Calcium Disorders

William E. Clutter, M.D.Associate Professor of Medicine

Department of Internal Medicine

Division of Endocrinology, Metabolism & Lipid Research

Calcium regulation

Albumin binding – ionized vs total calcium• Corrected Ca = Ca (mg/dl) + 0.8 (4 – albumin in g/dl)

Parathyroid hormone

1,25 (OH)2 Vitamin D

PTH-related peptide (PTHrP) Cytokines

Calcium balance

ECF CALCIUMGUT KIDNEY

BONE (1 kg)

Net 175 mg Net 175 mg

500 mg500 mg

1000 mg

Hypercalcemia: clinical signs GI:

• Nausea, vomiting, abdominal pain• Constipation

Renal:• Polyuria, dehydration• Renal failure

Neurological• Fatigue• Confusion• Stupor, coma

Hypercalcemia: major causes

Primary hyperparathyroidism (PHPT) Malignancy Others

Hyperparathyroidism: causes Primary

• Adenoma (90%)• Multiple gland enlargement (10%)

– MEN 1– MEN 2A– Familial hyperparathyroidism

• Carcinoma (<1%)• Familial benign hypercalcemia (FBH)

Secondary (normo- or hypocalcemic)• Renal failure• Vitamin D deficiency

Malignant hypercalcemia: major causes

PTHrP - mediated• Breast carcinoma

• Squamous carcinoma (lung, head & neck, esophagus)

• Renal carcinoma

Cytokine - mediated• Myeloma (lymphoma, leukemia)

Hypercalcemia: other causes

Drugs:• Vitamin D

• Calcium carbonate (milk alkali syndrome)

• Lithium

• PTH

• Vitamin A

Sarcoidosis, other granulomatous disorders Hyperthyroidism

Hypercalcemia: presentations

Chronic, mild-moderate• Often asymptomatic

• Cause: primary hyperparathyroidism

• Issues: parathyroidectomy or not

Acute, severe• Symptomatic

• Cause: malignant hypercalcemia (rarely others)

• Issues: treat hypercalcemia, find & treat cause

Primary hyperparathyroidism

F:M 3:1 Usually > 50 y/o Presentation:

• Asymptomatic hypercalcemia (>50%)

• Renal stones (20%)

• Decreased bone density

• Symptoms of hypercalcemia (<5%)

Hypercalcemia: evaluation

Duration >6 months or renal stones: PHPT Signs of malignancy, other rare causes Medications (including OTC, supplements) Family history

Plasma PTH• Normal or elevated: primary hyperpararthyroidism

• Low: other causes

Primary hyperparathyroidism: Rx

Indications for parathyroidectomy:• symptomatic hypercalcemia

• kidney stones

• bone density T-score < -2.5 SD

• plasma calcium >(ULN + 1) mg/dl

• age <50 years

• (urine calcium >400 mg/24 hr)

NIH consensus Panel JCEM 87:5353, 2002

Parathyroid Localization

Sestamibi scans

Left lower parathyroid adenoma Mediastinal parathyroid adenoma

Primary hyperparathyroidism: pitfalls Positive family history:

• Evaluate for MEN 1 or 2A• Evaluate for FBH

– FE Ca <0.01– Evaluate family – CaSR gene analysis

Concomitant vitamin D deficiency• PTH disproportionately high• More severe post-op hypocalcemia• Replete if 25-OH vitamin D <20 ng/dl

Primary hyperparathyroidism: pitfalls

Diagnose before imaging!• False positive and negative sestamibi scans

Normal ionized calcium:• Primary vs secondary hyperparathyroidism

Primary Hyperparathyroidism Follow-up of unoperated:

• Normal calcium intake• Annual calcium, creatinine• Biannual bone mass• Bisphosphonate for osteoporosis• Cinacalcet (calcimimetic) ?

Indications for surgery• Declining bone mass or renal function• Worsening hypercalcemia

Nonparathyroid hypercalcemia Repeat history (especially drugs) Vitamin D toxicity suspected: 25 (OH) vitamin D Sarcoidosis suspected: 1,25 (OH)2 vitamin D

Malignancy suspected:• SPEP, UPEP

• Bone scan

• Chest & abdominal CT

• Biopsy

• PTHrp

Severe hypercalcemia:

Principles of therapy• Expand ECF volume

• Increase urinary calcium excretion

• Decrease bone resorption

Indications for therapy• Symptoms of hypercalcemia

• Plasma [Ca] >12 mg/dl

Severe hypercalcemia: therapy Restore ECF volume

• Normal saline rapidly• Positive fluid balance >2 liters in first 24 hr

Saline diuresis• Normal saline 100-200 ml/hr (replace potassium)

Zoledronic acid 4 mg IV over 15 min• if plasma [Ca] >14 mg/dl or >12 mg/dl after

rehydration• Monitor plasma calcium QD

Myeloma or vitamin D toxicity:• prednisone 30 mg BID

Hypocalcemia: clinical signs

Paresthesias Tetany (carpopedal spasm) Trousseau’s, Chvostek’s signs Seizures Chronic: cataracts, basal ganglia Ca

Trousseau’s sign

Hypocalcemia: causes

Hypoparathyroidism• Surgical• Autoimmune• Magnesium deficiency

PTH resistance (pseudohypoparathyroism)

Vitamin D deficiency Vitamin D resistance

Other: renal failure, pancreatitis, tumor lysis

Hypocalcemia: evaluation

Confirm low corrected & ionized calcium History:

• Neck surgery

• Other autoimmune endocrine disorders

• Causes of Mg deficiency

• Malabsorption

• Family history

Hypocalcemia: evaluation

Physical exam:• Signs of tetany

• Signs of pseudohypoparathyroidism– Short metacarpals

– Short stature, round face

Lab• PTH

• Creatinine, Mg, P, alkaline phosphatase

• 25-OH vitamin D

Hypocalcemia: evaluation

Cause

Hypoparathyroidism

PTH resistance

Vitamin D deficiency

Vitamin D resistance

Phosphate

High

High

Low

Low

Other

PTH low

PTH high

25-OHD low

Alk phos

Normal

Normal

High

High

Hypocalcemia: acute therapy

IV calcium infusion• 1-2 gm Ca gluconate (10-20 ml) IV over 10 min

• 6 gm Ca gluconate/500 cc D5W over 6 hr

• Follow plasma Ca & P Q 4-6 hr & adjust rate

IV or oral calcitriol 0.25-2 mcg/day

Oral calcium carbonate 1-2 gm BID-TID

Hypocalcemia: chronic therapy

Oral calcitriol 0.25-2 mcg/day Calcium carbonate 1-2 gm BID-TID