Approach to asymptomatic creatine kinase elevation

Macro CK: An abnormal enzyme complex

About 4% of patients with asymptomatic or minimally symptomatic elevated CK have “macro CK,” an enzyme complex with an atypically high molecular mass and reduced clearance, resulting in abnormally high blood levels of CK. Macro CK type 1 is more common and is found in up to 1.2% of the general population: complexes are composed of CK and immunoglobulin and are associated with autoimmune diseases.^9,15 Macro CK type 2 complexes consist of CK and an undetermined protein and are associated with malignancies.

CK electrophoresis is required to detect macro CK. Types 1 and 2 can be distinguished by protein G affinity chromatography.^9,15 

Endocrine disorders

Muscle involvement in endocrine disorders often presents with muscle weakness in addition to muscle enzyme abnormalities.

Hypothyroidism often causes weakness, cramps, myalgia, and a mild to moderate serum CK elevation.¹⁶ Severe CK elevation has been reported to occur after vigorous exercise.¹⁷ Thyroid replacement usually results in normalization of serum CK levels in 1 to 2 months.¹⁸

Hyperthyroidism is typically associated with normal serum CK concentrations, but in rare cases it can cause rhabdomyolysis.¹⁹

NEUROMUSCULAR CAUSES ARE NOT ALWAYS WORTH PURSUING

Only after the nonneuromuscular causes of elevated CK have been ruled out should neuromuscular disorders be considered (Table 2). Evaluation with electromyography, nerve conduction studies, and muscle biopsy may lead to the diagnosis of a specific neuromuscular disorder: patients may be in the presymptomatic stage of disease and may or may not eventually develop muscle weakness or other symptoms.^20,21

Is testing needed?

Most adult dystrophies and metabolic myopathies have no available treatment and their course is often benign, particularly if they present only with asymptomatic elevated CK. The value of a potentially extensive, expensive, and invasive evaluation for a specific neuromuscular cause should be weighed against the limited yield and treatment options. Moreover, specialized testing such as biochemical muscle enzyme analysis, sarcolemmal protein staining, and genetic testing are not available at all centers.

The European Federation of Neurological Societies guidelines recommend biopsy for  patients with asymptomatic elevated CK who also have any of the following:

• Abnormal (myopathic) findings on electromyography
• CK more than three times the upper limit of normal
• Age less than 25
• Exercise intolerance.⁴

Idiopathic inflammatory myopathies rarely present with asymptomatic elevated CK.^22–26 In one study,²⁷ they were found in just 5% of patients with asymptomatic elevated CK.

Hypomyopathic dermatomyositis and inclusion body myositis can present with mild CK elevations with normal muscle strength, especially early in the disease course. A myositis subset of antisynthetase syndrome can present with mildly elevated CK and interstitial lung disease.²⁷ Many of the inflammatory myopathies respond to treatment so are worth investigating.

In view of complexities in diagnosis of these conditions, one should proceed with testing only after discussing it with patients. Referral to a rheumatology specialist is preferred.

MUSCLE BIOPSY, ELECTROMYOGRAPHY, AND NERVE CONDUCTION STUDIES

Electromyography, nerve conduction studies, or muscle biopsy, or a combination of these tests, is usually needed to investigate neuromuscular causes of elevated CK.

Muscle biopsy abnormalities are found in about two-thirds of cases of asymptomatic elevated CK, but most abnormalities include nonspecific myopathic changes that are not diagnostic. A muscle biopsy that may include special stains for sarcolemmal proteins for muscular dystrophy and biochemical muscle enzyme analysis for metabolic myopathies is diagnostic in only 20% to 25% cases of asymptomatic elevated CK on average, with a variation between different series of 0% to 79%.^7,21,27–33

Electromyography and nerve conduction studies alone add little to the workup of asymp­tomatic elevated CK apart from a modest negative predictive value and as a guide for muscle biopsy. For a very few neuromuscular disorders causing an elevated CK (eg, motor neuron disease, Charcot-Marie-Tooth disease, myotonic dystrophy), electromyography and nerve conduction studies could suffice to make the diagnosis. 

Electromyography and nerve conduction studies detect abnormalities in nearly half of cases of asymptomatic CK elevation,^{7,21,27,28,30,31,33} but, as with biopsy, most changes are nonspecific. Although electromyography and nerve conduction studies can help distinguish primary neuropathic from myopathic disorders, the sensitivity and specificity are low for diagnosis. Normal studies do not rule out a condition, and abnormal studies are not diagnostic of a particular condition, although completely normal studies provide strong evidence against a severe neuromuscular disorder.

Combined testing

Using combined muscle biopsy, electromyography, and nerve conduction studies, the likelihood of making a diagnosis in patients with asymptomatic elevated CK is 28% on average (range of studies 4%–79%),^{2,7,21,26–28,30–32} and findings are nonspecific in 30% to 40% of cases. Findings are normal in about 30% to 40% of cases, which are thus diagnosed as idiopathic asymptomatic elevated CK.^28–31,34

Prelle et al³¹ retrospectively reviewed the cases of 114 patients, ages 3 to 70, with incidentally discovered elevated CK and few or no symptoms, who underwent muscle biopsy, electromyography, and nerve conduction studies after nonneuromuscular causes were ruled out. Although muscle biopsy findings were abnormal in 39% of cases, a diagnosis was established in only 18% of cases after an extensive workup: the diagnosis was definitive in only 10% and included dystrophinopathies, metabolic myopathies, and rare noninflammatory myopathies. For the remaining 8%, the diagnosis was probable and included four cases of partial carnitine palmitoyl transferase deficiency, three cases of malignant hyperthermia, and two rare inherited disorders.

DNA testing

In women with a serum CK less than three times the upper limit of normal who have a family history of Duchenne or Becker muscular dystrophy, DNA analysis of blood lymphocytes identifies 70% of carriers.⁴

IDIOPATHIC ELEVATED SERUM CK

Rowland et al³⁵ first coined the term “idiopathic hyper-CK-emia” and defined it as persistent elevation of serum CK despite a normal neurologic examination and testing, including electromyography, nerve conduction studies, and muscle biopsy.^35,36 To receive this diagnosis, patients must also have no family history or clinical evidence of neuromuscular disease.

Idiopathic elevated serum CK is sometimes familial. In one study,³⁷ elevated CK was found in family members of 13 of 28 unrelated probands. In the 13 families, 41 individuals had elevated CK. Genetic studies revealed that the condition is genetically heterogeneous and autosomal dominant in at least 60% of cases, with higher penetrance  in men.

D’Adda et al26 followed 55 people with idiopathic elevated CK for 7 years. Ten percent were eventually diagnosed with a neuromuscular disorder, 10% developed malignancy, and the remaining 80% developed no new condition. The CK level normalized or decreased in many patients, but most continued to have persistent CK elevations with minimal or no symptoms.