Caveats in determining reference intervals for serum creatine kinase Brewster et al 1 recently determined reference intervals for serum creatine kinase (CK) at rest in a large random population sample. Upper reference limits were 2 to 5 times higher than reported by the assay manufacturer; and 13% of the white Europeans, 23% of South Asians, and 49% of the black people had values above the manufacturer- provided limits. The authors suggest that current refer- ence limits should be upward correct. In this study, health status of participants was evaluated through a questionnaire, and subjects with myopathy or a family history of myopathy and patients taking statins were properly excluded. 1 However, the authors did not consider some conditions (perhaps more familiar to neurologist dealing with neuromuscular disorders) that can be associated with asymptomatic hyperCKemia and, at least partially, might account for high CK values in their population sample. Alcoholism, cancer, celiac disease, subclinical hypothyroidism, con- nective tissue disorders, viral diseases, electrolyte imbal- ance, acanthocytosis, and many drugs other than statins (including β-blockers, angiotensin II receptor antago- nists, immunosuppressant, antiretrovirals, and antipsy- chotic) may cause hyperCKemia. 2 HyperCKemia may be the only sign of subclinical neuromuscular disorders. In case series, 30% to 44% of asymptomatic subjects with persistent hyperCKemia up to 5-fold the upper limit of normal (ULN) have myopathy. 3,4 Duchenne and Becker muscular dystrophy carriers and subjects susceptible to malignant hyperthermia (MH) frequently have isolated hyperCKemia, even less than 2-fold the ULN. 5 In both these conditions, clinical and familial history is often uneventful and hyperCKemia is the only source of suspicion. The estimated prevalence of these genetic abnormalities may be as great as 1:2500 and 1:3000, for dystrophinopathy carrier state and MH susceptibility, respectively. 6 Subjects carrying heterozygote mutations in genes responsible for autosomal recessive limb-girdle muscular dystrophies are usually asymptomatic and have hyperCKemia (2-50 times the ULN) in 36% of cases. 7 Limb-girdle muscular dystrophy carriers are often una- ware of their condition, as family history can be silent or incomplete. The prevalence of healthy carriers for limb- girdle muscular dystrophy type 2A, the most common form, was estimated to be 1:100 to 1:150 in different populations. 7 Finally, it is increasingly recognized that apparently healthy individuals may have idiopathic hyperCKemia, that is, persistent hyperCKemia that remains unexplained despite extensive investigations for histological changes, protein defects, and biochemical abnormalities currently associated with myopathies. 2-4 We have recently found that idiopathic hyperCKemia is often inherited as an autosomal dominant condition 8 and is associated with characteristic ultrastructural abnorm- alities, even in cases with CK levels 1.5 to 2 times the ULN (manuscript in preparation). We think that the study by Brewster et al 1 clearly indicates that reference intervals for serum CK should be upward revised, especially for South Asians and black people, as it is known that the race affects CK activity, but current reference limits were mostly determined in the white population. However, a precise estimation of reference limits should require a wider consideration of possible causes of hyperCKemia in selecting population samples. Otherwise, a low but not negligible risk exists to ignore conditions such us MH susceptibility and muscular dystrophy carrier state, which may be harmful to affected subjects or their offspring, when these present by only slight hyperCKemia. Am Heart J 2008;155:e5. 0002-8703/$ - see front matter doi:10.1016/j.ahj.2007.11.024 Margherita Capasso, MD, PhD Maria Vittoria De Angelis, MD, PhD Antonio Di Muzio, MD, PhD Antonino Uncini, MD Neuromuscular Diseases Unit Center for Excellence on Aging bG.dTAnnunzioQ University Foundation, Chieti, Italy E–mail: neurolab@unich.it References 1. Brewster LM, Mairuhu G, Sturk A, et al. Distribution of creatine kinase in the general population: implications for statin therapy. Am Heart J 2007;154:655-61. 2. Morandi L, Angelini C, Prelle A, et al. High plasma creatine kinase: review of the literature and proposal for a diagnostic algorithm. Neurol Sci 2006;27:303-11. 3. Joy JL, Oh SJ. Asymptomatic hyper-CK-emia: an electrophysiologic and histopathologic study. Muscle Nerve 1989;12:206-9. 4. Simmons Z, Peterlin BL, Boyer PJ, et al. Muscle biopsy in the evaluation of patients with modestly elevated creatine kinase levels. Muscle Nerve 2003;27:242-4. 5. Monsieurs KG, Van Broeckhoven C, Martin JJ, et al. Gly341Arg mutation indicating malignant hyperthermia susceptibility: specific cause of chronically elevated serum creatine kinase activity. J Neurol Sci 1998;154:62-5. 6. Rosenberg H, Davis M, James D, et al. Malignant hyperthermia. Orphanet J Rare Dis 2007;2:21. 7. Fanin M, Nascimbeni AC, Angelini C. Muscle protein analysis in the detection of heterozygotes for recessive limb girdle muscular dystrophy type 2B and 2E. Neuromuscul Disord 2006;16:792-9. 8. Capasso M, De Angelis MV, Di Muzio A, et al. Familial idiopathic hyper-CK-emia: an underrecognized condition. Muscle Nerve 2006;33:760-5.