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Hypercalcemia ppt.pptx
1.
2. INTRODUCTION
⚫Approx 1000 to 1200 g calcium present in adult
⚫99.3 % in bone & teeth as hydroxyapatitecrystals
⚫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.
⚫Metabolicacidosis decrease protein binding
increase ionized calcium.
⚫Metabolicalkalosis increase protein binding
decrease ionized calcium.
⚫Fall in pH byo.1 increases serum calcium by 0.1
mmol/L
⚫As ionized form is the active form of calcium, serum
calcium levelsshould be adjusted forabnormal 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)
14. TRPV5
• N glycosylated region
• Extracellular Klotho
acts
Phosphorylation
site for PKA & C.
PTH & tissue
kalikrienregulate
TRPV5 function
Required forchannel
assembly & protein
protein interaction
15. TRPV5
⚫100 times largerselectivity forcalcium, compared to
Na.
⚫Itsexpression in PM is limited
⚫Present in subcellularlocation, in intracellular
vesicles.
⚫Expressed on PM on stimulation.
⚫Present in closed and open state. Calciumenters
during open state.
⚫Internalized viadynamin and clathrin dependent
process.
18. CALBINDIN D 28k
⚫Vit D dependentcalcium binding protein.
⚫High calciumaffinity.
⚫Calcium bound to it is shuttled toward basolateral
membrane Caextrusion 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
expressionof
TRPV5 &
calbindin
D28k in DCT
& CNT !!?
23. HYPERCALCEMIA (definition)
⚫Serumcalcium > 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
⚫Relativelycommondisorder
⚫Incidence 1-2 case per 1000 adults.
⚫Higher incidence in South Africaand Scandinavia.
⚫Males > females: difference diminishes with increasing
age.
⚫Hypercalcemia from all cause increase with advancing
age.
25. Causes :
⚫Malignancyrelated :
⚫PTH related :
disorders.
⚫Milkalkali syndrome.
⚫Idiopathic infantile hypercalcemia ( Williams
syndrome) increased intestinal calciumabsorption.
• Humoral hypercalcemiaof malignancy :
lymphomas
⚫Vit D related : vit D t
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27. Presentation:
⚫The mnemonic "stones," "bones," "abdominal moans,"
and "psychic groans" describes the constellation of
symptomsand signs of hypercalcemia
⚫The historyof hypercalcemia is dependenton its cause
and the sensitivity of the individual to higher calcium
levels.
Mild increase :
Asymptomatic,
Ormay have recurring
problems like kidney
stones
Rapid rise or severe
hypercalcemia have
dramatic symptoms:
conusion, lethargy, may
lead todeath
29. PATHOPHYSIOLOGY:
⚫The CNS effectsare thought to bedue to thedirect
depressanteffectof hypercalcemia.
⚫Renal effects include nephrolithiasis from the
hypercalciuria.
⚫Distal renal tubularacidosis may be observed, and the
increase in urine pH and hypocitraturia also may
contributetostonedisease.
30. ⚫Nephrogenic diabetes insipidus occurs from medullary
calcium depositionand 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 tocause high gastrin
levels, which may contribute to peptic ulcer disease
and may lead to pancreatitis or the deposition of
calcium in any soft tissue
33. PRIMARY HYPERPARATHYROIDISM
⚫50% caseof hypercalcemia in general population.
⚫Prevalence : 1 %, 2% in post menopausal women.
⚫Peak incidence in 6th decade.
⚫Adenoma : singleenlarged parathyroid gland
responsible in 80-85% cases
⚫Hyperplasia : in 10-15% cases. Sporadic orpartof 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 overtosteitis fibrosacystica; in these patients the
parathyroid tumor is usually large (greaterthan 5.0 g).
35. ⚫Thediagnosisof PHPT is established by laboratory
testing showing hypercalcemia, inappropriately
normal orelevated blood levelsof
PTH, hypercalciuria, hypophosphatemia,phosphaturia
,and increased urinaryexcretion of cyclic adenosine
monophosphate
36. Treatment
⚫Parathyroidectomy indicated in all symptomatic
patients.
⚫Asymptomaticpatient :
• Serumcalcium > 1 mg/dl above normal,
• reduced bone mass (T-scoreof less than –2.5 at any site),
• GFR of less than 60 mL/min, or
• age younger than 50 years.
• Hypercalciuria (>400 mg calciumper 24 hours) is no
longerregardedasan indicationfor parathyroid
surgery, since hypercalciuria in PHPT was not
established asa risk factor for stone formation.
parathyroidectomy
If noneof above things met: annual monitoring of patient
forserum calcium, renal function, BMD
37. Pre operative localization of tumor
⚫Not needed in pt undergoing Sx for 1st time.
⚫Needed in ptswith no improvementwith prior
Sx, recurrence.
⚫Sestamibi scan : sensitive & mostpopulartechnique
⚫USG neck can also be used.
39. Familial Hypocalciuric
Hypercalcemia
⚫A raredisease (estimated prevalenceof 1 per 78,000)
⚫Autosomal dominant inheritance, high penetrance
⚫Loss-of-function mutations in the CASR gene located
on chromosomearm 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
complicationsassociated with elevated serum calcium
concentrations.
40. ⚫the PTH level is generally “inappropriately normal,”
⚫mild elevations in 15% to 20%
⚫Urinary calcium excretion is notelevated, as would be
expected in hypercalcemia.
⚫The fractional excretionof calcium is usually less than
1%
⚫Hypercalcemia in FHH has a generally benign course
and is resistant to medications, except forsomecases
successfully treated with the calcimimetic agent
cinacalcet
41. NEONATAL SEVERE
HYPERPARATHYROIDISM
⚫raredisorder, autosomal recessive,
⚫isoften reported in theoffspring of consanguineous
FHH parents,
⚫Characterized by severe hyperparathyroid
hyperplasia, elevation of PTH levels, severe
hyperparathyroid bonedisease, and elevated
extracellularcalcium levels.
⚫Treatment is total parathyroidectomy, followed by
vitamin D and calcium supplementation.
⚫Thisdisease is usually lethal withoutsurgical
intervention.
42. TREATMENT OF HYPERCALCEMIA
⚫Tailored to thedegree of hypercalcemia, theclinical
condition, and the underlying cause.
⚫Calciumcan bedecreased by :
• Increasing renal excretion of calcium
• Incresing movement of calcium into
bone
• Decreasing bone resorption
• Decreasing gi absorption of calcium
• Remoning calcium byother means
43. ⚫Patientswith mild hypercalcemia (<12 mg/dL) do not
require immediate treatment. They should stop any
medications implicated in causing
hypercalcemia, avoid volumedepletionand physical
inactivity, and maintain adequate hydration.
⚫Moderate hypercalcemia (12 to 14 mg/dL), especially if
acute and symptomatic, requires more aggressive
therapy.
⚫Patientswith severe hypercalcemia (>14 mg/dL), even
withoutsymptoms, 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. ⚫Oncevolumeexpansion is achieved, loopdiureticscan
begiven concurrentlywith saline to increase the
calciuresis by blocking the Na+-K+-2Cl– cotransporter
in the TAL.
⚫Doseof 40 to 80 mg every 6 hours, and this treatment
togetherwith saline therapy maydecrease serum
calciumconcentration by 2 to 4 mg/dL.
46. INHIBITION OF BONE RESORPTION
⚫BISPHOSPHONATES: the agents of choice in the
treatmentof mild tosevere hypercalcemia, especially
thatassociated with cancer.
⚫They are pyrophosphate analogs with a high affinity
for hydroxyapatite and inhibit osteoclast function in
areas of high bone turnover.
47.
48. ⚫Theclinical response takes 48 to 96 hoursand is
sustained forup to 3 weeks.
⚫Dosescan be repeated after 7 days.
⚫Fever is observed in aboutone fifth of patients taking
bisphosphonates;
⚫rare sideeffects includeacuterenal failure, collapsing
glomerulopathy, and osteonecrosisof the jaw.
⚫Thedosageof bisphosphonatesshould beadjusted in
patientswith preexisting kidney disease.
49. CALCITONIN
⚫Effective inhibitorof 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 toprovide initial treatmentof severe
hypercalcemia while waiting for the more sustained
effectof bisphosphonates to begin.
50.
51. EXTRACORPOREAL REMOVAL
⚫In severely hypercalcemic patients who are
comatose, have ECG changes, havesevere renal
failure, orcannot receiveaggressive
hydration, hemodialysiswith a low- or no-calcium
dialysate is an effective treatment.
⚫Continuousrenal replacement therapycan also be
used to treatsevere hypercalcemia.
⚫Theeffectof dialysis is transitory, and it must be
followed byother measures.
