Acetonaemia/Ketosis

Acetonaemia/Ketosis

The two names for this disease explain the basic principles well in a nutshell.
Acetonaemia - the first part of the word referring to Acetone (a breakdown product of fats when they are metabolised in the body) and aemia (referring to concentration in blood).
Ketosis refers in a similar way to the same principle – acetone is a type of ketone, therefore giving the name ketosis.

Cause

Ketosis is a metabolic disorder that occurs in cattle when energy demands exceed energy intake and result in a negative energy balance. Ketotic cows often have low blood glucose (blood sugar) concentrations. (When referring to ‘energy’, this term is usually referring to the amount or availability of glucose in the body – this is because glucose is the main energy store which most living things use in order to produce chemical energy which powers the biological processes of the body/cell).
When large amounts of body fat (adipose tissue) are utilised as an energy source (in place of glucose), in order to support production (e.g. high milk demands), fat (adipose tissue) is sometimes mobilised faster than the liver can properly metabolise it. When this situation occurs, ketone production exceeds ketone utilisation by the cow, and ketosis results.

This diagram explains how this occurs. At point 1, there is not enough glucose to supply the body’s energy demands; therefore adipose tissue (which is fat) is broken down to help correct this issue. Fatty acids are produced which, at point 2, enter the liver via the blood. These fatty acids undergo mitochondrial beta-oxidation (point 3) and produce acetyl-coenzyme A. This AcCoA enters the Krebs Cycle (a normal part of respiration) and produces energy; some of this AcCoA is converted to ketone bodies (acetone, acetoacetate, beta-hydroxybutyrate) which can then be used by other bodily tissues to produce energy (by reconverting the ketones back to AcCoA and hence allowing this AcCoA to produce energy in the Krebs Cycle).

Summary of the biochemistry of ketosis:

·         Low glucose concentration in body leads to a need for alternative energy production.

·         Fat tissues can be used as a substrate to produce energy.

·         Fat tissues are broken down into fatty acids, which are transported to the liver.

·         Fatty acids undergo Beta-mitochondrial oxidation in the liver.

·         This process produces Acetyl-Coenzyme A (AcCoA).

·         AcCoA is used to produce energy by action of the Krebs Cycle in the liver.

·         Some AcCoA is processed into ketone bodies, which are a source of energy for other tissues in the body. The conversion of AcCoA to ketones occurs when there is not enough energy in the liver cells in order to metabolise to AcCoA.

·         These ketone bodies are: acetone, acetoacetate and Beta-hydroxybutyrate.

·         When these ketones reach other tissues, cells can turn them back to AcCoA.

·         This AcCoA can then be used to produce energy.

So when ketosis is overused, there are too many ketones being produced – causing clinical disease.
It is important to realise that low level ketosis is completely natural and healthy, it is when ketosis becomes the main and only source of energy, that the process becomes a process for the health of the body.

In the beef cow, this is most likely to occur in late pregnancy when the cow’s appetite is at its lowest and the energy requirement of the growing cow is at its highest. Because the appetite is low, this means that glucose concentration is most likely to be low, leading to an increased chance of ketosis occurring.

In the dairy cow, the mismatch between input and output usually occurs in the first few weeks of lactation, because the cow is not able to eat enough to match the energy lost in milk. Milk production requires a lot of energy, so as glucose is used up, it is not being replaced sufficiently by the cow’s diet.

Symptoms

·         Reduced milk yield

·         Weight loss

·         Reduced appetite

·         Dull coat

·         Acetone (pear drop) smell of the breath and/or milk

·         Fever

·         In rare cases nervous signs develop such as excess salivation, licking, chewing, aggression or odd behaviour.

Treatment

The initial aim of treatment is to restore the lack of glucose in the body.

A quick-acting glucose supplement is required immediately. Follow up treatment is aimed at providing a long term supply of glucose.

Glucose replacement:

Intravenous administration of a dextrose solution by a vet is effective in short-term, but follow up treatment is necessary to avoid relapse. Drenching with propylene glycol or glycine has longer term effects. It also has the benefit of ease of administration (as it is a liquid that can be given orally by squirting down the throat). Treatment should be continued for two-four days.
Replacing the glucose deficit in the body should reduce the amount of ketones being produced.

Hormonal therapy:

Many of the long-acting corticosteroids (i.e. Cortisone) have beneficial effects in ketosis. They are administered using a single injection.

Their use is based upon their ability to break down protein in muscles to produce glucose, which immediately replenishes the depressed glucose levels. When using this type of therapy it is also important to supply a high concentration of glucose either as carbohydrate diet or as a liquid drench, in order to prevent the excessive breakdown of muscle protein.

This is a much less harmful process because ketones are not produced. The general principles of this therapy are that muscle tissue (protein) can be used in order to produce glucose. This process is generally known as gluco-neo-genesis. This means, synthesising glucose from non-carbohydrate sources. The protein in muscles is broken down to constituent amino acids (small complex molecules containing nitrogen) – the nitrogen is removed by process of deamination and from this urea is formed (which is processed into urine and excreted via the kidney) – this leaves the carbon skeleton which can then be used for protein synthesis, energy production or glucose production. The corticosteroids encourage this process.

Generally corticosteroids are only used in more advanced, serious cases.

Prevention

It is important to prevent ketosis from occurring, rather than treating cases as they appear.

Prevention depends on adequate feeding and management practices.
In times of feed deficiency because of drought or other reasons, the provision of supplementary feed with adequate amounts of carbohydrate is essential. The best feeds tend to be good quality hay, silage, or cereal grain.

The body condition of the dairy cow is important at calving. Cows should be on a rising plane of nutrition up to calving with the aim to calve in good condition.
After calving, the cow has the potential to reach maximum efficiency in milk production, but feed requirements for high production are often greater than the voluntary intake of pasture can provide.

Therefore an energy supplement is required and there is evidence that this will improve production and reproductive performance, and decrease the risk of ketosis. The best supplements are good quality hay, silage, or cereal grains. Supplements should be fed at least until the peak of lactation is reached or longer depending on the quality and quantity of available pasture.
Occasionally, very high-producing cows will be susceptible to ketosis every year. In these cases a preventive drenching program of propylene glycol immediately after calving may avert ketosis in individual problem cows.

To satisfy the requirements of milk production, the cow can draw on two sources of nutrients, food intake and body reserves. During early lactation, the energy intake is insufficient to meet the energy output in milk and the animal is in a negative energy balance. In conventional farming, this is considered to be a normal metabolic situation in high-yielding dairy cows. Cows in early lactation are, therefore, in a vulnerable situation, and any stress that causes a reduction in feed intake may lead to the onset of clinical ketosis.
If the feed intake of the cow is not sufficient to meet the demand for energy, there is insufficient ruminal production of propionic acid, the main precursor of glucose in ruminants, which results in hypoglycaemia. Hypoglycaemia leads to a mobilization of free fatty acids and glycerol from the fat stores. However, the liver cannot deal with the acetyl-CoA, which results from the oxidization of these fatty acids, because of a lack of energy. The excess acetyl-CoA is converted into the ketone bodies acetoacetate and β -hydroxybutyrate and, to a small extent, acetone (Figure 1). Tissues other than the liver can use ketone bodies, but if their production exceeds the rate at which they are used by muscle and other tissues, they accumulate, and ketosis is the result. Ketone bodies are excreted in milk and urine (Andrews, 1998; Holtenius and Holtenius, 1996).
The reduction of propionic acid production is usually the result of underfeeding or a reduced feed intake caused by inappetance. A period of inappetance is normal around calving, but may be exacerbated in the early post-partum period by a deterioration of forage quality, sudden changes in diet or excessive fatness at calving (Andrews et al., 1991; Higgins and Anderson, 1983). Other risk factors are month (more likely in winter), increasing parity, milk fever, ketosis in the previous lactation, increased 305-day milk yield in the previous lactation and the average milk protein percentage in the previous lactation (Rasmussen et al., 1999; Heuer et al., 2001; Wood et al., 2004;). Cows with milk fever have a greater decrease in feed intake after calving which exacerbates the negative energy balance, increasing the risk of ketosis (Goff, 2003).
Butyrate is a precursor of acetyl-CoA and is therefore ketogenic. In the UK, the butyric acid content of silage is of some importance in the aetiology of the disease, because wet conditions predispose to butyric fermentation of the silage. Silage intake containing high levels of butyric acid is also less palatable to cattle (Andrews et al., 1991).

This disease is most commonly seen in the immediate post-calving period where milk production is high and energy intake is reasonably low. This results in a high demand for glucose and hence, hypoglycaemia results, which leads to an intense need for the ketogenic pathway.