Endocrine - Parathyroid disease Flashcards
Physiological effects of PTH
Source of PTH
↑Ca ↓PO4 ↑ALP
- Increase Ca resorption from bone via osteoblasts and osteoclasts
- Increase reabsorption of Ca from DCT in kidneys, Decrease Phosphate reabsorption
- Increase intestinal uptake of Ca via formation of 1,25-dihydroxyvitamin D
Source: parathyroid chief cells
Physiological effects of Vitamin D
Sources of Vit D
Processing
↑Ca ↑PO4 ↑ALP
- Increase Ca uptake in intestine by increase Calcium Binding Protein
- Increase Calcium resorption from bone in high dose
- Increase Phosphate uptake in intestine
Processing: vitamin D3 or D2
→ 25-hydroxylation in liver → calcidiol (25-(OH)-D3)
→ 1-hydroxylation in kidney → calcitriol (1,25-(OH)2-D3)
Source:
→ Dietary: D3 from animal, D2 from plants
→ Sunlight: D3
Physiological effects of Calcitonin
Source of Calcitonin
↓Ca ↓PO4
(physiologically negligible to Ca homeostasis as thyroidectomy does NOT affect serum Ca)
- Decrease Osteoclast-mediated bone resorption
- Decrease reabsorption of Ca from DCT in Kidney, Increase Phosphate excretion
Source: thyroid parafollicular C cells
List all physiological factors that modulate serum Ca level
PTH
Calcitonin
Vitamin D
Albumin: Alb-bound Ca amounts to 40% of plasma Ca
Phosphate level (affect ionic calcium balance, can precipitate Ca out of serum)
Serum pH level (affect ionic calcium level, H+ ions compete with Ca2+ ions for binding sites on albumin)
Corrected Calcium
- Indications
- Formula
Indication: Any condition with hypoalbuminaemia (most Ca bind to albumin, remainder bind to globulin)
Total Calcium may be low but Ionized Calcium is normal
- Nephrotic syndrome
- Liver cirrhosis
- Malnutrition
- Protein-losing enteropathy
- Acute or chronic inflammation (negative phase reactant)
- Absorptive problem: e.g. IBS, Bowel cancer…etc
Formula = Total Ca (mmol/L) + [0.02 x (40 - albumin in g/L)]
Albumin-corrected Ca =
For each ↓1g/L in Alb below 40g/L, Ca should be adjusted ↑0.02mmol/L (provided that Alb is between 20-51).
Role of albumin in blood
- regulation of colloid osmotic pressure or protein concentration within the blood plasma
- transport of free fatty acids and other molecules to the liver (unconjugated bilirubin, metals, ions) for storage or utilization
- binding of drugs and alteration of pharmacokinetics (half-life, biological activity levels, metabolism)
- buffering plasma pH
- scavenging reactive oxygen species to avoid inflammation and associated damage
- functioning as a reservoir of nitric oxide for the regulation of blood pressure
- prevention of coagulation and platelet aggregation in an action similar to the commonly used anticoagulant heparin
- inhibits inflammatory mediators such as TNF-α and complement 5a (C5a) to reduce the overall inflammatory response
Causes of Hypercalcemia
- Hyperparathyroidism (Primary or tertiary)
- Hypercalcemia of Malignancy
- Excessive vitamin D or Calcium (Vit. D intoxication, Milk alkali syndrome)
- Granulomatous disease - Increase sensitivity to Vitamin D (e.g. Tuberculosis, Sarcoidosis)
- Hypocalciuric Hypercalcemia (Thiazide diuretics, Familial mutation of Calcium sensing receptor CaSR)
- Adrenal insufficiency
- Hyperthyroidism
Pathophysiology of adrenal insufficiency causing Hypercalcemia
Hypovolaemia > Reduced GFR > Reduced calcium filtration > Increase Calcium renal reabsorption
Increase 1-alpha- hydroxylase activity > Increase intestinal absorption of Calcium
Outline the flowchart for approaching hypercalcaemia
S/S hypercalacaemia
Mostly asymptomatic
□ Non-specific: fatigue, depression, drowsiness, malaise
□ Specific: usually clinically a/w dehydration
→ Stones: nephrocalcinosis, renal stones (if long-standing)
→ Bones: bone pain, osteoporosis (if hyperPTH)
→ Moans: constipation, anorexia, abdominal pain, PUD, pancreatitis
→ Thrones: polyuria, dehydration, polydipsia
→ Psychic overtones: confusion, depression, anxiety, hallucination
□ Others: band keratopathy, short QTc, distal RTA
Outline mild, moderate and severe hypercalcaemia levels
Mild:
Serum Ca < 3 mmol/L
Moderate:
Serum Ca 3.0 - 3.5 mmol/L
Severe:
Serum Ca > 3.5 mmol/L
Management of mild symptomatic hypercalcaemia
- Avoid aggravating factors
- Maintain hydration
- Avoid high calcium diet (>1000mg/day)
Management of moderate/ severe hypercalcaemia
- Rapid control of Ca level
- Early Dx of underlying cause
Medical options:
- Fluid replacement with Saline +/- Loop diuretics
- IV bisphosphonate (Zoledronic acid or Pamidronate)
- Calcitonin (subcutaneous)
- Glucocorticoids (Prednisolone)
- Monoclonal antibodies against RANKL
- Dialysis
Fluid replacement for HyperCa
MoA, Monitoring
MoA:
- Infuse normal saline > inhibition of sodium reabsorption in PCT and Loop of Henle > Excretion of Calcium
Monitoring:
- Infusion rate depends on age, comorbid conditions (HF, CKD…etc)
- Monitor electrolytes and fluid balance
- Add Loop diuretics (Frusemide) if develop edema after rehydration
IV bisphosphonate for hyperCa
MoA
Indication
Time course
S/EE
MoA:
Inorganic pyrophosphate analog absored to surface of bone hydroxyapatite > Interfere with osteoclast-mediated bone resorption > Decrease Ca release from bone
Indication: Moderate to severe HyperCa
Time course: 1-2 days to take effect, 2-4 days for maximum effect
S/E: Osteonecrosis of jaw, Atypical fracture, Flu-like symptoms, renal impairment
Calcitonin for HyperCa
MoA
Time course
S/E
MoA: Increase renal Ca excretion and decrease bone resorption
Time course: Rapid onset, give subcutaneously every 12 hours (Salmon Calcitonin)
S/E: Nausea, Hypersensitivity reaction, Tachyphylaxis
Glucocorticoids for HyperCa
MoA
Indication
MoA: Decrease Calcitriol production by activated mononuclear cells
Indications:
- Excessive ingestion or admin. of Vitamin D
- Endogenous overproduction of calcitriol - Granulomatous diseases, lymphoma…etc
Monoclonal Ab against RANKL for HyperCA
MoA
Indication
Precaution
MoA:
Block the action of RANK Ligand released by Osteoblasts that increase formation, activity and survival of osteoclasts
Decrease bone resorption and Ca release
Indication:
Refractory Tx to IV bisphosphonate
Contraindicated for IV bisphosphonate due to renal failure (Denosumab not excreted through kidneys)
Persistent HyperCa due to malignancy
Precaution: Vitamin D depletion before admin.
Dialysis for HyperCa
Indication
Very severe HyperCa (Serum Ca > 4.5 mmol/L)
Refractory severe hyperCa complicated by renal failure (renders other therapy ineffective/ contraindicated)
Most common cause of hypercalcaemia
Epidemiology
Subtypes
Primary hyperparathyroidism
Epidemiology:
- 6th-7th decade
- F:M - 2-3:1
- 1-2/1000
Types:
- Solitary parathyroid adenoma (85%)
- Parathyroid hyperplasia (10-15%)
- Double adenoma (1-2%)
- Parathyroid carcinoma (1%)
Symptoms of severe hyperCa
Constitutional: Weakness, tiredness, anorexia
GIT: Nausea, vomiting, constipation
Nephrogenic DI: Thirst, dry mouth, polyuria
Neural: Mental confusion and drowsiness
Complications of severe hyperCa
Renal:
Renal stone, nephrocalcinosis, hypertension, renal failure
Bone:
Osteoporosis, bone pain, fracture, Parathyroid bone disease
Gastrointestinal:
Epigastric pain, dyspepsia
MSS:
Calcification of cartilage, joint pain
Endocrine: Multiple endocrine neoplasia (MEN1, MEN2)
Pharmacological effect of PTH on bones
Intermitted low dose (Teriparatide) - Anabolic action with increase BMD (indicated Osteoporosis)
Continuous high dose - Bone resorption (esp. cortical bone more than trabecular bone)
Features of parathyroid bone disease
Cystic osteitis fibrosa and osteopenia
Bone pain, subperiosteal resorption (esp. at phalanges)
Bone deformity: Bone cysts (esp. at central medullary parts of MCP, ribs and pelvis)
Osteoclastoma or Brown Tumors (esp. at trabecular portions of jaw, long bones and ribs)
Pathological fractures
Skull ‘salt and pepper’ appearance
Investigations for asymptomatic primary hyperparathyroidism
Biochemistry:
- Calcium, Phosphate, ALP
- Urea. Creatinine, eGFR (treatment guidance)
- 25 hydroxyvitamin D (for deficiency)
- PTH by immunoassay
Bone:
- DXA scan for BMD (at distal radius, hip or lumbar spine) for osteoporosis
- Vertebral spine assessment by X-ray or Vertebral fracture assessment by DXA
Urine:
24h urine calcium and creatinine
Abdominal:
Urinary stones by KUB, USG, CT
Optional: Bone turnover markers, TBS score by DXA, High-res peripheral quantitative CT
Indications for surgery in asymptomatic Primary hyperparathyroidism
Age under 50
Serum calcium >0.25 mmol/L
DXA T-score < -2.5 at lumbar spine, total hip, femoral neck or distal radius
Renal:
- Creatinine clearance <60cc/ min
- 24h urine calcium > 400mg/day
- Presence of nephrolithiasis or nephrocalcinosis by imaging
Monitoring asymptomatic primary hyperparathyroidism without surgery
Annual serum calcium measurement
DXA scan ever 1-2 years at 3 sites
X-ray of VFA spine if indicated
Renal: Annual eGFR, serum creatinine
Renal stone suspected: 24h biochemical stone profile, renal imaging
Pre-operative localization of primary hyperparathyroidism
Surgical planning by imaging:
- Parathyroid ultrasound (pre-op or intra-op)
- Nuclear scintigraphy (Tc-99m Sestamibi scan)/ SPECT
- CT with contrast - 4DCT scan
- MRI
MoA of Tc-99m of parathyroid glands
Tc-99m taken up by mitochondria-rich oxyphil cells in parathyroid gland
Planar images obtained shortly after injection and again at 2 hours to find foci of retained radio tracer activity
List all surgical options for primary hyperparathyroidism
Minimal invasive approach
Multi-glandular disease:
- Subtotal parathyroidectomy - resect 3.5 glands and preserve 50-80mg vascularized gland
- Total thyroidectomy - with autotransplantation to forearm or cryopreservation for later transplant
Intra-operative monitoring technique during parathyroid surgery
PTH half-life - 4 minutes in pt with normal renal function
Drop in serum PTH: 5-10mins
Miami Criterion - 50% fall in PTH compared to highest of either pre-manipulation or pre-excision sample
Serum calcium takes 1-2 days to fall so NOT USED for intra-op monitoring
Advantages and pre-requisites of Minimally invasive parathyroid surgery
Advantages:
- Improve cosmesis
- Short hospital stay
- Decrease wound pain
- Reduce morbidity
- Decrease overall cost
Pre-requisites
- Pre-operative or intra-operative localization
- Intra-operative PTH assay monitoring
Cause of secondary and tertiary hyperparathyroidism
Secondary: Physiological response to hypocalcemic state > increase PTH secretion
Tertiary: Prolonged secondary hyperparathyroidism > Parathyroid hyperplasia > autonomous secretion of PTH
Medical treatment option of Primary hyperparathyroidism
MoA
Indication
Calcimimetics: mimic calcium by allosteric action on Calcium Sensing Receptor
Indication:
- Surgery not appropriate or contraindicated
- Severe hypercalcemia unable to undergo parathyroidectomy
- Only normalize serum Ca, no effect on BMD
+ regular monitoring of annual serum Ca, DXA of 3 sites and Xray spine
+ eGFR and Creatinine + biochemical stone profile and imaging if needed
Tumors most linked with hypercalcemia
Lung (Squamous cell)
Breast
head and neck (Squamous)
Kidney
Myeloma
Lymphoma
Mechanisms of hypercalcemia of malignancy
- PTH-related peptide - PTHrP secretion
- Bone metastases with direct local destruction or induction of local osteolysis by tumor cells
- Lymphokine production that activate osteoclasts by hematological cancer (e.g. Multiple Myeloma)
- Extra-renal production of 1,25 dihydroxy-vitamin D (e.g. Adult T-cell lymphoma)
Hypocalcemia
- Cut-off
Serum Ca under 1.9mmol/L
S/S of hypocalcaemia
hypoCa leads to generalized hyperexcitability, symptomatic when [Ca] <2mmol/L
Sequence: sensory symptoms → latent tetany → gross spasm → laryngospasm → arrhythmia
CATS - Convulsion, Arrhythmia, Tetany, Seizures and sensory changes
□ Sensory changes: paraesthesia, perioral numbness
□ Tetany: muscle spasms, convulsions, stridor (laryngeal spasm)
→ Carpopedal spasm: hand and feet spasms with hand adopting characteristic ‘main d’accoucheur’ appearance71
→ Chvostek’s sign: tapping CN VII branches triggers facial twitching
→ Trousseau’s sign: inflation of BP cuff >sysBP triggers carpal spasm within 3min
□ Seizures: generalized tonic-clonic, absence, focal
□ Heart: long QT, T wave inversion, arrhythmias (eg. TdP)
Investigations for PTH-independent hyperCa
screen for occult malignancy should be done:
□ CXR for CA lung
□ Serum/urine protein electrophoresis for multiple myeloma
□ Mammogram
□ CT abdomen, thorax
Management of hypercalcaemia of malignancy
Management:
□ Acute Tx for severe hyperCa → IV saline, bisphosphonate ± calcitonin
□ Novel agents
MAb vs RANKL, eg. denosumab
Recombinant OPG
□ Monitor underlying tumour status ± modification of Tx (frequently a sign of tumour progression
S/S of chronic hypoCa
□ Chronic effects:
→ Neurological: basal ganglion calcification, generalized epilepsy, psychosis
→ Musculoskeletal: rickets, osteomalacia, dental hypoplasia
→ Dermatological: alopecia, brittle nails, dry skin
→ Others: cataract
HypoCa causes
Management of HypoCa
look for causes and treat accordingly!
Severe or symptomatic: Ca < 1.9
→ IV 10% Ca gluconate infusion
→ Close monitoring of serum Ca
→ECG and cardiac monitoring
Mild: Ca > 1.9
First-line: Oral Ca replacement - Caltrate, Oscal, Calcium gluconate
Second-line: add vitamin D
Third-line: 1,25-(OH)2-D3 added
Explain why most chronic renal failure presents with hypoCa
Mechanism:
→ ↓renal Ca reabsorption
→ ↓renal vitamin D3 formation
→ PO4 retention → ↑bound Ca + metastatic calcification
→ Uraemia → poor appetite → ↓GI/oral intake
→ Uraemia → bone resistance to PTH
Typical serum Ca level under HypoMg
classically a/w hypoK + hypoCa refractory to replacement
□ Mechanism: ↓PTH action and secretion
□ Mx: IV MgSO4 if severe, Mylanta / Mg tri if mild
Pseudohypoparathyroidism
- Cause
- S/S
- Dx
PseudohypoPTH (PHP):
□ Cause: maternal GNAS1 mutation (encoding for Gsα gene important for PTHr)
□ S/S: typically presents with Biochemical hypoPTH (↓Ca, ↑PO4) with ↑PTH and parathyroid hyperplasia Albright hereditary osteodystrophy (AHO) with mental retardation, short stature and shortened 4th and 5th metacarpals
□ Diagnosis: genetic testing
Causes of Vitamin D failure
failure: a/w a biochemical picture of ↓Ca ↓PO4
□ Causes:
↓intake: malnutrition, malabsorption
↓metabolism: ↓di-hydroxylation (liver disease), ↓hydroxylation (renal disease)
↓response: type II vitamin D-dependent rickets, type I vitamin D-dependent rickets
↑clearance of calcitriol: nephrotic syndrome, drugs (Dilantin, alcohol, glutethimide)
Investigation for Vitamin D failure
25-(OH)-D3 reflects level of intake and production
- Low → nutritional insufficiency
1,25-(OH)2-D3 reflects level of active hormone
- High/normal → type II vitamin D-dependent rickets (VDDR)
Cause: vitamin D receptor defect, NOT amenable to calcitriol replacement
- Low → type I vitamin D-dependent rickets (VDDR)
Cause: 1α-hydroxylase deficiency, amenable to calcitriol replacement
