CASE III:

Signalment

2 years-old, Nelore, Bos Indicus.

History

In the last 2 years several cattle in this farm developed a wasting syndrome and locomotor difficulties with kneeling posture.

Gross Pathology

Affected cow showed cachexia. The arteries, mainly the aorta, had diffusely rigid walls and were variably thickened. Their walls were expanded by extensive, coalescing, irregular, variably sized, gritty (mineralized) intramural plaques and nodules. These changes were most notable from the luminal (endothelial)

surface. The aortic semilunar valves were moderately thickened, irregular, and lacked their normal elasticity due to mineralization. The lung lobes failed to collapse and showed inelastic areas with a pumice stone-like appearance. Other lesions included kidneys with whitish areas in the cortex and medulla, calcified tendons and ligaments, Skeletal muscles had opaque and rough plaques of mineralization

Laboratory Results

None available

Microscopic Description

At areas of thickening the aorta wall, there are extensive mineral deposits in the intima which extends to the media disrupting the elastic lamina. Extensive multifocal mineral deposits thicken the perimysium of skeletal muscle. In these areas, the vessels show mineralization of the intima.

Contributor's Morphologic Diagnoses:

Aorta, tunica intima and media: mineralization, diffuse and severe

Skeletal muscle: perimysium: mineralization, multifocal and severe

Contributor's Comment:

Enzootic calcinosis refers to a group of diseases characterized by extensive mineral deposition in soft tissues, induced by ingestion of calcinogenic compounds present in certain toxic plants. Of the calcinogenic plants known to cause this condition, Solanum glaucophyllum (S. malacoxylon), a perennial shrub native to South America, is one of the most extensively studied. Enzootic calcinosis induced by this plant causes considerable economic losses to the livestock industry. Other plants are well-recognized causes of Enzootic calcinosis worldwide, including Solanum torvum, S. esuriale, S. verbascifolium, Nierembergia veitchii, N. rivularis, Cestrum diurnum, Trisetum flavescens, Stenotaphrum secundatum. All of these plants are within the Solanaceae family4-13, except for T. flavescens2 and possibly S. secundatum1, which is a grass in the family Poaceae. Animals in several parts of the world develop calcinosis from consuming specific toxic plants. The disease has been found in many countries and are responsible for great financial loss in livestock. Cattle, sheep, goats, horses and pigs develop calcinosis and the disease receives different denomination depending on the country (Table 1)6. As can be seen, in spite of the knowledge developed, some cases of calcinosis remain without a known cause in Israel, India, Nigeria6 and Brazil5. The slides submitted to this case study are from a bovive that was grazing in a Cerrado area where S. glaucophyllum and N. veitchii do not occurs5.

Calcinogenic plants contain one or more steroidal glycosides that are biologically active analogues of vitamin D3. Hydrolytic enzymes in intestinal, ruminal or other tissues or in the bacterial flora can cleave the sugar residue

from the glycoside, releasing the steroidal fragment, in most cases 1,25(OH)2D3. This excess of vitamin D hormone stimulates a calcium-binding protein synthesis and calcium and phosphate absorption, producing hypercalcemia and/or hyperphosphatemia. The hypercalcemic state depress PTH secretion and stimulates calcitonin secretion from the C cells of the thyroid. The formation of endogenous 1,25(OH)2D3 is inhibited because of the hypoparathyroidism, hypercalcemia, and/or hyperphosphatemia. The hypercalcitonism coupled with the hypercalcemia and hyperphosphatemia results in osteopetrosis. The excessively absorbed mineral cannot be physiologically accommodated, and the deposition in soft tissues results in calcinosis. It is suggested that 1,25(OH)2D3 induces cellular differentiation and the synthesis of a calcifiable matrix. Calcium salts are deposited in soft tissues, including the aorta, heart, kidney, tendons and ligaments3,6,10,12,13.

Calcinogenic plants intoxication produces rapid wasting and marked elevations of the calcium and phosphate levels in the blood. The patterns of these elevations of blood electrolytes as well as the soft tissue mineralization are comparable to those produced by intoxication by vitamin D. The typical wasting syndrome is seen clinically when animals are forced to eat large quantities of the leaves. The animals develop kyphosis with contraction of the tendons and ligaments, resulting in an inability to completely to straighten their front limbs and to a complete kneeling posture.. Contraction of the abdominal aponeurosis gives a unique tucked-up line to the abdomen, resulting in affected animals having a racehorse-like appearance. Many animals develop severe vascular and pulmonary disease as a result of irregular or occasional exposure to the plant because of mineralization and ossification of interalveolar septa in the lung adult animals are most commonly affected, usually producing progressive debility. The earliest signs are those of stiffness and wasting. There is subtle progression to permanent lameness resulting from contraction of the tendons. At this stage, affected animals often are excitable, tire easily if made to exercise, and may show signs of acute cardiac insufficiency. If they are removed from affected areas, the stiffness, and deformity are not lessened, but the wasting is stopped, and the animals gain weight if good pasture is available1,2,4,5,7-9,11.

Necropsy examination reveals widespread mineralization of tissues, particularly the aorta, heart, and lungs, often with areas of ossification. Frequently major arteries including the thoracic aorta, and pulmonary arteries has mineralized irregular plates in the endothelial surface that were inelastic, firm, and thickened. Soft tissue calcification can also be observed on Skeletal muscles, heart, lungs, and kidneys1,2,4,5,7-9,11.

The main histological findings include calcium deposits in soft tissues like degenerated and mineralized elastic fibers of intima and media of the vessels, degeneration, necrosis and calcification of Skeletal and cardiac muscle fibers. The kidneys can show severe mineralization of the arteries and the interstitium2,4,5,7-9,11.

Contributing Institution

Universidade Federal de Mato Grosso, Faculdade de Medicina Veterin?ria, Hospital Veterin?rio, Laborat?rio de Patologia Veterin?ria,
https://www.ufmt.br/ufmt/site/

JPC Diagnoses

1. Skeletal muscle: Mineralization, chronic, multifocal to coalescing, severe, with fibrosis and myocyte degeneration, necrosis, atrophy, and loss.

2. Aorta: Mineralization, chronic, multifocal to coalescing, severe, with myxomatous degeneration, fibrosis, and smooth muscle hypertrophy, hyperplasia, and disarray.

JPC Comment

The contributor provides an outstanding review of enzootic calcinosis due to Vitamin D analog-containing plants.

A review of other causes of soft tissue mineralization is likely useful at this point. There are five basic mechanisms of soft tissue mineralization: dystrophic, metastatic, idiopathic, iatrogenic, and calciphylaxis.

Dystrophic calcification is the most common form of tissue mineralization. Dystrophic calcification results from mineral deposition in injured and dead cells. This form of mineralization results from both intracellular and extracellular events. Cellular damage leads to calcium influx into the cell, where it is initially sequestered within mitochondria. Another event preceding dystrophic mineralization is the release of phosphate-binding proteins within the cell.14 Cellular damage progresses; irreversible mitochondrial damage results in the release of calcium within the cytoplasm, which, bound with phosphate, results in the formation of crystalline mineral. Extracellular factors which influence the rate and extent of dystrophic mineralization include ischemia and chronic inflammation. Inflammatory mediators such as tumor necrosis factor, interleukin-1 beta, and IL-6 also contribute to dystrophic mineralization.14 Serum calcium and phosphorus levels are within normal limits.

Metastatic calcification is a systemic manifestation of abnormal calcium and phosphorus levels in the blood. When the calcium-phosphorus product exceeds 70 mg/dL, metastatic calcification will occur. Tissues where this process typically occurs are those that experience rapid changes in pH and have high levels of carbonic anhydrase. These include the kidney, lung, gastric mucosa, and subpleural intercostal musculature. In the kidney and lung, mineralization is concentrated in the basement membranes of vessels and the alveolar septa. In the gastric mucosa, the middle stripe of the gastric fundus is typically affected. This form of calcification may resolve with correction of the abnormal levels of calcium and phosphorus (if possible ? a common cause is chronic renal failure, which is not truly correctable). Metastatic calcification of the lung (inappropriately named "uremic pneumonitis") is likely the most life-threatening form of metastatic calcification, as it is exceedingly difficult to transfer oxygen across a mineralized alveolar septum and vascular basement membrane.

Idiopathic calcification, as the name suggests, results from deposition of calcium salts in the presence of normal calcium and phosphorus levels and in the absence of tissue damage. A common example of idiopathic calcification in dogs is calcinosis cutis, in which dermal collagen is mineralized in animals with hypercortisolism. Less common forms include various types of tumoral calcinosis, which is also most common in dogs.

Iatrogenic calcification, as the name implies, is that which is often seen in animals being treated with calcium- or phosphorus-containing substances. One of the more common causes of this is seen in animals that are treated with intravenous administration of calcium gluconate used in the management of eclampsia, cardiac dysrhythmia due to hyperkalemia, and hypoparathyroidism.

Finally, today's case is an excellent example of the fifth cause of tissue mineralization, calciphylaxis. Calciphylaxis is the term used for systemic calcification in animals that are sensitized by ingestion or administration of so-called calciphylaxis-inducing agents (to include vitamin D analogs, as seen in this case, or parathyroid hormone) and subsequently exposed to a challenge substance such as trauma, iron, or aluminum.15

The changes noted in the aorta are difficult to sort out based solely on an HE section. A Movat's trichrome is extremely helpful in degenerative changes affecting arteries, and is a must in this case. As this stain provides differential staining of smooth muscle, collagen, and elastin, it is excellent for differentiating and characterizing these common components of degenerating arteries. On the H&E section in this case, areas of proliferating ground substance and collagen are extremely difficult to differentiate, and application of Movat's pentachrome allowed for trainees to properly identify degenerative changes in the aorta.

References


Click the slide to view.


03-1. Skeletal muscle, ox.


03-2. Heart with aorta , ox.


03-3. Aorta and skeletal muscle , ox.


03-4. Aorta , ox.


03-5. Skeletal muscle , ox.


03-6. Skeletal muscle , ox.


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