parathyroid gland and its disorders in detail trousseau sign calcium levels

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Parathyroid Gland - Anatomy, Physiology, and Disorders

Anatomy and Embryology

Humans normally have four parathyroid glands, located in close proximity to the superior and inferior poles of the thyroid lobes.

Superior parathyroids: derived from the endoderm of the 4th pharyngeal pouch
Inferior parathyroids: derived from the 3rd pharyngeal pouch (along with the thymus)
Supernumerary (extra) glands occur in 3-5% of the population and may be found ectopically along the migratory path, within the thymus, or within the thyroid

Each gland weighs approximately 35-40 mg normally. The chief cells secrete PTH; oxyphil cells appear after puberty and their function remains uncertain.

PTH: Structure and Secretion

PTH is an 84-amino acid peptide encoded by the PTH gene on chromosome 11p15. The mature peptide is secreted after cleavage of prepro-PTH → pro-PTH → PTH.

Calcium-Sensing Receptor (CaSR)

Parathyroid cells express the G protein-coupled calcium-sensing receptor (CaSR). When extracellular Ca²⁺ rises:

CaSR activation → phospholipase C stimulation → IP₃ accumulation → ↑ intracellular Ca²⁺
This reduces PTH secretion and increases urinary calcium excretion

Conversely, hypocalcemia releases CaSR inhibition, rapidly increasing PTH secretion.

PTH Actions (The Calcium-Phosphate Axis)

PTH and calcium-phosphate regulation showing parathyroid gland, bone, kidney, and gut interactions

PTH-calcium-phosphate regulation - Goldman-Cecil Medicine

PTH acts on three main organs:

Organ	Effect
Kidney	↑ Ca²⁺ reabsorption (TRPV5, NCX1); ↑ phosphate excretion (via NPT2A, NPT2C); activates 1α-hydroxylase → ↑ 1,25(OH)₂D (calcitriol)
Bone	Stimulates osteoblasts → activates osteoclasts → ↑ Ca²⁺ and PO₄³⁻ release from bone
Gut	Indirectly (via calcitriol) → ↑ intestinal Ca²⁺ absorption (NPT2B inhibited for phosphate)

Net result: PTH raises serum Ca²⁺ and lowers serum phosphate.

FGF23 (from osteocytes) works in opposition, promoting phosphate excretion and inhibiting calcitriol production.

Calcium Homeostasis

Normal serum calcium: 8.5-10.5 mg/dL (total); ionized Ca²⁺ 4.5-5.0 mg/dL

Forms of circulating calcium:

~45% bound to albumin
~10% bound to anions (citrate, phosphate, bicarbonate)
~45% free ionized (the physiologically active fraction)

Correcting for Albumin

Corrected Ca²⁺ = Measured Ca²⁺ + 0.8 × (4 - albumin g/dL)

In hypoalbuminemia: total Ca²⁺ falls but ionized Ca²⁺ may be normal ("false hypocalcemia"). In alkalosis or citrate excess, ionized Ca²⁺ falls with minimal change in total calcium.

PTH/Ca²⁺ Pattern Table (Henry's Clinical Diagnosis)

Condition	Ionized Ca²⁺	PTH	Cause
Normocalcemia	Normal	Normal	-
Hypoparathyroidism	Low	Low	Parathyroid glands
Vitamin D deficiency / renal failure	Low	High	Secondary HPT
Primary hypercalcemia (malignancy etc.)	High	Low	CHIMPS*
Primary hyperparathyroidism	High	High	Parathyroid adenoma/hyperplasia

CHIMPS = Cancer, Hyperthyroidism, Iatrogenic, Multiple myeloma, hyperParathyroidism, Sarcoidosis

Parathyroid Disorders

1. Primary Hyperparathyroidism (PHPT)

Etiology

Solitary parathyroid adenoma: ~85% of cases
Multiglandular hyperplasia: ~15% (often familial)
Parathyroid carcinoma: <1%
Familial forms: MEN 1 (parathyroid + pituitary + pancreas), MEN 2A (parathyroid + medullary thyroid Ca + pheochromocytoma), HPT-JT syndrome, familial isolated hyperparathyroidism (FIHP)

Pathophysiology

Autonomous PTH secretion → hypercalcemia. The CaSR set-point is raised, so PTH secretion continues inappropriately despite elevated calcium.

Clinical Features - "Moans, Groans, Pains, and Stones"

System	Manifestations
Renal	Nephrolithiasis (calcium oxalate/phosphate), nephrocalcinosis, polyuria, polydipsia
Musculoskeletal	Bone pain, osteopenia, osteoporosis, fractures, osteitis fibrosa cystica (subperiosteal resorption, "salt-and-pepper" skull, brown tumors), proximal myopathy
GI	Nausea, vomiting, constipation, anorexia, peptic ulcers, pancreatitis
Neuropsychiatric	Fatigue, lethargy, depression, confusion, coma
Cardiac	Shortened QT interval, bradycardia, 1st-degree AV block, arrhythmias

Hypercalcemia is usually modest (<11 mg/dL) in PHPT; severe symptoms more likely in malignancy

Diagnosis

Elevated serum Ca²⁺ + elevated (or "inappropriately normal") PTH
24-hour urine calcium elevated (helps distinguish from FHH where urine Ca is low)
Imaging: sestamibi scan, ultrasound, 4D CT for localization preoperatively

Indications for Surgery (Parathyroidectomy)

Serum Ca²⁺ > 1 mg/dL above upper normal
Creatinine clearance <60 mL/min
24h urine Ca >400 mg or increased nephrolithiasis risk
T-score < -2.5 (osteoporosis) at any site
Age <50 years
Patient preference / unable to participate in surveillance

Medical Management

Cinacalcet (calcimimetic): allosteric CaSR activator, 30 mg BID up to 90 mg BID - lowers PTH and serum Ca
Bisphosphonates: for bone protection
Hydration + loop diuretics for acute hypercalcemia

2. Secondary Hyperparathyroidism

PTH rises in response to persistent hypocalcemia (appropriate response)
Most common cause: chronic kidney disease (CKD) - low calcitriol + hyperphosphatemia → low Ca²⁺ → ↑PTH
Also: vitamin D deficiency, malabsorption
Serum Ca²⁺ is low or normal, PTH is elevated
Treatment: Phosphate binders, vitamin D supplementation (calcitriol), cinacalcet

3. Tertiary Hyperparathyroidism

Develops in longstanding secondary hyperparathyroidism (typically CKD)
Parathyroid glands become autonomous - PTH secretion persists despite normocalcemia or even hypercalcemia
Presumed progression: polyclonal hyperplasia → monoclonal autonomous adenoma
Serum Ca²⁺ is elevated, PTH is markedly elevated
Definitive treatment: subtotal or total parathyroidectomy

4. Hypoparathyroidism

Causes

Category	Examples
Surgical (most common)	Post-thyroidectomy, post-parathyroidectomy
Parathyroid agenesis	DiGeorge syndrome (22q11.2 deletion - no parathyroids + thymus)
Autoimmune	Isolated or polyglandular autoimmune syndrome type 1 (APS-1 / APECED)
Infiltration	Hemochromatosis, amyloidosis, sarcoidosis, Wilson's disease, thalassemia
Radiation	External beam or ¹³¹I therapy
Functional	Hypomagnesemia (blocks PTH secretion AND causes PTH resistance)
Genetic	PTH gene mutations, activating CaSR mutations (autosomal dominant hypocalcemia)
Hungry bone disease	Post-parathyroidectomy rapid calcium uptake by bones

Clinical Features of Hypocalcemia

Neuromuscular (most prominent):

Circumoral and peripheral paresthesia (tingling)
Muscle cramps and tetany
Carpopedal spasm
Chvostek sign and Trousseau sign (see below)
Laryngospasm / bronchospasm
Seizures (focal, petit mal, grand mal)

Cardiac:

QT prolongation
Impaired cardiac inotropy, dysrhythmias

Other:

Depression, anxiety, irritability, confusion
Cataracts (chronic hypocalcemia)
Abnormal dentition and skeletal malformations (congenital)
Papilledema (intracranial hypertension)

Treatment

Acute/symptomatic: IV calcium gluconate (10 mL of 10% solution) slowly
Chronic: Oral calcium carbonate + active vitamin D (calcitriol 0.25-1 mcg/day)
Correct concurrent hypomagnesemia
"Hungry bone" post-parathyroidectomy: may require IV calcium for weeks

5. Pseudohypoparathyroidism (PHP)

Hypocalcemia + hyperphosphatemia + elevated PTH + tissue resistance to PTH
Magnesium and calcidiol levels are normal
Confirmed by PTH infusion test: normal PTH → ↑ urinary cAMP and phosphate; in PHP, this response is absent
Associated with Albright's hereditary osteodystrophy (PHP type 1a): short stature, round face, brachydactyly, obesity, subcutaneous ossifications

Trousseau Sign

Definition: The development of carpal spasm (carpopedal spasm) when a sphygmomanometer cuff is inflated over the brachial artery to a pressure above systolic blood pressure and maintained for 3 minutes.

What is seen: The hand adopts a characteristic posture with:

Wrist flexion
MCP flexion
IP extension
Thumb adduction (the "obstetric hand" or "main d'accoucheur")

Mechanism: Occluding circulation renders the peripheral nerve ischemic. Ischemia lowers the threshold for spontaneous depolarization in the setting of low ionized calcium, producing involuntary muscle contraction.

Specificity vs. Chvostek: Trousseau sign is more specific for hypocalcemia than Chvostek sign. Chvostek (tapping the facial nerve anterior to the ear causing facial muscle contraction) can be positive in ~10-25% of normal individuals.

Clinical use: If positive, hypocalcemia should be confirmed by direct measurement of ionized calcium. In mild tetany where spontaneous spasm is not yet evident, Trousseau sign can unmask latent tetany.

Summary: Calcium Levels and Key Disorders

Condition	Serum Ca²⁺	PTH	Phosphate	Key feature
Primary hyperparathyroidism	↑	↑	↓	Adenoma; "stones, moans, groans"
Secondary hyperparathyroidism	↓ or N	↑↑	↑ (in CKD)	Appropriate response to CKD/Vit D deficiency
Tertiary hyperparathyroidism	↑	↑↑↑	Variable	Autonomous glands in CKD
Hypoparathyroidism	↓	↓ or absent	↑	Post-surgical most common
Pseudohypoparathyroidism	↓	↑↑	↑	PTH resistance; Albright's phenotype
Malignancy (PTHrP)	↑	↓	↓	Lung/renal/breast Ca; PTHrP not detected by PTH assay
FHH (familial hypocalciuric hypercalcemia)	↑	N or ↑	N	Low urine Ca/Cr ratio; CaSR mutation
Vitamin D deficiency	↓ or N	↑	↓	Secondary HPT; rickets/osteomalacia

Sources: Goldman-Cecil Medicine, 2 Vol. Set, Ch. 227 | Mulholland & Greenfield's Surgery, 7e, Ch. 76 | Frameworks for Internal Medicine, Ch. 5 | National Kidney Foundation Primer on Kidney Diseases, 8e | Henry's Clinical Diagnosis and Management by Laboratory Methods, Table 9.8 | Brenner and Rector's The Kidney, 2-Vol. Set

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