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Cystic Fibrosis

Cystic Fibrosis

  Cystic Fibrosis is a disease characterized by an insufficient production (or enough production but with an abnormal molecular structure) of CFTR which is an acronym for cystic fibrosis transmembrane regulator, a protein that plays a major role in our respiratory system. CFTR protein is usually found on pulmonary cell surfaces and they assist in pulmonary functions by regulating the exchange of sodium, H2O and chloride ions throughout the cell membrane. Periodic or chronic sinusitis and lung infections are very common in cystic fibrosis.

  “Changing diagnostic criteria and methods as well as improvements in clinical outcome have influenced the epidemiology of cystic fibrosis. Estimates of disease incidence are around 1 in 3,000 live births in persons of northern European descent, with Ireland having the highest incidence at 1 in 1,400 live births. Incidence varies according to race and ethnicity; only 1 in 4,000 to 10,000 Latin Americans and 1 in 15,000 to 20,000 African Americans have cystic fibrosis, with even lower incidence rates in people of Asian background. These estimates are based on information from western countries — epidemiological data are missing for large regions of the world, including the Middle East, Asia and Africa. Importantly, some small populations in Eastern Europe have very high incidence rates, specifically Albania, where the incidence was noted to be 1 in 555. This high incidence is also reflected in data noting very high incidence in Albanian immigrants to northern Italy. The introduction of prenatal genetic screening in western countries seems to correlate with decreasing incidence in some countries. Although the incidence is decreasing, data from registries suggest that the prevalence is increasing because of improvements in survival.” 1

“Cystic fibrosis (CF) manifests as a clinical syndrome characterized by chronic sinopulmonary infection as well as by gastrointestinal, nutritional, and other abnormalities. The genetic basis for CF (Cystic fibrosis) is a well-characterized, severe monogenic recessive disorder, found predominantly in Caucasian populations of European ancestry that arises from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. While the gene defect results in a myriad of medical problems for the patient, the most meddlesome clinical feature, chronic pulmonary infection with Pseudomonas aeruginosa, allows the basic pathologic process in CF (Cystic fibrosis) to be designated an infectious disease. Ultimately, 80 to 95% of patients with CF (Cystic fibrosis) succumb to respiratory failure brought on by chronic bacterial infection and concomitant airway inflammation.” 2

The transmission of cystic fibrosis occurs at a genetic level. Genes such as the G551D and the Delta F508 can suffer from mutations causing cystic fibrosis in two separate ways:

  G551D mutations will give rise to the so called ‘door-jamming mutation’. This faulty mechanism is a result of the CFTR protein channel becoming closed and therefore, not allowing the proper ions to flow in and out of cells.

  Delta F508 mutations will cause the CFTR protein being synthesized within the cell but is never able to reach the cell membrane where it is supposed to perform its function.

 

Cystic
Fig. 1. Cystic Fibrosis Gene (3)

 

“The presence of two mutant genes (g) is needed for CF (Cystic Fibrosis) to appear. Each parent carries one defective gene (g) and one normal gene (G). The single normal gene is sufficient for normal function of the mucus glands, and the parents are therefore CF (Cystic Fibrosis)-free. Each child has a 25 percent risk of inheriting two defective genes and getting CF (Cystic Fibrosis), a 25 percent chance of inheriting two normal genes, and a 50 percent chance of being an unaffected carrier like the parents.”4

The absence or structural inadequacy of CFTR causes normal fluids in the pulmonary air passages, ducts in the pancreas, reproductive system and gastrointestinal tract, to become thicker and mucus-like instead of thin and watery as it should be. As a result of the production of this thick mucus, some of the above-mentioned areas can become obstructed, cause higher frequency of infections and reduce those organs’ ability to function.

Cystic Fibrosis is Systemic

As mentioned in the previous paragraph, cystic fibrosis is not limited to affecting the lungs exclusively.  Instead, it affects us at several systemic levels:

“The organs in which clinical abnormalities have been documented most in CF (Cystic Fibrosis) are the airways, pancreas, and sweat gland. Basic physiological defects predispose the airways to chronic, recurrent infections with associated tissue inflammation that result in progressive deterioration of pulmonary function due to endobronchitis, inspissations, bronchiectasis, and parenchymal destruction. Unfortunately, the link between the chronic respiratory infections uniquely characterized by a mucoid form of Pseudomorws aeruginosa and the abnormal physiological phenomena is not known. Therapy is usually focused on mechanical assistance in clearing the airways of sputum and intermittent administration of antibiotics to suppress pulmonary infection. The loss of parenchymal tissue leads to respiratory failure, which may be complicated by pulmonary hypertension and cor pulmonale. More than 90% of the mortality in cystic fibrosis is due to pulmonary complications.”5

Pulmonary Level: A lack of CFTR causes our lungs to produce thick mucus instead of a watery film. This heightened mucus-like environment induces greater chances of infection as well as the mechanical disadvantage of having the patient’s air passages becoming blocked or congested. In the long run, this chronic obstruction or congestion further damages pulmonary tissue.

  “Soon after birth, initial infection with bacterial pathogens commences and is associated with an intense neutrophilic response localized to the peribronchial and endobronchial spaces. Early airway infection and inflammation in CF (Cystic Fibrosis) can have regional heterogeneity that complicates understanding the causal and temporal relationship between initial infection and airway inflammatory response. Several studies in toddlers and older children with CF (Cystic Fibrosis) have shown a robust inflammatory response in the airways in both bacterial culture–positive and culture-negative patients; some studies show a greater inflammatory response in those patients with at least 5 x 104 cfu/ml of bacteria in their bronchoalveolar lavage (BAL) fluid. At this point, pathologic changes become more evident with mucopurulent plugging of small and medium size bronchioles. In older individuals with CF (Cystic Fibrosis), persistent neutrophils dominate airway inflammation with elevated interleukin (IL)-8 and neutrophil elastase. Airways become dilated and bronchiectatic, secondary to proteolysis and chondrolysis of airway support tissue. In later stages, lung parenchyma becomes affected by atelectasis, pneumonia, and encroachment by enlarging airways. Many secondary consequences of bronchiectasis ensue, including hypertrophy of bronchial circulation and formation of bronchial cysts. A later and less common consequence is pulmonary hypertension.” 6

 

Fig. 2. Mucus plugging with airway inflammation. A slightly dilated peripheral bronchus at low power, with surrounding alveolar tissue from a Young adult with CF. The bronchus is filled with inflammatory cells and mucus. The peribronchial región is also filled with inflammatory cells (primarily neutrophils).  By contrast, the parenchyma is spared both inflammation and scarring. (7)

 

Pancreatic Level: The pancreas drains its normal content into the intestinal system via several ducts. If these ducts become blocked or congested, the body will not receive the necessary hormones such as insulin, leading to cystic fibrosis-induced diabetes. This congestion also causes the pancreatic tissue to scar, affecting the patient long-term as well.

“As with the lung, the pancreas also shows progressive deterioration with age. Again, the ducts of the pancreas appear to obstruct with inspissation. Luminal obstruction and dilation of the secretory acini and ducts seem to be followed by atrophy and degeneration of the exocrine parenchyma. The endocrine pancreas appears to survive this destruction remarkably well, although incidence of glucose intolerance increases with age. In general, pancreatic insufficiency is manageable clinically with supplemental pancreatic enzymes that usually suffice to maintain nutrition.” 8

Hepatic Level: Like the pancreas, the liver uses ducts to drain necessary content that our bodies use. Since these ducts become blocked or congested, cystic fibrosis may lead to hepatic cirrhosis.

  Reproductive Level: Mucus-like congestions may cause infertility in both men and women.

Gastrointestinal Level: Due to blockages or congestions, surgery may be required to relieve the digestive system.

“It is the consensus of the panel that the diagnosis of CF (Cystic Fibrosis) should be based on the presence of one or more characteristic phenotypic features (Table II), a history of CF (Cystic Fibrosis) in a sibling, or a positive newborn screening test result plus laboratory evidence of a CFTR (cystic fibrosis transmembrane conductance regulator) abnormality as documented by elevated sweat chloride concentration, or identification of mutations in each CFTR (cystic fibrosis transmembrane conductance regulator) gene known to cause CF (Cystic Fibrosis) or in vivo demonstration of characteristic abnormalities in ion transport across the nasal epithelium.” 9

 

Fig. 3. Phenotypic features consistent with a diagnosis of CF (10)

 

  Thanks to advances in medicine and the relentless pursuit of knowledge in the science world, life expectancy has dramatically improved. Roughly 60 years ago, it was difficult for children with cystic fibrosis to go through their youths unscathed. In contrast, today’s person with cystic fibrosis is expected to arrive at, at least 40 years of age with proper management and treatment. The ethnic group most affected by this condition is of Caucasian descent but it can affect people of all races with a rarer frequency of occurrence.

Early Diagnosis of Cystic Fibrosis

  “Newborn screening for cystic fibrosis has been controversial because of its cost, the creation of anxiety around the procedure in seemingly healthy infants and the lack of established pulmonary treatments for infants. The cost of treatment has been shown to be reduced in patients who have been diagnosed through newborn screening compared with those who have had later diagnoses. A randomized controlled trial has clearly shown the efficacy of screening and has provided evidence of nutritional — but not respiratory — benefits. However, a factor in the unexpectedly poor respiratory outcomes in that study might have been failure to apply modern infection control precautions in one of the participating centers. Much evidence shows benefit when comparing outcomes before and after the introduction of screening. For example, The London Cystic Fibrosis Collaboration showed that infants diagnosed later (in the first 2 years of life) had airway obstruction at presentation, even if they had had no respiratory symptoms or signs, and this never recovered despite specialist treatment. By comparison, the outcomes in babies diagnosed by screening were much more favorable. Another benefit of newborn screening is that parents have the opportunity to make informed choices about antenatal diagnosis in future pregnancies.” 11

Lung Transplantation is a Real Possibility?

  “Lung transplantation is the established treatment for patients with end-stage pulmonary disease. The outcomes for patients undergoing transplantation for cystic fibrosis have rapidly improved and median survival now approaches or even exceeds 10 years in many treatment centers. Timely referral and close communication between the cystic fibrosis and transplant centers is required to provide sufficient time for assessment of suitability (of the donor and of the recipient), to determine whether indications are met and to establish that there are no foreseeable contraindications. Donor allocation programmes vary globally but aim to prioritize those waiting for transplants who have the most limited pre-transplant survival. Adjunctive therapies, including noninvasive ventilation, can function as a bridge to transplantation. The most common cause of graft failure following lung transplantation is bronchiolitis obliterans, which is thought to be a form of chronic allograft rejection.” 12

 

References:

(1, 11, 12) Cystic fibrosis. Ratjen, F., Bell, S.C., Rowe, S.M., Goss, C.H., Quittner, A.L. & Bush, A. Nature Reviews. 2015. https://www.researchgate.net/publication/277350830_Cystic_fibrosis

(2) Lung Infections Associated with Cystic. Lyczak, J.B., Cannon, C.L. & Pier, G.B. Clinical Microbiology Reviews. 2002. https://cmr.asm.org/content/15/2/194.full

(3, 4) Cystic Fibrosis. National Heart, Lung, and Blood Institute (NHLBI). National Institutes of Health. 1995. https://www.cdc.gov/scienceambassador/documents/cystic-fibrosis-fact-sheet.pdf

(5, 8) Cystic fibrosis: a disease in electrolyte transport. Quinton, P.M. The FASEB Journal. 1990. https://pdfs.semanticscholar.org/dcbf/a0480e17cc46d51a9b182b041ead4dd935b1.pdf

(6, 7) Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis. Gibson, R.L., Burns, J.L., &  Ramsey, B.W. https://www.atsjournals.org/doi/full/10.1164/rccm.200304-505SO

(9, 10) The diagnosis of cystic fibrosis: A consensus. Rosenstein, B.J. & Cutting, G.R. The Journal of Pediatrics. 1998. https://www.sifc.it/sites/default/files/ScreeningTestSudore_Rosenstein_Diagnosi_di_FC_Consensus_statement_1998.pdf

 

María Laura Márquez
13 October, 2018

Written by

María Laura Márquez, general doctor graduated from The University of Oriente in 2018, Venezuela. My interests in the world of medicine and science, are focused on surgery and its breakthroughs. Nowadays I practice my profession...read more:

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