Clinicopathological Phenotype of Autosomal Recessive Cholesterol Deficiency in Holstein Cattle

Mock, T.; Mehinagic, K.; Menzi, F.; Studer, E.; Oevermann, A.; Stoffel, M.H.; Drögemüller, C.; Meylan, M.; Regenscheit, N.

The most consistent clinical features in the CD calves were intermittent diarrhea and failure to thrive associated with hypocholesterolemia and low triglyceride concentrations. While the clinical signs were unspecific and of moderate intensity, the CD-affected animals had distinctly lower blood cholesterol and triglyceride values than the control calves. The 2.5year-old heifer showed similarly low values in cholesterol and triglycerides, but the most prominent clinical features (after resolution of the stomatitis) were the neurologic symptoms. However, this animal had also shown intermittent diarrhea as a calf, based on which the pedigree of the heifer was reviewed, and it was subjected to a genetic test. Indeed, the pathological phenotype of the homozygous APOB mutant heifer was comparable to the phenotype of the 5 affected calves. Taking the pathological findings of steatorrhea, the histological and TEM phenotype of lipid vacuole accumulation within the enterocytes of the tips of the villi in the small intestine and the clinical symptoms of hypocholesterolemia, low triglyceride concentration, and the neurologic symptoms into account, bovine CD is highly similar to human FHBL. 4, 5 Acanthocytosis, described as one of the earliest laboratory features of FHBL in humans, was present in one calf. 5, 6 Over 60 truncating APOB mutations have been identified as causes for FHBL. 5 We previously demonstrated that the mutant proteins in the liver do not fulfill any physiological function in cattle homozygous for the bovine APOB mutation. 3 Therefore, it is highly probable that both physiological APOB protein isoforms are missing. Currently, it is not known if mutant APOB proteins are expressed in CD-affected cattle or not, and this should be subject to further investigation. 3 Impaired function of human APOB-100 protein results in decreased triglyceride export (by LDL receptormediated endocytosis) from the liver, which in turn leads to the development of fatty liver. 7 None of the investigated cattle had signs of fatty liver (hepatic steatosis), leading to the assumption that hepatic steatosis due to APOB-100 protein dysfunction is not a feature of CD in cattle. Alternatively, the absence of hepatic steatosis in our CD calves and heifer might be explained by the differences in fat metabolism between ruminants and humans. In humans, most of the de novo fatty acid synthesis takes place in the liver with glucose as a basic substrate. 8, 9 In ruminating animals, acetate absorbed from the rumen is the substrate for direct de novo synthesis of fatty acids. 8 Acetate is produced by microbial fermentation of cellulose in the rumen and stored in adipose tissue as well as used for milk fat synthesis in the mammary gland of lactating animals. 8, 10 Thus, the main site of fatty acid synthesis in ruminants is the adipose tissue and the mammary gland, not the liver. 8, 11 However, this applies to ruminating animals, ie, in our case animals no. 1 and 6, as calves no. 2-5 were still mostly fed with milk. Therefore, intestinal absorption may still have played a more important role in lipid intake and digestive processes in these calves may have been more comparable to the human fat metabolism. This explanation is supported by the fact that the calves on a diet milk based were cachectic, whereas the 2 ruminating animals had still some abdominal fat reserves. This might suggest that the specific metabolism of ruminants allows for the accumulation of some fat reser