HYPERCALCEMIA & TUMOR LYSIS SYNDROME
Dr. Gaurav Kumar
PGT ; Radiotherapy
MCH
Hypercalcemia: Calcium levels above normal physiological range i.e. 9-11 mg/dl.
Hypercalcemia
Symptomatic Asymptomatic
Mild (<12mg/dl) Severe (>12mg/dl)
CAUSES OF HYPERCALCEMIA
1] PARATHYROID RELATED
A) PRIMARY HYPERPARATHYROIDISM(Renal Calcium Absorption <99%)
i. solitary adenomaii. Multiple endocrine neoplasia
B) LITHIUM THERAPY
C) FAMILIAL HYPOCALCIURIC HYPERCALCEMIA(Renal Calcium Absorption >99%)
2] MALIGNANCY RELATED :
A) SOLID TUMORS WITH METASTASIS (BREAST)
B) SOLID TUMOR WITH HUMORAL MEDIATION OF HYPERCALCEMIA
C) HEMATOLOGIC MALIGNANCIES
3] VITAMIN D-RELATED :
A) VITAMIN D INTOXICATION
B) 1,25(OH)₂D , SARCOIDOSIS , OTHER GRANULOMATOUS DS.
C) IDIOPATHIC HYPERCALCEMIA OF INFANCY
4] ASSOCIATED WITH HIGH BONE TURNOVER :
A) HYPERTHYROIDISM
B) IMMOBILISATION
C) THIAZIDES
D) VIT-A INTOXICATION
5] ASSOCIATED WITH RENAL FAILURE :
A) SECONDARY HYPERPARATHYROIDISM
B) ALUMINUM INTOXICATION
C) MILK ALKALI SYNDROME
CLINICAL FEATURES :
Mild Hypercalcemia: (11-11.5 mg/dl)Trouble concentrating , Personality changes ,
depression , peptic ulcer disease , nephrolithiasis ,increased fracture risk
Severe Hypercalcemia : (>12 mg/dl)Lethargy , Stupor , Coma
GI symptoms like nausea , anorexia , constipation or pancreatitis
Psychic Moans
Malignancy Related Hypercalcemia:
.2nd Most common cause
. 20% cancer patient
.Common causes: lung Ca (squamous variety) , Renal
neoplasms , Metastatic Ca Breast , hematological malignancies
DIAGNOSIS :
ALBUMIN CONC. IN BLOOD ( 50% calcium is bound
to albumin)IF NORMAL
PTH level
PTH + Calcium + phosphate PTH + Calcium
Primary Hyperparathyroidism Malignancy or
Granulomatous ds.
Cont.
0.2 mg/dl is added to total Calciumfor every 1 gm /dl decrease in Albumin conc. and vice versa
PHPTH vs Malignancy
PHPTH
• Healthy
• Asymptomatic
• Calcium ranging from high normal to less than 1 greater than the upper limit of normal
• PTH elevated
MALIGNANCY
• Usually obvious by the time of dx
• Sicker, symptomatic inpatients
• Calcium usually over 13
• Solid tumors, leukemias, MM
• PTH-rp, or elevated calcitriol
MECHANISMS OF HYPERCALCEMIA IN MALIGNANCY
1] Tumor releases PTHrP (parathyroid related peptide)which acts on bones causing increased resorption and thus
increased blood calcium levels.E.g- Squamous cell cancer of lung, Renal neoplasms
2] Tumor may cause Bone Marrow invasion,BM reacts by producing Lymphokines and Cytokines (IL-2, TNF), which inturncauses local destruction of bones by OAF (osteoclast activating
factor).E.g- Multiple myeloma, leukemias
3] Increased 1,25(OH)₂D by Abnormal Lymphocytes,which causes increased renal & gastric reabsorption of Calcium.
E.g- Lymphomas
HUMORAL HYPERCALCEMIA OF MALIGNANCY
PTH like factor
Activates PTH1R
Action as parathyroid hormone
Increased Calcium
Decreased PTH secretion
TREATMENT
1] CONTROL OF MALIGNANCY(Since it is reversible cause of hypercalcemia)
2] REDUCE CALCIUM LEVELSMild Hypercalcemia- Hydration (0.9% N.S) enoughSevere Hypercalcemia- Can be managed by
i) Decrease Skeletal Releaseii) Decrease Intestinal Absorption
iii) Increase Renal Excreation
A] DECREASE BONE RESORPTIONi) Bisphosphonates (onset of action 1-2 days)
ii) Calcitonin (within hours)iii) Mithramycin -seldom usediv) Gallium Nitrate-rarely used
v) Glucocorticoidsvi) Phosphate Therapy
B] INCREASED RENAL EXCRETIONi) Forced Diuresis (Hydration along with frusemide /
Ethacrynic Acid)ii) Glucocorticoids
iii) Calcitonin
C] DECREASE INTESTINAL ABSORPTIONi) Glucocorticoids
ii) Hydration
TREATMENT ALGORYTHMRestore Normal Hydration
Isotonic Saline Infusion (upto 3-4 lits or more)
Frusemide (Twice daily 40mg)
Add Calcitonin within 24 hrs(2-8 U/kg) & Bisphosphonates (Zolendronate 4-8 mg/5 min infusion)
More aggressive hydration (6 lits or more) and frequent dosing of Frusemide for life threatening hyperCalcaemia.
“painful bones, renal stones, abdominal groans, psychic moans, and neuropsychiatric overtones”
TUMOR LYSIS SYNDROME
TUMOR LYSIS SYNDROME is characterised by Hyperuricemia , Hyperkalemia ,
Hyperphosphatemia and Hypocalcaemia caused by the destruction of large number of
rapidly proliferating neoplastic cells.
PATHOPHYSIOLOGYDestruction of large number of neoplastic cell
Release of cellular contents in blood
a) Increased serum uric acidb) Increased serum Phosphatesc) Increased serum Potassiumd) Decreased serum Calcium
Increased Uric acid Increased Lactic acid
Acidosis
Dehydration
Uric acid precipitation in Tubules , Medulla , Collecting Ducts of kidney
Renal Failure
HOW TO DIFFERENTIATE RENAL FAILURE DUE TO ACUTE
HYPERURICEMIA FROM OTHER CAUSES?
Urinary Uric Acid : Urinary CreatinineIf > 1 Acute HyperuricemiaIf < 1 Other Causes
HYPERPHOSPHATEMIA
Phosphates binds to Serum Calcium
Calcium Phosphates
Deposits in Renal Tubule Decrease Serum Calcium
Renal Failure Hypocalcemia
Fatal Neuromuscular Irritation and Tetany
HYPERKALEMIA
Increased Potassium in serum Renal Failure
Life Threatining Hyperkalemia
Ventricular Arrythmias & Sudden Death
TYPES OF TLS :
1] THERAPEUTIC 2] SPONTANEOUS
i)DURING THERAPY SPONTANEOUS ii)AFTER THERAPY NECROSIS
(1-5 DAYS) WITHOUT TREATMENT
COMMONLY ASSOCIATED MALIGNANCIES
i) Burkitt‘s Lymphomaii) ALL
iii)Other high Grade Lymphomas*Rarely with Solid Neoplasms and Chronic Leukemias
COMMONLY ASSOCIATED TREATMENT MODALITIES
i) GLUCOCORTICOIDSii) HORMONAL AGENTS e.g- Letrozole , Tamoxifen
iii) MONOCLONAL ANTIBODIES e.g – Rituximab , Gemtuzumabiii) CHEMOTHERAPEUTIC DRUGS
MANAGEMENT OF TUMOR LYSIS i) Maintain Hydration (Normal or ½ normal saline)
3000 ml/m² per dayii) Keep Urine pH at 7.0 or greater (Sodium bicarbonate)
iii) Allopurinol at 300 mg/m²per day
24-48 hours
Serum Uric acid >8 mg/dl Serum Uric acid <8 mg/dlSerum creatinine >1.6 mg/dl Serum Creatinine <1.6 mg/dl
Correct treatable Renal Failure Start ChemotherapyStart Rasburicase 0.2 mg/kg i.v Bicarbonate OFF
Cont.
IF
Serum K⁺ >6.0 meq/dl
Serum Uric Acid >10 mg/dl
Serum Creatinine >10 mg/dl
Serum phosphate >10 meq/dl
Symptomatic HypoCalcemia present
Hemodialysis
Thank you