Creatinine Kinase: A test done from muscle memory or clinical reasoning?

Abstract

Introduction Creatinine kinase (CK) is a common lab ordered by generalists and specialists that is often misinterpreted. Given its prevalent use, we highlight a case that outlines pitfalls of the test. The case is of a gentleman who is referred to a neuromuscular clinic for weakness and an elevated CK. However, during the COVID-19 pandemic, this was initially a video visit, which then serves to highlight the challenges of video visits. In this report, we primarily aim to highlight an algorithm to evaluate CK in the presence of weakness. Secondary objectives include reviewing common pitfalls of CK testing, especially with the rising trend of video visits. Practically, total CK enzyme activity (IU/L) is measured with a photometric assay utilizing the enzymatic rate method to calculate the rate of phosphate transfer from phosphocreatine to adenosine diphosphate per minute. Tissue isoform assays fractionate total CK using antibodies to CK-MM (skeletal muscle), CK-MB (cardiac muscle), or CK-BB (brain). Male sex, black race, younger age, and exercise are the most common reasons for normal physiologic increases in CK, possibly due to differences in muscle or total body mass and the permeability of the sarcolemma to CK.1–3 Exercise causes transient increases in CK over 24-48 hours, followed by return to baseline over 7+ days. Pathologic CK elevation is associated with myopathies or muscle injury, but can also occur in neurogenic disorders due to impaired muscle membrane integrity secondary to muscle degeneration from axonal loss.4–6 Other causes of CK elevation include race, medication use, systemic disorders (e.g. acute renal failure, malignancy, viral illness), and endocrine abnormalities.4, 5, 7 Of these, statin-induced CK elevation is most commonly observed.3 In clinical settings, assay manufacturers provide a CK reference range assuming a gaussian distribution (0-180 IU/L). This results in high false-positive rates as population CK distribution is skewed toward higher values.5 For this reason, recent practice guidelines recommend using a upper limit of normal (ULN) threshold at the 97.5th percentile rather than manufacturer-quoted ULN (Table 2).2,4,7,8 Using these guidelines, the prevalence of incidentally elevated CK in asymptomatic patients is 5.3%, with persistent unexplained elevation in 1.3%.9 CK elevation can vary based on sex. In a cohort of musculoskeletal patients with elevated CK 29% were female (F) and 44% were male (M). Sensitivity using the 97.5th percentile versus manufacturer’s guidelines was 29%(F)/60%(M) versus 50%(F)/80%(M) and sensitivity was 80%(F)/80%(M) versus 70%(F)/67%(M), respectively.4 When using a cutoff of 1.5xULN instead of the 97.5th percentile, sensitivity for diagnosing myopathy decreased by 37%. CK > 1000 IU/L had a high likelihood for myopathy (11.0).6,7 Thus, increasing the ULN improves specificity and decreases the false positive rate when evaluating CK elevation.1,6,7 The cost of total CK to Medicare is $6.51. Total CK with isoenzymes is $13.39.