This storage material had the characteristic ultrastructural appearance and location of that found in alpha-1-antitrypsin deficiency1,2, an inherited disorder in which a single amino acid substitution on the a-1-AT molecule interferes with secretion and results in a build-up of mutant a-1-AT in the rough endoplasmic reticulum3, with hepatotoxic results. There is some controversy as to whether or not the smooth ER is also involved2. The identity of the stored material in this case was confirmed by immunohistochemistry (fig.5), and blood work done on the day of the biopsy reported a serum a-1-AT level at 40% of the low normal value. This is higher than that expected for the ZZ phenotype of the disease, but consistent with the SZ and MS phenotypes. Subsequent protein electrophoresis confirmed an SZ phenotype.
This case is an example of the use of EM in identifying a metabolic storage disease from biopsy material. The quite characteristic ultrastructural appearance and site of the storage material in alpha-1-antitrypsin deficiency leaves little room for diagnostic doubt even in phenotypes with fairly subtle hepatocytic storage. EM diagnosis or confirmation can be rapid, inexpensive and certain in such cases.
n.b. The coincidence of cystic fibrosis and alpha-1-antitrypsin deficiency is clinically significant because high neutrophil proteinase activity in the lung, for which a-1-AT is antidotal, is thought to encourage the earlier establishment of Pseudomonas aeruginosa infection in these patients. Doring et al 4 report that a-1-AT deficiency may thus exacerbate the course of C.F. They also point out an interesting diagnostic complication, that P. aeruginosa infection can also increase serum a-1-AT levels, which may cause a congenitally low level to go undetected in the laboratory. Tissue diagnosis, and particularly E.M., may thus be even more crucial in assessing C.F. patients with early onset liver disease.
Society for Ultrastructural Pathology