Hasan AYDIN, MD Yeditepe University Hospital Endocrinology and Metabolism Hypercalcemic Disorders.
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Transcript of Hasan AYDIN, MD Yeditepe University Hospital Endocrinology and Metabolism Hypercalcemic Disorders.
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