Cystic fibrosis (CF)
Is a genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine.
Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. 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.
• Clubbed fingers is a symptom of disease, often of the heart or lungs which cause chronically low blood levels of oxygen. Diseases which cause malabsorption, such as cystic fibrosis or celiac disease can also cause clubbing.
CF is inherited in an autosomal recessive manner. It is caused by the presence of mutations in both copies of the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein.
Those with a single working copy are carriers and otherwise mostly normal.
CFTR is involved in 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.
CF is most common among people of Northern European ancestry and affects about one out of every 3,000 newborns. About one in 25 people is a carrier. It is least common in Africans and Asians.
It was first recognized as a specific disease by Dorothy Andersen 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 and cysts that form within the pancreas.
► Signs and symptoms
The main signs and symptoms of cystic fibrosis are salty-tasting skin, poor growth, and poor weight gain despite normal food intake, accumulation of thick, sticky mucus, frequent chest infections, and coughing or shortness of breath.
Males can be infertile due to congenital absence of the vas deferens.
Symptoms often appear in infancy and childhood, such as bowel obstruction due to meconium ileus in newborn babies. As the children grow, they exercise to release mucus in the alveoli. Epithelial cells in the person have a mutated protein that leads to abnormally viscous mucus production. The poor growth in children typically presents as an inability to gain weight or height at the same rate as their peers, and is occasionally not diagnosed until investigation is initiated for poor growth. The causes of growth failure are multifactorial and include chronic lung infection, poor absorption of nutrients through the gastrointestinal tract, and increased metabolic demand due to chronic illness.
♦ Lungs and sinuses
Lung disease results from clogging of the airways due to mucus build-up, decreased mucociliary clearance, and resulting inflammation. Inflammation and infection cause injury and structural changes to the lungs, leading to a variety of symptoms.
* In the early stages, incessant coughing, copious phlegm production, and decreased ability to exercise are common. Many of these symptoms occur when bacteria that normally inhabit the thick mucus grow out of control and cause pneumonia.
* In later stages, changes in the architecture of the lung, such as pathology in the major airways (bronchiectasis), further exacerbate difficulties in breathing.
Other signs include coughing up blood (hemoptysis), high blood pressure in the lung (pulmonary hypertension), heart failure, difficulties getting enough oxygen to the body (hypoxia), and respiratory failure requiring support with breathing masks, such as bilevel positive airway pressure machines or ventilators.
Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa are the three most common organisms causing lung infections in CF patients.
In addition to typical bacterial infections, people with CF more commonly develop other types of lung disease.
Among these is allergic bronchopulmonary aspergillosis, in which the body's response to the common fungus Aspergillus fumigatus causes worsening of breathing problems.
Another is infection with Mycobacterium avium complex, a group of bacteria related to tuberculosis, which can cause lung damage and does not respond to common antibiotics.
People with CF are susceptible to getting a pneumothorax.
Mucus in the paranasal sinuses 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 polyps) 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 cause of death (about 80%) in patients at most CF centers.
Prior to prenatal and newborn screening, cystic fibrosis was often diagnosed when a newborn infant failed to pass feces (meconium). Meconium may completely block the intestines and cause serious illness.
This condition, called meconium ileus, occurs in 5–10% of newborns with CF. In addition, protrusion of internal rectal membranes (rectal prolapse) is more common, occurring in as many as 10% of children with CF, and it is caused by increased fecal volume, malnutrition, and increased intra–abdominal pressure due to coughing.
The thick mucus seen in the lungs has a counterpart in thickened secretions from the pancreas, an organ responsible for providing digestive juices that help break down food. These secretions block the exocrinemovement of the digestive enzymes into the duodenum and result in irreversible damage to the pancreas, often with painful inflammation (pancreatitis). The pancreatic ducts are totally plugged in more advanced cases, usually seen in older children or adolescents. This causes atrophy of the exocrine glands and progressive fibrosis.
The lack of digestive enzymes leads to difficulty absorbing nutrients with their subsequent excretion in the feces, a disorder known as malabsorption. Malabsorption leads to malnutrition and poor growth and development because of calorie loss.
Resultant hypoproteinemiamay be severe enough to cause generalized edema. Individuals with CF also have difficulties absorbing the fat-soluble vitamins A, D, E, and K.
In addition to the pancreas problems, people with cystic fibrosis experience more heartburn, intestinal blockage by intussusception, and constipation. Older individuals with CF may develop distal intestinal obstruction syndrome when thickened feces cause intestinal blockage.
Exocrine pancreatic insufficiency occurs in the majority (85% to 90%) of patients with CF. It is mainly associated with "severe" CFTR mutations, where both alleles are completely nonfunctional. 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 ducts, leading to liver damage. Over time, this can lead to scarring and nodularity (cirrhosis). The liver fails to rid the blood of toxins and does not make important proteins, such as those responsible for blood clotting. Liver disease is the third-most common cause of death associated with CF
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 (which normally connects the testes to the ejaculatory ducts of the penis), 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 and causes a lack of menstruation
CF is caused by a mutation in the gene cystic fibrosis transmembrane conductance regulator (CFTR). The most common mutation, ΔF508, 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; 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.
♦ Chronic infections
The lungs of individuals with cystic fibrosis are colonized and infected by bacteria from an early age. These bacteria, which often spread among individuals with CF, thrive in the altered mucus, which collects in the small airways of the lungs. This mucus leads to the formation of bacterial microenvironments known as biofilms that are difficult for immune cells and antibiotics to penetrate. Viscous secretions and persistent respiratory infections repeatedly damage the lung by gradually remodeling the airways, which makes infection even more difficult to eradicate.
Over time, both the types of bacteria and their individual characteristics change in individuals with CF.
In the initial stage, common bacteria such as S. aureus and H. influenzae colonize and infect the lungs.
Eventually, Pseudomonas aeruginosa (and sometimes Burkholderia cepacia) dominates.
By 18 years of age, 80% of patients with classic CF harbor P. aeruginosa, and 3.5% harbor B. cepacia. Once within the lungs, these bacteria adapt to the environment and develop resistance to commonly used antibiotics.
Pseudomonas can develop special characteristics that allow the formation of large colonies, known as "mucoid" Pseudomonas, which are rarely seen in people who do not have CF.
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 nebulizers) 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, Aspergillus terreus) and/or yeasts (such as Candida albicans); other filamentous fungi less commonly isolated include Aspergillus flavus and Aspergillus nidulans (occur transiently in CF respiratory secretions) and Exophiala dermatitidis and Scedosporium prolificans (chronic airway-colonizers); some filamentous fungi such as Penicillium emersonii and Acrophialophora fusispora are encountered in patients almost exclusively in the context of CF.
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 or Port-a-Cath. Inhaled therapy with antibiotics such as tobramycin, colistin, and aztreonam is often given for months at a time to improve lung function by impeding the growth of colonized bacteria. 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 may be used to treat Pseudomonas aeruginosa 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 2 years.
Antibiotics by mouth such as ciprofloxacin or azithromycin are given to help prevent infection or to control ongoing infection. The aminoglycoside antibiotics (e.g. tobramycin) used can cause hearing loss, damage to the balance system in the inner ear or kidney failure with long-term use. To prevent these side-effects, 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 therapy.
Lung transplantation often becomes necessary for individuals with CF as lung function and exercise tolerance 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.
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 was six months.
In 2010, survival is estimated to be 37 years for women and 40 for men.
♦ Quality of life
Chronic illnesses can be very 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 (QOL) of someone with CF and their ability to complete such tasks as everyday chores.
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".
Furthermore, many ways can improve the QOL in CF patients. Exercise is promoted to increase lung function. Integrating an exercise regimen into the CF patient's daily routine can significantly improve QOL.
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.
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 "Wehe dem Kind, das beim Kuß auf die Stirn salzig schmeckt, es ist verhext und muss bald sterben" or "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 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.
In 1936, Guido Fanconi described a connection between celiac disease, cystic fibrosis of the pancreas, and bronchiectasis.
In 1938, Dorothy Hansine Andersen published an article, "Cystic Fibrosis of the Pancreas and Its Relation to Celiac Disease: a Clinical and Pathological Study", in the American Journal of Diseases of Children. She was the first to describe the characteristic cystic fibrosis of the pancreas and to correlate it with the lung and intestinal disease prominent in CF. She also first hypothesized that CF was a recessive disease and first used pancreatic enzyme replacement to treat affected children.
In 1952, Paul di Sant'Agnese discovered abnormalities in sweat electrolytes; a sweat test was developed and improved over the next decade. The first linkage between CF and another marker (Paroxonase) was found in 1985 by Hans Eiberg, indicating that only one locus exists for CF. In 1988, the first mutation for CF, ΔF508 was discovered by Francis Collins, Lap-Chee Tsui, and John R. Riordan on the seventh chromosome. Subsequent research has found over 1,000 different mutations that cause CF. Because mutations in the CFTR gene are typically small, classical genetics techniques had been unable to accurately pinpoint the mutated gene. Using protein markers, gene-linkage studies were able to map the mutation to chromosome 7. Chromosome-walking and -jumping techniques were then used to identify and sequence the gene. In 1989, Lap-Chee Tsui led a team of researchers at the Hospital for Sick Children in Toronto that discovered the gene responsible for CF. CF represents a classic example of how a human genetic disorder was elucidated strictly by the process of forward genetics.
See also: List of people diagnosed with cystic fibrosis