CYSTIC FIBROSIS
- Introduction
Cystic fibrosis (CF) is an autosomal recessive disease that is most common amongst Caucasians (Calvez et al., 2017). CF is most common in children and has often been regarded as a children disease even though it has also been diagnosed in adults through methods such as sweat test (Calvez et al., 2017). The mutation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel gene is the cause of CF (Calvez et al., 2017). The common CF mutation is the phenylalanine gene deletion (Calvez et al., 2017). The gene deletion leads to the alteration of the CFTR protein (Calvez et al., 2017). The protein folds and is fast degraded (Calvez et al., 2017). Severe forms of pulmonary infections in CF patients are caused by Burkholderia cenocepaciai (Nunvar et al., 2017). The causes will be discussed later in detail. In the US, approximately 12 million people are CF carriers and each year 2,500 children are born with CF. About 30,000 Americans, 3,000 Canadians and 20,000 Europeans have CF. The disease affects Caucasian more often as compared to the other ethnic and racial groups. In Asian Americans, CF affects 1 in every 50,000 babies while it affects 1 in every 30,000 African American babies. Approximately 1 in every 22 Caucasians are carriers. CF patient’s conditions can have quality lives following early diagnosis and proper medical regime is followed.
- Symptoms:
- Respiratory Signs and Symptoms
The symptoms presented in the patients include the recurrent or chronic cough. The cough can be hacking and dry at the beginning. In the early stages, the cough produces mucoid while in the later stages, it produces purulent sputum. In the infants, there may be prolonged symptoms associated with bronchiolitis. In some patients, paroxysmal cough is followed by vomiting. The patients will also experience recurrent pneumonia, recurrent wheezing, pneumothorax (trapping of air or gas within the chest and lung walls), atypical asthma, digital clubbing (bulbous and enlargement of toes and fingers) and hemoptysis. In some cases, there may be history of chest pain, nasal polyps, hemoptysis (coughing up of blood), dyspnea on exertion, and recurrent sinusitis (Bennett et al, 20142). Nasal polyps refer to the fleshy growths that are found inside the nose. They occur to 15% to 20% of the CF patients. The other symptom is further, the allergic bronchopulmonary aspergillosis which affects 10% of the CF patients is also a symptom. It is an infection of the lungs or bronchi that can lead to inflammatory lesions formation.
- Digestive Signs and Symptoms
Meconium ileus may occur in 7-10% of the patients. For the patients with simple meconium ileus, they usually present abdominal distention when they are born (Doulgeraki et al., 2017). Eventually, it progresses to bilious vomiting, progressive failure in passing meconium and the progression in the distension of the abdomen. In the complicated cases of meconium ileus, the patients have severe distension of the abdomen at birth, accompanied by edema and erythema of the abdominal wall. Respiratory distress can occur in the severe cases of abdominal distension. In neonates, the symptoms may include various surgical findings at birth. The findings include perforation, meconium peritonitis, intestinal atresia and volvulus. The other symptom in the neonates is the intestinal obstruction when the child is born. In a few of the cases, the meconium passage may be delayed by between 24 and 48 hours after the birth of the baby. Moreover, there may be cases of prolonged cholestatic jaundice.
Children and infants are presented with increased stool frequency. This higher frequency suggests a failure to thrive, mal-absorption (presence of oil or fat drops in their stools), rectal prolapse or ileocecal (intussusception) (Doulgeraki et al., 2017). The patients that have pancreatic insufficiency will have mal-absorption of proteins, carbohydrates, and fats as well as fat-soluble vitamin deficiency. However, the carbohydrate malabsorption is not severe as compared with that of proteins and fats. The patient fails to thrive even in the cases where the patient has an adequate appetite, foul-smelling flatus or flatulence, abdominal pain that is recurrent. The malabsorption results in steatorrhea which is characterized by frequent, large, poorly formed, greasy and foul-smelling stool. Some patients present with anorexia without the occurrence of steatorrhea. Some of the patients may present with a history of gastrointestinal tract bleeding or jaundice as a consequence of the hepatobiliary involvement.
The abdominal symptoms (AS) are the hallmark of CF which is a multi-organ disease. The CF’s abdominal involvement is the least and insufficiently understood as it normally compared to the various pulmonary manifestations (Tabori et al., 2017). The study by Tabori et al., (2017) focused on the abdominal pain and the other non-pain abdominal symptoms, eating and appetite disorders as well as bowel movements and quality of life-related symptoms. The most abdominal symptoms that are noted in CF include lack of appetite, loss of taste, abdominal pain, flatulence, abdominal distention (Tabori et al., 2017). The most interesting element is that children experience more pain as compared to the adults while the abdominal distention is mostly reported in the adults (Tabori et al., 2017). The abdominal pain is mostly reported in the epigastric regions, umbilical and dorsum (Tabori et al., 2017). The pain reported in terms of frequency is at least once every week (Tabori et al., 2017). The abdominal pain in the majority of the CF patients is 45 minutes although the pain can last for 5 hours or longer (Tabori et al., 2017). The pain is most frequent during stressful events, just before the bowel movements and during meals (Tabori et al., 2017).
- How to Diagnose
There are a number of tests and methods that are used in the screening for cystic fibrosis. The most effective method that is used is the sweat test also known as the sweat chloride test. The test is used to measure the amount of salt that is present in the skin of the adult or child. The sweat test involves the use of pilocarpine – a chemical – and mild electric current to induce sweating on the skin. The skin is wrapped in a pad and plastic to absorb the sweat that is released (Langen et al., 2015). The sweat is collected for a period of 30 minutes. For children when the chloride (Cl-) concentration is higher than 60 mmol per liter, this is an indication that the patient has cystic fibrosis. However, when the concentration of chloride is higher than 80 mmol/L in adults, it is an indication of cystic fibrosis. This is because adults have higher amounts of chloride in their sweat as compared to children. Due to the low sweat production by newborn children, 50mg of sweat is collected for a period of 45 minutes, and then an immunoreactive trypsinogen test (IRT) is done instead of the sweat test (Kharrazi et al., 2015). However, when enough sweat can be collected in the newborns or infants who are less than three months, CF is indicated by chloride concentrations that are more than 40 mmol/L.
The second method of screening is the IRT. As stated above, this test is carried out on newborn babies who cannot produce enough sweat for the sweat test (Kharrazi et al., 2015). IRT test is undertaken by drawing the blood of the newborn baby a few days after birth. The blood test involves the evaluation of the protein trypsinogen presence. When the test is positive, CF can be confirmed through genetic testing or other forms of mutation analysis. The sensitivity of a combination of mutation analysis and IRT is between 90% and 100%.
Thirdly, there is the use of Nasal Potential Difference (NPD). NPD is carried out based on the electric potential differences that occur as sodium and chloride ions move across the cell membranes lining the airway (Ng et al., 2015). The electric potential differences are the amount of energy that is needed to move the electrical charge from one place to another. Surface electrodes are used to measure the NPD. The abnormal transport of Na+ and Cl- in the patients with CF is abnormal thus allowing for the determination. This test is applied and is very helpful in the cases where the genetic tests and the sweat tests are inconclusive.
Moreover, there is the genetic test or mutation analysis. This test analyzes the DNA for the presence of one of the mutations that can cause CF. A sample of the blood of the patient is collected for the testing. However, the test cannot detect all of the gene mutations that cause CF thus it has a sensitivity of approximately 80-85% (Ng et al., 2015). Further, it cannot be used to determine the symptom severity, i.e., it cannot be used to determine whether the CF will be mild or fatal based on the genotype. The test is mostly used in the cases where the sweat test is negative, but there are still suspicions that the patient may have CF.
Other methods of diagnosis include medical history where the physicians look for the various symptoms. The medical history can be analyzed beginning from infancy. The other diagnostic method is the family history. Since CF is a disorder that is inherited, the family history with CF is an indication that the gene is in the lineage (Ng et al., 2015). Finally, there is the prenatal CF diagnosis. The genetic testing can be done before birth by chorionic villus biopsy where the tissues that develop into the placenta are tested or amniocentesis where cells are removed from the amniotic fluid.
- Causes
The genetic causes of cystic fibrosis are discussed to illustrate the microscopic properties of the disease. Cystic fibrosis (CF) is caused by the CFTR (cystic fibrosis transmembrane regulator) gene mutation (Furgeri et al., 2018). The genetic mutation as a cause of CF has also been noted in Prados et al., (2017). The other cause is the presence of bronchiectasis as found in cross-sectional observational and descriptive study that was undertaken on patients who are older than 60 years in Madrid and Valencia in May 2012 (Prados et al., 2017). Bioactive lipids have also been considered to be markers in CF (Bragonzi et al., 2017). Moreover, the pathogenesis in CF may be contributed to by a host of proteases (Bragonzi et al., 2017).
The risk factors are discussed to illustrate the macroscopic properties of the disease. The risk factors include race and family history. CF is common amongst the Caucasians of Northern European ancestry or descent. However, the disease is known to occur amongst all ethnic groups. The carrier frequency for the Caucasians of the United States and Europe stands at about 1:25 while for other groups such as Iranians, the carrier frequency is 1:40. The most common CFTR gene mutation is the p. Phe508del. The frequency of the above gene mutation amongst the Caucasians is 70%, between 44% and 13% among Indians, Turkish, Arab and Turkish populations (Tabaripour et al., 2012). Further, the people who have a history of CF in the family also have an increased risk of the disorder. This is because the disorder is hereditary.
- Disease Pathophysiology
5.1 Physiological Processes/Mechanisms of Cystic Fibrosis
CF is characterized by an abnormality in the epithelial ion transport (Cholon & Gentzsch, 2017). This results from the mutation in the CFTR gene which is an ion channel that mediates chloride (Cl-) and HCO3- transport of absorptive and secretory epithelial cells in a number of organs such as intestines and lungs (Cholon & Gentzsch, 2017). The CFTR also leads to an increase in the Na+ uptake through the ENac channel (Cholon & Gentzsch, 2017). The enhanced update of Na+ leads to the airways dehydration as the salt saps up the water in the airways (Cholon & Gentzsch, 2017). This is the major cause of mortality and morbidity that are linked to CF as the airway surface liquid (ASL) homeostasis is disturbed leading to sticky and viscous mucus (Cholon & Gentzsch, 2017). The above abnormal mucus leads to airway obstruction, mucus stasis, inflammation, persistent infection and the increased decline of the functioning of the lung (Cholon & Gentzsch, 2017).
The patients also show platelet activation which is a market of the clinical status of the disease (Lindberg et al., 2018). The patient will experience increased platelet-monocyte complexes circulation (Lindberg et al., 2018). There is also an increase leukocyte activation levels (Lindberg et al., 2018). CFTR blockade has an impact on the release mediators by platelets which are involved in the inflammation response (Lindberg et al., 2018). The blockade of CFTR on the platelets reduces the formation of lipoxin A4 (LXA4) which is an anti-inflammatory mediator that helps in the modulation of neutrophil inflammation (Lindberg et al., 2018). The dysfunction of CF platelets can contribute to the chronic inflation which is a common mark of CF (Lindberg et al., 2018).
- Functional Changes Associated With Cystic Fibrosis
There are a number of functional changes that occur as a result of Cystic Fibrosis. The CFTR mutation leads to the defect of HCO3- and Cl- epithelial ion transport. This leads to the impairment of the mucociliary clearance (MCC) and airway surface liquid (ASL) due to the sticky and thick mucus that is produced. Secondly, the defective MCC also leads to chronic infections, bronchiectasis, and progression in the loss of the lung functions. Bronchotracheal HCO3- and Cl-secretion contribute to the MCC and ASL height through the effects of the mucin expansion and extracellular hydration. The defects in the HCO3- and Cl- as a result of CF leads to acidic and dehydrated ASL (Sellers et al., 2017). The epithelial Na+ channel deregulation leads to Na+ hyperabsorption. This dehydrates the ASL layer further. This leads water to move out of the mucus layer and out of the periciliary layer. The above coupled with an increase in the viscosity of the mucus as a result of the acidity leads to viscous and thick mucus which impairs the MCC and compresses the cilia.
- Normal Physiology
This section will discuss the normal physiology in relation to the pathophysiology and symptoms of cystic fibrosis. CFTR is an ABC transporter which has a modular design made up of two membrane-spanning domains (MSDS) and 2 nucleotide-binding domains (NBDs) (Wang et al., 2014). The NBDs use the ATP hydrolysis energy to pump various substrates across the cell membranes through the use of MSDs formed transmembrane pathways (Wang et al., 2014). The mature form (Wild-type CFTR ¬ 170-kDa) is a member of the ABC (ATP –binding cassette) transporter superfamily (Calvez et al., 2017). The CFTR chloride channel stated above is regulated by protein divalent cations, protein kinases, phosphatases and the protein-protein interactions (Calvez et al., 2017).CFTR, as an ABC transporter, is unique in that it functions as a selective and low conductance gated channel of chloride through the ATP hydrolysis and binding cycles at the NBDs (Wang et al., 2014). Bozoky et al. (2013) noted that CFTR gene is tightly regulated by a disorder and intrinsic protein segment that is distinguished by a regulatory domain (RD) (Bozoky et al., 2013). The RD are the various consensus phosphorylation sites (Bozoky et al., 2013).
- Disease Treatments
There are a number of treatment options for CF that are currently available. First, there are the medications. Some antibiotics are prescribed to the patients to help them get rid of the lung infection and other infections. The antibiotics are administered in capsules, tablets, and liquids. In the very severe cases, infusions or injections can be used. The other medications that are also used include the mucus-thinning medication which is administered to make the mucus less sticky and thinner. This helps the patient to cough the mucus thus significantly improving the function of the lung. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and ibuprofen are also used to reduce fever and pain associated with CF. Bronchodilators are also used to relax the muscle of the tubes that carry air to the lungs. This help in increasing the airflow in the airways. The medications are taken through the use of nebulizers or inhalers. CFTR modulators have been used in the last ten years to target the primary defect directly (Hagemeijer et al., 2007). There is also the use of Omalizumab which helps in the stabilization of the lung function which leads to the improvement of patient’s nutritional status (Perisson et al., 2017)
The second treatment option is the Chest Physical Therapy. This is done to loosen the thick mucus found in the lung. This makes it easier for the patient to cough the mucus up (Ari, 2015). The treatment is performed between 1-4 times per day. The commonest technique used is by placing the patients head over the edge of the bed and clapping with cupped hands on the side of the chest. Mechanical devices are also used in the chest therapy. Such devices include inflatable vest which removes the chest mucus through high-frequency vibrations. Chest clappers can also be used to imitate the effects of the cupped hands clapping along the chest.
Pulmonary rehabilitation (PR) is also used for the treatment of CF. It is a program that is made up of exercise and education to help the patient to increase their stamina, manage their breathing and decrease the episodes of breathlessness brought about by the mucus blockage of the airways. The PR combines diet, education, breathing techniques and exercise to help the patients have control of their symptoms and a better quality of life. The research is also focused on therapies that would help to increase the quality of life and the life expectancy of the patients (Kerem, 2017).
Finally, there are surgical procedures which include surgical insertion of feeding tubes, lung transplant, and bowel surgery. Bowel surgery involves the removal of a specific section of the bowel. It is done to relieve the bowel blockages. The surgical insertion of the feeding tube is done directly into the stomach in the cases where the CF interferes with the nutrient absorption and digestion (Ari, 2015). The lung transplant is undertaken to replace a damaged lung with a healthy lung. The lung transplant is mostly used when the CF causes the patient to have severe breathing difficulties. In some severe cases, both lungs can be removed. However, there are grave complications to this procedure as it can lead to pneumonia and other ailments.
- Future
The current research is focused on the medications and other methods of treatment that can be used in the patients with CF such as the application of gene therapy. The focus is on medications as well as surgical procedures. The future research on CF is focused on the clinical evaluation of the impacts of the drugs that have been developed for instance the ivacaftor that was approved by the FDA in 2012 (Hubert et al., 2018). There are a number of possible research areas screening for torsional bone strength and bone density for children with CF. Research can also be undertaken to determine the effects of protective commensal migration on the pathogen colonization of the lungs of patients with CF.
- Conclusion
CF is an autosomal recessive disease that is most common amongst Caucasians children. The mutation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel gene is the cause of CF. There is a number of categories of symptoms such as the digestive and respiratory symptoms. The symptoms indicate what should be looked at in the patients. The causes are both genetic and family related. CFTR is an ABC transporter which has a modular design made up of two MSDs and 2 NBDs. CF is characterized by an abnormality in the epithelial ion transport. CFTR modulators have been used in the last ten years to target the primary defect directly. There are a number of treatment methods that are applied to improve the quality of life of the CF patients and also reduce the pain while increasing their lifespan. Current research is focused on improving life expectancy and the effectiveness of the drugs. CF patient’s conditions can have quality lives following early diagnosis, and the proper medical regime is followed.
References
Ari, A. (2015). Use of Aerosol Drug Therapy in Pulmonary Rehabilitation. Toraks Cerrahisi Bulteni, 6(1), 69-76.
Bennett, D. S., Kane, M., Aramburo, M., & Varlotta, L. (2014). Monitoring and Blunting as Predictors of Internalizing Symptoms Among Youths With Cystic Fibrosis. Children’s Health Care, 44(2), 155-168.
Bozoky, Z., Krzeminski, M., Chong, P. A., & Forman-Kay, J. D. (2013). Structural changes of CFTR R region upon phosphorylation: a plastic platform for intramolecular and intermolecular interactions. FEBS Journal, 280(18), 4407-4416.
Bragonzi, A., Horati, H., Kerrigan, L., Lorè, N. I., Scholte, B. J., & Weldon, S. (2017). Inflammation and host-pathogen interaction: Cause and consequence in cystic fibrosis lung disease. Journal of Cystic Fibrosis, 1-6.
Calvez, M., Benz, N., Huguet, F., Saint-Pierre, A., Rouillé, E., Coraux, C., Trouvé, P. (2017). Buserelin alleviates chloride transport defect in human cystic fibrosis nasal epithelial cells. PLOS ONE, 12(11), 1-21.
Cholon, D. M., & Gentzsch, M. (2017). Recent progress in translational cystic fibrosis research using precision medicine strategies. Journal of Cystic Fibrosis, 1-9.
Doulgeraki, A., Petrocheilou, A., Petrocheilou, G., Chrousos, G., Doudounakis, S., & Kaditis, A. G. (2017). Body composition and lung function in children with cystic fibrosis and meconium ileus. European Journal of Pediatrics, 176(6), 737-743.
Furgeri, D. T., Marson, F. A., Correia, C. A., Ribeiro, J. D., & Bertuzzo, C. S. (2018). Cystic fibrosis transmembrane regulator haplotypes in households of patients with cystic fibrosis. Gene, 641, 137-143.
Hagemeijer, M. C., Siegwart, D. J., Strug, L. S., Cebotaru, L., Torres, M. J., Sofoluwe, A., & Beekman, J. M. (2007). Translational research to enable personalized treatment of cystic fibrosis. Journal of Cystic Fibrosis, 1-6.
Hubert, D., Dehillotte, C., Munck, A., David, V., Baek, J., Mely, L., …Lemonnier, L. (2018). Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp- CFTR mutation after 1 and 2 years of treatment with ivacaftor in a real- world setting. Journal of Cystic Fibrosis, 17(1), 89-95.
Kerem, E. (2017). Cystic fibrosis: Priorities and progress for future therapies. Paediatric Respiratory Reviews, 24, 14-16.
Kharrazi, M., Yang, J., Bishop, T., Lessing, S., Young, S., Graham, S., & … Feuchtbaum, L. (2015). Newborn Screening for Cystic Fibrosis in California. Pediatrics, 136(6), 1062-1072.
Langen, A. V., Dompeling, E., Yntema, J., Arets, B., Tiddens, H., Loeber, G., & Dankert- Roelse, J. (2015). Clinical evaluation of the Nanoduct sweat test system in the diagnosis of cystic fibrosis after newborn screening. European Journal of Pediatrics, 174(8), 1025-1034.
Lindberg, U., Svensson, L., Hellmark, T., Segelmark, M., & Shannon, O. (2018). Increased platelet activation occurs in cystic fibrosis patients and correlates to clinical status. Thrombosis Research, 162, 32-37.
Ng, R. Y., Marson, F. L., Ribeiro, J. D., Ribeiro, A. F., Bertuzzo, C. S., Ribeiro, M. O., & … Sakano, E. (2015). Nasal Potential Difference in Cystic Fibrosis considering Severe CFTR Mutations. Disease Markers, 1-11.
Nunvar, J., Capek, V., Fiser, K., Fila, L., & Drevinek, P. (2017). What matters in chronic Burkholderia cenocepacia infection in cystic fibrosis: Insights from comparative genomics.PLOS Pathogens, 13(12), 1-24.
Perisson, C., Destruys, L., Grenet, D., Bassinet, L., Derelle, J., Sermet-Gaudelus, I., …Corvol, H. (2017). Omalizumab treatment for allergic bronchopulmonaryaspergillosis in young patients with cystic fibrosis. Respiratory Medicine, 133, 12-15.
Prados, C., Lerín, M., Cabanillas, J., Gómez-Carrera, L., Álvarez-Sala, R., Martinez, M., …Quirós, S. (2017). How are the ancient cystic fibrosis patients? Cystic fibrosis diagnosed over 60 years-old. Respiratory Medicine Case Reports, 21, 49-51.
Sellers, Z. M., Illek, B., Figueira, M. F., Hari, G., Joo, N. S., Sibley, E., … Wine, J. J. (2017). Impaired PGE2-stimulated Cl- and HCO3- secretion contributes to cystic fibrosis airway disease. PLOS ONE, 12(12), 1-20.
Tabaripour, R., Niaki, H. A., Douki, M. R., Bazzaz, J. T., Larijani, B., & Yaghmaei, P. (2012). Poly Thymidine Polymorphism and Cystic Fibrosis in a Non-Caucasian Population. Disease Markers, 32(4), 241-246.
Tabori, H., Arnold, C., Jaudszus, A., Mentzel, H., Renz, D. M., Reinsch, S., … Mainz, J. G. (2017). Abdominal symptoms in cystic fibrosis and their relation to genotype, history, clinical and laboratory findings. PLOS ONE, 12(5), 1-19.
Wang, Y., Wrennall, J. A., Cai, Z., Li, H., & Sheppard, D. N. (2014). Understanding how cystic fibrosis mutations disrupt CFTR function: From single molecules to animal models. The International Journal of Biochemistry & Cell Biology, 52, 47-57.