Pathogenesis

The type and concentration of α₁-AT are inherited as a series of codominant alleles on chromosomal segment 14q31-32.3. See Chapter 349.5 for discussion of genotypes and liver disease. The autosomal recessive deficiency affects 1/1,600-2,500 people, or ∼100,000 people in the USA but is underdiagnosed. It occurs most commonly in whites of Northern European ancestry, but recent surveys reveal significant prevalence in populations from the Middle East and North Africa, Central and Southern Africa, and Central and Southeast Asia. Worldwide there are an estimated 116,000,000 carriers and 1,100,000 subjects with severe α₁-AT deficiency. The normal α₁-AT PiM protein is secreted by the liver into the circulation at a rate of ∼34 mg/kg/day; it is also produced by lung epithelial cells and monocytes. Mutant protein is not produced (null), or is misfolded (PiZ and others); it can polymerize in the endoplasmic reticulum or be degraded, with subsequent low serum levels. Early adult-onset emphysema associated with α₁-AT deficiency occurs most commonly with PiZZ (mutation in SERPINA1 gene), although Pi (null) (null) and, to a lesser extent, other mutant Pi types such as SZ have been associated with emphysema.

α₁-AT and other serum antiproteases help inactivate proteolytic enzymes released from dead bacteria or leukocytes in the lung. Deficiency of these antiproteases leads to an accumulation of proteolytic enzymes in the lung, resulting in destruction of pulmonary tissue with subsequent development of emphysema. Furthermore, polymerized mutant protein in the lungs may be proinflammatory. The concentration of proteases (elastase) in the patients’ leukocytes may also be an important factor in determining the severity of clinical pulmonary disease with a given level of α₁-AT.

Clinical Manifestations

Most patients who have the PiZZ defect have little or no detectable pulmonary disease during childhood. A few have early onset of chronic pulmonary symptoms, including dyspnea, wheezing, and cough, and panacinar emphysema has been documented by lung biopsy; it is probable that these findings occur secondarily to infection, causing inflammation with consequent early disease. Smoking greatly increases the risk of emphysema in patients with mutant Pi types. Although newborn screening to identify children with PiZZ phenotype does not affect parental smoking habits, it does decrease smoking rates among affected adolescents.

Physical examination in childhood is usually normal. It very rarely reveals growth failure, an increased anteroposterior diameter of the chest with a hyperresonant percussion note, crackles if there is active infection, and clubbing. Severe emphysema can depress the diaphragm, making the liver and spleen more easily palpable.

Laboratory Findings

Serum immunoassay measures low levels of α₁-AT; normal serum levels are 150-350 mg/dL. Serum electrophoresis reveals the phenotype, and genotype is determined by polymerase chain reaction. In the rare patient with lung disease in adolescence, chest radiograph reveals overinflation with depressed diaphragms. Chest CT can show more hyperexpansion in the lower lung zones, with occasional bronchiectasis; CT densitometry can be a sensitive method to follow changes in lung disease. Lung function testing is usually normal in children, but it can show airflow obstruction and increased lung volumes, particularly in adolescents who smoke.

Treatment

Therapy for α₁-AT deficiency is intravenous replacement with enzyme derived from pooled human plasma. A level of 80 mg/dL is protective for emphysema. This target level for augmentation therapy is usually achieved with doses of 60 mg/kg IV weekly and results in the appearance of the transfused antiprotease in pulmonary lavage fluid. The Food and Drug Administration has approved the use of purified blood-derived human enzyme for ZZ and null-null patients. Replacement therapy appears most beneficial for those with moderately severe obstructive lung disease (forced expiratory volume in 1 sec [FEV₁] is 30-65% of predicted) or those with mild lung disease experiencing a rapid decline in lung function. Augmentation therapy is not indicated for persons with the MZ Pi type who have pulmonary disease, because their disease is not due to enzyme deficiency. Recombinant sources of α₁-AT are under development, but current products are rapidly cleared from the circulation when given intravenously; they may be useful for inhalation therapy. Inhalation of the plasma-derived product is under evaluation. Lung transplantation has been performed for end-stage disease.

Supportive Therapy

Standard supportive therapy for chronic lung disease includes aggressive treatment of pulmonary infection, routine use of pneumococcal and influenza vaccines, bronchodilators, and advice about the serious risks of smoking. Such treatment is also indicated for asymptomatic family members found to have PiZZ or null-null phenotypes, but not those with MZ Pi type. The clinical significance of the SZ Pi type is unclear, but nonspecific treatment is reasonable. All persons with low levels of serum antiprotease should be warned that the development of emphysema is partially mediated by environmental factors and that cigarette smoking is particularly deleterious. Although identification of affected persons could help prevent development of obstructive lung disease, population screening programs are currently suspended; however, there is increased emphasis on targeted screening programs.