfaces of cells lining the respiratory tract, which moves mucus up and out of the lungs.

Mucolytic An agent that dissolves or destroys mucin, the chief component of mucus.

Pancreatic insufficiency Reduction or absence of pancreatic secretions into the digestive system due to scarring and blockage of the pancreatic duct.

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: <www.cff.org>.

WEB SITES

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

Richard Robinson Rosalyn Carson-DeWitt, MD

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cystic fibrosis

cystic fibrosis (sĬs´tĬk fībrō´sĬs), inherited disorder of the exocrine glands (see gland), affecting children and young people; median survival is 25 years in females and 30 years in males. It is caused by a genetic abnormality in the CF transmembrane conductance regulator (CFTR) gene that results in a misshapen CFTR protein and the consequent disruption of chloride transfer across cell membranes. As a result, chloride ions build up in the cells of the lungs and other organs. Water stays inside the cells to dilute the chloride rather than being drawn out of the cells by normal chloride movement and the normal secretions of the organs thicken. Mucus in the exocrine glands becomes thick and sticky and eventually blocks the ducts of these glands (especially in the pancreas, lungs, and liver), forming cysts. The disease also causes the sweat glands to secrete excessive salt, causing heat prostration in hot weather. Symptoms, which vary according to the severity of the condition and the glands involved, include a distended abdomen; diarrhea; bulky, foul-smelling stools; and malnutrition. Medical problems include nasal polyps and sinus disease, repeated respiratory infections, infertility, liver disease, and diabetes. Diagnosis is confirmed by a sweat test or measurement of transmembrane potential.

Treatment consists of dietary adjustment (low fat–high calorie) and the administration of vitamins, pancreatin, and antibiotics to ward off secondary infections. Special measures are necessary to decrease the viscosity of pulmonary secretions; aerosol application of recombinant human DNase, an enzyme that digests the sticky extracellular DNA that helps form these viscous secretions, was approved in 1993. In some cases lung transplantation (see transplantation, medical) is helpful. The identification of the abnormal gene (1989) paved the way for gene therapy aimed at altering the genetic structure by transferring to the patient cells with normal CFTR genes.

Identification of the genes has also made genetic testing and diagnosis possible. Evolutionary biologists have suggested that the gene, which must be inherited from both parents to cause the disorder, affords carriers some protection against cholera, a disease that kills through profound loss of fluids.

See P. Davis, Cystic Fibrosis (1993); M. E. Hodson and D. M. Geddes, Cystic Fibrosis (1994).

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cystic fibrosis

cystic fibrosis (CF, fibrocystic disease of the pancreas, mucoviscidosis) n. a hereditary disease affecting cells of the exocrine glands; the faulty gene responsible for the most common form of CF has been identified as lying on chromosome no. 7 and is recessive, i.e. both parents of the patient can be carriers without being affected by the disease. The abnormality results in the production of thick mucus, which obstructs the intestinal glands (causing meconium ileus in newborn babies), pancreas (causing deficiency of pancreatic enzymes resulting in malabsorption and failure to thrive), and bronchi (causing bronchiectasis). Respiratory infections, which may be severe, are a common complication.
www.cftrust.org.uk Website of the Cystic Fibrosis Trust

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Cystic Fibrosis

CYSTIC FIBROSIS

DEFINITION


Cystic fibrosis (CF) is a hereditary disease that affects the lungs, digestive system, sweat glands, and male reproductive organs.

DESCRIPTION


Cystic fibrosis affects the body's ability to move salts and water in and out of cells. This defect causes the lungs and pancreas to secrete (release) thick mucus. The mucus blocks various passageways in the body, preventing them from functioning normally.

CF affects about thirty thousand children and young adults in the United States. About three thousand babies are born with the condition each year in this country. The disorder primarily affects people of white, northern European ancestry. Nonwhite populations have a much lower rate of cystic fibrosis.

There is no cure for CF. However, symptoms of the disease can be treated. Proper care and treatment can greatly improve the lifestyle of a person with the condition. For example, prompt attention to digestive and respiratory (breathing) problems has extended the lives of many patients. At one time, children with CF usually died by the age of two years. Today, many people with CF live beyond the age of thirty.

CAUSES


Cystic fibrosis is a genetic disorder. Genes are the chemical units in every cell that tell cells what functions they should perform and what substances they should manufacture in order to operate normally. Genes can be damaged in a variety of ways. For example, certain chemicals contained in the foods we eat can damage a gene. When that happens, the gene is no longer able to give correct instructions to a cell and the cell does not have the information it needs to produce all the substances it requires to stay healthy. When this happens, a medical problem develops in some part of the body.

Genes are passed down from one generation to the next. A person whose body contains a damaged gene may pass that gene to his or her children. The children may develop the same genetic disorder that the parent had.

Cystic fibrosis is caused by a defect in the gene known as the CFTR gene. The abbreviation CFTR stands for cystic fibrosis transmembrane conductance regulator. The CFTR gene carries instructions for the production of mucus in cells. Mucus is a mixture of water, salts, sugars, and proteins. Its job is to cleanse, lubricate, and protect passageways in the body.

Cells that contain a defective CFTR gene have lost the ability to make mucus properly. The mucus they produce has too little water in it and is thick and syrupy. This mucus does not improve the functioning of passageways in the body. Instead, it causes them to become clogged. Substances that are supposed to pass through passageways, such as air and blood, are unable to flow normally and the symptoms of CF begin to appear.

Cystic Fibrosis: Words to Know

CFTR:
An abbreviation for cystic fibrosis transmembrane conductance regulator, a chemical that controls the amount of water in mucus.
Genes:
Chemical units that carry the information that tells cells what functions to perform.
Genetic disorder:
A medical condition caused when a person has one or more defective genes.
Meconium ileus:
A condition that appears in newborn babies with cystic fibrosis, in which the baby's first bowel movement is abnormally dark, thick, and sticky.
Mucolytic:
Any type of medication that breaks up mucus and makes it flow more easily.
Mucus:
A mixture of water, salts, sugars, and proteins, which has the job of cleansing, lubricating, and protecting passageways in the body.
Pancreas:
An organ near the stomach that secretes enzymes needed to digest food.
Screening:
Using a test or group of tests to look for some specific medical disorder.

SYMPTOMS


The most severe symptoms of CF occur in two body systems: the gastrointestinal (digestive) system and the respiratory tract. CF also affects the sweat glands and the male reproductive organs.

Gastrointestinal System

One of the first symptoms of CF in young babies is meconium ileus (pronounced muh-KO-nee-um ILL-ee-us). Meconium ileus is characterized by a thick, sticky, dark stool. The stool has these features because the mucus it contains is thicker than normal. Meconium ileus is also marked by abdominal swelling and vomiting. The presence of meconium ileus is a strong indication of cystic fibrosis.

A defective CFTR gene also causes damage to the pancreas. The pancreas provides enzymes needed in the digestion of food. Enzymes are chemicals present in all cells that make possible hundreds of different chemical reactions. If these enzymes are not present, necessary chemical reactions may not occur. In the case of CF, the pancreas makes a very thick type of mucus. The mucus blocks openings in the pancreas and enzymes produced by the pancreas cannot get out of the organ. Food passes through the stomach without being digested.

Failure to digest food can produce a number of symptoms. The feces may become bulky, oily, and foul-smelling. The patient may constantly be hungry because food that is eaten is not digested. The patient may not grow to normal size without the nutrients provided by food. Over time, other symptoms that may develop include malnutrition, anemia (see anemias entry), bloating, and loss of appetite.

Respiratory Tract

The most life-threatening symptoms of CF occur in the lungs. The job of the lungs is to take oxygen from the air and deliver it to blood. Blood then takes oxygen to the cells of the body, where it is used to make energy.

The mucus that lines the lungs has a number of functions. One function is to prevent infection of the lungs. The mucus captures bacteria, viruses, fungi, and other agents that might cause disease. It then passes these materials back out of the lungs and into the throat. From there, they can be coughed up or swallowed.

In patients with CF, the mucus in the lungs becomes much thicker. Disease-causing agents are still captured, but they cannot be passed back into the throat very easily. Instead, the thick mucus holds bacteria, viruses, and other organisms in the lining of the lungs. The longer these organisms remain there, the greater the chance they will cause an infection of the lungs.

The presence of organisms in the lungs causes the immune system to become active. The immune system is a network of organs, tissues, cells, and chemicals designed to protect the body against infection by foreign agents. The immune system sends specialized cells to fight the disease-causing organisms trapped in the patient's lungs. These cells cause the lungs to become inflamed and swollen. The inflammation and swelling may close down passageways in the lungs, making it difficult for air to pass in and out of the lungs.

The thick mucus that lines the lungs also makes it more difficult for air to pass through the lungs. Patients may find themselves gasping for breath in order to get enough air. They may also begin to develop the symptoms of emphysema (see emphysema entry).

Sweat Glands

A defective CFTR gene can also affect the formation of sweat. A person with cystic fibrosis has sweat that is much saltier than normal. This problem is usually not serious except during heavy exercise or hot weather. In such cases, patients with CF usually eat more salty foods to make up for the salt lost in their sweat.

Male Reproductive System

Abnormally thick mucus can block the vas deferens in males. The vas deferens are tubes through which sperm passes. If these tubes are blocked, males are not able to produce sperm and are, therefore, infertile (incapable of producing children).

DIAGNOSIS


A number of factors may suggest that a child be tested for cystic fibrosis. The presence of any of the described symptoms may lead to such tests. These symptoms include gastrointestinal or respiratory problems that do not disappear, and the presence of salty sweat. A baby born with meconium ileus will be tested before leaving the hospital. Some hospitals now require routine CF screening for newborn babies.

The easiest and most accurate test for CF is a sweat test. A sample of an individual's sweat is collected. The sample is then tested for salt content. If the salt content is 1.5 to 2 times greater than normal, the individual probably has CF.

Genetic testing can also be used to diagnose CF. A small blood or tissue sample is taken from the patient. The sample can then be analyzed to determine whether the individual's CFTR gene is normal or defective. The presence of a defective gene means that the person has cystic fibrosis.

Screening of newborn babies is done with a test known as the IRT test. This test measures the amount of a particular chemical in the blood known as immunoreactive trypsinogen (pronounced trip-SIN-uh-juhn). Babies with CF have a high level of this chemical.

TREATMENT


There is no cure for cystic fibrosis, but there are many types of treatment that can help patients live longer and more comfortable lives. Early diagnosis is an important element of treatment. With proper management, many people with CF engage in the full range of normal activities.

Nutrition

People with CF often do not receive full benefit from the foods they eat. They may need a high calorie diet with vitamin supplements. In addition, pancreatic enzyme pills are often recommended. The pills provide enzymes to the patient's digestive system that would normally come from a healthy pancreas.

Some people cannot absorb enough nutrients from foods even with special diets and enzyme pills. For these people, tube feeding is an option. A tube is inserted through the nose or through a hole made in the abdominal wall. Food can be supplied through the tube at any time of the day or night, allowing constant intake of high-quality nutrients. The feeding tube may be removed during the day, allowing the patient to eat meals normally.

Respiratory Health

The key to survival for many patients with CF is careful monitoring of the respiratory system. Lung function tests are done frequently. These tests measure the amount of air the person's lungs are able to take in. Sputum (spit) tests are done to find out what kinds of bacteria are present in the lung and how many there are. Chest X rays monitor any changes in the size and shape of the lungs.

An important element of good respiratory health is exercise. Exercise keeps the lungs healthy, active, and free of bacteria.

Clearing mucus from the lungs also helps protect against infection. Physical therapists have developed a number of techniques to help CF patients prevent mucus from collecting in the lungs. For example, a patient may lie on his or her stomach on a tilted surface with the head downward. An assistant then thumps on the patient's rib cage to help loosen mucus.

Drugs also can help maintain healthy lungs. For example, bronchodilators (pronounced brong-ko-die-LATE-urs) are substances that cause small air passages in the lungs to expand, allowing air to flow more freely. A group of drugs known as mucolytics (pronounced myu-kuh-LIH-tiks) also may be used. Mucolytics help loosen mucus and allow it to be expelled from the lungs more easily.

The use of antibiotics also may be necessary. Some doctors have their patients take antibiotics continuously to protect against lung infections. Other doctors use antibiotics only when an infection has actually developed.

In extreme cases, patients with CF may need oxygen therapy. Oxygen therapy is a procedure in which patients breathe air that is rich in oxygen. The higher oxygen content makes it easier for the body to get the oxygen it needs without working too hard.

Lung transplantation is a treatment of last resort. However, this form of treatment has its own set of problems. The drugs used during and after a

transplant operation cause severe problems of their own. One such problem is the weakening of the immune system.

On a long-term basis, the best hope for treating CF may be genetic therapy. Genetic therapy is a procedure by which correct copies of the CFTR gene are injected into a patient. The hope is that the correct genes will take over the task that the defective CFTR genes are unable to perform. Although much research is being done in this area, gene therapy is still in the experimental phase.

Alternative Treatment

Alternative practitioners recommend many of the same treatments used in traditional medicine. For example, they suggest the use of mucolytics to thin mucus and pancreatic enzymes to aid in digestion.

Efforts are also made to improve the patient's overall health and immune system. A variety of herbs is available to achieve these goals. In addition, hydrotherapy (water therapy) techniques may be helpful in relaxing the body and helping the patient breathe better.

EXPERIMENTING WITH GENE THERAPY

It may be possible to cure cystic fibrosis with gene therapy. The problem is to find ways to get good copies of the CFTR gene into a patient's body. Scientists are now working on techniques for accomplishing this goal.

One approach is to make good copies of the CFTR gene in the laboratory. These copies are then combined with viruses. Viruses are very good at infecting cells. This property is usually not beneficial for humans because it is the reason people become ill with viral diseases.

The combination of CFTR gene and virus is made into a nasal spray. Some fat droplets are also added to the spray. The fat serves as a carrier that takes the virus and gene to cells in the patient's body. If all works well, the virus enters cells in the patient's body, bringing the good copy of the CFTR gene with it. The gene begins to function properly, and the patient is cured.

Trials of the new nasal spray have been going on since the mid-1990s. The first step in the trials is to make sure that the spray does not harm people. The second step is to find out if the spray really works. That is, does it actually deliver good genes to the patient's body?

PROGNOSIS


The key to a good prognosis for cystic fibrosis is early detection and treatment. The effectiveness and variety of treatment methods greatly increased during the 1980s and 1990s. About half of all patients living with CF during this time could expect to live past the age of thirty. Researchers predict that a person born in the late 1990s with the disorder can expect to live to the age of forty.

PREVENTION


Since CF is a genetic disorder, there is no way to prevent the condition. However, couples who wish to have children may want to be tested for the presence of a defective CFTR gene. If that gene is present, it may be passed to any future children, placing those children at risk for cystic fibrosis.

FOR MORE INFORMATION


Books

Harris, Ann, and Maurice Super. Cystic Fibrosis: The Facts. New York: Oxford University Press, 1995.

Hopkins, Karen. Understanding Cystic Fibrosis. Jackson: University Press of Mississippi, 1998.

Orenstein, David. Cystic Fibrosis: A Guide for Patients and Family. Philadelphia: Lippincott-Raven, 1997.

Silverstein, Alvin, Robert Silverstein, and Virginia B. Silverstein. Cystic Fibrosis. New York: Franklin Watts, 1994.

Organizations

Cystic Fibrosis Foundation. 6931 Arlington Road, Bethesda, MD 20814. (301) 9514422. http://www.cff.org.

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Cystic Fibrosis

Cystic Fibrosis

Rachels Story

What Is Cystic Fibrosis?

What Causes Cystic Fibrosis?

How Do Doctors Know Someone Has CF?

A Morning Ritual for Rachel

Living with CF

Resources

Cystic fibrosis is an inherited condition in which glands produce excessively sticky mucus. The sticky material clogs the lungs, liver pancreas, and intestines and makes it difficult to breathe and to digest food properly.

KEYWORDS

for searching the Internet and other reference sources

Chest physical therapy

Gene therapy

Mucoviscidosis

Phenylalanine

Pulmonary system

Rachels Story

Rachels parents were worried. They believed they provided all the proper care Rachel needed, just as they had for their older daughter when she was a baby. But Rachel failed to gain as much weight as other children her age, even though she seemed to have the typical appetite of an infant. Rachel also seemed to have more colds than other children had and a lot more colds than her older sister ever had. She coughed often and breathed with a wheezing sound. Then, around the time of her second birthday, Rachel developed pneumonia*.

* pneumonia
is an inflammation of the lungs, usually caused by bacteria, viruses, or chemical irritants.

Rachels failure to gain weight and her frequent respiratory infections led her doctor to suspect that Rachel had cystic fibrosis (SIS-tik fy-BRO-sis), which is usually known by its initials, CF. Tests confirmed the diagnosis.

CF is a hereditary disease that affects about 30,000 children and adults in the United States. It is the most common hereditary condition that affects people of European ancestry, occurring in 1 of every 2,000

live births. About 1,000 new cases of CF are diagnosed each year in the United States, usually by the time children reach their third birthday.

What Is Cystic Fibrosis?

Cystic fibrosis is a chronic, hereditary disease that affects many of the bodys organ systems. In CF, some of the thin, easy-flowing mucus* in the bodys respiratory and digestive systems become thicker. Glands* in the body produce mucus to do such things as lubricate the lungs, trap dust and bacteria that is inhaled through the nose, and protect the lining of the intestines from the acidic fluids that help digest food.

* mucus
is a combination of water, salt, cells, and other material that forms a coating that lines the respiratory and digestive systems.
* glands
are groups of cells that act on substances in the bloodstream to change them for use in other parts of the body or to remove them from the body.

The glands in people with CF, however, produce sticky mucus that clogs the passageways in the lungs, which makes it difficult to breathe and leads to infections. The sticky mucus also blocks the easy flow of digestive acids and enzymes from the pancreas* and liver* to the intestines. Without adequate amounts of these digestive fluids in the intestines, people with CF cannot break down their food into the substances the body needs for nourishment.

* pancreas
is an organ in the upper abdomen that secretes enzymes to help with digestion.
* liver
is a large organ with many functions, including secreting the digestive fluid bile.

What Causes Cystic Fibrosis?

CF is caused by a mutation in a gene* on chromosome 7. Chromosome 7 is one of 23 pairs of chromosomes that are part of each persons genetic makeup. The CF gene causes the production of a protein that lacks an important amino acid*, phenylalanine (fen-il-AL-a-neen). Without that amino acid, the protein hinders the ability of mucus to obtain the proper amounts of water and salt from the body, which the mucus needs to maintain its thin and easy-flowing texture. This turns the mucus into a dense, sticky substance that clogs the respiratory and digestive systems.

* genes
are chemicals in the body that help determine a persons characteristics, such as hair or eye color. They are inherited from a persons parents and are contained in the chromosomes found in the cells of the body.
* amino acids
are the chief components of proteins.

The obstructions in the lungs make it hard to breathe and can increase the risk of infections. The problems in the digestive system prevent the body from getting all the nutrients it needs from food. It also means people

with CF often have thicker, foul-smelling bowel movements, because fat in food cannot be broken down by digestive fluids and absorbed.

A person may carry the CF gene on one of the two copies of chromosome 7 and not have any signs of CF. This person is called a carrier*. Parents can pass the CF gene to many generations of offspring. When a person has the CF gene on both copies of chromosome 7, then that person will have CF. When parents are both carriers, such as Rachels parents, their children have a one in four chance of having CF. Estimates are that 10 million Americans, or 1 out of 29, carry the CF gene.

* carriers
are people who have the genes for a disease without having the disease itself.

How Do Doctors Know Someone Has CF?

As far back as the 1600s, there were descriptions of children with symptoms of cystic fibrosis. It was not until 1938 that it was recognized as a separate disease, because lung infections are common to many conditions. Even today, the symptoms of CF sometimes can be confused with pneumonia or asthma.

Symptoms

Cystic fibrosis affects each person differently. Many people with CF do not appear to be severely ill. In general, people with CF have some or all of these symptoms:

  • Salty-tasting skin and sweat
  • Persistent cough or wheezing
  • Many respiratory infections
  • Bulky, smelly stools or bowel movements
  • Nasal polyps (small growths in the nose)
  • Enlargement of the fingertips and toes (clubbing)

Also, people with CF may eat large amounts of food but still be hungry. The food is not being digested properly, because the mucus is blocking the ability of digestive enzymes* and acids to break down food and absorb nutrients. Large portions of the poorly digested food are passed out during bowel movements. The individual may lose weight.

* enzymes
are natural substances that speed up specific chemical reactions in the body.

Later the pancreas may clog up and fail to secrete the enzymes essential to normal digestion. The liver becomes clogged, which may lead to cirrhosis (si-RO-sis), a condition in which the liver becomes hardened and fails. Diabetes also develops frequently in people with CF as they get older.

Diagnosis Doctors may begin to suspect CF soon after birth when the baby becomes ill with repeated respiratory infections, fails to gain weight despite a healthy appetite, and shows other symptoms of CF. In addition, about 10 percent of infants with CF have intestinal blockage due to thick mucus that is apparent at birth. Many of the symptoms of CF are common in people who do not have the disease, but there are tests to confirm a person has CF.

A sweat test is considered the best method to diagnose cystic fibrosis because it is relatively easy to perform and is accurate. The test determines the salt content of perspiration. Although sweat can seem salty in people without CF, the level of salt in the perspiration of people with CF is higher. A more complicated test looks for the CF gene on both copies of chromosome 7.

A Morning Ritual for Rachel

After her doctor determined that Rachel had cystic fibrosis, her parents worried she would not have a chance to do many of the same things as her older sister or other children. But as she grew, Rachel went to school, participated in sports, and did many other everyday activities.

Most people with CF get treatment that involves helping them breathe more easily and digest food better, which makes day-to-day activities less difficult. Although their symptoms can range from mild to severe, many people with CF receive treatments similar to Rachels.

For example, Rachel receives chest physical therapy. Each morning, her parents vigorously thump Rachels back and chest to help loosen the thick mucus in her lungs so she can cough it out. They learned the technique from a physical therapist after Rachel was diagnosed with CF.

Coughing is one of the main ways that people with CF can clear the mucus from their lungs. In school, Rachels teachers were told to expect her to cough often. Although the teacher and the students knew Rachel had CF, they did not make a big deal about her coughing. Rachel kept her own box of tissues on her desk, so she could cough the mucus into it and toss it into a nearby garbage can.

Turning on the CF Gene

In 1989, scientists discovered the location of the CF gene. If they could replace the defective gene with a normal gene, then they would be able to cure the cells that produce the defective CF protein. This would mean the mucus in the respiratory and digestive systems would be thin and easy flowing as opposed to thick and sticky.

In 1990, two teams of researchers were able to correct CF cells in lab dishes, by adding normal copies of the gene. In the spring of 1993 the first experimental dose was given to a person with CF. In October 1993, scientists determined that gene treatment had repaired a damaged gene in a human patient.

Gene therapy is a complicated experimental process. Scientists are beginning to understand what methods can be used to deliver the gene to the parts of the body where it can do its work. And they are studying how often the treatment would need to be repeated to assure the best results.

It could be that the gene therapy never would be able fix all of the defective genes, but it might cause enough of them to work properly to improve the quality of life for people with CF.

Rachel also participated in physical education classes. Exercise is another way that people with CF loosen the mucus in their lungs. Sometimes Rachel got tired more quickly than the other children, because she could not breathe as easily. But she joined in many of the exercises and games on most days.

At lunch and other times she ate a meal or snacks, Rachel took pills. The pills contained enzymes to help her digest food. Without them, the mucus in her digestive system would prevent her from getting the nutrients she needs from food. Even with the enzyme pills, Rachel and others with CF often need to take vitamin supplements and eat a diet rich in nutrients to assure they get the proper nourishment.

Rachel and others with CF also take antibiotics to prevent or treat lung infections. Sometimes, the antibiotics are taken as pills or inhaled into the lungs using a device called a nebulizer. People with CF also sometimes take prescription medications that thin the mucus and help reduce lung inflammation, which makes breathing easier and helps reduce the number of lung infections.

Perhaps the most exciting news for people with CF like Rachel was the discovery of the CF gene in 1989. It has led to research into gene therapy.

Living with CF

Once, CF almost always caused death in childhood. But treatments in recent decades have allowed many people with cystic fibrosis to live into adulthood. As with children, the symptoms for an adult can range from mild to severe, but eventually the recurring infections in the lungs begin to damage the lungs ability to function. This is the usual reason people with CF eventually die.

The Cystic Fibrosis Foundation says that now the average life expectancy of people with CF is 31 years. That is many years longer than in the past, but it still means only half of the people with CF will live that long. About half will live longer. With treatment, people with CF are able to do many of the things that other people do. And with work continuing in gene therapy, there is optimism that CF research is advancing toward a cure.

Boomer Fights Back

When Gunnar Esaison was diagnosed in 1993 with cystic fibrosis, his father, Boomer Esaison, decided to fight back. The Cincinnati Bengals quarterback, National Football League star, and television sports reporter had been a fierce competitor for many years. Now, his greatest battle became the fight against CF.

The NFL star started the Boomer Esaison Foundation, with the main goal being to find a cure for CF. The Foundation supports basic research and clinical trials for new CF treatments.

See also

Asthma

Genetic Diseases

Pneumonia

Resources

Books

Grinshaw, Joshua. My Heart Is Full of Wishes. Austin, TX: Raintree-Steck-Vaughn, 1995. A young boy with CF describes his dreams.

Harris, Ann. Cystic Fibrosis: The Facts. New York: Oxford University Press, 1995.

Silverstein, Alvin. Cystic Fibrosis. New York: Venture Books, 1994.

Organization

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

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cystic fibrosis

cystic fibrosis Hereditary glandular disease in which the body produces abnormally thick mucus that obstructs the breathing passages, causing chronic lung disease. There is a deficiency of pancreatic enzymes, an abnormally high salt concentration in the sweat and a general failure to gain weight. The disease is treated with antibiotics, pancreatic enzymes and a high-protein diet; sufferers must undergo vigorous physiotherapy to keep the chest as clear as possible.

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cystic fibrosis

cystic fibrosis A genetic disease due to a failure of the normal transport of chloride ions across cell membranes. This results in abnormally viscous mucus, affecting especially the lungs and secretion of pancreatic juice, hence impairing digestion.

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cystic fibrosis

cys·tic fi·bro·sis • n. a hereditary disorder affecting the exocrine glands. It causes the production of abnormally thick mucus, leading to the blockage of the pancreatic ducts, intestines, and bronchi.

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Cystic Fibrosis

Cystic Fibrosis

Cystic fibrosis (CF) is one of the most common genetic diseases and one of the best known to the general public. There are approximately one thousand new cases of CF in the United States every year, and approximately thirty thousand people in the country are currently affected. In many ways, it has come to be viewed, along with sickle-cell disease, as a prototypical recessive genetic disorder, one that can teach us a great deal about the molecular basis of disease, population genetics, and delivery of genetic screening services.

Clinical Features

CF is a multisystem disease, affecting a number of different organs and tissues throughout the body. Most of these manifestations have in common the production of abnormally viscous secretions from glands and surface epithelial cells . In the lung the mucus secretions from the bronchial epithelial cells are unusually thick. They are difficult to clear properly from the airway passages and, instead, tend to collect and obstruct the bronchial tree, while providing a perfect culture medium for dangerous bacteria. Over time, repeated bacterial infections damage and destroy the lung tissue, leading to chronic breathing problems and, eventually, to the loss of viable lung function. Indeed, the pulmonary manifestations of the disease are the main cause of death in most CF patients.

Obstruction in other organs is also seen. In the pancreas it leads to an insufficiency of pancreatic enzymes and malabsorption during digestion; in the nose and sinuses, it produces chronic sinusitis; and in the intestines, in a small minority of newborn infants with CF, it produces an often fatal condition called meconium ileus. Altered secretions also occur in the sweat glands, so that the sweat of CF patients has an abnormally high salt content. In fact, in the early days of medicine, the diagnosis of CF was often made by licking the skin and tasting the sweat! One additional mysterious clinical feature of CF occurs only in men with the disorder: They are infertile due to blockage or congenital absence of the vas deferens, the tube through which sperm pass prior to ejaculation.

Laboratory Diagnosis

Since the clinical symptoms of CF are so varied, diagnosis is aided by laboratory tests. For many years the only definitive test available was sweat chloride analysis, which detects and quantifies the abnormally high salt concentrations in the sweat of CF patients. Since the causative gene was discovered in 1989, as described below, patients can now also be diagnosed by DNA testing, which detects mutations in the gene.

Mode of Inheritance

CF is a classical autosomal recessive disease, in which affected patients are born to parents who are both carriersthat is, they have a mutation in one of their two CF genes. Carrier couples have a one-in-four risk of producing an affected child with each pregnancy. The carriers themselves are completely asymptomatic and even have normal sweat chloride tests.

Treatment

There is still no cure for this disease, but supportive therapies have improved markedly in the last twenty years. The recurrent lung infections are now much better controlled with powerful, new-generation antibiotics, though, unfortunately, many patients eventually develop infections with drug-resistant bacteria. A variety of approaches are used to break up and remove the thick mucus secretions in the lung, including mucolytic (mucusbreaking) agents, bronchodilators, and chest physical therapy. One type of mucolytic treatment is DNase, a DNA-destroying enzyme that breaks up the long, sticky DNA strands left by dying cells. Some patients with end-stage lung disease can be rescued by lung transplantation. Patients with pancreatic obstruction can be managed with pancreatic enzyme supplements, and affected men with vas deferens obstruction have been able to father children by a technique called sperm aspiration, followed by in vitro fertilization.

The ultimate hope for the cure of CF lies in gene replacement therapy. A number of clinical trials are under way, most attempting to deliver the normal CF gene to the bronchial epithelium by aerosol spray, using a viral vector (usually adenovirus, a common respiratory virus that naturally targets the desired tissue). Thus far the attempts have not been completely successful, as most patients develop an immune response against the virus during the course of therapy. But with the median life expectancy of CF patients now at thirty years just through conventional therapies, the hope is that many CF patients alive today will survive long enough to avail themselves of gene therapy once it is perfected.

The Cystic Fibrosis Gene and CFTR Protein

The identification of the causative gene for CF in 1989 represented one of the great triumphs of molecular genetic research up to that time. With the gene's identification having preceded the official start of the Human Genome Project by one year, the search for the CF gene proceeded without the benefits of the fully mapped genome that we have today. Hence, some of the techniques used to identify the CF gene, such as "gene walking" and "gene jumping," are no longer used extensively.

The CF gene was identified through linkage analysis and positional cloning . Whereas nowadays the map of the human genome is saturated with these markers, which serve as convenient "signposts" in gene mapping studies, this was not the case when the CF mapping was done, and more laborious, brute-force techniques such as those mentioned above had to be employed. Thus, it was dramatic news indeed when the causative gene was found on chromosome 7.

As might have been expected based on the secretory defects in the disease, the gene, dubbed "cystic fibrosis transmembrane conductance regulator" (CFTR ), encodes an ion-channel protein in epithelial cell membranes. The gene is quite large250,000 nucleotidesand the spectrum of mutations in CF patients continues to grow. At the time of this writing, more than 950 different mutations have been reported. Most of these are quite rare and may only be found in individual families. A few are more common, most notably a three-nucleotide deletion of codon 508, called ΔF508, which is found in approximately 70 percent of Caucasian CF carriers. Several others are present in 1 percent to 3 percent of carriers, while the remainder are very rare, except for some that are found at higher frequency in particular ethnic and racial groups (such as W1282X in the Ashkenazi-Jewish population and 3120+1GA in the African-American population).

The ΔF508 mutation in the CFTR gene deletes a phenylalanine amino acid from the final protein. Like other membrane proteins, CFTR is made at the endoplasmic reticulum in the interior of the cell, and must be transported to the plasma membrane to function. The absence of this amino acid results in improper folding of the CFTR protein within the endoplasmic reticulum, which causes it to be degraded by the cell's protein-recycling machinery before it reaches the membrane. Some of the less common mutations prevent any protein synthesis by introducing a stop codon into the gene, while others allow the protein to reach the membrane but without functioning properly.

The CFTR protein forms a pore to allow chloride ions to pass through the plasma membrane. The full range of functions served by this pore is not known, but the sticky secretions of CF are believed to result when chloride ions in the salty fluid secreted by the epithelial cells cannot be recovered by the membrane protein.

Cystic Fibrosis DNA Testing and Screening

The discovery of the CFTR gene raised hopes that the detection of mutations at the DNA level could supplement the traditional sweat test for CF diagnosis and, more importantly, might be used to identify carriers in the general population so that they could be offered genetic counseling. Unfortunately, these goals have been hampered by the large number of possible mutations in the gene, since present-day DNA tests can detect only a small subset of them. As in most recessive diseases, the vast majority of carriers have no family history of the disorder and do not discover that they are carriers until they happen to have a child with another carrier, giving birth to their first affected child.

CF is an appealing target for population carrier screening simply because of the relatively high carrier frequency in the general population. One in twenty-nine Caucasians, one in forty-six Hispanics, one in sixty-five African Americans, and one in ninety Asian Americans are carriers. It is not known why the mutation frequency is so high, especially in European populations. Some have proposed, using the analogy of the sickle-cell gene conferring relative resistance to malaria, that the mutations must have a protective effect against some disease appearing in European history, such as cholera or tuberculosis.

But all of this is just speculation. DNA screening of the entire adult population could potentially identify those couples at risk, who could then be offered prenatal diagnosis, affording couples the opportunity to consider their options. After several pilot studies and much debate at the national level, it has now been recommended that screening for the twenty-five most frequent CFTR mutations be offered to all couples expecting a child or planning a pregnancy. So most of the students reading this book will eventually be offered this DNA test!

see also Cell, Eukaryotic; Gene Discovery; Gene Therapy; Genetic Counseling; Heterozygote Advantage; Human Disease Genes, Identification of; Inheritance Patterns; Population Screening; Proteins.

Wayne W. Grody

Bibliography

Welsh, Michael J., and Alan E. Smith. "Cystic Fibrosis." Scientific American 273 (1995): 53-59.

Internet Resources

"Airway Clearance Techniques." University of Wisconsin Medical School. <http://www2medsch.wisc.edu/childrenshosp/CF/cfpages/cpt2.html>.

Cystic Fibrosis Foundation. <http://www.cff.org>.

Grody, Wayne W., et al. "Laboratory Standards and Guidelines for Population-Based Cystic Fibrosis Carrier Screening." Genetics in Medicine 3 (2001): 149-154. <http://www.acmg.net>.

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Cystic Fibrosis

Cystic Fibrosis

Definition

Cystic fibrosis (CF) is an inherited disease that affects the lungs, digestive system, and sweat glands, and causes infertility in males. 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, an inflammatory response that blocks passageways—particularly airway passages—and therefore prevents proper functioning of the affected areas.

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

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. Several decades ago, most children with CF died by the age of two years. By the end of the twentieth century, about one-half of all people with CF lived past 31 years of age. That median age is expected to grow as new treatments are developed. It is estimated that a person born in 2001 with CF has a median expected life span of about 40 years.

Genetic profiles

Cystic fibrosis is a genetic disease, meaning it is caused by a defect passed on through the genes. Genes, found in the nucleus of all body 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 cystic fibrosis transmembrane conductance regulator (CFTR) gene, when defective, causes CF. A simple defect in this gene leads to all the consequences of CF. There are more than 500 known defects in the CFTR gene that can cause CF. However, mutation delta F508 in exon 10 is present in about 70% of CF chromosomes worldwide.

Genes can be thought of as long strings of chemical words, each made of chemical letters called nucleotides. Just as rearranging its letters can change a word and changing a word can change a sentence, 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 properly perform its function.

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 from 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 does not 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 (including insulin) into the intestine, causing serious impairment of digestion, especially of fats, which may lead to malnutrition. Mucus in the lungs may plug the airways, preventing good air exchange and, ultimately, leading to emphysema or COPD. The mucus is also a rich source of nutrients for bacteria, leading to frequent infections such as sinusitis, bronchitis, and gastritis.

Inheritance factor

To understand the inheritance pattern of CF, it is important to realize that genes actually have two functions. First, they serve as the blueprint for the production of proteins. Second, they are the material of inheritance: parents pass on characteristics to their children by combining the genes in egg and sperm to make a new individual.

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 children.

When two carriers have children, they have a one-in-four chance of having a child with CF each time they conceive, 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.

There are large differences in the frequency of mutated CF genes among different ethnic populations. For example, the frequency is highest in populations of northern-European descent—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 whether or not 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 expect that the high mortality rate for CF patients before reaching childbearing age would quickly lead to the loss of the mutated gene from the population. It appears, however, that carriers may be protected from the intense diarrhea and eventual death by dehydration caused by cholera and typhoid fever. (This so-called "heterozygote advantage" is seen in some other genetic disorders, including sickle-cell anemia.) Some researchers believe that when these epidemics spread through early European populations, which were then much smaller, they would wipe out vast numbers in that population. However, people who carried one copy of the CF gene would have a greater chance of survival and so, therefore, would the defective gene. The incidence of the gene, then, would increase to a high level within that population. In hot climates, where dehydration from chronic excessive salt loss (perspiring) caused more deaths than occasional bouts of life-threatening diarrhea, the CF gene never gained the foothold it did in the colder European countries. Also, some researchers propose that CF heterozygotes are more resistant to asthma.

Causes and 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; gastrointestinal symptoms are often the first to appear.

Gastrointestinal system

Ten to fifteen 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 mucus 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 a "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 (including insulin) that help 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 already inflamed pancreatic duct. Eventually, the duct becomes completely closed off by subsequent 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 poorly digested and absorbed, a person with CF is often ravenously hungry, underweight, and shorter than expected for a given age. When CF is not treated for a longer period, a child may develop symptoms of malnutrition, including anemia, bloating, and—paradoxically—appetite loss. The rib cage may eventually become barrel-shaped as the patient struggles with breathing and with the formation of emphysema-like symptoms.

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

Gall stones affect approximately 10% 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, 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 (telescoping), in which part of the intestinal tube slips over an adjoining part, cutting off blood supply.

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

Respiratory tract

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

Swelling of the sinus mucus membrane lining is common in people with CF. This usually shows up on x ray and may aid the diagnosis of CF. However, this swelling, called pansinusitis, rarely causes problems unless there is blockage and infection. Children with CF have a high rate of infection of the sinuses, requiring antibiotic therapy to prevent the infection from proceeding to the lungs.

Nasal polyps, or growths, affect about one in five people with CF. These growths are not cancerous and do not require removal unless they block nasal drainage enough to cause chronic sinus infections. However, they are usually treated medically before surgery is considered. 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 hyperinflammatory state of the membranes causes production of a thick, sticky mucus (that is actually the body's attempt to soothe the affected area). However, this mucus increases the likelihood of infection, decreases the ability to protect against infection, and causes further blockage of normal functioning in the airways. This blockage, in turn, exacerbates the inflammation and swelling. The functional capacity of the lungs is therefore severely compromised and may ultimately lead to emphysema. People with CF will live with chronic obstructive pulmonary disease (COPD) or bacteria residing in their lungs. 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, called cilia, on the surface of these passageways slowly move mucus out of the lungs and up the bronchus to the trachea and 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 ciliary movement of debris out of the lungs and increases the irritation and existing inflammation of airways and 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 their 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 that is resistant to most current antibiotics. (Burkholderia cepacia was formerly known as Pseudomonas cepacia.) The fungus Aspergillus fumigatus may infect older children and adults.

The body's response to inflammation and 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 cell constituents serve as messengers to enhance the production of both inflammatory and antiinflammatory cells and mediators.

As mucus accumulates it can plug up the smaller passageways in the lungs, decreasing functional lung volume. Inhaling enough air (oxygen) can become difficult; fatigue, 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 or impairment lead to "digital clubbing," in which the last joint of the fingers and toes becomes slightly enlarged and the distal fingernail edges curl around and over the enlarged fingertip.

Sweat glands

The CFTR protein helps to regulate the amount of salt in perspiration. People with CF have perspiration with a higher salt content than normal, and measuring the saltiness of a person's sweat is a key 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, and require electrolyte supplementation. Heat prostration is marked by lethargy, weakness, and loss of appetite, and should be treated as an emergency condition, especially in children and the elderly.

Fertility

Ninety-eight 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 difficulty conceiving 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 CF who have good lung health usually have no problems with pregnancy, while those with ongoing lung infection often do poorly. The potential for digestive disruption from intestinal displacement may also pose problems, regardless of lung function.

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 one child has already manifested the disease. Some hospitals now 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 analyzed for its salt content. A person with CF will have salt concentrations that are one and one-half to two 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 have the disease will test negatively.

Genetic testing

The discovery of the CFTR gene mutation 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, it is important to remember that 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, both to determine if they will develop CF and if they are carriers. This aids in their own family planning. If the sibling has no symptoms, determining carrier status is often delayed until the teen years or later, when persons are closer to needing the information to make decisions.

Newborn screening

Some states now require screening of all newborns for CF using a test known as the IRT test—a blood test that measures the level of immunoreactive trypsinogen. Babies with CF generally have higher levers of IRT; however, this test is not an accurate predictor as it gives many false positive results immediately after birth. A second test is therefore required several weeks later for validation. A second positive result indicates the need to conduct a sweat test.

Treatment

There is no cure for cystic fibrosis. Treatment has advanced considerably since the mid-1900s, 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 a young child. With proper management, many people with CF may participate 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 regularly monitored. 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 at a time. Because of incomplete absorption even with pancreatic enzymes, a person with CF needs to take in about 30% 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, but the high calorie diet does not include increased fat intake (above normal).

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 a person is sleeping, allowing constant intake of high-quality nutrients. The feeding tube may be removed or temporarily occluded during the day, allowing the patient to take food by mouth.

Respiratory health

The key to maintaining respiratory health in a person with CF is regular monitoring and early treatment. Pulmonary 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 are performed with the patient inhaling radioactive contrast gas that helps define areas on the lungs not visible with x rays. Pulmonary circulation may be monitored by injection of a radioactive substance into the bloodstream.

People with CF live with chronic bacterial colonization. This means that their lungs are constantly host to several species of bacteria. Good general health, especially good nutrition, may keep the immune system functioning well, decreasing the frequency with which the resistant bacterial colonies multiply and cause infection or attack lung tissue. Exercise is also important to promote pulmonary health, and people with CF are encouraged to maintain a regular exercise program.

Clearing mucus from the lungs also helps prevent infection, and mucus control is an important aspect of CF management. Bronchial drainage (postural drainage) allows gravity to aid the mucociliary escalator. For this technique the patient lies on a tilted surface with head downward (Trendelenburg); alternately on the stomach, back, or side, depending on the section of lung to be drained. An assistant performs respiratory percussion techniques with varying strokes, rhythms, and hand positions, moving systematically over the patient's chest, rib cage, and upper back to help loosen 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, such as diaphragmatic breathing, and rib cage expansion and locking that allows the diaphragm freedom of movement, may also help clear the lungs.

Several drugs are available to prevent the airways from becoming clogged with mucus. Bronchodilators can help open up the airways, steroids reduce inflammation, and mucolytics loosen secretions. Surfactants are used to reduce the surface tension of the mucus, like a detergent breaks the surface tension of water and oils. Acetylcysteine (Mucomyst) has been used as a mucolytic for many years but now is less frequently prescribed, while DNase (Pulmozyme) is a newer product gaining in popularity. DNase is an enzyme that helps break down the DNA from dead white blood cells and bacteria found in thick mucus.

People with CF may contract cross-infected bacteria from other persons with CF. 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 always practical (since CF is a familial disease and CF clinics are a major site of care), nor does it meet the psychological and social needs of patients. At a minimum, CF centers recommend avoiding prolonged close contact between people with CF, and the use of scrupulous hygiene techniques, 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 for patients with CF only during an infection, while others prefer long-term prophylactic 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 for patients with CF, by necessity, may be prolonged and aggressive.

Supplemental oxygen may be needed as lung disease in CF progresses. In some cases, respiratory failure episodes require the temporary use of a ventilator to perform the work of breathing until the patient can begin to regain control and be weaned from the machine.

Lung transplantation is another option for people with CF, although the number of people who receive them is still much lower than those who need them. Transplantation is not a cure, however, and has been likened to trading one disease for another because long-term immunosuppression is required, increasing the likelihood of contracting opportunistic infections. About 50% of adults and more than 80% of children with CF who receive lung transplants live longer than two years posttransplant. Liver transplants may also be required for people with CF whose livers have been damaged by fibrosis.

Long-term use of ibuprofen as an antiinflammatory agent has been shown to help some people with CF. Close medical supervision is necessary, however, since the effective dose for patients with CF is high and not everyone benefits. Ibuprofen at these higher doses interferes with kidney function and, if taken together with aminoglycoside antibiotics, may cause kidney failure.

A number of experimental treatments are under 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% of those with CF.

Gene therapy has become the most ambitious approach to curing CF. In this set of techniques, copies of the healthy CFTR gene are delivered to affected cells, where they are accepted 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 so far, including immune resistance, very short life-cycle duration of the introduced gene, and inadequately widespread distribution.

Alternative treatment

In homeopathic medicine the primary goal is to address the symptoms of CF in order to enhance quality of life. It is not yet possible to treat the cause, owing to the genetic basis of the disease. Homeopathic medicine seeks to treat the whole person, however, and in cystic fibrosis, this approach may include:

  • mucolytics to help thin the mucous
  • supplementation of pancreatic enzymes to assist in digestion
  • addressing respiratory symptoms to open lung passages
  • hydrotherapy techniques (such as nighttime mist tents) to help ease respiratory symptoms and help the body eliminate mucus from the lungs
  • immune enhancements (such as vitamin supplementation) to help prevent development of secondary infections
  • dietary enhancements and adjustments to treat digestive and nutritional problems

Prognosis

Approximately half of all people with CF live past the age of 30 years; however, because of earlier intervention and enhanced treatment, a person born in 2001 with CF may be expected, on average, to live to 40 years of age.

KEY TERMS

Carrier— In CF, a person with one copy of a defective gene who does not have the disease it causes but can pass along the defective gene to offspring.

COPD (Chronic obstructive pulmonary disease)— A progressive disease process that commonly stems from smoking. COPD is characterized by difficulty breathing, wheezing, and a chronic cough.

Cystic fibrosis transmembrane conductance regulator (CFTR)— The protein responsible for regulating chloride movement across cells in some tissues. When a person has two defective copies of the CFTR gene, cystic fibrosis is the result.

Emphysema— A pathologic accumulation of residual air in organs or tissues. This term is especially applied to the condition when in the lungs.

Gastrostomy tube— A tube that is inserted through a small incision in the abdominal wall and that extends through the stomach wall into the stomach for the purpose of introducing parenteral feedings.

Jejunostomy tube— A tube inserted through the abdominal wall and into the small intestine for the purpose of introducing parenteral feeding.

Lung surfactant— A surface active agent that renders the alveolar surfaces hydrophobic and prevents the lung filling with water by capillary action.

Meconium ileus— Obstructed bowel due to impacted, tenacious, meconium (infant's first stool).

Mucociliary escalator— The coordinated action of tiny projections on the surfaces of cells lining the respiratory tract that moves mucus up and out of the lungs.

Mucolytic— An agent that dissolves or destroys mucin, the chief component of mucus.

Nasogastric tube— A tube inserted through the nose, extending through the pharynx and esophagus, and into the stomach for the purpose of introducing parenteral feeding.

Pancreatic insufficiency— Reduction or absence of pancreatic secretions into the digestive system due to scarring and blockage of the pancreatic duct.

People with CF may lead relatively normal lives. Careful consideration of the effects pregnancy may have on a woman with CF is essential before beginning a family. Issues of parental longevity and the potential for the child to be a carrier are also concerns. Although most men with CF are functionally sterile, new procedures for removing sperm from the testes are being attempted that may offer more men suffering from CF the chance to become fathers.

Health care team roles

A pediatrician usually makes the initial diagnosis of CF. Family physicians, internists, and pulmonologists can manage persons with CF. Radiologists take images to document the extent of CF. Nurses, respiratory therapists, physical therapists, and nutritionists provide symptomatic treatments and supportive services. Surgeons are needed if transplantation is required.

Prevention

As of 2001 there was no way to prevent the development of CF in a person with two defective copies of the relevant gene from both parents. Adults with a family history of CF may obtain a genetic test of their carrier status for purposes of family planning. Prenatal testing is also available to determine the genetic status of the infant with regard to CF.

Resources

BOOKS

Boat, Thomas F. "Cystic Fibrosis." In Nelson Textbook of Pediatrics, 16th ed. Eds. Richard E. Behrman, et al. Philadelphia: Saunders, 2000, 1315-1327.

Boucher, Richard C. "Cystic Fibrosis." In Harrison's Principles of Internal Medicine, 14th ed. Eds. Anthony S. Fauci, et al. New York: McGraw-Hill, 1998, 1488-1451.

Gold, Susan D. Cystic Fibrosis. Berkeley Heights: Enslow Publishers, Inc., 2000.

Orenstein, David M., and Robert C. Stern, eds. Treatment of the Hospitalized Cystic Fibrosis Patient. New York: Marcel Dekker, 1998.

Orenstein, David M., Robert C. Stern, and Beryl J. Rosenstein. Cystic Fibrosis: Medical Care. Philadelphia: Lippincott Williams & Wilkins, 2000.

Welsh, Michael J. "Cystic Fibrosis." In Pocket Companion to Cecil Textbook of Medicine. 21st ed. Eds. Lee Goldman and J. Claude Bennett. Philadelphia: W.B. Saunders, 2000, 401-405.

Yankaskas, James R., and Michael R. Knowles. Cystic Fibrosis in Adults. Philadelphia: Lippincott Williams & Wilkins, 1999.

PERIODICALS

Abbott, J., M. Dodd, L. Gee, and K. Webb. "Ways of Coping with Cystic Fibrosis: Implications for Treatment Adherence." Disability and Rehabilitation 23, no. 8 (2001): 315-324.

Braekeleer, M.D., G. Bellis, G. Rault, C. Allard, M. Milot, and F. Simard. "Disease Knowledge in a High-Risk Population for Cystic Fibrosis." Patient Education and Counseling 43, no. 3 (2001): 265-270.

Dakin, C., R.L. Henry, P. Field, and J. Morton. "Defining an Exacerbation of Pulmonary Disease in Cystic Fibrosis." Pediatric Pulmonology 31, no. 6 (2001): 436-442.

Kurland, G., and D.M. Orenstein. "Lung Transplantation and Cystic Fibrosis: The Psychosocial Toll." Pediatrics 107, no. 6 (2001): 1419-1420.

Truby, H., and A.S. Paxton. "Body Image and Dieting Behavior in Cystic Fibrosis." Pediatrics 107, no. 6 (2001): E92.

Wilson, D.C., M. Rashid, P.R. Durie, A. Tsang, D. Kalnins, M. Andrew, M. Corey, J. Shin, E. Tullis, and P.B. Pencharz. "Treatment of Vitamin K Deficiency in Cystic Fibrosis: Effectiveness of a Daily Fat-Soluble Vitamin Combination." Journal of Pediatrics 138, no. 6 (2001): 851-855.

ORGANIZATIONS

American Lung Association. 1740 Broadway, New York, NY 10019. (212)-315-8700. 〈http://www.lungusa.org/diseases/lungtb.html〉.

American Thoracic Society. 1740 Broadway, New York, NY 10019. (212) 315-8700. 〈http://www.thoracic.org〉.

Canadian Cystic Fibrosis Foundation. 2221 Yonge Street, Suite 601, Toronto, Ontario, M4S 2B4. (416) 485-9149. 〈http://www.ccff.ca/home.cfm〉.

Cystic Fibrosis Foundation. 6931 Arlington Road, Bethesda, Maryland 20814. (301) 951-4422 or (800) 344-4823. 〈http://www.cff.org〉.

International Association of Cystic Fibrosis Adults. 〈http://ourworld.compuserve.com/homepages/FAntognini/iacfa.htm〉.

OTHER

American Association for Respiratory Care. 〈http://www.aarc.org/patient_education/iq_tests/cf/cf_form.html〉.

CF Web. 〈http://www.cf-web.org〉.

Cystic-L. 〈http://cystic-l.org〉.

Merck Manual. 〈http://www.merck.com/pubs/mmanual/section19/chapter267/267a.htm〉.

Michigan State University (testing). 〈http://www.phd.msu.edu/cf/cfhome.html〉.

National Institute of Diabetes and Digestive and Kidney Diseases. 〈http://www.niddk.nih.gov/health/endo/pubs/cystic/cystic.htm〉.

National Library of Medicine. 〈http://www.nlm.nih.gov/pubs/cbm/cystic_fibrosis.html〉 and 〈http://www.nlm.nih.gov/medlineplus/cysticfibrosis.html〉.

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Cystic Fibrosis

Cystic Fibrosis

The genetic basis of CF

Clinical manifestations in CF

Treating CF

Gene therapy for CF

A test for the CF gene

Resources

PERIODICALS

Cystic fibrosis (CF) is genetic disease characterized by defects in the bodys ability to transport within and between cells a molecule called chloride. Abnormalities in CF have been described in several organs and tissues, including the airways, pancreas, bile ducts, gastrointestinal tract, and sweat glands. Lung function is often normal at birth; however, airway obstruction and inflammation as well as bacterial colonization are characteristically seen in the CF airways. The pathophysiological consequences that follow are believed to stem from repetitive cycles of bacterial infection, which contributes to a progressive deterioration in lung function.

In the United States, the disease affects about one in every 3, 900 babies born annually, and it is estimated that approximately 30, 000 Americans are afflicted with this disease. The genetic defect that causes CF is most common in people of northern European descent. It is estimated that one in 25 of these individuals are carriers of a defective gene that causes CF. Currently, there is no cure for CF and the disease can be fatal. In the past, individuals with CF would die sometime during childhood. With new drugs and treatments, the usual age of survival has increased to about the mid-thirties.

The genetic basis of CF

CF is a homozygous recessive genetic disorder. In this type of disorder, two defective copies of the gene, one from each parent, must combine to produce the disease. If two people who each carry the defective copy of the gene have a child, chances are that one in four of their offspring will have CF.

In 1989, a team of researchers located the defective CF gene, which was found to be located on chromosome 7. Genes are segments of deoxyribonucleic acid (DNA) that code for certain proteins. If the sequence of DNA mutates in a gene, the protein for which it encodes also can change. In CF, a change or mutation in the DNA sequence of the gene can lead to the production of a defective version of an important protein. This protein is called the cystic fibrosis trans-membrane conductance regulator, or CFTR. The protein works as an ion pump within the cell membrane and regulates the movement of sodium and chloride (electrolytes that makeup salt) into and out of cells. In people with CF, this pump does not work properly. As a result, water is retained within the cells. A dry, sticky mucus also builds up in the tissues that are affected.

Clinical manifestations in CF

Most of the symptoms of CF are related to the sticky mucus that clogs the lungs and pancreas. People with CF have difficulty breathing and are highly susceptible to bacterial infections of the lungs. Normally, bacteria are expelled from the lungs by coughing and the movement of mucus up the airways to the throat where the bacteria can be expelled. In people with CF, the mucus is too thick to be removed and bacteria are able to inhabit the lungs and cause infection.

In addition to the airways, other tissues are affected in CF. The abnormalities found in these tissues are characterized by abnormally thick and dehydrated secretions, which appear to cause obstruction resulting in organ dysfunction. For example, the pancreatic ducts are obstructed resulting in tissue degeneration, fibrosis (scarring), and organ dysfunction. The pancreas secretes enzymes during digestion that break food into smaller pieces so that the body can absorb nutrients. Enzymes speed up chemical reactions and the enzymes in the pancreas are important for digestion of foods. Failure of the pancreas to function normally results in pancreatic enzyme insufficiency, which is observed in approximately 85% of CF patients. Without treatment, enzyme deficiency results in protein and fats being poorly digested, which can lead to malnutrition.

In the gastrointestinal tract (the organ that digests and processes broken down food), accumulation of mucous secretions also occurs. Dehydrated intestinal contents combined with abnormal mucous secretions are thought to predispose patients to bowel obstruction, which is a characteristic symptom in 1020% of CF newborns. The bile ducts of CF patients can also be obstructed, producing gall bladder disease and elevations in liver function enzymes, occasionally leading to liver failure.

Greater than 95% of males with CF are infertile due to structural alterations in the reproductive tract that results in the sperm being incapable of fertilization, or azoospermia. These structures include the vas deferens and seminal vesicles, which are both an important part of the male reproductive tract and contribute to transportation of the sperm. If the vas deferens is absent at birth, it is a condition called congenital bilateral absence of the vas deferens (CBAVD). CBAVD is characteristic in male CF patients. Reduced fertility has also been noted in females with CF and may be related in part to abnormal mucous composition in their reproductive tract.

In the sweat gland, a characteristically detectable salty sweat represents the traditional gold standard test for diagnosing CF. Testing for CF involves analyzing sweat for elevated levels of salt. The ducts of the sweat glands normally function to reabsorb sodium and chloride across the water impermeable tissues. In CF, failure to reabsorb chloride ions in the ducts results in sodium and chloride, or salts, to be concentrated in sweat. Clinical manifestations include a predisposition to dehydration.

Despite the multi-organ involvement of the disease, respiratory failure is the primary cause of death in more than 90% of CF patients. Current hypotheses suggest that, in the CF airways, defective electrolyte transport results in alterations in the volume of liquid that covers the airways, the salt content, and/or mucus composition, which leads to thick mucus secretions that cannot be easily cleared out of the airways. The resulting airway microenvironment is conducive to chronic bacterial colonization and infection by specific bacterial pathogens, including Streptococcus pneumoniae, Hemophilus pneumoniae, and Staphylococcus aeureus. These bacteria typically infect the lungs of CF children. Adults are most susceptible to Pseudomonas aeurginosa infection. A rare type of bacteria called Pseudomonas cepacia currently infects people with CF at alarming rates. Pseudomonas cepacia causes a severe infection and hastens lung damage leading to an earlier death. These infections, coupled with an abnormal inflammatory response, leads to airway destruction and death in the vast majority of CF patients.

The CF gene was identified by researchers in 1989. There are many mutations (over 1, 000) that cause CF. Some of these mutations cause a less severe disease; others cause a more severe disease. However, the same gene mutation in different people will not always result in the same symptoms.

Treating CF

Currently, no cure for CF exists. Treatment of the disease mainly involves alleviating symptoms caused by the build-up of mucus. To combat the lung infections, many persons with CF are given large doses of antibiotics to prevent a severe, life-threatening infection. Some people undergo a course of antibiotics four times a year, on a predetermined schedule. Mucus in the lungs also can be broken down by drugs called mucolytic agents. These agents can be orally. Other drugs are inhaled as aerosols.

A drug called Pulmozyme is an enzyme which breaks down the excess DNA present in the mucus of CF patients that accumulates as a result of the inflammatory process. Pulmozyme helps to thin the mucus, allowing it to be more easily expelled. Clearing the thick mucus from the lungs can also be accomplished by physiotherapy. Physiotherapy includes breathing exercises and percussion, the administration of blows to the back and chest to loosen the mucus.

To control the malabsorption of nutrients, many people with CF take pancreatic enzymes in pill form with every meal. A diet high in fat, protein, and carbohydrates is also recommended to increase the nutrient intake. Multi-vitamins can also help prevent deficiencies of certain vitamins. When these methods do not result in adequate weight gain some people supplement their diets with a nutrient-rich solution infused through a tube placed in the stomach. Newer advances in the types of pancreatic enzymes and nutritional supplements offered to CF patients are helping to avoid malnutrition.

A number of other recent therapies are available for CF patients. These include an inhaled form of the antibiotic called tobramycin. Previously given intravenously to treat infections, inhaled tobramycin appears to improve lung function, while avoiding some of the detrimental side effects associated with tobraymycin that is given intravenously. There are also other exciting development drugs that are aimed at improving the function of the protein defective in CF.

Gene therapy for CF

Researchers hoped that by discovering of the gene responsible for CF, a genetic approach to curing

KEY TERMS

Allele Any of two or more alternative forms of a gene that occupy the same location on a chromosome.

CF transmembrane conductance regulator A protein that acts as a pump in the cell membranes of airway and pancreas cells. The pump regulates the transport of sodium and chloride into and out of cells.

Homozygous recessive disorder Genetic disorder caused by the presence of two defective alleles.

Liposome A sphere composed of lipid.

Percussion A technique in which blows are administered to the back and chest to loosen mucus in the respiratory tract.

the disease will be developed. In gene therapy, a normal gene is inserted into cells to replace the defective gene. In most gene therapy experiments, cells from an affected organ are removed from the body and infected with a virus that has been modified to carry the normal gene. The newly infected cells are then put back into the body. In CF, this method has not yet been successful. The primary reason is that the lungs are equipped with a complex barrier, preventing successful penetration and delivery of the normal gene.

Before gene therapy can be considered, researchers must overcome several obstacles. The most important obstacle is the use of viruses as carriers for the normal genes. Some scientists feel that viruses are too dangerous, especially for patients who already have a chronic disease. Current studies are underway to investigate the use of liposomes, or small microscopic spheres consisting of a fatty-substance called a lipid, to transport the corrected gene.

A test for the CF gene

Recently researchers have located a number of defects on particular genes that appear to be responsible for the majority of CF cases. Knowing the location of these gene mutations makes it possible to test for carriers of the disease (individuals who have only one defective gene copy, and therefore have no symptoms themselves). Currently the test detects about 85% of the most common CF gene mutations, which can be determined by extracting DNA from a persons

blood, cheek cells, or saliva. Some researchers feel that this detection rate is still too low and that testing should be performed only on persons who have a familial history of CF or are Northern European by descent. Others argue that because the test is relatively inexpensive and easy to perform the test should be offered to everyone. At this time, testing for the gene responsible for CF remains controversial. In particular, testing parents prior to or during a pregnancy to determine their carrier status has resulted in controversy.

In 2005, scientists identified a protein that is key to developing inflammation in lung tissues when a person with CF has a lung infection. Called interleukin-23 (IL-23), the protein causes an immune response that is nevershut offbecause the lungs of persons with CF are chronically infected with bacteria. The continual immune response causes chronic inflammation in lung tissues and leads to lung damage. Scientists are investigating anti-inflammatory drugs specific to this particular chronic immune response in lung tissue, which could preserve lung tissue and function, and extend the life of persons with CF.

See also Genetic disorders; Respiratory diseases; Respiratory system.

Resources

BOOKS

Kepron, Wayne. Cystic Fibrosis: Everything You Need to Know (Your Own Personal Health). Toronto: Firefly, 2003.

Orenstein, David M. Cystic Fibrosis: Medical Care. Philadelphia: Lippincott Williams & Wilkins Publishers, 2000.

Shale, Dennis J. Cystic Fibrosis. BMJ Books, 2002.

PERIODICALS

Cohn, L.Mucus in Chronic Airway Diseases: Sorting out the Sticky Details.J Clin Invest. 116(2) (Feb 2006):3068.

OTHER

Cystic Fibrosis Foundation.About Cystic Fibrosis<http//www.cff.org/about_cf/what_is_cf.cfm> (January 15, 2003).

Bryan Cobb, PhD

Kathleen Scogna

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Cystic fibrosis

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.

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.

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. Several decades ago most children with CF died by age two years; today, 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.

Genetic profile

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 change in this gene leads to all the consequences of CF. There are over 500 known changes in the CFTR gene that can cause CF. However, 70% of all people with an abnormal CFTR gene have the same defect, known as delta-F508.

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 changes 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 does not 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.

To understand the inheritance pattern of CF, it is important to realize that genes actually have two functions. First, as noted above, they serve as the blueprint for the production of proteins. Second, they are the material of inheritance: parents pass on characteristics to their children by combining the genes in egg and sperm to make a new individual.

Each person actually has two copies of each gene, including the CFTR gene, in each of his or her 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 or 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 will know whether or not 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 now 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.

Signs and 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

Ten to fifteen 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 a "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, which 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% of adults with CF. Liver problems are less common, but can be caused by the build-up of fat within the liver. Complications of liver enlargement may include internal hemorrhaging, 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 fewer than 10% of people with CF do not have gastrointestinal symptoms. Most of these people do not have the delta-F508 mutation, but rather 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 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 will 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, which traps foreign particles including bacteria and viruses. Tiny hair-like projections called cilia 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 is resistant to most current antibiotics (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

Ninety-eight 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 now 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 one-and-one-half to two 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. Siblings in these families are also usually tested, both 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 or her carrier status is often delayed until the teen years or later, when he or she is closer to needing the information to make decisions.

Newborn screening

Some states now require screening of newborns for CF, using a test known as the IRT test. This is a blood test which 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 and management

There is no cure for cystic fibrosis. Treatment has advanced considerably in the past several decades, 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% 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. Bronchial 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 can help open up the airways; steroids reduce inflammation; and mucolytics loosen secretions. Acetylcysteine (Mucomyst) has been used as a mucolytic for many years but is not prescribed frequently now, 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 is another option for people with CF, although the number of people who receive them is still 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% of adults and more than 80% of children who receive lung transplants live longer than two years. Some CF patients whose livers have been damaged by fibrosis also undergo liver transplants.

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 are currently 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% of those with CF.

Gene therapy is currently the most ambitious approach to curing CF. In this set of techniques, nondefective 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 so far, including immune resistance, very short duration of the introduced gene, and inadequately widespread delivery.

Alternative treatment

In homeopathic medicine, the symptoms of the disease would be addressed to enhance the quality of life for the person with cystic fibrosis. Treating the cause of CF, because of the genetic basis for the disease, is not possible. Homeopathic medicine seeks to treat the whole person, however, and in cystic fibrosis, this approach might include:

  • Mucolytics to help thin mucous.
  • Supplementation of pancreatic enzymes to assist in digestion.
  • Respiratory symptoms can be addressed to open lung passages.
  • Hydrotherapy techniques to help ease the respiratory symptoms and help the body eliminate mucus.
  • Immune enhancements can help prevent the development of secondary infections.
  • Dietary enhancements and adjustments are used to treat digestive and nutritional problems.

Prognosis

People with CF may lead relatively normal lives. The possible effect of pregnancy on the health of a woman with CF requires careful consideration before beginning a family, as do issues of longevity, and their 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 today with CF is expected, on average, to live to age 40.

Resources

BOOKS

Gehehrter, Thomas, Francis Collins, and David Ginsburg. Principles of Medical Genetics. Baltimore: Williams & Wilkins, 1998.

Harris, Ann, and Maurice Super. Cystic fibrosis: The facts. New York; Oxford, UK: Oxford University Press, 1995.

Orenstein, David. Cystic fibrosis: A guide for patient and family. Philadelphia; New York: Lippincott-Raven, 1997.

ORGANIZATIONS

Cystic Fibrosis Foundation. 6931 Arlington Rd., Bethesda, MD 20814. (301) 951-4422. <http://www.cff.org>.

WEBSITES

Cystic Fibrosis Information. <http://cf-web.mit.edu/index.html>.

Edward Rosick, DO, MPH, MS

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Cystic Fibrosis

Cystic fibrosis

Cystic fibrosis (CF) is genetic disease characterized by defects in the transport of a molecule called chloride. Abnormalities in CF have been described in several organs and tissues, including the airways, pancreas, bile ducts, gastrointestinal tract, sweat glands , and male reproductive. Lung function is often normal at birth ; however, airway obstruction and inflammation as well as bacterial colonization are characteristically seen in the CF airways. The pathophysiological consequences that follow are believed to stem from repetitive cycles of bacterial infection , which contributes to a progressive deterioration in lung function.

In the United States, the disease affects about one in every 3,900 babies born annually, and it is estimated that approximately 30,000 Americans are afflicted with this disease. The genetic defect that causes CF is most common in people of northern European descent. It is estimated that one in 25 of these individuals are carriers of a defective gene that causes CF. Currently, there is no cure for CF and the disease can be fatal. In the past, individuals with CF would die sometime during childhood. With pharmacological intervention due to drug discovery from many years of research, the age of survival has increased 31 years.

The genetic basis of CF

CF is a homozygous recessive genetic disorder. In this type of disorder, two defective copies of the gene, one from each parent, must combine to produce the disease. If two people who each carry the defective copy of the gene have a child, chances are that one in four of their offspring will have CF.

In 1989, a team of researchers located the defective CF gene, which was found to be located on chromosome 7. Genes are segments of deoxyribonucleic acid (DNA) that code for certain proteins . If the sequence of DNA mutates in a gene, the protein for which it encodes also can change. In CF, a change or mutation in the DNA sequence of the gene can lead to the production of a defective version of an important protein. This protein is called the cystic fibrosis transmembrane conductance regulator, or CFTR. The protein works as an ion pump within the cell membrane and regulates the movement of sodium and chloride (electrolytes that makeup salt ) into and out of cells. In people with CF, this pump does not work properly. As a result, water is retained within the cells. A dry, sticky mucus builds up in the tissues that are affected.

Clinical manifestations in CF

Most of the symptoms of CF are related to the sticky mucus that clogs the lungs and pancreas. People with CF have difficulty breathing and are highly susceptible to bacterial infections of the lungs. Normally, bacteria are expelled from the lungs by coughing and the movement of mucus up the airways to the throat where the bacteria can be expelled. In people with CF, the mucus is too thick to be removed and bacteria are able to inhabit the lungs and cause infection.

In addition to the airways, other tissues are affected in CF. The abnormalities found in these tissues are characterized by abnormally thick and dehydrated secretions, which appear to cause obstruction resulting in organ dysfunction. For example, the pancreatic ducts are obstructed resulting in tissue degeneration, fibrosis (scarring), and organ dysfunction. The pancreas secretes enzymes during digestion that break food into smaller pieces so that the body can absorb nutrients . Enzymes speed up chemical reactions and the enzymes in the pancreas are important for digestion of foods. Failure of the pancreas to function normally results in pancreaticenzyme insufficiency, which is observed in approximately 85% of CF patients. Without treatment, enzyme deficiency results in protein and fats being poorly digested, which can lead to severe malnutrition .

In the gastrointestinal tract (the organ that digests and processes broken down food), accumulation of mucous secretions also occur. Dehydrated intestinal contents combined with abnormal mucous secretions are thought to predispose patients to bowel obstruction, which is a characteristic symptom in 10–20% of CF newborns. The bile ducts of CF patients can also be obstructed, producing gall bladder disease and elevations in liver function enzymes, occasionally leading to liver failure.

Greater than 95% of males with CF are infertile due to structural alterations in the reproductive tract that results in the sperm being incapable of fertilization , or azoospermia. These structures include the vas deferens and seminal vesicles, which are both an important part of the male reproductive tract and contribute to transportation of the sperm. If the vas deferens is absent at birth, it is a condition called congenital bilateral absence of the vas deferens (CBAVD). CBAVD is characteristic in male CF patients. Reduced fertility has also been noted in females with CF and may be related in part to abnormal mucous composition in their reproductive tract.

In the sweat gland, a characteristically detectable salty sweat represents the traditional gold standard test for diagnosing CF. Testing for CF involves analyzing sweat for elevated levels of salt. The ducts of the sweat glands normally function to reabsorb sodium and chloride across the water impermeable tissues. In CF, failure to reabsorb chloride ions in the ducts results in sodium and chloride, or salts, to be concentrated in sweat. Clinical manifestations include a predisposition to dehydration.

Despite the multi-organ involvement of the disease, respiratory failure is the primary cause of death in more than 90% of CF patients. Current hypotheses suggest that, in the CF airways, defective electrolyte transport results in alterations in the volume of liquid that covers the airways, the salt content, and/or mucus composition, which leads to thick mucus secretions that cannot be easily cleared out of the airways. The resulting airway microenvironment is conducive to chronic bacterial colonization and infection by specific bacterial pathogens , including Streptococcus pneumoniae, Hemophilus pneumoniae, and Staphylococcus aeureus. These bacteria typically infect the lungs of CF children. Adults are most susceptible to Pseudomonas aeurginosa. A rare type of bacteria called Pseudomonas cepacia currently infects people with CF at alarming rates. Pseudomonas cepacia causes a severe infection and hastens lung damage leading to an earlier death. These infections, coupled with an abnormal inflammatory response, leads to airway destruction and death in the vast majority of CF patients.

The CF gene was identified by researchers in 1989. There are many mutations (over 1,000) that cause CF. Some of these mutations cause a less severe disease; others cause a more severe disease. However, the same gene mutation in different people will not always have the same clinical manifestations.


Treating CF

Currently, no cure for CF exists. Treatment of the disease mainly involves alleviating symptoms caused by the build-up of mucus. To combat the lung infections, many patients are given large doses of antibiotics to prevent a severe, life-threatening infection. Some people undergo a course of antibiotics four times a year, on a predetermined schedule. Mucus in the lungs also can be broken down by drugs called mucolytic agents. These agents can be orally. Other drugs are inhaled as aerosols .

A drug called Pulmozyme is an enzyme which breaks down the excess DNA present in the mucus of CF patients that accumulates as a result of the inflammatory process. Pulmozyme helps to thin the mucus, allowing it to be more easily expelled. Clearing the thick mucus from the lungs can also be accomplished by physiotherapy. Physiotherapy includes breathing exercises and percussion, the administration of blows to the back and chest to loosen the mucus.

To control the malabsorption of nutrients, many people with CF take pancreatic enzymes in pill form with every meal. A diet high in fat , protein, and carbohydrates is also recommended to increase the nutrient intake. Multi-vitamins can also help prevent deficiencies of certain vitamins. When these methods do not result in adequate weight gain some people supplement their diets with feeding tubes, or a nutrient-rich solution infused through a tube placed in the stomach. Newer advances in the types of pancreatic enzymes and nutritional supplements offered to CF patients are helping such patients avoid malnutrition.

A number of other recent therapies are available for CF patients. These include an inhaled form of the antibiotic called tobramycin. Previously given intravenously to treat infections, inhaled tobramycin appears to improve lung function, while avoiding some of the detrimental side effects associated with IV tobraymycin. There are also other exciting development drugs that are aimed at improving the function of the protein defective in CF.


Gene therapy for CF

Researchers hoped that by discovering of the gene responsible for CF, a genetic approach to curing the disease will be developed. In gene therapy , a normal gene is inserted into cells to replace the defective gene. In most gene therapy experiments, cells from an affected organ are removed from the body and infected with a virus that has been modified to carry the normal gene. The newly infected cells are then put back into the body. In CF, this method has not yet been successful. The primary reason is that the lungs are equipped with a complex barrier, preventing successful penetration and delivery of the normal gene.

In 1994, researchers successfully transferred a virus containing the normal CFTR gene into four CF patients. The patients inhaled the virus into the nasal passages and lungs. An adenovirus, the virus used to carry the gene, is considered to be relatively safe but can cause several undesirable side effects. Nevertheless, one patient in this experiment developed side effects including headache, fatigue, and fever. It is unclear whether the experiment improved mucus clearance in the lungs or if the corrected gene produced adequate amounts of the corrected protein.

Before gene therapy can be considered, researchers must overcome several obstacles. The most important obstacle is the use of viruses as carriers for the normal genes. Some scientists feel that viruses are too dangerous, especially for patients who already have a chronic disease. Current studies are underway to investigate the use of liposomes, or small microscopic spheres consisting of a fatty-substance called a lipid , to transport the corrected gene.


A test for the CF gene

Recently researchers have located a number of defects on particular genes that appear to be responsible for the majority of CF cases. Knowing the location of these gene mutations makes it possible to test for carriers of the disease (individuals who have only one defective gene copy, and therefore have no symptoms themselves). Currently the test detects 85% of all CF gene mutations, which can be determined by extracting DNA from a persons blood , cheek cells, or saliva. Some researchers feel that this detection rate is still too low and that testing should be performed only on persons who have a familial history of CF or are Northern European by descent. Others argue that because the test is relatively inexpensive and easy to perform the test should be offered to everyone. At this time, testing for the gene responsible for CF remains controversial. In particular, testing parents prior to or during a pregnancy to determine their carrier status has resulted in controversy.

See also Genetic disorders; Respiratory diseases; Respiratory system.

Resources

books

Kepron, Wayne. Cystic Fibrosis: Everything You Need to Know (Your Own Personal Health). Toronto: Firefly, 2003.

Orenstein, David M. Cystic Fibrosis: Medical Care. Philadelphia: Lippincott Williams & Wilkins Publishers, 2000.

Shale, Dennis J. Cystic Fibrosis. BMJ Books, 2002.

periodicals

"Gene therapy for CF reaches Human Lungs." Science News 146 (September, 3 1994): 149.

Johnson, Larry G. "Gene Therapy for CF." Chest 107 (February 1995): 775–815.

other

Cystic Fibrosis Foundation. "About Cystic Fibrosis." (cited January 15, 2003) <http//www.cff.org/about_cf/what_is_cf.cfm>.


Bryan Cobb
Kathleen Scogna

KEY TERMS

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Allele

—Any of two or more alternative forms of a gene that occupy the same location on a chromosome.

CF transmembrane conductance regulator

—A protein that acts as a pump in the cell membranes of airway and pancreas cells. The pump regulates the transport of sodium and chloride into and out of cells.

Homozygous recessive disorder

—Genetic disorder caused by the presence of two defective alleles.

Percussion

—A technique in which blows are administered to the back and chest to loosen mucus in the respiratory tract.

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Cystic Fibrosis

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.

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.

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. Several decades ago most children with CF died by age two years; today, 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.

Genetic profile

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 change 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% of all people with an abnormal CFTR gene have the same defect, known as delta-F508.

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 changes 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 does not 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.

To understand the inheritance pattern of CF, it is important to realize that genes actually have two functions. First, as noted above, they serve as the blueprint for the production of proteins. Second, they are the material of inheritance: parents pass on characteristics to their children by combining the genes in egg and sperm to make a new individual.

Each person actually has two copies of each gene, including the CFTR gene, in each of his or her 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 or 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 will know whether or not 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 now 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.

Signs and 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

Ten to fifteen 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 a "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, which 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% of adults with CF. Liver problems are less common, but can be caused by the build-up of fat within the liver. Complications of liver enlargement may include internal hemorrhaging, 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, intus-susception, in which part of the intestinal tube slips over an adjoining part, cutting off blood supply.

Somewhat fewer than 10% of people with CF do not have gastrointestinal symptoms. Most of these people do not have the delta-F508 mutation, but rather 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 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 will 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, which traps foreign particles including bacteria and viruses. Tiny hair-like projections called cilia 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 is resistant to most current antibiotics (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

Ninety-eight 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 now 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 one-and-one-half to two 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. Siblings in these families are also usually tested, both 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 or her carrier status is often delayed until the teen years or later, when he or she is closer to needing the information to make decisions.

Newborn screening

Some states now require screening of newborns for CF, using a test known as the IRT test. This is a blood test which 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 and management

There is no cure for cystic fibrosis. Treatment has advanced considerably in the past several decades, 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% 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. Bronchial 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 can help open up the airways; steroids reduce inflammation; and mucolytics loosen secretions. Acetylcysteine (Mucomyst) has been used as a mucolytic for many years but is not prescribed frequently now, 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 is another option for people with CF, although the number of people who receive them is still 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% of adults and more than 80% of children who receive lung transplants live longer than two years. Some CF patients whose livers have been damaged by fibrosis also undergo liver transplants.

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 are currently 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% of those with CF.

Gene therapy is currently the most ambitious approach to curing CF. In this set of techniques, nondefective 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 so far, including immune resistance, very short duration of the introduced gene, and inadequately widespread delivery.

Alternative treatment

In homeopathic medicine, the symptoms of the disease would be addressed to enhance the quality of life for the person with cystic fibrosis. Treating the cause of CF, because of the genetic basis for the disease, is not possible. Homeopathic medicine seeks to treat the whole person, however, and in cystic fibrosis, this approach might include:

  • Mucolytics to help thin mucous.
  • Supplementation of pancreatic enzymes to assist in digestion.
  • Respiratory symptoms can be addressed to open lung passages.
  • Hydrotherapy techniques to help ease the respiratory symptoms and help the body eliminate mucus.
  • Immune enhancements can help prevent the development of secondary infections.
  • Dietary enhancements and adjustments to treat digestive and nutritional problems.

Prognosis

People with CF may lead relatively normal lives. The possible effect of pregnancy on the health of a woman with CF requires careful consideration before beginning a family, as do issues of longevity, and their 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 today with CF is expected, on average, to live to age 40.

Resources

BOOKS

Gehehrter, Thomas, Francis Collins, and David Ginsburg. Principles of Medical Genetics. Baltimore: Williams & Wilkins, 1998.

Harris, Ann, and Maurice Super. Cystic fibrosis: The facts. New York; Oxford, UK: Oxford University Press, 1995.

Orenstein, David. Cystic fibrosis: A guide for patient and family. Philadelphia; New York: Lippincott-Raven, 1997.

ORGANIZATIONS

Cystic Fibrosis Foundation. 6931 Arlington Rd., Bethesda, MD 20814. (301) 951-4422. <http://www.cff.org>.

WEBSITES

Cystic Fibrosis Information. <http://cf-web.mit.edu/index.html>.

Edward Rosick, DO, MPH, MS

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