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 body’s 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 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 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 person’s

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 never”shut off“because 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):306–8.

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