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

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

Distribution Of Calcium

CALCIUM

ECF8.5-10.6 mg/dl

2.25-2.65 mmol//l

ICFCYTOPLASMIC FREE

50-100 nmol/l

PROTEIN BOUND45%

DIFFUSIBLEULTRAFILTRABLE

55%

IONIZED45%

COMPLEXED10%90% ALBUMIN

10% GLOBULIN

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]

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

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

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CALCIUM HOMEOSTASIS

DIETARY CALCIUM

INTESTINAL ABSORPTIONORGAN PHYSIOLOGY

ENDOCRINE PHYSIOLOGY

DIETARY HABITS,

SUPPLEMENTSBLOOD CALCIUM

BONE

KIDNEYS

URINE

THE ONLY “IN”

THE PRINCIPLE “OUT”

ORGAN PHYS.

ENDOCRINE PHYS.

ORGAN, ENDOCRINE

TRANSCELLULAR CALCIUM ABSORPTION

TRPV5

NUCLEUS

CCALBINDIN D9k

NCX1 PMCA1b CaSR

calcium

LUMEN

BLOOD

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

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

DISTAL TUBULE CALCIUM ABSORPTION

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

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

PTH/Calcium HomeostasisLow 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.

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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

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

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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)

Calcium Homeostasis

PTH• 4 PT glands• 84 AA

hormone• Low Ca

stimulates it

Calcitriol (D)• Active bone

formation• Main effect is

on the Gut• PTH Vit. D

Calcitonin• Para follicular C

of Thyroid• 34 AA

hormone• On Kidney

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FUNCTIONS

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

Grades Of Hypercalcemia

HypercalcemiaI.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

Diagnostic Approach

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%

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).

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

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

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.

Clinical (>12)1. Renal : NDI , Stone, Nephrocalcinosis2. Gi :Nausea/Vomiting, Constipation, Peptic

ulcer, Pancreatitis3. Neuro :Weakness, Drowsiness4. Cardio : Short Qt(<0.3),broad T, Heart Block,

Vent Arrhythmia, asystole5. Musculo : Cramps, Bone Pain, Pathologic Fx6. Others : Band Keratopathy

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.