Adrenal Gland Disorders

Question 1

what are the 7 golden rules of endocrinology?

Answer 1

1. Everything is logical
2. hormones are regulated by feedback
3. Think in diagnostic pairs (Hypo-Pituitary-endo axis)
4. Hormone deficiency - stimulation test (to see if you can bring it up)
5. Hormone excess - suppression test (to see if you can supress hormone)
6. Think first - then examine clinically –> then measure hormones –> then do imaging
7. There are few but important exceptions too all rules

Question 2

what happens in adrenal insufficiency?
include symptoms and signs

Answer 2

lack of cortisol, aldosterone and DHEA

lack of cortisol symptoms:
- muscle weakness
- fatigue
- anorexia

lack of cortisol signs:
- weight loss
- hyperpigmentation

lack of aldosterone symptoms:
- nausea
- vomiting
- abdominal pain
- salt craving

lack of aldosterone signs:
- hypotension
- hyponatraemia (low blood Na+)
- hyperkalemia (high blood K+)

lack of DHEA/ androgens symptoms:
- loss of libido in women

lack of DHEA/ androgen signs:
- loss of public hair in women

Question 3

why do ppl with adrenal insufficiency have hyperpigmentation?

Answer 3

Adrenal insufficiency so you have low cortisol
hypothalamus releases lots of CRH & anterior pituitary releases lots of ACTH
hyperpigmentation caused by an increased production of α-melanocyte-stimulating-hormone (αMSH). Both MSH and ACTH originate from the pro-hormone POMC.
both ACTH & MSH (cleavage product of CRH) lead to increased melanin production

Question 4

what does ACTH not regulate?

Answer 4

ACTH regulates cortisol and androgen production but does not regulate aldosterone production.

Question 5

what are diagnostic pairs?

Answer 5

Cortisol and ACTH are a diagnostic pair. Low cortisol but high ACTH means lack of responsiveness of adrenal gland –> adrenal insufficiency
Aldosterone and renin are diagnostic pair. A low aldosterone but high renin means lack of responsiveness of adrenal gland –> adrenal insufficiency

Question 6

what is primary adrenal insufficiency?

Answer 6

Adrenal gland are damaged not able to produce cortisol, aldosterone or androgens anymore
You have increased ACTH (measured) and CRH levels.
You’ll usually see an atrophic and fibrotic adrenal gland

Question 7

what is the cause of primary adrenal insufficiency?

Answer 7

Can be due to surgical removal of adrenals (this will be very obvious by looking at medical records)
The most common cause is auto-immune adrenalitis - Addison’s disease
Antibodies will be present
If there are no antibodies and the patient is a male patient you must check for presence of very long chain fatty acids to exclude adrenoleukodystrophy or adrenolymyloneuopathy
If both are negative you should do a CT scan to exclude bilateral adrenal haemorrhage or to exclude TB which can cause infections of adrenal gland
You can exclude congenital adrenal hyperplasia by measuring precursor that are accumulating in front of enzymatic block

Question 8

what is secondary adrenal insufficiency?

Answer 8

Lack of ACTH being produced by the anterior pituitary gland (hypopituitarism) - low cortisol and androgen production
Aldosterone production is not affected as it is regulated via renin-angiotensin system
Note other hypothalamic-pituitary axes may also be affected (look out for these)

Question 9

what is the cause of secondary adrenal insufficiency?

Answer 9

Due to a tumour on the pituitary gland or tumour on hypothalamus resulting in hypopituitarism.
Iatrogenic: Sometimes people are treated with exogenous glucocorticoids e.g. prednisolone or dexamethasone to suppress the immune system to treat rheumatoid arthritis or asthma. This can also lead to secondary AI as high circulating levels of synthetic glucocorticoids suppress the hypothalamus and pituitary via negative feedback causing ACTH insufficiency. So you need to switch the medication to wake up hypothalamus and the pituitary gland (can take a long time depending on how long you were on the medication)

Question 10

what are the 2 diagnosis methods for Adrenal Insufficiency?

Answer 10

1: Via symptoms & signs and measuring hormones levels e.g. cortisol,
High ACTH = primary
Low ACTH = secondary

2: When in doubt you can also do a Stimulation Test as well
Short Synacthen test (SST)
Inject ACTH24 into the blood stream
If adrenal gland fails to respond to exogenous ACTH by producing more cortisol you have adrenal insufficiency. (normal would show high cortisol)

Question 11

what is the drug for Adrenal Insufficiency? (glucocorticoids)

Answer 11

We treat adrenal deficiency with:
Hydrocortisone (cortisol - active)
Or
Cortisone Acetate (cortisone - inactive)
Used due to lack of access to hydro-cortisone
Hydrocortisone is preferred as cortisone has variable effects in patients due to problems with conversion in the kidneys.

Both prednisolone and dexamethasone are also synthetic versions of cortisol.
They are longer lasting and have a stronger binding to glucocorticoid receptors than hydrocortisone and so are more powerful –> lower dosage required.
Equivalent anti-inflammatory effects

Question 12

what is in 20mg hydrocortisone?

Answer 12

20 mg hydrocortisone:
= 25 mg cortisone acetate
= 0.25 mg dexamethasone
= 4 mg prednisolone
= 5 mg prednisone
Note how inactive forms require a high dose as they need to be converted (not all mass is active hormone)

Question 13

what is the drug for Adrenal Insufficiency? (mineralcorticoids)

Answer 13

Hydrocortisone (active hormone) can also act at the mineralocorticoid receptors, but not as much as fludrocortisone (synthetic aldosterone)
100 µg (0.1mg) Fludrocortisone = 40 mg Hydrocortisone
If daily Hydrocortisone Dose >50 mg, Fludrocortisone (FC) can be paused as hydrocortisone covers the need by binding to MR as well.
Otherwise patient with Primary AI take 100-250 µg FC/day
Dexamethasone has NO mineralocorticoid activity even though it is the strongest glucocorticoid
So, if you replace hydrocortisone with dexamethasone you need to observe fludrocortisone levels as well, may need to increase them.

Question 14

what is the LT treatment for adrenal insufficiency?

Answer 14

Long-term treatment
Replace glucocorticoid with Hydrocortisone 15mg AM, 10mg PM
Replace mineralocorticoid with Fludrocortisone 100-200 µg/day
(only in primary, not necessary in secondary AI as renin-angiotensin system)
Adrenal androgens are replaced with DHEA (in women who have deficiency leading to low libido, low energy)

Question 15

what is acute adrenal insufficiency (Adrenal crisis)?

Answer 15

Acute adrenal crisis is a life-threatening state caused by insufficient levels of cortisol
Rapid onset –> Medical Emergency –> Fast reaction saves lives –> Patients goes into a shock
Treat shock:
Rehydration with generous saline infusion
Immediate injection of hydrocortisone 100mg, followed by continuous hydrocortisone infusion 200mg/24hr
Don’t delay by doing diagnosis procedures

Question 16

what are the risk factors for adrenal crisis?

Answer 16

Risk factors for adrenal crisis are physical and emotional stress triggers:
Fever
Hypoglycemia
Hypotension
Infection
Dehydration
Trauma
Surgery - In the past people did not know cortisol levels needed to be increased during surgery so patients with adrenal insufficiency who underwent surgery often died.
These are all moments where cortisol levels need to be raised but this is not possible.

Question 17

what do ppl with adrenal insufficiency have to carry?
how does it affect their routine?

Answer 17

Patients who have adrenal insufficiency often carry a steroid card and/or medic-alert bracelet to identify their exogenous steroid dependence to HCP.

They also have to follow this routine:
Sick Day Rule 1 - Moderate stress
In case of a fever, an infection requiring antibiotics or minor surgery (under local anesthesia) you must double the daily glucocorticoid dose
Sick Day Rule 2 - Severe stress
From trauma, major surgery, persistent vomiting, colonoscopy, active labour you require an immediated injection of 100mg hydrocortisone i.v. or i.m (self inject in muscle), followed by continuous infusion of 200mg of Hydrocortisone/24hr or repeated i.m. injections
All patients with adrenal insufficiency must have Hydrocortisone Emergency Self-Injection Kit.
Must have training for themselves and relatives on how to use it

Question 18

what can adrenal insufficiency result in?
what are the major causes of this?

Answer 18

Death
Major causes are
1: Doctor and nurses don’t know how to treat it so deny hydrocortisone injection during crisis
2: Patient reluctant to self-inject glucocorticoids.
Hydrocortisone does not affect pregnancy as it does not cross the placenta.

Question 19

what can excess glucocorticoid lead to?

Answer 19

Cushing’s Syndrome:
Symptoms & signs that reflect prolonged and inappropriately high exposure of tissues to glucocorticoids.
Clinical features specific to Cushing’s Syndrome:
Purple stretch mark due to rapid weight gain (central obesity) and more sensitive skin (more prone to bruising)
Proximal myopathy: difficult to get up from a chair without hands and difficultly climbing stairs due to muscle atrophy
Osteoporosis with vertebral fractures in the lumbar spine (loss in height)

Question 20

what are the clinical features of cushings syndrome?

Answer 20

Clinical features that are common but not specific:
Central obesity
Moon face
Hypertension
Buffalo hump
Impaired glucose tolerance/diabetes
Decreased linear growth in children which results in weight gain and decreasing growth velocity

Question 21

what are the 3 causes of excess glucocorticoid?

Answer 21

Iatrogenic – prolonged overexposure to synthetic corticosteroids during treatment of e.g. an autoimmune disease

ACTH-dependent: (body makes too much ACTH)
Cushing’s disease: Tumour of the pituitary - overproducing ACTH (75%)
Ectopic Cushing’s: Ectopic tumour: ACTH-secreting tumour outside the pituitary or adrenal glands
- small cell lung carcinoma - tumour characterised by differentiation into the neuroendocrine system and the secretion of hormones eg. ACTH
- carcinoid - a slow-growing type of neuroendocrine tumour originating in the cells of the neuroendocrine system e.g. found hidden in pancreas

ACTH independent: (body makes too much cortisol)
Adrenal Cushing syndrome: Adrenocortical adenoma/carcinoma results in overproduction of cortisol

Question 22

what are the different methods in diagnosing Cushing’s?

Answer 22

Dexamethasone overnight suppression test (DST)
1mg dexamethasone given at night (cortisol should be low)
This will go and bind to receptors on the pituitary and hypothalamus for many hours
Next morning take blood for serum cortisol 8-9 am
In healthy people cortisol will be less than 50nmol/l because ACTH and CRH downregulated –> endogenous cortisol suppressed
Cushing’s syndrome: cortisol secretion is autonomous (due to tumour on adrenal gland or pituitary) & not responsive to feedback so should remain high

Other methods:
24 hr urinary free cortisol –> greater than 130µg
Midnight cortisol test as normal people cortisol is low at night.
Done by taking blood or saliva at night.
This will tell is they have Cushing’s as cortisol it will be high throughout the night.
Must perform at least two of the three tests with both positive to confirm Cushing’s.

Question 23

what differential diagnosis is done to find cause of cushings?

Answer 23

9am plasma ACTH
- If ACTH is suppressed - cause is adrenal
- ACTH normal/high despite too much cortisol - pituitary/ectopic

pituitary or ectopic?
- high dose DST (2mg every 6 hours for 48hrs) - pituitary tumour may respond to such high levels through negative feedback causing ACTH suppression and therefore a decrease in cortisol levels. but ectopic tumour will not respond so ACTH will remain high
- CRH test (100𝜇g iv). CRH administration results in an excessive rise in plasma ACTH and serum cortisol in patients with pituitary Cushing’s disease, whilst this is rarely seen in patients with ectopic ACTH secretion.
- Inferior petrosal sinus sampling (IPSS) is an invasive procedure in which ACTH levels are sampled from the veins that drain the pituitary gland; these levels are then compared with the ACTH levels in the peripheral blood to determine whether a pituitary tumour (as opposed to an ectopic source of ACTH) is responsible for ACTH-dependent Cushing syndrome. This is done with injection of CRH to see if you can stimulate the production of ACTH.
Post CRH
>3.3:1 central:peripheral = pituitary source
<1.8:1 central:peripheral = ectopic source

Imaging after biochemistry
- If ACTH is low in 9am plasma ACTH test - successfully you perform adrenal imaging via CT scan
- If ACTH is high scan the pituitary –> MRI

• You should not do this right away as 5% of pop have nodule in adrenal without over production
• 10% of patients have tiny nodule in pituitary gland which causes no effect so need to start with biochemistry.
  BIOCHEMISTRY before imaging golden rule.

Question 24

explain the 2 different treatments that treat cushings?

Answer 24

Surgery
Pituitary (Cushing’s disease) - transsphenoidal surgery
Remove only the pituitary tumours, try to leave as much of the pituitary gland intact
Bilateral adrenalectomy for Cushing’s disease
However, can lead to Nelson’s syndrome: the term used to describe an enlargement of ACTH producing tumour in the pituitary gland, following surgical removal of both adrenal glands in a patient with Cushing’s disease
Laparoscopic adrenalectomy for adrenal adenoma- removal of an adrenal gland using the ‘keyhole’ (laparoscopic) surgical method.
open adrenalectomy for adrenal carcinoma
(Adrenalectomy is the removal of one or both adrenal glands)

Drugs
Block cortisol-producing adrenal enzymes - metyrapone, ketoconazole, etomidate (temporary solution).
Block glucocorticoid receptor (RU486)
Disrupt adrenal redox balance & thereby disrupts steroidogenesis & cell proliferation. This is done using mitotane.