Adrenal physiology and diseases

Question 1

What are the 3 zones of the adrenal glands and what does each produce?

Answer 1

Zona glomerulosa- mineralocorticoids such as aldosterone Zona fasciculata- Glucocorticoids such as cortisone Zona reticulata- Weak androgens

Question 2

Draw the cortisol and aldosterone pathway.

Answer 2

Question 3

Draw the RAAS pathway.

Answer 3

Question 4

What is the biochemical function of aldosterone?

Answer 4

Aldosterone acts on the renal distal convoluted tubule and leads to increased sodium intake from the glomerular filtrate and increased potassium excretion.

Question 5

What are the 4 most common causes of primary adrenocortical insufficiency? Which are the most common in the UK and in the third world?

Answer 5

Autoimmune adrenalitis

Malignancy

Infiltration- sarcoidosis, amyloidosis, haemochromatosis

Infection- TB, AIDS-> CMV, Fungal

Question 6

What are the signs and symptoms of primary adrenocortical insufficiency and Addison’s disease?

Answer 6

Weakness and fatigue, buccal hyperpigmentation (splice product of ACTH produced alpha melanocyte stimulating hormone), anorexia and weight loss, abdo pain, postural hypotension. Secondary sexual characteristic loss in women.

Question 7

What investigations should be used to diagnose primary adrenal insufficiency?

Answer 7

Electrolytes- low Na, High K, high urea.

Serum cortisol and ACTH- undetectable cortisol is diagnostic of adrenal insufficiency. Simulatenous 9am cortisol and ACTH will show low cortisol with high ACTH

Short synachten test- Measure cortisol -> give 250ug of synacthen, measure cortisol 30/60 mins later

Long synacthen test- measure cortisol-> give 1mg IM depot synachten-> measure cortisol at regular intervals up to 24 hours

TFTs

Plasma renin is increased

Question 8

Which investigation into adrenal insufficiency is used to distinguish primary from secondary disease? How is it able to do this?

Answer 8

long synachthen test. Differentiation of 2ary and 1ary afrenal failure can be made more reliably following 3 days IM ACTH 1Mg. This is because the test relies on the ability of the atrophic adrenal glands to respond to ACTH in 2ary adrenocortical failure whereas, in 1ary adrenal failure, the diseased gland is already maximally stimulated and will not respond.

Question 9

The patient has confirmed adrenal insufficiency. Which investigations are used to establish the cause of primary adrenal insufficiency?

What imaging modality is most frequently used and what does it typically show?

Answer 9

1. Adrenal autoantibodies- especially anti-21hydroxylase.
2. Percutaneous CT guided biopsy
3. Plasma renin and aldosterone
4. Serum biochemical markers of infection

Imaging- adrenal enlargement, with or without calcification, may be seen on CTAbdo, This uggests TB, infiltration or metastatic disease

Question 10

What is the treatment for Primary Addison’s?

Answer 10

Replace glucocorticoids- oral hydrocortisone 20mg morning 10mg late afternoon

Replace mineralocorticoid- fludrocortisone- only necessary in primary adrenal failure

Treatment is for life

Question 11

What are the two most common cause of an acute adrenal insufficiency?

Answer 11

1. Infection
2. Bilateral adrenal infarction

Question 12

Give 4 clinical features of acute adrenal adrenal insufficiency?

Answer 12

1. shock
2. hypotension
3. abdominal pain
4. unexplained fever

Question 13

What is the management of acute adrenal insufficiency? What should you be careful of in this management?

Answer 13

• Large volumes of 0.9% saline may be required to reverse dehydration
• 100mg IV hydrocortisone, followed by 100mg Im hydrocortisone6 hourly until the patient can take oral therapy
• Investigate and treat underlying cause
• In chronic hyponatraemia, rapid correction of the deficit exposes the patient to the risk of central pontine myelinolysis. If plasma sodium is <120mmol/L aim to correct by no more than 10mmol/L in the first 24 hours

Question 14

What is conn’s syndrome? What is the cause? What triad of signs should make you think Conn’s? Is renin up or down?

Answer 14

• Primary hyperaldosteronism.
• Adenoma of the zona glomerulosa.
• Hypertension, hyperkalaemia, alkalosis.
• Renin is low in Conn’s

Question 15

What is the most common cause of primary hyperaldoteronism?

Answer 15

bilateral hyperplasia

Question 16

What is the treament of primary hyperaldosteronism?

Answer 16

The treatment for hyperaldosteronism depends on the underlying cause. In patients with a single benign tumor (adenoma), surgical removal (adrenalectomy) is curative. This operation is usually performed laparoscopically, through several very small incisions. After successful adrenalectomy, approximately 95% of patients notice significant improvement in their hypertension. Of this 95%, one third are cured of high blood pressure and the rest are on fewer medications or lower dosages. For patients with bilateral hyperplasia, the best treatment is a medication called an aldosterone-antagonist (spironolactone, eplerenone) which blocks the effect of aldosterone. In addition, patients are maintained on a low salt diet.

Question 17

What is a phaeochromocytoma?

What urinary sign can be seen to help make a diagnosis?

Answer 17

Benign tumour of the adrenal medulla which leads to hypersecretion of adrenaline and noradrenaline.

24 hour urinary catecholamines.

Question 18

Which two enzymes are essential for cortisol synthesis?

Answer 18

17a-hydroxylase and 21 hydroxylase

Question 19

What is the HPA axis for cortisol?

Answer 19

hypothalamus->crh->anterior pituitary->ACTH

Question 20

How does cortisol increase vascular tone?

Answer 20

Increases blood vessels sensitivity to catecholamines

Question 21

Give 5 functions of cortisol.

Answer 21

Sodium retention

Insulin anatagonism

Decrease muscle

Increased bone resorption

Anti inflammatory

Increased arteriolar tone

Foetal maturation

Question 22

What are the two main distinctions in categorising Cushing’s?

Answer 22

ACTH dependent or independent

Question 23

What are the top 3 causes fo ACTH dependent cushings syndrome?

Answer 23

Pituitary adenoma (Cushing’s disease)

Ectopic ACTH syndrome

Ectopic CRH secretion

Question 24

What are the top 3 cause of ACTH independent Cushing’s syndrome?

Answer 24

Adrenal adenoma

Adrenal carcinoma

Nodular hyperplasia

Question 25

What facial signs are present in Cushing’s?

Answer 25

Round plethoric complexion, acne, hirsutism, hair thinning

Question 26

What are the skin signs of Cushing’s syndrome?

Answer 26

Thin and fragile, purple striae on abdomen, breasts, thighs, easy bruising, tinea versicolor

Question 27

What muscle signs are present in Cushing’s?

Answer 27

proximal weakness

Question 28

What are the 2 first line outpatient investigations of Cushing’s?

Answer 28

• 2-3x 24 hour urinary cortisol test (relatively high rate of false negatives)
• Overnight dexamthasone suppression test. Administration of 1mg of dexamthasone, measure serum cortisol at 9am next morning (reading should be below 50).

Question 29

What are the 2 first line inpatient investigations into Cushing’s syndrome?

Answer 29

Midnight cortisol measurement (cortisol should be low)

Low dose dexamethasone suppression test- patients take 6-hourly 0.5mg dexamethasone for 48 hours. This should lead to the lowest point.

Question 30

When a patient is confirmed as having Cushing’s, the next step is to determine the cause? How is this done?

Answer 30

Serum basal ACTH

Question 31

In ACTH independent disease what is the first line investigation?

Answer 31

MRI following gadolinium enhancement

Question 32

What invasive investigation can be used to determine between central and ectopic ACTH secretion?

Answer 32

Inferior petrosal sinus sampling

Question 33

What imaging investigation is used to spot pituary adenomas?

Answer 33

MRI or CT head

Question 34

Does dexamethasone suppress ectopics?

Answer 34

No

Question 35

What are the 3 treatments of Cushing’s disease in descending order of prevalence?

Answer 35

Transphenoidal surgery

Pituitary radiotherapy

Adrenalectomy

Question 36

What are the 3 medical options for Cushings syndrome? What are their MOAs ans SEs?

Answer 36

• Metyrapone is 1st line. 11B hydroxylase inhibitor (blocks cortisol synthesis). Nausea and increased mineralocorticoids and androgens.
• Ketoconazole- direct P450 enzyme inhibitor. Abnormalities of liver function, gynaecomastia.
• Mitotane-inhibits steroidogenesis at the side chain cleavage, 11- and 18-hydroxylase and 3b hydroxysteroid dehydrogenase. Nausea, cerebellar disturbance, somnolence

Question 37

What is the definition of adrenal insufficiency?

Answer 37

Adrenal insufficiency is defined by the lack of cortisol, i.e. glucocorticoid deficiency, and may be due to destruction of the adrenal cortex (1°, Addison’s disease and congenital adrenal hyperplasia (CAH)) or due to disordered pituitary and hypothalamic function (2°)

Question 38

What is the most frequent cause of adrenal insufficiency?

Answer 38

• The most frequent cause is hypothalamic–pituitary damage, which is the cause of AI in 60% of affected patients.

Question 39

What are the causes of secondary adrenal insufficiency?

Answer 39

• Lesions of the hypothalamus and/or pituitary gland
• Tumours—pituitary tumour, metastases, craniopharyngioma.
• Infection—tuberculosis.
• Inflammation—sarcoidosis, histiocytosis X, haemochromatosis, lymphocytic hypophysitis.
• Iatrogenic—surgery, radiotherapy.
• Other—isolated ACTH deficiency, trauma.
• Suppression of the hypothalamo–pituitary–adrenal axis
• Glucocorticoid administration.
• Cushing’s disease (after pituitary tumour removal)

Question 40

Is skin pigmentation observed in primary or secondary Addison’s disease? Why?

Answer 40

• Primary only.
• There is no pigmentation because ACTH and POMC secretion is reduced. Lack of stimulation of skin MC1R due to ACTH deficiency results in pale skin appearance.