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
