Severe lactic acidosis is a rare but life-threatening complication related to the use of nucleoside analogues. Pathophysiological mechanisms involve a drug-induced mitochondrial dysfunction, leading to impaired cellular breathing. To date, no specific treatment has proved to be effective, and severe lactic acidosis induced by nucleoside analogues is constantly fatal. Experimental evidence suggests that nucleoside analogues induce l-carnitine deficiency [1], which may contribute to the occurrence of lactic acidosis. We report the successful use of l-carnitine to treat severe lactic acidosis and hepatic failure in a patient treated by nucleoside analogues.
A 34-year-old HIV-infected man presented to the hospital with abdominal pain, nausea and vomiting. He had been on stavudine, didanosine and saquinavir for 11 months when he stopped taking antiretroviral drugs because of progressive abdominal pain, nausea and vomiting. Two weeks later, he was admitted in the emergency department because of worsening abdominal signs and altered consciousness. On clinical evaluation, he had lost 8 kg over the past 6 weeks. Body temperature was 36°C, arterial blood pressure was 90/40 mmHg, heart rate was 130 bpm, and respiratory rate was 30 rpm. An abdominal ultrasound revealed hepatic steatosis, mild oedematous pancreatitis, and a moderate peritoneal effusion. Analysis of arterial blood gases revealed severe metabolic acidosis (pH 6.98) secondary to increased plasma lactate concentration (23.5 mmol/l, N < 2.2). Liver function tests showed cytolysis, cholestasis and significant hepatic dysfunction with a decrease in coagulation factors (II 40%, V 39%, VII + X 37%). The blood lipase level was significantly increased (886 UI /l, N < 40). Microbiological assays were negative and hepatitis tests were non-reactive. The patient was then admitted to the intensive care unit, where haemodialysis was initiated. After an initial improvement in both clinical and acid-base status, acidosis progressed and was quickly associated with impaired conciousness and respiratory distress requiring mechanical ventilation. At this time, determination of blood l-carnitine levels revealed normal total carnitine levels but a decreased free carnitine : total carnitine ratio. Consequently, sequential infusion of l-carnitine (50 mg/kg per day) was started. Thirty-six hours after the initiation of l-carnitine therapy, the patient's neurological status improved allowing extubation, whereas lactates decreased and acidosis was quickly balanced. Blood lactates returned to normal on day 15, whereas the prothrombin rate was already normal on day 6. l-Carnitine was stopped at day 15 and the remainder of the clinical course was uneventful. All biochemical parameters were normal when the patient was discharged from the hospital (day 45).
The use of nucleoside analogues is associated with decreased intracellular l-carnitine levels [1]. l-Carnitine is an important cofactor for the intramitochondrial transportation of fatty acids. l-Carnitine also directly stimulates phase IV of the mitochondrial breathing cycle, and prevents the detrimental effect of octanoic acid on the cytochrome C oxidase [2]. As a result, l-carnitine deficiency is associated with impaired ATP production [3] and lactic acidosis [4]. In vitro, l-carnitine reversed alterations of mitochondrial structure and restored mitochondrial function in cultures of myocytes incubated with zidovudine [5]. We report survival in a patient treated with intravenous l-carnitine for severe lactic acidosis induced by nucleoside analogues. This case suggests that l-carnitine could be used as a specific treatment in severe acidosis secondary to nucleoside analogue-induced mitochondriopathy.
Yann-Erick Claessens
Alain Cariou
Jean-Daniel Chiche
Gaëlle Dauriat
Jean-François Dhainaut
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