Definitions Aetiology Presentation Investigations Complications Management Prognosis Clinical scenario.

Addison’s, Cushing’s & Acromegaly

Tom Collins

Objectives

Definitions Aetiology Presentation Investigations Complications Management Prognosis Clinical scenario

Addison’s DiseaseDefinition Autoimmune

destruction of the adrenal gland resulting in failure of adrenal steroid hormone production

Cortisol & Aldosterone

Lets take a step back…

Adrenal failure:1. Primary adrenal failure

› Atrophy/destruction of the adrenal gland

2. Secondary adrenal failure› Inadequate ACTH production

3. Tertiary adrenal failure› Failure of CRH production

Aetiology

1. 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

Aetiology cont.

2. Secondary adrenal failure› Acute steroid withdrawal

3. Tertiary adrenal failure› Chronic high dose glucocorticoid therapy› Sarcoidosis› Tumour› Cranial irradiation

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

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)

ComplicationsAddisonian 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 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.

AetiologyCortisol

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!

•Myopathy•Striae•Bruising•Osteoporosis

Catabolic effects

•Diabetes•Truncal obesity•Supraclavicular fat pad

Glucocorticoid effects

•Hypertension•Hypokalaemia

Mineralocorticoid effects

Acronyms

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

hypertension/hypokalaemia

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

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 › 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› 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

PathophysiologyCause

Pituitary adenomaEctopic production

GH secretion

Insulin-like growth factors

Arteriolar muscle

hypertrophyHypertension

Anti-insulin effect

Diabetes

Soft tissue growth

Big tong

ueBig lips

Boggy

palms

Cardiomyopat

hyColorectal canc

er

Sweat gland

hypertrophyExcess sweating

Bone growt

hTypical facies

PresentationUsually 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

What should you do O/E?Observe: As previous slideHands: Size – compare with your own Thenar eminence – wasting Check median nerve sensation Sweaty? ‘Bogginess’ of palms Skinfold thickness – increased in active diseaseAsk for BPNeck Check for goitre JVPVisual fields and acuityStand from seated position

Investigations Bedside

› 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

› 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?

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