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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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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 polymers.8 A ...