Mitochondrial myopathy caused by chronic use of nucleoside (acid) analogs in patients with chronic hepatitis B (CHB) is mainly characterized by muscle weakness and myalgia.Cases with prominent manifestations of respiratory failure and multisystem symptoms have not been reported.
We report a case of mitochondrial myopathy associated with chronic hepatitis B treatment with entecavir.The patient was a 54-year-old man who had been treated with entecavir for 9 years.Hepatitis B virus (HBV) DNA was negative during treatment, and liver function was normal.However, from the 5th year of treatment, malaise, loss of appetite, and smell disturbance gradually appeared. Respiratory failure was a prominent manifestation in the later stage of disease progression.Diagnosis is based on histopathological examination.After discontinuation of entecavir, olfactory disturbance, hypoxemia, and gastrointestinal symptoms gradually improved.
Mitochondrial myopathy is a rare side effect of entecavir that can be diagnosed by muscle biopsy.Although the incidence is extremely low, severe cases can lead to respiratory failure.We should get enough attention in clinical practice.
At present, the efficacy and safety of long-term use of nucleoside (acid) analogs (NAs) in patients with chronic hepatitis B (CHB) are widely recognized, but there are also rare adverse reactions, such as NAs-related mitochondria with muscle weakness and muscle weakness. Myopathy with symptoms such as pain [1,2,3,4].Recently, we observed a case of NAs-related mitochondrial myopathy with respiratory failure as a prominent manifestation, accompanied by multi-system symptoms such as fatigue, loss of appetite, and smell disturbance after 5 years of entecavir use.In addition, we performed a literature review of other cases of entecavir-related myopathy in patients with chronic hepatitis B.
The patient was a 54-year-old man with a history of CHB for more than 20 years.In April 2011, due to abnormal liver function [alanine aminotransferase (ALT) 80-160 U/L], hepatitis B virus (HBV) DNA 10E+07 copies/ml, hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) positive, he was diagnosed with HBeAg positive CHB and started on entecavir (0.5 mg/d).Retests performed after 24 weeks of treatment showed HBV DNA < 500 copies/ml and normal ALT.The patient continued to take entecavir and was followed up regularly.Beginning in May 2016, the patient gradually developed fatigue and loss of appetite, and visited the local hospital several times.Physical examination showed no positive signs.Auxiliary examination results: blood routine, liver and kidney function, electrocardiogram were normal, and HBV DNA was lower than 100 copies/ml.No special handling is done.In December 2018, the patient developed anosmia.In March 2019, the patient had repeated coughing, expectoration with white sputum, and mild difficulty breathing after upper respiratory tract infection.No fever or other discomfort was observed.But these symptoms are mostly tolerable and do not require further treatment.
In August 2019, he completely lost his sense of smell and went to the otolaryngology department of Beijing Tongren Hospital.Diagnostic tests include nasal endoscopy, computed tomography (CT), and magnetic resonance imaging (MRI) of the sinuses.The results showed that the nasal septum was curved to the right, and no nasal mucosa edema, nasal polyps or space-occupying lesions were found.In terms of olfactory disturbance, no special treatment was given.During the same period, the patient’s fatigue and loss of appetite increased, and his body weight decreased by 3 kg in the past year (by July 2020, the weight continued to drop by about 5 kg).Gastroscopy and colonoscopy were performed at a local hospital.These examinations revealed only colon polyps, which were held under the endoscope with forceps.No other anomalies were found.In December 2019, the patient went to a local hospital for treatment due to aggravated cough and sputum, white sputum and shortness of breath.Laboratory results were as follows: Arterial blood gas analysis: pH 7.38 (7.35-7.45), arterial partial pressure of oxygen (PaO2) 61.8 mmHg↓ (80-100), arterial partial pressure of carbon dioxide (PaCO2) 65.7 mmHg↑ (32-45).Serum muscle enzymes: creatine kinase-cardiac band (CK-MB) 35.9 U/L↑ (0-25), lactate dehydrogenase (LDH) 253 U/L↑ (120-250), hydroxybutyrate dehydrogenase Enzyme (HBDH) 237 U/L ↑ (72–182), creatine kinase (CK) 123.9 U/L (50–310).Lung function: forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) 67% (65.9-89.5), FEV1 1.60 L (51% of predicted value), FVC 2.38 L (61% of predicted value) and negative bronchioles Expansion tests suggest a possible restrictive lung ventilation disorder.Chest CT showed mild consolidation in the right lower lung.Routine blood, C-reactive protein, liver and kidney function, and echocardiography were normal, and HBV DNA was less than 100 IU/ml.The patient was diagnosed with chronic obstructive pulmonary disease and type II respiratory failure.Theophylline and albuterol were given, but they were not effective.With piperacillin-sulbactam combined with levofloxacin anti-infective therapy, cough and expectoration improved for a period of time.However, these symptoms continued to recur after discontinuation of the drug, and the patient’s shortness of breath did not improve significantly.
On January 14, 2020, the patient went to the Department of Respiratory Medicine of Peking Union Medical College Hospital for arterial blood gas analysis.The results are as follows: Resting state: pH 7.35, PaO2 66 mmHg↓, PaCO2 65 mmHg↑, oxygen saturation (SO2) 92.1%↓, lactate 4.3 mmol/L↑ (0.5-1.6).After deep breathing: pH 7.40, PaO2 107 mmHg, PaCO2 50 mmHg↑, SO2 98.3%, lactate 6.5 mmol/L↑.After 6 minutes walking test (walking 510m): pH 7.29↓, PaO2 74 mmHg↓, PaCO2 56 mmHg↑, SO2 93.7%↓, lactate 11.5 mmol/L↑.Blood gas test results and previous pulmonary imaging findings could not explain the patient’s clinical symptoms.Blood lactate was significantly elevated after exercise.Considering the possible pathological changes in mitochondria closely related to lactate metabolism, the diagnosis of neuromuscular myopathy cannot be ruled out.Supplementary related examinations: blood routine, urine routine, and stool examination are basically normal; liver function, coagulation function, immunoglobulin (IgG/IgM/IgA), complement (C3/C4), antinuclear antibody, extractable nuclear antigen, anti-infection The neutrophil cytoplasmic antibody profile, erythrocyte sedimentation rate, and C-reactive protein were within the normal range; HBV DNA < 100 IU/ml.Serum muscle enzymes showed CK-MB 20.1 μg/L↑ (0-3.6), LDH 372 U/L↑, CK 165 U/L (24-195).No pathological changes were detected by ECG and echocardiography.Repeated pulmonary function tests showed FEV1/FVC 85.85%, FEV1 1.82 L (58% of predicted value), FVC 2.12 L (55% of predicted value), residual capacity/predicted value 149%.Based on the patient’s findings, shortness of breath due to polymyositis or heart disease was ruled out.PaO2 of the patient improved significantly after deep breathing.Considering the absence of obstructive ventilatory dysfunction, decreased FVC may be associated with neuromuscular myopathy.Specially invited neurologist for consultation.
Further examination after neurology consultation, tumor markers (AFP, CA242, SCCAg, PSA, CEA, CA199, CA125, CA724, CA153, NSE, TPS, Cyfra211, ProGRP), anti-Hu, anti-Yo and anti-Ri type, Hematuria immunofixation electrophoresis, serum protein electrophoresis, blood homocysteine, folic acid, vitamin B12 or thyroid function.No abnormal signal was found in the MRI of the lower extremities of the muscles in each group, and the muscle gap was clear.Paraneoplastic syndromes, autoimmune diseases and neurological damage caused by deficiency of folic acid and vitamin B12 were excluded.Considering the significant increase in blood lactate after exercise, further electromyography and muscle biopsy are recommended to determine the presence of nerve conduction and muscle mitochondrial lesions.However, due to the impact of the COVID-19 pandemic, the exam cannot be taken and is planned to take place in the future.Hypoxemia and possible mitochondrial myopathy were initially diagnosed after neurology consultation.The patient was given vitamin B1 10 mg 3 times a day, vitamin B complex 1 tablet 3 times a day, and mecobalamin 0.5 mg 3 times a day for neurotrophic therapy, and budesonide suspension 1 mg/time, daily 2 sessions of aerosol inhalation therapy.Entecavir continues to be used for hepatitis B treatment.
After the above treatment, the patient’s symptoms did not improve, and even worsened occasionally.In May 2020, the patient entered a coma with blood gas values of pO2 20-30 mmHg↓ and pCO2 83 mmHg↑.He underwent a tracheostomy and ventilator-assisted ventilation at a local hospital.On July 2, after the patient’s condition was stable, the blood gas was rechecked, pH 7.38, PaO2 57.9 mmHg↓, PaCO2 48.1 mmHg↑, lactate 3.5 mmol/L↑, indicating improvement.To confirm the diagnosis, the patient went to the Department of Neurology, Peking Union Medical College Hospital for examination.The following results were obtained, electromyography: upper and lower extremity nerves and parasternal muscles showed normal conduction.The pathology report of the quadriceps muscle biopsy showed myogenic changes, slightly different muscle fiber size, mild atrophy of scattered muscle fibers, mild staining of cytochrome c oxidase in a few muscle fibers, and uneven red fibers suspicious for modified Gomori trichrome staining (The patient No muscle biopsy results prior to initial entecavir treatment).Diagnosed with mitochondrial myopathy on July 11.Given that mitochondrial myopathy is associated with entecavir, it is recommended to discontinue entecavir.
One month after entecavir was discontinued, the patient’s shortness of breath improved.Examination showed HBV DNA 1E + 03 IU/ml and normal ALT.Blood gas tests performed 4 months after entecavir discontinuation (November 17) showed marked improvement: PaO2 77.9 mmHg↓, PaCO2 39.7 mmHg, and lactate 2.4 mmol/L↑.However, some parameters deteriorated: ALT 333 u/L ↑, aspartate aminotransferase (AST) 153 u/L ↑ and HBV DNA 8 E + 07 IU/ml.Therefore, the patient went to the outpatient department of Beijing You’an Hospital on December 3, 2020.Consider reactivation of hepatitis B due to virological rebound and biochemical abnormalities.Patients are advised to take tenofovir alafenamide 1 tablet (25 mg) once a day for treatment.Meanwhile, he was closely monitored for respiratory symptoms and mitochondrial myopathy.Follow-up in March 2021 found that the patient did not take alafenamide and tenofovir because of the risk of respiratory failure caused by alafenamide and tenofovir, and only received diammonium glycyrrhizinate and polyene phosphatidylcholine.His liver function indexes decreased (ALT 81.1 u/L↑, AST 71.4 u/L↑, HBV DNA 8 E + 07 IU/ml) but did not recover.At that time, entecavir treatment had been discontinued for 8 months.His sense of smell improved slightly (a pungent odor could be discerned).Shortness of breath, fatigue, loss of appetite and other symptoms improved.Blood lactate has dropped to 2.1 mmol/L↑.Compared with the previous time, serum muscle enzymes did not decrease: CK-MB 42.6 u/L↑, LDH 350 u/L↑, HBDH 309 u/L↑, CK 222.The electrocardiogram is still normal.
The last follow-up time was August 2021. The patient had reduced shortness of breath and fatigue, and could tolerate activities of daily living.However, the tracheostomy needs to remain open when the patient is lying flat at night.The patient’s liver function parameters were not completely normalized (ALT 33.2 u/L, AST 47.1 u/L↑).HBV DNA was 8.97E + 07 IU/ml.Serum muscle enzymes decreased (CK-MB 40.9 u/L↑, LDH 287 u/L↑, HBDH 278 u/L↑, CK 154 u/L↑).Blood lactate decreased to normal (1.3 mmol/L).
Both domestic and foreign hepatitis B guidelines recommend that patients with chronic hepatitis B should receive NAs treatment for a long time to reduce the recurrence caused by drug withdrawal.However, with the long-term use of NAs, reports of NAs-related mitochondrial myopathy have gradually increased, although the majority of case reports were predominantly of the limb muscles in patients treated with telbivudine, lamivudine, or adefovir. weakness and myalgia [1, 5, 6, 7, 8, 9].Respiratory muscle involvement with respiratory failure as the main manifestation and olfactory disturbance has not been reported.
As early as 2009, our team found that telbivudine combined with interferon in the treatment of chronic hepatitis B can cause peripheral neuritis accompanied by AST [159.6 u/L (77.5, 299.4)] and ALT [72.4 u/L (60.6 , 98) were significantly increased.)] DNA < 500 copies/ml.Some cases showed abnormal CK and CK-MB, and even degenerative changes in toenails .Therefore, combination therapy with interferon and telbivudine is no longer recommended.However, with the promotion of NAs monotherapy, there have been reports that NAs can cause mitochondrial myopathy.The main mechanism may be that NAs not only inhibit HBV DNA polymerase, but also affect human mitochondrial DNA polymerase, resulting in insufficient synthesis of respiratory chain-related enzymes, energy metabolism disorders, and ultimately mitochondrial myopathy .Mitochondrial lesions can affect tissues and organs throughout the body, and the abundance of mitochondria in brain, nerve, and muscle tissue makes them vulnerable due to their high reliance on oxidative metabolism.Most of the previous studies have reported isolated mitochondrial myopathy, that is, mitochondrial myopathy involving only the skeletal muscle system.In the cases reported in this study, in addition to the usual musculoskeletal limb muscle involvement, severe respiratory muscle involvement was observed.In addition, the involvement of multiple systems has been found, including the nervous system and the digestive system.It is rare for a patient to be diagnosed 5 years after the onset of the disease and after several hospital visits.
Although the patient’s blood gas test results showed type II respiratory failure, hypoxemia and CO2 retention improved significantly after deep breathing, indicating the absence of ventilatory obstruction.The patient had no history of smoking or cardiopulmonary disease, and the auxiliary examination of chest muscle function and nerve conduction was normal.The restrictive disturbance of ventilatory function may be caused by dyskinesia of the respiratory muscles.In addition to muscle involvement, this patient also had olfactory nerve involvement, which is rare.Mitochondria are important energy supply factories in the body, and their pathological changes can affect multiple organs and systems.Therefore, for CHB patients treated with NAs for a long time, if they have clinical symptoms that are difficult to explain by routine examination, the possibility of mitochondrial myopathy should be considered.
Three cases of entecavir-related myopathy have been reported previously, with onset time ranging from 10 days to 5 years, and manifested as myalgia or muscle weakness in the extremities.CK and/or LDH and HBDH in these 3 patients were increased to varying degrees, and the symptoms of myopathy gradually eased after drug withdrawal, and the level of kinase decreased [3,11,12].Of the 3 cases, 2 developed hepatitis B virus rebound and elevated transaminases after drug withdrawal.After lamivudine combined with adefovir treatment for 2 months  and lamivudine monotherapy for 1 month , the liver function and HBV DNA of these two patients returned to normal, and neither occurred during treatment. Adverse reactions.However, there are no follow-up reports on subsequent long-term treatment of these cases or whether the myopathy recurred.Our patient also experienced hepatitis reactivation after discontinuation of entecavir, which is in line with current indications for HBV antiviral therapy.However, both NAs and interferons carry therapeutic risks.The former may lead to the recurrence of respiratory failure, while the latter may cause additional adverse reactions during clinical application.The patient consulted a neurologist and antiviral therapy was not recommended.However, the patient has been taking hepatoprotective drugs for more than 8 months, and the transaminase level has not recovered.If the liver is repeatedly inflamed over a long period of time, liver failure and cirrhosis may occur.Therefore, how this patient will be treated in the future remains unknown.
In conclusion, chronic hepatitis B long-term use of entecavir can cause mitochondrial myopathy.Although the incidence is extremely low, the disease is very serious and should be paid enough attention in clinical practice.
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This research was supported by the Capital Health Research and Development Project (2020-1-2181).Funding agencies had no role in the design of the study, the collection, analysis and interpretation of data, and the writing of the manuscript.
The First Department of Liver Disease Center, Beijing You’an Hospital, Capital Medical University, Beijing, 100069
XC and XL designed this study.XL, AS and SZ collected data.LX drafted the manuscript.XC contributed to interpretation of results for important intellectual content and key revisions of the manuscript, and provided financial support for the project leading to this publication.Final manuscript read and approved by all authors.
All procedures performed in studies involving human participants were in compliance with institutional and/or national research council ethical standards and the Declaration of Helsinki (revised 2013).
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Lin, X., Song, A., Zheng, S. et al.Respiratory failure is a major manifestation of entecavir-associated mitochondrial myopathy: a case report.BMC Infectious Diseases 22, 188 (2022).https://doi.org/10.1186/s12879-022-07159-y
Post time: Mar-01-2022