Cystic
Fibrosis Information
A small Directory
Cystic
fibrosis (CF),
also called mucoviscidosis, is a hereditary disease that affects the entire
body, causing progressive disability and early death. Formerly known as cystic
fibrosis of the pancreas, this entity has
increasingly been labeled simply "cystic fibrosis". Life expectancy
is on average 37.5 years old.Difficulty breathing and insufficient enzyme
production in the pancreas are the most common symptoms. Thick mucous
production as well as a low immune system results in frequent lung
infections, which are 
treated, though not
always cured, by oral and intravenous antibiotics and other medications. A
multitude of other symptoms, including sinus infections, poor growth, diarrhea, and potential infertility (mostly in males, due
to the condition Congenital bilateral absence of the vas Deferens) result from the
effects of CF on other parts of the body. Often, symptoms of CF appear in
infancy and childhood; these include meconium ileus, failure to thrive, and recurrent lung
infections.Cystic fibrosis is one of the most common
life-shortening, childhood-onset inherited diseases. In the United States, 1 in
3900 children is born with CF. It is most common among Europeans and Ashkenazi Jews; one in twenty-two
people of European descent carry one gene for CF, making it the most common genetic
disease among such people.Individuals with cystic fibrosis can
be diagnosed prior to birth by genetic testing (See also Dor Yeshorim) or in early childhood by a sweat test. Newborn screening
tests are increasingly common and effective. There is no cure for CF, and most
individuals with cystic fibrosis die young — many in their 20s and 30s from
lung failure although with many new treatments being introduced the life
expectancy of a person with CF is increasing. Ultimately, lung transplantation is often necessary as
CF worsens.CF is caused by a mutation in a gene called the cystic fibrosis transmembrane
conductance regulator (CFTR). The product of this gene helps create 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 name cystic
fibrosis refers to the characteristic 'fibrosis' (tissue scarring) and cyst
formation within the pancreas, first recognized in the 1930s.
Symptoms
and signs
The
symptoms of cystic fibrosis depend on the age of an individual, the extent the
disease affects specific organs, prior therapy, and the types of infections
experienced. Cystic fibrosis affects the entire body and impacts growth, breathing, digestion,
and reproduction. The newborn period may be marked by poor weight
gain and intestinal blockage caused by thick feces. Other symptoms of CF
appear during the remainder of childhood and early adulthood. These include
continued problems with growth, the onset of lung disease, and increasing
difficulties with poor absorption of vitamins and nutrients by the
gastrointestinal tract. In addition, difficulties with fertility may become
apparent when reproduction is attempted.
Lung
and sinus disease
Lung
disease results from clogging of airways due to inflammation. Inflammation and infection cause
injury to the lungs and structural changes that lead 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 of CF,
changes in the architecture of the lung further exacerbate chronic difficulties
in breathing.
Aspergillus
fumigatus - A
common fungus which can lead to worsening lung disease in people with CF
Other
symptoms include coughing up blood (hemoptysis), changes in the major
airways in the lungs (bronchiectasis), high blood pressure in the lung (pulmonary hypertension), heart failure, difficulties getting enough oxygen to the body, and
respiratory failure requiring support with breathing masks such as bilevel positive airway pressure machines or ventilators. 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 These polyps can block the nasal passages and
increase breathing difficulties.
Gastrointestinal, liver
and pancreatic disease
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 10% of newborns with CF.In addition,
protrusion of internal rectal membranes (rectal prolapse) is more common in CF
because of increased fecal volume, malnutrition, and increased intra–abdominal
pressure due to coughing. The thick
mucus seen in the lung has its counterpart in thickened secretions from the
pancreas, an organ responsible for providing digestive juices which help break down
food. These secretions block the movement of the digestive enzymes into the gut
and result in irreversible damage to the pancreas, often with painful
inflammation (pancreatitis).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. 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 also develop distal intestinal obstruction syndrome when thickened feces
cause intestinal blockage. 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 cirrhosis, in which the liver
fails to clean the blood of toxins and does not make important proteins such as those
responsible for blood clotting.
Endocrine
disease and growth
Clubbing
- Patients with CF
can often have enlargement of their fingers, Extreme case shown here.
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 diabetes. Vitamin D is involved
in calcium and phosphorus regulation. Poor uptake
of vitamin D from the diet because of malabsorption leads 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 on their bones. Poor growth is a hallmark of CF. Children
with CF typically do not gain weight or height at the same rate as their peers
and occasionally are not diagnosed until investigation is initiated for poor
growth. The causes of growth failure are multi–factorial and include chronic
lung infection, poor absorption of nutrients through the gastrointestinal
tract, and increased metabolic demand due to chronic illness.
Infertility
Infertility affects both men and
women. At least 97 percent of men with cystic fibrosis are infertile. 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 issues due to thickened cervical mucus or malnutrition. In severe
cases, malnutrition disrupts ovulation and causes amenorrhea.
Diagnosis and
monitoring
Cystic fibrosis may be diagnosed by newborn screening, sweat testing, or genetic testing. As of 2006 in the
United States, ten percent of cases are diagnosed shortly after birth as part
of newborn screening programs. The newborn screen identifies decreased amounts
of the enzyme trypsin. However, most states
and countries do not screen for CF routinely at birth. Therefore, most
individuals are diagnosed after symptoms prompt an evaluation for cystic
fibrosis. The most commonly used form of testing is the sweat test. Sweat
testing involves application of a medication that stimulates sweating (pilocarpine) to one electrode of an apparatus and running
electric current to a separate electrode
on the skin. This process, called iontophoresis, causes sweating; the
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. CF can also be
diagnosed by identification of mutations in the CFTR gene. A
multitude of tests is 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. Examination of the sputum under a microscope is used to identify
which bacteria are causing infection so that effective antibiotics can be given. 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
problems, vitamin deficiencies, and the onset of
diabetes. DEXA scans can screen for osteoporosis and testing for fecal elastase can help diagnose
insufficient digestive enzymes.
Prenatal
diagnosis
Couples
who are pregnant or who are planning a pregnancy can themselves be tested for
CFTR gene mutations to determine the likelihood that their child will be born
with cystic fibrosis. Testing is typically performed first on one or both
parents and, if the risk of CF is found to be high, testing on the fetus can then be performed. Cystic fibrosis testing is
offered to many couples in the US. The American College of
Obstetricians and Gynecologists recommends testing for couples who have a personal
or close family history of CF as well as couples at high risk because of their
ethnicity. Because
development of CF in the fetus requires each parent to pass on a mutated copy
of the CFTR gene and because CF testing is expensive, testing is often
performed on just one parent initially. If that parent is found to be a carrier
of a CFTR gene mutation, the other parent is then tested to calculate the risk
that their children will have CF. CF can result from more than a thousand
different mutations and, as of 2006, it is not possible to test for each one. Testing
analyzes the blood for the most common mutations such as ΔF508 — most commercially
available tests look for 32 or fewer different mutations. If a family has a
known uncommon mutation, specific screening for that mutation can be performed.
Because not all known mutations are found on current tests, a negative screen
does not guarantee that a child will not have CF. In addition, because the
mutations tested are necessarily those most common in the highest risk groups,
testing in lower risk ethnicities is less successful because the mutations
commonly seen in these groups are less common in the general population. Couples who
are at high risk for having a child with CF will often opt to perform further
testing before or during pregnancy. In vitro fertilization with preimplantation genetic diagnosis offers the possibility
to examine the embryo prior to its placement
into the uterus. The test, performed 3 days after fertilization, looks for the presence
of abnormal CF genes. If two mutated CFTR genes are identified, the embryo is
excluded from 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, so 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.
Pathophysiology
Cystic
fibrosis occurs when there is a mutation in the CFTR gene. The protein created
by this gene is anchored to the outer membrane of cells in the sweat
glands, lung, 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 chloride from outside the
cell into the cell. When the CFTR protein does not work, chloride is trapped
outside the cell. Because chloride is negatively charged, positively charged ions also cannot 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 of
CF is not well understood. One theory suggests that the lack of chloride
absorption through the CFTR protein leads to the accumulation of nutrient–rich
mucus in the lungs which 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 feces,
etc.
The
role of chronic infection in lung disease
The lungs
of individuals with cystic fibrosis are colonized and infected by bacteria from
an early age. These bacteria, which often spread amongst individuals with CF,
thrive in the altered mucus, which collects in the small airways of the lungs. This
mucus encourages the development of bacterial microenvironments (biofilms) that are difficult for
immune cells (and antibiotics) to penetrate. The lungs respond to repeated
damage by thick secretions and chronic infections by gradually remodeling the
lower airways (bronchiectasis), making infection even
more difficult to eradicate. Over time,
both the types of bacteria and their individual characteristics change in
individuals with CF. Initially, common bacteria such as Staphylococcus aureus and Hemophilus influenzae colonize and infect the
lungs. Eventually, however, Pseudomonas aeruginosa (and sometimes Burkholderia cepacia) dominates. Once within
the lungs, these bacteria adapt to the environment and develop resistance to commonly used antibiotics. Pseudomonas
can develop special characteristics which allows the formation of large
colonies — these strains are known as "mucoid" Pseudomonas and
are rarely seen in people who 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 health care setting and health care
providers are encouraged to wear gowns and gloves when examining patients with
CF in order to limit the spread of virulent bacterial strains. Often, patients
with particularly damaging bacteria will attend clinics on different days and
in different buildings than those without these infections.
Molecular biology
CFTR
protein - Molecular
structure of the CFTR protein
The CFTR gene is found at the q31.2 locus of chromosome 7, is 180,000 base pairs long, and creates a
protein which is 1,480 amino acids long. 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 seventy percent of CF
worldwide and ninety percent of cases in the United States. There are over 1,400 other mutations which can produce
CF, however.
Antibiotics
to treat lung disease
Antibiotics
are given whenever pneumonia is suspected or there has been a decline in lung
function. Antibiotics are often chosen based on information about prior
infections. 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. This prolonged therapy
often necessitates hospitalization and insertion of a more permanent IV such as a PICC line or Port-a-Cath. Inhaled therapy with
antibiotics such as tobramycin and colistin 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 sometimes given to
help prevent infection or to control ongoing infection. Some individuals spend
years between hospitalizations for antibiotics, while others require several
antibiotic treatments each year.Several common antibiotics such as
tobramycin and vancomycin can cause hearing loss 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 methods to treat lung disease
Several mechanical techniques are used to dislodge sputum
and encourage its expectoration. In the hospital setting, physical therapy is
utilized; a therapist pounds an individual's chest with his or her hands
several times a day. 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, now integrate a cough assistance phase, as well as a vibration phase
for dislodging secretions. Biphasic Cuirass Ventilation is also shown to provide a bridge to
transplantation. These are portable and adapted for home use. Aerobic exercise is of great benefit to people with cystic fibrosis. Not
only does exercise increase sputum clearance, but it improves cardiovascular
and overall health. Aerosolized medications which 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, breathing support from machines may become
necessary. Individuals with CF may need to wear special masks at night that
help push air into their lungs. These machines, known as bilevel positive airway pressure (BiPAP) ventilators, help prevent low blood oxygen
levels during sleep. BiPAP may also be used during physical therapy to improve
sputum clearance. During severe illness, people with CF
may need to have a tube placed in their throats and their breathing
supported by a ventilator.
Treatment
of other aspects of CF
Intracytoplasmic
sperm injection is used to provide fertility for men with cystic fibrosis.
Newborns with meconium ileus typically require surgery while
adults with distal intestinal obstruction syndrome typically do not. Treatment
of pancreatic insufficiency by replacement of missing digestive enzymes allows
the gut to properly absorb nutrients and vitamins that would otherwise be lost
in the feces. Even so, most individuals with CF take additional amounts of
vitamins A, D, E, and K and eat high calorie meals. It should be noted,
however, that nutritional advice given to patients is, at best, mixed: often,
literature encourages the eating of high-fat foods without differentiating
between saturated and unsaturated fats/trans-fats: this lack of clear information runs counter to
health advice given to the general population, and creates the risk of further
serious health problems for people with cystic fibrosis as they grow older. So
far, no large-scale research has been carried out into the incidence of atherosclerosis and coronary heart disease in adults with cystic fibrosis.The diabetes common to many CF patients is typically treated with insulin injections or an insulin pump. Development of osteoporosis can be prevented by increased intake of
vitamin D and calcium and can be treated by bisphosphonates. 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. 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 may be overcome with intracytoplasmic sperm injection. Third party reproduction is also a possibility for women with CF.
Transplantation and gene therapy
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 would contain bacteria that could infect the transplanted
lung. A pancreatic or liver transplant may be performed at the same time in
order to alleviate liver disease and/or diabetes. Lung transplantation is
considered when lung function approaches a point where it threatens survival or
requires assistance from mechanical devices. Gene therapy holds promise as a potential avenue to cure cystic fibrosis. Gene
therapy attempts to place a normal copy of the CFTR gene into affected cells. Studies
have shown that to prevent the lung manifestations of cystic fibrosis, only
5–10% the normal amount of CFTR gene expression is needed. Many approaches have been theorized and
several clinical trials have been initiated but, as of 2006, many hurdles still
exist before gene therapy can be successful.
The Cystic Fibrosis
Foundation:
http://www.cff.org/
Hi! My name is Norma Kennedy Plourde, and I live in Baker Lake, New
Brunswick, Canada. I happen to have Cystic Fibrosis. My CF affects mostly my
lungs and my digestive system. I get frequent respiratory infections, so I take
antibiotics a lot, and my pancreas doesn't secrete enzymes, so I take
pancreatic enzymes, plus a lot of other medications. I also happen to have
Rheumatoid Arthritis. I am a 45 y.o. woman, have been married for 25 years, and
am fortunate enough to have a beautiful, healthy 23 year old daughter without
CF. I am a Registered Nurse, and worked in a hospital setting for 9 years, but
no longer work due to my illnesses. I would like to educate and inform as many
people as I can about CF. It is a genetic disease that affects approximately
3,000 people in Canada, and 30,000 in the US, plus many more throughout the
world. It is a disease that affects the exogenous secreting glands of the body,
and generates thickened secretions, therefore blocking proper functioning of
certain organs. The organs most affected are the lungs and pancreas, therefore
affecting breathing and digestion, but certain other organs are affected also. There
is no cure as of yet, but we hope there soon will be. Research is ongoing, and
great strides are being made! Whereas 30 years ago, not many people with CF
lived past childhood, nowadays many can live into their 30's or more. Unfortunately,
many people with CF are still dying way too early. Please support CF
research...that is our only hope. I hope that this site will helped you to learn more
about CF. See
my site:
http://www3.nbnet.nb.ca/normap/CF.htm
More Information and Support:
http://cystic-l.org/
Signs and tests
In
May 2005, the U.S. Food and Drug Administration approved the first DNA-based blood
test to help detect CF. The test looks for variations in a gene known to cause
the disease. Other tests use to diagnose CF include:
Upper GI and
small bowel series
Measurement of
pancreatic function
Cystic fibrosis may alter the results of the following tests:
See
our Blog, Best News for You:
http://www.generalfoundation.wordpress.com
