Cystic fibrosis

Cystic fibrosis (also known as CF or mucoviscidosis) is a common disease which affects the entire body, causing progressive disability and often early death. The name cystic fibrosis refers to the characteristic scarring (fibrosis) and cyst formation within the pancreas, first recognized in the 1930s.
Difficulty breathing is the most serious symptom and results from frequent lung infections that are treated, though not cured, by antibiotics and other medications. A multitude of other symptoms, including sinus infections, poor growth, diarrhea, and infertility result from the effects of CF on other parts of the body.

CF is caused by a mutation in the gene for the protein cystic fibrosis transmembrane conductance regulator (CFTR). This gene is required to regulate the components of sweat, digestive juices, and mucus. Although most people without CF have two working copies of the CFTR gene, only one is needed to prevent cystic fibrosis. CF develops when neither gene works normally. Therefore, CF is considered an autosomal recessive disease. The gene for CF conveys a degree of resistance to cholera, potentially explaining its persistence in the population.

CF is most common among Caucasians and Ashkenazi Jews; one in 25 people of European descent carry one gene for CF. Approximately 30,000 Americans have CF, making it one of the most common life-shortening inherited diseases. Individuals with cystic fibrosis can be diagnosed before birth by genetic testing, or by a sweat test in early childhood. Ultimately, lung transplantation is often necessary as CF worsens.


Signs and symptoms


The hallmark symptoms of cystic fibrosis are salty tasting skin, poor growth and poor weight gain despite a normal food intake, accumulation of thick, sticky mucus,frequent chest infections and coughing or shortness of breath.
Males can be infertile due to congenital absence of the vas deferens.
Symptoms often appear in infancy and childhood, such as bowel obstruction due to meconium ileus in newborn babies.
As the child grows, he or she will need to exercise to release mucus in the alveoli.
Ciliated epithelial cells in the patient have a mutated protein that leads to abnormally viscous mucus production.
The poor growth in children typically presents as an inability to gain weight or height at the same rate as their peers and is occasionally not diagnosed until investigation is initiated for poor growth.
The causes of growth failure are multi-factorial and include chronic lung infection, poor absorption of nutrients through the gastrointestinal tract, and increased metabolic demand due to chronic illness.

In rare cases, cystic fibrosis can present as a coagulation disorder.
Young children are especially sensitive to vitamin K malabsorptive disorders because only a very small amount of vitamin K crosses the placenta, leaving the child with very low reserves. Because factors II, VII, IX, and X (clotting factors) are vitamin K–dependent, low levels of vitamin K can result in coagulation problems. Consequently, when a child presents with unexplained bruising, a coagulation evaluation may be warranted to determine whether there is an underlying disease.

Lung and sinus

Lung disease results from clogging of the airways due to mucus build-up, decreased mucociliary clearance and resulting inflammation.
Inflammation and infection will cause injury and structural changes to the lungs, leading to a variety of symptoms. In the early stages, incessant coughing, copious phlegm production, and decreased ability to exercise are common. Many of these symptoms occur when bacteria that normally inhabit the thick mucus grow out of control and cause pneumonia. In later stages, changes in the architecture of the lung such as pathology in the major airways (bronchiectasis) further exacerbate difficulties in breathing. Other symptoms include coughing up blood (hemoptysis), high blood pressure in the lung (pulmonary hypertension), heart failure, difficulties getting enough oxygen to the body (hypoxia), and respiratory failure requiring support with breathing masks such as bilevel positive airway pressure machines or ventilators.
Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa are the three most common organisms causing lung infections in CF patients.
In addition to typical bacterial infections, people with CF more commonly develop other types of lung disease. Among these is allergic bronchopulmonary aspergillosis, in which the body's response to the common fungus Aspergillus fumigatus causes worsening of breathing problems. Another is infection with Mycobacterium avium complex (MAC), a group of bacteria related to tuberculosis, which can cause further lung damage and does not respond to common antibiotics.

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 as many as 10% to 25% of CF patients.
These polyps can block the nasal passages and increase breathing difficulties.

Cardiorespiratory complications are the most common cause of death (~80%) in patients followed by most CF centers in the United States.

Gastrointestinal

Prior to prenatal and newborn 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 which help break down food. These secretions block the exocrine movement of the digestive enzymes into the duodenum and result in irreversible damage to the pancreas, often with painful inflammation (pancreatitis). The pancreatic 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 hypoproteinemia may be severe enough to cause generalized edema.
Individuals with CF also have difficulties absorbing the fat-soluble vitamins A, D, E, and K. In addition to the pancreas problems, people with cystic fibrosis experience more heartburn, intestinal blockage by intussusception, and constipation.
Older individuals with CF may develop distal intestinal obstruction syndrome when thickened feces cause intestinal blockage.
Exocrine pancreatic insufficiency occurs in the majority (85% to 90%) of patients with CF.
It is mainly associated with "severe" CFTR mutations, where both alleles are completely nonfunctional (e.g. ΔF508/ΔF508).[12] It occurs in 10% to 15% of patients with one "severe" and one "mild" CFTR mutation where there still is a little CFTR activity, or where there are two "mild" CFTR mutations.
In these milder cases, there is still sufficient pancreatic exocrine function so that enzyme supplementation is not required.
There are usually no other GI complications in pancreas-sufficient phenotypes, and in general, such individuals usually have excellent growth and development.
Despite this, idiopathic chronic pancreatitis can occur in a subset of pancreas-sufficient individuals with CF, and is associated with recurrent abdominal pain and life-threatening complications.

Thickened secretions also may cause liver problems in patients with CF. Bile secreted by the liver to aid in digestion may block the bile 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.

Endocrine

The pancreas contains the islets of Langerhans, which are responsible for making insulin, a hormone that helps regulate blood glucose. Damage of the pancreas can lead to loss of the islet cells, leading to a type of diabetes that is unique to those with the disease.
This cystic fibrosis related diabetes (CFRD) shares characteristics that can be found in Type 1 and Type 2 diabetics, and is one of the principal non-pulmonary complications of CF.
Vitamin D is involved in calcium and phosphate regulation. Poor uptake of vitamin D from the diet because of malabsorption can lead to the bone disease osteoporosis in which weakened bones are more susceptible to fractures.
In addition, people with CF often develop clubbing of their fingers and toes due to the effects of chronic illness and low oxygen in their tissues.


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.
These men make normal sperm but are missing the tube (vas deferens), which connects the testes to the ejaculatory ducts of the penis.
Many men found to have congenital absence of the vas deferens during evaluation for infertility have a mild, previously undiagnosed form of CF.
Some women have fertility difficulties due to thickened cervical mucus or malnutrition. In severe cases, malnutrition disrupts ovulation and causes amenorrhea.

Cause
Cystic fibrosis has an autosomal recessive pattern of inheritance

CF is caused by a mutation in the gene cystic fibrosis transmembrane conductance regulator (CFTR). The most common mutation, ΔF508, is a deletion (Δ) of three nucleotides that results in a loss of the amino acid phenylalanine (F) at the 508th (508) position on the protein. This mutation accounts for two-thirds (66-70%) of CF cases worldwide and 90 percent of cases in the United States; however, there are over 1,400 other mutations that can produce CF. Although most people have two working copies (alleles) of the CFTR gene, only one is needed to prevent cystic fibrosis. CF develops when neither allele can produce a functional CFTR protein. Thus, CF is considered an autosomal recessive disease.

The CFTR gene, found at the q31.2 locus of chromosome 7, is 230,000 base pairs long, and creates a protein that is 1,480 amino acids long. Structurally, CFTR is a type of gene known as an ABC gene.[13] The product of this gene (the CFTR) is a halide anion channel important in creating sweat, digestive juices and mucus. This protein possesses two ATP-hydrolyzing domains which allows the protein to use energy in the form of ATP. It also contains two domains comprising 6 alpha helices apiece, which allow the protein to cross the cell membrane. A regulatory binding site on the protein allows activation by phosphorylation, mainly by cAMP-dependent protein kinase.The carboxyl terminal of the protein is anchored to the cytoskeleton by a PDZ domain interaction.

In addition, there is increasing evidence that genetic modifiers besides CFTR modulate the frequency and severity of the disease. One example is mannan-binding lectin, which is involved in innate immunity by facilitating phagocytosis of microorganisms. Polymorphisms in one or both mannan-binding lectin alleles that result in lower circulating levels of the protein are associated with a threefold higher risk of end-stage lung disease, as well as an increased burden of chronic bacterial infections.


Pathophysiology
Molecular structure of the CFTR protein

There are several mechanisms by which mutations cause problems with the CFTR protein. ΔF508, for instance, creates a protein that does not fold normally and is degraded by the cell. Several mutations that are common in the Ashkenazi Jewish population result in proteins that are too short because production is ended prematurely. Less common mutations produce proteins that do not use energy normally, do not allow chloride, iodide and thiocyanate to cross the membrane appropriatelym or are degraded at a faster rate than normal. Mutations may also lead to fewer copies of the CFTR protein being produced.

The protein created by this gene is anchored to the outer membrane of cells in the sweat glands, lungs, pancreas, and other affected organs. The protein spans this membrane and acts as a channel connecting the inner part of the cell (cytoplasm) to the surrounding fluid. This channel is primarily responsible for controlling the movement of halogen from inside to outside of the cell; however, in the sweat ducts it facilitates the movement of chloride from the sweat into the cytoplasm. When the CFTR protein does not work, chloride and thiocyanate are trapped inside the cells in the airway and outside in the skin. Then hypothiocyanite, OSCN, cannot be produced by immune defense system.
Because chloride is negatively charged, positively charged cations cross into the cell because they are affected by the electrical attraction of the chloride ions. Sodium is the most common ion in the extracellular space and the combination of sodium and chloride creates the salt, which is lost in high amounts in the sweat of individuals with CF. This lost salt forms the basis for the sweat test

How this malfunction of cells in cystic fibrosis causes the clinical manifestations is not well understood. One theory suggests that the lack of halogen and pseudohalogen (mainly, chloride, iodide and thiocyanate) exodus through the CFTR protein leads to the accumulation of more viscous, nutrient-rich mucus in the lungs that allows bacteria to hide from the body's immune system. Another theory proposes that the CFTR protein failure leads to a paradoxical increase in sodium and chloride uptake, which, by leading to increased water reabsorption, creates dehydrated and thick mucus. Yet another theory focuses on abnormal chloride movement out of the cell, which also leads to dehydration of mucus, pancreatic secretions, biliary secretions, etc. These theories all support the observation that the majority of the damage in CF is due to blockage of the narrow passages of affected organs with thickened secretions. These blockages lead to remodeling and infection in the lung, damage by accumulated digestive enzymes in the pancreas, blockage of the intestines by thick faeces, etc.

Chronic infections

The lungs of individuals with cystic fibrosis are colonized and infected by bacteria from an early age. These bacteria, which often spread among individuals with CF, thrive in the altered mucus, which collects in the small airways of the lungs. This mucus leads to the formation of bacterial microenvironments known as biofilms that are difficult for immune cells and antibiotics to penetrate. Viscous secretions and persistent respiratory infections repeatedly damage the lung by gradually remodeling the airways which makes infection even more difficult to eradicate.


Over time, both the types of bacteria and their individual characteristics change in individuals with CF. In the initial stage, common bacteria such as Staphylococcus aureus and Hemophilus influenzae colonize and infect the lungs. Eventually, Pseudomonas aeruginosa (and sometimes Burkholderia cepacia) dominates. By 18 years of age, 80% of patients with classic CF harbor P. aeruginosa, and 3.5% harbor B. cepacia.
Once within the lungs, these bacteria adapt to the environment and develop resistance to commonly used antibiotics. Pseudomonas can develop special characteristics that allow the formation of large colonies, known as "mucoid" Pseudomonas, which are rarely seen in people that do not have CF.

One way in which infection has spread is by passage between different individuals with CF. In the past, people with CF often participated in summer "CF Camps" and other recreational gatherings.
Hospitals grouped patients with CF into common areas and routine equipment (such as 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 routinely isolated from one another in the healthcare setting and healthcare providers are encouraged to wear gowns and gloves when examining patients with CF to limit the spread of virulent bacterial strains.

CF patients may also have their airways chronically colonized by filamentous fungi (such as Aspergillus fumigatus, Scedosporium apiospermum, Aspergillus terreus) and/or yeasts (such as Candida albicans); other filamentous fungi less commonly isolated include Aspergillus flavus and Aspergillus nidulans (occur transiently in CF respiratory secretions), and Exophiala dermatitidis and Scedosporium prolificans (chronic airway-colonizers); some filamentous fungi like Penicillium emersonii and Acrophialophora fusispora are encountered in patients almost exclusively in the context of CF.Defective mucociliary clearance characterizing CF is associated with local immunological disorders. In addition, the prolonged therapy with antibiotics and the use of corticosteroid treatments may also facilitate fungal growth. Although the clinical relevance of the fungal airway colonization is still a matter of debate, filamentous fungi may contribute to the local inflammatory response, and therefore to the progressive deterioration of the lung function, as often happens with allergic broncho-pulmonary aspergillosis (ABPA) - the most common fungal disease in the context of CF, involving a Th2-driven immune response to Aspergillus.


Diagnosis and monitoring
The location of the CFTR gene on chromosome 7

Cystic fibrosis may be diagnosed by many different categories of testing including those such as, newborn screening, sweat testing, or genetic testing. As of 2006 in the United States, 10 percent of cases are diagnosed shortly after birth as part of newborn screening programs. The newborn screen initially measures for raised blood concentration of immunoreactive trypsinogen. Infants with an abnormal newborn screen need a sweat test in order to confirm the CF diagnosis. In many cases, a parent makes the diagnosis because the infant tastes salty.[12] Trypsinogen levels can be increased in individuals who have a single mutated copy of the CFTR gene (carriers) or, in rare instances, in individuals with two normal copies of the CFTR gene. Due to these false positives, CF screening in newborns can be controversial.
Most states and countries do not screen for CF routinely at birth. Therefore, most individuals are diagnosed after symptoms (e.g. sinopulmonary disease and GI manifestations) prompt an evaluation for cystic fibrosis. The most commonly used form of testing is the sweat test. Sweat-testing involves application of a medication that stimulates sweating (pilocarpine). In order to deliver the medication through the skin, iontophoresis is used to, whereby one electrode is placed onto the applied medication and an electric current is passed to a separate electrode on the skin. The resultant sweat is then collected on filter paper or in a capillary tube and analyzed for abnormal amounts of sodium and chloride. People with CF have increased amounts of sodium and chloride in their sweat. In opposite, people with CF have less thiocyanate and hypothiocyanite in their saliva (Minarowski et al.) and mucus (Banfi et al.). CF can also be diagnosed by identification of mutations in the CFTR gene.

A multitude of tests are used to identify complications of CF and to monitor disease progression. X-rays and CAT scans are used to examine the lungs for signs of damage or infection. The examination of the sputum is required to isolate organisms which may be causing an infection or colonising the lower respiratory tract so that effective antimicrobial therapy can be provided. Culture for organisms such as Burkholderia (previously Pseudomonas) cepacia is required for candidates of Lung transplantation as persistent bacterial colonisation reduces the chances of survival.

Pulmonary function tests measure how well the lungs are functioning, and are used to measure the need for and response to antibiotic therapy. Blood tests can identify liver abnormalities, vitamin deficiencies, and the onset of diabetes. DXA scans can screen for osteoporosis and testing for fecal elastase can help diagnose insufficient digestive enzymes.

In individuals with a mild mutation in the CFTR gene the sweat test may be near normal (i.e. a chloride concentration of less than 60mM/L). As an adjunct to diagnosis, the nasal transepithelial potential difference (TEPD) may be used. Due to abnormalities in the CFTR gene in exocrine glands, chloride secretion is reduced and sodium and water reabsorption is increased. The net effect of the preceding is a more negative baseline resulting in a higher than normal TEPD that can be used as an ancillary or necessary form of diagnosis for mild mutations.


People with CF may be listed in a disease registry that allows researchers and doctors to track health results and identify candidates for clinical trials.

Prenatal

Couples who are pregnant or who are planning a pregnancy can themselves be tested for CFTR gene mutations to determine the degree of risk that their child will be born with cystic fibrosis. Testing is typically performed first on one or both parents and, if the risk of CF is found to be high, testing on the fetus can then be performed. The College of Obstetricians and Gynecologists (ACOG) recommends testing for couples who have a personal or close family history of CF, and they recommend that carrier testing be offered to all Caucasian couples and be made available to couples of other ethnic backgrounds.

Because development of CF in the fetus requires each parent to pass on a mutated copy of the CFTR gene and because CF testing is expensive, testing is often performed initially on one parent. If that parent is found to be a carrier of a CFTR gene mutation, the other parent is then tested to calculate the risk that their children will have CF. CF can result from more than a thousand different mutations, and as of 2006 it is not possible to test for each one. Testing analyzes the blood for the most common mutations such as ΔF508—most commercially available tests look for 32 or fewer different mutations. If a family has a known uncommon mutation, specific screening for that mutation can be performed. Because not all known mutations are found on current tests, a negative screen does not guarantee that a child will not have CF.
In addition, because the mutations tested are necessarily those most common in the highest risk groups, testing in lower risk ethnicities is less successful because the mutations commonly seen in these groups are less common in the general population. These couples may therefore consider testing through labs that offer CF screens with a high number of mutations tested.

Couples at high risk for having a child with CF will often opt to perform further testing before or during pregnancy. In vitro fertilization with preimplantation genetic diagnosis offers the possibility to examine the embryo prior to its placement into the uterus. The test, performed three days after fertilization, looks for the presence of abnormal CF genes. If two mutated CFTR genes are identified, the embryo is not used for embryo transfer and an embryo with at least one normal gene is implanted.

During pregnancy, testing can be performed on the placenta (chorionic villus sampling) or the fluid around the fetus (amniocentesis). However, chorionic villus sampling has a risk of fetal death of 1 in 100 and amniocentesis of 1 in 200 a recent study has indicated this may be much lower, approximately 1 in 1,600.
In any case, the benefits must be determined to outweigh these risks prior to going forward with testing. Alternatively, some couples choose to undergo third party reproduction with egg or sperm donors.

Economically, for carrier couples of cystic fibrosis, when comparing preimplantation genetic diagnosis (PGD) with natural conception (NC) followed by prenatal testing and abortion of affected pregnancies, PGD provides net economic benefits up to a maternal age of approximately 40 years, after which NC, prenatal testing and abortion has higher economic benefit.


Management

The cornerstones of management are proactive treatment of airway infection, and encouragement of good nutrition and an active lifestyle. Management of cystic fibrosis continues throughout a patient's life, and is aimed at maximizing organ function, and therefore quality of life. At best, current treatments delay the decline in organ function. Because of the wide variation in disease symptoms treatment typically occurs at specialist multidisciplinary centers, and is tailored to the individual. Targets for therapy are the lungs, gastrointestinal tract (including pancreatic enzyme supplements), the reproductive organs (including assisted reproductive technology (ART)) and psychological support.

The most consistent aspect of therapy in cystic fibrosis is limiting and treating the lung damage caused by thick mucus and infection, with the goal of maintaining quality of life. Intravenous, inhaled, and oral antibiotics are used to treat chronic and acute infections. Mechanical devices and inhalation medications are used to alter and clear the thickened mucus. These therapies, while effective, can be extremely time-consuming for the patient. One of the most important battles that CF patients face is finding the time to comply with prescribed treatments while balancing a normal life.

In addition, therapies such as transplantation and gene therapy aim to cure some of the effects of cystic fibrosis. Gene therapy aims to introduce normal CFTR to airway. Theoretically this process should be simple as the airway is easily accessible and there is only a single gene defect to correct. There are two CFTR gene introduction mechanisms involved, the first use of a viral vector (adenovirus, adeno-associated virus or retro virus) and secondly the use of liposome. However there are some problems associated with these methods involving efficiency (liposomes insufficient protein) and delivery (virus provokes an immune response).

Antibiotics

Many CF patients are on one or more antibiotic at all times, even when they are considered healthy, in order to prophylactically suppress infection. Antibiotics are absolutely necessary whenever pneumonia is suspected or there has been a noticeable decline in lung function, and are usually chosen based on the results of a sputum analysis and the patient's past response. Many bacteria common in cystic fibrosis are resistant to multiple antibiotics and require weeks of treatment with intravenous antibiotics such as vancomycin, tobramycin, meropenem, ciprofloxacin, and piperacillin.[citation needed] This prolonged therapy often necessitates hospitalization and insertion of a more permanent IV such as a peripherally inserted central catheter (PICC line) or Port-a-Cath. Inhaled therapy with antibiotics such as tobramycin, colistin, and cayston is often given for months at a time in order to improve lung function by impeding the growth of colonized bacteria.
Oral antibiotics such as ciprofloxacin or azithromycin are given to help prevent infection or to control ongoing infection.
The aminoglycoside antibiotics (e.g. tobramycin) used can cause hearing loss, damage to the balance system in the inner ear or kidney problems with long-term use.In order to prevent these side-effects, the amount of antibiotics in the blood are routinely measured and adjusted accordingly.


Other treatments for lung disease

Several mechanical techniques are used to dislodge sputum and encourage its expectoration. In the hospital setting, chest physiotherapy (CPT) is utilized; a respiratory therapist percusses an individual's chest with his or her hands several times a day, to loosen up secretions. Devices that recreate this percussive therapy include the ThAIRapy Vest and the intrapulmonary percussive ventilator (IPV). Newer methods such as Biphasic Cuirass Ventilation, and associated clearance mode available in such devices, integrate a cough assistance phase, as well as a vibration phase for dislodging secretions. These are portable and adapted for home use.
Physiotherapy is essential to help manage an individual’s chest on a long term basis, and can also teach techniques for the older child and teenager to manage themselves at home. Aerobic exercise is of great benefit to people with cystic fibrosis. Not only does exercise increase sputum clearance but it also improves cardiovascular and overall health.

Aerosolized medications that help loosen secretions include dornase alfa and hypertonic saline. Dornase is a recombinant human deoxyribonuclease, which breaks down DNA in the sputum, thus decreasing its viscosity.N-Acetylcysteine may also decrease sputum viscosity, but research and experience have shown its benefits to be minimal.
Albuterol and ipratropium bromide are inhaled to increase the size of the small airways by relaxing the surrounding muscles.

As lung disease worsens, mechanical breathing support may become necessary. Individuals with CF may need to wear special masks at night that help push air into their lungs. These machines, known as bilevel positive airway pressure (BiPAP) ventilators, help prevent low blood oxygen levels during sleep. BiPAP may also be used during physical therapy to improve sputum clearance.
During severe illness, a tube may be placed in the throat (a procedure known as a tracheostomy) to enable breathing supported by a ventilator.

Transplantation

Lung transplantation often becomes necessary for individuals with cystic fibrosis as lung function and exercise tolerance declines. Although single lung transplantation is possible in other diseases, individuals with CF must have both lungs replaced because the remaining lung might contain bacteria that could infect the transplanted lung. A pancreatic or liver transplant may be performed at the same time in order to alleviate liver disease and/or diabetes.
Lung transplantation is considered when lung function declines to the point where assistance from mechanical devices is required or patient survival is threatened.This point typically occurs when lung function declines to approximately 20 to 30 percent,[citation needed] however there is a small time frame when transplantation is feasible as the patient must be healthy enough to endure the procedure.

Treatment of other aspects
Intracytoplasmic sperm injection can be used to provide fertility for men with cystic fibrosis

Newborns with meconium ileus (bowel 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. Even so, most individuals with CF are advised take additional amounts of vitamins A, D, E, and K and eat high-calorie meals.[citation needed] So far, no large-scale research involving the incidence of atherosclerosis and coronary heart disease in adults with cystic fibrosis has been conducted. This is likely due to the fact that the vast majority of people with cystic fibrosis do not live long enough to develop clinically significant atherosclerosis or coronary heart disease.

Diabetes is the most common non-pulmonary complication of CF. It mixes features of type 1 and type 2 diabetes, and is recognized as a distinct entity, cystic fibrosis-related diabetes (CFRD). While oral anti-diabetic drugs are sometimes used, the only recommended treatment is the use of insulin injections or an insulin pump and, unlike in type 1 and 2 diabetes, dietary restrictions are not recommended.

Development of osteoporosis can be prevented by increased intake of vitamin D and calcium, and can be treated by bisphosphonates, although adverse effects can be an issue.Poor growth may be avoided by insertion of a feeding tube for increasing calories through supplemental feeds or by administration of injected growth hormone.

Sinus infections are treated by prolonged courses of antibiotics. The development of nasal polyps or other chronic changes within the nasal passages may severely limit airflow through the nose, and over time reduce the patient's sense of smell. Sinus surgery is often used to alleviate nasal obstruction and to limit further infections. Nasal steroids such as fluticasone are used to decrease nasal inflammation.
Female infertility may be overcome by assisted reproduction technology, particularly embryo transfer techniques. Male infertility caused by absence of the vas deferens may be overcome with testicular sperm extraction (TEST), collecting sperm cells directly from the testicles. If the collected sample contains too few sperm cells to likely have a spontaneous fertilization, intracytoplasmic sperm injection can be performed.
Third party reproduction is also a possibility for women with CF.


Prognosis

Life expectancy for people with CF depends largely upon access to health care. In 1959, the median age of survival of children with cystic fibrosis was six months. In the United States, the life expectancy for infants born in 2008 with CF is 37.4 years, based upon data compiled by the Cystic Fibrosis Foundation.
The median survival age in Americas has increased from 24 in 1982 to 47.7 in 2007, based on data compiled by the Canadian Cystic Fibrosis Foundation.

The U.S. Cystic Fibrosis Foundation compiles lifestyle information about American adults with CF. In 2004, the foundation reported that 91% had graduated from high school and 54% had at least some college education. Employment data revealed 12.6% of adults were disabled and 9.9% were unemployed. Marital information showed that 59% of adults were single and 36% were married or living with a partner. In 2004, 191 American women with CF were pregnant.


Epidemiology
Mutation Frequency
worldwide
ΔF508 66%-70%
G542X 2.4%
G551D 1.6%
N1303K 1.3%
W1282X 1.2%
All others 27.5%

Cystic fibrosis is the most common life-limiting autosomal recessive disease among people of European heritage.
In the United States, approximately 30,000 individuals have CF; most are diagnosed by six months of age. Canada has approximately 3,000 citizens with CF. Approximately 1 in 25 people of European descent, and one in 30 of Caucasian Americans, is a carrier of a cystic fibrosis mutation. Although CF is less common in these groups, approximately 1 in 46 Hispanics, 1 in 65 Africans and 1 in 90 Asians carry at least one abnormal CFTR gene.


Although technically a rare disease, cystic fibrosis is ranked as one of the most widespread life-shortening genetic diseases. It is most common among nations in the Western world. An exception is Finland, where only one in 80 people carry a CF mutation.[85] In the United States, 1 in 4,000 children are born with CF. In 1997, about 1 in 3,300 caucasian children in the United States was born with cystic fibrosis. In contrast, only 1 in 15,000 African American children suffered from cystic fibrosis, and in Asian Americans the rate was even lower at 1 in 32,000.


Cystic fibrosis is diagnosed in males and females equally. For unclear reasons, males tend to have a longer life expectancy than females some recent studies suggest this gender gap may no longer exist in younger patients with access to excellent health care facilities, while a recent study from Ireland identified a link between the female hormone oestrogen and worse CF outcomes

The distribution of CF alleles varies among populations. The frequency of ΔF508 carriers has been estimated to be 1:200 in northern Sweden, 1:143 in Lithuanians, and 1:38 in Denmark. No ΔF508 carriers were found among 171 Finns and 151 Saami people.ΔF508 does occur in Finland, but it is a minority allele there.
Cystic fibrosis is known to occur in only 20 families (pedigrees) in Finland.


Theories about prevalence

The ΔF508 mutation is estimated to be up to 52,000 years old. Numerous hypotheses have been advanced as to why such a lethal mutation has persisted and spread in the human population. Other common autosomal recessive diseases such as sickle-cell anemia have been found to protect carriers from other diseases, a concept known as heterozygote advantage. Resistance to the following have all been proposed as possible sources of heterozygote advantage:

* Cholera: With the discovery that cholera toxin requires normal host CFTR proteins to function properly, it was hypothesized that carriers of mutant CFTR genes benefited from resistance to cholera and other causes of diarrhea.
Further studies have not confirmed this hypothesis.
* Typhoid: Normal CFTR proteins are also essential for the entry of Salmonella typhi into cells, suggesting that carriers of mutant CFTR genes might be resistant to typhoid fever. 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, is not immediately explicable.
* Diarrhea: It has also been hypothesized that the prevalence of CF in Europe might be connected with the development of cattle domestication. In this hypothesis, carriers of a single mutant CFTR chromosome had some protection from diarrhea caused by lactose intolerance, prior to the appearance of the mutations that created lactose tolerance.
* Tuberculosis: Another possible explanation is that carriers of the gene could have some resistance to TB.


History
National Library of Medicine photo of Dorothy Hansine Andersen. Andersen first described cystic fibrosis in 1938.

Although the entire clinical spectrum of CF was not recognized until the 1930s, certain aspects of CF were identified much earlier. Indeed, literature from Germany and Switzerland in the 18th century warned Wehe dem Kind, das beim Kuß auf die Stirn salzig schmekt, er ist verhext und muss bald sterbe or "Woe is the child who tastes salty from a kiss on the brow, for he is cursed, and soon must die," recognizing the association between the salt loss in CF and illness.

In the 19th century, Carl von Rokitansky described a case of fetal death with meconium peritonitis, a complication of meconium ileus associated with cystic fibrosis. Meconium ileus was first described in 1905 by Karl Landsteiner.
In 1936, Guido Fanconi published a paper describing a connection between celiac disease, cystic fibrosis of the pancreas, and bronchiectasis.

In 1938 Dorothy Hansine Andersen published an article, "Cystic Fibrosis of the Pancreas and Its Relation to Celiac Disease: a Clinical and Pathological Study," in the American Journal of Diseases of Children. She was the first to describe the characteristic cystic fibrosis of the pancreas and to correlate it with the lung and intestinal disease prominent in CF.She also first hypothesized that CF was a recessive disease and first used pancreatic enzyme replacement to treat affected children. In 1952 Paul di Sant' Agnese discovered abnormalities in sweat electrolytes; a sweat test was developed and improved over the next decade.

In 1988 the first mutation for CF, ΔF508 was discovered by Francis Collins, Lap-Chee Tsui and John R. Riordan on the seventh chromosome. Subsequent research has found over 1,000 different mutations that cause CF.

Because mutations in the CFTR gene are typically small, classical genetics techniques had been unable to accurately pinpoint the mutated gene.[106] Using protein markers, gene-linkage studies were able to map the mutation to chromosome 7. Chromosome-walking and -jumping techniques were then used to identify and sequence the gene. In 1989 Lap-Chee Tsui led a team of researchers at the Hospital for Sick Children in Toronto that discovered the gene responsible for CF. Cystic fibrosis represents the first genetic disorder elucidated strictly by the process of reverse genetics.


Research

Gene therapy has been explored as a potential cure for cystic fibrosis. Ideally, gene therapy attempts to place a normal copy of the CFTR gene into affected cells. Transferring the normal CFTR gene into the affected epithelium cells would result in the production of functional CFTR in all target cells, without adverse reactions or an inflammation response. Studies have shown that to prevent the lung manifestations of cystic fibrosis, only 5–10% the normal amount of CFTR gene expression is needed. Multiple approaches have been tested for gene transfer, such as liposomes and viral vectors in animal models and clinical trials. However, both methods were found to be relatively inefficient treatment options.
The main reason is that very few cells take up the vector and express the gene, so the treatment has little effect. Additionally, problems have been noted in cDNA recombination, such that the gene introduced by the treatment is rendered unusable.

Another approach is to develop drugs that will get the ribosome to overcome the stop code and synthesize a full-length CFTR protein. About 10% of CF result from a premature stop code in DNA, leading to early termination of protein synthesis and truncated proteins. Aminoglycoside antibiotics interfere with DNA synthesis and error-correction. In some cases, they can cause the cell to overcome the stop code, insert a random amino acid, and express a full-length protein.
The aminoglycoside gentamicin has been used to treat lung cells from CF patients in the laboratory to induce the cells to grown full-length proteins.

Liver cancer

Liver cancer is cancer that begins in the cells of your liver. Your liver is a football-sized organ that sits in the upper right portion of your abdomen, beneath your diaphragm and above your stomach.

Liver cancer is one of the most common forms of cancer in the world, but liver cancer is uncommon in the United States. Rates of liver cancer diagnosis are increasing in the United States.

Symptoms

Most people don't have signs and symptoms in the early stages of primary liver cancer. When symptoms do appear, they may include:

■Losing weight without trying

■Loss of appetite

■Upper abdominal pain

■Nausea and vomiting

■General weakness and fatigue

■An enlarged liver

■Abdominal swelling

■Yellow discoloration of your skin and the whites of your eyes (jaundice)

Causes

It's not clear what causes most cases of liver cancer. But in some cases, the cause is known. For instance, chronic infection with certain hepatitis viruses can cause liver cancer.

Liver cancer occurs when liver cells develop changes (mutations) in their DNA — the material that provides instructions for every chemical process in your body. DNA mutations cause changes in these instructions. One result is that cells may begin to grow out of control and eventually form a tumor — a mass of malignant cells.

Types of liver cancer

Primary liver cancer, which begins in the cells of the liver, is divided into different types based on the kind of cells that become cancerous. Types include:

■Hepatocellular carcinoma (HCC). This is the most common form of primary liver cancer in both children and adults. It starts in the hepatocytes, the main type of liver cell.

■Cholangiocarcinoma. This type of cancer begins in the small tube-like bile ducts within the liver. This type of cancer is sometimes called bile duct cancer.

■Hepatoblastoma. This rare type of liver cancer affects children younger than 4 years of age. Most children with hepatoblastoma can be successfully treated.

■Angiosarcoma or hemangiosarcoma. These rare cancers begin in the blood vessels of the liver and grow very quickly.

Risk factors

■Your sex. Men are more likely to develop liver cancer than are women.

■Your age. In North America, Europe and Australia, liver cancer most commonly affects older adults. In developing countries of Asia and Africa, liver cancer diagnosis tends to occur at a younger age — between 20 and 50.

■Chronic infection with HBV or HCV. Chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) increases your risk of liver cancer.

■Cirrhosis. This progressive and irreversible condition causes scar tissue to form in your liver and increases your chances of developing liver cancer.

■Certain inherited liver diseases. Liver diseases that can increase the risk of liver cancer include hemochromatosis, autoimmune hepatitis and Wilson's disease.

■Diabetes. People with this blood sugar disorder have a greater risk of liver cancer than do people who don't have diabetes.

■Nonalcoholic fatty liver disease. An accumulation of fat in the liver increases the risk of liver cancer.

■Exposure to aflatoxins. Consuming foods contaminated with fungi that produce aflatoxins greatly increases the risk of liver cancer. Crops such as corn and peanuts can become contaminated with aflatoxins.

■Excessive alcohol consumption. Consuming more than a moderate amount of alcohol can lead to irreversible liver damage and increase your risk of liver cancer.

■Obesity. Having an unhealthy body mass index increases the risk of liver cancer.

Tests and diagnosis

Tests and procedures used to diagnose liver cancer include:

■Blood tests. Blood tests may reveal liver function abnormalities.

■Imaging tests. Your doctor may recommend imaging tests, such as an ultrasound, computerized tomography (CT) scan and magnetic resonance imaging (MRI).

■Removing a sample of liver tissue for testing. During a liver biopsy, a sample of tissue is removed from your liver and examined under a microscope. Your doctor may insert a thin needle through your skin and into your liver to obtain a tissue sample. Liver biopsy carries a risk of bleeding, bruising and infection.

Determining the extent of the liver cancer

Once cancer is diagnosed, your doctor will work to determine the extent (stage) of the liver cancer. Staging tests help determine the size and location of cancer and whether it has spread. Imaging tests used to stage liver cancer include CT, MRI, chest X-ray and bone scan.

The stages of liver cancer are:

■Stage I. At this stage, liver cancer is a single tumor confined to the liver that hasn't grown to invade any blood vessels.

■Stage II. Liver cancer at this stage can be a single tumor that has grown to invade nearby blood vessels, or it can be multiple small tumors in the liver.

■Stage III. This stage may indicate that the cancer is composed of several larger tumors. Or cancer may be one large tumor that has grown to invade the liver's main veins or to invade nearby structures, such as the gallbladder.

■Stage IV. At this stage, liver cancer has spread beyond the liver to other areas of the body.

Treatments and drugs

Treatments for primary liver cancer depend on the extent (stage) of the disease as well as your age, overall health and personal preferences.

The goal of any treatment is to eliminate the cancer completely. When that isn't possible, the focus may be on preventing the tumor from growing or spreading. In some cases only comfort care is appropriate. In this situation, the goal of treatment is not to remove or slow the disease but to help relieve symptoms, making you as comfortable as possible.

Liver cancer treatment options may include:

■Surgery to remove a portion of the liver. Your doctor may recommend partial hepatectomy to remove the liver cancer and a small portion of healthy tissue that surrounds it if your tumor is small and your liver function is good.

■Liver transplant surgery. During liver transplant surgery, your diseased liver is removed and replaced with a healthy liver from a donor. Liver transplant surgery may be an option for people with early-stage liver cancer who also have cirrhosis.

■Freezing cancer cells. Cryoablation uses extreme cold to destroy cancer cells. During the procedure, your doctor places an instrument (cryoprobe) containing liquid nitrogen directly onto liver tumors. Ultrasound images are used to guide the cryoprobe and monitor the freezing of the cells. Cryoablation can be the only liver cancer treatment, or it can be used along with surgery, chemotherapy or other standard treatments.

■Heating cancer cells. In a procedure called radiofrequency ablation, electric current is used to heat and destroy cancer cells. Using an ultrasound or CT scan as a guide, your surgeon inserts several thin needles into small incisions in your abdomen. When the needles reach the tumor, they're heated with an electric current, destroying the cancer cells.

■Injecting alcohol into the tumor. During alcohol injection, pure alcohol is injected directly into tumors, either through the skin or during an operation. Alcohol dries out the cells of the tumor and eventually the cells die.

■Injecting chemotherapy drugs into the liver. Chemoembolization is a type of chemotherapy treatment that supplies strong anti-cancer drugs directly to the liver. During the procedure, the hepatic artery — the artery from which liver cancers derive their blood supply — is blocked, and chemotherapy drugs are injected between the blockage and the liver.

■Radiation therapy. This treatment uses high-powered energy beams to destroy cancer cells and shrink tumors. During radiation therapy treatment, you lie on a table and a machine directs the energy beams at a precise point on your body. Radiation side effects may include fatigue, nausea and vomiting.

■Targeted drug therapy. Sorafenib (Nexavar) is a targeted drug designed to interfere with a tumor's ability to generate new blood vessels. Sorafenib has been shown to slow or stop advanced liver cancer from progressing for a few months longer than with no treatment. More studies are needed to understand how this and other targeted therapies may be used to control advanced liver cancer

Prevention

Get vaccinated against hepatitis B

You can reduce your risk of hepatitis B by receiving the hepatitis B vaccine, which provides more than 90 percent protection for both adults and children. Protection lasts years and may even be lifelong. The vaccine can be given to almost anyone, including infants, older adults and those with compromised immune systems.

Take measures to prevent hepatitis C

No vaccine for hepatitis C exists, but you can reduce your risk of infection.

■Know the health status of any sexual partner. Don't engage in unprotected sex unless you're absolutely certain your partner isn't infected with HBV, HCV or any other sexually transmitted disease. If you don't know the health status of your partner, use a condom every time you have sexual intercourse.

■Don't use IV drugs, but if you do, use a clean needle. The best way to protect yourself from HCV is to not inject drugs. But if that isn't an option for you, make sure any needle you use is sterile, and don't share it. Contaminated drug paraphernalia is a common cause of hepatitis C infection. Take advantage of needle-exchange programs in your community and consider seeking help for your drug use.

■Seek safe, clean shops when getting a piercing or tattoo. Needles that may not be properly sterilized can spread the hepatitis C virus. Before getting a piercing or tattoo, check out the shops in your area and ask staff about their safety practices. If employees at a shop refuse to answer your questions or don't take your questions seriously, take that as a sign that the facility isn't right for you.

Ask your doctor about liver cancer screening

Screening for liver cancer hasn't been definitively proved to reduce the risk of dying of liver cancer. For this reason, many medical groups don't recommend liver cancer screening. However, the American Association for the Study of Liver Diseases recommends liver cancer screening for those thought to have a high risk, including people who have:

■Hepatitis B and one or more of the following apply: are an Asian male older than 40, Asian female older than 50, or African and older than 20; have liver cirrhosis; or have a family history of liver cancer

■Liver cirrhosis from alcohol use

■Hepatitis C infection

■An inherited form of hemochromatosis

■Primary biliary cirrhosis

■Nonalcoholic fatty liver disease

The kidneys

Where the kidneys are?
The kidneys are two bean-shaped organs about the same size as a fist. They are located near the middle of the back, one on either side of the spine.

The kidneys are part of the body system called the urinary system. This system filters waste products out of the blood and makes urine. It is made up of the
• Kidneys
• Ureters
• Bladder
• Prostate (in men)
• Urethra

What the kidneys do?
The kidneys filter the blood. As the blood passes through the kidneys, waste products and unneeded water are collected and turned into urine.
The urine is gathered in an area called the renal pelvis at the centre of each kidney. From here it drains into the bladder down a tube called the ureter. There are 2 ureters - one from each kidney. Another tube called the urethra carries the urine from the bladder out of the body.

Inside the kidney, the blood is filtered through very small networks of tubes called nephrons. Each kidney has about 1 million nephrons. Inside the nephrons, waste products in the blood move across from the bloodstream (the capillaries) into the urine-carrying tubes inside the nephron. These tubes are called tubules. As the blood passes through the blood vessels of the nephron, all unwanted waste is taken away. Any chemicals needed by the body are kept or returned to the bloodstream by the nephrons. In this way, the kidneys help to regulate the levels of chemicals in the blood such as sodium and potassium, and keep the body healthy.
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Hormones from the kidneys:
As well as filtering waste products, the kidneys produce three important hormones
• Erythropoietin (EPO) tells the bone marrow to make red blood cells
• Renin regulates blood pressure
• Calcitriol (a form of Vitamin D) helps the intestine to absorb calcium from the diet, and so helps to keep the bones healthy
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The kidneys’ blood supply
The kidneys have a very rich blood supply. The blood needs to pass through in large quantities so that it can be filtered well, and all the waste products can be removed. The main blood supply carrying blood to each kidney is called the renal artery.
There are also large blood vessels carrying the cleaned blood away from each kidney. These are called the renal veins.
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The adrenal glands
Above each kidney, there is a small gland called the adrenal gland (‘ad renal’ means next to the kidney). The adrenal glands make hormones. They make
• A natural steroid hormone called cortisol
• A hormone that helps to regulate the body’s water balance called aldosterone
• Adrenaline
• Another adrenaline-like hormone called noradrenaline
If you have a kidney removed, you may have the adrenal gland above it removed too. This depends on where in your kidney the cancer is. If there is any chance that cancer cells could be left behind with your adrenal gland, then your surgeon will remove it.
The adrenal hormones are vital for life. You will be perfectly well with only one adrenal gland. Your other one will make all the hormones you need. If you have both kidneys and adrenal glands removed, you will have to take hormone tablets every day.
Risks and causes of kidney cancer


How common kidney cancer is
Kidney cancer is the 11th most common cancer diagnosed in the UK, with over 7,800 people diagnosed each year. Nearly 2 out 3 people diagnosed (62%) are over 65 years old. Kidney cancer is rare in people under 50. It affects many more men than women. This could be because in the past more men smoked cigarettes. Smoking increases your risk of getting kidney cancer.



Obesity
Obesity increases the risk of getting kidney cancer, particularly clear cell cancer. 'Obese' means that your body mass index is over 30. Or more roughly, that your weight is at least 25% higher than the top of the range for your height. Body mass index (BMI) is worked out by comparing your height and weight. Being overweight causes changes in hormones in the body, particularly for women. It could be this change in the body’s hormone balance that increases the risk of kidney cancer.


Smoking
If you smoke then your risk of getting kidney cancer could be double that of a non-smoker. The longer you continue to smoke and the higher the number of cigarettes you smoke, the higher the risk becomes. But if you stop smoking then your risk of getting kidney cancer will probably fall.


Kidney disease
People with kidney failure have to have their blood filtered by machine about twice a week. This is called dialysis. People having long term kidney dialysis have an increased risk of developing kidney cysts and this increases the risk of kidney cancer. The longer you are on dialysis, the greater your risk of kidney cancer. But this is probably because you needed dialysis due to kidney disease. The dialysis itself is not directly related to the cancer risk.


Faulty genes and inherited conditions
A small number of people inherit a tendency to develop kidney cancer. This is called hereditary or familial kidney cancer. The increased risk of cancer is related to an inherited faulty gene. Changes in the DNA that makes up the gene make it behave in an abnormal way and this can increase your risk of cancer. Scientists are finding out which genes carry these mistakes in the DNA. In the future this could help doctors predict who is at risk of getting hereditary kidney cancer.
People with kidney cancer who have these genetic conditions often have cancer in both kidneys (bilateral kidney cancer). They may also have several tumours in each kidney. They often develop the cancer at a younger age than people with non-inherited cancers..
The inherited conditions that greatly increase the risk of kidney cancer include
• Von Hippel-Lindau (VHL) syndrome
• Tuberous sclerosis
• Birt-Hogg-Dube syndrome
• Hereditary non vHL clear cell and papillary renal cell cancer
Von Hippel-Lindau (VHL) syndrome
Von Hippel-Lindau syndrome is an inherited cancer syndrome. The VHL gene runs through affected families. People who carry the gene have an increased risk of developing several quite rare cancers in the brain, spine, pancreas, eyes and inner ear. About 40% of people with vHL get kidney cancer.
Tuberous sclerosis
Tuberous sclerosis is another condition caused by a faulty gene. About 1 in 3 cases are inherited. But the other 2 out of 3 occur because the gene has mutated in those people for the first time. It can cause skin, brain and heart problems, as well as kidney disease. People with TS have an increased risk of kidney cysts and kidney cancer.
Birt-Hogg-Dube syndrome
Birt-Hogg-Dube syndrome is another inherited condition. It causes many benign tumours to develop in the hair follicles of the skin. These usually develop on the face, neck and trunk. People that carry this gene are at increased risk of kidney cancer.
Hereditary clear cell and papillary renal cell cancer
Hereditary clear cell kidney cancer and hereditary papillary kidney cancers are both caused by inherited faulty genes. They are dominant genetic conditions. This means that you only have to inherit the faulty gene from one parent. Even so, they are both very rare.


Chemicals at work
Sometimes, hazardous substances in the workplace can increase the risk of kidney cancer. There is evidence that working with coke ovens or blast furnaces in the iron or steel industries increases kidney cancer risk.
Asbestos might also increase the risk of kidney cancer. Asbestos can cause other types of cancer in the lung and mesothelium. The mesothelium is a sheet of tissue that surrounds and supports some body organs. People in a variety of occupations were exposed to asbestos in the past, including builders, car mechanics and shipyard workers.
Exposure to cadmium (a type of metal) and organic solvents, particularly trichloroethylene, may also be risk factors for kidney cancer. The risk if you work with cadmium is known to be greater if you also smoke.
Other occupations that may increase the risk of kidney cancer include dry cleaning and the petrochemical industry.


High blood pressure
Some research studies have found a link between high blood pressure or high blood pressure medicines and kidney cancer. It is more likely that high blood pressure is the link, rather than the medications. High blood pressure is a known risk factor for kidney disease in general.


Mild painkillers
Some mild painkilling drugs have been linked to increased kidney cancer risk. One drug that could definitely increase the risk was phenacetin, but this has been taken off the market in the UK. Other painkillers, such as aspirin, paracetamol, and a group of drugs known as 'non steroidal anti inflammatory drugs' (NSAIDs) may increase the risk of kidney cancer slightly. NSAIDs include ibuprofen (Nurofen). Research into painkillers and kidney cancer risk is at a relatively early stage. It is unlikely that occasional use or low dose use would be harmful. For example, some studies have only found a slight link with regular use of paracetamol.


Diet
Apart from obesity, we aren't sure what part diet plays in kidney cancer. Eating large amounts of well cooked meat or having a high fat intake may increase the risk. People who eat enough fruit and vegetables may lower their risk of kidney cancer. At this point, there isn't enough evidence to say for sure. But following these sort of dietary guidelines can lower your risk of other cancers, as well as heart disease. So you certainly won't be doing yourself any harm if you improve your diet. The risk of kidney cancer is slightly lower in people who drink alcohol compared to non-drinkers. However, alcohol increases the risk of several other cancers.
Symptoms of kidney cancer

Blood in the urine
This is the most common symptom of kidney cancer. Your doctor may call this haematuria. About half of those diagnosed with kidney cancer will have this symptom when they first go to the doctor.
The blood does not have to be there all the time. It can come and go. Sometimes, the blood cannot be seen by the naked eye but can be picked up by a simple urine test. If you ever see blood in your urine, you should go to the doctor.
Remember - most people who go to the doctor with blood in their urine do not have kidney cancer. In the majority of cases, blood in the urine is caused by an infection, enlargement of the prostate, or kidney stones. Even so, a doctor should always investigate blood in the urine. As the bleeding can come and go, both the doctor and the patient may get the impression that the problem has gone away. This can mean that an early, treatable cancer in the kidney or bladder is allowed to grow to the stage where it may not be so easy to treat.


A lump or mass in the area of the kidney
If you feel a lump or swelling in the area of your kidneys, you should go straight to your doctor. Most kidney cancers are too small for you or a doctor to feel. But it is possible for the kidneys to be scanned to check for cancer.

Other more vague symptoms
Some people can have other symptoms, which can be vague. These are
• Tiredness
• Loss of appetite
• Weight loss
• A high temperature and very heavy sweating
• A pain in the side that won’t go away
• A general feeling of poor health
A high temperature and sweats can be caused by an infection, and your doctor may want to rule this out first.
High blood pressure and having fewer red blood cells than normal (anaemia) can also be symptoms of kidney cancer. These symptoms are related to the hormones that the kidneys produce.
Types of kidney cancer



Renal cell cancer
Renal cell cancer is the most common type of kidney cancer in adults. More than 8 in every 10 (80%) kidney cancers. Renal cell cancer is also called renal adenocarcinoma or hypernephroma. In renal cell cancer the cancerous cells are found in the lining of the tubules (the smallest tubes inside the nephrons that help filter the blood and make urine).
There are several types of renal cell cancer that can be identified by looking at the cancer cells under a microscope. The main ones are:
• Clear cell
• Papillary (Types 1 and 2)
• Chromophobe
• Oncocytic
• Collecting duct
All these types of renal cell cancer may also occur in a different form, known as 'sarcomatoid' type.
Clear cell cancer is the most common type of renal cell cancer. The others are much less common. Often kidney cancers contain more than one of these cell types. If a kidney cancer is a sarcomatoid type it may have a worse outlook than nonsarcomatous kidney cancers. Generally, how quickly growing the cancer is likely to be is graded in a particular way, by looking at the cells under a microscope. The kidney cancer grading system is called the Fuhrman system.
All these types of renal cell cancer, and all grades, are treated the same way. The grading may give the doctor some idea of how quickly or slowly the cancer is likely to grow. It may help the doctor decide on the treatment you need. For example, for a cancer that is likely to grow quickly, a specialist may be more likely to suggest additional treatment as well as surgery to try to lower the risk of the cancer coming back.


Other types of kidney cancer
Another type of kidney cancer is called transitional cell cancer (TCC) of the renal pelvis. It is less common. About 7 or 8 out of every 100 (7 to 8 %) kidney cancers. The treatment for this type of kidney cancer is similar to the treatment for bladder cancer.
A type of kidney cancer called Wilms' tumour can affect children. This is different from kidney cancer in adults. For information about these rare types of kidney cancer look in the help and support section for organisations that produce information about kidney cancer. They will be able to give you the information you need about your type of cancer.

Tests for kidney cancer


Tests for kidney cancer
Usually, you begin by seeing your family doctor who will ask you about your general health and examine you. Your GP will ask you to give a urine sample. He or she will test the urine for small amounts of blood (haematuria) which can be a sign of kidney cancer. The doctor may also take some blood to do other tests. Your doctor should refer you to see a specialist at the hospital if you have blood in your urine. It is important that you tell the doctor if anyone else in your family has had kidney cancer.
At the hospital
The specialist will begin by asking you about your medical history and symptoms. You will have more urine and blood tests. The specialist will look at your kidneys using either an ultrasound scan, a test called an intravenous pyelogram (IVP) or a CT urogram.
If you have blood in your urine, you will probably need to have a cystoscopy so that the doctor can check inside your bladder. The doctor will use a cystoscope, which is a long, thin, flexible tube that is put into your urethra and up into the bladder. You can have a cystoscopy under local or general anaesthetic.


Usually, you begin by seeing your family doctor who will ask you about your general health and examine you.
Your GP will ask you to give a urine sample. They will test for small amounts of blood (haematuria) which can be a sign of kidney cancer. Often the amount of blood in the urine is so small that it can't be seen but it can be picked up by the test. The doctor may also take some blood to do other tests. They may do a physical examination to feel for any lumps or swelling. But because the kidneys are deep inside the body, the doctor may not be able to feel small tumours.
Your doctor should refer you to see a specialist at the hospital if you have blood in your urine. It is important that you tell the doctor if anyone else in your family has had kidney cancer. This could help the doctor decide what tests to do.
There are guidelines for GPs to help them decide who needs an urgent referral to a specialist.

Going to the hospital
The specialist will begin by asking you about your medical history and symptoms. If your urine test has picked up blood then the doctor will run more tests on your urine. You will be asked to have more blood tests.
It is important for the doctor to take a look at your kidneys with an
• Ultrasound or
• Intravenous pyelogram (IVP)
You will probably need to have a cystoscopy so that the doctor can check inside your bladder to make sure that any blood in your urine isn't coming from there.

Ultrasound scan
Ultrasound can show any growths inside the kidney.


IVP (intravenous pyelogram)
IVP is also sometimes called intravenous urogram or IVU. A dye is injected into your bloodstream during this test. Very rarely someone has an allergic reaction to this dye. If this has happened to you before, tell your doctor before the test. A short time after injection of the dye you have X-rays of the kidneys, ureters and bladder. The dye can show any growths in the tubes inside or leading from the kidneys.


CT urogram
You may have a CT urogram instead of an IVP. Or you may have both tests. For a CT urogram you have an injection of a dye into a vein and may also be asked to swallow a special liquid containing barium. Then a CT scanner takes a series of X-rays to give a detailed picture of the kidneys, ureters and bladder.


Cystoscopy
Your doctor may also want to look directly inside your bladder because this is part of the same body system as your kidneys. You might have this test if you have blood in your urine. To do this test the doctor will use a cystoscope, which is a type of telescope that is put into your urethra and up into the bladder. You can have a cystoscopy under local or general anaesthetic. You may have a cystoscopy under local anaesthetic at your first appointment because it can be done quickly and simply.


Stages of kidney cancer

Stages of kidney cancer
The stage of a cancer tells the doctor how far it has spread. Treatment is often decided according to the stage. Cancer stage can be written using number stages or using the TNM system. The T stands for tumour, the N for nodes and the M for metastases (cancer spread).
TNM stages
In stage T1 the tumour is no more than 7cm across and is completely inside the kidney. In T2 it is larger but still completely inside the kidney. In T3 it has spread to the tissues immediately surrounding the kidney. In T4 it has spread further away.
N0 means there is no cancer in any lymph nodes. In N1 the cancer has spread to one nearby lymph node only, and in N2 to more than one. M1 means the cancer has spread and M0 means it has not. If it has spread it is called advanced kidney cancer.
Number stages
Stages 1 and 2 are the same as T1 and T2, above. In stage 3 the cancer has grown into the adrenal gland, or one of the major veins nearby. It is in no more than one nearby lymph node. In stage 4 the cancer has grown into the surrounding tissues and there is more than one lymph node containing cancer cells, OR the cancer has spread to another part of the body.
Grade
The more abnormal cancer cells look under the microscope, the higher their grade. Low grade cancers usually grow more slowly and are less likely to spread.

What staging is
The stage of a cancer tells the doctor how far it has spread. The tests and scans you have to diagnose your cancer will give some information about the stage. It is important because treatment is often decided according to the stage of a cancer. There are two ways of writing cancer stage. The number stages (usually stage 1 to stage 4) and the TNM system.
The TNM system is a staging system that is common to all cancers. The T stands for tumour; the N for nodes and the M for metastases (the doctors' word for cancer spread). With this combination of letters and numbers, doctors can accurately describe the size of your cancer and whether it has spread to lymph nodes or elsewhere in the body. There is more about the TNM staging system in the stages of a cancer section.


The 'T' stages of kidney cancer
The 'T' stages are
• T0 - there is no evidence of a primary tumour in the kidney
• T1 - the tumour is no more than 7cm across and is completely inside the kidney
• T2 - the tumour is more than 7cm across, but is still completely inside the kidney
• T3 - the cancer has spread through the kidney capsule, to a major vein, the adrenal gland or other tissues immediately surrounding the kidney
• T4 - the cancer has spread further than the tissues immediately surrounding the kidney
You may hear your doctor talk about T1a or T1b. T1a means you have a tumour that is less than 4cm across. T1b means the kidney tumour is between 4 and 7cm across. This is being introduced because it is important for surgeons. If you have a smaller tumour, it may be possible to remove just the cancer and leave the rest of the kidney behind (nephron sparing surgery).



The ‘N’ stages of kidney cancer
These tell the doctor if the cancer has spread to your lymph nodes. There are four lymph node stages in kidney cancer. These are
• N0 - No cancer in any lymph nodes
• N1 - Cancer spread to one nearby lymph node only
• N2 - Cancer spread to more than one nearby lymph node
Doctors often call lymph nodes that contain cancer 'positive lymph nodes'. If you have cancer in your lymph nodes, then your kidney cancer has begun to spread. Your doctor may want you to have further treatment after your surgery.

The 'M' stages of kidney cancer
As with most cancers, there are two stages for metastases (or cancer spread). Either the cancer has spread (M1) or it hasn't (M0).


The number stages - stage 1 to stage 4
By combining the T, N & M stagings of your tumour, your doctor will give it an overall stage. This is important for deciding which treatment is best for you. There are 4 stages for kidney cancer. They are
• Stage 1 - The cancer is less than 7cm across and is completely inside the kidney
• Stage 2 - The cancer is more than 7cm across but is still completely inside the kidney
• Stage 3 - The cancer has grown into the adrenal gland, or one of the major veins nearby. There is no more than one nearby lymph node containing cancer cells
• Stage 4 - The cancer has grown into the surrounding tissues and there is more than one lymph node containing cancer cells OR the cancer has spread to another part of the body
Doctors tend to use Roman numerals for writing down cancer stage. So you may see stage written as I, II, III, or IV.


The grade of your cancer
The grade of your cancer is decided by the appearance of the cancer cells under the microscope. The more they look like normal kidney cells, the lower the grade of your cancer. The more abnormal (and so less like normal kidney cells) the cancer cells look, the higher the grade of your cancer. Generally speaking, low grade cancers tend to grow more slowly and are less likely to spread than high grade cancers.
The main factor for deciding which treatment is best for you is whether your cancer has spread away from the kidney or not.

Surgery
Surgery is the main treatment for kidney cancer that has not spread. Stage 1 and 2 kidney cancer is often cured with surgery. Even some stage 3 cancers can be cured if it is possible to remove all the cancer.
Removing a kidney is called a nephrectomy. This comes from the Greek word for kidney, ‘nephros’. You may have either the whole kidney or part of the kidney removed
• Radical nephrectomy means removing the whole kidney
• Partial nephrectomy means removing part of the kidney
Surgeons sometimes call partial nephrectomy 'nephron sparing surgery'. The nephron is the working unit of the kidney that filters the blood. So this just means that your surgeon is trying to leave some functioning kidney behind after the operation to remove the cancer. Generally, nephron sparing surgery (partial nephrectomy) is suitable for you if
• You have a small kidney tumour (the exact size limit varies, but less than 7 cm across at the very most)
• You only have one kidney, and that has a tumour in it
• You have cancer in both kidneys
• Your unaffected kidney doesn't work as well as it should
If you do not have at least one working kidney, then you will have to have kidney dialysis for the rest of your life. Dialysis is a way of doing the job your kidneys would do if they were working properly. That is, removing the waste products and extra water that you don’t need from your body.


If you can’t have surgery
It may not be possible for you to have surgery because you have other medical problems. In this case the doctor might use
• Radiotherapy
• Arterial embolisation
• Experimental treatment methods


Radiotherapy
Radiotherapy treats cancer by using high energy rays that destroy the cancer cells, while doing as little harm as possible to normal cells. It is only helpful in a relatively small number of people with cancer of the kidney. It is not often used with kidney cancer that is likely to be curable. But it can be useful for shrinking the cancer and controlling pain or bleeding. You may be offered radiotherapy after surgery if your surgeon thinks some cancer cells may have been left behind after your operation.


Biological therapy
Biological therapies are treatments that use natural substances from the body, or drugs made from these substances. Some clinical trials are using the biological therapies interferon or interleukin (IL-2) to try to stop kidney cancer from coming back after surgery. Doctors call this adjuvant treatment.


Arterial embolisation
Arterial embolisation blocks the blood vessels to the area of the kidney containing the cancer. This reduces the supply of oxygen and food to the cancer, and may make it shrink. This is not a cure, however. The cancer is not removed and there is a high chance of cells breaking away in the future and spreading to other parts of the body. Embolisation is also sometimes used before surgery to reduce the risk of bleeding.
This minor operation is done in the X-ray department. You will have to stay in hospital at least overnight, so you will be admitted to a ward. You will be asked to change into a hospital gown and will be taken to the X-ray department.
You will be asked to lie on the X-ray table. Then you will be given something to make you sleepy. The doctor will give you some local anaesthetic and then put a long tube (a catheter) into the main blood vessel in your groin. Watching on an X-ray screen, the doctor will feed the catheter up through your blood vessels until it is in exactly the right place. Then, the doctor will inject small pieces of gelatine sponge or some plastic beads into the main blood vessels that carry blood to the kidney. Then the catheter will be removed. You will have a tight dressing put on to the small wound site in your groin and you will be taken back to the ward to rest. You will not be allowed to get up for at least 4 hours in case moving around makes the wound bleed. You will be asked to stay in hospital overnight. If there is no bleeding from your groin, you will be able to go home the following day.
Side effects
You may have some pain for 12 to 24 hours following this treatment. You will be given painkillers while you are in hospital and to take home with you. If you are still having pain after the painkillers, do tell your nurse or doctor and ask for more or something stronger.
The aim of the treatment is to kill off the cancer in your kidney. When the cancer cells die off, they may release toxins into your bloodstream. These toxins can cause
• Fever
• Sweats
• Weakness and lack of energy
These side effects will wear off after a few days. At least they are a sign that your treatment is working! If you find them troublesome, try taking paracetamol every 6 hours until the side effects improve.


Experimental treatments
There are several different methods of killing (or 'ablating') kidney tumours being investigated. There is information on all these in our kidney cancer research page. They include
• Cryotherapy - freezing the tumour
• Radio frequency ablation (RFA) - killing the tumour with heat
• HIFU - high intensity ultrasound, which also produces heat to kill the tumour
These techniques can all be done in different ways. They can be used during a regular operation. But researchers and doctors are working on ways to use them that are 'less invasive'. For example, RFA may be done by putting probes through the skin so you don't have to have an operation. We must stress, though, that these are all experimental techniques. They have to be tested, and those who have taken part in trials followed up for some years, before we can be sure that they work as well as surgery to remove kidney cancer.