Download Alpha-1 Antitrypsin Deficiency

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Alpha-1 Antitrypsin Deficiency
Alpha-1 antitrypsin, also referred to
as A1P1, AAT deficiency, AAT, genetic
or inherited emphysema or simply
alpha-1 is the most common genetic
cause of emphysema in adults. The
liver also produces alpha-1-antitrypsin.
Deficiency of the protein results in
destruction of hepatocytes and,
ultimately, cirrhosis. AAT may also
affect the skin, the feature of which is
panniculitis, an inflammation of the
fat under the skin. Diagnosis of AAT is
typically missed or delayed, disallowing
the opportunity for early treatment
and maintenance of pulmonary and
hepatic function. This continuing
education offering will define AAT
and its clinical manifestations and
review both pharmacologic and nonpharmacologic therapy options.
Pathophysiology
Trypsin is a normally occurring enzyme
whose primary function is to break
down protein to aid digestion. Per
the normal negative feedback loop as
seen in the illustration, when trypsin is
no longer needed it is important that
its production cease and continued
breakdown not occur. Thus, the body
generates antitrypsin, specifically
alpha-1 antitrypsin (AAT). Alpha-1
antitrypsin is a protease inhibitor —
it inhibits the action of trypsin. AAT
protects tissues from the enzyme’s
inflammatory cells, especially the
neutrophil elastase. Without alpha-1
antitrypsin (i.e. a deficiency), elastase
is free to break down elastin, an
important contributor to lung
elasticity. Elastin breakdown results
in destruction of lung, leading to such
complications such as emphysema
or COPD. In emphysema, the alveoli
break down and block the area,
preventing the exchange of air. These
patients can inhale sufficiently, but
they cannot effectively exhale. Such
emphysema can occur as a result of the
deficient level of alpha-1 antitrypsin.
In fact, alpha-1 antitrypsin is the most
common genetic cause of emphysema
in adults. The result is progressive,
irreversible, chronic obstructive lung
disease (COPD).
With the mutated gene there is
also impaired secretion from the
liver. Either the gene is targeted for
destruction or it doesn’t polymerize
but stays in the endoplasm where it
will destroy liver tissue. Liver damage
is less common than lung damage
but can be seen in both children and
adults. Alpha-1 antitrypsin is the most
common cause of liver disease in the
pediatric population. The only available
treatment for liver damage, however, is
liver transplant.
Pattern of Heredity
Alpha-1 antitrypsin is an autosomal
recessive disorder. Since it is recessive,
a person can only inherit the disease
when he or she inherits a defective
gene from both parents. Refer to
the diagram illustrating the pattern
of heredity. Consider M as the
normal gene, Z or S as abnormal. In
C O N T I N U I N G
E D U C A T I O N
P R O G R A M
A person who inherits the normal
gene from both parents will present
with normal serum level and function
of alpha-1 antitrypsin. Heterozygotes
typically have lower than normal serum
alpha-1 antitrypsin levels, but do not
manifest symptoms of the disease. If a
person inherits the Z gene from both
parents, he or she is a PiZZ, the most
severe form of the deficiency.
There are about 75 different phenotypes
of alpha-1 antitrypsin deficiency.
Most common are the M, Z, S and null
phenotypes. The presence of an SZ or
null gene also indicates disease.
The incidence of the most common
phenotype, ZZ, is about 1 in 3,000 in
the US, similar to the incidence of cystic
fibrosis. This equates to approximately
100,000 individuals. Unfortunately,
only about 10% of those patients, or
10,000 persons, are ever diagnosed.
Given the fact that an estimated 3% of
patients with emphysema or COPD are
likely to have AAT, that is another nearly
1M patients not diagnosed. Alpha-1
antitrypsin deficiency is most common
in Caucasians, less common in the
African American population and rare
in the Asian population. About 1 in 37
persons are heterozygotes.
Alpha-1 antitrypsin deficiency mimics
the symptoms of such respiratory
diseases as asthma, allergies, COPD or
chronic bronchitis. Misdiagnosis is all
too common with an average of 7 to
10 years from symptom development
to actual diagnosis. Unfortunately,
2 by the time diagnosis is made, much
opportunity to prevent lung or liver
damage is missed. And, since alpha-1
antitrypsin deficiency is so rare, many
community practitioners are not
aware of and do not test for alpha-1
antitrypsin deficiency.
Clinical
Presentation
portal hypertension and succumb
to complications before age 12
ƒƒ Another 25% will die of the same
process by age 20
ƒƒ Approximately 25% have liver
fibrosis but minimal hepatic
dysfunction and can live to
adulthood
ƒƒ 25% show no evidence of
progressive disease
Patients typically present with an
insidious but progressive shortness of
breath at a relatively early age, increased
airflow obstruction, year-round allergy
symptoms and a chest x-ray revealing
hyperinflation of the bases of the lungs
and a symmetrical loss of lung tissue
vascularity. Patients also present with
such symptoms as pursed-lip breathing
and chronic, often productive, cough.
About 20-30% of alpha-1 patients
have concomitant bronchitis, up to a
third of the patients also have asthma.
There is a significantly increased risk
of lung tissue damage in patients who
smoke and/or are exposed to toxins or
pollutants.
Approximately 12-15% of adult patients
with the ZZ phenotype present with
liver disease. The risk increases in
those persons who abuse alcohol
or are exposed to environmental or
occupational toxins.
About 12-15% of patients with alpha-1
present with liver involvement as well.
Alpha-1 is the most common form
of liver disease in children and the
most common genetic reason for liver
transplant in pediatrics in general. Of
children with PiZZ phenotype:
As mentioned above, the ZZ phenotype
is the most severe phenotype and
accounts for 95% of symptomatic
patients with AAT deficiency. There are a
number of other variant phenotypes as
well, with their own symptom profiles.
ƒƒ Up to 25% develop cirrhosis and
Some patients may present with the
skin condition panniculitis. Panniculitis
is an inflammation of fat beneath
the skin, often developing after an
incident of trauma, which causes skin
to harden and form lumps, lesions and
patches. Panniculitis is treatable with
augmentation therapy.
Diagnosis
The chart below illustrates the impact
of the various phenotypes on the serum
Range of Alpha-1 PI serum concentrations by genotype
60
Serum Concentration (µM)
this diagram, the “grandfather” is a
heterozygote (formerly referred to as a
carrier) — he has one normal gene and
one abnormal gene. He will not have
the disease but, if matched with another
heterozygote, could pass it on. In this
case the grandmother does have the
disease (ZZ). Refer to the middle row.
Two of the children inherited a Z from
mom and a Z from dad and therefore
have the disease. The third inherited the
M from dad and the Z from mom, so is
a heterozygote. In the next generation
you see a person who is neither afflicted
or a heterozygote. She inherited the M
gene from both parents.
50
40
30
20
11 µM
protective
threshold
10
0
MM MS SS MZ SZ ZZ
Alpha-1 Antitrypsin Pi Type
VOLUME 5
therapy will not prevent or reverse
lung damage. It should, however,
slow the damage and functional
decline and enhance survival.
Augmentation therapy has also been
shown to decrease infection rates. It
is reserved for the most symptomatic
patients.
How Alpha-1 is Inherited
Augmentation therapy is the only
FDA-approved treatment for alpha1antitrypsin deficiency. It consists
of weekly IV infusions of alpha-1
antitrypsin derived from human
plasma. The therapy is administered IV
at 60 mg/kg of body weight, typically
over 60-80 minutes. Augmentation
therapy has an approximate 6 day
half-life, thus weekly infusions are
required to maintain serum levels
and keep the patients symptom-free.
levels of alpha-1 antitrypsin. The MM
phenotype presents with normal serum
ATT levels while at the other end of the
spectrum is ZZ which has significantly
low levels and is the most symptomatic.
In addition to assessing serum levels,
diagnosis of alpha-1 antitrypsin
deficiency is supported by several other
tests. A chest x-ray shows the typical
abnormalities at the base of the lungs.
Pulmonary function tests (PFTs), an
exercise test and arterial blood gas (ABG)
measurement all indicate the degree
of lung dysfunction. Liver function
tests (LFTs) identify the presence and
severity of liver dysfunction.
As stated above, alpha-1 antitrypsin
deficiency looks like emphysema —
but it is important to determine the
actual type of emphysema in order
to support effective treatment. With
acquired emphysema the serum
alpha-1 antitrypsin levels are normal.
It is usually associated with a smoking
history, primarily affects the upper
lobes of the lungs and is diagnosed
in an older population. Whereas with
alpha-1 emphysema, serum levels are
low, it is primarily the base of the lungs
that are affected and is early onset.
Patients may present with co-morbid
condition such as asthma or pulmonary
infection, but are also at risk for such
complications as cor pulmonale
(enlargement of the right ventricle of
the heart as a response to increased
resistance in the lungs), pulmonary
hypertension (high blood pressure that
affects only the arteries in the lungs
and the right side of the heart), and
hypoxemia.
Pharmacologic
Treatment
Pharmacologic treatment options
include bronchodilators to lessen
airway obstruction, anti-infectives
which should be administered early
and aggressively in order to minimize
the risk of damage to lung tissue, and
augmentation replacement therapy.
Augmentation is just that — it
augments low serum levels of alpha-1
antitrypsin with additional alpha-1
antitrypsin. Augmentation therapy is
indicated in patients with established
airflow obstruction as well as in lung
transplant patients during times of
rejection or dysfunction, infection or
exacerbation. Increasing the serum
levels of alpha-1 antitrypsin is not a
cure for the disease. Augmentation
While the first dose is administered
in a monitored setting, it is generally
expected that patients be able to selfinfuse in their homes. Some patients
may be best treated in an Ambulatory
Infusion Suite (AIS). As with any home
infusion therapy, patient education,
return demonstration, compliance
and response to therapy must be
monitored.
Augmentation therapy is generally
well-tolerated. Serious side effects
are rare although such side effects as
drowsiness, dizziness, headache, cold
symptoms, pain, bleeding, or a warm,
tingling feeling at the injection site,
and gastrointestinal symptoms have
been reported in a small percent of
patients.
Augmentation
Therapy Options
ƒƒ AralastNP
ƒƒ Glassia™
ƒƒ Prolastin®
ƒƒ Zemaira®
continued on back 
C O N T I N U I N G E D U C AT I O N 3
continued from page 3
Liver Transplant
Non-pharmacologic
Treatment
In addition to pharmacologic interventions,
pulmonary rehabilitation, lifestyle changes and current
immunizations are important. Smokers must stop
smoking and should avoid lung irritants. Patients should
aerobically exercise. Strategies to support nutrition
are also important. Patients are often so fatigued that
even eating is a challenge and malnutrition is a risk.
Symptomatic Alpha-1 patients should be evaluated in
terms of their oxygen levels.
Lung Transplant
Lung transplant may be an option when the patient‘s
pulmonary function has declined to a point where
therapies are no longer viable. At 84.1, 60.6, and 47.6
percent at 1, 3 and 5 years respectively, survival rates for
AAT patients are comparable to that with other disease
states for transplant.1
In general, routine post-transplant augmentations
therapy is not recommended, as insufficient supportive
data is available. However, given the detection of
significant increase in elastase activity measured in the
bronchoalveolar lavage of post-transplant patients during
symptomatic respiratory episodes, many clinicians support
the use of augmentation therapy during episodes of lung
inflammation, including chronic rejection and infection.
For patients with liver disease, liver transplant is the only option.
Augmentation therapy does not have an impact.
Screening
The option for testing patients for alpha-1 antitrypsin is a
sensitive issue. Certainly, ethical principles must be considered.
It is essential that patients make an autonomous decision based
on accurate information, including of the risks and benefits of
knowing/not knowing.
It is recommended that family members already displaying
symptoms be told that the test is available and discuss their
options with their healthcare providers or a genetic counselor.
Regardless of the ultimate decision a family member makes, it
is important that everyone understand their risks and at least
know to make lifestyle changes.
The World Health Organization (WHO), the American Thoracic
Society (ATS), and the European Respiratory Society (ERS) each
recommend alpha-1 screening for all patients with COPD,
bronchiectasis, or asthma that is not controlled with usual
medications. It should also be considered and screened for in
patients with emphysema developing before age 45, pneumonia
unresponsive to antibiotics, unexplained liver disease and signs of
panniculitis or a specific form of vasculitis. Siblings and offspring of
persons with alpha-1 or patients with a history of a family member
who dies of unknown lung or liver disease should also be screened.
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© 2014 Coram LLC | COR16019-0714
Healthline Self-Assessment Quiz
Alpha-1 Antitrypsin Deficiency
LEARNING OBJECTIVES
LEARNING GOAL
To understand the clinical disease state
of Antitrypsin Deficiency, treatment
options and screening.
At the end of this program, the reader will be able to:
1. Define Alpha-1 Antitrypsin Deficiency
2. Identify the three primary systems affected by Alpha-1 Antitrypsin Deficiency
3. Describe clinical manifestations of AAT lung disease
4. Identify augmentation therapy options
5. List non-pharmaceutical therapy interventions
SELF-ASSESSMENT QUESTIONS
In the Quiz Answers section on the next page, circle the correct answer for each question. To obtain
two (2.0) contact hours toward CE credit, the passing score is 100%. Return your Self-Assesment Quiz
to Coram via email, fax or mail. See the next page for details on how to return to your quiz. Please
allow approximately seven days to process your test and receive your certificate upon achieving a
passing score.
1. A deficiency of alpha-1 antitrypsin:
7. Augmentation therapy
a. Primarily affects primarily the lung, liver and skin
a. Will reverse lung damage
b. Allows elastase to breakdown elastin
b. Should enhance survival
c. Results in the most common genetic cause of
emphysema in adults
c. Decreases infection rates
d. A and C
e. A, B and D
e. All of the above
2. Alpha-1 antitrypsin is the most common cause of liver
disease in the pediatric population.
a. True
b. False
3. The only available treatment for liver damage is liver
transplant.
a. True
b. False
4. Symptoms of alpha-1 antitrypsin deficiency are clearly
differentiable from those of, for example as asthma,
allergies, COPD or chronic bronchitis.
d. Is applicable for use in all phenotypes
f. C and D
g. B and C
8. Augmentation therapy is typically required in the first
three months post-lung transplant.
a. True
b. False
9. AAT screening should be considered for all of the
following EXCEPT:
a. Any patient with COPD, bronchiectasis, or asthma.
b. Patients with early onset emphysema developing
(before age 45)
c. Pneumonia unresponsive to antibiotics
a. True
d. Unexplained liver disease
b. False
e. Signs of panniculitis
5. Which AAT phenotype presents with the lowest levels of
alpha-1 antitrypsin:
a. MM
b. MZ
c. Null
d. ZZ
6. Augmentation therapy provides additional alpha-1
antitrypsin to enhance low or absent levels.
a. True
b. False
f. Siblings and offspring of persons with alpha-1 or
patients with a history of a family member who dies
of unknown lung or liver disease should also be
screened
10.It is essential that patients make an autonomous
decision regarding AAT screening based on accurate
information, including of the risks and benefits of
knowing/not knowing.
a. True
b. False
VOLUME 5
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Alpha-1 Antitrypsin Deficiency
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