From Wikipedia, the free encyclopedia Cystic fibrosis
Cystic fibrosis
Cystic fibrosis velops when neither gene works normally and therefore
has autosomal recessive inheritance.
Classification and external resources CF is most common among Caucasians; one in 25 peo-
ple of European descent carries one allele for CF.[3][4]
The World Health Organization states that "In the
European Union 1 in 2000-3000 newborns is found to be
affected by CF".[5]
Individuals with cystic fibrosis can be diagnosed be-
fore birth by genetic testing, or by a sweat test in early
childhood. Ultimately, lung transplantation is often nec-
essary as CF worsens.
Signs and symptoms
A breathing treatment for cystic fibrosis, using a mask
nebuliser and a ThAIRapy Vest
ICD-
ICD-10 E84
ICD-
ICD-9 277.0
OMIM 219700
DiseasesDB 3347
MedlinePlus 000107
eMedicine ped/535
MeSH D003550
A diagram showing clinical manifestations of cystic fibrosis[6]
mucoviscidosis)
Cystic fibrosis (also known as CF or mucoviscidosis is
a recessive genetic disease affecting most critically the
The hallmark symptoms of cystic fibrosis are salty tasting
lungs, and also the pancreas, liver, and intestine. It is
skin,[7] poor growth and poor weight gain despite a nor-
characterized by abnormal transport of chloride and
mal food intake,[8] accumulation of thick, sticky mu-
sodium across epithelium, leading to thick, viscous secre-
cus,[9] frequent chest infections and coughing or short-
tions.[1]
ness of breath.[10] Males can be infertile due to congenital
The name cystic fibrosis refers to the characteristic
absence of the vas deferens.[11] Symptoms often appear
scarring (fibrosis) and cyst formation within the pan-
in infancy and childhood, such as bowel obstruction due
creas, first recognized in the 1930s.[2] Difficulty breathing
to meconium ileus in newborn babies.[12] As the child
is the most serious symptom and results from frequent
grows, they must exercise to release mucus in the alve-
lung infections that are treated with, though not cured
oli.[13] Ciliated epithelial cells in the patient have a mu-
by, antibiotics and other medications. Other symptoms,
tated protein that leads to abnormally viscous mucus
including sinus infections, poor growth, diarrhea, and in-
production.[9] The poor growth in children typically pre-
fertility affect other parts of the body.
sents as an inability to gain weight or height at the same
CF is caused by a mutation in the gene for the protein
rate as their peers and is occasionally not diagnosed until
cystic fibrosis transmembrane conductance regulator
investigation is initiated for poor growth. The causes of
(CFTR). This gene is required to regulate the components
growth failure are multi-factorial and include chronic
of sweat, digestive juices, and mucus. Although most peo-
lung infection, poor absorption of nutrients through the
ple without CF have two working copies of the CFTR
gastrointestinal tract, and increased metabolic demand
gene, only one is needed to prevent cystic fibrosis. CF de-
due to chronic illness.[8]
1
From Wikipedia, the free encyclopedia Cystic fibrosis
In rare cases, cystic fibrosis can manifest itself as a co- breathing problems. Another is infection with Mycobac-
agulation disorder. A double recessive allele is needed for terium avium complex (MAC), a group of bacteria related
cystic fibrosis to be apparent. Young children are espe- to tuberculosis, which can cause a lot of lung damage and
cially sensitive to vitamin K malabsorptive disorders be- does not respond to common antibiotics.[18]
cause only a very small amount of vitamin K crosses the Mucus in the paranasal sinuses is equally thick and
placenta, leaving the child with very low reserves. Be- may also cause blockage of the sinus passages, leading
cause factors II, VII, IX, and X (clotting factors) are vit- to infection. This may cause facial pain, fever, nasal
amin K–dependent, low levels of vitamin K can result in drainage, and headaches. Individuals with CF may de-
coagulation problems. Consequently, when a child pre- velop overgrowth of the nasal tissue (nasal polyps) due
sents with unexplained bruising, a coagulation evalua- to inflammation from chronic sinus infections.[19] Recur-
tion may be warranted to determine whether there is an rent sinonasal polyps can occur in as many as 10% to 25%
underlying disease.[14] of CF patients.[16] These polyps can block the nasal pas-
sages and increase breathing difficulties.[20][21]
Lung and sinus Cardiorespiratory complications are the most com-
mon cause of death (~80%) in patients followed by most
CF centers in the United States.[16]
Gastrointestinal
Prior to prenatal and newborn screening, 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%[16][22] of newborns with
CF. In addition, protrusion of internal rectal membranes
Respiratory infections in CF varies according to age. (rectal prolapse) is more common, occurring in as many
as 10% of children with CF,[16] and it is caused by in-
Green = Pseudomonas aeruginosa
creased fecal volume, malnutrition, and increased in-
Brown = Staphylococcus aureus
Blue = Haemophilus influenzae tra–abdominal pressure due to coughing.[23]
Red = Burkholderia cepacia complex The thick mucus seen in the lungs has a counterpart
in thickened secretions from the pancreas, an organ re-
Lung disease results from clogging of the airways due to sponsible for providing digestive juices that help break
mucus build-up, decreased mucociliary clearance and re- down food. These secretions block the exocrine move-
sulting inflammation.[15][16] Inflammation and infection ment of the digestive enzymes into the duodenum and
cause injury and structural changes to the lungs, lead- result in irreversible damage to the pancreas, often with
ing to a variety of symptoms. In the early stages, in- painful inflammation (pancreatitis).[24] The pancreatic
cessant coughing, copious phlegm production, and de- ducts are totally plugged in more advanced cases, usually
creased ability to exercise are common. Many of these seen in older children or adolescents.[16] This causes at-
symptoms occur when bacteria that normally inhabit the rophy of the exocrine glands and progressive fibrosis. [16]
thick mucus grow out of control and cause pneumonia. The lack of digestive enzymes leads to difficulty ab-
In later stages, changes in the architecture of the lung sorbing nutrients with their subsequent excretion in the
such as pathology in the major airways (bronchiectasis) feces, a disorder known as malabsorption. Malabsorption
further exacerbate difficulties in breathing. Other symp- leads to malnutrition and poor growth and development
toms include coughing up blood (hemoptysis), high blood because of calorie loss. Resultant hypoproteinemia may
pressure in the lung (pulmonary hypertension), heart be severe enough to cause generalized edema.[16] Indi-
failure, difficulties getting enough oxygen to the body viduals with CF also have difficulties absorbing the fat-
(hypoxia), and respiratory failure requiring support with soluble vitamins A, D, E, and K.
breathing masks such as bilevel positive airway pressure In addition to the pancreas problems, people with
machines or ventilators.[17] Staphylococcus aureus, Hae- cystic fibrosis experience more heartburn, intestinal
mophilus influenzae, and Pseudomonas aeruginosa are the blockage by intussusception, and constipation.[25] Older
three most common organisms causing lung infections in individuals with CF may develop distal intestinal obstruc-
CF patients.[16] In addition to typical bacterial infections, tion syndrome when thickened feces cause intestinal
people with CF more commonly develop other types of blockage.[26]
lung disease. Among these is allergic bronchopulmonary Exocrine pancreatic insufficiency occurs in the ma-
aspergillosis, in which the body’s response to the com- jority (85% to 90%) of patients with CF.[16] It is mainly as-
mon fungus Aspergillus fumigatus causes worsening of sociated with "severe" CFTR mutations, where both alle-
2
From Wikipedia, the free encyclopedia Cystic fibrosis
les are completely nonfunctional (e.g. ΔF508/ΔF508).[16] Infertility
It occurs in 10% to 15% of patients with one "severe"
Infertility affects both men and women. At least 97% of
and one "mild" CFTR mutation where there still is a little
men with cystic fibrosis are infertile, but not sterile and
CFTR activity, or where there are two "mild" CFTR mu-
can have children with assisted reproductive tech-
tations.[16] In these milder cases, there is still sufficient
niques.[34] These men make normal sperm but are miss-
pancreatic exocrine function so that enzyme supplemen-
ing their vas deferens, which connects the testes to the
tation is not required.[16] There are usually no other GI
ejaculatory ducts of the penis.[35] Many men found to
complications in pancreas-sufficient phenotypes, and in
have congenital absence of the vas deferens during eval-
general, such individuals usually have excellent growth
uation for infertility have a mild, previously undiagnosed
and development.[16] Despite this, idiopathic chronic
form of CF.[36] Some women have fertility difficulties due
pancreatitis can occur in a subset of pancreas-sufficient
to thickened cervical mucus or malnutrition. In severe
individuals with CF, and is associated with recurrent ab-
cases, malnutrition disrupts ovulation and causes amen-
dominal pain and life-threatening complications. [16]
orrhea.[37]
Thickened secretions also may cause liver problems
in patients with CF. Bile secreted by the liver to aid in di-
gestion may block the bile ducts, leading to liver damage. Cause
Over time, this can lead to scarring and nodularity (cir-
rhosis). The liver fails to rid the blood of toxins and does
not make important proteins such as those responsible
for blood clotting.[27][28] Liver disease is the third most
common cause of death associated with CF.[16]
Endocrine
Clubbing in the fingers of a person with cystic fibrosis
Cystic fibrosis has an autosomal recessive pattern of inheri-
tance
The pancreas contains the islets of Langerhans, which
are responsible for making insulin, a hormone that helps
CF is caused by a mutation in the gene cystic fibrosis
regulate blood glucose. Damage of the pancreas can lead
transmembrane conductance regulator (CFTR). The most
to loss of the islet cells, leading to a type of diabetes
common mutation, ΔF508, is a deletion (Δ) of three nu-
that is unique to those with the disease.[29] This cystic
cleotides[38] that results in a loss of the amino acid
fibrosis-related diabetes (CFRD) shares characteristics
phenylalanine (F) at the 508th position on the protein.
that can be found in Type 1 and Type 2 diabetics, and
This mutation accounts for two-thirds (66-70%[16]) of CF
is one of the principal non-pulmonary complications of
cases worldwide and 90% of cases in the United States;
CF.[30] Vitamin D is involved in calcium and phosphate
however, there are over 1500 other mutations that can
regulation. Poor uptake of vitamin D from the diet be-
produce CF.[39] Although most people have two working
cause of malabsorption can lead to the bone disease os-
copies (alleles) of the CFTR gene, only one is needed to
teoporosis in which weakened bones are more suscepti-
prevent cystic fibrosis. CF develops when neither allele
ble to fractures.[31] In addition, people with CF often de-
can produce a functional CFTR protein. Thus, CF is con-
velop clubbing of their fingers and toes due to the effects
sidered an autosomal recessive disease.
of chronic illness and low oxygen in their tissues.[32][33]
The CFTR gene, found at the q31.2 locus of chromo-
some 7, is 230,000 base pairs long, and creates a protein
3
From Wikipedia, the free encyclopedia Cystic fibrosis
that is 1,480 amino acids long. Structurally, CFTR is a creas, and all other remaining exocrine glands in the
type of gene known as an ABC gene.[17] The product of body. The protein spans this membrane and acts as a
this gene (the CFTR) is a chloride ion channel important channel connecting the inner part of the cell (cytoplasm)
in creating sweat, digestive juices and mucus. This pro- to the surrounding fluid. This channel is primarily re-
tein possesses two ATP-hydrolyzing domains, which al- sponsible for controlling the movement of halogens from
lows the protein to use energy in the form of ATP. It inside to outside of the cell; however, in the sweat ducts
also contains two domains comprising 6 alpha helices it facilitates the movement of chloride from the sweat in-
apiece, which allow the protein to cross the cell mem- to the cytoplasm. When the CFTR protein does not work,
brane. A regulatory binding site on the protein allows ac- chloride and thiocyanate[42] are trapped inside the cells
tivation by phosphorylation, mainly by cAMP-dependent in the airway and outside in the skin. Then hypothio-
protein kinase.[17] The carboxyl terminal of the protein cyanite, OSCN, cannot be produced by immune defense
is anchored to the cytoskeleton by a PDZ domain interac- system.[43][44] Because chloride is negatively charged,
tion.[40] this creates a difference in the electrical potential inside
In addition, there is increasing evidence that genetic and outside the cell causing cations to cross into the cell.
modifiers besides CFTR modulate the frequency and Sodium is the most common cation in the extracellular
severity of the disease. One example is mannan-binding space and the combination of sodium and chloride cre-
lectin, which is involved in innate immunity by facilitat- ates the salt, which is lost in high amounts in the sweat of
ing phagocytosis of microorganisms. Polymorphisms in individuals with CF. This lost salt forms the basis for the
one or both mannan-binding lectin alleles that result in sweat test.[17]
lower circulating levels of the protein are associated with Most of the damage in CF is due to blockage of the
a threefold higher risk of end-stage lung disease, as well narrow passages of affected organs with thickened secre-
as an increased burden of chronic bacterial infections.[16] tions. These blockages lead to remodeling and infection
in the lung, damage by accumulated digestive enzymes
Pathophysiology in the pancreas, blockage of the intestines by thick fae-
ces, etc. There are several theories on how the defects
in the protein and cellular function cause the clinical ef-
fects. One theory is that the lack of halogen and pseudo-
halogen (mainly, chloride, iodide and thiocyanate) exit-
ing 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, cre-
ates dehydrated and thick mucus. Yet another theory is
that abnormal chloride movement out of the cell leads to
dehydration of mucus, pancreatic secretions, biliary se-
cretions, etc.[17]
Molecular structure of the CFTR protein
There are several mutations in the CFTR gene, and dif-
Chronic infections
ferent mutations cause different defects in the CFTR pro- The lungs of individuals with cystic fibrosis are colonized
tein, sometimes causing a milder or more severe disease. and infected by bacteria from an early age. These bacte-
These protein defects are also targets for drugs which ria, which often spread among individuals with CF, thrive
can sometimes restore their function. ΔF508-CFTR, which in the altered mucus, which collects in the small airways
occurs in >90% of patients in the U.S., creates a protein of the lungs. This mucus leads to the formation of bac-
that does not fold normally and is degraded by the cell. terial microenvironments known as biofilms that are dif-
Other mutations result in proteins that are too short ficult for immune cells and antibiotics to penetrate. Vis-
(truncated) because production is ended prematurely. cous secretions and persistent respiratory infections re-
Other mutations produce proteins that do not use energy peatedly damage the lung by gradually remodeling the
normally, do not allow chloride, iodide and thiocyanate airways, which makes infection even more difficult to
to cross the membrane appropriately,[41] or are degraded eradicate.[45]
at a faster rate than normal. Mutations may also lead to Over time, both the types of bacteria and their in-
fewer copies of the CFTR protein being produced.[17] dividual characteristics change in individuals with CF.
The protein created by this gene is anchored to the In the initial stage, common bacteria such as Staphylo-
outer membrane of cells in the sweat glands, lungs, pan- coccus aureus and Hemophilus influenzae colonize and in-
4
From Wikipedia, the free encyclopedia Cystic fibrosis
fect the lungs.[16] Eventually, Pseudomonas aeruginosa (and
sometimes Burkholderia cepacia) dominates. By 18 years
of age, 80% of patients with classic CF harbor P. aerugi-
nosa, and 3.5% harbor B. cepacia.[16] Once within the lungs,
these bacteria adapt to the environment and develop re-
sistance 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.[45]
One way infection spreads is by passing between dif-
ferent individuals with CF.[46] In the past, people with
CF often participated in summer "CF Camps" and other
recreational gatherings.[47][48] Hospitals grouped pa-
tients with CF into common areas and routine equipment
(such as nebulizers)[49] was not sterilized between in-
dividual patients.[50] 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 health-
care providers are encouraged to wear gowns and gloves
when examining patients with CF to limit the spread of
virulent bacterial strains.[51]
CF patients may also have their airways chronically
colonized by filamentous fungi (such as Aspergillus fumi-
gatus, 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 respirato-
ry secretions), and Exophiala dermatitidis and Scedosporium
prolificans (chronic airway-colonizers); some filamentous
fungi like Penicillium emersonii and Acrophialophora fusispo-
ra are encountered in patients almost exclusively in the
context of CF.[52] Defective mucociliary clearance charac-
terizing CF is associated with local immunological disor-
ders. In addition, the prolonged therapy with antibiotics
and the use of corticosteroid treatments may also facili-
tate fungal growth. Although the clinical relevance of the
fungal airway colonization is still a matter of debate, fil-
amentous fungi may contribute to the local inflammato-
ry response, and therefore to the progressive deteriora-
tion of the lung function, as often happens with aller-
gic broncho-pulmonary aspergillosis (ABPA) - the most
common fungal disease in the context of CF, involving a
Th2-driven immune response to Aspergillus.[52][53]
Diagnosis and monitoring
Cystic fibrosis may be diagnosed by many different meth-
ods including newborn screening, sweat testing, and ge-
netic testing. As of 2006 in the United States, 10 percent
of cases are diagnosed shortly after birth as part of new-
born screening programs. The newborn screen initially
measures for raised blood concentration of immunore-
active trypsinogen.[54] Infants with an abnormal new-
born screen need a sweat test to confirm the CF diagno-
sis. In many cases, a parent makes the diagnosis because
5
From Wikipedia, the free encyclopedia Cystic fibrosis
The location of the CFTR gene on chromosome 7 mutations are found on current tests, a negative screen
does not guarantee that a child will not have CF.[61]
the infant tastes salty.[16] Trypsinogen levels can be in- During pregnancy, testing can be performed on the
creased in individuals who have a single mutated copy placenta (chorionic villus sampling) or the fluid around
of the CFTR gene (carriers) or, in rare instances, in in- the fetus (amniocentesis). However, chorionic villus sam-
dividuals with two normal copies of the CFTR gene. Due pling has a risk of fetal death of 1 in 100 and amniocen-
to these false positives, CF screening in newborns can tesis of 1 in 200;[62] a recent study has indicated this may
be controversial.[55][56] Most states and countries do not be much lower, approximately 1 in 1,600.[63]
screen for CF routinely at birth. Therefore, most individ- Economically, for carrier couples of cystic fibrosis,
uals are diagnosed after symptoms (e.g. sinopulmonary when comparing preimplantation genetic diagnosis
disease and GI manifestations[16]) prompt an evaluation (PGD) with natural conception (NC) followed by prenatal
for cystic fibrosis. The most commonly used form of test- testing and abortion of affected pregnancies, PGD pro-
ing is the sweat test. Sweat-testing involves application vides net economic benefits up to a maternal age of ap-
of a medication that stimulates sweating (pilocarpine). proximately 40 years, after which NC, prenatal testing
To deliver the medication through the skin, iontophore- and abortion has higher economic benefit.[64]
sis is used to, whereby one electrode is placed onto the
applied medication and an electric current is passed to Management
a separate electrode on the skin. The resultant sweat is
then collected on filter paper or in a capillary tube and While there are no cures for cystic fibrosis there are sev-
analyzed for abnormal amounts of sodium and chloride. eral treatment methods. The management of cystic fi-
People with CF have increased amounts of sodium and brosis has improved significantly over the past 70 years.
chloride in their sweat. In opposite, people with CF have While infants born with cystic fibrosis 70 years ago would
less thiocyanate and hypothiocyanite in their saliva (Mi- have been unlikely to live beyond their first year, infants
narowski[57] et al.) and mucus (Banfi et al.). CF can also today are likely to live well into adulthood. Recent ad-
be diagnosed by identification of mutations in the CFTR vances in the treatment of cystic fibrosis have meant
gene.[58] that an individual with cystic fibrosis can live a fuller life
People with CF may be listed in a disease registry that less encumbered by their condition. The cornerstones
allows researchers and doctors to track health results of management are proactive treatment of airway infec-
and identify candidates for clinical trials.[59] tion, and encouragement of good nutrition and an ac-
tive lifestyle. Management of cystic fibrosis continues
Prenatal throughout a patient’s life, and is aimed at maximizing
organ function, and therefore quality of life. At best, cur-
Couples who are pregnant or planning a pregnancy can rent treatments delay the decline in organ function. Be-
have themselves tested for the CFTR gene mutations to cause of the wide variation in disease symptoms treat-
determine the risk that their child will be born with cys- ment typically occurs at specialist multidisciplinary cen-
tic fibrosis. Testing is typically performed first on one ters, and is tailored to the individual. Targets for therapy
or both parents and, if the risk of CF is high, testing on are the lungs, gastrointestinal tract (including pancreatic
the fetus is performed. The American College of Obstetri- enzyme supplements), the reproductive organs (includ-
cians and Gynecologists (ACOG) recommends testing for ing assisted reproductive technology (ART)) and psycho-
couples who have a personal or close family history of logical support.[54]
CF, and they recommend that carrier testing be offered The most consistent aspect of therapy in cystic fibro-
to all Caucasian couples and be made available to couples sis is limiting and treating the lung damage caused by
of other ethnic backgrounds.[60] thick mucus and infection, with the goal of maintaining
Because development of CF in the fetus requires each quality of life. Intravenous, inhaled, and oral antibiotics
parent to pass on a mutated copy of the CFTR gene and are used to treat chronic and acute infections. Mechani-
because CF testing is expensive, testing is often per- cal devices and inhalation medications are used to alter
formed initially on one parent. If testing shows that par- and clear the thickened mucus. These therapies, while
ent is a CFTR gene mutation carrier, the other parent is effective, can be extremely time-consuming for the pa-
tested to calculate the risk that their children will have tient. One of the most important battles that CF patients
CF. CF can result from more than a thousand different face is finding the time to comply with prescribed treat-
mutations, and as of 2006 it is not possible to test for each ments while balancing a normal life.
one. Testing analyzes the blood for the most common In addition, therapies such as transplantation and
mutations such as ΔF508—most commercially available gene therapy aim to cure some of the effects of cystic fi-
tests look for 32 or fewer different mutations. If a family brosis. Gene therapy aims to introduce normal CFTR to
has a known uncommon mutation, specific screening for airway. Theoretically this process should be simple as the
that mutation can be performed. Because not all known airway is easily accessible and there is only a single gene
6
From Wikipedia, the free encyclopedia Cystic fibrosis
defect to correct. There are two CFTR gene introduction itive airway pressure (BiPAP) ventilators, help prevent
mechanisms involved, the first use of a viral vector (ade- low blood oxygen levels during sleep. BiPAP may also be
novirus, adeno-associated virus or retro virus) and sec- used during physical therapy to improve sputum clear-
ondly the use of liposome. However there are some prob- ance.[74] During severe illness, a tube may be placed in
lems associated with these methods involving efficiency the throat (a procedure known as a tracheostomy) to en-
(liposomes insufficient protein) and delivery (virus pro- able breathing supported by a ventilator.
vokes an immune response). For children living with CF, preliminary studies show
pediatric massage therapy may improve patients and
Antibiotics their families quality of life, though more rigorous stud-
Many CF patients are on one or more antibiotics at all ies must be done.[75]
times, even when healthy, to prophylactically suppress
infection. Antibiotics are absolutely necessary whenever Transplantation
pneumonia is suspected or there has been a noticeable Lung transplantation often becomes necessary for indi-
decline in lung function, and are usually chosen based on viduals with cystic fibrosis as lung function and exercise
the results of a sputum analysis and the patient’s past re- tolerance declines. Although single lung transplantation
sponse. This prolonged therapy often necessitates hos- is possible in other diseases, individuals with CF must
pitalization and insertion of a more permanent IV such have both lungs replaced because the remaining lung
as a peripherally inserted central catheter (PICC line) or might contain bacteria that could infect the transplanted
Port-a-Cath. Inhaled therapy with antibiotics such as to- lung. A pancreatic or liver transplant may be performed
bramycin, colistin, and aztreonam is often given for at the same time in order to alleviate liver disease and/
months at a time to improve lung function by impeding or diabetes.[76] Lung transplantation is considered when
the growth of colonized bacteria.[65][66][67] Oral antibi- lung function declines to the point where assistance from
otics such as ciprofloxacin or azithromycin are given to mechanical devices is required or patient survival is
help prevent infection or to control ongoing infec- threatened.[77]
tion.[68] The aminoglycoside antibiotics (e.g. tobramycin)
used can cause hearing loss, damage to the balance sys- Treatment of other aspects
tem in the inner ear or kidney problems with long-term
use.[69] To prevent these side-effects, the amount of an-
tibiotics in the blood are routinely measured and adjust-
ed accordingly.
Other treatments for lung disease
Several mechanical techniques are used to dislodge spu-
tum and encourage its expectoration. In the hospital set-
ting, 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. De-
vices that recreate this percussive therapy include the
ThAIRapy Vest and the intrapulmonary percussive ven-
tilator (IPV). Newer methods such as Biphasic Cuirass
Ventilation, and associated clearance mode available in Intracytoplasmic sperm injection can be used to provide fertili-
such devices, integrate a cough assistance phase, as well ty for men with cystic fibrosis
as a vibration phase for dislodging secretions. These are
portable and adapted for home use.[70] Newborns with CF typically require surgery, whereas
Aerosolized medications that help loosen secretions adults with distal intestinal obstruction syndrome typi-
include dornase alfa and hypertonic saline.[71] Dornase is cally do not. Treatment of pancreatic insufficiency by re-
a recombinant human deoxyribonuclease, which breaks placement of missing digestive enzymes allows the duo-
down DNA in the sputum, thus decreasing its viscosi- denum to properly absorb nutrients and vitamins that
ty.[72] Denufosol is an investigational drug that opens would otherwise be lost in the feces.So far, no large-scale
an alternative chloride channel, helping to liquefy mu- research involving the incidence of atherosclerosis and
cus.[73] coronary heart disease in adults with cystic fibrosis has
As lung disease worsens, mechanical breathing sup- been conducted. This is likely due to the fact that the vast
port may become necessary. Individuals with CF may majority of people with cystic fibrosis do not live long
need to wear special masks at night that help push air enough to develop clinically significant atherosclerosis
into their lungs. These machines, known as bilevel pos- or coronary heart disease.
7
From Wikipedia, the free encyclopedia Cystic fibrosis
Diabetes is the most common non-pulmonary com- more positive outlook for themselves. Furthermore,
plication of CF. It mixes features of type 1 and type 2 there are many ways to improve the QOL in CF patients.
diabetes, and is recognized as a distinct entity, cystic Exercise is promoted to increase lung function. The fact
fibrosis-related diabetes (CFRD).[78][79] While oral anti- of integrating an exercise regime into the CF patient’s
diabetic drugs are sometimes used, the only recommend- daily routine can significantly improve the quality of
ed treatment is the use of insulin injections or an insulin life.[89] There is no definitive cure for Cystic Fibrosis.
pump,[80] and, unlike in type 1 and 2 diabetes, dietary re- However, there are diverse medications used such as,
strictions are not recommended.[78] mucolytics, bronchodilators, steroids and antibiotics that
Development of osteoporosis can be prevented by in- have the purpose of loosening mucus, expanding air-
creased intake of vitamin D and calcium, and can be ways, decreasing inflammation and fighting lung infec-
treated by bisphosphonates, although adverse effects can tions.[90]
be an issue.[81] Poor growth may be avoided by insertion
of a feeding tube for increasing calories through sup-
plemental feeds or by administration of injected growth
Prognosis
hormone.[82] The prognosis for cystic fibrosis in the U.S. has improved
Sinus infections are treated by prolonged courses of due to earlier diagnosis through screening, better treat-
antibiotics. The development of nasal polyps or other ment and access to health care. Patient compliance is ma-
chronic changes within the nasal passages may severely jor factor—patients that are more aggressive in following
limit airflow through the nose, and over time reduce the treatment recommendations live longer.
patient’s sense of smell. Sinus surgery is often used to al- In 1959, the median age of survival of children with
leviate nasal obstruction and to limit further infections. cystic fibrosis in the U.S. was six months. Now, it is 37.4
Nasal steroids such as fluticasone are used to decrease years.[91] In Canada, median survival increased from 24
nasal inflammation.[83] Female infertility may be over- years in 1982 to 47.7 in 2007.[92]
come by assisted reproduction technology, particularly The U.S. Cystic Fibrosis Foundation reported that in
embryo transfer techniques. Male infertility caused by 2008, 92% had graduated from high school and 66% had
absence of the vas deferens may be overcome with tes- at least some college education. 15% of adults were dis-
ticular sperm extraction (TEST), collecting sperm cells abled and 7% were unemployed. 54.8% of adults were sin-
directly from the testicles. If the collected sample con- gle and 40.1% were married or living with a partner. In
tains too few sperm cells to likely have a spontaneous fer- 2008, 240 American women with CF were pregnant.[93]
tilization, intracytoplasmic sperm injection can be per-
formed.[84] Third party reproduction is also a possibility
for women with CF.
Epidemiology
Cystic fibrosis is the most common life-limiting autoso-
mal recessive disease among people of European her-
Quality of life itage.[95] In the United States, approximately 30,000 indi-
Chronic illnesses are very difficult to manage. Cystic fi- viduals have CF; most are diagnosed by six months of age.
brosis (CF) is a chronic illness that affects the “digestive In Canada, there are approximately 3,000 people with CF.
and respiratory tracts resulting in generalized malnutri- Approximately 1 in 25 people of European descent, and
tion and chronic respiratory infections”.[85] The thick se- one in 30 of Caucasian Americans,[96] is a carrier of a
cretions clog the airways in the lungs, which often cause cystic fibrosis mutation. Although CF is less common in
inflammation and severe lung infections.[86] Therefore, these groups, approximately 1 in 46 Hispanics, 1 in 65
mucus makes it challenging to breathe. If it is compro- Africans and 1 in 90 Asians carry at least one abnormal
mised, it affects the quality of life of someone with CF, CFTR gene.[97][98]
and their ability to complete such tasks as everyday Although technically a rare disease, cystic fibrosis is
chores. It is important for CF patients to understand the ranked as one of the most widespread life-shortening ge-
detrimental relationship that chronic illnesses place on netic diseases. It is most common among nations in the
the quality of life. According to Schmitz and Goldbeck Western world. An exception is Finland, where only one
(2006), the fact that Cystic Fibrosis significantly increases in 80 people carry a CF mutation.[99] In the United States,
emotional stress on both the individual and the family, 1 in 4,000 children are born with CF.[100] In 1997, about
“and the necessary time-consuming daily treatment rou- 1 in 3,300 caucasian children in the United States was
tine may have further negative effects on quality of life born with cystic fibrosis. In contrast, only 1 in 15,000
(QOL)”.[87] However, Havermans and colleagues (2006) African American children suffered from cystic fibrosis,
have shown that young outpatients with CF that have and in Asian Americans the rate was even lower at 1 in
participated in the CFQ-R (Cystic Fibrosis Questionnaire- 32,000.[101]
Revised) “rated some QOL domains higher than did their Cystic fibrosis is diagnosed in males and females
parents”.[88] Consequently, outpatients with CF have a equally. For reasons that remain unclear, data has shown
8
From Wikipedia, the free encyclopedia Cystic fibrosis
Mutation Frequency
94]
worldwide[94]
ΔF508 66%-70%[16]
G542X 2.4%
G551D 1.6%
N1303K 1.3%
W1282X 1.2%
All others 27.5%
that males tend to have a longer life expectancy than fe- caused by lactose intolerance, prior to the
males,[102][103] however recent studies suggest this gen- appearance of the mutations that created lactose
der gap may no longer exist perhaps due to improve- tolerance.[114]
ments in health care facilities,[104][105] while a recent • Tuberculosis: Another possible explanation is that
study from Ireland identified a link between the female carriers of the gene could have some resistance to
hormone oestrogen and worse outcomes in CF.[106] TB.[115][116]
The distribution of CF alleles varies among popula-
tions. The frequency of ΔF508 carriers has been estimat-
ed at 1:200 in northern Sweden, 1:143 in Lithuanians, and
History
1:38 in Denmark. No ΔF508 carriers were found among
171 Finns and 151 Saami people.[107] ΔF508 does occur in
Finland, but it is a minority allele there. Cystic fibrosis
is known to occur in only 20 families (pedigrees) in Fin-
land.[108]
Hypotheses about prevalence
The ΔF508 mutation is estimated to be up to 52,000 years
old.[109] Numerous hypotheses have been advanced as to
why such a lethal mutation has persisted and spread in
the human population. Other common autosomal reces-
sive diseases such as sickle-cell anemia have been found
to protect carriers from other diseases, a concept known
as heterozygote advantage. Resistance to the following
have all been proposed as possible sources of heterozy-
gote advantage:
• Cholera: With the discovery that cholera toxin
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.[110] Further studies have
not confirmed this hypothesis.[111][112]
• Typhoid: Normal CFTR proteins are also essential for
the entry of Salmonella Typhi into cells,[113]
suggesting that carriers of mutant CFTR genes might National Library of Medicine photo of Dorothy Hansine Ander-
be resistant to typhoid fever. No in vivo study has yet sen. Andersen first described cystic fibrosis in 1938.
confirmed this. In both cases, the low level of cystic
fibrosis outside of Europe, in places where both It is supposed that CF appeared about 3,000 BC as a cause
cholera and typhoid fever are endemic, is not of migration of peoples, gene mutations, and new con-
immediately explicable. ditions in nourishment.[117] Although the entire clinical
• Diarrhea: It has also been hypothesized that the spectrum of CF was not recognized until the 1930s, cer-
prevalence of CF in Europe might be connected with tain aspects of CF were identified much earlier. Indeed,
the development of cattle domestication. In this literature from Germany and Switzerland in the 18th
hypothesis, carriers of a single mutant CFTR century warned Wehe dem Kind, das beim Kuß auf die Stirn
chromosome had some protection from diarrhea salzig schmekt, er ist verhext und muss bald sterbe or "Woe to
9
From Wikipedia, the free encyclopedia Cystic fibrosis
the child who tastes salty from a kiss on the brow, for he and express the gene, so the treatment has little effect.
is cursed and soon must die," recognizing the association Additionally, problems have been noted in cDNA recom-
between the salt loss in CF and illness.[117] bination, such that the gene introduced by the treatment
In the 19th century, Carl von Rokitansky described a is rendered unusable.[124] Gene therapy has made mas-
case of fetal death with meconium peritonitis, a compli- sive advances in the way that cystic fibrosis has been
cation of meconium ileus associated with cystic fibrosis. treated throughout the world[citation needed]. With the help
Meconium ileus was first described in 1905 by Karl Land- of the Cystic Fibrosis Trust, which has a league of highly
steiner.[117] In 1936, Guido Fanconi published a paper de- professional gene therapists, both somatic and Adeno-
scribing a connection between celiac disease, cystic fi- associated viral vector have made advances. The Aden-
brosis of the pancreas, and bronchiectasis.[118] oviridae, or more commonly known as the cold virus, is
In 1938 Dorothy Hansine Andersen published an ar- genetically altered, allowing the CFTR gene to enter lung
ticle, "Cystic Fibrosis of the Pancreas and Its Relation to cells.
Celiac Disease: a Clinical and Pathological Study," in the
American Journal of Diseases of Children. She was the first Small molecules
to describe the characteristic cystic fibrosis of the pan- A number of small molecules that aim at compensating
creas and to correlate it with the lung and intestinal dis- various mutations of the CFTR gene are under develop-
ease prominent in CF.[2] She also first hypothesized that ment. One approach is to develop drugs that get the ri-
CF was a recessive disease and first used pancreatic en- bosome to overcome the stop codon and synthesize a
zyme replacement to treat affected children. In 1952 Paul full-length CFTR protein. About 10% of CF result from a
di Sant’ Agnese discovered abnormalities in sweat elec- premature stop codon in the DNA, leading to early ter-
trolytes; a sweat test was developed and improved over mination of protein synthesis and truncated proteins.
the next decade.[119] These drugs target nonsense mutations such as G542X,
In 1988 the first mutation for CF, ΔF508 was discov- which consists of the amino acid glycin in position 542
ered by Francis Collins, Lap-Chee Tsui and John R. Rior- being replaced by a stop codon. Aminoglycoside antibi-
dan on the seventh chromosome. Subsequent research otics interfere with DNA synthesis and error-correction.
has found over 1,000 different mutations that cause CF. In some cases, they can cause the cell to overcome the
Because mutations in the CFTR gene are typically stop codon, insert a random amino acid, and express a
small, classical genetics techniques had been unable to full-length protein.[125] The aminoglycoside gentamicin
accurately pinpoint the mutated gene.[120] Using protein has been used to treat lung cells from CF patients in the
markers, gene-linkage studies were able to map the mu- laboratory to induce the cells to grow full-length pro-
tation to chromosome 7. Chromosome-walking and - teins.[126] Another drug targeting nonsense mutations is
jumping techniques were then used to identify and se- ataluren, which is undergoing Phase III clinical trials as
quence the gene.[121] In 1989 Lap-Chee Tsui led a team of of October 2011.[127]
researchers at the Hospital for Sick Children in Toronto Ivacaftor (Kalydeco), approved for use by the FDA in
that discovered the gene responsible for CF. Cystic fibro- the United States in January 2012[128], targets the muta-
sis represents the first genetic disorder elucidated strict- tion G551D (glycin in position 551 is substituted with as-
ly by the process of reverse genetics. partic acid). VX-809 aims at F508del (phenylalanin in po-
sition 508 is missing).[129]
Research
Antibiotics
Gene therapy A combined antibiotic of fosfomycin and tobramycin is
Gene therapy has been explored as a potential cure for being researched by the FDA (Phase 2) for its use in peo-
cystic fibrosis. Ideally, gene therapy attempts to place a ple with Pseudomonas colonization[130].
normal copy of the CFTR gene into affected cells. Trans-
ferring the normal CFTR gene into the affected epithe- See also
lium cells would result in the production of functional
• List of people diagnosed with cystic fibrosis
CFTR in all target cells, without adverse reactions or an
• 65 Redroses
inflammation response. Studies have shown that to pre-
vent the lung manifestations of cystic fibrosis, only
5–10% the normal amount of CFTR gene expression is References
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versus pyocyanin. Immunol. Res. 2008
• Fungal etiology Um i think in CF-associated • Fischer H. Mechanism and function of DUOX in
infections reviewed extensively by Pihet et al.: Pihet epithelia of the lung. Antioxid Redox Signal.
M, Carrere J, Cimon B, Chabasse D, Delhaes L, 2009;11(10):1-13.
Symoens F, Bouchara JP (June 2009). "Occurrence • Pedemonte N, Caci E, Sondo E, Caputo A, et al.
and relevance of filamentous fungi in respiratory Thiocyanate transport in resting & IL-4-stimulated
secretions of patients with cystic fibrosis--a review". human bronchial epithelial cells: role of pendrin and
Med Mycol. 47 (4): 387–97. doi:10.1080/ anion channels. J Immunol. 2007;178(8):5144-53.
13693780802609604. PMID 19107638. • Wijkstrom-Frei C, El-Chemaly S, Ali-Rachedi R,
• Mowska, Patryk, Daniel Lorentzen, Katherine Gerson C, Cobas MA, Forteza R, Salathe M, Conner
Excoffon, Joseph Zabner, Paul B. McCray, William M. GE. Lactoperoxidase and human airway host defense.
Nauseef, Corinne Dupuy, and Botond Bánfi. A novel Am J Respir Cell Mol Biol 2003;29(2):206-12.
host defense system of airways is defective in cystic • Xu Y, Szep S, Lu Z. The antioxidant role of
fibrosis. American Journal of Respiratory and Critical thiocyanate in the pathogenesis of cystic fibrosis and
Care Medicine, 1 Nov. 2006. Web. 26 Nov. 2009 other inflammation related diseases, PNAS. 2009; Early
• Childers M, Eckel G, Himmel A, Caldwell J. A new edition, November 16
model of cystic fibrosis pathology: lack of transport
of glutathion and its thiocyanate conjugates. Med
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External links
• Conner GE, Salathe M, Forteza R Lactoperoxidase and • Cystic fibrosis at the Open Directory Project
hydrogen peroxide metabolism in the airway, AmJ • cf at NIH/UW GeneTests
Respir Crit Care Med 2002 Dec 15;166 (12 Pt2):S57-1 Review • Search GeneCards for genes involved in Cystic
• Conner GE, Wijkstrom-Frei C, Randell SH, Fernandez Fibrosis
VE, Salathe M. The lactoperoxidase system links • Cystic Fibrosis Mutation Database
anion transport to host defense in cystic fibrosis. • Online Mendelian Inheritance of Man summary of
FEBS Lett. 2007;581(2):271-8. Cystic Fibrosis
Retrieved from "http://en.wikipedia.org/w/index.php?title=Cystic_fibrosis&oldid=474528638"
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