Parathyroid glands

What it normally does

• The hormone-making cells of the parathyroid (chief cells) read blood calcium directly, through a G-protein coupled receptor sitting on their surface [calcium-sensing receptor, CaSR]. It is wired the opposite way to most hormone loops: when calcium binds the receptor, parathyroid hormone (PTH) secretion is switched OFF. Let calcium fall a few hundredths of a millimole and the receptor empties and PTH is released from preformed granules within seconds to minutes. Only the free, unbound fraction counts [ionised calcium, roughly half the total; about 40% is bound to albumin and about 10% complexed to citrate, phosphate and bicarbonate], so the gland is blind to a total calcium that is low only because albumin is low. Binding to albumin is pH-dependent: alkalosis drives calcium onto albumin and drops the ionised fraction without changing the total.

  Explains primary hyperparathyroidism as a gland that has stopped listening to that receptor; explains why an inherited faulty receptor resets the whole thermostat upwards (familial hypocalciuric hypercalcaemia); explains why a drug that sensitises the CaSR silences the gland (cinacalcet); explains why you correct calcium for albumin, or measure the ionised fraction, before you believe the number in front of you; and explains why an anxious hyperventilating patient can get perioral tingling and carpal spasm on a perfectly normal total calcium.

• PTH raises calcium by three routes at once. Bone: it binds PTH1 receptors on osteoblasts and osteocytes, not on osteoclasts, and makes them release RANKL, which recruits and activates osteoclasts to dissolve mineral [indirect resorption]. Kidney, part one: it turns up calcium reabsorption in the distal convoluted tubule and at the same time pulls the sodium-phosphate cotransporters out of the proximal tubule membrane, dumping phosphate into the urine. Kidney, part two: it switches on 1-alpha-hydroxylase in the proximal tubule, the enzyme that makes the active form of vitamin D [calcitriol], and calcitriol is what actually absorbs calcium from the gut. Net result: calcium up, phosphate down.

  Explains the fingerprint of every PTH problem — calcium and phosphate move in opposite directions — explains why bone is the currency the body spends to defend blood calcium, and explains why a working kidney is required for PTH to do two of its three jobs at all.

• There are usually four glands (about 10-15% of people have a fifth or a missing one), each about the size of a grain of rice, lying on the back of the thyroid and fed by tiny end branches of the inferior thyroid artery. Position is variable: the lower pair share a pharyngeal-pouch origin with the thymus and migrate with it, so they can end up anywhere from high in the neck near the carotid bifurcation to the mediastinum. PTH itself has a half-life in blood of only two to four minutes.

  Explains why hypocalcaemia after thyroid surgery appears within a day rather than weeks — bruise or divide the supply and the hormone is gone from the blood within the hour; explains why measuring PTH on the operating table (a fall of more than half within about 10 minutes) confirms an adenoma has been removed before the patient is closed; and explains why localisation imaging (sestamibi scan, 4D-CT) comes before the knife rather than after.

• Ionised calcium sits on the outside of nerve and muscle membranes and screens the surface charge, holding the firing threshold of voltage-gated sodium channels away from the resting potential. Drop it and those channels open too easily, so nerves fire on their own [neuromuscular irritability]. In cardiac muscle, low calcium prolongs the plateau of the action potential, so the QT interval lengthens on the ECG. Raise it and the opposite happens: nerves become sluggish and hard to excite, and the QT shortens.

  Explains the entire clinical picture of hypocalcaemia — tingling around the mouth and in the fingertips, cramps, Chvostek and Trousseau signs, laryngeal spasm, seizures at the extreme, long QT — and the mirror picture in hypercalcaemia: constipation, confusion, drowsiness, short QT. It also explains why a falling calcium after neck surgery is treated the same day rather than watched.

What goes wrong

• Primary hyperparathyroidism← from “The hormone-making cells of the parathyroid (c…”

  One gland grows a benign adenoma (about 85% of cases) whose cells have lost normal CaSR feedback — the setpoint at which calcium shuts them up is reset far too high. They secrete PTH as though calcium were low, however high it climbs. Multigland hyperplasia accounts for most of the rest and is the pattern seen in MEN1 (where hyperparathyroidism is usually the first manifestation) and, less often, MEN2A; carcinoma is rare (under 1%). All three arms of PTH then run flat out: bone resorbs, the distal tubule holds calcium while the proximal tubule wastes phosphate, and calcitriol drives gut absorption. The loop is not broken by the rising calcium because the gland is no longer listening to it.

  High calcium with a PTH that is not suppressed is parathyroid until proven otherwise. High calcium with a PTH crushed near zero, in someone unwell in a hospital bed, is malignancy (PTHrP from a squamous tumour, or bony metastases). Those two account for the overwhelming majority of hypercalcaemia you will meet.

  You would find: Calcium high (above about 2.60 mmol/L) with a PTH that is frankly high or — just as damning — sitting comfortably in the normal range. A normal gland faced with that calcium would have shut PTH down to almost nothing, so a 'normal' PTH here is inappropriately non-suppressed. Phosphate low or low-normal, urine calcium normal or high, ALP raised if bone is involved. Most Australian cases are now found by accident on a routine biochemistry panel in a postmenopausal woman; the classically quoted annual incidence is around 1 in 500 women over 50. The classic 'stones, bones, abdominal moans and psychic groans' — renal colic, osteoporosis (cortical bone first, so the distal radius), constipation, peptic ulcer, pancreatitis, low mood and poor concentration — is now the tail of the distribution, not the presentation. Definitive treatment is surgical removal of the offending gland.

• Familial hypocalciuric hypercalcaemia (FHH)← from “The hormone-making cells of the parathyroid (c…”

  An inherited inactivating mutation of the calcium-sensing receptor, passed on autosomal dominantly. The receptor is half deaf — and it is the same receptor in two places. In the parathyroid, the gland thinks calcium is lower than it is and keeps PTH going. In the thick ascending limb of the kidney, where that receptor normally tells the tubule to stop reabsorbing calcium once levels are high, the same deafness means the kidney keeps clawing calcium back. The thermostat has simply been reset upwards, and the whole system defends the new setpoint.

  The whole point of knowing FHH is to not operate. Taking out glands does not fix it — the faulty receptor is in every gland and in the kidney too, and the calcium comes straight back. Check a urine calcium before anyone books a neck.

  You would find: Mildly raised calcium with a PTH that is normal or mildly high — on the panel alone, indistinguishable from mild primary hyperparathyroidism. The urine gives it away: urine calcium is inappropriately LOW, not high. A calcium/creatinine clearance ratio below 0.01 points to FHH, above 0.02 to primary hyperparathyroidism (the gap between is indeterminate and may need genetic testing). It is lifelong, present since childhood, causes no stones and no bone disease, and other family members have the same numbers.

• Secondary and tertiary hyperparathyroidism← from “PTH raises calcium by three routes at once. Bo…”

  Anything that holds calcium down chronically will drive the glands, and they hypertrophy under years of stimulus. Two drivers matter in Australia. First, vitamin D deficiency: no substrate for calcitriol, so gut calcium absorption falls, calcium drifts down, and PTH rises to defend it — largely by stripping bone. Second, chronic kidney disease: the failing kidney can neither excrete phosphate nor make calcitriol. Phosphate rises and complexes calcium; calcitriol falls, so the gut absorbs less and the direct calcitriol brake on PTH gene transcription in the gland is lost; both push calcium down and PTH up. FGF23 from bone rises early to force phosphate out and further suppresses calcitriol. If the glands grow large enough for long enough, some clones stop responding to calcium at all and secrete autonomously — now calcium goes HIGH [tertiary hyperparathyroidism], classically becoming obvious after a kidney transplant restores renal function but leaves the overgrown glands behind.

  Secondary means the glands are doing the right thing about a real problem: PTH high, calcium LOW. Primary means the glands are doing the wrong thing: PTH high, calcium HIGH. Once you have sorted that, phosphate names the cause of the secondary: high phosphate says kidney, low phosphate says vitamin D.

  You would find: PTH high with calcium low or low-normal: that is the definition of secondary. Phosphate then names the driver — LOW or normal phosphate with a 25-OH vitamin D under 50 nmol/L means deficiency; HIGH phosphate with a low eGFR means kidney disease. Raised ALP, bone pain, proximal muscle weakness, fragility fractures; in advanced renal disease, vascular and soft-tissue calcification. In tertiary disease the calcium turns high while PTH stays high. Vitamin D deficiency is common here despite the sunshine — deeply pigmented skin, covering dress, housebound and residential aged-care residents, and southern states through winter. End-stage kidney disease falls hardest on Aboriginal and Torres Strait Islander Australians, at several times the national rate overall and many times higher again in remote central Australia, so renal bone disease is disproportionately their disease, striking younger and often while dialysing far from home and Country.

• Hypocalcaemia after thyroid surgery (surgical hypoparathyroidism)← from “There are usually four glands (about 10-15% of…”

  In a total thyroidectomy the parathyroids sit millimetres from the operative field, on vessels the surgeon may have to divide. Bruised, devascularised or unintentionally removed glands stop secreting, and with a PTH half-life of two to four minutes the hormone has vanished from the blood within the hour. Distal tubule calcium reabsorption stops, calcitriol production stops so the gut stops absorbing, and the bone efflux stops. Calcium falls over the next 24 to 72 hours. Phosphate, no longer being dumped into urine, RISES. Most glands are stunned rather than dead and recover over weeks to months: transient hypocalcaemia is common (reported in up to a quarter to a third of total thyroidectomies), while permanent hypoparathyroidism is quoted at roughly 1-3% in high-volume practice and higher after extensive or repeat surgery. Severe hypomagnesaemia produces the same low calcium with a low or inappropriately normal PTH by a different route (phosphate is not typically high here) — magnesium is required both for PTH release and for PTH signalling in target tissues, so it blocks secretion and causes end-organ resistance — and that hypocalcaemia will not correct until the magnesium is replaced.

  Low calcium with HIGH phosphate and a low PTH means the glands are gone. Low calcium with LOW phosphate and a high PTH means vitamin D deficiency and glands that are working hard. Phosphate tells you which side of the gland the problem sits on. And check magnesium in any hypocalcaemia that will not correct.

  You would find: Tingling around the mouth and in the fingertips first, then cramps, then carpopedal spasm. Tapping over the facial nerve twitches the lip (Chvostek sign, present in a minority of normal people so not specific); a blood pressure cuff held above systolic for a few minutes brings on carpal spasm (Trousseau sign, the more specific of the two). Long QT on the ECG. Laryngospasm and seizures at the extreme. Bloods: corrected or ionised calcium low, phosphate HIGH, PTH low or undetectable, and magnesium sent at the same time. Calcium is checked as routine after thyroidectomy — a fall on the first postoperative morning, or an undetectable PTH a few hours after the operation, identifies who needs replacement before the symptoms arrive.

• Hungry bone syndrome after parathyroidectomy← from “PTH raises calcium by three routes at once. Bo…”

  Remove the adenoma or the hyperplastic glands after long, severe hyperparathyroidism and the drive to resorb bone disappears within minutes. A skeleton that has been stripped for years flips abruptly to avid mineralisation and pulls calcium, phosphate and magnesium out of the blood faster than the gut and any remaining glands can supply them. Unlike surgical hypoparathyroidism, the remaining parathyroid tissue here is working normally — the calcium is being consumed, not left unsupported. (The two can coexist after a difficult parathyroidectomy, which is why PTH is measured as well as phosphate.)

  Both post-surgical hypocalcaemias present with tingling and tetany; the phosphate separates them. Glands gone means phosphate HIGH. Bone hungry means phosphate LOW.

  You would find: Profound, prolonged hypocalcaemia starting a day or two after parathyroidectomy and lasting days to weeks, with calcium AND phosphate AND magnesium all low and ALP high. The low phosphate is the giveaway that separates it from hypoparathyroidism, where phosphate is high. Risk is highest after severe disease — very high PTH, high ALP, overt bone disease — so it is seen most in dialysis patients coming to parathyroidectomy. The symptoms are the same tingling, cramps and tetany, because the falling ionised calcium is destabilising the same membranes.

What we give, and how it works

Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.