Cystic fibrosis (CF) is a rare
genetic disorder
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
that affects mostly the
lungs, but also the
pancreas
The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an en ...
,
liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
,
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...
s, and
intestine.
[ Long-term issues include ]difficulty breathing
Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing disc ...
and coughing up mucus
Mucus ( ) is a slippery aqueous secretion produced by, and covering, mucous membranes. It is typically produced from cells found in mucous glands, although it may also originate from mixed glands, which contain both serous and mucous cells. It ...
as a result of frequent lung infections
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of ...
.[ Other signs and symptoms may include sinus infections, poor growth, fatty stool, clubbing of the fingers and toes, and infertility in most males.][ Different people may have different degrees of symptoms.][
Cystic fibrosis is inherited in an autosomal recessive manner.][ It is caused by the presence of mutations in both copies of the ]gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
for the cystic fibrosis transmembrane conductance regulator
Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the ''CFTR'' gene.
Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked wi ...
(CFTR) protein.[ Those with a single working copy are carriers and otherwise mostly healthy.] CFTR is involved in the production of sweat, digestive fluids, and mucus. When the CFTR is not functional, secretions which are usually thin instead become thick. The condition is diagnosed by a sweat test and genetic testing.[ Screening of infants at birth takes place in some areas of the world.][
There is no known cure for cystic fibrosis.][ Lung infections are treated with ]antibiotics
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention o ...
which may be given intravenously, inhaled, or by mouth.[ Sometimes, the antibiotic ]azithromycin
Azithromycin, sold under the brand names Zithromax (in oral form) and Azasite (as an eye drop), is an antibiotic medication used for the treatment of a number of bacterial infections. This includes middle ear infections, strep throat, pneumo ...
is used long term.[ Inhaled ]hypertonic saline
Saline (also known as saline solution) is a mixture of sodium chloride (salt) and water. It has a number of uses in medicine including cleaning wounds, removal and storage of contact lenses, and help with dry eyes. By injection into a vein ...
and salbutamol may also be useful.[ Lung transplantation may be an option if lung function continues to worsen.][ Pancreatic enzyme replacement and ]fat-soluble vitamin
A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an essential micronutrient that an organism needs in small quantities for the proper functioning of its metabolism. Essential nutri ...
supplementation are important, especially in the young.[ Airway clearance techniques such as chest physiotherapy have some short-term benefit, but long-term effects are unclear.] The average life expectancy is between 42 and 50 years in the developed world
A developed country (or industrialized country, high-income country, more economically developed country (MEDC), advanced country) is a sovereign state that has a high quality of life, developed economy and advanced technological infrastruct ...
. Lung problems are responsible for death in 80% of people with cystic fibrosis.[
CF is most common among people of ]Northern European
The northern region of Europe has several definitions. A restrictive definition may describe Northern Europe as being roughly north of the southern coast of the Baltic Sea, which is about 54°N, or may be based on other geographical factors ...
ancestry, for whom it affects about 1 out of 3,000 newborns,[ and among which around 1 out of 25 people is a carrier.][ It is least common in Africans and Asians, though it does occur in all races.] It was first recognized as a specific disease by Dorothy Andersen
Dorothy Hansine Andersen (May 15, 1901 – March 3, 1963) was an American physician, pediatrician, and pathologist who was the first person to identify cystic fibrosis, the first to describe the disease, and the one to name it. in 1939, she was ...
in 1938, with descriptions that fit the condition occurring at least as far back as 1595. The name "cystic fibrosis" refers to the characteristic fibrosis
Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...
and cyst
A cyst is a closed sac, having a distinct envelope and division compared with the nearby tissue. Hence, it is a cluster of cells that have grouped together to form a sac (like the manner in which water molecules group together to form a bubble) ...
s that form within the pancreas
The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an en ...
.
Signs and symptoms
Cystic fibrosis typically manifests early in life. Newborns and infants with cystic fibrosis tend to have frequent, large, greasy stools (a result of malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract. Impairment can be of single or multiple nutrients depending on the abnormality. This may lead to malnutrition and a variety ...
) and are underweight for their age. 15–20% of newborns have their small intestine blocked by meconium, often requiring surgery to correct. Newborns occasionally have neonatal jaundice
Neonatal jaundice is a yellowish discoloration of the white part of the eyes and skin in a newborn baby due to high bilirubin levels. Other symptoms may include excess sleepiness or poor feeding. Complications may include seizures, cerebral pal ...
due to blockage of the bile duct
A bile duct is any of a number of long tube-like structures that carry bile, and is present in most vertebrates.
Bile is required for the digestion of food and is secreted by the liver into passages that carry bile toward the hepatic duct. It ...
s. Children with cystic fibrosis lose excessive salt in their sweat, and parents often notice salt crystallizing on the skin, or a salty taste when they kiss their child.
The primary cause of morbidity
A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...
and death in people with cystic fibrosis is progressive lung disease, which eventually leads to respiratory failure
Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a rise ...
. This typically begins as a prolonged respiratory infection that continues until treated with antibiotics. Chronic infection of the respiratory tract is nearly universal in people with cystic fibrosis, with ''Pseudomonas aeruginosa
''Pseudomonas aeruginosa'' is a common encapsulated, gram-negative, aerobic–facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, ''P. aerug ...
'', fungi, and mycobacteria all increasingly common over time. Inflammation of the upper airway results in frequent runny nose
Rhinorrhea, rhinorrhoea, or informally runny nose is the free discharge of a thin mucus fluid from the nose; it is a common condition. It is a common symptom of allergies ( hay fever) or certain viral infections, such as the common cold or COVI ...
and nasal obstruction
Nasal congestion is the blockage of nasal breathing usually due to membranes lining the nose becoming swollen from inflamed blood vessels.
Background
In about 85% of cases, nasal congestion leads to mouth breathing rather than nasal breathin ...
. Nasal polyp
Nasal polyps (NP) are noncancerous growths within the nose or sinuses. Symptoms include trouble breathing through the nose, loss of smell, decreased taste, post nasal drip, and a runny nose. The growths are sac-like, movable, and nontender, tho ...
s are common, particularly in children and teenagers. As the disease progresses, people tend to have shortness of breath
Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing di ...
, and a chronic cough that produces sputum. Breathing problems make it increasingly challenging to exercise, and prolonged illness causes those affected to be underweight for their age. In late adolescence or adulthood, people begin to develop severe signs of lung disease: wheezing, digital clubbing, cyanosis, coughing up blood, pulmonary heart disease
Pulmonary heart disease, also known as cor pulmonale, is the enlargement and failure of the right ventricle of the heart as a response to increased vascular resistance (such as from pulmonic stenosis) or high blood pressure in the lungs.
Chroni ...
, and collapsed lung (atelectasis
Atelectasis is the collapse or closure of a lung resulting in reduced or absent gas exchange. It is usually unilateral, affecting part or all of one lung. It is a condition where the alveoli are deflated down to little or no volume, as distinct ...
or pneumothorax
A pneumothorax is an abnormal collection of air in the pleural space between the lung and the chest wall. Symptoms typically include sudden onset of sharp, one-sided chest pain and shortness of breath. In a minority of cases, a one-way valve i ...
).
In rare cases, cystic fibrosis can manifest itself as a coagulation disorder. Vitamin K
Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation ...
is normally absorbed from breast milk, formula, and later, solid foods. This absorption is impaired in some CF patients. Young children are especially sensitive to vitamin K malabsorptive disorders because only a very small amount of vitamin K crosses the placenta, leaving the child with very low reserves and limited ability to absorb vitamin K from dietary sources after birth. Because clotting factors II, VII, IX, and X are vitamin K–dependent, low levels of vitamin K can result in coagulation problems. Consequently, when a child presents with unexplained bruising, a coagulation evaluation may be warranted to determine whether an underlying disease is present.
Lungs and sinuses
Lung disease results from clogging of the airways due to mucus build-up, decreased mucociliary clearance
Mucociliary clearance (MCC), mucociliary transport, or the mucociliary escalator, describes the self-clearing mechanism of the airways in the respiratory system. It is one of the two protective processes for the lungs in removing inhaled particl ...
, and resulting inflammation
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
. In later stages, changes in the architecture of the lung, such as pathology in the major airways ( bronchiectasis), further exacerbate difficulties in breathing. Other signs include high blood pressure in the lung ( pulmonary hypertension), heart failure, difficulties getting enough oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as ...
to the body ( hypoxia), and respiratory failure requiring support with breathing masks, such as bilevel positive airway pressure
Positive airway pressure (PAP) is a mode of respiratory ventilation used in the treatment of sleep apnea. PAP ventilation is also commonly used for those who are critically ill in hospital with respiratory failure, in newborn infants ( neonate ...
machines or ventilators
A ventilator is a piece of medical technology that provides mechanical ventilation by moving breathable air into and out of the lungs, to deliver breaths to a patient who is physically unable to breathe, or breathing insufficiently. Ventilators ...
. '' Staphylococcus aureus'', ''Haemophilus influenzae
''Haemophilus influenzae'' (formerly called Pfeiffer's bacillus or ''Bacillus influenzae'') is a Gram-negative, non-motile, coccobacillary, facultatively anaerobic, capnophilic pathogenic bacterium of the family Pasteurellaceae. The bacter ...
'', and ''Pseudomonas aeruginosa
''Pseudomonas aeruginosa'' is a common encapsulated, gram-negative, aerobic–facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, ''P. aerug ...
'' are the three most common organisms causing lung infections in CF patients.[ In addition, opportunistic infection due to ''Burkholderia cepacia'' complex can occur, especially through transmission from patient to patient.
In addition to typical bacterial infections, people with CF more commonly develop other types of lung diseases. Among these is ]allergic bronchopulmonary aspergillosis
Allergic bronchopulmonary aspergillosis (ABPA) is a condition characterised by an exaggerated response of the immune system (a hypersensitivity response) to the fungus ''Aspergillus'' (most commonly ''Aspergillus fumigatus''). It occurs most oft ...
, in which the body's response to the common fungus
A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from t ...
'' Aspergillus fumigatus'' causes worsening of breathing problems. Another is infection with ''Mycobacterium avium
''Mycobacterium avium ''complex is a group of mycobacteria comprising ''Mycobacterium intracellulare'' and ''Mycobacterium avium'' that are commonly grouped because they infect humans together; this group, in turn, is part of the group of nontu ...
'' complex, a group of bacteria related to tuberculosis
Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, i ...
, which can cause lung damage and do not respond to common antibiotics.
Mucus in the paranasal sinus
Paranasal sinuses are a group of four paired air-filled spaces that surround the nasal cavity. The maxillary sinuses are located under the eyes; the frontal sinuses are above the eyes; the ethmoidal sinuses are between the eyes and the sphenoid ...
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 headaches. Individuals with CF may develop overgrowth of the nasal tissue (nasal polyp
Nasal polyps (NP) are noncancerous growths within the nose or sinuses. Symptoms include trouble breathing through the nose, loss of smell, decreased taste, post nasal drip, and a runny nose. The growths are sac-like, movable, and nontender, tho ...
s) due to inflammation from chronic sinus infections. Recurrent sinonasal polyps can occur in 10% to 25% of CF patients.[ These polyps can block the nasal passages and increase breathing difficulties.
Cardiorespiratory complications are the most common causes of death (about 80%) in patients at most CF centers in the United States.][
]
Gastrointestinal
In addition, protrusion of internal rectal
The rectum is the final straight portion of the large intestine in humans and some other mammals, and the gut in others. The adult human rectum is about long, and begins at the rectosigmoid junction (the end of the sigmoid colon) at the le ...
membranes (rectal prolapse
A rectal prolapse occurs when walls of the rectum have prolapsed to such a degree that they protrude out of the anus and are visible outside the body. However, most researchers agree that there are 3 to 5 different types of rectal prolapse, depen ...
) is more common, occurring in as many as 10% of children with CF,[ and it is caused by increased fecal volume, ]malnutrition
Malnutrition occurs when an organism gets too few or too many nutrients, resulting in health problems. Specifically, it is "a deficiency, excess, or imbalance of energy, protein and other nutrients" which adversely affects the body's tissues ...
, and increased intra–abdominal pressure due to coughing.
The thick mucus seen in the lungs has a counterpart in thickened secretions from the pancreas
The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an en ...
, an organ responsible for providing digestive juices that help break down food. These secretions block the exocrine
Exocrine glands are glands that secrete substances on to an epithelial surface by way of a duct. Examples of exocrine glands include sweat, salivary, mammary, ceruminous, lacrimal, sebaceous, prostate and mucous. Exocrine glands are one of t ...
movement of the digestive enzymes into the duodenum and result in irreversible damage to the pancreas, often with painful inflammation (pancreatitis
Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic pancr ...
). The pancreatic duct
The pancreatic duct, or duct of Wirsung (also, the major pancreatic duct due to the existence of an accessory pancreatic duct), is a duct joining the pancreas to the common bile duct. This supplies it with pancreatic juice from the exocrine pancr ...
s are totally plugged in more advanced cases, usually seen in older children or adolescents.[ This causes atrophy of the exocrine glands and progressive fibrosis.][
Individuals with CF also have difficulties absorbing the fat-soluble vitamins A, D, E, and K.]
In addition to the pancreas problems, people with CF experience more heartburn
Heartburn, also known as pyrosis, cardialgia or acid indigestion, is a burning sensation in the central chest or upper central abdomen. Heartburn is usually due to regurgitation of gastric acid (gastric reflux) into the esophagus. It is the m ...
, intestinal blockage by intussusception, and constipation
Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...
. Older individuals with CF may develop distal intestinal obstruction syndrome, which occurs when feces becomes thick with mucus (inspissated Inspissation is the process of thickening by dehydration.
Intentional use
Inspissation is the process used when heating high-protein containing media; for example to enable recovery of bacteria for testing. Once inspissation has occurred, any stain ...
) and can cause bloating, pain, and incomplete or complete bowel obstruction.
Exocrine pancreatic insufficiency occurs in the majority (85% to 90%) of patients with CF.[ It is mainly associated with "severe" CFTR mutations, where both alleles are completely nonfunctional (e.g. ]ΔF508
Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the ''CFTR'' gene.
Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked wit ...
/ΔF508).[ It occurs in 10% to 15% of patients with one "severe" and one "mild" CFTR mutation where little CFTR activity still occurs, or where two "mild" CFTR mutations exist.][ In these milder cases, sufficient pancreatic exocrine function is still present so that enzyme supplementation is not required.][ Usually, no other GI complications occur in pancreas-sufficient phenotypes, and in general, such individuals usually have excellent growth and development.][ Despite this, idiopathic chronic pancreatitis can occur in a subset of pancreas-sufficient individuals with CF, and is associated with recurrent abdominal pain and life-threatening complications.][
Thickened secretions also may cause liver problems in patients with CF. Bile secreted by the liver to aid in digestion may block the ]bile duct
A bile duct is any of a number of long tube-like structures that carry bile, and is present in most vertebrates.
Bile is required for the digestion of food and is secreted by the liver into passages that carry bile toward the hepatic duct. It ...
s, leading to liver damage. Impaired digestion or absorption of lipids can result in steatorrhea. Over time, this can lead to scarring and nodularity (cirrhosis
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue rep ...
). The liver fails to rid the blood of toxins and does not make important proteins, such as those responsible for blood clotting
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanis ...
. Liver disease is the third-most common cause of death associated with CF.[
Around 5–7% of people experience ]liver damage
Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.
Signs and symptoms
Some of the si ...
severe enough to cause symptoms: typically gallstone
A gallstone is a stone formed within the gallbladder from precipitated bile components. The term cholelithiasis may refer to the presence of gallstones or to any disease caused by gallstones, and choledocholithiasis refers to the presence of mi ...
s causing biliary colic
Biliary colic, also known as symptomatic cholelithiasis, a gallbladder attack or gallstone attack, is when a colic (sudden pain) occurs due to a gallstone temporarily blocking the cystic duct. Typically, the pain is in the right upper part of th ...
.
Endocrine
The pancreas contains the islets of Langerhans
The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% of ...
, which are responsible for making insulin, a hormone that helps regulate blood glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...
. Damage to the pancreas can lead to loss of the islet cells, leading to a type of diabetes unique to those with the disease. This cystic fibrosis-related diabetes shares characteristics of type 1 and type 2 diabetes, and is one of the principal nonpulmonary complications of CF.
Vitamin D is involved in calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...
and phosphate
In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid .
The phosphate or orthophosphate ion is derived from phosph ...
regulation. Poor uptake of vitamin D from the diet because of malabsorption can lead to the bone disease osteoporosis in which weakened bones are more susceptible to fractures.
Infertility
Infertility affects both men and women. At least 97% of men with cystic fibrosis are infertile, but not sterile, and can have children with assisted reproductive techniques. The main cause of infertility in men with CF is congenital absence of the vas deferens
Congenital absence of the vas deferens (CAVD) is a condition in which the vasa deferentia reproductive organs fail to form properly prior to birth. It may either be unilateral (CUAVD) or bilateral (CBAVD).
Signs and symptoms
The vas deferens con ...
(which normally connects the testes
A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testoste ...
to the ejaculatory duct
The ejaculatory ducts (''ductus ejaculatorii'') are paired structures in male anatomy. Each ejaculatory duct is formed by the union of the vas deferens with the duct of the seminal vesicle. They pass through the prostate, and open into the ureth ...
s of the penis
A penis (plural ''penises'' or ''penes'' () is the primary sexual organ that male animals use to inseminate females (or hermaphrodites) during copulation. Such organs occur in many animals, both vertebrate and invertebrate, but males d ...
), but potentially also by other mechanisms such as causing no sperm, abnormally shaped sperm, and few sperm with poor motility. Many men found to have congenital absence of the vas deferens during evaluation for infertility have a mild, previously undiagnosed form of CF. Around 20% of women with CF have fertility difficulties due to thickened cervical mucus or malnutrition. In severe cases, malnutrition disrupts ovulation
Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilize ...
and causes a lack of menstruation.
Causes
CF is caused by a mutation in the gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
cystic fibrosis transmembrane conductance regulator
Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the ''CFTR'' gene.
Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked wi ...
(''CFTR''). The most common mutation, ΔF508
Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the ''CFTR'' gene.
Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked wit ...
, is a deletion ( Δ signifying deletion) of three nucleotides that results in a loss of the amino acid phenylalanine (F) at the 508th position on the protein. This mutation accounts for two-thirds (66–70%[) of CF cases worldwide and 90% of cases in the ]United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...
; however, over 1500 other mutations can produce CF. Although most people have two working copies (alleles) of the ''CFTR'' gene, only one is needed to prevent cystic fibrosis. CF develops when neither allele can produce a functional CFTR protein. Thus, CF is considered an autosomal recessive disease.[
The ''CFTR'' gene, found at the q31.2 ]locus
Locus (plural loci) is Latin for "place". It may refer to:
Entertainment
* Locus (comics), a Marvel Comics mutant villainess, a member of the Mutant Liberation Front
* ''Locus'' (magazine), science fiction and fantasy magazine
** ''Locus Award' ...
of chromosome 7
Chromosome 7 is one of the 23 pairs of chromosomes in humans, who normally have two copies of this chromosome. Chromosome 7 spans about 159 million base pairs (the building material of DNA) and represents between 5 and 5.5 percent of the total D ...
, is 230,000 base pairs long, and creates a protein that is 1,480 amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
s long. More specifically, the location is between base pair 117,120,016 and 117,308,718 on the long arm of chromosome 7, region 3, band 1, subband 2, represented as 7q31.2. Structurally, the ''CFTR'' is a type of gene known as an ABC gene. The product of this gene (the CFTR protein) is a chloride ion channel important in creating sweat, digestive juices, and mucus. This protein possesses two ATP-hydrolyzing domains, which allows the protein to use energy in the form of ATP. It also contains two domains comprising six alpha helices
The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...
apiece, which allow the protein to cross the cell membrane. A regulatory binding site
In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...
on the protein allows activation by phosphorylation, mainly by cAMP-dependent protein kinase
In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulat ...
. The carboxyl terminal of the protein is anchored to the cytoskeleton
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is com ...
by a PDZ domain interaction. The majority of CFTR in the lung's passages is produced by rare ion-transporting cells that regulate mucus properties.
In addition, the evidence is increasing that genetic modifiers besides ''CFTR'' modulate the frequency and severity of the disease. One example is mannan-binding lectin
Mannose-binding lectin (MBL), also called mannan-binding lectin or mannan-binding protein (MBP), is a lectin that is instrumental in innate immunity as an opsonin and via the lectin pathway.
Structure
MBL has an oligomeric structure (400-700 kDa) ...
, which is involved in innate immunity
The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
by facilitating phagocytosis
Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...
of microorganisms. Polymorphisms in one or both mannan-binding lectin alleles that result in lower circulating levels of the protein are associated with a threefold higher risk of end-stage lung disease, as well as an increased burden of chronic bacterial infections.[
]
Carriers
Up to one in 25 individuals of Northern European ancestry is considered a genetic carrier
A hereditary carrier (genetic carrier or just carrier), is a person or other organism that has inherited a recessive allele for a genetic trait or mutation but usually does not display that trait or show symptoms of the disease. Carriers are, ho ...
. The disease appears only when two of these carriers have children, as each pregnancy between them has a 25% chance of producing a child with the disease. Although only about one of every 3,000 newborns of the affected ancestry has CF, more than 900 mutations of the gene that causes CF are known. Current tests look for the most common mutations.
The mutations screened by the test vary according to a person's ethnic group or by the occurrence of CF already in the family. More than 10 million Americans, including one in 25 white Americans, are carriers of one mutation of the CF gene. CF is present in other races, though not as frequently as in white individuals. About one in 46 Hispanic Americans, one in 65 African Americans, and one in 90 Asian Americans carry a mutation of the CF gene.
Pathophysiology
Several mutations in the ''CFTR'' gene can occur, and different mutations cause different defects in the CFTR protein, sometimes causing a milder or more severe disease. These protein defects are also targets for drugs which can sometimes restore their function. ΔF508-CFTR gene mutation, which occurs in >90% of patients in the U.S., creates a protein that does not fold normally and is not appropriately transported to the cell membrane, resulting in its degradation.
Other mutations result in proteins that are too short (truncated) because production
Production may refer to:
Economics and business
* Production (economics)
* Production, the act of manufacturing goods
* Production, in the outline of industrial organization, the act of making products (goods and services)
* Production as a stati ...
is ended prematurely. Other mutations produce proteins that do not use energy (in the form of ATP) normally, do not allow chloride, iodide, and thiocyanate to cross the membrane appropriately, and degrade at a faster rate than normal. Mutations may also lead to fewer copies of the CFTR protein being produced.
The protein created by this gene is anchored to the outer membrane of cells in the sweat glands, lungs, pancreas, and all other remaining exocrine glands in the body.
The protein spans this membrane and acts as a channel
Channel, channels, channeling, etc., may refer to:
Geography
* Channel (geography), in physical geography, a landform consisting of the outline (banks) of the path of a narrow body of water.
Australia
* Channel Country, region of outback Austral ...
connecting the inner part of the cell (cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
) to the surrounding fluid. This channel is primarily responsible for controlling the movement of halide anions from inside to outside of the cell; however, in the sweat ducts, it facilitates the movement of chloride from the sweat duct into the cytoplasm. When the CFTR protein does not resorb ions in sweat ducts, chloride and thiocyanate released from sweat glands are trapped inside the ducts and pumped to the skin.
Additionally hypothiocyanite Hypothiocyanite is the anion SCNsup>− and the conjugate base of hypothiocyanous acid (HOSCN). It is an organic compound part of the thiocyanates as it contains the functional group SCN. It is formed when an oxygen is singly bonded to the thiocyana ...
, OSCN, cannot be produced by the immune defense system. Because chloride is negatively charged, this modifies the electrical potential inside and outside the cell that normally causes cations to cross into the cell. Sodium is the most common cation in the extracellular space. The excess chloride within sweat ducts prevents sodium resorption by epithelial sodium channels and the combination of sodium and chloride creates the salt, which is lost in high amounts in the sweat of individuals with CF. This lost salt forms the basis for the sweat test.
Most of the damage in CF is due to blockage of the narrow passages of affected organs with thickened secretions. These blockages lead to remodeling and infection in the lung, damage by accumulated digestive enzymes in the pancreas, blockage of the intestines by thick feces, etc. Several theories have been posited on how the defects in the protein and cellular function cause the clinical effects. The most current theory suggests that defective ion transport leads to dehydration in the airway epithelia, thickening mucus. In airway epithelial cells, the cilia exist in between the cell's apical surface and mucus in a layer known as airway surface liquid (ASL). The flow of ions from the cell and into this layer is determined by ion channels such as CFTR. CFTR not only allows chloride ions to be drawn from the cell and into the ASL, but it also regulates another channel called ENac, which allows sodium ions to leave the ASL and enter the respiratory epithelium. CFTR normally inhibits this channel, but if the CFTR is defective, then sodium flows freely from the ASL and into the cell.
As water follows sodium, the depth of ASL will be depleted and the cilia will be left in the mucous layer. As cilia cannot effectively move in a thick, viscous environment, mucociliary clearance is deficient and a buildup of mucus occurs, clogging small airways. The accumulation of more viscous, nutrient-rich mucus in the lungs allows bacteria to hide from the body's immune system, causing repeated respiratory infections. The presence of the same CFTR proteins in the pancreatic duct and sweat glands in the skin also cause symptoms in these systems.
Chronic infections
The lungs of individuals with cystic fibrosis are colonized and infected by bacteria from an early age. These bacteria, which often spread among individuals with CF, thrive in the altered mucus, which collects in the small airways of the lungs. This mucus leads to the formation of bacterial microenvironments known as biofilm
A biofilm comprises any syntrophic consortium of microorganisms in which cells stick to each other and often also to a surface. These adherent cells become embedded within a slimy extracellular matrix that is composed of extracellular ...
s that are difficult for immune cells and antibiotics to penetrate. Viscous secretions and persistent respiratory infections repeatedly damage the lung by gradually remodeling the airways, which makes infection even more difficult to eradicate. The natural history of CF lung infections and airway remodeling is poorly understood, largely due to the immense spatial and temporal heterogeneity both within and between the microbiomes of CF patients.
Over time, both the types of bacteria and their individual characteristics change in individuals with CF. In the initial stage, common bacteria such as ''S. aureus'' and ''H. influenzae'' colonize and infect the lungs.[ Eventually, '']Pseudomonas aeruginosa
''Pseudomonas aeruginosa'' is a common encapsulated, gram-negative, aerobic–facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, ''P. aerug ...
'' (and sometimes '' Burkholderia cepacia'') dominates. By 18 years of age, 80% of patients with classic CF harbor ''P. aeruginosa'', and 3.5% harbor ''B. cepacia''.[ Once within the lungs, these bacteria adapt to the environment and develop resistance to commonly used antibiotics. ''Pseudomonas'' can develop special characteristics that allow the formation of large colonies, known as "mucoid" ''Pseudomonas'', which are rarely seen in people who do not have CF.] Scientific evidence suggests the interleukin 17
Interleukin 17 family (IL17 family) is a family of pro-inflammatory cystine knot cytokines. They are produced by a group of T helper cell known as T helper 17 cell in response to their stimulation with IL-23. Originally, Th17 was identif ...
pathway plays a key role in resistance and modulation of the inflammatory response during ''P. aeruginosa'' infection in CF. In particular, interleukin 17-mediated immunity plays a double-edged activity during chronic airways infection; on one side, it contributes to the control of ''P. aeruginosa'' burden, while on the other, it propagates exacerbated pulmonary neutrophilia and tissue remodeling.
Infection can spread by passing between different individuals with CF. In the past, people with CF often participated in summer "CF camps" and other recreational gatherings. Hospitals grouped patients with CF into common areas and routine equipment (such as nebulizer
In medicine, a nebulizer (American English) or nebuliser (British English) is a drug delivery device used to administer medication in the form of a mist inhaled into the lungs. Nebulizers are commonly used for the treatment of asthma, cystic fibro ...
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 now routinely isolated from one another in the healthcare setting, and healthcare providers are encouraged to wear gowns and gloves when examining patients with CF to limit the spread of virulent bacterial strains.
CF patients may also have their airways chronically colonized by filamentous fungi (such as ''Aspergillus fumigatus'', ''Scedosporium apiospermum
''Pseudallescheria boydii'' is a species of fungus classified in the Ascomycota. It is associated with some forms of eumycetoma/ maduromycosis and is the causative agent of pseudallescheriasis. Typically found in stagnant and polluted water, it ...
'', ''Aspergillus terreus
''Aspergillus terreus'', also known as ''Aspergillus terrestris'', is a fungus (mold) found worldwide in soil. Although thought to be strictly asexual until recently, ''A. terreus'' is now known to be capable of sexual reproduction. This saprotr ...
'') and/or yeasts (such as ''Candida albicans
''Candida albicans'' is an opportunistic pathogenic yeast that is a common member of the human gut flora. It can also survive outside the human body. It is detected in the gastrointestinal tract and mouth in 40–60% of healthy adults. It is usu ...
''); other filamentous fungi less commonly isolated include ''Aspergillus flavus
''Aspergillus flavus'' is a saprotrophic and pathogenic fungus with a cosmopolitan distribution. It is best known for its colonization of cereal grains, legumes, and tree nuts. Postharvest rot typically develops during harvest, storage, and/or ...
'' and ''Aspergillus nidulans
''Aspergillus nidulans'' (also called ''Emericella nidulans'' when referring to its sexual form, or teleomorph) is one of many species of filamentous fungi in the phylum Ascomycota. It has been an important research organism for studying eukaryo ...
'' (occur transiently in CF respiratory secretions) and '' Exophiala dermatitidis'' and ''Scedosporium prolificans
''Lomentospora prolificans'' is an emerging opportunistic fungal pathogen that causes a wide variety of infections in immunologically normal and immunosuppressed people and animals. It is resistant to most antifungal drugs and infections are often ...
'' (chronic airway-colonizers); some filamentous fungi such as ''Penicillium emersonii'' and '' Acrophialophora fusispora'' are encountered in patients almost exclusively in the context of CF. Defective mucociliary clearance characterizing CF is associated with local immunological disorders. In addition, the prolonged therapy with antibiotics and the use of corticosteroid treatments may also facilitate fungal growth. Although the clinical relevance of the fungal airway colonization is still a matter of debate, filamentous fungi may contribute to the local inflammatory response and therefore to the progressive deterioration of the lung function, as often happens with allergic bronchopulmonary aspergillosis – the most common fungal disease in the context of CF, involving a Th2-driven immune response to ''Aspergillus'' species.
Diagnosis
In many localities all newborns are screened for cystic fibrosis within the first few days of life, typically by blood test for high levels of immunoreactive trypsinogen Measurement of immunoreactive trypsinogen (IRT) in blood of newborn babies is an assay in rapidly increasing use as a screening test for cystic fibrosis (CF).
In CF, there is poor release from pancreatic ducts. Trypsinogen is a pancreatic enzyme pr ...
. Newborns with positive tests or those who are otherwise suspected of having cystic fibrosis based on symptoms or family history, then undergo a sweat test. An electric current is used to drive pilocarpine
Pilocarpine is a medication used to reduce pressure inside the eye and treat dry mouth. As eye drops it is used to manage angle closure glaucoma until surgery can be performed, ocular hypertension, primary open angle glaucoma, and to bring abo ...
into the skin, stimulating sweating. The sweat is collected and analyzed for salt levels. Having unusually high levels of chloride in the sweat suggests CFTR
Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the ''CFTR'' gene.
Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked wi ...
is dysfunctional; the person is then diagnosed with cystic fibrosis. Genetic testing is also available to identify the CFTR mutations typically associated with cystic fibrosis. Many laboratories can test for the 30–96 most common CFTR mutations, which can identify over 90% of people with cystic fibrosis.
People with CF have less thiocyanate and hypothiocyanite Hypothiocyanite is the anion SCNsup>− and the conjugate base of hypothiocyanous acid (HOSCN). It is an organic compound part of the thiocyanates as it contains the functional group SCN. It is formed when an oxygen is singly bonded to the thiocyana ...
in their saliva and mucus (Banfi et al.). In the case of milder forms of CF, transepithelial potential difference Transepithelial potential difference (TEPD) is the voltage across an epithelium, and is the sum of the membrane potentials for the outer and inner cell membranes.
TEPD in the nose
The diagnosis of cystic fibrosis (CF) is usually based on high swea ...
measurements can be helpful. CF can also be diagnosed by identification of mutations in the CFTR gene.
In many cases, a parent makes the diagnosis because the infant tastes salty.[ Immunoreactive trypsinogen levels can be increased in individuals who have a single mutated copy of the ''CFTR'' gene (carriers) or, in rare instances, in individuals with two normal copies of the ''CFTR'' gene. Due to these ]false positive
A false positive is an error in binary classification in which a test result incorrectly indicates the presence of a condition (such as a disease when the disease is not present), while a false negative is the opposite error, where the test resul ...
s, CF screening in newborns can be controversial.
By 2010 every US state had instituted newborn screening programs and , 21 European countries had programs in at least some regions.
Prenatal
Women who are pregnant or couples planning a pregnancy can have themselves tested for the ''CFTR'' gene mutations to determine the risk that their child will be born with CF. Testing is typically performed first on one or both parents and, if the risk of CF is high, testing on the fetus is performed. The American College of Obstetricians and Gynecologists
The American College of Obstetricians and Gynecologists (ACOG) is a professional association of physicians specializing in obstetrics and gynecology in the United States. Several Latin American countries are also represented within Districts of ...
recommends all people thinking of becoming pregnant be tested to see if they are a carrier.
Because development of CF in the fetus requires each parent to pass on a mutated copy of the ''CFTR'' gene and because CF testing is expensive, testing is often performed initially on one parent. If testing shows that parent is a ''CFTR'' gene mutation carrier, the other parent is tested to calculate the risk that their children will have CF. CF can result from more than a thousand different mutations. , typically only the most common mutations are tested for, such as ΔF508[ Most commercially available tests look for 32 or fewer different mutations. If a family has a known uncommon mutation, specific screening for that mutation can be performed. Because not all known mutations are found on current tests, a negative screen does not guarantee that a child will not have CF.
During pregnancy, testing can be performed on the placenta ( chorionic villus sampling) or the fluid around the fetus (]amniocentesis
Amniocentesis is a medical procedure used primarily in the prenatal diagnosis of genetic conditions. It has other uses such as in the assessment of infection and fetal lung maturity. Prenatal diagnostic testing, which includes amniocentesis, is n ...
). However, chorionic villus sampling has a risk of fetal death of one in 100 and amniocentesis of one in 200; a recent study has indicated this may be much lower, about one in 1,600.
Economically, for carrier couples of cystic fibrosis, when comparing preimplantation genetic diagnosis
Preimplantation genetic diagnosis (PGD or PIGD) is the genetic profiling of embryos prior to implantation (as a form of embryo profiling), and sometimes even of oocytes prior to fertilization. PGD is considered in a similar fashion to prenatal ...
(PGD) with natural conception (NC) followed by prenatal testing and abortion of affected pregnancies, PGD provides net economic benefits up to a maternal age around 40 years, after which NC, prenatal testing, and abortion have higher economic benefit.
Management
While no cures for CF are known, several treatment methods are used. The management of CF has improved significantly over the past 70 years. While infants born with it 70 years ago would have been unlikely to live beyond their first year, infants today are likely to live well into adulthood. Recent advances in the treatment of cystic fibrosis have meant that individuals with cystic fibrosis can live a fuller life less encumbered by their condition. The cornerstones of management are the proactive treatment of airway infection, and encouragement of good nutrition and an active lifestyle. Pulmonary rehabilitation
Pulmonary rehabilitation, also known as respiratory rehabilitation, is an important part of the management and health maintenance of people with chronic respiratory disease who remain symptomatic or continue to have decreased function despite stand ...
as a management of CF continues throughout a person's life, and is aimed at maximizing organ function, and therefore the quality of life. Occupational therapists use energy conservation techniques (ECT) in the rehabilitation process for patients with Cystic Fibrosis. Examples of energy conservation techniques are ergonomic principles, pursed lip breathing, and diaphragmatic breathing. Patients with CF tend to have fatigue and dyspnoea due to chronic pulmonary infections, so reducing the amount of energy spent during activities can help patients feel better and gain more independence. At best, current treatments delay the decline in organ function. Because of the wide variation in disease symptoms, treatment typically occurs at specialist multidisciplinary centers and is tailored to the individual. Targets for therapy are the lungs, gastrointestinal tract (including pancreatic enzyme supplements), the reproductive organs
A sex organ (or reproductive organ) is any part of an animal or plant that is involved in sexual reproduction. The reproductive organs together constitute the reproductive system. In animals, the testis in the male, and the ovary in the female, a ...
(including assisted reproductive technology), and psychological support.
The most consistent aspect of therapy in CF is limiting and treating the lung damage caused by thick mucus and infection, with the goal of maintaining quality of life
Quality of life (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...
. Intravenous, inhaled
Inhalation (or Inspiration) happens when air or other gases enter the lungs.
Inhalation of air
Inhalation of air, as part of the cycle of breathing, is a vital process for all human life. The process is autonomic (though there are exceptions ...
, 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. Oxygen therapy at home is recommended in those with significant low oxygen levels. Many people with CF use probiotics
Probiotics are live microorganisms promoted with claims that they provide health benefits when consumed, generally by improving or restoring the gut microbiota. Probiotics are considered generally safe to consume, but may cause bacteria- host i ...
, which are thought to be able to correct intestinal dysbiosis and inflammation, but the clinical trial evidence regarding the effectiveness of probiotics for reducing pulmonary exacerbations in people with CF is uncertain.
Antibiotics
Many people with CF are on one or more antibiotics at all times, even when healthy, to prophylactically suppress infection. Antibiotics are absolutely necessary whenever pneumonia is suspected or a noticeable decline in lung function is seen, and are usually chosen based on the results of a sputum analysis and the person's past response. This prolonged therapy often necessitates hospitalization and insertion of a more permanent IV such as a peripherally inserted central catheter
A peripherally inserted central catheter (PICC or PIC line), less commonly called a percutaneous indwelling central catheter, is a form of intravenous access that can be used for a prolonged period of time (e.g., for long chemotherapy regimens ...
or Port-a-Cath
In medicine, a port is a small medical appliance that is installed beneath the skin. A catheter (plastic tube) connects the port to a vein. Under the skin, the port has a septum (a silicone membrane) through which drugs can be injected and blood ...
. Inhaled therapy with antibiotics such as tobramycin
Tobramycin is an aminoglycoside antibiotic derived from '' Streptomyces tenebrarius'' that is used to treat various types of bacterial infections, particularly Gram-negative infections. It is especially effective against species of ''Pseudomonas ...
, colistin
Colistin, also known as polymyxin E, is an antibiotic medication used as a last-resort treatment for multidrug-resistant Gram-negative infections including pneumonia. These may involve bacteria such as ''Pseudomonas aeruginosa'', '' Klebsiella ...
, and aztreonam
Aztreonam, sold under the brand name Azactam among others, is an antibiotic used primarily to treat infections caused by gram-negative bacteria such as ''Pseudomonas aeruginosa''. This may include bone infections, endometritis, intra abdominal ...
is often given for months at a time to improve lung function by impeding the growth of colonized bacteria. Inhaled antibiotic therapy helps lung function by fighting infection, but also has significant drawbacks such as development of antibiotic resistance, tinnitus, and changes in the voice. Inhaled levofloxacin
Levofloxacin, sold under the brand name Levaquin among others, is an antibiotic medication. It is used to treat a number of bacterial infections including acute bacterial sinusitis, pneumonia, H. pylori (in combination with other medications), ...
may be used to treat ''Pseudomonas aeruginosa
''Pseudomonas aeruginosa'' is a common encapsulated, gram-negative, aerobic–facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, ''P. aerug ...
'' in people with cystic fibrosis who are infected. The early management of Pseudomonas aeruginosa infection is easier and better, using nebulised antibiotics with or without oral antibiotics may sustain its eradication up to two years. When choosing antibiotics to treat CF patients with lung infections caused by ''Pseudomonas aeruginosa'' in people with cystic fibrosis, it is still unclear whether the choice of antibiotics should be based on the results of testing antibiotics separately (one at a time) or in combination with each other.
Antibiotics by mouth such as ciprofloxacin or azithromycin
Azithromycin, sold under the brand names Zithromax (in oral form) and Azasite (as an eye drop), is an antibiotic medication used for the treatment of a number of bacterial infections. This includes middle ear infections, strep throat, pneumo ...
are given to help prevent infection or to control ongoing infection. The aminoglycoside
Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). The term can also refer ...
antibiotics (e.g. tobramycin) used can cause hearing loss
Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spoken ...
, damage to the balance system in the inner ear or kidney failure with long-term use. To prevent these side-effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
s, the amount of antibiotics in the blood is routinely measured and adjusted accordingly.
All these factors related to the antibiotics use, the chronicity of the disease, and the emergence of resistant bacteria demand more exploration for different strategies such as antibiotic adjuvant In pharmacology, an adjuvant is a drug or other substance, or a combination of substances, that is used to increase the efficacy or potency of certain drugs. Specifically, the term can refer to:
* Adjuvant therapy in cancer management
* Analgesi ...
therapy. Currently, no reliable clinical trial evidence shows the effectiveness of antibiotics for pulmonary exacerbations in people with cystic fibrosis and ''Burkholderia cepacia'' complex or for the use of antibiotics to treat nontuberculous mycobacteria
Nontuberculous mycobacteria (NTM), also known as environmental mycobacteria, atypical mycobacteria and mycobacteria other than tuberculosis (MOTT), are mycobacteria which do not cause tuberculosis or leprosy (also known as Hansen's disease). NTM do ...
in people with CF.
Other medication
Aerosolized medications that help loosen secretions include dornase alfa
Dornase alfa (proprietary name Pulmozyme from Genentech) is a highly purified solution of recombinant human deoxyribonuclease I (rhDNase), an enzyme which selectively cleaves DNA. Dornase alfa hydrolyzes the DNA present in sputum/mucus of cy ...
and hypertonic
In chemical biology, tonicity is a measure of the effective osmotic pressure gradient; the water potential of two solutions separated by a partially-permeable cell membrane. Tonicity depends on the relative concentration of selective membrane- ...
saline. Dornase is a recombinant human deoxyribonuclease Deoxyribonuclease (DNase, for short) refers to a group of glycoprotein endonucleases which are enzymes that catalyze the hydrolytic cleavage of phosphodiester linkages in the DNA backbone, thus degrading DNA. The role of the DNase enzyme in cells ...
, which breaks down DNA in the sputum, thus decreasing its viscosity. Dornase alpha improves lung function and probably decreases the risk of exacerbations but there is insufficient evidence to know if it is more or less effective than other similar medications. Dornase alpha may improve lung function, however there is no strong evidence that it is better than other hyperosmolar therapies.
Denufosol, an investigational drug, opens an alternative chloride channel, helping to liquefy mucus. Whether inhaled corticosteroids
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...
are useful is unclear, but stopping inhaled corticosteroid therapy is safe. There is weak evidence that corticosteroid treatment may cause harm by interfering with growth. Pneumococcal vaccination
Pneumococcal vaccines are vaccines against the bacterium '' Streptococcus pneumoniae''. Their use can prevent some cases of pneumonia, meningitis, and sepsis. There are two types of pneumococcal vaccines: conjugate vaccines and polysaccharide v ...
has not been studied . , there is no clear evidence from randomized controlled trials that the influenza vaccine is beneficial for people with cystic fibrosis.
Ivacaftor
Ivacaftor is a medication used to treat cystic fibrosis in people with certain mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (primarily the G551D mutation), who account for 4–5% cases of cystic fibrosis. It ...
is a medication taken by mouth for the treatment of CF due to a number of specific mutations responsive to ivacaftor-induced CFTR protein enhancement.[ It improves lung function by about 10%; however, it is expensive.] The first year it was on the market, the list price was over $300,000 per year in the United States.[ In July 2015, the U.S. Food and Drug Administration approved lumacaftor/ivacaftor. In 2018, the FDA approved the combination ivacaftor/tezacaftor; the manufacturer announced a list price of $292,000 per year. Tezacaftor helps move the CFTR protein to the correct position on the cell surface, and is designed to treat people with the F508del mutation.
In 2019, the ]combination drug
A combination drug or a fixed-dose combination (FDC) is a medicine that includes two or more active ingredients combined in a single dosage form. Terms like "combination drug" or "combination drug product" can be common shorthand for a FDC prod ...
elexacaftor/ivacaftor/tezacaftor marketed as ''Trikafta'' in the United States, was approved for CF patients over the age of 12. In 2021, this was extended to include patients over the age of 6. In Europe this drug was approved in 2020 and marketed as ''Kaftrio''. It is used in those that have a f508del mutation, which occurs in about 90% of patients with cystic fibrosis.[ According to the ]Cystic Fibrosis Foundation
The Cystic Fibrosis Foundation (CFF) is a 501(c)(3) non-profit organization in the United States established to provide the means to cure cystic fibrosis (CF) and ensure that those living with CF live long and productive lives. The Foundation pr ...
, "this medicine represents the single greatest therapeutic advancement in the history of CF, offering a treatment for the underlying cause of the disease that could eventually bring modulator therapy to 90 percent of people with CF." In a clinical trial, participants who were administered the combination drug experienced a subsequent 63% decrease in pulmonary exacerbations and a 41.8 mmol/L decrease in sweat chloride concentration. By mitigating a repertoire of symptoms associated with cystic fibrosis, the combination drug significantly improved quality-of-life metrics among patients with the disease as well. The combination drug is also known to interact wit
CYP3A inducers
such as carbamazepine used in the treatment of bipolar disorder, causing elexafaftor/ivacaftor/tezacaftor to circulate in the body at decreased concentrations. As such, concomitant use is not recommended. The list price in the US is going to be $311,000 per year; however, insurance may cover much of the cost of the drug.
Ursodeoxycholic acid
Ursodeoxycholic acid (UDCA), also known as ursodiol, is a secondary bile acid, produced in humans and most other species from metabolism by intestinal bacteria. It is synthesized in the liver in some species, and was first identified in bile of ...
, a bile salt
Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts.
P ...
, has been used, however there is insufficient data to show if it is effective.
Nutrient supplementation
It is uncertain whether vitamin A
Vitamin A is a fat-soluble vitamin and an essential nutrient for humans. It is a group of organic compounds that includes retinol, retinal (also known as retinaldehyde), retinoic acid, and several provitamin A carotenoids (most notably ...
or beta-carotene supplementation have any effect on eye and skin problems caused by vitamin A deficiency.
There is no strong evidence that people with cystic fibrosis can prevent osteoporosis by increasing their intake of vitamin D
Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group are vitamin D3 (c ...
.
For people with vitamin E
Vitamin E is a group of eight fat soluble compounds that include four tocopherols and four tocotrienols. Vitamin E deficiency, which is rare and usually due to an underlying problem with digesting dietary fat rather than from a diet low in vi ...
deficiency and cystic fibrosis, there is evidence that vitamin E supplementation may improve vitamin E levels, although it is still uncertain what effect supplementation has on vitamin E‐specific deficiency disorders or on lung function.
Robust evidence regarding the effects of vitamin K
Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation ...
supplementation in people with cystic fibrosis is lacking as of 2020.
Various studies have examined the effects of omega-3 fatty acid supplementation for people with cystic fibrosis but the evidence is uncertain whether it has any benefits or adverse effects.
Procedures
Several mechanical techniques are used to dislodge sputum and encourage its expectoration. One technique good for short-term airway clearance is chest physiotherapy where a respiratory therapist percusses an individual's chest by hand several times a day, to loosen up secretions. This "percussive effect" can be administered also through specific devices that use chest wall oscillation
Chest wall oscillation is when devices are used in airway clearance therapy to clear excess mucus from lung airways (bronchi and bronchioles). It is principally used in the treatment of cystic fibrosis, but is gaining use in the treatment of othe ...
or intrapulmonary percussive ventilator
Airway clearance therapy is treatment that uses a number of airway clearance techniques to clear the respiratory airways of mucus and other secretions. Several respiratory diseases cause the normal mucociliary clearance mechanism to become impair ...
. Other methods such as biphasic cuirass ventilation
An iron lung is a type of negative pressure ventilator (NPV), a mechanical respirator which encloses most of a person's body, and varies the air pressure in the enclosed space, to stimulate breathing.Shneerson, Dr. John M., Newmarket Genera ...
, and associated clearance mode available in such devices, integrate a cough assistance phase, as well as a vibration phase for dislodging secretions. These are portable and adapted for home use.[
Another technique is positive expiratory pressure physiotherapy that consists of providing a back pressure to the airways during expiration. This effect is provided by devices that consists of a mask or a mouthpiece in which a resistance is applied only on the expiration phase. Operating principles of this technique seems to be the increase of gas pressure behind mucus through ]collateral ventilation Collateral ventilation (CV) is a back-up system of alveolar ventilation that can bypass the normal route of airflow when airways are restricted or obstructed. The pathways involved include those between adjacent alveoli (pores of Kohn), between bro ...
along with a temporary increase in functional residual capacity preventing the early collapse of small airways during exhalation.
As lung disease worsens, mechanical breathing support may become necessary. Individuals with CF may need to wear special masks at night to help push air into their lungs. These machines, known as bilevel positive airway pressure
Positive airway pressure (PAP) is a mode of respiratory ventilation used in the treatment of sleep apnea. PAP ventilation is also commonly used for those who are critically ill in hospital with respiratory failure, in newborn infants ( neonate ...
(BiPAP) ventilators, help prevent low blood oxygen levels during sleep. Non-invasive ventilators may be used during physical therapy to improve sputum clearance. It is not known if this type of therapy has an impact on pulmonary exacerbations or disease progression. It is not known what role non-invasive ventilation therapy has for improving exercise capacity in people with cystic fibrosis. However, the authors noted that "non‐invasive ventilation may be a useful adjunct to other airway clearance techniques, particularly in people with cystic fibrosis who have difficulty expectorating sputum." During severe illness, a tube may be placed in the throat (a procedure known as a tracheostomy
Tracheotomy (, ), or tracheostomy, is a surgical airway management procedure which consists of making an incision (cut) on the anterior aspect (front) of the neck and opening a direct airway through an incision in the trachea (windpipe). The r ...
) to enable breathing supported by a ventilator.
For children, preliminary studies show massage therapy
Massage is the manipulation of the body's soft tissues. Massage techniques are commonly applied with hands, fingers, elbows, knees, forearms, feet or a device. The purpose of massage is generally for the treatment of body stress or pain. In Eu ...
may help people and their families' quality of life.
Some lung infections require surgical removal of the infected part of the lung. If this is necessary many times, lung function is severely reduced. The most effective treatment options for people with CF who have spontaneous or recurrent pneumothoraces is not clear.
Transplantation
Lung transplantation may become necessary for individuals with CF as lung function and exercise tolerance
Exercise intolerance is a condition of inability or decreased ability to perform physical exercise at the normally expected level or duration for people of that age, size, sex, and muscle mass. It also includes experiences of unusually severe post ...
decline. Although single lung transplantation is possible in other diseases, individuals with CF must have both lungs replaced because the remaining lung might contain bacteria that could infect the transplanted lung. A pancreatic or liver transplant may be performed at the same time to alleviate liver disease and/or diabetes. Lung transplantation is considered when lung function declines to the point where assistance from mechanical devices is required or someone's survival is threatened. According to Merck Manual
''The Merck Manual of Diagnosis and Therapy'', referred to as ''The Merck Manual'',
is the world's best-selling medical textbook, and the oldest continuously published English language medical textbook. First published in 1899, the current print e ...
, "bilateral lung transplantation for severe lung disease is becoming more routine and more successful with experience and improved techniques. Among adults with CF, median survival posttransplant is about 9 years."
Other aspects
Newborns with intestinal obstruction typically require surgery, whereas adults with distal intestinal obstruction syndrome typically do not. Treatment of pancreatic insufficiency by replacement of missing digestive enzymes allows the duodenum to properly absorb nutrients and vitamins that would otherwise be lost in the feces. However, the best dosage and form of pancreatic enzyme replacement is unclear, as are the risks and long-term effectiveness of this treatment.
So far, no large-scale research involving the incidence of atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no s ...
and coronary heart disease
Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pl ...
in adults with cystic fibrosis has been conducted. This is likely because the vast majority of people with cystic fibrosis do not live long enough to develop clinically significant atherosclerosis or coronary heart disease.
Diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
is the most common nonpulmonary complication of CF. It mixes features of type 1 and type 2 diabetes, and is recognized as a distinct entity, cystic fibrosis-related diabetes. While oral antidiabetic drug
Drugs used in diabetes treat diabetes mellitus by altering the glucose level in the blood. With the exceptions of insulin, most GLP receptor agonists ( liraglutide, exenatide, and others), and pramlintide, all are administered orally and are t ...
s are sometimes used, the recommended treatment is the use of insulin injections or an insulin pump
An insulin pump is a medical device used for the administration of insulin in the treatment of diabetes mellitus, also known as continuous subcutaneous insulin therapy.
The device configuration may vary depending on design. A traditional pump ...
, and, unlike in type 1 and 2 diabetes, dietary restrictions are not recommended.[ While Stenotrophomonas maltophilia is relatively common in people with cystic fibrosis, the evidence about the effectiveness of antibiotics for ''S. maltophilia'' is uncertain.
]Bisphosphonate
Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis. They are called bisphosphonates because they ...
s taken by mouth or intravenously
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
can be used to improve the bone mineral density in people with cystic fibrosis. When taking bisphosphates intravenously, adverse effects
An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complica ...
such as pain and flu-like symptoms can be an issue. The adverse effects of bisphosphates taken by mouth on the gastrointestinal tract are not known.
Poor growth may be avoided by insertion of a feeding tube
Eating (also known as consuming) is the ingestion of food, typically to provide a heterotrophic organism with energy and to allow for growth. Animals and other heterotrophs must eat in order to survive — carnivores eat other animals, herbi ...
for increasing food energy through supplemental feeds or by administration of injected growth hormone
Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in h ...
.
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 person's sense of smell. Sinus surgery is often used to alleviate nasal obstruction and to limit further infections. Nasal steroids such as fluticasone propionate
Fluticasone propionate, sold under the brand names Flovent and Flonase among others, is a steroid medication. When inhaled it is used for the long term management of asthma and COPD. In the nose it is used for hay fever and nasal polyps. It ...
are used to decrease nasal inflammation.
Female infertility may be overcome by assisted reproduction
Assisted reproductive technology (ART) includes medical procedures used primarily to address infertility. This subject involves procedures such as in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), cryopreservation of gametes ...
technology, particularly embryo transfer
Embryo transfer refers to a step in the process of assisted reproduction in which embryos are placed into the uterus of a female with the intent to establish a pregnancy. This technique (which is often used in connection with in vitro fertilizati ...
techniques. Male infertility caused by absence of the vas deferens may be overcome with testicular sperm extraction
Testicular sperm extraction (TESE) is a surgical procedure in which a small portion of tissue is removed from the testicle and any viable sperm cells from that tissue are extracted for use in further procedures, most commonly intracytoplasmic sperm ...
, collecting sperm cells directly from the testicles. If the collected sample contains too few sperm cells to likely have a spontaneous fertilization, intracytoplasmic sperm injection
Intracytoplasmic sperm injection (ICSI ) is an in vitro fertilization (IVF) procedure in which a single sperm cell is injected directly into the cytoplasm of an egg. This technique is used in order to prepare the gametes for the obtention of em ...
can be performed. Third party reproduction
Third-party reproduction or donor-assisted reproduction is any human reproduction in which DNA or gestation is provided by a third party or donor other than the one or two parents who will raise the resulting child. This goes beyond the tradi ...
is also a possibility for women with CF. Whether taking antioxidants affects outcomes is unclear.
Physical exercise is usually part of outpatient care for people with cystic fibrosis. Aerobic exercise seems to be beneficial for aerobic exercise capacity, lung function and health-related quality of life; however, the quality of the evidence was poor.
Due to the use of aminoglycoside antibiotics, ototoxicity is common. Symptoms may include "tinnitus, hearing loss, hyperacusis, aural fullness, dizziness, and vertigo".
Gastrointestinal
Problems with the gastrointestinal system including constipation and obstruction of the gastrointestinal tract including distal intestinal obstruction syndrome are frequent complications for people with cystic fibrosis. Treatment of gastrointestinal problems is required in order to prevent a complete obstruction, reduce other CF symptoms, and improve the quality of life. While stool softeners, laxatives, and prokinetics (GI-focused treatments) are often suggested, there is no clear consensus from experts at to which approach is the best and comes with the least risks. Mucolytics or systemic treatments aimed at dysfunctional CFTR are also sometimes suggested to improve symptoms.
Prognosis
The prognosis for cystic fibrosis has improved due to earlier diagnosis through screening and better treatment and access to health care. In 1959, the median age of survival of children with CF in the United States was six months.
In 2010, survival is estimated to be 37 years for women and 40 for men. In Canada, median survival increased from 24 years in 1982 to 47.7 in 2007. In the United States those born with CF in 2016 have an predicted life expectancy of 47.7 when cared for in specialty clinics.
In the US, of those with CF who are more than 18 years old as of 2009, 92% had graduated from high school, 67% had at least some college education, 15% were disabled, 9% were unemployed, 56% were single, and 39% were married or living with a partner.
Quality of life
Chronic illnesses can be difficult to manage. CF is a chronic illness that affects the "digestive and respiratory tracts resulting in generalized malnutrition and chronic respiratory infections". The thick secretions clog the airways in the lungs, which often cause inflammation and severe lung infections. If it is compromised, it affects the quality of life of someone with CF and their ability to complete such tasks as everyday chores.
According to Schmitz and Goldbeck (2006), CF significantly increases emotional stress on both the individual and the family, "and the necessary time-consuming daily treatment routine may have further negative effects on quality of life". However, Havermans and colleagues (2006) have established that young outpatients with CF who have participated in the Cystic Fibrosis Questionnaire-Revised "rated some quality of life domains higher than did their parents". Consequently, outpatients with CF have a more positive outlook for themselves. As Merck Manual
''The Merck Manual of Diagnosis and Therapy'', referred to as ''The Merck Manual'',
is the world's best-selling medical textbook, and the oldest continuously published English language medical textbook. First published in 1899, the current print e ...
notes, "with appropriate support, most patients can make an age-appropriate adjustment at home and school. Despite myriad problems, the educational, occupational, and marital successes of patients are impressive."
Furthermore, there are many ways to enhance the quality of life in CF patients. Exercise is promoted to increase lung function. Integrating an exercise regimen into the CF patient's daily routine can significantly improve quality of life. No definitive cure for CF is known, but diverse medications are used, such as mucolytics, bronchodilators, steroids, and antibiotics, that have the purpose of loosening mucus, expanding airways, decreasing inflammation, and fighting lung infections, respectively.
Epidemiology
Cystic fibrosis is the most common life-limiting autosomal recessive disease among people of European heritage. In the United States, about 30,000 individuals have CF; most are diagnosed by six months of age. In Canada, about 4,000 people have CF. Around 1 in 25 people of European descent, and one in 30 of white Americans, is a carrier of a CF mutation. Although CF is less common in these groups, roughly one in 46 Hispanic
The term ''Hispanic'' ( es, hispano) refers to people, cultures, or countries related to Spain, the Spanish language, or Hispanidad.
The term commonly applies to countries with a cultural and historical link to Spain and to viceroyalties forme ...
s, one in 65 Africans, and one in 90 Asians carry at least one abnormal ''CFTR'' gene. Ireland has the world's highest prevalence of CF, at one in 1353.
Although technically a rare disease, CF is ranked as one of the most widespread life-shortening genetic diseases. It is most common among nations in the Western world. An exception is Finland
Finland ( fi, Suomi ; sv, Finland ), officially the Republic of Finland (; ), is a Nordic country in Northern Europe. It shares land borders with Sweden to the northwest, Norway to the north, and Russia to the east, with the Gulf of B ...
, where only one in 80 people carries a CF mutation. The World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of ...
states, "In the European Union, one in 2000–3000 newborns is found to be affected by CF". In the United States, one in 3,500 children is born with CF. In 1997, about one in 3,300 white children in the United States was born with CF. In contrast, only one in 15,000 African American children have it, and in Asian Americans, the rate was even lower at one in 32,000.
Cystic fibrosis is diagnosed equally in males and females. For reasons that remain unclear, data have shown that males tend to have a longer life expectancy than females, though recent studies suggest this gender gap may no longer exist, perhaps due to improvements in health care facilities. A recent study from Ireland identified a link between the female hormone estrogen and worse outcomes in CF.
The distribution of CF alleles varies among populations. The frequency of ΔF508 carriers has been estimated at one in 200 in northern Sweden, one in 143 in Lithuanians, and one in 38 in Denmark. No ΔF508 carriers were found among 171 Finns and 151 Saami people
The Sporting Arms and Ammunition Manufacturers' Institute (SAAMI, pronounced "Sammy") is an association of American manufacturers of firearms, ammunition, and components. SAAMI is an accredited standards developer that publishes several Ame ...
. ΔF508 does occur in Finland, but it is a minority allele there. CF is known to occur in only 20 families (pedigrees) in Finland.
Evolution
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
Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red bl ...
have been found to protect carriers from other diseases, an evolutionary trade-off known as heterozygote advantage
A heterozygote advantage describes the case in which the heterozygous genotype has a higher relative fitness than either the homozygous dominant or homozygous recessive genotype. Loci exhibiting heterozygote advantage are a small minority of ...
. Resistance to the following have all been proposed as possible sources of heterozygote advantage:
* Cholera: With the discovery that cholera toxin
Cholera toxin (also known as choleragen and sometimes abbreviated to CTX, Ctx or CT) is AB5 multimeric protein complex secreted by the bacterium ''Vibrio cholerae''. CTX is responsible for the massive, watery diarrhea characteristic of cholera i ...
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
Typhoid fever, also known as typhoid, is a disease caused by ''Salmonella'' serotype Typhi bacteria. Symptoms vary from mild to severe, and usually begin six to 30 days after exposure. Often there is a gradual onset of a high fever over several d ...
: 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 typhoid, is a disease caused by '' Salmonella'' serotype Typhi bacteria. Symptoms vary from mild to severe, and usually begin six to 30 days after exposure. Often there is a gradual onset of a high fever over several ...
. No ''in vivo'' study has yet confirmed this. In both cases, the low level of cystic fibrosis outside of Europe, in places where both cholera and typhoid fever are endemic
Endemism is the state of a species being found in a single defined geographic location, such as an island, state, nation, country or other defined zone; organisms that are indigenous to a place are not endemic to it if they are also found else ...
, is not immediately explicable.
* Diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...
: The prevalence of CF in Europe might be connected with the development of cattle domestication. In this hypothesis, carriers of a single mutant ''CFTR'' had some protection from diarrhea caused by lactose intolerance
Lactose intolerance is a common condition caused by a decreased ability to digest lactose, a sugar found in dairy products. Those affected vary in the amount of lactose they can tolerate before symptoms develop. Symptoms may include abdominal pai ...
, before the mutations that created lactose tolerance appeared.
* Tuberculosis
Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, i ...
: Another possible explanation is that carriers of the gene could have some resistance to tuberculosis. This hypothesis is based on the thesis that ''CFTR'' gene mutation carriers have insufficient action in one of their enzymes – arylsulphatase - which is necessary for ''Mycobacterium tuberculosis'' virulence. As ''M. tuberculosis'' would use its host's sources to affect the individual, and due to the lack of enzyme it could not presents its virulence, being a carrier of ''CFTR ''mutation could provide resistance against tuberculosis.
History
CF is supposed to have appeared about 3,000 BC because of migration of peoples, gene mutations, and new conditions in nourishment.[ Although the entire clinical spectrum of CF was not recognized until the 1930s, certain aspects of CF were identified much earlier. Indeed, literature from Germany and Switzerland in the 18th century warned ("Woe to the child who tastes salty from a kiss on the brow, for he is cursed and soon must die"), recognizing the association between the salt loss in CF and illness.]
In the 19th century, Carl von Rokitansky
Baron Carl von Rokitansky (german: Carl Freiherr von Rokitansky, cs, Karel Rokytanský; 19 February 1804 – 23 July 1878) was a Bohemian physician, pathologist, humanist philosopher and liberal politician, founder of the Viennese School of Medi ...
described a case of fetal death with meconium peritonitis, a complication of meconium ileus associated with CF. Meconium ileus was first described in 1905 by Karl Landsteiner
Karl Landsteiner (; 14 June 1868 – 26 June 1943) was an Austrian-born American biologist, physician, and immunologist. He distinguished the main blood groups in 1900, having developed the modern system of classification of blood groups from ...
. In 1936, Guido Fanconi described a connection between celiac disease
Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine, where individuals develop intolerance to gluten, present in foods such as wheat, rye and barle ...
, cystic fibrosis of the pancreas, and bronchiectasis.
In 1938, Dorothy Hansine Andersen
Dorothy Hansine Andersen (May 15, 1901 – March 3, 1963) was an American physician, pediatrician, and pathologist who was the first person to identify cystic fibrosis, the first to describe the disease, and the one to name it. in 1939, she was a ...
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
''JAMA Pediatrics'' is a monthly peer-reviewed medical journal published by the American Medical Association. It covers all aspects of pediatrics. The journal was established in 1911 as the ''American Journal of Diseases of Children'' and rename ...
''. She was the first to describe the characteristic cystic fibrosis of the pancreas and to correlate it with the lung and intestinal disease prominent in CF. She also first hypothesized that CF was a recessive disease and first used pancreatic enzyme replacement to treat affected children. In 1952, Paul di Sant'Agnese discovered abnormalities in sweat electrolytes; a sweat test was developed and improved over the next decade.
The first linkage between CF and another marker (paraoxonase
Paraoxonases are a family of mammalian enzymes with aryldialkylphosphatase activity. There are three paraoxonase isozymes, which were originally discovered for their involvement in the hydrolysis of organophosphates.
Research has indicated the ...
) was found in 1985 by Hans Eiberg, indicating that only one locus exists for CF. In 1988, the first mutation for CF, ΔF508
Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the ''CFTR'' gene.
Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked wit ...
, was discovered by Francis Collins
Francis Sellers Collins (born April 14, 1950) is an American physician-geneticist who discovered the genes associated with a number of diseases and led the Human Genome Project. He is the former director of the National Institutes of Health (N ...
, Lap-Chee Tsui
Lap-Chee Tsui (; born 21 December 1950) is a Chinese-born Canadian geneticist and served as the 14th Vice-Chancellor and President of the University of Hong Kong.
Personal life
Tsui was born in Shanghai. He grew up in Kowloon, Hong Kong and at ...
, and John R. Riordan on the seventh chromosome. Subsequent research has found over 1,000 different mutations that cause CF.
Because mutations in the ''CFTR'' gene are typically small, classical genetics
Classical genetics is the branch of genetics based solely on visible results of reproductive acts. It is the oldest discipline in the field of genetics, going back to the experiments on Mendelian inheritance by Gregor Mendel who made it possible ...
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
Primer walking is a technique used to clone a gene (e.g., disease gene) from its known closest markers (e.g., known gene). As a result, it is employed in cloning and sequencing efforts in plants, fungi, and mammals with minor alterations. This te ...
and chromosome jumping Chromosome jumping is a tool of molecular biology that is used in the physical mapping of genomes. It is related to several other tools used for the same purpose, including chromosome walking.
Chromosome jumping is used to bypass regions difficul ...
techniques were then used to identify and sequence
In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is calle ...
the gene. In 1989, Lap-Chee Tsui led a team of researchers at the Hospital for Sick Children in Toronto
Toronto ( ; or ) is the capital city of the Canadian province of Ontario. With a recorded population of 2,794,356 in 2021, it is the most populous city in Canada and the fourth most populous city in North America. The city is the anch ...
that discovered the gene responsible for CF. CF represents a classic example of how a human genetic disorder was elucidated strictly by the process of forward genetics
Forward genetics is a molecular genetics approach of determining the genetic basis responsible for a phenotype. Forward genetics provides an unbiased approach because it relies heavily on identifying the genes or genetic factors that cause a partic ...
.
Research
People with CF may be listed in a disease registry Disease or patient registries are collections of secondary data related to patients with a specific diagnosis, condition, or procedure, and they play an important role in post marketing surveillance of pharmaceuticals. Registries are different from ...
that allows researchers and doctors to track health results and identify candidates for clinical trials.
Gene therapy
Gene therapy
Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human DN ...
has been explored as a potential cure for CF. Results from clinical trials have shown limited success , and using gene therapy as routine therapy is not suggested. A small study published in 2015 found a small benefit.
The focus of much CF gene therapy research is aimed at trying to place a normal copy of the ''CFTR'' gene into affected cells. Transferring the normal ''CFTR'' gene into the affected epithelium cells would result in the production of functional CFTR protein in all target cells, without adverse reactions or an inflammation response. To prevent the lung manifestations of CF, only 5–10% the normal amount of CFTR gene expression is needed. Multiple approaches have been tested for gene transfer, such as liposomes and viral vectors in animal models and clinical trials. However, both methods were found to be relatively inefficient treatment options, mainly because very few cells take up the vector and express the gene, so the treatment has little effect. Additionally, problems have been noted in cDNA recombination, such that the gene introduced by the treatment is rendered unusable. There has been a functional repair in culture of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients.
Phage therapy
Phage therapy
Phage therapy, viral phage therapy, or phagotherapy is the therapeutic use of bacteriophages for the treatment of pathogenic bacterial infections. This therapeutic approach emerged at the beginning of the 20th century but was progressively re ...
is being studied for multidrug resistant bacteria in people with CF.
Gene modulators
A number of small molecules that aim at compensating various mutations of the ''CFTR'' gene are under development. CFTR modulator therapies have been used in place of other types of genetic therapies. These therapies focus on the expression of a genetic mutation instead of the mutated gene itself. Modulators are split into two classes: potentiators and correctors. Potentiators act on the CFTR ion channels that are embedded in the cell membrane, and these types of drugs help open up the channel to allow transmembrane flow. Correctors are meant to assist in the transportation of nascent proteins, a protein that is formed by ribosomes before it is morphed into a specific shape, to the cell surface to be implemented into the cell membrane.
Most target the transcription stage of genetic expression. One approach has been to try and develop medication that get the ribosome to overcome the stop codon
In molecular biology (specifically protein biosynthesis), a stop codon (or termination codon) is a codon (nucleotide triplet within messenger RNA) that signals the termination of the translation process of the current protein. Most codons in mess ...
and produce a full-length CFTR protein. About 10% of CF results from a premature stop codon in the DNA, leading to early termination of protein synthesis and truncated proteins. These drugs target nonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a ''nonsense codon'' in the transcribed mRNA, and in leading to a truncated, incomplete, and usually nonfunctional protein produc ...
s such as G542X, which consists of the amino acid glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid ( carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinog ...
in position 542 being replaced by a stop codon. Aminoglycoside antibiotics interfere with protein synthesis and error-correction. In some cases, they can cause the cell to overcome a premature stop codon by inserting a random amino acid, thereby allowing expression of a full-length protein. Future research for these modulators is focused on the cellular targets that can be effected by a change in a gene's expression. Otherwise, genetic therapy will be used as a treatment when modulator therapies do not work given that 10% of people with cystic fibrosis are not affected by these drugs.
Elexacaftor/ivacaftor/tezacaftor was approved in the United States in 2019 for cystic fibrosis. This combination of previously developed medicines is able to treat up to 90% of people with cystic fibrosis.[ This medications restores some effectiveness of the CFTR protein so that it can work as an ion channel on the cell's surface.
]
Ecological therapy
It has previously been shown that inter-species interactions are an important contributor to the pathology of CF lung infections. Examples include the production of antibiotic degrading enzymes such as β-lactamases and the production of metabolic by-products such as short-chain fatty acids (SCFAs) by anaerobic species, which can enhance the pathogenicity of traditional pathogens such as Pseudomonas aeruginosa. Due to this, it has been suggested that the direct alteration of CF microbial community composition and metabolic function would provide an alternative to traditional antibiotic therapies.
Society and culture
* '' Sick: The Life and Death of Bob Flanagan, Supermasochist'', a 1997 documentary film
* '' 65 Redroses'', a 2009 documentary film
* '' Breathing for a Living'', a memoir by Laura Rothenberg
Laura Elizabeth Rothenberg (February 3, 1981 – March 20, 2003) was an American author. She wrote a memoir describing her life with cystic fibrosis called ''Breathing for a Living''.
Biography
Laura Rothenberg was born February 3, 1981 and sh ...
* ''Every Breath I Take, Surviving and Thriving With Cystic Fibrosis'', book by Claire Wineland
Claire Lucia Wineland (April 10, 1997 – September 2, 2018) was an American activist, author, speaker and social media personality. Through her non-profit organization, Claire's Place Foundation, she provided support to children and famili ...
* ''Five Feet Apart
''Five Feet Apart'' is a 2019 American romantic drama film directed by Justin Baldoni (in his directorial debut) and written by Mikki Daughtry and Tobias Iaconis. The film was inspired by Claire Wineland, who suffered from cystic fibrosis. H ...
'', a 2019 romantic drama film starring Cole Sprouse
Cole Mitchell Sprouse (born August 4, 1992) is an American actor and photographer. He is known for his role as Cody Martin on the Disney Channel series ''The Suite Life of Zack & Cody'' (2005–2008) and its spin-off series ''The Suite Life on ...
and Haley Lu Richardson
Haley Lu Richardson (born March 7, 1995) is an American actress. Following early television roles on the Disney Channel sitcom ''Shake It Up'' (2013) and the ABC Family supernatural drama '' Ravenswood'' (2013–2014), she acted in the coming-of- ...
* '' Orla Tinsley: Warrior'', a 2018 documentary film about CF campaigner Orla Tinsley
* The performance art
Performance art is an artwork or art exhibition created through actions executed by the artist or other participants. It may be witnessed live or through documentation, spontaneously developed or written, and is traditionally presented to a pu ...
of Martin O'Brien
* Continent Chasers, a traveller and CF patient documenting travel and CF blogs
continentchasers.com
Notes
References
Further reading
*
External links
Search GeneCards for genes involved in cystic fibrosis
Cystic Fibrosis Mutation Database
*
{{Authority control
Channelopathies
Autosomal recessive disorders
Pancreas disorders
Lung disorders
Respiratory diseases
Steatorrhea-related diseases