Tumor lysis syndrome

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Tumor lysis syndrome
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Tumor lysis syndrome (TLS) is a group of metabolic abnormalities that can occur as a complication from the treatment of cancer, where large amounts of tumor cells are killed off (lysed) from the treatment, releasing their contents into the bloodstream. [1] This occurs most commonly after the treatment of lymphomas and leukemias and in particular when treating non-Hodgkin lymphoma, acute myeloid leukemia, and acute lymphoblastic leukemia. [2] [3] This is a potentially fatal complication and people at an increased risk for TLS should be closely monitored while receiving chemotherapy and should receive preventive measures and treatments as necessary. [4] [3] TLS can also occur on its own (while not being treated with chemotherapy) although this is less common. [4] [5]

Contents

Tumor lysis syndrome is characterized by high blood potassium (hyperkalemia), high blood phosphate (hyperphosphatemia), low blood calcium (hypocalcemia), high blood uric acid (hyperuricemia), and higher than normal levels of blood urea nitrogen (BUN). [4] These changes in blood electrolytes and metabolites are a result of the release of cellular contents of dying cells into the bloodstream. [4] In this respect, TLS is analogous to rhabdomyolysis, with comparable mechanism and blood chemistry effects but with different cause. In TLS, the breakdown occurs after cytotoxic therapy or from cancers with high cell turnover and tumor proliferation rates. [4] The metabolic abnormalities seen in tumor lysis syndrome can ultimately result in serious complications such as acute uric acid nephropathy, acute kidney failure, seizures, cardiac arrhythmias, and death. [6] [7]

Signs and symptoms

Acute uric acid nephropathy (AUAN) due to hyperuricosuria has been a dominant cause of acute kidney failure, but with the advent of effective treatments for hyperuricosuria, AUAN has become a less common cause than hyperphosphatemia. [ citation needed ] Two common conditions related to excess uric acid, gout and uric acid nephrolithiasis, are not features of tumor lysis syndrome.[ citation needed ]

Risk factors

Risk factors for tumor lysis syndrome depend on several different characteristics of the patient, the type of cancer, and the type of chemotherapy used. [14]

Tumor characteristics: Tumors with a high cell turnover rate, rapid growth rate, and high tumor bulk tend to be more associated with the development of tumor lysis syndrome. The most common tumors associated with this syndrome are poorly differentiated lymphomas (such as Burkitt's lymphoma), other Non-Hodgkin Lymphomas (NHL), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). [3] Other cancers (such as melanoma) have also been associated with TLS but are less common.

Patient characteristics: Certain patient-related factors can affect the development of clinical tumor lysis syndrome. These factors include elevated baseline serum creatinine, kidney failure, dehydration, and other issues affecting urinary flow or the acidity of urine. [14]

Chemotherapy characteristics: Chemo-sensitive tumors, such as lymphomas, carry a higher risk for the development of tumor lysis syndrome. Those tumors that are more responsive to a chemotherapy agent carry a higher TLS risk. [7] 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". [13]

Diagnosis

TLS should be suspected in people with large tumor burden who develop acute kidney failure along with hyperuricemia (> 15 mg/dL) or hyperphosphatemia (> 8 mg/dL). [ medical citation needed ] (Most other acute kidney failure occurs with uric acid < 12 mg/dL and phosphate < 6 mg/dL). [ citation needed ] Acute uric acid nephropathy is associated with little or no urine output. [ citation needed ] The urinalysis may show uric acid crystals or amorphous urates. [ citation needed ] 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 kidney failure.[ citation needed ]

Cairo-Bishop definition

In 2004, Cairo and Bishop defined a classification system for tumor lysis syndrome. [15]

A grading scale (0–5) is used depending on the presence of lab TLS, serum creatinine, arrhythmias, or seizures.

Howard definition

In 2011, Howard proposed a refinement of the standard Cairo-Bishop definition of TLS accounting for 2 limitations: [2]

Moreover, any symptomatic hypocalcemia should constitute clinical TLS. [2]

Prevention

It is important to prevent life-threatening manifestations associated with TLS which include acute kidney injury, hyperkalemia (which may cause cardiac arrhythmias), and or hypocalcemia (which may cause cardiac arrhythmias and neuromuscular irritability). [2]

Acute kidney injury: Patients at risk for developing TLS (e.g. patients about to receive chemotherapy for a cancer with a high cell turnover rate, especially lymphomas and leukemias) should receive appropriate intravenous hydration in order to improve blood flow to the kidneys, maximize urine output, and ultimately prevent precipitation of uric acid crystals that can lead to acute kidney injury. [2] [4] A diuretic may also be indicated to further increase urine output in addition to intravenous hydration. [2] [4] Another approach to prevent damage to the kidneys is to prevent the buildup of uric acid during TLS, and this can be accomplished with use of allopurinol or rasburicase. [2] Allopurinol (a xanthine oxidase inhibitor, which inhibits uric acid production) works by preventing the formation of uric acid following tumor cell lysis. [4] [13] Rasburicase is a synthetic urate oxidase enzyme and acts by degrading uric acid. [16] [17] It is not recommended to alkalinize urine in the management of TLS. [2] [4]

Hyperkalemia: Monitoring potassium levels in the blood frequently and cardiac monitoring (given the risk of cardiac arrhythmias) are important components in the prevention of adverse consequences in TLS. [2] Other strategies, such as limiting oral intake of potassium, and excreting potassium through the gastrointestinal tract using agents such as oral sodium polystyrene sulfonate, can be beneficial. [2] [4] Insulin therapy (in conjunction with glucose administration) as well as beta-receptor agonists (such as albuterol) can also be used, but are temporary interventions, [2] and potassium is not excreted from the body. [ citation needed ] Hemodialysis and hemofiltration can also be used as options to remove potassium from the bloodstream when hyperkalemia is present. [2]

Hypocalcemia: Hyperphosphatemia is a common finding in TLS, and high phosphorus levels can in turn contribute to hypocalcemia. Therefore, phosphate binders may be beneficial in preventing this form of hypocalcemia. [2]

Treatment

Treatment is first targeted at the specific metabolic disorder.

In general, rasburicase and hydration are the mainstays of treatment in patients with clinical evidence of tumor lysis syndrome. [18] A loop diuretic may also be indicated to maintain appropriate production of urine by the kidneys. [18] Further treatment is targeted towards the specific metabolic abnormalities present in patients with TLS (see "main articles" linked above). Mild hyperkalemia without symptoms can be treated with a loop diuretic and sodium polystyrene sulfonate, while a temporizing agent such as rapid acting insulin (in conjunction with glucose) and an agent to stabilize cardiac membranes such as calcium carbonate may be given in cases of severe hyperkalemia. [18] Concerning symptoms related to hypocalcemia (e.g. seizures) in TLS patients can be treated with calcium gluconate. [18] Tumor lysis patients may ultimately also require renal replacement therapy such as through hemodialysis if indicated. [18]

Prognosis

The rate of mortality from tumor lysis syndrome may vary widely depending on the type of underlying malignancy. [19] However, the occurrence of acute kidney injury is concerning given the high mortality that is generally associated with it. [2]

Related Research Articles

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 a product of the metabolic breakdown of purine nucleotides, and it is a normal component of urine. High blood concentrations of uric acid can lead to gout and are associated with other medical conditions, including diabetes and the formation of ammonium acid urate kidney stones.

<span class="mw-page-title-main">Kidney stone disease</span> Formation of mineral stones in the urinary tract

Kidney stone disease, also known as renal calculus disease, nephrolithiasis or urolithiasis, is a crystallopathy where a solid piece of material develops in the urinary tract. Renal calculi typically form in the kidney and leave the body in the urine stream. A small calculus may pass without causing symptoms. If a stone grows to more than 5 millimeters, it can cause blockage of the ureter, resulting in sharp and severe pain in the lower back that often radiates downward to the groin. A calculus may also result in blood in the urine, vomiting, or painful urination. About half of people who have had a renal calculus are likely to have another within ten years.

<span class="mw-page-title-main">Gout</span> Form of arthritis causing swollen joints

Gout is a form of inflammatory arthritis characterized by recurrent attacks of pain in a red, tender, hot, and swollen joint, caused by the deposition of needle-like crystals of uric acid known as monosodium urate crystals. Pain typically comes on rapidly, reaching maximal intensity in less than 12 hours. The joint at the base of the big toe is affected (Podagra) in about half of cases. It may also result in tophi, kidney stones, or kidney damage.

<span class="mw-page-title-main">Rhabdomyolysis</span> Human disease (condition) in which damaged skeletal muscle breaks down rapidly

Rhabdomyolysis is a condition in which damaged skeletal muscle breaks down rapidly, often due to high intensity exercise over a short period. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of the muscle breakdown products, such as the protein myoglobin, are harmful to the kidneys and can cause acute kidney injury.

<span class="mw-page-title-main">Allopurinol</span> Medication

Allopurinol is a medication used to decrease high blood uric acid levels. It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy. It is taken orally or intravenously.

<span class="mw-page-title-main">Hyperuricemia</span> Excess uric acid in the blood

Hyperuricaemia or hyperuricemia is an abnormally high level of uric acid in the blood. In the pH conditions of body fluid, uric acid exists largely as urate, the ion form. Serum uric acid concentrations greater than 6 mg/dL for females, 7 mg/dL for males, and 5.5 mg/dL for youth are defined as hyperuricemia. The amount of urate in the body depends on the balance between the amount of purines eaten in food, the amount of urate synthesised within the body, and the amount of urate that is excreted in urine or through the gastrointestinal tract. Hyperuricemia may be the result of increased production of uric acid, decreased excretion of uric acid, or both increased production and reduced excretion.

<span class="mw-page-title-main">Hypocalcemia</span> Low calcium levels in ones blood serum

Hypocalcemia is a medical condition characterized by low calcium levels in the blood serum. The normal range of blood calcium is typically between 2.1–2.6 mmol/L, while levels less than 2.1 mmol/L are defined as hypocalcemic. Mildly low levels that develop slowly often have no symptoms. Otherwise symptoms may include numbness, muscle spasms, seizures, confusion, or in extreme cases cardiac arrest.

<span class="mw-page-title-main">Hyperkalemia</span> Excess potassium in the blood

Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0 mmol/L (3.5 and 5.0 mEq/L) with levels above 5.5 mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occasionally when severe it can cause palpitations, muscle pain, muscle weakness, or numbness. Hyperkalemia can cause an abnormal heart rhythm which can result in cardiac arrest and death.

<span class="mw-page-title-main">Electrolyte imbalance</span> Abnormality in the concentration of electrolytes in the body

Electrolyte imbalance, or water-electrolyte imbalance, is an abnormality in the concentration of electrolytes in the body. Electrolytes play a vital role in maintaining homeostasis in the body. They help to regulate heart and neurological function, fluid balance, oxygen delivery, acid–base balance and much more. Electrolyte imbalances can develop by consuming too little or too much electrolyte as well as excreting too little or too much electrolyte. Examples of electrolytes include calcium, chloride, magnesium, phosphate, potassium, and sodium.

<span class="mw-page-title-main">Urate oxidase</span> Pseudogene in the species Homo sapiens

The enzyme urate oxidase (UO), uricase or factor-independent urate hydroxylase, absent in humans, catalyzes the oxidation of uric acid to 5-hydroxyisourate:

<span class="mw-page-title-main">Lesch–Nyhan syndrome</span> Rare genetic disorder

Lesch–Nyhan syndrome (LNS) is a rare inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This deficiency occurs due to mutations in the HPRT1 gene located on the X chromosome. LNS affects about 1 in 380,000 live births. The disorder was first recognized and clinically characterized by American medical student Michael Lesch and his mentor, pediatrician William Nyhan, at Johns Hopkins.

This is a list of terms related to oncology. The original source for this list was the US National Cancer Institute's public domain Dictionary of Cancer Terms.

<span class="mw-page-title-main">Rasburicase</span> Pharmaceutical drug

Rasburicase, sold under the brand name Elitek in the US and Fasturtec in the EU, is a medication that helps to clear uric acid from the blood. It is a recombinant version of urate oxidase, an enzyme that metabolizes uric acid to allantoin. Urate oxidase is known to be present in many mammals but does not naturally occur in humans. Rasburicase is produced by a genetically modified Saccharomyces cerevisiae strain. The complementary DNA (cDNA) coding for rasburicase was cloned from a strain of Aspergillus flavus.

<span class="mw-page-title-main">Crush syndrome</span> Medical condition

Crush syndrome is a medical condition characterized by major shock and kidney failure after a crushing injury to skeletal muscle. Crush injury is compression of the arms, legs, or other parts of the body that causes muscle swelling and/or neurological disturbances in the affected areas of the body, while crush syndrome is a localized crush injury with systemic manifestations. Cases occur commonly in catastrophes such as earthquakes, to individuals that have been trapped under fallen or moving masonry.

<span class="mw-page-title-main">Clofarabine</span> Chemical compound

Clofarabine is a purine nucleoside antimetabolite marketed in the United States and Canada as Clolar. In Europe and Australia/New Zealand the product is marketed under the name Evoltra. It is FDA-approved for treating relapsed or refractory acute lymphoblastic leukaemia (ALL) in children after at least two other types of treatment have failed. Some investigations of effectiveness in cases of acute myeloid leukaemia (AML) and juvenile myelomonocytic leukaemia (JMML) have been carried out. Ongoing trials are assessing its efficacy for managing other cancers.

<span class="mw-page-title-main">Hypouricemia</span> Lack of uric acid in the blood

Hypouricemia or hypouricaemia is a level of uric acid in blood serum that is below normal. In humans, the normal range of this blood component has a lower threshold set variously in the range of 2 mg/dL to 4 mg/dL, while the upper threshold is 530 μmol/L (6 mg/dL) for women and 619 μmol/L (7 mg/dL) for men. Hypouricemia usually is benign and sometimes is a sign of a medical condition.

Acute uric acid nephropathy is a rapidly worsening (decreasing) kidney function that is caused by high levels of uric acid in the urine (hyperuricosuria).

<span class="mw-page-title-main">Dent's disease</span> Medical condition

Dent's disease is a rare X-linked recessive inherited condition that affects the proximal renal tubules of the kidney. It is one cause of Fanconi syndrome, and is characterized by tubular proteinuria, excess calcium in the urine, formation of calcium kidney stones, nephrocalcinosis, and chronic kidney failure.

<span class="mw-page-title-main">Hyperuricosuria</span> Excess uric acid in the urine

Hyperuricosuria is a medical term referring to the presence of excessive amounts of uric acid in the urine. For men this is at a rate greater than 800 mg/day, and for women, 750 mg/day. Notable direct causes of hyperuricosuria are dissolution of uric acid crystals in the kidneys or urinary bladder, and hyperuricemia. Notable indirect causes include uricosuric drugs, rapid breakdown of bodily tissues containing large quantities of DNA and RNA, and a diet high in purine.

Leukostasis is a medical emergency most commonly seen in patients with acute myeloid leukemia. It is characterized by an extremely elevated blast cell count and symptoms of decreased tissue perfusion. The pathophysiology of leukostasis is not well understood, but inadequate delivery of oxygen to the body's cells is the result. Leukostasis is diagnosed when white cell plugs are seen in the microvasculature. The most common symptoms are dyspnea and hypoxia, usually accompanied by visual changes, headaches, dizziness, confusion, somnolence, and coma. Prompt treatment is required since, if left untreated, it has a very high mortality rate. Treatments aim to rapidly reduce white blood cell counts while also treating the underlying disorder.

References

  1. ↑ Davidson MB, Thakkar S, Hix JK, Bhandarkar ND, Wong A, Schreiber MJ (April 2004). "Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome". The American Journal of Medicine. 116 (8): 546–554. doi:10.1016/j.amjmed.2003.09.045. PMID   15063817.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Howard SC, Jones DP, Pui CH (May 2011). "The tumor lysis syndrome". The New England Journal of Medicine. 364 (19): 1844–1854. doi:10.1056/NEJMra0904569. PMC   3437249 . PMID   21561350.
  3. 1 2 3 Cairo MS, Coiffier B, Reiter A, Younes A (May 2010). "Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus". British Journal of Haematology. 149 (4): 578–586. doi: 10.1111/j.1365-2141.2010.08143.x . PMID   20331465. S2CID   29473031.
  4. 1 2 3 4 5 6 7 8 9 10 Coiffier B, Altman A, Pui CH, Younes A, Cairo MS (June 2008). "Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review". Journal of Clinical Oncology. 26 (16): 2767–2778. doi:10.1200/JCO.2007.15.0177. PMID   18509186.
  5. ↑ Belay Y, Yirdaw K, Enawgaw B (2017). "Tumor Lysis Syndrome in Patients with Hematological Malignancies". Journal of Oncology. 2017: 9684909. doi: 10.1155/2017/9684909 . PMC   5688348 . PMID   29230244.
  6. ↑ Cheuk DK, Chiang AK, Chan GC, Ha SY (March 2017). "Urate oxidase for the prevention and treatment of tumour lysis syndrome in children with cancer". The Cochrane Database of Systematic Reviews. 2017 (3): CD006945. doi:10.1002/14651858.CD006945.pub4. PMC   6464610 . PMID   28272834.
  7. 1 2 Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE (2014). Aebeloff's Clinical Oncology (Fifth ed.). Philadelphia: Elsevier Saunders. ISBN   978-1-4557-2865-7.
  8. ↑ Viera AJ, Wouk N (September 2015). "Potassium Disorders: Hypokalemia and Hyperkalemia". American Family Physician. 92 (6): 487–495. PMID   26371733.
  9. ↑ Schafer AL, Shoback DM (2000), Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, et al. (eds.), "Hypocalcemia: Diagnosis and Treatment", Endotext, South Dartmouth (MA): MDText.com, Inc., PMID   25905251 , retrieved 2022-03-11
  10. ↑ Rampello E, Fricia T, Malaguarnera M (August 2006). "The management of tumor lysis syndrome". Nature Clinical Practice. Oncology. 3 (8): 438–447. doi: 10.1038/ncponc0581 . PMID   16894389. S2CID   23245352.
  11. ↑ Moossa AR, Schimpff SC, Robson MC (1991). Comprehensive textbook of oncology. Vol. 2. Lippincott Williams & Wilkins. ISBN   9780683061475 . Retrieved 2 May 2012. ... result in severe metabolic derangements (e.g., hyperuricemia, hypocalcemia, lactic acidosis, and the acute tumor lysis syndrome) which require expeditious management. Hyperuricemia Uric acid is the end product of purine catabolism.
  12. ↑ Darmon M, Malak S, Guichard I, Schlemmer B (September 2008). "Acute tumor lysis syndrome: a comprehensive review". Revista Brasileira de Terapia Intensiva. 20 (3): 278–285. doi: 10.1590/S0103-507X2008000300011 . PMID   25307096.
  13. 1 2 3 Weeks AC, Kimple ME (26 August 2015). "Spontaneous Tumor Lysis Syndrome: A Case Report and Critical Evaluation of Current Diagnostic Criteria and Optimal Treatment Regimens". Journal of Investigative Medicine High Impact Case Reports. 3 (3): 2324709615603199. doi:10.1177/2324709615603199. PMC   4748506 . PMID   26904699.
  14. 1 2 Coiffier B, Riouffol C (February 2007). "Management of tumor lysis syndrome in adults". Expert Review of Anticancer Therapy. 7 (2): 233–239. doi:10.1586/14737140.7.2.233. PMID   17288532. S2CID   41115749.
  15. ↑ Cairo MS, Bishop M (October 2004). "Tumour lysis syndrome: new therapeutic strategies and classification". British Journal of Haematology. 127 (1): 3–11. doi: 10.1111/j.1365-2141.2004.05094.x . PMID   15384972. S2CID   35738745.
  16. ↑ Jones GL, Will A, Jackson GH, Webb NJ, Rule S (June 2015). "Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology". British Journal of Haematology. 169 (5): 661–671. doi: 10.1111/bjh.13403 . PMID   25876990. S2CID   46803727.
  17. ↑ Cammalleri L, Malaguarnera M (March 2007). "Rasburicase represents a new tool for hyperuricemia in tumor lysis syndrome and in gout". International Journal of Medical Sciences. 4 (2): 83–93. doi:10.7150/ijms.4.83. PMC   1838823 . PMID   17396159.
  18. 1 2 3 4 5 Tosi P, Barosi G, Lazzaro C, Liso V, Marchetti M, Morra E, et al. (December 2008). "Consensus conference on the management of tumor lysis syndrome". Haematologica. 93 (12): 1877–1885. doi: 10.3324/haematol.13290 . hdl: 11585/72920 . PMID   18838473. S2CID   7146760.
  19. ↑ Durani U, Shah ND, Go RS (December 2017). "In-Hospital Outcomes of Tumor Lysis Syndrome: A Population-Based Study Using the National Inpatient Sample". The Oncologist. 22 (12): 1506–1509. doi:10.1634/theoncologist.2017-0147. PMC   5728022 . PMID   28904174.
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