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Difficulty: HardNeoplastic Processes

A 28-year-old man of Mediterranean descent is admitted to the oncology unit for initiation of induction chemotherapy. He was recently diagnosed with a highly aggressive B-cell non-Hodgkin lymphoma characterized by a t(8;14)t(8;14) chromosomal translocation. Baseline laboratory studies show a serum uric acid level of 11.5 mg/dL11.5 \text{ mg/dL}, lactate dehydrogenase of 1,250 U/L1,250 \text{ U/L}, and a serum creatinine of 1.1 mg/dL1.1 \text{ mg/dL}. To mitigate the risk of an impending oncologic emergency, the patient is administered a recombinant enzyme therapy that directly degrades uric acid into a highly soluble inactive metabolite. Forty-eight hours later, the patient develops sudden-onset fatigue, scleral icterus, and dark urine. His hemoglobin concentration has decreased from 14.2 g/dL14.2 \text{ g/dL} to 8.4 g/dL8.4 \text{ g/dL}. A peripheral blood smear reveals the presence of bite cells. The medication that precipitated this patient's acute deterioration is absolutely contraindicated in individuals who have a primary hereditary inability to synthesize adequate amounts of which of the following molecules?

  1. Nicotinamide adenine dinucleotide phosphateAnswer
  2. B
    Reduced glutathione
  3. C
    Adenosine triphosphate
  4. D
    Uric acid
  5. E
    Methylated thiopurine metabolites

Answer

Nicotinamide adenine dinucleotide phosphate
The correct answer is nicotinamide adenine dinucleotide phosphate (NADPH). The patient was administered rasburicase (recombinant urate oxidase) to manage impending tumor lysis syndrome from his high-grade Burkitt lymphoma. Rasburicase catalyzes the oxidation of uric acid to the highly soluble allantoin, but this reaction concurrently produces hydrogen peroxide (H2O2H_2O_2). In erythrocytes, H2O2H_2O_2 is detoxified to water by glutathione peroxidase, a reaction that requires the oxidation of reduced glutathione. To maintain a steady supply of reduced glutathione, glutathione reductase must utilize NADPH. NADPH is generated exclusively via the pentose phosphate pathway by the enzyme glucose-6-phosphate dehydrogenase (G6PD). Patients with G6PD deficiency (common in those of Mediterranean or African descent) cannot synthesize adequate amounts of NADPH during times of high oxidative stress. Consequently, administering rasburicase to these patients leads to massive accumulation of H2O2H_2O_2, denaturation of hemoglobin (forming Heinz bodies, which macrophages bite out to form bite cells), and acute hemolytic anemia. Therefore, rasburicase is absolutely contraindicated in G6PD deficiency, a condition defined by the primary hereditary inability to synthesize adequate NADPH.

Step-by-Step Solution

1
Identify the primary oncologic diagnosis and its associated risk.
The patient has Burkitt lymphoma (t(8;14)t(8;14)) with highly elevated LDH and uric acid, indicating a high tumor burden and impending tumor lysis syndrome (TLS).
Recognizing the risk of TLS dictates the necessary prophylactic management sequence.
2
Identify the specific pharmacologic intervention administered.
The patient received rasburicase, a recombinant urate oxidase that degrades uric acid to allantoin.
The stem describes a recombinant enzyme that directly degrades uric acid, which distinguishes it from allopurinol (which prevents synthesis).
3
Determine the pathophysiologic mechanism of the patient's acute deterioration.
Rasburicase produces hydrogen peroxide (H2O2H_2O_2) as a byproduct. The patient developed acute oxidative hemolytic anemia (jaundice, dark urine, dropping hemoglobin, bite cells) from this oxidative stress.
Connecting the drug's biochemical mechanism of action to the adverse clinical presentation is required to identify the underlying contraindication.
4
Identify the underlying hereditary defect and its primary biochemical product.
The patient has glucose-6-phosphate dehydrogenase (G6PD) deficiency, an absolute contraindication to rasburicase. G6PD normally synthesizes nicotinamide adenine dinucleotide phosphate (NADPH).
NADPH is essential for regenerating reduced glutathione, which detoxifies H2O2H_2O_2 in erythrocytes. Without NADPH, hemolysis occurs.

Key Concept

Rasburicase, utilized for tumor lysis syndrome, produces hydrogen peroxide and is strictly contraindicated in patients with G6PD deficiency due to their inability to synthesize adequate NADPH for erythrocyte oxidative defense.
Estimated Time:1m 30s
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Topics

Neoplastic Processes

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