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Numerous intracytoplasmic globules

Intracytoplasmic eosinophilic globules are numerous.

Such globules represent polymerized mutant protein retained in the rough endoplasmic reticulum of the hepatocyte.

PAS stain highlights the cytoplasmic globules which are numerous.

Immunostaining for alpha-1 antitrypsin can also be used to confirm this diagnosis.

Cirrhosis is present, and is found in approximately 37% of adult PiZZ patients at the time of death.


Alpha 1-antitrypsin (AAT) deficiency is an inherited metabolic disease in which mutations in the coding sequence of the serine protease inhibitor, alpha 1-antitrypsin. Misfolding of the protein leads to sequestration of AAT within the endoplasmic reticulum of the hepatocyte, preventing its export. Therefore there is a deficiency in the circulating alpha 1-antitrypsin concentration, predisposing to early-onset panlobular emphysema, even in nonsmokers (Black). Also, abnormal accumulation of the glycoprotein in hepatocytes results in programmed cell death, hepatic inflammation, fibrosis, and cirrhosis.

The gene for alpha 1-antitrypsin is on the long arm of chromosome 14, and has been mapped to 14q31–32 (Darlington). The condition is inherited as an autosomal recessive disorder with codominant expression, as each allele contributes 50% of the total circulating enzyme inhibitor. To date, more than 100 alleles have been identified.

Phenotypes are classified by protein product migration patterns in gel electrophoresis, which define the allelic genotypes. Disease states are associated with mutations in the normal gene product, designated PiM, which yields the most common deficiency variants PiS (expressing 50–60% of AAT compared to normal levels) and PiZ (expressing 10–20% of AAT). PiZ is most commonly secondary to a single amino acid substitution of lysine for glutamate at position 342 in the coding sequence.

For example, PiMM designates the normal homozygous phenotype (or the wild-type) with normal serum levels of AAT. PiSS, PiMZ or PiSZ would be heterozygotes which would have approximately 40-60% of normal levels of AAT, whereas PiZZ individuals would have less than 15% of normal levels.

The mechanisms of lung and liver injury are different. Lung injury results from a deficiency in circulating alpha 1-antitrypsin, allowing uninhibited proteolytic damage to the connective tissue of the lung. Lung injury is therefore regarded to occur as a result of "loss of function," while in contrast, liver disease occurs because of "gain of function", as the retained alpha 1-antitrypsin glycoprotein in the endoplasmic reticulum contributes directly to liver injury.


Severe alpha 1-antitrypsin deficiency (PiZZ) is found in approximately 1:3500 live births. It may present with asymptomatic abnormal liver enzymes indistinguishable from other causes of abnormal enzymes, clinical manifestations of advanced cirrhosis, or hepatocellular carcinoma.


Currently there is no approved treatment for the liver disease due to alpha 1-antitrypsin deficiency, apart from liver transplantation. Patients with emphysema may be given intravenous purified pooled human plasma alpha 1-antitrypsin, known as "augmentation therapy"


Just over one-third of susceptible adults with the most severe phenotype, PiZZ, develop clinically significant liver injury (Fairbanks). The clinical presentation of liver disease is variable, and the predisposing genetic and environmental factors that allow some individuals to liver disease while sparing others remain unknown.


AAT deficiency is an autosomal recessive disorder with codominant expression, as each allele contributes 50% to the gene product.

PiMM is the homozygous wildtype with normal levels of AAT. The most common mutations are designated PiZ or PiS, and thus, PiMZ or PiSZ heterozygotes would have reduced levels of AAT. PiZZ individuals have the most reduced levels and thus, would be most likely to have clinical symptoms.

The clinical presentation is varied and can range from chronic hepitatis, cirrhosis to hepatocellular carcinoma.


Fairbanks KD, Tavill AS. Liver disease in alpha 1-antitrypsin deficiency: a review.Am J Gastroenterol. 2008 Aug;103(8):2136-41.

Black, LF, Kueppers, F. Alpha 1-antitrypsin deficiency in nonsmokers. Am Rev Respir Dis 1978

Darlington, GJ, Astrin, KH, Muirhead, SP, et al. Assignment of human alpha 1-antitrypsin to chromosome 14 by somatic cell hybrid analysis. Proc Natl Acad Sci USA 1982

Eriksson, S, Carlson, J, Velez, R. Risk of cirrhosis and primary liver cancer in alpha 1-antitrypsin deficiency. N Engl J Med 1986;314:736–739

Last updated: 2012-07-08
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