Patrick Chariot

Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion

Zidovudine is known to be responsible for a mitochondrial myopathy with ragged-red fibres and mitochondrial DNA depletion in muscle. Lactic acidosis alone or associated with hepatic abnormalities has also been reported. A single report mentioned the concomitant occurrence of muscular and hepatic disturbances and lactic acidosis in a patient receiving zidovudine, but muscle and liver tissues were not studied. A 57-year-old man with AIDS, who had been treated with zidovudine for 3 years, developed fatigue and weight loss. Serum creatine kinase and hepatic enzyme levels were high. Lactic acidosis was present. Liver biopsy showed diffuse macrovacuolar and microvacuolar steatosis. After withdrawal of zidovudine, creatine kinase, aspartate aminotransferase, and alanine aminotransferase levels normalised within 5 days, and lactacidaemia decreased. Acidosis persisted. The patient became confused and febrile and died 8 days after detection of high blood lactic acid. A muscle sample obtained at autopsy showed mitochondrial abnormalities with ragged-red fibres and lipid droplet accumulation. Southern blot analysis showed depletion of mitochondrial DNA, affecting skeletal muscle and liver tissue. No depletion was found in myocardium and kidney. This case emphasises that zidovudine treatment can induce mitochondrial multisystem disease, as revealed in our case by myopathy, liver steatosis and lactic acidosis.

Cellular and mitochondrial toxicity of zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) on cultured human muscle cells.

Zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) are the reference antiretroviral therapy in patients with AIDS. A toxic mitochondrial myopathy can be observed in patients treated with AZT, but not with ddI and ddC. All 3 compounds can inhibit mitochondrial (mt)DNA polymerase and cause termination of synthesis of growing mtDNA strands and mtDNA depletion. The propensity to injure particular target tissues is unexplained. In our work, cultured muscle cells prepared from human muscle biopsies, were exposed to various concentrations of AZT (4-5000 micromol/l), ddI (5-1000 micromol/l) and ddC (1-1000 micromol/l) for 10 days. We evaluated cell proliferation and differentiation and measured lipid droplet accumulation, lactate production and respiratory chain enzyme activities. All 3 compounds induced a dose-related decrease of cell proliferation and differentiation. AZT seemed to be the most potent inhibitor of cell proliferation. AZT, ddI and ddC induced cytoplasmic lipid droplet accumulations, increased lactate production and decreased activities of COX (complex IV) and SDH (part of complex II). NADHR (complex I) and citrate sinthase activities were unchanged. Zalcitabine (ddC) and, to a lesser extent, ddI, were the most potent inhibitors of mitochondrial function. In conclusion, AZT, ddI and ddC all exert cytotoxic effects on human muscle cells and induce functional alterations of mitochondria possibly due to mechanisms other than the sole mtDNA depletion. Our results provide only a partial explanation of the fact that AZT, but not ddI and ddC, can induce a myopathy in HIV-infected patients. AZT myopathy might not simply result from a direct mitochondrial toxic effect of crude AZT.

Skeletal muscle involvement in human immunodeficiency virus (HIV)–infected patients in the era of highly active antiretroviral therapy (HAART)

Skeletal muscle involvement can occur at all stages of human immunodeficiency virus (HIV) infection, and may represent the first manifestation of the disease. Myopathies in HIV‐infected patients are classified as follows: (1) HIV‐associated myopathies and related conditions, including HIV polymyositis, inclusion‐body myositis, nemaline myopathy, diffuse infiltrative lymphocytosis syndrome (DILS), HIV‐wasting syndrome, vasculitic processes, myasthenic syndromes, and chronic fatigue; (2) muscle complications of antiretroviral therapy, including zidovudine and toxic mitochondrial myopathies related to other nucleoside‐analogue reverse‐transcriptase inhibitors (NRTIs), HIV‐associated lipodystrophy syndrome, and immune restoration syndrome related to highly active antiretroviral therapy (HAART); (3) opportunistic infections and tumor infiltrations of skeletal muscle; and (4) rhabdomyolysis. Introduction of HAART has dramatically modified the natural history of HIV disease by controlling viral replication, but, in turn, lengthening of the survival of HIV‐infected individuals has been associated with an increasing prevalence of iatrogenic conditions. Muscle Nerve, 2005

Muscle disorders associated with cyclosporine treatment

Alone or as part of a multidrug immunosuppressive regimen, cyclosporine A (CsA) has been reported in isolated case studies as a cause of muscle disorders. We reviewed the current knowledge on muscle toxicity of CsA and discussed the possible role of mitochondrial dysfunction in the genesis of CsA‐associated myopathy. A systematic review using Medline® and Current Contents® databases combined with a manual literature search allowed us to select 56 references. We identified 34 patients with muscle disorders possibly related to CsA, usually manifesting by myalgia or muscle weakness and plasma creatine kinase elevation. Only 2 of 34 patients were treated with CsA alone. Experimental studies have shown that administration of CsA to rats reduces capillary density in extensor digitorum longus, skeletal muscle mitochondrial respiration, and endurance exercise capacity. Cyclosporine has been shown to inhibit the mitochondrial permeability transition pore. Whether identified interactions between CsA and mitochondria can explain CsA‐associated myopathy is still unclear.

Acute rhabdomyolysis in patients infected by human immunodeficiency virus

To delineate the spectrum of rhabdomyolysis associated with human immunodeficiency virus (HIV) infection, we reviewed the clinical and pathologic data from nine HIV-infected individuals with acute rhabdomyolysis, and pooled data with those of 11 previously reported cases. Patients with rhabdomyolysis were at all stages of HIV infection and could be classified into three groups: (1) HIV-associated rhabdomyolysis (7 of 20), including rhabdomyolysis in primary HIV infection, recurrent rhabdomyolysis, and isolated rhabdomyolysis; (2) rhabdomyolysis induced by drugs (6 of 20), including didanosine; and (3) rhabdomyolysis at the end stage of acquired immunodeficiency syndrome (7 of 20), including opportunistic infections of muscle and rhabdomyolysis without a definite cause. Because prognosis, in part, depends on the cause of rhabdomyolysis, recognition of drug-induced or opportunistic infectious muscle disorders is required.

Guidelines for doctors attending detainees in police custody: a consensus conference in France

Medical practice in police custody needs to be harmonized. A consensus conference was held on 2–3 December 2004 in Paris, France. The health, integrity, and dignity of detainees must be safeguarded. The examination should take place in the police station so that the doctor can assess the conditions in which the detainee is being held. If the minimum conditions needed for a medical examination are not available, the doctor may refuse to express an opinion as to whether the detainee is fit to be held in custody or may ask for the detainee to be examined in a hospital. Doctors are subject to a duty of care and prevention. They should prescribe any ongoing treatment that needs to be continued, as well as any emergency treatment required. Custody officers may monitor the detainee and administer medication. However, their role should not be expected to exceed that required of the detainee’s family under normal circumstances and must be specified in writing on the medical certificate. Doctor’s opinion should be given in a national standard document. If the doctors consider that the custody conditions are disgraceful, they may refuse to express an opinion as to whether the detainee is fit for custody.

Myopathy and HIV infection.

Skeletal muscle involvement may occur at all stages of HIV infection. The most simple classification of muscular disorders in HIV-infected patients is 1) HIV-associated myopathies, 2) zidovudine myopathy, 3) HIV wasting syndrome, and 4) opportunistic infections and tumoral infiltrations of muscle. Immunohistology for major histocompatibility complex class I antigen and histochemical reaction for cytochrome c oxidase are helpful in correctly classifying a myopathy as HIV polymyositis or zidovudine myopathy. Studies of cytokine expression in HIV-infected patients and of supplementation with compounds such as carnitine or micronutrients such as selenium might yield new insights into the pathogenesis and treatment of the various AIDS-associated muscular disorders.

Alcohol and substance screening and brief intervention for detainees kept in police custody. A feasibility study

BACKGROUND Screening and brief intervention programs related to addictive disorders have proven effective in a variety of environments. Both the feasibility and outcome of brief interventions performed in police custody by forensic physicians are unknown. Our objectives were to characterize addictive behaviors in detainees and to evaluate the feasibility of a brief intervention at the time of the medical examination in police custody. METHODS This prospective study included 1000 detainees in police custody who were examined by a physician for the assessment of fitness for detention. We used a standardized questionnaire and collected data concerning individual characteristics, addictive disorders, and reported assaults or observed injuries. RESULTS 944 men and 56 women (94-6%) were studied. We found an addictive disorder in 708 of 1000 cases (71%), with the use of tobacco (62%), alcohol (36%), cannabis (35%), opiates (5%), and cocaine (4%) being the most common. A brief intervention was performed in 544 of these 708 cases (77%). A total of 139 of the 708 individuals (20%) expressed a willingness to change and 14 of 708 (2%) requested some information on treatment options. The main reasons why brief interventions were not performed were aggressive behaviors, drowsiness, or fanciful statements by the detainee. CONCLUSION Brief interventions and screening for addictive behaviors in police custody are feasible in the majority of cases. The frequent link between addictive behaviors and the suspected crimes highlights the value of such interventions, which could be incorporated into the public health mission of the physician in police custody.

Tubular aggregates and partial cytochrome c oxidase deficiency in skeletal muscle of patients with AIDS treated with zidovudine

SummaryWe report on two patients, who had myalgias while receiving long-term zidovudine treatment for an HIV infection, in whom muscle biopsy findings included a partial cytochrome c oxidase (CCO) deficiency, a feature of zidovudine myopathy, and tubular aggregates, a finding hitherto unreported in HIV-infected patients. The CCO deficit was observed in 28% and 24% of muscle fibers, respectively. Tubular aggregates were the prominent histopathological feature in patient 1, and were detected by systematic electron microscopy in patient 2. Inflammation and myonecrosis were not detected. In patient 1, the typical mitochondrial and myofibrillar changes of zidovudine myopathy were present and 12% of fibers showed tubular aggregates. The aggregates were not stained at CCO reaction, and 96% of myofibers enclosing tubular aggregates showed a decreased CCO activity. This suggested more than a chance association between mitochondrial dysfunction and the formation of tubular aggregates. We conclude that tubular aggregates are detected in some patients treated by zidovudine, and that the finding could be related to the long-term administration of the drug.

Fitness for detention in police custody: A practical proposal for improving the format of medical opinion

Health issues among arrestees are a worldwide concern for which only local policies have been established. Physicians attending detainees in police custody are expected to decide whether the detainees health status is compatible with detention in a police station and make any useful observations. A high degree of heterogeneity in the information collected by the physician and transmitted to the police has been observed. We analyzed the content and limitations of available documents and developed a model that could serve as a guide for any attending physician. The document presented here has been used in France on over 50,000 occasions since June 2010. We developed a two-page template consisting of (1) a standard medical certificate to be sent to the authority who requested the doctors attendance and (2) a confidential medical record, not sent to the requesting authority. We evaluated perceived health by the three global health indicators of the Minimum European Health Module and used DSM IV criteria for the evaluation of addictive disorders. In the case of recent traumatic injuries, the certificate has also included the collection of data on traumatic injuries and the contexts of their occurrence. The proposed certificate achieved several goals, by protecting the interests of the person examined, in case of poor conditions of arrest or detention, protecting doctors in cases of legal proceedings, and allowing epidemiological data to be collected. The certificate may also contribute to an international awareness of medical care for detainees in police custody.