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Abstract：
BACKGROUND: Current treatment options for chronic hepatitis B (CHB) are pegylated interferon alpha and nucleoside analogues (NAs). NAs have relatively fewer side effects than interferon alpha, and generally well tolerated. Previously 12.9% of patients on telbivudine treatment were reported to develop severe elevation of serum creatine phosphokinase (CPK) levels, but related clinical disease, like lactic acidosis (LA) and rhabdomyolysis (RM) were rare. The pathophysiology may be mitochondrial toxicity, for the NAs inhibit not only hepatitis B virus (HBV) polymerase, but also the host mitochondrial DNA polymerase γ. As mitochondria are the main sites of oxidative phosphorylation, there will be an increase of pyruvate reduction to lactic acid and insufficient adenosine triphosphate. The accumulation of lactic acid causes LA, while lack of energy leads to cell dysfunction and mitochondria-associated disease, including RM. All five NAs, except tenofovir, have been reported causing LA and RM. Here we report the first case of CHB patients developing fatal LA and RM during telbivudine and tenofovir treatment.
METHODS: The patient is a 51-year-old man who was hospitalized in November 2015. He had taken telbivudine regularly because of CHB. Later, tenofovir was added to antiviral treatment because of HBV resistance. Then he had myalgia, chest tightness and anorexia. The blood lactate was 12.7 mmol/L. The arterial blood gas analysis showed pH 7.25, base excess 21.1 mmol/L. CPK was 991 U/L, myoglobin was 1745 ng/ml and creatine was 83 μmol/L. Abdomen magnetic resonance revealed cirrhosis. Muscle biopsy revealed myogenic lesion with abnormality of mitochondria and fat metabolism. The patient was diagnosed with Hepatitis B envelope Antigen positive CHB, cirrhosis, LA and RM characterized by myalgia and elevated myoglobin. He was given tenofovir alone as antiviral treatment instead. After hemodialysis and 4 weeks` treatment of corticosteroids, his symptoms recovered, and blood lactate gradually returned to a normal range.
CONCLUSIONS: This case shows that tenofovir may trigger muscle damage and fatal RM in combination with telbivudine treatment in CHB patients. Thus, patients receiving tenofovir and telbivudine should be closely monitored for muscular abnormalities, blood lactate level and other mitochondrial toxicity associated side effects.
METHODS: The patient is a 51-year-old man who was hospitalized in November 2015. He had taken telbivudine regularly because of CHB. Later, tenofovir was added to antiviral treatment because of HBV resistance. Then he had myalgia, chest tightness and anorexia. The blood lactate was 12.7 mmol/L. The arterial blood gas analysis showed pH 7.25, base excess 21.1 mmol/L. CPK was 991 U/L, myoglobin was 1745 ng/ml and creatine was 83 μmol/L. Abdomen magnetic resonance revealed cirrhosis. Muscle biopsy revealed myogenic lesion with abnormality of mitochondria and fat metabolism. The patient was diagnosed with Hepatitis B envelope Antigen positive CHB, cirrhosis, LA and RM characterized by myalgia and elevated myoglobin. He was given tenofovir alone as antiviral treatment instead. After hemodialysis and 4 weeks` treatment of corticosteroids, his symptoms recovered, and blood lactate gradually returned to a normal range.
CONCLUSIONS: This case shows that tenofovir may trigger muscle damage and fatal RM in combination with telbivudine treatment in CHB patients. Thus, patients receiving tenofovir and telbivudine should be closely monitored for muscular abnormalities, blood lactate level and other mitochondrial toxicity associated side effects.
摘要：
背景：目前慢性乙型肝炎（CHB）的治疗选择是聚乙二醇化干扰素α和核苷类似物（NAs）。NAs的副作用相对比干扰素α少，一般耐受性良好。以前，据报道，在替比夫定治疗的患者中有12.9％出现血清肌酸磷酸激酶（CPK）水平严重升高，但是相关的临床疾病，乳酸性酸中毒（LA）和横纹肌溶解症（RM）很少见。病理生理学可能是线粒体毒性，对于NAs不仅抑制乙型肝炎病毒（HBV）聚合酶，而且宿主线粒体DNA聚合酶γ。由于线粒体是氧化磷酸化的主要位点，丙酮酸对乳酸的还原会增加，三磷酸腺苷不足。乳酸的积累导致LA,而缺乏能量会导致细胞功能障碍和线粒体相关疾病，包括RM。所有五个NAs，除了替诺福韦,已被报告导致LA和RM。在这里，我们报告了在替比夫定和替诺福韦治疗期间发展致命的LA和RM的CHB患者的第一例。
方法：患者为一名51岁男性，于2015年11月住院。由于CHB，他定期服用替比夫定。稍后，替诺福韦被添加到抗病毒治疗，因为HBV耐药。然后他有肌痛，胸闷和厌食症。血乳酸为12.7mmol/L动脉血气分析显示pH7.25，碱过量21.1mmol/L。CPK为991U/L,肌红蛋白为1745ng/ml，肌酸为83μmol/L。腹部磁共振显示肝硬化。肌肉活检显示肌源性病变伴线粒体和脂肪代谢异常。患者被诊断为乙型肝炎包膜抗原阳性CHB，肝硬化,以肌痛和肌红蛋白升高为特征的LA和RM。他单独给予替诺福韦作为抗病毒治疗。血液透析和糖皮质激素治疗4周后，他的症状恢复了,血乳酸逐渐恢复正常。
结论：该病例表明替诺福韦与替比夫定联合治疗CHB患者可能引发肌肉损伤和致命的RM。因此，接受替诺福韦和替比夫定的患者应密切监测肌肉异常，血乳酸水平和其他线粒体毒性相关的副作用。
方法：患者为一名51岁男性，于2015年11月住院。由于CHB，他定期服用替比夫定。稍后，替诺福韦被添加到抗病毒治疗，因为HBV耐药。然后他有肌痛，胸闷和厌食症。血乳酸为12.7mmol/L动脉血气分析显示pH7.25，碱过量21.1mmol/L。CPK为991U/L,肌红蛋白为1745ng/ml，肌酸为83μmol/L。腹部磁共振显示肝硬化。肌肉活检显示肌源性病变伴线粒体和脂肪代谢异常。患者被诊断为乙型肝炎包膜抗原阳性CHB，肝硬化,以肌痛和肌红蛋白升高为特征的LA和RM。他单独给予替诺福韦作为抗病毒治疗。血液透析和糖皮质激素治疗4周后，他的症状恢复了,血乳酸逐渐恢复正常。
结论：该病例表明替诺福韦与替比夫定联合治疗CHB患者可能引发肌肉损伤和致命的RM。因此，接受替诺福韦和替比夫定的患者应密切监测肌肉异常，血乳酸水平和其他线粒体毒性相关的副作用。
