We describe a 62-year-old male who was diagnosed with HIV-1 in 2001 and died with lactic acidosis under treatment with didanosine and stavudine. At that time, his CD4+T-lymphocyte count was 4/μl and HIV viral load was 135 815 copies/ml. He had suffered from recurrent herpes simplex infections and meningitis due to listeria. Comorbidities included ethanol-induced liver cirrhosis (Child B) and renal insufficiency (glomerular filtration rate 20 ml/min), probably secondary to arterial hypertension. Highly active antiretroviral HIV therapy (HAART) was initiated immediately and consisted of stavudine, didanosine and efavirenz. After 4 months of HAART, the viral load was below 50 copies/ml and the CD4 count was 319/μl. After 16 months of HAART, the patient was well, immunologically and virologically stable, but had developed a hyperlactatemia without acidosis (serum lactate 3.7 mmol/l, normal <2.2). Two months later, the patient presented to the emergency room with fatigue, weight loss, persisting cough, ascites and a urinary tract infection with Escherichia coli (CRP 100 mg/l). Parenteral treatment with ampicillin/ sulbactam was initiated. One week later, the CRP had fallen to 22 mg/l. All of a sudden, the patient was found pulseless. He was resuscitated and ventilated. The circulation required hemodynamic stabilization with catecholamines; renal failure was treated with continuous veno-venous haemodialysis. On admission to the ICU, there was persistent severe lactic acidosis (pH 6.9, lactate 27 mmol/l). HAART was discontinued immediately and intravenous uridine was administered (2 g of uridine/h for 10 h/day). Despite these measures, the patient died from multiorgan failure after 3 days without evidence of infection. Postmortem, mitochondrial (mt)DNA copy numbers of the patient's liver, skeletal muscle, heart and kidney were measured by quantitative PCR and compared with those of nine control autopsies [1]. mtDNA levels were found to be profoundly depleted in all patient tissues analyzed. The liver had 7%, the kidney had 20%, the skeletal muscle had 28% and the heart had 72% of the mean mtDNA copy numbers measured in control autopsy tissue. Using PCR, we then analyzed the mtDNA of heart and skeletal muscle for the presence of large-scale deletions [1]. Whereas none of the control tissues harboured any mtDNA rearrangements, eight mtDNA deletions were found in the heart of the patient and three in his skeletal muscle. Sequencing confirmed the DNA fragments to be of mitochondrial origin. Western blotting of skeletal muscle and heart protein extracts showed that the expression of the mtDNA-encoded respiratory chain component cytochrome coxidase II was depressed in relation to the nucleus (nDNA) encoded subunit IV of the same enzyme (Table 1). Spectrophotometric measurements revealed that the activities of respiratory chain enzymes, which require an intact mitochondrial genome (cytochrome c oxidase and nicotinamide adenine dinucleotide hydrogen dehydrogenase), were reduced in both tissues. In contrast, nDNA encoded activities (succinate dehydrogenase and citrate synthase) were preserved (Table 1). The musculoskeletal and myocardial ultrastructure of both organs was characterized by mitochondrial swelling and small fat vacuoles. The crystal architecture of the mitochondria was lost; some organelles were filled with electron dense material (not shown).Table 1: Mitochondrial parameters in patient tissues in comparison with autopsy material from nine controls deemed free of organ pathology.The present study is the first investigation of multiple organs in fatal lactic acidosis. We have demonstrated severe biochemical and ultrastructural damage of the mitochondria secondary to HAART-induced quantitative and qualitative mtDNA lesions. Lactic acidosis is a life-threatening complication of HAART. The onset is often abrupt, with uncharacteristic muscular, cardiac or hepatic symptoms. The outcome can be fatal due to liver failure and cardiac arrhythmia [2]. Didanosine and stavudine are strong inhibitors of polymerase-gamma, which are known to induce mtDNA depletion in subcutaneous adipose tissue and in liver [3]. The mtDNA deletions are explained by the fact that any respiratory chain dysfunction promotes the liberation of reactive oxygen species (ROS) in the respiratory chain. ROS then in turn are known to either attack the respiratory chain itself or to induce mitochondrial mutations [4]. Thus, a vicious circle composed of interconnected mtDNA and respiratory chain insults may arise that could contribute to organ failure. Our autopsy data suggest that mtDNA depletion with didanosine and stavudine is not confined to liver and adipose tissue. Therefore, the term ‘lipodystrophy’, which is commonly used for these metabolic complications, is a misnomer; mitochondrial toxicity should rather be regarded as multisystem. It is obvious that long-term antiretroviral treatment with the responsible nucleoside/nucleotide reverse transcriptase inhibitors should be avoided. Supportive therapy of established hyperlactatemia and lactate acidosis may include uridine supplementation, which in preclinical and clinical studies has demonstrated efficacy on the mitochondrial toxicity in several organs, as well as on hyperlactatemia [5–7]. Acknowledgements Jan Thoden and Dirk Lebrecht contributed equally to this work.
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Nov 22, 2008
E Padmini + 2
Open Access