Addison’s, Cushing’s & Acromegaly

1. Addison’s, Cushing’s & Acromegaly Tom Collins

2. Objectives • Definitions • Aetiology • Presentation • Investigations • Complications • Management • Prognosis • Clinical scenario

3. Addison’s Disease Definition • Autoimmune destruction of the adrenal gland resulting in failure of adrenal steroid hormone production Cortisol & Aldosterone

4. Lets take a step back… Adrenal failure: • Primary adrenal failure • Atrophy/destruction of the adrenal gland • Secondary adrenal failure • Inadequate ACTH production • Tertiary adrenal failure • Failure of CRH production

5. Aetiology • Primary adrenal failure • Autoimmune • Infection (TB, HIV) • Invasion from mets (lymphoma, breast, lung) • Haemorrhage (anticoagulants, Waterhouse-Friedrichsen Syndrome • Infiltration (amyloid, sarcoid, haemochromatosis) • Congenital adrenal hyperplasia • Drugs (eg ketoconazole, phenytoin, rifampicin) ADDISON’S

6. Aetiology cont. 2. Secondary adrenal failure • Acute steroid withdrawal • Tertiary adrenal failure • Chronic high dose glucocorticoid therapy • Sarcoidosis • Tumour • Cranial irradiation

7. Presentation • Non-specific symptoms: • Abdominal pain • Nausea • Diarrhoea • Lassitude • Dizziness • Due to postural hypotension • Pigmentation • Buccal • Scars • Palmar creases • Generalised • Hypoglycaemia • Cortisol is one of the main insulin antagonists

8. Investigations • Bed side • Lying and standing BP • ECG • Blood glucose • Bloods • U+Es • Serum cortisol (best to be done in the morning) • Adrenal autoantibodies • Imaging • MRI head • CT abdo • Special tests • Short synacthen test (confirm the Dx) • Long synacthen test (test response of adrenals)

9. Complications Addisonian crisis • Occurs when the physiological demand for these hormones exceeds the ability of adrenal glands to produce them • ie, patients with chronic adrenal insufficiency when subject to an intercurrent illness or stress • Major or minor infections • Injury • Surgery • Burns • Pregnancy • General anaesthesia • Abrupt withdrawal of steroids • Waterhouse-Friedrichsen syndrome • Present with hypovolaemic shock and profound hypoglycaemia • MEDICAL EMERGENCY!

10. Management Chronic adrenal failure • Glucocorticoid replacement • Hydrocortisone • Double dose if intercurrent illness, infection or surgery • Mineralocorticoid replacement • Fludrocortisone Addisonian Crisis • IV fluids • High dose hydrocortisone • Dopamine (if hypotension persists) • Treat precipitant • Monitor U+Es and glucose

11. Associated diseases • Hypothyroidism • T1DM • Pernicious anaemia • Vitiligo • Premature ovarian failure

12. Cushing’s

13. Cushing’s Syndrome or Disease? Cushing’s Syndrome definition: • The clinical condition resulting from prolonged exposure to glucocorticoids from an exogenous or endogenous cause. Cushing’s Disease definition: • The clinical condition resulting from prolonged exposure to glucocorticoids from a pituitary adenoma.

14. Aetiology • Pituitary adenoma • 70% • F>M • Ectopic ACTH production • 14% • SCLC • Carcinoid tumour • Adrenal adenoma • 10% • Adrenal carcinoma • 5% • Adrenal hyperplasia • 1%

15. Presentation • Use whatever helps you remember!

16. Acronyms • S – spinal tenderness • W – weight (central obesity) • E – easy bruising • D – diabetes • I – interscapular fat pad • S – striae • H – hypertension/hypokalaemia

17. Investigations • Bedside • 24 hour urinary free cortisol (to confirm Cushing’s syndrome) • Bloods • U+Es (<3.2 suggests ectopic ACTH production) • Imaging • MRI head (for pituitary adenoma) • CT chest (for SCLC) • Special tests → to determine the cause • Serum ACTH • Dexamethasone suppression test • Distinguishes the ACTH dependent causes

18. Complications • Same as complications of steroid use • A common question in Finals! • If struggling to remember don’t panic! • What can they lead on to? • Eg Diabetes and its complications, cardiovascular disease, infections

19. Management • Distinction: • Nelson’s syndrome – post-adrenalectomydevelopment of a locally aggressive pituitary tumour (corticotrophinoma) due to lack of negative feedback. Treat the cause! • Conservative • Stop medications! • Exercise • Diet • Smoking cessation • Medical • Metyrapone (blocks cortisol synthesis) • Ketoconazole (inhibits cytochrome P450) • Mitotane (adrenolytic agent) → adrenal carcinoma • Radiotherapy (adjuctive therapy/for relapse/if surgery inappropriate/in children – when pituitary adenoma) • Surgical • Trans-sphenoidaladenomectomy • Bilateral adrenalectomy (can’t locate tumour/recurrence post-surgery) • Removal of ACTH secreting tumour

20. Prognosis • If treated very good prognosis • Resolution of physical features and psychological disorders • Follow up needed for osteoporosis, glucose intolerance, DM, HTN, subtle mood changes, obesity • Untreated = <5 years • Cardiovascular disease • Infection

21. Acromegaly Definition: • A hormonal disorder that develops when the pituitary gland produces too much growth hormone during adulthood

22. Aetiology • Pituitary adenoma (≈99%) • Ectopic production (≈1%) • Usually a carcinoid tumour • Pancreas • Lung • Adrenals

23. Pathophysiology

24. Presentation Usually a spot diagnosis • Typical facies • Prominent supra-orbital ridges • Big ears, nose, lips, tongue • Prognathism • Wide separation of teeth • May complain of: • Headache • Numbness/tingling in hands • Excessive sweating • Vision problems • Hoarse voice • Obstructive sleep apnoea • Muscle weakness

25. What should you do O/E? Observe: As previous slide Hands: • Size – compare with your own • Thenar eminence – wasting • Check median nerve sensation • Sweaty? • ‘Bogginess’ of palms • Skinfold thickness – increased in active disease Ask for BP Neck • Check for goitre • JVP Visual fields and acuity Stand from seated position

26. Investigations • Distinction: • Random GH measurements not helpful because GH secreted in pulsatile manner. • False positives for OGTT + GH • Pregnancy • Puberty • Hepatic disease • Renal disease • Anorexia nervosa • DM • Bedside • BP • Urine dip • BM • ECG • Echocardiogram • Bloods • IGF levels • Imaging • MRI head • Colonoscopy (if ≥50 years) • Special tests • Oral GTT with GH measurement

27. Management • Conservative • Exercise • Diet • Smoking cessation • Medical • Octreotide& Lanreotide (somatostatin analogues) • Bromocriptine & cabergoline(dopamine agonists) • Metformin • Pegvisomant (GH receptor antagonist) • Radiotherapy (as adjuvant/when surgery inappropriate) • Surgical • Trans-sphenoidaladenomectomy • Follow up: • Yearly GH & IGF-1 measurement + OGTT, visual fields, CV assessment. IGF Insulin resistance

28. Complications • Hypertension (increased risk of stroke & IHD) • Diabetes • Cardiomyopathy • LVH • Colorectal cancer • ≈5% associated with MEN-1 → Remember ‘3Ps’ • Parathyroid hyperplasia/adenoma • Pancreatic endocrine tumours • Pituitary adenoma • Mortality increased 2-3x

29. Clinical scenario 28 year old woman is seen in outpatients. She has been referred by her GP who has been unable to find a cause for her symptoms. She has a 6 month history of intermittent abdominal pain which varies in site and intensity. She has also experienced some occasional diarrhoea. She feels generally weak and off her food. She has lost a stone over this period. On examination she has pigmented palmar creases and buccal mucosa but no other specific findings. Her BP is 100/70 lying down, you try to stand her to check it again but she feels dizzy and light headed and has to sit down. You check her BM and it is 2.9. Addison’s disease

30. What are your differentials for this lady? How would you investigate her? How would you manage her? What are the complications of Cushing’s disease? What is the difference between Cushing’s syndrome and Cushing’s disease?

31. Questions?

32. References • Medicine at a glance • Ask Dr Clarke • Patient.co.uk • Oxford handbook of clinical medicine • www.mayoclinic.com • Special thanks to Dr Thomas Marshall