α1-Antitrypsin Deficiency (AATD)

α1-Antitrypsin deficiency (AATD) is a relatively common inherited disorder. It primarily presents with early-onset panacinar lung emphysema and with liver cirrhosis in a minority of the patients. Cardiac arrest in association with general anesthesia has been described.

α1-Antiprotease Deficiency; Hereditary Pulmonary Emphysema; AATD.

Worldwide, approximately 1:2000 to 1:4000 newborns have AATD. This disorder is found in all ethnic groups but most frequently in Caucasians.

AATD is inherited in an autosomal recessive pattern. In the majority of patients, the parents are carriers (heterozygous for the defect) but show no symptoms of the disease. A gene called SERPINA1 (Serine [or cysteine] proteinase inhibitor, clade A [AAT], member 1) is responsible for production of AAT and has been mapped to 14q32.1.

The SERPINA1 gene comes in many alleles (>100 different phenotypic variants of AATD have been identified). Most people (approximately 90%) are homozygous for the M version (PiMM, where Pi = proteinase inhibitor), which is characterized by normal levels of AAT (serum levels 20-60 mmol/l). Two altered alleles of the SERPINA1 gene result in moderately low to very low AAT levels and are called the S and Z allele, respectively. Individuals with a PiZZ (AAT serum level 3.3-7 mmol/l) or PiSZ phenotype are at high risk to develop AATD. In fact, the PiZZ phenotype is responsible for almost all the cases of AAT-related emphysema and liver disease. In general, individuals with a PiMS or PiSS genotype can produce enough AAT to prevent lung damage. In general, a serum level of approximately 11 mmol/l and higher is considered sufficient to prevent lung damage. However, patients with the PiMZ genotype (carrier) who smoke are at increased risk for lung disease. In a rare variant, termed the 00 (null-null) phenotype, no AAT is produced.

AAT is a glycoprotein with a molecular weight of 54 kDa. It is produced in hepatocytes and mononuclear phagocytes. The genetic defect in AATD alters the molecule (misfolding secondary to substitution of alanine for valine at amino acid residue 213 and substitution of lysine for glutamate at amino acid residue 342 of AAT) such that, although synthesized, it cannot be released from the endoplasmic reticulum, where a significant part is degraded but the rest accumulates in the form of insoluble intracellular globular inclusions. The inclusion can easily be identified on routine (H and E) and periodic acid-Schiff (PAS)-stained liver biopsies (except in the Pi00 genotype, where AAT production is completely absent). AAT serum levels in PiZZ patients are approximately 10 to 15% of normal values, meaning that 85 to 90% of AAT produced remains intracellularly, of which a significant part is degraded; the rest accumulates. The major function of AAT is inhibition of several mainly neutrophil-derived proteases, particularly at sites of inflammation where high amounts of active serine proteases (elastase, trypsin, cathepsin G, proteinase 3) are released from infiltrating polymorphonuclear cells. (Obviously, the synonymous but more general term α1-antiproteinase deficiency is more appropriate; nevertheless AATD is the commonly used name for the disease.) AAT normally is released from hepatocytes into the blood circulation, where it circulates unbound and diffuses into pulmonary interstitial and alveolar lining fluids. Neutrophil elastase, which normally is released during phagocytosis of organisms or particles in the alveoli, is inactivated by AAT. The resulting imbalance between proteases and antiproteases in the lungs is responsible for unimpeded destruction of elastin and collagen in the alveolar walls. This process results in progressive panacinar lung emphysema initially with distension of the alveolus and the alveolar duct, but it also affects the respiratory bronchioles. This process is more pronounced at the base of the lungs. Because smokers have an increased number of neutrophils and macrophages (and therefore increased elastase levels) in the alveoli but they also have decreased antielastase activity (oxidants in cigarette smoke inhibit AAT), destruction is amplified by smoking. Why only 10 to 15% of patients with the PiZZ phenotype develop liver disease, which seems to be associated with accumulation of AAT in hepatocytes in the form of insoluble globules, is unknown. This theory is supported by the observation that patients with the 00 (null-null) phenotype (completely absent AAT synthesis) may suffer from emphysema like patients with the ZZ and SZ phenotype, but they do not show signs of cirrhosis or liver cancer. However, other genetic factors and a specific sensitivity in some patients seem to be involved in the pathogenesis of liver disease. Antitrypsin acts as an acute phase protein, and its serum level may increase significantly in response to inflammation and fever. Prevention and early treatment of these symptoms in PiZZ homozygote infants seems important. Serum levels also may increase in association with neoplasias, pregnancy, and oral contraceptives.

On routine serum electrophoresis, more than 90% of the α1-globulin fraction is made up of AAT. Hence, a missing α1-peak is suggestive of AATD. However, direct measurement of serum AAT levels is possible, and patients with low or borderline serum AAT levels should undergo phenotyping to confirm the diagnosis of AATD. A direct test for the presence or absence of the PiZ allele is available and more sensitive. The severity of emphysema is best documented with standard pulmonary function tests. The majority of patients are diagnosed with AATD secondary to their symptoms and often present with moderate-to-severe airflow obstruction with a reduction in forced expired volume in the first second (FEV1) to 30 to 40%. Increased lung volumes (a consequence of increased residual volume because of air trapping) and reduced vital capacity usually are present. Prenatal diagnosis of AATD is available.

In the first 2 decades of life, liver disease is the main manifestation of AATD; lung problems evolve later in life (see below). Among adolescents with the PiZZ phenotype, lung function appears to be normal. Lung disease usually does not present until the late fourth or early fifth decade of life. It starts with intermittent symptoms such as dyspnea initially on strenuous exertion only (cardinal symptom), wheezing, chronic cough, and spirometric evidence of obstructive airway disease. Many patients initially are falsely labeled as having asthma. Bronchiectases and pulmonary cysts may occur later in life. Occasionally, the pulmonary disease is rapidly progressive, most often seen in patients with preexisting liver disease secondary to AATD. Panacinar emphysema is characterized by hyperinflated, hyperlucent lung bases and bullae formation on chest x-ray film, all secondary to destruction of normal lung tissue. Oligemia resulting from the rarefaction or lack of regular branching vessels also has been used as a criterion. Clinical features that indicate the possibility of AATD and should trigger further evaluation include emphysema and recurrent bronchitis in younger adults (age 30-45 years), particularly in nonsmokers and patients with a positive family history for emphysema of the basal lung areas and occasionally adult-onset asthma. The decline in FEV1 in healthy adults is estimated to be approximately 30 ml/year, but may be as high as 300 ml/year in adults with the PiZZ phenotype. Mortality rate is inversely proportional to the decline in FEV1. Emphysema is the cause of death in almost three fourths of AATD patients; the majority of patients die before age 60 years. This is especially true for patients who were diagnosed with AATD because of symptoms and not as a result of a screening process. Most patients initially respond to bronchodilator therapy (β-adrenergic drugs, inhaled steroids). Oral corticosteroids usually are reserved for acute exacerbations with increased cough and sputum production. Theophylline has been used in the past but is no longer the first-line treatment. However, some patients may experience a relief in their degree of dyspnea, so some pneumologists advocate a therapeutic trial in a subgroup of patients. Weekly intravenous replacement therapy of AAT (made from pooled, purified, human plasma protein concentrate) is available. Restoration of serum and alveolar AAT concentrations to protective levels seems to have beneficial effects, but the treatment is expensive. In any patient presenting with chronic liver disease, not only AAT serum levels but also the Pi phenotype should be determined, as AAT serum concentration alone may be misleading because AAT is also an acute phase protein (see Pathophysiology) and may be falsely elevated. The clinical range of liver disease is wide and includes neonatal cholestasis, neonatal or juvenile micronodular cirrhosis, chronic hepatitis, and hepatocellular carcinoma (more common in males). However, only approximately 10 to 15% of neonates with the PiZZ phenotype show signs of liver disease, most commonly starting as cholestatic jaundice, which in most cases resolves in the first months of life. It also may result in fatal liver failure, esophageal varices, and bleeding complications. Chronic liver disease accounts for approximately 10% of deaths related to AATD. Hepatosplenomegaly may persist even after jaundice resolves and may result in hypersplenism with thrombocytopenia. Liver transplant has been used successfully to treat not only liver failure but also the enzyme defect. Patients with end-stage lung disease can be treated with lung or combined heart-lung transplant.

Lung function should be assessed by spirometry to determine forced vital capacity and FEV1. Measuring lung volumes (ideally by plethysmography) and diffusing capacity may be required for special circumstances. Chest radiograph is strongly recommended. Hepatic function (serum concentrations of transaminases, bilirubin, albumin; activated partial thromboplastin time; international normalized ratio) should be assessed in all patients with low or borderline levels of AAT. A complete blood cell count including platelets (hypersplenism) should be obtained because of potential bleeding issues (e.g., esophageal varices, bleeding ulcers). Given the reduced pulmonary function and the increased risk for airway complications in most of these patients, lung function and respiratory tract infections should be optimized and treated before the patient undergoes anesthesia. Review and evaluate bronchodilator therapy (β-adrenergic agents, inhaled steroids) to maximize lung function. Cor pulmonale can be present in patients with long-standing pulmonary disease. If in doubt, ECG and transthoracic echocardiography should be performed. Because fever and infections result in elevated serum AAT levels in healthy individuals but mainly increased intracellular levels in AATD patients, avoid anesthesia under these circumstances, although it probably does not affect the short-term course of the disease.

AATD patients are subject to all the complications typical for patients with chronic obstructive pulmonary disease (pneumonia, pneumothorax, acute airway obstruction, respiratory failure) well known from chronic cigarette smoking. (Hyper)reactive airway disease poses a significant risk in these patients. Significant air trapping requiring emergency sternotomy and cardiopulmonary bypass secondary to cardiac arrest has been described in AATD patients undergoing heart-lung transplant. If permitted by the surgical procedure, maintenance of spontaneous ventilation (mask or laryngeal mask airway) probably is advantageous in these patients. Three pediatric AATD cases have been reported. General anesthesia (two with halothane; one case not specified) administered for minor surgical procedures resulted in accelerated hepatic failure and death of the patients. The exact cause of fatal deterioration could not be determined, but general anesthesia (halothane?) was considered the main culprit.

Use of halothane in patients with AATD-related liver disease probably is not advisable. Nonsteroidal antiinflammatory drugs should be used carefully in the presence of liver disease (bleeding complications). Stress ulcer prophylaxis may be indicated, depending on the kind of surgery.

Kartagener Syndrome: Inherited polymalformative syndrome characterized by bronchiectasis, situs inversus, and chronic sinusitis.

Mucoviscidosis: Congenital multiorgan disease affecting mainly the lungs, liver, and pancreas. Frequent lung infections, hemoptysis, intolerance to exercise, presence of clubbing fingers suggesting pulmonary hypertension, rectal prolapse, and nasal polyps.