As such, lung disease and liver disease of A1AT deficiency appear unrelated, and the presence of one does not appear to predict the presence of the other. Between 10 and 15% of people with the PiZZ genotype will develop liver fibrosis or liver cirrhosis, because the A1AT is not secreted properly and therefore accumulates in the liver. The mutant Z form of A1AT protein undergoes inefficient protein folding (a physical process where a protein chain achieves its final conformation). 85 percent of the mutant Z form are unable to be secreted and remain in the hepatocyte. Nearly all liver disease caused by A1AT is due to the PiZZ genotype, although other genotypes involving different combinations of mutated alleles (compound heterozygotes) may also result in liver disease. A liver biopsy in such cases will reveal PAS-positive, diastase-resistant inclusions within hepatocytes. Unlike glycogen and other mucins which are diastase sensitive (i.e., diastase treatment disables PAS staining), A1AT deficient hepatocytes will stain with PAS even after diastase treatment - a state thus referred to as "diastase resistant". The accumulation of these inclusions or globules is the main cause of liver injury in A1AT deficiency. However, not all individuals with PiZZ genotype develop liver disease (incomplete penetrance), despite the presence of accumulated mutated protein in the liver. Therefore, additional factors (environmental, genetic, etc.) likely influence whether liver disease develops. Diagnosis
The gold standard of diagnosis for A1AD consists of blood tests to determine the phenotype of the AAT protein or genotype analysis of DNA.
Four percent of them carry the PiZ allele; between 1 in 625 and 1 in 2000 are homozygous.Another study detected a frequency of 1 in 1550 individuals. The highest prevalence of the PiZZ variant was recorded in the northern and western European countries with mean gene frequency of 0.0140. Worldwide, an estimated 1.1 million people have A1AT deficiency and roughly 116 million are carriers of mutations.A1AD is one of the most common genetic diseases worldwide and the second most common metabolic disease affecting the liver. History
A1AD was discovered in 1963 by Carl-Bertil Laurell (1919–2001), at the University of Lund in Sweden. Laurell, along with a medical resident, Sten Eriksson, made the discovery after noting the absence of the α1 band on protein electrophoresis in five of 1500 samples; three of the five patients were found to have developed emphysema at a young age.The link with liver disease was made six years later, when Harvey Sharp et al. described A1AD in the context of liver disease. Research
Recombinant and inhaled forms of A1AT are being studied. References
External links

Alpha-1-antitrypsin deficiency on Orphanet