What are the causes of high serum creatine kinase (CK) levels?

Schapira and colleagues reported high levels of serum aldolase in patients with muscular dystrophy (Schapira et al 1953). In 1958, Setsuro Ebashi, then one of world's leading muscle biochemists, introduced the use of creatine kinase (CK) as the most muscle-specific enzyme (Ebashi et al 1959), and it rapidly became the routine measure of muscle disease (Ozawa et al 1999).
The new guidelines of the European Federation of Neurological Societies defined hyperCKemia as CK more than 1.5 times the upper limit of normal (Kyriakides et al 2010). Normal data have come mostly from studies of white Europeans (Caucasians), but normal values are affected by race and gender (Neal et al 2009).
Causes of High serum CK levels
  • Muscular dystrophies
  • Inflammatory myopathies
  • Toxic myopathies
  • Metabolic myopathies
  • Mitochondrial myopathies
  • Myoglobinuria
It is not clear why there are normally any soluble muscle enzymes in the blood. Layzer pointed out that “soluble” means the protein molecules are not bound tightly to the muscle cytoskeleton (Layzer 1985). He suggested that the enzymes leak from broken or malfunctioning surface membranes. Leakage seems to continue endlessly. The enzymes are cleared from the blood by the reticuloendothelial system and by renal excretion (Lang 1981).
An increased serum CK level is, therefore, taken to mean that the integrity of the skeletal muscle membrane has been affected; an increased serum CK level is also a hallmark of muscle disease, either hereditary or acquired. Persistently high CK levels, however, are also found occasionally in asymptomatic, healthy-appearing people.
Rowland and colleagues first used the term “idiopathic hyperCKemia” to describe 9 men and 2 women with unexplained and persistent hyperCKemia (Rowland et al 1980). None had received medication or injections that would damage muscle, and exercise was not a factor. None had a family history of muscle disease or malignant hyperthermia, and there were no abnormalities on neurologic examination. Electromyographic studies did not reveal evidence of myopathy, and muscle biopsies were histologically normal in all 7 so studied. The term was also used later by Afifi and others (Afifi 1998).
Since this original description, others have suggested additional criteria. By definition, there must be an absence of known causes of hyperCKemia, including strenuous exercise, metabolic disorder (eg, hypokalemia, hypothyroidism, or parathyroid disease), family history of neuromuscular disease, medication- or drug-induced hyperCKemia (including alcohol), or recent intramuscular injections (which may be surreptitious). As knowledge of and testing for neuromuscular disease continues to improve, patients with previously unknown causes of hyperCKemia later qualified for a molecular diagnosis. Therefore, the diagnosis for undiagnosed, persistently high serum CK could be “asymptomatic hyperCKemia,” which may not later prove to be “idiopathic.”
Many asymptomatic people have levels 2 times the upper limit of normal, so it is uncertain what level ought to lead to other diagnostic studies. Certainly, levels 5 times normal should be heeded, even if asymptomatic. Also, abnormal levels in a patient with new-onset myalgia, cramps, or symptomatic weakness warrant evaluation. Severe muscle cramps may cause slight CK elevation, and their mere presence does not necessarily imply an underlying muscle disease. Furthermore, active denervating conditions such as motor neuron disease are frequently associated with CK elevation. As a matter of fact, spinobulbar muscular atrophy (Kennedy disease), unlike amyotrophic lateral sclerosis, may be associated with CK levels as high as 8 times normal (Chahin and Sorenson 2009). In a patient with hyperCKemia, the finding of a myopathic pattern in the EMG, with or without evident limb weakness, is another indication for further evaluation, particularly if spontaneous activity is found in muscles of limbs or thoracic paraspinal areas.


Brainin M, Barnes M, Baron JC, Gilhus NE, Hughes R, Selmaj K, Waldemar G; Guideline Standards Subcommittee of the EFNS Scientific Committee. Guidance for the preparation of neurological management guidelines by EFNS scientific task forces – revised recommendations 2004. Eur J Neurol. 2004 Sep;11(9):577-81. Electronic copies: Available in Portable Document Format (PDF) from the European Federation of Neurological Societies Web site.
Continuing Medical Education questions available from the European Federation of Neurological Societies Web site.