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