Endocrine JC037: Confused And Dehydrated: Hypercalcaemia, Hypocalcaemia

Question 1

Organs involved in Ca homeostasis

Answer 1

1. Parathyroid glands
2. Kidneys
3. Bones
4. Intestines

Question 2

***Parathyroid hormone, Vitamin D, Calcitonin

Answer 2

Parathyroid hormone:
1. ↑ Ca resorption from bone via osteoblasts + osteoclasts
2. ↑ Ca reabsorption from DCT
3. ***↓ PO4 reabsorption from PCT
4. Indirect effect: ↑ Ca uptake from intestine via its effect on formation of 1,25(OH)2D3 (Calcitriol) in kidney

Vitamin D:
1. ↑ Ca uptake in intestine by ↑ Ca binding protein
2. ***↑ PO4 absorption in intestine
3. ↑ Ca resorption from bone (in high doses)

Calcitonin:
1. ↓ Osteoclast mediated bone resorption
2. ↓ Ca reabsorption from kidney

Question 3

Other factors affecting Ca homeostasis

Answer 3

1. ***Albumin (50% of plasma Ca)
2. ***PO4 (affect ionic balance of Ca via PTH action)
3. ***pH (affect ionic Ca level)
   - acidosis —> carboxyl groups on albumin becomes neutral —> Ca cannot bind —> release more free ionised Ca —> HyperCa
   - alkalosis —> carboxyl groups on albumin becomes -ve (COO-) —> Ca bind to albumin —> less free ionised Ca —> HypoCa

Question 4

Adjusted / Corrected Ca

Answer 4

Hypoalbuminaemia —> Total Ca may be low but Ionised Ca normal

***Corrected Ca = Total Ca + [0.02 x (40 - albumin)]
- only an approximation
- derived from cirrhosis patient (other patient groups not much evidence)
- measurement of ionised Ca is better

Example:
Total Ca: 2.2 (low) (normal: 2.2-2.6)
Albumin: 25 (low, ∵ nephrotic syndrome, cirrhosis)
Corrected Ca = 2.2 + [0.02 x (40-25)] = 2.2 + 0.3 = 2.5 (normal)
—> Pseudohypocalcaemia (could be due to nephrotic syndrome / cirrhosis)
—> Ionised Ca will be normal

Question 5

***Causes of HyperCa

Answer 5

1. Hyperparathyroidism
   - ***Primary (common)
   - Tertiary
2. ***Hypercalcaemia of malignancy
3. Excessive administration of Vit D / Ca
   - ***Vit D intoxication
   - Milk alkali syndrome (past, excessive intake of Ca + absorbable alkali)
4. ↑ Sensitivity to Vit D
   - ***Granulomatous disease: TB, Sarcoidosis
5. ***Hypocalciuric hypercalcaemia
   - Thiazide diuretics
   - Familial (AD: mutation of Ca sensing receptor CaSR)
6. Uncommon causes
   - ***Adrenal insufficiency
   - Hyperthyroidism (∵ ↑ bone remodelling, will normalise after adequate treatment of hyperthyroidism)

Question 6

Adrenal insufficiency and Hypercalcaemia

Answer 6

Unknown mechanism

Possible mechanisms:
- Hypovolaemia —> ↓ GFR —> ↓ Ca filtered —> ↑ Ca renal reabsorption
- ↑ 1α-hydroxylase activity —> ↑ Calcitriol —> ↑ Ca intestinal absorption

Question 7

Approach to HyperCa

Answer 7

Measure serum **total + **ionised Ca

1. Normal Ca
   - haemoconcentration / serum protein abnormality
2. Genuine ↑ Ca
   (—> History, P/E, electrolytes, BUN, creatinine, PO4, ALP)
   —> ***Serum PTH

—> Normal (inappropriately normal) / High PTH
—> ***PTH-dependent HyperCa

—> Low (i.e. Suppressed PTH)
—> **PTH-independent HyperCa
—> Search for malignancy (CXR, Serum / Urine immunoelectrophoresis IEP, Mammogram, Abdominal / Chest CT)
—> Yes: **Malignancy-associated HyperCa —> Therapy for cancer, Bisphosphonate
—> No: Evaluate for other causes of PTH-independent HyperCa

Question 8

Classification of HyperCa

Answer 8

Asymptomatic / Mildly symptomatic HyperCa:
- Serum Ca <3
- **N+V, fatigue
- management:
—> **adequate hydration
—> avoid factors that aggravate hyperCa (e.g. OTC Ca supplement)
—> avoid high Ca diet (>1000 mg/day)

Moderate HyperCa:
- Serum Ca 3-3.5

Severe HyperCa:
- Serum Ca **>3.5
- **↓ general sensorium, ↓ consciousness, dehydration, renal failure
- management:
—> rapid control of Ca levels
—> early diagnosis of cause

Question 9

***Management of HyperCa

Answer 9

1. Fluid replacement (Normal saline), Loop Diuretic
2. IV Bisphosphonate
3. Calcitonin
4. Glucocorticoids (suppress granulomatous diseases)
5. Monoclonal Ab against RANKL (Denosumab)
6. Dialysis

Question 10

1. Fluid replacement

Answer 10

1. **Normal saline Volume expansion
   - **Excretion of Ca achieved by ***inhibition of Na reabsorption in PCT, LoH
   - Rate of saline infusion depends on other factors e.g. age, comorbid conditions (heart failure, CKD etc.) —> avoid fluid overload
2. Monitor electrolytes (Ca, PO4) + fluid balance
3. ***Loop diuretics only if patients develop edema

Question 11

2. IV Bisphosphonates

Answer 11

• Useful agents in moderate / severe hyperCa
• IV Pamidronate / Zoledronate (Zometa)

MOA:
- Nonhydrolyzable analogs of inorganic pyrophosphate
- Adsorb to surface of bone hydroxyapatite —> interfere with osteoclast-mediated bone resorption

Administration:
- Serum Ca might begin to ↓ in 1-2 days, but max effect occurs in ***2-4 days
- repeat dosing after minimum of 7 days

SE:
- flu-like symptoms
- ***renal impairment (CI in eGFR <35) (Zoledronate <30; Alendronate <35 (SpC Medicine))
- erosive esophagitis
- adynamic bone
- osteonecrosis of jaw (prolonged use)
- atypical fractures (prolonged use)

Question 12

3. Calcitonin

Answer 12

• Relatively weak agent but works ***rapidly within hours
• Good choice for CKD (if Bisphosphonate CI)

MOA:
- ↑ Renal Ca excretion
- ↓ Bone resorption

Administration:
- SC every 12 hours (salmon calcitonin 4 IU/kg)
- Nasal sprays not efficacious for treatment of hyperCa (for ***pain control in osteoporosis only)

SE:
- Tachyphylaxis
- Nausea
- Hypersensitivity reaction (rare)

Question 13

4. Glucocorticoids

Answer 13

MOA:
- ***↓ Calcitriol production by activated mononuclear cells

Indications:
1. Excessive administration / ingestion of Vit D (**Vit D intoxication)
2. Endogenous overproduction of Calcitriol (e.g. chronic **granulomatous diseases, lymphoma)

Administration:
- Prednisolone 20-40 mg/day

Question 14

5. Monoclonal Ab against RANKL

Answer 14

MOA:
- inhibit RANKL —> inhibit function / survival of osteoclasts —> inhibit excessive bone resorption

Indications:
1. **Refractory hyperCa despite treatment with IV bisphosphonate
2. CI for IV bisphosphonate due to severe renal impairment
3. Useful agents in hyperCa of **malignancy with persistent hyperCa

Denosumab not excreted through kidneys —> can be given in CKD

Effect:
- ↓ Serum Ca in ***2-4 days

Administration:
- Ensure Vit D repleted before administration —> ∵ Vit D deficiency / CKD can go into severe hypoCa after denosumab

Question 15

6. Dialysis

Answer 15

• Reserved for very severe forms of hyperCa (e.g. Serum Ca ***>4.5)
• ***Refractory server hyperCa complicated by renal failure which renders other forms of therapy ineffective / CI

Question 16

Primary hyperparathyroidism

Answer 16

• Autonomous ↑ in PTH from PTH gland
• ***Most common cause of HyperCa
• Prevalence ~1-2/1000
• Peaks in 6th-7th decade
• F:M ~2-3:1

Causes:
1. **Solitary parathyroid adenoma (~85%)
2. **Hyperplasia (~10-15%)
3. Double adenoma (1-2%)
4. Parathyroid carcinoma (~1%)

S/S:
- Classical symptoms are RARE (bones, stones, abdominal groans, psychiatric overtones)
—> Bones: Osteoporosis, Fragility fracture
—> Stones: Renal stones
—> Abdominal groans: Anorexia, Nausea, Constipation
—> Psychiatric overtones: Fatigue, Weakness, Depressed mood, Psychosis

Clinical presentation:
1. Incidental finding of mild hyperCa (common nowadays)

2. Symptoms of severe hyperCa
   - weakness, tiredness, anorexia
   - N+V, constipation, thirst, dry mouth, **polydipsia, **polyuria (∵ hyperCa —> insensitive to ADH in Distal tubule —> cause ***Nephrogenic DI)
   - mental confusion, drowsiness
3. Renal complications
   - renal stone, nephrocalcinosis, hypertension, renal failure
4. Bone complications
   - osteoporosis, bone pain, fractures
5. GI manifestations
   - epigastric pain / dyspepsia
6. Joint pain
   - ***calcification of cartilage
7. Multiple endocrine neoplasia (***MEN syndrome)
   - MEN1, 2A

Question 17

PTH action on bone

Answer 17

Rmb:
- Continuously high level (e.g. Primary Hyperparathyroidism) —> ↑ Bone resorption (with cortical bone worse than trabecular bone)
- Intermittent low dose (e.g. Teriparatide (recombinant PTH)) —> ***Anabolic action with ↑ BMD

Question 18

Bone disorders in Hyperparathyroidism

Answer 18

1. Demineralisation with weakening of bones / even fracture
   - Low BMD esp. in ***cortical bone more common (e.g. distal 1/3 of forearm)
   (Spine, Hip more trabecular bone than cortical bone)
2. Parathyroid bone disease (late presentation)
   - Cystic osteitis fibrosa (Brown tumour) + osteopenia
   - Bone pain, subperiosteal resorption
   - Bone deformities
   —> severe bone disease now uncommonly seen

X-ray features:
1. Osteoclastic resorption of smaller trabeculae

2. ***Subperiosteal resorption
   - most evidence on phalanges
3. ***Bone cysts
   - mostly in central medullary portions of shafts of MCP, ribs, pelvis
   - haemorrhage within —> Brown tumour
4. ***Osteoclastomas / Brown tumours
   - made up of numerous multinucleated osteoclasts with stromal cells and matrix in trabecular portions of jaw, long bones and ribs
5. ***Skull salt and pepper appearance
6. ***Pathological fractures

Question 19

***Investigation for asymptomatic Primary Hyperparathyroidism

Answer 19

記: 睇血, 尿, 骨, 石

Basic
1. Biochemistry
- **Ca, **PO4
- **25OH Vit D (Calcidiol, check if Vit D deficiency —> disease more active when Vit D deficient (stimulate PTH) —> correction of Vit D —> ↓ PTH level)
- **ALP (check **GGT to confirm bone origin)
- **Urea, Creatinine, eGFR (check if Ca already affect kidneys)

2. ***PTH by 2nd / 3rd gen immunoassay

Complications
3. DXA for BMD (***3 site DXA: lumbar spine / hip / distal 1/3 radius)
- T score <= -2.5 (if peri/post-menopausal women + men >=50)
- Z score <= -2.5 (premenopausal / men <50)

4. Vertebral spine assessment (X-ray / Vertebral fracture assessment by DXA)
   - exclude vertebral collapse
5. **24 hour urine for Ca, Cr (for **fractional excretion of Ca) (—> exclude FHH (self notes))
6. Abdominal imaging by KUB, USG kidneys, CT scan for urinary stones
7. Optional
   - Bone turnover markers
   - Trabecular bone score (TBS) by DXA
   - High resolution peripheral quantitative CT (HRpQCT)

Question 20

Indications of Surgery in ***Asymptomatic PHPTH

Answer 20

Look at several parameters:
1. **Serum Ca level (0.25 mmol/L / 1 mg/dL above ULN, ?>3, high likelihood of complications)
2. **Osteoporosis (T-score <-2.5) / Vertebral fracture
3. **eGFR <60
4. **24 hour urine Ca >400 + ↑ stone risk by biochemical stone risk analysis
- exclude FHH (by fractional excretion of Ca) —> low FECa in FHH (vs high in PHPTH)
5. **Presence of nephrolithiasis / nephrocalcinosis by X-ray, USG, CT
6. **Young <50

If not undergo surgery, monitor
1. Serum Ca annually
2. DXA every 1-2 years
3. RFT annually

Question 21

Pre-op preparation: Preoperative localisation

Answer 21

• guide surgeon planning surgical strategy
• ***NOT diagnostic procedure
• negative / discordant imaging studies should NOT inhibit referral to an experienced parathyroid surgeon

1. **USG Parathyroid
   - Pre-op / Intra-op
   - Limited in its ability to evaluate **retroesophageal lesions / ***mediastinal parathyroid glands
2. **Nuclear Scintigraphy
   - **99mTc-Sestamibi Scan / Single photon emission CT (SPECT)
   - 99mTc-Sestamibi Scan taken up by mitochondria in thyroid + parathyroid tissue, but only retained by **mitochondria-rich oxyphil cells in parathyroid glands + is longer than in thyroid tissue
   - Difference in retention —> determine whether there is parathyroid adenoma
   - Planar images obtained shortly after injection and again at ~2 hours to identify foci of **retained radiotracer activity consistent with a ***hyper-functioning parathyroid tissue
3. CT
   - 4D contrast parathyroid (multiple scans obtained after administration of **IV contrast)
   - Parathyroid adenomas have **rapid contrast uptake + washout
   - High radiation exposure
4. MRI

(5. Operative: Cervical exploration (SpC Medicine))

Question 22

Surgery: Minimally invasive approach

Answer 22

• Subjected to multiple interpretations (already localised the lesion)
• Commonly imply ***image-guided, focused operation
• Under local / regional anaesthesia
• Small incisions
• Open technique / Endoscopic approaches
• Curative results can >98% + nerve injury rates <1%

Potential advantages:
1. Improve cosmesis
2. ↓ hospital stay
3. ↓ wound pain
4. ↓ morbidity
5. ↓ overall cost

Prerequisites:
1. Pre-op / Intra-op localisation
2. ***Intraoperative PTH assay (monitor PTH intraoperatively)

Question 23

Intraoperative PTH assay

Answer 23

• To monitor success of Parathyroid surgery
• t1/2 of PTH: ***3.5-4 mins (very short) in patients with normal renal function
• ↓ in serum PTH: 5-10 mins
• ↓ in Ca: 24-48 hours
• 7 min incubation + 15 min assay result
• **Miami criterion: **50% ↓ of PTH 10 mins post-excision compared to highest (i.e. baseline) of either premanipulation / pre-excision sample
  —> can be sure that parathyroid adenoma has been resected

Question 24

Parathyroid surgery for Multi-glandular disease

Answer 24

1. Subtotal parathyroidectomy
   - resection of 3.5 glands
   - preserve 50-80mg vascularised gland
2. Total parathyroidectomy
   - total parathyroidectomy with immediate autotransplantation to forearm
   - cryopreservation for possible delayed autotransplantation

SpC Revision:
Primary HPT:
- Focused approach parathyroidectomy / 4-gland exploration

Secondary HPT:
- Total parathyroidectomy + reimplantation

Tertiary HPT:
- Subtotal parathyroidectomy / Total parathyroidectomy + reimplantation

Question 25

Secondary / Tertiary Hyperparathyroidism

Answer 25

• Physiological response of PTH secretion to **Hypocalcaemic state (e.g. chronic renal failure (deficient conversion to active Vit D), Vit D deficiency)
  —> Secondary hyperparathyroidism (Low / Normal Ca)
  —> Prolonged Secondary hyperparathyroidism may result in **parathyroid hyperplasia + autonomous secretion of PTH
  —> Tertiary hyperparathyroidism + HyperCa

Question 26

Medical management of Primary Hyperparathyroidism

Answer 26

**Calcimimetics (Cinacalcet)
- mimic action of Ca on tissues by allosteric action of Ca-sensing receptor expressed in various tissues
- for patients whom parathyroidectomy indicated but surgery not clinically appropriate / contraindicated
- for severe hyperCa unable to undergo surgery
- **effective in ↓ + normalising serum Ca
- **less effective in ↓ serum PTH
- **no consistent observed effects on BMD

Question 27

***Hypercalcaemia of Malignancy

Answer 27

Tumours most commonly linked with HyperCa:
1. Lung (squamous cell)
2. Breast
3. Head + Neck (squamous cell)
4. Kidney
5. Myeloma
6. Lymphoma

Mechanisms:
1. ***Bone metastasis with direct local destruction / induction of local osteolysis by tumour cells

2. Humoral mediated hyperCa (***PTH-related peptide; PTHrP)
   - e.g. Non-metastatic solid tumours (SCC lung / H+N), RCC, Bladder, Breast, Ovarian carcinoma
3. ***Lymphokine production by haematological malignancies that activate osteoclasts (e.g. multiple myeloma)
4. Extra-renal production of ***Calcitriol (e.g. Adult T-cell lymphoma)

Rmb: PTH ***suppressed (vs PHPTH: PTH high / inappropriately normal)

Question 28

Hypocalcaemia

Answer 28

Approach:
1. Confirm genuine hypoCa —> look at **Albumin levels —> need to adjust / measure ionised Ca
2. Check PTH (normally should be **High, if Low: Hypoparathyroidism)

Causes:
1. **Vit D deficiency (diet, malabsorption, chronic liver / renal disease)
2. **Hypoparathyroidism (idiopathic, familia, post-surgical (common after thyroidectomy / parathyroidectomy))
3. **Mg deficiency
4. Cytotoxic drug-induced hypoCa (e.g. Cisplatin)
5. Pancreatitis
6. Rhabdomyolysis
7. Large volume blood transfusion
8. Rare
- **Pseudohypoparathyroidism (PTH resistance, post-receptor defect —> patients will have short stature, brachydactyly, ↑↑ PTH)
- Abnormal Vit D synthetic pathway (1α-hydroxylase deficiency / Cacitriol resistance)

S/S:
- Symptoms of HypoCa typically develop when adjusted serum Ca **<1.9 mmol/L (although varies)
- Also depends on **Rate of ↓ of Ca

Clinical presentation (CATS: Convulsion, Arrhythmia, Tetany, Spasm):
1. **Perioral / Digital paresthesia
2. Neuromuscular irritability (Trousseau’s sign, **Chvostek’s sign)
- Tetany + Carpopedal spasm
3. Convulsion
4. **Laryngeal spasm —> respiratory depression
5. **ECG: Prolonged QT interval (do ECG once Ca <2!!!)

Question 29

Treatment of HypoCa

Answer 29

Most important: Look for cause + treat accordingly!

Mild (Adjusted Ca >1.9):
1. ***Oral Ca replacement
- Caltrate
- Oscal
- Ca gluconate

2. ***Vit D replacement (for Vit D deficiency)
   - consider adding if no response after 2-4g Ca

Symptomatic / Severe (Adjusted Ca <1.9):
1. **ECG + Cardiac monitoring
2. **IV Ca gluconate infusion
3. Monitor Ca closely (Q6-8h)

Question 30

***Common clinical scenarios

Answer 30

1. Primary hyperparathyroidism
   - Ca: ↑
   - PO4: ↓ / low-normal
   - PTH: ↑ / inappropriately normal
2. Primary hypoparathyroidism
   - Ca: ↓
   - PO4: ↑ (∵ lack of PTH —> lack PO4 clearance) / high-normal
   - PTH: ↓ / inappropriately normal
3. Secondary hyperparathyroidism
   Chronic renal failure
   - Ca: ↓ / low-normal (∵ poor calcitriol conversion)
   - PO4: **↑ (impaired clearance ∵ poor renal function)
   - PTH: normal / **↑ (compensatory)
4. Tertiary hyperparathyroidism
   - Ca: ↑
   - PO4: ↑
   - PTH: ↑
5. Vit D insufficiency (insufficient sunlight)
   - Ca: ↓ (∵ impaired intestinal absorption) / normal
   - PO4: ↓ (∵ impaired intestinal absorption) / normal
   - PTH: ↑ (compensatory)
6. Vit D intoxication
   - Ca: ↑ (∵ ↑ intestinal absorption)
   - PO4: ↑ (∵ ↑ intestinal absorption)
   - PTH: ↓ (suppressed)
7. Bone metastasis
   - Ca: normal / **↑ (∵ bone destruction)
   - PO4: normal
   - PTH: normal / **↓ (suppressed)
8. PTH-rP
   - Ca: ↑
   - PO4: ↓
   - PTH: normal / ***↓ (suppressed)