Etiology
Cystic fibrosis is a genetic disorder that causes thick mucus to build up in the respiratory system and in the pancreas. Cystic fibrosis, or mucoviscidosis, is an inherited disease that affects the exocrine glands. It is expressed only in the homozygous state without X chromosomal linkage. This genetic disease is often referred to as autosomal recessive. This means that children born to parents who each carry one recessive gene for the disease have a 25% chance of inheriting both copies of the defective gene–and with them the disease (Brown, 2008).
The responsible for cystic fibrosis is located on the long arm of chromosome seven. This gene encodes a protein nss 1480 amino acids called the cystic fibrosis transmembrane conductance regulator (CFTR) (Loughlin & Eigen, 1994). Three bases are deleted and a phenylalanine is removed, 70% of the CF cases. The remaining cases of Cystic Fibrosis are determined by over 300 other mutations of this gene. The CFTR protein, which is, mutated normally, forms a chloride channel. More research is being done to see exactly how mutation causes a defect in the chloride transport system.
The airways become chronically colonized with bacteria that cannot be eradicated, leading to bronchitis, bronchiectasis, and finally, pulmonary fibrosis with respiratory failure (Aitken & Fiel, 1993). The underlying cause of the disease cystic fibrosis is known to be a gene mutation, but how this promotes lung infections was unclear.
Signs and Symptoms
- Earliest signs:
- meconium ileus, which is a small bowel obstruction caused by viscid stool
- Other signs:
- chronic cough
- frequent foul-smelling stools
- persistent upper respiratory infections
- Symptoms:
- malnutrition
- barrel-chest deformity
- growth retardation,
- cyanosis
- use of accessory muscles of respiratory
- sinusitis
- chronic nasal congestion
- rhinitis &nasal polyp
As the disease progresses, lung collapse, excessive mucus in the bronchi or abscesses are possible. The sweat of a patient with CF is very salty. Many years ago before CF was known people would say, “Woe to that child which when kissed on the forehead tastes salty. He is bewitched and soon must die.” (Welsh & Smith 1995). This was before technological advances, which allow children to live past infancy and hopefully into adulthood.
Cystic fibrosis can be fatal if the mucus blocks the lungs. Patients may suffer from pneumonia caused by bacterial infections. Other serious complications include respiratory failure, diabetes, enlarged heart, liver cirrhosis, intestinal blockage, pancreatic dysfunction, sodium deficiency, and sterility.
Abdominal cramps, malnutrition, growth retardation, and coughing are all symptoms associated with cystic fibrosis. However, the increased salinity of sweat is the most useful test to diagnose the disease. It is difficult to predict when any of these symptoms will appear or how severe they will be. While the disease used to be fatal to nearly all children who developed it, more than 50% of cystic fibrosis patients now live longer than thirty years.
Diagnosis
Cystic fibrosis can be diagnosed in a few ways. Most cases are diagnosed by the age of one year. Generally 15-20% of patients have a neonatal intestinal obstruction due to meconium ilieus or meconium plug syndrome. The severity of the manifestations of CF differs somewhat depending on the person’s genotypic heterogeneity.
The test most widely used is the sweat test. This measures the amount of chloride content in the patient’s perspiration. A chloride concentration greater than 60mEq/L is indicative of a cystic fibrosis diagnosis, however, this test is repeated. A patient must have at least two positive sweat tests before he is diagnosed with CF; this is done to cut down on false positive due to lab error or technical problems.
Some early radiographic findings are hyperinflation of the chest and bronchial wall thickening. As the disease progresses, changes include areas of infiltrate, adenopathy, and atelectasis. Advanced stages of the disease show segmental or lobular atelectasis, bleb formation, bronchiectasis, and pulmonary artery and right ventricular enlargement. Mucoid impactions of dilated bronchi are also characteristic. This looks like branching, finger-like opacifications on chest radiographs.
The final way CF may be diagnosed is through genetic screening. This is done before a pregnancy and its usefulness is limited. The gene responsible for cystic fibrosis has been isolated and detected as discussed previously. However, the variety of mutations that occur make gene screening difficult. At this time it is not possible to detect every mutation for cystic fibrosis. Therefore, not every person who has cystic fibrosis will be diagnosed.
In 1990, researchers used laboratory cell cultures to correct the genetic defect that causes cystic fibrosis. They knew that the accumulation of mucus was caused by a blockage of the cell channel used to regulate the flow of sodium and chloride ions (Na+ and Cl–) in and out of the cell. The proper balance of these ions maintains the water balance of the mucus outside the cell. This equilibrium is controlled by a specific protein produced by two copies of a single gene. If both genes are defective, cystic fibrosis occurs.
People with cystic fibrosis are highly susceptible to respiratory infections and are typically malnourished due to the malfunctioning of the pancreas. No cure for cystic fibrosis exists, and the disease is invariably fatal. Ninety-five percent of cystic fibrosis deaths are caused by lung complications; the other 5% are due to liver failure.
However, individuals afflicted with cystic fibrosis must constantly cope with the mucus which accumulates in the lungs, pancreas, and intestine. They are prone to lung infections, especially with the bug Pseudomonas aeruginosa.
A limited number of types of organisms are responsible for these infections, with Staphylococcus aureus and Pseudomonas aeruginosa being of primary importance. In the pre-antibiotic era, greater than 90% of deaths due to infection were caused by S. aureus and death usually occurred in the first 2 years of life. With the advent of effective antistaphylococcal therapy, life spans increased and P. aeruginosa became the pathogen of primary importance. P. aeruginosa isolates recovered from patients with cystic fibrosis have a unique phenotypic characteristic referred to as “mucoid” (Gilligan, 1991).
The mucoid phenotype is due to the production of a mucoid exopolysaccharide. A mucoid exopolysaccharide is believed to play a central role in the establishment of chronic pseudomonal lung infection. A third organism, Pseudomonas cepacia, has recently been detected in the airways of older patients with cystic fibrosis and is associated with increased mortality. The virulence of P. cepacia is not understood, but the organism is extremely refractory to antimicrobial therapy.
Enterobacteriaceae, appear to play a secondary role in airway infection. Aspergillus fumigatus is the most important fungal agent causing allergic bronchopulmonary disease. The role of viruses has only recently been examined. At least in some patients with cystic fibrosis, respiratory syncytial virus may be important in predisposing to sub-sequent bacterial infection (Gilligan, 1991).
Relative to the above, a study conducted by Dr. Erich Gulbins showed for the first time that an increase of ceramide is critically involved. They provide potential mechanisms how ceramide could contribute to the development of Pseudomonas aeruginosa infections in cystic fibrosis patients.
Although airway obstruction and chronic endobronchial infection have long been recognized as major factors in the pathogenesis of lung disease in cystic fibrosis (CF), only recently has it been recognized that the inflammatory process itself may be responsible in a major way for destroying the lungs. The most characteristic feature of inflammation in the CF lung is the persistent infiltration of massive numbers of neutrophils into the airways. Although neutrophils help to control infection, when present in great excess, they cause more harm than good.
Genetic defect hinders the proper absorption of salt into lung epithelial cells, in turn, the resultant excess salt content inhibits a naturally occurring antimicrobial agent produced by these epithelial cells. With this natural defense system disabled, the immune system compensates by mounting a strong attack on bacteria. Unfortunately, this immune response is so overwhelming that it causes inflammation of the lung’s minute branching airways, which further exacerbates the formation of mucus.
Treatment and Prognosis
A treatment plan is based on the individual’s severity of the disease. The patient is usually given enzymes to take when eating. This allows the body to uptake the nutrients needed from the food patients eat. The biggest problem for Cystic Fibrosis patients is pulmonary complications. As stated previously, respiratory infections are common and cause damage to the lungs. To combat these problems antibiotic therapy is given in the early stages of the disease. It is sometimes used just for infections and other times used for a preventive measure. Bronchiodilators and aerosolization techniques, as well as postural drainage and percussion are used to break up the excessive mucus.
Although these treatments allow patients to live longer and more productive lives, eventually the lungs become damaged and respiratory failure occurs.
Some technological advances have increased life expectancy for cystic fibrosis patients’ through lung transplants. Once, a CF patient has a lung transplant their new lungs will be free of cystic fibrosis. However, new problems await them. Some of the complications that may occur are postoperative bleeding, primary graft failure, bronchial stenosis, infection, acute and chronic allograft rejection, hypertension, and osteoporosis (Kotloff & Zuckerman 1996).
The good news is that one enzyme, dubbed Asm, is in large part responsible for this build-up, so treatment aimed at blocking this enzyme might reduce lung infections in people with Cystic Fibrosis.
Suppression of inflammation can be achieved by use of several available agents. A recent multicenter study evaluated the role of alternate-day oral corticosteroid (prednisone) therapy in patients with mild to moderate CF lung disease. It is recommended that prednisone be given for no longer than six months and with close clinical monitoring. Because the benefits of oral corticosteroids are apparent, current studies have turned to the efficacy of inhaled corticosteroids on lung function in individuals with CF. An alternative to corticosteroids are the non-steroidal anti-inflammatory drugs (NSAIDs). This agent may slow the progression of lung disease without serious side effects.
Other potentially useful anti-inflammatory agents include alpha–1 antitrypsin (A1AT), pentoxifylline and secretory leukocyte protease inhibitor (SLPI). A1AT is a naturally occuring anti-protease that helps limit the inflammatory damage in the CF lung but is overwhelmed by the presence of large quantities of neutrophil elastase. A pilot study disclosed aerosolized A1AT increased the amount of the protein in the lung and suppressed elastase activity.
Often, antihistamines and decongestants are prescribed to open air passages.
Cough suppressants are avoided since coughing helps to loosen the mucus in the trachea and lungs. Antibiotics help to treat pneumonia, and studies of the over-the-counter anti-inflammatory drug ibuprofen indicate that it can slow pulmonary decline.
Recent study is currently investigating gene therapy as an approach to treating cystic fibrosis. The process involves inserting a copy of the normal cystic fibrosis gene into a virus that has been altered not to cause disease. The virus is then inserted into lung cells removed from a cystic fibrosis patient. Researchers have found that the normal gene reaches the DNA of the lung cells and begins producing the correct protein, leading to decreased mucus secretion.
Researchers at the National Institutes of Health have developed a “gene-assist” drug called CPX that helps promote chloride ion transport. With the development of new genetic testing technologies, physicians are able to test for a wider variety of the most common cystic fibrosis mutations known.
It has become clear that inflammation begins at a very early stage and progresses throughout life, gradually worsening and destroying the lungs. For these reasons, anti-inflammatory therapy should be initiated in early life. Additional studies are necessary to define the optimal anti-inflammatory drugs and regimens, and to confirm their long-term safety and efficacy.
References
Kotloff, R. & Zuckerman, J. (1996). Lung transplantation for cystic fibrosis. Chest 109, 787-798.
Loughlin, G. & Eigen, H. (1994). Respiratory Disease in Children. Baltimore, Maryland; Williams & Wilkins.
Welsh, M. & Smith, A. (1995). Cystic fibrosis. Scientific American. 273.52-58.
Aitken, ML & Fiel, SB. (1993). Cystic Fibrosis. PubMed 39(1): 1-52. University of Washington, Seattle. Web.
Gilligan, P.H. (1991). Clinical Microbiology. Microbiology of airway disease in patients with cystic fibrosis. 35-51 1900735 (P.S.E.B.) Cited: 75. Pseudomas Infections-Etiology. BioInfoBank Papers 1703. Web.
Brown, A. J. (2008). Reasons for Cystic Fibrosis infections uncovered. Nature Medicine. Yahoo News.com. Web.