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 abnormally thick mucus that blocks passageways and prevents proper function.
CF affects approximately 30,000 children and young adults in the United States and 70,000 people worldwide. Each year, about 1,000 babies are born with CF. CF primarily affects people of white northern-European descent (1 in 3,200). Rates are much lower in Hispanic (1 in 9,200), African-American (1 in 15,000) and Asian (1 in 31,000) populations.
Most children with CF are diagnosed by age two, and many 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 1950s, children with CF rarely lived past age 6, today about half of all people with CF live past age 37, with the median life span expected to increase as treatments are improved.

Causes and symptoms

Causes

Cystic fibrosis is an inherited disease, meaning it is caused by a defect in the individual's genes. Genes 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 cystic fibrosis transmembrane conductance regulator (CFTR) gene. A defect in this single gene causes all the consequences of CF. There are over 1,600 known defects in the CFTR gene that can cause CF. However, about 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 defective CFTR protein does not allow chloride ions out of mucus-producing cells. With less chloride leaving the cells, less water leaves, and mucus becomes thick and sticky. The mucus can no longer move freely through the passageways, and they become clogged. In the pancreas, clogged passageways prevent secretion of digestive enzymes into the intestine, causing serious impairment of digestion-especially the digestion of fat-which can 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 has two copies of each gene, including the CFTR gene, in each of their cells in their body except for eggs (ova) or sperm. In the cells that produce sperm and eggs the two copies of the gene separate, so that each egg or sperm contains only one copy of each gene. At fertilization, when sperm and egg unite, the newly created cell once again has two copies of each gene, one contributed by the mother (egg) and one from the father (sperm).
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. According to the Cystic Fibrosis Foundation, approximately one in every 29 Americans of Northern European descent is a carrier of the mutated CF gene, while only one in 46 Hispanic Americans, one in 65 African Americans and one in 90 Asian Americans are carriers. Since carriers are symptom-free, people will not know whether they are carriers unless there is a family history of the disease.
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, (i.e., 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 often 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 phenomenon, called "heterozygote advantage," is seen in some other genetic disorders, including sickle-cell anemia, and allows the harmful defective genes to remain in the gene pool with a fairly high frequency.

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

Seven to ten 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.
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 1 insulin-dependent diabetes.
Gallstones 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: 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, throat, trachea (or windpipe), bronchi (which branch off from the trachea within each lung), smaller bronchioles, and 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 usually does not 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.
People with CF have a decreased ability to protect against infection. 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, and 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 people with 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 block 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 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 experiencing 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 vasa deferentia, the tubes 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, although 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 continue the pregnancy. Siblings in these families are usually tested to determine if they have undiagnosed CF and to learn if they are carriers in order to aid in their own family planning. If the sibling has no symptoms, determining carrier status may be delayed until the late teen years or later, when the individual is closer to needing the information to make reproductive decisions.

Newborn screening

Some states now 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 in those without it. This test gives many false positive results immediately after birth, and thus requires a second test several weeks later. A second positive result normally is 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 help keep the immune system healthy and may decrease the frequency with which these bacterial colonies begin a symptomatic 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.
Mucus control is an important aspect of CF management. Clearing mucus from the lungs helps to prevent infection. 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 (e.g., albuterol [AccuNeb, Proventil]) open up the airways; steroids reduce inflammation; and mucolytics (e.g., dornase alfa [Pulmozyme]) loosen secretions and help break 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 the bacterium Burkholderia cepacia, which rarely is not 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. 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 and successful for people with CF, although the number of people who receive a lung transplant is limited by the number of available lungs and is 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. Liver transplants also may be done for CF patients whose livers have been damaged by fibrosis.
Long-term use of ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID) 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.
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.
Many clinical trials of new therapies and treatment regimens are currently underway. A list of clinical trials can be found at http://clinicaltrials.gov/. Treatment is provided without charge to volunteers.

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 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, 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.
In 2009, the median survival age for people with CF was 37 years. Because of better and earlier treatment, a person born today with CF is expected, on average, to live to age 40. End-stage lung disease is the most common cause of death in people with CF.

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.