Laboratory Investigation of Endocrine Disorders

Question 1

Briefly describe hypothalamic-pituitary-thyroid axis

Answer 1

Circulating TH levels under negative feedback control at hypothalamic and pituitary levels

Synthesis and release of TH controlled by TSH

T4 main hormone secreted by thyroid, T3 is more biologically active – mostly formed by peripheral conversion from T4

Question 2

Thyroid hormones - use

Answer 2

Essential for normal growth and development

Question 3

Thyroid hormones - effect

Answer 3

Increase basal metabolic rate (BMR) and affect many metabolic processes

Effects are mediated via activation of nuclear receptor

Question 4

Thyroid hormones - synthesis

Answer 4

Synthesized in thyroid via series of enzyme catalysed reactions, beginning with uptake of iodine into gland

Synthesis and release controlled by TSH

Question 5

Thyroid hormones - T3 vs T4

Answer 5

T4 main hormone secreted by thyroid, T3 is more biologically active – mostly formed by peripheral conversion from T4

Question 6

Disorders of thyroid function - describe the names

Answer 6

Terminology: euthyroid (normal range), hypothyroid (below), hyperthyroid (above)

Primary hyper/hypothyroidism: dysfunction is in thyroid gland

Secondary: problem is with pituitary or hypothalamus (tertiary)

Question 7

Hyperthyroidism - define

Answer 7

Excessive production of thyroid hormones (thyrotoxicosis)

Question 8

Hyperthyroidism - clinical features

Answer 8

Weight loss, heat intolerance, palpitations, goitre, eye changes (Graves)
In extreme: thyroid storm

Question 9

Causes of hyperthyroidism

Answer 9

Graves disease (most common)
  - due to stimulatory TSH-R antibodies
Toxic multinodular goiter
Toxic adenoma
Secondary: excess TSH production (rare)

Question 10

Hypothyroidism - define

Answer 10

Deficient production of thyroid hormones

Question 11

Hypothyroidism - clinical features

Answer 11

Clinical features

weight gain, cold intolerance, lack of energy, goitre

congenital - developmental abnormalities

Question 12

Hypothyroidism - investigations

Answer 12

Raised TSH, reduced fT4

Reduction in TSH and T4 suggests secondary (hypopituitarism)

Question 13

Causes of hypothyroidism

Answer 13

Autoimmune thyroiditis (Hashimoto’s)
- thyroid peroxidase antibodies (anti-TPO)
Iodine defficiency
Toxic adenoma
Secondary – lack of TSH

Question 14

Describe functional zonation of cortex

Answer 14

Blood flows from outer cortex to inner medulla

Layer-specific enzymes; steroid synthesis in one layer can inhibit different enzymes in subsequent layers

Results in functional zonation of cortex with different hormones made in each layer

Question 15

CYP21A - function and deficiency

Answer 15

CYP21A is the gene for 21-hydroxylase. It’s deficiency is the major cause of congenital adrenal hyperplasia.

Question 16

Mineralocorticoids: action

Answer 16

Mineralocorticoids: salt and water balance in order to maintain plasma volume: maintenance of blood pressure over the long term

Question 17

Glucocorticoids: action

Answer 17

Glucocorticoids: metabolism and immune function

Stress increases release, but minimal levels essential for normal function

Question 18

Control of adrenal steroid secretion - list

Answer 18

Cortisol: synthesis and release regulated by hypothalamic-pituitary-adrenal axis (CRH, ACTH)

Aldosterone: controlled by RAAS

Adrenal androgens: ACTH (not gonadotropins)

Question 19

Explain effect on cortisol reading due to its rhythm

Answer 19

Cortisol secretion fluctuates in a circadian rhythm, which means a random plasma cortisol reading cannot exclude abnormality, unless way outside of normal range.

Question 20

Hyper-function of the adrenal cortex

Answer 20

Aldosterone excess:
Conn’s syndrome

Cortisol excess:
Cushing’s syndrome

Question 21

What could cause hyperaldosteronism

Answer 21

Possibilities: renal artery stenosis, renin-producing tumour (reninoma – rare, but well-described), anything that stimulates RAAS.

Question 22

Dexamethasone suppresion test - high vs low dose comparison

Answer 22

Dexamethasone: exogenous steroid

Low doses will normally supress ACTH secretion via negative feedback

Low dose fails to supress ACTH secretion with pituitary disease (Cushing’s)

Higher dose will supress ACTH secretion in Cushing’s

No supresssion with low or high dose: suggests ectopic source of ACTH (e.g., tumour elsewhere

Question 23

Cushing’s disease - dexamethasone suppression test + plasma ACTH result

Answer 23

DST:
Low dose = no suppression
High dose = suppression

Plasma ACTH = high

Question 24

Adrenal tumour disease - dexamethasone suppression test + plasma ACTH result

Answer 24

DST:
Low dose = no suppression
High dose = no suppression

Plasma ACTH = low

Question 25

Ectopic ACTH - dexamethasone suppression test + plasma ACTH result

Answer 25

DST:
Low dose = no suppression
High dose = no suppression

Plasma ACTH = very high

Question 26

Adrenocortical insufficiency - primary vs secondary

Answer 26

Primary adrenocortical failure – Addison’s disease (typically autoimmune)

Secondary – impaired ACTH release
Head trauma, tumour, surgery
Abrupt steroid withdrawal

Question 27

Addison’s disease effects

Answer 27

Loss of:
Cortisol
Androgens
Aldosterone

High ACTH

Question 28

Addison’s disease - action

Answer 28

Loss of –ve fb from cortisol will compromise the VP system

Question 29

Addison’s disease - cause

Answer 29

Usually autoimmune

Question 30

Dynamic tests of adrenal function - purpose

Answer 30

Assess ability of adrenal to produce cortisol in response to ACTH

Question 31

Describe short synacthen test

Answer 31

Measure baseline cortisol (9am) and 30 min after 250 µg synacthen (synthetic ACTH) i.m.

Adrenal insufficiency is excluded by an increase in cortisol of >200 nmol/L and/or a 30 min value >550

Question 32

Describe longs ynacthen test

Answer 32

Adrenal cortex ‘shuts down’ in absence of stimulation by ACTH – time needed to regain responsiveness

3-day stimulation with i.m. synacthen

In secondary (but not primary) adrenal insufficiency cortisol increases by >200 nmol/L over baseline

Long test not often necessary since ACTH assay can distinguish