1

• 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

• Most often asymptomatic – Incidental Dx

• Mild Hypercalcemia is asymptomatic

• Most important cause is hyper parathyroid

• DD is needed to decide the treatment

• Optimal step by step evaluation is a must.

3

• 98% of the body calcium is in the skeleton

• Only 2% is circulation and only half of this is free calcium (ionized Ca++)

• This only is physiologically active

• The reminder 1% is bound to proteins

• Direct measurement of free Calcium ??

4

5

6

(1,000 mg/day)

7

Hormone

Effect Bone Gut Kidney

PTH Ca Po4

Increases Osteoclasts

Indirect via Vit. D

Ca reabPo4 exr.

Vitamin D3

Ca Po4

No direct action

Ca Po4 absorption

No direct effect

Calcitonin

Ca Po4

Inhibits Osteoclasts

No direct effect

Ca & Po4 excretion

8

Corrected total calcium (mg%) =

[(Measured total calcium mg%) +

{(4.4 - measured albumin g%) x 0.8}]

Example:

[12.0 + {(4.4 – 2.4) x 0.8}] =

[ 12.0 + (2 x 0.8)] = 12.0 + 1.6 = 13.6

mg%9

Calcitriol (Active)

Supplements Vitamin D 2

10

11

12

13

14

15

• More than 90 percent of hypercalcemia cases are

Primary hyperparathyroidism and malignancy

• These conditions must be differentiated early

to provide optimal treatment & accurate prognosis

• Humoral hypercalcemia of malignancy implies a very limited life expectancy — only a matter of weeks

• Primary hyperparathyroidism has a benign course.

16

• Primary hyperparathyroidism

• Sporadic, familial, associated with

Multiple Endocrine Neoplasia (MEN I or II)

• Tertiary hyperparathyroidism

• Associated with chronic renal failure

• PTH due to Vitamin D deficiency17

• Vitamin D intoxication

• Iatrogenic Vitamin D injections

• Usually 25-hydroxyvitamin D2 in

over-the-counter supplements

• Granulomatous disease –

Sarcoidosis, Berylliosis, Tuberculosis

• Hodgkin’s lymphoma

18

• Humoral hypercalcemia of malignancy (mediated by PTHrP) – common cause

• Solid tumors, especially lung, head and neck squamous cancers

• Renal Cell Carcinoma (RCC)

• Local osteolysis (mediated by cytokines)

• Multiple Myeloma

• Breast cancer19

• Thiazide diuretics (usually mild) - common

• Lithium for depressive illnesses

• Milk-alkali syndrome (calcium + antacids)

• Vitamin A intoxication (including

analogs used to treat acne)

20

• Hyperthyroidism

• Adrenal insufficiency

• Acromegaly

• Pheochromocytoma

21

• Familial hypocalciuric hypercalcemia (FHH)

mutated calcium-sensing receptor gene

• Immobilization, with high bone turnover (e.g., Paget’s disease, bedridden child)

• Recovery phase of Rhabdomyolysis

22

23

Renal “stones”

• Nephrolithiasis

• Nephrogenic Diabetes Insipidus

• Dehydration

• Nephrocalcinosis

24

Skeleton “bones”

• Bone pains

• Arthritis

• Osteoporosis

• Osteitis fibrosa cystica in HPTH

25

Abdominal “Moans”

• Nausea, vomiting

• Severe anorexia, weight loss

• Constipation (not relieved by Rx.)

• Abdominal pain (vague and diffuse)

• Pancreatitis

• Peptic ulcer disease26

Psychological “Groans”

• Impaired concentration

• Impaired memory, Depression

• Confusion, stupor, coma

• Lethargy and severe fatigue

• Extreme muscle weakness

• Corneal calcification (band keratopathy)

27

Cardiovascular

• Hypertension, Increased risk of CHD

• ECG changes of shortened QT interval, PR prolonged, QRS widened, ST , Bradycardia

• Cardiac arrhythmias; Vascular calcification

Others

• Itching (Generalized Pruritus)

• Keratitis, conjunctivitis28

29

Hypocalcemia

Normal calcium

30

31

Endocrine

32

33

• Increased screening for serum Ca++ and• Wider availability of I-PTH assay• 80% of cases single parathyroid adenoma• Usually benign adenoma or hyperplasia• Rarely parathyroid cancer• High PTH in the setting of hypercalcemia• Slowly progressive – Sestamibi N-scan• 25% require surgery – RLN paralysis

34

64 yrs male - “hyper parathyroid storm” with a serum calcium level

of 16.4 mg%

• Serum calcium level > 12 mg % at any time

• Episodes of hyper parathyroid crisis

• Marked hypercalciuria (urinary Ca++ > 400 mg /day)

• Nephrolithiasis; Impaired renal function

• Osteitis fibrosa cystica – Thinning of cortical bone

• Reduced bone density by DEXA scan (Z score < 2)

• Classic neuromuscular symptoms, Proximal muscle weakness and atrophy, Hyper reflexia and ataxia

• Age younger than 50 years

35

36

• 25 OH - Vitamin D2 is the supplemental Vit D

• Level of 25 OH – Vitamin D3 is to be measured

• Macrophages in the granulomas, lymphomas cause extra renal conversion of 25 OH form

to the1,25 hydroxy derivative –the active Calcitriol

• PTH levels are suppressed; Calcitriol levels • Stop the offending use of Vitamin D • Glucocorticoids – for over one month or more• Manage hypercalcemia vigorously

37

• Most commonly mediated by systemic PTHrP

• Humoral Hypercalcemia of malignancy

• PTHrP mimics the bone & renal effects of PTH

• Normal Calcitriol and suppressed PTH levels

• Excessive bone lysis due to primary or bone secondaries can cause hypercalcemia

• MM and metastatic Br Ca present in this way. • In Osteolytic hypercalcemia, SAP is markedly • Hodgkin’s lymphoma – production of

Calcitriol

• Thiazide diuretics increase renal calcium resorption and cause mild hypercalcemia• Resolves after discontinuing the drug• Thiazide unmasks hyperparathyroidism• Milk–alkali syndrome – Ca + Antacids• Lithium – the set point for PTH • Excess Vitamin A - bone resorption and causes hypercalcemia.

38

• FHH – Familial Hypocalciuric Hypercalcemia• AD – 100% penetrance – Ca-R gene mutation• Moderate hypercalcemia with normal/ PTH• 24 hour urinary calcium is very low• No benefit from parathyroidectomy• High bone turnover in Paget’s disease or

prolonged immobilization• Recovery phase of Rhabdomyolysis

39

• Ca <12 but > 10.3 mg% – no appreciable clinical benefit – they need evaluation

• Any patient with Serum Ca > 12 mg% should be aggressively treated

• Ca > 14 mg% is Hypercalcemic crisis

• Always correct the Ca value for Sr Albumin

40

41

• Vigorous I.V. Nacl Diuresis – N Saline

• Adequate hydration – urine out put must be maintained 200 ml/hour = 5 L /day

• The safest and most effective treatment of Hypercalcemic crisis is saline rehydration

• Once the urine out put is maintained – give I.V. Furosemide – a loop diuretic in low doses of 10 to 20 mg

• ERT - might be beneficial in PMW – new RCT

42

• In severe hypercalcemia refractory to saline diuresis

• Calcitonin (Zycalcit, Miacalcin) 6 -8 U/kg IM/SC (400 i.u) given every six hours.

• This treatment has a rapid onset but short duration of effect

• Patients develop tolerance to the calcium-lowering effect of Calcitonin.

43

• Zoledronic acid (Zometa) - 4 mg IV diluted in 100 ml of N Saline - over at least 15’ once a M

• Pamindronate (Pamidria) - 60 mg IV infusion over 4 h initial – repeated after a month

• Etidronate (Didronel) - 7.5 mg/kg IV over 4 h daily for 3-7 d; dilute in at least 250 ml of sterile N Saline

• They inhibit bone resorption, inhibit the Osteoclastic activity.

44

• Dialysis for refractory Hypercalcemic crisis

• Parathyroidectomy for adenomas

• Rx. of the underlying cause – Eliminate drugs

• Plicamycin (Mithracin) 25 mcg/kg/d IV for 4 d

• Gallium nitrate (Ganite) 100 mg/m2/d IV for 5 days in 1 L of NS or 5% Dextrose

• Cinacalcet (Sensipar) - 30 mg PO od – (increases sensitivity of calcium sensing receptor)

45

• Hypercalcemia is often asymptomatic• Screen all suspected by doing Sr Calcium• If elevated, do I-PTH and follow algorithm• 90% Hyperparathyroidism and malignancy• Vitamin D toxicity is an important cause• Thiazide diuretics common cause, Vitamin A• Adequate hydration - N Saline + Furosemide• Calcitonin + Zoledronic acid main stay of Rx.

46