內分泌代謝・OET 待命 24 小時

Glucose homeostasis depends on the coordinated, opposing actions of insulin and glucagon, both secreted within the pancreatic islets. Beta cells release insulin, which drives glucose into muscle and fat and suppresses hepatic gluconeogenesis. Alpha cells release glucagon, which mobilises hepatic glycogen and raises glucose. Glucagon can therefore be used to treat severe hypoglycaemia; its glucose-raising action does not make it a treatment for hyperglycaemia. Diabetes is diagnosed when fasting glucose is at least 7.0 mmol/L, a two-hour or random value reaches 11.1 mmol/L, or HbA1c reaches 6.5 per cent. Type 1 disease is autoimmune insulitis with absolute insulin deficiency and antibodies to GAD65 and IA-2. Type 2 disease is insulin resistance with relative deficiency, and islet amyloid derived from amylin fills the islets of most patients.

Insulin resistance rarely travels alone. The metabolic syndrome is diagnosed when three of five features coexist: central obesity, raised triglycerides, low HDL cholesterol, raised blood pressure and impaired fasting glucose. LDL cholesterol is deliberately absent from the list. Insulin resistance changes the quality of lipoproteins, producing small dense LDL particles, rather than raising the LDL concentration. Consequently, a waist of 108 centimetres, triglycerides of 2.4 mmol/L and HDL of 0.9 mmol/L announce the syndrome before glucose rises far.

Metformin remains first line because it suppresses hepatic glucose output without provoking hypoglycaemia. Its hazards are lactic acidosis in renal failure, so it is withheld around iodinated contrast and avoided below an eGFR of 30, and vitamin B12 deficiency after years of use. The choice of the second agent is now decided by the organs at risk rather than by HbA1c alone. SGLT2 inhibitors and GLP-1 receptor agonists reduce weight and protect the kidney and heart, whereas DPP-4 inhibitors are weight neutral. Sulfonylureas carry the highest hypoglycaemia risk, pioglitazone is contraindicated in heart failure, and thiazide diuretics raise glucose without ever causing hypoglycaemia.

The earliest sign of diabetic kidney disease is microalbuminuria, detected as an albumin-to-creatinine ratio above 2.5 mg/mmol in men and 3.5 mg/mmol in women. At this stage creatinine and eGFR are still normal, and an ACE inhibitor or angiotensin receptor blocker slows progression. Retinopathy is screened by retinal photography, neuropathy by the ten-gram monofilament, and vessels are protected by blood pressure below 130/80 mmHg and LDL below 1.8 mmol/L. When a diabetic foot ulcer overlies bone, bone biopsy rather than a surface swab remains the gold standard for osteomyelitis.

Targets must fit the person. A general adult aims for an HbA1c below 7.0 per cent, and a young patient with short disease duration may aim below 6.5. A frail octogenarian is safer at 8.0 to 8.5 per cent, because hypoglycaemia causes falls, arrhythmias and cognitive harm. Hypoglycaemia itself is most often caused by sulfonylureas or insulin, not by insulinoma. The conscious patient takes fifteen grams of glucose and rechecks in fifteen minutes; the unconscious patient receives intravenous dextrose or intramuscular glucagon. C-peptide separates the causes: it is high with insulinoma and low when insulin has been injected.

The central distinctions can be recalled as follows.

All patients with albuminuria or heart failure gain kidney and heart protection from an SGLT2 inhibitor, independent of HbA1c.
Is the glucose near normal yet the patient vomiting on empagliflozin? Suspect euglycaemic ketoacidosis and stop the drug on sick days.
On the diagnostic list for metabolic syndrome sit waist, triglycerides, HDL, blood pressure and fasting glucose, never LDL.
Lucid targets protect: HbA1c below 7 per cent for most adults, but 8.0 to 8.5 for the frail elderly, because hypoglycaemia harms faster.

The thyroid secretes predominantly thyroxine, or T4, much of whose physiological activity depends on its conversion to the more potent hormone T3. Peripheral deiodinase removes one iodine to make T3, roughly three to four times more potent. In starvation or critical illness the enzyme instead produces inactive reverse T3, so T3 falls while reverse T3 rises. This sick euthyroid pattern needs no thyroid replacement. Hormone excess accelerates every system, bringing weight loss, heat intolerance, tremor and atrial fibrillation. Deficiency slows everything, producing weight gain, bradycardia, delayed reflex relaxation and non-pitting myxoedema.

Two axes sort almost every thyroid result. In primary disease TSH and free T4 move in opposite directions. In central disease they move together, or TSH sits inappropriately within the normal range while free T4 is low. Consequently, a lone TSH cannot exclude pituitary failure, and central replacement is titrated to free T4. Hashimoto thyroiditis carries anti-thyroid peroxidase antibodies that grind the gland down towards hypothyroidism. Graves' disease carries TSH receptor antibodies that stimulate the gland, and the same antibodies inflame orbital fibroblasts. Orbitopathy therefore runs independently of hormone levels, and smoking is its strongest modifiable risk.

Carbimazole is the first-line thionamide, usually continued for twelve to eighteen months. Propylthiouracil is reserved for the first trimester and for thyroid storm, because it also blocks peripheral conversion of T4 to T3. Fever or sore throat on either drug means stopping it and checking the neutrophil count the same day. Agranulocytosis affects roughly two to five patients per thousand, mostly within the first three months. Radioiodine is definitive but contraindicated in pregnancy and breastfeeding; conception must wait six months, and active orbitopathy may worsen. Surgery suits a compressive goitre, suspected malignancy or a pregnant patient intolerant of drugs. Established hypothyroidism in pregnancy needs a dose increase of about 25 to 30 per cent.

Thyroid storm is treated with every lever at once. Propylthiouracil is given first, and iodine follows about an hour later. Iodine given earlier would become substrate for new hormone. Propranolol controls the rate and blocks conversion, while hydrocortisone covers relative adrenal insufficiency. Amiodarone is avoided because each tablet carries a heavy iodine load. At the opposite extreme, myxoedema coma receives intravenous levothyroxine only after hydrocortisone, to avoid precipitating an adrenal crisis.

A nodule is assessed with TSH and ultrasound. A low TSH prompts a radionuclide scan for a hot nodule; otherwise suspicious features lead to fine-needle aspiration, the gold standard before surgery. Papillary carcinoma accounts for 80 to 85 per cent of cancers, shows psammoma bodies, spreads by lymphatics and has the best prognosis. Follicular carcinoma spreads by blood and cannot be diagnosed by aspiration, because malignancy depends on capsular invasion. Medullary carcinoma arises from C cells, secretes calcitonin, and belongs to MEN2 through the RET gene. Differentiated cancers are followed with thyroglobulin, medullary cancer with calcitonin and CEA.

The central distinctions can be recalled as follows.

All primary thyroid disorders move TSH and free T4 in opposite directions, whereas central disease pairs a low free T4 with an inappropriately normal TSH.
Is there fever or a sore throat on carbimazole? Stop the drug and check the neutrophil count the same day.
On the storm protocol, propylthiouracil precedes iodine by about an hour, and amiodarone is never used to control the rate.
Luminal iodine uptake is diffusely high in Graves' disease but low in painful subacute thyroiditis, which is treated with anti-inflammatories rather than thionamides.

Calcium balance reflects coordinated exchanges between bone, kidney and intestine, regulated principally by parathyroid hormone and active vitamin D. Parathyroid hormone resorbs bone, retains calcium in the kidney, excretes phosphate and activates vitamin D. Active vitamin D absorbs both calcium and phosphate from the gut. Calcitonin and FGF-23 pull the other way, and every calcium disorder leaves the residue of this contest. Because PTH and vitamin D both raise calcium but move phosphate in opposite directions, the phosphate is the second number to read. High calcium with low phosphate points to parathyroid hormone; high calcium with high phosphate tells a different story.

Primary hyperparathyroidism is a single adenoma in about 80 per cent of cases. Its signature is high calcium, low phosphate and high chloride, with a hyperchloraemic acidosis. An inappropriately raised or even normal PTH in the presence of hypercalcaemia confirms the diagnosis. Outpatient hypercalcaemia is usually parathyroid; inpatient hypercalcaemia is usually malignancy. Cancer raises calcium through PTH-related peptide, and the true PTH is suppressed. Familial hypocalciuric hypercalcaemia mimics the adenoma, but an inactivating CASR mutation keeps the urine calcium-to-creatinine clearance ratio below 0.01, and it never needs surgery. Chronic kidney disease drives secondary hyperparathyroidism with low or normal calcium and high phosphate. Once the glands become autonomous, calcium flips upward and the disease is tertiary.

The clinical picture is stones, bones, groans and psychiatric overtones. Polyuria arises from calcium-induced nephrogenic diabetes insipidus, bone pain from osteitis fibrosa cystica. Hypercalcaemia depresses neuromuscular function, causing weakness, constipation, drowsiness and a short QTc. Hypocalcaemia excites it, producing paraesthesia, tetany, Chvostek and Trousseau signs and a long QTc. Reversing these two directions is the commonest examination error.

Severe hypercalcaemia, above 3.5 mmol/L with symptoms, is an emergency, and the treatment order is a chain of logic. Dehydration lowers the filtration rate and traps calcium, so intravenous saline restores volume and flushes calcium first. Thiazides are absolutely contraindicated because they reduce urinary calcium excretion. Loop diuretics are added only for overload. Zoledronic acid treats the cause by suppressing osteoclasts, but it takes two to four days. Calcitonin acts within hours and fades within two days, so it bridges the gap. Denosumab serves refractory or renal cases, glucocorticoids treat lymphoma and granulomatous disease, and dialysis rescues the failing kidney.

Hypocalcaemia is assessed in a fixed order. Corrected calcium equals measured calcium plus 0.02 multiplied by 40 minus the albumin in grams per litre. Then PTH separates parathyroid failure from downstream causes. Then magnesium is checked, because hypomagnesaemia suppresses PTH and blocks its action, so calcium cannot be replaced until magnesium is. Alkalosis binds calcium to albumin and lowers ionised calcium, which is why hyperventilation causes tetany. Osteoporosis is diagnosed at a T-score of minus 2.5 or below, or clinically after a hip or vertebral fragility fracture. Antiresorptives suppress osteoclasts, whereas intermittent teriparatide builds bone, because continuous PTH erodes and pulsed PTH restores.

The central distinctions can be recalled as follows.

All cases of primary hyperparathyroidism show high calcium, low phosphate and high chloride with a PTH that fails to fall.
Is the PTH suppressed with a high calcium? Look for malignancy and PTH-related peptide rather than the parathyroid glands.
On the emergency ladder, saline comes first, thiazides are forbidden, calcitonin bridges the hours and zoledronic acid works in days.
Lucid rule for hypocalcaemia: correct for albumin, measure PTH, then replace magnesium before any calcium will rise.

Diabetic ketoacidosis and the hyperosmolar hyperglycaemic state share impaired insulin action, but differ in the relative contributions of ketogenesis, dehydration and hyperosmolality. Diabetic ketoacidosis arises from absolute insulin deficiency. The body behaves as if starving, lipolysis releases fatty acids, and the liver converts them into ketoacids. The hyperosmolar hyperglycaemic state arises when a little insulin remains. That remnant cannot control glucose, but it suppresses lipolysis and ketogenesis, so acidosis is absent. Glucose instead climbs above 33 mmol/L, osmotic diuresis becomes torrential, and the effective osmolality exceeds 320 mOsm/kg. Ketoacidosis is defined by a pH below 7.3, a bicarbonate below 18 mmol/L and strongly positive ketones. It is typical of type 1 disease, although type 2 patients under severe stress or on SGLT2 inhibitors are not immune.

The acid-base picture is a high anion gap metabolic acidosis with respiratory compensation. Ketoacids consume bicarbonate, and Kussmaul breathing lowers carbon dioxide to defend the pH. The expected carbon dioxide follows Winter's formula, 1.5 times the bicarbonate plus 8. A value above prediction signals a tiring patient and a mixed disorder. Two electrolytes deceive. Measured sodium is diluted as glucose draws water from cells, so it must be corrected upward before dehydration is judged. Potassium is shifted out of cells by insulin deficiency and acidosis, so the serum value is normal or high while the total body store is depleted.

Treatment therefore follows a fixed sequence: fluid, potassium, then insulin. Isotonic saline restores perfusion, one litre in the first hour. Potassium is read before insulin is started. Below 3.3 mmol/L, insulin is withheld until potassium is replaced. Between 3.3 and 5.2 mmol/L, 20 to 30 mmol is added to each litre. Above 5.2 mmol/L, none is given yet. A fixed-rate intravenous infusion of 0.1 units per kilogram per hour then follows. Oral hypoglycaemic agents have no place. Once glucose falls below about 14 mmol/L, 10 per cent dextrose is added, and the insulin continues until ketones are below 0.6 mmol/L, pH exceeds 7.3 and the anion gap has closed. Basal insulin is given before the infusion stops.

Bicarbonate is not routine. It is considered only when the pH is below 6.9, because earlier use deepens hypokalaemia, shifts the oxygen dissociation curve leftward and may paradoxically acidify the brain. Cerebral oedema is the feared complication in children and young adults. Headache, a falling heart rate with rising blood pressure and a declining conscious level demand immediate treatment. Glucose should fall by roughly 3 mmol/L per hour, never faster.

Prevention is the sick-day rule. Basal insulin is never omitted, glucose is checked every two to four hours, and ketones are measured whenever glucose exceeds 15 mmol/L or vomiting begins. Ketones above 1.5 mmol/L or an inability to keep fluids down mean hospital, not waiting. Hypoglycaemia sits at the other end of the same axis. A conscious patient takes fifteen grams of glucose and rechecks after fifteen minutes; an unconscious patient receives intravenous dextrose or intramuscular glucagon, the counter-regulatory hormone from alpha cells.

The central distinctions can be recalled as follows.

All ketoacidosis is high anion gap metabolic acidosis with Kussmaul compensation, defined by pH below 7.3, bicarbonate below 18 and positive ketones.
Is the potassium below 3.3 mmol/L? Replace it first and withhold insulin, because the serum value hides a total-body deficit.
On glucose falling below 14 mmol/L, dextrose is added and the insulin continues until the ketones, not the sugar, have cleared.
Lumen of the collecting duct overflowing with glucose defines the hyperosmolar state: glucose above 33, osmolality above 320, pH above 7.3.

The assessment of amenorrhoea in a person of reproductive age begins by excluding pregnancy before investigating other causes. Secondary amenorrhoea is defined as three months without menses in a woman who previously cycled. Primary amenorrhoea means no menarche by fifteen, or no secondary sexual characteristics by thirteen. Once pregnancy is excluded, TSH and prolactin measurements help identify common, potentially treatable endocrine causes. FSH then separates ovarian failure, where it is high, from hypothalamic or pituitary causes, where it is low. A progestogen challenge that produces a withdrawal bleed proves the presence of oestrogen and an open outflow tract.

The cycle itself runs on a single act of positive feedback. Low oestradiol in the early follicular phase suppresses FSH, whereas sustained high oestradiol before ovulation triggers the LH surge. Ovulation follows the surge by roughly ten to twelve hours, and the corpus luteum survives a fixed fourteen days unless hCG rescues it. Production is shared between two cells: LH drives theca cells to make androgens, and FSH drives granulosa cells to aromatise them into oestradiol. GnRH must arrive in pulses; continuous agonist exposure downregulates the axis, which is precisely how fibroids and precocious puberty are treated.

Polycystic ovary syndrome is a chain that starts with insulin. Hyperinsulinaemia stimulates theca androgen synthesis and suppresses hepatic SHBG, so free androgen rises, follicles arrest and ovulation fails. The Rotterdam criteria require two of three features: oligo-anovulation, clinical or biochemical hyperandrogenism, and polycystic morphology, now twenty or more follicles per ovary or a volume of ten millilitres. Obesity and insulin resistance, however common, are not criteria. Chronic anovulation leaves the endometrium under unopposed oestrogen, and hyperplasia and carcinoma follow over years.

Management follows what the woman wants. For an overweight woman not yet seeking pregnancy, weight loss of five to ten per cent is first-line and often restores ovulation. Cyclic progestogen at least every three months, or the combined pill, protects the endometrium. When conception is desired, letrozole now outperforms clomiphene for live birth, with metformin as a second-line adjunct. Hirsutism responds to the combined pill, with spironolactone added when needed.

Primary amenorrhoea is read along one axis: breasts, then hair, then uterus. Breasts without axillary or pubic hair mark complete androgen insensitivity, 46,XY, where testicular anti-Müllerian hormone has removed the uterus. Breasts and hair without a uterus mark Müllerian agenesis, 46,XX, which demands renal imaging. Without breasts, a high FSH indicates Turner syndrome and a low FSH indicates Kallmann syndrome with anosmia. Outflow obstruction such as an imperforate hymen must never be treated with progestogen to induce a bleed.

Later life brings its own rules. Menopause is confirmed by an FSH above forty with a low oestradiol, and hormone therapy adds progestogen only when a uterus remains. Postmenopausal bleeding is endometrial cancer until sampling proves otherwise, even though atrophy is the commonest cause.

All amenorrhoea is investigated with a pregnancy test before any hormone, and three months defines the secondary form.
Is the Rotterdam diagnosis made from two of three features, with obesity and insulin resistance excluded from the criteria?
On the endometrium, unopposed oestrogen from chronic anovulation causes hyperplasia, so cyclic progestogen protects it.
Luteal life is fixed at fourteen days, LH drives theca androgens, FSH drives granulosa aromatisation, and letrozole leads ovulation induction.

As lipid-soluble hormones, glucocorticoids cross cell membranes and bind intracellular receptors, linking an extracellular signal to changes in gene expression. The complex alters gene transcription and induces lipocortin, also called annexin-1, which inhibits phospholipase A2. Prostaglandin and leukotriene synthesis fall at their source, which explains an onset measured in hours rather than seconds. Long-term use resorbs bone, impairs osteoblasts and reduces intestinal calcium absorption, so osteoporosis is the commonest chronic complication. Hyperglycaemia, central obesity, cataract, impaired healing and peptic ulceration follow, and active ulceration is a contraindication.

The most dangerous consequence is silent. Exogenous cortisol suppresses ACTH, and the zona fasciculata atrophies within weeks of a course above physiological doses. Abrupt cessation, or an intercurrent illness without a dose increase, leaves no cortisol to meet the stress, and adrenal crisis follows. Because aldosterone answers to renin and potassium rather than ACTH, secondary insufficiency spares the mineralocorticoid axis: potassium remains normal and pigmentation is absent. Primary Addison's disease, by contrast, shows hyperkalaemia, salt wasting and pigmentation from the high ACTH. Treatment cannot wait for confirmation: hydrocortisone 100 mg intravenously, then 200 mg over twenty-four hours, with rapid saline. Sick-day rules then prevent recurrence, doubling the oral dose when unwell and giving intramuscular hydrocortisone if vomiting.

Normal physiology explains each of these rules. Cortisol peaks in the early morning under the suprachiasmatic clock and ACTH pulses. ACTH signals through cAMP and protein kinase A, and StAR protein, which carries cholesterol into the mitochondrion, sets the rate of all steroid synthesis. The cortex is layered salt, sugar, sex from outside inwards, and high potassium stimulates the glomerulosa directly. In 21-hydroxylase deficiency, blocked cortisol and aldosterone remove negative feedback, ACTH rises and precursors divert into androgens, giving virilisation with salt loss.

Endocrine drugs are best remembered by the station at which they act. Methimazole inhibits thyroid peroxidase and is first-line for hyperthyroidism, whereas propylthiouracil also blocks peripheral conversion of T4 to T3 and is reserved for thyroid storm and the first trimester. Bisphosphonates, denosumab, raloxifene and calcitonin all reduce resorption, whereas intermittent teriparatide is the only anabolic agent; continuous PTH, as in disease, destroys bone. Alendronate is taken fasting and upright to protect the oesophagus.

Diabetes drugs follow the same logic. Sulfonylureas close the beta-cell K-ATP channel regardless of glucose, so hypoglycaemia and weight gain follow. Repaglinide shares the mechanism but is excreted in bile and suits renal impairment. Metformin suppresses hepatic gluconeogenesis and risks lactic acidosis with alcohol. GLP-1 agonists must be injected and reduce weight. SGLT2 inhibitors now treat heart failure and chronic kidney disease, yet they are withheld before surgery to prevent euglycaemic ketoacidosis. No oral agent treats type 1 diabetes.

Selective oestrogen receptor modulators differ by tissue: clomiphene blocks hypothalamic receptors to raise gonadotrophins, tamoxifen antagonises the breast but stimulates the endometrium, and raloxifene spares the uterus. Growth hormone deficiency receives somatropin, Laron syndrome receives IGF-1, and acromegaly receives octreotide, never growth hormone.

All long-term glucocorticoid courses suppress ACTH, so they are tapered slowly and doubled on sick days.
Is the potassium normal and the skin unpigmented? Then the insufficiency is secondary, because aldosterone still answers to renin.
On suspicion of adrenal crisis, hydrocortisone 100 mg intravenously precedes the cortisol result, followed by 200 mg over twenty-four hours.
Lumbar bone density falls fastest on glucocorticoids, so alendronate reduces resorption while intermittent teriparatide alone builds bone.

Two principal cellular lineages provide a useful framework for understanding the major thyroid carcinomas: follicular epithelial cells and parafollicular C cells. Follicular epithelium gives rise to papillary, follicular and, by dedifferentiation, anaplastic carcinoma. Parafollicular C cells stand apart and produce medullary carcinoma. Papillary carcinoma, the commonest, is diagnosed by nuclear features: ground-glass chromatin, grooves and intranuclear pseudoinclusions, often with psammoma bodies and a BRAF V600E mutation. Prominent nucleoli are not among them. Follicular carcinoma looks identical to adenoma on cytology, so capsular or vascular invasion on histology, not aspiration, separates the two. Anaplastic carcinoma presents as a rapidly enlarging hard mass in an older patient and carries TP53 mutations.

Medullary carcinoma behaves as its lineage predicts. C cells secrete calcitonin, deposit amyloid in the stroma, spread mainly through lymphatics and never trap iodine, so radioiodine is useless and calcitonin with CEA becomes the follow-up marker. Thyroglobulin serves the follicular-derived tumours instead. About a quarter of medullary cancers are hereditary, driven by germline RET mutations. MEN2A combines medullary carcinoma, phaeochromocytoma and parathyroid hyperplasia; MEN2B combines medullary carcinoma, phaeochromocytoma and mucosal neuromas with a marfanoid habitus, but spares the parathyroids. One rule is absolute: phaeochromocytoma must be excluded or treated before the thyroid is removed, or catecholamine release under anaesthesia will provoke a hypertensive crisis.

The parathyroids are read along three axes: calcium, phosphate and PTH. PTH keeps calcium in and drives phosphate out. Primary hyperparathyroidism, usually a single adenoma, therefore shows high calcium, low phosphate and high PTH, with a tendency to hyperchloraemic acidosis. Secondary hyperparathyroidism in chronic kidney disease shows low or normal calcium, high phosphate and a compensatory high PTH. When years of stimulation make the glands autonomous, calcium flips from low to high and tertiary disease has arrived. Malignancy raises calcium through PTHrP or bone metastases, and PTH is suppressed, which separates it from every parathyroid cause. Cinacalcet sensitises the calcium-sensing receptor, so PTH and calcium both fall.

Removing or bruising the parathyroids reverses the equation. After thyroidectomy, calcium falls while phosphate rises, nerves become hyperexcitable, and perioral tingling, Chvostek's and Trousseau's signs and carpopedal spasm appear, sometimes with a prolonged QT interval. Symptomatic hypocalcaemia receives intravenous calcium gluconate on a monitor, followed by oral calcium and calcitriol. Magnesium must be checked, because hypomagnesaemia blocks PTH release. Laryngospasm and haematoma both threaten the airway.

The rest of the head and neck follows similar rules. Thymoma accompanies myasthenia gravis, and thymic carcinoma is usually squamous. Pleomorphic adenoma, the commonest salivary tumour, contains chondromyxoid stroma, whereas Warthin tumour shows oncocytic epithelium with lymphoid stroma and is linked to smoking. Mucoepidermoid carcinoma, not squamous carcinoma, is the commonest salivary malignancy. Nasopharyngeal carcinoma is driven by Epstein-Barr virus, oropharyngeal carcinoma by HPV-16 with a better prognosis, and erythroplakia carries a far higher malignant risk than leukoplakia.

All medullary thyroid carcinomas arise from C cells, secrete calcitonin, deposit amyloid and ignore radioiodine.
Is the RET mutation germline? Then MEN2 is present, and phaeochromocytoma is excluded before any thyroid surgery.
On the three axes, primary hyperparathyroidism reads high calcium and low phosphate, secondary reads low calcium and high phosphate.
Lumps aside, the glands behind the thyroid keep calcium in and phosphate out, so their loss brings tetany treated with calcium gluconate.