Cystic Fibrosis: An Overview

By Abigail Miller

February 28, 2013 NDFS 356

INTRODUCTION Cystic fibrosis (CF) is one of the most common life-shortening disorders in Europe and North America (1). It is a simple disease to understand and diagnose, but there is still no known cure. For people with CF, treatment is a daily battle. The lungs are the most severely affected organ in CF patients, but this disease also takes its toll on the digestive system, liver, and sex organs. Fortunately, medical treatments have greatly improved over the last two decades and as a result life quality and expectancy has increased dramatically. In addition to medical treatments nutritional therapies have improved to enhance patient health. CF is a common life-threatening chronic disease, but thanks to great innovations the outlook for patients is constantly improving. PREVALENCE AND ETIOLOGY People of European decent are most commonly affected by CF. There is a prevalence of .74 and .80 of 10,000 people in Europe and the United States respectively (2). Approximately 30,000 individuals in the United States currently have CF, and another 10 million are carriers (3). CF is an autosomal recessive disorder, so a defective gene must be inherited from both parents to cause the disease. This disease is strictly genetic, and thus the only risk factor is having parents who are carriers of mutant CFTR genes. This fact would typically not be known unless a family member has had CF. COURSE OF DISEASE Origin CF is caused by an imbalance of chloride ions resulting from the dysfunction of a single protein. This protein pumps chloride ions across epithelial cells and it is called the Cystic Fibrosis Trasmembrane Regulator (CFTR). There are over 1400 types of mutations to the CFTR gene that can cause cystic fibrosis (4). In each of these mutations chloride cannot pass normally

through the cell membrane. Sodium is the positive ion that counterbalances chlorides negative charge. When chloride does not pass through the membrane sodium is reabsorbed into the cell (1). Water follows sodium, leaving little water outside the endothelial cell. Dehydrated secretions become extremely thick (1). These viscous secretions are the hallmark of CF. Lungs The thick secretions of CF first affect the lungs. In a normal lung the airway surface liquid of the lung delicately maintains the function of cilia, which are present along the pulmonary epithelium (5). The cilia are constantly beating mucus out of the lungs and into the throat. In CF the surface liquid is so thick that cilia are unable to function and remove the mucus. Bacteria easily culture in the stagnant environment of the affected lungs (5). Pseudomonas aeruginosa is the most common bacteria to take advantage of the CF lung. Most CF patients find themselves in the hospital because of bacterial infections. Pseudomonas aeruginosa is present in 80-58% of adults with CF (6). This bacterium is resistant to antibiotic drugs and its presence triggers symptoms similar to bronchitis (6). Eventually this leads to decreased lung function and poor clinical status for the patients. In children with CF the most common infections come from both Staphylococcus aureus and Haemophilus influenza (6). Frequent pneumonia and bronchitis symptoms lower the quality of life for CF patients. In addition to the pulmonary effects of CF, the digested system is affected. Digestive System Pancreatic insufficiency is a common side effect of CF. The pancreas secretes enzymes into the small intestine that are essential for proper digestion and absorption of nutrients to occur. Eighty Five percent of CF patients require pancreatic enzyme replacement therapy as a result of pancreatic insufficiency. Pancreatic secretions are sent out in a watery basic secretion.

Bicarbonate is an essential part of the pancreatic secretion, and this molecule is added through a chloride-bicarbonate anion exchange that cannot occur normally in CF (7). Resulting thick sections are not basic enough to counterbalance hydrochloric acid in the chyme. In addition the high viscosity of the secretions block the acini, and eventually the acinar cells. These cells then begin to be digested by zymogens that are unintentionally activated while still in the pancreas (7). Inflammation ensues and pancreatic activity becomes even more impaired. In the end CF patients see maldigestion of both fats and protein as evidenced by steatorrhea and poor growth (7). The appearance of steatorrhea indicates that pancreatic lipase secretion is below 10% (7). Malnutrition is a serious complication of CF that is treated with medical nutritional therapy. This problem often begins in the womb. As the pancreas degrades, so do the insulin-producing beta cells. This leads to diabetes in 1/3 of adult CF patients (6). Cystic fibrosis related diabetes is a recent problem that has developed as the life expectancy for CF patients has increased (8). To screen for this comorbidity, CF patients should be given frequent oral glucose tolerant tests. CF patients should not be given the same treatment regimen as a type one diabetic for several reasons. First, CF patients have very high calorie needs low carbohydrate diets would not be appropriate (8). Most importantly CF patients already have high treatment demands that require a lot of time and energy, adding strict diet and glucose monitoring to this routine would most likely lead to poor compliance (8). Insulin therapy is appropriate for many cystic fibrosis related diabetics, and must be incorporated. Meconium ileus is one of the first signs of cystic fibrosis. In utero babies begin swallowing amniotic fluid, and they begin to digest some organic material such as skin cells. With this first exposure to digestion they begin to form soft stools. In CF infants this first stool is

so dense that it becomes lodged at the distal end of the ileus (9). Enemas are used to wash this out after the infant is born, but when this method fails surgery is required (9). This is often the first sign of cystic fibrosis. Adults can suffer from a condition similar to meconium ileus known as distal intestinal obstruction syndrome. This occurs once again at the distal end of the ileum where the intestines narrow (9). This condition causes severe abdominal pain to the CF patient. Although the cause for this disorder is not fully understood it is believed to be caused by a lack of lubrication within the bowel (9). This condition can be corrected by using an enema, or by digestions of a lubricant called polyethylene glycol (9). A milder symptom of poor bowel lubrication is constipation, but when this symptom persists it can lead to a rectal prolapse (9). Other Affected Organs The liver is often damaged in CF patients. Liver disease is the third leading cause of death in CF patients (10). It is thought that this damage begins when pancreatic enzymes become activated in the common bile duct (9). This causes focal biliary fibrosis, which appears in most CF patients although it is asymptomatic. If damage and scarring are severe enough they can lead to cirrhosis, a condition that is present in 5-10% of CF patients (10). In these cases verices form to redirect blood flow and these new weak vessels easily hemorrhage; to avoid this liver transplants are recommended (10). CF affects fertility, though the affect is much more severe in men than women. Nearly all men with CF are infertile due to their lack of an epididymis or vas deferens (9). It is thought that the epididymis, which is a collecting duct, is blocked by mucus and destroyed (9). This absence occurs before birth in 95% of males with CF (9). In women all sexual organs are present and functioning. Their fertility problems stem from mucus that blocks the cervix during intercourse

and prevents sperm from entering the uterus (9). Even when pregnancy is an option, there are moral dilemmas. It is only in recent years that people have lived long enough to have children, but the life expectancy for people with CF is still only 37. If they choose to have a child they may not be able to care for their child long. In addition if their husband is a carrier there is a 50% chance of passing on their incurable disease. Ultimately the choice to become pregnant must be a personal choice made by each woman. DIAGNOSIS CF is diagnosed when two or more typical disease symptoms are present and laboratory testing confirms a defect in the CFTR gene. Laboratory tests usually consist of a chloride sweat test. This test inexpensively identifies 99% of CF cases (11). This test is performed by stimulating sweat production via pilocarpine iontophoresis. The sweat is collected on preweighed gauze and the chloride concentration is analyzed. CF is diagnosed when the chloride concentration is greater than 60 mEq/L (11). For the one percent of patients who have negative results, extensive laboratory testing can positively or negatively diagnose the disease by examining the CFTR genome (11). When parents have evidence that their child is at high risk for CF there are neonatal screenings that can be performed. These are done by taking blood samples from the baby which are examined for increased levels of immunoreactive trpysinogen (12). This protein has been linked to CF and it is produced by the pancreas. MEDICAL TREATMENT Many types of medical treatment aim to loosen and clear mucus from the airways. One such technique involved positioning the CF patient with their head facing down and then thumping the chest lightly with cupped hands (13). The therapy should be light enough that it does not interrupt breathing, as this would be counter-productive. This technique is referred to as

postural drainage and percussion therapy (13). This therapy is very effective, but it requires about 3 30 minute sessions per day with a trained caregiver (14). The inconvenience of this traditional therapy resulted in poor compliance; consequently new methods for mechanically loosening mucus have been developed. Many drugs have been developed to treat CF patients. Recombinant human DNase is the only drug that has been proven to loosen sputum (15). A six month trial showed improve lung quality in CF patients who used this medication (15). Hypertonic salines can be inhaled to osmotically attract water to epithelial tissues; inhaled mannitol has shown similar effects (15). Antibiotic drugs are used to treat lung infections in CF patients. Anti-inflammatory drugs are used to combat inflammation that results from the bacterial presence. Another type of therapy that has been investigated is topical CFTR gene replacement therapy, but a Cochrane review found this treatment to be ineffective (16). One of the most common and convenient techniques today is high-frequency chest wall oscillation. This therapy is administered through an inflatable vest that compresses against the patients chest and sends strong pulsing air through the vest to generate the oscillation (14). This technique does not require any assistance or trained caregivers and can easily be done in the patients home. This advice has also proven to be very effective in loosening and removing mucus. The patient excretes the mucus through a tube that they place in their mouth during therapy. Another mechanical device that can be used in therapy is a mechanical percussor. This device is less convenient because it requires someone to hold the device to the patients back and chest during therapy. Breathing techniques can allow patients to both loosen and clear excess mucus. One breathing technique is called the active cycle of breathing. In this cycle patients go through two

phases of heavy breathing and controlled breathing followed by forced expiration (13). This technique allows patients to clear mucus from smaller airways. Other breathing techniques use masks to increase positive expiratory pressure (PEP) (13). Examples include the Pari-PEP and Astra-tech PEP masks. With these devices CF patients are forced to increase the expiratory force, freeing mucus in the lungs (13). Exercise is an effective treatment of CF. Increased exercise helps to increase VO2 max and it also helps to clear sputum (13). Exercise should be encouraged for all patients at a level they can handle. Patients should be encouraged to find sports or exercises that they enjoy to increase their compliance, but also enjoyment and quality of life. Aerobic training, weight resistance, and general exercise all have beneficial effects (13). One of the most aggressive treatments for CF is a lung transplant. Lung transplants are high risk procedures which are only performed in patients with severe lung damage who are not responding to other treatments (17). Mortality rates for this procedure have been estimated to be between 5 and 20 percent however the five year survival rates reveal the success of these transplants (17). Among patients who do not receive transplants the 5 year survival rate is 33% compared to 72% for those who do undergo the procedure. Many people have turned to alternative therapies for CF. In 2008 it was determined that 75% of CF patients used complementary and alternative medicines in additions to their regular treatments (18). Garlic and garlic capsules have been used by some patients for its alleged antibacterial effects against P. aeruginosa (18). Garlics positive effects were studied by measuring the FEV1 on CF patients before and after extended garlic capsule intake. There was a small effect seen by Smith et al but there were only 26 participants in this study (18). Another common herb used to combat cystic fibrosis is gingseng. This is also used for its antimicrobial

properties and some studies have reported small decreases in P. aeruginosa infections (18). Finally curcumin is used. This herb is believed to specifically treat the cause of cystic fibrosis by increasing the effect of CFTR. These effects have been seen in animal studies but more research is needed before it can be used clinically (18). Nutrition in Cystic Fibrosis With the high prevalence of malabsorption in CF it is vital that anthropometric measurements are taken regularly and often. Infant height, weight, and head circumference should be checked every other week if the patient is failing to thrive (13). Once a good nutrition regimen is planned and growth is normal he or she should be examined every two months (13). Weight measurements should be taken by the same staff member on the same scale for consistency. All growth should be plotted on growth charts. Another good measuring tool is the weight for height percentage; this measurement can give a good idea of appropriate weight gain (13). It is essential that CF patients, especially children, are monitored for appropriate growth and nutrition status. Nutrition status can be measured in several ways. Malabsorption is important to measure in CF patients. The gold standard is the three-day fecal fat test (13). This is conducted by collecting a stool sample while the patient consumes their usual diet. The patient consumes carmine markers at the beginning and end of the study (13). The patient is instructed to keep a detailed food diary for the duration of the study to measure fat content (13). At the end of the study fecal fat x 100 is subtracted from dietary fat and the result is expressed as the coefficiency of absorption (13). If excess fat is excreted patient nutrition and medical therapy should be adjusted. Another way to assess absorption is by measuring stool fecal elastase (13). If very low

levels are present it demonstrates pancreatic insufficiency and the patient should begin pancreatic enzyme replacement therapy (PERT) (13). CF patients have significantly increased caloric requirements. To assess each patients requirements basal metabolic rate (BMR) can be calculated using a Deltatrac machine if available (13). Otherwise the World Health Organization has an equation that can be used to calculate BMR. Then the daily energy expenditure should be calculated by multiplying the BMR by an activity and a disease coefficient (13). It steatorrhea is present it should be factored into the equation by multiplying the daily energy expenditure by .93 over the percent of fat absorption (13). Accurate knowledge of energy expenditure is vital to patient health. For 80-85% of CF patients their medical nutritional therapy will include PERT (7). This therapy helps to curb the effects of pancreatic insufficiency by oral intake of pancreatic enzymes. The enzymes are in enteric-coated microspheres so that they are not denatured in the stomach (4). The degree of pancreatic insufficiency and the amount of food eaten are taken into account to decide dosage for each meal (4). Steatorrhea, growth, and fecal elastase can all be measured to determine efficacy of PERT. Dietary requirements are increased in CF. Patients should increase their protein intake. This increase however is already met in the typical North American diet (4). Fat requirements are the most noticeably increase as they allow for high levels of compact energy. CF patients should get 35-40% of their calories from fat (4). Fat soluble vitamins are not well absorbed or distributed despite increased fat intake. For this reason there are increased recommendations for vitamins A, D, E, and K in CF patients (4). Sodium requirements are also increased because excess sodium is lost in epithelial excretions (4).

PROGNOSIS Thanks to recent medical advances CF patients are living longer, better lives. According to the United Kingdoms annual data report for 2010, the average life expectancy for cystic fibrosis patients is 41.4 years (15). In 1998 the life expectancy was only 30 years (1). This is partially due to the ease of new therapies such as high-frequency chest wall oscillation, which are substituting manually therapies that required the help of trained caregivers for several hours per day. This ease allows better compliance with therapies. People who have CF can now lead more normal lives. CONCLUSION CF is a prevalent, destructive, chronic disease, but new medical advancements are enhancing the prognosis for future generations. This disease is caused by a chloride ion imbalance that results in the formation of thick mucus on epithelial tissues. This viscous mucus affects the lungs, gastrointestinal system, liver, and sexual organs of patients. Advanced medical treatments are now making it easier for patients to manage their disease in the comfort of their own home. These advancements allow patients to have better compliance to their prescribed treatments. In addition medical therapies such as PERT allow patients to have better nutritional status that allow for better health and more energy. The new medical advancements have made it possible to increase patient life expectancy to over the age of 40 in recent year, and treatments continue to improve. Thanks to a better understanding and new therapies for CF the day to day burden of patients has been alleviated and patients have a chance to enjoy life.

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