Histopathologic and Ultrastructural Alterations of White Liver Disease in Sheep Experimentally Depleted of Cobalt

Abstract

Many cobalt-deficient sheep develop liver lesions known as ovine "white liver" disease, but the etiology of these changes is controversial. It has been suggested that cofactors are required for development of liver damage in cobalt-deficient sheep. In this study, one group of lambs (n = 5) was fed a diet low in cobalt (4.5 micrograms/kg) while a group of control lambs (n = 4) received the same diet after it had been supplemented with cobalt (1000 micrograms/kg). All cobalt-depleted lambs had reduced growth rate, anorexia, lacrimation, and alopecia, and they eventually became emaciated (mean body weight at end of study: 83% of initial body weight). Plasma concentrations of bilirubin and serum activity of glutamate-oxaloacetate transferase were elevated in these animals, while plasma concentrations of vitamin B12 were reduced (less than 220 pmol/L from day 42). Fatty degeneration of the liver associated with reduced concentrations of vitamin B12 (14.5 pmol/g) was seen in these animals at necropsy at 196 days. Microscopic liver lesions included accumulation of lipid droplets and lipofuscin particles in hepatocytes, dissociation and necrosis of hepatocytes, and sparse infiltration by neutrophils, macrophages, and lymphocytes. Ultrastructural hepatocytic alterations included swelling, condensation and proliferation of mitochondria, hypertrophy of smooth endoplasmic reticulum, vesiculation and loss of arrays of rough endoplasmic reticulum, and accumulation of lipid droplets and lipofuscin granules in cytoplasm of hepatocytes. No liver lesions were seen in control lambs. The results of this study indicate that cofactors are not a prerequisite to development of hepatic damage in cobalt-deficient sheep. Reduced activities of the vitamin B12-dependent enzymes, methylmalonyl CoA mutase and methionine synthase, and lipid peroxidation are of likely pathogenetic importance in the development of the lesions.

Degenerative Liver Disease in Young Beagles with Hereditary Cobalamin Malabsorption Because of a Mutation in the Cubilin Gene

“…This finding may also be linked to hyperhomocysteinemia secondary to cobalamin deficiency, because it has been shown experimentally that hyperhomocysteinemia induces expression and synthesis of monocyte chemoattractant protein‐1 and other mediators of inflammation such as nuclear factor kappa B, interleukin (IL)‐1b, IL‐6, and IL‐8 in liver tissue homogenates, suggesting that homocysteine may contribute to chronic inflammation in the liver 17, 21. Degenerative liver disease is well described in lambs and goats with decreased cobalt intake and hypocobalaminemia 12, 13, 22. Features of ovine white liver disease are fatty changes, hepatocellular degeneration around central veins, and lipofuscin accumulation in hepatocytes and Kupffer cells 12, 22.…”

“…Similar to human patients, dogs typically present at a young age with inappetence, weakness, and failure to thrive 4, 5, 6, 8, 11. Although liver disease is recognized in cobalamin‐deficient farm animals, especially lambs,12, 13 it has not been reported in dogs suffering from hereditary cobalamin malabsorption. The aim of the present case series was to describe the clinical and histopathologic findings of liver disease in 2 client‐owned beagles suffering from genetically confirmed cobalamin malabsorption.…”

Abnormal Increase in the Expression Level of Proliferating Cell Nuclear Antigen (PCNA) in the Liver and Hepatic Injury in Rats with Dietary Cobalamin Deficiency

“…In addition, in sheep with Cbl deficiency induced by the depletion of cobalt in their diet, abnormal accumulation of lipids and functional disorder are observed in the liver (13)(14)(15). However, mechanisms by which these abnormalities observed in the liver are induced by Cbl deficiency have not yet been well studied.…”

Hepatic Lipodystrophy in Galloway Calves

“…3,18,56 In addition, qualitative and quantitative species differences in the liver capacity of glucuronidation are said to be responsible for insensitivity to senecio-alkaloids of some animal species. 16 A further type of hepatic lipidosis associated with encephalopathy, named ''white liver disease,'' has been described concurrently with cobalt deficiency in sheep 22,24 and goats, 21 causing a decreased activity of the vitamin B12-dependent enzymes methyl-malonyl-CoA mutase 23 and methionine synthase 22 and a consequent accumulation of branched-chain fatty acids (BCFAs) in hepatocytes. 24 Histologically, livers were characterized by fatty degeneration of hepatocytes, cholangiolar hyperplasia, and hepatic megalocytosis similar to the findings observed in this study but also by a prominent lipofuscin accumulation in degenerated hepatocytes and in Kupffer cells, 24,50,51 which was absent in the cases described here.…”