This document discusses calcium homeostasis and hypercalcemia. It notes that approximately 1000-1200 mg of calcium is present in an adult, mostly in bone. It describes the distribution and protein binding of calcium in extracellular fluid and intracellular fluid. Factors that influence calcium absorption in the gut and renal handling of calcium are outlined. Mechanisms involved in response to changes in serum calcium levels, including the roles of TRPV5 calcium channels and calbindin D28k protein, are summarized. Causes, clinical features, pathophysiology, and treatment approaches for hypercalcemia and various hypercalcemic disorders like primary hyperparathyroidism and familial hypocalciuric hypercalcemia are described.

1. ATUL DESAI
21/5/12

2. INTRODUCTION
 Approx 1000 to 1200 g calcium present in adult
 99.3 % in bone & teeth as hydroxyapatite crystals
 0.6% in soft tissues
 0.1% in ECF.

3. DISTRIBUTION OF CALCIUM
CALCIUM
ECF
8.5-10.6 mg/dl
2.25-2.65 mmol//l
ICF
CYTOPLASMIC FREE
50-100 nmol/l
PROTEIN BOUND
45%
DIFFUSIBLE
ULTRAFILTRABLE
55%
IONIZED
45%
COMPLEXED
10%
90% ALBUMIN
10% GLOBULIN

4. Protein binding of calcium
 Influenced by pH.
 Metabolic acidosis decrease protein binding
increase ionized calcium.
 Metabolic alkalosis  increase protein binding
decrease ionized calcium.
 Fall in pH by o.1 increases serum calcium by 0.1
mmol/L
 As ionized form is the active form of calcium, serum
calcium levels should be adjusted for abnormal serum
albumin levels.

5. Corrected calcium
 For every 1-g/dL drop in serum albumin below 4
g/dL, measured serum calcium decreases by 0.8
mg/dL.
 Corrected calcium = measured Ca+ [0.8x(4-measured
albumin)] (Calcium in mg/dl; albumin in g/dl)

6. FUNCTIONS
 Muscle contraction
 Neuromuscular / nerve conduction
 Intracellular signalling
 Bone formation
 Coagulation
 Enzyme regulation

7. CALCIUM HOMEOSTASIS

8. INTESTINAL HANDLING OF
CALCIUM
 Approx 1000 mg calcium ingested per day.
 200 mg absorbed.
 Mainly in duodenum & jejunum.
 Absorption is both passive and active
 Passive : paracellular route, non saturable, 5 %
ingested Ca absorbed by this route.
 Active: transcellular: receptor mediated, 25% ingested
Ca absorbed.

9. TRANSCELLULAR CALCIUM
ABSORPTION
TR
PV
5
NUCLE
US
CCALBINDIN
D9k
NCX1 PMCA1b CaSR
calcium
LUMEN
BLOOD

10. Factors affecting calcium
absorption in gut
 Increased  Decreased
• Vit D
• Ingestion with alkali
• PTH
• GH
• Acidic milieu
• High po4 content in
diet
• High veg fibre
• High fat content
• Corticosteroid
treatment
• Estrogen deficiency
• Advanced age
• Gastrectomy
• Intestinal
malabsorption
syndrome
• DM
• Renal failure

11. RENAL HANDLING OF CALCIUM
 8-10 g calcium filtered across the glomerulus per day.
 200 mg = 2 % is excreted
 Rest reabsorbed across renal tubules.
• PCT: 60-65%
• mTALH: 20 %
• DCT, CNT : 5%
PASSIVE
ACTIVE

12. DISTAL TUBULE CALCIUM
ABSORPTION

13. TRPV5
 Member of TRP channel
superfamily.
 Has intracellular NH2 &
CHO terminals.
 6 trans membrane
segments.
 A hydrophobic stretch =
pore forming
region, between
segments 5 & 6

14. TRPV5
• N glycosylated region
• Extracellular Klotho
acts
Phosphorylation
site for PKA & C.
PTH & tissue
kalikrien regulate
TRPV5 function
Required for channel
assembly & protein
protein interaction

15. TRPV5
 100 times larger selectivity for calcium, compared to
Na.
 Its expression in PM is limited
 Present in subcellular location, in intracellular
vesicles.
 Expressed on PM on stimulation.
 Present in closed and open state. Calcium enters
during open state.
 Internalized via dynamin and clathrin dependent
process.

16. Regulators of TRPV5

17. DRUGS AFFECTING TRPV5
 TACROLIMUS : decreased expression of TRPV5 also of
calbindin D9k : mechanism ?
thus causes hypercalciuria.
Cyclosporine downregulates only
calbindin not TRPV5

18. CALBINDIN D 28k
 Vit D dependent calcium binding protein.
 High calcium affinity.
 Calcium bound to it is shuttled toward basolateral
membrane Ca extrusion systems.

19. Effect of diuretics on renal calcium
handling
 Furosemide:
NKCC2
ROMK
NK
ATPase
NA
2Cl
K
LUMEN +
CALCIUM CALCIUM
mTALH
lumen blood
• Increases the
expression of
TRPV5 &
calbindin
D28k in DCT
& CNT !!?

20. Thiazide diuretics
 Increase calcium reabsorption.
 Mechanism: 2 hypothesis proposed.
 First hypothesis : ECF
depletion
Decreased calcium filtrate
Increased water & Na absortion in PCT
driving increased Ca absorption in PCT

21.  Second hypothesis: increased NaCa exchanger in BL
membrane of DCT & CNT. Not proved.

22. Response to change in serum
calcium levels

23. HYPERCALCEMIA (definition)
 Serum calcium > 10.5 mg/dl (>2.5 mmol/l)
 Ionized calcium > 5.3 mg/dl (1.3 mmol/L)
 Mild :Total ca 10.5-11.9 mg/dl (2.5-3 mmol/l) (i 5.6-8
mg/dl; 1.4-2 mmol/l)
 Moderate : Total ca 12-13.9 mg/dl (3-3.5mmol/l)
i ca 8-10 mg/dl (2-2.5 mmol/l)
 Severe : Total ca 14-16 mg/dl (3.5-4 mmol/l)
i ca 10-12 mg/dl (2.5-3 mmol/l)

24. Epidemiology
 Relatively common disorder
 Incidence 1-2 case per 1000 adults.
 Higher incidence in South Africa and Scandinavia.
 Males > females: difference diminishes with increasing
age.
 Hypercalcemia from all cause increase with advancing
age.

25. Causes :
 Malignancy related :
 PTH related :
 Vit D related : vit D toxicity or granulomatous
disorders.
 Related to high bone turnover :
 Milk alkali syndrome.
 Idiopathic infantile hypercalcemia ( Williams
syndrome)  increased intestinal calcium absorption.
• Humoral hypercalcemia of malignancy :
increased PTHrP (80%)
• Osteolytic hypercalcemia from osteoclastic
activity and bone resorption surrounding the
tumor tissue (20%)
• Secretion of active vitamin D by some
lymphomas
• Ectopic PTH secretion - Very rare
◦Primary hyperparathyroidism
■Solitary adenoma
■Generalized hyperplasia
■Multiple endocrine neoplasia type
1 or type 2A
◦Lithium-related release of PTH
◦Familial cases of high PTH
90%
• Hyperthyroidism
• Immobilization (Paget's’
disease)
• Thiazides
• Vit A intoxication
• Breast CA
• Lung CA
• RCC
• Multiple myeloma
• Leukemia, lymphoma

26. Causes:
 Familial hypocalciuric hypercalcemia (decreased renal
calcium excretion)
 Mutations of the calcium-sensing receptor
■Familial benign hypocalciuric hypercalcemia
■Neonatal severe hyperparathyroidism
 Uncertain mechanism
■Hypophosphatasia
■Subcutaneous fat necrosis
■Blue diaper syndrome
■Dietary phosphate deficiency

27. Presentation:
 The mnemonic "stones," "bones," "abdominal moans,"
and "psychic groans" describes the constellation of
symptoms and signs of hypercalcemia
 The history of hypercalcemia is dependent on its cause
and the sensitivity of the individual to higher calcium
levels.
Mild increase :
Asymptomatic,
Or may have recurring
problems like kidney
stones
Rapid rise or severe
hypercalcemia have
dramatic symptoms:
conusion, lethargy, may
lead to death

28. CLINICAL FEATURES:

29. PATHOPHYSIOLOGY:
 The CNS effects are thought to be due to the direct
depressant effect of hypercalcemia.
 Renal effects include nephrolithiasis from the
hypercalciuria.
 Distal renal tubular acidosis may be observed, and the
increase in urine pH and hypocitraturia also may
contribute to stone disease.

30.  Nephrogenic diabetes insipidus occurs from medullary
calcium deposition and inhibition of aquaporin-2.
 Renal function may decrease due to hypercalcemia-
induced renal vasoconstriction or if hypercalcemia is
prolonged  calcium deposition (nephrocalcinosis)
and interstitial renal disease.

31.  Prolonged hypercalcemia tends to cause high gastrin
levels, which may contribute to peptic ulcer disease
and may lead to pancreatitis or the deposition of
calcium in any soft tissue

32. WORK UP
HIGH

33. PRIMARY HYPERPARATHYROIDISM
 50% case of hypercalcemia in general population.
 Prevalence : 1 %, 2% in post menopausal women.
 Peak incidence in 6th decade.
 Adenoma : single enlarged parathyroid gland
responsible in 80-85% cases
 Hyperplasia : in 10-15% cases. Sporadic or part of MEN
 Carcinoma : 0.05-1%

34. PHPTH : PRESENTATION
 80 % cases: asymptomatic, diagnosed on routine lab
finding of increased serum calcium
 20-25% cases: chronic course with mild or intermittent
hypercalcemia, recurrent renal stones, complication of
nephrolithiasis
 5-10% have severe and symptomatic hypercalcemia
and overt osteitis fibrosa cystica; in these patients the
parathyroid tumor is usually large (greater than 5.0 g).

35.  The diagnosis of PHPT is established by laboratory
testing showing hypercalcemia, inappropriately
normal or elevated blood levels of
PTH, hypercalciuria, hypophosphatemia,phosphaturia
,and increased urinary excretion of cyclic adenosine
monophosphate

36. Treatment
 Parathyroidectomy indicated in all symptomatic
patients.
 Asymptomatic patient :
• Serum calcium > 1 mg/dl above normal,
• reduced bone mass (T-score of less than –2.5 at any site),
• GFR of less than 60 mL/min, or
• age younger than 50 years.
• Hypercalciuria (>400 mg calcium per 24 hours) is no
longer regarded as an indication for parathyroid
surgery, since hypercalciuria in PHPT was not
established as a risk factor for stone formation.
parathyroidectomy
If none of above things met: annual monitoring of patient
for serum calcium, renal function, BMD

37. Pre operative localization of tumor
 Not needed in pt undergoing Sx for 1st time.
 Needed in pts with no improvement with prior
Sx, recurrence.
 Sestamibi scan : sensitive & most popular technique
 USG neck can also be used.

38. Pharmacotherapy:
 Indications: patient refuses surgery, or surgery
contraindicated, or pt with asymptomatic
hypercalcemia.
 Agents used :
calcimimetic, bisphosphonates, estrogens, SERMS.

39. Familial Hypocalciuric
Hypercalcemia
 A rare disease (estimated prevalence of 1 per 78,000)
 Autosomal dominant inheritance, high penetrance
 Loss-of-function mutations in the CASR gene located
on chromosome arm 3q
 Hypercalcemia, and relative hypocalciuria.
 The hypercalcemia is typically mild to moderate (10.5
mg/Dl to 12 mg/dL)
 Affected patients do not exhibit the typical
complications associated with elevated serum calcium
concentrations.

40.  the PTH level is generally “inappropriately normal,”
 mild elevations in 15% to 20%
 Urinary calcium excretion is not elevated, as would be
expected in hypercalcemia.
 The fractional excretion of calcium is usually less than
1%
 Hypercalcemia in FHH has a generally benign course
and is resistant to medications, except for some cases
successfully treated with the calcimimetic agent
cinacalcet

41. NEONATAL SEVERE
HYPERPARATHYROIDISM
 rare disorder, autosomal recessive,
 is often reported in the offspring of consanguineous
FHH parents,
 Characterized by severe hyperparathyroid
hyperplasia, elevation of PTH levels, severe
hyperparathyroid bone disease, and elevated
extracellular calcium levels.
 Treatment is total parathyroidectomy, followed by
vitamin D and calcium supplementation.
 This disease is usually lethal without surgical
intervention.

42. TREATMENT OF HYPERCALCEMIA
 Tailored to the degree of hypercalcemia, the clinical
condition, and the underlying cause.
 Calcium can be decreased by :
• Increasing renal excretion of calcium
• Incresing movement of calcium into
bone
• Decreasing bone resorption
• Decreasing gi absorption of calcium
• Remoning calcium by other means

43.  Patients with mild hypercalcemia (<12 mg/dL) do not
require immediate treatment. They should stop any
medications implicated in causing
hypercalcemia, avoid volume depletion and physical
inactivity, and maintain adequate hydration.
 Moderate hypercalcemia (12 to 14 mg/dL), especially if
acute and symptomatic, requires more aggressive
therapy.
 Patients with severe hypercalcemia (>14 mg/dL), even
without symptoms, should be treated intensively.

44. Volume Repletion and Loop
Diuretics
 Correction of the ECF volume
is the first and the most
important step in the
treatment of severe
hypercalcemia from any
causes.
 Volume repletion can lower
calcium concentration by
approximately 1 to 3 mg/dL
by increasing GFR and
decreasing sodium and
calcium reabsorption in
proximal and distal tubules.

45.  Once volume expansion is achieved, loop diuretics can
be given concurrently with saline to increase the
calciuresis by blocking the Na+-K+-2Cl– cotransporter
in the TAL.
 Dose of 40 to 80 mg every 6 hours, and this treatment
together with saline therapy may decrease serum
calcium concentration by 2 to 4 mg/dL.

46. INHIBITION OF BONE RESORPTION
 BISPHOSPHONATES: the agents of choice in the
treatment of mild to severe hypercalcemia, especially
that associated with cancer.
 They are pyrophosphate analogs with a high affinity
for hydroxyapatite and inhibit osteoclast function in
areas of high bone turnover.

48.  The clinical response takes 48 to 96 hours and is
sustained for up to 3 weeks.
 Doses can be repeated after 7 days.
 Fever is observed in about one fifth of patients taking
bisphosphonates;
 rare side effects include acute renal failure, collapsing
glomerulopathy, and osteonecrosis of the jaw.
 The dosage of bisphosphonates should be adjusted in
patients with preexisting kidney disease.

49. CALCITONIN
 Effective inhibitor of osteoclast bone resorption.
 Rapid action <12 hrs.
 Effect is transient, minimal toxicity
 Dose: 4-8 U/kg SC Q6-12 hrs
 Its role is mainly to provide initial treatment of severe
hypercalcemia while waiting for the more sustained
effect of bisphosphonates to begin.

51. EXTRACORPOREAL REMOVAL
 In severely hypercalcemic patients who are
comatose, have ECG changes, have severe renal
failure, or cannot receive aggressive
hydration, hemodialysis with a low- or no-calcium
dialysate is an effective treatment.
 Continuous renal replacement therapy can also be
used to treat severe hypercalcemia.
 The effect of dialysis is transitory, and it must be
followed by other measures.