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Rhabdomyolysis following coronary angiography: an unexpected detection on 99mTc-methyl diphosphonate bone scintigraphy

Bone scintigraphy is an appropriate tool in the management of cancers for the detection of bone metastasis. Technetium 99 m-methylene diphosphonate (99mTc-MDP) is commonly used as a bone-seeking agent. The bones take up 99mTc-MDP through a process called chemisorption, which is more evident in areas of increased osteoblastic activities. Nevertheless, extra-osseous 99mTc-MDP uptake is an infrequent occurrence, which warrants a thorough clinical assessment to evaluate such findings. An example of extraosseous uptake discovery is rhabdomyolysis, which requires prompt recognition and immediate management. Rhabdomyolysis secondary to an adverse reaction towards iodinated contrast material is a rare condition that warrants a high index of clinical suspicion. We present a case of a 75-year-old gentleman with underlying benign prostatic hypertrophy, and chronic kidney disease who had undergone a coronary angiography examination and intervention for ischemic heart disease. Pre-scheduled bone scintigraphy with 99mTc-MDP for the work-up of raised serum prostate-specific antigen (PSA) was performed 2 weeks post coronary angiography examination. Whole-body bone scan with single-photon emission computed tomography/computed tomography (SPECT/CT) images showed an unexpected finding of extensive extra-osseous uptake in the muscles and soft tissues. Additional investigations confirmed the diagnosis of rhabdomyolysis. Nevertheless, despite the prompt recognition, administration of treatment and supportive care, the patient succumbed to life-threatening complications. This case highlights the importance of recognising and identifying the pattern of extra-osseous uptake on bone scintigraphy imaging to ensure early intervention of severe and life-threatening conditions such as rhabdomyolysis.


Background
Bone scintigraphy is an appropriate tool in the management of cancers for the detection of bone metastasis. Technetium 99 m-methylene diphosphonate ( 99m Tc-MDP), Technetium 99 m-hydroxyethylene diphosphonate ( 99m Tc-HDP) and Technetium 99 m-hydroxy methylene diphosphonate ( 99m Tc-HMDP) are common bone-seeking agents. The bones take up these agents by the mechanism of chemisorption, which is aided by increased osteoblastic activity and regional hyperperfusion [1]. Nevertheless, the detection of extra-osseous 99m Tc-MDP uptake is an infrequent occurrence, which warrants a thorough clinical assessment to evaluate such findings. An example of extra-osseous finding is rhabdomyolysis, which requires prompt recognition and immediate medical management. Rhabdomyolysis secondary to an adverse reaction towards iodinated contrast agents is a rare condition that warrants a high index of clinical suspicion, as demonstrated in this case.

Case presentation
We report a case of a 75-year-old gentleman with underlying benign prostatic hypertrophy (BPH), chronic kidney disease (stage 3B) and ischemic heart disease. For the past 2 years, he had experienced lower urinary tract symptoms, i.e., increased urinary frequency, urgency, incomplete voiding and nocturia. He denied any constitutional symptoms and had no family history of malignancy. The digital rectal examination noted an enlarged prostate gland with a slightly prominent median sulcus suggestive of benign prostatic hyperplasia (BPH). His serum prostate-specific antigen (PSA) was elevated, measuring 115 ng/ml (normal value range, < 4 ng/ml). Recently, he also complained about worsening chest pain and lower back pain. Nevertheless, he was ambulating fairly well and was independent in his activities of daily living (ADL).
He eventually underwent a coronary angiogram in June 2020 for his worsening chest pain, which showed severe three-vessel disease. At that time, he was managed conservatively whereby he was prescribed with anticoagulant therapy, and the dosage of his other medications was optimised. Upon discharge, however, he complained of persistent chest pain thus was readmitted for urgent percutaneous coronary intervention. Stenting was done in the left main stem, left anterior descending and left circumflex arteries.
Upon discharge, he developed progressive weakness of his lower limbs associated with bilateral thigh pain, which limited his mobility. Consequently, he became wheelchair bound within a month. He sought treatment at the nearest hospital; his symptoms were initially attributed to bilateral knee osteoarthritis based on the Xray examination of his knees.
Subsequently, because of elevated serum PSA, he was worked up for prostate cancer and referred for bone scintigraphy to assess for possible bone metastasis. 99m Tc-MDP bone scintigraphy was performed approximately 1-month post coronary angiography and intervention. He received 18.99 mCi (702.63 mBq) of 99m Tc-MDP, and whole-body planar imaging was performed 3 h later (Fig. 1). Upon reviewing the planar imaging, a complementary SPECT/CT was performed which revealed a focus of increased tracer uptake in the mid shaft of the right humerus as well as intense muscular uptake at the bilateral pectoral muscles, muscles around the scapular, tensor fascia lata and quadriceps femoris (Fig. 2). Additionally, there was prominent diffuse soft tissue tracer uptake in the background that could have been contributed by poor renal function. It was concluded that the intense and diffuse muscular uptake was likely due to myositis/generalised rhabdomyolysis. Upon further questioning, he admitted to a previous history of a fall 3 years ago in which he sustained a fracture to his right arm. However, he denied any recent history of strenuous activity or trauma.
The nuclear medicine team alerted the primary team regarding his bone scan findings. Hence, the primary team admitted him for further medical management because of suspected rhabdomyolysis. Clinically, the patient was conscious and orientated to time, place and person. His biochemical markers were elevated, indicating acute on chronic kidney injury (urea, 50 mmol/L; creatinine, 700 mmol/L). His creatinine phosphokinase (CPK) was markedly elevated, measuring 26,000 U/L (normal range, 22-198 U/L). His arterial blood gases revealed metabolic acidosis. His condition was attributed to rhabdomyolysis secondary to contrast-induced nephropathy. Subsequently, he underwent haemodialysis (HD) to treat the uraemia and metabolic acidosis.
The initial HD was performed without any extraction and was uneventful. Post HD, serum creatinine reduced from 700 to 408 mmol/L, and urea reduced from 50 to 33.0 mmol/L. The CPK level also reduced from 26000 to 18562 U/L. The patient was also started on intravenous normal saline infusion and had adequate urine output. A second HD was performed, during which he developed sudden shortness of breath and hypotension. Unfortunately, shortly afterwards, he developed acute coronary syndrome and despite best effort to resuscitate him, he succumbed and passed away.

Discussion
Unexpected extraosseous findings in bone scintigraphy need further attention by the reporting physician as it is pertinent towards the diagnosis of undetected disease pathology. In cases of soft tissue uptake of 99m Tc-MDP, the aetiology is often multifactorial and mainly due to the presence of extracellular calcium and phosphate ions which forms calcium phosphate salts [1]. Particular to this patient, the cause of the generalised muscular uptake on bone scintigraphy was due to rhabdomyolysis. Common etiological factors of this condition include trauma, excessive strenuous activity, muscle ischemia, genetic, drugs and toxins [2]. There have been limited publications that have identified generalised muscular uptake on bone scintigraphy that have been attributed to rhabdomyolysis, inflammatory muscle disease, traumatic myositis, polymyositis and dermatomyositis [3,4].
In this instance, our patient who was initially referred to rule out bone metastasis was incidentally suspected of having rhabdomyolysis based on the bone scintigraphy findings. The bone scintigraphy findings suggestive of rhabdomyolysis prompted immediate hospital admission and institution of treatment, which helped in changing the course of the management of this patient. The diagnosis of rhabdomyolysis was confirmed biochemically, as evidenced by more than 100-fold increase in serum CPK levels. We believed that the patient's underlying chronic kidney disease and recent contrast media-induced nephrotoxicity were the aggravating factors to induce rhabdomyolysis. The prompt commencement of HD in this patient helped to alleviate the derangement of his renal function. Furthermore, aided by supportive therapies such as intravenous fluid administration and bicarbonates, his renal function improved, and the metabolic acidosis was neutralised. Unfortunately, due to the severity of the condition coupled with his comorbidities, the patient succumbed to his illness.
Renal failure is one of the major complications of rhabdomyolysis. There are several mechanisms in which rhabdomyolysis can lead to renal toxicity, such as the formation of intratubular myoglobin casts, renal vasoconstriction and direct toxicity of myoglobin to renal tubular cells [2]. It can cause severe morbidity and mortality from cardiac arrhythmia, hypovolemia, acute kidney injury, electrolyte imbalances and metabolic acidosis if left untreated [5]. A CPK cut-off value of 5000 U/L has been proposed to indicate the risk of developing AKI or death [6].
Furthermore, iodinated contrast material is a rare cause of non-traumatic rhabdomyolysis, and to the best of our knowledge, it has only been reported in a few publications [6][7][8]. Additionally, the prevalence of acute kidney injury after intravenous contrast media administration in patients with underlying chronic kidney disease was quoted to be 4%, and it is found to be > 10% in patients who had undergone percutaneous transluminal coronary angioplasty (PTCA) intra-arterially [8].
Interestingly, Moriarty et al. reported an unfortunate case of fatal rhabdomyolysis with anuric acute kidney injury secondary to the iodinated contrast material used during endoscopic retrograde cholangiopancreatography (ERCP) in a pancreatic carcinoma patient [7]. Another publication reported a patient who presented with giddiness and generalised muscle weakness of the upper and lower limbs, who was then diagnosed with rhabdomyolysis secondary to a recent iodinated contrast-enhanced computed tomography examination [9]. More interestingly, a case of rhabdomyolysis that presented with symptoms of profound weakness and delayed hypercalcemia was noted to occur after the initiation of high dose simvastatin combined with a history of recent coronary angiography and stenting procedure [10]. It is noteworthy that our patient was given rosuvastatin, instead of simvastatin, which was initiated postangiography. As simvastatin is lipophilic, it has a higher tendency to interact with muscle tissues and lead to rhabdomyolysis [10]. Whereas rosuvastatin is a hydrophilic agent that dissolves well in water, hence, producing significantly less adverse effects with regards to muscle tissue damage. Furthermore, a review by Mendes et al. also showed that the incidence of rhabdomyolysis was higher amongst patients receiving simvastatin compared to rosuvastatin [11]. Thus, we believe that the initiation of rosuvastatin in this patient was unlikely an attributing factor for the development of rhabdomyolysis.
The uniqueness of our case is the fact that the remarkable findings on the bone scintigraphy alerted us to the patient's life-threatening condition.

Conclusion
Although rare, iodinated contrast media-induced rhabdomyolysis is a serious complication that ought to be considered when dealing with atypical clinical presentations resulting from contrast media administration. A comprehensive approach in interpreting extraosseous uptake in 99m Tc-MDP bone scintigraphy and an inclusive clinical approach with a high clinical index of suspicion can ensure that this life-threatening condition is not missed. Prompt diagnosis and intervention can improve the outcome in an otherwise high mortality related condition.