Tumor lysis syndrome
Encyclopedia
In medicine
(oncology
and hematology
), tumor lysis syndrome (TLS) is a group of metabolic
complications that can occur after treatment of cancer
, usually lymphoma
s and leukemia
s, and sometimes even without treatment. These complications are caused by the break-down products of dying cancer cells and include hyperkalemia
, hyperphosphatemia
, hyperuricemia
and hyperuricosuria
, hypocalcemia, and consequent acute uric acid nephropathy
and acute renal failure
.
, and leukemias, such as acute lymphoblastic leukemia
(ALL) and acute myeloid leukemia
(AML). Other cancers (such as melanoma
) have also been associated with TLS but are less common.
Usually, the precipitating medication regimen includes combination chemotherapy
, but TLS can be triggered in cancer patients by steroid
treatment alone, and sometimes without any treatment—in this case the condition is referred to as "spontaneous tumor lysis syndrome".
. Potassium
is mainly an intracellular
ion
. High turnover of tumor cells leads to spill of potassium into the blood. Symptoms usually do not manifest until levels are high (> 7 mmol/dL) [normal 3.5-5.0 mmol/dL] and they include
Hyperphosphatemia
. Like potassium, phosphate
s are also predominantly intracellular. Hyperphosphatemia causes acute renal
failure in tumor lysis syndrome, because of deposition of calcium phosphate
crystals in the renal parenchyma
.
Hypocalcemia. Because of the hyperphosphatemia, calcium
is precipitated to form calcium phosphate, leading to hypocalcemia. Symptoms of hypocalcemia include (but are not limited to):
Hyperuricemia
and hyperuricosuria
. Acute uric acid nephropathy
(AUAN) due to hyperuricosuria has been a dominant cause of acute renal failure but with the advent of effective treatments for hyperuricosuria, AUAN has become a less common cause than hyperphosphatemia. Two common conditions related to excess uric acid
, gout
and uric acid nephrolithiasis, are not features of tumor lysis syndrome.
Pretreatment spontaneous tumor lysis syndrome. This entity is associated with acute renal failure due to uric acid nephropathy prior to the institution of chemotherapy and is largely associated with lymphomas and leukemias. The important distinction between this syndrome and the post-chemotherapy syndrome is that spontaneous TLS is not associated with hyperphosphatemia. One suggestion for the reason of this is that the high cell turnover rate leads to high uric acid levels through nucleobase
turnover but the tumor reuses the released phosphate for growth of new tumor cells. In post-chemotherapy TLS, tumor cells are destroyed and no new tumor cells are being synthesized.
may show uric acid crystals or amorphous urates. The hypersecretion of uric acid can be detected with a high urine uric acid - creatinine ratio > 1.0, compared to a value of 0.6-0.7 for most other causes of acute renal failure.
A grading scale (0-5) is used depending on the presence of lab TLS, serum creatinine, arrhythmias, or seizures.
(a xanthine oxidase
inhibitor, which inhibits uric acid production) as well as adequate IV hydration to maintain high urine output (> 2.5 L/day).
Rasburicase
(Uricase) is an alternative to allopurinol and is reserved for patients who are high-risk in developing TLS. It is a synthetic urate oxidase
enzyme and acts by degrading uric acid.
Alkalinization of the urine with acetazolamide
or sodium bicarbonate
is controversial. Routine alkalinization of urine above pH of 7.0 is not recommended. Alkalinization is also not required if uricase is used.
Acute renal failure prior to chemotherapy. Since the major cause of acute renal failure in this setting is uric acid build-up, therapy consists of rasburicase
to wash out excessive uric acid crystals as well as a loop diuretic
and fluids. Sodium bicarbonate should not be given at this time. If the patient does not respond, hemodialysis
may be instituted, which is very efficient in removing uric acid, with plasma uric acid levels falling about 50% with each six hour treatment.
Acute renal failure after chemotherapy. The major cause of acute renal failure in this setting is hyperphosphatemia, and the main therapeutic means is hemodialysis. Forms of hemodialysis used include continuous arteriovenous hemodialysis (CAVHD), continuous venovenous hemofiltration (CVVH), or continuous venovenous hemodialysis (CVVHD).
Medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
(oncology
Oncology
Oncology is a branch of medicine that deals with cancer...
and hematology
Hematology
Hematology, also spelled haematology , is the branch of biology physiology, internal medicine, pathology, clinical laboratory work, and pediatrics that is concerned with the study of blood, the blood-forming organs, and blood diseases...
), tumor lysis syndrome (TLS) is a group of metabolic
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
complications that can occur after treatment of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, usually lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
s and leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
s, and sometimes even without treatment. These complications are caused by the break-down products of dying cancer cells and include hyperkalemia
Hyperkalemia
Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...
, hyperphosphatemia
Hyperphosphatemia
Hyperphosphatemia is an electrolyte disturbance in which there is an abnormally elevated level of phosphate in the blood. Often, calcium levels are lowered due to precipitation of phosphate with the calcium in tissues.-Signs and symptoms:...
, hyperuricemia
Hyperuricemia
Hyperuricemia is a level of uric acid in the blood that is abnormally high. In humans, the upper end of the normal range is 360 µmol/L for women and 400 µmol/L for men.-Causes:...
and hyperuricosuria
Hyperuricosuria
Hyperuricosuria is a medical term referring to the presence of excessive amounts of uric acid in the urine. Notable direct causes of hyperuricosuria are dissolution of uric acid crystals in the kidneys or urinary bladder, and hyperuricemia...
, hypocalcemia, and consequent acute uric acid nephropathy
Acute uric acid nephropathy
Acute uric acid nephropathy is a rapidly worsening kidney function that is caused by high levels of uric acid in the urine .-Causes:...
and acute renal failure
Acute renal failure
Acute kidney injury , previously called acute renal failure , is a rapid loss of kidney function. Its causes are numerous and include low blood volume from any cause, exposure to substances harmful to the kidney, and obstruction of the urinary tract...
.
Cause and risk factors
The most common tumors associated with this syndrome are poorly differentiated lymphomas, such as Burkitt's lymphomaBurkitt's lymphoma
Burkitt's lymphoma is a cancer of the lymphatic system...
, and leukemias, such as acute lymphoblastic leukemia
Acute lymphoblastic leukemia
Acute lymphoblastic leukemia is a form of leukemia, or cancer of the white blood cells characterized by excess lymphoblasts.Malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow. ALL causes damage and death by crowding out normal cells in the bone...
(ALL) and acute myeloid leukemia
Acute myeloid leukemia
Acute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...
(AML). Other cancers (such as melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
) have also been associated with TLS but are less common.
Usually, the precipitating medication regimen includes combination chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, but TLS can be triggered in cancer patients by steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
treatment alone, and sometimes without any treatment—in this case the condition is referred to as "spontaneous tumor lysis syndrome".
Symptoms and pathogenesis
HyperkalemiaHyperkalemia
Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...
. Potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
is mainly an intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
. High turnover of tumor cells leads to spill of potassium into the blood. Symptoms usually do not manifest until levels are high (> 7 mmol/dL) [normal 3.5-5.0 mmol/dL] and they include
- cardiacHeartThe heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
conduction abnormalities (can be fatal) - severe muscle weakness or paralysis
Hyperphosphatemia
Hyperphosphatemia
Hyperphosphatemia is an electrolyte disturbance in which there is an abnormally elevated level of phosphate in the blood. Often, calcium levels are lowered due to precipitation of phosphate with the calcium in tissues.-Signs and symptoms:...
. Like potassium, phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
s are also predominantly intracellular. Hyperphosphatemia causes acute renal
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
failure in tumor lysis syndrome, because of deposition of calcium phosphate
Calcium phosphate
Calcium phosphate is the name given to a family of minerals containing calcium ions together with orthophosphates , metaphosphates or pyrophosphates and occasionally hydrogen or hydroxide ions ....
crystals in the renal parenchyma
Parenchyma
Parenchyma is a term used to describe a bulk of a substance. It is used in different ways in animals and in plants.The term is New Latin, f. Greek παρέγχυμα - parenkhuma, "visceral flesh", f. παρεγχεῖν - parenkhein, "to pour in" f. para-, "beside" + en-, "in" + khein, "to pour"...
.
Hypocalcemia. Because of the hyperphosphatemia, calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
is precipitated to form calcium phosphate, leading to hypocalcemia. Symptoms of hypocalcemia include (but are not limited to):
- tetanyTetany (medical sign)Tetany is a medical sign consisting of the involuntary contraction of muscles, which may be caused by disease or other conditions that increase the action potential frequency...
- seizures
- mental retardation / dementia
- parkinsonian (extrapyramidal) movement disorders
- papilledemaPapilledemaPapilledema is optic disc swelling that is caused by increased intracranial pressure. The swelling is usually bilateral and can occur over a period of hours to weeks. Unilateral presentation is extremely rare....
- emotional instability / agitation / anxiety
- myopathyMyopathyIn medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
Hyperuricemia
Hyperuricemia
Hyperuricemia is a level of uric acid in the blood that is abnormally high. In humans, the upper end of the normal range is 360 µmol/L for women and 400 µmol/L for men.-Causes:...
and hyperuricosuria
Hyperuricosuria
Hyperuricosuria is a medical term referring to the presence of excessive amounts of uric acid in the urine. Notable direct causes of hyperuricosuria are dissolution of uric acid crystals in the kidneys or urinary bladder, and hyperuricemia...
. Acute uric acid nephropathy
Acute uric acid nephropathy
Acute uric acid nephropathy is a rapidly worsening kidney function that is caused by high levels of uric acid in the urine .-Causes:...
(AUAN) due to hyperuricosuria has been a dominant cause of acute renal failure but with the advent of effective treatments for hyperuricosuria, AUAN has become a less common cause than hyperphosphatemia. Two common conditions related to excess uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
, gout
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
and uric acid nephrolithiasis, are not features of tumor lysis syndrome.
Pretreatment spontaneous tumor lysis syndrome. This entity is associated with acute renal failure due to uric acid nephropathy prior to the institution of chemotherapy and is largely associated with lymphomas and leukemias. The important distinction between this syndrome and the post-chemotherapy syndrome is that spontaneous TLS is not associated with hyperphosphatemia. One suggestion for the reason of this is that the high cell turnover rate leads to high uric acid levels through nucleobase
Nucleobase
Nucleobases are a group of nitrogen-based molecules that are required to form nucleotides, the basic building blocks of DNA and RNA. Nucleobases provide the molecular structure necessary for the hydrogen bonding of complementary DNA and RNA strands, and are key components in the formation of stable...
turnover but the tumor reuses the released phosphate for growth of new tumor cells. In post-chemotherapy TLS, tumor cells are destroyed and no new tumor cells are being synthesized.
Diagnosis
TLS should be suspected in patients with large tumor burden who develop acute renal failure along with hyperuricemia (> 15 mg/dL) or hyperphosphatemia (> 8 mg/dL). (Most other acute renal failure occurs with uric acid < 12 mg/dL and phosphate < 6 mg/dL). Acute uric acid nephropathy is associated with little or no urine output. The urinalysisUrinalysis
A urinalysis , also known as Routine and Microscopy , is an array of tests performed on urine, and one of the most common methods of medical diagnosis...
may show uric acid crystals or amorphous urates. The hypersecretion of uric acid can be detected with a high urine uric acid - creatinine ratio > 1.0, compared to a value of 0.6-0.7 for most other causes of acute renal failure.
Cairo-Bishop Definition
In 2004, Cairo and Bishop defined a classification system for tumor lysis syndrome.- Laboratory tumor lysis syndrome: abnormality in two or more of the following, occurring within three days before or seven days after chemotherapy.
- uric acid > 8 mg/dL or 25% increase
- potassium > 6 meq/L or 25% increase
- phosphate > 4.5 mg/dL or 25% increase
- calcium < 7 mg/dL or 25% decrease
- Clinical tumor lysis syndrome: laboratory tumor lysis syndrome plus one or more of the following:
- increased serum creatinine (1.5 times upper limit of normal)
- cardiac arrhythmia or sudden death
- seizure
A grading scale (0-5) is used depending on the presence of lab TLS, serum creatinine, arrhythmias, or seizures.
Prevention
Patients about to receive chemotherapy for a cancer with a high cell turnover rate, especially lymphomas and leukemias, should receive prophylactic oral or IV allopurinolAllopurinol
Allopurinol is a drug used primarily to treat hyperuricemia and its complications, including chronic gout.- Mechanism of action :...
(a xanthine oxidase
Xanthine oxidase
Xanthine oxidase Xanthine oxidase Xanthine oxidase (XO (sometimes 'XAO'), a form of xanthine oxidoreductase that generates reactive oxygen species. Is an enzyme that catalyzes the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid...
inhibitor, which inhibits uric acid production) as well as adequate IV hydration to maintain high urine output (> 2.5 L/day).
Rasburicase
Rasburicase
Rasburicase is a recombinant version of a urate oxidase enzyme that occurs in many mammals but not in humans.-Uses:Rasburicase is approved for use by the U.S...
(Uricase) is an alternative to allopurinol and is reserved for patients who are high-risk in developing TLS. It is a synthetic urate oxidase
Urate oxidase
The enzyme urate oxidase , or uricase or factor-independent urate hydroxylase, catalyzes the oxidation of uric acid to 5-hydroxyisourate:-Structure:...
enzyme and acts by degrading uric acid.
Alkalinization of the urine with acetazolamide
Acetazolamide
Acetazolamide, sold under the trade name Diamox, is a carbonic anhydrase inhibitor that is used to treat glaucoma, epileptic seizures, Idiopathic intracranial hypertension , altitude sickness, cystinuria, and dural ectasia...
or sodium bicarbonate
Sodium bicarbonate
Sodium bicarbonate or sodium hydrogen carbonate is the chemical compound with the formula Na HCO3. Sodium bicarbonate is a white solid that is crystalline but often appears as a fine powder. It has a slightly salty, alkaline taste resembling that of washing soda . The natural mineral form is...
is controversial. Routine alkalinization of urine above pH of 7.0 is not recommended. Alkalinization is also not required if uricase is used.
Treatment
Treatment is first targeted at the specific metabolic disorder.Acute renal failure prior to chemotherapy. Since the major cause of acute renal failure in this setting is uric acid build-up, therapy consists of rasburicase
Rasburicase
Rasburicase is a recombinant version of a urate oxidase enzyme that occurs in many mammals but not in humans.-Uses:Rasburicase is approved for use by the U.S...
to wash out excessive uric acid crystals as well as a loop diuretic
Loop diuretic
Loop diuretics are diuretics that act on the ascending loop of Henle in the kidney. They are primarily used in medicine to treat hypertension and edema often due to congestive heart failure or renal insufficiency...
and fluids. Sodium bicarbonate should not be given at this time. If the patient does not respond, hemodialysis
Hemodialysis
In medicine, hemodialysis is a method for removing waste products such as creatinine and urea, as well as free water from the blood when the kidneys are in renal failure. Hemodialysis is one of three renal replacement therapies .Hemodialysis can be an outpatient or inpatient therapy...
may be instituted, which is very efficient in removing uric acid, with plasma uric acid levels falling about 50% with each six hour treatment.
Acute renal failure after chemotherapy. The major cause of acute renal failure in this setting is hyperphosphatemia, and the main therapeutic means is hemodialysis. Forms of hemodialysis used include continuous arteriovenous hemodialysis (CAVHD), continuous venovenous hemofiltration (CVVH), or continuous venovenous hemodialysis (CVVHD).