Mineral Metabolism: Calcium, Phosphorus & Iron

A high-yield integrative topic bridging biochemistry and medicine. It links three hormones (PTH, calcitonin, vitamin D) governing calcium-phosphorus homeostasis with the molecular handling of iron (DMT1, ferroportin, transferrin, ferritin, hepcidin) and the trace elements copper and zinc. Expect questions on transport proteins, deficiency syndromes, and lab cut-offs.

Calcium & Phosphorus: Distribution and Forms

The adult body contains ~1–1.2 kg of calcium, of which 99% is in bone (as hydroxyapatite, Ca₁₀(PO₄)₆(OH)₂) and only ~1% in the extracellular fluid and soft tissues. Plasma calcium (normal 8.5–10.5 mg/dL, or 2.1–2.6 mmol/L) exists in three fractions:

Fraction	Approx. %	Notes
Ionised (free) Ca²⁺	~50%	Biologically active; tightly regulated (4.4–5.2 mg/dL)
Protein-bound (mainly albumin)	~40%	Falls in hypoalbuminaemia
Complexed (citrate, phosphate, bicarbonate)	~10%	Diffusible but inactive

High-yield: For every 1 g/dL fall in albumin, total calcium falls by ~0.8 mg/dL, but ionised calcium is unchanged. Corrected Ca = measured Ca + 0.8 × (4 − albumin). Always interpret total calcium with albumin.

Alkalosis increases protein binding of calcium → ionised Ca falls → tetany (e.g., hyperventilation, vomiting). Acidosis does the opposite. This is why a patient hyperventilating shows carpopedal spasm despite normal total calcium.

Phosphorus: ~85% in bone, normal serum 2.5–4.5 mg/dL (higher in children due to growth). Phosphate and calcium have an inverse relationship driven largely by PTH and FGF23.

Hormonal Regulation: The Three Players

Parathyroid hormone (PTH)

• 84-amino-acid peptide from chief cells of parathyroid glands; biologically active N-terminal 1–34 fragment.
• Stimulus for release: low ionised Ca²⁺ (sensed by the calcium-sensing receptor, CaSR, a GPCR on chief cells). High Mg also activates CaSR; severe hypomagnesaemia paradoxically suppresses PTH secretion → refractory hypocalcaemia.
• Net effect: raises serum Ca, lowers serum phosphate.

PTH actions (Bone, Kidney, Intestine — indirect):

1. Bone → stimulates osteoblasts to express RANKL → osteoclast activation → resorption releases Ca and PO₄.
2. Kidney → increases distal tubular Ca reabsorption; inhibits proximal phosphate reabsorption (phosphaturia); stimulates 1α-hydroxylase → more calcitriol.
3. Intestine → indirect, via calcitriol → ↑Ca and PO₄ absorption.

High-yield: PTH is phosphaturic — it lowers serum phosphate. So in primary hyperparathyroidism: ↑Ca, ↓PO₄, ↑PTH. In CKD (secondary hyperPTH): ↑PO₄ retention drives the picture.

Vitamin D (calcitriol)

Synthesis pathway (memorise the hydroxylation sites):

7-dehydrocholesterol (skin + UVB) → cholecalciferol (D₃) → 25-hydroxylation in LIVER (25-OH-D, calcidiol) → 1α-hydroxylation in KIDNEY (1,25-(OH)₂-D, calcitriol)

• Storage/best status marker = 25-OH-D (long half-life ~2–3 weeks).
• Active form = 1,25-(OH)₂-D (calcitriol).
• Renal 1α-hydroxylase is stimulated by PTH, low phosphate, and low calcium; inhibited by FGF23 and calcitriol itself (feedback).
• Calcitriol acts on the nuclear VDR → induces calbindin, TRPV6 channel, and the basolateral Ca²⁺-ATPase in enterocytes → ↑intestinal Ca AND PO₄ absorption. It is the only hormone that raises both.

High-yield: In sarcoidosis, TB, and lymphomas, macrophages express extrarenal 1α-hydroxylase unregulated by PTH → hypercalcaemia with suppressed PTH and high calcitriol. Treat with steroids.

Calcitonin

• 32-aa peptide from parafollicular C cells of thyroid.
• Released in response to hypercalcaemia; inhibits osteoclasts → lowers Ca (minor physiological role in adults).
• Tumour marker for medullary thyroid carcinoma (MTC); also raised in MEN 2.

FGF23 (the "phosphatonin")

• Secreted by osteocytes in response to high phosphate/calcitriol.
• Effects: phosphaturia (downregulates NaPi cotransporters) AND inhibits 1α-hydroxylase (lowers calcitriol). Requires Klotho as co-receptor.
• Excess FGF23 → oncogenic osteomalacia, X-linked & autosomal dominant hypophosphataemic rickets.

Parameter	PTH	Calcitriol	Calcitonin	FGF23
Serum Ca	↑	↑	↓	↔/↓
Serum PO₄	↓	↑	↓	↓
Renal 1α-hydroxylase	↑	↓ (self)	–	↓
Main source	Parathyroid	Kidney	C cells	Osteocytes

Disorders of Calcium

Hypercalcaemia — most common causes: primary hyperparathyroidism (outpatient) and malignancy (inpatient). Malignancy acts via PTHrP (squamous cell lung, renal, breast), osteolytic metastases, or tumour calcitriol.

Mnemonic for hypercalcaemia symptoms: "Stones, Bones, Groans, Thrones, and Psychiatric Overtones" — renal stones, bone pain, abdominal groans (pancreatitis, constipation, peptic ulcer), polyuria, depression/confusion. ECG: short QT.

Hypocalcaemia — hypoparathyroidism (post-thyroidectomy), vitamin D deficiency, CKD, hypomagnesaemia, pseudohypoparathyroidism.

• Signs: Chvostek sign (tap facial nerve → twitch), Trousseau sign (BP cuff → carpopedal spasm). ECG: prolonged QT.

High-yield: Pseudohypoparathyroidism type 1a (Albright hereditary osteodystrophy) = end-organ resistance to PTH from a Gsα defect → ↓Ca, ↑PO₄, but HIGH PTH. Phenotype: short stature, round face, short 4th/5th metacarpals.

Iron Metabolism

Total body iron ~3–4 g. ~65% in haemoglobin, ~25% stored (ferritin/haemosiderin), rest in myoglobin and enzymes. There is no regulated route of iron excretion — balance is controlled entirely at the level of absorption.

Absorption (duodenum & upper jejunum)

Dietary Fe³⁺ → reduced to Fe²⁺ by duodenal cytochrome b (DCYTB) + vitamin C → enters enterocyte via DMT1 (apical) → either stored as ferritin (lost when cell sloughs) or exported across basolateral membrane via FERROPORTIN → oxidised back to Fe³⁺ by HEPHAESTIN → loaded onto TRANSFERRIN in plasma.

• Haem iron (meat) is absorbed more efficiently via a separate haem transporter, independent of DMT1.
• Enhancers: vitamin C, gastric acid, meat. Inhibitors: phytates, tannins (tea), antacids/PPIs, calcium.

Key proteins

Protein	Role	Clinical note
DMT1 (DCT1/Nramp2)	Apical Fe²⁺ uptake into enterocyte	Also moves Fe out of endosome
Ferroportin	Only known cellular Fe exporter (enterocyte, macrophage, hepatocyte)	Target of hepcidin
Transferrin	Plasma Fe³⁺ transport (binds 2 Fe³⁺)	Reflects TIBC; ↑ in iron deficiency
Transferrin receptor (TfR)	Cellular Fe uptake by endocytosis	sTfR ↑ in IDA, normal in ACD
Ferritin	Intracellular storage (soluble)	Best marker of body iron stores; acute-phase reactant
Haemosiderin	Insoluble storage aggregate	Seen in iron overload; Prussian blue stain

Hepcidin — the master regulator

• Synthesised by the liver; the central negative regulator of iron.
• Hepcidin binds ferroportin → internalises and degrades it → blocks iron export from enterocytes and macrophages → lowers serum iron.
• ↑Hepcidin when iron is high or in inflammation (IL-6 driven) → iron trapped in macrophages → anaemia of chronic disease.
• ↓Hepcidin in iron deficiency, hypoxia, and hereditary haemochromatosis (HFE mutation, C282Y) → unchecked absorption → overload.

High-yield: Inflammation → IL-6 → ↑hepcidin → ferroportin degraded → iron sequestered in macrophages → low serum iron, low TIBC, HIGH ferritin = the signature of anaemia of chronic disease.

Iron deficiency vs anaemia of chronic disease

Parameter	Iron deficiency anaemia	Anaemia of chronic disease
Serum iron	↓	↓
TIBC (transferrin)	↑	↓ or normal
Transferrin saturation	↓	↓ or normal
Serum ferritin	↓ (<15–30 ng/mL)	↑/normal (acute-phase)
Soluble TfR	↑	Normal
Hepcidin	Low	High
Marrow iron stores	Absent	Present (but blocked)

High-yield: Serum ferritin <15 ng/mL is virtually diagnostic of iron deficiency (most specific test). Bone marrow iron stain (Prussian blue) remains the gold standard but is rarely needed.

Copper Metabolism

• Absorbed in stomach/duodenum; carried first loosely on albumin, then on caeruloplasmin (carries ~90% of plasma copper). Excreted in bile.
• Cofactor for: cytochrome c oxidase, lysyl oxidase (collagen/elastin crosslinking), tyrosinase, superoxide dismutase, dopamine β-hydroxylase, and caeruloplasmin/ferroxidase (oxidises Fe²⁺→Fe³⁺ for transferrin loading).

Feature	Menkes disease	Wilson disease
Defect	ATP7A (X-linked) — defective Cu absorption/export from gut	ATP7B (AR) — defective biliary Cu excretion + caeruloplasmin loading
Net Cu state	Deficiency	Overload (toxic deposition)
Serum Cu/caeruloplasmin	Low	Low caeruloplasmin, ↑urinary & free Cu
Hallmarks	Kinky/steely hair, hypopigmentation, arterial tortuosity, neurodegeneration	Kayser-Fleischer rings, hepatolenticular degeneration, basal ganglia signs, psychiatric features
Mechanism of signs	Failed lysyl oxidase, tyrosinase, etc.	Cu deposition in liver, brain (lenticular), cornea

High-yield: Wilson disease — low serum caeruloplasmin, high 24-h urinary copper, KF rings on slit-lamp. Treatment: D-penicillamine (chelator) or trientine; zinc blocks intestinal absorption. Both Menkes and Wilson involve copper-transporting ATPases (ATP7A = Absorption/Menkes; ATP7B = Biliary/Wilson).

Zinc Metabolism

• Cofactor for >300 enzymes; component of zinc-finger transcription factors, carbonic anhydrase, alcohol dehydrogenase, alkaline phosphatase, matrix metalloproteinases.
• Deficiency causes: acrodermatitis enteropathica (AR defect in ZIP4/SLC39A4 intestinal transporter) — periorificial & acral dermatitis, alopecia, diarrhoea, poor wound healing, impaired taste (hypogeusia), growth retardation, hypogonadism.
• Also seen in TPN, malabsorption, alcoholism, chronic diarrhoea.

High-yield: The classic triad of zinc deficiency = dermatitis + diarrhoea + alopecia. Acrodermatitis enteropathica responds dramatically to oral zinc.

Diagnosis & Investigations of Choice

• Calcium status: ionised calcium (most accurate) or albumin-corrected total calcium.
• Vitamin D status: serum 25-OH-D (NOT calcitriol).
• Hyperparathyroidism: intact PTH + calcium + phosphate; localise with sestamibi (MIBI) scan.
• Iron deficiency: serum ferritin (best); supportive — low MCV/MCH, ↑RDW, ↑TIBC, ↓transferrin saturation (<16%).
• Iron overload/haemochromatosis: transferrin saturation >45% + ferritin; confirm with HFE genotyping; MRI for hepatic iron.
• Wilson disease: low caeruloplasmin, ↑24-h urinary Cu, KF rings, liver biopsy Cu quantification.

Management / Drug of Choice (quick map)

• Symptomatic hypercalcaemia: IV normal saline → bisphosphonates (zoledronate) for malignancy; calcitonin for rapid but transient lowering.
• Acute hypocalcaemia/tetany: IV calcium gluconate (preferred over calcium chloride peripherally); correct magnesium first if low.
• Vitamin D deficiency rickets/osteomalacia: cholecalciferol; renal failure → give active calcitriol/alfacalcidol (kidney can't 1α-hydroxylate).
• Iron deficiency: oral ferrous sulphate (best absorbed on empty stomach with vitamin C); IV iron if intolerant/malabsorption.
• Wilson disease: D-penicillamine/trientine + zinc; Menkes: copper-histidine injections (limited benefit).

Complications

• Chronic hypercalcaemia → nephrocalcinosis, renal stones, pancreatitis, peptic ulcer.
• Chronic hypocalcaemia → cataracts, basal ganglia calcification, prolonged QT/arrhythmia.
• Vitamin D deficiency → rickets (children: bowing, rachitic rosary, widened epiphyses) / osteomalacia (adults: Looser zones/pseudofractures).
• Iron overload → cirrhosis, hepatocellular carcinoma, "bronze diabetes," cardiomyopathy, hypogonadism.
• CKD-MBD → renal osteodystrophy, vascular calcification.

Key Differentials (rapid frame)

1. Hypercalcaemia + ↑PTH → primary/tertiary hyperPTH or familial hypocalciuric hypercalcaemia (FHH, CaSR mutation — low urinary Ca, no treatment needed).
2. Hypercalcaemia + ↓PTH → malignancy (PTHrP), granulomatous disease, vitamin D toxicity.
3. Microcytic anaemia → iron deficiency vs thalassaemia vs ACD vs sideroblastic — distinguished by ferritin, TIBC, RDW, and HbA₂.
4. Hypocalcaemia + ↑PO₄ + ↑PTH → pseudohypoparathyroidism or CKD.
5. Hypocalcaemia + ↑PO₄ + ↓PTH → true hypoparathyroidism.

Recently asked / exam angle

• Ferroportin is the only cellular iron exporter and the target of hepcidin — a repeated single-best-answer.
• Which enzyme reduces dietary iron at the brush border → DCYTB / duodenal cytochrome b (Fe³⁺→Fe²⁺).
• Hepcidin source = liver; raised by IL-6 → links to anaemia of chronic disease.
• Best marker of iron stores = ferritin; best marker of vitamin D status = 25-OH-D.
• ATP7A vs ATP7B (Menkes vs Wilson) and the "kinky hair" vs "KF ring" pairing.
• Caeruloplasmin's ferroxidase activity — copper deficiency can cause a microcytic anaemia mimicking iron deficiency.
• PTH is phosphaturic; FGF23 + Klotho axis in hypophosphataemic rickets.
• Acrodermatitis enteropathica → ZIP4 (SLC39A4) and the dermatitis–diarrhoea–alopecia triad.
• Severe hypomagnesaemia suppresses PTH → refractory hypocalcaemia (correct Mg first).
• Albumin correction formula for total calcium.

Rapid revision

1. 99% of body calcium is in bone; ionised Ca (~50%) is the active, regulated fraction.
2. PTH raises calcium and lowers phosphate (phosphaturic); secreted via CaSR sensing low Ca.
3. Vitamin D activation: 25-OH in liver, 1α-OH in kidney; 25-OH-D is the status marker, calcitriol the active form.
4. Calcitriol is the only hormone that increases intestinal absorption of both Ca and phosphate.
5. Calcitonin (C cells) lowers Ca and is a tumour marker for medullary thyroid carcinoma.
6. FGF23 (osteocytes, needs Klotho) is phosphaturic and suppresses 1α-hydroxylase.
7. Iron has no excretory regulation — control is at duodenal absorption; DMT1 in, ferroportin out.
8. Hepcidin degrades ferroportin; ↑ by inflammation (IL-6), ↓ in iron deficiency and haemochromatosis.
9. Iron deficiency: ↓ferritin, ↑TIBC, ↑sTfR. ACD: ↑/normal ferritin, ↓TIBC, normal sTfR.
10. Ferritin <15 ng/mL = iron deficiency; ferritin is also an acute-phase reactant.
11. Wilson = ATP7B, low caeruloplasmin, KF rings, treat with penicillamine; Menkes = ATP7A, kinky hair.
12. Zinc deficiency = acrodermatitis enteropathica (ZIP4): dermatitis + diarrhoea + alopecia.