Alpha1 Antitrypsin Deficiency

8 Interesting Facts of Alpha1 Antitrypsin Deficiency

  1. Alpha₁-antitrypsin deficiency is an autosomal codominant genetic disorder most common in White people with Northern European ancestry 
  2. Inheritance of 2 deficiency alleles (most commonly, PI*ZZ phenotype) or a null phenotype results in deficiency of protease inhibitor in the lungs, with proteolytic destruction of alveoli and early onset of emphysematous chronic obstructive pulmonary disease, typically before age 45 years; the carrier state (one normal and one Z allele) usually does not result in disease
  3. Some patients with PI*ZZ or other mutant phenotypes develop liver disease in childhood or adulthood, which may progress ultimately to cirrhosis
  4. In all patients with a risk factor for alpha₁-antitrypsin deficiency or with fixed obstructive pulmonary disease, test for deficiency with serum quantitative alpha₁-antitrypsin level; if it is low, follow up with phenotyping (by electrophoresis) or genotyping
  5. Chronic obstructive pulmonary disease may be minimal in nonsmoking people with alpha₁-antitrypsin deficiency, but it is more rapidly progressive and severe in those who smoke and those exposed to occupational or environmental respiratory toxins or irritants; smoking cessation and protection from respiratory irritants is crucial
  6. Chronic obstructive pulmonary disease due to alpha₁-antitrypsin deficiency is managed in the same way as “usual” disease (ie, disease not related to deficiency), although it may be more difficult to treat
  7. Only specific therapy for chronic obstructive pulmonary disease related to alpha₁-antitrypsin deficiency is weekly IV augmentation with purified human alpha₁-antitrypsin (ie, alpha₁–proteinase inhibitor [human]); this decreases the rate of worsening of emphysema but may not decrease exacerbations
  8. There is no specific treatment for liver disease related to alpha₁-antitrypsin deficiency. Liver transplant improves survival for end-stage liver disease 
  • Disease frequently goes unrecognized in symptomatic patients, with diagnostic delays averaging 5 to 7 years. Consider the possibility in all patients with early-onset chronic obstructive pulmonary disease or unexplained liver disease 
  • Alpha₁-antitrypsin deficiency is an autosomal codominant genetic disorder most common in White people with Northern European ancestry 
  • Inheritance of 2 deficiency alleles (most commonly, PI*ZZ phenotype) results in deficiency of protease inhibitor in the lungs, with proteolytic destruction of alveoli and early onset of emphysema; disease is more severe in people who smoke
  • Less commonly, presents as liver disease (including asymptomatic elevation of liver enzyme levels), as early as the neonatal period or in adulthood
  • Rarely, the clinical presentation is as vasculitis or panniculitis

Clinical Presentation


  • Presentation of pulmonary disease
    • Usually asymptomatic in childhood
      • Exceptions
        • Asthma risk is increased; if asthma is present, there may be chronic or recurrent episodes of wheezing, dyspnea, and cough
        • In a child with many pulmonary infections, development of chronic pulmonary disease due to alpha₁-antitrypsin deficiency may be accelerated, and emphysema may slowly develop during adolescence
    • In early adulthood
      • Symptoms are consistent with asthma and chronic obstructive pulmonary disease, but they tend to be more severe, recurrent, and difficult to manage than those of “usual” chronic obstructive pulmonary disease, especially in people who smoke
        • Chronic cough
        • Dyspnea on exertion or at rest
        • Wheezing
        • Recurrent episodes of exacerbation of symptoms, with or without sputum production
      • Bronchiectasis is a less common alternative presentation in adults, with daily mucopurulent sputum production
    • Family history may be significant for asthma, chronic obstructive pulmonary disease, or bronchiectasis in both smoking and nonsmoking patients
  • Presentation of liver disease
    • May present with neonatal jaundice (comprises 5% of idiopathic cases) 
      • Jaundice, acholic stools in first week of life 
      • Neonatal symptoms typically completely resolve within months, but they may persist, leading to cirrhosis and need for liver transplant in childhood
      • May be asymptomatic even in the presence of abnormal liver function test results
    • Alternatively, liver disease may present in adulthood, especially in elderly nonsmoking PI*ZZ persons without chronic obstructive pulmonary disease
      • May be asymptomatic even in the presence of abnormal liver function test results
      • Chronic nonviral hepatitis may progress to cirrhosis, with associated symptoms of jaundice, fatigue, weight loss, and increased abdominal girth
    • May report family history of unexplained liver disease, including cirrhosis or hepatocellular carcinoma
  • Rare clinical presentations
    • Panniculitis
      • Painful nodules, sometimes at the site of recent trauma, and fever
    • Vasculitis
      • Symptoms are multisystemic, often including fever, weight loss, and respiratory, renal, and dermatologic symptoms

Physical examination

  • In children 
    • Findings are usually normal
    • Rarely, there may be increased anteroposterior diameter of chest with diaphragmatic depression, or wheeze
  • In adults
    • Increased anteroposterior diameter of chest due to hyperinflation (ie, barrel chest)
    • Pulmonary examination findings reflect level of disease progression; they may be normal until late in course of disease
      • Pursed lip breathing (in advanced disease)
      • During exacerbation, breathing may be labored, with nasal flare and use of accessory respiratory muscles
      • Decreased breath sounds on auscultation, with prolonged expiratory phase
      • Wheezing, sibilant rales, and/or rhonchi on auscultation
  • If liver disease is present
    • Jaundice and icteric sclerae may be seen
    • Abdominal examination findings reflect stage of liver disease; liver may be small and firm or large and tender with associated signs of cirrhosis, such as spider angiomas, ascites, and (in men) gynecomastia or testicular atrophy
    • Hepatomegaly may be detected in neonatal cases
  • Alternative presentations
    • Necrotizing panniculitis
      • Tender violaceous or erythematous nodules that may be ulcerated
      • Fever
      • Hyperpigmented, atrophic scars may be present from previous episodes of panniculitis
      • Evidence of local physical trauma may be present and may cause a lesion to develop
    • Vasculitis
      • Physical findings reflect the distribution of vasculitis; skin findings may include palpable purpura and ulcerations

Causes and Risk Factors


  • Inherited genetic abnormality that results in decreased production and/or activity of alpha₁-antitrypsin 
    • Alpha₁-antitrypsin is produced in hepatocytes and then circulates throughout the body
    • Alpha₁-antitrypsin is somewhat misnamed; it inhibits not only the protease trypsin but also a wide spectrum of other proteases, especially elastase released from neutrophils in the pulmonary alveoli (which is why it is also called alpha₁–proteinase inhibitor or alpha₁-antiproteinase)
    • Low level or absence of alpha₁-antitrypsin (or normal level but with dysfunction/low activity) results in increased elastase activity in the pulmonary alveoli, with proteolytic degradation of alveolar walls resulting in emphysema or sometimes bronchiectasis
    • Liver disease is caused by a different mechanism
      • PI*ZZ and a few other mutant alleles produce structurally abnormal alpha₁-antitrypsin, which is retained in the endoplasmic reticulum of hepatocytes, causing cellular damage (also results in decreased circulating levels of alpha₁-antitrypsin)
    • Unopposed proteolysis in the subcutis and dermis, leading to local skin necrosis, may result in panniculitis
    • Alpha₁-antitrypsin deficiency is also associated with antiproteinase 3–positive (c-ANCA-positive) vasculitis, such as in granulomatosis with polyangiitis (ie, Wegener granulomatosis), although the mechanism is poorly understood
    • Different allele combinations are associated with normal, low, or absent levels of circulating alpha₁-antitrypsin; persons with only 1 defective allele may not present with clinical features of alpha₁-antitrypsin deficiency

Risk factors and/or associations

  • Typically asymptomatic in childhood, with development of chronic obstructive pulmonary disease by age 45 years in adults with phenotype PI*ZZ, the most common deficiency-state phenotype; disease may not be detected until as late as the sixth decade, or never, in some nonsmoking people 
  • Among people with phenotype PI*ZZ, males appear to have an increased risk for developing cirrhosis compared with females 
  • Autosomal codominant inheritance 
  • SERPINA1 gene (OMIM *107400), located on long arm of chromosome 14 (14q31-32.3), encodes alpha₁-antitrypsin 
  • More than 150 allele variants of the protease inhibitor system have been described 
    • Only about 12 allele variants are associated with an increased risk for lung or liver disease 
    • Different allele combinations are associated with various levels of circulating alpha₁-antitrypsin
      • Variants are identified by their migration position on gel electrophoresis from A to Z 
    • Most common alleles include:
      • M (normal allele)
        • Normal phenotype is PI*MM
      • S (leading to a mild decrease in circulating alpha₁-antitrypsin)
      • Z (leading to low levels, associated with severe alpha₁-antitrypsin deficiency)
        • PI*ZZ comprises 95% of those with clinical disease 
      • Null allele (no detectable synthesis of alpha₁-antitrypsin)
      • Patients with severe alpha₁-antitrypsin deficiency are those with PI*ZZ, PI*Z(null), and PI*(null)(null) phenotypes
    • Terminology
      • Genotype (describes the specific allelic combination found on allele-specific gene amplification tests or other gene sequencing techniques)
      • Phenotype (describes alpha₁-antitrypsin variants according to their protein expression)
  • Prevalence varies significantly among ethnic groups 
  • Z allele occurs most frequently in White people with Northern European ancestry 
  • In the United States
    • 1 in 17 have at least 1 allele associated with some degree of risk for alpha₁-antitrypsin deficiency (ie, S or Z allele) 
    • 1 in 6211 are homozygous for the Z allele 
    • Uncommon among African Americans and Hispanic Americans 
Other risk factors/associations
  • Smoking increases risk of chronic obstructive pulmonary disease and greatly increases progression of disease and decreases survival in patients with PI*ZZ alpha₁-antitrypsin deficiency
    • After age 60 years, survival of patients with ZZ phenotype is only 10% in patients who smoke compared with 60% in nonsmoking patients 
  • Smoking also increases risk of development of chronic obstructive pulmonary disease in patients heterozygous for the Z allele (eg, PI*MZ, which occurs in about 3% of North Americans) 

Diagnostic Procedures

Primary diagnostic tools

  • Alpha₁-antitrypsin deficiency is a laboratory diagnosis (not a clinical diagnosis)
  • Clinical practice guidelines vary slightly in recommendations on targeted testing for alpha₁-antitrypsin deficiency
    • WHO, Alpha-1 Foundation, and European Respiratory Society recommend testing for alpha₁-antitrypsin deficiency in all patients diagnosed with emphysema; WHO includes adults and adolescents diagnosed with asthma
      • Alpha-1 Foundation also recommends testing in all people with the following: 
        • Unexplained chronic liver disease
        • Necrotizing panniculitis
        • Granulomatosis with polyangiitis (antiproteinase 3–positive [c-ANCA-positive] vasculitis)
        • Unexplained bronchiectasis
        • Family members of people in whom an abnormal gene for alpha₁- antitrypsin has been found
          • Genetic counseling should be offered and implications of results discussed before testing is done
    • Canadian guidelines recommend testing for deficiency in any person with chronic obstructive pulmonary disease diagnosed before age 65 years or with a smoking history of less than 20 pack-years 
    • NICE recommends testing in patients with early onset emphysema if there is minimal smoking history or a positive family history 
  • Testing strategy
    • Determine serum alpha₁-antitrypsin level as initial diagnostic test 
      • Alpha₁-antitrypsin is an acute-phase reactant, so if it is measured during an acute inflammatory event, the higher level may falsely suggest normal alpha₁-antitrypsin status 
      • For this reason, European Respiratory Society recommends simultaneous measurement of C-reactive protein to aid in interpretation (ie, elevated C-reactive protein with a normal alpha₁-antitrypsin level may be consistent with a deficiency of alpha₁-antitrypsin) 
    • If level is low, proceed to phenotyping (by immunoelectrophoresis) and/or genotyping (by polymerase chain reaction assay and/or gene sequencing) 
    • If not already done, genotyping may be required to resolve discrepant results on serum alpha₁-antitrypsin level and phenotyping 
    • For patients being tested because of family history of alpha₁-antitrypsin deficiency or unexplained liver disease or vasculitis:
      • Disease may occur in PI*Z heterozygotes, and the plasma alpha₁-antitrypsin level may be normal in that case; phenotyping is required 
  • If alpha₁-antitrypsin deficiency is confirmed, assess baseline pulmonary status with complete pulmonary function testing (spirometry, static lung volumes, diffusing capacity); a chest CT is also recommended for patients who are symptomatic or have abnormal pulmonary function tests 
    • Some authorities suggest that spirometry is sufficient 
  • Assess baseline hepatic status with serum transaminase levels, platelet count, a measure of synthetic function such as INR or albumin level, and liver ultrasound 
  • Liver biopsy is not indicated for purposes of establishing the diagnosis of alpha₁-antitrypsin deficiency, but it is indicated in patients with clinically overt liver disease to stage the disease 


  • Serum alpha₁-antitrypsin level
    • Readily available in most laboratories
    • Laboratory may report the serum level either as micromolar concentration (µmol/L; µM) or in milligrams per deciliter (mg/dL)
      • Normal level considered to be 120 to 200 mg/dL for PI*MM phenotype 
      • Protective threshold value is widely considered to be 57 mg/dL (11µM) 
      • PI*ZZ phenotype usually results in level of less than 50 mg/dL 
  • Phenotype testing
    • Performed by immunoelectrophoresis
    • Identifies specific alleles present by migration speed of their protein product
  • Genotype testing
    • Performed by polymerase chain reaction or similar method
    • Gene sequencing may be appropriate to identify null alleles


  • Alpha₁-antitrypsin deficiency is not diagnosed with imaging, but imaging done in the evaluation of dyspnea or of abnormal pulmonary function test results may find some characteristics of deficiency-related chronic obstructive pulmonary disease
    • Chest radiography
      • Emphysema due to alpha₁-antitrypsin deficiency is seen as predominantly lower lobe hyperlucency, as opposed to the more common pattern of central hyperlucency in “usual” chronic obstructive pulmonary disease
      • Flattened and lowered diaphragm
      • Exaggerated verticality of heart with increased anteroposterior diameter of chest
      • Vascular markings are decreased, mainly in the lower zones
      • Chest radiograph findings may be normal until late in disease
    • CT with or without IV contrast
      • Most sensitive modality for assessing diffuse lung disease, including emphysema
      • Shows lower lobe predominance; defines extent of involvement, and may demonstrate bronchiectasis not visualized by chest radiography
  • Liver ultrasound
    • Often able to detect liver surface nodularity (most accurate radiologic sign of cirrhosis)
    • In patients with known cirrhosis, ultrasound is recommended as a screening tool for hepatocellular carcinoma

Functional testing

  • Pulmonary function testing
    • Spirometry
      • Indicated for all patients in whom this diagnosis is considered or established 
      • Measures FVC, the total volume of air forcibly exhaled from the point of maximal inspiration
      • Measures FEV per second, which is a portion of the FVC; FEV₁ is the volume of air exhaled in the first second of expiration
      • Obtain FEV₁ with patient in sitting position, 10 to 15 minutes after administration of a short-acting β₂-agonist or 30 to 45 minutes after a short-acting anticholinergic or a combination bronchodilator
      • Postbronchodilator FEV₁/FVC less than 0.7 provides evidence of persistent airflow limitation, confirming diagnosis of chronic obstructive pulmonary disease
    • Static lung volumes
      • Alpha-1 Foundation guideline recommends baseline testing at time of diagnosis 
      • Includes end-inspiratory volume, expiratory reserve volume, inspiratory reserve volume, residual volume, and tidal volume 
        • Total lung capacity equals residual volume plus expiratory reserve volume plus tidal volume plus inspiratory reserve volume
      • Increases in residual volume, total lung capacity or ratio of residual volume/total lung capacity suggest hyperinflation and obstructive disease 
    • Diffusing capacity of carbon monoxide
      • Alpha-1 Foundation guideline recommends baseline testing at time of alpha₁-antitrypsin deficiency diagnosis 
      • Measure of gas exchange (ie, ventilation/perfusion function) 
      • Low level is a more specific indicator of emphysema than spirometry 


  • A needle is inserted into the liver either transcutaneously, transvenously, or laparoscopically
    • Most often performed under ultrasonographic guidance
  • Tissue is removed for histologic examination
  • Staging of fibrosis and grade of inflammation in patients with alpha₁-antitrypsin deficiency and clinical evidence of liver disease
  • Unexplained bleeding or coagulopathy indicated by abnormal INR, thrombocytopenia, or increased bleeding time
  • Lack of available blood products
  • Inability to identify appropriate biopsy site by percussion or ultrasonography 
  • Uncooperative patient 
  • Hemorrhage
  • Puncture of viscera
  • Sepsis
  • Histopathology may find characteristic intracytoplasmic eosinophilic globules associated with alpha₁-antitrypsin deficiency, but more important for management is the degree of inflammation and fibrosis

Differential Diagnosis

Most common

  • Chronic obstructive pulmonary disease unrelated to alpha₁-antitrypsin deficiency (“usual” chronic obstructive pulmonary disease)
    • Typically associated with cigarette smoking or other environmental exposures
    • Clinical presentation is generally the same, although usual chronic obstructive pulmonary disease presents symptomatically and radiographically at a later age and may progress more slowly
    • Postbronchodilator FEV₁/FVC less than 0.7 provides evidence of persistent airflow limitation, confirming diagnosis of chronic obstructive pulmonary disease of any cause
    • Radiographically, usual chronic obstructive pulmonary disease with emphysema appears as hyperinflation and increased radiolucency of lungs, particularly in central and upper lung segments
    • Vascular markings are decreased, mainly in upper zones, in contrast to preponderance of lower zone disease in alpha₁-antitrypsin deficiency–related emphysema
    • Alpha₁-antitrypsin level in reference range makes deficiency unlikely (rare exception would be normal level but impaired function of protein)
  • Cystic fibrosis
    • Autosomal recessive genetic disorder that affects respiratory, gastrointestinal, and other systems
    • Respiratory symptom onset is typically at a much younger age (infancy) than that of alpha₁-antitrypsin deficiency with recurrent sinopulmonary infection and eventually development of bronchiectasis
    • Hepatic steatosis and biliary fibrosis may develop in childhood; meconium ileus and other forms of ileus occur in infancy and childhood
    • Exocrine pancreatic insufficiency is common
    • Confirm diagnosis with quantitative sweat chloride testing (elevated level in cystic fibrosis) and genetic testing
  • Primary ciliary dyskinesia
    • Autosomal recessive disorder causing upper and lower respiratory tract symptoms that begin in early infancy
    • Chronic rhinosinusitis and persistent otitis media are common
    • Chest radiography often shows bilateral lung hyperinflation, peribronchial infiltrates, and lobar atelectasis
    • CT often finds bronchiectasis of anatomic right middle lobe or lingula, even in young children
    • Situs inversus totalis occurs in half of patients with primary ciliary dyskinesia
    • Transmission electron microscopy on curettage from nasal epithelium or endobronchial brushing is diagnostic of structural defects within the cilium (however, a significant proportion of children with the disorder may have a normal test result)
  • Liver disease unrelated to alpha₁-antitrypsin deficiency
    • Multiple pathologic processes may result in liver disease which is symptomatic, evident on physical examination, and/or evident on laboratory testing
    • In the neonate and infant, otherwise unexplained cholestasis may be due to alpha₁-antitrypsin deficiency in a small percentage of cases
      • More commonly it is due to a variety of infectious, genetic, or metabolic abnormalities causing mechanical obstruction of bile flow or impairment of hepatic excretory function and bile secretion
      • Assessment should include a logical, stepwise evaluation of bilirubin level, urine and serum bile acid levels, hepatic synthetic function, sweat chloride level and mutation analysis, thyroid function tests, urine and serum levels of amino acids and urine-reducing substances, alpha₁-antitrypsin level, and hepatic imaging
    • In older children and adults, evaluate liver disease according to stage of presentation (eg, asymptomatic elevation of liver enzyme levels versus advanced cirrhosis) and suspected cause
      • Include a careful history of exposures to potential causes (eg, infectious and toxic agents including prescribed medications, illicit drugs, alcohol, or industrial compounds), testing for infectious hepatitis and autoimmune diseases, imaging, and perhaps liver biopsy
    • In all patients with unexplained liver disease, obtain alpha₁-antitrypsin quantitative test to rule out alpha₁-antitrypsin deficiency 
  • Panniculitis unrelated to alpha₁-antitrypsin deficiency
    • Alpha₁-antitrypsin deficiency that presents as panniculitis must be differentiated from panniculitis due to other causes
    • Other potential causes include:
      • Local trauma
      • Infection (especially fungal or mycobacterial)
      • Pancreatic (enzymatic) panniculitis
      • Erythema induratum (nodular vasculitis)
    • Clinical differentiation may be difficult if panniculitis is the sole presentation
      • Spontaneous ulceration may occur in cases associated with alpha₁-antitrypsin deficiency; ulceration is unusual in panniculitis due to other causes 
    • Definitive differentiation typically requires consultation with a dermatologist and dermatopathologist review of biopsy tissue

Treatment Goals

  • Stop smoking
  • Control symptoms of chronic obstructive pulmonary disease with usual medical care
  • Prevent progression of chronic obstructive pulmonary disease with augmentation therapy
  • Control symptoms of liver disease with usual medical care and liver transplant if indicated

Admission criteria

  • There are no specific admission criteria for alpha₁-antitrypsin deficiency; exacerbations of chronic obstructive pulmonary disease and symptomatic liver disease may require admission

Recommendations for specialist referral

  • Pulmonologist for patients with lung disease, for consideration of alpha₁-antitrypsin augmentation therapy
  • Gastroenterologist/hepatologist for liver biopsy and management of liver disease (if present), including coordination of transplant if necessary

Treatment Options

Pulmonary disease

  • Protect the lungs from environmental and infectious insult; this may stabilize the disease 
    • If patient smokes, recommend and facilitate smoking cessation, reinforcing the fact that continuing to smoke will drastically worsen pulmonary disease; also recommend avoidance of environmental particulates, dust, and fumes 
    • Administer pneumococcal vaccine and annual influenza vaccine 
  • Manage chronic obstructive pulmonary disease as in patients without alpha₁-antitrypsin deficiency. This is standard, although there is little supporting evidence for this approach, and more research is needed to determine if alternative approaches may be preferable
    • Because acute infection poses the threat of increased elastolytic burden in people with alpha₁-antitrypsin deficiency, early antibiotic therapy for all purulent exacerbations is recommended 
  • IV augmentation is the only disease-specific therapy in alpha₁-antitrypsin deficiency 
    • 2015 RAPID randomized controlled trial (Intravenous Augmentation Treatment and Lung Density in Severe α1-Antitrypsin Deficiency) demonstrated treatment benefit as measured by CT density 
    • 2016 Cochrane systematic review did not find benefit based on composite outcome measures, including FEV₁ and quality of life; therefore, it did not recommend augmentation therapy, although it was widely criticized by pulmonary specialists 
    • 2017 systematic review confirmed significant benefit in slowing emphysema using serial CT density measurement; this outcome may correlate with mortality 
      • Slows CT density change by 0.79 g/L/year versus placebo 
  • IV augmentation is widely but not universally recommended
    • Alpha-1 Foundation recommends IV augmentation therapy for patients with an FEV₁ less than or equal to 65% predicted, and suggests that it be discussed with patients whose FEV₁ is greater than 65% 
      • Guideline recommends against use in the following situations:
        • PiMZ genotype
        • Absence of airflow obstruction
        • Current smokers
        • For treatment of liver disease due to alpha₁-antitrypsin deficiency
        • After liver transplantation (AAT production normalizes)
    • American Thoracic Society/European Respiratory Society (2003) guidelines support augmentation therapy in alpha₁-antitrypsin deficiency patients with established airflow obstruction; a subsequent European Respiratory Society statement restates and reinforces the recommendation
      • European Respiratory Society recommends against use in the following situations: 
        • PiSZ or PiMZ genotype
        • Current smokers
    • 2012 Canadian guidelines recommend consideration of treatment for all nonsmoking or ex-smoking patients with chronic obstructive pulmonary disease (FEV₁ of 25%-80% of predicted) attributable to emphysema and documented alpha₁-antitrypsin deficiency (level of 11 μmol/L or less) who are receiving optimal pharmacologic and nonpharmacologic therapies (including comprehensive case management and pulmonary rehabilitation) 
    • NICE guidelines recommend against augmentation therapy 
  • Lung transplant can be considered for selected patients with end-stage lung disease; improves quality of life but impact on survival is unclear, as study results have been mixed 
    • Outcomes are inferior compared with those for chronic obstructive pulmonary disease not related to alpha₁-antitrypsin deficiency 
  • Lung volume reduction surgery can palliate dyspnea and provide a bridge to lung transplant (limited evidence) 
    • Guidelines differ in their recommendations; European Respiratory Society supports consideration in selected patients, while Alpha-1 Foundation recommends against it
  • Endobronchial valves or coils have improved FEV₁, 6-minute walking distance and quality of life when placed in patients with emphysema, but experience in patients with emphysema due to alpha₁- antitrypsin deficiency is limited 

Liver disease

  • Protect the liver from further damage
    • Administer hepatitis A and B vaccines
    • Counsel to avoid excessive alcohol consumption 
  • Manage hepatic cirrhosis as per appropriate clinical practice guidelines
  • Liver transplant can be considered for end-stage liver disease
    • Cures cirrhosis caused by alpha₁-antitrypsin deficiency
      • 1-, 3-, 5-, and 10-year posttransplant survival rates of 86%, 83%, 80%, and 72%, respectively, for the PI*ZZ phenotype 
    • Restores normal alpha₁-antitrypsin production/serum levels 
    • However, lung disease persists after transplant 
      • FEV₁ may continue to worsen (this phenomenon is observed but the mechanism is poorly understood)

Necrotizing panniculitis

  • Alpha-1 Foundation recommends IV augmentation therapy for this manifestation of alpha₁-antitrypsin deficiency 

Disease-specific therapy (augmentation) is not recommended for patients who do not yet have evidence of end-organ disease; however, once the genetic condition is detected, patients should adhere to recommendations to avoid damage to lungs or liver

Drug therapy

  • Purified human alpha₁-antitrypsin
    • Alternative terminology is alpha₁–proteinase inhibitor (human)
      • Alpha-1-Proteinase Inhibitor (Human) Solution for injection; Adults: 60 mg/kg IV infusion once weekly. Different products are infused at different rates. Infuse at a rate of approximately 0.08 mL/kg/minute for Zemaira, Aralast NP, Prolastin, and Prolastin-C. For Glassia, infuse at a rate not to exceed 0.2 mL/kg/minute IV. If needed for patient comfort or adverse reactions, reduce the infusion rate.

Nondrug and supportive care

Smoking cessation

  • Evidence-based strategies include nicotine replacement products, pharmacotherapy (eg, bupropion, varenicline), and counseling
    • High-quality evidence indicates that a combination of pharmacotherapy and high-intensity behavioral treatment is more effective than high-intensity behavioral treatment alone 
    • Some evidence indicates that high-intensity behavioral treatment is more effective than low-intensity or usual care 
  • Nicotine replacement therapy may also be supplemented with agents shown to mitigate the effects of withdrawal; a combination of nicotine replacement plus sustained-release bupropion is recommended 
  • Withdrawal agents may also be used instead of nicotine replacement therapy when it is contraindicated; varenicline and sustained-release bupropion are first line choices

First line pharmacotherapy to aid in smoking cessation.

PharmacotherapyOdds ratio of success
Combination nicotine patch (longer than 14 weeks) plus ad lib nicotine gum or spray3.6
Varenicline 2 mg/day3.1
Nicotine patch plus bupropion sustained-release2.5
Nicotine patch plus nortriptyline2.3
Nicotine nasal spray2.3
High-dose (greater than 25 mg) nicotine patch2.3
Nicotine patch plus inhaler2.2
Nicotine gum2.2
Varenicline 1 mg/day2.1
Nicotine inhaler2.1
Bupropion sustained-release2
Nicotine patch plus second-generation antidepressant (paroxetine, venlafaxine)2
Regular dose nicotine patch used for either 6 to 14 weeks or for longer than 14 weeks1.9

Citation: Data from Agency for Healthcare Research and Quality: Treating Tobacco Use and Dependence: 2008 Update. AHRQ website. Published 2008. Reviewed October 2018. Accessed March 15, 2019.


  • Yearly spirometry in all patients after alpha₁-antitrypsin deficiency is identified, whether symptomatic or not; European Respiratory Society suggests assessment of gas exchange (eg, diffusion capacity) as well 
  • The role of follow-up with CT densitometry in routine practice is unclear 
  • All patients should be evaluated yearly for possible liver disease by physical examination, with liver function tests (including INR and platelet count) and ultrasonographic examination 
  • For patients with cirrhosis, Alpha-1 Foundation recommends ultrasound every 6 months to monitor for onset of hepatocellular carcinoma 
    • Based on the American Association for the Study of Liver Disease guideline, although there are no studies or recommendations specific to liver disease due to alpha₁-antitrypsin deficiency


  • Chronic obstructive pulmonary disease leading to pulmonary hypertension, right-sided heart failure, and respiratory failure
  • Liver disease leading to cirrhosis, hepatocellular carcinoma, and liver failure


  • Prognosis is variable and depends on genotype and phenotype of disease. Patients with clinically evident liver and lung disease have progressive disease that worsens at varied rates
  • People with alpha₁-antitrypsin deficiency who smoke are more likely than nonsmoking counterparts to develop chronic obstructive pulmonary disease, to have progression at an earlier age, and to have worse outcomes 
  • Patients with deficiency-related lung disease and FEV₁ below 20% of predicted have a 2-year mortality of 40% 
  • Patients with end-stage liver disease treated with liver transplant have 1-, 3-, 5-, and 10-year posttransplant survival rates of 86%, 83%, 80%, and 72%, respectively, for the PI*ZZ phenotype; however, pulmonary function may continue to worsen 

Screening and Prevention


At-risk populations

  • Recommended for siblings of a patient with alpha₁-antitrypsin deficiency 
  • Consider for: 
    • Adults and adolescents with a child, a parent, or a distant relative homozygous for alpha₁-antitrypsin deficiency alleles
    • Adults and adolescents with a sibling, a child, a parent, or a distant relative heterozygous for an alpha₁-antitrypsin deficiency allele
    • Adults and adolescents with a family history of obstructive lung disease or liver disease 

Screening tests 

  • Serum alpha₁-antitrypsin level
  • Phenotype testing (serum electrophoresis)
  • DNA amplification for screening is possible but is not routine


de Serres FJ et al: Ethnic differences in alpha-1 antitrypsin deficiency in the United States of America. Ther Adv Respir Dis. 4(2):63-70, 2010


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