Tumour lysis syndrome (TLS)
is an important metabolic disorder
frequently encountered
in the management of a variety
of cancers including lymphoma,
leukemia, neuroblastoma
and small cell lung cancer.
The acute tumour lysis
syndrome (ATLS) may be a dramatic
complication of anticancer
therapy. It occurs mostly in
haematological malignancies
and less commonly in solid
tumours. Spontaneous tumour
lysis syndrome (STLS) has
been reported more frequently
in Burkitts lymphomas than in
other haematological tumours
and exceptionally in solid
tumours like small-cell lung
carcinoma and germ-cell
tumours . Delayed recognition
can result in biochemical abnormalities
resulting in lifethreatening
complications
such as renal failure,
arrhythmias and seizures. Identification
of high-risk patients
and early recognition of the
syndrome is crucial in early institution
of appropriate prophylaxis
and treatment.
Metabolic abnormalities
In patients with myeloproliferative
diseases or hematopoietic
*MM Institute of Medical Sciences and
Research, Mullana (Ambala).
** National Institute of Immunology, New
Delhi.
Correspondence: Dr KK Swami, Asst
Prof, Dept of Biochemistry, Block D-66,
Medical College Campus, MMI Medical
Sciences & Research, Mullana (Ambala)
Haryana
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hematopoietic
malignancies, nucleic acids
are catabolised as a result
of increased turnover of malignant
cell populations. This results
in an increase in purine
catabolism, leading to hyperuricemia.
Aggressive cancer
chemotherapy, radiotherapy or
immunotherapy causes an increase
in cell lysis and release
of intracellular molecules (potassium,
phosphorus and
nucleic acid) into the bloodstream
and results in four
metabolic abnormalities: hyperuricemia,
hyperphosphatemia,
hyperkalemia and hypocalcemia.
The large amounts of
intracellular contents released
cannot be processed and excreted
by the kidneys. When
renal excretory capacities are
exceeded, patients develop
acute renal failure secondary
to precipitation of uric acid in
the renal tubules. Hyperuricemia
is the leading disorder responsible
for TLS and its consequences
(Table 1).
Hyperuricemia
Uric acid is a weak organic acid
(pKa 5.8), and poorly water
soluble at acidic pH. It derives
partly from diet and partly from
endogenous biosynthesis and it
is eliminated by enteric (25-35%)
Table 1 : Metabolic imbalance in TLS
| Hyperuricemia |
> 4.76 mol/l (8mg/dl) |
| Hyperphos- phatemia |
> 2.1 mmol/l (children)
or > 1.45 mmol/l (adults) |
|
Hyperkalemia
|
> 6mmol/l
|
|
Hypocalcemia
|
> 1.75mmol/l
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and renal (65-75%) ways. Hyperuricemia
(uric acid blood level
over 8 mg/dl or 4.76 ėmol/l),
infact, is considered its biochemical
hallmark, because the
precipitation of uric acid is possible
when uric acid exceeds the
limit of solubility (about 4.20
ėmol/l at 37°C). It is already
present at the diagnosis or it
develops within 48-72 hours after
the neoplastic treatment.
The impact of hyperuricemia
and deposition of monosodium
urate (tophi) is widely felt because
it may cause pathologic
consequences in several organs,
such as kidney, brain, subcutaneous
tissues or joints. Kidney
is one of the most involved organs
in case of hyperuricemia,
because it is the main site of uric
acid excretion.
Its impairment
may be of different types. Hyperuricemia
is a cause of urolithiasis.
Calculi, predominantly
composed of uric acid, represent
around 13 percent of human
kidney stones. It is also possible
in acute urate nephropathy, due
to dramatic and rapid increase
of uricemia and renal handling
of uric acid and urate. The crystals
precipitate and obstruct tubules
of distal nephrons and collecting
ducts, where pH is acidic.
The result is a tubular necrosis and acute renal
failure (ARF)
because of internal
obstruction
of urinary
flow. After the
disruption of tubules,
crystals
start to accu-
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mulate in the interstice.
Crystallisation is worsened by
volume depletion (frequently in
neoplastic patients owing to
vomiting, diarrhea and fever),
that compromises glomerular
filtration and increases urate
concentration in distal tubule.
Also, low urine pH reduces uric
acid solubility, worsening
crystallisation.
The most frequent causes of
ARF are the cytostatic therapies
in patients with cancer or
blastic crisis in acute leukaemia.
The consequent massive
cellular lysis exceeds the
renal excretory ability. ARF is
reversible with early treatment.
Calculi are rarely described in
this kind of renal damage. When
uric acid exceeds renal capacity
of elimination, it precipitates
into renal tubules. So, a vicious
circle is created because the
consequent renal functional impairment
worsens hyperkalemia
and hyperphosphatemia;
phosphorus and calcium bind
themselves and precipitate
within kidneys. Hyperuricemia
and hyperphosphatemia severely
worsen renal functionality;
hyperkalemia and hypocalcemia
compromise regular
cardiac rhythm causing
arrhythmias, sometimes mortal,
and neuromuscular function,
with potential tetany, convulsion
and cramping. Being the
clearance of uric acid, potassium,
calcium and phosphate
mainly renal, kidneys are overloaded,
until their excretion ability
is saturated with great difficulties
to eliminate electrolytes,
toxic substances and drugs,
with consequent risk of accumulation
and toxicity.
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Hyperkalemia
Hyperkalemia is the most dangerous
immediate consequence of TLS. It results in cardiovascular,
neuromuscular and GI irritability
and leads to delayed
cardiac conduction and
repolarisation. These changes
can lead to atrioventricular
block, ventricular tachycardia,
ventricular fibrillation, or asystole.
The cardiac effects of hyperkalemia
can be exacerbated.
by hyponatremia
and hypocalcemia.
The
neuromuscular
effects of hyperkalemia
include
muscle weakness
and irritability,
cramps,
twitching and
paresthesias in
the form of tingling
and burning
Hypocalcemia
The inverse relationship between
calcium and phosphorus,
hypocalcemia results from increased
phosphorous binding
to the calcium in the bloodstream,
forming calcium phosphate
salts.
Laboratory determinations
The prevention and early detection
of metabolic abnormalities
related to TLS include assessment
of both laboratory
data and symptoms related to
elevated levels of uric acid, potassium,
phosphorous. Close
monitoring of metabolic parameters
includes serum electrolytes
(Na+, K+, Ca++, Cl-, P),
uric acid, LDH and renal function
studies, including BUN
and creatinine. Monitoring of
laboratory values should take
place every 6 to 8 hours during
the first 72 hours after induction
chemotherapy. TLS is defined
as the presence of at least
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phosphates
are not soluble in alkaline
urine, and (ii)
to prevent alkalosis,
which may predispose
the patient to
neuromuscular irritability
by exacerbating
hypocalcemia.
 Monitor serum
electrolyte and uric
acid levels for evidence
of fluid volume
overload secondary
to aggressive
hydration.
Instruct patients
to report symptoms
indicating electrolyte
disturbances.
Recent advances
in the understanding
of urate
metabolism, development
of new
urate lowering
drugs and application
of biomarkers,
calculation method
and prognostic
models to identify
high risk patients
will pave the way for
improving the management
of tumour
lysis syndrome.
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renal failure associated to
spontaneous tumour lysis syndrome
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