Nodular regenerative hyperplasia (NRH) is an uncommon hepatic lesion often associated with noncirrhotic portal hypertension (PHT). We have noted that NRH and PHT are frequent occurrences in a colony of dogs with the genetic storage disease, mucopolysaccharidosis I (MPS-I). This observation provides the opportunity to study the histology and pathogenesis of NRH and noncirrhotic PHT in a new animal model. Thirteen of 32 dogs (41%) with MPS-I developed multiple portocaval shunts between 4 and 48 months of age that were grossly visible at necropsy. Seven of the 13 developed marked ascites, whereas all those without shunts and littermates (n = 24) heterozygous for the mutated alpha-L-iduronidase allele (carriers unaffected by the storage disease) did not. The large and medium-sized portal veins were widely patent without thrombosis or vascular malformations. Hepatic parenchymal fibrosis was absent or mild and did not correlate with shunt formation. All 32 livers had varying degrees of diffuse periportal hepatocellular hyperplasia with multifocal atrophy and compression of centrolobular cords (NRH) most prominent in dogs with shunts. Many small portal veins were reduced in diameter or absent, especially in animals with shunts. Noncirrhotic PHT and NRH appear to be related to the obliteration of small portal veins in these dogs, but the pathogenesis of this vascular change remains unknown.

Enzyme replacement is a potential therapy for mucopolysaccharidosis I (MPS I), a lysosomal storage disorder caused by alpha-L-iduronidase deficiency. Previous work showed improvement in the tissues of MPS I dogs treated intravenously for 3 months with recombinant human alpha-L-iduronidase (25,000 units or approximately 0.1 mg/kg/week). We have now treated an MPS I-affected dog for 13 months to assess the clinical effects of enzyme replacement. The treated dog gained more weight, was more active, and had less joint stiffness than the untreated littermate. Biochemical and histologic studies demonstrated uptake of alpha-L-iduronidase and decreased lysosomal storage in the liver, kidney, spleen, lymph nodes, synovium, adrenals, and lungs. The brain had detectable enzyme activity and decreased glycosaminoglycan storage although histologic improvement was not evident. Cartilage and heart valve did not show any detectable improvement. A fivefold higher dose (approximately 0.5 mg/kg) administered five times over 10 days to two other dogs resulted in higher tissue enzyme activity and similarly decreased glycosaminoglycan storage and excretion. Antibodies to human alpha-L-iduronidase were induced in all treated dogs and may be associated with immune complex deposition and proteinuria. Recombinant canine alpha-L-iduronidase also induced antibody formation to a similar degree. The results support the conclusion that enzyme replacement is a promising therapy for MPS I though immunologic complications may occur.

The storage of glycosaminoglycans (GAGs) within cells of the central nervous system of dogs with mucopolysaccharidosis I (MPS I) was studied. Lectins that detect these stored GAGs were applied to formalin fixed tissues from 5 MPS I-affected dogs, 2 of which were previously treated by littermate bone marrow transplantation (BMT), and from 2 unaffected littermate controls.In all transplant recipients there was reduced reactivity of the central nervous system (CNS) neurons with soybean agglutinin and horse gram agglutinin indicating that BMT results in reduced levels of those GAGs stored excessively in MPS I. Wheat germ agglutinin was found to react less strongly with cells from treated or untreated dogs despite its predicted binding to sugars in GAGs that are known to accumulate in MPS I. These findings, coupled with previously reported total brain GAG content, show that neuronal storage of GAG is reduced following BMT in canine MPS I. (The J Histotechnol 14:183, 1991)

Morphological changes in neurons with inborn defects of the lysosomal hydrolase, α-l-iduronidase, and with concomitant storage of glycosaminoglycans, were evaluated by Golgi staining in two animal models and compared to a similar study of a child with the same disease. Cortical pyramidal neurons in feline mucopolysaccharidosis type I often displayed axon hillock enlargements (meganeurites) and/or ectopic, secondary neuritic processes sprouting from this same region of the cell. The latter structures were prominent and often appeared longer than similar neurites reported in other neuronal storage discases. Although most meganeurites were aspiny, a few were observed which possessed spine-like processes or neurites. Other than these morphological changes in cortical pyramidal neurons, few other cell types displayed abnormalities demonstrable by Golgi impregnation. In the canine model of this disorder, abnormal Golgi-impregnated cortical neurons resembled more closely those seen in human mucopolysaccharidosis. That is, they possessed meganeurites which typically were aspiny in appearance. Ectopic neurite growth was not observed on any Golgi-impregnated neurons in the cases of canine or human mucopolysaccharidosis used in this study. The latter finding given the advanced ages of these cases, is consistent with the view that ectopic neuritogenesis seen in neuronal storage diseases may be subject to a developmental window, albeit one open well beyond the period of early postnatal maturation.

Veterinary Clinical PathologyVolume 7, Issue 2 p. 13-13 A Computerized Retrospective Study of Liver Enzyme Concentrations in Dogs Robert M. Shull D.V.M., Robert M. Shull D.V.M. College of Veterinary Medicine Cornell University Ithaca, New YorkSearch for more papers by this authorJohn B. Tasker D.V.M., Ph.D., John B. Tasker D.V.M., Ph.D. College of Veterinary Medicine Cornell University Ithaca, New YorkSearch for more papers by this authorFrederick L. Hiltz Ph.D., Frederick L. Hiltz Ph.D. College of Veterinary Medicine Cornell University Ithaca, New YorkSearch for more papers by this author Robert M. Shull D.V.M., Robert M. Shull D.V.M. College of Veterinary Medicine Cornell University Ithaca, New YorkSearch for more papers by this authorJohn B. Tasker D.V.M., Ph.D., John B. Tasker D.V.M., Ph.D. College of Veterinary Medicine Cornell University Ithaca, New YorkSearch for more papers by this authorFrederick L. Hiltz Ph.D., Frederick L. Hiltz Ph.D. College of Veterinary Medicine Cornell University Ithaca, New YorkSearch for more papers by this author First published: July‐August 1978 https://doi.org/10.1111/j.1939-165X.1978.tb00784.xCitations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume7, Issue2July‐August 1978Pages 13-13 RelatedInformation