Addison’s, Cushing’s & Acromegaly Tom Collins

Objectives Definitions Aetiology Presentation Investigations Complications Management Prognosis Clinical scenario

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

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

Aetiology Primary adrenal failure ADDISON’S 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

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

Presentation Non-specific symptoms: Dizziness Pigmentation 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

Investigations Bed side Bloods Imaging Special tests 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)

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!

Management Chronic adrenal failure Addisonian Crisis 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

Associated diseases Hypothyroidism T1DM Pernicious anaemia Vitiligo Premature ovarian failure

Cushing’s

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.

Aetiology Pituitary adenoma 70% F>M Ectopic ACTH production 14% Cortisol Endogenous ACTH dependent ACTH independent Exogenous Steroid use Pituitary adenoma 70% F>M Ectopic ACTH production 14% SCLC Carcinoid tumour Adrenal adenoma 10% Adrenal carcinoma 5% Adrenal hyperplasia 1%

Presentation Use whatever helps you remember! Catabolic effects Myopathy Striae Bruising Osteoporosis Glucocorticoid effects Diabetes Truncal obesity Supraclavicular fat pad Mineralocorticoid effects Hypertension Hypokalaemia

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

Investigations Bedside Bloods Imaging 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

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

Management Treat the cause! Conservative Medical Surgical Distinction: 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-sphenoidal adenomectomy Bilateral adrenalectomy (can’t locate tumour/recurrence post-surgery) Removal of ACTH secreting tumour Distinction: Nelson’s syndrome – post-adrenalectomy development of a locally aggressive pituitary tumour (corticotrophinoma) due to lack of negative feedback.

Prognosis If treated very good prognosis Untreated = <5 years 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

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

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

Pathophysiology Cause Big tongue Big lips Boggy palms Cardiomyopathy Ectopic production Pituitary adenoma GH secretion Insulin-like growth factors Arteriolar muscle hypertrophy Hypertension Anti-insulin effect Diabetes Soft tissue growth Big tongue Big lips Boggy palms Cardiomyopathy Colorectal cancer Sweat gland hypertrophy Excess sweating Bone growth Typical facies

Presentation Usually a spot diagnosis Typical facies May complain of: 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

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

Investigations Bedside Bloods Imaging Special tests BP Urine dip BM ECG Echocardiogram Bloods IGF levels Imaging MRI head Colonoscopy (if ≥50 years) Special tests Oral GTT with GH measurement 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

Management Conservative Medical Surgical Follow up: 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-sphenoidal adenomectomy Follow up: Yearly GH & IGF-1 measurement + OGTT, visual fields, CV assessment. IGF Insulin resistance

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

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

What are your differentials for this lady 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?

Questions?

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