Endocrinology
1. What this chapter covers, and how NEET PG actually tests it
Endocrine stems give a set of hormone values, or a clinical picture with one abnormal result, and ask for the level of the lesion or the next test.
The organising principle is that you never interpret a hormone alone; you interpret it against its trophic partner.
| Target hormone | Trophic hormone | Interpretation |
|---|---|---|
| Low | High | Primary gland failure |
| Low | Low or normal | Secondary, pituitary or hypothalamic failure |
| High | Low | Autonomous gland, primary excess |
| High | High or normal | Secondary excess, or resistance |
A normal trophic hormone in the presence of an abnormal target hormone is never reassuring, because the trophic hormone should have moved in the opposite direction. An inappropriately normal value is functionally an abnormal one, and that reasoning is examined constantly.
2. Thyroid
2.1 Interpreting the tests
Thyroid stimulating hormone is the first test because the pituitary responds logarithmically to small changes in free thyroxine, so it moves before the peripheral hormone leaves the reference range.
| Pattern | Diagnosis |
|---|---|
| High stimulating hormone, low thyroxine | Primary hypothyroidism |
| High stimulating hormone, normal thyroxine | Subclinical hypothyroidism |
| Low stimulating hormone, high thyroxine | Primary hyperthyroidism |
| Low stimulating hormone, low thyroxine | Secondary hypothyroidism |
Autoimmune thyroiditis is the commonest cause of hypothyroidism where iodine intake is sufficient, and iodine deficiency remains the commonest cause worldwide.
2.2 Hyperthyroidism
Graves disease gives a diffuse goitre with a bruit, ophthalmopathy and pretibial myxoedema, none of which occurs in other causes, and it is confirmed by stimulating hormone receptor antibodies.
Radioiodine uptake separates the causes into two groups, and this is the single most useful discriminator.
| High uptake | Low uptake |
|---|---|
| Graves disease | Subacute thyroiditis |
| Toxic multinodular goitre | Silent and postpartum thyroiditis |
| Toxic adenoma | Exogenous thyroxine ingestion |
Low uptake means the thyroid is not making hormone but releasing preformed hormone from damaged follicles, or the hormone is coming from outside, so antithyroid drugs are useless in that group.
Subacute thyroiditis is painful with a raised erythrocyte sedimentation rate and follows a viral illness, and it is self-limiting with a hypothyroid phase before recovery.
Thyroid storm is precipitated by infection, surgery or iodine load and is treated with a beta blocker, a thionamide, iodine given at least an hour after the thionamide, and corticosteroid.
The order matters: iodine given first would provide substrate for hormone synthesis, so the thionamide must block synthesis before iodine is administered.
2.3 Nodules and cancer
| Type | Feature |
|---|---|
| Papillary | Commonest; lymphatic spread; Orphan Annie nuclei and psammoma bodies |
| Follicular | Haematogenous spread; diagnosis requires capsular or vascular invasion |
| Medullary | Parafollicular C cells; calcitonin; associated with multiple endocrine neoplasia type 2 |
| Anaplastic | Elderly, rapidly fatal |
Fine needle aspiration cannot distinguish follicular adenoma from carcinoma, because the distinction rests on capsular and vascular invasion, which requires the whole capsule and therefore excision.
2.4 Thyroid disease in pregnancy
Propylthiouracil is used in the first trimester and carbimazole thereafter, which is one of the few instances in medicine where a drug is deliberately switched mid-pregnancy.
The reason is that carbimazole carries a small risk of specific fetal malformations during organogenesis, while propylthiouracil carries a risk of maternal hepatotoxicity that accumulates with duration of use.
Each drug is therefore used during the period when its particular hazard matters least.
Untreated maternal hypothyroidism impairs fetal neurodevelopment, so thyroxine requirements rise by roughly a quarter to a third in early pregnancy and the dose is increased as soon as pregnancy is confirmed rather than waiting for a test result.
3. Diabetes
3.1 Diagnosis
| Test | Diagnostic threshold | Prediabetes |
|---|---|---|
| Fasting plasma glucose | 126 mg/dL or above | 100 to 125 |
| Two-hour value on tolerance test | 200 mg/dL or above | 140 to 199 |
| Glycated haemoglobin | 6.5 per cent or above | 5.7 to 6.4 |
| Random glucose with symptoms | 200 mg/dL or above | Not applicable |
A single abnormal result requires confirmation unless the patient has unequivocal symptoms with a random value above the threshold.
Glycated haemoglobin is misleading whenever red cell lifespan is altered, so it is falsely low in haemolysis and blood loss and falsely high in iron deficiency.
3.2 Management
Metformin remains first-line, and it acts chiefly by reducing hepatic gluconeogenesis rather than by stimulating insulin.
Two newer classes are now chosen for their organ protection rather than their glucose lowering.
Sodium-glucose cotransporter 2 inhibitors are indicated where there is chronic kidney disease or heart failure, and glucagon-like peptide 1 agonists where there is obesity or established atherosclerotic disease.
Screening for complications follows a fixed schedule: annual retinal examination, urinary albumin-to-creatinine ratio and foot examination, beginning at diagnosis in type 2 and after five years in type 1.
The foot examination checks pulses, protective sensation and skin integrity together, because ulceration requires neuropathy and ischaemia rather than either alone.
Loss of protective sensation is what allows an ulcer to form unnoticed, so a patient who cannot feel a monofilament is at risk regardless of how good the circulation is.
Glycated haemoglobin targets are individualised rather than universal, being tighter in the young with long life expectancy and looser in the elderly, where hypoglycaemia causes more harm than modest hyperglycaemia.
The difference in timing exists because type 2 diabetes has usually been present for years before it is diagnosed, whereas the onset of type 1 is abrupt and known.
3.3 The acute emergencies
| Feature | Diabetic ketoacidosis | Hyperosmolar state |
|---|---|---|
| Typical glucose | Above 250 mg/dL | Above 600 mg/dL |
| Ketones | Marked | Minimal |
| pH | Below 7.3 | Above 7.3 |
| Osmolality | Variable | Above 320 |
| Usual type | Type 1 | Type 2 |
Management in both begins with fluid, not insulin, because the deficit is largely volume and starting insulin first drives glucose and water into cells and worsens circulatory collapse.
Potassium must be checked before insulin is started, and insulin is withheld if the level is below 3.3, because insulin drives potassium intracellularly and can precipitate fatal arrhythmia in a patient whose total body potassium is already depleted.
The serum potassium in ketoacidosis is typically normal or high on presentation despite a large total body deficit, because acidosis shifts potassium out of cells.
3.4 Insulin and the morning hyperglycaemia problem
Basal insulin covers the fasting state and prandial insulin covers meals, and the pattern of hyperglycaemia identifies which is inadequate.
A raised fasting glucose with acceptable postprandial values indicates insufficient basal cover, while the reverse indicates insufficient prandial cover.
Morning hyperglycaemia has two opposite causes and the treatment differs completely.
| Phenomenon | Mechanism | Three-in-the-morning glucose | Action |
|---|---|---|---|
| Dawn phenomenon | Overnight surge in growth hormone and cortisol | Normal or high | Increase evening basal insulin |
| Somogyi effect | Nocturnal hypoglycaemia with counter-regulatory rebound | Low | Reduce evening basal insulin |
Measuring the glucose in the early hours is what distinguishes them, and increasing insulin in a patient with the Somogyi effect makes the morning reading worse rather than better.
Maturity-onset diabetes of the young should be suspected in a young non-obese patient with a strong autosomal dominant family history and no autoantibodies, since some subtypes respond to sulfonylureas rather than requiring insulin.
4. Adrenal
4.1 Cortisol excess
Screening uses the overnight low-dose dexamethasone suppression test, twenty-four hour urinary free cortisol or late-night salivary cortisol, and two abnormal results are required.
Once excess is established, corticotropin localises the lesion.
| Corticotropin | Source |
|---|---|
| Suppressed | Adrenal tumour, or exogenous steroid |
| Raised | Pituitary adenoma or ectopic secretion |
High-dose dexamethasone then separates the two raised-corticotropin causes, because a pituitary adenoma retains some feedback sensitivity and suppresses, while an ectopic source does not.
Exogenous corticosteroid is by far the commonest cause of Cushing syndrome overall, and it is the first thing to exclude.
4.2 Cortisol deficiency and other adrenal disease
Addison disease gives hyperpigmentation, hyponatraemia, hyperkalaemia and postural hypotension, and the short corticotropin stimulation test confirms it.
Hyperpigmentation occurs only in primary adrenal failure, because it requires the high corticotropin that arises when the adrenal cannot respond, and its absence in a hypoadrenal patient points to pituitary disease.
Congenital adrenal hyperplasia is most often twenty-one hydroxylase deficiency, producing raised seventeen hydroxyprogesterone with salt wasting and virilisation.
The two rarer forms cause hypertension rather than salt loss, because the blocked pathway accumulates mineralocorticoid precursors instead of losing them.
Phaeochromocytoma is diagnosed by plasma free metanephrines, and alpha blockade must precede beta blockade, since unopposed alpha stimulation after beta blockade causes a hypertensive crisis.
Primary hyperaldosteronism presents as hypertension with hypokalaemia and is screened by the aldosterone to renin ratio, in which aldosterone is high while renin is suppressed.
5. Pituitary and posterior pituitary
Acromegaly is screened with insulin-like growth factor 1 and confirmed by failure of growth hormone to suppress during a glucose tolerance test.
A random growth hormone level is useless because secretion is pulsatile, which is why an integrated measure is used instead.
Prolactinoma is the one pituitary tumour treated medically first, since dopamine agonists shrink even large tumours, whereas other pituitary macroadenomas are managed surgically.
Any pituitary stalk lesion raises prolactin modestly by removing dopaminergic inhibition, so a mildly raised prolactin does not by itself indicate a prolactinoma.
| Feature | Diabetes insipidus | Syndrome of inappropriate antidiuresis |
|---|---|---|
| Serum sodium | High | Low |
| Urine osmolality | Inappropriately low | Inappropriately high |
| Volume status | Dehydrated | Euvolaemic |
Central and nephrogenic diabetes insipidus are separated by the response to desmopressin, which concentrates the urine only when the kidney can still respond.
The syndrome of inappropriate antidiuresis is a diagnosis of exclusion, requiring normal thyroid, adrenal and renal function, since hypothyroidism and cortisol deficiency both produce an identical biochemical picture.
That exclusion matters clinically as well as academically, because treating an undiagnosed adrenal insufficiency with fluid restriction rather than steroid is dangerous.
Chronic hyponatraemia must be corrected slowly, because rapid correction causes osmotic demyelination, and the brain that has adapted over days cannot readapt over hours.
The reverse error is equally harmful: acute severe hyponatraemia with seizures requires prompt hypertonic saline, since the risk of cerebral oedema then outweighs the risk of demyelination.
6. Calcium and the parathyroids
| Type | Calcium | Parathyroid hormone | Setting |
|---|---|---|---|
| Primary | High | High or inappropriately normal | Adenoma |
| Secondary | Low or normal | High | Chronic kidney disease, vitamin D deficiency |
| Tertiary | High | High | Long-standing secondary becoming autonomous |
Primary hyperparathyroidism is most often found incidentally on a routine calcium measurement rather than through the classical presentation of stones, bones, abdominal groans and psychic moans.
Malignancy is the commonest cause of hypercalcaemia in hospital inpatients, and it suppresses parathyroid hormone, which separates it immediately from primary hyperparathyroidism.
Hypocalcaemia produces perioral tingling, carpopedal spasm, and the Chvostek and Trousseau signs, and the commonest cause is inadvertent parathyroid damage during thyroid surgery.
Serum calcium must be corrected for albumin, since roughly half of circulating calcium is protein bound and only the ionised fraction is active, so a hypoalbuminaemic patient can appear hypocalcaemic while being physiologically normal.
6.1 Osteoporosis
Osteoporosis is defined densitometrically by a T score of minus 2.5 or below at the hip or spine, with osteopenia between minus 1 and minus 2.5.
The T score compares the patient with a young adult peak, while the Z score compares them with age-matched peers, and a markedly low Z score is what suggests a secondary cause rather than ordinary age-related loss.
Bone mineral density is normal in osteomalacia, which is a mineralisation defect rather than a loss of bone, and the two are separated by the alkaline phosphatase and the vitamin D level rather than by densitometry.
Bisphosphonates remain first-line treatment, and they work by inhibiting osteoclast-mediated resorption rather than by stimulating bone formation.
Adequate calcium and vitamin D are required alongside any antiresorptive agent, because suppressing resorption without providing substrate can precipitate hypocalcaemia.
7. The multiple endocrine neoplasia syndromes
| Syndrome | Components |
|---|---|
| Type 1 | Parathyroid, pancreatic islet, pituitary |
| Type 2A | Medullary thyroid carcinoma, phaeochromocytoma, parathyroid |
| Type 2B | Medullary thyroid carcinoma, phaeochromocytoma, marfanoid habitus, mucosal neuromas |
Both type 2 syndromes involve medullary thyroid carcinoma and phaeochromocytoma, and the third component distinguishes them.
In any patient with medullary thyroid carcinoma, phaeochromocytoma must be excluded before surgery, because operating on an unrecognised phaeochromocytoma precipitates a hypertensive crisis.
8. Worked examples
Example 1. A patient has low thyroxine with a thyroid stimulating hormone in the middle of the reference range. What does this indicate?
Secondary hypothyroidism. A low thyroxine should have driven the stimulating hormone up, so a normal value is inappropriately normal and indicates pituitary or hypothalamic failure.
Example 2. A thyrotoxic patient has a painful gland, raised sedimentation rate and low radioiodine uptake. What is the treatment?
Not antithyroid drugs. This is subacute thyroiditis, with release of preformed hormone from a damaged gland rather than excess synthesis, so treatment is a beta blocker and an anti-inflammatory while it resolves.
Example 3. A patient in ketoacidosis has a serum potassium of 3.0. What must be done before insulin?
Potassium replacement. Insulin drives potassium into cells, and starting it at this level can precipitate fatal arrhythmia in a patient whose total body potassium is already severely depleted.
Summary
Never interpret a hormone alone; interpret it against its trophic partner.
An inappropriately normal trophic hormone is functionally abnormal, since it should have moved the other way.
Thyroid stimulating hormone is the first test because it moves before thyroxine leaves the reference range.
Autoimmune thyroiditis causes most hypothyroidism where iodine is sufficient; iodine deficiency causes most worldwide.
Graves gives a diffuse goitre with ophthalmopathy and pretibial myxoedema, which no other cause produces.
Radioiodine uptake divides thyrotoxicosis into synthesis excess and release of preformed hormone.
Antithyroid drugs are useless in the low-uptake group.
In thyroid storm the thionamide precedes iodine by at least an hour, or iodine would supply substrate.
Papillary carcinoma spreads by lymphatics; follicular by blood, and needs excision because invasion cannot be seen on aspiration.
Diabetes is diagnosed at a fasting glucose of 126, a two-hour value of 200, or a glycated haemoglobin of 6.5 per cent.
Glycated haemoglobin is falsely low in haemolysis and falsely high in iron deficiency.
Metformin remains first line and acts mainly by reducing hepatic gluconeogenesis.
Sodium-glucose cotransporter 2 inhibitors are chosen for kidney disease and heart failure, and glucagon-like peptide 1 agonists for obesity and atherosclerotic disease.
Complication screening starts at diagnosis in type 2 and after five years in type 1, because type 2 has been present unrecognised.
Both diabetic emergencies begin with fluid, not insulin.
Potassium is checked before insulin and replaced first if below 3.3.
Serum potassium is normal or high in ketoacidosis despite a large total body deficit.
Cushing screening needs two abnormal tests, then corticotropin localises the lesion.
High-dose dexamethasone suppresses a pituitary adenoma but not an ectopic source.
Exogenous steroid is the commonest cause of Cushing syndrome overall.
Hyperpigmentation occurs only in primary adrenal failure, because it requires high corticotropin.
Twenty-one hydroxylase deficiency causes salt wasting; the rarer forms cause hypertension.
Alpha blockade must precede beta blockade in phaeochromocytoma.
Acromegaly is screened with insulin-like growth factor 1, since random growth hormone is pulsatile and useless.
Prolactinoma is the one pituitary tumour treated medically first.
Malignant hypercalcaemia suppresses parathyroid hormone, separating it from primary hyperparathyroidism.
Both multiple endocrine neoplasia type 2 syndromes include medullary thyroid carcinoma and phaeochromocytoma.
Exclude phaeochromocytoma before operating on medullary thyroid carcinoma.
Propylthiouracil is used in the first trimester and carbimazole thereafter, each avoiding the period when its own hazard matters most.
Thyroxine requirements rise by a quarter to a third in early pregnancy and the dose is increased as soon as pregnancy is confirmed.
Morning hyperglycaemia is dawn phenomenon if the three-in-the-morning glucose is normal or high, and Somogyi effect if it is low.
Osteoporosis is a T score of minus 2.5 or below, while a low Z score suggests a secondary cause.
Bone density is normal in osteomalacia, which is a mineralisation defect rather than bone loss.
Correct serum calcium for albumin, since only the ionised fraction is physiologically active.
Inappropriate antidiuresis is a diagnosis of exclusion, since hypothyroidism and cortisol deficiency mimic it exactly.
Chronic hyponatraemia is corrected slowly to avoid osmotic demyelination, but acute hyponatraemia with seizures needs prompt hypertonic saline.
