Endocrine pathology

Question 1

Pituitary gland

Answer 1

The pituitary gland sits in the sella turcica of the sphenoid bone and is attached to the hypothalamus. It is composed of two parts which are embryologically and functionally distinct.

Question 2

anterior pituitary hormones

Answer 2

The anterior pituitary secretes six hormones: growth hormone (GH), prolactin, follicle stimulation hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH) and adrenocorticotrophic hormone (ACTH).
The secretion of all six anterior pituitary hormones is in turn regulated by hormones from the hypothalamus, which reach the pituitary through a portal system and blood vessels.

Question 3

posterior pituitary hormones

Answer 3

The posterior pituitary secreted antidiuretic hormone (ADH) and oxytocin. Both hormones are actually synthesised in the hypothalamus and then pass down nerve fibres in the pituitary stalk to be secreted by the posterior pituitary.

Question 4

Pituitary adenoma

Answer 4

Pituitary adenomas are the most common disease of the anterior pituitary. They are tumours derived from the glandular tissue of the anterior pituitary. Most cases are sporadic but they may occur as part of the MEN 1 syndrome.

Question 5

effects of pituitary adenomas

Answer 5

Pituitary adenomas may cause clinical effects in two main types:
1. Mass effects:
• Bitemporal hemianopia (because the tumour causes compression of the optic chiasm and thus affects the optic nerves).
• Diplopia (the tumour causes compression of cranial nerves III, IV or VI)
• Non-specific symptoms related to any intracranial mass e.g. headache.

2. Endocrine effects: 
• Functional adenomas may produce symptoms related to excess hormone secretion (most commonly prolactin, GH and ACTH). Because of this, functional tumours are often very small at presentation. 
• Non- functional adenomas do not produce hormones. Non-functional tumours are often larger at presentation  because they present via mass effects rather endocrine dysfunction. Many non-functional adenomas remain tiny and never come to clinical attention because they do not cause mass effects.

Question 6

Prolactinoma

Answer 6

Prolactinomas are pituitary adenomas which produce excess prolactin.
They are the most common type of functional adenoma.

Question 7

How do prolactinomas present?

Answer 7

The presentation depends on the patient’s age and sex:
Women of reproductive age
• Commonly present with:
○ Either oligomenorrhoea (infrequent or very light menstruation - 4-9 periods in a year)
○ Or galactorrhoea (the spontaneous flow of milk from the breast unassociated with pregnancy or breast feeding).
• These patients often have very small tumours and so present early.

Men and post-menopausal women
• Usually present with mass effects such as a headache or visual disturbance. However, they may present with symptoms such as galactorrhoea.
• The tumours are typically larger at presentation.

Question 8

What do ACTH secreting adenomas present as?

Answer 8

ACTH-secreting adenomas present as Cushing’s syndrome.

Question 9

What do GH secreting adenomas present as?

Answer 9

GH-secreting pituitary adenomas present as acromegaly.

Question 10

Wha is acromegaly?

Answer 10

Acromegaly is a rare clinical syndrome resulting from excess secretion of growth hormone.

The somatic and metabolic effects of chronic GH hypersecretion are predominantly mediated by high levels of insulin-like growth factor-1 (IGF-1). IGF-1 is secreted by the liver.

Question 11

What are the clinical features of acromegaly?

Answer 11

Acromegalic facies:

• Protruding supraorbital ridges
• Enlarged nose
• Coarse facial features
• Porgnathia

Headaches 
Thickened calvaria 
LVH 
HTN 
Insulin resistance 
Hepatomegaly 
Large hands 
Thickened skin 
Hyperostosis 
Impotence and loss of libido (amenorrhea in women) 
Degenerative joint disease 
Peripheral neuropathy (nerve compression) 
Large feet and heel pad

Question 12

Acromegaly is life threatening T/F?

Answer 12

Acromegaly is a serious condition in which there is doubling in mortality compared with normal populations:
• This is mainly due to high incidence of cardiovascular disease due to left ventricular hypertrophy and hypertension.
Acromegaly is diabetogenic state (i.e. it causes insulin resistance), which is a strong risk factor for cardiovascular disease

Question 13

What does a TSH secreting adenoma result in?

Answer 13

TSH-secreting adenomas are rare.
The TSH stimulates the thyroid gland causing hyperthyroidism, presenting clinically thyrotoxicosis. It is important to remember that a TSH-secreting pituitary adenoma is a very rare cause of thyrotoxicosis.

Question 14

What are the commonest causes of thyrotoxicosis?

Answer 14

The commonest causes of thyrotoxicosis are:
• Graves disease (about 80% of cases)
• Toxic multinodular goitre (a nodule within a multinodular goitre which autonomously secretes thyroid hormones independently of TSH).
• A functional thyroid adenoma (a follicular adenoma producing thyroid hormones)
Other causes of thyrotoxicosis include drugs (such as amiodarone) and certain types of thyroiditis.

Question 15

Function of the adrenal gland

Answer 15

The adrenal glands are paired glands that are situated in the retroperitoneum superior to the kidneys. The adrenal gland is functionally divided into the cortex and medulla:
- The cortex is composed of the zona glomerulosa, zona fasciculata and zona reticularis which secrete mineralocorticoids (mainly aldosterone), glucocorticoids (mainly cortisol) and androgens respectively.
The medulla which secretes catecholamines (adrenaline and noradrenaline).

Question 16

Describe the HPA axis, using cortisol as an example?

Answer 16

The hypothalamus secretes corticotrophin releasing hormone (CRH) which stimulates the anterior pituitary to secrete adrenocorticotrophic hormone (ACTH). ACTH acts on the adrenal gland to stimulate release of cortisol. Cortisol has a negative feedback effect on the hypothalamus and anterior pituitary: it supresses the secretion of CRH and ACTH respectively.

Question 17

What are the clinical features of cushings syndrome?

Answer 17

Poor hair 
Hirsutism (women) 
Poor healing 
Bruising 
Petechiae 
Poor nails 
Proximal myopathy 
Peripheral neuropathy 
Plethora 
Moon face 
Buffalo hump 
Abdominal obesity 
Striae 
Osteoporosis 
DM 
HTN 
Immunocompromise

Question 18

What is Cushing’s syndrome?

Answer 18

Cushing’s syndrome is to due persistent excess circulating glucocorticoids.

Question 19

What are the causes of cushing’s syndrome?

Answer 19

1. The commonest cause is exogenous administration of glucocorticoids to treat other diseases. The adrenal cortices undergo atrophy because of the negative feedback effect of the exogenous glucocorticoids on the HPA axis: the production of CRH and ACTH is suppressed and so the adrenal cortices undergo atrophy.
   
   2. The second most common cause is a pituitary adenoma secreting ACTH.
      Cushing’s syndrome due to an ACTH-secreting pituitary adenoma is called Cushing’s disease.
      The adrenal cortices undergo hyperplasia in response to the effect of the circulating ACTH.
   3. An adrenal cortical adenoma which secretes cortisol may also cause Cushing’s syndrome. The tumour arises from a cell in the zona fasciculata.
   4. A paraneoplastic syndrome. The tumour cells of certain cancers, in particular small cell lung cancer, may produce ACTH which results in increased secretion of cortisol by the adrenal gland and Cushing syndrome.

Question 20

Blood pressure equation?

Answer 20

BP = TPR x CO

Question 21

What is the main determinant of TPR?

Answer 21

The calibre (diameter) of arterioles

Question 22

What is the main determinant of CO?

Answer 22

Circulatory volume (determined by renal sodium handling)

In general, factors which cause an increase in Na+ retention by the kidneys will tend to raise blood pressure.
• This is because sodium and water reabsorption by the kidneys is coupled i.e. an increase in sodium reabsorption will also cause an increase in water reabsorption. The increase in water reabsorption results in an increase in circulatory volume, thus raising blood pressure. [Remember that cardiac output = stroke volume x heart rate. In a physiological setting, the stroke volume is determined mainly by the circulatory volume].

Question 23

Primary hyperaldosteronism

Answer 23

Primary hyperaldosteronism refers to excess aldosterone production by the adrenal cortex.
It is usually caused by:
• Either bilateral idiopathic adrenal hyperplasia. It used to be thought this was an uncommon cause but is now thought to account for 60-70% of cases.
• Or by an aldosterone-producing adrenal cortical adenoma. This is Conn’s syndrome and accounts for about 30-40% of cases of primary aldosteronism.

Question 24

What is the physiological function of aldosterone?

Answer 24

Aldosterone is a key component of the renin-angiotensin-aldosterone (RAA) system.
The physiological function of the RAA system is to regulate fluid balance and blood pressure.
Normally, if blood pressure falls for some reason, there is reduced blood flow in the renal artery. This stimulates the release of renin from the kidney which leads to the production of angiotensin II. Angiotensin II has a number of effects which help raise the blood pressure back to normal:
• It stimulates the release of aldosterone from the adrenal cortex. Aldosterone increases sodium (and water) reabsorption by the kidney tubules, which increases blood volume and raises blood pressure.
• It causes vasoconstriction of systemic arterioles, which raises blood pressure.
• It stimulates release of ADH by posterior pituitary which stimulates reabsorption of water.
The restoration of normal blood pressure and normal blood flow through the renal artery causes a reduction in the secretion of renin and thus down-regulation of the RAA system (i.e. negative feedback).

Question 25

What is the effect of hyperaldosteronism?

Answer 25

In hyperaldosteronism there is breakdown of the normal negative feedback loop so that there is excess (i.e. inappropriately high) aldosterone circulating in the blood.
This causes excess sodium and water reabsorption by the kidneys and vasoconstriction of systemic arterioles. The net result is high blood pressure.

Question 26

What does excess aldosterone result in?

Answer 26

Excess aldosterone results in:

• Excess Na+ reabsorption into blood –> Hypernatraemia
• Excess K+ loss into urine –> hypokalaemia

The excess Na+ retention results in excess H20 reabsorption –> increased circulatory volume –> increased CO –> Increased BP.

Question 27

Phaeochromocytoma

Answer 27

Neuroendocrine tumour of the adrenal medulla.

The tumour secretes excessive amounts of catecholamines (usually adrenaline) and causes high blood pressure.

Excess catecholamines –> Increased vasoconstriction and heart rate –> increased TPR and CO –> Increased BP.

Question 28

Clinical features of phaemochromocytoma?

Answer 28

Usually they are asymptomatic, but some patients may report symptoms related to episodic increases in circulation catecholamines such as throbbing headache, sweating and palpitations

Question 29

Why is its important to identify phaeochromocytoma?

Answer 29

It is important to identify phaeochromocytoma because it is a treatable cause of hypertension.

Question 30

What is the investigation and treatment of phaeochromocytoma?

Answer 30

A patient’s blood pressure often returns to normal following surgical excision.
• The specific investigation is a 24hr urine collection for catecholamine and metanephrine measurement. Refer to clinical chemistry for further details.

Question 31

What is the rule of 10 in phaeochromocytoma?

Answer 31

“Rule of 10s” which apply to phaeochromocytomas:
- 10% are extra-adrenal i.e. they occur outside the adrenal gland in sites such as the carotid body. By convention, extra-adrenal tumours are usually called paragangliomas (rather than phaeochromocytomas).
- 10% are bilateral
- 10% behave in a malignant fashion i.e. they invade adjacent tissues and metastasise.
10% are not associated with hypertension

Question 32

What germline mutations are phaeochromocytoma associated with?

Answer 32

Historically, it was thought that about 10% of phaeochromocytomas occurred as part of familial syndrome. However it is now recognised that up to 25-30% of cases are familial i.e. they are associated with germline mutations in certain genes:
- RET gene (which causes MEN type 2)
- NF1 gene (which causes neurofibromatosis type 1)
- VHL gene (which causes von Hippel-Lindau disease)
SDHB, SDHC and SDHD genes (three genes encoding subunits within the succinate dehydrogenase complex. SDH is involved in mitochondrial electron transport and oxygen sensing).