Malignant hyperthermia susceptibility revealed by increased serum creatine kinase concentrations during statin treatment

EDITOR: Two patients, with no personal or family history of any muscular symptoms, malignant hyperthermia (MH) susceptibility or anaesthetic complications, were referred to our laboratory for preoperative contracture tests for assessment of increased serum creatine kinase (CK) concentrations following statin treatment. They were both determined as malignant hyperthermia susceptible (MHS). A 44-yr-old male first presented with muscle cramps and fatigue after 24 months of treatment with atorvastatin followed by cerivastatin for a familial hypercholesterolaemia. CK concentrations in the serum were measured for the first time following unexplained muscular symptoms (523 IU L−1, control range 40-250 IU L−1) and remained elevated despite stopping the statin therapy (2-4 times the upper limit of normal). Thirty-four months later, the patient underwent vastus lateralis muscle biopsy during regional anaesthesia at the MH unit of Lille, France. In vitro contracture test (IVCT) was performed according to the protocols of both the European and North American MH groups (MHG). Individuals are considered MHS if any one of the muscle strips tested exceeds the diagnostic criteria (halothane - increased basal contracture of at least 0.2 g at 2% (European Protocol) and at least 0.5 g with 3% (North American Protocol); 2 mmol caffeine - increased basal tension of at least 0.2 g). All muscle strips tested with halothane exhibited an abnormal response: 1.2, 1.8 g with 2% and 1.9 g with 3%. At 2 mmol caffeine concentration, the fourth strip exhibited an abnormal increase in tension: 0.2 g (threshold of positivity). The patient was classified as MHS. The results of IVCT performed in family members are shown in Figure 1.Figure 1: Case 1 - Results of IVCT performed in family members. ➝: patient referred for preoperative assessment of increased serum CK concentrations; ▪: MHS; ?: risk of MH.Histopathological and histoenzymatic analyses for myopathy were conducted and also showed only mild myogenic modifications, without central core disease. Genetic analysis of 16 known mutations in the ryanodine receptor (RYR) Type I was conducted at the University of Grenoble, France. None of the known mutations were identified in this patient. Another 49-yr-old male presented muscle cramps, fatigue and increased serum CK concentrations (390 IU L−1, control range 20-195 IU L−1) after 14 months of atorvastatin treatment. Serum CK concentrations remained elevated despite stopping the statin therapy (3-4 times upper limit of normal). IVCT was performed according to both the European and North American MHGs' protocols 12 months after the statin was discontinued. All three muscle strips tested with halothane exhibited an abnormal response: 0.55, 0.3 g with 2% (European Protocol) and 2.6 g with 3% (North-American Protocol). At 2 mmol caffeine concentration, another strip exhibited an abnormal increase in tension: 0.3 g. The patient was classified as MHS. Histopathological and histoenzymatic analyses were normal. Electron microscopy disclosed central cores occurring in less than 2% of muscle fibres. Genetic analysis of the 16 known mutations in the RYR Type I was conducted and none were identified in this patient. These cases were reported in May 2002 at the Annual European Malignant Hyperthermia Meeting in Antwerp, Belgium. Hydroxymethylglutaryl-coenzyme A (HMG CoA) reductase inhibitors or statins reduce cholesterol production in the liver. Occasional side effects include myotoxicity with an incidence of 1-7%, increased CK concentrations, myalgias worsened by exertion and rarely the life-threatening syndrome of acute rhabdomyolysis [1]. The mechanism underlying the myotoxicity of HMG CoA reductase inhibitors has not been delineated. However, the decrease of coenzyme Q10 (CoQ10) synthesis also induced by statins could result in a deficit in mitochondrial energy metabolism (Fig. 2). CoQ10 plays a major role in intra-mitochondrial electron transport during oxidative phosphorylation and ATP production [2].Figure 2: HMG CoA reductase inhibitors myotoxicity hypothesis.MH is a subclinical genetic autosomal dominant disease of skeletal muscle, which classically presents upon exposure to triggering agents such as halogenated volatile anaesthetics and succinylcholine. Susceptibility to MH is identified unequivocally by the IVCT [3]. A persistent increase in serum CK concentrations (excluding recent surgery, intramuscular injections, strenuous exercise and muscular dystrophy) has been shown to be associated with a positive IVCT in 49% of patients [4]. According to the clinical advice on the use and safety of statins, should unexplained muscular symptoms arise, associated with an increase in serum CK concentrations, treatment should be stopped [5]. We believe that a subclinical underlying MH myopathy could be unmasked by the occurrence of HMG CoA reductase inhibitors-associated rhabdomyolysis. The fact that IVCT was performed, in both patients, several months (34 months for Case 1, 12 months for Case 2) after the statins were stopped, strongly suggests that positive IVCT did not result from a nonspecific direct effect of the statin. The hypothesis, that IVCT lacks specificity for MH susceptibility, is contrary to the results of a multicentre study which determined European MHG sensitivity and specificity of IVCT as the observed sensitivity was 99% and the specificity was 93.6% which increased to 98% after exclusion of the equivocal results [6]. Moreover, in our Case 1, IVCT in other family members proved a familial characteristic, negating the possibility of a false-positive result and confirming a pre-existing subclinical myopathy. Our results suggest that the development of muscle cramps and fatigue with an elevation in CK during statin therapy should alert anaesthetists to consider the possibility of MH. If clinical symptoms and the CK concentrations do not normalize, triggering anaesthetic agents should be avoided, and IVCT and genetic analysis performed. The genetic analysis was performed in Laboratorie de Biochimie de L'ADN-EA 2943, CHU Grenoble, France, by N. MONNIER. R. Krivosic-Horber T. Dépret Department of Anaesthesia and Intensive Care 1; University Hospital; Lille, France J. M. Wagner Department of Anaesthesia and Intensive Care; University Hospital; Strasbourg, France C. A.