Investigation for statin intolerance reveals possible Charcot-Marie-Tooth disease in a coronary patient: A case report

Posted on by admin

CASE REPORT

Hippokratia 2023, 27(4): 155-157

Sotiriadou M, Manani M, Kouzoukidou E, Oikonomidou E
Health Center of Evosmos, Thessaloniki, Greece

Abstract

Background: Statin regimens are essential for managing lipids and preventing cardiovascular diseases, both in primary and secondary prevention, alongside lifestyle changes. There are, however, some side-effects associated with statin intake, such as an elevation of creatine kinase  (CK) and myopathy.

Case description: This case describes a coronary patient with high low-density lipoprotein cholesterol (LDL-C) who was undertreated due to elevated CK levels and myopathy initially linked to statin use. A proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) replaced statin therapy; however, the existence of persisting/recurrent symptoms or CK elevation posed the need for further investigation. A neurological examination, an electromyography (EMG), and a nerve conduction study (NCV) revealed an underlying sensorimotor polyneuropathy, probably Charcot-Marie-Tooth disease.

Conclusions: Persistent muscle symptoms in patients receiving statins should not be always attributed solely to statin intake. Further neurological evaluation could reveal underlying hereditary sensorimotor polyneuropathies. PCSK9i could serve as the therapy of choice in such cases, as additional drug-induced myopathy could pose severe problems for those patients. HIPPOKRATIA 2023, 27 (4):155-157.

Keywords: Statins, low-density lipoprotein cholesterol, LDL-C, creatinine kinase, myopathy, proprotein convertase subtilisin/kexin type 9 inhibitor, PCSK9i, Charcot-Marie-Tooth

Corresponding author: Melani Sotiriadou MD, MSc, PhD, Cardiologist, Health Center of Evosmos, 2 Tegopoulou Christou & Perikleous str, 56224 Thessaloniki, Greece, tel: +302310387772, e-mail: melinaki-83@hotmail.com

Introduction

Statins are mainly used to prevent atherosclerosis and cardiovascular disease (CVD) by lowering low-density lipoprotein cholesterol (LDL-C) levels. They also provide additional cardiovascular protective effects, including anti-inflammatory and antioxidant properties. An evaluation of total cardiovascular (CV) risk should be individualized to guide statin therapy, determining the appropriate statin regimen and dose. Patients with established coronary artery disease (CAD) are advised to aim for stricter LDL-C goals, often requiring high-intensity statins at the highest tolerated doses, potentially in combination with other medications1,2.

Statin intolerance or failure to achieve therapeutic LDL-C serum levels are not rare when discussing lipid-control strategies1,2. The adverse effects of statins from the liver, expressed by an increase in liver enzymes, or those from muscles such as myalgia, myopathy with or without Creatinine Kinase (CK) elevation, usually lead to statin interruption1,2. However, regarding symptoms from muscles, especially in the absence of excessive exercise or drug interactions with statins, further investigation might sometimes reveal other underlying conditions, such as neuromuscular diseases or sensorimotor polyneuropathies, responsible for these side-effects2,3. 

Case report

A 66-year-old man with an early set up of CAD at the age of 42 years old, having undergone a coronary artery bypass graft surgery (CABG), visited our Cardiology Primary Care Unit complaining about myalgia expressed after trying to control LDL-C with several statins.

The patient was initially treated with atorvastatin/ezetimibe 20/10 mg once daily with an LDL-C count of 140 mg/dl and a CK count of 550 (normal range: 35-232) U/L. He reported myalgia and LDL-C was always out of the therapeutic range, resulting in CAD relapse1,2. Up-titration of atorvastatin from 20 to 40 mg or attempts with other statins led to further myopathy and CK elevation up to 1000 U/L. Statin withdrawal slightly improved symptoms and lowered CK, but LDL-C remained even higher. Statin therapy was aborted and a proprotein convertase subtilisin/kexin type 9 inhibitor(PCSK9i), evolocumab 140 mg (one injection per 15 days) on top of ezetimibe 10 mg daily, was prescribed2,4. The LDL-C remained below 55 mg/dl2 and CK was about 340 U/L.

Due to the never-normalized CK levels and their worsening even after mild exercise, the patient was referred for neurological evaluation3. He complained merely of numbness and paresthesia on distal extremities, with no motor signs; however, neurological examination revealed mild distal muscle weakness, more evident in the lower extremities, foot drop, absent tendon reflexes, reduced vibration sense, as well as the characteristic pes cavus and sphyrodactyli3,5. An electromyography (EMG) and a nerve conduction study (NCV) were performed, and findings were consistent with severe mixed sensorimotor polyneuropathy of both upper and lower limbs, possibly in the setting of hereditary etiology (Table 1)3,5,6. Further evaluation of the patient’s personal and family record, as well as appropriate genetic testing was advised with Charcot-Marie-Tooth being the most likely diagnosis6,7. 

Discussion

It is highly recommended that patients with CAD should be treated with high-dose statin therapy to achieve an LDL-C level of <1.4 mmol/L (<55 mg/dl) or at least a reduction of about 50 % from baseline1,2. If the LDL-C goal is not reached using statin therapy or combinations with ezetimibe, or in the case of statins’ side effects, a cost-effective PCSK9i could be favorable8,9. Since a PCSK9i was prescribed earlier, a relapse in CAD could have been avoided in the reported patient10.

Statins are usually well tolerated but patients can experience adverse effects on muscles such as myalgia, myopathy, CK elevation, and rhabdomyolysis. Attending physicians should be aware if CK levels remain relatively high even after statins wash-out, tend to elevate even after mild exercise, and ask for further evaluation for causes other than simple statin intolerance2,3,7.

Charcot-Marie-Tooth disease appears to be the most common type of hereditary peripheral polyneuropathy presenting with a length-dependent, progressive motor and sensory neuropathy of demyelinating or axonal type3,6. Due to its insidious onset and slow progression, the diagnosis is often delayed. Certain mutations responsible for the disease, like the myelin protein zero (MPZ), null mutation, or the mitochondrial trifunctional protein, pose a greater risk for CK elevations or myopathy, as shown from phenotype grouping6,7. In such cases, a further complication of statin therapy with drug-induced myopathy could pose a serious problem5,7,11.

This case report appears to be unique as it not only deals with statin-induced myopathy usually described in the bibliography but also with an entirely original stepwise evaluation of a patient with symptomatic CK elevation, in the end discovering an undiagnosed for years rare hereditary peripheral polyneuropathy responsible for the clinical manifestations from muscles. Moreover, our case study favors using a PCSK9i as a first-choice hypolipidemic treatment in patients with known neuromuscular diseases. The situation is especially true for those with CAD who would not benefit solely from the use of ezetimibe or low-dose statins. Such an indication for neuromuscular diseases has yet to be established in the existing guidelines for managing hyperlipidemias1,2.

A limitation of the case report is the inability to generalize the findings of our approach to such a rare clinical condition to larger populations. Undoubtedly, we describe a rare case and propose a stepwise evaluation and therapy of such patients. However, systematic studies in this field should be encouraged.

In conclusion, patients with CAD should be treated for hyperlipidemia according to current guidelines without delay1,2. CK elevation and/or myopathy should not always be attributed solely to statins. Attending physicians should thoroughly evaluate any patient on statin therapy with elevated CK levels and myalgia, especially when CK remains high after statin withdrawal. This is for rare underlying neuromuscular diseases for which statins might be contraindicated or responsible for destabilization3,11. Moreover, a PCSK9i might be the therapy of choice since such a diagnosis is established. Such an agent’s prescription should probably be encouraged even without first administering statins11.

Conflicts of Interest

The Authors declare no conflicts of interest.

References

  1. Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, Funck-Brentano C, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020; 41: 407-477.
  2. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020; 41: 111-188.
  3. Murakami T, Garcia CA, Reiter LT, Lupski JR. Charcot-Marie-Tooth disease and related inherited neuropathies. Medicine (Baltimore). 1996; 75: 233-250.
  4. Sullivan D, Olsson AG, Scott R, Kim JB, Xue A, Gebski V, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA. 2012; 308: 2497-2506.
  5. Bienfait HM, Baas F, Koelman JH, de Haan RJ, van Engelen BG, Gabreëls-Festen AA, et al. Phenotype of Charcot-Marie-Tooth disease Type 2. Neurology. 2007; 68: 1658-1667.
  6. Szigeti K, Lupski JR. Charcot-Marie-Tooth disease. Eur J Hum Genet. 2009; 17: 703-710.
  7. Taniguchi T, Ando M, Okamoto Y, Yoshimura A, Higuchi Y, Hashiguchi A, et al. Genetic spectrum of Charcot-Marie-Tooth disease associated with myelin protein zero gene variants in Japan. Clin Genet. 2021; 99: 359-375.
  8. Cho L, Dent R, Stroes ESG, Stein EA, Sullivan D, Ruzza A, et al. Persistent Safety and Efficacy of Evolocumab in Patients with Statin Intolerance: a Subset Analysis of the OSLER Open-Label Extension Studies. Cardiovasc Drugs Ther. 2018; 32: 365-372.
  9. Ferri N, Ruscica M, Lupo MG, Vicenzi M, Sirtori CR, Corsini A. Pharmacological rationale for the very early treatment of acute coronary syndrome with monoclonal antibodies anti-PCSK9. Pharmacol Res. 2022; 184: 106439.
  10. Giugliano RP, Pedersen TR, Park JG, De Ferrari GM, Gaciong ZA, Ceska R, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet. 2017; 390: 1962-1971.
  11. Guan Y, Zhang Y, Shen XM, Zhou L, Shang X, Peng Y, et al. Charcot-Marie-Tooth Disease With Episodic Rhabdomyolysis Due to Two Novel Mutations in the β Subunit of Mitochondrial Trifunctional Protein and Effective Response to Modified Diet Therapy. Front Neurol. 2021; 12: 694966.