Endocrine and Metabolic Diseases p1223-1275

Question 1

The pituitary gland is composed of two embryologically distinct portions: an adenohypophysis and the neurohypophysis. What is a further division of these structures and what is ultimately released by these portions of the pituitary gland?

Answer 1

Adenohypophysis is broken into the pars distalis, pars tuberalis, and pars intermedia.

The neurohypophysis releases oxytocin and ADH, and also contributes to tissues of the pars intermedia.

The pars distalis (corticotrophs) processes POMC into ACTH.

The pars intermedia processes POMC into alpha-melanocyte stimulating hormone, beta-endorphin and corticotropin-like intermediate lobe peptide.

Question 2

The role of alpha-melanocyte stimulating hormone (a-MSH) has not been fully elucidated in horses. What are some roles of a-MSH found in other species or in research?

Answer 2

a-MSH is a integral mediator in control of energy hemostasis (animals and humans lacking functional receptors are obese, plasma a-MSH has been found to be positively correlated to obesity in horses).

a-MSH is a potent anti inflammatory agent (inhibition of NF-kappaB by LPS and INF-gamma; NF-kappaB activation and pro inflammatory cytokine release of TNF-alpha, IL-1beta and IL-6 are all decreased following a-MSH administered).

Question 3

What is the pathological hallmark of equine PPID?

Answer 3

Hypertrophy, hyperplasia and microadenoma or macroadenoma of the pars pituitary. This leads to increased secretion of POMC peptides.

Question 4

How does dopamine play a role in the pathology of PPID?

Answer 4

There is an apparent loss of dopamine inhibition, possibly due to loss of functional periventricular dopaminergic neurons or dopaminergic neurodegeneration. Neurodegeneration could be due to oxidative stress; dopaminergic neurons are more vulnerable because dopamine metabolism produces free radicals.

Question 5

What was a proposed mechanism linking laminitis and PPID? Why has this been refuted and what is the new proposal?

Answer 5

It was thought that the high circulating cortisol levels in horses with PPID contributed to the development of laminitis. Experimental laminitis has not been induces using corticosteroids and there is an absence of hypercortiolemia or adrenal hyperplasia in most horses with PPID.

A new proposal is that hyperinsulinemia induces endocrinopthaic laminitis. Sustained administration of a high concentration of insulin or dextrose has been shown to induce laminitis that is similar both clinically and histologically. There has also been documentation of a strong association between serum insulin concentration and naturally occurring laminitis.

Question 6

PU/PD is seen in some horses with PPID. What are 3 mechanisms for how this occurs?

Answer 6

1. Compression of the pars nervosa, decreasing the ADH production
2. Osmotic diuresis secondary to hyperglycemia and glucose rica
3. Cortisol induced

Question 7

List 3 antemortem tests for PPID.

Answer 7

1. Overnight dexamethasone suppression test
2. Measurement of endogenous plasma ACTH
3. TRHS and ACTH release

Question 8

Describe the overnight dexamethasone suppression test when used to diagnose PPID and how it no longer is the gold standard for diagnosing.

Answer 8

Horses would be given IM dexamethasone, which acts as negative feedback in unaffected horses, thus resulting in a decrease in cortisol levels (19 hours after). This test does not diagnose horses in the early stages of PPID.

Question 9

How does administration of thyrotropin-releasing hormone help diagnose PPID?

Answer 9

TRH is a physiologic releasing factor of the equine pars intermedia. Measurement of endogenous ACTH then can directly assess the pars intermedia response.

Question 10

When the seasonality affect diagnosing of PPID?

Answer 10

Between August and October, horses tested in the northern hemisphere will yield a higher hormone response or concentration when compared to horses tested between November and July.

Question 11

Which zone of the adrenal gland is described here? 
Secretes mineralocorticoids (aldosterone) in response to hypotension and electrolyte derangements. 

A. Zona glomerulosa
B. Zona fasiculitis
C. Zona reticularis

Answer 11

A. Zona glomerulosa

Question 12

Which zone of the adrenal gland is described here? 
Secretes glucocorticoids (cortisol) after being stimulated by ACTH, once the hypothalamic-pituitary-adrenal axis has been stimulated by physiologic or pathological stressors 

A. Zona glomerulosa
B. Zona fasiculitis
C. Zona reticularis

Answer 12

B. Zona fasciulitis

Question 13

Which zone of the adrenal gland is described here?
Secretes adrenal androgens (DHEA and androstenedione)

A. Zona glomerulosa
B. Zona fasiculitis
C. Zona reticularis

Answer 13

C. Zona reticularis

Question 14

Steroid hormones are lipophilic and thus carried in the plasma how?

Answer 14

Protein bound, whether it be albumin or cortisol-binding-globulin.

Question 15

Where is cortisol stored after it is synthesized in the adrenocortical cells? What are some important roles of glucocorticoids?

Answer 15

It is not stored where it is made, instead after synthesis, it is secreted into systemic circulation immediately. Glucocorticoids are important for maintaining blood pressure, provision of energy to tissues and controlling an appropriate inflammatory response.

Question 16

What kind of pattern of secretion does cortisol have?

Answer 16

Ultradian and circadian rhythms have cortisol secretions peaking in the morning and the nadir in the evening.

Question 17

What are ways that the HPA axis function differs in foals compared to adults and other species?

(4)

Answer 17

1. The HPA axis maturation begins just before parturition and continues several weeks post parturition.
2. Foals may have an impaired sensitivity to ACTH and/or limited cortisol synthetic ability
3. Adrenocortical function may not be fully mature at birth.
4. Foals likely have a decreased cortisol-binding globulin, leading to rapid excretion of free cortisol (preferentially excreted). Foal then appear able to increase cortisol synthesis; though still lower total cortisol in foals compared to adults.

Question 18

What is the primary stimulus for aldosterone synthesis from the adrenal glands?

Answer 18

Hypotension,hyperkalemia and increased plasma osmolarity stimulate the RAAS system, ultimately causing angiotensin II to stimulate the adrenal glands.

Question 19

What is aldosterone’s role?

Answer 19

Aldosterone ultimately initiates transcription of genes necessary for sodium/potassium transport. The activity of apical membrane sodium channels is increased, thus encourages water resorption and K+ excretion.

Question 20

Describe CIRCI and what population of animals it is found to affect.

Answer 20

Critical illness-related corticosteroid insufficiency is defined as an insufficient cortisol response or inadequate cortisol activity for the existing degree of critical illness. This should be considered in any critically ill horse or foal, but particularly in septic foals and horses with evidence of a systemic inflammatory response.

Question 21

There are a combination of factors that are likely involved with the development of HPA axis dysfunction, in CIRCI. List some of these.

Answer 21

1. Direct damage to the HPA axis components from the primary disease
2. Inhibition of cortisol production by medications used to treat the primary disease
3. Suppression of activity of one or more components of the HPA axis by infectious organisms or the patient’s own immune and inflammatory response

Question 22

How does the proinflammatory cytokine TNF-alpha play a role in the development of CIRCI in horses?

Answer 22

TNF-alpha can directly impair both pituitary ACTH release and adrenocortical synthesis of cortisol.

Question 23

Studies have shown a decrease in plasma high-density lipoproteins in critically ill individuals. How does this affect animals with CIRCI?

Answer 23

Corticosteroid synthesis can be limited by the low cholesterol availability.

Question 24

How is physiologic stimulation of sweating achieved in the horse?

Answer 24

Sweating is an alpha-adrenergic activation, both by direct neural stimulation and circulating catecholamines.

Question 25

What are some proposed causes of anhidrosis in horses?

5

Answer 25

1. Sweat gland atrophy (do no know if this is a primary or secondary development)
2. Genetic predisposition
3. Chronic stimulation of living in a hot, humid environment, leads to down regulation and/or desensitization of alpha-adrenoreceptors
4. May have an immunologic pathogenesis
5. Expression of water channel aquaporin-5 decreased

Question 26

How can anhidrosis in horses be definitively diagnosed?

Answer 26

Use of six serial 10-fold dilutions of an alpha2-adrenergic agonist such as terbutaline, intradermally along the neck or the pectoral region.

Question 27

There are two congenital hypothyroidism syndromes in foals. What are the causes and how do these different syndromes present?

Answer 27

Hypothyroid foals come from dams that have ingested either too much or too little iodine, or goitrogenic plants. Another syndrome can be seen to be caused by diet deficiency or toxicity (nitrate, low iodine, low selenium or goitrogenic plants).

The first syndrome sees foals with goiter, weakness, musculoskeletal problems and delayed bone development (carpal and tarsal bones).

The next syndrome can be characterized by foals with born after increased gestation length, mandibular prognathism, flexural limb deformities, ruptured digital extensor tendons and incomplete ossification.

Question 28

In what form is most of body calcium stored?

A. Ionized calcium
B. Free calcium
C. Hydroxyapatite
D. Protein bound

Answer 28

C. Hydroxyapatite; phosphorus is also stored in this manner

Question 29

How is calcium changed by pH?

Answer 29

Calcium normally binds to anionic or negatively charged proteins. This affinity is affected by pH. In an acidic environment, calcium Ca2+’s affinity to bind is decreased, thus increasing plasma Ca2+. Vice versa, in an alkaline environment, Ca2+’s affinity increases, thus decreasing plasma Ca2+.

Question 30

Horses have distinct features when it comes to calcium metabolism. List a few.

Answer 30

Increased urinary excretion, poorly regulated intestinal calcium absorption, high serum total and ionized calcium concentrations, low serum concentrations of vitamin D metabolites and decreased parathyroid gland sensitivity to Ca2+

Question 31

If serum Ca2+ is decreased, what are hormones and body systems work to increase this back to normal?

Answer 31

A decrease in serum Ca2+ causes PTH secretion to occur from the parathyroid gland, after a CaReceptor senses the change in serum concentration. PTH then increases renal absorption of Ca in the distal nephron, decreases PO4 in the proximal tubule, stimulates renal calcitriol synthesis in the proximal tubules, and stimulates osteoclasts activity in bone.

Calcitriol (Vitamin D) is responsible for increasing intestinal absorption of Ca2+ and PO4, as well as renal absorption. It also acts as a negative feedback to PTH.

Question 32

List Vitamin D’s effects on the intestine, kidney, bone, and the parathyroid gland.

Answer 32

Intestine - absorption of Ca2+ and PO4 is increased, through mediation by Na+/PO4 cotransporters
Kidney - absorption of Ca2+ and PO4 is increased, through mediation by Na+/PO4 cotransporters
Bone - increases bone matrix synthesis and mineralization and stimulates osteoclastic activity and bone resorption
Parathyroid gland - inhibits chief cell proliferation, PTH synthesis and secretion

Question 33

What is calcitonin, where does it come from and what is its role?

Answer 33

Secreted by the parafollicular cells of the thyroid gland, in response to hypercalcemia. Inhibits osteoclast function and bone resorption and decreases renal reabsorption of Ca2+ and PO4.

Question 34

Describe the pathogenesis of big head disease in horses.

Answer 34

Big head disease occurs due to hyperphosphatemia. Excessive dietary PO4 reduces intestinal calcium absorption, and with the high phosphorus, parathyroid cell hyperplasia and excess PTH stimulation occurs. The hyperphosphatemia also inhibits renal calciferol synthesis. Calcium phosphate precipitates occur, and further PTH secretion. PTH increases osteoclastic activity, bone resorption and bone loss.

Facial bone loss with excessive accumulation of subperiosteal unmineralized connective tissue, results in facial enlargement (big head).

Question 35

How does low extracellular calcium affect nerve conduction?

Answer 35

Low serum concentration of this mineral lowers the potential difference across the nerve and muscle cell membrane. This difference is closer to the threshold potential, making nerves more excitable, causing muscle fasciculations or tremors.

Question 36

How does the level of extracellular calcium affect the amount of acetylcholine that is released at NMJs?

Answer 36

The amount of acetylcholine that is released at NMJs is directly related to the amount of calcium available at the NMJ. This in turn is correlated to the amount of extracellular calcium that is available.

Question 37

List some clinical contributions of hypocalcemia in the dairy cow.

Answer 37

Metritis, mastitis, retained placenta.

Question 38

What is the fastest way to restore normal plasma Ca concentrations?

Answer 38

IV injection of calcium salts, 2 g of Ca per 100 kg of body weight, at a rate of 1 g/min.

Question 39

How does a metabolic alkalosis predispose cattle to milk fever and subclinical hypocalcemia?

Answer 39

[Ca2+] plasma concentration decreases when in an basic pH due to an increased affinity for binding to negatively charged proteins. The metabolic alkalosis also changes the conformation of the receptor for PTH to bind and thus lowers the sensitivity of tissues to PTH.

Question 40

What causes metabolic alkalosis in dairy cows?

Answer 40

Diets high in potassium can ultimately lead to hypocalcemia in cattle. There is a shift in the dissociation equilibrium of water. The number of positively charged H+ cations will decrease and the number of OH- anions increases to maintain the electroneutrality.

Question 41

In terms of the DCAD diet, what changes should be made to prevent metabolic alkalosis in close up cows?

Answer 41

Lower K+ and increase Cl-.

Question 42

How does hypomagnesemia cause hypocalcemia?

Answer 42

Moderate hypomagnesemia interferes with PTH action on tissues. Adenylate cyclase and phospholipase C have a Mg++ binding site that must be occupied by an Mg ion for full activity. Severe hypomagnesemia can inhibit PTH secretion.

Question 43

Why is magnesium an important cation? How is it regulated?

Answer 43

This mineral plays a important oral as a cofactors for enzymatic reactions vital to every major metabolic pathway. Maintenance relies almost entirely on continuous dietary Mg absorption.

Question 44

What clinical signs are seen with hypomagnesemia? What other low mineral is typically seen in conjunction?

Answer 44

These animals typically have hyperexcitability, tetany, convulsions, and often sudden death. These animals often have hypocalcemia as well.

Question 45

In what ways does the rumen play a role in hypomagnesemia?

Answer 45

1. Low Mg content of forages and inadequate dietary supplementation.
2. High dietary K can reduce the ability of the rumen to absorb Mg, by depolarizing the apical membrane of the ruminal epithelium, and reducing the electromotive potential needed to drive Mg across the ruminal wall.
3. Lush high-moisture pastures increase motility and Mg can leave the rumen before it is absorbed

Question 46

How can ionophores increase Mg absorption in the rumen? I

Answer 46

Ionophores can improve activity of the Na-linked Mg transport system int he rumen, increasing Mg absorption efficiency approximately 10%.

Question 47

In what areas are extracellular P lost from the body?

Answer 47

Saliva, urine, fecal loss, into bone, for bone and muscle growth, milk production

Question 48

What are two factors that affect salivary phosphate secretion?

Answer 48

Amount of time spent ruminating and PTH secretion

PTH secretion stimulates parotid salivary P secretion and can increase salivary phosphate secretion twofold to threefold.

Question 49

List some effects of chronic phosphorus deficiency in cattle and sheep.

Answer 49

Beef cattle may take 3 or more years to reach market weight. Brood cows may become pregnant every other year.

Sheep may be slightly more resistant to phosphate deficiency, as they are able to be successfully raised on the same pasture cattle cannot.

Question 50

Distinguish between rickets and osteomalacia. Describe how Ca, P and Vitamin D play a role in abnormalities of bone growth.

Answer 50

Rickets is a disease of young animals in which the cartilagenous matrix at the growth plate and osteoid matrix fail to mineralized, during bone remodeling. Osteomalacia is seen in adults where the osteoid matrix fails to mineralize.

P deficiency causes an osteoid matrix to form but not mineralize, leading to bones that are bendable before breaking.

Ca deficiency causes an osteoid matrix to not form at all (osteoporosis) or the osteoid matrix to fill with fibrous tissue (osteodystrophy)

Vit D deficiency causes a mixed lesion of the aforementioned. Secretion of type X collagen by the chondrocytes is reduced, leading to rickets. Programmed apoptosis of chondrocytes is prevented by Vit D deficiency, leading to failure of space for blood vessel invasion of the phases and osteoblasts cells bone formation.

Question 51

How is hypophosphatemia related to hemoglobinuria?

Answer 51

It has been proposed as a postparturient problem, in cows that have been treated for ketosis. Severe hypophosphatemia depresses the ability of erythrocytes to produce ATP, which then lessens the power of ATP driven sodium pumps. As intracellular sodium rise, the cells become rigid and eventually rupture as they travel through capillary beds.

These cattle typically are low in selenium, copper and energy.

Question 52

What in a cow’s history may predispose them to developing hypokalemia?

Answer 52

Lactating under 60 DIM. Significant anorexia for 1 week. Repeated administration of isoflupredone acetate. Multiple doses of dextrose and insulin.

Question 53

What cardiac arrhythmias can accompany hypokalemia syndrome in cattle?

Answer 53

Ventricular tachycardia, accelerated escape ventricular rhythm, atrial fibrillation

Question 54

Where is a majority of potassium located in the body? What drives the internal balance of potassium OUT of this location? And vice versa?

Answer 54

98% of potassium is located intracellular. Hypomagnesemia, acidosis, exercise and weight loss drive potassium OUT of the cell. Insulin, aldosterone, catecholamines, glucose, vitamin B12 and alkalosis drives potassium INTO the cell.

Question 55

Describe the arrhythmogenic electrical activity changes implicated in hypokalemia.

Answer 55

1. Hyperpolarization of the cardiac cell resulting in spontaneous automatic activity
2. Slow conduction caused by increased differences between resting membrane potential and threshold potential
3. Increased action potential duration as a result of slow repolarization
4. Depressed fast responses because of higher membrane potential when a slow repolarizing cell is stimulated
5. Slow responses in fibers normally exhibiting fast responses
6. Conduction block

Question 56

What are the almost pathognomonic clinical signs of hypokalemia in cattle? What levels of potassium are associated with this syndrome?

Answer 56

Flaccid paralysis and s-shaped neck. Potassium levels lower than 2.5 mmol/L.

Question 57

How should potassium be dosed to correct a hypokalemia animal?

Answer 57

KCl dose of 60-100 g/100 kg of body weight. Do not exceed an IV dose of 0.5 mEq /kg/hour.