JPC SYSTEMIC PATHOLOGY
Signalment (JPC #2019268): A mature, female New Zealand white rabbit
HISTORY: This rabbit became depressed and emaciated.
HISTOPATHOLOGIC DESCRIPTION: Bone: Diffusely, thickening the epiphyseal, metaphyseal, and cortical bone, as well as the few remaining medullary trabeculae, are variably thick bands of lamellar bone (osteosclerosis) lined by wide seams of a deeply basophilic matrix with numerous embedded osteoblasts. Layers of lamellar bone are separated by prominent irregular basophilic lines (cementing lines). Cementing lines are frequently smoothly contoured (resting lines) and rarely are scalloped (reversal lines). There is a generalized absence of osteoclastic activity. The articular cartilage is either thin and irregular or thickened. Focally, the thickened cartilage contains variably sized clefts or is multifocally frayed with small clefts running perpendicular to the joint space (fibrillation). There are focal erosions with thinning of the underlying cartilage and irregularly clustered chondrocytes (chondrones). The articular cartilage is multifocally eosinophilic (loss of proteoglycans). There are multifocal areas along the margin of the bone where the periosteum and adjacent bone is thickened, undulant, irregular and punctuated by remodeling and areas of basophilic matrix.
- Bone: Osteosclerosis, diffuse, moderate, with osteoblast hyperplasia and abundant basophilic osteoid matrix, New Zealand White rabbit, lagomorph.
- Articular cartilage: Degeneration, diffuse, moderate, with multifocal erosions, fibrillation.
CONDITION: Hypervitaminosis D
- Intestinal uptake of calcium is not influenced by Vitamin D in rabbits and is proportional to their diet and rely on renal excretion to regulate serum calcium levels
- Hypercalcemia in rabbits leads to hypercalcemia arteriosclerosis
- Vitamin D functions to maintain serum calcium via 3 mechanisms:
- Increasing intestinal absorption of calcium (and phosphorus);
- Enhancing parathyroid hormone (PTH) dependent renal tubular resorption of calcium (and excretion of phosphorus);
- Enhancing parathyroid hormone (PTH) dependent mobilization of calcium (and phosphorus) from bone
- Vitamin D is also required for mineralizing osteoid to form bone
- Normal sources of vitamin D include:
- Provitamin D2 (ergosterol), from plants > converted to vitamin D2 (ergocalciferol) by exposure to UV light
- Provitamin D3 (7-dehydrocholesterol) from animal tissues > converted to vitamin D3 (cholecalciferol) in skin by exposure to UV light
- Sources of intoxication:
- Acute intoxication; most common in dogs and cats:
- Cholecalciferol rodenticide intoxication
- Chronic intoxication; more common in rabbits; cattle, horses and sheep:
- Iatrogenic: Excessive dietary supplementation
- Ingestion of plants containing the toxic principle 1,25-dihydroxycholecalciferol-glycoside (most active form of vitamin D3): Solanum malacoxylon, Cestrum diurnum, and Trisetum flavescens, and alfalfa
- Acute intoxication; most common in dogs and cats:
- Excess vitamin D is stored mainly in fat and is released as the fat is metabolized
- Vitamin D3 is considered more toxic than vitamin D2
- "Hyena disease" in calves: Has been associated with Vitamin A toxicity; experimentally induced by injecting newborn calves with a combination of high doses of vitamins A and D on day 1 after birth, and daily oral feeding of exceedingly high doses of Vitamin A mixed with milk substitute for up to 8 weeks; "hyena disease" results from relative underdevelopment of the caudal body structures due to premature growth-plate closure in long bones of the pelvic limbs and lumbosacral vertebrae and, to a lesser extent, the pectoral limbs; the role of Vitamin D is not clear, but is thought to be a factor
- Soft tissue changes: Most common in the acute toxicosis
- Increased vitamin D2, D3 or 1, 25- dihydroxycholecalciferol-glycoside > increased osteoclastic activity; decreased urinary excretion and increased intestinal absorption of calcium > hypercalcemia and metastatic calcification
- Tissues with an alkaline compartment are predisposed to mineralization (intima and media of arteries, endocardium, myocardium, gastric mucosa, lung and kidney)
- Bone changes: Most common in the chronic toxicosis
- Osteosclerosis or osteopenia of bone depending on dietary calcium and pattern of exposure
- First response is widespread, intense osteoclastic activity
- With continued administration: Abnormal matrices produced by osteoblasts continue to accumulate and obliterate the cancellous spaces, forming a mosaic of basophilic matrix, eosinophilic matrix, and newly formed, coarse, woven bone separated by resting lines
- Intermittent administration causes surges of osteosynthetic activity with abnormal matrix deposition, maturation, and mineralization, which produce multiple layers separated by broad, basophilic resting lines
TYPICAL CLINICAL FINDINGS:
- Depression, loss of appetite, dehydration
- Cessation of growth or weight loss, progressive emaciation and weakness
- Impaired mobility
- Polydipsia, polyuria, and reduced urine specific gravity
- Hypercalcemia, hyperphosphatemia early; return to normal with chronicity
TYPICAL GROSS FINDINGS:
- Acute toxicosis:
- Gastric and small intestinal hemorrhage with areas of myocardial discoloration
- Kidneys and other organs: Multifocal tan to gray mineralized areas in the cortices
- Heart, endocardium and arteries (generally aorta and large arteries): Raised mineralized irregularities on both intimal and adventitial surfaces
- Chronic toxicosis:
- Bone: Long bones especially; epiphyses and growth plates are normal; thickened sclerotic metaphyses; loss of metaphyseal spongiosa extending into diaphysis; sparse marrow, replaced by dilated veins and loose connective tissue
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Pathognomonic bone lesions:
- Acute toxicosis: severe osteopenia with abundant osteoclasts in Howship’s lacunae
- Chronic toxicosis: Osteoblastic production of fibrillary, highly basophilic matrix that irregularly coats the surface of trabeculae, endosteum and the periosteal cortex
- Rarefaction or osteosclerosis of bone depending on level of dietary calcium and exposure to excess vitamin D
- Soft tissue mineralization, especially fibroelastic tissues and basement membranes of renal tubules and glomerular capsule, tunica intima and media of aorta and large vessels
- Kidney: mineralization of tubular and glomerular basement membranes
ADDITIONAL DIAGNOSTIC TESTS:
- Serology to look for elevated serum calcium and phosphorus
- Other toxic osteodystrophies:
- Vitamin A: Excessive retinoids found in plants (sweet potatoes) and meat (liver) or drug toxicity; causes multifocal premature closures of growth plates with growth deformities, osteoporosis and pathologic fractures; retinoids cause degeneration and necrosis of chondrocytes and osteoblasts in growing animals; stimulate osteoblasts in adult animals
- Lead: Ingestion of lead-based paints; causes characteristic “lead line”, an osteosclerotic band of bone parallel to the growth plate; acid-fast lead inclusions within the osteoclasts; lead is toxic to osteoclasts and bone mineral containing lead is somewhat resistant to osteoclasis
- Fluoride: Ingestion of rock phosphates naturally high in fluoride; grazing pastures with high fluoride (nature or contamination); causes osteosclerosis at chronic low toxic levels; chronic higher levels cause osteopenia and periosteal bone formation; low levels of fluoride are stimulatory to osteoblasts; the mechanism of higher levels of chronic fluoride are unclear; may be a direct toxic injury to osteoblasts
- Spontaneous atherosclerosis of New Zealand white rabbits; inherited disorder of aortic calcification; lesions seen in rabbits as young as 6 weeks of age
- Iatrogenic overdoses, accidental dietary over-supplementation or cholecalciferol rodenticide exposure can cause significant disease in most species
- Grazing animals, vitamin D glycoside-containing plant toxicity is the most frequent cause: Solanum malacoxylon, Cestrum diurnum, and Trisetum flavescens
- Cattle: chronic infection by Mycobacterium avium paratuberculosis (Johne’s disease) can lead to mineralization of vessels and heart
- Cats appear to be more sensitive to vitamin D toxicity than dogs
- Chronic vitamin D toxicity and FeLV infection are causes of osteopetrosis in the cat
- Guinea pig, hyperphosphatemia is a more consistent finding in vitamin D toxicosis while serum calcium levels are a poor indicator of vitamin D status.
- Two-toed sloths: renal disease and vitamin D toxicity were suspected of causing soft tissue mineralization
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