Cystic Fibrosis: Causes, Symtoms, And Developments In Treatment

Introduction

A few centuries ago, the European folklores stated that any child that had salty-tasting skin had been bewitched and eventually would die soon. Furthermore, the medical texts from 1595 had been found and the symptom in skin had been linked with the damage of pancreas. This type of disease was first discovered and described in 1938 by Dr. Dorothy Andersen, an American pathologist. At that time, based on her study of children that died of malnutrition, the disease was called “cystic fibrosis of pancreas”, in which the pancreas was damaged and not able to secret its enzyme to digest the food. Thus, CF was not the unknown disease anymore after 1938. However, aside from the obstruction of pancreatic duct that caused by the disorder of mucus, the other symptoms of the disease were still undiscovered.

In 1946, Dr. Paul di Sant’Agnese, a researcher and clinician, had found a way to treat children with CF by using inhaled antibiotic. Two years after that, there was an intense heatwave that lasted for a week and affected the northeastern part of the US. In New York City, the temperature reached around 42 degree Celsius. At least 33 people were killed and children were suffered the most. During that time, he saw them coming in the hospitals with symptoms such as dehydration and fever. Five years after the heatwave stroke NYC, he showed that people having CF would have higher level of salt in their sweat, which eventually led to the sweat test that is being used nowadays and simultaneously confirmed the folklores in the past.

In 1983, the failure to transport chloride ions from inside to outside the cell and vice versa, which then came with the higher level of sodium absorption, had been detected as a basic defect of CF. In 1989, the defective gene that coded for the cystic fibrosis transmembrane conductance regulator (CFTR) channel was ultimately discovered and the disease was finally fully comprehended. Hence, new therapies had been developed and the rate of survival dramatically increased to mid-50s for males and mid-40s for females.

Cause

CF is a hereditary disease and caused by the mutation in the gene that codes for CFTR channel. As CF is an autosomal recessive disease, children having CF must receive both defective genes from their parents. Further, children inheriting one healthy gene and one defective gene would still be healthy. However, they would be a carrier of the disease, which could be able to transfer the CF to their offspring.

More specifically, there are reportedly more than 1000 alleles, which cause CF and are more than enough to study. Nonetheless, there is a very common mutation that accounts for 70% of the CF cases in the US, which is F508. Human has 46 chromosomes and CFTR gene resides on the long arm of chromosome number 7. By being able to sequence the amino acid sequence of the CFTR gene, the amino acid that is deleted is revealed. More precisely, the normal sequence of the CFTR gene that codes for the CFTR channel is Isoleucine 506, Isoleucine 507, Phenylalanine 508, Glycine 509, and Valine 510. When a person’s CFTR gene is mutated, three nucleotides (CTT) are deleted, which results in the deletion of Phenylalanine 508. Subsequently, this mutation is called F508.

In normal person, CFTR channel is responsible for moving chloride ions in and out of the cells, which is essential for water movement in tissues. This, in turn, is very important for producing a normal mucus. Normal and healthy mucus would work as a substance to allow smooth movement in the respiratory, digestive, reproductive, and other systems. In a person with CF, the mutated CFTR channel is not able to move chloride ions, which consequently upsets the balance of water movement and other electrolytes. Hence, the result is going to be the abnormal mucus that is thicker and stickier and also dehydrated, which stands still and blocks the flowing air or enzyme or sperm.

Symptoms

Unfortunately, CF is a disease that affects a lot of different organs. Subsequently, people having CF would suffer from many symptoms. They would have a very salty-tasting skin. Their hearts are enlarged due to the increased pressure in lung. Also, their dehydrated bile in liver would create gallstones. However, CF mainly affects the respiratory, digestive, and reproductive systems in human.

First, for the respiratory system, mucus building up blocks the airway, that leads to persistent coughing and short breath. Even though cough is natural and needed to clear the airway, normal people would not cough every time except CF patients. Fifty percent of 10-month-old infants with CF were observed to frequently cough, which then caused lung infection.

Second, for digestive system, mucus is going to block the pancreatic duct. Almost 90% of people having CF cannot produce a sufficient amount of enzyme. As a result, their body is unable to break down the food and absorb the nutrients including fat, protein, and carbohydrate. Thus, loss of weight and malnutrition are mainly the symptoms that CF patients are going to suffer. Moreover, there is a possibility that it could lead to cystic fibrosis-related diabetes (CFRD).

Third, for reproductive system, males are the ones that are mainly affected. Their vas deferens, which is responsible for transporting sperms, would be blocked by mucus. This condition is called “Congenital bilateral absence of the vas deferens” (CBAVD) and 90% of males having CF are infertile.

Traditional treatment

It is critically essential for CF patients to remove the abnormal mucus from their body to allow everything to move freely. Nevertheless, there is unfortunately no cure for CF. Thus, treatments are only going to help in easing the symptoms and preventing the disease from getting worse. As stated, CF mainly affects respiratory and digestive systems, which treatment is going to focus on.

Physical therapies and daily exercises might help improve the physical condition of the patients. More specifically, studies have shown that people that have CF would have low-quality sleep and suffer from anxiety and depression. In this situation, it was discovered that yoga therapy would be able to help as it relieves the pain in joints, reduces anxiety, and improves sleep quality. Medicines and antibiotics could be used to reduce infection and thin the layer of mucus.

Furthermore, a healthy meal plan which is calorie-high would help the patient in nutrition issue. In addition, pancreatic enzyme replacement, which comes in capsule form, would be able to break down the food since in each capsule, there is a small amount of digestive enzyme, which will be released whenever the capsule reaches the small intestine. In case the patients are in need of vitamins, vitamin supplements would be a great help.

Developing Treatment

There have been many efforts trying to find a cure for CF. Clustered Regularly Interspaced Short Palindromic Repeats​ (CRISPR)​ is the first one that is being researched and developed. It is considered as a new way to cure CF. Generally, CRISPR is the process of gene editing that is derived from prokaryotes. More specifically, when a disease is caused by a mutation in a specific gene, CRISPR is able to address the mutation and fix the mutation by itself. In this case, CFTR gene that codes for CFTR channel was mutated due to the deletion of the three nucleotides. CRISPR would recognize the wrong DNA sequence, cut it out, and the cell could be able to fill the correct sequence into the space of the knocked-out sequence.

Moreover, in 2012, there was a study that proposed a way to correct the F508 mutation on the chromosome number 7 by using zinc-finger nucleases (ZFNs). Even though the efficiency is below the hypothesized level, this method would potentially be a great way to cure CF besides CRISPR.

Summary

Cystic Fibrosis is a childhood disease that could lead to the death of children because many of them cannot live until their adulthood. Simply by a deletion of three base pairs on the gene that codes for CFTR channel, it could affect many organs in the body, mainly lung and digestive system. By not being able to transport the chloride ions in and out of the cell, thicker and stickier mucus is built up and block the airway, pancreatic duct, vas deferens in males, and many other organs. It also creates a lot of severe symptoms that the patients have to suffer including persistent coughing, lung infection, salty-tasting skin, malnutrition, and gallstones. CF is currently hard to find a way to cure. Nevertheless, researchers and doctors are making progress in finding a better treatment and hopefully a cure. CRISPR and the process using ZFNs have proved to be very likely possible to cure CF since they both can potentially correct the mutation F508, which is common in 70% of all the people that have CF. Meanwhile, physical therapies, healthy diet plan, medicines, and antibiotics could be utilized to minimize the effects that CF has on humans.

References

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