Measuring serum creatine kinase (CK) is an important part of the evaluation of patients with muscle weakness or myalgia, and of assessing patients with myopathies or rhabdomyolysis. But elevated CK sometimes is an incidental finding in a patient without muscle-related symptoms or with only minimal nonspecific muscle symptoms (eg, cramps, spasms, fatigue) that do not significantly interfere with activities of daily living. This condition is sometimes referred to as “asymptomatic hyper-CK-emia.” Four other muscle enzymes that may also be elevated are aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and aldolase.
This review focuses on the evaluation of patients with elevated CK without significant muscle-related symptoms and proposes an algorithm for this purpose (Figure 1).
CURRENT THRESHOLDS MAY BE LOW
What appears to be an elevated CK level may in fact be normal, and it is important to determine in the initial assessment whether a CK value is truly abnormal.
Most laboratories use the central 95% of observations in white people as a reference range for serum CK, assuming that levels have a gaussian (bell-shaped) distribution, which is usually about 0 to 200 IU/L. Using these parameters, an abnormal CK level was observed in 19% of men and 5% of women in a study of nearly 1,000 healthy young people,1 leading to overdiagnosis.
The actual distribution of serum CK levels in a healthy population is markedly skewed toward higher values and is nongaussian.1–3 A 97.5% normal threshold is associated with a much lower false-positive rate and is recommended by the European Federation of Neurological Societies (now the European Academy of Neurology).4 This group also recommends pursuing further investigation only for patients whose level is at least 1.5 times the upper limit of normal; this threshold results in only a small reduction in sensitivity.
CK levels vary significantly by sex and race.5 Possible reasons include differences in muscle mass or total body mass and inherited differences in the permeability of the sarcolemma to CK.6 There is also a small reduction in CK levels as people age.2
The European Federation of Neurological Societies suggests redefining elevated CK as values 1.5 times beyond the upper limit of normal. Based on a 97.5% threshold and normal values determined by Brewster et al3 for black and white men and women, the following thresholds can be used to help decide whether to pursue further evaluation4:
- White women—325 IU/L
- White men—504 IU/L
- Black women—621 IU/L
- Black men—1,200 IU/L
PHYSICAL ACTIVITY RAISES CK
CK levels transiently rise after exercise or heavy manual labor. Serum CK levels may increase to as much as 30 times the upper limit of normal within 24 hours of strenuous physical activity, then slowly decline over the next 7 days. The degree of CK elevation depends on the type and duration of exercise, with greater elevation in those who are untrained.2,4
In assessing asymptomatic or minimally symptomatic CK elevation, the test should be repeated after 7 days without exercise. A large community study in Norway found that repeat CK levels in people with incidentally discovered elevated CK were normal after 3 days of rest in 70% of cases.2
NEED TO BE INVESTIGATED
Asymptomatic or minimally symptomatic elevated CK can be due to a primary neuromuscular disease or a variety of nonneuromuscular causes.
Patients who still have elevated CK after taking into account the 97.5% threshold, repeat testing after a week of rest, and a level more than 1.5 times the upper limit of normal for sex and race should first be evaluated for the many nonneuromuscular conditions that can cause elevated CK (Table 1).7–9
Cardiac causes should be evaluated by history and physical examination, electrocardiography, and possibly testing for cardiac troponins.
Drugs commonly elevate CK
Prescription drugs and supplements are an important and common cause of CK elevation, so it is important to carefully review medications the patient is taking.
Statins can cause myalgia, muscle weakness, and rhabdomyolysis. Up to 5% of users develop CK elevation, typically 2 to 10 times the upper limit of normal.10 CK usually drops after stopping statins but may require weeks to months to normalize. Rarely, statin users develop a serious immune-mediated necrotizing myopathy.11–13
The diversity of response to statin therapy appears to have a genetic basis. The SEARCH Collaborative Group14 conducted a genome-wide association study of 300,000 markers in 85 patients with definite or incipient myopathy and in 90 controls, all of whom were taking simvastatin 80 mg daily. They identified a single-nucleotide polymorphism in the SLCO1B1 gene on chromosome 12 that was strongly associated with a higher risk of statin-induced myopathy.
Patients with statin-related myopathy seem to have a higher frequency of occult metabolic muscle disease than the general population, also suggesting genetic susceptibility, although ascertainment bias could be a factor.14
Mechanisms of CK elevation in response to statins include increased muscle membrane fragility due to decreased cholesterol content, inhibition of isoprenoid production (a necessary step in the synthesis of membrane proteins), and depletion of ubiquinone, leading to mitochondrial dysfunction.