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.
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.
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 (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 have alpha-1 antitrypsin deficiency.
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 (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 , 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.
Symptoms and Signs of Alpha-1 Antitrypsin Deficiency
Neonates with hepatic involvement present with cholestatic jaundice and hepatomegaly during the first week of life; jaundice usually resolves by 2 to 4 months of age. Cirrhosis may develop in childhood or adulthood (symptoms and signs of cirrhosis Symptoms and Signs 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 and hepatocellular carcinoma Symptoms and Signs Hepatocellular carcinoma usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more are discussed elsewhere in THE MANUAL). Adults with emphysema have symptoms and signs of COPD Symptoms and Signs 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 , including dyspnea, cough, wheezing, and prolonged expiration.
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 , 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
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
As a group, people with severe alpha-1 antitrypsin deficiency who have never smoked have a normal life expectancy and only moderate impairment of pulmonary function. The most common cause of death in alpha-1 antitrypsin deficiency is emphysema, followed by 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 , often with hepatocellular carcinoma Hepatocellular Carcinoma Hepatocellular carcinoma usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more .
Treatment of Alpha-1 Antitrypsin Deficiency
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.
For severely impaired people < 60 years, lung transplantation Lung and Heart-Lung Transplantation Lung or heart-lung transplantation is an option for patients who have respiratory insufficiency or failure and who remain at risk of death despite optimal medical treatment. The most common... read more should be considered. Lung volume reduction in treating the emphysema of alpha-1 antitrypsin deficiency is controversial.
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.
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.