Case Report

Carboplatin: a new cause of severe type B lactic acidosis secondary to mitochondrial DNA damage^?,??

Abstract

In adults, type B lactic acidosis is rare and generally associated with a toxin, particularly metformin or antire- troviral nucleosides analogues. We report a case of lactic acidosis caused by carboplatin in a 50-year-old woman suffering from primary peritoneal carcinoma. She was admitted for severe lactic acidosis (pH 6.77, lactate 19 mmol/L) associated with multiple organ failure (PaO₂/FiO₂ 96, creatinine 231 umol/L, aspartate aminotransferase N25 000 UI, factor V 13%) occurring during the sixth carboplatin cycle. In the absence of sepsis, internal bleeding, alcohol poisoning, or other causes of lactic acidosis, the hypothesis of mitochondrial DNA (mtDNA) damage secondary to carboplatin and subsequent Mitochondrial dysfunction leading to increase in glycolysis and lactic acidosis was suspected. L-Carnitine therapy associated with aggressive Intensive care support led to a progressive improvement (pH 7.29, bicarbonate 24 mmol/L, lactate 7.8 mmol/L), but life support was withdrawn on day 7 because of peritoneal relapse. A respiratory chain dysfunction of enzyme activities encoded by mtDNA and multiple mtDNA deletions were found in muscle and liver tissue. It is generally accepted that carboplatin toxicity results in bone marrow suppression, renal dysfunction, or neurotoxicity and that platinating agents have no direct mitochondrial effect. However, although very unusual, emergency physicians must be aware that carboplatin can cause mitochondrial toxicity and trigger lactic acidosis.

A 50-year-old woman with primary peritoneal carcinoma treated with cytoreductive surgery followed by carboplatin (360 mg/m²)- and paclitaxel (175 mg/m²)-based chemother- apy with the intent to treat with at least 6 cycles was admitted for lactic acidosis (LA). Her medical history was remarkable for Hashimoto thyroiditis (levothyroxine 150 ug/d), depres- sion (paroxetine 20 mg/d), and familial primary peritoneal carcinoma. Paclitaxel was withdrawn after the fourth cycle

^? Research support: none.

^?? The authors declare that there are no conflicts of interest.

for neurotoxicity. During the sixth cycle of carboplatin chemotherapy (360 mg/m²), the patient complained of dyspnea, abdominal pain, and weakness. Physical examina- tion revealed ascites, severe overhydration, and neurotoxic- ity. Hematologic parameters, electrolytes status, serum creatinine, and hepatic test results were in the reference ranges. Twelve hours later, her clinical status worsened and she was admitted because of confusion, hypothermia (32.7?C), tachypnea (40 breaths per minute), tachycardia (93 beats per minute), and hypotension (blood pressure 90/34 mm Hg). Laboratory showed LA (pH 6.99, PaCO₂ 19.5 mm Hg, bicarbonate b5 mmol/L, lactate 17.2 mmol/L), acute kidney injury (creatinine 135 umol/L), and hepatic failure (aspartate aminotransferase 3 175 UI, alanine aminotrans- ferase 3408 UI, factor V 13%). There was no suspicion of illicit drug; screening result for toxics was negative. The patient was treated with mechanical ventilation, norepineph- rine, hemodiafiltration, corticotherapy, amikacin, and piper- acillin-tazobactam. During the next 2 days, her condition and LA worsened (pH 6.77, lactate 19 mmol/L, aspartate aminotransferase N25 000 UI, platelet count 38.109/L). As blood cultures were negative and no sepsis was documented, a diagnosis of probable mitochondrial cytopathy was considered and L-carnitine infusion was started (100 mg/ [kg d]). With this treatment, the patient’s condition progressively improved during the next 5 days (pH 7.29, bicarbonate 24 mmol/L, lactate 7.8 mmol/L). Life support was withdrawn on day 7, following the discovery of peritoneal relapse. The patient died a few hours later. A respiratory chain dysfunction was confirmed by impaired oxidation rates, deficit in complex I activity in muscle, an immediate postmortem hepatic biopsy, and multiple mito- chondrial DNA (mtDNA) deletions (Table 1).

Lactic acidosis characterized by metabolic acidosis with a blood lactate level greater than 5 mmol/L is traditionally interpreted as a marker of tissue hypoxia and anaerobic metabolism. This view has recently been challenged with the evidence that during some shock states, hyperlactacidemia is at least in part secondary to an increased aerobic glycolysis (type A) [1]. Type B LA, a Rare condition, is related to Metabolic disorders (errors in metabolism), underlying disease (Hepatic dysfunction, Hematologic malignancy), or a toxin. Many drugs may induce LA, metformin and nucleosides analogues being the main toxic causes. Lactic acidosis is a rare complication of extensive solid cancer with

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Table 1 Mitochondrial respiratory chain activities and mtDNA analysis in muscle, liver biopsies, lymphocytes, and fibroblasts

Abnormal values are in bold. The control values are in range values (n = 25).C indicates complex; CS, Citrate synthase.

^a In nanomoles O₂ per minute per milligram protein.

^b In nanomoles per minute per milligram protein.

^c Mitochondrial DNA analysis by long-range polymerase chain reaction.

metastatic hepatic lesions or hematologic malignancies [2,3]. Even in the presence of oxygen, elevated rates of lactate production can occur in cancer cells, the imbalance between lactate production and its hepatic clearance leading to LA. However, in the absence of metastatic hepatic lesions, as in our case, a drug-induced mitochondrial toxicity may explain LA and multiple organ failure. The occurrence of LA 6 weeks after paclitaxel withdrawal and a few hours after chemotherapy suggested in the absence of shock, convul- sions, or toxic ingestion a carboplatin-related mitochondrial dysfunction. The impaired pyruvate oxidation, deficiencies of muscle and liver complex I activity, a complex encoded by mtDNA, and the discovery of mtDNA deletions confirmed our hypothesis of a carboplatin-induced mitochondrial toxicity triggering LA.

Whereas paclitaxel induces mitochondrial apoptosis [4], platinating agents have no direct mitochondrial effects. The cytotoxic lesion of platinating agents is thought to be the platinum intrastand cross-link that forms on DNA and activation of apoptotic cascades via the endoplasmic reticulum stress pathway, both of which induce cellular

apoptosis [5-7]. Pathogenic mutations in polymerase ?, twinkle, or thymidine phosphorylase genes were associated with mtDNA deletions and/or mtDNA depletions in muscle biopsies, whereas these deletions are usually not observed in cultured skin fibroblasts or lymphocytes [8]. This is assuming different behavior in response to a poorly understood mechanism for each tissue. Furthermore, recent data showed evidence of real relationship between mutations in Krebs cycle enzymes and predisposition to an inherited tumor syndrome [9]. Thus, such patients treated by carboplatin can possibly exhibit a severe mitochondrial dysfunction. Moreover, cisplatin increases kidney loss of carnitine leading to a carnitine deficiency, which may be responsible for impaired fatty acid ?– oxidation [10]. Severe LA during carboplatin therapy has never been reported so far, but Di Cataldo et al [11] described mtDNA deletions and secondary Fanconi syndrome during carboplatin treatment.

The clinical course of our patient was similar to the one observed in LA related to nucleoside analogues. Thus, we used L-carnitine, a cornerstone cofactor in mitochondrial

Case Report

metabolism interacting with the ?-oxidation respiration

References

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circle, which may have an antiapoptotic activity [10,12]. On the other hand, L-carnitine efficiency for the treatment of neurotoxicity induced by platinating agents was recently documented [13]. Carnitine efficacy in our patient is difficult to evaluate, but vasopressor doses could be dramatically decreased a few hours after its initiation (results not showed) followed by a progressive improvement secondary either to the supportive care or to the beginning of mtDNA repair.

Our case suggests that carboplatin can be responsible for DNA damage and subsequent mitochondrial dysfunction leading to increase in glycolysis and LA.

Francois Gilles Brivet MD AP-HP, Medical Intensive Care Department Antoine Beclere Hospital, 92141 Clamart, France

EA 4046, Paris XI University E-mail address: [email protected]

Abdelhamid Slama PhD

AP-HP, Biochemistry Department, Bicetre Hospital

94270 Le Kremlin Bicetre, France

Dominique Prat MD AP-HP, Medical Intensive Care Department Antoine Beclere Hospital, 92141 Clamart, France

Frederic Marc Jacobs MD AP-HP, Medical Intensive Care Department Antoine Beclere Hospital, 92141 Clamart, France

EA 4046, Paris XI University

doi:10.1016/j.ajem.2010.07.005

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