Abstract
Herein, we describe a case of acute rhabdomyolysis in a man in his early 50s undergoing haemodialysis and receiving the antiviral drug, telbivudine, for chronic hepatitis B virus (HBV) infection. Following diagnosis by electromyography (EMG), magnetic resonance image (MRI) scans and laboratory data (i.e., elevated serum creatinine kinase (CK) and myoglobin) telbivudine was discontinued and the patient was treated with methylprednisolone. While his CK and myoglobin levels decreased rapidly, his muscle weakness and pain improved slowly. Learning points include: patients undergoing haemodialysis and concomitantly receiving antiviral treatment for HBV, should have their serum levels of CK and myoglobin monitored regularly; treatment with corticosteroids maybe required; relief from rhabdomyolysis-induced muscle weakness and pain may be slow due to nerve fibre damage.
Background
Rhabdomyolysis is characterized by the rapid destruction of striated muscle. 1 Clinical manifestations of the condition include muscular aches, weakness and tea-coloured urine. An elevated level of plasma creatine kinase (CK) is its most sensitive laboratory indicator and rhabdomyolysis is diagnosed when serum CK is ≥1000 units/l or ≥5 times the normal range upper limit. 1 Hyperkalaemia and acute renal failure (ARF) are two major life-threatening complications of the condition.2,3 Common causes of rhabdomyolysis are varied and include, exposure to toxins, trauma, consumption of illicit drugs, alcohol or medicines. 4 Among the latter, telbivudine is an antiviral drug that has been associated with rhabdomyolysis and other serious side effects such as neuropathy and lactic acidosis in patients with chronic hepatitis B (Table 1).5–11 However, to-date, there are no reported cases of rhabdomyolysis caused by telbivudine in patients undergoing haemodialysis.
Telbivudine-associated rhabdomyolysis in patients with chronic hepatitis B.
Abbreviations: AKI, acute kidney injury; CRRT, continuous renal replacement therapy; F, female; HD, haemodialysis; LA, lactic acidosis; M, male; MOF, multiple organ failure; MP, methylprednisolone; PTR, physical therapy and rehabilitation; RML, rhabdomyolysis.
Few therapeutic options are available for rhabdomyolysis. 12 Aggressive fluid replacement is the first-line treatment, 12 but this is not suitable for patients undergoing haemodialysis because it may cause acute heart failure or acute pulmonary oedema. 13 Alternatively, corticosteroids have been shown to be effective against rhabdomyolysis caused by various aetiologies (Table 2).6,7,14–20 Here, we report the first case of rhabdomyolysis in a patient undergoing dialysis treatment who was receiving telbivudine for hepatitis B virus infection.
Use of corticosteroids in patients with rhabdomyolysis.
Abbreviations: DXM, dexamethasone; F, female; IMNM, Immune-mediated necrotizing myopathy; M, male; MP, methylprednisolone; PD, prednisolone.
Case report
A man in his early 50s presented to our hospital because of muscle pain and weakness. A renal biopsy taken seven years previously had been used to diagnose IgA nephropathy and for the past five years he had undergone haemodialysis. In addition, he had received the antiviral drug, entecavir for seven years because he was hepatitis B e-antigen (HBeAg)-positive. However, due to drug supply issues, for the past six months his treatment had been changed from entecavir to telbivudine (600 mg qd).
At the time of hospital admission, his laboratory data showed that his CK levels were ∼40 times the normal range upper limit (i.e., 6710 u/l vs 0–173 u/l), myoglobin was ∼80 times higher (i.e., >12000 mg/ml vs 0–155 mg/ml) and his lactate dehydrogenase (LDH) levels were almost double (i.e., 439 u/l vs 109–250 u/l). Electromyography (EMG) showed multiple peripheral neuropathies and axonal injury in both motor and sensory nerves, with a predominant sensory nerve injury. In addition, the degree of sensory impairment in his lower limbs was more severe than in his upper limbs. A magnetic resonance image (MRI) scan showed the presence of inflammatory oedema in bilateral calf muscles (Figure. 1). These findings were consistent with a diagnosis of acute rhabdomyolysis.
Magnetic resonance image (MRI) of lower extremity. T2-weighted MRI scans showing the affected areas of the muscle as uniformly high signal intensity (red arrows).
On the basis of the above clinical data, and after excluding other common causes of rhabdomyolysis, such as toxins, trauma, illicit drugs and alcoholism, the patient was diagnosed with telbivudine-induced rhabdomyolysis and treatment with this drug was immediately discontinued. The frequency of haemodialysis was increased to counteract the adverse effects of rhabdomyolysis, but after one week the patient’s condition worsened, as indicated by unabated muscle pain and increased levels of CK, LDH, creatinine kinase-myocardial band (CK-MB) and myoglobin (Figure. 2).
Protein levels related to rhabdomyolysis, before and after treatment with corticosteroids.
Following, treatment with IV methylprednisolone 40 mg/day for seven days, the patient’s levels of CK, CK-MB, myoglobin and LDH decreased rapidly while his muscle pain gradually abated. Subsequently, the patient received oral prednisone 30 g/day and each week the treatment was reduced by 5 mg per week. During the methylprednisolone treatment period, HBV DNA levels were also monitored and no HBV activity was detected.
Following four weeks of treatment with corticosteroids, the patient’s CK, CK-MB, myoglobin and LDH levels were within the normal range, but his muscle weakness and pain remained. At that time, the patient purchased a supply entecavir from another hospital and re-started his antiviral treatment. At a follow-up two months later, his muscle weakness and pain had been significantly relieved.
The reporting of this study conforms to CARE guidelines. 21 Written informed consent was obtained from the patient to publish his anonymised data. The study was approved by the Institute’s Committee on Human Research at the Sixth Affiliated Hospital of the Sun Yat-sen University.
Discussion
Acute rhabdomyolysis is a severe disease that can be life-threatening without prompt treatment. Its pathophysiological mechanism involves activation of a series of chain reactions triggered by increases in intracellular calcium, that result in activation of phospholipase A2, the continuous contraction of muscular cells, mitochondrial dysfunction, excessive oxygen free radical production and eventually, cell apoptosis. 22 Although rhabdomyolysis may be caused by several factors, 4 few case reports have described this clinical syndrome caused by antiviral drugs.
Telbivudine is a nucleoside analogue used in the treatment of chronic HBV infection. However, in humans, this class of drug has the potential to inhibit DNA polymerase gamma, which can result in a reduction in mitochondrial DNA that ultimately will lead to various clinical manifestations of mitochondrial toxicity, such as neuropathy, myopathy and lactic acidosis. 7 This present case report describes the occurrence of rhabdomyolysis in a patient undergoing haemodialysis who was receiving telbivudine. Although aggressive fluid replacement is the first-line treatment for rhabdomyolysis, it was not suitable for this patient because of his concomitant haemodialysis. 13 Initially, we attempted to suppress rhabdomyolysis progression by intensive dialysis, but this was also ineffective. However, the patient's condition gradually improved following treatment with IV methylprednisolone. Our findings are in agreement with others who also found that methylprednisolone improved symptoms in patients with telbivudine-induced rhabdomyolysis. 6 Indeed, corticosteroids have also proven to be useful for the treatment of rhabdomyolysis of different origins (Table 2). However, the precise role of corticosteroids in alleviating telbivudine-induced rhabdomyolysis remains unclear. Studies have shown that rhabdomyolysis and metabolic decompensation can be caused by pro-inflammatory cytokines,23–25 which is consistent with the ability of corticosteroids to inhibit rhabdomyolysis progression. In our case, while corticosteroid therapy rapidly reduced serum CK and myoglobin levels, the patient’s muscle weakness and pain were relieved gradually. This may be a reflection of the damage caused to nerve fibres which takes a considerable time to repair.
In summary, the present case report shows an example of the successful administration of corticosteroids for the treatment of acute rhabdomyolysis caused by telbivudine in a patient with HBV undergoing haemodialysis. This present case report provides useful clinical information for physicians. Firstly, in patients undergoing haemodialysis and concomitantly receiving antiviral treatment for HBV, serum levels of CK and myoglobin should be monitored regularly. Secondly, the progression of rhabdomyolysis may not be prevented by haemodialysis alone; timely use of corticosteroids maybe required. Finally, relief from rhabdomyolysis-induced muscle weakness and pain may be slow (our patient required two months). This is possibly related to the extent of nerve fibre damage. There are approximately 296 million people worldwide infected with HBV 26 and a significant number of these will be receiving antiviral drugs. Therefore, attention should be paid to antiviral drug-induced rhabdomyolysis in this population.
