3. Common condition
◦ Prevalence of <2 % in the general population
◦ 4% in the hospital population
Malignancy commonest cause in hospital patients
Primary hyperparathyroidism commonest in
general population
Pathophysiology
Occurs when calcium influx into the ECF from the
intestine and/or bone exceeds renal calcium
excretory capacity.
4. Hypercalcemia is defined as total serum calcium >
10.2 mg/dl(>2.5 mmol/L ) or ionized serum
calcium > 5.6 mg/dl ( >1.4 m mol/L )
Severe hypercalemia is defined as total serum
calcium > 14 mg/dl (> 3.5 mmol/L)
Hypercalcemic crises is present when severe
neurological symptoms or cardiac arrhythmias are
present in a patient with a serum calcium > 14
mg/dl (> 3.5 mmol/L).
5.
6. • Concentration in ECF maintained within narrow limit
(2.2 – 2.6 mmol/L) by a control of hormones:
a)Parathyroid hormone (PTH)
b)Calcitriol (1,25-dihydroxycholecalciferol)
c)Calcitonin- minor role
Principle organ systems :
a)Gut
b)Bone
c)Kidneys
7.
8. Bone
◦ Inhibits osteoblasts
◦ Accelerates osteoclastic bone resorption
Kidneys
◦ Increases renal tubular reabsorption of Ca
◦ Increases PO4 excretion
◦ Increases calcitriol activity (1-hydroxylation) indirectly
raises [Ca]
Gut
◦ Does not directly affect GIT absorption of Ca
◦ Effects are mediated indirectly through regulation of
synthesis of calcitriol
10. 32- amino acid hormone
Produced Parafollicular C cells of thyroid
Weak inhibitor of osteoclasts
Opposes PTH effects of kidneys
◦ Promotes Ca and PO4 excretion
Its exact physiological role in human is
uncertain
◦ Has few long term effects on serum Ca
11.
12. COMMON
• Hyperparathyroidism
• Primary
• Tertiary
• Malignant disease
• Solid organ tumour
• Haematological
LESS COMMON
Thyrotoxicosis
Vit D intoxication
Thiazide diuretics
F. hypercalciuric hypercalcaemia
Sarcoidosis
UNCOMMON
Milk-alkali syndrome
Immobilization
Lithium
Tuberculosis
Acute adrenal failure
Diuretic phase of ARF
Idiopathic hypercalcaemia of
infancy
13. Most common
Hypercalcaemia of
malignancy
◦ Solid tumours
◦ Haematological
malignancies
Primary
Hyperparathyroidism
(PHPT)
Less common
Adrenal insufficiency
Vitamin D intoxication
Drug treatment
Chronic Renal Failure
Endocrine
◦ Thyrotoxicosis
Sarcoidosis
Immobilisation
14. 30% of pts with Ca will develop hyperCa
Pathophysiology
1. Local osteolytic hyperCa due to direct effects of
bone mets
2. Humoral hyperCa of malignancy (HHM)
Secretion of PTHrp by malignant tumours
3. 1,25(OH)2 Vit D – secreting lymphomas
4. Ectopic secretion of PTH (very rare)
15. LOH accounts for 20% of cases of
hypercalcemia of malignancy.
Extensive bone lysis due to tumor
metastases
Characterized by ↑Ca, N/↑ se PO4,↓PTH, ↑ALP,
↑24(h) urinary calcium excretion, increase
marker of bone resorption.
16. Result from the production of PTHrP
Most often have squamous ca (
lung, esophagous, head, neck, cervic,ovary)
Has N-terminal amino acid sequence similar to
PTH
Permit binding of identical receptors and
stimulation of second messanger, (cAMP).
Thus, able to induce actions of PTH
• Increase bone resorption↑Ca, ↓PTH
• Inhibit proximal tubule phosphate transport
↓PO4
17. Multiple myeloma
◦ Release of osteoclast activating factors by the
tumour cells
◦ IL-1B, lymphotoxin, TNF, IL-6, macrophage
CSF, hepatocyte GF
◦ Actions: stimulates osteoclastic activity
In Hodgkin lymphoma,
◦ induced by production of 1,25(OH)2D
◦ Malignant lymphocyte & macrophage converting the
25(OH)D to 1,25(OH)D
bone resorption and intestinal Ca2+ absorption
18. 1 HPTH is the leading cause of hyperCa.
Often, pts are women in their 50s who have
parathyroid adenoma
Incidence ; 1 in 500 to 1 in 1000
Occur sporadically or assoc with MEN Type
1or 2
19. In primary HPTH due to adenomas,
◦ PTH secretion is independent of the negative
feedback mechanism
◦ :. Secretion continues despite elevated Ca2+ level.
Pathophysiology
◦ Excess PTH leads to
Direct increase in renal Ca absorption
Increase in serum Calcitriol Increasing GIT Ca
absorption
Increase bone turnover, resorption > formation
20.
21. Diagnosis = Hypercalcaemia + raised [iPTH]
Additional lab findings
- ↓ serum phosphate
- urinary excretion of Ca2+ ( PTH amount of filtered
Ca2+ > normal resorptive capacity of the kidney xs Ca2+
secreted in urine)
-↑ Se ALP (when bone disease present)
-↑ se Cl and ↓ se Bicarb
- ↑1,25 (OH)2D
-bone markers(↑bone specific ALP,osteocalcin)
Other Ix
◦ Sestamibi scan of the Parathyroid
23. In ESRF, prolonged hypocalcaemia will cause
autonomous PTH secretion by parathyroid.
This in turn will cause hypercalcaemia (Tertiary
hyperparathyroidism)
Hypercalcaemia may manifest for the first time in
patient post renal transplant when there is
normalization of calcitriol production
Increases the PTH effect on bone Directly enhances
intestinal Ca absorption
24. ◦ Pt with sarcoidosis have increased sensitivity to
vitamin D.
◦ High Ca may develop in normocalcaemic pt after
minimal intake of vit D and sunlight exposure
◦ Caused by increase production of 1,25(OH)2D
from non-renal sites.
◦ Macrophage from sarcoid granuloma may cause
1-hydroxylation of 25-(OH)D to produce calcitriol
Ca 2+
◦ High/inappropriately elevated se 1,25(OH)D
despite PTH level is suppressed and se PO4 is
relatively elevated.
25. Thiazide diuretics:
◦ Enhance ca reabsorption in the distal tubule
↓urinary ca excretion.
• Rarely cause Ca in N persons, but lead to Ca in
pt with underlying bone resorption (eg in
hyperparathyroidism)
• Mild hypercalcaemia,↓/N PTH
Lithium therapy:
◦ Increased PTH secretion Increasing set point
of PTH, hence higher [Ca] to switch off PTH
◦ Lab ix: high Ca, PTH, low urinary 24(h) calcium
26. The most commonly available vit D
supplement 25-(OH)Vit D
◦ Excess of VIT D 25000-50000 IU/week
◦ Resulting primarily from a combination of increase
bone resorption of calcium and increase bone
reabsortion
◦ Lab ix: ↑Ca, ↑Po4,↓/N PTH, ↑25(OH)D, N/slightly
25(OH)D
27. In immobilization,
Decreased stimulus to bone formation and
continued resorption rapid efflux of ca fr
bone suppresed PTH 1,25(OH) D results in
hypercalciuria
Hypercalcemia seen if there is pre-existing
increased bone turnover
Paget’s disease
Hyperparathyroid
Malignancy associated hypercalcemia
28. Prev – milk alkali syndrome
◦ Milk-alkali syndrome: ingestion of
milk/antacids(alkaline) for treatment of dyspepsia .
Alkali increases renal reabsorption of filtered calcium.
Precise mechanism unknown
Calcium-alkali syndrome
◦ Due to Rx of osteoporosis
◦ Triad of hypercalcemia,systemic alkalosis and renal
insufficiency.
◦ Lab Ix: ↑ca,↓/ N PTH,↑/N PO4, ↓urinary 24 (h) Ca
29. Hypercalcaemia seen in pt treated with
◦ Calcium carbonate or calcium acetate to bind
dietary phosphate
◦ Calcitriol ( to reverse hypocalcaemia and
secondary hyperparathyroidism)
Endocrine
◦ Thyrotoxicosis-mild hypercalcemia
◦ Thyroid hormoneIncreased bone resorption
ratereleases ca into circulation suppress PTH
low 1,25(OH)D
30. How to approach?
- Medical History
- Physical Examination
What Investigations?
-Lab
-Others
31. Acute or Unknown duration
◦ PTH high; Acute paratyroid crisis
◦ PTH low ; CA, PTHrp
Chronic duration month
◦ PTH low ; granulomatous dz, Milk
alkali, Li,thiazide, Immobilization, Vit
D,Thyrotoxicosis
◦ PTH high ; 1,3 ry hyper PTH, MEN
34
32. Re-review History
1. Acute or Chronic ??????
Classic presentation very rare
– Stones
– Bones
– Abdominal groans
– Psychic moans
Subtle manifestations more common
– Fatigue
– Weakness
– Arthralgias
– Depression
– Impairment of intellectual performance
Associated conditions
– Pseudogout
– Nephrolithiasis
– Evidence of MEN
33. Review medications
– Thiazides
– Lithium
– Antacids
– Food additives
Pursue symptoms of underlying malignancy
– Breast
– Lung
– Hematological
Past History of head and neck irradiation during
childhood
Family history
Risk factor of Ca
34. Step 1
– Confirm hypercalcemia
– Ionized calcium
– Serum albumin levels
– Correction for the measured calcium (low
albumin)
Step 2
– Once obvious causes ruled out, obtain serum intact
PTH
35. Step 3: Measurement of the serum PTH
concentration.
Ca, iPTH ;
1ry HyperPTH, Familial (MENI and MENII),Ectopic PTH secretion
by tumors (rare)
– Ca, N / iPTH;
– Malignancy associated
• Osteolytic
• Humoral
• Vitamin D mediated
• Intoxication
• Granulomatous disorders
• Thyrotoxicosis
• Prolonged immobilization
• Acute /chronic renal failure
• Milk alkali syndrome
• Drug:Thiazide,Lithium
36. Step 4: Measurement of the serum phosphate
concentration.
◦ Ca, PO4 ;
1ry HyperPTH, PTHrP SCC
◦ Ca, N / PO4 ;
3ry HyperPTH, Granulomatous dz, lymphoma, Vit D
overdose , Immobilization, Metastatic bone dis. Milk
Alkali Syndrome
39
37. Measurement urinary calcium excretion
◦ Urinary calcium excretion is usually raised or high-
normal:
◦ hyperparathyroidism,hypercalcemia of
malignancy,granulomtous disease,Vit D excess
3 disorders in which an increase in renal
calcium reabsorption leads to relative
hypocalciuria (<2.2 mmol/day):
◦ The milk-alkali syndrome
◦ Thiazide diuretics
◦ Familial hypocalciuric hypercalcemia (children)
40
38. Next step…
Analyze vitamin d metabolite levels
◦ Elevated 25(OH)D Vit D intoxication
◦ High 1,25 (OH)D Primary HPTH
sarcoidoisis & granulomatous dz
Analyze serum PTH-related protein level
(PTHrp)
◦ May help in diagnosis of occult cancer –
associated hypercalcemia.
41
39. 42
PTH PTHrP 1,25D Ca
1ry HyperPTH -
2nd
HyperPTH - -
3ry HyperPTH - -
CA High -
Granuloma High
40. ◦ Se Immunoglobulin/ Serum/urine
electrophoresis Multiple myeloma
◦ Thyroid function test Thyrotoxicosis
◦ Renal function test to assses renal function
◦ Liver function testraised ALP level suggest bone
involvement
◦ raised serum bicarb suggest Milk-alkali syndrome
◦ Chest xray reveal sign of sarcoidoisis & lung ca
◦ Mamogrambreast ca
43
41. DDX Ca PO4 PTH PTHrP 1,25(OH)D U Ca
Malignancy
1)Solid tumor
2)Humoral
↑
↑
N/↑
↓
↓
↓
N
↑↑
↓
↓/N
↑
↓/N
Pry PTH ↑ ↓ ↑ N ↑ ↑
Granulomatous
disease
↑ ↑ ↓ N ↑↑ ↑
Vit D excess ↑ ↑ ↓ N ↑↑ ↑
Thiazide ↑/N ↑ ↓/N N N ↓
Milk alkali
syndrome
↑/N ↑ ↓/N N N ↓
42.
43.
44. 1st step in Mx – Stabilising the pt!
Correct hypovolemia wt isotonic saline infusion
and to promote renal excretion of calcium
◦ Replenish body fluids
2-4 L of IV normal saline per day
45. 2nd Step
◦ Diuresis with furosemide
3rd Step
◦ Administration of bisphosphonates
◦ Zoledronate or Pamidronate
Block osteoclast activity and bone resorption
Reduce malignant bone pain
Delay onset of progressive bone disease in various Ca
46. Acute parathyroid crisis urgent
parathyroidectomy
For symptomatic PHPT
◦ Those <50 years
◦ Who cannot participate in appropriate follow up
◦ Ca level > 0.25 mmol/l above upper limit
◦ Complications of PHPT
Osteoporosis
Nephrocalcinosis
Severe psychoneurologic disorder
47. Review / remove any known agents that
cause / aggravate hypercalcaemia
◦ Medications
Thiazide
Lithium
Over the counter supplements
48. Hypercalcaemia has a wide differential diagnosis
and several investigations may be required to
determine the underlying cause.
Clues pointing to the Dx of underlying disease
can be obtained from careful history taking and
physical examination.
Lab tests should be requested based on clinical
suspicion.
Long term control of hypercalcaemia is best
achieved by identifying and treating the
underlying disease.