Alpha-1 Anti-trypsin Deficiency: What is it and how is it treated?

Lawrence Martin, M.D., FACP, FCCP

Clinical Professor of Medicine
Case Western Reserve University School of Medicine, Cleveland
Board Certified in Pulmonary and Sleep Medicine

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    What is alpha-1 anti-trypsin deficiency?

    Alpha-1 antitrypsin (α-1 AT) deficiency is an inherited disorder that, in its severe form, can cause lung and liver disease. It is diagnosed by a blood test that shows a lower than normal amount of the α-1 AT protein. Its effects may show up in childhood, as an adult, or never. Women and men are affected equally. It is more common in whites than in blacks.

    How does deficiency of α-1 AT cause disease?

    Normally, our liver makes alpha-1 antitrypsin. The purpose of α-1 AT is to prevent trypsin and other natural proteins from breaking down normal tissues, particularly the connective tissue in lungs. These proteins are called "proteases." They are secreted in white blood cells, and their purpose is to fight bacteria that cause infection. However, an excess amount of proteases can can also attack healthy lung tissue. Alpha-1 antitrypsin prevents that from happening. α-1 AT is more accurately termed alpha-1-antiprotease. However, most physicians refer to the disease as α-1 AT deficiency.

    With the genetic defect, the α-1 AT made in the liver is deformed, and doesn't enter the blood stream to circulate where it's needed. The deformed α-1 AT stays in the liver where it can do damage, although liver disease is mainly in newborns and children.

    The lung problem resulting from α-1 AT deficiency is emphysema, the same condition seen in many heavy smokers without α-1 AT deficiency. It shows up as shortness of breath, wheezing and recurrent lung infections that don't respond well to treatment.

    The liver problem that may develop is cirrhosis, which is scarring of the liver, the same type of condition seen in some severe alcoholics who don't have α-1 AT deficiency. As a rule, cirrhosis from α-1 AT deficiency develops much sooner in life (infancy or early childhood) than does emphysema from α-1 AT deficiency (30s or later).

    A much rarer manifestation of α-1 AT deficiency is a skin disease called "necrotizing panniculitis." It shows up as painful lumps under or on the surface of the skin.

    This is a simplistic framework, because there are several varieties of deficiency, and a spectrum of disease.

    What are the varieties of α-1 AT deficiency?

    The genetic defect may or may not lead to disase. People with low levels of α-1 AT are further characterized by their "phenotype." The normal phenotype for α-1 AT is MM, which means one normal gene from each parent. There are many phenotypes, with principal ones shown below. In the aggregate they give a spectrum of risk for developing emphysema. If you have a low level of α-1 AT, the lab will (or should) also provide the phenotype.

    Phenotype - risk for emphysema

    True plasma level (μmol/L)

    MM - No increase in risk

    MZ - Possible mild increase

    SS - No increase

    SZ - Mild increase

    ZZ - High risk (80-100%)

    Null/Null - High risk (100% by age 30)

    20 - 53

    12 - 35

    15 - 33

    8 - 19



    Data are adapted from Characteristics of alpha-1 antitrypsin phenotypes (originally published in Amer Review Respiratory Disease 1989;140:1494).

    These risks pertain to emphysema, but cirrhosis may also occur, due to α-1 AT accumulation in the liver. However, in a subgroup of patients who are "null" there won't be any liver disease, since no α-1 AT is made.

    How many people have α-1 AT deficiency?

    Probably most people who have α-1 AT deficiency don't know about it, because they don't smoke and are not sick. The estimated prevalence ranges from 1 in every 3000 to 1 in every 5000 people. At present it's estimated that less than 6% of severely deficient people are currently identified.

    What happens if you have a deficiency of α-1 AT?

    It depends on 1) How severe it is and 2) Your smoking history.

    Three out of 4 adults with severe α-1 AT deficiency will get emphysema, sometimes before age 40. SMOKERS WITH α-1 AT DEFICIENCY ARE AT MUCH GREATER RISK OF DEVELOPING EMPHYSEMA. Children with α-1 AT deficiency can develop liver problems that last their whole lives.

    Cigarette smoke is harmful not only because it directly affects the lungs (it's the major cause of emphysema without α-1 AT deficiency), but it also decreases the activity of α-1 AT. Cigarette smoking accelerates the onset of symptomatic disease by approximately 10 years.

    I have emphysema from smoking. What are my chances of also having α-1 AT deficiency?

    An estimated 1-3% of patients with diagnosed COPD (chronic obstructive pulmonary disease), which encompasses both emphysema and chronic bronchitis, have α-1 AT deficiency. Symptoms include progressive shortness of breath, cough, sputum production and/or wheezing.

    How do I know if I have α-1 AT deficiency?

    A simple blood test can tell if you have the deficiency. Most hospital laboratories report serum α-1 AT levels in milligrams per decimeter (mg/dl), with a reference range of approximately 100-300 mg/dL; these levels overestimate the true level, which is given in umol/L, by 35-40%. Generally a conversion factor will be available to convert the mg/dl value into umol/L.

    For example, the lab reports α-1 AT is 100 mg/dl and the conversion factor is x .185, the "true value" is 18.5 umol/L, which is slightly low (see table above). Since the value is reduced, the lab should also perform an analysis of the phenotype.

    If you have α-1 AT deficiency, your family members should also take the blood test. Brothers and sisters of someone with α-1 AT deficiency have a 1 in 4 chance of inheriting the genes that cause α-1 AT deficiency. Children of a parent with α-1 AT deficiency should also be tested.

    Is there a cure? What is the treatement?

    There is no cure, but there is treatment to slow down the disease process.

    First, if you smoke you MUST stop. Smoking accelerates the disease. Second, if you have lung disease you should be receiving appropriate treatment, same as if you didn't have α-1 AT deficiency.

    Specific treatment is with an intravenous infusion of Alpha-1-Proteinase Inhibitor (Human). This replacement therapy for the α-1 AT deficiency is a protein that comes from donated human plasma. It is not recommended for α-1 AT deficiency UNLESS the patient has symptomatic and/or progressive emphysema. Replacement therapy is not appropriate for liver disease patients; if liver disease is severe, transplantation may be needed. Replacement therapy is also not recommended in pediatric patients. There are three manufacturers of alpha-1 protease, with brand names Prolastin, Aralast and Zemaira.

    Prolastin, The manufacturer Talecris states on their web site:
    "Alpha1-Proteinase Inhibitor (Human) is indicated for chronic replacement therapy of individuals having congenital deficiency of alphα-1 PI (alpha1-antitrypsin deficiency) with clinically demonstrable panacinar emphysema. Weekly Prolastin therapy has demonstrated a low occurrence of side effects. In clinical studies with Prolastin, reactions were observed in 1.16% of infusions, the most common events being fever (0.77%), light-headedness (0.19%), and dizziness (0.19%). As with all plasma-derived therapeutics, the potential to transmit infectious agents cannot be totally eliminated. Individuals with selective IgA deficiencies who have known antibody against IgA (anti-IgA antibody) should not receive Prolastin, since these patients may experience severe reactions, including anaphylaxis, to IgA which may be present."

    Aralast. The manufacturer Baxter states on their web site:
    "ARALAST is indicated for chronic augmentation therapy in patients having congenital deficiency of A1-PI with clinically evident emphysema. ARALAST is not indicated as therapy for lung disease patients in whom congenital A1-PI deficiency has not been established. Important Safety Information. ARALAST is contraindicated in individuals with selective IgA deficiencies (IgA level less than 15mg/dL) who have known antibody against IgA, since they may experience severe reactions, including a severe, potentially life-threatening allergic reaction to IgA, which may be present. ARALAST is made from human plasma. It may carry a risk of transmitting infectious agents, e.g. viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The most common symptoms during the clinical study were headache (0.3%) and sleepiness (0.3%). Post market adverse event data have indicated reports of infusion site pain associated with the administration of ARALAST."

    Zemaira. The manufacturer CSL Behring states on their web site:
    "Zemaira is indicated for chronic augmentation and maintenance therapy for adults with alpha1-proteinase inhibitor (A1-PI) deficiency and emphysema. Clinical data demonstrating the long-term effects of chronic augmentation therapy with Zemaira are not available. As with other Alphα-1 therapies, Zemaira may not be appropriate for the following adult individuals as they may experience severe reactions, including anaphylaxis: individuals with a known hypersensitivity and/or history of anaphylaxis or severe systemic reaction to A1-PI products or their components and individuals with selective IgA deficiencies who have known antibodies against IgA. In clinical studies, the following treatment-related adverse reactions were reported in 1% of subjects: asthenia (fatigue), injection-site pain, dizziness, headache, paresthesia (tingling), and pruritus (itching). Zemaira is derived from human plasma. As with all plasma-derived products, the risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated."

    Finally, in the most severe cases lung transplantation may be considered.

    How does a patient get intravenous therapy for α-1 AT deficiency?

    If a patient is diagnosed with unequivocal alpha-1 antitrypsin deficiency AND disease resulting from that deficiency, he or she may be referred for once-a-week replacement infusions. treatment may be given in any medical office equipped for IV infusions (such as an outpatient cancer center), in a hospital or in the patient's home. There is a national network of nurses certified in alpha-1-care.

    What are the phenotypes of α-1 AT deficiency?

    More than 100 phenotypic variants of α-1 AT deficiency have been identified, but phenotype ZZ is responsible for nearly all cases of α-1 AT deficiency emphysema and liver disease (see table, above). ZZ phenotype serum levels range from 2.5-7 μmol/L, about 10-20% of the reference range levels. Other phenotypes associated with α-1 AT emphysema and liver disease include SZ and Z/Null. Null/Null is not associated with liver disease but is associated with α-1 AT deficiency emphysema.

    Should I get tested before having children?

    It's not a routine test, premarital or otherwise, and will likely not be covered by insurance. However, if there is history of α-1 AT deficiency in your nuclear family and you are planning on having children, you could discuss testing with your physician. Be aware that most physicians are not knowledgeable about this condition (one reason being that it's not a routine test), so any abnormal result will raise a lot more questions and likely require specialty referral.

    Where can I obtain more information?

    • The Alpha-1 National Association, 1-800-4ALPHα-1, can help in locating physicians with experienced treating this condition. 275 West Street, Suite 210, Annapolis, Maryland 21401, Phone 800-521-3025, fax 410-216-6983

    • AlphaNet, AlphaNet, Inc, 2937 SW 27th Ave, Suite 305, Coconut Grove, FL 33133, phone 800-577-2638

    • Alpha-1-Foundation, Alpha-1 Foundation, 2937 SW 27th Avenue, Suite 302, Miami, FL 33133, phone 877-2CUREA1 or 877-228-7321, fax 305-567-1317

    • Alpha-1 Advocacy Alliance, phone 866-FOR-A1AA or 866-367-2122

    Chronic cough, Rhinitis and Sinusitis - a Primer for Patients, Physicians Assistants, Nurse Clinicians AND Physicians | Table of Drugs used to treat rhinitis & sinusitis | 10 Common Myths, Misconceptions, Errors and Mistakes about Chronic Cough

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Copyright © 2009 Lawrence Martin, M.D.
Posted December 8, 2008; revised April 3, 2009