Adrenal gland and HAC Flashcards
1
Q
Where is the adrenal gland located?
A
Next to the kidneys in the retroperitoneal space
Craniomedial on kidneys
Elongated and asymmetrical
2
Q
Zones of the adrenal glands
A
Cortex - Zona reticularis, fasciulata, glomerulosa
Medulla
3
Q
What do the zones of the adrenal gland secrete?
A
Medulla - catecholamines
Zona reticularis- androgens
Zona fasciulata- Glucocorticoids
Zona glomerulosa - mineralocorticoids
4
Q
What % of the adrenal gland is made up of cortex and medulla?
A
Cortex = 80-90%
Medulla= 10-20%
5
Q
What is the adrenal medulla made of and what does it originate from?
A
Made of neuroendocrine tissue
Originates from the autonomic nervous system
Has sympathetic ganglion cells
6
Q
How are steroid hormones synthesised?
A
Cholesterol-> pregnenolone by P450 side chain cleavage
Pregnenolone converted into diff corticoids based on the zone
Rate limiting step is P450 as it is stimulated by ACTH
7
Q
What kind of corticoid is cortisol?
A
GLucocorticoid
8
Q
What corticoids are corticosteroids>
A
gluco and mineralocorticoids
9
Q
What is ACTH releasing hormone also called?
A
CRH (Cortico tropin releasing hormone)
10
Q
How is glucocorticoid release controlled?
A
CRH -> hypothalamus to portal capillary system
CRH = corticotrophin cells in AP release ACTH
ACTH in systemic circulation to adrenal glands to stim synthesis or glucocorticoids (mainly cortisol)
11
Q
What is ACTH synthesised from?
A
Pro opio mealono cortin (POMC)
12
Q
What action does POMC go through before the formation of polypeptides>
A
POMC undergoes post translation modifications before it is proteolytically cleaved to form polypeptides
First stage occurs in pars distalis releasing ACTH
13
Q
What is the action of glucocorticoids?
A
Glucocort in blood w 90% bound to plasma protein
Bind to target cell membrane or cytosolic receptors
Receptor steroid complexes are transported to the nucleus
= ALTERED GENE EXPRESSION
14
Q
Within the cell what is the role of glucocorticoids?
A
Stimulate gluconeogenesis and glycogenolysis
Cause proteolysis and lipolysis
15
Q
Role of glucocorticoids on different organs
A
Fat - mobilisation from peripheral stores
Muscle catabolism
Liver - gluconeogenesis (oppose insulin)
Kidney- inc GFR block ADH
Skin - follicular atrophy
Bone - reduce Ca+
Brain- thirst and hunger
16
Q
What is the role of glucocorticoids in the immune system?
A
Release neutrophils from marginated pool
Down regulates immune responses (T cells function and recruitment and B cell activation)
17
Q
What type of corticoid is aldosterone?
A
Mineralocorticoid
Class of steroid hormone based on effect on salt and water balance
18
Q
How is the release of mineralocorticoids controlled?
A
Main stim for aldosterone = Low BP
High serum potassium also stimulates release
Role of ACTH is minor
19
Q
What are the functions of aldosterone?
A
Role in reg of BP
Acts on cells of DCT and collecting duct to inc reabsorption of Na. Ca and H20)
Stimulates the secretion of potassium into tubular lumen
20
Q
What kind of hormones are androgens?
A
Steroid hormones
Stimulate development and maintenance of male characteristics
21
Q
What are androgens precursors for?
A
Oestrogens
22
Q
What are the most important androgens?
A
Testosterone
DHT
DHEA
androstenedione
23
Q
What is Hyperadrenocorticism?
A
Excessive production of steroid hormones especially glucocorticoids
Clinical signs often relate to abnormal circulating concentrations of steroid hormones
Cushings
24
Q
What is hypoadrenocorticism?
A
Under secretion of glucocorticoids and mineralocorticoids
Addisions
25
What are the 2 forms of hyperadrenocorticism?
iatrogenic
Spontaneous
- pit dependent and adrenal dependent
26
What is pituitary dependent HyperAC?
Most common 80-90% of cases
Excess ACTH secretion = bilateral adrenal hyperplasia
27
What is adrenal dependent HyperAC
10-20% of cases
Independent of pituitary control
Low ACTH
28
What pathology is seen with PD hyperAC?
Microadenomas <10mm in pars distalis or intermedia
Normal negative feedback mechanisms fail
Microadenomas are slow growing and cause neuro signs
29
What pathology is seen in AD hyperAC?
Unilateral adrenal enlargment cause atrophy on contralaterla side
Independent of ACTH( low or undetectable)
50% partly calcified regardless of tumour type
30
What is the signalment for AD and PD hyperAC?
AD = older dogs (females - larger dog breeds)
PD = middle aged dogs(poodle daschunds, terriers no sex predis)
31
Outline the development of hyperadrenocorticism
Onset usually insidious
Initially intermittent
Develops rapidly
Affects lots of organs (pretty much every system)
32
What are the clinical signs of hyper AC?
PU/PD
Pot belly
polyphagia
skin change
hepatomegaly
muscle wastage and weakness
lethargy
repro changes
panting
33
What causes the pot belly with hyper AC?
redistribution of fat into the abdomen
hepatomegaly
wasting and weakness of muscles
34
Why does PUPD occur with hyperAC?
Antagonism of ADH, inc GFR and inhibition of ADH
35
Why does polyphagia occur with hyperA?
direct effect of glucocorticoids
36
Why does muscle wastage occur with hyperAC?
Protein catabolism
decreased muscle mass esp over limbs, spine and temporal regions
Excessive panting and poor exercise toleranxe
37
Why does skin change with hyperAC?
Bilaterally symmetrical alopecia
Thin skin - reduced elasticity
Scale and comedones
Slow wound healing - inhibition of fibroblast proliferation and collagen
38
What are the treatments fore hyperAC?
Trilostane - hydroxysteroid dehydrogenase inhibitor
Mitotane- chemical ablation of adrenal cortex but medulla spared
Adrenalectomy or hypophysectomy (replacement therapy req)
39
What is the signalment and clinical signs for cats with hyperAC?
uncommon as cats are most resistant to effects of glucocorticoids
middle aged <
Approx 75-80% AD
Clinical signs
PUPD
skin fragility
Pendulous abdomen
UTI
40
Why is is difficult to diagnose hyper adrenocorticism?
AD and PD both inc cortisol levels in the same way as stress and chronic illness
PD affects pit gland AD affects adrenal
41
What tests would present a high suspicion index for hyperadrenocorticism?
Blood test - biochem and CBC
Urinalysis
Imaging
Specific diagnostic tests
42
What are the parameters that should change on blood test for hyperAC?
Elevated
- ALP
-ALT
- Cholesterol
- Bile acids
- fasting glucose
Reduced
- Urea (BUN)
43
Which CBC parameters would suggest hyperAC?
Neutrophilia - high
Lymphopenia - low
44
What should urinalysis show with hyperAC?
Low USG- hyposthenuric
UTI evidence
45
What are the radiogrphic findings with hyperAC?
Hepatomegaly
calcinosis cutis
distended bladder
adrenal enlargement/ calcified
Tracheal and bronchial wall mineralisation
Pulmonary metastasis
Osteoporosis
46
Osteoporosis
cause weak and brittle bones
47
What is the LDDS test?
Exogenous glucocorticoid administration should = reduced ACTH
Expected findings normal= cortisol release from adrenal
Spontanous HAC= reduced or absent response
48
What % of PDHAC and ADHAC should a highly sensitive LDDS test detect?
90-95%
positive result with low dose dexamethasone test = cortisol greater than 50nmol/l at 8 hours
Limited use at differentiating PD and AD HAC
49
Why is there a need to determine between PD and AD hyperAC?
AD more resistant to medical management
PD prognosis is better
AD - adrenalectomy = only option
50
What test differentiates between AD and PD hyperAC?
HDDS
Endogenous ACTH
Adrenal imaging
Pituitary imaging
51
What is the role of the HDDS test?
inc dose fo dex inhibits cortisol in some cases of PDH
in PD high dose inhibits pit ACTH secretion through neg feedback suppressing cortisol
Adrenocortical tumours are autonomous so cortisol is not suppressed as ACTH is already suppressed
52
Why is HDDS not used anymore?
25-30% of cases fail to suppress with HDDS
53
Why can endogenous ACTH be used to diagnose AD hyper AC? UNSURE
PDH falls within the normal range
54
What is the expected outcome for ADH and PDH with adrenal imaging?
PDH- symmetrically enlarged and normal conformation
ADH- will have one enlarged gland and one atrophied gland (may see invasion of malignant tumour)
55
Why is pituitary imaging not used?
Needs CT or MRI but are both expensive
Size difference is not clearly defined
Useful if neruo signs are present as can look for large pituitary tumour
56
What tests are required for PPID?
History and physical exam
Biochemistry - hyperglycaemia, hyperinsulinaemia, hypertriglyceridemia
CBC- neutrophilia and lymphopenia
Resting ACTH
TRH stim
DST
Combined DST-TRH test
Insulin
POMC
57
What is the role of RAAS in the control of mineralocorticoid release?
Renin carried out angiotensinogen-> angiotensin I
ACE carries out Angiotensin I-> II
Angiotensin II= vasoconstrictor \
Angiotensin II= stimulates aldosterone release from adrenal cortex
58
How is a decrease in BP detected?
Renin release stimulated by
1. baroreceptors in afferent arteriole
2. cells of macula densa in distal tubule
3. Cardiac and arterial baroreceptors
59
What stimulates macula densa cells in DCT?
Stimulated by a reduction in NaCl delivery
60
What is the function of aldosterone?
Regulates BP acting on distal tubules and collecting ducts
- Inc reabsorption of ions and water - conserving Na
Secretes potassium
Increase in water retention increases BV so BP
61
What are the classifications for hypoadrenocorticism?
Primary - loss of adrenal cortex (addisons)
Secondary - deficiency of ACTH
Iatrogenic - exogenous steroids
62
What occurs in primary HypoAC?
deficiency of glucocorticoids (cortisol) and a deficiency of mineralocorticoids (aldosterone)
Loss of 85-90% of the adrenal cortex
63
What are the different causes of Addison's disease in dogs?
Idiopathic atrophy, probably immune mediated destruction
Iatrogenic - Mitotane, trilostane, bilateral adrenalectomy
64
How is iatrogenic hypoadrnocorticism characterised?
Exogenous steroids cause adrenal atrophy
Cortisol deficiency only
Patient may show signs of cushings
Patient may develop signs of addisons disease if steroids are abruptly discontinued
Can be life threatening
65
WHat is the signalment for addisons disease?
Young to middle aged dogs
70% females
Any breed but breed dispositions
rare in cats
66
Which breeds of dogs are predisposed to addisons?
Collies
bearded collies
Portuguese water dog
Leonberger
Great dane
Rottweiler
WHTH
soft coated wheaten terrier
67
Outline the pathophysiology of hypoadrenocorticism?
Aldosterone deficiency = Loss of Na, Cl and H2O, retention of K+ and H+, Pre renal failure
Glucocorticoid deficiency= decreased stress tolerance , GI signs, weakness, appetite loss and impaired gluconeogenesis
68
Compare chronic and acute hypoAC?
Chronic = waxing waning with non specific signs
Acute= addisonian crisis form with marked hypovolaemia and azotaemia
69
What clinical signs are expected with chronic hypoAC?
Anorexia
Vomiting
Diarrhoea
PUPD
weakness
Lethargy
Depression
Appear normal between bouts esp after fluid therapy/ steroids
70
What clinical signs are expected with acute hypoAC?
signs caused by hypovolaemic shock
Collapsed
Paradox of relative brachycardia caused by hypokalaemia
abdo pain caused by pancreatitis
71
What clinical pathology is expected with hypoAC?
Lack of stress leucogram - no neutrophilia or lymphopenia
Anaemia
Lower erythrocytosis - lack of cortisol
GI blood loss
72
What are the clinical findings for hypoAC on biochemistry?
hyperkalaemia
hyponatraemia
hypochloridaemia
Na:K ration <23
all due to aldosterone deficiency - dec renal tubular resorption of Na and Cl and dec excretion of K+
73
What clinical pathology is expected with hypoAC and urinalysis?
Azotaemia ( inc renal parameters)
Hypoglycaemia - 27%
dec USG ( inappropriately low in dehydrated animal)
74
What changes are seen on ECG with hypoAC?
Changes related to hyperkalaemia
- bradycardia
peaked T waves
Widened QRS
Decrease in P wave or disappearance
Ventricular asystole
75
How is a hypoAC diagnosis made?
High index of suspicion
ACTH stimulation test
- Measure cortisol in flat line stimulation
Dex can be used prior to test as therapy
76
How is hypoAC treated?
Mineralocorticoids
GLucocorticoids - in acute crisis or times of stress
77
What is the embryological origin of the adrenal gland?
Neuroectoderm
78
Phaeochromocytoma
Tumour that starts in the inner medulla of the adrenal gland
79
What is meant by a functional tumour of the adrenal gland?
Produces hormones
80
What structures may be invaded by an adrenal tumour?
Vena cava
Aorta
Kidney
Renal vessels
81
Which receptors do epinephrine and nor epinephrine bind to?
Alpha and beta
2 types of alpha and 3 types of beta
82
What do alpha 1 receptors activate?
Activate phospholipase which increases the activity of protein kinase 2
83
What happens at alpha 2 receptors?
inhibition of catecholamine release, Inhibit adenylate cyclase which decreases the activity of protein kinase A
84
What do Beta receptors activate?
Adenyl cyclase increasing the activity of protein kinase A
85
What affect does catecholamine have on energy substrates?
Mobilise substrates of remediate energy - glycogenolysis, gluconeogenesis, lipolysis
86
Which arm of the ANS is the adrenal gland associated?
Sympathetic
87
What drug is appropriate for bronchodilation?
Clenbuterol
88
What drug is appropriate for vasodilation?
Prazosin
89
What drug is appropriate for sedation?
detomidine
90
What clinical signs are associated with phaeochromocytoma?
Tachycardia
hypertension
Panting
Diarrhoea
Constibation
PUPD
Weight loss
Restlessness
High blood glucose - insulin resistance
91
What are the 4 potentials used to differentiate between PDH and ADH?
Endogenous ACTH
LDDS
HDDS
Imaging adrenals
Imaging pituitary
92
What separates the pituitary from the brain?
Diaphragma sell ( part of the dura mata)
93
What do the cells of the pars distalis secrete?
Somatotrophs- GH
Lactotrophs - prolactin
Corticotrophs- POMC, ACTH, betalipotropin
Gonadotrophs- FSH and LH
Thyrotrophs- TSH
94
What causes equine cushings disease?
A pars intermedia adenoma causes excessive production of POMCs-derived peptides
95
What is the pathogenesis of PPID?
Lack of inhibitory control of pars intermedia cell function = adenoma
Inhibition mediated by hypothalamuc dopamine on D2
Neurodegeneration of periventricular neurones so impaired -ve feedback
96
What is the role of D2 receptors?
inihibition of the expression of POMC mRNA expression and instead POMC hormone release
97
Why do we treat PPID with D2 agonists?
PPID = dec peripheral cleavage of POMC peptides which remain active
D2 agonists fixes clinical signs of PPID and decreases ACTH conc in most cases
98
What factors in other species other than horses can regulated melanotrope function?
TRH
Serotonin
GABA
99
What are the clinical signs of PPID?
Hirutism
Weight loss
PUPD
Laminitis
Recurring infections
Poor performance
Pot belly
Docility
Neuro signs
Infertility
100
What is hirtuism?
Coat does not shed
Occurs with PPID as chronic elevation of MSH, pit compression on hypothalamic thermo centre, inc production of androgens
101
Why does laminitis occur with PPID?
high glucocorticoid conc
persistent hyperinsulinaemia and persistent hyperglycaemia = laminitis
102
Why does PUPD occur with PPID?
Pit compression= decr secretion of ADH
ACTH inhibits ADH action
Hyperglycaemia causes osmotic diuresis
103
Why does weight loss occur with PPID?
Glucocorticoids have a catabolic effect on skeletal muscles
104
Why does lethargy occur with PPID?
Beta endorphin is increased
105
Why does neuro impairment occur with PPID?
Blindness from compr of optic chiasm
Narcolepsy unknown
106
Why is there impaired response to infection with PPID?
Inc conc of immunosuppressive hormones such as cortisol, alpha MSH, beta endorphin
107
What predisposes a horse to PPID?
>15 years
No gender prevalence
108
Expectations of biochemistry of horse with PPID?
hyperglycaemia, hyperinsulinaemia
Hypertriglyceridaemia
Neutrophilia and lymphopaenia
109
What can we test for with PPID?
resting ACTH
TRH stimulation
DST
Combined DST-TRH test
Insulin levels
POMC
110
How is DST carried out for PPID?
Standard DST: Baseline at 8,12, 16, 20 ,24
40ug/kg dex IM
Normal horses fall to >30% of baseline cortistol concentration
Overnight DST: baseline 4-6pm
40ug/kg dex IM
Last sample 15-20 hours
Normal horses show suppression of plasma cortisol
111
What is the TRH stim test testing for?
Cortisol
Relies on aberrant response of pit adenoma to TRH w subsequent further release of ACTH
112
How is TRH stim test carried out?
Baseline blood sample is taken
1mg TRH is given IV
A blood sample is taken 30 mins later
Cortisol conc is then measured for both samples
113
What would be PPID response to TRH stim test?
Cortisol concentration should inc by 25-50% in horses w PPID
Only 41 % sensitive 92% specificity
114
What is the gold standard TRH test?
ACTH response to TRH
relies on abberant response of pitui adenoma to TRH w subsequent further release of ACTH
1. A blood sample is taken
2. 1mg of TRH is administered IV
3. Another blood sample is taken 10 minutes later
4. The ACTH concentration is measured
Pos = ACTH higher than 110mg/ml at 10 mins
Used for normal resting ACTH but high clinical suspicion
sens 77 spec 82
115
How is the combined DST-TRH test carried out?
Baseline sample
Dexamethasone
Sample 3 hourse after dex + TRH
Blood sample 30 mins after TRH
Blood sample 24 hours after dex
Positive if cortisol is >1ug /dL
Sens 88 Spec 76
116
What is resting insulin?
Evaulation of insulin resistance
Reasonable sensitivity low specificity
Need to rule out EMS
Negative prognostic value
117
How can POMC be measured?
Beta-endorphin
Alpha MSG
CLIP
Disproportionately higher than ACTH in horses with PPID
Not validated in horses
118
How can diagnosis of PPID be made via imaging?
CT, MRI , might identify pituitary enlargement
CT: difficult positioning
MRI: might be useful but hardly available
Require GA
Costly
Poor sensitivity
119
Why is ACTH stimulation test not used in horses?
Iatrogenic ACTH will not stimulate cortisol production from the adrenal glands which are already maximally stimulated
Means that it is useless in horses because Equine cushings disease is central and not peripheral in origin
120
What is the effect of catecholamines binding to alpha receptors?
Vasoconstriction
Pupil dilation
Intestinal relaxation
Pilomotor contraction
Bladder sphincter contraction
121
What is the affect of catecholamines binding to Beta 1 receptors?
Increased heart rate
Increased contractility
122
What is the affect of catecholamines binding to Beta 2 receptors?
Vasodilation
Bronchodilation
Glycogenolysis
Lipolysis
123
What is the signal transduction of catecholamines?
Bind to receptors and activate second messengers
Often G protein coupled receptors
124
Give some examples of pathways for signal transduction of catecholamines
Adenyl cyclase
Phospholipase C, IP3, DAG
Ion channels
125
What is the function of adenyl cyclase beta receptors?
1. Bind to cell surface receptor
1. Activates G protein which stimulates adenylyl cyclase
2. Generates cyclic AMP (cAMP)
3. Activates protein kinase A
4. The protein kinase A is phosphorylated
5. this causes a biological response
126
What are the affects of cAMP?
catalytic subunit of protein kinase A enters the nucleus
This binds to the cAMP-response element binding protein and phosphorlyates
CREB binds to CRE and changes gene expression
127
What is the effect of cAMP on the heart?
Ca+ ion channel opening time is prolonged which in turn strengthnes the contractions
Increase uptake into SR at the end of contraction= shortens contraction
128
What is the phospholipase C alpha receptor transduction pathway?
The hormone binds to the cell surface receptor
The activated phospholipas C via the G protein
Phospholipid PIP2 is broken down to IP and DAG
129
Importances of medullary hormones
- Medullary epinephrine and norepinephrine have the same general effects as the sympathetic nervous system
- There is a widespread and simultaneous stimulation of tissue via nervous and endocrine systems
- Medullary hormones result in additional effects on tissues without direct sympathetic innervation
- For example- metabolic acitions appropriate fight or flight
130
How do catecholamines affect stressed animals?
Stress hyperglycaemia can occur due to persistent activation of catecholamines that therefore increase the available blood glucose
131
How does the metabolic effect of catecholamines increase fatty acid levels and why?
1. Hormone-sensitive lipase (HSL) is stimulated by catecholamines
2. Therefore the triglycerides stored in adipose tissues is hydrolysed to yield glycerol and three fatty acids
this glycerol can be used for glucose
3. Higher circulating plasma fatty acid levels are used for energy
132
List the 3 importance of medullary epinephrine
Metabolic stimulus
Cardiac effects
Blood vessels within the muscle
133
hat is the overall effect of norepinephrine?
Has a more profound effect on the blood vessels
This increases total peripheral resistance
Raises blood pressure
134
What is the overall effect of epinephrine?
Has a more profound effect on the heart
Increases heart rate and contractility
This increases cardiac output
