Hasan AYDIN, MD

Yeditepe University Hospital

Endocrinology and Metabolism

Hypercalcemic Disorders

Etiologies of HypercalcemiaIncreased GI Absorption

Milk-alkali syndromeElevated calcitriol Vitamin D excess

Excessive dietary intakeGranulomatous diseases

Elevated PTH Hypophosphatemia

Increased Loss From BoneIncreased net bone resorption

Elevated PTH HyperparathyroidismMalignancy Osteolytic metastases PTHrP secreting tumor

Increased bone turnoverPaget’s disease of boneHyperthyroidism

Decreased Bone Mineralization

Elevated PTH

Aluminum toxicity

Decreased Urinary Excretion

Thiazide diuretics

Elevated calcitriol

Elevated PTH

ETIOLOGY

T Thiazide, other drugs - Lithium

R RabdomyolysisA AIDSP Paget’s disease,

Parental nutrition, Pheochromocytoma, Parathyroid disease

V VitaminsI ImmobilizationT ThyrotoxicosisA Addison’s diseaseM Milk-alkali syndromeI Inflammatory

disordersN Neoplastic related

diseaseS Sarcoidosis

Approx. 80% of all cases are caused by Malignancy or Primary Hyperpathyroidism

CLASSIFICATION

PTH-Dependent Hypercalcemia

Primary hyperparathyroidism

Tertiary hyperparathyroidism

Familial hypocalciuric hypercalcemia

Lithium-asociated hypercalcemia

CLASSIFICATION

NeoplasmsPTHr-P dependentOther humoral syndromesOsteolytic metastases and

multiple myelomaExcessVitamin

D/1,25(OH)2DVitamin D ingestion1,25(OH)2D intoxicationToicaşl vitamin D

analoguesSarcoidosis and other

granulomatous diseasesWilliams syndrome

HyperthyroidismAdrenal insufficiencyRenal failureİmmobilizationJansen’s metapyseal

chondrodysplasiaDrugs

Vitamin A intoxicationMilk alkali syndromeThiazide diureticsTheophylline

PTH-Independent Hypercalcemia

CLINICAL MANIFESTATIONS

GI- Anorexia, Nausea, Vomiting, Constipation and rarely acute

Pancreatitis.

CVS- Hypertension, shortened QT interval

RENAL- Thirst, Polyuria, Polydipsia, and occasionally Nephrocalcinosis.

CNS- Cognitive difficulties, Apathy, Drowsiness, Obtundation, or even

Coma.

-Anxiety, Depression, Psychosis

Ectopic Calcifications- Nephrocalcinosis, calcifications of blood

vessels, band keratopathy

SYMPTOMS

More than 50% of all patients with primary

hyperparathyroidism are asymptomatic when hypercalcemia is first

discovered.

COMPLICATIONSSinus bradycardia

Increase in the degree of a heart block

Cardiac arrhythmia

Hypertension

Pancreatitis

Peptic ulcer disease

Nephrolithiasis

Accelerated vascular calcification

Diagnostic Yield in Hypercalcemia

Investigation Potential Information

Full Blood Count Anemia suggest non-parathyroid etiology if renal function normal

ESR Usually over 80 in myeloma

Plasma chloride Upper normal in hypepararthyroidism

Plasma bicarbonate Low normal in hypepararthyroidism

Creatinine Significantky raised in tertiay hyperparathyroidism of renal failure.Moderately raised in renal impairement secondary to hypercalcemia

Plasma protein electrophoresis Monoclonal band suggest myeloma

Urinary immunelectrophoresis Presece of light chain suggest myeloma

Plasma phosphate Low normal in primary hyperparathyroidism unless renal function impaired

Plasma PTH Upper normal or raised in hyperparathyroidismSuppressed with other causes of hypercalcemia

Steroid suppression test Sarcoid hypercalcemia alwasy suppress, hyperparathyroid never, malignanat causes occasionally

24 h urine calcium Decreased in FHH

Chest X-ray Neoplasms, hilar LAP in sarcoidosis

Isotope bone scan ‘Hot spots’ suggest metastases

X-ray hands Subperiosteal erosions suggest hyperparathyroidism

HYPERCALCEMIA

PTH highHyperparathroidism

PTH - N or LowMalig- prim. or mets

Vit highconsider Sarcoidosis

CXR

Consider other*Hyperthyroidism

*Milk-alkali syndrome*Familial hypocalciuric hypercalcemia

If cause remain unclearmeasure Vit D

Measure PTH

Determine wheather hypercalcemia is real, measure ionized Caadjust for change in serum albumin level, careful drug hx Li, Vit D or A,

SERUM CALCIUM> 10.6

MANAGEMENT OF SYMPTOMATIC HYPERCALCEMIA

General measuresSaline diuresis

Specific measuresGlucocorticoidsPhosphate infusionBisphosphonatesCalcitoninDialysis

LOOP DIURETICS

Facilitate urinary excretion of calciumBy inhibiting calcium reabsorption in the thick ascending limb of the loop of Henle.

Guard against volume overloadVolume expansion must precede the administration of furosemide, because the drug’s effect depends on delivery of calcium to the ascending limb. Needs frequent measurement of lytes and water

CALCITONINNot as effective as bisphosphonate, tachyphylaxis quickly occurs and limits therapeutic efficacy

MITHRAMYCIN Toxic effect limits it’s use, reserved for difficult cases of

hypercalcemia that are related to malignancy

GALLIUM NITRATENeed to infuse it over 5 days, nephrotoxity limits it’s use, not used frequently

CORTICOSTEROIDSFor myeloma, lymphoma, Sarcoidosis, or vit D toxicity decrease GI absorption, 200-300mg hydrocort for upto 5 days, slow response limits it’s use

HEMODIALYSISZero or low calcium bath, In selected condition, eg-hypercalcemia complicated by renal failure

BISPHOSPHONATES

Structurally related to pyrophosphate.

P-C-P bound is a back bone that renders them resistant to

phosphates.

They bind to hydroxyapatite in bone and inhibit the

dessolution of crystals.

Their great affinity for bone and their resistance to

degradation account for their extremely long half life in

bone.

Poor GI absorption- <10%

ETIDRONATE PAMIDRONATE CLODRONATE

CHOICE OF AGENT

Mild (<12 mg/dl)-Hydration with saline.

Moderate(>15mg/dl) with moderate symptoms-

Bisphosphonate.

Severe life threatening( >15mg/dl) - Saline + Calcitonin

+ mithramycin, alternatively bisphosphonate, if

steroids sensitive + steroids.

Hypercalcemia secondary to malignancy- survival

after the appearance of hypercalcemia is very

poor - median of 3 months.

SPECIFIC CAUSES OF HYPERCALCEMIA

FAMILIAL HYPOCALCIURIC HYPERCALCEMIA

Autosomal dominantInactivating mutation of calcium sensing

receptorShift in the set point for suppression of PTHStarts at birthSerum Ca mild/moderately elevatedUrinary calcium excretion low/normalUrinary CCa/CCr <0,1PTH normal/Slightly elevatedMultiple, slightly enlarged, policlonal glandsUsually asymptomaticSurgery not effective

Lithium Toxicity

5% of casesDue to:

Increse in the set-point for PTH secretionIncrease in tubular reabsorption of calcium

After years of treatmentElevation in calcium and PTHEnlargement of parathyroidsAfter withdrawal, Ca and PTH returns

normal within several months

Hypercalcemia of Malignancy

Most common cause in hospitalized patients

Most common in Sq. Cell Ca., Breast. Renal Bladder Ca, MM, Lymphoma

Uncommon in colon and prostate ca.Occurs in the late course of malignancyDehydration, immobilization and treatment

with certain drugs contribute to or potentiate development of hypercalcemia

Hypercalcemia of Malignancy

Specific causes of hypercalcemiaDirect invasion of bone (local osteolysis)-20-40%Tumor production of circulating factors (PTHrP)

that osteoclastic resorption of bone (humoral hypercalcemia of malignancy)-40-50%

Ectopic production of 1,25 (OH)2D3 (lymphomas)Ectopic production of PTH (Lung, Ovary, Thyroid)Concomitant malignancy and PHP or

granulomatous diseaseTreatment with estrogen and antiestrogen

(tamoxifen)

Vitamin D Intoxication

>100,000 units/day

25(OH)D level 5-10x high despite N/slightly

elevated 1,25(OH)2D3

Hypercalcemia and hypercalciuria

N/V, weakness, altered consciousness

Persist for weeks to months after discontinuation

of medication

Use of steroids (prednisone 40-60 mg/day)

Granulomatous Diseases

Hypercalcemia in 10%, hypercalciuria 50% of sarcoidosis

Correlate with degree of severity and level of ACE

CausesHigh level of 1,25(OH)2D3Overproduction of bone resorbing cytokinesProduction of PTHrP

Treatment with steroids (prednisone 40-60 mg/d)

Hyperthyroidism

15-50% of cases

By direct stimulation of ostoclastic bone

resorption

Ca levels rarely exceed 11 mg/dL

Low PTH, Low 1,25(OH)2D3, Hypercalciuria

Β-Blockers (propronalol 20-40 qid)

Vitamin A Intoxication

>50,000 IU/day

Treatment with cis-retinoic acid or all-

transretinoic acid

Dry skin, pruritus, headache, bone pain

By direct stimulation of bone resorption

Treatment with hydration and steroids

Adrenal Insufficiency

CausesVolume depletion with hemoconcentration

Increased tubular reabsorption of calcium,

Increased skeletal release of calciumTreatment

Correction of volume depletionSteroids

Thiazide Diuretics

Rarely cause hypercalcemia by themselves

Causes↑ renal tubular reabsorption of Ca

↑ bone resorption activityDiuretic-induced volume depletion

Milk Alkali Syndrome

Ingestion of excessive amounts of milk (calcium supplements) or soluble alkali (antacids)

Acute formTriad of hypercalcemia, metabolic alkalosis,

renal failureTreatment with rehydration and if necessary

dialysisChronic form (Burnett syndrome)

Soft tissue calcifications in kidney and nephrocalcinosis

Progressive renal insufficiency

Immobilization

Increased bone resorption

Hypercalciuria, ↓ PTH and 1,25(OH)2D3

Bisphosphonates ± Calcitonin

Williams Syndrome

Supravalvular aortic stenosis, elfin facies, mental retardation

Hypercalcemia in infancy (↑ 1,25(OH)2D3)

Jansen’s Metaphyseal Chondrodisplasia

Short stature, hypercalcemiaSimilar to PHPPTH-R activating mutation

HEREDITARY PRIMARY HYPERPARATHYROIDISM SYNDROMES

MEN 1

Familial Hypocalciuric Hypercalcemia

Neonatal Severe Hyperparathyroidism

MEN 2a

Hyperparathyroidism-Jaw Tumor Syndrome

MEN 1Parathyroid, enteropancreatic, pituitary and

other tumors (85 % HP, 35 % Z-E, 25 % Prolactinoma)

Otosomal dominantInactivating MEN 1 gene germ-line mutationStarting age : 25Urinary calcium excretion normal-highHigh PTHMultiple abnormal glands

90 % cure after PTX

MEN 2A

Pheochromocytoma, medullary thyroid CA,

mild hyperparathyroidism

Activating mutation of the RET proto-

oncogene

Otosomal dominant