Back to: eMedicine Specialties > Medicine, Ob/Gyn, Psychiatry, and Surgery >

Pulmonology

Alpha1-Antitrypsin Deficiency
Last Updated: February 14, 2002

Synonyms and
related keywords:
alpha-1 antiprotease
deficiency, alpha1
antiprotease
deficiency, alpha-1
antitrypsin deficiency,
AAT Rate this Article
Email to a Colleague

AUTHOR INFORMATION Section 1 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Author: Paul Fairman, MD, Medical Director of Lung Transplant Service, Professor,
Department of Internal Medicine, Divisions of Pulmonary and Critical Care Medicine,
Medical College of Virginia
Paul Fairman, MD, is a member of the following medical societies: American College
of Chest Physicians, American College of Physicians, American Physiological Society,
American Thoracic Society, International Society for Heart and Lung Transplantation,
Society of Critical Care Medicine, and Southern Medical Association
Editor(s): Ryland P Byrd, Jr, MD, Chief of Pulmonary Medicine, Medical Director of
Respiratory Therapy, Quillen VA Medical Center, Associate Professor, Department of
Internal Medicine, Division of Pulmonary Medicine, Quillen College of Medicine;
Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Om
Prakash Sharma, MD, Professor, Department of Medicine, Division of Pulmonary and
Critical Care Medicine, University of Southern California; Timothy D Rice, MD,
Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent
Medicine, St Louis University; and Zab Mohsenifar, MD, Director, Division of
Pulmonary/Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical
Center; Professor, Department of Internal Medicine, University of California at Los
Angeles School of Medicine
INTRODUCTION Section 2 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Background: Alpha1-antitrypsin (AAT) deficiency is one of the most common inherited

disorders among whites. Its primary manifestation is early-onset panacinar emphysema.
A minority of patients develops hepatic cirrhosis. Slowly progressive dyspnea is the
primary symptom, although many patients initially have symptoms of cough, sputum
production, or wheezing.

Pathophysiology: The genetic defect in AAT deficiency results in a molecule that

cannot be released from its production site in hepatocytes. Low serum levels of the
protein result in low alveolar concentrations, where the AAT molecule normally would
serve as protection against antiproteases. The resulting protease excess destroys
alveolar walls and causes emphysema.

Frequency:

 In the US: This genetic defect affects 1 per 3000-5000 individuals. AAT is 1 of the
3 most common lethal genetic diseases among whites. The other 2 common fatal
genetic defects are cystic fibrosis and Down syndrome.
  Internationally: Similar rates are found among whites worldwide.

Mortality/Morbidity: Specific morbidity and mortality rates are unknown. Not all patients
with homozygous deficiency develop symptomatic emphysema or cirrhosis; however,
among those who develop symptomatic disease, the mortality rate is very high.

Race: Racial groups other than whites are affected rarely.

Sex: Women and men are affected in equal numbers.

Age: The enzyme deficiency is present from birth and can be an unusual cause of
neonatal jaundice. Symptomatic emphysema develops in the fourth decade of life in
smokers and a decade later in nonsmokers.

CLINICAL Section 3 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

History: Symptoms of AAT deficiency emphysema are limited to the respiratory system.

 Dyspnea is the symptom that characterizes and eventually dominates AAT

deficiency.

o Similar to other forms of emphysema, the dyspnea of AAT deficiency

initially is evident only with strenuous exertion. Over several years, it
eventually limits even mild activities.

o Patients with AAT deficiency frequently develop dyspnea 20-30 years

earlier (age 30-45 y) than smokers with emphysema and without AAT
deficiency.

o Cigarette smoking accelerates the progression of emphysema in patients

with AAT deficiency; symptoms develop about 10 years earlier in AAT-
deficient individuals who smoke regularly.

 Other symptoms, including cough, sputum production, and wheezing, may

predominate in the early stages of disease.

 Symptoms initially are intermittent, and, if wheezing is the predominant symptom,

patients often are told they have asthma.

 If recurrent episodes of cough are most prominent, patients may be treated with
multiple courses of antibiotics and evaluated for sinusitis, postnasal drip, or
gastroesophageal reflux.

 By the time dyspnea becomes the dominant manifestation and a diagnosis is

established, most patients will have seen several physicians over several years.

Physical: No single physical sign confirms a diagnosis of AAT deficiency emphysema.

Signs characteristic of increased respiratory work, airflow obstruction, and hyperinflation
eventually develop but are dependent on the severity of emphysema at the time of
diagnosis.

 Increased respiratory work is evident as tachypnea, scalene and intercostal

muscle retraction, and tripod position.

 Airflow obstruction manifests as pursed-lip breathing, wheezing, and pulsus

paradox.

 Hyperinflation results in barrel chest, increased percussion note, decreased

 breath sound intensity, and distant heart sounds.

 Patients with mild emphysema generally have no abnormal findings on physical

examination. Even moderate disease may be evident only when a complicating
acute intercurrent infection occurs. Most of the signs generally considered a part
of emphysema (from any cause) are signs of moderate-to-severe disease; mild-
to-moderate disease is missed easily if the physician relies solely on the physical
examination findings.

Causes: The name of this disease originated from a deficiency of the serum
antiprotease, originally called AAT. The responsible genetic defect affects 1 in 3000-
5000 individuals, making it 1 of the 3 most common lethal genetic diseases among
whites. The other 2 common fatal genetic defects are cystic fibrosis and Down
syndrome. Fortunately, not every individual with AAT deficiency develops clinically
significant disease.

 The major biochemical activity of the AAT molecule is inhibition of several

neutrophil-derived proteases (eg, trypsin, elastase, proteinase 3, cathepsin G),
and, therefore, the protein is more accurately termed alpha1 antiprotease.
However, most physicians, and virtually all patients, refer to the disease as AAT
deficiency.

 The protein is synthesized predominantly by hepatocytes. After its release from

the liver, it circulates unbound and diffuses into interstitial and alveolar lining
fluids. Its principle function in the lung is to inactivate neutrophil elastase, an
enzyme that is released during normal phagocytosis of organisms or particulates
in the alveolus. Alpha1 antiprotease constitutes about 95% of all the antiprotease
activity in human alveoli, and neutrophil elastase is considered the protease
largely responsible for alveolar destruction.

 In healthy persons, alpha1 antiprotease serves as a protective screen that

prevents alveolar wall destruction. Individuals with the AAT genetic defect do not
release alpha1 antiprotease from the liver, and the alveoli lack protection. The
imbalance of proteases-antiproteases in the alveolus leads to unimpeded
neutrophil elastase digestion of elastin and collagen in the alveolar walls and
progressive emphysema.

 Cigarette smoking accelerates the onset of symptomatic disease by

approximately 10 years by increasing the number of neutrophils in the alveolus
and inactivating the remaining small amounts of antiprotease.

 The production of alpha1 antiprotease is controlled by a pair of genes at the

protease inhibitor (Pi) locus. Nearly 24 variants of the alpha1 antiprotease
molecule have been identified, and all are inherited as codominant alleles. The
most common (90%) allele is M (PiM), and homozygous individuals (MM)
produce normal amounts of alpha1 antiprotease (serum levels of 20-53 mol/L).
Deficient levels of alpha1 antiprotease are associated with allele Z (homozygous
PiZ, serum level 3.4-7 mol/L). Serum levels greater than 11 mol/L appear to be
protective. Emphysema develops in most (but not all) individuals with serum
levels less than 9 mol/L.

DIFFERENTIALS Section 4 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Bronchiectasis
Bronchitis
Chronic Bronchitis
Chronic Obstructive Pulmonary Disease
Emphysema
Kartagener Syndrome
Other Problems to be Considered:

Immotile cilia syndrome

Cystic fibrosis

WORKUP Section 5 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Lab Studies:

 Serum AAT levels

o To identify disease, determine serum AAT levels.

o Testing is readily available in most clinical laboratories and is underutilized.

o Clinical features that suggest the possibility of AAT deficiency and the need
for serum testing include emphysema at an early age, emphysema in a
nonsmoker (or light smoker), a family history of emphysema, emphysema of
the lower lungs (as determined by chest radiograph), adult-onset asthma,
and recurrent bronchitis.

o Serum testing is a screening procedure. Test most patients with chronic or

recurrent respiratory symptoms (dyspnea, cough, wheezing) at least once.

o Most hospital laboratories report serum AAT levels in mg/mL, with a

reference range of approximately 100-300 mg/mL. Levels less than 80
mg/mL suggest a significant risk for lung disease.

o Reference laboratories usually report the serum levels in micromolar

concentration, with a reference range of 20-60 mol/L and a threshold level
for emphysema at 11 mol/L.

 Phenotyping

o Test patients with low or borderline serum levels with phenotyping. Use an
experienced reference laboratory for this test. Free genetic screening kits
are available through Bayer Laboratories at 800-288-8371, and samples can
be processed for free at the AAT Deficiency Detection Center, University of
Utah, 801-328-4662.

o Phenotyping is required to confirm the presence of AAT deficiency. Do not

initiate AAT replacement therapy without testing.

o More than 100 different phenotypic variants of AAT deficiency have been
identified, but 1 phenotype, PiZZ, is responsible for nearly all cases of AAT
emphysema and liver disease. PiZZ phenotype serum levels range from 3.4-
7 mol/L, about 10-20% of the reference range levels.

 Functional assay of alpha1 antiprotease

o In rare circumstances, a third test is utilized to evaluate a patient with clinical

features that are highly suggestive of AAT deficiency but whose serum levels
are within the reference range.

o Specialized laboratories can perform a functional assay of alpha1

antiprotease, which measures the ability of the patient's serum to inhibit
 human leukocyte elastase. Such a defect is rare.

 Evaluate hepatic function in patients with low or borderline levels of AAT. Measure
serum transaminases, bilirubin, albumin, and routine clotting function (activated
partial thromboplastin time and international normalized ratio).

Imaging Studies:

 Chest radiograph

o AAT deficiency emphysema produces a hyperlucent appearance because

healthy tissue has been destroyed.

o The process is not uniform; certain areas are affected more than others.

o Affected regions also are described as oligemic because they lack the
normal rich pattern of branching blood vessels.

o An unusual characteristic in AAT emphysema is the basilar distribution of

abnormalities found in approximately 75% of PiZZ patients; however,
cigarette smoking is associated with more severe apical disease.

 High-resolution CT scan

o High-resolution CT (HRCT) scan of the chest demonstrates widespread

abnormally low attenuation areas resulting from a lack of lung tissue. As in
smoking-related emphysema, the appearance has been described as a
simplification of lung architecture. As tissue is lost, pulmonary vessels
appear smaller, fewer in number, and farther spread apart.

o Mild forms of AAT disease can be missed by HRCT scan, but, when the
disease is moderate, discerning the panlobular nature of the process and the
characteristic lower zone predominance is possible.

o Very severe forms may be indistinguishable from severe centrilobular

emphysema.

Other Tests:

 The severity of emphysema is best documented with standard pulmonary function

tests. Spirometric determination of forced vital capacity (FVC) and forced expired
volume in 1 second (FEV1) are essential. Determining lung volume (preferably by
plethysmography) and measuring diffusing capacity provide additional valuable
information.

 Patients who are symptomatic at the time of diagnosis usually demonstrate

moderate-to-severe airflow obstruction with an FEV 1 in the range of 30-40% of the
predicted value. Also, reduced vital capacity and increased lung volumes
secondary to air trapping (residual volume >120% of predicted value) usually are
present. Diffusing capacity values are reduced substantially (<50% of predicted
value) in most symptomatic patients. AAT-deficient individuals who are identified by
screening programs or because a relative has been diagnosed with the disease
may have few or no abnormalities.

Histologic Findings: All forms of emphysema destroy alveolar walls and leave
permanent abnormal enlargement of the airspace distal to the terminal bronchiole. In AAT
deficiency, the emphysematous areas are distributed uniformly throughout the acinus
(lobule) and, for reasons that are not known, primarily in the basilar portions of the lung.
This contrasts with centrilobular emphysema characteristic of cigarette smoking, which
predominantly affects the respiratory bronchioles in the central portion of the lobule,
usually initially at the apex of the lung.
 TREATMENT Section 6 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Medical Care: Preventing or slowing the progression of lung disease is the major goal of
AAT deficiency management. Facilitate this goal by decreasing any proinflammatory
stimuli in the alveolus, including smoking, asthma, or respiratory infection. Alternatively,
augmenting or replacing the deficient enzyme, and thereby moderating inflammatory
stimuli, is possible. Most patients are identified only after they develop lung disease, and
the goals of treating AAT deficiency emphysema are similar to those for treating all forms
of emphysema.

 Quitting smoking
o No treatment for emphysema has a greater effect on survival than quitting
smoking.
o Make a concerted effort to inform patients about the serious consequences
of smoking on AAT deficiency and provide them with one of the many aids to
help them quit.
o Remember the 4 stages in the process of helping patients become
nonsmokers—(1) ask about smoking habits; (2) advise about health effects;
(3) assist the patient with encouragement, education, and nicotine
replacement; and (4) arrange follow-up.
o Most patients with AAT deficiency quit successfully.

 Improving lung function

o Provide similar efforts to improve lung function in patients with AAT
deficiency emphysema as those provided to patients with emphysema from
the usual causes.
o Administer beta-adrenergic agents and ipratropium bromide bronchodilators
to maximize lung function. Metered-dose inhalers are the preferred method
of administration because they have a lower incidence of adverse effects
than other routes. No matter how they are administered, no evidence
indicates that these drugs have any long-term effect on disease progression.
o Theophylline may lessen the degree of dyspnea in some individuals, and a
therapeutic trial may be indicated for selected patients. The therapeutic
range of theophylline is relatively small, and its metabolism frequently is
altered by other drugs or illness, which can lead to frequent episodes of drug
toxicity or the need for frequent monitoring of serum levels.
o Inhaled corticosteroids have not been studied in patients with AAT deficiency
emphysema, but many patients have significant broncho-reactivity and, in
this group, inhaled steroids probably help control symptoms.
o Reserve oral corticosteroids for acute exacerbations with increased cough
and sputum. Long-term administration of corticosteroids does not protect the
lung from progressive emphysema, but it is associated with a long list of
detrimental adverse effects. Limit their use to brief courses lasting 1-2
weeks. Institute therapy to prevent osteoporosis when administering longer
courses.

 Preventing respiratory infections

o Pneumonia and annual influenza vaccines will help prevent respiratory
infections.
o Aggressively treating infections that occur despite prophylaxis may help
decrease the potential for additional lung injury from an influx of neutrophils
into the alveolus.

 Pulmonary rehabilitation
o According to a National Institutes of Health (NIH) workshop, pulmonary
rehabilitation is defined as "a multi-disciplinary continuum of services
directed to persons with pulmonary disease and their families, usually by an
interdisciplinary team of specialists, with the goal of achieving and
maintaining the individual's maximum level of independence and function in
 the community."
o Most programs combine education, exercise conditioning, breathing training,
chest physical therapy, and respiratory muscle training with nutritional
counseling and psychological support.
o Therapy does not improve pulmonary function test results, but well-
controlled studies documented significant improvement in exercise
endurance, exercise work capacity, level of dyspnea, quality of life, and
reducing health-related expenses.

 Reducing hypoxemia
o Hypoxemia accelerates mortality in patients with severe airflow obstruction,
and oxygen supplementation prolongs survival for this group.
o Oxygen also increases exercise capacity, improves mental performance,
decreases dyspnea with exercise, and improves sleep quality.
o Stable patients with resting hypoxia benefit most if they wear their oxygen
mask continuously. The benefits for patients with hypoxemia only during
exercise or sleep are not as clear, and oxygen may be prescribed for those
intervals when the oxygen saturation is likely to be low.

 Replacing enzymes
o AAT-deficient individuals who have or show signs of developing significant
emphysema can be treated with Prolastin, a pooled, purified, human plasma
protein concentrate replacement for the missing enzyme that has been
screened for HIV and hepatitis viruses. It also is heat-treated as an
additional precaution against transmission of infection. Immunize patients
against hepatitis regardless.
o Weekly intravenous infusions of Prolastin restore serum and alveolar AAT
concentrations to protective levels. Although other regimens for
administration have proven to provide similar serum levels, only the weekly
infusion schedule has US Food and Drug Administration approval.
o No controlled studies have proven that intravenous augmentation therapy
improves survival or slows the rate of emphysema progression. Results from
the NIH patient registry and a comparison of Danish and German registries
have been published, and both suggest that augmentation therapy has
beneficial effects. Although they were not controlled treatment trials, the
similarity of the results suggests that the findings are significant.
o The NIH report described an overall death rate 1.5 times higher for those
who did not receive augmentation therapy and a rate of FEV 1 decline (54
mL/y) in AAT-deficient individuals approximately twice that of healthy
nonsmokers but approximately 50% that of smokers (108 mL/y). Prolastin
treatment did not improve the average FEV1 decline (54 mL/y); however,
participants with moderate airflow obstruction (FEV 1 35-49% of predicted
value) experienced a slower rate of decline (mean difference 27 mL/y).
These findings bolster the long-held belief that augmentation therapy
provides clinical benefit. No firm guidelines have been developed for
initiating or continuing augmentation therapy.
o Most pulmonary physicians require the serum level to be below the threshold
protective value and that the patient have 1 or more of the following: signs of
significant lung disease such as chronic productive cough or unusual
frequency of lower respiratory infection, airflow obstruction, accelerated
decline of FEV1, or chest radiograph or CT scan evidence of emphysema.
o The American Thoracic Society recommends starting treatment when the
FEV1 is less than 80% of the patient's predicted value.

Surgical Care: Two surgical approaches may help selected patients with AAT deficiency.

 Volume reduction surgery

o This procedure has generated nationwide interest and hope for patients with
all types of emphysema.

o Selected patients with severe emphysema and significant air trapping have
 experienced symptomatic improvement by removing the most severely
affected 20-35% of each lung. Spirometry and exercise tolerance generally
improve following postoperative recovery. Dyspnea generally is diminished.
The effects on blood gas values are variable.

o Some of the enthusiasm for the procedure has waned, even as surgical
mortality rates have diminished, because the duration of improvement
seems to be brief; an accelerated rate of FEV1 decline appears to occur after
the surgery.

o A randomized controlled trial (National Emphysema Treatment Trial)

currently is recruiting patients at 17 medical centers around the country to
clarify the benefits and risks associated with the surgery.

o Because experience is limited, whether AAT deficiency emphysema patients

fare better or worse with this surgery is unknown.

 Lung transplantation

o Transplantation is the second surgical option for patients with severe AAT
emphysema.

o If patients are at substantial risk of early mortality and are otherwise healthy,
they may be candidates for lung transplantation.

o Contact a local transplant center before patients become too ill (cachexia,
inactivity, frequent infections). Unfortunately, the average waiting time for a
transplant in the United States is 18-24 months, and the uncertainties of
emphysema exacerbations and complications that might prevent
transplantation make it imperative that patients be referred well in advance
of need.
o Offer patients with an FEV1 less than 35% of predicted value (5-y mortality
rate of 50%), especially men or individuals with substantial broncho-
reactivity, the opportunity to discuss the option with a transplant physician.

Consultations: The diagnosis of AAT deficiency emphysema is not difficult, but most
physicians will have no experience treating a patient, providing counseling, or answering
the questions that an uncommon hereditary disorder generates. Several visits with a
specialist in the first year usually are enough to meet a patient's needs. The Alpha-1
National Association, 1-800-4ALPHA-1, http://www.alpha1.org/ can facilitate locating
physicians with interest and experience in caring for these patients.

Diet: Patients with advanced chronic obstructive lung disease are characterized by a
significant reduction in fat-free muscle mass. This pulmonary cachexia is common in
patients with AAT deficiency and is associated with a decline in clinical status. The
syndrome is a result of multiple factors, including hypermetabolism, drug therapy,
inactivity, and aging. Prolonged glucocorticoid administration accelerates the process.
Protein-calorie supplementation as one component of a comprehensive treatment
program may reverse the loss of muscle mass, and dietary counseling may aid patients at
high nutritional risk. Providing more fat-based nonprotein calories may benefit patients
with respiratory failure who are on mechanical ventilation, but, other than this special
circumstance, little evidence exists to suggest that this dietary manipulation aids
ambulatory patients.

Activity: Dyspnea limits activity, which results in deconditioning and further reductions in
activity levels. Encourage all patients with lung disease to maintain activity levels.
Pulmonary rehabilitation programs and patient support groups are particularly helpful.

MEDICATION Section 7 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography
Treat airflow obstruction and symptoms resulting from AAT deficiency in a manner similar
to emphysema. Bronchodilators may provide relief of some symptoms. Use antibiotics to
treat bacterial complications, including pneumonia or purulent bronchitis. Neither
bronchodilators nor antibiotics demonstrate any effect on disease progression. Similarly,
corticosteroids may provide some short-term relief but have no proven long-term benefit in
inhaled or oral preparations. Because of their long-term adverse effects, avoid oral
steroids. Prescribe oxygen if patients are hypoxemic. Consider replacement (or
augmentation) therapy to slow the progression of emphysema.

Drug Category: Respiratory enzymes -- For chronic replacement in individuals with

clinically demonstrable panacinar emphysema.

Alpha1 protease inhibitor (Prolastin) --

Sterile, stable, lyophilized preparation of
purified human alpha1 antiprotease inhibitor
prepared from pooled human plasma.
Indicated as replacement (or augmentation)
for normal serum alpha1 antiprotease to
Drug Name prevent progression of emphysema. Each
unit of plasma is tested for HIV, hepatitis B,
and hepatitis C before inclusion in the
product. Product is heat-treated to reduce
potential risk of infectious agent transmission.
To date, no cases of viral infections have
been attributed to the product.
Adult Dose 60 mg/kg IV qwk
Pediatric Dose Not recommended
Documented hypersensitivity; selective IgA
Contraindications
deficiency; known anti-IgA antibody
Interactions None reported
C - Safety for use during pregnancy has not
Pregnancy
been established.
Administer within 3h of reconstitution; do not
mix with other drugs; caution in patients at
Precautions risk for circulatory overload; recipients should
be immunized against hepatitis B using a
licensed hepatitis B vaccine
FOLLOW-UP Section 8 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Further Outpatient Care:

 Measuring pulmonary function yearly permits better counseling and planning for
interventions such as initiating replacement therapy (if not already started) or
transplantation preparation.

 Repeat influenza vaccination yearly.

Transfer:

 AAT deficiency is a rare problem, yet it demands substantial expertise for

appropriate management and counseling. Physicians without specific training in the
management of this disease or without the time to obtain the necessary expertise
should not hesitate to transfer the care of patients to a physician or center with the
necessary experience. The Alpha-1 National Association, 1-800-4-ALPHA-1 or
http://www.alpha1.org/ can help to identify physicians with experience in the
management of this disorder.
Deterrence/Prevention:

 Instruct patients with homozygous deficiency to avoid exposure to cigarette smoke.

Chemical exposures also might have detrimental effects on pulmonary function, but
no studies have been conducted to show a relationship between employment and
progression of airflow obstruction.

Complications:

 AAT-deficient patients are subject to all the complications characteristic of patients

with chronic obstructive pulmonary disease from cigarette smoking. Complications
may include pneumothorax, pneumonia, acute exacerbation of airflow obstruction,
and respiratory failure.

Prognosis:

 The major manifestation of AAT deficiency in the first 2 decades of life is liver
disease; pulmonary manifestations appear later. Lung function appears to be
normal among PiZZ adolescents when compared to a similar matched group with
alpha1 antiprotease levels within the reference range. FVC, FEV 1, residual volume,
and total lung capacity measurements were not different between the 2 groups.
Lung function begins to decline at some later point. FEV 1 decreases in adult PiZZ
patients at 51-317 mL per year (estimated decline in healthy patients is 30 mL/y).

o In the NIH registry, PiZZ individuals had a 16% chance of surviving to age 60
years in contrast to an 85% chance for the general US population.
Emphysema was the most common cause of death (72%), and chronic liver
disease was second (10%).

o In the Danish registry, the outlook was better, especially for nonindex cases
involving nonsmokers. In this group, survival closely approximated that of
the healthy Danish population. The Danish registry confirmed the poor
outlook for index cases and the additional mortality risk among smoking
patients.

 Prognosis is dependent on how patients are identified. Patients found as a result of

screening often have a prognosis near that of healthy people. Those identified
because of their symptoms face a more limited future. Specific features that
portend a poorer prognosis include the following:

o More severe degree of airflow obstruction (FEV 1 >50%, 5-y mortality rate is
4%; FEV1 35-49%, 5-y mortality rate is 12%; FEV1 <35, 5-y mortality rate is
50%)

o Significant bronchodilator response (>12% and >200 mL)

o Smoking

o Male sex

Patient Education:

 Excellent educational resources are available through the Alpha-1 National

Association. This patient advocacy group offers a telephone hotline (1-800-
4ALPHA-1), a national newsletter (Alpha-1 News), an internet site
(http://www.alpha1.org/), and local support groups that provide information and
support for patients, their families, and care givers.

MISCELLANEOUS Section 9 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Medical/Legal Pitfalls:

 Most patients with symptomatic AAT deficiency have seen several physicians over
several years before their underlying problem is recognized and diagnosed. A
patient could claim that (1) the physician failed to establish a diagnosis even though
diagnostic testing was readily available and inexpensive, (2) that appropriate
treatment was delayed, (3) that specific educational and counseling opportunities
were missed, and (4) that all of these harmed the patient.

Special Concerns:

 Direct population screening studies in Sweden and the United States identified 1 in
3000-5000 whites with the PiZZ phenotype. These studies suggest that about
70,000-100,000 individuals in the United States may have severe AAT deficiency,
but fewer than 10,000 have been recognized, and fewer than 50% of these are
receiving replacement therapy. Most of the 10,000 patients (approximately 80%)
were identified because they were symptomatic; the remaining 20% are relatives of
index cases. If estimates are correct, an additional 60,000-90,000 AAT-deficient
individuals remain unidentified in the country. This suggests that physicians may be
missing cases and that some affected individuals may have not yet developed
significant disease. Evidence for both of these possibilities exists.

 Genetic screening of population groups poses several risks, including potential

adverse psychological consequences and insurance or employment discrimination.
However, it also offers the option of earlier care for patients with mild forms of
disease, the opportunity for family and individual counseling about the risks of
cigarette smoking, and encouragement to not start the habit. Assist those patients
who smoke with efforts to stop. Genetic counseling may be particularly helpful, but
families and affected individuals derive substantial support through the Alpha-1
National Association (http://www.alpha1.org/).

PICTURES
Section 10 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Caption: Picture 1. Close-up chest radiographic view of right lower zone of a 39-
year-old woman with alpha1-antitrypsin (AAT) deficiency. Normal lung markings are
absent in the costophrenic angle. Some lung markings are present in the pericardiac
region, but even these are diminished.

View Full Size Image

eMedicine Zoom View

(Interactive!)

Picture Type: X-RAY Picture Type: X-RAY

Caption: Picture 2. CT scan of the right middle and right lower lobes in a 38-year-
old patient with alpha1-antitrypsin (AAT) deficiency. The entire middle lobe and
much of the lower lobe are emphysematous; normal lung structures have been
replaced by abnormal airspaces. Only the posterior portions of the right lower lobe
maintain a normal architecture.

View Full Size Image

 eMedicine Zoom View
(Interactive!)
Picture Type: CT
Caption: Picture 3. This graph outlines alpha1-antitrypsin (AAT) levels and risk of
lung disease for the 5 most common phenotypes of AAT deficiency. The dashed line
at 11 mol/L (80 mg/mL) represents the threshold level below which emphysema is
common.

View Full Size Image

eMedicine Zoom View

(Interactive!)
Picture Type: Graph
BIBLIOGRAPHY Section 11 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

 Alpha-1-Antitrypsin Deficiency Registry Study Group: Survival and FEV1 decline in

individuals with severe deficiency of alpha1-antitrypsin. The Alpha-1-Antitrypsin
Deficiency Registry Study Group. Am J Respir Crit Care Med 1998 Jul; 158(1): 49-
59[Medline].
 American Thoracic Society: Guidelines for the approach to the patient with severe
hereditary alpha- 1-antitrypsin deficiency. American Thoracic Society. Am Rev
Respir Dis 1989 Nov; 140(5): 1494-7[Medline].
 Brantly ML, Paul LD, Miller BH: Clinical features and history of the destructive lung
disease associated with alpha-1-antitrypsin deficiency of adults with pulmonary
symptoms. Am Rev Respir Dis 1988 Aug; 138(2): 327-36[Medline].
 Celli BR: Pulmonary rehabilitation for patients with advanced lung disease. Clin
Chest Med 1997 Sep; 18(3): 521-34[Medline].
 Fishman AP: Pulmonary rehabilitation research. Am J Respir Crit Care Med 1994
Mar; 149(3 Pt 1): 825-33[Medline].
 Seersholm N, Wencker M, Banik N: Does alpha1-antitrypsin augmentation therapy
slow the annual decline in FEV1 in patients with severe hereditary alpha1-
antitrypsin deficiency? Wissenschaftliche Arbeitsgemeinschaft zur Therapie von
Lungenerkrankungen (WATL) alpha1-AT study group. Eur Respir J 1997 Oct;
10(10): 2260-3[Medline].
 Seersholm N, Kok-Jensen A, Dirksen A: Survival of patients with severe alpha 1-
antitrypsin deficiency with special reference to non-index cases [published errata
appear in Thorax 1994 Nov;49(11):1184 and 1998 Jan;53(1):78]. Thorax 1994 Jul;
49(7): 695-8[Medline].
 Stoller JK, Smith P, Yang P: Physical and social impact of alpha 1-antitrypsin
deficiency: results of a survey. Cleve Clin J Med 1994 Nov-Dec; 61(6): 461-
7[Medline].
 Sveger T, Piitulainen E, Arborelius M Jr: Lung function in adolescents with alpha 1-
antitrypsin deficiency. Acta Paediatr 1994 Nov; 83(11): 1170-3[Medline].
 Thelin T, Sveger T, McNeil TF: Primary prevention in a high-risk group: smoking
habits in adolescents with homozygous alpha-1-antitrypsin deficiency (ATD). Acta
Paediatr 1996 Oct; 85(10): 1207-12[Medline].

Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies
daily. The authors, editors, and publisher of this journal have used their best efforts to provide information that is up-to-date and accurate
and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and
human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this article do not
warrant the information in this article is accurate or complete, nor are they responsible for omissions or errors in the article or for the results
of using this information. The reader should confirm the information in this article from other sources prior to use. In particular, all drug
doses, indications, and contraindications should be confirmed in the package insert. FULL DISCLAIMER

Alpha1-Antitrypsin Deficiency excerpt

© Copyright 2002, eMedicine.com, Inc.