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The classical, most common form of alpha-1-antitrypsin (a1AT) deficiency is caused by homozygosity (ZZ) for the autosomal co-dominant Z mutant allele of a1AT.1 This is referred to as “PIZZ” in World Health Organization nomenclature.2 ZZ homozygotes may be as common as 1 in 2000 births in many North American and European populations, although the disease is under-recognized and many patients go undiagnosed. The mutant Z gene is especially common in populations derived from Scandinavian or British Isles gene pools (Figure 26–1).

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FIGURE 26–1
Graphic Jump Location

Political map of Western European Nations overlaid with indicators of relatively increased a1AT mutant gene frequencies. Red lines circumscribe areas of original populations of high frequency of the a1AT mutant Z gene and yellow lines areas of a1AT mutant S gene high frequency. Thicker lines denote areas of highest frequency in original populations in Scandinavia, especially Denmark, and the Iberian Peninsula.

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a1AT is a glycoprotein primarily synthesized in the liver, which is normally secreted into the serum where its function is to inhibit non-specific, neutrophil protease-induced host tissue injury.3–5 The protein product of the mutant Z gene accumulates within hepatocytes rather than being efficiently secreted. The result is a “deficient” level of a1AT in serum. ZZ homozygous adults have a markedly increased risk of developing emphysema by a loss-of-function mechanism in which insufficient circulating a1AT is available in the lung to inhibit connective tissue breakdown by neutrophil proteases. Within the hepatocyte, the accumulated a1AT mutant Z protein may attain an altered conformation in which many a1AT mutant Z molecules aggregate to form large polymers. ZZ homozygous children and adults may develop liver disease and hepatocellular carcinoma because the intracellular accumulation of a1AT mutant Z protein triggers cell death and chronic liver injury.6,7 There are many other, uncommon a1AT alleles, other than the normal, wild-type M and the most common disease-associated Z allele. Most of the other alleles are not associated with liver disease, with the notable exception of the S mutant allele which when present in a compound heterozygote with Z, a so-called SZ heterozygote, can cause liver and lung disease in some patients.

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The critical step in the pathophysiology of a1AT deficiency is retention and accumulation of the newly synthesized mutant Z protein molecule within the endoplasmic reticulum (ER) of hepatocytes (Figure 26–2).8,9 The liver synthesizes large quantities of a1AT protein every day. During biosynthesis, the a1AT mutant Z gene is appropriately transcribed, and then the nascent mutant Z polypeptide chain is assembled on the ribosome and translocated into the ER lumen in the usual way. However, in the ER the mutant Z protein molecule folds slowly and inefficiently into its final, secretion-competent conformation. The mutant Z molecule may attain a variety of abnormal conformations including a unique state in which multiple molecules aggregate to form large protein ...

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