Endocrinology: Pathology - Adrenal cortex and medulla

Question 1

List six causes of Cushing syndrome. Which of these are ACTH-dependent and which are ACTH-independent? Which is most common?

Answer 1

1. Exogenous glucocorticoids (most common)

ACTH-dependent:
2. ACTH-secreting pituitary adenomas (most common ACTH-dependent, 70%; “Cushing disease”)
3. Corticotroph cell hyperplasia (primary or secondary due to hypothalamic dysfunction with raised CRH)
4. Ectopic ACTH secretion by non-pituitary tumours

ACTH-independent:
5. Primary adrenal neoplasm
6. Primary cortical hyperplasia (rare)

Question 2

What is the most common non-pituitary tumour to secrete ACTH?

Answer 2

Small cell lung Ca

Question 3

Which primary adrenal neoplasm causes more marked hypercortisolism?

Answer 3

Carcinoma

Question 4

What are the four morphological patterns seen in the adrenal gland in the setting of hypercortisolism, and what causes each?

Answer 4

1. Focal atrophy: due to exogenous glucocorticoids
2. Diffuse hyperplasia: due to ACTH-dependent causes
3. Micronodular and macronodular hyperplasia: primary hyperplasia
4. Pituitary adenoma or carcinoma

Question 5

What derangements in serum ACTH and response to dexamethasone suppression test are seen in the setting of pituitary causes of Cushing syndrome vs ectopic ACTH syndromes vs adrenal tumours?

Answer 5

Pituitary causes:
- Increased ACTH
- No change in ACTH or urinary cortisol excretion with low doses
- Reduced ACTH and suppression of urinary cortisol excretion with higher doses

Ectopic ACTH:
- Increased ACTH
- No change in ACTH or urinary cortisol excretion with low or high doses

Adrenal tumours:
- Decreased ACTH (due to negative feedback)
- No change in ACTH or urinary cortisol excretion with low or high doses

Question 6

List three causes of primary hyperaldosteronism. Which of these is most common?

Answer 6

1. Bilateral idiopathic hyperaldosteronism (most common, 60%)
2. Adrenocortical neoplasm (aldosterone-producing adenoma, adrenocortical carcinoma)
3. Primary familial hyperaldosteronism (including glucocorticoid-suppressible)

Question 7

What is Conn syndrome?

Answer 7

Hyperaldosteronism caused by aldosterone-secreting adenoma

Question 8

Describe three broad causes of secondary hyperaldosteronism with specific examples of each

Answer 8

1. Decreased renal perfusion (e.g. renal artery stenosis, arteriolar nephrosclerosis)
2. Arterial hypovolaemia and oedema (e.g. CCF, cirrhosis, nephrotic syndrome)
3. Pregnancy

Question 9

What is the pathogenesis of pregnancy-induced hyperaldosteronism?

Answer 9

Due to oestrogen-induced increase in plasma renin

Question 10

What is the difference in plasma renin activity between primary and secondary causes of hyperaldosteronism?

Answer 10

Primary: decreased plasma renin activity with increased aldosterone:renin activity ratio (must be confirmed with aldosterone suppression test)
Secondary: increased plasma renin activity

Question 11

Describe the clinical presentation of primary and secondary hyperaldosteronism

Answer 11

Both present with HTN, and Na+ and fluid retention
Primary hyperaldosteronism may also present with hypokalaemia

Question 12

Describe two broad causes of primary adrenocortical insufficiency with specific examples of each

Answer 12

1. Loss of cortex (e.g. congenital hypoplasia, AI adrenalitis, infection, systemic AI conditions such as sarcoidosis and amyloidosis, metastatic carcinoma)
2. Failure of metabolism (e.g. congenital hyperplasia, drug- or steroid-induced ACTH inhibition)

Question 13

Describe two broad causes of secondary adrenocortical insufficiency with specific examples of each

Answer 13

1. Hypothalamic-pituitary disease (e.g. neoplasm, infection, infiltrative disease such as sarcoidosis, inflammation)
2. Hypothalamic-pituitary suppression (e.g. long-term steroid administration, steroid-producing neoplasms)

Question 14

What are the three syndromes that adrenocortical insufficiency may present as?

Answer 14

1. Primary acute adrenocortical insufficiency
2. Primary chronic (Addison disease) adrenocortical insufficiency
3. Secondary adrenocortical insufficiency

Question 15

Give three causes of primary ACUTE adrenocortical insufficiency

Answer 15

1. Acute stress (e.g. surgery, infection) in setting of chronic adrenocortical insufficiency
2. Rapid withdrawal of exogenous steroids after prolonged treatment
3. Massive adrenal haemorrhage (e.g. in newborns, Waterhouse-Friderichsen syndrome)

Question 16

What is Waterhouse-Friderichsen syndrome? Who does it most commonly affect?

Answer 16

Acute adrenal failure due to adrenal haemorrhage secondary to severe bacterial infection
More common in children

Question 17

What is the usual causative organism in Waterhouse-Friderichsen syndrome? What are some other implicated organisms?

Answer 17

N. meningitidis
May also be caused by Pseudomonas, streptococcus, Haemophilus influenzae, staphylococci

Question 18

Four features of Waterhouse-Friderichsen syndrome

Answer 18

1. Sepsis
2. Hypotension -> shock
3. DIC with widespread purpura
4. Acute adrenocortical insufficiency

Question 19

What causes >90% of cases of Addison disease?

Answer 19

Autoimmune adrenalitis
Tuberculosis
AIDS
Metastatic cancers

Question 20

What is the most common cause of Addison disease?

Answer 20

Autoimmune adrenalitis

Question 21

Which two autoantibodies are implicated in autoimmune adrenalitis?

Answer 21

Antibodies to 21-hydroxylase and 17-hydroxylase

Question 22

What are the two underlying syndromes which cause autoimmune adrenalitis and what are their other features?

Answer 22

1. APS1: with polyendocrinopathy and skin changes (due to AIRE mutation)
2. APS2: with autoimmune thyroiditis or T1DM, no skin changes

Question 23

What are the most common infectious causes of Addison disease?

Answer 23

Tuberculosis
Fungi (e.g. Histoplasma capsulatum)

Question 24

How does AIDS cause adrenal insufficiency?

Answer 24

May be due to opportunistic infection (e.g. CMV, MAC) or malignancy (e.g. Kaposi sarcoma)

Question 25

Which two metastatic cancers most commonly cause Addison disease?

Answer 25

Lung Breast

Question 26

Describe five clinical features of Addison disease

Answer 26

1. Non-specific progressive weakness and fatigue 2. GI disturbances: anorexia, nausea and vomiting, diarrhoea, weight loss 3. Hyperpigmentation 4. Hypoaldosteronism: hyperkalaemia, Na+ and fluid loss leading to volume depletion and hypotension 5. Acute crisis if stressed

Question 27

Three clinical features of acute adrenal crisis

Answer 27

1. Intractable vomiting 2. Abdominal pain 3. Cardiovascular collapse

Question 28

What causes the hyperpigmentation seen in Addison disease?

Answer 28

Due to increased production of POMC, precursor to ACTH but also MSH -> stimulates melanocytes

Question 29

Which clinical feature of Addison disease differentiates it from secondary causes of adrenocortical insufficiency?

Answer 29

Hyperpigmentation not seen in secondary adrenocortical insufficiency (because ACTH release is decreased)

Question 30

What is phaeochromocytoma?

Answer 30

Adrenal medullary neoplasm composed of chromaffin cells which secrete catecholamines (but may also secrete peptide hormones or other steroids, including cortisol)

Question 31

What is the "rule of 10s" of phaeochromocytoma?

Answer 31

- 10% extra-adrenal ("paragangliomas") - 10% sporadic cases are bilateral (50% if familial) - 10% malignant - 10% not associated with HTN - Now 25% (previously thought to be 10%) associated with germline mutations (e.g. von Hippel-Lindau, NF1, Sturge-Weber, MEN)

Question 32

Describe the clinical presentation of phaeochromocytoma

Answer 32

90% have HTN Two-thirds present with paroxysmal catecholamine release, characterised by episodic diaphoresis, headache, anxiety, tremor, visual disturbance, abnormal pain and nausea

Question 33

List three malignancies associated with MEN-1. Which of these are most common?

Answer 33

3 (+1) P's: 1. Parathyroid (most common) 2. Pancreas (endocrine) 3. Pituitary (usually Prolactinoma)

Question 34

List three malignancies associated with MEN-2

Answer 34

1. Phaeochromocytoma 2. Medullary carcinoma 3. Parathyroid hyperplasia

Question 35

What is pre-eclampsia and how does it present?

Answer 35

Systemic syndrome characterised by widespread maternal endothelial dysfunction, likely due to placental ischaemia Presents with HTN, oedema and proteinuria (usually in third trimester)

Question 36

In which demographic is pre-eclampsia more common?

Answer 36

Primiparas

Question 37

Five symptoms which suggest severe pre-eclampsia (with likelihood of transition to eclampsia)

Answer 37

1. Hypercoagulability 2. AKI 3. Pulmonary oedema 4. Headache 5. Visual disturbances

Question 38

What is eclampsia?

Answer 38

Severe form of pre-eclampsia characterised by seizures

Question 39

What is HELLP syndrome? How common is it?

Answer 39

Occurs in 10% of women with eclampsia Characterised by: - Haemolysis - Elevated Liver enzymes - Low Platelets

Question 40

Describe the three pathogenic factors involved in pre-eclampsia

Answer 40

1. Abnormal placental vasculature -> placental ischaemic 2. Endothelial dysfunction 3. Coagulation abnormalities: decreased PGI2, increased thromboxane

Question 41

Six morphological features seen in the placenta in pre-eclampsia

Answer 41

1. Placental infarcts and villous ischaemia with hypovascularity 2. Fibrinoid necrosis 3. Retroplacental haemorrhage 4. Intramural lipid deposition 5. Prominent syncytial knots 6. Thickened trophoblastic basement membrane