Alpha 1 antitrypsin deficiency or α1-antitrypsin deficiency or is an inherited disorder that may cause lung disease and liver disease.
The signs and symptoms of the condition and the age at which they appear vary among individuals. It is an autosomal-codominant condition with more than 120 alleles identified. Out of them PiZZ, is responsible for nearly all cases of Alpha 1 antitrypsin deficiency emphysema and liver disease.
It is one of the most common inherited disorders among white people. The median time between the observation of symptoms and diagnosis is approximately 8 years.
Alpha 1 antitrypsin deficiency has been identified in all populations, but it is most common in individuals of Northern Europe. About 1-5% patients diagnosed as chronic obstructive pulmonary disease are estimated to have alpha 1 antitrypsin deficiency.
Women and men are affected in equal numbers with this disease.
Alpha1-antitrypsin deficiency was first described by Laurell and Eriksson in 1963.
The condition is often underdiagnosed because of its presentation similar to other respiratory illnesses.
Pathophysiology of Alpha 1 Antitrypsin Deficiency
Alpha1-antitrypsin is the prototype member of the serine protease inhibitor superfamily of proteins. Alpha1 antitrypsin deficiency is caused by mutations in the SERPINA1 gene located in the long arm of chromosome 14.
Alpha 1 antitrypsin is produced in the liver. One of the functions of this enzyme is to protect the lungs from neutrophil elastase, an enzyme that can digest connective tissue. It also causes inhibition of several neutrophil-derived proteases like trypsin, elastase, proteinase 3, cathepsin G. [Therefore, the alpha 1-antiprotease is a better term]
The genetic defect alters the configuration of the alpha 1-antitrypsin molecule and prevents its release from hepatocytes resulting in decrease in serum levels of alpha 1-antitrypsin.
This leads to low concentration in alveoli and normal protection rendered by alpha 1 antitrypsin against proteases such as neutrophil elastase is reduced.
The lungs are continuously exposed to airborne pathogens, which results in an immune response characterized by local release of oxidants and proteases like neutrophil elastase. Alpha1-antiprotease or alpha 1 antitrypsin keeps these proteases in check and protect the lungs from unregulated protease activity that could cause alveolar wall destruction.
In individuals with the alpha 1 antitrypsin deficiency, alveoli lack antiprotease protection leading to unopposed neutrophil elastase digestion of band collagen in the alveolar walls and progressive emphysema.
There is also evidence that alpha1-antiprotease may inhibit alveolar cell apoptosis and protect against emphysema in the absence of neutrophilic inflammation.
In liver, accumulation of excess alpha1-antitrypsin in hepatocytes due to defective secretion causes destruction of these cells, and ultimately liver disease.
Serum levels of alpha 1 antitrypsin greater than 11 µmol/L appear to be protective. Emphysema develops in most individuals with serum levels less than 9 µmol/L.
SERPINA1 is the gene on the chromosome 14 that encodes the protein Alpha 1-antitrypsin..
Over 75 mutations of the SERPINA1 gene have been identified.
The most common type of allele for Alpha 1 antitrypsin deficiency is Z allele which is formed by mutation in exon 5 [single base-pair substitution] to produce allele Z which causes alpha 1-antitrypsin deficiency. If both the allele are substituted, it is denoted as PiZZ.
Other genotypes associated with severe alpha1-antitrypsin deficiency include PiSZ, PiZ/Null, and PiNull.
[Null means that copy of allele is not functional at all and would not produce the enzyme].
Most patients with clinical disease are homozygous SS or ZZ or heterozygous MS, MZ, or SZ.
The levels of alpha 1 antitrypsin in different phenotype are
- PiMM: 100% (normal)
- PiMS: 80%
- PiSS: 60%
- PiMZ: 60%
- PiSZ: 40%
- PiZZ: 10-15% (severe alpha 1 antitrypsin deficiency)
Patients with the null gene for alpha 1-antitrypsin will not produce any alpha1-antitrypsin and almost all of them develop emphysema by 30 years of age.
It is noteworthy that patients with null gene do not develop liver disease because of a lack of production, and thus accumulation, of alpha1-antitrypsin in the hepatocytes.
- Cigarette smoking
- Accelerates the onset of symptomatic disease by 10 years
- Causes increase in the number of neutrophils and neutrophil elastase in the alveolus
- Inactivating the remaining small amounts of antitrypsin enzyme.
- Exposures to dust and fumes – causes inflammation which can also cause the recruitment of neutrophils to the alveoli.
Associated conditions with Alpha 1 Antitrypsin Deficiency
Following conditions are associated with alpha 1 antitrypsin deficiency, occurring due to reduced levels in blood, lungs and accumulation of mutated molecule in the liver
- Granulomatosis with polyangiitis
- Pelvic organ prolapse
- Primary sclerosing cholangitis
- Autoimmune hepatitis
- Emphysema, predominantly involving the lower lobes and causing bullae
- Secondary Membranoproliferative Glomerulonephritis
- Hepatocellular carcinoma (liver)
- Bladder carcinoma
- Gallbladder cancer
- Lung cancer
Presentation of Alpha Antitrypsin Deficiency
The major manifestation of Alpha1-antitrypsin deficiency in the first 2 decades of life is liver disease pulmonary manifestations appear later.
The disease could present as of neonatal jaundice and hepatitis in newborns, cholestatic jaundice in infants and in children as hepatic cirrhosis or liver failure.
Alpha1-antitrypsin deficiency is a leading condition requiring liver transplantation in children.
Adults with alpha-1 antitrypsin deficiency usually develop symptoms of lung disease between ages 20 and 50. The disease peaks in fifth decade of life. Smokers with disease present a decade early. Severe forms of the disease may present as early as third decade.
Adults may develop liver disease (jaundice), cirrhosis and are also at risk of developing a type of liver cancer called hepatocellular carcinoma.
Rarely, people with alpha 1 antitrypsin deficiency may develop panniculitis, characterized by hardened skin with painful lumps or patches. This can occur at any age.
Not every individual with Alpha 1 antitrypsin deficiency develops clinically significant disease.
The common presenting symptoms are
- Shortness of breath
- Cough with sputum production
- Unintentional weight loss
- Recurring respiratory infections
Patients may have been recurrently treated for asthma or respiratory infections without being diagnosed for alpha 1 antitrypsin deficiency.
Eventually emphysema develops and dyspnea is the symptom that eventually dominates alpha 1 antitrypsin deficiency presentation.
Initially the dyspnea is evident only with strenuous exertion but over time it limits even mild activities. By the time dyspnea becomes the dominant manifestation and a diagnosis is established, usually several years pass.
Patients with Alpha 1 antitrypsin deficiency frequently develop dyspnea 20-30 years earlier (at age 30-45 y) than do smokers with emphysema and normal alpha1-antitrypsin levels.
The physical examination may reveal, depending on the severity, though these are not specific findings –
- Increased respiratory work
- Scalene and intercostal muscle retraction,
- Tripod position.
- Airflow obstruction
- Pursed-lip breathing
- Pulsus paradoxus.
- Barrel chest
- Increased percussion note
- Decreased breath sound intensity
- Distant heart sounds.
Mild-to-moderate disease may not have the findings.
Approach to Diagnosis
Alpha 1 antitrypsin deficiency remains undiagnosed in many patients. It is estimated that about 1% of all COPD patients actually have alpha 1 antitrypsin deficiency .
Thus, testing should be performed for all patients of
- Emphysema at an early age <45 years
- Emphysema in a patient with the absence of a recognized risk factor [smoking or occupational 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 cause
- Family history of emphysema, bronchiectasis, liver disease, or panniculitis.
- A sibling with the disease
The initial test performed is serum alpha 1 antitrypsin deficiency level. A low-level of alpha 1 antitrypsin deficiency confirms the diagnosis and warrants further assessment with phenotyping and genotyping.
- Autoimmune Hepatitis
- Chronic Obstructive Pulmonary Disease
- Cystic Fibrosis
- Kartagener Syndrome
- Viral Hepatitis
Serum alpha1-antitrypsin levels
Serum alpha1-antitrypsin levels are used to identify disease and determine levels. The study is most commonly performed by nephelometry.
Normal serum alpha1-antitrypsin levels are 100-300 mg/dL [20-60 µmol/L]. Levels less than 80 mg/dL [11 µmol/L] suggest a significant risk for lung disease.
Serum alpha1-antitrypsin concentration alone has a low sensitivity for detecting alpha 1 antitrypsin deficiency. Phenotyping is required to confirm alpha1-antitrypsin deficiency
Phenotyping is done in patients with serum levels of alpha 1 antitrypsin.
Isoelectric focusing is the most commonly used method to definitively detect the alpha1-antitrypsin phenotype.
A free Alpha-1 Test Kit (finger-stick test) from the Alpha-1 Research Registry is available [ associated with the Alpha-1 Association.].
Functional assay of alpha1-antiprotease
This test is rarely required. It is done in patients with clinical features that are highly suggestive of alpha 1 antitrypsin deficiency but whose serum levels are within the reference range.
It measures the ability of the patient’s serum to inhibit human leukocyte elastase, a rare defect.
It uses DNA extracted from circulating mononuclear blood cells and is done by DNA amplification techniques.
These should be done 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).
- Hyperlucency because of destruction of healthy tissue, certain areas being affected more than others.
- Loss of the normal rich pattern of branching blood vessels.
- Basilar emphysema [smoking causes apical emphysema]
High-resolution CT scanning
High-resolution CT scanning of the chest demonstrates widespread hypoattenuating areas resulting from a lack of lung tissue. Smaller and fewer pulmonary vessels are noted.
Mild forms of alpha1-antitrypsin disease can be missed on CT but in moderate disease, the panlobular nature of the process and the characteristic lower zone predominance can be noticed.
Severe forms may be indistinguishable from severe centrilobular emphysema.
Heatomegaly, cirrhotic changes or hepatocellular carcinoma may be found on CT abdomen.
Pulmonary Function Tests
- Spirometery for forced vital capacity (FVC) and forced expired volume in 1 second (FEV1)
- Determination of lung volume by plethysmography
Body mass index, airflow obstruction, dyspnea, and exercise capacity index is a 4-step evaluation of patients with chronic obstructive lung to determine severity of disease.
Treatment of Alpha 1 Antitrypsin Deficiency
Preventing or slowing the progression of lung disease is the major goal. This is achieved by
- Decreasing any proinflammatory stimuli in the alveolus – smoking, asthma, or respiratory infection
- Improve pulmonary functions
- Augmenting or replacing the deficient enzyme
To decrease the risk of liver disease, vaccination against hepatitis A and B is carried.
No treatment for emphysema has a greater effect on survival than quitting smoking.
Improvement of Lung function
- Metered-dose inhalers of short acting beta-adrenergic agents and ipratropium bromide bronchodilators
- Long-acting inhaled beta-adrenergic drugs and anticholinergics
- Inhaled corticosteroids
- Oral corticosteroids for acute exacerbation
- Theophylline – May lessen the degree of dyspnea
Preventing Respiratory Infections
Aggressive treatment of infections may help decrease the potential for additional lung injury. Periodic vaccination for Pneumonia and influenza vaccination and early antibiotic therapy for all exacerbation with purulent sputum should be done.
- Exercise conditioning
- Breathing training
- Chest physical therapy
- Respiratory muscle training with
- Psychological support.
Oxygen supplementation increases exercise capacity, improves performance, decreases dyspnea with exercise, and improves sleep quality.
Stable patients with resting hypoxia benefit most if they wear their oxygen mask continuously.
Enzyme Replacement or Augmentation Therapy
IV augmentation therapy is the only treatment specific for alpha 1 antitrypsin deficiency. Currently, three preparations – Prolastin, Aralast and Zemaira are available.
Weekly IV infusions of alpha1-antitrypsin protein concentrates restore serum and alveolar alpha1-antitrypsin concentrations to protective levels.
There are no firm guidelines for augmentation therapy yet. Most of the doctors recommend it in following conditions
- Serum level to be below the threshold protective value and
- The patient have one or more of the following
- signs of significant lung disease: chronic productive cough or unusual frequency of lower respiratory infection
- Airflow obstruction
- Accelerated decline of FEV1
- Evidence of emphysema on chest xray or CT
Use of alpha1-antitrypsin augmentation in patients after lung transplantation for alpha 1 antitrypsin deficiency is not supported by evidence yet.
Augmentation therapy is not appropriate for liver-affected patients.
Two surgical approaches may help selected patients with emphysema due alpha 1 antitrypsin deficiency.
Volume Reduction Surgery
Volume-reduction surgery in selected patients with severe emphysema and significant air trapping have leads to symptomatic improvement. The surgery reduces severely affected 20-35% of each lung. Spirometry and exercise tolerance generally improve and dyspnea generally is diminished.
However, the duration of improvement seems to be brief.
This is indicated in patients at high risk of early mortality but are not very ill.
Liver transplantation is the definitive treatment for advanced liver disease.
- Measuring pulmonary function regularly
- Repeat influenza vaccination yearly
- Pneumococcal vaccination every 5 years.
- Periodic evaluations of liver function PiZZ type
- Ultrasound monitoring every 6-12 months is to detect early fibrotic changes and hepatocellular carcinoma in cases of established liver disease.
Prognosis & Complications
Complications may include pneumothorax, pneumonia, acute exacerbation of airflow obstruction, and respiratory failure.
Patients diagnosed by screening often have a prognosis like that of healthy people. Patients diagnosed after symptoms have established have worse prognosis.
Poor prognosis is found in
- Severe airflow obstruction
- FEV1 >50%, 5 year mortality rate is 4%
- FEV1 35-49%, 5 year mortality rate is 12%
- FEV1 < 35, 5 year mortality rate is 50%
- Significant bronchodilator response (>12% and >200 mL)
- Male sex