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Brief aetiology (Introduction)

 * Hypocalcaemia occurs just before or after parturition
 * A depression of the levels of ionised calcium in tissue fluids (the basic biochem of milk fever)
 * A transient period of subclinical hypocalcaemia (total plasma calcium <1.9mmol/L) occurs at onset of lactation, caused by an imbalance between calcium output in the colostrum and influx of calcium to the extracellular pool from intestine and bone
 * The onset of lactation results in a sudden large demand on the calcium homeostasis
 * A cow can lose nine times as much calcium in a single milking as that present in the entire plasma calcium pool of the cow
 * Calcium lost from the plasma pool must be replaced by increasing intestinal absorption and bone resorption of calcium.
 * During dry period, calcium requirements are minimal but at parturition the cow must mobilise 30g or more of calcium into the calcium pool per day

Detailed physiology

 * endocrine pathways involved in parturition and lactation
 * calcium balance and metabolism (dietary sources, production by the body, homeostasis)

Failure of homeostasis (processes involved in development of hypocalcaemia)

 * Hypocalcaemia occurs in spite of apparently adequate function of the parathyroid and vitD endocrine system, and most cows adapt within 48hrs after calving by increases in plasma conc of parathyroid hormone and D vit at the onset of hypocalcaemia
 * They mobilise calcium by increasing intestinal absorption and bone resorption
 * About 5-20% of adult cows are unable to maintain plasma Ca and consequently develop severe hypocalcaemia (total plasma calcium <1.0-1.4 mmol/L)
 * This requires treatment
 * Most likely in adult dairy cows in third parity and older
 * 4-9% with low case fatality
 * Most commonly within 48h after calving but also occurs several weeks before or after
 * Prepartum diets high in Ca are common factors
 * 3 progressively worst stages that include clinical signs: anorexia, ruminal atony, scant faeces, inactivity, general muscular weakness leading to sterna recumbency with lateral kink of neck, circulatory collapse with collapsed veins and weak pulse, dry muzzle, mental depression, hypothermia, weak heart sounds, dilated and sluggish pupils, ruminal stasis and bloat, lateral recumbency, tachycardia, death in few to several hours
 * <span style="font-family: "Arial","sans-serif"; font-size: 12.0pt; line-height: 115%;">Clinical pathology: hypocalcaemia, hypophosphatemia, variable serum magnesium, increased creatine phosphokinase (CPK), and aminotransferase (AST) due to ischemic muscle necrosis
 * <span style="font-family: "Arial","sans-serif"; font-size: 12pt; line-height: 115%;">Diagnostic confirmation: hypocalcaemia and response to treatment with calcium borogluconate IV. Also calcium chloride in oral gel.
 * <span style="font-family: "Arial","sans-serif"; font-size: 12.0pt; line-height: 115%;">Clinical pathology: hypocalcaemia, hypophosphatemia, variable serum magnesium, increased creatine phosphokinase (CPK), and aminotransferase (AST) due to ischemic muscle necrosis
 * <span style="font-family: "Arial","sans-serif"; font-size: 12pt; line-height: 115%;">Diagnostic confirmation: hypocalcaemia and response to treatment with calcium borogluconate IV. Also calcium chloride in oral gel.
 * <span style="font-family: "Arial","sans-serif"; font-size: 12pt; line-height: 115%;">Diagnostic confirmation: hypocalcaemia and response to treatment with calcium borogluconate IV. Also calcium chloride in oral gel.
 * <span style="font-family: "Arial","sans-serif"; font-size: 12pt; line-height: 115%;">Diagnostic confirmation: hypocalcaemia and response to treatment with calcium borogluconate IV. Also calcium chloride in oral gel.
 * <span style="font-family: "Arial","sans-serif"; font-size: 12pt; line-height: 115%;">Diagnostic confirmation: hypocalcaemia and response to treatment with calcium borogluconate IV. Also calcium chloride in oral gel.

<span style="font-family: "Arial","sans-serif"; font-size: 12.0pt; line-height: 115%;">Three factors affect calcium homeostasis and variations in one or more of them may be important in causing the disease in any individual. > <span style="font-family: "Arial","sans-serif"; font-size: 12pt; line-height: 115%;">Recent studies have shown that the secretion of these two hormones is similar in most cows with or without milk fever. However, about 20% of cows treated for parturient paresis experience relapsing episodes of hypocalcaemia which require further treatment. These cows fail to produce adequate levels of 1,25-dihydroxyvitamin D at the onset of lactation (non-relapsing cows have a two-fold greater production of D). Following treatment of hypocalcaemia with calcium salts IV and restoration of ruminal and intestinal motility, non-relapsing cows establish calcium homeostasis over the next 3-4 days by increasing intestinal absorption of calcium which is activated by a sufficient levels of 1,25-dihydroxyvitamin D. In relapsing cows, even when rumen and intestinal motility is restored by treatment, hypocalcaemia and paresis are likely to occur because of insufficient 1,25-dihydroxyvitamin D. These cows may remain in this stage of prolonged hypocalcaemia for several days and only after a few days and several repeated treatments with calcium will the plasma levels of D increase to an adequate level to maintain calcium homeostasis. > <span style="font-family: "Arial","sans-serif"; font-size: 12pt; line-height: 115%;">It is also unlikely that the parathyroid hormone-related protein in the colostrum of milk fever cows is involved in the disease.
 * 1) <span style="font-family: "Arial","sans-serif"; font-size: 12.0pt; line-height: 115%;">Excessive loss of calcium in the colostrum beyond the capacity of absorption from the intestines, and the mobilisation from the bones to replace. Variations in susceptibility between cows could be due to variations in the conc of calcium in the milk and the volume of milk secreted.
 * 2) <span style="font-family: "Arial","sans-serif"; font-size: 12.0pt; line-height: 115%;">Impairment of absorption of calcium from intestine at parturition.
 * 3) <span style="font-family: "Arial","sans-serif"; font-size: 12.0pt; line-height: 115%;">Mobilisation of calcium from storage in the skeleton may not be sufficiently rapid to maintain normal serum levels. The calcium mobilisation rate and the immediately available Ca reserves are sufficiently reduced in cows in later pregnancy to render them incapable of withstanding the expected loss of calcium in the milk. In older cows, bone resorption makes only a minor contribution to the total rate of calcium mobilisation at parturition and is therefore of minor importance in the prevention of periparturient hypocalcaemia. Osteoblasts are the only type of bone cell to express the 1,25-(OH) ₂ <span style="font-family: "Arial","sans-serif"; font-size: 12pt; line-height: 115%;">D receptor protein and the decrease in the numbers of osteoblasts with increasing age could delay the ability of bone to contribute calcium to the plasma calcium pool. (receptor conc declines with age = less able to respond to 1,25-dihydroxyvitamin D = takes longer to adapt intestinal calcium absorption mechanisms to the lactation demand). <span style="font-family: "Arial","sans-serif"; font-size: 12.0pt; line-height: 115%;">It was once postulated that failure to secrete sufficient levels of parathyroid hormone or 1,25-dihydroxyvitamin D was the primary defect in cows which developed milk fever. While it is accepted that the calcium homeostatic mechanisms regulated by parathyroid hormone and 1,25-dihydroxyvitamin D fail to maintain normal blood Ca conc resulting in severe hypocalcaemia, the nature of the endocrine defect is not well understood.

Factors involved in developing hypocalcaemia
<span style="font-family: "Arial","sans-serif"; font-size: 12.0pt; line-height: 115%;">Disease occurs most commonly in high-producing adult lactating dairy cattle <span style="font-family: "Arial","sans-serif"; font-size: 12.0pt; line-height: 115%;">Lactating beef cows are affected less commonly

//<span style="font-family: "Arial","sans-serif"; font-size: 12pt; line-height: 115%;">Age // <span style="font-family: "Arial","sans-serif"; font-size: 12pt; line-height: 115%;">Mature dairy cows are most commonly affected in the 5-10 year age group, although rare cases have been observed at the first and second calvings. Hypocalcaemia at calving is also age related and most marked in cows at their 3rd to 7th parturition (infrequent at first)

//<span style="font-family: "Arial","sans-serif"; font-size: 12pt; line-height: 115%;">Breed // <span style="font-family: "Arial","sans-serif"; font-size: 12pt; line-height: 115%;">Differences in susceptibility between breeds but differences are small. Field observations for years suggested that Jersey’s are most susceptible but the reported 33% was observed in a sample compared with 9.6% incidence in other breeds – may be associated with the older age of many Jersey cows

//<span style="font-family: "Arial","sans-serif"; font-size: 12pt; line-height: 115%;">Individual cows // <span style="font-family: "Arial","sans-serif"; font-size: 12pt; line-height: 115%;">and to some extent families of cows, are more susceptible than others. The disease tends to recur at successive parturitions. Heritability of susceptibility to milk fever and hypocalcaemia has been assessed as insignificant. Complete milking in the first 48hr after calving as opposed to normal sucking by a calf, appears to be a precipitating factor. Several studies have reported that the incidence of milk fever is positively associated with the level of milk production

//<span style="font-family: "Arial","sans-serif"; font-size: 12pt; line-height: 115%;">Time of occurrence // <span style="font-family: "Arial","sans-serif"; font-size: 12pt; line-height: 115%;">Occurs at 3 main stages in the lactation cycle. Most prepartum cases occur in the last few days of pregnancy and during parturition but rare cases occur several weeks before calving. Some cases will occur a few hours before parturition or at the time of parturition when the attendant expects the cow to calve and the second stage of parturition does not occur because of uterine inertia due to hypocalcaemia. Most cases occur within 48hr after calving and the danger period extends up to about the 10th postpartum day. Occasional cases occur 6-8 weeks after parturition (mid-lactation). Such cases are most often recurrences of the disease in highly susceptible cows which were affected at calving. There is a special susceptibility at estrus, when the depression of appetite by the elevation of blood oestrogen levels may be a significant factor. The plasma levels of phosphorus also decrease and the plasma levels of magnesium increase as occurs at the time of parturition. Episodes of subclinical hypocalcaemia occur in up to 50% of adult cows during the first few weeks of lactation. It is suggested that these ‘calcium cyclers’ are animals whose calcium homeostatic mechanisms have not adapted well enough.

//<span style="font-family: "Arial","sans-serif"; font-size: 12pt; line-height: 115%;">Stressors // <span style="font-family: "Arial","sans-serif"; font-size: 12.0pt; line-height: 115%;">Starvation for 48hrs also causes severe depression of serum calcium levels (may be of importance in cows that develop hypocalcaemia at times other than in the postparturient period).

> <span style="font-family: "Arial","sans-serif"; font-size: 12pt; line-height: 115%;">The adaptation mechanism is directly related to the efficiency of intestinal absorption of Ca, which decreases with age
 * <span style="font-family: "Arial","sans-serif"; font-size: 12.0pt; line-height: 115%;">Serum Ca levels decline in all adult cows at calving due to the onset of lactation, but the decline can go to lower levels in some cows than in others and it is this difference which results in the varying susceptibility of animals to parturient paresis
 * <span style="font-family: "Arial","sans-serif"; font-size: 12.0pt; line-height: 115%;">First calf heifers rarely develop milk fever because while some degree of hypocalcaemia occurs during the first few days of lactation, they are able to adapt rapidly to the high demands of calcium for lactation
 * <span style="font-family: "Arial","sans-serif"; font-size: 12pt; line-height: 115%;">With increasing age, this adaptation process is decreased and results in moderate to severe hypocalcaemia in most adult cows

References (in the format of WRITTEN COMMUNICATION IN THE AGRICULTURAL AND NATURAL RESOURCE SCIENCES manual)
Kimura, K., Reinhardt, T.A. and Goff, J.P. (2006), ‘Parturition and hypocalcaemia blunts calcium signals in immune cells of dairy cattle’, // Journal of Dairy Science // vol. 89, pp. 2588-2595 Peacock, M. (2010), ‘Calcium Metabolism in Health and Disease’, // Clinical Journal of the American Society of Nephrology // vol.5, pp. s23-s30 Oba, M., Oakley, A.E. and Tremblay, G.F. (2011), ‘Dietary Ca concentration to minimise the risk of hypocalcaemia in dairy cows is affected by the dietary cation-anion difference’, // Animal Feed Science and Technology // vol. 164, pp. 147-153 Goff, J.P., Ruiz, R. and Horst, R.L. (2004), ‘Relative acidifying activity of anionic salts commonly used to prevent milk fever’, // Journal of Dairy Science // vol. 87, pp. 1245-1255 Horst, R.L., Goff, J.P. and Reinhardt, T.A. (2005), ‘Adapting to the transition between gestation and lactation: Differences between rat, human and dairy cow’, // Journal of Mammary Gland Biology and Neoplasia // vol. 10, no. 2, pp. 141-156 Bigras-Poulin, M. & Tremblay, A. (1998), ‘An epidemiological study of calcium metabolism in non-paretic postparturient Holstein cows’, // Preventive Veterinary Medicine //vol. 35, pp. 195-207 Goff, J.P. (2008), ‘The monitoring, prevention, and treatment of milk fever and subclinical hypocalcaemia in dairy cows’, // The Veterinary Journal // vol. 176, pp. 50-57

Radositis, O.M., Gay, C.C., Hinchcliff, K.W. and Constable, P.D. (2007), 'Veterinary Medicine - A textbook of the diseases of cattle, horses, sheep, pigs and goats,' Saunders Elsevier, worldwide (Sydney)