Cystic Fibrosis

Cystic fibrosis is a genetic disease that primarily affects the lungs however, it also affects the gastrointestinal tract and pancreas.  Salt is not properly transported away from the cells, which causes the lungs, intestines, and other organs to break down.  As a result, mucus builds us and blocks the airways it traps bacteria and causes infection. It affects about 30,000 young people in the United States, predominantly white children.
The disease is very rare in Asians.  Only five patients in Korea,  one in 90,000 Asian infants in Hawaii and one in 350,000 live births in Japan have been reported.  One baby in every 2,000 births has the disease.  About one third of cystic fibrosis patients are adults.  Males are more likely to get the disease than females. Fifty percent of those that are diagnosed with cystic fibrosis will die by the age of thirty.  About 85 percent of children are diagnosed within the first five years of their lives.  The other 10 to 15 percent will be diagnosed after the age of 18.
As it has already been stated, children inherit cystic fibrosis from their parents.  Both parents must carry the gene they may or may not have the disease.  If two parents are carriers of cystic fibrosis, 50 percent of their children will be carriers, 25 percent will have the disease, and 25 percent will not be affected.  If one parent has cystic fibrosis and the other is a carrier, 50 percent of their children will have it and the other 50 percent will be carriers.  Amniocentesis is an optional prenatal test for cystic fibrosis.  Doctors examine the amniotic fluid from the fetus for abnormal genes.  Families have been shown to benefit from the screening of newborns for cystic fibrosis. They have a choice diagnosis and early detection or prevention. Today, CF newborn population screening is current in several countries  Australia, France, the UK, and almost all the states in the U.S.

Scientists used genetic markers to locate the cystic fibrosis gene.  The closer the marker sequence lies to the gene that causes CF, the more often it will be inherited along with the defective CF gene in people who have the disease.  In 1989, researchers identified the Cystic Fibrosis Transmembrane Regulator (CFTR) gene that contained 500,000 nucleotides of DNA.

CFTR belongs to a family of transmembrane proteins called adenosine triphosphate (ATP) binding cassette transporters, and functions as a chloride channel in apical membranes. From there, researchers looked for certain characteristics that indicated the presence of the gene.  The CFTR gene contained mutations in cystic fibrosis patients only.  In 1990, researchers confirmed that CFTR could restore the transport of salt to cells.

There are 250,000 possible positions on the DNA chain of the cystic fibrosis gene.  The defect lies on the 508 position of the DNA strand.  Its called the delta F508 defect- the delta (d) standing for deletion, the F for the particular building-block that is missing (phenylalanine).  In total, there are 800 other gene defects that can produce cystic fibrosis. In the Israeli population, there are about five mutations of cystic fibrosis genetic screening for cystic fibrosis has been available since 1999, particularly for the Jewish population.  The screening is to find out which individuals are carriers of the disease.  In Minas Gerais, Brazil, researchers found eight CFTR gene mutations in cystic fibrosis patient through neonatal screening.  Those mutations are F508del, G542X, R1162X, N1303K, W1282X, G85E, 31201GA, and 7111GT.

The Cystic Fibrosis Neonatal Screening Program of Minas Gerais State diagnosed 111 newborn patients with cystic fibrosis through a mandatory screening program from July 2003 to April 2008.  Researchers used a PCR test to make the diagnoses.  The F508del mutation was detected in 48 percent of the cystic fibrosis chromosomes.  Researchers detected less than 6 percent each of the other seven mutations.  The chart below shows the cycle of cystic fibrosis.

Some symptoms of cystic fibrosis are recurrent cough, wheezing, phlegm production that is yellowgreen, coughing up blood, bulky, smelly stools, and pain in nasal or facial sinuses.  Currently, there is not a cure for cystic fibrosis, but there are various treatments available.  Each year, approximately 200 patients with CF, including approximately 25 children, undergo lung transplantation in the United States. Lung transplantation is currently the only definitive treatment for advanced cystic fibrosis.  The survival rate is about 55 percent for three years.  Respiratory failure is responsible for 95 percent of all cystic fibrosis-related deaths.  A lung transplant is a very serious operation both lungs are replaced.  Lung transplantation should be a last resort the patient cannot carry out daily activities like working or walking a dog.  Lung function continues to decline in spite of therapy.

There are three types of lung transplant procedures.  The first is the heart-lung transplant.  This was actually the first successful way to transplant lungs.  It was first performed in 1983.  However, it had major consequences.  It damaged the patients platelets.  This resulted in heavy, post-operative bleeding.  The patient received heparin to thin the blood.  Also, the patient was kept on a heart-lung bypass machine to maintain blood flow.

The most favored procedure is the bilateral sequential lung transplant.  Surgeons remove one diseased lung and replace it with a donor one.  The new lung starts to work immediately.  Next, surgeons replace the other lung.  There is no need for a heart-lung bypass machine.  The final procedure is living donor lobar transplants.  Patients can avoid being on a waiting list for organs. The demand for transplantable lungs is determined both by the nature of lung disease and by the policies of the waiting list. It didnt give you an idea of how severe the disease really was.  There is also competition among transplant centers for money.
Everything is also very technical and routine.  Doctors use live donors two donors are used for one transplant procedure.  The donors give up half of one lung, which decreases their total lung capacity by 20 percent, which is not noticeable with breathing.

A lung transplant is not advisable if the patient is HIV-positive, has severe malnutrition or osteoporosis, cancer, acute fungal infection or tuberculosis, hepatitis B, or other organ failure.  Also, the chest cavity must be a compatible size that enables the new lungs to fit.  As with any organ transplant, the recipients body can reject the new set of lungs.  There is also the risk of infection, hypertension, and kidney failure.

Cystic fibrosis also affects glucose metabolism.  CF-related diabetes (CFRD) has emerged as the most common comorbidity (two or more existing diseases).  It is similar to both Type I and Type II diabetes with a few differences that include respiratory infection and inflammation, malnutrition, and gastrointestinal malfunctions. It is more prevalent as patients become adult.  About 50 percent of those with CFRD have it by age 30.  It causes severe insulin deficiency.  There are also decreased survival rates for those with the disease.  Insulin therapy is best with a high-calorie, high-fat diet.

Some other treatment options are inhalers like albuterol.  Chest pounding and aerobic exercise loosen mucus there are also medicines that thin the mucus to limit infection.  In 2005, researchers engineered the parainfluenza virus (PIV) that causes the common cold to help cystic fibrosis tissues clear themselves of mucus.  PIV targeted ciliated human airway epithelial cells (HAE).  These cells make up 70 percent of the airway surface lining and express the CFTR gene.  Thus PIV combined with CFTR was able to infect 60 percent of the cystic fibrosis cells within five minutes.  This might be an effective treatment.

Doctors recommend that patients have annual flu and pneumonia vaccinations.  With the emergence of the H1N1 virus in 2009, this is now a new consideration.  In July 2009, patients at the Prince Charles Hospital Adult Cystic Fibrosis Center in Queensland, Australia were experiencing flu-like symptoms such as sore throat, headache, runny nose, and gastrointestinal symptoms.  The nursing staff took swab samples from each patient, two from the nose and one from the throat.  About 4.4 percent of them tested positive for H1N1.  Many of them were under the age of 28 years.  Those that tested positive were treated with oseltamivir for five days or hospitalized for about two days.  Those with more severe lung disease and poor nutrition had a longer hospital stay.  In spite of the pandemic, cystic fibrosis patients were able to successfully manage H1N1.

Regional cystic fibrosis centers provide conventional treatment programs.  Some of the areas of focus are nutritional and psychosocial support (genetic counseling), pancreatic enzyme replacement, treatment of respiratory tract infections, and the clearance and reduction of lower airway secretions.  Doctors can also prescribe antibiotics to slow disease progression.

Good nutrition is important for everyone, but it is especially necessary for those with cystic fibrosis. They tend to develop malnutrition since there is usually some problem with some part of the digestive system.  It is possible to develop indigestion, heartburn, nausea, and vomiting (Kepron, 56).  Malnutrition can develop through increased energy losses, decreased energy intake, and through increased energy expenditure.  Of course, there will also be a deficiency in necessary vitamins, minerals, and supplements.

Vitamin A is necessary for normal vision and normal cell growth. It is found in carrots, milk, egg yolk and leafy green vegetables. Those that are deficient in vitamin A usually experience night blindness.  Fortunately, vitamin A deficiency isnt common.  Vitamin E is prevalent in oils from fish, soybeans, corn, and sunflower.  Since its found in virtually all foods, it is hard for the body to lack in it.  If it does, it affects the nervous system.

A shortage of vitamin K typically would only be a problem for babies however, research shows that vitamin K deficiency can be a problem at any age.  In one survey, 58 of patients with cystic fibrosis had laboratory evidence of vitamin K deficiency (Durie, 935).  These patients have liver disease, pancreatic failure, or gastrointestinal problems that affect the bile acids.

The 25 hydroxyvitamin D (250 HD) level determines the degree of vitamin D insufficiency.  A level that is less than 30 ngmL is considered to be insufficient  (Anis, 1).  Patients should have their vitamin D levels checked once a year.  Studies at cystic fibrosis centers show that more than 90 percent of patients have a vitamin D deficiency (Aris, 2).  Some of the causes are reduced body fat, reduced vitamin D absorption, and reduced exposure to sunlight.  Patients that take vitamin D orally have impaired absorption because the intestines fail to absorb all fat-soluble vitamins.  The best source of vitamin D is from sunlight however, certain antibiotics cause patients to be photosensitive.  Children develop rickets as a result of vitamin D deficiency.

If cystic fibrosis patients arent getting enough vitamins from food, they can take supplements. A multivitamin that contains vitamins A, E, D, and K would work.  Patients need 5,000 to 10, 000 international units (iu) per day of vitamin A, 400 to 800 iu daily of vitamin D, 200 to 400 iu daily of vitamin E, and 2 mg daily of vitamin K.

Iron, calcium, and some fatty acids are essential.  Low iron can result in anemia this is very common.  Doctors can check the iron levels of their patients.  They can prescribe iron pills if necessary.  Lack of calcium is very common in cystic fibrosis patients since many tend to develop osteoporosis.  Having fatty acids in the diet can promote good pancreatic enzyme replacement.  Many cystic fibrosis patients have problems with their pancreas.
The increase in the energy requirements, the decrease in intake, and the greater dietary deficiencies are related to the deterioration of pulmonary function, anorexia, vomiting, pancreatic insufficiency, chronic inflammatory activity, biliary complications and intestinal complications, resulting in a loss of lean body mass and impaired immune function.  Cystic fibrosis patients need 120 to 150 percent more of the recommended daily allowances.  In 1993, the Latin-American Cystic Fibrosis Registry demonstrated that over 50 of the patients were below the 3rd percentile for weight and that 46.7 of the patients were below the same percentile in relation to height for age.

Children with cystic fibrosis need to consume enough calories to support their immune system and to promote healing and growth of their lungs.  It is suggested that children eat more and drink high-energy milk shakes as snacks.  Unfortunately, pancreatic insufficiency is common in cystic fibrosis patients.  That means that the body will not properly absorb nutrients.  Pancreatic enzyme supplements replace the natural enzymes that get trapped in the pancreas by the mucous plugs that block the pancreatic ducts.  Sleep disorders, like sleep apnea, are common in children with cystic fibrosis.  Habitual snoring is a common symptom.  It is often associated with growth failure.  Once the child has a tonsillectomy, there is improved sleep patterns, less snoring, and weight gain.

As it has already been stated, osteoporosis is common in cystic fibrosis patients.   There are also other unusual problems that are associated with cystic fibrosis such as arthritis and Hypertrophic Pulmonary Osteoarthropathy (HPOA). It causes pain around the forearms or the lower legs due to inflammation.  Patients may also develop skin rashes.  Adults with severe lung disease tend to develop HPOA and skin rashes.  The rash consists of small spots that develop below the knee.  It typically goes away without treatment.  Pneumotosis Intestinalis is a rare bowel disorder that is produced by very small pockets of air in the surface lining of the large bowel.  Nobody knows the reason that the small pockets of air appear there.  Cystic fibrosis patients may also develop kidney stones they develop more than the average person.

Small Intestine Bacterial Overgrowth (SIBO) is common in 30 to 50 percent of cystic fibrosis patients.  Because it can affect the digestive system in a dramatic way, patients should get tested frequently.  The Hydrogen Breath test is a common means of detection.  However, Aleksandra Lisowska, Jerzy Wjtowicz, and JarosBaw Walkowiak hypothesized that cystic fibrosis patients produce more methane than hydrogen.  They studied 62 patients with cystic fibrosis ages 5 to 17 years.  They fasted overnight, and they were given oral doses of glucose in water.  The team collected breath samples at 15-minute intervals for two hours.   A positive BT was defined as fasting hydrogen e 20 ppm or fasting methane e 10 ppm or a rise of e 12 ppm hydrogen or e 6 ppm methane over baseline during the test.

About 37.1 percent of those patients had abnormal breath test results.  About 17.7 percent of cystic fibrosis patients were diagnosed with SIBO.  They proved that SIBO is common in cystic fibrosis patients, and that measuring both hydrogen and methane improves the sensitivity of the breath test.
The medium survival age for patients with cystic fibrosis is 35 or more years. In the 1950s, life expectancy was less than one year. Death occurs from pulmonary complications (e.g., pneumonia, pneumothorax, or hemotysis) or as a result of terminal chronic respiratory failure and cor pulmonale. Many people are surprised to live as long as they have with the disease.  Many are aware of the risks that are associated with having a lung transplant.  Usually, a childs condition is not so severe that he or she needs a lung transplant.  Surgeons dont perform many lung transplants for cystic fibrosis.  There are many centers in the United States that perform lung transplants there are not that many available in the United Kingdom and Canada.   The outcomes of a lung transplant depend on four factors  a) physical variables, b) the patient, c) the lung transplant and cystic fibrosis center used, d) infectious agents.

Scientists have attempted to do gene therapy on the lungs.  It is easiest to introduce gene therapy into the lungs as an aerosol solution.  Scientists can produce a normal CFTR gene artificially.  The goal is to introduce into airway cells to produce normal CFTR protein to reduce further infections and inflammation.  To do this, the gene has to act like a virus.  Viruses enter the body and take over a cells function by replicating its own genetic material.  They tried introducing the CFTR gene with an adenovirus they used an adenovirus since it commonly affects the respiratory system and causes cold-like symptoms.  The therapy worked at first, but the body has antibodies to fight off the adenovirus.

Currently, the more promising treatments for cystic fibrosis can fix the causes and not the symptoms of the disease.  As with most diseases, taking medications to treat the symptoms can sometimes have side effects that are worse than the disease itself.  The root cause of cystic fibrosis is a defective gene.  Further, there are mutations of the CFTR gene.  You can break that down to classes of mutations.  CFTR is either not synthesized (I), inadequately processed (II), not regulated (III), shows abnormal conductance (IV), has partially defective production (V), or has accelerated degradation (VI).  The first three classes are associated with pancreatic insufficiency.  The latter three are associated with a sufficient pancreas.

CFTR dysfunctions have led to new treatment options. One is Cystic Fibrosis Transmembrane Regulator Replacement Pharmacotherapy.  This affects intracellular functions, like trafficking, expression, and functioning of CFTR.  It is designed to target the classes of mutations that were previously discussed.  Denufosal and Lancovutide are drugs designed to stimulate chloride channels due to a lack of secretion by CFTR.  Another possible treatment option is to use an osmotic agent like hypertonic saline to increase airway fluid.

In conclusion, there is no cure for cystic fibrosis.  Scientists are developing new treatment options that could potentially treat the causes instead of the symptoms. Over the past few years, scientists have been thinking of developing new aerosol devices for cystic fibrosis.  If parents know that they are carriers or recipients of the disease, they should have their newborns screened.  Patients should consider lung transplantation if they have sever lung disease with their quality of life deteriorating.  Cystic fibrosis patients can take supplements for vitamin and mineral deficiency.  In this 21st century, scientist should be able to make progress with this disease.


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