The term “asymptomatic hyperCKemia” indicates a finding of persistent and abnormally high serum levels of creatine kinase (CK) in an asymptomatic person, whether or not the etiology has been found. The range of elevation varies widely depending on the cause and precipitating factors. There are many causes of asymptomatic hyperCKemia. Statin myotoxicity is probably the most common cause because use of these drugs has become so prevalent and so widespread. Other drugs and toxins, trauma, and diverse myopathies are other causes. Sometimes no etiology is identified, and monitoring is recommended. This article reviews the differential diagnosis, diagnostic workup, prognosis, and management of asymptomatic hyperCKemia. Special situations involve pregnancy or anesthesia. The authors call attention to the discovery of more genetic disorders as causes of asymptomatic hyperCKemia.
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• Asymptomatic hyperCKemia is frequently encountered in medical practice.
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• Statin use is probably the most common cause of asymptomatic hyperCKemia.
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• The National Lipid Association (NLA) recommends no change of statin therapy for patients with asymptomatic CK levels of 3 to 10 times the upper limit of normal.
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• The workup needed for asymptomatic hyperCKemia is controversial.
Historical note and terminology
The diagnostic use of serum levels of sarcoplasmic enzymes dates to 1953 when Schapira and colleagues reported high levels of serum aldolase in patients with muscular dystrophy (63). This was soon confirmed in many laboratories (60) and extended to phosphohexose isomerase and other soluble enzymes (59). 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 (19), and it rapidly became the routine measure of muscle disease (50).
The guidelines of the European Federation of Neurological Societies defined hyperCKemia as CK more than 1.5 times the upper limit of normal (38).
Normal data have come mostly from studies of white Europeans (Caucasians), but normal values are affected by race and gender (48).
High serum CK levels are found in many muscular dystrophies as well as inflammatory, toxic, metabolic, and mitochondrial myopathies. The highest values are seen during attacks of myoglobinuria (“rhabdomyolysis”), a clinical syndrome of diffuse myalgia, myoglobinuria, and, often, renal failure.
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 (40). 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 (39).
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 (61). 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 (02).
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) may be associated with CK levels as high as 8 times normal (12). 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.