What is cystic fibrosis ?
Cystic fibrosis (CF) is a recessive inherited disease, wherein mucus is secreted in several places in the body is abnormal tough. The most important places where the viscous mucus is formed are the lungs, the gastrointestinal tract, the liver, the pancreas, and the testes.
Symptoms can manifest itself in infancy, mostly by growth retardation and chronic respiratory infections. Especially through the respiratory patients have a significantly lower life expectancy than normal. The reduced production of pancreatic enzymes causes thereby a delayed growth, a fatty diarrhea and a deficiency of fat-soluble vitamins. In boys can occur infertility. In newborns there is often a metabolic disorder known as meconium ileus.
History of cystic fibrosis
In 1938 Dorothy Hansine Andersen published an article about CF. In this they described the characteristics of the disease, such as those located in the pancreas, the lungs and digestive revealed. They thereby also voiced the assumption that CF is a recessive genetic disease, and first used pancreatic enzyme to treat children. In 1952 discovered Paul di Sant 'Agnese in sweat electrolyte abnormalities of CF patients. In the next decade, a sweat test was developed and further improved. Interestingly, already around 1700 was warned in German and Swiss textbooks: "Wehe dem Kind, das auf die beim Kuß Stirn salzig schmekt, there Verhext ist und muss bald sterben," which translated reads: "Woe to the child that kisses forehead tastes salty because it is doomed and will die soon, "indicating that they realized early on the relationship between the disease and the high salt content of the sweat. CF-patients always have an elevated salt content, in particular sodium chloride in their sweat. If this initial screening test sweat test is often used before proceeding to DNA research.
Carl von Rokitansky described a case of fetal death due meconiumperitonitis. This creates an inflammation of the peritoneum (peritonitis) by a break in the intestinal wall. This is a complication of meconium ileus (bowel obstruction caused by meconium), which is associated with CF. Meconium ileus was first described in 1905 by Karl Landsteiner. In 1936, Guido Fanconi published an article which described the relationship between meconium ileus, fibrosis of the pancreas, and bronchiectasis.
In 1988 the first mutation of CF was ΔF508 on chromosome 7 discovered by Francis Collins, Lap-Chee Tsui and John R. Riordan. In subsequent investigation it was found to 1,000 different mutations that could lead to CF. In 1989 a team of researchers led by Lap-Chee Tsui at the Hospital for Sick Children in Toronto, the gene that causes CF. It should be localized with the help of protein markers and gene linkage studies, the mutation in the CF gene on chromosome 7. Then, the gene was finally identified with special techniques and determined its DNA sequence.
Heredity
It is the most common autosomal recessive genetic disease in Western Europe, about 1 in 32 people to know the Caucasian population is heterozygous carrier of the disease without itself. When a carrier is therefore occur no signs of disease on. Parents who are both carriers have a 1 in 4 chance of having a child with cystic fibrosis. Based on these numbers would be affected in Caucasian populations 1 in 4096 (1/32 x 1/32 x 1/4) births. Partly due to genetic counseling and abortion CF in practice less, viz. 1 in 4750. In the Netherlands, every year about 40-45 people born with this condition. It is estimated that there are about 1,300 patients in 2008, with cystic fibrosis.
The relatively frequent occurrence of heterozygous carriers of the CF gene is probably explained by a positive selection effect, allowing wearers have an evolutionary advantage. There is a presumption that they have a lower risk of diarrheal diseases (including cholera) dies.
Cystic fibrosis causes at the molecular level
The deviation is caused by a defect in a protein that regulates the transport of chloride ions through the cell membrane. (Cystic Fibrosis Transmembrane conductance Regulator (CFTR)). This protein is located in the membranes of mucus producing cells, and normally provides for the transport of chloride ions. (The CFTR protein is a cAMP-regulated Cl-channel.) If this transport is going to be functioning normally water along with the transported ions (osmotic effect) so that it remains mucus secreted by the cell thinner. Loss of the CFTR-function leads to secretion of mucus tougher (increased viscosity), which in turn causes the cilia in the airway mucus in which work less well (reduced mucociliary clearance), making it easier to bacterial infections arise.
The gene for the cystic fibrosis trans-membrane regulator is located on the long arm of chromosome 7 (7q31). Usually (in 70% of cases), it is a deletion of a phenylalanine codon at position 508 (ΔF508).
Cystic Fibrosis Symptoms
Clinical symptoms are seen in organs in which mucus production plays a role, such as the lung, the gastrointestinal tract and urinary-forming and reproductive organs. Patients develop bronchitis or pneumonia. Also, the ducts of the pancreas can clog making for digestive disorders. As a result, fat absorption in the digestive tract is not as good as possible. To compensate for this should be a CF patient eat more than the average in order to remain on the body weight. Also vitamin recording may be disturbed which results in a deteriorated condition. One of the earliest manifestations of the disease is an obstruction of the intestines (also called ileus) by meconium. This is the first stool of the newborn child.
Furthermore, patients have a too large salt in the sweat secretion (normally lost in sweat chloride actively pumped back, which does not work well at CF), and loss of glucose in the urine. The main cause of death in these patients in respiratory failure is caused by infection with Pseudomonas aeruginosa bacterium strains. These strains undergo a mucoid conversion ("change of the mucus'): biofilms are formed in the lungs that are impervious to polymorphonuclear white blood cells of the type. Also, intensive antibiotic therapy works less and less well. The mucoid conversion means a worsening of the disease and worsening prognosis. Antibiotics from the group consisting of the macrolides (azithromycin, clarithromycin etc.) are not able to kill the Pseudomonas but disturb the Quorum sensing of the Pseudomonas (in addition to a number of other effects). Quorum sensing is by the bacterium is able to determine how many other bacteria in the vicinity. With sufficiently large numbers of this is, inter alia, a signal to the change of the metabolism and the production of biofilms. Because of the disturbance of these Quorum sensing the mucoid conversion is slowed down and the biofilm is partially degraded. As a result, the survival of enhances CF patients with chronic Pseudomonas infection.
An additional complication of the mucoid conversion is the emergence of mutant strains of bacteria that are resistant to antibiotics. There is a chance that CF patients infected each other with this. For that reason, since 2005, following a foreign policy of segregation effect. These CF patients is strongly advised to have mutual physical contact or hold meetings with mutual strict hygiene rules. For contact with healthy people no special hygiene rules because cystic fibrosis is not a contagious disease.
New insights and improved treatment, the life expectancy in recent decades have greatly improved: the patients took born in the 50s only 10% of the adult age; of those who were born in the 70s about 60% reached their 25th birthday. The life expectancy of the total group of patients continues to show an upward trend and is currently (2011) 40 to 50 years, but with large differences between patients.
Make all newborns with CF today to be a reasonable chance of old, cystic fibrosis remains a serious disease with a very different course. There prenatal diagnosis can be done, with the possibility, in the case of a fruit affected to decide on abortion. Probably this in the Netherlands per year is currently (2005) prevent the birth of approximately 10 new cases. A reliable CF test as part of the heel prick in newborns has been introduced since May 1, 2011. The number of adult patients in the Netherlands now amounts to 600 (2007).
Cystic fibrosis treatment
Although CF is one of the first diseases in which it was thought to use of gene therapy, this is not yet succeeded; One of the problems is that the required healthy gene is so large that it does not fit into any of the viral vectors used now. People with CF die mainly due to respiratory problems.
The treatment is mainly directed at the lungs to maintain as clean as possible and to remove the mucus as well as possible. This can be through sports and physical therapy. In addition, to detect and combat the cause infections at an early stage. Most CF patients are treated at home as much as possible. In terminal lung failure is sometimes considered a lung transplant. In a survey of more than 500 such cases, however, American researchers published in 2007 that lung transplantation in children with cystic fibrosis only in very few cases, a life-prolonging effect.
With a high-calorie diet and supplementary digestive enzymes (pancreatic enzymes) can be compensated for a less effective digestion to a great extent. This is an attempt to prevent a patient from entering a downward spiral of infections-decreased appetite malnutrition-more infections etc.
Since 2012 there is ivacaftor in the market. It is the first drug that registered address the cause of cystic fibrosis at the cellular level. It works only at 3 to 5% of the population carrying a particular class III mutation, mainly the G551D mutation.