Adrenal Glands Flashcards
Different zones of adrenals and what they produce
Medulla - catecholamines
Inner reticularis - androgens (and some glucocorticoids)
Middle fasiculata - glucocorticoids (some androgens)
Outer glomerulosa - aldosterone (low CYP17)
Physiological effects of glucocorticoids (7)
Stimulate hepatic gluconeogenesis and glycogenesis
Enhance protein and fat catabolism
Permissive actions on many metabolic reactions, such as lipolysis and calorigenesis
Maintain vascular reactivity to catecholamines.
Maintain normal BP
Counteract the effects of stress on GI mucosa and maintain normal function
Influence digestion and intestinal absorption by increasing the expression of brush border enzymes and mitochondrial enzymes
Suppresses ADH (vasopressin) release
Activity on mineralocorticoid receptors (inactivated to cortisone by locally produced enzymes in aldosterone target tissues)
Also antiinflammatory (PLA2 inhibition and reduced production of COX)
Stimuli for Aldosterone release and effects of aldosterone action
reduced BP (ECV) sensed by juxtaglomeruli cells
–> RAAS –> AngII AT2 receptor on adrenal stimulates aldosterone release –> Na retention (indirect water conservation) and AngII mediated vasoconstriction
–> expands plasma volume and increases total peripheral resistance
Increased K+ –> aldosterone (independent of RAAS) –> Na+ reabsorption causes electrochemical gradient favouring K+ excretion
Effects of long term mineralocorticoid excess
fibrosis and proliferation of vascular endothelial smooth muscle (contributes to hypertension)
And fibrosis and remodelling in the heart and kidney
Stimuli for cortisol release from adrenal glnads
CRH from hypothalamus stimulates release of ACTH from pituitary corticotrophs
(increased by stress, pain, cold, hypoxaemia and hypoglycaemia)
Also modulated by Leptin, Ghrelin, ADH and Inflammatory cytokines
Release of CRH and ACTH inhibited by negative feedback from cortisol and ACTH. As well as indirectly by somatostatin from hypothalamus
Cause of PDH
adenomas (which can be invasive or macroadenomas) or less commonly carcinomas. Thought to be caused by somatic mutation of a single corticotroph leading to clonal expansion
Hypothalamic theory that excess CRH stimulation of pituitary or there is reduced sensitivity to cortisol feedback → pituitary hyperplasia and excessive secretion of ACTH
5 main effects of chronic cortisol excess
Protein and lipid catabolism
Gluconeogenesis/insulin resistance
Immune suppression
Anti-inflammatory/delayed wound healing
Altered arachidonic acid pathway
Mechanisms of hypertension in HAC
Possibly due to cortisol activation of renal mineralocorticoid receptors (normally inactivated in tissue but this process is overwhelmed) –> Na and water retention
Excessive secretion of renin
Enhanced vascular sensitivity to pressors
Reduced vasodilatory PGI2 (due to suppression of COX enzyme synthesis and PLA2)
How does HAC alter coagulation
Hypercoagulable state due to Increased production of procoagulant factors and impaired fibrinolysis pathway
Levels of procoagulation factors II, V, VII, IX, X, XII, and fibrinogen are significantly increased in dogs with HAC, and antithrombin was significantly decreased in another study
Also causes thrombocytosis and may alter TXA2 expression
Cause of food dependent HAC
Thought to be expression of GIP receptors on the adrenal cortex –> food cauusing release of cortisol
Dx by feeding and seeing >50% increase in UCCR after meals.
Normal ACTHST and LDDST
TVJ 2018 review of HAC investigation - recommendation on pituitary imaging
Routine pituitary imaging should be considered as part of the evaluation of a dog with newly-diagnosed PDH even if no clinical evidence of a large pituitary mass is present, especially if the client is willing to consider radiation therapy if a large pituitary mass is identified
If no mass is seen, the dog should be treated medically with no follow-up imaging required. If a mass 3 to 7 mm in diameter is seen, medical treatment of the HAC should be administered and imaging should be repeated in 12 to 18 months. If the mass is more than 8 mm in diameter, radiation therapy should be pursued
Common HAC comorbidities/complications in dogs
Diabetes (10-14% of dogs with HAC);
GBM (HAC in 2-30% of affected dogs, possibly due to more unconjugated bile acids → mucosal irritation in GB or increased leptin and altered GB motility);
Pancreatitis (conflicting evidence, but do see increased cPLi which may reflect subclinical injury, long term studies do not support association with AP);
Urolithiasis (increased calciuresis due to reduced reabsorption);
PTE (2.7-15% of HAC cases)
Common systemic signs of HAC in dogs and their pathophys
Promotes lipolysis and protein catabolism → cachexia, muscle loss, weight gain, weakness, pot-belly, organomegaly, polyphagia, hepatomegaly, obesity
→ myopathy from pseudomyotonia (degenerative myopathy) = severe muscle stiffness. Did not improve with Tx of HAC.
Polyuria: inhibits the action of ADH in renal tubules, also inhibits ADH release. Increased urinary Ca excretion. Also increases GFR. May increase risk of UTI
→ large pituitary masses may cause a secondary CDI through direct compression of posterior pituitary.
→ increased risk of Ca-Ox uroliths.
- Antiinflammatory and immunosuppressive: inhibition of PLA2 prevents PG synthesis and GRE modulate gene expression for proinflammatory cytokines including NKkB.
→ secondary infections (UTI, Resp); delayed wound healing
Panting: respiratory muscle weakness and reduced pulmonary compliance; pulmonary hypertension (PTE, fibrosis, altered PGI2) increased abdominal pressure; direct effect of cortisol on resp centre in brain
Skin changes: Alopecia due to follicular atrophy; calcinosis cutis (altered collagen structure to organic matrix that binds Ca)
- Behavioural: may be due to mass effect or hypertension or clot. Dogs with microtumour less likely to develop deficits.
Hypertension and hypercoag on other cars
Different Endocrine tests for HAC and their sens/spec (6)
UCCR - Sens 75-100%; Spec 21-82%
Lower specificity for differentiating non-adrenal illness from HAC (increases with multiple samples). High sensitivity means good to r/o HAC
LDDST - Sens 85-97%; Spec 70% (complete suppression has NPV of 95%, lack of suppression PPV 76%)
JSAP 2023 - 30 dogs, Sens 85; Spec 100%
May lack suppression or escape suppression (or >50% of basal value if not completely suppressed)
False negatives with occult disease; false positives with non-adrenal illness. More sensitive for diagnosis of ADH
ACTHST - Sens 85% ADH 60-85% PDH; Spec 60 ADH, 90% PDH
Low sensitivity for AT, higher cutoff improves specificity (lower specificity reported when control dogs have NAI)
Less affected by non-adrenal illness or environmental stress
JVIM 2018 - baseline cortisol did not affect test interpretation (post cortisol sens 81; spec 100%)
HDDST- used to differentiate ADH from PDH, but only aids in differentiation of additional 33% that do not have traditional ‘escape’ pattern of LDDST
Endogenous ACTH: discriminates PDH from ADH very labile and sample handling is important. Newer sandwich technique measurements have lower limit of detection.
Also identify ectopic ACTH production
Does not differentiate PDH from normal due to pulsatile release. Stress/NAI also impact levels.
CRH - differentiation of PDH from ADH
Sens 100%; Spec 67%.
UCCR + Dexamethasone suppression
Recent publication on monitoring of Trilostane Tx
JVIM 2020 study compared ACTHST, pre/post pill cortisol, ALP/AST, Haptoglobin, USG, UCCR and owner Questionnaire as gold standard (which did not include quantification of water intake).
→ Haptoglobin was significantly correlated with score and identified 90% of well controlled dogs. Was the best parameter assessed but overlap b/w well and undercontrolled dogs was present
→ time of day prepill sampling was not standardised and may have affected the results for this method.
–> no dogs with over-dose so unclear how other tests differentiated those cases (perhaps more important than adequate control)
→ No variable consistently discriminated dogs on adequate dose from those undercontrolled based on CS. Need to have well defined treatment goals to guide approach.
MOA of trilostane
AEs
competitive inhibition of 3B-HSD that converts pregnenolone to progesterone → reduced cortisol synthesis. Fully reversible and should not affect mineralocorticoid production. Efficacy 90% in PDH, MST 660-880d, comparison with untreated dogs in 2017 showed longer MST (inherent bias due to owner decision to treat).
QoL improved on treatment based on owner survey scores
AEs: lethargy, hypoNa hyperK, vomiting, diarrhoea, inappetence (usually only in initial Tx). Need to assess for iatrogenic hypoA.
Adrenocortical necrosis reported in rare cases, usually reversible but can last weeks to months (25% did not recover in one study)
Other drugs reported for use in canine PDH
Mitotane- adrenocorticolytic chlorinated hydrocarbon, converted to active metabolite in adrenal tissue then covalently binds adrenal proteins.
Initial loading phase until CS improve and cortisol 30-150 (variable time), then weekly maintenance.
AEs: GI, neurological, hepatotoxicity, iatrogenic mineralocorticoid deficiency (need to measure aldosterone as ACTHST does not predict), mortality in up to 12% with destructive protocol.
Pasireotide - somatostatin analogue, inhibits ACTH release from corticotrophs. Recent trial in 9 dogs, 6 dogs had reduction in pituitary tumour size.
Ketoconazole - inhibits steroid biosynthesis at high concentrations.
Selegiline - MOA inhibitor (increases dopamine in brain → tonic ACTH release suppression), inhibits ACTH release, monitor CS.
Non-medical Tx of DH in dogs
VCNA 2021 review of surgical PDH management:
In theory the best treatment for PDH will attack the source of disease and not the secondary adrenal affects.
Hypophysectomy - 86-95% remission, recurrence 25%; 12-20% mortality (highly specialised). Shorter survival for larger tumours, higher remission if and longer survival if smaller (JAAHA 2021)
AEs: Acute onset CDI (78% transient) → hypernatraemia, KCS, secondary hypoTH. Need to Tx with DDAVP, GCS and levothyroxine
RT - more used ot reduce tumour size if causing neurological signs. MST 12-25 months. Tumour size reduces in most, but functional capacity and time to size reduction are highly variable.
JVIM 2023 500-700d survival times.
Bilateral adrenalectomy - need ongoing hypoA management.
Pre-sx treatment with trilostane for adrenal tumours - evidence/arguments for and against
AVJ 2020 - retrospective study showing no pretreatment in 65 dogs, post-op clopidogrel if ROTEM hypercoag, intraop hydrocortisone for all and home with pred tapered over 4 weeks. DOCP if bilateral adrenalectomy.
Need for trilostane pre-treatment depends on case but likely unnecessary, consider anti-hypertensive therapy if clinically indicated or anti-coagulant (though no strong evidence exists for use of either improving outcome)
AEs: pancreatitis, PTE (consider clopidogrel); AKI, DIC; Addisonian crisis (post-op cortisol supplementation indicated)
FOR: improve metabolic derangements, healing alterations.
Reduce risk of thromboembolic or wound healing complications
AGAINST - delays surgery, could increase risk of complications, how long to delay when we know trilostane is not likely to get complete control in AT
Added expense for owners
Clinical signs in cats with HAC
Risk of secondary infections and poor wound healing
- Skin fragility: steroid related fibroblast inhibition, curling of ear tips
PUPD, PP → reported but have high concurrent rate of DM and hyperTH and CKD which complicates interpretation
