Hypocalcaemia in the Dairy Cow and the associated physiological effects

Figure 1: Dairy Cow

Introduction

Hypocalcaemia, also known as “milk fever” and “post-parturient paresis” is a well-known production disease. It mainly effects dairy cows and is characterised by a decrease of calcium in the blood. It’s occurrence is usually in the first few days after the onset of lactation when the demand of calcium for milk production exceeds the bodies capabilities to mobilise sufficient amounts of calcium reserves. It can be divided into both clinical and sub clinical types, one of the major clinical symptoms being recumbency of the animal at which stage urgent veterinary attention is required. Hypocalcaemia is a major disease affecting diary farmers all over the world as it results in economical loss and decreased productivity.

Pathophysiology of hypocalcemia

As aforementioned, hypocalcaemia is a production disease. It occurs during the periparturient period, which is defined as the four weeks pre and post parturient and can be considered the period in which the animals is at the greatest risk of disease due to the series of homeorhetic processes occurring at this time. These processes are long term physiological adaptations in response to changes of state for example the transition from non-lactating to lactating. They involve adjusting metabolism, allowing the animals to adapt to challenges provoked by these altered states. Hypocalcaemia can be a consequence of defective homeorhetic change, the altered metabolism which is due to the transition from non lactating to lactating is to be considered a more profound cause than parturition itself with regards the pathogenesis of hypocalcaemia.This is due to the fact that blood calcium loss to milk may reach 50g/day or even surpass this amount which is significant.

The estimated daily calcium requirement pre calving is just 30g, which is divided evenly between faecal and urinary loss as well as fetal growth. This requirement can only be supplied by the enhanced calcium absorption from both the rumen and intestines along side calcium mobilisation from the tissues, in particular from bone. There is a strict range within which calcium in the blood must be maintained (2.0-2.5mmol/L). In order to keep calcium levels within this narrow range it is essential to enforce physiological controls. Calcitonin, Parathyroid hormone and 1.25(OH)2D3 are the 3 physiological controls of calcium metabolism. Calcitonin is released in response to increased blood calcium levels and so works to reduce this heightened level back to within the narrow needed range by initiating calcium deposition. Both Parathyroid hormone (PTH) and 1.25(OH)2D3 have an opposite effect to calcitonin causing the liberation of calcium in order to increase lowered blood calcium levels. PTH has a more pertinent role in these processes as in addition to its own calcium metabolic effects it also operates as the regulator for the hydroxylation of 25 hydroxycholecalciferol to 1.25(OH)2D3 in the kidney (De Garis and Lean, 2008).

Vitamin D is a member of the steroid hormone family which can be synthesised from cholesterol found in the body although most of its precursors derive from dietary sources. Cholesterol can be converted into cholecalciferol via 7 dehydrocalciferol in the skin by UV light. Cholecalciferol is a natural component found in feed stuff and is transformed to 25(OH)2D3 in the liver and finally renal 1 alpha hydroxylase enzyme produces the active metabolite of the hormone which is 1.25(OH)2D3. The kidney enzyme is directly regulated by PTH which when it’s levels are reduced leads to increased activity of another renal enzyme 24,25 dihydroxycholecalciferol which is completely inactive. The kidney has central role in the activation and deactivation hormone synthetic pathways of Vitamin D. It is lipid soluble and so therefore is transported in the blood bound to a specific globulin (transcalciferin).

The efficiency of the absorption of calcium from the intestines and mobilisation from the bone is decreased as a result increased dietary levels of calcium.The animal however has a limit in its capability to respond to the increased calcium metabolic demands by the speed at which the increased intestinal absorption and calcium movement from the bone may happen (Ramberg, 1995).The animal is dependant upon a consistency in its dietary calcium supply (Hove, 1984) and may be susceptible to hypomotililty of the intestines as a result of the hypocalcaemia (Moodie et al, 1962). If an animal is artificially induced into a hypocalcaemic state it will initially result in sub clinical symptoms such as decrease in ruminal contractions appearing before the development of clinical hypocalcaemic signs (Huber et al, 1981). The ceasing of ruminal motility is an important component in the initiation of hypocalcaemia as even a short period of static alimentary state can develop acute hypocalcaemia as a result of a decreased intestinal absorption of calcium (Moodie et al, 1962).

Almost all of the body calcium reserves are of bone origin. The mobilisation of calcium from the bone may have a variable onset as the process is of a reduced speed in older animals and animals on a preparturion diet high in calcium (Ramberg et al, 1984). Animals, in particular cows, are more dependent upon intestinal absorption of calcium as apposed to bone resorption in order for calcium homeostasis to be maintained. This is why it is important for the dietary calcium level to be increased post parturesis rather than pre. It has been shown that animals with a precalving diet that is low in calcium show a high blood plasma level of 1.25(OH)2D3 which increases intestinal calcium absorption. (Green at al, 1981) Those animals that are consuming a high precalving calcium diet are associated with having a raised blood plasma level of vitamin D metabolites that are acting as an antagonist of 1.25(OH)2D3 therefore having an inhibitory effect on the intestinal calcium absorption resulting in the onset of hypocalcaemia (Horst et al, 1983).

It is believed that hypocalcaemia occurring in dairy cows is due mainly to dietary factors, it can be caused by high DCAD (dietary cation – anion differences) as well as high Potassium. A hypothesis was put in place and tested by J. P Goff stating the almost cascade like occurrence of events that is generated by feeding preparatum cows high DACD (high diet of alfalfa hay) which results finally in hypocalcaemia. In the same experiment a portion of the cows were also fed a low DCAD diet, but this did not have the same hypocalcaemia inducing effect (Goff, 2014).

Charbonneaur developed a DCAD equation using milliequivents of (NA + K) – (Cl +0.6S) which was used to detect the risk of development of hypocalcaemia (Charbonneau et al, 2006). It’s proven yet not understood fully how you can prevent hypocalcaemia by balancing high DCAD with increased addition of anions to the diet (Goff et al, 2014).

The high DACD causes reduced sensitivity to Parathyroid hormone or the idea has also been presented that the preparturition cows tissues my undergo” temporary refraction of PTH” which results in pseudohypoparathyroid state and reduces Calcium homeostatic reations. Which can also be associated with the idea that the response of preparturition and lactating cattle to exogenous PTH was significantly different, with the lactating cattle reacting more positively (Goff et al, 2014). PTH is produced by the chief cells of the parathyroid gland and regardless to its close proximity to the thyroid gland they function independently of one another. The PTH is responsible for maintaining normal calcium (phosphorus and magnesium) plasma levels this is essential for muscle contraction, electrical conduction of impulses and many other vital body functions. The release of PTH is initiated by a low calcium level in the blood resulting in release of bone calcium by osteolysis to restore plasma calcium levels. It will also cause increased absorption of calcium due to its stimulating production of 1.25 Dihydroxyvitamin D by the kidneys which in turn increases the calcium absorption within the intestines by facilitating the calcium binding protein (CaBp) of intestinal mucosa cells (Szent Istvan,2014). So Vitamin D enchances utilization of the calcium “reserve” It also regulates the release of urinary calcium as well as many other regulatory factors. PTH will also reduce urinary excretion of calcium in both low DCAD by 16% and high DACD by 30% cattle due to PTH stimulation (Goff et al,2014). Schonwillie et al experiment showed evidence that if the high calcium excreted by low DACD was reduced by renal reabsorption could be useful in maintaining calcium homeostasis (Schonewille et al, 1999).

High blood calcium will supress PTH and cause release of calcitonin from the thyroid gland it acts to slow down osteoclast activity in bones and so reduce blood calcium level. DCAD main effect is on the acid- base balance; high DCAD results in metabolic alkalosis while the low DCAD results in metabolic acidosis which is a result of the cation/anion levels in the blood (Lean et al, 2006). It has been suspected that the” PTH receptor G complex is altered” during metabolic alkalosis reducing the binding capacity to PTH and so resulting in the reduced sensitivity to PTH (pseudohypoparathyroidism) (Martig and Mayer, 1973). The parathyroid gland has a role in recognising hypocalcaemia and increasing PTH secretion. However low DACD which causing metabolic acidosis restores tissues sensitivity to PTH and so calcium homeostasis is maintained and no milk fever develops. The hypothesis was tested by PTH injections into the gluteal muscles of cows fed either a low or high DCAD diet. If hypercalcaemia is detected calcitonin will be released which will have an antagonist effect on calcium homeostasis and so reduce plasma calcium levels (Omdahl et al, 2002).Calcitonin is produced by the parafollicular cells of the thyroid gland it also can decrease the release of 1.25 dehydroxyvitamin D.

1.25 Dihydroxyvitamin D (Calcitriol) is essential to utilize dietary calcium and so inhibits development of hypocalcaemia. The production of both calcium and 1.25 dihyrdoxyvitamin D is slower in those cows fed a high DACD diet (Goff et al, 2014). The treatment for milk fever is intravenous calcium however in severe cases of hypocalcaemia relapses can be seen, this has been proven to be a result of the slow stimulation of 1.25 dehydroxyvitamin D production (Goff et al, 1989). Hypercalcemia and calcitonin reduce the production of renal 1.25 dehydroxyvitamin D (Hove et al, 1984). It is proven that high DACD can result in reduced ionized calcium which is the major driving force for calcium homeostasis.

Theoretically a low calcium should induce tectonic seizure (grass tetany) however instead paralysis occurs this is a result of muscle contraction not being completely dependent on calcium levels alone but rather the ratio of calcium:magnesium. This particular cation balance is particularly specific to cattle. Magnesium is a major risk factor in low plasma concentrations for hypocalcaemia as it is thought to decrease endogenous PTH secretion.

Figure 2: Ca/Mg graph

Prevention

The periparturient cow undergoes a transition from non-lactating to lactating at calving. They are greatly challenged to maintain a calcium homeostasis despite the constant loss in milk. If they fail to compensate for the calcium lost, hypocalcaemia occurs. This may be life threatening and also can be considered a “gateway” for many other production diseases (Goff, 2007).

The cow must be prepared for this drastic change in order to avoid and prevent milk fever. The main preventatives used are regarding the regulation of the cow’s diet before calving. The body itself also has its own preventative methods. In order to replace the calcium lost in milk, the body can both withdraw reserves from the bone as well as increasing the absorption of dietary calcium in the intestines. Although the animal has its own preventative methods, the most influential factor being PTH, however it’s also vital to regulate their diet as a further method of prevention. Mr Bhanugopan carried out an experiment in Australia in regards to the effectiveness of farmers practicing milk fever control strategies. This experiment was carried out in the form of questionnaire. It was evident that those farms with low milk fever outbreaks actively practiced control strategies. Such strategies were feeding of cows separately, increase of grain feeding and reduced potassium rations preparatum and then after calving a commercial ration mix is usually given. The need for such control measures is growing due to the increasing metabolic demand on dairy cows which is maintained through diet or reserves otherwise this will result in development of diseases due to homeostatic mechanism breakdown. Feeding of grain low in calcium and helps prepare rumen for high energy feeds given post calving (Bhanugopan, 2014).

The ratio of absorbable anions/cations in the diet determines the acid/base balance and therefore pH of the blood. It is of high importance to include readily absorbable anions such as chlorine, sulphates and phosphates to the diet prior to calving. This will increase the proton concentration which in turn decreases the pH of the blood making it more acidic and solving the alkalosis (Ender et al, 1971).

Hypomagnesia is also a precursor to developing hypocalcaemia as it affects calcium metabolism by decreasing the secretion of PTH (Littledike et al, 1983), and also the tissue sensitivity to it (Rude, 1998). Magnesium therapy is an effective way to not only restore magnesium but indirectly restores the calcium concentration. The administration of either calcium or vitamin D to the diet pre-calving is however, proven to be ineffective as a prevention of milk fever. The increase of dietary Mg prior to parturesis is a simple treatment in order to avoid hypomagnesia and consequently, hypocalcaemia. Severe cases of hypomagnesia (and hypocalcaemia) can result in tetany (complete paralysis, convulsions, recumbency) which can only be treated by the slow addition of Mg and Ca salts intravenously.

Addition of calcium to the diet does not prevent milk fever. It is important to actually decrease dietary calcium before the cow gives birth in order to avoid production disease. An experiment carried out identified that different breeds can be more prone to developing hypocalcaemia for example Jersey cows.Jersey cows are managed by hay feeding during the dry period and calcium supplement is given 24 hours before calving. Although normally dietary reduction of a cow’s calcium preparatum stimulates calcium homeostasis. Supplementation post calving is also a vital control strategy with grain and calcium both provided for 24 hours post calving to maintaining calcium supply (Harris, 2006). These processes prepare the cow so that at birth, the drained calcium can be quickly replaced by the already prepared reserves from the bone. Calcium in the diet can be reduced by the addition of a zeolite (Ca absorber) which binds calcium so that it passes in excretion with the faeces (Thilsing-Hansen et al, 1983) or more easily by the administration of vegetable oils which also bind calcium, making an insoluble soap which prevents absorption (Wilson, 2003). Administration of high doses of vitamin D 10-14 days before calving can increase the intestinal absorption of calcium and sometimes prevent milk fever but can also cause damage to the soft tissue of the animal (Goff, 2007). A more effective and safe mechanism is the addition of 1,25-dihydroxy vitamin D where the timing of administration is of importance for a maximal effect (Goff and Horst, 1990).

Giving the cow calcium supplements orally at calving can also help in preventing hypocalcaemia, but not treat it). This increases the soluble Ca amounts which result in the movement of Ca across the intestinal tract by passive diffusion between the epithelial cells (Goff, 2007). Calcium propionate is most commonly used as it doesn’t damage tissue (Petirson et al, 1998) unlike calcium chloride which can result in metabolic acidosis (Goff and Horst, 1990). Dosage at calving and also 24hrs later give the best results. “More than 60% of farmers reported using feed supplements or some form of nutritional strategy to reduce the incidence of MF” Increased time between calving and first lactation can result in greater chance of hypocalcaemia (Mulligan and Doherty, 2008).

Treatment

It is important to treat milk fever in cattle as early as possible, especially if the case results in recumbency. The high pressure exerted by the massive weight of the cow can result in “crush syndrome” causing ischemia (reduction of blood supply) of muscles and nerves followed by necrosis. There is a relatively short time space in which the cow can be treated before the hypocalcaemia affects the animal’s heart inducing fatal arrhythmia. The milk fever is alleviated simply by an IV injection of Ca salts (usually Ca borogluconate). The necessary guidelines for the amount injected are around 2g Ca/100kg body weight. It’s important not to administer all at once but slowly, around 1g/min. The Ca may also be injected subcutaneously but the absorption in this way is variable and possibly not as effective. In this way, the cow may require 6-10 injections in widely separated spots which can have a major impact on the quality of meat (Goff, 2007).

Production diseases

The period of peak incidence for production diseases is 3 weeks pre-birth until 3 weeks post-birth and can extend into lactation (Grummer, 1995). The cow can experience peri-parturient immunosuppression which is caused by numerous factors. Hypocalcaemia results in immunosuppression; the defective immune system is the main cause of retained placenta and dystocia. Production diseases such as milk fever result in a “cascade effect” of disease; decreasing fertility, milk production and increasing lameness (Mulligan, 2007). The onset of milk fever also greatly increases the risk of mastitis in the following lactation (Curtis et al, 1983). Dairy cows which are in a negative energy balance before calving are more likely to experience displaced abomasum, as well as ruminal acidosis and laminitis (Enemark, 2008). This shows the complex connections of production diseases and the importance to prevent and treat them in order to avoid major loss in both productivity and health of the livestock.

Economy and Welfare

Dairy cattle have under gone intense genetic selection and improvement for optimal milk yield which increases greatly the demand of nutrients from their body. The annual yield per cow has increased from 2850 to 5500L/per cow per lactation this is majorly caused by the increased genetic selection as well as improved nutritional and farm management practices (Mulligan and Doherty, 2008). These high stresses on the body could possibly lead to ill health and infertility. Fertility of the postpartum period is negatively influenced by the incidence of anestrus, which may be an indication of suboptimal conditions which may include inadequate peripartum nutrition or pathologic conditions. The lactation period of the cow is approximately 305 day duration. During lactation the cow falls into a negative energy balance which reduces their body weight which is replenished during the dry period preceding parturition this is essential for fertility. In some cases production diseases may be considered as a “man-made” problem (Payne, 1972). The transition cow undergoes extreme endocrine changes, experiences immunosuppression and has to cope with sudden dietary changes leading to digestive disturbances. All these factors as well as environmental stressors to the cow (eg. normal herd group changes) are the major inducers of the production diseases (Mulligan, 2007).

Although many experiments carried out investigating tissue responsiveness before parturition does not help explain how tissues will respond at the time of calving, which identifies the difficulty of pinpointing the main issue or it may be the fact this is a highly complicated interaction of many metabolic and hormonal factors. The complex interaction of production diseases make it quite hard to control while keeping the interests of both the health of the animal as well as its productivity. As long as the pressure for increased productivity remains, hypocalcaemia will be an inevitable problem facing dairy farmers worldwide.

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