Textbook Reading

METABOLIC
EMERGENCIES
Devita, Hellman, Rosenberg. Cancer: Principles and
Practice of Oncology 10th edition. Wolters Kluwer
Health/Lippincott Williams & Wilkins Publishers.
2015
INTRODUCTION
• Increased awareness and
improved prophylaxis 
helped preempt some
metabolic emergencies
• Prompt recognition and the
rapid institution of adequate
therapy are essential to
successful outcome.
 TUMOR LYSIS
SYNDROME AND
HYPERURICEMIA
GENERAL
• Tumor cell death with the release of
intracellular contents can lead to a
constellation of metabolic abnormalities
= the tumor lysis syndrome (TLS).
• Occurs most frequently  Following
administration of cytotoxic
chemotherapy to patients with
hematologic malignancies, with a
large percentage of proliferating, drug-
 TUMOR LYSIS
SYNDROME AND
HYPERURICEMIA
 TUMOR LYSIS
SYNDROME AND
HYPERURICEMIA
GENERAL
• A few hours to a few days after the
initiation of therapy  cell death
leads to the release of potassium,
phosphate, uric acid, and other
purine metabolites  overwhelming
the kidney’s capacity for clearance
(hyperkalemia, hyperphosphatemia
and secondary hypocalcemia, and
hyperuricemia  progress = acute
 TUMOR LYSIS
SYNDROME AND
HYPERURICEMIA
GENERAL
 TUMOR LYSIS
SYNDROME AND
HYPERURICEMIA
GENERAL
 TUMOR LYSIS
SYNDROME AND
HYPERURICEMIA
GENERAL
• Incidence :
• The highest incidence (42%) = patients with
rapidly growing, chemosensitive myelo-
lymphoproliferative malignancies with
high white blood cell counts (acute
leukemias) OR large bulky adenopathy
(high-grade non-Hodgkin lymphomas [NHL],
especially Burkitt lymphoma)
• A Pan-European retrospective chart review =
• 3.4% acute myeloid leukemia (AML)
 TUMOR LYSIS
SYNDROME AND
HYPERURICEMIA
PATHOGENESIS
• Cell lysis  release of
contents at a rate 
exceeding the kidney’s
clearance capacity =
most important
etiologic factor in TLS
• Hyperkalemia
• Falling adenosine
triphosphate (ATP)
levels before cell lysis
 TUMOR LYSIS
SYNDROME AND
HYPERURICEMIA
PATHOGENESIS
• Hyperphosphatemia
• The initial adaptation :
increased urinary
excretion and
decreased tubular
reabsorption of
phosphate  transport
becomes saturated 
phosphorus levels rise,
the calcium phosphorus
 TUMOR LYSIS
SYNDROME AND
HYPERURICEMIA
PATHOGENESIS
• Hypocalcemia leads to
increased levels of
parathyroid hormone 
decreased proximal
tubule phosphate
reabsorption 
accentuating
hyperphosphaturia
and the risk of calcium
phosphate crystals in
 TUMOR LYSIS
SYNDROME AND
HYPERURICEMIA
 TUMOR LYSIS
SYNDROME AND
HYPERURICEMIA
THERAPY
• In adults, preventive beginning
preferably 24 hours before
chemotherapy administration :
• Foremost hydration
• Allopurinol
• Oral phosphate binders
 TUMOR LYSIS
SYNDROME AND
HYPERURICEMIA
THERAPY
• The strategies of therapy :
• (1) continue to rely on the triad of
aggressive hydration, management of
electrolyte disturbances, and institution of
allopurinol beginning immediately upon
presentation;
• (2) evaluate patients for their TLS risk
and administer a single 3-mg dose of
rasburicase at presentation to patients with
“high risk disease”
 TUMOR LYSIS
SYNDROME AND
HYPERURICEMIA
THERAPY
• Aggressive hydration :
• At least 3,000 mL/m2 per day, when
possible delaying tumor therapy so
hydration can be administered
• Urine alkalinization remains controversial
as it favors precipitation of calcium/phosphate
complexes in renal tubules
• Administration of 100 mEq sodium
bicarbonate will maintain urine pH above 7.5, a
pH that is needed not because of uric acid,
which has a pKa of 5.4 (so that above a pH of
 TUMOR LYSIS
SYNDROME AND
HYPERURICEMIA
THERAPY
• Hyperkalemia  treated aggressively =
calcium gluconate antagonizes cardiac
effects of hyperkalemia and can be
especially helpful if there is concomitant
hypocalcemia.
• Sodium bicarbonate corrects acidemia and
shifts potassium back into cells  administering
hypertonic dextrose and insulin can augment
this
• Loop diuretics can eliminate excess potassium
in patients without renal failure 
 TUMOR LYSIS
SYNDROME AND
HYPERURICEMIA
THERAPY
• Hyperphosphatemia and its
resultant hypocalcemia = require oral
phosphate binders except to
manage hyperkalemia avoid calcium
administration (can promote
metastatic calcifications)
 TUMOR LYSIS
SYNDROME AND
HYPERURICEMIA
THERAPY
• Hyperuricemia
• Allopurinol, an analog of the purine
base hypoxanthine  inhibiting
xanthine oxidase
• Uric acid levels usually do not fall until after
48 to 72 hours of treatment
• Increase in plasma hypoxanthine and
xanthine levels  increased renal excretion of
both metabolic products  may precipitate
contributing to acute renal failure.
 TUMOR LYSIS
SYNDROME AND
HYPERURICEMIA
THERAPY
• Hyperuricemia
 TUMOR LYSIS
SYNDROME AND
HYPERURICEMIA
THERAPY
• Hyperuricemia
• Rasburicase
• Uric acid levels fall to 0.5 to 1 mg/dL within 4
hours of rasburicase injection
• More expensive  A 5-day course of
rasburicase = 15,000 times of a 5-day course
of allopurinol =15 to 30 times more than
intravenous allopurinol
• The manufacturer = dose 0.2 mg/kg for up to
5 days (http://products.
sanofi.us/elitek/elitek.html)
 TUMOR LYSIS
SYNDROME AND
HYPERURICEMIA
THERAPY
• Hyperuricemia
 CANCER AND
HYPONATREMI
A GENERAL
• Hyponatremia = serum
sodium <130 mEq/L 
incidence = 3.7%.
• Clinical manifestations :
• Anorexia
• Nausea
• Asthenia
• Impaired consciousness
progressing to coma
• Generalized hypotonia
 CANCER AND
HYPONATREMIA
PATHOGENESIS
• Hyponatremia  effect a surrogate for
hypoosmolality and these terms are
usually synonymous.
• Normal plasma osmolality = 280 to 295
mOsm/kg through :
• (1) thirst perception
• (2) control of free water clearance in the
kidney by ADH also known as AVP
• (3) renal sodium excretion regulated by
ANP and the renin angiotensin system
 CANCER AND
HYPONATREMIA
PATHOGENESIS
• Hyponatremia secondary to inappropriate
secretion of AVP (or ADH; syndrome of
inappropriate antidiuretic hormone
[SIADH] or syndrome of inappropriate
antidiuresis) = paraneoplastic
syndrome, or as a complication of
therapy
• SIADH = hypo-osmolar or dilutional
hyponatremia with excessive
natriuresis. Hyponatremia occurs
because AVP secretion continues even after
 CANCER
AND
HYPONATR
EMIA
 CANCER
AND
HYPONATREM
IA
 CANCER AND
HYPONATREMIA
 LACTIC ACIDOSIS
AND CANCER
GENERAL
• Lactic acidosis = a pH ≤7.35, with
plasma lactate concentration
≥5 meq/L.
• The occurrence of metabolic
acidosis in patients with cancer 
poor prognosis.
 LACTIC ACIDOSIS
AND CANCER
PATHOGENESIS
• Lactic acid  production under hypoxia in
all tissues  release into the circulation 
90%metabolized in the liver  converted to
pyruvate  10% metabolized or excreted by
the kidney
• Tumor cells rely on anaerobic glycolysis
disproportionately  producing large
quantities of lactate  an imbalance
between lactate production  utilization by
the liver
 LACTIC ACIDOSIS
AND CANCER
PATHOGENESIS
• Contributes to hypoglycemia.
• The high frequency of liver involvement in
adults with lymphoma and leukemia 
lactic acidosis supports the possibility
reduced hepatic lactate utilization
• The loss of mitochondrial membrane
potential (Δψm) during programmed
cell death or apoptosis --> glycolysis
with accumulation of lactic acid and acidosis
 LACTIC ACIDOSIS
AND CANCER
THERAPY
• (1) aggressively support blood pressure
with fluids and vasopressors to
preclude generalized hypoperfusion
• (2) use of sodium bicarbonate  impact
hemodynamic function and the response to
catecholamines
• (3) hemodialysis and hemofiltration
with a bicarbonate-based replacement fluid
• (4) correction of the underlying causes
HYPERCALCEMIA AND
CANCER
GENERAL
• Most common paraneoplastic
syndrome (10% to 30%)
• Symptoms :
• Nausea
• Vomiting
• Constipation
• Polyuria
• Disorientation
HYPERCALCEMIA AND
CANCER
PATHOGENESIS
• Hypercalcemia  result of focal bone destruction
(osteolytic)  mediated by local (paracrine) factors factors
secreted by tumor cells infiltrating bone including cytokines
and growth factors that stimulate osteoclasts directly or
indirectly via osteoblast-mediated upregulation of osteoclast-
activating factors.
• The systemic factor most commonly secreted by tumor cells,
parathyroid hormone–related protein (PTHrP) 
mediates a humoral hypercalcemia of malignancy.
• Found in approximately 80% of hypercalcemic patients with cancer.
• The common amino terminus binds the same cell surface receptor in
bone and kidney and stimulates increases in bone resorption and renal
tubular calcium reabsorption leading to hypercalcemia.
• PTHrP can synergize local (paracrine) factors including interleukin-1,
interleukin-6 and tumor necrosis factor-α further contributing to
hypercalcemia.
HYPERCALCEMIA AND
CANCER
PATHOGENESIS
• Hypercalcemia  result of focal bone destruction
(osteolytic)  mediated by local (paracrine) factors factors
secreted by tumor cells infiltrating bone including cytokines
and growth factors that stimulate osteoclasts directly or
indirectly via osteoblast-mediated upregulation of osteoclast-
activating factors.
• The systemic factor most commonly secreted by tumor cells,
parathyroid hormone–related protein (PTHrP) 
mediates a humoral hypercalcemia of malignancy.
• Found in approximately 80% of hypercalcemic patients with cancer.
• The common amino terminus binds the same cell surface receptor
in bone and kidney  stimulates increases in bone resorption and
renal tubular calcium reabsorption  hypercalcemia.
• PTHrP can synergize local (paracrine) factors including
interleukin-1, interleukin-6 and tumor necrosis factor-α 
hypercalcemia.
HYPERCALCEMIA AND
CANCER
PATHOGENESIS
• Some lymphomas secrete the active form of
vitamin D, 1,25 dihydroxyvitamin D 
enhancing osteoclastic bone resorption
and intestinal calcium absorption.
• Hypercalcemia induces an osmotic diuresis,
while inhibiting ADH  polyuria together with
nausea and vomiting lead to progressive
dehydration, reduced glomerular filtration,
and increased calcium resorption  worsening
the hypercalcemia.
HYPERCALCEMIA AND
CANCER
PATHOGENESIS
• Some lymphomas secrete the active form of
vitamin D, 1,25 dihydroxyvitamin D 
enhancing osteoclastic bone resorption
and intestinal calcium absorption.
• Hypercalcemia induces an osmotic diuresis,
while inhibiting ADH  polyuria together with
nausea and vomiting lead to progressive
dehydration, reduced glomerular filtration,
and increased calcium resorption  worsening
the hypercalcemia.
HYPERCALCEMIA AND
CANCER
THERAPY
• Therapeutic interventions depend on the
presentation.
• Asymptomatic patients with a serum calcium
level of ≤3.25 mmol/L = conservative
• Symptomatic patients or those with a serum
calcium level >3.25 mmol/L = immediate
aggressive measures.
• Hydration results at most in only a mild (0.5
mmol/L [∼2 mg/dL]) decrease in serum
calcium levels  After adequate hydration, 20
to 40 mg of intravenous furosemide
HYPERCALCEMIA AND
CANCER
THERAPY
• Bisphosphonates
• The cornerstone of therapy for malignancy-associated
hypercalcemia.
• The affinity of bisphosphonates for hydroxyapatite leads
to their concentration in bone at the interface and they
are internalized by osteoclasts at the time of bone
resorption.
• (1) Clodronate, a second-generation bisphosphonate of
intermediate potency, is usually given orally and achieves
normocalcemia in 80% of cases. One-fifth of those treated
have an increase in creatinine. In the palliative setting,
clodronate can be given subcutaneously with mild local
reaction in one-third as the principal side effect.
HYPERCALCEMIA AND
CANCER
THERAPY
• Bisphosphonates
• (2) Pamidronate, a nitrogen-containing bisphosphonate,
achieves normocalcemia in as many as 90% of patients, for
a longer period of time than clodronate.
• (3) Zoledronate, a third-generation bisphosphonate
containing a heterocyclic nitrogen, is considered the current
best choice, with normalization of serum calcium in 4 to 10
days that lasts 4 to 6 weeks in 90% of patients. A Cochrane
Database Review reported no significant adverse effects
associated with bisphosphonate administration and found
no evidence of superiority of any specific
aminobisphosphonate or nonaminobisphosphonate for any
outcome, although zoledronate appeared superior to
placebo and etidronate in improving overall survival.
HYPERCALCEMIA AND
CANCER
THERAPY
• Bisphosphonates
• Most effective in the therapy of hypercalcemia
associated with multiple myeloma, but are also
efficacious in solid tumors with skeletal
metastases.
• Less effective in the treatment of patients with
humoral-mediated hypercalcemia  no effect on
tubular calcium reabsorption mediated by
humoral factors, including PTHrP
• Alternative : Gallium nitrate, plicamycin
(mithramycin), and calcitonin
HYPERCALCEMIA AND
CANCER
THERAPY
• Osteoprotegerin (OPG)
• Soluble receptor that inhibits bone resorption by inhibiting
osteoclast differentiation
• Part of a cytokine system that belongs to the tumor
necrosis factor superfamily  The components : the
ligand RANKL (receptor activator of nuclear factor-κΒ
ligand), its specific receptor RANK (receptor activator of
nuclear factor-κΒ) and OPG, a soluble “decoy” receptor.
• By binding to RANK, RANKL enhances bone resorption by :
• (1) increasing osteoclast formation from hematopoietic precursors,
• (2) increasing osteoclast activity
• (3) inhibiting osteoclast apoptosis.
HYPERCALCEMIA AND
CANCER
THERAPY
• Denosumab
• A fully human monoclonal antibody with a high
affinity and specificity for RANKL, is approved by the US
Food and Drug Administration “for prevention of skeletal-
related events in patients with bone metastases from solid
tumors . . . but is not indicated for the prevention of
skeletal-related events in patients with multiple myeloma.”
• A study of patients with advanced cancer and persistent
hypercalcemia after incomplete response or relapse after
recent bisphosphonate treatment found that while
denosumab effectively lowered serum calcium in 80% of
patients, the response was maintained a median of 26 days,
compared within a median of 18 days after receiving the
last dose of intravenous bisphosphonate.
 CANCER-RELATED
HEMOLYTIC UREMIC
SYNDROMEGENERAL
• The hemolytic uremic syndrome (HUS) = a
microvascular disorder characterized histopathologically
by disseminated microthrombi occluding the
microvasculature.
• Often associated with the presence of large von
Willebrand factor multimers capable of agglutinating
circulating platelets
• The hallmark of a Coombs negative hemolytic anemia
with an elevated schistocyte count  fragmentation
of erythrocytes as they pass through clogged arterioles.
• The disseminated microthrombi lead to ischemic organ
damage, most commonly in kidneys and brain, with
renal insufficiency, and a range of neurologic symptoms.
 CANCER-RELATED
HEMOLYTIC UREMIC
SYNDROME
PATHOGENESIS
• (1) as a manifestation of the cancer itself
• (2) as a complication of chemotherapy
• (3) in the setting of bone marrow transplantation
• (4) more recently as a problem in patients receiving
antibodies and immunotoxins
• A 1986 review of chemotherapy-related HUS implicated
mitomycin-C and 5-fluoruracil as the most frequent culprits
 Other agents that have been implicated in the etiology of
this syndrome include bleomycin, cisplatin, cytosine
arabinoside, daunomycin, deoxycoformycin, estramustine,
and methyl-CCNU
 CANCER-RELATED
HEMOLYTIC UREMIC
SYNDROME
PATHOGENESIS
• (1) as a manifestation of the cancer itself
• (2) as a complication of chemotherapy
• (3) in the setting of bone marrow transplantation
• (4) more recently as a problem in patients receiving
antibodies and immunotoxins
• A 1986 review of chemotherapy-related HUS implicated
mitomycin-C and 5-fluoruracil as the most frequent culprits
 Other agents that have been implicated in the etiology of
this syndrome include bleomycin, cisplatin, cytosine
arabinoside, daunomycin, deoxycoformycin, estramustine,
and methyl-CCNU
 CANCER-RELATED
HEMOLYTIC UREMIC
SYNDROME
PATHOGENESIS
• The clinical manifestations of fulminant HUS =
• Classic pentad of microangiopathic hemolytic
anemia,
• Thrombocytopenia
• Fever
• Rapidly progressive renal failure
• Neurological deficits
• Acute respiratory distress syndrome
 CANCER-RELATED
HEMOLYTIC UREMIC
SYNDROME
PATHOGENESIS
• Blood pressure should be controlled.
• The value of steroids is uncertain
precluding their routine use.
• Hemodialysis is indicated in patients with
renal failure.
• The efficacies of therapeutic plasma
exchange using fresh frozen plasma as the
substitution fluid and of immunoadsorption
chromatography are arguable
Thank You!