Tuesday, 30 April 2013

Ketosis and Pregnancy Toxaemia

Hi :) In this post we’ll take a look at the epidemiology, pathogenesis, treatment and prevention of ketosis and pregnancy toxaemia.


Ruminants rely on gluconeogenesis in order to produce glucose and use it as a source of energy. When these animals are in late pregnancy and lactation they need larger amounts of energy than normal and this may drain glucose supplies. When the ruminant body requires extra energy, it mobilises fat and this causes the release of NEFAs (Non Esterified Fatty Acids) into the circulation. NEFAs can be toxic when they reach a certain concentration in the blood and so the body converts them into ketone bodies. The tissues that are able to use ketone bodies for energy do so and this spares blood glucose for those tissues that have an absolute requirement for glucose.

However, the use of ketone bodies is saturable and when saturation occurs, pathological ketosis happens. This is characterised by hypoglycaemia, ketonaemia and ketonuria.


Ketosis is most common in dairy cows and there is a higher risk of developing this disease during the first 6 weeks of lactation. Other risk factors include:
§  60 days post calving
§  Increased age
§  Increased milk production
§  Low energy, high protein diets
§  Obesity at calving.
In addition, ketosis usually develops secondary to another disease. There is also low heritability and ketosis can be sub-clinical or clinical.


As explained earlier, ruminants rely on gluconeogenesis in order to maintain glucose homeostasis and during late pregnancy and lactation these animals are often in a negative energy balance. Because of this NEFAs are mobilised from adipose tissues and this is stimulated by low glucose and insulin and high amounts of lipolytic hormones.

The NEFAs can either enter the ketogenic pathway where they are oxidised in the liver to become ketone bodies, or the esterification pathway where they are converted to triglycerides in the liver. If the NEFAs enter the ketogenic pathway, the cow is predisposed to ketogenesis. Low glucose availability favours ketogenesis. Ketosis occurs when the uptake of ketones by tissues is saturated and the level of ketone in the blood is elevated.

There are three types of ketosis: alimentary ketosis, primary under feeding and secondary under feeding ketosis.

Alimentary Ketosis

 This condition is associated with the feeding of poor quality silage that have high levels of preformed butyrate. Butyrate is a precursor for ketones and so high levels of butyrate predispose the animal to developing alimentary ketosis. In addition, these poor quality feeds often have poor palatability and this may contribute to the development of underfeeding ketosis.

Primary Underfeeding 
This occurs when poor quality feed is given to cattle in poor body condition. These feeds have poor quality roughage, low protein and insufficient concentrates. This means that there is limited gluconeogenesis occurring from the feed. As a result, more adipose tissue must be mobilised which means that, ultimately, more NEFAs are converted to ketones and this predisposes the animal to developing ketosis.

Secondary Ketosis

 Secondary ketosis results in a decreased food intake secondary to an underlying disease (such as abomasal displacement, toxaemia, metritis, mastitis, acidosis etc.) As a result of reduced feed intake, less propionate (a volatile fatty acid) is produced in the gut which means that there is a lower rate of glucose synthesis. Thus, more adipose tissue has to be mobilised which means that more NEFAs are converted to ketones. This predisposes the animal to developing ketosis.


Treatments aim to restore blood glucose levels and correct the clinical signs of ketosis. There are two main methods of treatment: replacement therapy and hormonal/supportive therapy.

Replacement Therapy

This form of treatment administers propionate precursors (e.g. propylene glycol) as a drench or in feed. These are converted to pyruvate and oxaloacetate after being absorbed through the wall of the rumen. Intravenous glucose therapy can also be used if the animal is looking particularly bad.

Hormonal / Supportive Therapy

Corticosteroids are commonly used in this form of treatment as they cause a decrease in the use of glucose by peripheral tissues and increased Acetyl CoA utilisation. Some people may use anabolic steroids which stimulate appetite and decrease the level of ketones in the blood. B Group vitamins may also be given as Niacin increases blood glucose and decreases the ketone concentration of the blood. Digestive tract stimulants may also help a poor appetite.


In order to avoid ketosis, one should avoid poor quality silages that may contain large amounts of butyrate particularly in the 60days after calving. The body condition score should also be managed carefully as scores over 3.5 greatly increase the risk of ketosis (this is because there is more fat to mobilise). The cow should also receive adequate amounts of forage, vitamins and minerals in their diet. Animals at risk of developing ketosis should also be identified early to start preventative measures. The use of monensin, an ionophore can also reduce the risk of ketosis.

Pregnancy Toxaemia

Like ketosis, pregnancy toxaemia is also a disorder of energy and protein metabolism. It affects sheep, cattle and goats and similar to ketosis and causes hepatic lipidosis (fatty liver). It is more common in animals that have twins and triplets.


Pregnancy Toxaemia is most prevalent in very late gestation (the four weeks preceding parturition) where there is a declining plane of nutrition. The presence of multiple foetuses also increases the risk of developing this disorder as well as younger growing animals. Stress also increases the risk.


In late pregnancy the foetus, placenta and uterus have an increased demand for glucose and amino acids. It is often difficult for the animal to meet these requirements especially if it is on a poor quality forage. This problem is compounded by the fact that the loss of nutrients to the foetus is irreversible.

With sheep in late gestation, the requirements for glucose by the foetus each day exceeds the glucose available in the blood by four times. Thus there is a need for substantial amounts of gluconeogenesis. In addition, the mother has decreased insulin sensitivity late in lactation and this reduces the use of glucose by peripheral tissues and increases the lipid and ketone metabolism. This results in fatty acids being mobilised from body stores and transported to the liver to form triacylglycerol’s (TAGs). The excess TAG results in hepatic lipidosis (fatty liver) and pregnancy toxaemia.  

The TAGs are may be oxidised via the TCA cycle. If they aren’t oxidised they are converted to ketone bodies which are acidic, this may lead to metabolic acidosis.

Pregnancy toxaemia is associated with hypoglycaemia, increased levels of NEFAs in the blood plasma, hyperketonaemia, and ketonuria. It may also lead to an enlarged, fat infiltrated liver and the kidney, heart and adrenal glands may show signs of fat infiltration.


The treatment of pregnancy toxaemia involves providing gluconeogenic precursors such as glycerol. Any electrolyte imbalance or dehydration should also be corrected and the foetus should be removed. This can be done via a caesarean or by inducing parturition. Corticosteroids may also be administered as this will increase the amount of endogenous gluconeogenic precursors present as well as the amino acids for gluconeogenesis. It also has the effect of inducing pregnancy. Better quality feed should also be provided to the herd.


In order to prevent pregnancy toxaemia it is important to provide the animal with dry matter that has sufficient energy, protein, mineral and vitamin content to meet or slightly exceed the nutrient requirements. Additional supplements should also be given to animals with multiple pregnancies and those that have low body condition scores.

Parasites should also be controlled and a healthy body condition should be maintained. Stressful events, such as bad weather, should also be avoided when possible. Ionophores may be helpful and trace and macro- elements should be provided.

That’s all for this post, see you next time :)

Monday, 29 April 2013

Pigments, Infiltrates and Storage Diseases

Pigments, Infiltrates and Storage Diseases are a result of the accumulation of either a normal substance in abnormal amounts or an abnormal substance inside cells or between them. These diseases can be inherited or acquired and may cause organ dysfunction but in some cases are incidental findings. In this post we’ll take a look at haemosiderosis, anthracosis, lipofuscinosis, amyloidosis, and hyperbilirubinaemia.We'll also look at how storage diseases, in particular: lysosomal storage diseases, work.

Infiltrations and Pigmentations

Pigments can either be exogenous or endogenous. Examples of exogenous pigments include tattoo inks and carbon pollutants. Endogenous pigments can be physiological or pathological and include: haemosiderin, bilirubin, melanin and lipofuscin.


Anthracosis refers to the local accumulation of black carbon particles in the lungs and draining lymph nodes as a result of long-term exposure to polluted air. The carbon is taken up by macrophages which then travel to the lymph nodes and interstitium. The carbon is inert and so it has no effect on the function of the organ. Histologically, anthracosis is seen as blue-black fine granules within macrophages around airways and lymphatics in the lungs. Anthracosis is not a pathological disease and is instead usually an incidental finding.

Lipofuscin is known as the ‘wear and tear’ pigment and appears as a feint yellow-brown colour histologically under the haematoxylin and eosin stain. This compound consists of complexes of lipid-protein substances that are derived from the peroxidation of lipids in cell membranes. The presence of lipofuscin is associated with:
·         Aging: continuous exposure throughout life to environmental factors generates free radicals
·         Diets high in fat
·         Vitamin E deficiency: Vit E is incorporated into the membrane and helps to prevent peroxidation.

Lipofuscin will accumulate in non-dividing cells as well as liver cells. In addition, it may accumulate in muscle cells such is seen in alimentary lipofuscinosis.

Haemosiderin is a yellow-brown iron containing pigment derived from the breakdown of haemoglobin. Abnormal quantities of haemosiderin may accumulate within macrophages, at sites of haemorrhage as well as in the liver, spleen or kidney. The accumulations may result in haemosiderosis which, grossly, can cause a brown discoloration of the tissue.

Haemochromatosis is a group of genetic defects which cause generalised abnormal storage or abnormal increase in absorption of iron. This is always pathological and leads to tissue damage.

Amyloid is an extracellular deposit and when present in large amounts can cause organs to be large, pale and waxy. Generally, amyloid is an insoluble beta-pleated sheet which is deposited extracellularly and is resistant to proteolysis. It may arise from several different compounds.

Amyloidosis is the abnormal accumulation of amyloid. Systemic forms of amyloidosis is cause amyloid deposits in many tissues (usually the kidney, liver and spleen). The reactive form of amyloidosis affects the kidney liver and spleen and is often associated with a persistent inflammatory disease. Immune amyloid is a result of the neoplasm of plasma cells.

Bilirubin is an orange pigment derived from the breakdown of heme. In excess amounts it causes tissues to appear yellow and this is known as jaundice or icterus and this is seen in the sclera, mucous membranes or the aorta’s lining. There are three forms of icterus:
1.       Haemolytic: this is when there is an increased breakdown of erythrocytes. There may be haemoglobinaemia, haemoglobinurea and increase in unconjugated bilirubin in the blood.
2.       Toxic: this is where there is damage to the liver so that hepatocytes are unable to conjugate bilirubin (bilirubin is toxic in its unconjugated form). As a result of this there is an increase in free bilirubin in the blood with no evidence of haemolysis.
3.       Obstructive: this is where there is obstruction to the excretion of conjugated bile as a result of blockage of the bile duct system. This causes an increase in the amount of conjugated bilirubin in the blood. In addition, there may be no or reduced amounts of serum, urine urobilinogen and pale faeces.

Storage Diseases

Storage diseases involve the accumulation of a macromolecular substance in a tissue and this is due to the inadequate production of a specific catabolic enzyme.

This is usually the result of homozygous autosomal recessive patterns of transmission of a familial genetic defect. The defect in the gene may be due to:
·         A fault in the operator gene and the allele may be switched off
·         A fault in the regulator gene so that the allele may produce a greatly reduced quantity of enzyme.
·         A base change in the structural gene may produce a defective enzyme with reduced activity.

Lysosomal Storage Disease

These diseases are the most important group of storage diseases. It involves the accumulation of abnormal quantities of cellular material within secondary lysosomes.

Lysosomes are small bodies with the cytoplasm that contain about 40 hydrolytic enzymes enclosed within a membrane. Lysosomes are responsible for the turnover of macromolecules within the cell. When these macromolecules are broken down in the lysosome, residual material may accumulate within the cell. Clinically many lysosomal storage diseases show neurological changes.

That's all for now, if you have any questions please let me know :)

Sunday, 28 April 2013

Adaptive Tissue Responses

When tissues are damaged, cell injury will occur. This injury can be reversible up to a point but if the harmful stimulus is too severe, the cell will die. Sometimes, the cell doesn’t die, but adapts to the stimulus in order to survive. In order to do this, the tissue uses Adaptive Tissue Responses, such as atrophy, hyperplasia, hypertrophy and metaplasia (we’ll be covering these in this post).

Adaptive changes are reversible changes (however, some pathological conditions can prevent this from happening) in mature cells and tissues after growth has occurred. The ability of a tissue to adapt is dependent on several factors including: vulnerability to certain agents, state of differentiation, blood supply, nutrition, and previous state of the cell (i.e. is it trying to adapt to another harmful stimulus?).


Atrophy is defined as a reduction in the size or amount of an organ, tissue or cell. This is due to a decrease in the size and/or number of its specialised cells or organelles. Atrophy may be physiological (for example: when the thymus decreases in size with age) or pathological (e.g. Disuse atrophy).

Several causes of atrophy exist, these include:
o    Decreased blood supply
o    Loss of innervation: normal function of skeletal muscle depends on intact innervation. Damage to a nerve leads to rapid muscle atrophy of those muscle fibres supplied by the nerve.
o    Decreased workload: e.g. skeletal muscle atrophy occurs soon after a broken limb is immobilised in a cast.
o    Prolonged pressure: chronic tissue compression will result in atrophy of the surrounding tissues that have been compressed. This is likely due to the ischaemic change caused by the compressed blood vessels and lower blood supply to the area. E.g. A tumour that slowly enlarges will cause atrophy of the surrounding compressed tissues.
o    Loss of hormonal/endocrine stimulation: many endocrine glands depend on hormonal stimulation for normal metabolism and function. Interruption of these signals results in atrophy. This is seen in the testes of males who take anabolic steroids.
o    Physiological: This is a common occurrence in early development as well as later in life.
o    Lack of nutrition: Significant protein and energy malnutrition will result in catabolism of the skeletal muscle after other stores of energy in the body have been exhausted. This results in muscle wasting.
o    Senile atrophy: The aging process is associated with tissue and organ atrophy due to the loss of cells. This is mainly seen in cells made up of predominantly permanent cell populations.

 A loss of cells in atrophy is due to an increase in apoptosis while a decrease in the size of cells is due to an increase in catabolic processes relative to anabolic processes.


Hypertrophy is the opposite of atrophy and results in an increase in the size of an organ or tissue due to an increase in size of its specialised cells. Hypertrophy doesn’t result in more cells, just larger ones. The increase in size is due to an increase in the number of organelles within the cells. It is often seen in cells that have an increased workload but aren’t able to divide.  

Hypertrophy may be physiological or pathological and is either compensatory or hormonal. An example of compensatory hypertrophy is seen when a kidney is removed from an animal or when there is increased workload in cardiac or skeletal muscle. This type of atrophy tries to achieve homeostasis. An example of hormonal atrophy is during pregnancy which causes hypertrophy of the uterus.

Hypertrophy can be triggered by mechanical or trophic stimuli, such as growth factors, hormones and cytokines. The mechanism of hypertrophy involves signal transduction pathways which lead to the induction of many genes which in turn stimulate the synthesis of many cellular proteins which results in an increase in organelles and size.


Hyperplasia is the increase in the size of an organ due to an increase in the number of its specialised cells. It too, may be due to physiological or pathological causes and it can only occur in stable or labile cell types. Physiological and pathological hyperplasia can be further categorised as follows:
o    Compensatory: E.g. haematopoietic system after blood loss, lymph nodes after infection.
o    Reparatory: to restore tissue architecture or function
o    Hormonal: e.g. normal cyclical changes in the mammary gland or endometrium.
This condition is usually caused by increased local production of growth factors, increased levels of growth factor receptors on the responding cells, or activation of specific intracellular signalling pathways. These changes result in the production of transcription factors which switch on various genes which ultimately results in cellular proliferation.


Metaplasia results in a change from one type of specialised, fully differentiated adult cell to another type of stem cell (that is usually less specialised). This is a protective mechanism as the cell is replaced with another type of cell that is more suitable to withstand the stressor. In this process, some functions are lost. It involves the reprogramming of stem cells by cytokines, growth factors and extracellular matrix components. The cells themselves don’t magically change into different cells. Instead, the stem cells are told to differentiate into a type of cell that they normally wouldn’t. An example of metaplasia is connective tissue metaplasia. This is when cartilage, bone or adipose tissue form in organs that do not normally contain these cells.

That’s all for this post, see you next time :)