Cystic fibrosis by alicejenny


									•   Disease Description

    Cystic fibrosis (CF) is a chronic,
    progressive, and frequently fatal
    genetic (inherited) disease of the
    body's mucus glands. CF primarily
    affects the respiratory and digestive
    systems in children and young adults.
    Sweat glands and the reproductive
    system also are usually involved. On
    average, individuals with CF have a
    lifespan of about 30 years.


    CF is an autosomal recessive disorder caused
    by mutations in the CFTR (cystic fibrosis
    transmembrane conductance regulator) gene.
    Heterozygous carriers (those who have
    inherited only one copy of the altered gene)
    are asymptomatic. Two altered genes must be
    present for CF to appear. This means that if
    both parents are CF carriers, their offspring
    would only express CF symptoms if they had
    inherited one defective copy of the CFTR gene
    from each parent.
• How do people inherit cystic fibrosis?
• This condition is inherited in an
  autosomal recessive pattern, which
  means two copies of the gene in each
  cell are altered. Most often, the parents
  of an individual with an autosomal
  recessive disorder each carry one copy
  of the altered gene but do not show
  signs and symptoms of the disorder.
• Lung
• Most fatalities associated with CF result from
  progressive lung disease. For individuals
  with CF, the lungs are normal in utero, at
  birth, and after birth, before the onset of
  infection and inflammation (except possibly
  for the presence of dilated submucosal gland
  ducts in the airways). Shortly after birth,
  many patients with CF acquire a lung
  infection, which incites an inflammatory
  response. Infection becomes established
  with a distinctive bacterial flora. A repeating
  cycle of infection and neutrophilic
  inflammation develops.
• Cleavage of complement receptors CR1 and
  C3bi and immunoglobulin G (IgG) by
  neutrophil elastase (NE) results in failure of
  opsonophagocytosis, leading to bacterial
  persistence. NE also causes production of
  the neutrophil chemoattractant interleukin
  (IL)–8 from epithelial cells and elastin
  degradation, and it acts as secretogogue,
  thereby contributing to persistence of
  inflammation and infection, structural
  damage, impaired gas exchange, and,
  ultimately, end-stage lung disease and early
• Intestine
• Defects in CFTR lead to reduced chloride
  secretion with water following into the gut.
  This may result in meconium ileus at birth
  and in distal intestinal obstruction syndrome
  (DIOS) later in life. In addition, other
  pathologic disorders complicate the simple
  relationship between the apical chloride and
  water secretion and the disease. The
  pancreatic insufficiency (PI) decreases the
  absorption of intestinal contents. Mechanical
  problems associated with inflammation,
• and strictures may predispose the
  patient to sludging of intestinal
  contents, leading to intestinal
  obstruction by fecal impaction or to
  intussusception. Adhesions may form,
  leading to complete obstruction. A
  complete obstruction may require
  resection, leading to loss of absorptive
  epithelium of the distal ileum.
• Pancreas
• As a part of normal digestion, stomach acid
  is neutralized by pancreatic bicarbonate,
  leading to the optimal pH for pancreatic
  enzyme action. Reduced bicarbonate
  secretion in response to secretin stimulation
  has been demonstrated in patients with CF
  with both PI and pancreatic sufficiency (PS).
  Reduced bicarbonate secretion affects the
  digestion so that neither endogenous nor
  exogenous pancreatic enzymes can work at
  their optimal pH.
• Other factors, such as reduction of
  water content of secretions,
  precipitation of proteins, and plugging
  of ductules and acini, prevent the
  pancreatic enzymes from reaching the
  gut. Autodigestion of the pancreas
  occasionally leads to pancreatitis. Most
  patients with CF (90-95%) have
  pancreatic enzyme insufficiency and
  present with digestive symptoms
  and/or failure to thrive early in life.
  However, onset of PI varies and may
  occur in patients older than 6 months.
• Some patients never develop PI.
  Patients with PI typically present with
  poor weight gain in association with
  frequent stools that are malodorous,
  greasy, and associated with flatulence
  and colicky pain after feeding. The
  combination of increased energy intake
  demand at baseline, the added energy
  intake demand of chronic disease,
  difficulty sustaining energy uptake
  because of malabsorption, and
  anorexia associated with ongoing lung
  inflammation leads to poor weight gain.
• Liver
• Absence of functional CFTR in
  epithelial cells lining the biliary
  ductules leads to reduced secretion of
  chloride and reduction in passive
  transport of water and chloride,
  resulting in increased viscosity of bile.
  The biliary ductules may be plugged
  with secretions. If this process is
  extensive, obstructive cirrhosis
  complicated by esophageal varices,
  splenomegaly, and hypersplenism may
• Gallstones are more prevalent in
  patients with CF than in age-matched
  control subjects. As many as 15% of
  young adults with CF have gallstones,
  irrespective of the status of the
  pancreatic function. Abnormal mucin in
  the gallbladder and malabsorption of
  bile acids in a patient with PI result in a
  higher frequency of gallstones.
• Secondary involvement of the liver
  may also occur because of
  involvement of other organs; for
  example, malnutrition may be
  associated with hepatic steatosis,
  and right heart failure caused by
  chronic hypoxia may result in
  passive congestion of the liver.
• PI predisposes patients to poor
  absorption of fat-soluble
  vitamins A, D, E, and K.
  Symptomatic deficiency of any
  of these vitamins can occur
  before diagnosis or as a later
  complication of the disease.
• Cystic fibrosis is an inherited
  disease of the mucus glands that
  affects many body systems. In
  particular, this disorder causes
  progressive damage to the
  respiratory system and chronic
  digestive system problems.
• CF is a disease of exocrine gland
  function, involving multiple organ
  systems and chiefly resulting in
  chronic respiratory infections,
  pancreatic enzyme insufficiency, and
  associated complications in untreated
  patients. Pulmonary involvement
  occurs in 90% of patients surviving the
  neonatal period. End-stage lung
  disease is the principal cause of death.
• Mucus is a slippery substance that
  lubricates and protects the linings of
  the airways, digestive system,
  reproductive system, and other organs
  and tissues. In people with cystic
  fibrosis, the body produces mucus that
  is abnormally thick and sticky
• . This
       abnormal mucus can
 obstruct the airways, leading to
 severe problems with breathing
 and bacterial infections in the
• These infections cause chronic
  coughing, wheezing, and inflammation.
  Over time, mucus buildup and
  infections result in permanent lung
  damage, including the formation of
  scar tissue (fibrosis) and cysts in the
• Most people with cystic fibrosis also have
  digestive problems because thick, sticky
  mucus interferes with the function of the
  pancreas. The pancreas is an organ that
  produces insulin (a hormone that helps
  control blood sugar levels) and enzymes that
  help digest food. Mucus blocks the ducts of
  the pancreas, preventing these enzymes
  from reaching the intestines to aid digestion.
• Problems with digestion can lead to
  diarrhea, malnutrition, poor growth,
  and weight loss. Some babies with
  cystic fibrosis have meconium ileus, a
  blockage of the intestine that occurs
  shortly after birth.
• Men with cystic fibrosis are often
  unable to father a child (infertile)
  because the tubes that carry sperm (the
  vas deferens) are blocked by mucus
  and do not develop properly. Infertility
  is also possible, though less common,
  in women with cystic fibrosis
• What is the official name of the CFTR
• The official name of this gene is
  “cystic fibrosis transmembrane
  conductance regulator (ATP-
  binding cassette sub-family C,
  member 7).”
• Pathophysiology: CF is caused by defects in
  the gene for cystic fibrosis transmembrane
  conductance regulator (CFTR), which
  encodes for a protein that functions as a
  chloride channel and is regulated by cyclic
  adenosine monophosphate (cAMP).
  Mutations in the gene for CFTR (CFTR) result
  in abnormalities of cAMP-regulated chloride
  transport across epithelial cells on mucosal
• Defective CFTR results in decreased
  secretion of chloride and increased
  reabsorption of sodium and water across
  epithelial cells. Resultant reduced height of
  epithelial lining fluid and decreased
  hydration of mucus results in mucus that is
  stickier to bacteria, which results in infection
  and inflammation. These abnormalities result
  in viscid secretions in the respiratory tract,
  pancreas, gastrointestinal tract, sweat
  glands, and other exocrine tissues.
  Increased viscosity of these secretions
  makes them difficult to clear.
• What is the normal function of the CFTR
• The CFTR gene provides instructions for
  making a protein called the cystic fibrosis
  transmembrane conductance regulator. This
  protein functions as a channel across the
  membrane of cells that produce mucus,
  sweat, saliva, tears, and digestive enzymes.
  The channel transports negatively charged
  particles called chloride ions into and out of
• The transport of chloride ions helps
  control the movement of water in
  tissues and maintain the fluidity of
  mucus and other secretions. Mucus is
  a slippery substance that lubricates
  and protects the lining of the airways,
  digestive system, reproductive system,
  and other organs and tissues.
• The CFTR protein also regulates the
  function of other channels, such as
  those that transport positively charged
  particles called sodium ions across cell
  membranes. These channels are
  necessary for the normal function of
  organs such as the lungs and
• caused by mutations in the CFTR gene
  – More than 1,000 mutations in the CFTR
    gene have been identified in people with
    cystic fibrosis. Most of these mutations
    change a single protein building block
    (amino acid) in the CFTR protein or delete
    a small amount of DNA from the CFTR
• Disease-causing mutations in the CFTR gene
  alter the production, structure, or stability of
  the chloride channel. All of these changes
  prevent the channel from functioning
  properly, which impairs the transport of
  chloride ions and the movement of water into
  and out of cells. As a result, cells that line
  the passageways of the lungs, pancreas, and
  other organs produce mucus that is
  abnormally thick and sticky. The abnormal
  mucus obstructs the airways and glands,
  leading to the characteristic signs and
  symptoms of cystic fibrosis.
• Some mutations in the CFTR gene have been
  identified in people with isolated problems
  affecting the digestive or respiratory system.
  For example, mutations in the CTFR gene
  have been found in some cases of idiopathic
  pancreatitis, an inflammation of the pancreas
  that causes abdominal pain, nausea,
  vomiting, and fever. In these cases, the
  cause of the inflammation is unknown, but
  CFTR mutations may be a risk factor.
• Changes in the CFTR gene also have been
  associated with chronic inflammation of the
  tissues that line the sinuses (rhinosinusitis).
  This condition causes sinus pain and
  pressure, headache, fever, and nasal
  congestion or drainage. Other respiratory
  problems, including several conditions that
  partially block the airways and interfere with
  breathing, are also associated with CFTR
• These conditions include
  bronchiectasis, which damages the
  passages leading from the windpipe to
  the lungs (the bronchi), and allergic
  bronchopulmonary aspergillosis, which
  results from hypersensitivity to a
  certain type of fungal infection.
  Additional genetic and environmental
  factors likely play a part in determining
  the risk of these complex conditions.
• Symptoms
• Because there are more than 1,000 mutations
  of the CF gene, symptoms differ from person
  to person. But in general they include:
• No bowel movements in first 24 to 48 hours
  of life
• Stools that are pale or clay colored, foul
  smelling, or that float
• Infants may have salty-tasting skin
• Recurrent respiratory infections, such as
  pneumonia or sinusitis
• Coughing or wheezing
• Weight loss, or failure to gain weight
  normally in childhood
• Diarrhea
• Delayed growth
• Fatigue
• CF does not follow the same pattern in all
  patients but affects different people in
  different ways and to varying degrees. The
  basic problem, however, is the same—an
  abnormality in the glands that produce or
  secrete sweat and mucus. Sweat cools the
  body; mucus lubricates the respiratory,
  digestive, and reproductive systems and
  prevents tissues from drying out, protecting
  them from infection.
  Loss of excessive amounts of salt in sweat
  can upset the balance of minerals in the
  blood, which may cause abnormal heart
  rhythms. Shock also is a risk.
• Thick accumulations of mucus in the
  intestines and lungs result in
  malnutrition, poor growth, frequent
  respiratory infections, breathing
  difficulties, and eventually permanent
  lung damage. Lung disease is the
  cause of death in most patients.
• Pancreatic enzymes to replace those
  that are missing.
• Vitamin supplements, especially
  vitamins A, D, E, and K.
• Inhaled bronchodilators, such as
  albuterol (Proventil, Ventolin), help
  open the airways.
• Various other medical problems may
  include inflammation of the nasal
  sinuses, nasal polyps, clubbing of
  fingers and toes, pneumothorax
  (rupture of lung tissue and trapping of
  air between the lung and chest wall),
  coughing of blood, heart enlargement,
  abdominal pain and discomfort,
  gassiness, and rectal prolapse. Liver
  disease, diabetes, pancreatic
  inflammation, and gallstones also
  occur in some people with CF.
• 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:
• Sweat chloride test. This is the standard diagnostic
  test for CF. A high salt level in the patient's sweat
  indicates the disease.
• Fecal fat test
• Upper GI and small bowel series
• Measurement of pancreatic function
• Cystic fibrosis may alter the results of the following
• Trypsin and chymotrypsin in stool
• Secretin stimulation test
• Chest x-ray or CT scan
• Lung function tests
• Pulmonary function testing (PFT)
  – Standard spirometry may not be
    reliable until patients are aged 5-6
    years; however, some younger
    patients can be taught to do
    reproducible maneuvers. Partial flow-
    volume curves may show
    abnormalities, in addition to an
    elevated airway resistance, and
• The recently described forced
  oscillation technique (FOT), which uses
  the impulse oscillometry system (IOS),
  can be used successfully in younger
  children. Airway resistance measured
  by IOS has been found to be similar to
  the airway resistance measured by
  body plethysmography, and this
  technique has been successfully used
  to measure lung function in young
  patients with CF unable to perform
• Typically, peripheral airway involvement
  resulting from CF manifests as an
  obstructive defect with airtrapping and
  hyperinflation; oxyhemoglobin desaturation
  may occur because of a ventilation-perfusion
  mismatch. In the early stages, forced
  expiratory volume in 1 second (FEV1) may be
  normal and forced expiratory flow (FEF) after
  25-75% of vital capacity has been expelled
  (FEF 25-75) is reduced, suggesting small
  airway involvement. As the disease
  progresses, FEV1 is also reduced.
• The associated airtrapping results in an
  elevated ratio of residual volume to
  total lung capacity (RV/TLC). With
  hyperinflation, TLC is also increased. In
  patients with advanced disease,
  extensive lung changes with fibrosis
  are reflected as restrictive changes
  characterized by declining TLC and
  vital capacity.
• Bronchoalveolar lavage: Airway
  inflammation is the hallmark of CF lung
  disease. Studies suggest airway
  inflammation even in the absence of
  infection. Bronchoalveolar lavage fluid
  usually shows a high percentage of
  neutrophils, and recovery of
  Pseudomonas aeruginosa from
  bronchoalveolar lavage fluid supports
  the diagnosis of CF in a clinically
  atypical case
• Sputum microbiology: The most
  common bacterial pathogens in the
  sputum of patients with CF are
  Haemophilus influenzae,
  Staphylococcus aureus, P aeruginosa,
  Burkholderia cepacia, Escherichia coli,
  and Klebsiella pneumoniae. Findings of
  P aeruginosa, especially the mucoid
  form, support the diagnosis of CF in
• Immunoreactive Trypsinogen Test (IRT) is
  used for newborns who do not produce
  enough sweat for the sweat test. In the IRT
  test, blood drawn 2 to 3 days after birth is
  analyzed for a specific protein called
  trypsinogen. Positive IRT tests must be
  confirmed by sweat and other tests.
  Other tests that can assist in the diagnosis of
  CF include chest X rays, lung function tests,
  sputum (phlegm) cultures, and stool
  examinations to help identify typical
  digestive abnormalities.
• Molecular Genetic Testing involves
  carrier screening and direct DNA
  analysis. Current tests, however,
  cannot detect all of the more than
  900 gene mutations, and so the
  tests are only 80% to 85% accurate
• CF once was always fatal in childhood.
  Better treatment methods developed
  over the past 20 years have increased
  the average lifespan of CF patients. At
  present, neither gene therapy nor any
  other kind of treatment exists for the
  basic causes of CF, although several
  drug-based approaches are being
• In the meantime, doctors can only ease the
  symptoms of CF or slow the progress of the
  disease so the patient's quality of life is
  improved. This is achieved by antibiotic
  therapy combined with treatments to clear
  the thick mucus from the lungs. The therapy
  is tailored to the needs of each patient. For
  patients whose disease is very advanced,
  lung transplantation may be an option.
• Treatment
• An early diagnosis of CF and a
  comprehensive treatment plan can
  improve both survival and quality of
  life. Specialty clinics for cystic fibrosis
  may be helpful and can be found in
  many communities.
• Treatment includes:
• Antibiotics for respiratory infections.
• DNAse enzyme replacement therapy. The
  medication dornase (Pulmozyme) contains
  an enzyme that thins the mucus and makes it
  easier to cough up.
• Pain relievers. Research has shown that the
  pain reliever ibuprofen may slow lung
  deterioration in some children with cystic
  fibrosis. The results were most dramatic in
  children ages 5 to 13.
• Postural drainage and chest percussion.
• Lung transplant may be considered in some
• Prevention
• There is no way to prevent cystic
  fibrosis. Screening of family members
  of a cystic fibrosis patient may detect
  the cystic fibrosis gene in between 60
  and 90% of carriers, depending on the
  test used.
• Expectations (prognosis)
• Disease registries now show that 40% of
  patients with cystic fibrosis are over age 18.
• Today, the average life span for those who
  live to adulthood is approximately 35 years, a
  dramatic increase over the last three
• Death is usually caused by lung
• Complications
• The most common complications are chronic respiratory
• Pneumonia, recurrent
• Pneumothorax
• Coughing up blood
• Chronic respiratory failure
• Cor pulmonale
• Liver disease
• Diabetes
• Osteoporosis and arthritis

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