Ann Clin Neurophysiol.  2017 Jan;19(1):40-45. 10.14253/acn.2017.19.1.40.

Mitochondrial myopathies caused by prolonged use of telbivudine

• Lee JM
• Shin JH
• Park YE
• Kim DS

• KMID: 2367993
• DOI: http://doi.org/10.14253/acn.2017.19.1.40

Abstract

BACKGROUND
Telbivudine is a nucleoside analogue used for the treatment of chronic hepatitis B, but it often develops mitochondrial toxicity leading to symptomatic myopathy. In this study, three patients with telbivudine induced myopathy were enrolled in order to investigate the nature and pathogenesis of mitochondrial toxicity caused by long-term use of telbivudine.
METHODS
Clinical features, laboratory findings, muscle pathology, and quantitation of mitochondrial DNA were studied in three patients.
RESULTS
Patients presented with progressive muscle weakness with high serum creatine kinase levels. Light microscopic findings of muscle pathology showed ragged red fibers that reacted strongly with succinate dehydrogenase stain, but negative for cytochrome c oxidase activities. Electron microscopy revealed abnormal mitochondrial accumulation with rod shaped inclusions. The quantitative peroxidase chain reaction showed a depletion of mitochondrial DNA in skeletal muscle of the patients.
CONCLUSIONS
Nucleoside analogues including telbivudine are potent inhibitors of viral DNA polymerases. However, they are not specific for viral DNA and can disturb mitochondrial replication at the same time. All nucleotide analogues should be used with close clinical observation in order to avoid development of mitochondrial myopathy.

Keyword

Telbivudine; DNA polymerase gamma; Creatine kinase

MeSH Terms

Creatine Kinase
DNA, Mitochondrial
DNA, Viral
Electron Transport Complex IV
Hepatitis B, Chronic
Humans
Microscopy, Electron
Mitochondrial Myopathies*
Muscle Weakness
Muscle, Skeletal
Muscular Diseases
Pathology
Peroxidase
Succinate Dehydrogenase
Creatine Kinase
DNA, Mitochondrial
DNA, Viral
Electron Transport Complex IV
Peroxidase
Succinate Dehydrogenase

Figure

• 

  Fig. 1. Light microscopic findings of patient 1 (A-D), 2 (E-H), and 3 (I-L). In patient 1, single ragged red fiber (asterisk) is observed in serial sections, which is deficient for cytochrome oxidase activity (C) and strongly reactive to succinate dehydrogenase stain (D). In addition, some necrotic and regenerating fibers are observed (A, B). In patient 2, only a few regenerating fibers are observed (E) without evident ragged red fiber (F, H). However, COX negative fibers are abundant (G, black dots). In patient 3, necrotic and regenerating fibers are scattered (I), and a few ragged red fibers (J, arrowhead) with in-creased succinate dehydrogenase activity (L, white dots) are observed. Many muscle fibers are deficient for cytochrome oxidase activities (K, black dots) (A, E, I: hematoxyline and eosin stain, B, F, J: modified Gomori-trichrome stain, C, G, K: cytochrome oxidase stain, D, H, L: succinate dehydrogenase stain. An 100 μm scale bar was used).

• 

  Fig. 2. Electron microscopic findings of patient 1 (A, B), 2 (C, D), and 3 (E, F) (scale bar, 2 μm). The rod shaped inclusions are observed within mitochondria (arrows, A). The double-membrane vesicle (long arrowheads) encircling abnormal mitochondria is observed, which indicates the autophagic vesi-cles (B). Abnormal accumulation of mitochondria is observed in degenerated fibers and between myofibrils (C-E). Mitochondria in degenerated fiber is enlarged and abnormally shaped (black short arrowheads, F).

• 

  Fig. 3. Quantitative PCR analysis showed mtDNA/nuclear DNA ratio was markedly reduced in comparison to the normal control (12.4% of normal control in patient 1, 18.3% in patient 2, and 3.5% in patient 3). PCR, peroxidase chain reaction; mtDNA, mitochondrial DNA.

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