Overview of Hypercalcemia. Causes, diagnosis and management in a Developing Country. Starting with a simple case.

1. Department CME 2023
Hypercalcemia
Dr Jasmial
21.02.23

2. Patient SG
32 yo female
2020: B cell type Hodgkins Lymphoma (Responded to 6 cycles CHOP)
2022: Lymphadenopathy recurred so planned for Overseas tx.
Presenting with
• 1-2 days of ALOC
• 3 days of immobility after a fall
• 3 weeks of increasing weakness, fatigue, body pains

3. Exam
Initially had low BPs with HR 120, afebrile and GCS 14 (Confusion)
Sparse hair growth, cachexic (estimated 35kg)
+Pallor +Cervical lymphadenopathy
Chest: Clear lungs and dual regular HS
Abdo: No organomegaly
Ext: Left leg unilateral swelling.
Right leg flexed, shortened and tender at hip

4. • QT shortening
HR 160 QTc is 0.27
Normal 0.35-0.43
• T wave flattening
• J wave
• ST elevations

5. BC NG48hr
Rt 11cm Lt 10cm Regular
outlines No hydronephrosis
Liver 11cm Spleen 12cm
Left Leg doppler: No DVT

7. Initial Assessment
1. Clinical Sepsis
2. Pathological Rt. NOF Fracture
3. Hypercalcemia Sec malignancy
4. Anemia
5. Hyponatremia

8. Progress
Day 1
• Escalated to Piptaz
• IVF 3L normal saline
• Allopurinol 100mg OD (TLS)
• Alendronate PO 35mg daily for 2 days. 1 dose documented
Day 2
• Persistently Tachycardic/Tachypnoeic then desaturated
• Escalated to ICU- Non invasive ventilation only
• Planned for chemo once settles

9. Progress
Day 3
• FB In 3000 Out 600mls
• 2 units PRBC given
Day 4
• FB In 1300 Out 600mls
• Inc NGT aspirate noted
• Stat Lasix 20mg given

10. Progress
Day 5
• FB In 2600 Out 1300 in AM
• Calcitonin 1600 SC BD charted -NA
• Denosumab 60mg SC charted -NA
• Prednisone 40mg OD
• FB In 4500 Out 1000
• Lactate 7.2 Grossly fluid overloaded
• Worsening desaturation and BPs dropping.

11. Hypercalcemia Overview

12. Calcium Metabolism
99% is in bones- Hydxyroyapatite
1% extracellular
• Bound : 45%- Useless
• Chelated -5%- For transport across membrames (-CO3, -PO4, Oxalate)
• Free/ Ionised- 50%- Interacts with cells
Intracellular calcium doesn’t contribute to homeostasis except in
Parathyroid gland.

13. Parathyroid Hormone (Batman)
In response to decrease in intracellular calcium levels in PT
gland
• Kidney: Inc Ca absorption in Asc loop of henle, DCT and
CD
• Gut: Makes mitochondira of PCT secrete Vit D3 which
increases absorption of Calcium
• Bone: Stimulates osteoclast activity in the bones to
increase Ca

14. Calcitonin (Joker)
Secreted by Thyroid Para-follicular cells In response to
increase in Calcium levels
• Renals: Dec Ca reabsorption so inc urine excretion
• Gut: Dec absorption
• Bone: Inc Osteblast activity

15. Vitamin D (Robin)
Mitochondria of PCT releases Inactive Vit D3, and activated
is 1,25 Dihydroxy Vit D3
• Ensures gut absorption in Small bowel actively and
passively in rest of bowels.
• Acts on Calbindin in the intestinal mucosa and Plasma
membrane pumps
• Will contribute to Osteoclast activity if renals aren’t able
to reabsorb enough

16. Factors Affecting Measured Calcium Levels
1. Standing/ Venous Stasis/Immobility
• Hemoconcentration increases Bound calcium concentrations
2. Prolonged tourniquet use and fist clenching
• 2% and 8% inc in free calcium respectively
3. . Exercise
• Mechanism unclear. Transient decrease in free calcium
4. Calcium rich foods
• Few hours of elevation. Need 6 hours fasting bloods if elevated
levels seen
5. Drugs

17. Factors Affecting Measured Calcium Levels
6. pH imbalance from serious illness
• Severe Alkalosis increases bound protein so decreases free calcium
(~0.36mmol)
• -Resp causes, Bicarb administration, HF, RF, Toxic shock
• Severe Acidosis vice versa
• Increases free/ionized calcium levels
7. Abnormal protein levels
• Albumin, Globulins (Immunoglobs too)
8. Blood Transfusions
• Increased chelation by citrate preservative binding to free calcium
9. Hyperlipidemia

18. “ International federation of Clinical Chemistry and Laboratory
Medicine states Total Calcium may be used as a surrogate for Ionized
Calcium in patients who do not have pH or Protein abnormalities “
-https://www.aacc.org/cln/articles/2019/june/ionized-versus-albumin-adjusted-total-calcium
MOH Labs use: Ion selective Electrodes
Ideally in critical, CRF, CLD patients :
Ionised levels in anaerobic sample measured within an 1 hour of
collection placed on ice to prevent pH alterations.

19. Calcium Correction
Payne Formula (Developed using healthy patients and underestimtes Free
calcium in albumins higher than 40)
cCa = Ca + 0.02( 40-Serum Alb)
mmol/L g/L
(If Result in mg/dL ÷ 4)
Does not do well in critically ill and Renal Failure patients and alb >40

20. Hypercalcemia- mmol/L
Total Ionized
Normal 2.2- 2.65 1.1- 1.3
Mild 2.65- 3 1.4- 2
Moderate 3- 3.5 2- 2.5
Severe >3.5 >2.5

21. Types of Hypercalcemia
90% is malignancy or hyperparathyroidism
1. PTH Mediated
• Increased Bone resorption leading to it
• Usually sustained for years, and asymptomatic
2. Non-PTH Medicated Hypercalcemia
• Malignancy (TLS, Malig-Breast, bone, renal, Hematological)
• Granulamatous disease like TB
• Usually rapid and progressive
• Medications: Thiazides, Lithium, Theophyline, Vit A/D
• Hyperthyroidism
• Familial Benign, Pheochromocytoma, Adrenal insufficiency,
Parenteral nutrition, Milk alkali syndrome

22. Clinically
Depends on chronicity of buildup
Often Asymptomatic
• Neuropsychiatric: Anxiety, depression, Cognitive then lethargy,
confusion, stupor (>3.5)
• GIT: Constipation, Nausea then pancreatitis, PUD
• Renal: DI, Polyuria, Nephrolithiasis, RTA, AKI
• CVS: Arrythmias, Calcification of structures
• MSK: Muscle weakness, Hyporeflexia, Bone pain
and fractures
Neuropsychiatric
Anxiety, depression, Cognitive then lethargy, confusion,
stupor (>3.5)
GIT Constipation, Nausea then pancreatitis, PUD
Renal DI, Polyuria, Nephrolithiasis, RTA, AKI
CVS Arrythmias, Calcification of structures
MSK
Muscle weakness, Hyporeflexia, Bone pain and fractures

23. • Signs of Malignancy
• Dehydration
• Rare sign: Band
Keratopathy

24. Treatment
1. Hydrate
1. Volume Restore with N/Sal in short term-
2. then Dehydrate
1. Loop Diuretics- Blocks Ca and Na reabsorption in Loop of Henle
2. Replace other electrolyes lost (Mg, K, Chl
3. Weight Bearing Mobilisation
4. Reduce Calcium and Vitamin D
1. Dietary intake
2. Prednisone in Extrarenal synthesis of Vit D3
3. Gut binding with oral phosphate

25. 5. Biphosphonates after hydration
Inhibit Osteclastic activity
1. Zoledronic acid 4mg IV over 15mins ($640 at Oceania)
2. Pamidronate 60mg IV over 2 hours- Safer than 1 in renal impairment
($37 at Oceania)
3. Etidronate IV- Reduces bone formation, no change to renals
4. Alondronate PO- Better for long term, not for acute/Severe

26. 6. Calcitonin
Onset in 2hrs till 6-8. 9% Reduction if BD
Less effective after several days use
7. Mithramycin
8. Denosumab- Monocloncal Antibody inhibiting Osteoclasts
9. Oral Phosphates as mid-Long term tx

27. Treatment
1. Mild 2.6-3
1. May not need treatment
2. Avoid aggravating factors
3. Adequate Hydration
2. Moderate 3-3.5
1. If Acutely rising then treat- Saline hydration and Biphosphonates

28. Treatment
3. Severe >3.5
• Treat aggressively regardless of symptoms
• IV Saline + SC Calcitonin 4u/Kg + IV Biphosphanate / Denosumab
• Saline and Calcitonin reduce levels within 24 hours
• If in Renal/ Cardiac failure, introduce Loop diuretics
• Biphophonates preferred in malignancy and to be given slower if
renal impairment
• Monitor Vit D levels. Possible to have deficiency in malignancy
• Dialysis: Last resort. Needs adjustment. Low calcium High
phosphate