1. Cushings, Addisons and Acromegaly
Dr J Storrow
FY2

2. Objectives Brief overview of the pituitary gland
Brief overview of all three conditions
Review:
aetiology
presentation
investigations
complications
prognosis
Brief case presentations
Revision tips

3. Pituitary gland Anterior and Posterior Anterior hormones (FLAT-GP):
F – FSH
L – LH
A – ACTH
T – TSH
G – GH
P – Prolactin
Posterior hormones (OA) :
O – Oxytocin
A – ADH

4. HPA axis

5. Definitions Cushings Addisons Acromegaly
Increased glucocorticoid exposure
Addisons
Chronic primary adrenocortical insufficiency
Acromegaly
Increased growth hormone production

6. Cushings

7. Disease vs. Syndrome
Cushings Disease is the result of a pituitary tumour secreting inappropriate ACTH
Cushings Syndrome causes the same symptoms, but is caused by overproduction of adrenal hormones. It encompasses all other forms of Cushings
Basically:
Disease = increased cortisol from pituitary
Syndrome = all other sources

8. Aetiology Harvey Cushing in 1932 Endogenous Causes: 65% = pituitary
25% = adrenals
10% = ectopic source (small cell lung ca), non-pituitary, ACTH producing tumour
Exogenous Causes:
Iatrogenic Steroids (Asthma, RA, palliative)
Higher incidence in people with: DM, HTN, Obesity and Osteoporosis
= Females 5:1 ratio and ages 25-40

9. S&S SWEDISH S – Spinal tenderness W – Weight gain E – Easily bruise
D – Diabetes
I – Intercapsular fat pad
S – Striae
H – HTN

10. Differential Diagnosis
Pseudo-Cushingoid:
Chronic severe anxiety and/or depression
Prolonged excess alcohol consumption
Obesity
Poorly controlled diabetes
HIV infection

11. Investigations Bedside? Bloods tests – which and why? Special tests:
FBC – raised WCC
U/E – low K
Special tests:
Cortisol at midnight and 0900 (loss of diurnal variation – should be low at midnight <550) – less reliable
24 hour urinary cortisol – 3 collections
24 hour salivary cortisol sampling
Dexamethasone Suppression Test

12. Dexamethasone Suppression Test
Overnight Low dose = Baseline reading, Dex 1mg given at 11pm, measure cortisol at 8am
If cortisol low (<50nmol/L) = normal
If cortisol high (>50nmol/L) = investigate further – Cushings syndrome
Localising the lesion:
Plasma ACTH
if undetectable = adrenal cause (as adrenal cause independent of ACTH)
If detected – proceed to high dose dex suppression test
High dose
if >90% suppression – pituitary
if less/no suppression – ectopic source

13. Investigations If any positive - imaging: CT of adrenals MRI pituitary
If ?ectopic:
CXR
CT =/- MRI of neck, thorax, abdomen

14. Management
Always split in to:
Conservative
Medical
Surgical

15. Management
Drug therapy remains very important for normalising cortisol levels. Medical treatment can also be used in patients who are unwilling or unfit for surgery.
Metyrapone, ketoconazole, and mitotane can all be used to lower cortisol by directly inhibiting synthesis and secretion in the adrenal gland.
The treatment of choice in most patients is surgical but the metabolic consequences increase the risk of surgery:
increased tissue fragility
poor wound healing
HTN and DM

16. Surgical Treatment Pituitary tumours: Adrenocortical tumours:
trans-sphenoidal microsurgery. Radiation therapy may be used as an adjunct for patients who are not cured. Bilateral adrenalectomy may be necessary to control toxic cortisol levels.
Adrenocortical tumours:
require surgical removal – can develop Nelsons Syndrome
Removal of neoplastic tissue is indicated for ectopic ACTH production. Metastatic spread makes a surgical cure unlikely or impossible. Bilateral adrenalectomy is indicated if necessary to control toxic cortisol levels.

17. Prognosis
Patients with incompletely controlled Cushing's syndrome have a five-fold excess mortality.
Premature death in untreated Cushing's syndrome are caused by vascular disease (MI/CVA), uncontrolled DM and infections.
The usual course is chronic, with cyclical exacerbations and rare remissions.
The prognosis is better with surgery.
The rare adrenocortical carcinomas have a 5-year survival rate of 30% or less.

18. Addisons

19. Aetiology Dr Thomas Addison in 1855 True Addisons:
Affects 1 in in UK – rare
Common presentation between 30 and 50
Affects women more
70-90% have autoimmune basis – cytotoxic T cells
Clinical and biochemical insufficiency only occurs once >90% of the gland is destroyed.
Primary = adrenals
Secondary = pituitary
Tertiary = hypothalamus

20. Aetiology continued TB (most common worldwide)
infections – AIDS, fungal
Adrenal haemorrhage (caused by sepsis, meningitis)
Metastatic spread to adrenals
Amyloidosis
Adrenalectomy
Genetic/congenital defects
Addsions = long term steroids leading to suppression of HPA axis

21. S&S

22. Investigations Bedside? Blood tests: Low Na, low cortisol
Low aldosterone causing high K,
High adrenocorticotrophic hormone (ACTH)
Low glucose
High TSH – indicates what?
Imaging?
CXR – why?
CT/MRI adrenals

23. Investigations - Synacthen Test
Nightmare for busy house officer!
How do you perform it?
Measures cortisol
Short – no cortisol produced (no response)
Long allows differentiation
Primary – No cortisol produced (ACTH high) = adrenal
Secondary – Cortisol produced (ACTH low) = pit
If initial cortisol is >140 nmol/L and second cortisol is > nmol/L, this excludes Addison's disease (most common finding!) The test can be performed at any time of day.

24. Management C, M, S (no surgical) Conservative = lifestyle
MedicAlert bracelet and steroid card.
Importance of not missing steroids.
Intercurrent illness - if tolerating oral medication then the dose should be doubled until better
Medical = Replace steroids
Glucocorticoid replacement - hydrocortisone is the mainstay of treatment; dose divided into two thirds in the morning and one third in the late afternoon (thus stimulating the normal diurnal adrenal rhythm).
Mineralocorticoid replacement - this is usually required in primary adrenal insufficiency – Fludrocortisone (what else used for – clue = elderly who fall)

25. Complications – Addisonian Crisis
severe dehydration
pale, cold, clammy skin
sweating
rapid, shallow breathing
dizziness
severe vomiting and diarrhoea
severe muscle weakness
headache
severe drowsiness or loss of consciousness
coma and death

26. Treatment of crisis Medical emergency Bloods, large bore cannula
Seek help if you suspect
Iv Hydrocortisone
Iv fluids
Iv glucose if needed

27. Prognosis Depends upon the underlying cause
In those patients in whom the prognosis is not affected by the underlying pathology, replacement therapy should result in a return to health with a normal life expectancy.

28. Acromegaly

29. Aetiology Pituitary tumour >99% (very rarely ectopic (carcinoid)
M:F = 1:1
30-50y old
5% genetic association with MEN1
GH stimulates soft tissue and skeletal growth through increased secretion of IGF-1 and secretion inhibited by somatostatin

30. S&S A – Arthopathy B – BP high C – Carpal tunnel D – Diabetes & HF
E – Enlarged tongue/heart
F – Field defect - hemianopia

31. Investigations Bedside? Bloods?
Random GH levels – not helpful (stress/sleep/pregnancy)
IGF-1 increased in 75% people
Special tests:
OGTT:
Measure glucose and GH at 0,30,60,90,120,150 mins
Normally glucose causes GH suppression
If Acromegaly – no GH suppression
False +ves – puberty, pregnancy, hepato-renal disease, anorexia, DM

32. Investigations
Imaging:
MRI pituitary
Visual fieds and acuity
ECG/Echo

33. Treatment – C,M,S Medical: Somatostatin analogues - Octreotide
Inhibit GH secretion
Monthly IM injection
Controls GH and IGF1 in 60%
GH recpetor antagonists – Pegvisomant
Supresses IGF1 in 90% but GH levels rise
Can cause tumour size to increase

34. Surgical Trans-sphenoidal surgery
Cures 80% microadenomas and 40% macroadenomas
Can try radiotherapy if surgery inappropriate – can take years to work

35. Complications Impaired GT – 40%
DM – 20% (GH counter regulates insulin)
Vascular – HTN, LVH, IHD/CVA
Malignancy – colonic polyps – controversial
Mortality 2-3 times (vascular risk)

36. Case presentations
30 year old woman presents feeling unwell and dizzy, loss of weight, decreased libido and darker skin but also some areas of very light skin. Treated for anorexia 2 years ago
50 year old man presents saying his rings are becoming tighter on his hands and he’s had to buy bigger shoes. Keeps walking into things
30 year old woman has noticed weight gain especially around face and abdomen, hair loss, bruises easily, urinating more often

37. Revision Tips Look at the patient and around the patient’s bedside
Think logically:
S&S lead to what investigations which leads to management which leads to complications which leads to prognosis
Management in to conservative, medical, surgical
Investigations: start bedside then move to desk then walk to xray etc:
Obs, urine dip, ECG, BM, clinical exam
Bloods, Iv fluids, VTE (anti-coag?), Kardex (meds)
CXR, AXR, USS, CT/MRI
If endocrine – consider bloods for other pituitary hormones
Hyperprolactinaemia is most common disorder

38. Tips for finals/FY1 Be nice to nurses/pharmacists/physios
Always ask if you don’t know what to do (inc exams – shows safety and professionalism)
Prioritise jobs
THINK LOGICALLY – start with basic things
Learn sepsis six
Learn medical emergencies – you might just save a life
Hyperkalaemia
Massive UGI bleed
Anaphylaxis
DKA
Meningitis
Seizures + status
Hypoglycaemia