Cystic Fibrosis

Introduction

Breathing and eating are functions that most individuals do without thinking. Individuals with cystic fibrosis (CF), however, must pay careful attention to even basic body functions. Due to a defect in their genetic structure, CF patients must deal with the adversely affected organ systems of their body in order to sustain life. As the most common life-threatening, genetically-inherited disorder in Caucasian Americans, CF causes an array of health problems ranging from nutritional deficiencies to lung damage.

What is it?

Cystic Fibrosis (CF) is a genetically-inherited medical condition that affects many systems of the body. Normally, specialized cells secrete watery, thin liquids such as mucus, sweat, and digestive juices. In patients with CF, defects of a gene known as CFTR alter the function of a protein that regulates ion transport, which is the normal movement of sodium, chloride, and water in the body. This alteration causes secretions to be abnormally heavy, thick, and sticky. As a result, these thick secretions accumulate and cause problems in the respiratory, reproductive, and digestive systems of the body. For example, the presence of these abnormal secretions in the lungs can often make it difficult for an individual with CF to breathe normally. Many times, this uncharacteristically thick fluid can build up in the digestive tract, making it harder to digest foods.

A CFTR abnormality also increases the salt level in sweat produced by individuals with CF. In fact, a sweat test is the classic diagnostic test for CF. A high salt level in the sweat strongly suggests CF. Confirmation or evidence for diagnosis of CF may be made in a number of ways:

• Trypsin test- a test used to evaluate the pancreatic (pancreas gland) function of an individual by detecting amounts of trypsin (a product of the pancreas) in the stool.
• Pulmonary function tests- tests used to evaluate lung function/breathing ability.
• Chest x-ray findings- tests used to detect the presence of mucus deposits in the lungs.
• Genetic tests- tests used to detect the presence of genetic defects that are indicative of cystic fibrosis.

What causes it?

The cause of CF was a mystery until the 1940s, when it was linked with the inability to clear mucus from the lungs. Even then, treatment was essentially supportive and few individuals with CF survived childhood. As recently as 1970, the average age of survival for a CF patient was only 16 years. In 1989, however, researchers discovered the cystic fibrosis transmembrane conductance regulator (CFTR) the gene involved in CF. Any of several possible CFTR mutations may result in CF. While CF still has no cure, improved treatments for the disease now allow patients to live relatively comfortable lives well into their adult years. In 2006 the median survival age was increased to nearly 37 years, an increase of more than five years since 2002.

Who has it?

According to the Cystic Fibrosis Foundation, about 1000 Americans are newly diagnosed with cystic fibrosis (CF) each year. In the United States, the incidence of cystic fibrosis is greatest among the Caucasian population, at a rate of about one affected individual in 3,200 live births. The condition is much less common in the Hispanic-American (about one in 9,500 live births), African-American (about one in 15,300 live births), and Asian-American (about one in 32,000 live births) populations. About 30,000 people in the US are affected by this genetic disorder.

Roughly 5% (nearly 10 million people) of the U.S. population may have a defective CF gene without knowing that they do. CF is a recessive genetically-inherited disorder, which means that both parents must carry the defective gene in order to have a child with CF. These CF "carriers" have no symptoms of the disease and they are not ill. Their children, however, have a 25% chance of having CF and a 50% chance of being a carrier of the genetic defect. Unfortunately, the offspring of two individuals with CF will inherit the genetic disorder.

In 2003, CF was most commonly diagnosed at the age of 6 months and nearly 80% of CF patients were diagnosed by the age of 3. However, due to the advancement of medical technology, healthcare professionals are currently utilizing new methods to diagnose CF earlier in an infant's life. The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR), the gene involved in CF, may help provide a more accurate method of detecting the beginning stages of CF. By identifying the genetic defect associated with the development of cystic fibrosis earlier in the disease, potentially life-threatening complications such as meconium ileus (bowel blockage), may be avoided.

What are the risk factors?

Cystic fibrosis (CF) is not a contagious disease, meaning that it cannot be passed from individual to individual through physical contact. Because it is inherited, an individual is at risk for developing CF if his or her parents are both carriers of the defective gene. CF also occurs more frequently in various ethnic population groups. For example, individuals of Northern European descent have a higher incidence of CF. In comparison, Hispanic-, African-, and Asian-Americans populations have smaller chances of having the disease.

What are the symptoms?

Cystic Fibrosis (CF) is associated with a wide variety of symptoms that affect many normal functions of the body. The main organ systems affected by CF include the gastrointestinal, respiratory, sweat gland, reproductive, hematologic (blood), and bone/joint systems. Even though general symptoms are common among individuals with CF, the number and severity of symptoms may vary from patient to patient.

General symptoms of CF include:

• Gastrointestinal system
  • Bowel blockage
  • Diarrhea
  • Foul-smelling stools
  • Stomach cramping and pain
  • Vomiting
• Respiratory system
  • Coughing or wheezing
  • Nasal growths (polyps)
  • Repeated respiratory infections (ie. pneumonia or bronchitis)
  • Thick mucus and sputum
• Reproductive system
  • Infertility
• Hematologic system
  • Anemia (decrease in number or composition of blood cells)
  • Bleeding disorders (inability to clot)
• Bone/Joint system
  • Arthritis
  • Chronic bone/joint pain
  • Decreased ability to grow
  • Osteoporosis
• Miscellaneous
  • Clubbing (enlargement and swelling of the fingertips and toes)
  • Liver damage
  • Salty skin and sweat
  • Weight loss

How is it treated?

Currently, there is no cure for cystic fibrosis (CF). However, technological advancements in medicine allow many individuals with CF to live into adulthood. However, CF patients who do live longer are at a higher risk of developing complications of the disease such as lung infections and bowel blockage. It is important to note, however, that the severity, number, and type of symptoms can vary widely from patient to patient. Additionally, because CF affects many different systems of the body, a wide variety of techniques and medications are used to treat the condition and its complications. While the treatment of CF depends upon the severity, stage, and progression of the disease; general goals are:

1. to ensure adequate calorie and nutrient consumption
2. to increase airflow in the lungs
3. to decrease the volume and thickness of lung mucus
4. to prevent/treat infection in the lungs

There are currently 115 Cystic Fibrosis Foundation (CFF) treatment centers scattered throughout the United States. These unique treatment centers specialize in diagnosing and treating cystic fibrosis. For more information regarding CFF treatment centers, you can visit the following link: http://www.cff.org.

Nonpharmacologic (non-drug) therapies

Nutrition/Exercise

CF patients often do not absorb enough calories, protein, and vitamins from their usual daily diet to maintain adequate nutrition. As a result, individuals with CF are advised to increase their daily intake of calories to 120%-150% of the recommended daily allowance (RDA). CF patients should also increase the amount of protein in their usual daily diet by 200% of the RDA of protein. Nutritional supplements, such as Ensure, Sustical, and Scandishakes, may help CF patients maintain the amount of nutrients they require each day.

CF patients should exercise as tolerated to help loosen mucus build-up so that it may be removed more easily. Exercise also helps to expand the lungs and increase lung capacity (amount of air the lungs are able to hold). However, exercise may not be appropriate for all CF patients. It is important for patients to talk with their doctor before beginning to exercise.

Chest physiotherapy/postural drainage/percussion/chest vest

Because CF can cause patients to produce abnormally thick and sticky mucus, a variety of methods are available to help remove the secretions. Postural drainage is an alternative process used to help clear mucus from the lungs by altering the patient's position. Classic techniques, such as chest percussion (tapping on the chest and back) and the chest vest (a vibrating vest) have also been used to help dislodge and remove excessive mucus in the lungs of CF patients. In addition, innovative breathing devices, such as oscillatory positive expiratory pressure (OPEP) devices (such as the Acapella and the Flutter) can be used to loosen mucus. By exhaling into the OPEP device, vibrations are created which help move the abnormal secretions from the lungs.

Oxygen & Transplant

In severe cases of CF, the patient's damaged lung function could become life-threatening necessitating the need for an oxygen machine. If the physician determines that the patient is a good candidate for transplantation, he/she will be put on a lung transplant waiting list. It should be noted, however, that a lung transplant will not cure CF. Patients with the following conditions should not be considered for lung transplantation:

• Cancer
• HIV infection
• Major psychiatric illness
• Severe damage to other body organs
• Severe overweight

Pharmacological (drug) treatment

Digestive Enzymes

In patients with CF, defects of a gene known as CFTR alter the function of a protein that regulates ion transport, which is the normal movement of sodium, chloride, and water in the body. This alteration causes secretions to be abnormally heavy, thick, and sticky. Normally in healthy people, the pancreas is a gland that produces digestive enzymes (proteins that help break down food such as amylase, protease, and lipase) which are excreted through small channels into the small intestine when food is present. However, the abnormal mucus in CF patients clogs these channels in the pancreas, resulting in an insufficient amount of digestive enzymes in the stomach. As a result, food is not digested correctly and intestinal problems such as diarrhea and bowel blockage occur. Because CF patients usually do not have enough digestive enzymes in their intestines to break down the food they eat, they must take supplemental oral digestive enzymes. Ordinarily, digestive enzymes are taken with every meal or snack in often large doses.

Bronchodilators

Maintaining adequate airflow is important to CF patients because a reduction in the ability to breathe can often cause a great deal of anxiety as well as hypoxemic (lack of oxygen) complications. If CF patients do not obtain enough oxygen, the organs (such as the brain) of the patient are at great risk for obtaining damage. To combat this potential problem inhaled bronchodilators have been widely used to help maintain adequate airflow and lessen the breathing difficulties that CF patients experience.

Inhaled/oral corticosteroids and ibuprofen As a result of the numerous lung infections that CF patients experience, chronic inflammation of the lung tissue can occur. If the lung tissue remains inflamed for a great deal of time (days-months), damage can occur, thus resulting in the loss of lung function. In order to decrease the amount of lung inflammation, drugs such as corticosteroids (natural hormones normally made by the adrenal gland) can be prescribed. By decreasing the frequency and severity of lung inflammation, corticosteroids (such as prednisone) may prevent future lung problems. Non-steroidal anti-inflammatory drugs such as ibuprofen are another group of drugs that may help decrease the severity of symptoms in CF patients by decreasing inflammation. Because of potentially severe side effects, it is only appropriate to take ibuprofen exactly as your physician prescribes.

Mucolytic or Mucus-thinning drugs

Since CF causes patients to produce abnormally thick and sticky mucus, drugs that thin the mucus can be given to patients. Thin mucus is easier to be cleared from the lungs of individuals with CF, thus allowing them to breathe easier. For example, a drug called DNase (also known as recombinant human deoxyribonuclease or dornase alfa) works to thin mucus by breaking apart the genetic material (DNA) contained in the abnormally thick secretions. This action decreases the viscosity (thickness) of the secretions, therefore allowing the mucus to be easily cleared.

Antibiotics

Lung infections, in general, are difficult to control and cure. In CF patients, however, the challenge to treat lung infections increases. The bacteria that cause these lung infections are able to multiply and flourish in the presence of the sticky and thick secretions found in individuals with CF. Mucus can also prevent antibiotics from reaching the infection site, consequently making it more difficult to treat. In light of this complicated situation, new inhaled and oral (tablets and capsules) antibiotics have been developed to help control recurrent lung infections in CF patients.

Please click on the following links to learn more about the various drug treatments for CF.

Helping Yourself

Tips on how CF patients can stay healthy

1. Eat healthy! Make sure you eat a well-rounded, healthy diet. Individuals with CF need to consume additional calories to maintain adequate nutrition.
2. Drink it up! Make sure you drink enough water each day, especially if you play sports or exercise. It is usually recommended that patients with CF should drink one-half of their body weight in ounces of water, daily. For example, 180 lb of body weight = 90 oz. of water daily. Take that total amount of water and divide that into 8 or 10 oz. glasses of water. That is how much water you should drink everyday. By drinking enough water each day you can avoid dehydration. Dehydration can cause the mucus secretions in your lungs to become even thicker, causing it harder for you to breathe.
3. Immunize! Keep your immunization records up-to-date. Measles/Mumps/Rubella, Diphtheria/Tetanus/Pertussis, and Flu immunizations are important for individuals with CF because they help prevent future lung infections.
4. Stay Active! Try to live a normal lifestyle. Regular exercise can strengthen your respiratory system which will allow you to breathe easier. Also, participation in sports can increase your self-esteem and confidence.
5. Snuff it out! Do not smoke and eliminate smoke from your environment, as much as possible. The harmful toxins in tobacco smoke can lead to lung problems for all individuals, especially those with CF.
6. Wash up! Make sure that you maintain a high level of personal hygiene. By limiting your exposure to germs and bacteria, you may be able to avoid many infections. Wash your hands thoroughly several times a day, particularly:
   • At the doctor's office, waiting room, and lab
   • After coughing and sneezing
   • After using public restrooms
   • After touching public devices, such as telephones, handrails, or elevator buttons
7. Supplement your diet! Be sure to take a daily vitamin supplement in your diet, because individuals with CF often do not absorb enough vitamins from their daily diet.
8. Lift it up! Because people with CF are at risk for poor bone health, they are often at a higher risk of developing osteoporosis and bone fractures later in life. Weight-bearing exercises such as weight lifting, jogging, and dancing may strengthen your bones. Increasing your consumption of foods that contain calcium, increasing vitamin D through increased exposure to sunlight, and/or taking a calcium and vitamin D supplement may also help prevent the development of osteoporosis.

What is on the horizon?

Due to the advancements of medical technology, individuals with cystic fibrosis (CF) are living long into their adult years. As a result however, many older CF patients are developing a variety of complications of the disease that are more difficult to treat. In response, scientists and medical professionals continue to search for new, more effective diagnosis/treatment options for CF patients.

In 2005, the Food and Drug Administration (FDA) approved a new blood test that helps detect CF carriers. The "Tag-It Cystic Fibrosis Kit" directly analyzes an individual's DNA to determine whether or not a CF-related genetic defect is present. The genetic defect that causes cystic fibrosis can be described as a variation or a group of variations in a gene called the "cystic fibrosis trans-membrane conductance regulator" (CFTR) gene. This test should help determine the presence of the genetic variations in children as well as in adults who are carriers of the gene. Currently, the Tag-It Cystic Fibrosis Kit is only sold to specific labs located around the United States and is only available through physician referral.

Recent research focusing on the role of a protein called the cystic fibrosis transmembrane conductance regulator (CFTR) is starting to change the focus of cystic fibrosis treatment. The CFTR protein has been linked to the inability to clear mucus from the lungs and the abnormal ion movement often seen in CF patients. New therapeutic targets, medications, and therapies will most likely evolve around these new discoveries. In April 2007, Vertex Pharmaceuticals received approval from the FDA to start a phase IIa clinical trial to test the safety and efficacy of an experimental drug called "VX-770", a drug that may help to restore the function of the CFTR protein. The study will include CF patients and will aim to determine whether or not this new drug can help increase survival time. Another therapy that targets the CFTR protein, an experimental drug called "PTC- 124", has completed Phase I and II testing and has shown safety and tolerability as well as preliminary encouraging biologic results.

Drugs are also being developed to help correct the amount of salt transfer along the lining of cells in the lungs, which will help decrease the thickness of the mucus and secretions. One drug in particular, Denufosol (Inspire Pharmaceuticals, Inc.) recently completed Phase II trials to determine the effect of the drug on lung function in CF patients and demonstrated efficacy. A Phase III trial has begun.

Enzymes, called proteases (or neutrophil elastase inhibitors), normally found in the lungs have the potential to damage lung tissue. Damage can cause inflammation and decrease lung function. Healthy individuals produce substances called anti-proteases (or a1 antitrypsin and secretory leukoprotease inhibitor) that protect their lungs from the harmful effects of proteases. Patients with CF, however, do not make adequate amounts of anti-proteases. One area of research in CF treatment centers is on the development of anti-protease inhalers which should help decrease the inflammation and damage caused by natural proteases in CF patients.

According to the National Institute of Health (NIH), a new class of drugs is being developed for use in thinning mucus secretions for CF patients. These drugs derive from an unlikely source: toxins produced by tiny microorganisms that are responsible for the "red tides" that affect the coasts of Florida. The so-called "red tide toxin" can kill fish, contaminate shellfish, and create severe respiratory irritation in people. In attempting to combat the effects of red tide toxin, researchers have discovered that both a man-made compound known as -Naphthoyl-brevetoxin, and a natural compound, brevenal, that is produced by the organism itself behave much like the mucus-thinning drugs used to treat CF such as DNase (dornase alfa). The mechanism of action of the anti-toxin is unknown, but it is believed that it increases the movement of cilia (thin, hair-like projections that move liquid across the surface of lung cells) within the lung. Increased movement helps to keep mucus secretions from becoming stuck in the lungs. Additional studies will be needed to determine the safety of this medication and its potential for treating CF.

Experts are always looking at drugs that can help to reduce the inflammation of the lungs associated with CF. Researchers reported in late 2007 that the commonly prescribed anti-inflammatory/pain reliever, ibuprofen, was found to significantly slow the decline in lung function in children with CF, by almost 1/3. The concern with ibuprofen is the risk for increased ulceration and bleeding in the stomach and intestines with the dose that is required to be effective. Because of this risk, researchers continue to look for more options to treat the inflammation of CF.

Great advancements in gene technology have spurred a lot of excitement in healthcare professionals specializing in CF. Currently in development is a new technique used to insert healthy genes (called vectors) into the airways of CF patients. In the future, gene therapy may prove to be a vital element in the treatment of CF.

References

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ClinicalTrials.gov A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study of VX-770 to Evaluate Safety, Pharmacokinetics, and Biomarkers of CFTR Activity in Cystic Fibrosis (CF) Subjects With Genotype G551D http://clinicaltrials.gov/ct2/show/NCT00457821?term=VX-770&rank=1 Accessed February 2008.

Clinicaltrials.gov A Phase 2 Study of PTC124 as an Oral Treatment for Nonsense-Mutation-Mediated Cystic Fibrosis http://clinicaltrials.gov/ct2/show/NCT00234663?term=cystic+fibrosis&rank=7 Accessed February 2008.

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Cystic Fibrosis Health Condition Last Updated: February 2008

Note: The above information is intended to supplement, not substitute for, the expertise and judgment of your physician, pharmacist, or other healthcare professional. It is not intended to diagnose a health condition, but it can be used as a guide to help you decide if you should seek professional treatment or to help you learn more about your condition once it has been diagnosed.

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