approach and management of hypercalcemia

1. Hypercalcemia
• Commonly encountered in Practice
• Diagnosis often is made incidentally
• The most common causes are primary
hyperparathyroidism and malignancy
• Diagnostic work-up includes measurement of serum
calcium, intact parathyroid hormone (I-PTH), h/o any
medications
• Hypercalcemic crisis is a life-threatening emergency

2. Hypercalcemia
• The skeleton contains 98 percent of total body calcium;
the remaining 2 percent circulates throughout the body
• One half of circulating calcium is free (ionized) calcium,
the only form that has physiologic effects.
• The remainder is bound to albumin, globulin, and other
inorganic molecules

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
• Corrected calcium = (4.0 mg/dl - [plasma albumin]) X 0.8 +
[serum calcium]

5. CALCIUM PHYSIOLOGY:
BLOOD CALCIUM
• Blood Calcium Is Tightly Regulated
–Principle Organ Systems
–Gut, Bone, Kidneys
–Hormones
– Parathyroid Hormone (PTH),calcitonin,vitamin D
–Integrated Physiology Of Organ Systems And
Hormones Maintain Blood Calcium

6. CALCIUM PHYSIOLOGY:
BLOOD CALCIUM
• Calcium Flux Into And Out Of Blood
– “In” Factors: Intestinal Absorption, Bone Resorption
– “Out” Factors: Renal Excretion, Bone Formation (Ca
INCORPATION INTO BONE)
– Balance Between “In” And “Out” Factors
– Organ Physiology Of Gut, Bone, And Kidney
– Hormone Function Of PTH And Vitmamin D

7. CALCIUM HOMEOSTASIS
DIETARY CALCIUM
INTESTINAL ABSORPTION
ORGAN PHYSIOLOGY
ENDOCRINE PHYSIOLOGY
DIETARY HABITS,
SUPPLEMENTS
BLOOD CALCIUM
BONE
KIDNEYS
URINE
THE ONLY “IN”
THE PRINCIPLE “OUT”
ORGAN PHYS.
ENDOCRINE PHYS.
ORGAN,
ENDOCRINE

8. TRANSCELLULAR CALCIUM ABSORPTION
TRP
V5
NUCLEU
S
CCALBINDIN
D9k
NCX1 PMCA1b CaSR
calcium
LUMEN
BLOOD

9. 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

10. 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

11. DISTAL TUBULE CALCIUM ABSORPTION

12. KLOTHO
• Klotho is involved in the
– Renal control of calcium, phosphate and vitamin D
metabolism
– Suppresses phosphate re-absorption in renal
proximal tubule, by directly binding to FGF receptors
– Regulates Ca2+ re-absorption in the distal
convoluted tubule by
– Stabilizing the TRPV5 Ca2+ channel in the plasma membrane
Nephrol Dial Transplant 2007; 22: 1524–1526

13. KLOTHO
Inhibits renal 1-alpha 25 hydroxylase activity and thereby
Decreases circulating calcitriol levels
– Therefore appears to
– Synergize with the renal tubular effects of parathyroid hormone
(PTH) on Ca2+ and phosphate transport, whereas
– Antagonizes the stimulatory effect of PTH on calcitriol synthesis
by the kidney
Nephrol Dial Transplant 2007; 22: 1524–1526

14. PTH/Calcium Homeostasis
Low circulating serum calcium
concentrations stimulate the
parathyroid glands to secrete
PTH, which mobilizes calcium
from bones by osteoclastic
stimulation.
PTH also stimulates the
kidneys to reabsorb calcium
and to convert 25-
hydroxyvitamin D3 (produced
in the liver) to the active form,
1,25-dihydroxyvitamin D3,
which stimulates GI calcium
absorption.
High serum calcium
concentrations have a negative
feedback effect on PTH
secretion.

15. CALCIUM, PTH, AND VITAMIN D FEEDBACK
LOOPS
NORMAL BLOOD Ca
RISING BLOOD Ca
FALLING BLOOD Ca
SUPPRESS PTH
STIMULATE PTH
BONE RESORPTION
URINARY LOSS
1,25(OH)2 D PRODUCTION
BONE RESORPTION
URINARY LOSS
1,25(OH)2 D PRODUCTION

16. PTH
• Renal effects (steady state maintenance)
– Increased reabsorption of calcium
– Stimulation of 25(OH)D-1alpha-hydroxylase
• Bone effects (immediate control of blood Ca)
– Causes calcium bone release within minutes
– Chronic elevation increases bone remodeling and increased osteoclast-
mediated bone resorption
– However, PTH administered intermittently has been shown
to increase bone formation and this is a potential therapy for
osteoporosis

18. FUNCTION OF VITAMIN D
• Tissue Specificity
– Gut
– Stimulate Transepithelial Transport Of Calcium And Phosphate In The Small
Intestine (Principally Duodenum)
– Bone
– Stimulate Terminal Differentiation Of Osteoclasts
– Stimulate Osteoblasts To Stimulate Osteoclasts To Mobilize Calcium
– Parathyroid
– Inhibit Transcription Of The PTH Gene (Feedback Regulation)

19. Calcium Homeostasis

20. FUNCTIONS
• Muscle contraction
• Neuromuscular / nerve conduction
• Intracellular signalling
• Bone formation
• Coagulation
• Enzyme regulation

21. Grades Of Hypercalcemia

22. Hypercalcemia
I.Parathyroid-related
-Primary hyperparathyroidism
-Lithium therapy
-Familial hypocalciuric hypercalcemia
II. Malignancy-related
-Solid tumor with metastases (breast)
-Solid tumor with humoral mediation of hypercalcemia (lung, kidney)
-Hematologic malignancies (multiple myeloma, lymphoma, leukemia)
III. Vitamin D-related
-Vitamin D intoxication
- 1,25(OH)2D; sarcoidosis and other granulomatous diseases↑
-Idiopathic hypercalcemia of infancy
IV. Associated with high bone turnover
-Hyperthyroidism
-Immobilization
-Thiazides
-Vitamin A intoxication
V. Associated with renal failure
-Severe secondary hyperparathyroidism
-Aluminum intoxication
-Milk-alkali syndrome
Primary
hyperparathyroidism
and cancer account for
90% of cases of
hypercalcemia

23. Diagnostic Approach

24. 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%

25. Clinical 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).

26. Diagnosis
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

27. 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

28. Familial Hypocalciuric Hypercalcemia
• Caused by an inactivating MUTATION of calcium-sensing
receptors.
• Sensitivity of receptors to calcium DECREASES, requiring higher
calcium levels to suppress PTH secretion.
• Fractional excretion of calcium is lower than 1%, despite
hypercalcemia.
• Hypercalcemia in FHH has a generally benign course and is
resistant to medications, except for some cases successfully
treated with the calcimimetic agent cinacalcet.

29. Clinical (>12)
1. Renal : NDI , Stone, Nephrocalcinosis
2. Gi :Nausea/Vomiting, Constipation, Peptic
ulcer, Pancreatitis
3. Neuro :Weakness, Drowsiness
4. Cardio : Short Qt(<0.3),broad T, Heart
Block, Vent Arrhythmia, asystole
5. Musculo : Cramps, Bone Pain, Pathologic Fx
6. Others : Band Keratopathy

30. Symptoms
• Bones, stones, abdominal groans, and psychic moans.
• Malaise, fatigue, headaches, diffuse aches and pains,
constipation.
• Patients are often dehydrated
• Lethargy and psychosis when hypercalcemia is
severe.
• Calcifications in skin, cornea, conjunctiva, and
kidneys.