Cystic fibrosis (also known as
CF,
mucovoidosis, or
mucoviscidosis) is a
genetic disorderA genetic disorder is an illness caused by abnormalities in genes or chromosomes. While some diseases, such as cancer, are due in part to a genetic disorders, they can also be caused by environmental factors. Most disorders are quite rare and affect one person in every several thousands or millions...
known to be an inherited disease of the secretory glands, including the glands that make mucus and sweat.
The hallmarks of cystic fibrosis are salty tasting skin, normal appetite but poor growth and poor weight gain, excess mucus production, frequent chest infections and coughing/shortness of breath. Males can be
infertileInfertility 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 deferensCongenital 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:...
. Often, symptoms of CF appear in infancy and childhood. Meconium ileus is a typical finding in newborn babies with CF. As the child grows older, he or she will have to exercise to release mucus stuck to the alveoli. Cilial epithilial cells in the patient have a mutated protein that instead of creating the right resin that is used to prevent the alveoli from collapsing, it makes a thicker resin, mucus. This makes the oxygen extraction in the alveoli harder as the molecules must travel through the mucus leading to breathlessness. Since the mucus stays there most of the time bacteria will thrive in it, causing multiple chest infections.
Although technically a
rare diseaseA rare disease, sometimes known as an orphan disease, is any disease that is not common. Typically, a rare disease has such a low prevalence in a population that a physician in a busy general practice would not expect to see more than one case a year....
, cystic fibrosis is ranked as one of the most widespread life-shortening genetic diseases. It is most common among nations in the Western world; one in twenty-two people of Mediterranean descent is
a carrierA 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...
of one gene for CF, making it the most common genetic disease in these populations. An exception is
FinlandFinland , officially the Republic of Finland
, is a Nordic country and democracy situated in the Fennoscandian region of northern Europe. It borders Sweden on the west, Russia on the east, and Norway on the north, while Estonia lies to its south across the Gulf of 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.
Lung and sinus illness
Lung disease results from clogging the airways due to mucosa build-up and resulting
inflammationInflammation is 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 as well as initiate the healing process for the tissue. Inflammation is not a...
. Inflammation and infection cause injury and structural changes to the lungs, leading to a variety of symptoms. In the early stages, incessant coughing, vomiting, copious
phlegmPhlegm is a sticky fluid secreted by the mucous membranes of humans and other animals. 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...
production, and decreased ability to exercise are common. Many of these symptoms occur when
bacteriaThe bacteria are a large group of unicellular 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 of CF, changes in the architecture of the lung further exacerbate chronic difficulties in breathing. Other symptoms include coughing up blood (
hemoptysisHemoptysis 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 is...
), changes in the major airways in the lungs (
bronchiectasisBronchiectasis is a disease state defined by localized, irreversible dilation of part of the bronchial tree. It is classified as an obstructive lung disease, along with bronchitis and cystic fibrosis. Involved bronchi are dilated, inflamed, and easily collapsible, resulting in airflow obstruction...
), high
blood pressureBlood pressure is the pressure exerted by circulating blood on the walls of blood vessels, and is one of the principal vital signs. During each heartbeat, BP varies between a maximum and a minimum pressure...
in the lung (
pulmonary hypertensionIn 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
oxygenOxygen Oxygen Oxygen (acid, literally "sharp", from the taste of acids) and -γενής (-genēs) (producer, literally begetter) is the element with atomic number 8 and represented by the symbol O...
to the body (
hypoxiaHypoxia may refer to:* Hypoxia , reduced dissolved oxygen content of a body of water detrimental to aerobic organisms* Hypoxia , a pathological condition in which the body as a whole or region of the body is deprived of adequate oxygen supplyIn popular culture:* "Hypoxia" , a 2008 ambient song*...
), and respiratory failure requiring support with breathing masks such as bilevel positive airway pressure machines or
ventilatorsIn 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 or other suitable person compressing a bag or set of bellows...
. In addition to typical bacterial infections, people with CF more commonly develop other types of lung disease. Among these is
allergic bronchopulmonary aspergillosisIn 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
fungusA fungus is any member of a large group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. The Fungi are classified as a kingdom that is separate from plants, animals and bacteria...
Aspergillus fumigatusAspergillus fumigatus is a fungus of the genus Aspergillus, and is one of the most common Aspergillus species to cause disease in immuno-compromised individuals....
causes worsening of breathing problems. Another is infection with
Mycobacterium avium complexMycobacterium avium complex is a group of genetically related bacteria belonging to the genus Mycobacterium. It includes Mycobacterium avium subspecies avium , Mycobacterium avium subspecies hominis , and Mycobacterium avium subspecies paratuberculosis .Historically, MAC has also included...
(MAC), a group of bacteria related to
tuberculosisTuberculosis is a common and often deadly infectious disease caused by mycobacteria...
, which can cause further lung damage and does not respond to common antibiotics.
Mucus in the
paranasal sinusParanasal sinuses are air-filled spaces, communicating with the nasal cavity, within the bones of the skull and face.-Types in humans:Humans possess a number of paranasal sinuses, divided into subgroups that are named according to the bones within which the sinuses lie:*the maxillary sinuses, also...
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
headacheIn medicine a headache or cephalalgia is a symptom of a number of different conditions of the head. Some of the causes are benign while others are medical emergencies.There are a number of different classification systems for headaches...
s. Individuals with CF may develop overgrowth of the nasal tissue (
nasal polypNasal 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 moveable and non-tender.-Description:...
s) due to inflammation from chronic sinus infections. These polyps can block the nasal passages and increase breathing difficulties.
Gastrointestinal, liver and pancreatic disease
Prior to prenatal and
newborn screeningNewborn screening is the process of testing newborn babies for treatable genetic, endocrinologic, metabolic and hematologic diseases. Robert Guthrie is given much of the credit for pioneering the earliest screening for phenylketonuria in the late 1960s using blood samples on filter paper obtained...
, cystic fibrosis was often diagnosed when a newborn infant failed to pass feces (
meconiumMeconium 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
intestinesIn vertebrates, the small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where the vast majority of digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large...
and cause serious illness. This condition, called meconium ileus, occurs in 10% of newborns with CF. In addition, protrusion of internal
rectalThe 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 prolapseRectal 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 in CF because of increased fecal volume, malnutrition, and
increased intra–abdominal pressureThe Valsalva maneuver or Valsalva manoeuvre is performed by forcible 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, an organ responsible for providing
digestive juicesPancreatic juice is a liquid secreted by the pancreas, which contains a variety of enzymes, including trypsinogen, chymotrypsinogen, elastase, carboxypeptidase, pancreatic lipase, and amylase....
which help break down food. These secretions block the movement of the digestive enzymes into the
duodenumThe 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 (
pancreatitisPancreatitis is inflammation of the pancreas that can occur in two very different forms. Acute pancreatitis is sudden while chronic pancreatitis "is characterized by recurring or persistent abdominal pain with or without steatorrhea or diabetes mellitus."...
). The lack of digestive enzymes leads to difficulty absorbing nutrients with their subsequent excretion in the feces, a disorder known as
malabsorptionMalabsorption 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
malnutritionMalnutrition is the insufficient, excessive or imbalanced consumption of nutrients.A number of different nutrition disorders may arise, depending on which nutrients are under or overabundant in the diet....
and poor growth and development because of calorie loss. Individuals with CF also have difficulties absorbing the fat-soluble vitamins
AVitamin A is linked to a family of similarly shaped molecules, the retinoids, which complete the remainder of the vitamin sequence. Its important part is the retinyl group, which can be found in several forms. In foods of animal origin, the major form of vitamin A is an ester, primarily retinyl...
,
DVitamin D is a group of fat-soluble prohormones, the two major forms of which are vitamin D2 and vitamin D3 . Vitamin D obtained from sun exposure, food, and supplements, is biologically inert and must undergo two hydroxylation reactions to be activated in the body...
,
EVitamin E is a generic term for tocopherols and tocotrienols. Vitamin E is a family of α-, β-, γ-, and δ-tocopherols and corresponding four tocotrienols. Vitamin E is a fat-soluble antioxidant that stops the production of reactive oxygen species formed when fat undergoes oxidation...
, and
KVitamin K denotes a group of lipophilic, hydrophobic vitamins that are needed for the posttranslational modification of certain proteins, mostly required for blood coagulation...
. In addition to the pancreas problems, people with cystic fibrosis experience more
heartburnGastroesophageal reflux disease ', gastro-oesophageal reflux disease ', gastric reflux disease, or acid reflux disease is defined as chronic symptoms or mucosal damage produced by the abnormal reflux inthe esophagus....
, intestinal blockage by
intussusceptionAn intussusception is a medical condition in which a part of the small intestine has in-vaginated 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
constipationConstipation, costiveness, or irregularity is a condition of the digestive system in which a person experiences hard feces that are difficult to expel. This usually happens because the colon absorbs too much water from the food...
. Older individuals with CF may also develop
distal intestinal obstruction syndromeDistal 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.
Thickened secretions also may cause liver problems in patients with CF.
BileBile or gall is a bitter yellowish, blue and green fluid secreted by hepatocytes from the liver of most vertebrates. In many species, bile is stored in the gallbladder between meals and upon eating is discharged into the duodenum where the bile aids the process of digestion of lipids by...
secreted by the liver to aid in digestion may block the
bile ductA 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
cirrhosisCirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrous scar tissue as well as regenerative nodules , leading to progressive loss of liver function...
, in which the liver fails to rid the blood of toxins and does not make important
proteinProteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer chain are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues...
s such as those responsible for
blood clottingCoagulation is a complex process by which blood forms clots. It is an important part of hemostasis , 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...
.
Endocrine disease and growth
The
pancreasThe 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 an exocrine gland, secreting pancreatic juice containing digestive enzymes that pass to...
contains the
islets of LangerhansThe islets of Langerhans are the regions of the pancreas that contain its endocrine cells. Discovered in 1869 by German pathological anatomist Paul Langerhans, 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
glucoseGlucose , a monosaccharide also known as - grape sugar, blood sugar, or corn sugar, is a very important carbohydrate in biology. The living cell uses it as a source of energy and metabolic intermediate...
. Damage of the pancreas can lead to loss of the islet
cellThe cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of an organism that is classified as living, 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 and Type 2 diabetics and is one of the principal non-pulmonary complications of CF. Vitamin D is involved in
calciumCalcium 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 grey alkaline earth metal, and is the fifth most abundant element by mass in the Earth's crust...
and
phosphorusPhosphorus is the chemical element that has the symbol P and atomic number 15. A multivalent nonmetal of the nitrogen group, phosphorus is commonly found in inorganic phosphate rocks. Elemental phosphorus exists in two major forms - white phosphorus and red phosphorus...
regulation. Poor uptake of vitamin D from the diet because of malabsorption can lead to the bone disease
osteoporosisOsteoporosis is a disease of bone that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in bone is altered...
in which weakened bones are more susceptible to
fractureA 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
clubbingIn medicine, clubbing is a deformity of the fingers and fingernails that is associated with a number of diseases, mostly of the heart and lungs. Idiopathic clubbing can also occur...
of their fingers and toes due to the effects of chronic illness and
low oxygenHypoxia 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.
Poor growth is a hallmark of CF. Children with CF typically do not gain weight or height at the same rate as their peers, and occasionally are 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.
Infertility
InfertilityInfertility 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 percent of men with cystic fibrosis are infertile but are not sterile and can have children with assisted reproductive techniques. These men make normal
spermA sperm, from the ancient Greek word σπέρμα and and more commonly known as a sperm cell, is the haploid cell that is the male gamete. It joins an ovum to form a zygote. A zygote is a single cell, with a complete set of chromosomes, that normally develops into an embryo.Sperm cells contribute...
but are missing the tube (
vas deferensThe vas deferens , also called ductus deferens, , is part of the male anatomy of some species; they transport sperm from the epididymis in anticipation of ejaculation.-Structure:...
), which connects the
testesThe testicle is the male generative gland in animals.The etymology of the word is based on Roman law...
to the
ejaculatory ductThe Ejaculatory ducts are paired structures in male anatomy, about 2 cm in length.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 empty into the urethra at the Colliculus seminalis...
s of the
penisThe penis is an external sexual organ of certain biologically male organisms, in both vertebrates and invertebrates....
. Many men found to have
congenital absence of the vas deferensCongenital 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
ovulationOvulation is the process in the females menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum that participates in reproduction...
and causes amenorrhea.
Cause
CF is caused by a
mutationIn biology, a mutation is a randomly derived change to the nucleotide sequence of the genetic material of an organism.Mutations can be caused by copying errors in the genetic material during cell division, or by exposure to mutagens , or can be induced by the organism itself, by cellular processes...
in the
geneA gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain their cells and pass genetic traits to offspring...
cystic fibrosis transmembrane conductance regulatorCFTR is a human gene that provides instructions for making a protein called the cystic fibrosis transmembrane conductance regulator. This protein functions as an ion channel across the cell membrane...
(CFTR). The
product of this geneCystic fibrosis transmembrane conductance regulator is an ABC transporter-class protein and ion channel that transports chloride ions across epithelial cell membranes...
is a chloride ion channel important in creating sweat,
digestiveDigestion is the mechanical and chemical breaking down of food into smaller components, to a form that can be absorbed, for instance, by a blood stream. Digestion is a form of catabolism.that means break down of macro food molecules to smaller one....
juices and
mucusIn vertebrates, mucus is a slippery secretion produced by, and covering, mucous membranes. It is a viscous colloid containing antiseptic enzymes and immunoglobulins that serves to protect epithelial cells in the respiratory,...
. Although most people without CF 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. Therefore, CF is considered an autosomal recessive disease.
Pathophysiology
The protein created by this gene is anchored to the
outer membraneThe cell membrane is the biological membrane separating the interior of a cell from the outside environment....
of
cellThe cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of an organism that is classified as living, 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 glandSweat glands are exocrine glands, found in the skin of all mammal species, that are used for body temperature regulation. In humans a system of apocrine - and merocrine sweat glands is the main method of cooling. Many other mammals rely on panting or other means as a primary source of cooling, but...
s, lungs, pancreas, and other affected
organIn biology and anatomy, an organ is a collection of tissues joined in structural unit to serve a common function ....
s. The protein spans this membrane and acts as a
channelIon channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of all living 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 (
cytoplasmThe cytoplasm is the part of a cell that is enclosed within the cell membrane. In eukaryotic cells, the cytoplasm contains organelles, such as mitochondria, which are filled with liquid that is kept separate from the rest of the cytoplasm by biological membranes. The contents of the cell nucleus...
) to the
surrounding fluidExtracellular 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 chloride 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 is trapped inside the cells in the airway and outside in the skin. Because chloride is
negatively chargedElectric charge is a fundamental conserved property of some subatomic particles, which determines their electromagnetic interaction. Electrically charged matter is influenced by, and produces, electromagnetic fields...
, positively charged cations cross into the cell because they are affected by the
electrical attractionElectrostatics is the branch of science that deals with the phenomena arising from stationary or slow-moving electric charges.Since classical antiquity it was known that some materials such as amber attract light particles after rubbing. The Greek word for amber, ήλεκτρον , was the source of the...
of the chloride ions. Sodium is the most common ion in the extracellular space and the combination of sodium and chloride creates the
saltSodium chloride, also known as salt, common salt, table salt, or halite, is an ionic 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.
How this malfunction of cells in cystic fibrosis causes the clinical manifestations of CF is not well understood. One theory suggests that the lack of chloride exodus 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 systemAn immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumour 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 proposes 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 focuses on abnormal chloride movement
out of the cell, which also leads to dehydration of mucus, pancreatic secretions, biliary secretions, etc. These theories all support the observation that the majority 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.
Diagnosis and monitoring
Cystic fibrosis may be diagnosed by many different categories of testing including those such as,
newborn screeningNewborn screening is the process of testing newborn babies for treatable genetic, endocrinologic, metabolic and hematologic diseases. Robert Guthrie is given much of the credit for pioneering the earliest screening for phenylketonuria in the late 1960s using blood samples on filter paper obtained...
,
sweat testThe sweat test measures the concentration of chloride and sodium that is excreted in sweat. It is used to diagnose cystic fibrosis .-Background:...
ing, or
genetic testingGenetic testing allows the genetic diagnosis of vulnerabilities to inherit diseases, and can also be used to determine a child's paternity or a person's ancestry. Normally, every person carries two copies of every gene, one inherited from their mother, one inherited from their father. The human...
. 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 trypsinogenMeasurement 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 in order to confirm the CF diagnosis.
TrypsinogenTrypsinogen is the precursor form of the pancreatic enzyme trypsin or a zymogen. 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, even in individuals with two normal copies of the
CFTR gene. Due to these false positives, CF screening in newborns is somewhat controversial. Most states and countries do not screen for CF routinely at birth. Therefore, most individuals are diagnosed after symptoms 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 (
pilocarpinePilocarpine is a muscarinic 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 topical...
) to one
electrodeAn electrode is an electrical conductor used to make contact with a nonmetallic part of a circuit...
of an apparatus and running
electric currentElectric current can mean, depending on the context, a flow of electric charge or the rate of flow of electric charge ....
to a separate electrode on the skin. This process, called
iontophoresisIontophoresis is using a small electric charge to deliver a medicine or other chemical through the skin. Basically an injection without the needle...
, causes sweating; the sweat is then collected on filter paper or in a capillary tube and analyzed for abnormal amounts of
sodiumSodium is a metallic element with a symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals within "group 1"...
and
chlorideThe chloride ion is formed when the element chlorine picks up one electron to form an anion Cl
−...
. People with CF have increased amounts of sodium and chloride in their sweat. CF can also be diagnosed by identification of mutations in the CFTR gene.
A multitude of tests are used to identify complications of CF and to monitor disease progression.
X-raysRadiology is the branch or specialty of medicine that deals with the study and application of imaging technology like x-ray and radiation to diagnosing and treating disease....
and
CAT scansComputed tomography is a medical imaging method employing tomography created by computer processing. Digital geometry processing is used to generate a three-dimensional image of the inside of an object from a large series of two-dimensional X-ray images taken around a single axis of rotation.CT...
are used to examine the lungs for signs of damage or infection. The
examination of the sputumA sputum culture is a test to detect and identify bacteria or fungi that infect the lungs or breathing passages. Sputum is a thick fluid produced in the lungs and in the adjacent airways. A sample of sputum is placed in a sterile container and sent to the laboratory for testing...
is required to isolate organisms which may be causing an infection or colonising the lower respiratory tract so that
effectiveAntibiotic resistance is the ability of a microorganism to withstand the effects of antibiotics. It is a specific type of drug resistance. Antibiotic resistance evolves via natural selection acting upon random mutation, but it can also be engineered by applying an evolutionary stress on a population...
antimicrobial therapy can be provided. Culture for organisms such as Burkholderia (previously Pseudomonas) cepacia is required for candidates of Lung transplantation as persisant bacterial colonisation reduces the chances of survival.
Pulmonary function testsSpirometry is the most common of the Pulmonary Function Tests , measuring lung function, specifically the measurement of the amount and/or speed of air that can be inhaled and exhaled...
measure how well the lungs are functioning, and are used to measure the need for and response to antibiotic therapy.
Blood testA blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....
s can identify liver abnormalities,
vitamin deficienciesAvitaminosis is any disease caused by chronic or long-term vitamin deficiency or caused by a defect in metabolic conversion, such as tryptophan to niacin...
, and the onset of diabetes.
DEXA scansDual energy X-ray absorptiometry is a means of measuring bone mineral density . Two X-ray beams with differing energy levels are aimed at the patient's bones. When soft tissue absorption is subtracted out, the BMD can be determined from the absorption of each beam by bone...
can
screenScreening, in medicine, is a strategy used in a population to detect a disease in individuals without signs or symptoms of that disease. Unlike most medicine, in screening, tests are performed on those without any clinical indication of disease....
for osteoporosis and testing for
fecal elastaseFecal elastase refers to the testing of the concentration of the pancreatic elastase-1 enzyme found in fecal matter with an enzyme-linked immunosorbent assay . Results of this test can give a good indication of exocrine pancreatic status and is less invasive and expensive that the current “gold...
can help diagnose insufficient digestive enzymes.
Prenatal diagnosis
Couples who are pregnant or who are planning a pregnancy can themselves be tested for CFTR gene mutations to determine the likelihood 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 found to be high, testing on the
fetusA fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth. The plural is fetuses....
can then be performed. Cystic fibrosis testing is offered to many couples in the US. The
American College of Obstetricians and GynecologistsThe American College of Obstetricians and Gynecologists is a professional association of medical doctors specializing in obstetrics and gynecology in the United States. It has a membership of over 52,000 and represents 90 percent of U.S...
(ACOG) recommends testing for couples who have a personal or close family history. Additionally, ACOG recommends 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 on just one parent initially. If that parent is found to be a carrier of a CFTR gene mutation, the other parent is then 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. In addition, because the mutations tested are necessarily those most common in the highest risk groups, testing in lower risk ethnicities is less successful because the mutations commonly seen in these groups are less common in the general population. These couples may therefore consider testing through labs that offer CF screens with a high number of mutations tested.
Couples who are at high risk for having a child with CF will often opt to perform further testing before or during pregnancy. In vitro fertilization with
preimplantation genetic diagnosisIn medicine and genetics preimplantation genetic diagnosis refers to procedures that are performed on embryos prior to implantation, sometimes even on oocytes prior to fertilization. PGD is considered another way to prenatal diagnosis...
offers the possibility to examine the
embryoAn embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
prior to its placement into the uterus. The test, performed 3 days after fertilization, looks for the presence of abnormal CF genes. If two mutated CFTR genes are identified, the embryo is not used for
embryo transferEmbryo transfer refers to a step in the process of in vitro fertilization whereby one or several embryos are placed into the uterus of the female with the intent to establish a pregnancy.- Fresh versus frozen :...
and an embryo with at least one normal gene is implanted.
During pregnancy, testing can be performed on the
placentaThe placenta is an organ unique to mammals that connects the developing fetus to the uterine wall. The placenta supplies the fetus with oxygen and food, and allows fetal waste to be disposed of via the maternal kidneys...
(
chorionic villus samplingChorionic villus sampling is a form of prenatal diagnosis to determine chromosomal or genetic disorders in the fetus. It entails getting a sample of the chorionic villus and testing it...
) or the fluid around the fetus (
amniocentesisAmniocentesis , 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 extracted from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined...
). However,
chorionic villus samplingChorionic villus sampling is a form of prenatal diagnosis to determine chromosomal or genetic disorders in the fetus. It entails getting a sample of the chorionic villus and testing it...
has a risk of fetal death of 1 in 100 and amniocentesis of 1 in 200, although a recent study has indicated this may actually be much lower, perhaps 1 in 1,600,
http://www.webmd.com/content/article/129/117333.htm so the benefits must be determined to outweigh these risks prior to going forward with testing. Alternatively, some couples choose to undergo
third party reproductionThird party reproduction refers to a process where another person provides sperm or eggs or where another woman provides her uterus so that a woman can have a child. Thus the reproductive process goes beyond the traditional father-mother model. However, the third party's involvement is limited to...
with
eggEgg donation is the process by which a woman provides one or several eggs for purposes of assisted reproduction or biomedical research. For assisted reproduction purposes, egg donation involves the process of in vitro fertilization as the eggs are fertilized in the laboratory. After the eggs...
or
sperm donorsSperm donation is the name of the provision by a man, known as a sperm donor, of his semen with the intention that it be used to achieve a pregnancy and produce a baby in a woman who is not the man's sexual partner....
}.
The role of chronic infection in lung disease
The lungs of individuals with cystic fibrosis are colonized and infected by bacteria from an early age. These bacteria, which often spread amongst individuals with CF, thrive in the altered mucus, which collects in the small airways of the lungs. This mucus encourages the development of bacterial microenvironments (
biofilmA biofilm is an aggregate of microorganisms in which cells are stuck to each other and/or to a surface. These adherent cells are frequently embedded within a self-produced matrix of extracellular polymeric substance . Biofilm EPS, which is also referred to as "slime," is a polymeric jumble of...
s) that are difficult for immune cells (and antibiotics) to penetrate. The lungs respond to repeated damage by thick secretions and chronic infections by gradually remodeling the lower airways (
bronchiectasisBronchiectasis is a disease state defined by localized, irreversible dilation of part of the bronchial tree. It is classified as an obstructive lung disease, along with bronchitis and cystic fibrosis. Involved bronchi are dilated, inflamed, and easily collapsible, resulting in airflow obstruction...
), making 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 aureusStaphylococcus aureus is the most common cause of staph infections. It is a spherical bacterium, frequently part of the skin flora found in the nose and on skin. About 20% of the population are long-term carriers of S. aureus. S...
and
Hemophilus influenzae colonize and infect the lungs. Eventually, however,
Pseudomonas aeruginosaPseudomonas aeruginosa is a common bacterium which can cause disease in animals and 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 with little oxygen, and has thus colonised many natural and...
(and sometimes
Burkholderia cepaciaBurkholderia cepacia complex , or simply Burkholderia cepacia is a group of catalase-producing, non-lactose-fermenting Gram-negative bacteria composed of at least nine different species, including B. cepacia, B. multivorans, B. cenocepacia, B. vietnamiensis, B. stabilis, B. ambifaria, B. dolosa, B....
) dominates. Once within the lungs, these bacteria adapt to the environment and develop
resistanceAntibiotic resistance is the ability of a microorganism to withstand the effects of antibiotics. It is a specific type of drug resistance. Antibiotic resistance evolves via natural selection acting upon random mutation, but it can also be engineered by applying an evolutionary stress on a population...
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 in which infection has spread is by passage 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
nebulizerIn medicine, a nebulizer is a device used to administer medication to people in the form of a mist inhaled into the lungs. It is commonly used in treating cystic fibrosis, asthma, and other respiratory diseases....
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 in order to limit the spread of virulent bacterial strains. Often, patients with particularly damaging bacteria will attend clinics on different days and in different buildings than those without these infections.
Molecular biology
The
CFTR geneCFTR is a human gene that provides instructions for making a protein called the cystic fibrosis transmembrane conductance regulator. This protein functions as an ion channel across the cell membrane...
is found at the q31.2
locusIn the fields of genetics and evolutionary 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 pairIn molecular biology, two nucleotides on opposite complementary DNA or RNA strands that are connected via hydrogen bonds are called a base pair . In the canonical Watson-Crick base pairing, adenine forms a base pair with thymine , as does guanine with cytosine in DNA. In RNA, thymine is replaced...
s long, and creates a protein that is 1,480
amino acidAmino acids are molecules containing an amine group, a carboxylic acid group and one of the twenty R-groups. These molecules are particularly important in biochemistry, where this term refers to alpha-amino acids with the general formula H
2NCHRCOOH, where R is an organic substituent...
s long. The most common mutation, ΔF508, is a deletion (Δ) of three nucleotides that results in a loss of the amino acid
phenylalaninePhenylalanine is an α-amino acid with the formula HO
2CCHCH
2C
6H
5. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. The codons for
L-phenylalanine are UUU and UUC...
(F) at the 508th (508) position on the protein. This mutation accounts for two-thirds of CF cases worldwide and 90 percent of cases in the
United StatesThe United States of America is a federal constitutional republic comprising fifty states and a federal district...
; however, there are over 1,400 other mutations that can produce CF. In
CaucasianThe term Caucasian race has been used to denote the general physical type of some or all of the indigenous populations of Europe, North Africa, the Horn of Africa, West Asia, Central Asia, and South Asia...
populations, the frequency of mutations is as follows:
| Mutation |
Frequency
worldwide |
| ΔF508 |
66.0% |
| G542X |
2.4% |
| G551D |
1.6% |
| N1303K |
1.3% |
| W1282X |
1.2% |
| All others |
27.5% |
The distribution of these alleles varies among populations. The frequency of ΔF508 carriers has been estimated to be 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, and within these families ΔF508 occurs in 45% of chromosomes carrying a cystic fibrosis mutation.
There are several mechanisms by which these mutations cause problems with the CFTR protein. ΔF508, for instance, creates a protein that does not
foldProtein folding 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. Several mutations, which are common in the Ashkenazi Jewish population, result in proteins that are too short because
productionTranslation is the first stage of protein biosynthesis . Translation is the production of proteins by decoding mRNA produced in transcription. Translation occurs in the cytoplasm where the ribosomes are located. Ribosomes are made of a small and large subunit which surrounds the mRNA...
is ended prematurely. Less common mutations produce proteins that do not use energy normally, do not allow chloride 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.
Structurally, CFTR is a type of gene known as an
ABC geneATP-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...
. Its protein possesses two
ATP-hydrolyzingATP 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
energyIn physics, energy is a scalar physical quantity that describes the amount of work that can be performed by a force, an attribute of objects and systems that is subject to a conservation law...
in the form of
ATPAdenosine-5'-triphosphate is a multifunctional nucleotide that plays an important role in cell biology as a coenzyme, that is, 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 helicesA common motif in the secondary structure of proteins, the alpha helix is a right- or left-handed coiled conformation, resembling a spring, 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 siteIn 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, or more specifically, protein ligands—form a chemical bond....
on the protein allows activation by
phosphorylationPhosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation turns many protein enzymes on and off, causing or preventing the mechanisms of diseases such as cancer and diabetes....
, mainly by
cAMP-dependent protein kinaseprotein kinase A refers to a family of enzymes whose activity is dependent on the level of cyclic AMP in the cell, in cell biology. PKA is also known as cAMP-dependent protein kinase ). Protein kinase A has several functions in the cell, including regulation of glycogen, sugar, and lipid...
. The
carboxyl terminalThe C-terminus of a protein or polypeptide is the end of the amino acid chain terminated by a free carboxyl group...
of the protein is anchored to the
cytoskeletonThe cytoskeleton is a cellular "scaffolding" or "skeleton" contained within the cytoplasm. The cytoskeleton is present in all cells; it was once thought this structure was unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
by a PDZ domain interaction.
Management
The cornerstones of management are proactive treatment of
airway infectionRespiratory tract infections can refer to:* Lower respiratory tract infection* Upper respiratory tract infection...
, and encouragement of good nutrition and an active lifestyle. The treatment for 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. Treatment typically occurs at specialist multidisciplinary centres, and is tailored to the individual, because of the wide variation in disease symptoms. Targets for therapy are the lungs,
gastrointestinal tractThe human gastrointestinal tract , digestive tract, guts or gut is the system of organs within humans that takes in food, digests it to extract energy and nutrients, and expels the remaining matter...
(including
insulinInsulin is a hormone that has extensive effects on metabolism and other body functions, such as vascular compliance. 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, and stopping use of fat as an energy...
treatment and pancreatic enzyme supplements), the reproductive organs (including
Assisted Reproductive TechnologyAssisted 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. In addition, therapies such as
transplantationOrgan transplant is the moving of an organ from one body to another , for the purpose of replacing the recipient's damaged or failing organ with a working one from the donor site. Organ donors can be living or deceased...
and
gene therapyGene therapy is the insertion of genes into an individual's cells and tissues to treat a disease, such as a hereditary disease in which a deleterious mutant allele is replaced with a functional one. Although controversial, Gene Therapy can also be used for human genetic enhancement changing one's...
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).
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 lifeThe 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 political science. Quality of life should not be confused with the concept of...
.
IntravenousIntravenous therapy or IV therapy is the giving of liquid substances directly into a vein. It can be intermittent or continuous; continuous administration is called an intravenous drip. The word intravenous simply means "within a vein", but is most commonly used to refer to IV therapy...
,
inhaledInhalation is the movement of air from the external environment, through the air ways, and into the alveoli.Inhalation begins with the onset of contraction of the diaphragm, which results in expansion of the intrapleural space and an increase in negative pressure according to Boyle's Law...
, 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 to the patient. One of the most important battles that CF patients face is finding the time to comply with all the prescribed treatments while balancing a normal life.
Antibiotics to treat lung disease
Many CF patients are on one or more antibiotics at all times, even when they are considered healthy, to suppress the infection as much as possible. Antibiotics are absolutely necessary whenever pneumonia is suspected or there has been a noticeable decline in lung function. Antibiotics are usually chosen based on the results of a sputum analysis and the patient's past response. Many bacteria common in cystic fibrosis are resistant to multiple antibiotics and require weeks of treatment with intravenous antibiotics such as
vancomycinVancomycin is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of vancomycin-resistant...
,
tobramycinTobramycin sulfate is an aminoglycoside antibiotic used to treat various types of bacterial infections, particularly Gram-negative infections.-Mechanism of action:...
,
meropenemMeropenem is an ultra-broad spectrum injectable antibiotic used to treat a wide variety of infections, including meningitis and pneumonia. It is a beta-lactam and belongs to the subgroup of carbapenem, similar to imipenem and ertapenem. Meropenem was originally developed by Sumitomo Pharmaceuticals...
,
ciprofloxacinCiprofloxacin is a drug used to treat bacterial infections. It is a second generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops DNA and protein synthesis....
, and
piperacillinPiperacillin is an extended spectrum beta-lactam antibiotic of the ureidopenicillin class. It is normally used together with a beta-lactamase inhibitor such as tazobactam, which is commercially available as TAZOMEDTazocin, Zobactin or Zosyn...
. This prolonged therapy often necessitates hospitalization and insertion of a more permanent IV such as a
PICC lineA peripherally inserted central catheter is a form of intravenous access that can be used for a prolonged period of time...
or Port-a-Cath. Inhaled therapy with antibiotics such as tobramycin and
colistinColistin 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 polypeptide antibiotic...
is often given for months at a time in order to improve lung function by impeding the growth of colonized bacteria. Inhaled therapy with the antibiotic
aztreonamAztreonam is a synthetic monocyclic beta-lactam antibiotic originally isolated from Chromobacterium violaceum. It was approved by the U.S. Food and Drug Administration in 1986...
is also being developed and clinical trials have shown great promise. Oral antibiotics such as ciprofloxacin or
azithromycinAzithromycin is an azalide, a subclass of macrolide antibiotics.Azithromycin is one of the world's best-selling antibiotics, and is derived from erythromycin; however, it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring, thus...
are given to help prevent infection or to control ongoing infection. Some individuals spend years between hospitalizations for antibiotics, whereas others require several antibiotic treatments each year.
Several common antibiotics such as tobramycin and vancomycin can cause
hearing lossOtotoxicity 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 systemThe vestibular system, which contributes to our balance and our sense of spatial orientation, is the sensory system that provides the dominant input about movement and equilibrioception. Together with the cochlea, a part of the auditory system, it constitutes the labyrinth of the inner ear,...
in the
inner earThe inner ear is the bony labyrinth, a system of passages comprising two main functional parts:* The cochlea is the hearing part of the inner ear.* The semicircular canals , the utricle and the saccule are the balance part of the inner ear...
or
kidney problemsRenal failure or kidney failure is a situation in which the kidneys fail to function adequately. It is divided into acute and chronic forms; either form may be due to a large number of other medical problems....
with long-term use. In order to prevent these
side-effectAn adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dose. The meaning of this expression differs from the meaning of "side effect", as this last expression might also imply that the effects can be beneficial...
s, the amount of antibiotics in the blood are routinely measured and adjusted accordingly.
Other methods to treat 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 VestThe ThAIRapy Vest is a device and system for clearing excess mucus from lung airways . It is principally used in the treatment of cystic fibrosis, but is gaining use in the treatment of other diseases, such as bronchiectasis, COPD, cerebral palsy and muscular dystrophy, in which excessive mucus can...
(pioneered under Dr.
Warren J WarwickWarren J. Warwick is an American pediatrician, notable for inventing a mechanical vest for clearing the lungs of children with cystic fibrosis. He is Professor of Pediatric Pulmonology at the University of Minnesota and director from 1962 to 1999 of the Cystic Fibrosis Center at the University of...
at the University of Minnesota) and the
intrapulmonary percussive ventilatorIntrapulmonary 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 VentilationBiphasic 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, now integrate a cough assistance phase, as well as a vibration phase for dislodging secretions.
Biphasic Cuirass VentilationBiphasic 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...
is also shown to provide a bridge to transplantation. These are portable and adapted for home use.
Physiotherapy is essential to help manage an individuals chest on a long term basis, and can also teach techniques for the older child and teenager to manage themselves at home.
Aerobic exerciseAerobic exercise is exercise that involves or improves oxygen consumption by the body. Aerobic means "with oxygen", and refers to the use of oxygen in the body's metabolic or energy-generating process...
is of great benefit to people with cystic fibrosis. Not only does exercise increase sputum clearance but it also improves cardiovascular and overall health.
Aerosolized medications that help loosen secretions include
dornase alfaDornase 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
salineIn medicine, saline is a general term referring to a sterile solution of sodium chloride in water. It is used for intravenous infusion, rinsing contact lenses, and nasal irrigation. Saline solutions are available in various formulations for different purposes...
. Dornase is a
recombinantRecombinant DNA is a form of DNA that does not exist naturally, which is created by combining DNA sequences that would not normally occur together...
human
deoxyribonucleaseA deoxyribonuclease is any enzyme that catalyzes the hydrolytic cleavage of phosphodiester linkages in the DNA backbone. Deoxyribonucleases are thus one type of nuclease...
, which breaks down DNA in the
sputumSputum is matter that is expectorated from the respiratory tract, such as mucus or phlegm, mixed with saliva, which can then be spat from the mouth. It is usually associated with air passages in diseased lungs, bronchi, or upper respiratory tract...
, thus decreasing its
viscosityViscosity is a measure of the resistance of a fluid which is being deformed by either shear stress or extensional stress. In everyday terms , viscosity is "thickness." Thus, water is "thin," having a lower viscosity, while honey is "thick," having a higher viscosity...
.
N-AcetylcysteineAcetylcysteine , also known as N-acetylcysteine or N-acetyl-L-cysteine , is a pharmaceutical drug used mainly as a mucolytic agent and in the management of paracetamol overdose....
may also decrease sputum viscosity, but research and experience have shown its benefits to be minimal. Albuterol and ipratropium bromide are inhaled to increase the size of the small airways by relaxing the surrounding muscles.
As lung disease worsens, breathing support from machines 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, people with CF may need to have a
tubeIn medicine, intubation refers to the placement of a tube into an external or internal orifice of the body. Although the term can refer to endoscopic procedures, it is most often used to denote tracheal intubation. Tracheal intubation is the placement of a flexible plastic tube into the trachea to...
placed in their throats (a procedure known as a tracheostomy) and their breathing supported by a ventilator.
Treatment of other aspects of CF
Newborns with meconium ileus 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 faeces. Even so, most individuals with CF take additional amounts of vitamins
AVitamin A is linked to a family of similarly shaped molecules, the retinoids, which complete the remainder of the vitamin sequence. Its important part is the retinyl group, which can be found in several forms. In foods of animal origin, the major form of vitamin A is an ester, primarily retinyl...
,
DVitamin D is a group of fat-soluble prohormones, the two major forms of which are vitamin D2 and vitamin D3 . Vitamin D obtained from sun exposure, food, and supplements, is biologically inert and must undergo two hydroxylation reactions to be activated in the body...
,
EVitamin E is a generic term for tocopherols and tocotrienols. Vitamin E is a family of α-, β-, γ-, and δ-tocopherols and corresponding four tocotrienols. Vitamin E is a fat-soluble antioxidant that stops the production of reactive oxygen species formed when fat undergoes oxidation...
, and
KVitamin K denotes a group of lipophilic, hydrophobic vitamins that are needed for the posttranslational modification of certain proteins, mostly required for blood coagulation...
and eat high-calorie meals. It should be noted, however, that nutritional advice given to patients is, at best, mixed: Often, literature encourages the eating of high-fat foods without differentiating between
saturatedSaturated fat is fat that consists of triglycerides containing only saturated fatty acid radicals. There are several kinds of naturally occurring saturated fatty acids, which differ by the number of carbon atoms, ranging from 3 carbons to 36...
,
unsaturated fatAn unsaturated fat is a fat or fatty acid in which there are one or more double bonds in the fatty acid chain. A fat molecule is monounsaturated if it contains one double bond, and polyunsaturated if it contains more than one double bond. Where double bonds are formed, hydrogen atoms are...
, and
trans-fatsTrans fat is the common name for unsaturated fat with trans-isomer fatty acid. Trans fats may be monounsaturated or polyunsaturated but never saturated.Unsaturated fat is a fat molecule, containing one or more double bonds between the carbon atoms...
; this lack of clear information runs counter to health advice given to the general population, and creates the risk of further serious health problems for people with cystic fibrosis as they grow older. So far, no large-scale research involving the incidence of
atherosclerosisAtherosclerosis is the condition in which an artery wall thickens as the result of a build-up of fatty materials such as cholesterol...
and
coronary heart diseaseCoronary 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...
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.
The
diabetesDiabetes mellitus —often referred to simply as diabetes—is a condition in which the body either does not produce enough, or does not properly respond to, insulin, a hormone produced in the pancreas. Insulin enables cells to absorb glucose in order to turn it into energy...
common to many CF patients is typically treated with
insulinInsulin is a hormone that has extensive effects on metabolism and other body functions, such as vascular compliance. 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, and stopping use of fat as an energy...
injections or an
insulin pumpThe 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:...
. Development of osteoporosis can be prevented by increased intake of vitamin D and
calciumCalcium 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 grey alkaline earth metal, and is the fifth most abundant element by mass in the Earth's crust...
, and can be treated by
bisphosphonateIn pharmacology, bisphosphonates are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases....
s. Poor growth may be avoided by insertion of a
feeding tubeA 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 enteral feeding or tube feeding. Placement may be temporary for the treatment of acute conditions or lifelong in the case of chronic...
for increasing
calorieThe calorie is a pre-SI metric unit of energy. The unit was first defined by Professor Nicolas Clément in 1824 as a unit of heat. This definition entered 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 hormoneGrowth hormone is a protein-based poly-peptide hormone. It stimulates growth and cell reproduction and regeneration in humans and other animals. It is a 191-amino acid, single-chain polypeptide hormone that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of...
.
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
fluticasoneFluticasone is a synthetic glucocorticoid.Both the and propionate forms are used as topical anti-inflammatories:*Fluticasone propionate*Fluticasone furoate-See also:*Fluticasone furoate*Fluticasone propionate*Anti-inflammatory uses of glucocorticoids...
are used to decrease nasal inflammation. Female infertility may be overcome by
assisted reproductionIn vitro fertilisation is a process by which egg cells are fertilised by sperm outside the womb, in vitro. IVF is a major treatment in infertility when other methods of assisted reproductive technology have failed...
technology, particularly
embryo transferEmbryo transfer refers to a step in the process of in vitro fertilization whereby one or several embryos are placed into the uterus of the female with the intent to establish a pregnancy.- Fresh versus frozen :...
techniques. Male infertility may be overcome with
intracytoplasmic sperm injectionIntracytoplasmic sperm injection is an in vitro fertilization procedure in which a single sperm is injected directly into an egg...
. Third party reproduction is also a possibility for women with CF.
Transplantation and gene therapy
Lung transplantationLung 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 toleranceExercise 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 would 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 approaches a point where it threatens survival or requires assistance from mechanical devices. This point is typically when lung function declines to approximately 20 to 30 percent, however there is a small time frame when transplantation is feasible as the patient must be healthy enough to endure the procedure.
Gene therapyGene therapy is the insertion of genes into an individual's cells and tissues to treat a disease, such as a hereditary disease in which a deleterious mutant allele is replaced with a functional one. Although controversial, Gene Therapy can also be used for human genetic enhancement changing one's...
holds promise as a potential avenue to cure cystic fibrosis. Gene therapy attempts to place a normal copy of the
CFTR geneCFTR is a human gene that provides instructions for making a protein called the cystic fibrosis transmembrane conductance regulator. This protein functions as an ion channel across the cell membrane...
into affected cells. Studies have shown that to prevent the lung manifestations of cystic fibrosis, only 5–10% the normal amount of CFTR
gene expressionGene 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 rRNA genes or tRNA 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, at this time gene therapy is still a relatively inefficient treatment option. Ideally, transferring the normal CFTR gene into the affected epithelium cells would result in the production of functional
CFTRCystic fibrosis transmembrane conductance regulator is an ABC transporter-class protein and ion channel that transports chloride ions across epithelial cell membranes...
in all target cells, without adverse reactions or an inflammation response. But if too few cells take up the vector and express the gene, the treatment has little effect. Additionally, problems have been noted in cDNA recombination, such that the gene introduced by the treatment is rendered unusable.
Research
Since cystic fibrosis is a genetic disease, the only way to prevent or cure it would be with
gene therapyGene therapy is the insertion of genes into an individual's cells and tissues to treat a disease, such as a hereditary disease in which a deleterious mutant allele is replaced with a functional one. Although controversial, Gene Therapy can also be used for human genetic enhancement changing one's...
at an early age. Ideally, gene therapy could repair or replace the defective gene. Another option for treatment would be to give a person with cystic fibrosis the active form of the protein product that is scarce or missing.
Lung transplantationLung 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.
Foundations, trusts and organizations
There are many foundations and trusts dedicated to researching cures and treatments for cystic fibrosis, and assisting people suffering from the disease. A
list of cystic fibrosis organizations is available and more information can be found on the disease and living with cystic fibrosis from these organizations.
Prognosis
Average life expectancy is around 36.8 years according to the Cystic Fibrosis Foundation, although improvements in treatments mean persons born in recent years may expect to live longer.
Epidemiology
Cystic fibrosis is the most common life-limiting autosomal recessive disease among people of
EuropeEurope 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 water divide of the Ural Mountains, the Ural River, the Caspian Sea, the Caucasus Mountains , and the Black Sea to the southeast...
an heritage. In the United States, approximately 30,000 individuals have CF; most are diagnosed by six months of age.
CanadaCanada is a country occupying most of northern North America, extending 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 is a carrier of a cystic fibrosis mutation. Although CF is less common in these groups, approximately 1 in 46
HispanicHispanic is a term that historically denoted a relationship to the ancient Hispania . During the modern era, it took on a more limited meaning, relating to the contemporary nation of Spain....
s, 1 in 65 Africans and 1 in 90
AsiansAsian people or Asiatic people is a demonym for people from Asia. However, the use of the term varies by country and person, often referring to people from a particular region or subregion of Asia...
carry at least one abnormal CFTR gene.
Cystic fibrosis is diagnosed in males and females equally. For unclear reasons, males tend to have a longer
life expectancyLife expectancy is the expected number of years of life remaining at a given age. It is denoted by e
x, which means the average number of subsequent years of life for someone now aged x, according to a particular mortality experience...
than females , although recent studies suggest this gender gap may no longer exist in younger patients with access to excellent health care facilities . Similarly, life expectancy for people with CF depends largely upon access to health care. In 1959, the median age of survival of children with cystic fibrosis was six months. In the United States, the life expectancy for infants born in 2006 with CF is 36.8 years, based upon data compiled by the
Cystic Fibrosis FoundationThe Cystic Fibrosis Foundation is a non-profit organization in the United States established to provide the means to cure and control cystic fibrosis . The Foundation provides information about cystic fibrosis and finances CF research that aims to improve the quality of life for people with the...
.
The Cystic Fibrosis Foundation also compiles lifestyle information about American adults with CF. In 2004, the foundation reported that 91% had graduated
high schoolHigh school is the name used in some parts of the world, particularly in Scotland, Northern America and Oceania, to describe an institution that provides all or part of secondary education...
and 54% had at least some college education. Employment data revealed 12.6% of adults were disabled and 9.9% were unemployed. Marital information showed that 59% of adults were single and 36% were married or living with a partner. In 2004, 191 American women with CF were pregnant.
History
Cystic fibrosis (CF) was recognized as specific entity during the 1930s. There is nothing resembling CF described in the 1032 pages of Sir Frederick Still's 1927 Edition of Common Disorders and Diseases of Childhood. Formerly known as "cystic fibrosis of the
pancreasThe 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 an exocrine gland, secreting pancreatic juice containing digestive enzymes that pass to...
," this entity has increasingly been labeled simply "cystic fibrosis."
Indeed, literature from Germany and Switzerland in the 18th century warned, "
Wehe dem Kind, das beim Kuß auf die Stirn salzig schmekt, es ist verhext und muss bald sterben" — "Woe is the child who tastes salty when kissed on the forehead, for it 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 peritonitisMeconium peritonitis refers to rupture of the bowel prior to birth, resulting in fetal stool escaping into the surrounding space leading to inflammation . Despite the bowel rupture, many infants born after meconium peritonitis in utero have normal bowels and have no further issues...
, a complication of meconium ileus associated with cystic fibrosis. Meconium ileus was first described in 1905 by
Karl LandsteinerKarl Landsteiner , was an Austrian biologist and physician. He is noted for his development in 1901 of the modern system of classification of blood groups from his identification of the presence of agglutinins in the blood, and in 1930 he received the Nobel Prize in Physiology or Medicine. With...
. In 1936,
Guido FanconiGuido 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
bronchiectasisBronchiectasis is a disease state defined by localized, irreversible dilation of part of the bronchial tree. It is classified as an obstructive lung disease, along with bronchitis and cystic fibrosis. Involved bronchi are dilated, inflamed, and easily collapsible, resulting in airflow obstruction...
.
In 1938
Dorothy Hansine AndersenDorothy Hansine Andersen was the American 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 described the characteristic cystic fibrosis of the pancreas and correlated it with the lung and intestinal disease prominent in CF. She also first hypothesized that CF is a recessive disease and first used pancreatic enzyme replacement to treat affected children. In 1952 Paul di Sant' Agnese discovered abnormalities in
sweatSWEAT 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...
electrolyteIn chemistry, an electrolyte is any substance containing free ions that behaves as an electrically conductive medium, usually when in a solution...
s; a
sweat testThe sweat test measures the concentration of chloride and sodium that is excreted in sweat. It is used to diagnose cystic fibrosis .-Background:...
was developed and improved over the next decade.
In 1988 the first mutation for CF, ΔF508 on the seventh chromosome, was discovered by
Francis CollinsFrancis S. Collins , M.D., Ph.D., is an American physician-geneticist, noted for his landmark discoveries of disease genes and his leadership of the Human Genome Project and described as "one of the most accomplished scientists of our time"...
,
Lap-Chee TsuiTsui Lap-chee, OC, O.Ont is a Chinese geneticist and is currently the Vice-Chancellor of the University of Hong Kong, China.-Personal life:Tsui was born in Shanghai...
and John R. Riordan. Research has subsequently found over 1,000 different mutations that cause CF. Lap-Chee Tsui led a team of researchers at the
Hospital for Sick ChildrenThe Hospital for Sick Children, also known as SickKids, is a world-renowned children's hospital in Toronto, Ontario, Canada. It is a teaching hospital affiliated with the University of Toronto, and it is home to the world's second largest hospital-based paediatric research facility. It was...
in
TorontoToronto is the most populous city in Canada and the provincial capital of Ontario. It is located in Southern Ontario on the northwestern shore of Lake Ontario. With over 2.5 million residents, it is the fifth most populous municipality in North America...
that discovered the gene responsible for CF in 1989. Cystic fibrosis represents the first genetic disorder elucidated strictly by the process of
reverse geneticsReverse genetics is an approach to discovering the function of a gene that proceeds in the opposite direction of so called forward genetic screens of classical genetics...
.
Because mutations in the CFTR gene are typically small,
classical geneticsClassical genetics consists of the techniques 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
-jumpingChromosome jumping is a technique of molecular biology that is used as a tool 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
sequenceThe term DNA sequencing refers to sequencing methods for determining the order of the nucleotide bases—adenine, guanine, cytosine, and thymine—in a molecule of DNA....
the gene.
Theories about the prevalence of CF
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 advantageA heterozygote advantage describes the case in which the heterozygote genotype has a higher relative fitness than either the homozygote dominant or homozygote recessive genotype. This selection favoring the heterozygote is one of the mechanisms that maintain polymorphism and help to explain some...
. Resistance to the following have all been proposed as possible sources of heterozygote advantage:
- Cholera: With the discovery that cholera
Cholera, sometimes known as Asiatic or epidemic cholera, is an infectious gastroenteritis caused by enterotoxin-producing strains of the bacterium Vibrio cholerae. Transmission to humans occurs through eating food or drinking water contaminated with Vibrio cholerae from other cholera patients...
toxinA toxin is a poisonous substance produced by living cells or organisms ....
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 fever
Typhoid fever, also known as enteric fever, Salmonella typhi or commonly just typhoid, is an illness. Common worldwide, it is transmitted by the ingestion of food or water contaminated with feces from an infected person. The bacteria then perforate through the intestinal wall and are phagocytosed...
. 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 endemicIn 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 diarrhoea caused by lactose intolerance
Lactose intolerance is the inability to metabolize lactose, a sugar found in milk and other dairy products, because the required enzyme lactase is absent in the intestinal system or its availability is lowered. It is estimated that 75% of adults worldwide show some decrease in lactase activity...
, prior to the appearance of the mutations that created lactose tolerance.
- Tuberculosis: Poolman and Galvani from Yale University
Yale University is a private research university in New Haven, Connecticut, and a member of the Ivy League. Founded in 1701 in the Colony of Connecticut, the university is the third-oldest institution of higher education in the United States. Yale has produced many notable alumni, including five...
have added another possible explanation - that carriers of the gene have some resistance to TB.
External links