ERS10 Pathology Of Parathyroid Glands Flashcards
Normal parathyroid gland
Gross appearance:
- 4 glands (variable)
- Posterior aspect of 4 poles of thyroid gland (may be found along embryological line of descent from pharyngeal pouches to thymus)
- 20-35 mg
- 3-4 mm
- circumscribed
- outer surface of thyroid capsule, may invaginate into thyroid gland
Histology:
- ALL cells arranged in nests / trabeculae / acinar
- presence of intra-glandular adipose tissue
- cellularity ↓ with age + ↑ intraglandular adipose tissue
- rich vascular network
Cell types:
- Chief cells (majority):
- produce, store, secrete PTH
- polygonal shape
- well-defined cytoplasmic membrane
- pale eosinophilic to vacuolated cytoplasm - Water-clear cells (least common):
- Chief cells with abundant glycogen
- ***abundant clear, glycogen rich cytoplasm - Oxyphil cells:
- unknown function
- larger
- scattered throughout glands singly / in clusters
- abundant mitochondria
- dense, ***eosinophilic cytoplasm
Roles of Parathyroid hormone
Regulate Ca homeostasis
—> Overall effect: ↑ serum Ca level
Plasma free (ionised) Ca level ↓
—> stimulate parathyroid glands
—> secrete PTH
—> stimulates target organs (kidneys and bone) to release Ca
- Kidneys:
- ↑ tubular reabsorption of Ca
- ↑ urinary PO4 excretion —> ↓ serum PO4 (↓ binding and depletion of Ca)
- ↑ conversion of vit D to active dihydroxy form (1, 25 dihydroxy-D3) —> ↑ Ca absorption from GI tract - Bones:
- ↑ osteoclastic activity —> lamellar bone resorption (esp. metaphyses) —> release stored Ca - GI tract (indirect target)
***Causes of hypercalcaemia
↑ PTH:
(自己放多左, 太少Ca, 太少Calcitriol, 太多Pi)
1. Hyperparathyroidism
- Primary (autonomous, spontaneous overproduction of PTH)
- Secondary (secondary to chronic renal insufficiency)
- Tertiary (secondary to chronic renal insufficiency)
2. Familial hypocalciuric hypercalcaemia
↓ PTH: (自己放少左, 太多Ca, 太多Calcitriol) 1. Hypercalcaemia of malignancy - PTH-related protein-mediated osteolytic metastases 2. Vit D toxicity 3. Immobilisation 4. Drugs (Thiazides diuretics) 5. Granulomatous diseases (Sarcoidosis)
Primary hyperparathyroidism
- F:M = 4:1
- asymptomatic (usually detected incidentally)
- **Causes:
1. Parathyroid Adenoma (85-95%)
2. Primary hyperplasia of parathyroid gland (diffuse / nodular) (5-10%)
3. Parathyroid carcinoma (1%)
Signs and symptoms (Hypercalcaemia):
- ***bone pain, renal colic
- polyuria, polydipsia
- constipation, nausea
- peptic ulcers, pancreatitis, gallstones
- CNS manifestations (severe) (depression, lethargy, seizures weakness, hypotonia)
Blood test:
Inappropriate ↑ PTH (without stimuli)
—> ↑ urinary reabsorption of Ca + ↑ excretion of PO4 (+ ↑ bone resorption + ↑ Ca absoption)
—> ***↑ Ca + ↓ PO4 in blood
—> effects on bone (i.e. Renal osteodystrophy), kidney, other organs
Physiological effect:
- Skeletal changes (↑ osteoclastic activity, esp. in metaphyses of long bones)
- **Osteopenia —> thinning of bone cortex
- Osteitis fibrosa cystica —> loss of bone replaced by fibrous tissue in BM —> foci of haemorrhage + cysts
- **Brown tumour of hyperparathyroidism (fibrosis + haemorrhage + osteoclastic giant cells) - Kidney
- ***Nephrolithiasis
- Nephrocalcinosis (calcification of renal parenchyma: interstitium + tubules) —> CT - Other body parts
- ***Metastatic calcification (secondary to hypercalcaemia) —> gross / microscopic nodular deposits (e.g. stomach, lungs, myocardium, skin, blood vessels)
—> vs Dystrophic calcification (Ca deposits are secondary to tissue necrosis e.g. leiomyoma of uterus)
Brown tumour of hyperparathyroidism
Active bone resorption + fibrosis
Large lytic bone tumour
1. Numerous osteoclasts (multinucleated giant cells)
2. Haemorrhage, RBC, haemosiderin deposits —> Brown appearance
3. Ingrowth of vascularised fibrous tissue
—> identical to ***Giant cell tumour of bone
—> hyperparathyroidism must be excluded when making ddx by measuring PTH
Symptoms:
1. Bone pain, fractures
2. Osteolytic lesions on radiograph
—> ~ neoplasm
Parathyroid adenoma
- Benign tumour of parathyroid gland
- Sporadic / Hereditary
- Asymptomatic (incidentally detected by ↑ serum Ca)
Pathogenesis (sporadic):
- History of exposure to **ionising radiation in childhood / Secondary to **lithium therapy
- ***MEN1 (11q13) sporadic mutation of one/both copies (20-30%)
- **Cyclin D1 gene rearrangement (repositioned next to PTH gene (11p) —> **overexpression of Cyclin D1: component of cell cycle —> Chief cell proliferation) (10-20%)
Pathogenesis (hereditary) (less common):
Germline mutations —> 5-10% familial syndromes
MEN1 / MEN2A familial syndromes (X rmb):
- Hyperparathyroidism-jaw-tumour syndrome (HPT-JT)
- Familial isolated hyperparathyroidism (FIHP)
- Familial hypocalciuric hypercalcaemia
MEN1 (tumour suppressor gene encode for menin) —> Autosomal dominant germline mutation of MEN1 (11q13):
- Parathyroid Adenoma / ***Hyperplasia / Carcinoma
- Endocrine lesions: **Pituitary adenomas, **Pancreatic neuroendocrine tumours, ***Adrenal cortical adenoma/hyperplasia
- Non-endocrine lesions: angiofibromas, lipomas, leiomyomas
MEN2A —> Autosomal dominant germline mutation in RET-activating protooncogene (10q11.2)
- Parathyroid Adenoma / Hyperplasia
- Thyroid medullary carcinoma
- Adrenal pheochromocytomas
Gross appearance:
- Solitary, Larger, Heavier (0.5-5g)
- Well-circumscribed
- Soft, Tan nodular with thin delicate capsule
- ***Other 3 glands are normal / shrunken (∵ feedback inhibition by ↑ Ca)
Histology:
- ***Chief cells predominant in diffuse sheets
- ***Thin fibrous capsule
- ***Rim of compressed normal gland tissue on outside capsule
- Loss of intraglandular adipose tissue
- **Enlarged cells + Nuclear atypia (∵ degeneration) (common finding in endocrine neoplasm, does NOT indicate malignancy, **absence of mitotic figures —> distinguished from carcinoma)
Parathyroid hyperplasia
- Diffuse process involving ***ALL 4 glands —> NOT always appreciable
- One gland may be larger —> Differentiation from adenoma is difficult
Pathogenesis:
- 5-25% hereditary (MEN1 / MEN2A)
- other cause unclear
Commonest cell types:
- Chief cell hyperplasia (commonest)
- Water-clear cells hyperplasia (less common, more commonly seen in secondary hyperparathyroidism)
- Both cell types together (commonest)
(4. Oxyphil cells)
Histology:
- Cells arranged in Diffuse sheets / Multiple nodules / Trabecular
- Loss of intraglandular adipose tissue (this feature NOT used to differentiate from Adenoma)
Parathyroid carcinoma
- Usually ***ONE parathyroid gland involved
- 1/3 cases local recurrence, 1/3 distant dissemination
- Death often due to ***uncontrolled hypercalcaemia
Pathogenesis:
- Sporadic (most)
- Germline mutations (MEN1, MEN2A)
Signs and symptoms:
- fatigue, weakness, polyuria, polydipsia, renal and bone diseases (~ Hyperparathyroidism)
Blood test:
- ↑ serum Ca, PTH, ***Alkaline phosphatase
Gross appearance:
- Gray-white
- Irregular mass (***heavy >10g)
- **Dense fibrous capsule with **invasion of surrounding structures (e.g. thyroid)
- Prominent fibrous band within lesions
Histology:
- Nodules of carcinoma invading into adjacent tissue
- Cells in nodules / trabeculae
- Uniform nuclei + Prominent nucleoli + Absence of high-grade nuclear atypia
- Presence of many ***mitotic figures —> malignancy
Secondary hyperparathyroidism
Cause:
- Chronic renal failure —> Hyperphosphataemia + ↓ Calcitriol —> Hypocalcaemia —> ↑ PTH
(Other causes: inadequate Ca intake, Vit D deficiency / malabsorption)
Pathogenesis: Chronic renal failure —> 1. ↓ PO4 excretion —> Hyperphosphataemia —> PO4 bind to / directly suppress serum Ca —> ↓ serum Ca
- Loss of renal 1α-hydroxylase (needed for Calcitriol synthesis)
—> ↓ Calcitriol
—> ↓ GI absorption of Ca
End result:
**Chronic hypocalcaemia (high PO4 also directly stimulate PTH release)
—> **Parathyroid hyperplasia (in response to low Ca —> high PTH)
—> **↑ serum PTH
—> **↓/normal Ca
—> PTH may eventually back to normal
Physiological effect:
- Less prominent compared with Primary parathyroidism —> Overshadowed by those of chronic renal failure
Chronic renal failure manifestations:
- Fluid / Electrolyte imbalance (dehydration, edema, hyperkalaemia, metabolic acidosis, polyuria —> oligouria)
- Anaemia (↓ haematopoietin from kidney)
- Hypertension
- Uraemic pericarditis
- Skin changes (pruritis, dry skin, hyperpigmentation)
- Calciphylaxis
Blood test:
- Ca slightly ↓ / normal (compensatory ↑ in PTH levels —> sustain Ca level)
- ↑ PO4 level —> CaPO4 deposits in tunica media —> ischaemia / gangrene of end organ (***Calciphylaxis)
- ↑ PTH level
Tertiary hyperparathyroidism
Aka Refractory secondary hyperparathyroidism (in minority of patients)
Secondary hyperparathyroidism
—> prolonged stimulation of Parathyroid activity —> excessive
—> Development of ***Autonomous Parathyroid hyperplasia
—> Hyperplastic gland produce PTH regardless of serum Ca level
Histology:
- Chief cell hyperplasia (involve ALL glands)
- Nodular / Diffuse pattern
- Loss of intraglandular adipose tissue
Treatment:
- Parathyroidectomy (to control hyperparathyroidism)
Parathyroid hyperplasia —> Primary vs Tertiary Hyperparathyroidism
Primary hyperparathyroidism:
- asymptomatic / renal osteodystrophy
Tertiary hyperparathyroidism:
- chronic renal failure manifestations
**Blood profile:
Primary: ↑ Ca, ↓ PO4, ↑ PTH
Secondary: ↓/normal Ca, ↑ PO4, ↑ PTH
**Tertiary: ↑ Ca (by ↑↑ PTH), ↑↑ PO4, ↑↑ PTH
Hypercalcaemia of malignancy - PTH-related protein-mediated osteolytic metastases
Cancer:
- commonest cause of hypercalcaemia in adults
Pathogenesis:
1. Carcinoma
—> secretion of PTH-related protein (PTHrP)
—> binds to PTH receptor (same effects as PTH)
—> ↑ Ca
2. Osteolytic bone metastasis
Most common cancer to secrete PTHrP:
- Squamous cell carcinoma of lung
- Invasive carcinoma of breast
Blood test:
- Serum PTH: normal / ↓
Diagnostic algorithm of Hypercalcaemia
Ensure normal renal function, no drug causes
—> measure PTH
High PTH
- Hyperparathyroidism
- Urine Ca low —> Familial hypocalciuric hypercalcaemia
- Hypercalcaemia of malignancy cannot be excluded
Low PTH
- measure PTHrP —> High: suggest Hypercalcaemia of malignancy; Low: still cannot exclude malignancy
- Non-parathyroid causes: Vit D toxicity, Immobilisation, Granulomatous diseases (Sarcoidosis), Adrenal failure
Hypoparathyroidism
Uncommon
Causes:
- Iatrogenic: Surgical removal of parathyroid glands en bloc (most common)
- thyroid gland diseases / head+neck malignancies - Autoimmune (rare)
- mutations in autoimmune regulator (AIRE gene) with AutoAb against multiple endocrine organs - Congenital (rare)
- Di George syndrome —> deletion of 22q11.2 —> absence of parathyroid gland + thymic aplasia / cardiac defects (very rare)
Clinical manifestations:
1. Hypocalcaemia
- Secondary to Acute hypocalcaemia (surgical related):
—> neuromuscular symptoms (tingling, muscle spasms, facial grimacing)
—> arrhythmia
—> ↑ intracranial pressure / seizure (rare)
3. Chronic Hypoparathyroidism —> ↓ PO4 excretion —> Hyperphosphataemia —> CaPO4 deposit in various tissues —> Cataracts, Calcification of cerebral basal ganglia, Dental abnormalities
***Summary of Blood profile
Hyperparathyroidism
Primary: ↑ Ca, ↓ PO4, ↑ PTH
Secondary: ↓/normal Ca, ↑ PO4, ↑ PTH
Tertiary: ↑ Ca (by ↑↑ PTH), ↑↑ PO4, ↑↑ PTH
Hypoparathyroidism: ↓ Ca, ↑ PO4, ↓ PTH
