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Cystic fibrosis

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Cystic fibrosis
SpecialtyMedical genetics, pediatrics, pulmonology Edit this on Wikidata

Cystic fibrosis (CF), also called mucoviscidosis, is an autosomal, recessive, hereditary disease of the exocrine glands. It affects the lungs, sweat glands and the digestive system, causing chronic respiratory and digestive problems. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. It is the most common fatal autosomal recessive disease in Caucasians.

Symptoms

The first manifestation of CF is sometimes meconium ileus, occurring in 16% of infants who develop CF. [1]

Other symptoms of CF manifest during early childhood. Both lungs and pancreas produce abnormally viscous mucus. This mucus begins to build up and starts to clog the opening to the pancreas and the lungs. Pulmonary problems start from the constant presence of thick, sticky mucous and are one of the most serious complications of CF. The mucus in the lungs can become a growth medium for bacteria, resulting in chronic respiratory infections and eventual permanent damage to the lung tissue. During the end stage of CF, the patient experiences increased chest congestion, activity intolerance, increased crackles, and increased cough, which often contains sputum mixed with blood (hemoptysis) due to the bronchiole bleeding from the lung arteries. A chronic and loose sounding cough is common in people with CF. These thick secretions also obstruct the pancreas, preventing digestive enzymes from reaching the intestines to help break down and absorb food. Frequent and foul smelling stools are often an early sign of CF along with fatty oil that is visible in the stool. This can compromise growth and overall nutrition if proper treatment to aid digestion is not utilized early in life. As lung function deteriorates, CF patients can develop pulmonary hypertension, chronic bronchitis, and chronic dilation of the bronchioles (bronchiectasis). Lung abcess are very common. Death usually occurs from severe infection, pneumonia, or heart failure.

The disease can be diagnosed by symptoms such as a high salt concentration in a baby's sweat through a sweat test or by genetic testing. Prior to genetic testing, a sweat test was the gold standard for diagnosis of CF. CF is detectable during the newborn period as part of a newborn screening program, where early diagnosis and implementation of a prompt treatment regimen can greatly improve health outcomes. The disease can also be diagnosed prenatally through chorionic villus sampling or amniocentesis. CF prenatal screening of the mother (and, if indicated, the father) can be done by a relatively inexpensive and far less invasive blood test.

Pathophysiology

Cystic fibrosis is exclusively heritable as both parents must carry the recessive genes for a child to acquire the disease. At the genetic level, cystic fibrosis is most often the result of an in-frame deletion of three base pairs in the DNA. Cystic fibrosis results from the production of an abnormal form of a protein called cystic fibrosis transmembrane conductance regulator (CFTR). CFTR functions in transporting chloride ions across epithelial cells found in the lung and intestinal tract. In CF patients, CFTR does not function properly, causing accumulation of ions inside epithelial cells. Since water follows ions by osmosis, this results in water depletion and viscous mucus on the surface of alveoli. The most common CFTR protein abnormality is a mutation termed ΔF508, which is characterized by the 3-bp deletion of the DNA basepair sequence at chromosome location 7q31.1-31.2 that codes for the amino acid, phenylalanine.

Recent medical research is beginning to show that an imbalance of essential fatty acids may play a role in cystic fibrosis. Tissue samples from both mice, and more recently humans, with CF show an excess of arachidonic acid (AA) and a deficiency of docosahexaenoic acid (DHA). Research has also indicated that healthy individuals with one copy of the CF gene and one copy of the normal gene have fatty acid levels in between those of CF patients and people with no CFTR gene mutations. Further research is needed to show how this is linked to the CFTR gene defect and what implications this may have on treatment of cystic fibrosis.

The ΔF508 mutation is estimated to be up to 52,000 years old. Numerous hypotheses have been put forward as to why this recessive lethal mutation has persisted and spread in the human population. With the discovery that cholera toxin requires CFTR to function properly, it was hypothesized that carriers for cystic fibrosis benefited from resistance to cholera and other diarrhoeas (Gabriel 1994). Results of in vivo studies in mice and humans have not confirmed this hypothesis (Cuthbert 1995, Hogenauer 2000). Intact CFTR has also been found to be essential for the entry of Salmonella typhi into cells (Pier 1998), suggesting that carriers for cystic fibrosis might be resistant to typhoid fever. No in vivo study has yet confirmed this. In both cases, the low level of cystic fibrosis outside of Europe, in places where both cholera and typhoid fever are endemic, is not immediately explicable.

Biological biofilms have recently been shown to contribute to the difficulty of eradicating respiratory bacteria in CF patients (Hoiby 2002). Pseudomonas aeruginosa cells that infect CF patients tend to grow in a biofilm environment, and because of this they are not affected by antibiotics commonly used for CF, or by the body's host defenses.

Cell Biology

The ΔF508 mutation causes the protein to be unstable and the cell is confused into destroying the CFTR protein. It therefore never makes it to surface of the cell where it needs to be to perform its function. The mutation is temperature sensitive. In the laboratory, the cell can be tricked into not destroying the protein by incubating the cell at a lower temperature. When this occurs, the CFTR protein makes it to the surface of the cell and it is known to be fully functional. Unfortunately, this is not a therapeutic option, as unlike cells, patients cannot be grown at lower temperatures.

Complications

Cross-infection

In the past, CF patients often participated in summer "CF Camps" and other recreational gatherings. However, fears of cross-infection with Pseudomonas aeruginosa, MRSA, Burkholderia cepacia, and other bacteria have largely ended these social events. These infections thrive in the thick mucus of CF patients' lungs and cause increased respiratory problems, possibly leading to death. Therefore, CF patients who do not have a certain bacteria type are strongly advised not to meet with those who do. Because of this risk, CF patients are kept in isolation during hospital stays and special precautions must be taken. The cross-infection risk previously caused many CF clinics to recommend that patients live in isolation from one another and never meet. Recently, however, these views have changed out of concern for the patients' psychological well-being. Instead, CF patients are being encouraged to exercise caution, avoid direct physical contact, and consider wearing surgical masks when meeting one another.

Digestion

In addition to pulmonary infections, most people with CF also have problems with digestion, particularly the digestion of fats. This leads to malabsorption and difficulty gaining and maintaining weight, which in turn affects overall health. This is due to the abnormally sticky mucus that blocks the release of digestive enzymes from the pancreas. Pancreatic insufficiency is treated with supplemental enzymes. Usually water-miscible forms of the fat-soluble vitamins A, D, E, and K are required as the decreased fat absorption can lead to deficiencies of these vitamins.

Diabetes

CF patients also have an increased incidence of diabetes mellitus because of the pancreatic blockage. The chronic blocking causes the Islets of Langerhans to degrade over time and decrease insulin production, causing hyperglycemia. There is also evidence that patients with CF become more resistant to the insulin that is produced, this can be triggered by infections or treatment with corticosteroids. Diabetes in CF patients is commonly referred to as CFRD, cystic fibrosis related diabetes. A typical diabetic diet is not feasible and therefore insulin doses are instead adjusted to fit the typical high-calorie/high-fat CF diet.

Fertility

At least 97% of men with CF are sterile due to congenital bilateral aplasia of the vas deferens (CBAVD), an absence of the vas deferens. There are new technologies that are offering hope to men with CF who desire to father a child since sperm is present. This would involve aspiration and In vitro fertilization. Having a discussion with a fertility specialist would be helpful in those cases. Additionally, men who do not have cystic fibrosis but are born with congenital absence of the vas deferens have an increased risk being carriers of the CF gene.

Women with CF may also have impaired fertility, as thicker cervical mucus may prevent sperm from entering the uterus and thus reduce the likelihood of unassisted conception.

Other Complications

Many CF patients, to some degree, experience the widening of the tips of their fingers, known as "clubbing". The condition affects fingers and toes, and results in the tip of the digit being round and enlarged. This can also be seen in people with COPD or severe heart disease.

Since people with CF are prone to poor absorption of nutrients, osteoporosis can occur in early adulthood due to low bone density. It is important for people with CF to have regular DEXA scans to measure bone density and begin treatment if needed. When diagnosed early, treatment can help prevent more serious complications.

Some CF patients have hearing loss as a side effect of long-term use of ototoxic drugs such as Vancomycin or Aminoglycosides, which are used to combat lung infections. Although this side-effect is well-known and understood, these particular antibiotics are of high value in the treatment of CF patients, and often the hearing loss must be considered a necessary trade-off in order to preserve life and health.

Treatment

File:CF Treatment.jpg
A typical breathing treatment for Cystic Fibrosis, using a nebulizer and the ThAIRapy Vest
An intrapulmonary percussive ventilator machiene
A Pari nebulizer and a portable compressor
A pack of Pulmozyme or Dornase Alfa

Daily chest physiotherapy and aerosol breathing treatments are very commonly prescribed for CF patients. Typical physical therapy involves manual chest percussion (pounding), positive pressure techniques, and possibly use of a device such as the ThAIRapy Vest or the Intrapulmonary Percussive Ventilator (IPV) to achieve the same effect: loosening of the thick mucus. Aerosolized medicines commonly given include albuterol, ipratropium bromide and Pulmozyme to loosen secretions and decrease inflammation. It was found that CFers who surf were healthier; consequently, some hospitals use a nebulised 6%-10% Saline solution on those CFers who do not have asthma to loosen the secretions. Inhaled aminoglycoside antibiotics are sometimes given to fight infections. A number of pharmacological agents that help mucosal clearance are being used. N-acetylcysteine that solubilizes mucous glycoprotein, however, has not proved to be significantly effective. Pulmozyme, or recombinant human DNAse, decreases the viscosity of sputum by degrading the concentrated amount of DNA in the sputum of CF patients. DNAse treatment has been beneficial in increasing airflow during short-term use, and has also prolonged the interval between episodes of pulmonary exacerbations. [1]


Aerobic exercise is of great benefit to people with CF. Due to the severity of coughing and the subsequent spitting up of phlegm most CF patients are unwilling to, or are unable to exercise in public areas. Walking, riding in a forest, or swimming in a river provides a better alternative to exercising in public. These activities give the CFer the privacy to cough and clear their lungs of phlegm, and they don't have to worry about disturbing any other person who has not had experience with a Cystic Fibrosis patient. Exercising privately also has the added benefit of limiting exposure to other people and/or exercise equipment that can hold MRSA, B. cepacia, Pseudomonas, etc.

CF patients are typically hospitalized somewhat regularly, often every 6 months depending on the severity of the case. Patients often have intravenous antibiotics through a PICC line, Central Line, or Port-a-Caths.

Due to advances in medical treatment, the median life expectancy of a newborn with cystic fibrosis increased from 4 years (in the 1960s) to 35 years today. It is not unheard of to have patients, or PWCF (Person with Cystic Fibrosis) reaching ages of 40 or 50+. Modern treatment now includes the intake of digestion enzymes, nutritional supplements, percussion and postural drainage of the lungs, improved antibiotics and inhalation of aerosols containing medication. A few attempts at gene therapy were initially successful, but failed to produce acceptable long-term results.

Some cystic fibrosis patients go on to have a single or double lung transplant. This happens when lung functions decline and in the foreseeable future the patient will reach a point where available medical treatments hold very little continuing benefit.

Epidemiology

It is the most common genetic disease among people with European ancestry. Approximately one in every 25 people of European descent is a carrier of one of the cystic fibrosis mutations, having one normal gene and one CF gene.Whereas, the carrier rate is 1 in 17,000 live births of African Americans, and 1 in 90,000 live births of the Asian population of Hawaii.[2]

Since cystic fibrosis is recessive, both copies of the gene have to be CF genes to cause the symptoms that occur in about 1 in every 2500 children. The high incidence of this lethal gene can be explained by the fact that CF carriers, who don't show any symptoms, enjoy some protection against cholera, since the extreme water loss in the intestines is prevented. More recently, evidence suggests CF genes could give protection against typhoid fever. People from areas where cholera and typhoid fever are not problems show a much lower incidence of CF. Genetic counseling and genetic testing is recommended for families who may be carriers of cystic fibrosis.

Prevention

As CF is caused by a pair of recessive gene mutations, couples with the same CF mutation will have a one in four chance that their offspring is afflicted with CF. Prenatal and preconceptional screening will identify parents at risk to have offspring with CF. Different population groups have a different prevalence of CF, thus such screening tests will be most useful in populations with a high prevalence. According to ACOG, the risk of being a carrier for an abnormal gene sequence related to CF is 1/24 for Ashkenazi Jews, 1/25 for non-Hispanic Caucasians, 1/46 for Hispanic Americans, 1/ 65 for African Americans, and 1/94 for Asian Americans. Typically one partner is screened, and if found positive the other partner undergoes the test, but in situations of time constraints, i.e. during prenatal testing, both partners may undergo testing. Genetic testing examines a panel of the most common forms of gene mutations that can lead to CF, typically 23 mutations are checked. However as over 1,300 mutations are linked to CF, there remains a residual risk even in the presence of negative testing. Couples who undergo preconceptional testing can choose among several reproductive options, including PGD prior to establishing a pregnancy, prenatal fetal testing by chorionic villus sampling or amniocentesis, or the use of alternative gametes (third party reproduction).

History

Cystic fibrosis was first described as a disease in the late 1930s by Dorothy Hansine Andersen. In 1988, the first mutation for CF, ΔF508, was discovered by Francis Collins, Lap-Chee Tsui and John R. Riordan on the seventh chromosome of the human genome. Research has subsequently found over 1000 different mutations that may cause CF, however ΔF508 accounts for approximately 70% of CF patients in Europe (this percentage varies regionally). Lap-Chee Tsui led a team of researchers at the Genomic Biology Program of the Research Institute, at The Hospital for Sick Children in Toronto to discover the gene responsible for CF in 1989.

Notable people with cystic fibrosis

References

  • Gabriel SE, Brigman KN, Koller BH, Boucher RC, Stutts MJ (1994). "Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model". Science. 266: 107–9. PMID 7524148.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • Wiuf C (2001). "Do delta F508 heterozygotes have a selective advantage?". Genet Res. 78: 41–7. PMID 11556136.
  • Steve Conway. Jan, 2001. Seacroft and St James's University Hospitals, Leeds, UK. Pregnancy and fertility
  • Laura Bachrach, M.D 1994 Osteopenia and Osteoporosis in CF Patients
  • McCallum, Theresa J., Jeff M. Milunsky; et al. (2000). "Fertility in Men With Cystic Fibrosis". Chest. 118: 1059–1062. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  • Boucher RC (2004). "New concepts of the pathogenesis of cystic fibrosis lung disease". Eur Respir J. 23 (1): 146–58. PMID 14738247.
  • Gibson RL, Burns JL, Ramsey BW (2003). "Pathophysiology and management of pulmonary infections in cystic fibrosis". Am J Respir Crit Care Med. 168 (8): 918–51. PMID 14555458.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • Yankaskas JR, Marshall BC, Sufian B, Simon RH, Rodman D (2004). "Cystic fibrosis adult care: consensus conference report". Chest. 125 (1 Suppl): 1S–39S. PMID 14734689.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • Hoiby N (2002). "Understanding bacterial biofilms in patients with cystic fibrosis: current and innovative approaches to potential therapies". J Cyst Fibros. 1 (4): 249–54. PMID 15463822.
  • ^ Fauci et al.,Harrison's Principles of Internal Medicine, 16th Ed., p1546
  • ^ Fauci et al.,Harrison's Principles of Internal Medicine, 16th Ed., p1543

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