Cystic Fibrosis-Causes, Symptoms And Treatments

Cystic Fibrosis-Causes, Symptoms And Treatments

Cystic fibrosis (CF) is one of the most common genetically inherited diseases which can cause premature death in western populations, with 1 in 2000-3000 new born babies being found to be affected by Cystic fibrosis in Europe [1]. The disease is caused by defective chloride ion channels along the epithelial membrane of the lungs, pancreas and other organs; although there are several hypotheses as to how this dysfunction specifically gives rise to the typical symptoms. The complications associated with the disease are varied, the most significant being the build up of abnormally thick excess mucus which can cause impaired function of the lungs and other major organs. Fortunately research into new treatments has significantly improved the life expectancy of people suffering from this disease.

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This essay discusses the causes

Introduction
The name ‘cystic fibrosis’ refers to the generation of cysts in the pancreas and the formation of excess fibrous connective tissue in the lungs.

The internal organs which suffer the most damage as a result of this disease are the lungs and the pancreas; although a variety of other organs are also affected.

The first clinical recognition of cystic fibrosis didn’t occur until the 1930’s when its symptoms were observed and characterised by Dr. Dorothy Anderson. The recessive nature of the disease was confirmed in the mid-forties after an investigation involving over one hundred families; although the defective gene that causes the disease wasn’t isolated for another forty years when it was discovered in 1989 by reverse genetics. After the breakthrough in the forties general understanding of the disease increased steadily over the next couple of decades with a major clinical advancements in diagnostics occurring in the fifties with the development of the sweat test.

As cystic fibrosis is the result of an autosomal recessive disorder, the sufferer will have to of inherited two copies of the mutated gene (one from each parent) in order to be affected by the disease. The mutation takes place in a single gene on chromosome 7. This faulty gene leads to the development of a defective cystic fibrosis transmembrane conductance regulator (CFTR) protein. In healthy people the CFTR proteins form ion channels to transport chlorine ions across the epithelial membrane of the lungs, pancreas, sweat glands and other organs. It is also thought to regulate the activity of other chlorine-selective channels and some cation-selective (sodium ion) channels. Ions can then pass through these channels thereby maintaining the water potential of the cells. When the fine balance of ion concentration is affected less water is able to pass across the epithelial membrane by osmosis causing excess and highly viscous mucus to build up in the affected organs, resulting in severe long-term respiratory and digestive problems.

The human lungs are adapted for use in aerobic respiration by providing a thin, moist surface for gas exchange to take place between the pulmonary arteries and the external environment. For gas exchange to be effective the respiratory surface must comply with Fick’s law which requires that the surface area is large, moist and thin to enhance permeability. The resulting fibrosis caused by the disease greatly affects the permeability of the lungs and hence reduces their capacity for gas exchange.

Molecular mechanisms
There are over 1500 types of mutation which can cause a defect in the CFTR protein, the most common of which is a deletion of phenylalanine at position 508 (∆F508) which Is the cause of approximately two-thirds of CF cases. The mutations are categorised into six classes determined by their impact on the resulting functionality of the CFTR channels, ranging from reduced to complete non-function.

Class I, II and III mutations all result in the absence or substantial reduction of functional CFTR. Class I mutations cause a complete lack of protein production due to premature stop codons arising in the genetic code whereas class II mutations produce a protein that doesn’t fold properly and so is consequently degraded by the cell. In a class III mutation the lack of effective binding with ATP molecules leads to the defective regulation of CFTR and so again is classified as being non-functional. Classes IV and V still permit the development of functional CFTR albeit with reduced capacity for chloride ion transport or with reduced production of functional CFTR in general due to promoter mutations that decrease transcription [2]. Class VI mutations also produce functional CFTR although its degradation is greatly accelerated. The F508 deletion results in a class II mutation.

There are four main hypotheses as to how this defective gene causes disease although it is not known whether the disease is caused by one or a combination these hypotheses. Two of these, the low volume and high salt hypotheses, provide a detailed description of the complications that arise as a result of faulty CFTR by taking into account the composition of airway surface liquid (ASL).

Low volume hypothesis
In the case of the low volume hypothesis it was postulated that there is little to no difference in the salt concentration of ASL between healthy people and those suffering from cystic fibrosis.

This hypothesis suggests that the symptoms of cystic fibrosis are caused by a dysfunction of the CFTR gene resulting in damaged or ineffective sodium ion channels. The damage caused is ergogenic and reduces the inhibition of the ion channels leading to the excessive movement of sodium ions from the ASL into the airways. The increased concentration of positively charged sodium ions in the airways then drives the absorption of chlorine ions and water, reducing the volume of ASL and dehydrating mucus. The dehydrated mucus becomes highly viscous and the cilia present on epithelial cells which are used to aid the clearance of mucus and to increase lung surface area become compressed by the mucosal build up. This compression of cilia inhibits the clearance of mucus which then continues to build up, further reducing the lung surface area. The excess mucus can also form hypoxic niches that can harbour colonies of pseudomonas aeruginosa.

Build up of mucus physically reduces the lung surface area affecting the efficiency of gas exchange. The mucus build up also increases the compression of cilia on epithelial cells which inhibits clearance by cilia and coughing.

High salt hypothesis
The high salt hypothesis assumes that the airway surface liquid of healthy individuals has a relatively low salt concentration when compared to the ASL of cystic fibrosis sufferers. It suggests that the symptoms of the disease are caused by the disruption or complete absence of CFTR function which causes excess sodium and chloride ions to be retained in the ASL. This increased retention of chloride ions leads to the ASL having an abnormally negatively charged composition. This abnormality impairs the activity of the body’s natural bactericidal enzymes such as lysozyme which rely on electrostatic interactions to attach to the bacterial cell walls; thus allowing bacterial infection to persist in the hypoxic niches formed within the lungs.

Abnormally high inflammation
It has been speculated that the defective CFTR itself may be the cause of excessive inflammation in the airways. However there is limited evidence to suggest that the defective CFTR is a cause of excessive inflammation in itself but rather that it interferes with the regulation of autophagy. Autophagy is the process by which defective proteins are degraded in order to maintain the balance between the recycling and synthesis of cellular products, for example the degradation of defective CFTR by the cells own lysosomes. Research indicates that large amounts of defective CFTR inhibits autophagy, leading to an accumulation of aggresomes which can cause inflammation in the lungs [3]. The resulting inflammation is what gives rise to the characteristic scarring of lung tissue.

CFTR bind with P. Aeruginosa
Chronic bacterial infection is common amongst all cystic fibrosis sufferers, specifically the bacterial species pseudomonas aeruginosa which binds readily to the CFTR protein. In healthy people the body initiates an immune response in order to fight off the infection. In cystic fibrosis suffers there is enhanced binding between p. Aeruginosa and the CFTR protein, the bacterium is also able to bind without initiating an immune response. The compromised immune response combined with reduced ability to clear mucus due to compressed cilia further increases the risk of severe infection.

Symptoms
Visible characteristics typical amongst suffers include a slightly meagre appearance due to inefficient absorption of nutrients and the famously salty sweat used to confirm CF diagnosis. Low levels of oxygen in the tissues due to impaired gas exchange between the lungs and the bloodstream can cause clubbing of the fingers and toes

Salty sweat
The salty sweat associated with the disease like so many of its symptoms is again caused by faulty CFTR present on the sweat ducts. As sodium ions leave the sweat ducts through ion channels chloride ions follow through them through the CFTR protein channels. However, in cystic fibrosis patients dysfunctional CFTR channels prevent the outward flow of chloride ions from the sweat ducts. The resulting high chloride ion concentration in sweat ducts creates an electrochemical gradient which “pulls” more positively charged sodium ions into the ducts where the ions combine to form salt (NaCl). The salt is then secreted through pores in the skin resulting in very salty sweat as very little NaCl is reabsorbed. Salt sweat concentration of greater than 60mEq/L is generally considered significant enough to make a diagnosis, although further test may be required.

Although poor growth can pose its own health risks the most severe symptoms are caused by the diseases capacity to cause damage to the internal organs.

Endocrine
CF is commonly referred to as an exocrine disorder meaning the resulting dysfunction affects glands which secrete their products through a duct to the surface of the body or of an organ, sweat glands and pancreatic ducts being an example of this. However some complications can arise in the body’s endocrine glands, glands which secrete their product directly into the bloodstream. Disorders of the endocrine glands tend to affect the secretion of hormones. Damage to the islets of langerhans within the pancreas can impair the secretion of insulin which can eventually lead to CF related diabetes.

Pulmonary
Lungs are the predominant source of infection, vulnerable to different species of bacteria although P. Aeruginosa becomes predominant; eventually these bacterial colonies form a biofilm which is difficult to remove with antibiotic treatments. The thickening of mucus creates environmental niches suitable for harbouring bacteria. High levels of infection result in an inflammatory response which often leads to extensive tissue damage and scarring regarded as the characteristic fibrosis of the lungs. The resulting fibrosis damages the epithelium of the lungs, making gas-exchange inefficient. Thick mucus also physically reduces the surface area

Implications for other organs
The lungs aren’t the only organs that suffer damage as a re……

Cystic Fibrosis-Causes, Symptoms And Treatments