Endocrine 1 Flashcards
(102 cards)
1
Q
Hypothalamus and pituitary where located, composed of and parts
A
Hypothalamus
- Functionally diverse region of the brain
- Located in the diencephalon below the thalamus and above the pituitary
- Composed of anatomically distinct nuclei
• Pituitary gland
- Complex endocrine organ
- Located in the sella turcica at the base of the brain inferior to the hypothalamus
○ Only way to access through the roof of the mouth
- Two parts
○ Anterior pituitary -> collection of endocrine cells (adenohypophysis)
○ Posterior pituitary -> made up of neural tissue (neurohypophysis)
2
Q
what are the 2 hormones secreted from the posterior pituitary
A
1) Anti-diuretic Hormone (ADH)
2) Oxytocin
3
Q
ADH how synthesized and the 2 main functions
A
- Synthesis
- peptide hormone (9 aa)
- Produced in hypothalamus
» supraoptic and paraventricular nuclei
- Released by posterior pituitary
» Osmoreceptors: ECF osmolality
» Baroreceptors: Blood pressure/volume - Functions of ADH
- Acts on renal collecting ducts to increase water reabsorption from urine
» Binds on V2 receptors of principal cells (cAMP pathway)
- Increases vascular resistance
» Binds V1 receptors smooth muscle cells (PIP2 pathway)
4
Q
Oxytocin where produced, released and functions (where receptors located)
A
- Peptide hormone (9 aa)
○ Produced in supraoptic and paraventricular nuclei
○ Also acts as a neurotransmitter in brain - Released by posterior pituitary
○ Oxytocin receptors are on smooth muscle cells
§ mammary gland and uterus
○ Oxytocin receptor is a Gαq coupled rhodopsin type (class I) receptor.
5
Q
What are the 5 main steps in the mechanism of hormonal release from the posterior pituitary
A
- Large neuron bodies in supraoptic & paraventricular nuclei synthetise Oxytocin (OCT) and Anti-diuretic hormone (ADH)
- Travel down axons via hypothalamohypophyseal tract (Neurophysins serve as low affinity carrier proteins) to the synapse
- Secretion of OCT & ADH from the neurosecretory nerve endings is regulated by action potentials down the neuron
○ Signals are received from brain -> to the particular nucleus -> down the tract to the synapse - Nerve endings in the pituitary contain large numbers of OCT or ADH containing vesicles
- Released by exocytosis when the nerve terminals are depolarised.
6
Q
What are the 6 hormones released from the anterior pituitary
A
- Thyroid stimulating hormone (TSH)
- Adrenocorticotropic hormone (ACTH)
- Prolactin (PRL)
- Lutenizing hormone (LH)
- Follicle stimulating hormone (FSH)
- Growth hormone (GH)
7
Q
What are the 4 main steps in the mechanism of hormone release from anterior pituitary
A
- Inhibiting and releasing hormones secreted by small bodied neurons in various regions of the hypothalamus
- arcuate, periventricular and preoptic nuclei - Released into the hypothalamohypophyseal portal system to synaptic nob
- Released into primary capillary plexus within pituitary stalk and engages with certain cell types that result in release of anterior pituitary hormones (if interact with somatotrophs get release of growth hormone)
- Hormones move into a secondary capillary plexus within the anterior pituitary into draining veins
8
Q
Growth hormone what hypothalamic hormones are involved, where secreted, what also called, what is important for half life and the main function
A
Hypothalamus
- Growth hormone inhibition and releasing hormone
Anterior pituitary
somatotrophs release
Also called somatotrophin
- 50% circulates in complexes with soluble forms of GH receptor
○ GH binding protein (GHBP) -> increases the half-life of the hormone
Main function
- Responsible for postnatal somatic growth
- increasing the number of cells (hyperplasia)
- Increasing the size of cells (hypertrophy)
9
Q
What are the 3 main functions of growth hormone and how achieve theses
A
- Acute metabolic effects
- “Anti-insulin like” i.e. Mobilizes fat & conserves glucose
- Lipolysis in adipose tissue - decrease fat content
- Inhibition of glucose uptake by muscle
- Stimulation of gluconeogenesis by hepatocytes - Growth promoting
- GH causes release from liver of Insulin like growth factor (IGF-I)
○ Stimulates differentiation and proliferation of cells. - Growth of long bones
- GH caused bones to grow in length
- Causes proliferation and enlargement of chondrocytes (cartilage cells).
○ Causes the epiphyseal plate to increase in width
○ calcification of the extracellular matrix on the diaphyseal border and old nutrient deprived chondrocytes die and are cleared by osteoclasts then replaced by oestoblasts that deposit bone
10
Q
What are the 2 main growth hormone disorders, what result from, caused by and lead to
A
- Pituitary dwarfism
- Hyposecretion of GH during the growth years
- Genetic predisposition, tumours, infarcts & infections
- Causes slow bone growth, and early epiphyseal plates closure - Gigantism
- Hypersecretion of GH (early in life) results in gigantism
○ Possible due to pituitary tumour
- Abnormal increase in the length of long bones
- Larger muscle mass
11
Q
Feline acromegaly what is it caused by and lead to
A
Caused by a growth hormone- secreting tumour of the anterior pituitary
- Hypersecretion of GH during adulthood
○ 8-14yr old (more common in males)
- Further lengthening of the long bones cannot occur because the epiphyseal plates are already closed.
- Instead, the bones of the limbs, skull, and jaw thicken.
- Other tissues & organs also grow
○ the eyelids, paws, cheeks, lips, tongue, and nose enlarge, and the skin thickens.
12
Q
Feline acromegaly what are the 4 main clinical signs
A
1) Net weight gain of lean body mass in cats with uncontrolled diabetes (polydipsia, polyuria, and polyphagia).
2) Cardiomegaly (radiographic and echocardiographic), systolic murmurs & heart failure
3) Enlargements of extremities
4) Azotemia also develops in 50% cats
13
Q
Growth hormone secretion levels what occurs daily and throughout life
A
- Growth hormone secretion occurs as several pulses/day - spikes
○ Last from 10 to 30 min before returning to basal levels.
○ The largest GH peaks occurs about an hour after onset of sleep (diurnal secretion). - The amount and pattern of GH & IGF-I secretion changes throughout life.
○ Basal levels are highest in early life decline throughout adult life.
○ The amplitude and frequency of peaks is greatest during the pubertal growth spurt
14
Q
Regulation of growth hormone secretion what are the 3 main CNS inputs and list some GH release stimulators and inhibitors
A
CNS inputs via hypothalamus 1) pulsatile secretion 2) negative feedback 3) diurnal rhythms Stimulators of GH release include (among others) - hypoglycemia, - stress - dietary protein - low fatty acids - Exercise - Ghrelin (stomach hormone). Inhibitors of GH secretion include - high carbohydrate - negative feed back( IGF-I & GH -> result in release of growth hormone inhibiting hormone)
15
Q
Besides the release of growth hormone inhibiting hormone what is another inhibitory feedback that occurs
A
○ Somatostatin (GHIH) - has on receptor (inhibitory response)
§ Produce Gsα & Giα proteins regulate cAMP levels and GH secretion - decrease the release
16
Q
Describe the 3 parts of the adenohypophysis (anterior pituitary)
A
1) pars distalis the largest part; contains the bulk of the endocrine cells which secrete trophic hormones
2) pars tuberalis - consists of dorsal projections of endocrine cells along the infundibular stalk
- mainly acts as a scaffold for the portal blood vessels coursing from the median eminence to the pars distalis
3) pars intermedia - forms the junction between the pars distalis and the pars nervosa and contains endocrine cells
in all species except the horse, the pars intermedia is separated from the pars distalis by a cleft
17
Q
what is the anterior and posterior pituitary derived from
A
- the adenohypophysis (anterior pituitary) is derived from the ectoderm of Rathke’s pouch (craniopharyngeal duct)
- the neurohypophysis (posterior pituitary) is derived from the neuroectodermal downgrowth
18
Q
What are the potential consequences to the foetus and dam of failure of adequate in utero development of the pituitary or hypothalamus?
A
- prolongation of gestation, at least in ruminants
○ in ruminants, the signal for normal parturition at term is a rise in the foetal cortisol concentration, which requires an intact foetal hypothalamic-pituitary-adrenocortical axis and sufficient maturation of the adrenal cortices to respond to the foetal ACTH signal - can result in retarded foetal growth and development in late stages of gestation (due to inadequate production of such anabolic hormones as growth hormone, thyroxine and testosterone)
19
Q
List 3 syndromes where there is inadequate development of the pituitary or hypothalamus, what species and why occur
A
1) Anencepahly and Prosencephalic Agenesis (absence) -> ruminants
- early embryonic failure of the rostral neural tube
2) Prosenecphalic Hypoplasia (Holoprosencephaly) -> rostral tube closes but some degree of failure of prosencephalon to differentiate
- ewes consumed steriodal alkaloid-containing plant Veratrum californicum between days 9 and 14 of pregnanacy (severe expression is cyclopia)
3) Adenohypohydeal Hypoplasia -> Guernsey, Jersey and Swedish Red and White cattle as an autosomal recessive inherited condition characterised by prolonged gestation
20
Q
What is the craniopharyngeal duct (Rathke’s pouch) and what lesions can arise from remnants of this structure
A
dorsal evagination of oropharyngeal ectoderm that forms the anterior pituitary
Pituitary cysts can develop from this remnant as well as craniopharyngioma (a benign tumour derived from epithelial remnants of oropharyngeal ectoderm of the craniopharyngeal duct (Rathke’s pouch))
21
Q
In which species are developmental pituitary cysts most often diagnosed and What is their clinical significance?
A
- most often seen in dogs
- small cysts are asymptomatic but larger cysts may provoke clinical signs
- depend on the area it grows may occlude caudal nares -> respiratory distress OR compress pituitary, hypothalamus, optic chiasm etc. OR result in pituitary dwarfism
22
Q
Pituitary dwarfismwhich species is this condition most commonly seen and how does it manifest clinically?
A
Dogs - most often in German shepherd dogs but is also reported in Weimaraner, Spitz, toy pinscher and Karelian bear dogs
Clinically
- normal till 2 months then growth slows
- 3-4 months obvious runts never obtain full adult dimensiosn
- most have normal proportions but some chuncky square shape
- puppy coat retained lack of primary guard hairs (appear woolly)
- skin initially normal but becomes hyperpigmented, thin, wrinkled, scaly
23
Q
List 5 clinical consequences of large space-occupying mass in the pituitary
A
- compression adenohypophysis (hypothyroidism, hypoadrenocorticism, loss of libido, anoestrus, infertility)
- loss of protein anabolic effects of growth hormone (pituitary cachexia, dull and dry hair coat)
- diabetes insipidus (polyuria, polydipsia)
- cranial nerve deficits -> central blindness
- CND dysfunction -> behavioural, emotional disturbances, thermoregulation
24
Q
What is the most common type of pituitary neoplasm in dogs and what effect would such a tumour have in the adrenal glands?
A
Corticotroph (ACTH-secreting) Adenoma of Dogs
- ACTH secretion by the tumour -> bilateral enlargement of the adrenal glands due to hypertrophy and hyperplasia of cells of the zonae fasciculata and reticularis of the adrenal cortices
25
What is the most common type of pituitary neoplasm in horses, what are the typical clinical signs associated with such tumours and why do these signs develop
Melanotroph Adenoma of the Pars Intermedia of Horses
many of these clinical signs (e.g. polyphagia, PU/PD, sweating and failure to cyclically shed hair) are due to compression and dysfunction of the overlying hypothalamus - NOT AS MUCH DUE TO EXCESS HORMONES
26
What is the usual cause of acromegaly in cats and dogs
Cats
functional somatotroph adenomas of the pars distalis
Dogs
due to prolonged administration of synthetic progestagens
27
List 6 clinical signs of acromegaly
1) polyphagia
2) increase in body size and weight
3) enlargement of head, feet, abdomen and viscera
4) rapid claw growth
5) hypertrichosis (increased hairiness)
6) formation of excessive skin folds
28
What is the usual clinical signs of diabetes insipidus
inability to concentrate the urine -> polyuria secondary polydipsia to prevent dehydration
29
What is meant by the term central diabetes insipidus and what are some possible causes of this condition?
There is a partial or complete deficiency of ADH
Causes - any condition that damages the hypothalamic supraoptic nucleus, the infundibular stalk or the pars nervosa
1. most idiopathic
2. head trauma
2. congenital in some dogs
30
What is meant by the term nephrogenic diabetes insipidus and what are some possible causes of this condition?
Blood levels of ADH are normal to high but target cells in the distal renal tubules and collecting ducts are unable to respond
Causes
1) primary - congenital in various dog breeds
2) secondary - primary renal disease (e.g. pyelonephritis) or extrarenal disorders (e.g. pyometra, hypoadrenocorticism, hypercalcaemia, hypokalaemia) impair the renal response to ADH
31
What is the basic structure of the adrenal galnd
```
- bilateral structures encased in a connective tissue capsule
Consists of 2 layers
1) Cortex (80-90% of adrenal gland)
1. zona glomerulosa
2. zona fasciculta
3. zona reticularis
2) Medulla
- chromaffin cells (columnar shape and basophilic with granules) surrounding blood vessles
```
32
Describe the 3 layers of the cortex of the adrenal gland
1) Zona glomerulosa
§ The outermost zone and cells here are columnar in shape and are arranged in irregular cords
§ Creates aldosterone
2) Zona fasciculata
§ Middle zone and cells are polyhedral, with foamy appearance (lipid) and are arranged in straight cords radiating towards the medulla
§ Production of glucocorticoids such as cortisol
3) Zona reticularis
§ Cells are arranged in cords that run in many different directions and anastomose with one another
§ Produce Androgen precursors
33
Within the cortex of the adrenal glands what are the 3 areas and what hormones do they produce
1) Zona glomerulosa produces mineral corticoids such as aldosterone
2) Zona fasciculata produce glucocorticoids such as cortisol
3) Zona reticularis produce androgen precursors such as dehydroepiandrosterone (and some cortisol)
34
Steroid hormones produce from adrenal gland what is the rate limiting step, what produced where and how
- Cholesterol to pregnenolone rate limiting step is production of an enzyme which is activated by ACTH
- Zona fasiculata and reticularis have 17-alpha-hydroxylase which is necessary for synthesis of 17-hydroxypregnenolone and 17-hydroxyprogesterone so can form cortisol
- Zona reticularis can create dehydroepiandrosterone (DHEA) which is converted to testosterone and oestrogen in peripheral tissues
35
What is involved in the transport and removal of adrenocortical hormones
TRANSPORT
○ 90% of glucocorticoids in blood are bound to protein and have a relatively long half-life in blood ~ 60-90 min.
○ Cortisol is transported in blood bound to corticosteroid-binding globulin (transcortin), and albumin.
REMOVAL
- inactivated in the liver decreasing their bind to blood protein
- increased excretion in bile and urine
36
List the 4 steps on how cortisol and aldosterone exert their effects
1. Cortisol and aldosterone pass through the cell membrane and bind to a glucocorticoid receptor (GR) or mineralcorticoid receptors (MR) in the cytoplasm.
2. This binding of cortisol to its receptor allows the disassociation of heat shock proteins hsp90/70
3. Allows a homodimer to form that translocates to the nucleus.
4. Inside the nucleus, the receptor complex binds to specific DNA responsive elements to activate gene transcription.
- The mineralocorticoid receptor can binds both aldosterone and cortisol.
37
What are the 4 broad actions of glucocorticoids
1) within the endocrine system
2) anti-inflammatory
3) bone
4) delayed wound healing
38
Glucocorticoids what are the 4 main actions within the endocrine system and how achieve
1. Raise blood glucose by increasing liver output of glucose
○ Promotes gluconeogenesis by inducing the synthesis of gluconeogenic enzymes (side effect of diabetes)
○ Promotes proteolysis and inhibit protein synthesis thus freeing up amino acids for gluconeogenesis.
2. Induces mobilization of fat from subcutaneous adipose tissue.
3. Prior action of cortisol build-up of glycogen stores in liver and used as a substrate for glucagon and adrenaline
4. permissive hormone
○ In adipose tissue it must be present for catacholamines to stimulate hormone sensitive lipase
○ In liver other gluconeogenic hormones are ineffective without the permissive effect of glucocorticoids.
39
Glucocorticoid anti-inflammatory actions what are the 4 effects
1) Inhibits prostaglandin and leukotriene production by inhibiting phospholipase A2 and formation of arachidonic acid.
2) Decrease release of proinflammatory cytokines IL-1, IL-6 & TNF-a
3) Reduces IL-2 production inhibiting lymphocyte proliferation
4) Reduce expression of cell adhesion molecules important for cell extravasation from the blood
Immunosuppressive - SIDE EFFECT
40
Glucocorticoid bone and delayed wound healing functions what occurs
```
Bone
- High cortisol --> decreased bone mass
- Inhibits formation of calcitriol and calcium absorption
- Inhibits collagen synthesis
- Synergizes with PTH to break down bone
- Inhibits bone formation (reduce osteoblasts activity)
○ Osteoporosis - SIDE EFFECT
Delayed wound healing
- Inhibits collagen synthesis
```
41
Regulation of glycocorticoid secretion what are the 2 main mechanisms
1) Regulated via hypothalamus-pituitary axis - CRH & ACTH
- CRH released from the hypothalamus as a consequence of hypoglycaemia, stress, physical trauma (surgery, pain, anaesthetics), hypoxia, ADH, infection and diurnal secretion
○ Binds cell surface receptors on corticotrophs and, via Gs proteins and cAMP and releases ACTH from the anterior pituitary.
○ ACTH binds adrenal cortical cells via a MC2R receptor (member of melanocortin receptor family) and activates Gs proteins and cAMP.
○ This stimulates production of several key enzymes required for the synthesis of glucocorticoids, mineralcorticoids and the androgen precursosr DHEA.
2) Feed-back inhibition - homeostasis
○ Cortisol inhibits pituitary (ACTH release ) & hypothalamus (CRH release)
○ ACTH inhibits neuronal cells in the hypothalamus (CRH release).
42
What is the main function of aldosterone and the 3 ways it achieves this
- Promotes Na+ and water retention, and lowers plasma K+ concentration through increased K+ secretiom into tubular lumen
1) Upregulates and activates the basolateral Na+/K+ pumps and epithelial sodium channels in the collecting duct increasing Na reabsorption.
2) Stimulates Na+ and water reabsorption from the gut, salivary and sweat glands in exchange for K+.
3) Stimulates increased secretion of H+ via the H+/ATPase in the intercalated cells of the cortical collecting tubules
43
What is the main molecule involved in regulation of aldosterone and other signals involved
- Angiotensin II is the most important signal for aldosterone secretion.
○ Activates a Gq protein and (via PIP) activates enzymes needed for the production of aldosterone. Only formed in zona glomerulosa as the aldosterone synthetase enzyme is only found at this site.
- Other signals
○ K+ levels
○ Na+ (minor)
○ ACTH while not essential for aldosterone release is required for optimal secretion and for maintenance of the adrenal cortex. Cortisol may also activate mineralocorticoid receptors.
44
Biosynthesis of adrenalin and noradrenalin where occur and what are the 4 steps in the pathway
- Chromaffin cells in the adrenal medulla synthesize and secrete adrenalin and noradrenalin and norepinephrine.
1. Biosynthesis of catecholamines occurs in a stepwise manner starting with tyrosine and progression through DOPA, dopamine noradrenalin and adrenalin.
○ Key enzymes tyrosine hydroxylase & dopamine b hydroxylase stimulated by sympathetic stimulation
2. Cortisol stimulation activates Methyltransferase to convert noradrenaline to
3. Adrenalin and noradrenalin are stored secretory granules within the chromaffin cells.
4. Stimulation of nicotinic ACh receptors opens Ca2+ ion channels on chromaffin cells that produces a localized depolarization and entrance of Ca2+ resulting in exocytosis of adrenaline and noradrenaline.
45
What are the 2 main developmental defects of the adrenal cortex how common and what result in
1) Adrenal agenesis -> rare, unilateral incidental finding, bilateral is lethal due to absence of mineralocorticoids which is essential for fluid and electrolyte regulation
2) Accessory adrenocortical tissue -> common incidental finding, ectopic tissue responds to normal stimulus do no clinical disease
Typical sites include: adrenal capsule, periadrenal or perirenal adipose tissue, mesorchium
46
List the 2 main degenerative diseases of the adrenal cortex
1) adrenal mineralization
| 2) adrenal haemorrhage and necrosis
47
Adrenal mineralization what result from, which animal most common and what results in
Degenerative disease
- Deposition of calcium in the adrenal glands is common in cats (reported to affect up to 30% of cats) and occasionally occurs in dogs.
- Often bilateral
- Unknown cause and not associated with clinical disease but often detected on ultrasound
48
Adrenal haemorrhage and necrosis in what 3 situations does this occur
1. Neonates that suffer from hypoxia, dystocia, or postpartum stress (eg. exposure or hypothermia)
2. Animals that die during marked exertion (particularly racehorses)
3. Animals with severe septic disease - critical already but become worse with below:
§ This is known as Waterhouse-Friderichsen syndrome, where adrenal haemorrhage, adrenocortical necrosis and adrenal insufficiency exacerbate the effects of sepsis, often with concurrent DIC and shock.
49
What is the pathogenesis behind adrenal haemorrhage and necrosis
1) Adrenocortical infarction due to DIC or coagulopathy as well as high exertion (racehorses)
§ Adrenal circulatory system is a delicate sinusoidal plexus and very susceptible to damage
2) Sudden strong increase in ACTH secretion in response to stress
§ High doses of ACTH have been shown to be directly toxic to adrenocortical cells, and can produce haemorrhage and necrosis similar to that seen in Waterhouse-Friderichsen Syndrome
50
Adrenal cortical toxicity why is it susceptible to this, how significant and what two toxins are particularly important
- susceptible to toxicity due to its high blood supply, its robust lipid metabolism, and abundance of cytochrome P450 enzymes for biotransformation
- rarely clinically significant
Toxins
1) Mitotane -> older therapy for hyperadrenocorticism causes direct adrenal cortical necrosis
2) Trilostane -> control hyperadrenocorticism and results in adrenal cortical necrosis
51
Adrenal inflammation (adrenalitis) what suppresses this and what are the 3 main things that cause this
- High local glucocorticoid concentrations suppress local inflammation within the adrenal cortex and facilitate growth of infectious agents
Causes
1) Usually systemic infections
○ Bacterial septicaemias (eg. E. coli, Actinobacillus equili)
○ Viral diseases (eg. Equine herpesvirus 1) - herpes inclusions can be found here
○ Disseminated fungi (eg. Cryptococcus)
○ Protozoa (eg. Toxoplasma)
2) Damage from inflammation may be sufficient to impair adrenal function.
3) Autoimmune lymphocytic inflammatory destruction of the cortex also major cause of hypoadrenocorticism (see later)
52
Adrenocortical hyperplasia what are 3 main causes and the 2 forms
Causes
1. Prolonged stress (eg. cattle with ketosis, animals with prolonged and painful illnesses)
2. ACTH-secreting pituitary tumour
3. Idiopathic forms are seen in dogs (especially poodles) and may reflect defective cortisol feedback within the hypothalamus or pituitary
○ May be incidental but some of these animals may have hyperadrenocorticism
2 forms
1) Nodular hyperplasia (accessory cortical nodules)
2) diffuse adrenocortical hyperplasia
53
Nodular hyperplasia how common in what species, what do nodules look like and which area results in atypical hyperadrenocorticism
- Very common, especially in older horses, dogs and cats
○ Prevalence reported to be >95% in small animal adrenal glands
- Nodules usually < 1 cm diameter, well-demarcated, yellow, spherical nodules in the cortex or sometimes attached to the exterior of the capsule
- Usually bilateral and multiple nodules
- Nodules involving the zona reticularis are suggested as a cause of “atypical hyperadrenocorticism” – see section on hyperadrenocorticism
54
Diffuse adrenocortical hyperplasia what looks like grossly and what may coexist
- Uniform enlargement of the adrenal cortex due to marked hypertrophy and hyperplasia of lipid-laden cells of the zonae fasciculata and reticularis
- Usually bilateral
- May coexist with nodular hyperplastic foci
55
Adrenal neoplasia what species most common in, what are the 2 main types and what do they secrete
- Neoplasia most common in old dogs, ruminants (~8% of neoplasms in cattle) and occasionally horses
- Adrenocortical neoplasms may be functional or non-functional
- Functional neoplasms produce excessive cortisol (causing hyperadrenocorticism) or rarely excessive aldosterone (causing hyperaldosteronism)
56
Adrenocortical adenoma what type of neoplasia, what does it coexist with, what look like grossly and composed of
- Usually incidental necropsy findings if non-functional
- Usually solitary but can be bilateral
- Often coexist with multifocal nodular hyperplasia
- Well-demarcated, encapsulated, yellow foci which compress the adjacent cortex and medulla
- Composed of well-differentiated cells resembling normal cells of the zonae fasciculata and reticularis or uncommonly, zona glomerulosa
57
Adrenocortical carcinoma how compare to adenoma, what do to the adrenal gland and what look like grossly
- Usually larger than adenomas and more likely to be bilateral
- Often variegated yellow-red due to haemorrhage and necrosis
- Carcinomas usually completely obliterate the affected adrenal gland
- Aggressive malignancies which invades the surrounding tissue and local vessels (adrenal vein, vena cava, aorta) forming neoplastic thrombi, with metastasis to distant sites including liver and lung
○ Hard to remove due to the relationship with these structures
58
Hyperadrenocorticism what called, what are the 5 forms
All 5 together called - Cushing's syndrome
1) Pituitary-dependent Hyperplasia (PDH) (Cushing's disease)
2) Adrenal-dependent hyperadrenocorticism (ADH)
3) Iatrogenic
4) Exogenous ACTH secretion - rare
5) Food-dependent hyperadrenocorticism - rare
59
1. Pituitary-Dependent Hyperplasia (PDH) - AKA Cushing’s disease how common, what caued by and what results in
- PDH is the most common cause of spontaneous canine hyperadrenocorticism (approximately 80-85% of cases)
- Due to a functional ACTH-secreting adenoma in the anterior pituitary OR impairment of negative feedback of cortisol on ACTH secretion
- Excessive ACTH secretion causes bilateral hyperplasia of adrenal cortices (especially zonae fasciculata and reticularis)
- ACTH secretion and hence cortisol tends to be produced in irregular bursts in PDH
60
Adrenal-dependent hyperadrenocorticism (ADH) what causes, what % of cases, how cause hyperadrenocorticism and what result in in terms of adrenal gland
- Functional adrenocortical tumours account for approximately 15-20% of cases of spontaneous canine hyperadrenocorticism
- Functional tumours do not respond to normal regulation of cortisol secretion, and secrete excess cortisol independently of pituitary stimulation
- Non-neoplastic adrenal tissue in affected animals undergoes atrophy due to suppression of ACTH secretion by excess cortisol
- Adrenocortical tumours do not respond to ACTH; therefore, animals with ADH typically have one large adrenal (containing tumour) and one small adrenal (due to atrophy) - Bilateral adrenocortical atrophy
61
Iatrogenic hyperadrenocorticism what caused by and what leads to
- Caused by long-term medication with corticosteroids (typically chronic allergic or autoimmune diseases)
- Exogenous corticosteroids suppress ACTH secretion, and lack of ACTH stimulation causes bilateral adrenocortical atrophy (chiefly of the zonae fasciculata and reticularis)
Bilateral adrenocortical atrophy
62
Exogenous ACTH secretion causing hyperadrenocorticism what caused by and what associated with
- rare
- caused by non-pituitary neoplasms that secrete ACTH into circulation
- Appears to be very rare in veterinary medicine but possibly under-reported (may be difficult to distinguish from pituitary- dependent hyperadrenocorticism)
- Mostly associated with non-adrenal neuroendocrine neoplasia such as islet cell tumours
63
Food-dependent hyperadrenocorticism how common, what result from and what causes
- Secretion of excessive levels of cortisol in response to meals, with normal cortisol and ACTH levels at other times
Thought to be caused by abnormal expression of receptors for minor food-related hormones (such as gastric inhibitory peptide) on adrenocortical cells, resulting in oversecretion of cortisol when these hormones are secreted
64
Hyperadrenocorticism what does it mainly reflect and the 6 main areas of effects
- Clinical signs mostly reflect gluconeogenesis, lipolysis and protein catabolism, as well as immunosuppression
1. Skin
2. muscle
3. liver
4. immunosuppression
5. polyuria/polydipsia
6. miscellaneous
65
What are the 4 main effects on the skin of hyperadrenocorticism and how occur
1) Alopecia affecting friction sites, such as elbows, neck, tail and flanks (cortisol influences hair growth cycle).
○ Typically bilaterally symmetrical alopecia
○ Keratin accumulation in atrophic hair follicles (comedomes or “blackheads”)
2) Dermal atrophy - Thin skin which heals poorly due to catabolism of dermal collagen
3) Mineralization of dermal collagen fibres (calcinosis cutis) occurs in 30-40% of dogs
○ Try to push out through ulcerated skin
○ Dorsal midline, ventral abdomen and inguinal region most affected
4) Skin hyperpigmentation develops in some cases
○ Proposed pathogenesis: Melanocyte stimulation by ACTH or concurrent melanocyte-stimulating hormone (MSH) secretion by functional pituitary tumour.
§ However, this condition is also seen in cases without pituitary tumours (ie. cases with normal ACTH/MSH secretion), so this is unlikely to be the complete pathogenesis
66
What muscle and liver effects does hyperadrenocorticism have
2. Muscle
- Atrophy and catabolism of abdominal and limb musculature (causes weakness, tremors and pot-bellied appearance)
- Actually lose weight although look fat
3. Liver
- Glycogen accumulation within midzonal hepatocytes and hepatomegaly (termed “steroid hepatopathy”)
- Hepatic gluconeogenesis (production of glucose from non-carbohydrate sources such as lipids and amino acids) and glycogenesis (production of glycogen from glucose) both promoted by corticosteroids to provide readily accessible energy supply for stressful events
- Hepatic lipidosis may also occur if diabetes mellitus develops
67
What effects on immunosuppression and polyuria/polydipsia does hyperadrenocorticism have
4. Immunosuppression
- Suppression of inflammation and immunity by excess corticosteroids predispose to infections, especially of the skin and urinary tract
- Demodex mites -> normally suppressed
5. Polyuria/polydipsia
- Pathogenesis incompletely understood but corticosteroids appear to decrease renal sensitivity to anti-diuretic hormone
○ Primary polyuria with compensatory polydipsia
- Does NOT reflect osmotic diuresis due to hyperglycemia and glucosuria, as serum glucose levels do not exceed renal resorption threshold in cases of hyperadrenocorticism (unless secondary diabetes mellitus – see below)
68
What are 4 possible miscellaneous hyperadrenocortiocism effects
1) Polyphagia
○ Direct effect of corticosteroids, typically only seen in dogs
2) Diabetes mellitus
○ Gluconeogenesis causes persistent hyperglycemia and insulin antagonism
§ Low to moderate -> may cause diabetes mellitus
3) Vascular thrombosis
○ Excessive cortisol increases coagulation factors within blood - increase chance of thrombosis
○ Especially pulmonary thrombosis
4) Possible association with development of gall bladder mucocoeles - unknown
69
Hyperadrenocorticism in cats how common ,what is the main cause and effects
- Rare and nearly always pituitary-dependent (>95%)
○ Of the adrenal-dependent cases, approximately 50% adenomas and 50% carcinomas
Effects
- Alopecia and thin, easily torn skin (feline skin fragility syndrome) - tear of large chunks of skin
- Folded ear pinnae
- Pot-bellied appearance
- Hepatomegaly reflects mix of lipid and glycogen accumulation
- Secondary skin infections
70
Hyperadrenocorticism in ferrets what is the main cause and effects
- Functional cortical hyperplasia or adrenal neoplasia in ferrets secretes sex hormones (especially oestrogen) rather than corticosteroids
- Female to male ratio 2:1
Effects
- Female: Vulval swelling, pyometra (need to distinguish from persistent oestrus)
- Male: Prostatic cysts
- Either sex: Alopecia, bone marrow suppression (with anaemia and thrombocytopaenia) - oestrogen toxic to bone marrow
71
Hypoadrenocorticism how common in what species, what is deficient and the vague clinical signs
- Uncommon disease, most common in young adult dogs, rarely cats
- Disease reflects deficiency of glucocorticoids +/- mineralocorticoids
Vague clinical signs: lethargy, weight loss, weakness, vomiting, diarrhoea
72
What are the 3 causes/forms of hypoadrenocorticism what caused by and which secretion is affects
1. Primary adrenal hypoadrenocorticism (AKA Addison’s disease)
- Due to destruction of the adrenal cortices
○ Most commonly idiopathic immune-mediated destruction
○ May also be induced by adrenal toxicity, adrenalitis, or haemorrhage/necrosis
- Most common cause in small animals
- Requires severe bilateral loss of cortical tissue (>90% cortical loss)
- Both mineralocorticoid and glucocorticoid secretion impaired
2. Secondary/pituitary-dependent hypoadrenocorticism
- Due to inadequate ACTH secretion by the pituitary (eg. destruction by inflammation or neoplasia)
- Glucocorticoids deficiency only, mineralocorticoid secretion unaffected
3. Iatrogenic hypoadrenocorticism
- Temporary hypoadrenocorticism following sudden discontinuation of corticosteroid therapy
○ Glucocorticoid deficiency until signalling pathway stimulates the adrenals to start producing corticosteroids again
73
Hypoadrenocorticism what are the main effects
- Mineralocorticoid deficiency causes hypovolaemia (which may lead to hypovolaemic shock in severe cases), hyperkalaemia, hyponatraemia, hypochloridaemia and metabolic acidosis.
- Glucocorticoid deficiency results in poor stress tolerance and suppresses gluconeogenesis, leading to mild hypoglycemia
- Rarely also develop alopecia or hyperpigmentation
74
Hyperaldosteronism what are the 2 types and what called
1) primary hyperaldosteronism (Conns syndrome)
| 2) Secondary hyperaldosteronism
75
Primary hyperaldosteronism (Conn’s Syndrome) how common what caused by and effects
- Very rare disease caused by functional aldosterone-secreting adrenal adenoma or carcinoma
Effects
- Hypervolaemia due to hypernatraemia and water retention
- Muscle weakness and cardiac arrhythmias due to excessive potassium secretion and hypokalaemia
- Metabolic alkalosis due to excessive secretion of hydrogen ions (usually mild)
○ Reflects action of sodium/hydrogen pump in renal collecting ducts
76
Secondary hyperaldosteronism what caused by, what disease common with and effect
- Aldosterone hypersecretion stimulated by chronic systemic circulatory impairment, renal juxtaglomerular hypoperfusion, and overactivation of renin-angiotensin-aldosterone system
- Common in cases of left-sided congestive heart failure
- Hypervolaemia and hypertension can negatively impact cardiac function in cases of heart disease
77
Pathology of the adrenal medulla what is the main disease, what species affects, gross look and type
Pheochromocytoma
- Neoplasia of the adrenal medulla
- Dogs and cattle mostly affected
- May be unilateral or bilateral
- Typically large (often >10cm), multilobular tumours containing yellow-red areas of haemorrhage or necrosis
- May be functional or non-functional
○ Functional tumours secrete adrenalin and noradrenalin and cause sympathetic overload: tachycardia, hypertension, arteriosclerosis, myocardial hypertrophy, spontaneous haemorrhage (epistaxis, retinal haemorrhage), and hyperactivity
○ Renal hypertension may result in glomerulopathy
- May be benign or malignant
○ Malignant pheochromocytomas often locally invasive, with invasion of local vessels (particularly caudal vena cava) resulting in occlusion and neoplastic emboli
78
What are the 5 main effects of glucocorticoids
1. Antagonise effects of insulin – promote gluconeogenesis & glycogenolysis, & decrease G uptake by insulin sensitive tissues
2. Increase lipolysis, antagonise insulin leading to decreased lipoprotein lipase, increased liver low density lipoprotein synthesis
3. Suppress wound healing, inflammation and immunologic responsiveness
4. Stress leukogram – lymphopenia, eosinopenia, neutrophilia, monocytosis
5. Reduced urine concentration – inhibition of ADH action & secretion
79
What are the 4 main clinical findings of hyperadrenocorticism in dogs
1) polyuria/polydipsia
2) polyphagia
3) abdominal enlargement
3) muscle wastage and weakness
4) thin skin, alopecia, hyperpigmjentation, comedons, calcinosus cutis
80
What are the 5 main clinical findings associated with hyperadrenocorticism
1) insulin resistant diabetes mellitus
2) PU/PD
3) polyphagia
4) thin skin (easily torn), skin fragility, alopecia
5) pot belly
81
What are the 3 main clinical findings of hyperadrenocorticism in horses
1) seasonal variation in cortisol and ACTH (need to be considered for dancing)
2) hirsutism (excess body hair where normally not much)
3) PU/PD
82
What is the leukogram found in hyperadrenocorticism
- “Stress” leukogram
a. Lymphopenia
§ Most consistent finding across all species
§ Sequestration of lymphocytes in nodes, spleen and bone marrow
§ Lysis of thymic cortical lymphocytes and uncommitted lymphocytes
b. Mature Neutrophilia
§ Increased marrow release from storage pool
§ Decreased emigration into tissues (hypersegmented neutrophils in blood)
§ Shift from marginating pool to circulating pool
c. Monocytosis (dogs, occasionally cats)
§ Shift from marginating pool to circulating pool
d. Eosinopenia
§ Margination or sequestration in tissues
§ Inhibition of marrow release through inhibition of cytokines eg IL-5
- Mild thrombocytosis
- Increased platelet production – unproven mechanism
83
List and describe the 5 main biochemistry results with hyperadrenocorticism
1) Elevated ALP - induction of corticosteroid isoform (dogs) & steroid hepatopathy - most common in dogs
2) Hypercholesterolaemia & Hypertriglyceridaemia - LIPIDEMIA
○ Stimulation of VLDL synthesis in liver
○ Stimulation of hormone sensitive lipase
○ Inhibition of lipoprotein lipase through insulin antagonism
3) Hyperglycaemia
○ Insulin antagonism
○ Decreased GLUT-4 transporters
○ Stimulate gluconeogenesis
○ Stimulate glucagon release
4) Low TT4 – euthyroid sick syndrome - not symptomatic for low thyroid
5) Mild elevation in urea
○ prerenal azotaemia due to increased protein catabolism
○ Prone to gut ulceration
84
What are the 2 main Urinalysis results from hyperadrenocorticism and what leads to
1) Suboptimal urine concentration
○ inhibition of ADH action and release
2) Mild Proteinuria
○ Systemic Hypertension - hard to differentiate between renal disease
- Immunosuppression and dilute urine predisposing to urinary tract infection
85
What are the 2 main types of test options for hyperadrenocorticism in dogs and the tests within
1) Screening tests - confirm diagnosis
- Urinary cortisol-creatinine ratio
- Low dose dexamethasone suppression test
- ACTH stimulation test
- Cortisol-ACTH ratio
2) Localising tests - pituitary vs adrenal
- High dose dexamethasone suppression test
- ACTH level (endogenous ACTH)
- Adrenal Imaging - not for general GP - referral
86
What are the 3 main screening tests for hyperadrenocorticism
1) Urinary cortisol-creatine ratio (UCCR)
2) Low dose dexamethasone suppression test (LDDST)
3) ACTH stimulation test
87
Urinary cortisol-creatinine ratio (UCCR) what type of test, what is done, what is sensitivity and specificity and what is it mainly useful for
Screening test for hyperadrenocorticism
- Collect the urine and test the cortisol-creatinine ratio
- Highly sensitive test – will detect 75-100% of cases - mostly 100% will not miss diagnosis
○ Negative rule out Hyper A
- Poor specificity (20-25%) as UCCR will be elevated with stress or illness
- To improve specificity test free catch sample collected at home (to minimise stress)
- Useful as rule out test, but not a confirmatory test
88
Low dose dexamethasone suppression test (LDDST):
what type of test, what is done, sensitivity and specificty, what different results can lead to different suppression relate to
Screening test for hyperadrenocorticism
- Administration of dexamethasone in a normal animal causes negative feedback to pituitary resulting in reduced ACTH and thus reduced cortisol release
- High sensitivity (85-100%), moderate specificity (44-73%)
○ Dogs with adrenal tumours usually show lack of suppression
○ Dogs with pituitary dependant hyperA (PDH) can show partial suppression (75%) or no suppression (25%)
§ Partial suppression - KNOW IT IS PITUITARY NOT ADRENAL
- Stressed dogs can show partial or no suppression
89
Low dose dexamethasone suppression test what are the 4 main possibilities and what test results see with each
1) NORMAL
- Decrease cortisol 4-8 hours
2) PDH v1
- Most partial suppression - 75%
3) PDHv2
- Some may drop lower and then increase - still part of the 75% - PARTIAL SUPPRESSION
4) PDH/ADH
- Adrenal tumour not worried about feedback inhibition -> NO SUPPRESSION
- 25% of hyperA (PDH)
90
ACTH stimulation test what type of test, sensitivity and specificity, what result with certain disease and what mainly used for
- Generally has lower sensitivity (57-95%) than LDDST (sensitivity is lower for primary adrenal tumours 57-63%, and higher for PDH 80-83%) and higher specificity (59-93%) than LDDST
○ Big breed dogs more likely to have adrenal which is less senitive to therefore go for Dex test above
- Hyperadrenocorticism cases show excessive response to ACTH
- Gold standard test for diagnosis of iatrogenic hyperadrenocorticism.
- Used in monitoring response to therapy for Hyperadrenocorticism
- Used for Dx atypical HyperA, with measurement of cortisol & sex hormones (17-hydroxy-progesterone, adrostenedione, oestradiol)
- Not useful for testing for PPID in horses
91
How does the ACTH stim test work
Normally there is a capped limit of maximum cortisol however if large adrenal gland then there will be an increase in cortisol levels above capped
92
In choosing a screening test for hyperadrenocorticism what are the 4 things you assess
1) case (signalment, history, temperament, clinical signs etc),
2) owner finances
○ Dex good for localising if don’t have access to localising imaging or the owner cannot afford localising image
3) personal preference
4) access to localising tests
93
List the 3 main localising testes for hyperadrenocorticism
1) High dose dexamethasone suppression test
2) endogenous ACTH
3) adrenal imaging
94
High dose dexamethasone suppression test what sort of test, how common and what occurs with normal dog, adrenal tumor and pituitary dependent hyperA
Localising test for hyperA
- Localising test, uncommon use since ACTH measurement was available
- Normal dogs suppress at 4 & 8 hours
- Dogs with adrenal tumours fail to suppress
- Dogs with pituitary dependant hyperA show suppression in most cases (75%) however 20-25% of PDH cases fail to suppress
95
Endogenous ACTH what type of test what occurs with dog with pituitary depedent hyperA, adrenal tumours, horse with PPID and iatrogenic HyperA
Localising test for hyperA
- Dogs with pituitary dependant hyperA have normal to high levels
- Dogs with adrenal tumours have very low levels
- Horses with PPID have high levels (often assessed concurrently with insulin level)
- Iatrogenic HyperA cases have very low levels
96
Adrenal Imaging what type of test, what occurs with dog with pituitary dependent hyperA and adrenal tumours
Localising test for hyperA
- Dogs with pituitary dependant HyperA will have bilateral adrenal enlargement
- Dogs with adrenal tumours will have one large adrenal and one small adrenal gland
97
what are two hallmark signs of addisons disease
Hyperkalaemia and lack of stress leukogram
98
What are 5 main clinical signs of hypoadrenocorticism
1) weakness and lethargy
2) vomiting, dirrhoea, adbominal pain
3) collapse
4) PU/PD
5) GIT haemorrhage
NON-SPECIFIC SIGNS
99
what type of leukogram is seen with hypoadrenocorticism
- Lack of stress leukogram in an unwell dog (hypocortisolaemia) - should see lymphopenia
○ Lymphocyte count >2.4 x 109/L (sensitivity 49%, specificity 92%)
100
What are the 4 main things seen in biochemistry of dogs with hypoadrenocoticism
1) Electrolyte abnormalities (76% of cases)
○ Hyponatraemia, Hypochloridaemia, Hyperkalaemia
○ Low Na:K ratio <27:1(70% of cases, specificity 94%) due to renal Na wastage & reduced K excretion. Na:K <24 100% specificity - pretty good chance
2) Hypercalcaemia
3) hypoglycaemia
4) hypoalbuminea (GIT loss)
101
What are the 2 main urinalysis results from a og with hypoadrenocorticism
1) Azotaemia with suboptimal urine concentration (USG<1.030) (dehydration and renal Na wastage causing tubular dysfunction)
○ Look like renal failure as secondary effect on renal function
2) USG<1.030 (88% of cases) - suboptimal urine concentration
102
What is the main test for hypoadrenocorticism, how used, what seen with iatrogenic, primary hypoA and normal
ACTH stimulation test:
- Same protocol as for HyperA testing
- O and 1hr < 30 nmol/L (fail to stimulate)
- Same lack of response is seen with iatrogenic Hyperadrenocorticism as the exogenous cortisone causes adrenal atrophy through inhibition of ACTH release
- ACTH level is usually high (primary HypoA)
- Dogs with a basal cortisol level of >55 nmol/L are highly unlikely to have Hypoadrenocorticism
○ Can test the basal levels as the screening if want to know whether need to give cortisol quickly
