Alpha1-Antitrypsin Deficiency in COPD: Clinical Implications

, College of Physicians and Surgeons, Columbia University, NY

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Epidemiology and Clinical Features of Alpha1-ATD

In 1963, Laurell and Erikkson[1] first described the high prevalence of emphysema in certain families. Afflicted family members were found to have an absence of the alpha band on serum protein electrophoresis. Alpha1-ATD is one of the most common genetically-linked lethal diseases among Caucasians, affecting approximately 1 in every 4000 in the US (2% to 3% of all emphysema cases).[2] For reasons that are unclear, however, many cases remain undiagnosed. This autosomal recessive condition involves a substitution or deletion mutation of a single amino acid codon of the alpha1 gene, located on chromosome 14. It occurs almost exclusively in Caucasians, usually of Northern European descent, but is also occasionally found in patients of Hispanic origin.

Alpha1-ATD predisposes to the rapid development of panacinar (affecting the whole acinus, the basic unit of the lung) emphysema through destruction of extracellular tissue matrix elastin. The disease develops rapidly in smokers and leads to emphysema 10 to 15 years earlier than in nonaffected smokers.[3] The average age emphysema presents in those with alpha1-ATD is the mid forties. Without smoking, many individuals remain disease-free and may have a normal lifespan. In these cases alpha1-ATD is considered to predispose, but not cause, emphysema. Alpha1-ATD should be suspected in a young former or current smoker with or without a family history of lung disease, and with an obstructive pattern on spirometry. Unless the true etiology of the problem is suspected however, the primary diagnosis of asthma may be made.

Alpha1-ATD linked with more than just emphysema. "Emphysema" is the first disease that comes to mind when one thinks of alpha1-ATD. However, the disorder has been associated with other clinical conditions. For example, The Z phenotype (see Molecular Basis for Alpha1-ATD) is also associated with hepatitis in the newborn and in children. Pathologic changes in the liver may be of various types, including mild portal fibrosis, chronic active hepatitis, and cirrhosis in the adult; in early infancy, hepatocellular necrosis may occur. Liver disease, however, is unusual in the adult patient with alpha1-ATD and has generally not been found to occur in the presence of lung disease.[4] In addition, certain vasculitic disorders have been associated with heterozygous alpha1-ATD and include ANCA (anti-neutrophilic cytoplasmic antibody) positive Wegener's granulomatosis.[5] Cases of necrotizing panniculitis have also been described in association with abnormalities in alpha1-AT phenotype. However, unpublished results from the NHLBI (National Heart, Lung and Blood Institute) Registry of over 1000 patients found no association with these conditions.

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