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.