Cystic fibrosis
Encyclopedia
Cystic fibrosis is a recessive
genetic disease affecting most critically the lungs, and also the pancreas
, liver
, and intestine
. It is characterized by abnormal transport of chloride
and sodium
across epithelium
, leading to thick, viscous secretions .
The name cystic fibrosis refers to the characteristic scar
ring (fibrosis
) and cyst
formation within the pancreas
, first recognized in the 1930s
. Difficulty breathing is the most serious symptom and results from frequent lung infections
that are treated with, though not cured by, antibiotics and other medications. Other symptom
s, including sinus infections
, poor growth
, diarrhea
, and infertility
affect other parts of the body.
CF is caused by a mutation
in the gene
for the protein
cystic fibrosis transmembrane conductance regulator
(CFTR). This gene is required to regulate the components of sweat, digestive
juices, and mucus
. Although most people without CF have two working copies of the CFTR gene, only one is needed to prevent cystic fibrosis. CF develops when neither gene works normally and therefore has autosomal
recessive inheritance.
CF is most common among Caucasians
; one in 25 people of European descent carries
one allele
for CF.
Ireland
has both the highest incidence of CF in the world; 2.98 per 10,000 - and the highest carrier rate in the world with 1 in 19 individuals classed as carriers. Cystic fibrosis is Ireland's most common life-threatening inherited disease. Ireland also has the largest proportion of families with more than one child suffering from CF.
Individuals with cystic fibrosis can be diagnosed before birth by genetic testing
, or by a sweat test
in early childhood. Ultimately, lung transplantation
is often necessary as CF worsens.
, poor growth and poor weight gain despite a normal food intake, accumulation of thick, sticky mucus, frequent chest infections and coughing or shortness of breath. Males can be infertile
due to congenital absence of the vas deferens
. Symptoms often appear in infancy and childhood, such as bowel obstruction
due to meconium ileus in newborn babies. As the child grows, they must exercise to release mucus in the alveoli. Ciliated
epithelial cells
in the patient have a mutated protein that leads to abnormally viscous mucus production. The poor growth in children typically presents as an inability to gain weight or height at the same rate as their peers and is occasionally not diagnosed until investigation is initiated for poor growth. The causes of growth failure are multi-factorial and include chronic lung infection, poor absorption of nutrients through the gastrointestinal tract, and increased metabolic demand due to chronic illness.
In rare cases, cystic fibrosis can manifest itself as a coagulation disorder. A double recessive allele is needed for cystic fibrosis to be apparent. Young children are especially sensitive to vitamin K
malabsorptive disorders because only a very small amount of vitamin K crosses the placenta, leaving the child with very low reserves. Because factors II, VII, IX, and X (clotting factors) are vitamin K–dependent, low levels of vitamin K can result in coagulation problems. Consequently, when a child presents with unexplained bruising, a coagulation evaluation may be warranted to determine whether there is an underlying disease.
and resulting inflammation
. Inflammation and infection cause injury and structural changes to the lungs, leading to a variety of symptoms. In the early stages, incessant coughing, copious phlegm
production, and decreased ability to exercise are common. Many of these symptoms occur when bacteria
that normally inhabit the thick mucus grow out of control and cause pneumonia. In later stages, changes in the architecture of the lung such as pathology in the major airways (bronchiectasis
) further exacerbate difficulties in breathing. Other symptoms include coughing up blood (hemoptysis
), high blood pressure
in the lung (pulmonary hypertension
), heart failure, difficulties getting enough oxygen
to the body (hypoxia
), and respiratory failure requiring support with breathing masks such as bilevel positive airway pressure
machines or ventilators
. Staphylococcus aureus
, Haemophilus influenzae
, and Pseudomonas aeruginosa
are the three most common organisms causing lung infections in CF patients. In addition to typical bacterial infections, people with CF more commonly develop other types of lung disease. Among these is allergic bronchopulmonary aspergillosis
, in which the body's response to the common fungus
Aspergillus fumigatus
causes worsening of breathing problems. Another is infection with Mycobacterium avium
complex (MAC), a group of bacteria related to tuberculosis
, which can cause a lot of lung damage and does not respond to common antibiotics.
Mucus in the paranasal sinus
es is equally thick and may also cause blockage of the sinus passages, leading to infection. This may cause facial pain, fever, nasal drainage, and headache
s. Individuals with CF may develop overgrowth of the nasal tissue (nasal polyp
s) due to inflammation from chronic sinus infections. Recurrent sinonasal polyps can occur in as many as 10% to 25% of CF patients. These polyps can block the nasal passages and increase breathing difficulties.
Cardiorespiratory complications are the most common cause of death (~80%) in patients followed by most CF centers in the United States.
, cystic fibrosis was often diagnosed when a newborn infant failed to pass faeces (meconium
). Meconium may completely block the intestines
and cause serious illness. This condition, called meconium ileus, occurs in 5–10% of newborns with CF. In addition, protrusion of internal rectal
membranes (rectal prolapse
) is more common, occurring in as many as 10% of children with CF, and it is caused by increased fecal volume, malnutrition, and increased intra–abdominal pressure
due to coughing.
The thick mucus seen in the lungs has a counterpart in thickened secretions from the pancreas
, an organ responsible for providing digestive juices
that help break down food. These secretions block the exocrine movement of the digestive enzymes into the duodenum
and result in irreversible damage to the pancreas, often with painful inflammation (pancreatitis
). The pancreatic duct
s are totally plugged in more advanced cases, usually seen in older children or adolescents. This causes atrophy of the exocrine glands and progressive fibrosis.
The lack of digestive enzymes leads to difficulty absorbing nutrients with their subsequent excretion in the feces, a disorder known as malabsorption
. Malabsorption leads to malnutrition
and poor growth and development because of calorie loss. Resultant hypoproteinemia
may be severe enough to cause generalized edema. Individuals with CF also have difficulties absorbing the fat-soluble vitamins A
, D
, E
, and K
.
In addition to the pancreas problems, people with cystic fibrosis experience more heartburn
, intestinal blockage by intussusception
, and constipation
. Older individuals with CF may develop distal intestinal obstruction syndrome
when thickened feces cause intestinal blockage.
Exocrine pancreatic insufficiency occurs in the majority (85% to 90%) of patients with CF. It is mainly associated with "severe" CFTR mutations, where both alleles are completely nonfunctional (e.g. ΔF508/ΔF508). It occurs in 10% to 15% of patients with one "severe" and one "mild" CFTR mutation where there still is a little CFTR activity, or where there are two "mild" CFTR mutations. In these milder cases, there is still sufficient pancreatic exocrine function so that enzyme supplementation is not required. There are usually no other GI complications in pancreas-sufficient phenotypes, and in general, such individuals usually have excellent growth and development. Despite this, idiopathic chronic pancreatitis
can occur in a subset of pancreas-sufficient individuals with CF, and is associated with recurrent abdominal pain and life-threatening complications.
Thickened secretions also may cause liver problems in patients with CF. Bile
secreted by the liver to aid in digestion may block the bile duct
s, leading to liver damage. Over time, this can lead to scarring and nodularity (cirrhosis
). The liver fails to rid the blood of toxins and does not make important protein
s such as those responsible for blood clotting
. Liver disease is the third most common cause of death associated with CF.
contains the islets of Langerhans
, which are responsible for making insulin, a hormone that helps regulate blood glucose
. Damage of the pancreas can lead to loss of the islet cell
s, leading to a type of diabetes that is unique to those with the disease. This cystic fibrosis related diabetes (CFRD) shares characteristics that can be found in Type 1
and Type 2
diabetics, and is one of the principal non-pulmonary complications of CF. Vitamin D is involved in calcium
and phosphate
regulation. Poor uptake of vitamin D from the diet because of malabsorption can lead to the bone disease osteoporosis
in which weakened bones are more susceptible to fracture
s. In addition, people with CF often develop clubbing of their fingers and toes due to the effects of chronic illness and low oxygen
in their tissues.
affects both men and women. At least 97% of men with cystic fibrosis are infertile, but not sterile and can have children with assisted reproductive techniques. These men make normal sperm
but are missing the tube (vas deferens
), which connects the testes
to the ejaculatory duct
s of the penis
. Many men found to have congenital absence of the vas deferens
during evaluation for infertility have a mild, previously undiagnosed form of CF. Some women have fertility difficulties due to thickened cervical mucus or malnutrition. In severe cases, malnutrition disrupts ovulation
and causes amenorrhea.
CF is caused by a mutation
in the gene
cystic fibrosis transmembrane conductance regulator (CFTR). The most common mutation, ΔF508, is a deletion (Δ) of three nucleotides that results in a loss of the amino acid phenylalanine
(F) at the 508th position on the protein. This mutation accounts for two-thirds (66-70%) of CF cases worldwide and 90% of cases in the United States
; however, there are over 1500 other mutations that can produce CF. Although most people have two working copies (alleles) of the CFTR gene, only one is needed to prevent cystic fibrosis. CF develops when neither allele can produce a functional CFTR protein. Thus, CF is considered an autosomal recessive disease.
The CFTR gene, found at the q31.2 locus
of chromosome 7, is 230,000 base pair
s long, and creates a protein that is 1,480 amino acid
s long. Structurally, CFTR is a type of gene known as an ABC gene
. The product of this gene (the CFTR) is a chloride ion channel important in creating sweat, digestive
juices and mucus
. This protein possesses two ATP-hydrolyzing
domains, which allows the protein to use energy
in the form of ATP
. It also contains two domains comprising 6 alpha helices
apiece, which allow the protein to cross the cell membrane. A regulatory binding site
on the protein allows activation by phosphorylation
, mainly by cAMP-dependent protein kinase
. The carboxyl terminal
of the protein is anchored to the cytoskeleton
by a PDZ domain interaction.
In addition, there is increasing evidence that genetic modifiers besides CFTR modulate the frequency and severity of the disease. One example is mannan-binding lectin
, which is involved in innate immunity by facilitating phagocytosis of microorganisms. Polymorphisms
in one or both mannan-binding lectin alleles that result in lower circulating levels of the protein are associated with a threefold higher risk of end-stage lung disease, as well as an increased burden of chronic bacterial infections.
There are several mutations in the CFTR gene, and different mutations cause different defects in the CFTR protein, sometimes causing a milder or more severe disease. These protein defects are also targets for drugs which can sometimes restore their function. ΔF508-CFTR, which occurs in >90% of patients in the U.S., creates a protein that does not fold
normally and is degraded by the cell. Other mutations result in proteins that are too short (truncated) because production
is ended prematurely. Other mutations produce proteins that do not use energy normally, do not allow chloride
, iodide
and thiocyanate
to cross the membrane appropriately, or are degraded at a faster rate than normal. Mutations may also lead to fewer copies of the CFTR protein being produced.
The protein created by this gene is anchored to the outer membrane
of cell
s in the sweat gland
s, lungs, pancreas, and other affected organ
s. The protein spans this membrane and acts as a channel
connecting the inner part of the cell (cytoplasm
) to the surrounding fluid
. This channel is primarily responsible for controlling the movement of halogens from inside to outside of the cell; however, in the sweat ducts it facilitates the movement of chloride from the sweat into the cytoplasm. When the CFTR protein does not work, chloride and thiocyanate are trapped inside the cells in the airway and outside in the skin. Then hypothiocyanite
, OSCN, cannot be produced by immune defense system. Because chloride is negatively charged
, this creates a difference in the electrical potential inside and outside the cell causing cations to cross into the cell. Sodium is the most common cation in the extracellular space and the combination of sodium and chloride creates the salt
, which is lost in high amounts in the sweat of individuals with CF. This lost salt forms the basis for the sweat test.
Most of the damage in CF is due to blockage of the narrow passages of affected organs with thickened secretions. These blockages lead to remodeling and infection in the lung, damage by accumulated digestive enzymes in the pancreas, blockage of the intestines by thick faeces, etc. There are several theories on how the defects in the protein and cellular function cause the clinical effects. One theory is that the lack of halogen and pseudohalogen (mainly, chloride, iodide and thiocyanate) exiting through the CFTR protein leads to the accumulation of more viscous, nutrient-rich mucus in the lungs that allows bacteria to hide from the body's immune system
. Another theory is that the CFTR protein failure leads to a paradoxical increase in sodium and chloride uptake, which, by leading to increased water reabsorption, creates dehydrated and thick mucus. Yet another theory is that abnormal chloride movement out of the cell leads to dehydration of mucus, pancreatic secretions, biliary secretions, etc.
Over time, both the types of bacteria and their individual characteristics change in individuals with CF. In the initial stage, common bacteria such as Staphylococcus aureus
and Hemophilus influenzae colonize and infect the lungs. Eventually, Pseudomonas aeruginosa
(and sometimes Burkholderia cepacia
) dominates. By 18 years of age, 80% of patients with classic CF harbor P. aeruginosa, and 3.5% harbor B. cepacia. Once within the lungs, these bacteria adapt to the environment and develop resistance
to commonly used antibiotics. Pseudomonas can develop special characteristics that allow the formation of large colonies, known as "mucoid" Pseudomonas, which are rarely seen in people that do not have CF.
One way infection spreads is by passing between different individuals with CF. In the past, people with CF often participated in summer "CF Camps" and other recreational gatherings. Hospitals grouped patients with CF into common areas and routine equipment (such as nebulizer
s) was not sterilized between individual patients. This led to transmission of more dangerous strains of bacteria among groups of patients. As a result, individuals with CF are routinely isolated from one another in the healthcare setting and healthcare providers are encouraged to wear gowns and gloves when examining patients with CF to limit the spread of virulent bacterial strains.
CF patients may also have their airways chronically colonized by filamentous fungi (such as Aspergillus fumigatus, Scedosporium apiospermum, Aspergillus terreus) and/or yeasts (such as Candida albicans); other filamentous fungi less commonly isolated include Aspergillus flavus and Aspergillus nidulans (occur transiently in CF respiratory secretions), and Exophiala dermatitidis and Scedosporium prolificans (chronic airway-colonizers); some filamentous fungi like Penicillium emersonii and Acrophialophora fusispora are encountered in patients almost exclusively in the context of CF. Defective mucociliary clearance characterizing CF is associated with local immunological disorders. In addition, the prolonged therapy with antibiotics and the use of corticosteroid treatments may also facilitate fungal growth. Although the clinical relevance of the fungal airway colonization is still a matter of debate, filamentous fungi may contribute to the local inflammatory response, and therefore to the progressive deterioration of the lung function, as often happens with allergic broncho-pulmonary aspergillosis (ABPA) - the most common fungal disease in the context of CF, involving a Th2-driven immune response to Aspergillus.
Cystic fibrosis may be diagnosed by many different methods including newborn screening
, sweat test
ing, and genetic testing
. As of 2006 in the United States, 10 percent of cases are diagnosed shortly after birth as part of newborn screening programs. The newborn screen initially measures for raised blood concentration of immunoreactive trypsinogen
. Infants with an abnormal newborn screen need a sweat test to confirm the CF diagnosis. In many cases, a parent makes the diagnosis because the infant tastes salty. Trypsinogen
levels can be increased in individuals who have a single mutated copy of the CFTR gene (carriers) or, in rare instances, in individuals with two normal copies of the CFTR gene. Due to these false positives, CF screening in newborns can be controversial. Most states and countries do not screen for CF routinely at birth. Therefore, most individuals are diagnosed after symptoms (e.g. sinopulmonary disease and GI manifestations) prompt an evaluation for cystic fibrosis. The most commonly used form of testing is the sweat test. Sweat-testing involves application of a medication that stimulates sweating (pilocarpine
). To deliver the medication through the skin, iontophoresis
is used to, whereby one electrode
is placed onto the applied medication and an electric current
is passed to a separate electrode on the skin. The resultant sweat is then collected on filter paper or in a capillary tube and analyzed for abnormal amounts of sodium
and chloride
. People with CF have increased amounts of sodium and chloride in their sweat. In opposite, people with CF have less thiocyanate and hypothiocyanite
in their saliva (Minarowski et al.) and mucus (Banfi et al.). CF can also be diagnosed by identification of mutations in the CFTR gene.
People with CF may be listed in a disease registry
that allows researchers and doctors to track health results and identify candidates for clinical trial
s.
is performed. The American College of Obstetricians and Gynecologists (ACOG) recommends testing for couples who have a personal or close family history of CF, and they recommend that carrier testing be offered to all Caucasian couples and be made available to couples of other ethnic backgrounds.
Because development of CF in the fetus requires each parent to pass on a mutated copy of the CFTR gene and because CF testing is expensive, testing is often performed initially on one parent. If testing shows that parent is a CFTR gene mutation carrier, the other parent is tested to calculate the risk that their children will have CF. CF can result from more than a thousand different mutations, and as of 2006 it is not possible to test for each one. Testing analyzes the blood for the most common mutations such as ΔF508—most commercially available tests look for 32 or fewer different mutations. If a family has a known uncommon mutation, specific screening for that mutation can be performed. Because not all known mutations are found on current tests, a negative screen does not guarantee that a child will not have CF.
During pregnancy, testing can be performed on the placenta
(chorionic villus sampling
) or the fluid around the fetus (amniocentesis
). However, chorionic villus sampling
has a risk of fetal death of 1 in 100 and amniocentesis of 1 in 200; a recent study has indicated this may be much lower, approximately 1 in 1,600.
Economically, for carrier couples of cystic fibrosis, when comparing preimplantation genetic diagnosis (PGD) with natural conception (NC) followed by prenatal testing and abortion of affected pregnancies, PGD provides net economic benefits up to a maternal age of approximately 40 years, after which NC, prenatal testing and abortion has higher economic benefit.
, and encouragement of good nutrition and an active lifestyle. Management of cystic fibrosis continues throughout a patient's life, and is aimed at maximizing organ function, and therefore quality of life. At best, current treatments delay the decline in organ function. Because of the wide variation in disease symptoms treatment typically occurs at specialist multidisciplinary centers, and is tailored to the individual. Targets for therapy are the lungs, gastrointestinal tract
(including pancreatic enzyme supplements), the reproductive organs (including assisted reproductive technology
(ART)) and psychological support.
The most consistent aspect of therapy in cystic fibrosis is limiting and treating the lung damage caused by thick mucus and infection, with the goal of maintaining quality of life
. Intravenous
, inhaled
, and oral antibiotics are used to treat chronic and acute infections. Mechanical devices and inhalation medications are used to alter and clear the thickened mucus. These therapies, while effective, can be extremely time-consuming for the patient. One of the most important battles that CF patients face is finding the time to comply with prescribed treatments while balancing a normal life.
In addition, therapies such as transplantation
and gene therapy
aim to cure some of the effects of cystic fibrosis. Gene therapy aims to introduce normal CFTR to airway. Theoretically this process should be simple as the airway is easily accessible and there is only a single gene defect to correct. There are two CFTR gene introduction mechanisms involved, the first use of a viral vector (adenovirus, adeno-associated virus or retro virus) and secondly the use of liposome
. However there are some problems associated with these methods involving efficiency (liposomes insufficient protein) and delivery (virus provokes an immune response).
(PICC line) or Port-a-Cath. Inhaled therapy with antibiotics such as tobramycin, colistin
, and aztreonam
is often given for months at a time to improve lung function by impeding the growth of colonized bacteria. Oral antibiotics such as ciprofloxacin or azithromycin
are given to help prevent infection or to control ongoing infection. The aminoglycoside
antibiotics (e.g. tobramycin) used can cause hearing loss
, damage to the balance system
in the inner ear
or kidney problems
with long-term use. To prevent these side-effect
s, the amount of antibiotics in the blood are routinely measured and adjusted accordingly.
and the intrapulmonary percussive ventilator
(IPV). Newer methods such as Biphasic Cuirass Ventilation
, and associated clearance mode available in such devices, integrate a cough assistance phase, as well as a vibration phase for dislodging secretions. These are portable and adapted for home use.
Aerosolized medications that help loosen secretions include dornase alfa
and hypertonic saline
. Dornase is a recombinant
human deoxyribonuclease
, which breaks down DNA in the sputum
, thus decreasing its viscosity
. Denufosol
is an investigational drug that opens an alternative chloride channel, helping to liquefy mucus.
As lung disease worsens, mechanical breathing support may become necessary. Individuals with CF may need to wear special masks at night that help push air into their lungs. These machines, known as bilevel positive airway pressure
(BiPAP) ventilators, help prevent low blood oxygen levels during sleep. BiPAP may also be used during physical therapy to improve sputum clearance. During severe illness, a tube
may be placed in the throat (a procedure known as a tracheostomy) to enable breathing supported by a ventilator.
For children living with CF, preliminary studies show pediatric massage therapy may improve patients and their families quality of life, though more rigorous studies must be done.
often becomes necessary for individuals with cystic fibrosis as lung function and exercise tolerance
declines. Although single lung transplantation is possible in other diseases, individuals with CF must have both lungs replaced because the remaining lung might contain bacteria that could infect the transplanted lung. A pancreatic or liver transplant may be performed at the same time in order to alleviate liver disease and/or diabetes. Lung transplantation is considered when lung function declines to the point where assistance from mechanical devices is required or patient survival is threatened.
Newborns with CF typically require surgery, whereas adults with distal intestinal obstruction syndrome typically do not. Treatment of pancreatic insufficiency by replacement of missing digestive enzymes allows the duodenum to properly absorb nutrients and vitamins that would otherwise be lost in the feces.So far, no large-scale research involving the incidence of atherosclerosis
and coronary heart disease
in adults with cystic fibrosis has been conducted. This is likely due to the fact that the vast majority of people with cystic fibrosis do not live long enough to develop clinically significant atherosclerosis or coronary heart disease.
Diabetes
is the most common non-pulmonary complication of CF. It mixes features of type 1
and type 2
diabetes, and is recognized as a distinct entity, cystic fibrosis-related diabetes (CFRD). While oral anti-diabetic drug
s are sometimes used, the only recommended treatment is the use of insulin
injections or an insulin pump
, and, unlike in type 1 and 2 diabetes, dietary restrictions are not recommended.
Development of osteoporosis
can be prevented by increased intake of vitamin D and calcium
, and can be treated by bisphosphonate
s, although adverse effects
can be an issue. Poor growth may be avoided by insertion of a feeding tube
for increasing calorie
s through supplemental feeds or by administration of injected growth hormone
.
Sinus infections are treated by prolonged courses of antibiotics. The development of nasal polyps or other chronic changes within the nasal passages may severely limit airflow through the nose, and over time reduce the patient's sense of smell. Sinus surgery is often used to alleviate nasal obstruction and to limit further infections. Nasal steroids such as fluticasone
are used to decrease nasal inflammation. Female infertility may be overcome by assisted reproduction
technology, particularly embryo transfer
techniques. Male infertility caused by absence of the vas deferens
may be overcome with testicular sperm extraction
(TEST), collecting sperm cells directly from the testicles. If the collected sample contains too few sperm cells to likely have a spontaneous fertilization, intracytoplasmic sperm injection
can be performed. Third party reproduction is also a possibility for women with CF.
It is important for CF patients to understand the detrimental relationship that chronic illnesses place on the quality of life. According to Schmitz and Goldbeck (2006), the fact that Cystic Fibrosis significantly increases emotional stress on both the individual and the family, “and the necessary time-consuming daily treatment routine may have further negative effects on quality of life (QOL)”. However, Havermans and colleagues (2006) have shown that young outpatients with CF that have participated in the CFQ-R (Cystic Fibrosis Questionnaire-Revised) “rated some QOL domains higher than did their parents”. Consequently, outpatients with CF have a more positive outlook for themselves.
Furthermore, there are many ways to improve the QOL in CF patients. Exercise is promoted to increase lung function. The fact of integrating an exercise regime into the CF patient’s daily routine can significantly improve the quality of life. There is no definitive cure for Cystic Fibrosis. However, there are diverse medications used such as, mucolytics, bronchodilators, steroids and antibiotics that have the purpose of loosening mucus, expanding airways, decreasing inflammation and fighting lung infections.
In 1959, the median age of survival of children with cystic fibrosis in the U.S. was six months. Now, it is 37.4 years. In Canada, median survival increased from 24 years in 1982 to 47.7 in 2007.
The U.S. Cystic Fibrosis Foundation reported that in 2008, 92% had graduated from high school
and 66% had at least some college education. 15% of adults were disabled and 7% were unemployed. 54.8% of adults were single and 40.1% were married or living with a partner. In 2008, 240 American women with CF were pregnant.
Cystic fibrosis is the most common life-limiting autosomal recessive disease among people of Europe
an heritage. In the United States, approximately 30,000 individuals have CF; most are diagnosed by six months of age. Canada
has approximately 3,000 citizens with CF. Approximately 1 in 25 people of European descent, and one in 30 of Caucasian Americans, is a carrier of a cystic fibrosis mutation. Although CF is less common in these groups, approximately 1 in 46 Hispanic
s, 1 in 65 Africans and 1 in 90 Asians
carry at least one abnormal CFTR gene.
Although technically a rare disease
, cystic fibrosis is ranked as one of the most widespread life-shortening genetic diseases. It is most common among nations in the Western world. An exception is Finland
, where only one in 80 people carry a CF mutation. In the United States, 1 in 4,000 children are born with CF. In 1997, about 1 in 3,300 caucasian children in the United States was born with cystic fibrosis. In contrast, only 1 in 15,000 African American children suffered from cystic fibrosis, and in Asian Americans the rate was even lower at 1 in 32,000.
Cystic fibrosis is diagnosed in males and females equally. For reasons that remain unclear, data has shown that males tend to have a longer life expectancy
than females, however recent studies suggest this gender gap may no longer exist perhaps due to improvements in health care facilities, while a recent study from Ireland identified a link between the female hormone oestrogen and worse outcomes in CF.
The distribution of CF alleles varies among populations. The frequency of ΔF508 carriers has been estimated at 1:200 in northern Sweden, 1:143 in Lithuanians, and 1:38 in Denmark. No ΔF508 carriers were found among 171 Finns and 151 Saami people. ΔF508 does occur in Finland, but it is a minority allele there. Cystic fibrosis is known to occur in only 20 families (pedigrees) in Finland.
. Resistance to the following have all been proposed as possible sources of heterozygote advantage:
It is supposed that CF appeared about 3,000 BC as a cause of migration of peoples, gene mutations, and new conditions in nourishment. Although the entire clinical spectrum of CF was not recognized until the 1930s, certain aspects of CF were identified much earlier. Indeed, literature from Germany and Switzerland in the 18th century warned Wehe dem Kind, das beim Kuß auf die Stirn salzig schmekt, er ist verhext und muss bald sterbe or "Woe is the child who tastes salty from a kiss on the brow, for he is cursed, and soon must die," recognizing the association between the salt loss in CF and illness.
In the 19th century, Carl von Rokitansky described a case of fetal death with meconium peritonitis
, a complication of meconium ileus associated with cystic fibrosis. Meconium ileus was first described in 1905 by Karl Landsteiner
. In 1936, Guido Fanconi
published a paper describing a connection between celiac disease, cystic fibrosis of the pancreas, and bronchiectasis
.
In 1938 Dorothy Hansine Andersen
published an article, "Cystic Fibrosis of the Pancreas and Its Relation to Celiac Disease: a Clinical and Pathological Study," in the American Journal of Diseases of Children. She was the first to describe the characteristic cystic fibrosis of the pancreas and to correlate it with the lung and intestinal disease prominent in CF. She also first hypothesized that CF was a recessive disease and first used pancreatic enzyme replacement to treat affected children. In 1952 Paul di Sant' Agnese discovered abnormalities in sweat
electrolyte
s; a sweat test
was developed and improved over the next decade.
In 1988 the first mutation for CF, ΔF508 was discovered by Francis Collins
, Lap-Chee Tsui
and John R. Riordan on the seventh chromosome. Subsequent research has found over 1,000 different mutations that cause CF.
Because mutations in the CFTR gene are typically small, classical genetics
techniques had been unable to accurately pinpoint the mutated gene. Using protein markers, gene-linkage studies were able to map the mutation to chromosome 7. Chromosome-walking and -jumping
techniques were then used to identify and sequence
the gene. In 1989 Lap-Chee Tsui led a team of researchers at the Hospital for Sick Children
in Toronto
that discovered the gene responsible for CF. Cystic fibrosis represents the first genetic disorder elucidated strictly by the process of reverse genetics
.
has been explored as a potential cure for cystic fibrosis. Ideally, gene therapy attempts to place a normal copy of the CFTR gene into affected cells. Transferring the normal CFTR gene into the affected epithelium cells would result in the production of functional CFTR in all target cells, without adverse reactions or an inflammation response. Studies have shown that to prevent the lung manifestations of cystic fibrosis, only 5–10% the normal amount of CFTR gene expression
is needed. Multiple approaches have been tested for gene transfer, such as liposomes and viral vectors in animal models and clinical trials. However, both methods were found relatively inefficient treatment options. The main reason is that very few cells take up the vector and express the gene, so the treatment has little effect. Additionally, problems have been noted in cDNA recombination, such that the gene introduced by the treatment is rendered unusable. Gene therapy has made massive advances in the way that cystic fibrosis has been treated throughout the world. With the help of the Cystic Fibrosis Trust
, which has a league of highly professional gene therapists, both somatic and Adeno-associated viral vector have made advances. The Adenoviridae, or more commonly known as the cold virus, is genetically altered, allowing the CFTR gene to enter lung cells. They are currently stage 3 clinical trial
, and following the success of these trials, the treatment can become readily available and valid in the eyes of the medical world.
s that aim at compensating various mutations of the CFTR gene are under development. One approach is to develop drugs that get the ribosome to overcome the stop codon
and synthesize a full-length CFTR protein. About 10% of CF result from a premature stop codon in the DNA, leading to early termination of protein synthesis and truncated proteins. These drugs target nonsense mutation
s such as G542X, which consists of the amino acid glycin
in position 542 being replaced by a stop codon. Aminoglycoside antibiotics interfere with DNA synthesis and error-correction. In some cases, they can cause the cell to overcome the stop codon, insert a random amino acid, and express a full-length protein.
The aminoglycoside gentamicin
has been used to treat lung cells from CF patients in the laboratory to induce the cells to grown full-length proteins. Another drug targeting nonsense mutations is ataluren, which is undergoing Phase III clinical trials .
Ivacaftor
, also in Phase III trials, targets the mutation G551D (glycin in position 551 is substituted with aspartic acid
). VX-807
aims at F508del (phenylalanin in position 508 is missing).
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
genetic disease affecting most critically the lungs, and also the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
, liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, and intestine
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
. It is characterized by abnormal transport of chloride
Chloride
The chloride ion is formed when the element chlorine, a halogen, picks up one electron to form an anion Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. The chloride ion, and its salts such as sodium chloride, are very soluble in water...
and sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
across epithelium
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
, leading to thick, viscous secretions .
The name cystic fibrosis refers to the characteristic scar
Scar
Scars are areas of fibrous tissue that replace normal skin after injury. A scar results from the biological process of wound repair in the skin and other tissues of the body. Thus, scarring is a natural part of the healing process. With the exception of very minor lesions, every wound results in...
ring (fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
) and cyst
Cyst
A cyst is a closed sac, having a distinct membrane and division on the nearby tissue. It may contain air, fluids, or semi-solid material. A collection of pus is called an abscess, not a cyst. Once formed, a cyst could go away on its own or may have to be removed through surgery.- Locations :* Acne...
formation within the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
, first recognized in the 1930s
1930s
File:1930s decade montage.png|From left, clockwise: Dorothea Lange's photo of the homeless Florence Thompson show the effects of the Great Depression; Due to the economic collapse, the farms become dry and the Dust Bowl spreads through America; The Battle of Wuhan during the Second Sino-Japanese...
. Difficulty breathing is the most serious symptom and results from frequent lung infections
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
that are treated with, though not cured by, antibiotics and other medications. Other symptom
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
s, including sinus infections
Sinusitis
Sinusitis is inflammation of the paranasal sinuses, which may be due to infection, allergy, or autoimmune issues. Most cases are due to a viral infection and resolve over the course of 10 days...
, poor growth
Failure to thrive
Failure to thrive is a medical term which is used in both pediatric and adult human medicine, as well as veterinary medicine ....
, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, and infertility
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
affect other parts of the body.
CF is caused by a mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
in the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
for the protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
cystic fibrosis transmembrane conductance regulator
Cystic fibrosis transmembrane conductance regulator
Cystic fibrosis transmembrane conductance regulator is a protein that in humans is encoded by the CFTR gene.CFTR is a ABC transporter-class ion channel that transports chloride and thiocyanate ions across epithelial cell membranes...
(CFTR). This gene is required to regulate the components of sweat, digestive
Digestion
Digestion is the mechanical and chemical breakdown of food into smaller components that are more easily absorbed into a blood stream, for instance. Digestion is a form of catabolism: a breakdown of large food molecules to smaller ones....
juices, and mucus
Mucus
In vertebrates, mucus is a slippery secretion produced by, and covering, mucous membranes. Mucous fluid is typically produced from mucous cells found in mucous glands. Mucous cells secrete products that are rich in glycoproteins and water. Mucous fluid may also originate from mixed glands, which...
. Although most people without CF have two working copies of the CFTR gene, only one is needed to prevent cystic fibrosis. CF develops when neither gene works normally and therefore has autosomal
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
recessive inheritance.
CF is most common among Caucasians
Caucasian race
The term Caucasian race has been used to denote the general physical type of some or all of the populations of Europe, North Africa, the Horn of Africa, Western Asia , Central Asia and South Asia...
; one in 25 people of European descent carries
Genetic carrier
A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...
one allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
for CF.
Ireland
Ireland
Ireland is an island to the northwest of continental Europe. It is the third-largest island in Europe and the twentieth-largest island on Earth...
has both the highest incidence of CF in the world; 2.98 per 10,000 - and the highest carrier rate in the world with 1 in 19 individuals classed as carriers. Cystic fibrosis is Ireland's most common life-threatening inherited disease. Ireland also has the largest proportion of families with more than one child suffering from CF.
Individuals with cystic fibrosis can be diagnosed before birth by genetic testing
Genetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
, or by a sweat test
Sweat test
The sweat test measures the concentration of chloride that is excreted in sweat. It is used to screen for cystic fibrosis .-Background:Cystic fibrosis is caused by defects in a protein found in many tissues, including the airways and the sweat glands. As a result, these tissues do not work properly...
in early childhood. Ultimately, lung transplantation
Lung transplantation
Lung transplantation, or pulmonary transplantation is a surgical procedure in which a patient's diseased lungs are partially or totally replaced by lungs which come from a donor...
is often necessary as CF worsens.
Signs and symptoms
The hallmark symptoms of cystic fibrosis are salty tasting skinSkin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
, poor growth and poor weight gain despite a normal food intake, accumulation of thick, sticky mucus, frequent chest infections and coughing or shortness of breath. Males can be infertile
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
due to congenital absence of the vas deferens
Congenital absence of the vas deferens
Congenital absence of the vas deferens is a condition in which the vasa deferentia, male reproductive organs, fail to form properly prior to birth. It may either be unilateral or bilateral .-Presentation:...
. Symptoms often appear in infancy and childhood, such as bowel obstruction
Bowel obstruction
Bowel obstruction is a mechanical or functional obstruction of the intestines, preventing the normal transit of the products of digestion. It can occur at any level distal to the duodenum of the small intestine and is a medical emergency...
due to meconium ileus in newborn babies. As the child grows, they must exercise to release mucus in the alveoli. Ciliated
Cilium
A cilium is an organelle found in eukaryotic cells. Cilia are slender protuberances that project from the much larger cell body....
epithelial cells
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
in the patient have a mutated protein that leads to abnormally viscous mucus production. The poor growth in children typically presents as an inability to gain weight or height at the same rate as their peers and is occasionally not diagnosed until investigation is initiated for poor growth. The causes of growth failure are multi-factorial and include chronic lung infection, poor absorption of nutrients through the gastrointestinal tract, and increased metabolic demand due to chronic illness.
In rare cases, cystic fibrosis can manifest itself as a coagulation disorder. A double recessive allele is needed for cystic fibrosis to be apparent. Young children are especially sensitive to vitamin K
Vitamin K
Vitamin K is a group of structurally similar, fat soluble vitamins that are needed for the posttranslational modification of certain proteins required for blood coagulation and in metabolic pathways in bone and other tissue. They are 2-methyl-1,4-naphthoquinone derivatives...
malabsorptive disorders because only a very small amount of vitamin K crosses the placenta, leaving the child with very low reserves. Because factors II, VII, IX, and X (clotting factors) are vitamin K–dependent, low levels of vitamin K can result in coagulation problems. Consequently, when a child presents with unexplained bruising, a coagulation evaluation may be warranted to determine whether there is an underlying disease.
Lung and sinus
Lung disease results from clogging of the airways due to mucus build-up, decreased mucociliary clearanceMucociliary Clearance
Mucociliary clearance, also referred to as mucociliary apparatus or mucociliar clearance , derived from mucus , cilia and clearance describes the self-clearing mechanism of the bronchi.The main bronchi down to the alveoli are lined with a respiratory epithelium...
and resulting inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
. Inflammation and infection cause injury and structural changes to the lungs, leading to a variety of symptoms. In the early stages, incessant coughing, copious phlegm
Phlegm
Phlegm is a liquid secreted by the mucous membranes of mammalians. Its definition is limited to the mucus produced by the respiratory system, excluding that from the nasal passages, and particularly that which is expelled by coughing . Phlegm is in essence a water-based gel consisting of...
production, and decreased ability to exercise are common. Many of these symptoms occur when bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
that normally inhabit the thick mucus grow out of control and cause pneumonia. In later stages, changes in the architecture of the lung such as pathology in the major airways (bronchiectasis
Bronchiectasis
Bronchiectasis is a disease state defined by localized, irreversible dilation of part of the bronchial tree caused by destruction of the muscle and elastic tissue. It is classified as an obstructive lung disease, along with emphysema, bronchitis, asthma, and cystic fibrosis...
) further exacerbate difficulties in breathing. Other symptoms include coughing up blood (hemoptysis
Hemoptysis
Hemoptysis or haemoptysis is the expectoration of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis is the expectoration (coughing up) of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis ...
), high blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
in the lung (pulmonary hypertension
Pulmonary hypertension
In medicine, pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion...
), heart failure, difficulties getting enough oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
to the body (hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
), and respiratory failure requiring support with breathing masks such as bilevel positive airway pressure
Bilevel positive airway pressure
Bilevel positive airway pressure is a continuous positive airway pressure mode used during noninvasive positive pressure ventilation. It delivers a preset inspiratory positive airway pressure and expiratory positive airway pressure . BPAP can be described as a Continuous Positive Airway...
machines or ventilators
Mechanical ventilation
In medicine, mechanical ventilation is a method to mechanically assist or replace spontaneous breathing. This may involve a machine called a ventilator or the breathing may be assisted by a physician, respiratory therapist or other suitable person compressing a bag or set of bellows...
. Staphylococcus aureus
Staphylococcus aureus
Staphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...
, Haemophilus influenzae
Haemophilus influenzae
Haemophilus influenzae, formerly called Pfeiffer's bacillus or Bacillus influenzae, Gram-negative, rod-shaped bacterium first described in 1892 by Richard Pfeiffer during an influenza pandemic. A member of the Pasteurellaceae family, it is generally aerobic, but can grow as a facultative anaerobe. H...
, and Pseudomonas aeruginosa
Pseudomonas aeruginosa
Pseudomonas aeruginosa is a common bacterium that can cause disease in animals, including humans. It is found in soil, water, skin flora, and most man-made environments throughout the world. It thrives not only in normal atmospheres, but also in hypoxic atmospheres, and has, thus, colonized many...
are the three most common organisms causing lung infections in CF patients. In addition to typical bacterial infections, people with CF more commonly develop other types of lung disease. Among these is allergic bronchopulmonary aspergillosis
Allergic bronchopulmonary aspergillosis
In medicine, allergic bronchopulmonary aspergillosis is a condition characterised by an exaggerated response of the immune system to the fungus Aspergillus . It occurs most often in patients with asthma or cystic fibrosis...
, in which the body's response to the common fungus
Fungus
A fungus is a member of a large group of eukaryotic organisms that includes microorganisms such as yeasts and molds , as well as the more familiar mushrooms. These organisms are classified as a kingdom, Fungi, which is separate from plants, animals, and bacteria...
Aspergillus fumigatus
Aspergillus fumigatus
Aspergillus fumigatus is a fungus of the genus Aspergillus, and is one of the most common Aspergillus species to cause disease in individuals with an immunodeficiency....
causes worsening of breathing problems. Another is infection with Mycobacterium avium
Mycobacterium avium complex
Mycobacterium avium complex is a group of genetically related bacteria belonging to the genus Mycobacterium. It includes Mycobacterium avium and Mycobacterium intracellulare....
complex (MAC), a group of bacteria related to tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
, which can cause a lot of lung damage and does not respond to common antibiotics.
Mucus in the paranasal sinus
Paranasal sinus
Paranasal sinuses are a group of four paired air-filled spaces that surround the nasal cavity , above and between the eyes , and behind the ethmoids...
es is equally thick and may also cause blockage of the sinus passages, leading to infection. This may cause facial pain, fever, nasal drainage, and headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
s. Individuals with CF may develop overgrowth of the nasal tissue (nasal polyp
Nasal polyp
Nasal polyps are polypoidal masses arising mainly from the mucous membranes of the nose and paranasal sinuses. They are overgrowths of the mucosa that frequently accompany allergic rhinitis. They are freely movable and nontender.-Description:...
s) due to inflammation from chronic sinus infections. Recurrent sinonasal polyps can occur in as many as 10% to 25% of CF patients. These polyps can block the nasal passages and increase breathing difficulties.
Cardiorespiratory complications are the most common cause of death (~80%) in patients followed by most CF centers in the United States.
Gastrointestinal
Prior to prenatal and newborn screeningNewborn screening
Newborn screening is the process by which infants are screened shortly after birth for a list of disorders that are treatable, but difficult or impossible to detect clinically. Screening programs are often run by state or national governing bodies with the goal of screening all infants born in the...
, cystic fibrosis was often diagnosed when a newborn infant failed to pass faeces (meconium
Meconium
Meconium is the earliest stools of an infant. Unlike later feces, meconium is composed of materials ingested during the time the infant spends in the uterus: intestinal epithelial cells, lanugo, mucus, amniotic fluid, bile, and water. Meconium is almost sterile, unlike later feces, is viscous and...
). Meconium may completely block the intestines
Small intestine
The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...
and cause serious illness. This condition, called meconium ileus, occurs in 5–10% of newborns with CF. In addition, protrusion of internal rectal
Rectum
The rectum is the final straight portion of the large intestine in some mammals, and the gut in others, terminating in the anus. The human rectum is about 12 cm long...
membranes (rectal prolapse
Rectal prolapse
Rectal prolapse normally describes a medical condition wherein the walls of the rectum protrude through the anus and hence become visible outside the body.-Types:There are three chief conditions which come under the title rectal prolapse:...
) is more common, occurring in as many as 10% of children with CF, and it is caused by increased fecal volume, malnutrition, and increased intra–abdominal pressure
Valsalva maneuver
The Valsalva maneuver or Valsalva manoeuvre is performed by moderately forceful attempted exhalation against a closed airway, usually done by closing one's mouth and pinching one's nose shut...
due to coughing.
The thick mucus seen in the lungs has a counterpart in thickened secretions from the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
, an organ responsible for providing digestive juices
Pancreatic juice
Pancreatic juice is a liquid secreted by the pancreas, which contains a variety of enzymes, including trypsinogen, chymotrypsinogen, elastase, carboxypeptidase, pancreatic lipase, and amylase....
that help break down food. These secretions block the exocrine movement of the digestive enzymes into the duodenum
Duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...
and result in irreversible damage to the pancreas, often with painful inflammation (pancreatitis
Pancreatitis
Pancreatitis is inflammation of the pancreas. It occurs when pancreatic enzymes that digest food are activated in the pancreas instead of the small intestine. It may be acute – beginning suddenly and lasting a few days, or chronic – occurring over many years...
). The pancreatic duct
Pancreatic duct
The pancreatic duct, or duct of Wirsung , is a duct joining the pancreas to the common bile duct to supply pancreatic juices which aid in digestion provided by the "exocrine pancreas"...
s are totally plugged in more advanced cases, usually seen in older children or adolescents. This causes atrophy of the exocrine glands and progressive fibrosis.
The lack of digestive enzymes leads to difficulty absorbing nutrients with their subsequent excretion in the feces, a disorder known as malabsorption
Malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...
. Malabsorption leads to malnutrition
Malnutrition
Malnutrition is the condition that results from taking an unbalanced diet in which certain nutrients are lacking, in excess , or in the wrong proportions....
and poor growth and development because of calorie loss. Resultant hypoproteinemia
Hypoproteinemia
Hypoproteinemia is a condition where there is an abnormally low level of protein in the blood.One common cause is due to excess protein in the urine , which can be a medical sign of nephrotic syndrome....
may be severe enough to cause generalized edema. Individuals with CF also have difficulties absorbing the fat-soluble vitamins A
Vitamin A
Vitamin A is a vitamin that is needed by the retina of the eye in the form of a specific metabolite, the light-absorbing molecule retinal, that is necessary for both low-light and color vision...
, D
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
, E
Vitamin E
Vitamin E is used to refer to a group of fat-soluble compounds that include both tocopherols and tocotrienols. There are many different forms of vitamin E, of which γ-tocopherol is the most common in the North American diet. γ-Tocopherol can be found in corn oil, soybean oil, margarine and dressings...
, and K
Vitamin K
Vitamin K is a group of structurally similar, fat soluble vitamins that are needed for the posttranslational modification of certain proteins required for blood coagulation and in metabolic pathways in bone and other tissue. They are 2-methyl-1,4-naphthoquinone derivatives...
.
In addition to the pancreas problems, people with cystic fibrosis experience more heartburn
Gastroesophageal reflux disease
Gastroesophageal reflux disease , gastro-oesophageal reflux disease , gastric reflux disease, or acid reflux disease is chronic symptoms or mucosal damage caused by stomach acid coming up from the stomach into the esophagus...
, intestinal blockage by intussusception
Intussusception (medical disorder)
An intussusception is a medical condition in which a part of the intestine has invaginated into another section of intestine, similar to the way in which the parts of a collapsible telescope slide into one another. This can often result in an obstruction...
, and constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
. Older individuals with CF may develop distal intestinal obstruction syndrome
Distal intestinal obstruction syndrome
Distal intestinal obstruction syndrome involves blockage of the intestines by thickened stool and occurs in individuals with cystic fibrosis. DIOS was previously known as meconium ileus equivalent, a name which highlights its similarity to the intestinal obstruction seen in newborn infants with...
when thickened feces cause intestinal blockage.
Exocrine pancreatic insufficiency occurs in the majority (85% to 90%) of patients with CF. It is mainly associated with "severe" CFTR mutations, where both alleles are completely nonfunctional (e.g. ΔF508/ΔF508). It occurs in 10% to 15% of patients with one "severe" and one "mild" CFTR mutation where there still is a little CFTR activity, or where there are two "mild" CFTR mutations. In these milder cases, there is still sufficient pancreatic exocrine function so that enzyme supplementation is not required. There are usually no other GI complications in pancreas-sufficient phenotypes, and in general, such individuals usually have excellent growth and development. Despite this, idiopathic chronic pancreatitis
Chronic pancreatitis
Chronic pancreatitis is a long-standing inflammation of the pancreas that alters its normal structure and functions. It can present as episodes of acute inflammation in a previously injured pancreas, or as chronic damage with persistent pain or malabsorption....
can occur in a subset of pancreas-sufficient individuals with CF, and is associated with recurrent abdominal pain and life-threatening complications.
Thickened secretions also may cause liver problems in patients with CF. Bile
Bile
Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum...
secreted by the liver to aid in digestion may block the bile duct
Bile duct
A bile duct is any of a number of long tube-like structures that carry bile.Bile, required for the digestion of food, is excreted by the liver into passages that carry bile toward the hepatic duct, which joins with the cystic duct to form the common bile duct, which opens into the intestine.The...
s, leading to liver damage. Over time, this can lead to scarring and nodularity (cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
). The liver fails to rid the blood of toxins and does not make important protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s such as those responsible for blood clotting
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
. Liver disease is the third most common cause of death associated with CF.
Endocrine
The pancreasPancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
contains the islets of Langerhans
Islets of Langerhans
The islets of Langerhans are the regions of the pancreas that contain its endocrine cells. Discovered in 1869 by German pathological anatomist Paul Langerhans at the age of 22, the islets of Langerhans constitute approximately 1 to 2% of the mass of the pancreas...
, which are responsible for making insulin, a hormone that helps regulate blood glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
. Damage of the pancreas can lead to loss of the islet cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
s, leading to a type of diabetes that is unique to those with the disease. This cystic fibrosis related diabetes (CFRD) shares characteristics that can be found in Type 1
Diabetes mellitus type 1
Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...
and Type 2
Diabetes mellitus type 2
Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...
diabetics, and is one of the principal non-pulmonary complications of CF. Vitamin D is involved in calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
and phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
regulation. Poor uptake of vitamin D from the diet because of malabsorption can lead to the bone disease osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
in which weakened bones are more susceptible to fracture
Bone fracture
A bone fracture is a medical condition in which there is a break in the continuity of the bone...
s. In addition, people with CF often develop clubbing of their fingers and toes due to the effects of chronic illness and low oxygen
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
in their tissues.
Infertility
InfertilityInfertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
affects both men and women. At least 97% of men with cystic fibrosis are infertile, but not sterile and can have children with assisted reproductive techniques. These men make normal sperm
Spermatozoon
A spermatozoon is a motile sperm cell, or moving form of the haploid cell that is the male gamete. A spermatozoon joins an ovum to form a zygote...
but are missing the tube (vas deferens
Vas deferens
The vas deferens , also called ductus deferens, , is part of the male anatomy of many vertebrates; they transport sperm from the epididymis in anticipation of ejaculation....
), which connects the testes
Testicle
The testicle is the male gonad in animals. Like the ovaries to which they are homologous, testes are components of both the reproductive system and the endocrine system...
to the ejaculatory duct
Ejaculatory duct
-Anatomy:The ejaculatory ducts are paired structures in male anatomy. Each ejaculatory duct is formed by the union of the vas deferens with the duct of the seminal vesicle. They pass through the prostate, and open into the urethra at the Colliculus seminalis...
s of the penis
Penis
The penis is a biological feature of male animals including both vertebrates and invertebrates...
. Many men found to have congenital absence of the vas deferens
Congenital absence of the vas deferens
Congenital absence of the vas deferens is a condition in which the vasa deferentia, male reproductive organs, fail to form properly prior to birth. It may either be unilateral or bilateral .-Presentation:...
during evaluation for infertility have a mild, previously undiagnosed form of CF. Some women have fertility difficulties due to thickened cervical mucus or malnutrition. In severe cases, malnutrition disrupts ovulation
Ovulation
Ovulation is the process in a female's menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum . Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle...
and causes amenorrhea.
Cause
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
in the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
cystic fibrosis transmembrane conductance regulator (CFTR). The most common mutation, ΔF508, is a deletion (Δ) of three nucleotides that results in a loss of the amino acid phenylalanine
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
(F) at the 508th position on the protein. This mutation accounts for two-thirds (66-70%) of CF cases worldwide and 90% of cases in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
; however, there are over 1500 other mutations that can produce CF. Although most people have two working copies (alleles) of the CFTR gene, only one is needed to prevent cystic fibrosis. CF develops when neither allele can produce a functional CFTR protein. Thus, CF is considered an autosomal recessive disease.
The CFTR gene, found at the q31.2 locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
of chromosome 7, is 230,000 base pair
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
s long, and creates a protein that is 1,480 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s long. Structurally, CFTR is a type of gene known as an ABC gene
ATP-binding cassette transporter genes
ATP-binding cassette transporters are members of a protein superfamily that is one of the largest and most ancient families with representatives in all extant phyla from prokaryotes to humans...
. The product of this gene (the CFTR) is a chloride ion channel important in creating sweat, digestive
Digestion
Digestion is the mechanical and chemical breakdown of food into smaller components that are more easily absorbed into a blood stream, for instance. Digestion is a form of catabolism: a breakdown of large food molecules to smaller ones....
juices and mucus
Mucus
In vertebrates, mucus is a slippery secretion produced by, and covering, mucous membranes. Mucous fluid is typically produced from mucous cells found in mucous glands. Mucous cells secrete products that are rich in glycoproteins and water. Mucous fluid may also originate from mixed glands, which...
. This protein possesses two ATP-hydrolyzing
ATP hydrolysis
ATP hydrolysis is the reaction by which chemical energy that has been stored and transported in the high-energy phosphoanhydridic bonds in ATP is released, for example in the muscles, to produce work. The product is ADP and an inorganic phosphate, orthophosphate...
domains, which allows the protein to use energy
Energy
In physics, energy is an indirectly observed quantity. It is often understood as the ability a physical system has to do work on other physical systems...
in the form of ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
. It also contains two domains comprising 6 alpha helices
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
apiece, which allow the protein to cross the cell membrane. A regulatory binding site
Binding site
In biochemistry, a binding site is a region on a protein, DNA, or RNA to which specific other molecules and ions—in this context collectively called ligands—form a chemical bond...
on the protein allows activation by phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
, mainly by cAMP-dependent protein kinase
CAMP-dependent protein kinase
In cell biology, Protein kinase A refers to a family of enzymes whose activity is dependent on cellular levels of cyclic AMP . PKA is also known as cAMP-dependent protein kinase...
. The carboxyl terminal
C-terminal end
The C-terminus is the end of an amino acid chain , terminated by a free carboxyl group . When the protein is translated from messenger RNA, it is created from N-terminus to C-terminus...
of the protein is anchored to the cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
by a PDZ domain interaction.
In addition, there is increasing evidence that genetic modifiers besides CFTR modulate the frequency and severity of the disease. One example is mannan-binding lectin
Mannan-binding lectin
Mannose-binding lectin , also named mannose- or mannan-binding protein , is an important factor in innate immunity.-Function:MBL belongs to the class of collectins in the C-type lectin superfamily, whose function appears to be pattern recognition in the first line of defense in the pre-immune...
, which is involved in innate immunity by facilitating phagocytosis of microorganisms. Polymorphisms
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
in one or both mannan-binding lectin alleles that result in lower circulating levels of the protein are associated with a threefold higher risk of end-stage lung disease, as well as an increased burden of chronic bacterial infections.
Pathophysiology
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
normally and is degraded by the cell. Other mutations result in proteins that are too short (truncated) because production
Translation (genetics)
In molecular biology and genetics, translation is the third stage of protein biosynthesis . In translation, messenger RNA produced by transcription is decoded by the ribosome to produce a specific amino acid chain, or polypeptide, that will later fold into an active protein...
is ended prematurely. Other mutations produce proteins that do not use energy normally, do not allow chloride
Chloride
The chloride ion is formed when the element chlorine, a halogen, picks up one electron to form an anion Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. The chloride ion, and its salts such as sodium chloride, are very soluble in water...
, iodide
Iodide
An iodide ion is the ion I−. Compounds with iodine in formal oxidation state −1 are called iodides. This page is for the iodide ion and its salts. For information on organoiodides, see organohalides. In everyday life, iodide is most commonly encountered as a component of iodized salt,...
and thiocyanate
Thiocyanate
Thiocyanate is the anion [SCN]−. It is the conjugate base of thiocyanic acid. Common derivatives include the colourless salts potassium thiocyanate and sodium thiocyanate. Organic compounds containing the functional group SCN are also called thiocyanates...
to cross the membrane appropriately, or are degraded at a faster rate than normal. Mutations may also lead to fewer copies of the CFTR protein being produced.
The protein created by this gene is anchored to the outer membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
of cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
s in the sweat gland
Sweat gland
Sweat glands, or sudoriferous glands, are small tubular structures of the skin that produce sweat. There are two kinds of sweat glands:...
s, lungs, pancreas, and other affected organ
Organ (anatomy)
In biology, an organ is a collection of tissues joined in structural unit to serve a common function. Usually there is a main tissue and sporadic tissues . The main tissue is the one that is unique for the specific organ. For example, main tissue in the heart is the myocardium, while sporadic are...
s. The protein spans this membrane and acts as a channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
connecting the inner part of the cell (cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
) to the surrounding fluid
Extracellular fluid
Extracellular fluid usually denotes all body fluid outside of cells. The remainder is called intracellular fluid.In some animals, including mammals, the extracellular fluid can be divided into two major subcompartments, interstitial fluid and blood plasma...
. This channel is primarily responsible for controlling the movement of halogens from inside to outside of the cell; however, in the sweat ducts it facilitates the movement of chloride from the sweat into the cytoplasm. When the CFTR protein does not work, chloride and thiocyanate are trapped inside the cells in the airway and outside in the skin. Then hypothiocyanite
Hypothiocyanite
Hypothiocyanite is the anion [OSCN]- and the conjugate base of hypothiocyanous acid. It is an organic compound part of the thiocyanates as it contains the functional group SCN. It is formed when an oxygen is singly bonded to the thiocyanate group...
, OSCN, cannot be produced by immune defense system. Because chloride is negatively charged
Electric charge
Electric charge is a physical property of matter that causes it to experience a force when near other electrically charged matter. Electric charge comes in two types, called positive and negative. Two positively charged substances, or objects, experience a mutual repulsive force, as do two...
, this creates a difference in the electrical potential inside and outside the cell causing cations to cross into the cell. Sodium is the most common cation in the extracellular space and the combination of sodium and chloride creates the salt
Sodium chloride
Sodium chloride, also known as salt, common salt, table salt or halite, is an inorganic compound with the formula NaCl. Sodium chloride is the salt most responsible for the salinity of the ocean and of the extracellular fluid of many multicellular organisms...
, which is lost in high amounts in the sweat of individuals with CF. This lost salt forms the basis for the sweat test.
Most of the damage in CF is due to blockage of the narrow passages of affected organs with thickened secretions. These blockages lead to remodeling and infection in the lung, damage by accumulated digestive enzymes in the pancreas, blockage of the intestines by thick faeces, etc. There are several theories on how the defects in the protein and cellular function cause the clinical effects. One theory is that the lack of halogen and pseudohalogen (mainly, chloride, iodide and thiocyanate) exiting through the CFTR protein leads to the accumulation of more viscous, nutrient-rich mucus in the lungs that allows bacteria to hide from the body's immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. Another theory is that the CFTR protein failure leads to a paradoxical increase in sodium and chloride uptake, which, by leading to increased water reabsorption, creates dehydrated and thick mucus. Yet another theory is that abnormal chloride movement out of the cell leads to dehydration of mucus, pancreatic secretions, biliary secretions, etc.
Chronic infections
The lungs of individuals with cystic fibrosis are colonized and infected by bacteria from an early age. These bacteria, which often spread among individuals with CF, thrive in the altered mucus, which collects in the small airways of the lungs. This mucus leads to the formation of bacterial microenvironments known as biofilms that are difficult for immune cells and antibiotics to penetrate. Viscous secretions and persistent respiratory infections repeatedly damage the lung by gradually remodeling the airways, which makes infection even more difficult to eradicate.Over time, both the types of bacteria and their individual characteristics change in individuals with CF. In the initial stage, common bacteria such as Staphylococcus aureus
Staphylococcus aureus
Staphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...
and Hemophilus influenzae colonize and infect the lungs. Eventually, Pseudomonas aeruginosa
Pseudomonas aeruginosa
Pseudomonas aeruginosa is a common bacterium that can cause disease in animals, including humans. It is found in soil, water, skin flora, and most man-made environments throughout the world. It thrives not only in normal atmospheres, but also in hypoxic atmospheres, and has, thus, colonized many...
(and sometimes Burkholderia cepacia
Burkholderia cepacia complex
Burkholderia cepacia complex , or simply Burkholderia cepacia is a group of catalase-producing, non-lactose-fermenting Gram-negative bacteria composed of at least seventeen different species, including B. cepacia, B. multivorans, B. cenocepacia, B. vietnamiensis, B. stabilis, B. ambifaria, B....
) dominates. By 18 years of age, 80% of patients with classic CF harbor P. aeruginosa, and 3.5% harbor B. cepacia. Once within the lungs, these bacteria adapt to the environment and develop resistance
Antibiotic resistance
Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a...
to commonly used antibiotics. Pseudomonas can develop special characteristics that allow the formation of large colonies, known as "mucoid" Pseudomonas, which are rarely seen in people that do not have CF.
One way infection spreads is by passing between different individuals with CF. In the past, people with CF often participated in summer "CF Camps" and other recreational gatherings. Hospitals grouped patients with CF into common areas and routine equipment (such as nebulizer
Nebulizer
In medicine, a nebulizer is a device used to administer medication in the form of a mist inhaled into the lungs....
s) was not sterilized between individual patients. This led to transmission of more dangerous strains of bacteria among groups of patients. As a result, individuals with CF are routinely isolated from one another in the healthcare setting and healthcare providers are encouraged to wear gowns and gloves when examining patients with CF to limit the spread of virulent bacterial strains.
CF patients may also have their airways chronically colonized by filamentous fungi (such as Aspergillus fumigatus, Scedosporium apiospermum, Aspergillus terreus) and/or yeasts (such as Candida albicans); other filamentous fungi less commonly isolated include Aspergillus flavus and Aspergillus nidulans (occur transiently in CF respiratory secretions), and Exophiala dermatitidis and Scedosporium prolificans (chronic airway-colonizers); some filamentous fungi like Penicillium emersonii and Acrophialophora fusispora are encountered in patients almost exclusively in the context of CF. Defective mucociliary clearance characterizing CF is associated with local immunological disorders. In addition, the prolonged therapy with antibiotics and the use of corticosteroid treatments may also facilitate fungal growth. Although the clinical relevance of the fungal airway colonization is still a matter of debate, filamentous fungi may contribute to the local inflammatory response, and therefore to the progressive deterioration of the lung function, as often happens with allergic broncho-pulmonary aspergillosis (ABPA) - the most common fungal disease in the context of CF, involving a Th2-driven immune response to Aspergillus.
Diagnosis and monitoring
Newborn screening
Newborn screening is the process by which infants are screened shortly after birth for a list of disorders that are treatable, but difficult or impossible to detect clinically. Screening programs are often run by state or national governing bodies with the goal of screening all infants born in the...
, sweat test
Sweat test
The sweat test measures the concentration of chloride that is excreted in sweat. It is used to screen for cystic fibrosis .-Background:Cystic fibrosis is caused by defects in a protein found in many tissues, including the airways and the sweat glands. As a result, these tissues do not work properly...
ing, and genetic testing
Genetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
. As of 2006 in the United States, 10 percent of cases are diagnosed shortly after birth as part of newborn screening programs. The newborn screen initially measures for raised blood concentration of immunoreactive trypsinogen
Immunoreactive trypsinogen
Measurement of Immunoreactive trypsinogen in blood of newborn babies is an assay in rapidly increasing use as a screening test for cystic fibrosis.-External links:**...
. Infants with an abnormal newborn screen need a sweat test to confirm the CF diagnosis. In many cases, a parent makes the diagnosis because the infant tastes salty. Trypsinogen
Trypsinogen
Trypsinogen is the precursor form or zymogen of the pancreatic enzyme trypsin. It is found in pancreatic juice, along with amylase, lipase, and chymotrypsinogen. It is activated by enteropeptidase, which is found in the intestinal mucosa, to form trypsin. Once activated, the trypsin can activate...
levels can be increased in individuals who have a single mutated copy of the CFTR gene (carriers) or, in rare instances, in individuals with two normal copies of the CFTR gene. Due to these false positives, CF screening in newborns can be controversial. Most states and countries do not screen for CF routinely at birth. Therefore, most individuals are diagnosed after symptoms (e.g. sinopulmonary disease and GI manifestations) prompt an evaluation for cystic fibrosis. The most commonly used form of testing is the sweat test. Sweat-testing involves application of a medication that stimulates sweating (pilocarpine
Pilocarpine
Pilocarpine is a parasympathomimetic alkaloid obtained from the leaves of tropical American shrubs from the genus Pilocarpus. It is a non-selective muscarinic receptor agonist in the parasympathetic nervous system, which acts therapeutically at the muscarinic acetylcholine receptor M3 due to its...
). To deliver the medication through the skin, iontophoresis
Iontophoresis
Iontophoresis is a technique using a small electric charge to deliver a medicine or other chemical through the skin. It is basically an injection without the needle...
is used to, whereby one electrode
Electrode
An electrode is an electrical conductor used to make contact with a nonmetallic part of a circuit...
is placed onto the applied medication and an electric current
Electric current
Electric current is a flow of electric charge through a medium.This charge is typically carried by moving electrons in a conductor such as wire...
is passed to a separate electrode on the skin. The resultant sweat is then collected on filter paper or in a capillary tube and analyzed for abnormal amounts of sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
and chloride
Chloride
The chloride ion is formed when the element chlorine, a halogen, picks up one electron to form an anion Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. The chloride ion, and its salts such as sodium chloride, are very soluble in water...
. People with CF have increased amounts of sodium and chloride in their sweat. In opposite, people with CF have less thiocyanate and hypothiocyanite
Hypothiocyanite
Hypothiocyanite is the anion [OSCN]- and the conjugate base of hypothiocyanous acid. It is an organic compound part of the thiocyanates as it contains the functional group SCN. It is formed when an oxygen is singly bonded to the thiocyanate group...
in their saliva (Minarowski et al.) and mucus (Banfi et al.). CF can also be diagnosed by identification of mutations in the CFTR gene.
People with CF may be listed in a disease registry
Disease registry
Disease or patient registries are collections of secondary data related to patients with a specific diagnosis, condition, or procedure, and they play an important role in post marketing surveillance of pharmaceuticals...
that allows researchers and doctors to track health results and identify candidates for clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s.
Prenatal
Couples who are pregnant or planning a pregnancy can have themselves tested for the CFTR gene mutations to determine the risk that their child will be born with cystic fibrosis. Testing is typically performed first on one or both parents and, if the risk of CF is high, testing on the fetusFetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
is performed. The American College of Obstetricians and Gynecologists (ACOG) recommends testing for couples who have a personal or close family history of CF, and they recommend that carrier testing be offered to all Caucasian couples and be made available to couples of other ethnic backgrounds.
Because development of CF in the fetus requires each parent to pass on a mutated copy of the CFTR gene and because CF testing is expensive, testing is often performed initially on one parent. If testing shows that parent is a CFTR gene mutation carrier, the other parent is tested to calculate the risk that their children will have CF. CF can result from more than a thousand different mutations, and as of 2006 it is not possible to test for each one. Testing analyzes the blood for the most common mutations such as ΔF508—most commercially available tests look for 32 or fewer different mutations. If a family has a known uncommon mutation, specific screening for that mutation can be performed. Because not all known mutations are found on current tests, a negative screen does not guarantee that a child will not have CF.
During pregnancy, testing can be performed on the placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
(chorionic villus sampling
Chorionic villus sampling
Chorionic villus sampling , sometimes misspelled "chorionic villous sampling", is a form of prenatal diagnosis to determine chromosomal or genetic disorders in the fetus. It entails sampling of the chorionic villus and testing it...
) or the fluid around the fetus (amniocentesis
Amniocentesis
Amniocentesis is a medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections, in which a small amount of amniotic fluid, which contains fetal tissues, is sampled from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined for...
). However, chorionic villus sampling
Chorionic villus sampling
Chorionic villus sampling , sometimes misspelled "chorionic villous sampling", is a form of prenatal diagnosis to determine chromosomal or genetic disorders in the fetus. It entails sampling of the chorionic villus and testing it...
has a risk of fetal death of 1 in 100 and amniocentesis of 1 in 200; a recent study has indicated this may be much lower, approximately 1 in 1,600.
Economically, for carrier couples of cystic fibrosis, when comparing preimplantation genetic diagnosis (PGD) with natural conception (NC) followed by prenatal testing and abortion of affected pregnancies, PGD provides net economic benefits up to a maternal age of approximately 40 years, after which NC, prenatal testing and abortion has higher economic benefit.
Management
While there are no cures for cystic fibrosis there are several treatment methods. The management of cystic fibrosis has improved significantly over the past 70 years. While infants born with cystic fibrosis 70 years ago would have been unlikely to live beyond their first year, infants today are likely to live well into adulthood. Recent advances in the treatment of cystic fibrosis have meant that an individual with cystic fibrosis can live a fuller life less encumbered by their condition. The cornerstones of management are proactive treatment of airway infectionRespiratory tract infection
Respiratory tract infection refers to any of a number of infectious diseases involving the respiratory tract. An infection of this type is normally further classified as an upper respiratory tract infection or a lower respiratory tract infection...
, and encouragement of good nutrition and an active lifestyle. Management of cystic fibrosis continues throughout a patient's life, and is aimed at maximizing organ function, and therefore quality of life. At best, current treatments delay the decline in organ function. Because of the wide variation in disease symptoms treatment typically occurs at specialist multidisciplinary centers, and is tailored to the individual. Targets for therapy are the lungs, gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
(including pancreatic enzyme supplements), the reproductive organs (including assisted reproductive technology
Assisted reproductive technology
Assisted reproductive technology is a general term referring to methods used to achieve pregnancy by artificial or partially artificial means. It is reproductive technology used primarily in infertility treatments. Some forms of ART are also used in fertile couples for genetic reasons...
(ART)) and psychological support.
The most consistent aspect of therapy in cystic fibrosis is limiting and treating the lung damage caused by thick mucus and infection, with the goal of maintaining quality of life
Quality of life
The term quality of life is used to evaluate the general well-being of individuals and societies. The term is used in a wide range of contexts, including the fields of international development, healthcare, and politics. Quality of life should not be confused with the concept of standard of...
. Intravenous
Intravenous therapy
Intravenous therapy or IV therapy is the infusion of liquid substances directly into a vein. The word intravenous simply means "within a vein". Therapies administered intravenously are often called specialty pharmaceuticals...
, inhaled
Inhalation
Inhalation is the movement of air from the external environment, through the air ways, and into the alveoli....
, and oral antibiotics are used to treat chronic and acute infections. Mechanical devices and inhalation medications are used to alter and clear the thickened mucus. These therapies, while effective, can be extremely time-consuming for the patient. One of the most important battles that CF patients face is finding the time to comply with prescribed treatments while balancing a normal life.
In addition, therapies such as transplantation
Organ transplant
Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...
and gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
aim to cure some of the effects of cystic fibrosis. Gene therapy aims to introduce normal CFTR to airway. Theoretically this process should be simple as the airway is easily accessible and there is only a single gene defect to correct. There are two CFTR gene introduction mechanisms involved, the first use of a viral vector (adenovirus, adeno-associated virus or retro virus) and secondly the use of liposome
Liposome
Liposomes are artificially prepared vesicles made of lipid bilayer. Liposomes can be filled with drugs, and used to deliver drugs for cancer and other diseases. Liposomes are composite structures made of phospholipids and may contain small amounts of other molecules...
. However there are some problems associated with these methods involving efficiency (liposomes insufficient protein) and delivery (virus provokes an immune response).
Antibiotics
Many CF patients are on one or more antibiotics at all times, even when healthy, to prophylactically suppress infection. Antibiotics are absolutely necessary whenever pneumonia is suspected or there has been a noticeable decline in lung function, and are usually chosen based on the results of a sputum analysis and the patient's past response. This prolonged therapy often necessitates hospitalization and insertion of a more permanent IV such as a peripherally inserted central catheterPeripherally inserted central catheter
A peripherally inserted central catheter is a form of intravenous access that can be used for a prolonged period of time...
(PICC line) or Port-a-Cath. Inhaled therapy with antibiotics such as tobramycin, colistin
Colistin
Colistin is a polymyxin antibiotic produced by certain strains of Bacillus polymyxa var. colistinus. Colistin is a mixture of cyclic polypeptides colistin A and B. Colistin is effective against most Gram-negative bacilli and is used as a lingerdoodle. It is one of the last-resort antibiotics for...
, and aztreonam
Aztreonam
Aztreonam is a synthetic monocyclic beta-lactam antibiotic , with the nucleus based on a simpler monobactam isolated from Chromobacterium violaceum. It was approved by the U.S. Food and Drug Administration in 1986...
is often given for months at a time to improve lung function by impeding the growth of colonized bacteria. Oral antibiotics such as ciprofloxacin or azithromycin
Azithromycin
Azithromycin is an azalide, a subclass of macrolide antibiotics. Azithromycin is one of the world's best-selling antibiotics...
are given to help prevent infection or to control ongoing infection. The aminoglycoside
Aminoglycoside
An aminoglycoside is a molecule or a portion of a molecule composed of amino-modifiedsugars.Several aminoglycosides function as antibiotics that are effective against certain types of bacteria...
antibiotics (e.g. tobramycin) used can cause hearing loss
Ototoxicity
Ototoxicity is damage to the ear , specifically the cochlea or auditory nerve and sometimes the vestibular system, by a toxin. It is commonly medication-induced; ototoxic drugs include antibiotics such as the aminoglycoside gentamicin, loop diuretics such as furosemide, and platinum-based...
, damage to the balance system
Vestibular system
The vestibular system, which contributes to balance in most mammals and to the sense of spatial orientation, is the sensory system that provides the leading contribution about movement and sense of balance. Together with the cochlea, a part of the auditory system, it constitutes the labyrinth of...
in the inner ear
Inner ear
The inner ear is the innermost part of the vertebrate ear. In mammals, it consists of the bony labyrinth, a hollow cavity in the temporal bone of the skull with a system of passages comprising two main functional parts:...
or kidney problems
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
with long-term use. To prevent these side-effect
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s, the amount of antibiotics in the blood are routinely measured and adjusted accordingly.
Other treatments for lung disease
Several mechanical techniques are used to dislodge sputum and encourage its expectoration. In the hospital setting, chest physiotherapy (CPT) is utilized; a respiratory therapist percusses an individual's chest with his or her hands several times a day, to loosen up secretions. Devices that recreate this percussive therapy include the ThAIRapy VestThAIRapy Vest
The "Vest Airway Clearance System", a form of chest wall oscillation, is a device and system for clearing excess mucus from lung airways...
and the intrapulmonary percussive ventilator
Intrapulmonary percussive ventilator
Intrapulmonary percussive ventilators are machines which deliver short bursts of air through a mouthpiece to help individuals with lung disease clear sputum. The air is delivered at a rate of 150 times a minute and may be used with nebulized medication...
(IPV). Newer methods such as Biphasic Cuirass Ventilation
Biphasic Cuirass Ventilation
Biphasic cuirass ventilation is a method of ventilation which requires the patient to wear an upper body shell or cuirass, so named after the body armor worn by medieval soldiers. The ventilation is biphasic because the cuirass is attached to a pump which actively controls both the inspiratory and...
, and associated clearance mode available in such devices, integrate a cough assistance phase, as well as a vibration phase for dislodging secretions. These are portable and adapted for home use.
Aerosolized medications that help loosen secretions include dornase alfa
Dornase alfa
Dornase alfa is a highly purified solution of recombinant human deoxyribonuclease I , an enzyme which selectively cleaves DNA. Dornase alfa hydrolyzes the DNA present in sputum/mucus of cystic fibrosis patients and reduces viscosity in the lungs, promoting improved clearance of secretions...
and hypertonic saline
Saline (medicine)
In medicine, saline is a general term referring to a sterile solution of sodium chloride in water but is only sterile when it is to be placed intravenously, otherwise, a saline solution is a salt water solution...
. Dornase is a recombinant
Recombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
human deoxyribonuclease
Deoxyribonuclease
A deoxyribonuclease is any enzyme that catalyzes the hydrolytic cleavage of phosphodiester linkages in the DNA backbone. Thus, deoxyribonucleases are one type of nuclease...
, which breaks down DNA in the sputum
Sputum
Sputum is mucus that is coughed up from the lower airways. It is usually used for microbiological investigations of respiratory infections....
, thus decreasing its viscosity
Viscosity
Viscosity is a measure of the resistance of a fluid which is being deformed by either shear or tensile stress. In everyday terms , viscosity is "thickness" or "internal friction". Thus, water is "thin", having a lower viscosity, while honey is "thick", having a higher viscosity...
. Denufosol
Denufosol
Denufosol is an inhalable drug for the treatment of cystic fibrosis, being developed by Inspire Pharmaceuticals and sponsored by the Cystic Fibrosis Foundation...
is an investigational drug that opens an alternative chloride channel, helping to liquefy mucus.
As lung disease worsens, mechanical breathing support may become necessary. Individuals with CF may need to wear special masks at night that help push air into their lungs. These machines, known as bilevel positive airway pressure
Bilevel positive airway pressure
Bilevel positive airway pressure is a continuous positive airway pressure mode used during noninvasive positive pressure ventilation. It delivers a preset inspiratory positive airway pressure and expiratory positive airway pressure . BPAP can be described as a Continuous Positive Airway...
(BiPAP) ventilators, help prevent low blood oxygen levels during sleep. BiPAP may also be used during physical therapy to improve sputum clearance. During severe illness, a tube
Intubation
Tracheal intubation, usually simply referred to as intubation, is the placement of a flexible plastic or rubber tube into the trachea to maintain an open airway or to serve as a conduit through which to administer certain drugs...
may be placed in the throat (a procedure known as a tracheostomy) to enable breathing supported by a ventilator.
For children living with CF, preliminary studies show pediatric massage therapy may improve patients and their families quality of life, though more rigorous studies must be done.
Transplantation
Lung transplantationLung transplantation
Lung transplantation, or pulmonary transplantation is a surgical procedure in which a patient's diseased lungs are partially or totally replaced by lungs which come from a donor...
often becomes necessary for individuals with cystic fibrosis as lung function and exercise tolerance
Exercise intolerance
Exercise intolerance is a condition where the patient is unable to do physical exercise at the level or for the duration that would be expected of someone in his or her general physical condition, or experiences unusually severe post-exercise pain, fatigue, or other negative effects...
declines. Although single lung transplantation is possible in other diseases, individuals with CF must have both lungs replaced because the remaining lung might contain bacteria that could infect the transplanted lung. A pancreatic or liver transplant may be performed at the same time in order to alleviate liver disease and/or diabetes. Lung transplantation is considered when lung function declines to the point where assistance from mechanical devices is required or patient survival is threatened.
Treatment of other aspects
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
and coronary heart disease
Coronary heart disease
Coronary artery disease is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium with oxygen and nutrients. It is sometimes also called coronary heart disease...
in adults with cystic fibrosis has been conducted. This is likely due to the fact that the vast majority of people with cystic fibrosis do not live long enough to develop clinically significant atherosclerosis or coronary heart disease.
Diabetes
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
is the most common non-pulmonary complication of CF. It mixes features of type 1
Diabetes mellitus type 1
Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...
and type 2
Diabetes mellitus type 2
Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...
diabetes, and is recognized as a distinct entity, cystic fibrosis-related diabetes (CFRD). While oral anti-diabetic drug
Anti-diabetic drug
Anti-diabetic medications treat diabetes mellitus by lowering glucose levels in the blood. With the exceptions of insulin, exenatide, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents...
s are sometimes used, the only recommended treatment is the use of insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
injections or an insulin pump
Insulin pump
The insulin pump is a medical device used for the administration of insulin in the treatment of diabetes mellitus, also known as continuous subcutaneous insulin infusion therapy.The device includes:...
, and, unlike in type 1 and 2 diabetes, dietary restrictions are not recommended.
Development of osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
can be prevented by increased intake of vitamin D and calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
, and can be treated by bisphosphonate
Bisphosphonate
Bisphosphonates are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases...
s, although adverse effects
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
can be an issue. Poor growth may be avoided by insertion of a feeding tube
Feeding tube
A feeding tube is a medical device used to provide nutrition to patients who cannot obtain nutrition by swallowing. The state of being fed by a feeding tube is called gavage, enteral feeding or tube feeding...
for increasing calorie
Calorie
The calorie is a pre-SI metric unit of energy. It was first defined by Nicolas Clément in 1824 as a unit of heat, entering French and English dictionaries between 1841 and 1867. In most fields its use is archaic, having been replaced by the SI unit of energy, the joule...
s through supplemental feeds or by administration of injected growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
.
Sinus infections are treated by prolonged courses of antibiotics. The development of nasal polyps or other chronic changes within the nasal passages may severely limit airflow through the nose, and over time reduce the patient's sense of smell. Sinus surgery is often used to alleviate nasal obstruction and to limit further infections. Nasal steroids such as fluticasone
Fluticasone
Fluticasone is a synthetic glucocorticoid.Both the furoate and propionate forms are used as topical anti-inflammatories:*Fluticasone propionate*Fluticasone furoateTreatment of asthma - Fluticasone in combination with Salmeterol - "[]" - aerosol....
are used to decrease nasal inflammation. Female infertility may be overcome by assisted reproduction
In vitro fertilisation
In vitro fertilisation is a process by which egg cells are fertilised by sperm outside the body: in vitro. IVF is a major treatment in infertility when other methods of assisted reproductive technology have failed...
technology, particularly embryo transfer
Embryo transfer
Embryo transfer refers to a step in the process of assisted reproduction in which embryos are placed into the uterus of a female with the intent to establish a pregnancy...
techniques. Male infertility caused by absence of the vas deferens
Vas deferens
The vas deferens , also called ductus deferens, , is part of the male anatomy of many vertebrates; they transport sperm from the epididymis in anticipation of ejaculation....
may be overcome with testicular sperm extraction
Testicular sperm extraction
Testicular sperm extraction is the process of removing a small portion of tissue from the testicle under local anesthesia and extracting the few viable sperm cells present in that tissue for the purpose of intracytoplasmic sperm injection...
(TEST), collecting sperm cells directly from the testicles. If the collected sample contains too few sperm cells to likely have a spontaneous fertilization, intracytoplasmic sperm injection
Intracytoplasmic sperm injection
Intracytoplasmic sperm injection is an in vitro fertilization procedure in which a single sperm is injected directly into an egg.-Indications:...
can be performed. Third party reproduction is also a possibility for women with CF.
Quality of life
Chronic illnesses are very difficult to manage. Cystic fibrosis (CF) is a chronic illness that affects the “digestive and respiratory tracts resulting in generalized malnutrition and chronic respiratory infections”. The thick secretions clog the airways in the lungs, which often cause inflammation and severe lung infections. Therefore, mucus makes it challenging to breathe. If it is compromised, it affects the quality of life of someone with CF, and their ability to complete such tasks as everyday chores.It is important for CF patients to understand the detrimental relationship that chronic illnesses place on the quality of life. According to Schmitz and Goldbeck (2006), the fact that Cystic Fibrosis significantly increases emotional stress on both the individual and the family, “and the necessary time-consuming daily treatment routine may have further negative effects on quality of life (QOL)”. However, Havermans and colleagues (2006) have shown that young outpatients with CF that have participated in the CFQ-R (Cystic Fibrosis Questionnaire-Revised) “rated some QOL domains higher than did their parents”. Consequently, outpatients with CF have a more positive outlook for themselves.
Furthermore, there are many ways to improve the QOL in CF patients. Exercise is promoted to increase lung function. The fact of integrating an exercise regime into the CF patient’s daily routine can significantly improve the quality of life. There is no definitive cure for Cystic Fibrosis. However, there are diverse medications used such as, mucolytics, bronchodilators, steroids and antibiotics that have the purpose of loosening mucus, expanding airways, decreasing inflammation and fighting lung infections.
Prognosis
The prognosis for cystic fibrosis in the U.S. has improved due to earlier diagnosis through screening, better treatment and access to health care. Patient compliance is major factor -- patients that are more aggressive in following treatment recommendations live longer.In 1959, the median age of survival of children with cystic fibrosis in the U.S. was six months. Now, it is 37.4 years. In Canada, median survival increased from 24 years in 1982 to 47.7 in 2007.
The U.S. Cystic Fibrosis Foundation reported that in 2008, 92% had graduated from high school
High school
High school is a term used in parts of the English speaking world to describe institutions which provide all or part of secondary education. The term is often incorporated into the name of such institutions....
and 66% had at least some college education. 15% of adults were disabled and 7% were unemployed. 54.8% of adults were single and 40.1% were married or living with a partner. In 2008, 240 American women with CF were pregnant.
Epidemiology
| Mutation | Frequency worldwide |
|---|---|
| ΔF508 | 66%-70% |
| G542X | 2.4% |
| G551D | 1.6% |
| N1303K | 1.3% |
| W1282X | 1.2% |
| All others | 27.5% |
Cystic fibrosis is the most common life-limiting autosomal recessive disease among people of Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
an heritage. In the United States, approximately 30,000 individuals have CF; most are diagnosed by six months of age. Canada
Canada
Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...
has approximately 3,000 citizens with CF. Approximately 1 in 25 people of European descent, and one in 30 of Caucasian Americans, is a carrier of a cystic fibrosis mutation. Although CF is less common in these groups, approximately 1 in 46 Hispanic
Hispanic
Hispanic is a term that originally denoted a relationship to Hispania, which is to say the Iberian Peninsula: Andorra, Gibraltar, Portugal and Spain. During the Modern Era, Hispanic sometimes takes on a more limited meaning, particularly in the United States, where the term means a person of ...
s, 1 in 65 Africans and 1 in 90 Asians
Asian people
Asian people or Asiatic people is a term with multiple meanings that refers to people who descend from a portion of Asia's population.- Central Asia :...
carry at least one abnormal CFTR gene.
Although technically a rare disease
Rare disease
A rare disease, also referred to as an orphan disease, is any disease that affects a small percentage of the population.Most rare diseases are genetic, and thus are present throughout the person's entire life, even if symptoms do not immediately appear...
, cystic fibrosis is ranked as one of the most widespread life-shortening genetic diseases. It is most common among nations in the Western world. An exception is Finland
Finland
Finland , officially the Republic of Finland, is a Nordic country situated in the Fennoscandian region of Northern Europe. It is bordered by Sweden in the west, Norway in the north and Russia in the east, while Estonia lies to its south across the Gulf of Finland.Around 5.4 million people reside...
, where only one in 80 people carry a CF mutation. In the United States, 1 in 4,000 children are born with CF. In 1997, about 1 in 3,300 caucasian children in the United States was born with cystic fibrosis. In contrast, only 1 in 15,000 African American children suffered from cystic fibrosis, and in Asian Americans the rate was even lower at 1 in 32,000.
Cystic fibrosis is diagnosed in males and females equally. For reasons that remain unclear, data has shown that males tend to have a longer life expectancy
Life expectancy
Life expectancy is the expected number of years of life remaining at a given age. It is denoted by ex, which means the average number of subsequent years of life for someone now aged x, according to a particular mortality experience...
than females, however recent studies suggest this gender gap may no longer exist perhaps due to improvements in health care facilities, while a recent study from Ireland identified a link between the female hormone oestrogen and worse outcomes in CF.
The distribution of CF alleles varies among populations. The frequency of ΔF508 carriers has been estimated at 1:200 in northern Sweden, 1:143 in Lithuanians, and 1:38 in Denmark. No ΔF508 carriers were found among 171 Finns and 151 Saami people. ΔF508 does occur in Finland, but it is a minority allele there. Cystic fibrosis is known to occur in only 20 families (pedigrees) in Finland.
Theories about prevalence
The ΔF508 mutation is estimated to be up to 52,000 years old. Numerous hypotheses have been advanced as to why such a lethal mutation has persisted and spread in the human population. Other common autosomal recessive diseases such as sickle-cell anemia have been found to protect carriers from other diseases, a concept known as heterozygote advantageHeterozygote advantage
A heterozygote advantage describes the case in which the heterozygote genotype has a higher relative fitness than either the homozygote dominant or homozygote recessive genotype. The specific case of heterozygote advantage is due to a single locus known as overdominance...
. Resistance to the following have all been proposed as possible sources of heterozygote advantage:
- Cholera: With the discovery that choleraCholeraCholera is an infection of the small intestine that is caused by the bacterium Vibrio cholerae. The main symptoms are profuse watery diarrhea and vomiting. Transmission occurs primarily by drinking or eating water or food that has been contaminated by the diarrhea of an infected person or the feces...
toxinToxinA toxin is a poisonous substance produced within living cells or organisms; man-made substances created by artificial processes are thus excluded...
requires normal host CFTR proteins to function properly, it was hypothesized that carriers of mutant CFTR genes benefited from resistance to cholera and other causes of diarrhea. Further studies have not confirmed this hypothesis. - Typhoid: Normal CFTR proteins are also essential for the entry of Salmonella typhi into cells, suggesting that carriers of mutant CFTR genes might be resistant to typhoid feverTyphoid feverTyphoid fever, also known as Typhoid, is a common worldwide bacterial disease, transmitted by the ingestion of food or water contaminated with the feces of an infected person, which contain the bacterium Salmonella enterica, serovar Typhi...
. 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 endemicEndemic (epidemiology)In epidemiology, an infection is said to be endemic in a population when that infection is maintained in the population without the need for external inputs. For example, chickenpox is endemic in the UK, but malaria is not...
, is not immediately explicable. - Diarrhea: It has also been hypothesized that the prevalence of CF in Europe might be connected with the development of cattle domestication. In this hypothesis, carriers of a single mutant CFTR chromosome had some protection from diarrhea caused by lactose intoleranceLactose intoleranceLactose intolerance, also called lactase deficiency or hypolactasia, is the inability to digest and metabolize lactose, a sugar found in milk...
, prior to the appearance of the mutations that created lactose tolerance. - Tuberculosis: Another possible explanation is that carriers of the gene could have some resistance to TB.
History
In the 19th century, Carl von Rokitansky described a case of fetal death with meconium peritonitis
Meconium peritonitis
Meconium peritonitis refers to rupture of the bowel prior to birth, resulting in fetal stool escaping into the surrounding space leading to inflammation...
, a complication of meconium ileus associated with cystic fibrosis. Meconium ileus was first described in 1905 by Karl Landsteiner
Karl Landsteiner
Karl Landsteiner , was an Austrian-born American biologist and physician of Jewish origin. He is noted for having first distinguished the main blood groups in 1900, having developed the modern system of classification of blood groups from his identification of the presence of agglutinins in the...
. In 1936, Guido Fanconi
Guido Fanconi
Guido Fanconi was a Swiss pediatrician. He was born in Poschiavo, Canton Grisons in the Italian-speaking region of Switzerland. Fanconi is regarded as one of the founders of modern pediatrics....
published a paper describing a connection between celiac disease, cystic fibrosis of the pancreas, and bronchiectasis
Bronchiectasis
Bronchiectasis is a disease state defined by localized, irreversible dilation of part of the bronchial tree caused by destruction of the muscle and elastic tissue. It is classified as an obstructive lung disease, along with emphysema, bronchitis, asthma, and cystic fibrosis...
.
In 1938 Dorothy Hansine Andersen
Dorothy Hansine Andersen
Dorothy Hansine Andersen was the American physician who was "the first person to identify cystic fibrosis and the first American physician to describe the disease"...
published an article, "Cystic Fibrosis of the Pancreas and Its Relation to Celiac Disease: a Clinical and Pathological Study," in the American Journal of Diseases of Children. She was the first to describe the characteristic cystic fibrosis of the pancreas and to correlate it with the lung and intestinal disease prominent in CF. She also first hypothesized that CF was a recessive disease and first used pancreatic enzyme replacement to treat affected children. In 1952 Paul di Sant' Agnese discovered abnormalities in sweat
SWEAT
SWEAT is an OLN/TSN show hosted by Julie Zwillich that aired in 2003-2004.Each of the 13 half-hour episodes of SWEAT features a different outdoor sport: kayaking, mountain biking, ice hockey, beach volleyball, soccer, windsurfing, rowing, Ultimate, triathlon, wakeboarding, snowboarding, telemark...
electrolyte
Electrolyte
In chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....
s; a sweat test
Sweat test
The sweat test measures the concentration of chloride that is excreted in sweat. It is used to screen for cystic fibrosis .-Background:Cystic fibrosis is caused by defects in a protein found in many tissues, including the airways and the sweat glands. As a result, these tissues do not work properly...
was developed and improved over the next decade.
In 1988 the first mutation for CF, ΔF508 was discovered by Francis Collins
Francis Collins (geneticist)
Francis Sellers Collins , is an American physician-geneticist, noted for his discoveries of disease genes and his leadership of the Human Genome Project . He currently serves as Director of the National Institutes of Health in Bethesda, Maryland. Prior to being appointed Director, he founded and...
, Lap-Chee Tsui
Lap-Chee Tsui
Professor Lap-chee Tsui, OC, O.Ont is a Chinese-Canadian geneticist and currently the Vice-Chancellor and President of the University of Hong Kong.-Personal life:Tsui was born in Shanghai...
and John R. Riordan on the seventh chromosome. Subsequent research has found over 1,000 different mutations that cause CF.
Because mutations in the CFTR gene are typically small, classical genetics
Classical genetics
Classical genetics consists of the technique and methodologies of genetics that predate the advent of molecular biology. A key discovery of classical genetics in eukaryotes was genetic linkage...
techniques had been unable to accurately pinpoint the mutated gene. Using protein markers, gene-linkage studies were able to map the mutation to chromosome 7. Chromosome-walking and -jumping
Chromosome jumping
Chromosome jumping is a tool of molecular biology that is used in the physical mapping of genomes. It is related to several other tools used for the same purpose, including chromosome walking....
techniques were then used to identify and sequence
DNA sequencing
DNA sequencing includes several methods and technologies that are used for determining the order of the nucleotide bases—adenine, guanine, cytosine, and thymine—in a molecule of DNA....
the gene. In 1989 Lap-Chee Tsui led a team of researchers at the Hospital for Sick Children
Hospital for Sick Children
The Hospital for Sick Children – is a major paediatric centre for the Greater Toronto Area, serving patients up to age 18. Located on University Avenue in Downtown Toronto, SickKids is part of the city’s Discovery District, a critical mass of scientists and entrepreneurs who are focused on...
in Toronto
Toronto
Toronto is the provincial capital of Ontario and the largest city in Canada. It is located in Southern Ontario on the northwestern shore of Lake Ontario. A relatively modern city, Toronto's history dates back to the late-18th century, when its land was first purchased by the British monarchy from...
that discovered the gene responsible for CF. Cystic fibrosis represents the first genetic disorder elucidated strictly by the process of reverse genetics
Reverse genetics
Reverse genetics is an approach to discovering the function of a gene by analyzing the phenotypic effects of specific gene sequences obtained by DNA sequencing. This investigative process proceeds in the opposite direction of so-called forward genetic screens of classical genetics...
.
Gene therapy
Gene therapyGene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
has been explored as a potential cure for cystic fibrosis. Ideally, gene therapy attempts to place a normal copy of the CFTR gene into affected cells. Transferring the normal CFTR gene into the affected epithelium cells would result in the production of functional CFTR in all target cells, without adverse reactions or an inflammation response. Studies have shown that to prevent the lung manifestations of cystic fibrosis, only 5–10% the normal amount of CFTR gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
is needed. Multiple approaches have been tested for gene transfer, such as liposomes and viral vectors in animal models and clinical trials. However, both methods were found relatively inefficient treatment options. The main reason is that very few cells take up the vector and express the gene, so the treatment has little effect. Additionally, problems have been noted in cDNA recombination, such that the gene introduced by the treatment is rendered unusable. Gene therapy has made massive advances in the way that cystic fibrosis has been treated throughout the world. With the help of the Cystic Fibrosis Trust
Cystic Fibrosis Trust
The Cystic Fibrosis Trust, founded in 1964, is the United Kingdom’s only national charity dedicated to all aspects of cystic fibrosis . It funds research to treat and cure CF and aims to ensure appropriate clinical care and support for people with cystic fibrosis.-Objectives:Its objectives are:*To...
, which has a league of highly professional gene therapists, both somatic and Adeno-associated viral vector have made advances. The Adenoviridae, or more commonly known as the cold virus, is genetically altered, allowing the CFTR gene to enter lung cells. They are currently stage 3 clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
, and following the success of these trials, the treatment can become readily available and valid in the eyes of the medical world.
Small molecules
A number of small moleculeSmall molecule
In the fields of pharmacology and biochemistry, a small molecule is a low molecular weight organic compound which is by definition not a polymer...
s that aim at compensating various mutations of the CFTR gene are under development. One approach is to develop drugs that get the ribosome to overcome the stop codon
Stop codon
In the genetic code, a stop codon is a nucleotide triplet within messenger RNA that signals a termination of translation. Proteins are based on polypeptides, which are unique sequences of amino acids. Most codons in messenger RNA correspond to the addition of an amino acid to a growing polypeptide...
and synthesize a full-length CFTR protein. About 10% of CF result from a premature stop codon in the DNA, leading to early termination of protein synthesis and truncated proteins. These drugs target nonsense mutation
Nonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and in a truncated, incomplete, and usually nonfunctional protein product. It differs from a missense mutation, which is a point mutation...
s such as G542X, which consists of the amino acid glycin
Glycin
Glycin, or N-glycine, is N-substituted p-aminophenol. It is a photographic developing agent used in classic B&W developer solutions. It is a derivative of the amino acid glycine. When fresh, it is typically characterized as thin plates of white or silvery powder, turning brown with age...
in position 542 being replaced by a stop codon. Aminoglycoside antibiotics interfere with DNA synthesis and error-correction. In some cases, they can cause the cell to overcome the stop codon, insert a random amino acid, and express a full-length protein.
The aminoglycoside gentamicin
Gentamicin
Gentamicin is an aminoglycoside antibiotic, used to treat many types of bacterial infections, particularly those caused by Gram-negative organisms. However, gentamicin is not used for Neisseria gonorrhoeae, Neisseria meningitidis or Legionella pneumophila...
has been used to treat lung cells from CF patients in the laboratory to induce the cells to grown full-length proteins. Another drug targeting nonsense mutations is ataluren, which is undergoing Phase III clinical trials .
Ivacaftor
Ivacaftor
Ivacaftor is an experimental drug candidate for the treatment of cystic fibrosis, currently under development by Vertex Pharmaceuticals and the Cystic Fibrosis Foundation. The drug is designed to be effective in patients that have the G551D mutation in the defective protein that causes the disease...
, also in Phase III trials, targets the mutation G551D (glycin in position 551 is substituted with aspartic acid
Aspartic acid
Aspartic acid is an α-amino acid with the chemical formula HOOCCHCH2COOH. The carboxylate anion, salt, or ester of aspartic acid is known as aspartate. The L-isomer of aspartate is one of the 20 proteinogenic amino acids, i.e., the building blocks of proteins...
). VX-807
VX-807
VX-807 is an experimental drug for the treatment of cystic fibrosis. The drug is designed to be effective in patients that have the F508del mutation in the cystic fibrosis transmembrane conductance regulator , the defective protein that causes the disease...
aims at F508del (phenylalanin in position 508 is missing).
Further reading
- Fungal etiology Um i think in CF-associated infections reviewed extensively by Pihet et al.:
- Mowska, Patryk, Daniel Lorentzen, Katherine Excoffon, Joseph Zabner, Paul B. McCray, William M. Nauseef, Corinne Dupuy, and Botond Bánfi. A novel host defense system of airways is defective in cystic fibrosis. American Journal of Respiratory and Critical Care Medicine, 1 Nov. 2006. Web. 26 Nov. 2009
- Childers M, Eckel G, Himmel A, Caldwell J. A new model of cystic fibrosis pathology: lack of transport of glutathion and its thiocyanate conjugates. Med Hypotheses. 2007;68(1):101-12.
- Conner GE, Salathe M, Forteza R Lactoperoxidase and hydrogen peroxide metabolism in the airway, AmJ Respir Crit Care Med 2002 Dec 15;166 (12 Pt2):S57-1 Review
- Conner GE, Wijkstrom-Frei C, Randell SH, Fernandez VE, Salathe M. The lactoperoxidase system links anion transport to host defense in cystic fibrosis. FEBS Lett. 2007;581(2):271-8.
- Minarowski Ł, Sands D, Minarowska A, Karwowska A, Sulewska A, Gacko M, Chyczewska E. Thiocyanate concentration in saliva of cystic fibrosis patients. Folia Histochem Cytobiol. 2008;46(2):245-6.
- Rada B, Leto TL. Redox warfare between airway epithelial cells and Pseudomonas : dual oxidase versus pyocyanin. Immunol. Res. 2008
- Fischer H. Mechanism and function of DUOX in epithelia of the lung. Antioxid Redox Signal. 2009;11(10):1-13.
- Pedemonte N, Caci E, Sondo E, Caputo A, et al. Thiocyanate transport in resting & IL-4-stimulated human bronchial epithelial cells: role of pendrin and anion channels. J Immunol. 2007;178(8):5144-53.
- Wijkstrom-Frei C, El-Chemaly S, Ali-Rachedi R, Gerson C, Cobas MA, Forteza R, Salathe M, Conner GE. Lactoperoxidase and human airway host defense. Am J Respir Cell Mol Biol 2003;29(2):206-12.
- Xu Y, Szep S, Lu Z. The antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation related diseases, PNAS. 2009; Early edition, November 16