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Cushing’s, Addison’s and Acromegaly

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Presentation on theme: "Cushing’s, Addison’s and Acromegaly"— Presentation transcript:

1 Cushing’s, Addison’s and Acromegaly
Dr Edward Hutchison FY1 (Geriatrics)

2 Phase II Objectives 3.21: Investigations –
Request appropriately the more common tests of thyroid, adrenal and pituitary gland function, seeking advice where necessary. 3.23: Adrenal gland hormones Recognise signs and symptoms of Addison’s disease, confirm diagnosis and initiate immediate management of Addisonian crisis. Recognise symptoms and signs of Cushing’s syndrome, confirm diagnosis, participat in management of Addison’s disease and Cushing’s syndrome. 3.24: Pituitary gland hormones Recognise the circumstances when hypopituiarism might occur, recognise possibility of hypopituitism with ‘non-specific’ symptoms, investigate causes. Initiate investigation for posterior pituitary function in patients with polyuria. Recognise acromegaly, initiate investigation for acromegaly, outline to patients the possible treatments for acromegaly.

3 Aims HPA Axis Adrenal glands Cushing’s syndrome/disease Addison’s
Acromegaly

4 HPA Axis

5

6 Hypothalamus GnRH GHRH TRH Dopamine CRH
The hypothalamus controls body temperature, hunger, important aspects of parenting behaviours, thirst, fatigue, sleep and circadian rhythms. GnRH GHRH TRH Dopamine CRH

7 Pituitary Sphenoid sinus
Pituitary gland communicates with the hypothalamus via the hypophyseal tract. Split into anterior and posterior. Blood supply: hypothalamo-hypophyseal portal system Sphenoid sinus

8 Anterior Pituitary Hormones
ACTH FSH PRL LH TSH GH ACTH  adrenal glands  gluco/mineralocorticoids FSH  granulosa/sertoli cells  follicle growth/spermatogenesis LH  theca/leydig cells  oestrogen/testosterone production PRL  milk production TSH  stimulates thyroxine/triiodothyronine production GH  many effects (discussed later)

9 Posterior Pituitary Hormones
ADH Oxytocin

10 Adrenal Glands Remember: GFR!
Cortex split into glomerulosa, fasciculata and reticularis  aldosterones, cortisol and androgens respectively. Medulla secretes catecholamines under control of the sympathetic nervous system.

11 Functions of Cortisol? Insulin resistance/gluconeogenesis
Protein catabolism Immunosuppresion CVS regulation – e.g. increasing BP CNS actions – e.g. increased appetite, impaired memory Increased bone turnover Gastric acid secretion Reduced skin collagen Fluid retention

12 Right, now onto the stuff you actually want to know…

13 Cushing’s… …disease or syndrome?

14 Which is which? Syndrome Disease
Excessive activation of glucocorticoid receptors. Excessive production of ACTH caused by a pituitary adenoma.

15 Classification ACTH-dependent Pituitary adenoma
Ectopic ACTH production – e.g. small cell lung cancer, neuroendocrine tumours Iatrogenic – ACTH therapy ACTH-independent Iatrogenic – steroid therapy Adrenal adenoma/carcinoma Pseudo-Cushing’s EtOH excess Major depressive disorder Primary obesity

16 Clinical features Over to you…

17

18

19 Symptoms Depression Confusion Weight gain
Poor glucose control (diabetics) Weakness rising from a chair (proximal myopathy)

20 Investigation Bedside Blood Imaging

21 Overnight dexamethasone suppression test/
24hr urinary cortisol 48hr low-dose dexamethasone suppression test Confirmed Not excluded Abstinence Overnight dexamethasone test – give 1mg dexamethasone PO at midnight then measure 0900hrs cortisol. Cortisol <60 excludes Cushings Low-dose dexamethasone test – 0.5mg orally every 6 hours for 48 hours, sample urinary cortisol for second 24hrs. Serum levels at 0900 (at 48hours). Cushing’s excluded by urinary cortisol <100nmol/day or serum <60 at 48hrs. High-dose dexamethasone test – 2mg every 6 hours for 48 hours. Sample urinary cortisol over second day, <50% basal = pituitary cause, >50% = ectopic ACTH CRH test – 100µg ovine CRH IV and monitor plasma ACTH/cortisol over 2 hours. Peak cortisol >120% and ACTH >150% suggests pituitary dependent disease. Lesser responses suggest ectopic ACTH. Urinary free cortisol – collect over 24 hours Diurnal variation of cortisol – evening value >75% of morning indicates Cushing’s. Insulin tolerance test (NOT ROUTINELY PERFORMED) – peak plasma cortisol >120% excludes Cushing’s. Inferior venous petrosal sampling – catheters placed in both inferior petrosal sinuses, sampling these and peripheral blood for ACTH. ACTH in petrosal sinus >200% peripheral ACTH indicates pituitary disease, <150% indicates ectopic production. ?EtOH excess

22 ACTH level? ACTH level High
CRH test/48hr dexamethasone suppression test Suppressed MRI pituitary Not suppressed Ectopic source CXR, CT A/P, tumour markers Low/normal Adrenal cause CT adrenals ±adrenal venous sampling

23 Management Untreated Cushing’s disease has a 50% 5 year mortality
Conservative Medical Surgical Patient education Reduce oral steroid therapy if possible Inhibit biosynthesis of corticosteroids – e.g. ketoconazole and metyrapone Trans-sphenoidal resection of pituitary (requires lifelong hormone replacement). Laparoscopic resection of adrenal tumour. Ectopic ACTH: treat underlying cause ±bilateral adrenalectomy. Untreated Cushing’s disease has a 50% 5 year mortality

24 Remember Not only oral corticosteroids can cause Cushing’s syndrome, large amounts of topical and inhaled steroid may be absorbed into the systemic circulation. Patients on large amounts of oral corticosteroids will require their dose to be tapered slowly to avoid an Addisonian-like crisis. You also will need to manage the effect of long-term steroid therapy – e.g. diabetes, hypertension, thin skin, osteporosis.

25 (Or adrenal insufficiency, to be more correct).
Addison’s disease (Or adrenal insufficiency, to be more correct).

26 Definition? A syndrome resulting from inadequate secretion of corticosteroid hormones from progressive destruction of the adrenal cortex.

27 Causes A D I SO N – autoimmune (90% of cases) – degenerative (amyloid)
– drugs (e.g. ketoconazole) – infective (TB, HIV) – secondary (ACTH, hypopituitism) – other (e.g. adrenal bleeding) – neoplasia (metastases)

28 Clinical Features Over to you…

29 Which of these is most likely to prompt your investigations into possible adrenal insufficiency? Postural hypotension. Which are due to mineralocorticoid? Why do they get pigment changes? Pro-opiomelanocortin (POMC) gene synthesised by the anterior pituitary and is raised in response to low serum cortisol a ACTH production is increased. Associated autoimmune conditions: type 1 diabetes, pernicious anaemia, autoimmune thyroid disease, vitiligo  ask about FHx.

30 Investigations Test Bedside Lying/standing BP Bloods
U&Es – low Na+/high K+ Glucose – low Random serum cortisol Short synacthen test Plasma renin TFTs etc (?hypopituitism) FBC (?perncious anaemia) Gonadal function HIV test Plasma aldosterone Imaging AXR (?adrenal calcification CT or MRI of adrenals Random serum cortisol is of no use in ill patients  may be normal level but inappropriately low for the seriously ill patient Measure aldosterone as part of short synacthen test to indicate primary or secondary insufficiency. (Secondary = low ACTH)

31 The short synacthen test
Why do we do it? How do we do it? What result do we see in a positive test? (Ruling out Addison’s) Uses: diagnosis of primary or secondary adrenal insufficiency, assessment of the HPA axis in patients taking long-term glucocorticoid therapy. NOTE: relies on ACTH-dependent adrenal atrophy and therefore may not detect acute ACTH deficiency.

32 Positive test (ruling out Addisons):
250µg synacthen IM Positive test (ruling out Addisons): Plasma cortisol >460nmol/L at 30 minutes Serum cortisol at 0 minutes Serum cortisol at 30 minutes

33 Management Glucocorticoid replacement Mineralocorticoid replacement
Hydrocortisone BD, usually 15mg on waking/5mg around 1800hrs Excessive weight gain = over replacement Educate patient – increase hydrocortisone when unwell Mineralocorticoid replacement Fludrocortisone µg daily Titrate according to symptoms and U&Es

34 Addisonian Crisis Features: Severe shock – hypotension, tachycardia
Fever, abdominal pain, nausea & vomiting Hyponatraemia/hyperkalaemia ±hypercalcaemia, hypoglycaemia Management: ABCDE assessment Correct volume depletion Replace glucocorticoids Correct metabolic abnormalities Treat underlying cause Fludrocortisol is not needed during acute management Hyperkalaemia usually responds to fluid therapy but may need specific intervention Correct volume depletion with 0.9% NaCl – avoid when Na <125mmol/l. May cause central pontine demyelination

35 Acromegaly Bonus points, can you name these wrestlers?
Even more bonus points, can you name their signature move? Showstopper and no named special move (trick question!) but I believe he invented the tombstone…

36 Definition? A condition caused by excessive secretion of growth hormone

37 Most common cause? Pituitary macroadenoma

38 Your turn! Clinical features? What would you be looking for on examination?

39 Symptoms: headaches, sweating, hats/gloves too small, family commenting on change in appearance over years, Sx of carpal tunnel syndrome (night time paraesthesia and weakness associated with a median nerve injury). Sx of pituitary adenoma?

40

41 Impress your examiner…
What would you ask about/examine for to show off you were thinking about a pituitary adenoma in a patient you suspected had acromegaly in finals? Large pituitary macroadenoma disrupts communication from the hypothalamus leading to loss of dopamine inhibition of PRL secretion leading to hyperprolactinaemia. Hypopituitism

42 Investigations Bedside Collateral Hx Serial photographs BP ECG Bloods
Serum GH (unreliable) Oral glucose tolerance test Serum IGF-1 TFTs/FSH/LH/PRL etc Imaging CT/MRI brain Echo Other Colonoscopy Bedside – collateral hx (counts as Ix), serial photographs Administration of oral glucose should suppress GH of <0.5µg/L in normal subjects. In acromegaly, the GH does not suppress and paradoxically rises. Diagnosis difficult in diabetics because they do not have the insulin to respond to the glucose. You can measure IGF-1 (low in DM w/o acromegaly). Glucose stimulates IGF-1 that then suppresses GH

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44 Management Conservative: Medical (second line): Surgery (first line):
Patient education Medical (second line): Somatostatin analogues (octreotide, lanreotide) Dopamine agonists GH receptor antagonists (pegvisomant) Surgery (first line): Trans-sphenoidal surgical debulking of pituitary adenoma Radiotherapy: Employed if acromegaly persists after surgery Medical therapy does not shrink macroadenomas Medical and radiotherapy together may provide symptomatic relief in inoperable cases.

45 References Walker, BR., Colledge, NR., Ralston, SH., “Davidson’s Principles of Clinical Medicine” 21st edition, Churchill Livingstone, (2010). Kumar, P., Clarke, M. “Clinical Medicine” 7th edition, Saunders, 2009. Longmore, M. et al “Oxford Handbook of Clinical Medicine” 8th edition, Oxford University Press, 2010. https://lh5.googleusercontent.com/-qF8wwWfCtFI/TXRv47Ax4xI/AAAAAAAABR8/4jsTaDOngtc/s1600/Synacthen.JPG


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