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MBBS IV - Junior Clerkship WCS > JC 37 (Medicine) - Hyper- and Hypocalcaemia > Flashcards

JC 37 (Medicine) - Hyper- and Hypocalcaemia Flashcards

1
Q

Physiological effects of PTH

Source of PTH

A

↑Ca ↓PO4 ↑ALP

  1. Increase Ca resorption from bone via osteoblasts and osteoclasts
  2. Increase reabsorption of Ca from DCT in kidneys, Decrease Phosphate reabsorption
  3. Increase intestinal uptake of Ca via formation of 1,25-dihydroxyvitamin D

Source: parathyroid chief cells

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2
Q

Physiological effects of Vitamin D

Sources of Vit D

Processing

A

↑Ca ↑PO4 ↑ALP

  1. Increase Ca uptake in intestine by increase Calcium Binding Protein
  2. Increase Calcium resorption from bone in high dose
  3. 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

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3
Q

Physiological effects of Calcitonin

Source of Calcitonin

A

↓Ca ↓PO4

(physiologically negligible to Ca homeostasis as thyroidectomy does NOT affect serum Ca)

  1. Decrease Osteoclast-mediated bone resorption
  2. Decrease reabsorption of Ca from DCT in Kidney, Increase Phosphate excretion

Source: thyroid parafollicular C cells

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4
Q

List all physiological factors that modulate serum Ca level

A

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)

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5
Q

Corrected Calcium

  • Indications
  • Formula
A

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).

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6
Q

Role of albumin in blood

A
  1. regulation of colloid osmotic pressure or protein concentration within the blood plasma
  2. transport of free fatty acids and other molecules to the liver (unconjugated bilirubin, metals, ions) for storage or utilization
  3. binding of drugs and alteration of pharmacokinetics (half-life, biological activity levels, metabolism)
  4. buffering plasma pH
  5. scavenging reactive oxygen species to avoid inflammation and associated damage
  6. functioning as a reservoir of nitric oxide for the regulation of blood pressure
  7. prevention of coagulation and platelet aggregation in an action similar to the commonly used anticoagulant heparin
  8. inhibits inflammatory mediators such as TNF-α and complement 5a (C5a) to reduce the overall inflammatory response
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7
Q

Causes of Hypercalcemia

A
  1. Hyperparathyroidism (Primary or tertiary)
  2. Hypercalcemia of Malignancy
  3. Excessive vitamin D or Calcium (Vit. D intoxication, Milk alkali syndrome)
  4. Granulomatous disease - Increase sensitivity to Vitamin D (e.g. Tuberculosis, Sarcoidosis)
  5. Hypocalciuric Hypercalcemia (Thiazide diuretics, Familial mutation of Calcium sensing receptor CaSR)
  6. Adrenal insufficiency
  7. Hyperthyroidism
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8
Q

Pathophysiology of adrenal insufficiency causing Hypercalcemia

A

Hypovolaemia > Reduced GFR > Reduced calcium filtration > Increase Calcium renal reabsorption

Increase 1-alpha- hydroxylase activity > Increase intestinal absorption of Calcium

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9
Q

Outline the flowchart for approaching hypercalcaemia

A
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10
Q

S/S hypercalacaemia

A

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

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11
Q

Outline mild, moderate and severe hypercalcaemia levels

A

Mild:

Serum Ca < 3 mmol/L

Moderate:

Serum Ca 3.0 - 3.5 mmol/L

Severe:

Serum Ca > 3.5 mmol/L

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12
Q

Management of mild symptomatic hypercalcaemia

A
  1. Avoid aggravating factors
  2. Maintain hydration
  3. Avoid high calcium diet (>1000mg/day)
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13
Q

Management of moderate/ severe hypercalcaemia

A
  1. Rapid control of Ca level
  2. 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
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14
Q

Fluid replacement for HyperCa

MoA, Monitoring

A

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
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15
Q

IV bisphosphonate for hyperCa

MoA

Indication

Time course

S/EE

A

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

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16
Q

Calcitonin for HyperCa

MoA

Time course

S/E

A

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

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17
Q

Glucocorticoids for HyperCa

MoA

Indication

A

MoA: Decrease Calcitriol production by activated mononuclear cells

Indications:

  • Excessive ingestion or admin. of Vitamin D
  • Endogenous overproduction of calcitriol - Granulomatous diseases, lymphoma…etc
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18
Q

Monoclonal Ab against RANKL for HyperCA

MoA

Indication

Precaution

A

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.

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19
Q

Dialysis for HyperCa

Indication

A

Very severe HyperCa (Serum Ca > 4.5 mmol/L)

Refractory severe hyperCa complicated by renal failure (renders other therapy ineffective/ contraindicated)

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20
Q

Most common cause of hypercalcaemia

Epidemiology

Subtypes

A

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%)
21
Q

Symptoms of severe hyperCa

A

Constitutional: Weakness, tiredness, anorexia

GIT: Nausea, vomiting, constipation

Nephrogenic DI: Thirst, dry mouth, polyuria

Neural: Mental confusion and drowsiness

22
Q

Complications of severe hyperCa

A

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)

23
Q

Pharmacological effect of PTH on bones

A

Intermitted low dose (Teriparatide) - Anabolic action with increase BMD (indicated Osteoporosis)

Continuous high dose - Bone resorption (esp. cortical bone more than trabecular bone)

24
Q

Features of parathyroid bone disease

A

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

25
Q

Investigations for asymptomatic primary hyperparathyroidism

A

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

26
Q

Indications for surgery in asymptomatic Primary hyperparathyroidism

A

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
27
Q

Monitoring asymptomatic primary hyperparathyroidism without surgery

A

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

28
Q

Pre-operative localization of primary hyperparathyroidism

A

Surgical planning by imaging:

  • Parathyroid ultrasound (pre-op or intra-op)
  • Nuclear scintigraphy (Tc-99m Sestamibi scan)/ SPECT
  • CT with contrast - 4DCT scan
  • MRI
29
Q

MoA of Tc-99m of parathyroid glands

A

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

30
Q

List all surgical options for primary hyperparathyroidism

A

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
31
Q

Intra-operative monitoring technique during parathyroid surgery

A

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

32
Q

Advantages and pre-requisites of Minimally invasive parathyroid surgery

A

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
33
Q

Cause of secondary and tertiary hyperparathyroidism

A

Secondary: Physiological response to hypocalcemic state > increase PTH secretion

Tertiary: Prolonged secondary hyperparathyroidism > Parathyroid hyperplasia > autonomous secretion of PTH

34
Q

Medical treatment option of Primary hyperparathyroidism

MoA

Indication

A

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

35
Q

Tumors most linked with hypercalcemia

A

Lung (Squamous cell)

Breast

head and neck (Squamous)

Kidney

Myeloma

Lymphoma

36
Q

Mechanisms of hypercalcemia of malignancy

A
  1. PTH-related peptide - PTHrP secretion
  2. Bone metastases with direct local destruction or induction of local osteolysis by tumor cells
  3. Lymphokine production that activate osteoclasts by hematological cancer (e.g. Multiple Myeloma)
  4. Extra-renal production of 1,25 dihydroxy-vitamin D (e.g. Adult T-cell lymphoma)
37
Q

Hypocalcemia

  • Cut-off
A

Serum Ca under 1.9mmol/L

38
Q

S/S of hypocalcaemia

A

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)

39
Q

Investigations for PTH-independent hyperCa

A

screen for occult malignancy should be done:
□ CXR for CA lung
□ Serum/urine protein electrophoresis for multiple myeloma
□ Mammogram
□ CT abdomen, thorax

40
Q

Management of hypercalcaemia of malignancy

A

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

41
Q

S/S of chronic hypoCa

A

□ Chronic effects:
→ Neurological: basal ganglion calcification, generalized epilepsy, psychosis
→ Musculoskeletal: rickets, osteomalacia, dental hypoplasia
→ Dermatological: alopecia, brittle nails, dry skin
→ Others: cataract

42
Q

HypoCa causes

A
43
Q

Management of HypoCa

A

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

44
Q

Explain why most chronic renal failure presents with hypoCa

A

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

45
Q

Typical serum Ca level under HypoMg

A

classically a/w hypoK + hypoCa refractory to replacement
□ Mechanism: ↓PTH action and secretion
□ Mx: IV MgSO4 if severe, Mylanta / Mg tri if mild

46
Q

Pseudohypoparathyroidism

  • Cause
  • S/S
  • Dx
A

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

47
Q

Causes of Vitamin D failure

A

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)

48
Q

Investigation for Vitamin D failure

A

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

MBBS IV - Junior Clerkship WCS (131 decks)

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