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Cystic Fibrosis

Cystic Fibrosis is a Systemic Condition

  More than half a century ago, cystic fibrosis would claim the lives of many children due to a lack of understanding pertaining to the disease as well as the existence of unrefined treatment management techniques. Today, physicians screen for cystic fibrosis during very early infancy in order to begin preparing for the child’s life, should the infant test positive for the disease.

  Cystic fibrosis can only manifest itself in infants if both parents passed the gene down to it. The symptoms of cystic fibrosis can range from mild to severe and can differ between relatives. Because cystic fibrosis affects several organs, it can have different consequences at different anatomical levels.

  In the lungs and their corresponding airway passages, symptoms can manifest shortly after birth and include coughing, frequent infections, wheezing sounds, breathing difficulty or loss of breath and chronic allergies. The problems associated with cystic fibrosis are further exacerbated when taking into account the fact that recurrent infections and chronic congestion in the respiratory airways damage pulmonary tissue.

  “Over the past two decades, investigators have studied people with cystic fibrosis, who have disease causing CFTR (cystic fibrosis transmembrane regulator) mutations, at progressively earlier time points. We have learned that, by 3 years of age, bronchiectasis is present in nearly one in three children with cystic fibrosis, although the host defense defects that trigger infection continue to be debated. Even before symptom onset, pulmonary inflammation and infection are often present, although which comes first has been uncertain. As early as 3 months of age, most babies with cystic fibrosis have abnormal chest X-ray computed tomography (CT), although the relative contribution of inflammation, airway remodeling or other factors remains undefined. Moving to even earlier time points might reveal the origins of cystic fibrosis lung disease and thereby change clinical practice.” 1

  “Current evidence suggests that the CF (Cystic Fibrosis) lung is free of infection and not inflamed at the time of birth. Over the course of months to years, however, stigmata of first recurrent and then chronic infection begin to appear. Microbiologic studies reveal a fairly typical evolution of pathogens, with respiratory viruses, Haemophilus influenzae and Staphylococcus aureus, predominating early in life. With time, more problematic and increasingly resistant pathogens, including Pseudomonas aeruginosa and other Gram-negative bacteria (e.g. Burkholderia cepacia complex, Stenotrophomonas maltophilia, Achromobacter xylosoxidans), often dominate the clinical picture. Direct tests of systemic immunity, which are normal, and the absence of an infectious phenotype outside the respiratory tract suggest that a local defect in lung defense is responsible for the development of CF (Cystic Fibrosis) lung disease. In fact, the intense neutrophilic inflammatory response to airway infections is arguably more robust and persistent than in non-CF conditions, yet the CF (Cystic Fibrosis) lung ultimately fails to clear bacterial pathogens once they become established. It is this defect in innate airways defense that has been the focus of intense investigation and the recent target for therapies aimed at preventing or slowing the cascade of pathogenic events that culminate in progressive lung destruction.” 2

 

Fig. 1. Normal VS. Cystic Fibrosis (3)
Fig. 1. Normal VS. Cystic Fibrosis (3)

 

  “Normal airway epithelial cells regulate sodium (via ENaC) and chloride (via CFTR and CACC) transport in order to maintain an optimal periciliary liquid layer height in order to support cilial motion and to adequately hydrate the overlying mucus layer. As a result, MCC is maintained. CF (Cystic Fibrosis) epithelia are missing CFTR-mediated chloride transport and hyper absorb sodium (via ENaC). Despite partial compensation by chloride secretion through CACC, depletion of the PCL layer and mucus dehydration ensues, and MCC is slowed as the result.” 4

 

Fig. 2. Healthy Airways VS. Cystic Fibrosis (5)
Fig. 2. Healthy Airways VS. Cystic Fibrosis (5)

 

  Cystic Fibrosis also affects the gastrointestinal system. Signs of cystic fibrosis in the digestive tract include larger and greasier stools, pancreatitis, constipation, polydipsia, polyuria, inability to gain weight and excess perspiration. Mainly, the pancreas is negatively affected when speaking of gastrointestinal cystic fibrosis because the pancreatic ducts become clogged,  therefore making it difficult for the digestive system  to receive the pancreatic juices necessary for normal digestion.

  “For most people with CF (Cystic Fibrosis), the exocrine glands in the pancreas make such thick secretions that the digestive enzymes are not able to get through the pancreatic ducts and do not reach the small intestine. With no enzymes to break down food, the food is poorly digested and absorbed. Much of the proteins, fats and carbohydrates in food are not absorbed for use in the body. This is called malabsorption. Malabsorption of proteins and fats can lead to poor growth and malnutrition. Proteins are needed for growth and body tissue repair or healing. Fats are calorie-rich food sources and give the energy needed for growth and development and to stay healthy. Fat also is needed for absorption of some vitamins. For some people with CF (Cystic Fibrosis), the mucus that lubricates the intestines is so thick and sticky that it may block them. A blocked intestine needs special treatment.” 6 

  “Gastrointestinal tract manifestations of cystic fibrosis are related to mucous inspissation and dysmotility and include meconium ileus (MI), constipation, distal intestinal obstruction syndrome (DIOS), gastroesophageal reflux disease (GERD), and small bowel bacterial overgrowth. DIOS is caused by inspissated intestinal contents that completely or partially block the small intestinal lumen, most commonly at the ileocecal junction. This is thought to be related to a cascade of intestinal inflammation in the setting of the defect in the CFTR.” 7

  As previously mentioned, cystic fibrosis is a genetic disease that can only occur if a person carries two copies of this genetic mutation. Often, family  histories of cystic fibrosis  are lacking because it is not enough to possess ‘just’ one gene. Rather, people who only have one copy are referred to as carriers. Cystic fibrosis cannot be passed on through any other means except via the gene pool. Therefore, as far as risk factors are concerned, there is only one, i.e., both parents possessing a copy of the mutant gene responsible for incorrectly codifying CFTR (cystic fibrosis transmembrane regulator).

  The severity with which cystic fibrosis unfolds during a patient’s life depends on the class of CFTR protein function. These classes are easy to remember. CFTR protein function is classified as I, II, III, IV and V, with the lowest being the most ‘incompetent’ type of CFTR. Thus, the most severe form of cystic fibrosis is expected at class I, whereas class V indicates a mild manifestation of the condition.

  Age is also considered a risk factor because the longer a person has lived with cystic fibrosis, the more damaged the tissue in question, is likely to be.

  As for lifestyle risk factors, smoking is out of the question because of the further damage that smoke is known to cause. In terms of diet, people with cystic fibrosis must increase their caloric intake, in order to support proper growth that we all experience during the earlier stages of our lives. Naturally, exercise and an active lifestyle are good for the lungs and for the management of cystic fibrosis as well.

Cystic Fibrosis Complications

  Cystic fibrosis related Diabetes:

  “Diabetes is a common and important complication of cystic fibrosis, an autosomal recessive genetic disease due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Cystic fibrosis–related diabetes (CFRD) is associated with profound detrimental effects on the disease course and mortality and is expected to increase in prevalence as the survival of patients with cystic fibrosis continues to improve. Despite progress in the functional characterization of CFTR molecular defects, the mechanistic basis of CFRD (cystic fibrosis transmembrane regulator) is not well understood, in part because of the relative inaccessibility of the pancreatic tissue and the limited availability of representative animal models.” 8

  “CFRD (Cystic fibrosis related Diabetes) involves pathophysiological features of both type 1 and type 2 diabetes. CFRD (Cystic fibrosis related Diabetes) primarily results from insulin deficiency, but insulin resistance also plays a contributory role, and can become acutely severe during infection, pulmonary exacerbation and glucocorticoid usage. Abnormal function of chloride channels leads to accumulation of thick viscous secretions and causes obstructive damage to the exocrine pancreas with progressive fibrosis, fatty infiltration and amyloid deposition in the islets. This results in loss of beta, alpha and pancreatic polypeptide cells. Recently, it has been proposed that a combination of increased oxidative stress and an accumulation of misfolded CFTR (Cystic Fibrosis Related Bone Disease) proteins in the endoplasmic reticulum (ER) that may lead to ER stress and eventual apoptosis of the beta cell.” 9

 

Fig. 3. CFRD
Fig. 3. CFRD (10)

 

“Possible pathogenetic mechanisms in CFRD. Insulin resistance may also have a role in the setting of infections or glucocorticoid therapy. Modifier genes other than CFTR influence the risk of developing diabetes. ER, endoplasmic reticulum.” 11

Cystic Fibrosis Related Bone Disease:

  “Major contributing factors for CF-related bone disease include vitamin D and vitamin K malabsorption, poor nutritional status, physical inactivity, chronic inflammation, glucocorticoid therapy, delayed puberty and early hypogonadism. Recently there have been several studies demonstrating the direct impact of CFTR (Cystic Fibrosis Related Bone Disease) on bone mineral density in CF (Cystic Fibrosis). Furthermore, abnormalities in glucose and insulin regulation can also aggravate bone loss in patients with CF (Cystic Fibrosis).” 12

Cystic Fibrosis Related Chronic Rhinosinusitis:

“Patients with classical CF (Cystic Fibrosis) have a high incidence of CRS (Chronic Rhinosinusitis) with or without nasal polyps (NP) approaching 100%. Imbalance of electrolyte transport from CFTR (cystic fibrosis transmembrane regulator) dysfunction reduces airway surface liquid depth and increases the viscosity of mucins in the airway 30–60 times higher than seen in patients without CF (Cystic Fibrosis). Tenacious secretions and tissue inflammation block sinus ostia, which results in hypoxia, mucosal edema, and additional impairment of mucociliary function. Inflammation and remodeling promote the formation of NP that are present in up to 86% of patients with CF (Cystic Fibrosis) and increase in prevalence with age. The formation of neutrophil-laden polyposis is primarily driven by interleukin-8 in contrast to non-CF CRS (Chronic Rhinosinusitis) with NP (nasal polyps), which shows predominant eosinophilia and a T helper cell type 2-inflammatory cytokine profile .” 3

 

References:

(1)Origins of Cystic Fibrosis Lung Disease. Stoltz, D.A, Meyerholz, D.K. & Welsh, M.J. New England Journal of Medicine. 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916857/

(2, 3, 4) Pathophysiology of Cystic Fibrosis. Donaldson, S.H. & Boucher, R.C. Annales Nestlé. 2006. https://www.karger.com/Article/PDF/95374

(5, 6) An Introduction to Cystic Fibrosis. For Patients and Their Families. Cunningham, J.C. & Taussig, L.M. Cystic Fibrosis Foundation. (pg. 42, 63) https://www.cff.org/PDF-Archive/An-Introduction-to-Cystic-Fibrosis-for-Patients-and-Their-Families/

(7) Gastrointestinal Manifestations of Cystic Fibrosis. Sabharwal, S. Gastroenterology & Hepatology. 2016. https://europepmc.org/articles/PMC4865785;jsessionid=9BC66DD2A4DE97C0824D41056B78F19C

(8, 10, 11) Evolving Mechanistic Views and Emerging Therapeutic Strategies for Cystic Fibrosis–Related Diabetes. Yoon, J.C. Journal of the Endocrine Society. https://academic.oup.com/jes/article/1/11/1386/4582236

(9, 12) Diagnosis and Treatment of Endocrine Co-Morbidities in Patients with Cystic Fibrosis. Siwamogsatham, O., Alvarez, J & Tangpricha, V. Current Opinion in Endocrinology & Diabetes and Obesity. 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326081/

(13) Management of the Upper Airway in Cystic Fibrosis.  Illing, E.A. & Woodworth, B.A. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301682/

 

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, is focused on surgery and its greatest advances. Nowadays I practice my...read more:

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