Statin-induced rhabdomyolysis in a patient with SLCO1B1 gene abnormalities: a case report

Introduction

Background

Statins are a group of lipid-lowering medications commonly used in clinical practice. Side effects related to statin-associated skeletal muscle damage have been reported with a variety of clinical manifestations and varying degrees of severity including myalgia, myositis, and mild creatine kinase (CK) elevations to rhabdomyolysis with serum CK levels exceeding 10 times the upper limit of normal (1). Rhabdomyolysis is a serious life-threatening complication that can lead to acute kidney injury (AKI) and requiring dialysis (2).

Rationale and knowledge gap

The mechanism of statin-induced myopathy is still unclear; however, there are many factors that increase the risk of skeletal muscle damage in patients taking statins, including genetic abnormalities (3,4). Statin-induced rhabdomyolysis is the most serious and rare reported complication. A few case reports found mutations at different locations on SLCO1B1 gene, while others reported only clinical risk factors without genetic analysis (5-9). Further research is needed to identify the associated trigger factors that lead to severe myopathy such as rhabdomyolysis and to determine whether a combination of multiple risk factors may lead to serious statin-induced myopathy.

Objective

We report a rare clinical case of severe rhabdomyolysis complicated by the highest serum CK ever reported and AKI due to the use of the lipid-lowering drug simvastatin. We found that the patient had multiple risk factors for statin-induced rhabdomyolysis, including a history of high-dose simvastatin use, excessive physical exertion after injury, and especially an abnormality in the SLCO1B1 gene. We present this case in accordance with the CARE reporting checklist (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-150/rc).

Case presentation

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Ethics approval was obtained from the Hanoi Medical University Hospital Human Ethics Research Committee. Written informed consent was obtained from the patient for publication of this study. All patient information is kept confidential. A copy of the written consent is available for review by the editorial office of this journal.

A 53-year-old male patient presented to the Emergency & Intensive Care Unit, Hanoi Medical University Hospital in 2020 due to generalized muscle pain and weakness. Three weeks prior to this hospital presentation, the patient sustained a right foot injury after falling from a motorbike. The patient was diagnosed with closed fractures of the 3^rd and 4^th metatarsal bones with minimal displacement. He was discharged with a short leg cast and crutches; however, he voiced some challenges with using crutches and the effort required in using only his right side. Two weeks following the motorcycle accident the patient developed generalized muscular pain including in the neck, waist and limbs particularly in both thighs. The muscle weakness became progressively worse to the point that he could no longer walk. He also developed dark-colored urine.

At the time of presentation to hospital the patient was awake and his vital signs were as follows: heart rate 90 bpm, respiratory rate 20 bpm, oxygen saturation 98%, blood pressure 180/110 mmHg which was treated with the calcium channel blocker amlodipine. He had generalized muscle pain with quadriplegia: peripheral, flaccid paralysis, muscle strength 3/5 in the upper and 2/5 in the lower extremities with the absence of sphincter dysfunction. The patient had bilateral thigh swelling with no redness or warmth. His right foot had improved after 3 weeks of immobilization with reduced pain and swelling, palpable pulses and nil sign of infection.

The patient had dark-colored urine with a decreased output of less than 200 mL per day. Laboratory results were as follows: serum CK increased by 111,625 IU/L; aspartate aminotransferase (AST) 1,847 IU/L, alanine aminotransferase (ALT) 625 IU/L, urea 18.2 mmol/L, creatinine 361 µmol/L and blood gas showed metabolic acidosis within 24 hours (Table 1). Other serum electrolytes were within normal ranges. The patient was diagnosed with rhabdomyolysis and AKI. While the cause of rhabdomyolysis could be attributed to his foot injury or the increased pressure on his left side while using crutches, neither were severe enough to explain the muscle damage. It was therefore concluded that they were more likely to be contributing factors rather that the main cause.

Further investigation was carried out to find the primary cause of his rhabdomyolysis. Testing for human immunodeficiency virus (HIV) virus, hepatitis B, hepatitis C, Dengue, Epstein-Barr virus, cytomegalovirus, Leptospira, and Rickettsia all showed negative results. Electromyography demonstrated no neuromuscular damage. Biopsy results of left thigh muscle showed degeneration of skeletal muscle fibers, almost total hypotrophy, edematous stromal tissue, no inflammatory cell infiltration, and no signs of myositis. These results point to muscle necrosis, possibly due to drug toxicity. Upon review of his medical history, the patient had hypertension and dyslipidemia. His family medical history was unremarkable. His regular medications included amlodipine 5 mg/day and simvastatin 40 mg/day, which he had been taking for 5 months.

We suspected this patient’s condition was statin-associated rhabdomyolysis, a complication that has been reported with the use of lipid-lowering agents. Subsequently we conducted mutation analysis of SLCO1B1 gene using Sanger gene sequencing method. This gene encodes a protein and allows transportation of drugs, including statin drugs, into hepatocytes (10). The results showed that the patient had 1 nucleotide change on exon 5 of the SLCO1B1 gene. This mutation prevents the drug from being transported into the liver cells for metabolism, causing accumulation in the body and leading to skeletal muscle damage.

The patient was initially treated with aggressive fluid management using 0.9% sodium chloride, with 2,500 mL being administered on the first 24 hours; however, severe AKI resulted in fluid overload and metabolic acidosis. Treatment was then changed to renal replacement therapy (RRT) and unfractionated heparin to prevent deep vein thrombosis. The patient underwent daily RRT during the first week and every 2 days until the 21st day of treatment. Despite simvastatin use being discontinued from the first day of hospital admission, the serum CK levels slightly decreased on the third day after treatment but continued to rise and peaked on the fifth day at 490,941 IU/L. From the sixth day of treatment, the CK concentration gradually decreased and after three weeks, it had reached 537 IU/L (Figure 1). Corresponding to the serum CK concentration, the patient’s muscle strength began to improve after one week of treatment and after three weeks he was able to sit up and had regained muscle strength to 4/5. The patient’s AKI status stabilized more slowly, requiring RRT for 21 days. Following the RRT period the patient’s urine and plasma creatinine level gradually returned to normal range. The patient was then discharged to a local hospital for further treatment, including rehabilitation and kidney function monitoring. Follow-up after one month showed that the patient’s urine volume had returned to about 2,000 mL a day and after two months he could stand and tolerate gentle exercise. The use of statins was also discontinued from the time the patient was discharged until the next follow-up after two months, which was uneventful.

Figure 1 Plasma CK concentration during treatment. CK, creatine kinase.

Discussion

Rhabdomyolysis is a syndrome characterized by muscle necrosis and release of intracellular components of skeletal muscle into the circulation. Patients with rhabdomyolysis present with muscle pain and weakness with increased serum CK up to 5 times higher than the upper limit as well as myoglobinuria. Severe rhabdomyolysis can be life-threatening in association with electrolyte disturbances and acute renal failure (11). The classic cause of acute rhabdomyolysis is trauma, particularly entrapment syndrome. However, medical and recreation drugs are important causes of rhabdomyolysis (2).

Statins have lipid-lowering effects through inhibiting the cycle from acetoacetyl coenzyme A to cholesterol. The SLCO1B1 gene plays a crucial role in encoding the protein that transports statins into hepatocytes where they are metabolized. In hepatocytes, several statins (including simvastatin, lovastatin and atorvastatin) are metabolized via cytochrome P450 3A4 (CYP3A4) to their inactive form (2). Statins are the first-line drugs for the treatment of dyslipidemia. Currently, the drug is widely used in clinical practice due to its effectiveness and overall safety. Rhabdomyolysis remains a major concern with the clinical use of statins. Statin-induced rhabdomyolysis occurs with varying degrees of frequency and severity with frequency. Muscle aches and weakness occur with a relatively high frequency of 2 to 11 percent. Severe muscle damage such as rhabdomyolysis or immuno-necrotizing myopathy is rarer, occurring in 0.1% to 0.5% of cases (12-15).

The mechanism by which statins cause skeletal muscle damage remains unclear. Some studies have found that statins can inhibit the synthesis of coenzyme Q10 (CoQ10, ubiquinone), which plays a role in the production of energy for muscle cells. It is possible that the reduction of CoQ10 in myocytes contributes to statin-induced muscle damage (11). However, there are reports of risk factors associated with statin-associated myopathy, including:

• Genetic factors, as the SLCO1B1 gene encodes for the organic anion-transporting polypeptide 1B1 (OATP1B1) that is responsible for the uptake of most statins into hepatocytes. One study showed that mutations in the SLCO1B1 gene, specifically exon 5 mutations, were associated with an increased risk of statin muscle side effects (16).
• Statins metabolized via CYP3A4 (including simvastatin, lovastatin and atorvastatin) have the potential to interact with inhibitors of CYP3A4 or with drugs that are competitively metabolized via CYP3A4. The risk of muscle damage is increased when statins are used in combination with these drugs (common drugs such as cyclosporine, macrolide antibiotics, antiretroviral agents or hepatitis C protease inhibitors, etc.). Reports also show rhabdomyolysis due to drug interactions between statins and other drug groups such as simvastatin with clarithromycin or atorvastatin with colchicine (5,6).
• Patients with a history of underlying diseases including: hypothyroidism, acute renal failure, liver failure, vitamin D deficiency, chronic neuromuscular diseases.
• Excessive physical exertion may increase mitochondrial production, modulating antioxidant defense mechanisms in skeletal muscle thus increasing the risk of rhabdomyolysis. Patients on statins are advised to exercise gently while avoiding excessive exertion. Older age, female gender and people with a small body frame.

Our patient was admitted to the hospital with generalized myalgia, elevated plasma CK concentration, oliguria and elevated serum creatinine levels, resulting in the diagnosis of acute rhabdomyolysis complicated by AKI. Myoglobinuria was not performed due to objective conditions. At hospital admission, the patient complained his muscle pain and weakness after his trauma and leg exertion. The patient had used high dose of simvastatin without any side effects for five months; however, his medication history was not recorded. While the initial assessment missed the history of high-dose statin use, traumatic foot injury and leg exertion were inconsistent with severe rhabdomyolysis. We had to expanded the diagnosis of patient’s severe rhabdomyolysis etiologies such as myositis, infection, or drugs side effects. We then carefully obtained patient’s history of high dose simvastatin use for 5 months. Virus tests and muscle biopsy were also performed to rule out other myopathy etiologies. Suspicions were raised regarding the statin drug that the patient was taking. SLCO1B1 gene mutation testing was performed showing 1 nucleotide change on exon 5 of the SLCO1B1 gene, which further supported our diagnosis of statin-induced rhabdomyolysis. While the patient had been taking simvastatin for up to 5 months, he only recently developed symptoms of rhabdomyolysis. Therefore, it is suspected that his leg injury and excessive physical exertion after injury may have been the trigger factor.

Previous studies have shown the association between statin-induced myopathy and some factors such as SLCO1B1 genetic abnormalities. However, severe myopathy as rhabdomyolysis is rare and has only been reported in a few clinical cases and factors causing severe myopathy are ambiguous. There were reports of statin-induced rhabdomyolysis with serum CK levels of more than 10,000 IU/L that associated with some risk factors such as drug interaction or hypothyroidism. But further investigated for genetic abnormalities were not performed (5-7). Several studies reported statin-induced rhabdomyolysis in patients with SLCO1B1 genetic abnormalities. However, the highest serum CK level of these reports was only 50,000 IU/L (one-tenth of our report) and trigger factors for rhabdomyolysis were unclear (8,9). Because of the patient’s severe rhabdomyolysis in our report, we performed a comprehensive investigation to fully assess the risk factors. It may be explained that the combination of multiple risk factors including high doses of simvastatin, prolonged exertion and SLCO1B1 genetic abnormality resulted in the most severe myopathy in our report.

On admission our patient’s statin use was ceased. However, his plasma CK concentration did not decrease immediately despite receiving hemodialysis for AKI. CK plasma concentrations only began to decrease from the fifth day after treatment. The patient’s symptom onset was one week before admission and serum CK at admission was more than 100,000 IU/L. Late admission may explain failure of fluid therapy for preventing AKI. A clinical case report of rhabdomyolysis due to drug interaction between simvastatin and clarithromycin showed a similar clinical picture even though their patient did not receive RRT (5). Early detection of the signs of rhabdomyolysis and prompt treatment with intravenous fluids can help prevent patients from developing severe AKI, thus avoiding the need for RRT, reducing the length of hospital stay and shortening the patient’s recovery time.

The strengths of our case report are that we performed comprehensive investigations to fully assess the cause of rhabdomyolysis and serum CK was closely monitored daily during hospitalization. However, the study has some limitations. Myoglobinuria that is a diagnostic criterion for rhabdomyolysis was not performed. At the clinic, our patient was not warned about the muscle-related side effects of the simvastatin, so the patient did not initially disclose his medication history and the doctor omitted the history of statin use. This also requires clinicians to pay attention when prescribing statins to warn patients about skeletal muscle damage. Rhabdomyolysis can occur after a long period of stable drug use if there are trigger factors.

Conclusions

In patients treated for dyslipidemia with statins, early detection of symptoms of statin-induced rhabdomyolysis is crucial especially in high-risk patients such as those with SLCO1B1 gene abnormalities. Early and appropriate management is essential in order to avoid serious complications.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-150/rc

Peer Review File: Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-150/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-150/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Ethics approval was obtained from the Hanoi Medical University Hospital Human Ethics Research Committee. Written informed consent was obtained from the patient for publication of this study. All patient information is kept confidential. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004;292:2585-90. [Crossref] [PubMed]
2. Cabral BMI, Edding SN, Portocarrero JP, et al. Rhabdomyolysis. Dis Mon 2020;66:101015. [Crossref] [PubMed]
3. Elam MB, Majumdar G, Mozhui K, et al. Patients experiencing statin-induced myalgia exhibit a unique program of skeletal muscle gene expression following statin re-challenge. PLoS One 2017;12:e0181308. [Crossref] [PubMed]
4. Brunham LR, Baker S, Mammen A, et al. Role of genetics in the prediction of statin-associated muscle symptoms and optimization of statin use and adherence. Cardiovasc Res 2018;114:1073-81. [Crossref] [PubMed]
5. Ezad S, Cheema H, Collins N. Statin-induced rhabdomyolysis: a complication of a commonly overlooked drug interaction. Oxf Med Case Reports 2018;2018:omx104. [Crossref] [PubMed]
6. Sabanis N, Paschou E, Drylli A, et al. Rosuvastatin and Colchicine combined myotoxicity: lessons to be learnt. CEN Case Rep 2021;10:570-5. [Crossref] [PubMed]
7. Chiang WF, Chan JS, Hsiao PJ, et al. Case report: Rhabdomyolysis and kidney injury in a statin-treated hypothyroid patient-kill two birds with one stone. Front Med (Lausanne) 2022;9:1046330. [Crossref] [PubMed]
8. Niedrig DF, Pyra M, Lussmann R, et al. Rosuvastatin-induced rhabdomyolysis: case report and call for proactive multifactorial risk assessment and preventive management of statin therapy in high-risk patients. Eur J Hosp Pharm 2024;31:281-4. [Crossref] [PubMed]
9. Medwid S, Deckert R, Gryn SE, et al. SLCO1B1 variants in a patient of African ancestry presenting with rosuvastatin-induced rhabdomyolysis: A case report. Br J Clin Pharmacol 2025;91:232-5. [Crossref] [PubMed]
10. Pasanen MK, Fredrikson H, Neuvonen PJ, et al. Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther 2007;82:726-33. [Crossref] [PubMed]
11. Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med 2009;361:62-72. [Crossref] [PubMed]
12. Tobert JA. Efficacy and long-term adverse effect pattern of lovastatin. Am J Cardiol 1988;62:28J-34J. [Crossref] [PubMed]
13. Dujovne CA, Chremos AN, Pool JL, et al. Expanded clinical evaluation of lovastatin (EXCEL) study results: IV. Additional perspectives on the tolerability of lovastatin. Am J Med 1991;91:25S-30S. [Crossref] [PubMed]
14. Boccuzzi SJ, Bocanegra TS, Walker JF, et al. Long-term safety and efficacy profile of simvastatin. Am J Cardiol 1991;68:1127-31. [Crossref] [PubMed]
15. Pedersen TR, Berg K, Cook TJ, et al. Safety and tolerability of cholesterol lowering with simvastatin during 5 years in the Scandinavian Simvastatin Survival Study. Arch Intern Med 1996;156:2085-92. [Crossref] [PubMed]
16. Voora D, Shah SH, Spasojevic I, et al. The SLCO1B1*5 genetic variant is associated with statin-induced side effects. J Am Coll Cardiol 2009;54:1609-16. [Crossref] [PubMed]