By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: Elevated serum creatine kinase (CK) is considered the hallmark of myopathy, yet some patients with biopsy-proven myopathy have normal CK with elevated aldolase, a less-specific marker of muscle disease. Most of those cases ultimately prove to be dermatomyositis.
SOURCE: Soontrapa P, Shahar S, Eauchai L, et al. Disease spectrum of myopathies with elevated aldolase and normal creatine kinase. Eur J Neurol 2024;31:e16117.
Central to the clinical evaluation of muscle weakness is measurement of serum muscle enzymes, including creatine kinase (CK), aldolase, and less so, due to their ubiquity, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). CK, located on the inner mitochondrial membrane on myofibrils and in the muscle cytoplasm, is the best indicator of muscle injury. Aldolase, present in all tissue, is not as sensitive or specific as CK for muscle disease but occasionally may be elevated in patients with myositis and normal CK levels. In which muscle diseases does this occur?
Using the Mayo Clinic database, all patients age 18 years or older, seen between Dec. 1, 1994, and June 30, 2020, with an electromyography (EMG) diagnosis of myopathy, normal CK, and elevated aldolase, were identified. Exclusionary criteria included concomitant liver disease, hemolytic anemia, or incomplete clinical information. Nonspecific myositis was diagnosed if muscle biopsy showed significant inflammatory changes without characteristic features of dermatomyositis or inclusion body myositis, and overlap myositis or anti-synthetase syndrome could not be excluded because of inadequate clinical or serological information. Nonspecific myopathy was diagnosed when muscle biopsy demonstrated nonspecific myopathic features, including increased internal nuclei, fiber splitting, and rare necrotic or regenerating fibers, without inflammatory changes. Statistical analysis comprised the chi-squared or Fisher’s exact tests and the Wilcoxon rank sum test, with P < 0.05 considered statistically significant.
Among 1,782 patients with a myopathic EMG, normal initial CK, and elevated aldolase, myopathy was found on biopsy in 296 of 304 patients biopsied. Of these, 242 were excluded because of elevated CK found at the time of biopsy or thereafter, 19 because of concomitant liver disease, one because of autoimmune hemolytic anemia, and eight because of nonspecific findings on muscle biopsy, leaving 34 patients for analysis. Most patients were women, (n = 24, 69.6%), all 34 had predominant proximal muscle weakness, with additional mild distal weakness in eight, and eight were wheelchair dependent.
Immunomodulatory therapy was administered to 24 patients, of which 16 improved at five to seven months, and nine of 17 patients had normalization of aldolase by six months. Dermatomyositis (n = 8), overlap syndrome with myositis (n = 4), nonspecific myopathy (n = 4) (of which three patients had received prednisone five to 34 months prior to biopsy), and nonspecific myositis (n = 3) were the most common diagnoses found.
Critical illness myopathy, mixed connective tissue disease, and muscle graft versus host disease were found in two patients each, while amyloid, anti-synthetase syndrome, immune-mediated necrotizing myopathy, inclusion body myositis, vasculitic myopathy, eosinophilic fasciitis, and spontaneous diabetic myonecrosis were seen in one patient each. Genetic myopathy not otherwise characterized and myopathy with intramural blood vessel calcification rounded out the list, each seen in one patient.
Diagnostic features in eight CK normal-dermatomyositis patients also were compared to 24 age- and sex-matched elevated CK-dermatomyositis patients, among whom aldolase also was found to be elevated in 19 patients so tested. Cutaneous findings, fibrillation potentials on EMG, and lower erythrocyte sedimentation rate (ESR) were significantly more common in the latter than in the former, whereas perifascicular cytochrome c oxidase negative fibers were significantly associated with the former. Treatment response was comparable in these two dermatomyositis groups.
COMMENTARY
CK serum levels do not correlate with weakness or muscle inflammation in myositis, since both may be present with normal CK. Most often seen in dermatomyositis, the mechanism is poorly understood but may be caused by the presence, in some patients, of a CK enzyme inhibitor that underestimates CK activity. In such cases, other measurements may be used to assess disease activity, including aldolase, LDH, AST, ALT, or myoglobin. Even absent abnormal enzyme levels, elevations above the patient’s baseline may be significant. Furthermore, apart from serum levels, imaging of muscle using ultrasonography or magnetic resonance imaging may be helpful in the assessment of disease activity.
