eMedicine Specialties > Pulmonology > Obstructive Airways Diseases
Alpha1-Antitrypsin Deficiency: Differential Diagnoses & Workup
Updated: Apr 16, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Differential Diagnoses
Bronchiectasis
Bronchitis
Chronic Bronchitis
Chronic Obstructive Pulmonary Disease
Emphysema
Kartagener Syndrome
Other Problems to Be Considered
Immotile cilia syndrome
Cystic fibrosis
Workup
Laboratory Studies
- Serum alpha1-antitrypsin levels
- Used to identify disease and determine serum alpha1-antitrypsin (AAT) levels.
- Testing is readily available in most clinical laboratories and is inexpensive and underutilized. The AAT Deficiency Task Force of the American Thoracic Society (ATS) and European Respiratory Society (ERS) has published standards aimed at improving clinical recognition of alpha1-antitrypsin deficiency and avoiding underrecognition or misdiagnosis.
- Clinical features that suggest the possibility of alpha1-antitrypsin deficiency and the need for serum testing include emphysema at an early age (age of 45 y or less), emphysema in a patient with the absence of a recognized risk factor like smoking or occupational dust exposure, emphysema of the lower lungs, asthma with persistent airflow obstruction after treatment, unexplained liver disease, necrotizing panniculitis, antiproteinase 3-positive vasculitis (antineutrophil cytoplasmic antibody [C-ANCA]–positive vasculitis), bronchiectasis without a clear etiology and a family history of emphysema, bronchiectasis, liver disease, or panniculitis.4
- Serum testing is used for diagnostic testing and predispositional testing as in those patients with family histories compatible with alpha1-antitrypsin deficiency or with siblings with known alpha1-antitrypsin deficiency. However, guidelines from the ATS/ERS AAT Deficiency Task Force do not recommend predispositional fetal testing or population screening unless the prevalence of alpha1-antitrypsin deficiency is high (>1 case per 1500 population), smoking is prevalent, and adequate counseling services are available.
- Most hospital laboratories report serum alpha1-antitrypsin levels in milligrams per decimeter, with a reference range of approximately 100-300 mg/dL. Levels less than 80 mg/dL suggest a significant risk for lung disease.
- Reference laboratories usually report the serum levels in micromolar concentration, with a reference range of 20-60 µmol/L and a threshold level for emphysema at 11 µmol/L.
Graph outlines alpha1-antitrypsin (AAT) levels and risk of lung disease for the 5 most common phenotypes of AAT deficiency. Dashed line at 11 mmol/L (80 mg/mL) represents the threshold level below which emphysema is common.
- Phenotyping
- Test patients with low or borderline serum levels with phenotyping (serum levels <100 mg/dL). Use an experienced reference laboratory for this test. Phenotyping with dried blood-spot samples, by using a blood drop absorbed on special paper, permits easier transport of samples and is suitable for screening purposes, but the identification of a deficient variant should be confirmed with serum or plasma samples.
- Patients and healthcare providers can obtain a free Alpha-1 Test Kit (finger-stick test) from the Alpha-1 Research Registry at (877) 886-2383, which is associated with the Alpha-1 Association. The test sample can be submitted directly to the Registry at the Medical University of South Carolina. The test screens for the most common Z and S genotypes. If more extensive testing is needed to determine an alpha1-antitrypsin level, both patient and physician are notified. There is no charge for the Alpha-1 Screening Program.
- Phenotyping is required to confirm alpha1-antitrypsin deficiency. Do not initiate alpha1-antitrypsin replacement therapy without testing.
- More than 100 phenotypic variants of alpha1-antitrypsin deficiency have been identified, but 1 phenotype, PiZZ, is responsible for nearly all cases of AAT deficiency emphysema and liver disease. PiZZ phenotype serum levels range from 3.4-7 µmol/L, about 10-20% of the reference range levels. Other phenotypes associated with alpha1-antitrypsin emphysema and liver disease include PiSZ and PiZ/Null. PiNull/Null is not associated with liver disease but is associated with alpha1-antitrypsin deficiency emphysema.
- Functional assay of alpha1-antiprotease
- In rare circumstances, a third test is used to evaluate a patient with clinical features that are highly suggestive of alpha1-antitrypsin deficiency but whose serum levels are within the reference range.
- 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 extremely rare.
- Diagnosis at a molecular level (ie, genotyping) uses DNA extracted from circulating mononuclear blood cells. Test kits capable of detecting S and Z alleles on samples from mouth swabs have made genetic testing easier. These tests will, however, miss the rare null alleles.
- Evaluate hepatic function in patients with low or borderline levels of alpha1-antitrypsin. Measure serum transaminases, bilirubin, albumin, and routine clotting function (activated partial thromboplastin time and international normalized ratio).
Imaging Studies
- Chest radiography
- Alpha1-antitrypsin deficiency emphysema produces a hyperlucent appearance because healthy tissue has been destroyed.
- The process is not uniform; certain areas are affected more than others.
- Affected regions also are described as oligemic because they lack the normal rich pattern of branching blood vessels.
- An unusual characteristic in alpha1-antitrypsin deficiency is found in about two thirds of PiZZ patients; the emphysema has a striking basilar distribution. In contrast, cigarette smoking is associated with more severe apical disease.
Close-up chest radiograph of the 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.
- High-resolution CT scanning
- High-resolution CT (HRCT) scanning of the chest demonstrates widespread abnormally hypoattenuating 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 spread farther apart.
- Mild forms of alpha1-antitrypsin disease can be missed on HRCT scanning. However, when the disease is moderate, discerning the panlobular nature of the process and the characteristic lower zone predominance is possible.
- Severe forms may be indistinguishable from severe centrilobular emphysema.
CT scan of the right middle and right lower lobes in a 38-year-old patient with alpha1-antitrypsin (AAT) deficiency. 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.
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 have moderate-to-severe airflow obstruction with an FEV1 in the range of 30-40% of the predicted value.
- Reduced vital capacity and increased lung volumes secondary to air trapping (residual volume >120% of predicted value) are usually present.
- Diffusing capacity values are reduced substantially (<50% of predicted value) in most symptomatic patients.
- Alpha1-antitrypsin – 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 alpha1-antitrypsin deficiency, the emphysematous areas are distributed uniformly throughout the acinus (lobule) and, for reasons that are not known, more commonly 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, initially at the apex of the lung.
Staging
No specific grading system exists for AAT deficiency, but the severity of the emphysema that it creates can be staged using the body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index.5 This 4-step evaluation of patients with chronic obstructive lung disease appears to identify a population with limited survival who might benefit from intensified therapy. The index has not been evaluated in a population of individuals with AAT deficiency.
More on Alpha1-Antitrypsin Deficiency |
| Overview: Alpha1-Antitrypsin Deficiency |
 Differential Diagnoses & Workup: Alpha1-Antitrypsin Deficiency |
| Treatment & Medication: Alpha1-Antitrypsin Deficiency |
| Follow-up: Alpha1-Antitrypsin Deficiency |
| Multimedia: Alpha1-Antitrypsin Deficiency |
| References |
| Further Reading |
| « Previous Page | Next Page » |
References
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Further Reading
The following clinical trials are currently recruiting:
Keywords
alpha1-antitrypsin deficiency, alpha-1-antitrypsin, alpha-1 antiprotease deficiency, alpha1 antiprotease, AAT, early-onset panacinar emphysema, hepatic cirrhosis
