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Alpha-1 Antitrypsin Deficiency

By

Robert A. Wise

, MD, Johns Hopkins Asthma and Allergy Center

Last full review/revision Jun 2020| Content last modified Jun 2020
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Alpha-1 antitrypsin deficiency is congenital lack of a primary lung antiprotease, alpha-1 antitrypsin, which leads to increased protease-mediated tissue destruction and emphysema in adults. Hepatic accumulation of abnormal alpha-1 antitrypsin can cause liver disease in both children and adults. Serum alpha-1 antitrypsin level < 11 mmol/L (< 80 mg/dL) confirms the diagnosis. Treatment is smoking cessation, bronchodilators, early treatment of infection, and, in selected cases, alpha-1 antitrypsin replacement. Severe liver disease may require transplantation. Prognosis is related mainly to degree of lung impairment.

Pathophysiology of Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin is a neutrophil elastase inhibitor (an antiprotease), the major function of which is to protect the lungs from protease-mediated tissue destruction. Most alpha-1 antitrypsin is synthesized by hepatocytes and monocytes and passively diffuses through the circulation into the lungs; some is secondarily produced by alveolar macrophages and epithelial cells. The protein conformation (and hence functionality) and quantity of circulating alpha-1 antitrypsin are determined by codominant expression of parental alleles; > 90 different alleles have been identified and described by protease inhibitor (PI*) phenotype.

Liver

Inheritance of some variant alleles causes a change in conformation of the alpha-1 antitrypsin molecule, leading to polymerization and retention within hepatocytes. The hepatic accumulation of aberrant alpha-1 antitrypsin molecules causes neonatal cholestatic jaundice Neonatal Cholestasis Cholestasis is failure of bilirubin secretion, resulting in conjugated hyperbilirubinemia and jaundice. There are numerous causes, which are identified by laboratory testing, hepatobiliary scan... read more in 10 to 20% of patients; the remaining patients are probably able to degrade the abnormal protein, although the exact protective mechanism is unclear. About 20% of cases of neonatal hepatic involvement result in development of cirrhosis in childhood. About 10% of patients without childhood liver disease develop cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more as adults. Liver involvement increases the risk of liver cancer.

Lungs

In the lungs, alpha-1 antitrypsin deficiency increases neutrophil elastase activity, which facilitates tissue destruction leading to emphysema (especially in smokers, because cigarette smoke also increases protease activity). Alpha-1 antitrypsin deficiency accounts for 1 to 2% of all cases of chronic obstructive pulmonary disease Chronic Obstructive Pulmonary Disease (COPD) Chronic obstructive pulmonary disease (COPD) is airflow limitation caused by an inflammatory response to inhaled toxins, often cigarette smoke. Alpha-1 antitrypsin deficiency and various occupational... read more Chronic Obstructive Pulmonary Disease (COPD) (COPD). Alpha-1 antitrypsin deficiency most commonly causes early emphysema; symptoms and signs of lung involvement occur earlier in smokers than in nonsmokers but in both cases are rare before age 25. Some patients with bronchiectasis Bronchiectasis Bronchiectasis is dilation and destruction of larger bronchi caused by chronic infection and inflammation. Common causes are cystic fibrosis, immune defects, and recurrent infections, though... read more Bronchiectasis have alpha-1 antitrypsin deficiency.

Other tissues

Other disorders possibly associated with alpha-1 antitrypsin allele variants include panniculitis Panniculitis Panniculitis describes inflammation of the subcutaneous fat that can result from multiple causes. Diagnosis is by clinical evaluation and biopsy. Treatment depends on the cause. (See also Erythema... read more Panniculitis (an inflammatory disorder of the subcutaneous tissue), life-threatening hemorrhage (through a mutation that converts alpha-1 antitrypsin from a neutrophil elastase to a coagulation factor inhibitor), aneurysms, ulcerative colitis Ulcerative Colitis Ulcerative colitis is a chronic inflammatory and ulcerative disease arising in the colonic mucosa, characterized most often by bloody diarrhea. Extraintestinal symptoms, particularly arthritis... read more Ulcerative Colitis , antineutrophilic cytoplasmic antibody (ANCA)-positive vasculitis, and glomerular disease.

Classification of Alpha-1 Antitrypsin Deficiency

The normal PI phenotype is PI*MM. More than 95% of people with severe alpha-1 antitrypsin deficiency and emphysema are homozygous for the Z allele (PI*ZZ) and have alpha-1 antitrypsin levels of about 30 to 40 mg/dL (5 to 6 micromol/L). Prevalence in the general population is 1/1500 to 1/5000. Most are whites of Northern European descent; the Z allele is rare in people of Asian descent and blacks. Though emphysema is common among PI*ZZ patients, many nonsmoking patients who are homozygous for PI*ZZ do not develop emphysema; patients who do typically have a family history of COPD. PI*ZZ smokers have a lower life expectancy than PI*ZZ nonsmokers, who have a lower life expectancy than PI*MM nonsmokers and smokers. If they smoke, people who are PI*MZ heterozygous are more likely to experience more rapid decreases in forced expiratory volume in 1 second (FEV1) over time than do people in the general population.

Other rare phenotypes include PI*SZ and two types with nonexpressing alleles, PI*Z-null and PI*null-null (see table Expression of Phenotype in Alpha-1 Antitrypsin Deficiency Expression of Phenotype in Alpha-1 Antitrypsin Deficiency Alpha-1 antitrypsin deficiency is congenital lack of a primary lung antiprotease, alpha-1 antitrypsin, which leads to increased protease-mediated tissue destruction and emphysema in adults.... read more ). The null phenotype leads to undetectable serum levels of alpha-1 antitrypsin. Normal serum levels of malfunctioning alpha-1 antitrypsin may occur with rare mutations.

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Symptoms and Signs of Alpha-1 Antitrypsin Deficiency

Severity of pulmonary disease varies greatly depending on phenotype, smoking status, and other factors. Pulmonary function is well preserved in some PI*ZZ smokers and can be severely impaired in some PI*ZZ nonsmokers. PI*ZZ people identified in population surveys (ie, those without symptoms or pulmonary disease) tend to have better pulmonary function, whether they smoke or not, than do index people (those identified because they have pulmonary disease). Airflow obstruction occurs more frequently in men and in people with asthma Asthma Asthma is a disease of diffuse airway inflammation caused by a variety of triggering stimuli resulting in partially or completely reversible bronchoconstriction. Symptoms and signs include dyspnea... read more , recurrent respiratory infections, occupational dust exposure, and a family history of pulmonary disease.

Panniculitis Panniculitis Panniculitis describes inflammation of the subcutaneous fat that can result from multiple causes. Diagnosis is by clinical evaluation and biopsy. Treatment depends on the cause. (See also Erythema... read more Panniculitis , an inflammatory disorder of subcutaneous soft tissue, manifests as indurated, tender, discolored plaques or nodules, typically on the lower abdomen, buttocks, and thighs.

Diagnosis of Alpha-1 Antitrypsin Deficiency

  • Serum alpha-1 antitrypsin level

  • Genotyping

Alpha-1 antitrypsin deficiency is suspected in the following:

  • Smokers who develop emphysema before age 45

  • Nonsmokers without occupational exposures who develop emphysema at any age

  • Patients whose chest x-ray shows predominately lower lung emphysema

  • Patients with a family history of emphysema or unexplained cirrhosis

  • People with a family history of alpha-1-antitrypsin deficiency

  • Patients with panniculitis

  • Neonates with jaundice or liver enzyme elevations

  • Patients with unexplained bronchiectasis or liver disease

Diagnosis is confirmed by identifying serum alpha-1 antitrypsin levels < 80 mg/dL (< 15 micromol/L) if measured by the radial immunodiffusion method or levels < 50 mg/dL (< 9 micromol/L) if measured by nephelometry. Patients with low levels should have confirmation by genotyping.

Prognosis for Alpha-1 Antitrypsin Deficiency

Treatment of Alpha-1 Antitrypsin Deficiency

  • Supportive care

  • For pulmonary disease, often alpha-1 antitrypsin replacement

Treatment of pulmonary disease is with purified human alpha-1 antitrypsin (60 mg/kg IV over 45 to 60 minutes given once a week or 250 mg/kg over 4 to 6 hours given once a month [pooled only]), which can maintain the serum alpha-1 antitrypsin level above a target protective level of 80 mg/dL (35% of normal). Because emphysema causes permanent structural change, therapy cannot repair damaged lung structure or improve lung function but is given to halt progression. Treatment is expensive and is therefore reserved for nonsmoking patients who have two abnormal alleles, mild to moderately abnormal pulmonary function, and confirmation of diagnosis by low serum alpha-1 antitrypsin levels. It is not indicated for patients who have severe disease or for patients in whom one or both alleles are normal.

Smoking cessation Smoking Cessation Most smokers want to quit and have tried doing so with limited success. Effective interventions include cessation counseling and drug treatment, such as varenicline, bupropion, or a nicotine... read more , use of bronchodilators, and early treatment of respiratory infections are particularly important for patients with alpha-1 antitrypsin deficiency and emphysema.

Gene therapy is under study.

Treatment of liver disease is supportive. Enzyme replacement does not help because the disease is caused by abnormal processing rather than by enzyme deficiency. Liver transplantation Liver Transplantation Liver transplantation is the 2nd most common type of solid organ transplantation. (See also Overview of Transplantation.) Indications for liver transplantation include Cirrhosis (70% of transplantations... read more may be used for patients with liver failure.

Treatment of panniculitis is not well defined. Corticosteroids, antimalarials, and tetracyclines have been used.

Key Points

  • Suspect alpha-1 antitrypsin deficiency if patients have unexplained emphysema, liver disease (particularly in neonates), panniculitis, or bronchiectasis.

  • Diagnose using serum alpha-1 antitrypsin levels < 80 mg/dL (< 15 micromol/L) and confirm by genotyping.

  • Treat selected patients (nonsmoking patients in whom both alleles are abnormal and who have mild to moderately abnormal pulmonary function and low serum alpha-1 antitrypsin levels) with purified human alpha-1 antitrypsin.

  • Consider liver transplantation if liver failure develops.

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