The purpose of this paper is to review the etiology, pathophysiology, clinical manifestations, inheritance patterns, and recent advances in disease management of cystic fibrosis. Cystic fibrosis is a progressive and lethal disease resulting from an autosomal recessive gene (Singh, Rebordosa, Bernholz, & Sharma, 2015). The major problem associated with cystic fibrosis is the repeated lung infections that over time severely damage the lungs, scar and widen the passageways and limit the ability to breathe (Cystic Fibrosis Foundation, n.d.). As of 2013, there are an estimated 70,000 cystic fibrosis patients globally with 33,000 of them in the United States (Cystic Fibrosis Foundation, n.d.).
Most cystic fibrosis requires daily care and management of symptoms; however with today’s early screening and treatment, people with the disease are able to go to school and enter the work force. Now most people with cystic fibrosis live into their 20s and 30s and some into their 40s and 50s (Mayo Clinic, n.d.). Treatment involves physiotherapy to assist in clearing the mucus from the lungs and drug therapy to control respiratory infections. Treatment is also available to help with the digestion of food.
1. Etiology of Cystic Fibrosis
Cystic fibrosis is caused by a variety of mutations of the Cystic Fibrosis Transmembrane Conductance Regulator gene [CFTR (MIM#602421)], which is located on chromosome 7. The result is a defect in the ion channel that is responsible for the transport of chloride. At this point, more than 2007 variants have been reported (Silinas, et al., 2015). To date, 202 of the 2007 mutations have been characterized according to disease liability. Of the 202, 178 have been identified as causing cystic fibrosis, 12 do not cause the disease, and 12 are responsible for varying phenotypes (Silinas, et al., 2016). The remaining variants have a low occurrence and an undetermined disease liability (Silinas, et al., 2016).
2. Pathophysiology of Cystic Fibrosis
The defective gene targets the exocrine glands that produce mucus, digestive enzymes, and sweat. The secretions are normally thin and slippery. In those with cystic fibrosis, the genetic defect causes the secretions to become thick and sticky (Mayo Clinic, n.d.). The abnormally thick accumulation of mucus blocks tubes, ducts, and passages, and particularly affects the pancreatic ducts, bronchi and intestines. The blocked pancreatic ducts prevent digestive enzymes from entering the intestines, thus disrupting the body’s ability to absorb nutrients. The persistent lung infections are the result of the mucus obstructing the airways and trapping bacteria, which leads to damage to the lungs and ultimately respiratory failure (Cystic Fibrosis Foundation, n.d.). The reproductive system is also involved resulting in intertility (Skolnik, et al., 2015)
As Govan and Deretic (1996) point out, identifying the genetic defect causing cystic fibrosis is only half the battle. Research on the specific bacterium accompanying the disease is equally important. Due to impaired mucociliary clearance and the thick secretions, the lungs are an ideal environment for the colonization of bacteria, chronic infection and inflammation, and ultimately, bronchiectasis (Skolnik, et al., 2015). The cultured microbiome of cystic fibrosis lungs is well-understood and is distinct from other chronic diseases of the lungs. Research has established the classic cystic fibrosis pathogens as Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex and Haemophilus influenza. Emerging cystic fibrosis pathogens, such as mycobacteria, Stenotrophomonas maltophilia, and Achromobacter species have been identified over the last 20 years, but due to their transience, the clinical implications have yet to be confirmed (Skolnik, et al., 2015). Research is beginning on the emerging transient lung pathogens, such as Group A Streptococcus (Streptococcus pyogenes) (Skolnik, et al., 2015). Group A Streptococcus is a common enough human pathogen that is not often found in cystic fibrosis lungs. However, when it does occur, it can cause a more aggressive pulmonary infection than the more common lung pathogens.
The positive-stand RNA viruses (human rhinoviruses) are usually restricted to the upper airways in a healthy person. In cystic fibrosis lungs, the human rhinoviruses can cause the abnormal antiviral response of producing interferon β, which and further exacerbates inflamed lungs (Dauletbaev, et al., 2015). The thick mucus contains areas representing a range of oxygen availability from hypoxic to anoxic and thus becomes host to heterogeneous communities of microbes in different regions of the airways. This heterogeneity in the regions has an impact on the host and microbe colony interactions, which has implications for the development of the disease (Filkins & O’Toole, 2015).
3. Clinical Manifestations
As cystic fibrosis affects multiple organs to different degrees, it has a wide range of symptoms. Even within the same individual, symptoms may improve or worsen from time to time, or vary. Also, only 202 of the 2007 of the genetic defects in Cystic Fibrosis Transmembrane Conductance Regulator gene has been identified as causing cystic fibrosis and the others either have no impact or a varying phenotypic presentation (Silinas, et al., 2016). Therefore, the clinical manifestations of cystic fibrosis are complex. In the developed world, newborns are regularly screened for the genetic defects known to cause cystic fibrosis (Silinas, et al., 2016). The Mayo Clinic (n.d.) describes the respiratory symptoms and signs as a persistent cough producing a thick sputum, breathlessness, wheezing, intolerance to exercise, multiple lung infections, and a stuffy nose or inflamed nasal passages. The gastrointestinal symptoms and signs are poor weight and growth rate, greasy and foul-smelling stools, severe constipation, intestinal blockage, and rectal prolapse in a child. Also, individuals with cystic fibrosis have salty tasting skin. Among adults, the symptoms are more atypical and include diabetes, pancreatitis, and male infertility (Mayo Clinic, n.d.). In the U. S., suspected cystic fibrosis individuals are given a sweat chloride test follow up with genetic testing (Yadav & Lim, 2016). As cystic fibrosis genetic defects vary by race, genetic testing centers will vary the testing panel in accordance with the demographics of the local population (Yadav & Lim, 2016).
4. Inheritance Patterns
As an autosomal recessive gene, both parents have to be carriers for the genotype in order for the disease to be inherited. If a child inherits two cystic fibrosis defective genes, he or she will always have the disease. If only one defective gene is inherited, the child will be a carrier. As previously mentioned, not all of the 2007 mutations have been characterized. The mutations have been classified into three broad groups: unknown significance, varying clinical consequence, and not associated with cystic fibrosis. Mutations with unknown significance are those that have been identified in individuals with cystic fibrosis, but it is not known if they are implicated in the disease (Cystic Fibrosis Foundation, n.d.). Another group of genetic defects result in a variable clinical consequence. Of this group, some of the mutations result in cystic fibrosis and other times they do not, or they are rare and little research has been conducted with them. Some mutations are referred to as cystic fibrosis related mutations and are associated with one or two symptoms, but not full cystic fibrosis disease (Cystic Fibrosis Foundation, n.d.). An example of the clinical manifestations of cystic fibrosis related mutations are individuals who have sinus disease, chronic pancreatitis, and male infertility, but none of the other signs. The progression of disease can vary between patients with identical Cystic Fibrosis Transmembrane Conductance Regulator gene mutations, which indicates that other genetic modifiers contribute to the phenotype (Corvol, et al., 2012).
Although the worldwide prevalence is far from understood, Cystic Fibrosis Transmembrane Conductance Regulator gene disease-causing mutations appears to be unevenly represented across the globe. The most common variant, F508 del, represents up to 80% or over of all the cystic fibrosis alleles among Northern European groups, but declines to less than 50% among Mediterranean populations (Dodge, 2015). In East Asia, panbronchiolitis is recognized as a distinct disease and is often associated with cystic fibrosis mutations. However, the pancreas and sweat glands are not involved. Routine screening for cystic fibrosis is not standard in India. However, some small populations have been screened for cystic fibrosis mutations, including the common F 508 del, and the estimates suggest a higher prevalence than all of Europe (Dodge, 2015).
5. Recent Advances in Disease Management
In addition to physiotherapy, treatment for cystic fibrosis includes transplants and specific cystic fibrosis drug therapy. Lung transplant is a last resort therapy for end-stage patients and does bring about an improved quality of life and greater survival rate (Kubisa, et al., 2015). Since 1995, 7,000 adults and 1,200 children with cystic fibrosis have received lung transplants worldwide. Given that the mean survival rate for children following lung transplant is 4.9 years, and for adults, the survival rate is 8 years, Kubisa et al., (2015) advocate for conservative treatment for children for as long as possible. With improved surgical techniques and immunosuppressive regimens, liver transplants are now conducted. Pancreatic transplants are now being considered and may head off cystic fibrosis-related diabetes; however the surgical difficulties are considerable (Dodge, 2015).
Gene therapy has been conducted and consists of inserting a normal Cystic Fibrosis Transmembrane Conductance Regulator gene into a human cystic fibrosis genome. The individual then becomes a cystic fibrosis carrier with two genetic mutations and one normal gene. The one normal gene is sufficient for chloride transport and other cellular operations (Dodge, 2015). Legal and ethical considerations arise from allowing the changes into the germline and there is little information on the future impact of gene therapy (Dodge, 2015). According to Dodge (2015), cystic fibrosis specific drug therapy holds the greatest possibilities for managing the disease and positive clinical trials have been conducted in Israel. At this point, long term effects are unknown. However, the research and development costs are astronomical in developed countries and are out of the reach of poorer nations (Dodge, 2015).
In conclusion, cystic fibrosis is a complex disease with wide genotypic and phenotypic variation. Currently, cystic fibrosis patients can at best expect to live for approximately 40 years. Genetic counselling is available but as with any inherited disease, prenatal genetic analysis raises its own ethical and legal concerns.
References
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