Endocrine JC037: Confused And Dehydrated: Hypercalcaemia, Hypocalcaemia Flashcards
Organs involved in Ca homeostasis
- Parathyroid glands
- Kidneys
- Bones
- Intestines
***Parathyroid hormone, Vitamin D, Calcitonin
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
Other factors affecting Ca homeostasis
- ***Albumin (50% of plasma Ca)
- ***PO4 (affect ionic balance of Ca via PTH action)
- ***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
Adjusted / Corrected Ca
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
***Causes of HyperCa
- Hyperparathyroidism
- ***Primary (common)
- Tertiary - ***Hypercalcaemia of malignancy
- Excessive administration of Vit D / Ca
- ***Vit D intoxication
- Milk alkali syndrome (past, excessive intake of Ca + absorbable alkali) - ↑ Sensitivity to Vit D
- ***Granulomatous disease: TB, Sarcoidosis - ***Hypocalciuric hypercalcaemia
- Thiazide diuretics
- Familial (AD: mutation of Ca sensing receptor CaSR) - Uncommon causes
- ***Adrenal insufficiency
- Hyperthyroidism (∵ ↑ bone remodelling, will normalise after adequate treatment of hyperthyroidism)
Adrenal insufficiency and Hypercalcaemia
Unknown mechanism
Possible mechanisms:
- Hypovolaemia —> ↓ GFR —> ↓ Ca filtered —> ↑ Ca renal reabsorption
- ↑ 1α-hydroxylase activity —> ↑ Calcitriol —> ↑ Ca intestinal absorption
Approach to HyperCa
Measure serum **total + **ionised Ca
- Normal Ca
- haemoconcentration / serum protein abnormality - 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
Classification of HyperCa
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
***Management of HyperCa
- Fluid replacement (Normal saline), Loop Diuretic
- IV Bisphosphonate
- Calcitonin
- Glucocorticoids (suppress granulomatous diseases)
- Monoclonal Ab against RANKL (Denosumab)
- Dialysis
- Fluid replacement
-
**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 - Monitor electrolytes (Ca, PO4) + fluid balance
- ***Loop diuretics only if patients develop edema
- IV Bisphosphonates
- 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)
- Calcitonin
- 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)
- Glucocorticoids
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
- Monoclonal Ab against RANKL
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
- Dialysis
- 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
Primary hyperparathyroidism
- 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)
- 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 - Renal complications
- renal stone, nephrocalcinosis, hypertension, renal failure - Bone complications
- osteoporosis, bone pain, fractures - GI manifestations
- epigastric pain / dyspepsia - Joint pain
- ***calcification of cartilage - Multiple endocrine neoplasia (***MEN syndrome)
- MEN1, 2A
PTH action on bone
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
Bone disorders in Hyperparathyroidism
- 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) - 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
- ***Subperiosteal resorption
- most evidence on phalanges - ***Bone cysts
- mostly in central medullary portions of shafts of MCP, ribs, pelvis
- haemorrhage within —> Brown tumour - ***Osteoclastomas / Brown tumours
- made up of numerous multinucleated osteoclasts with stromal cells and matrix in trabecular portions of jaw, long bones and ribs - ***Skull salt and pepper appearance
- ***Pathological fractures
***Investigation for asymptomatic Primary Hyperparathyroidism
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)
- ***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)
- Vertebral spine assessment (X-ray / Vertebral fracture assessment by DXA)
- exclude vertebral collapse - **24 hour urine for Ca, Cr (for **fractional excretion of Ca) (—> exclude FHH (self notes))
- Abdominal imaging by KUB, USG kidneys, CT scan for urinary stones
- Optional
- Bone turnover markers
- Trabecular bone score (TBS) by DXA
- High resolution peripheral quantitative CT (HRpQCT)
Indications of Surgery in ***Asymptomatic PHPTH
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
Pre-op preparation: Preoperative localisation
- guide surgeon planning surgical strategy
- ***NOT diagnostic procedure
- negative / discordant imaging studies should NOT inhibit referral to an experienced parathyroid surgeon
-
**USG Parathyroid
- Pre-op / Intra-op
- Limited in its ability to evaluate **retroesophageal lesions / ***mediastinal parathyroid glands -
**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 - CT
- 4D contrast parathyroid (multiple scans obtained after administration of **IV contrast)
- Parathyroid adenomas have **rapid contrast uptake + washout
- High radiation exposure - MRI
(5. Operative: Cervical exploration (SpC Medicine))
Surgery: Minimally invasive approach
- 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)
Intraoperative PTH assay
- 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
Parathyroid surgery for Multi-glandular disease
- Subtotal parathyroidectomy
- resection of 3.5 glands
- preserve 50-80mg vascularised gland - 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
