Clinical manifestations

Presentation and course

Idiopathic hyperCKemia indicates persistently elevated CK with no symptoms or minimal symptoms, such as muscle aches at rest or with exercise, muscle cramps, or stiffness, for which no clear etiology is found with appropriate evaluation. On examination, there should be no weakness, wasting, loss or increase of tendon reflexes, or fasciculations.

On the other hand, asymptomatic hyperCKemia indicates persistent CK elevation without symptoms, whether or not an exact etiology has been found. Under these conditions the diagnosis should start with the name of the condition, and the subordinate diagnosis might be listed as (2) asymptomatic hyperCKemia secondary to (1).

Persistent hyperCKemia is an elevation of CK in more than one blood sample drawn within an interval of at least 1 month.

Prognosis and complications

Several studies have attempted to delineate the clinical course and prognosis of patients with asymptomatic hyperCKemia. In one series, 31 consecutive patients with idiopathic hyperCKemia were extensively investigated with ancillary tests and followed for a mean of seven years (56). This follow-up led to a specific diagnosis in only one patient, and that diagnosis was deemed unrelated to the high CK levels. No patient had major clinical deterioration, leading to the conclusion that asymptomatic hyperCKemia, if the first evaluation is thorough, is not a precursor to neuromuscular disease and that long-term follow-up is not necessary. Similarly, D’Adda and colleagues found that only 1 of 93 subjects with hyperCKemia developed limb-girdle weakness. CK levels later became normal in 12 subjects (15).

Reijneveld and colleagues tried to determine if exercise leads to larger increases in serum CK activity and more symptoms in patients with idiopathic hyperCKemia than in normal subjects (57). They found similar changes in groups with or without resting high CK levels. In both submaximal and maximal exercise sessions, there was no significant difference in serum CK activity over time. They concluded that increased vulnerability to exercise is not the cause of idiopathic hyperCKemia. There is no evidence that high CK levels increase the risk of exercise-induced muscle damage.

Clinical vignette

A 70-year-old woman had been taking cerivastatin for 18 months when the dose was reduced from 8 mg daily to 2 mg in July 2001. In August 2001, treatment was discontinued, and the drug was taken off the market because it had caused fatal rhabdomyolysis. Using an assay that gave a normal maximum of 225 units, the patient’s values were 260 on March 13; 390 on May 22; 725 on June 28; 321 on August 23; and 507 on November 20.

Throughout this period the patient had arthralgia but not myalgia, and she had no symptoms of limb weakness. She had nocturnal hamstring cramps once a night about four times a week but never had pigmenturia or renal pain. There was no abnormality on neurologic examination in December 2001, and the mild elevation of serum CK was not considered a deterrent to continue medication. Noteworthy was persistence of the high levels months after drug therapy had ceased despite the lack of myalgia or weakness. In December 2006, the patient reported no change in her symptoms, and she had taken statin drugs throughout the interval. Her physician reported CK values in the range of 180 to 480. The modest abnormalities were deemed to be of no clinical significance. The diagnosis in this case was persistent asymptomatic hyperCKemia secondary to statin therapy.

Biological basis

Etiology and pathogenesis

By definition, the etiology is unknown in idiopathic hyperCKemia. If the cause is known, “asymptomatic hyperCKemia” or “hyperCKemia” can be used in conjunction with the name of the myopathy (asymptomatic hyperCKemia secondary to ………). Known causes of unexplained, asymptomatic elevations in CK level are discussed in the differential diagnosis section of this article.

Creatine kinase protein is located on the inner mitochondrial membrane, on myofibrils, and in the muscle cytoplasm; it is involved in cellular energy storage and transfer, catalyzing the reversible phosphorylation of creatine by ATP. Elevation of serum CK activity may occur when CK leaks into the blood from disintegrated muscle cells or through muscle membranes that are physically intact but functionally leaky (78). Elevated CK in certain denervating conditions is even more challenging. The specific pathophysiology of hyperCKemia depends on the underlying cause.

Similar to other enzymes with macro variants, two macro CK variants, which can cause hyperCKemia, were identified using electrophoresis and immunoinhibition assay (88; 42). Macro CK type 1 is a complex of CK isoenzyme, mostly CK-BB, and immunoglobulin IgG and, to a lesser extent, IgA and IgM. Its prevalence is 0.43% to 1.6% (84; 42). It was reported mainly in patients with autoimmune diseases (42), but also in healthy individuals (88). Unlike type 1 macro CK, type 2 is oligomeric mitochondrial CK. Its prevalence is 0.5% to 2.6% (77), and up to 3.7% in hospitalized patients (76). Type 2 macro CK is more common in patients with malignant cell proliferation and liver disease (76; 42). It has also been commonly reported in patients with HIV who are on tenofovir (66).

Epidemiology

Little information is available about the relative causes. In modern life, statin therapy has become an important cause and is expected to be more widespread with the stringent criteria of lipid control (37). Hereditary myopathies are increasingly recognized.

Prevention

There seems to be no way to prevent idiopathic hyperCKemia. Similarly, asymptomatic hyperCKemia cannot be prevented in a carrier of a gene with hereditary myopathy. Drug-induced syndromes, however, may be controlled.

Differential diagnosis

Asymptomatic hyperCKemia secondary to toxins and drugs. A multitude of toxins and drugs, including alcohol and cocaine, colchicine, antimalarials, penicillamine, zidovudine, cholesterol-lowering agents (eg, statins, fibrates, niacin), antipsychotics, beta-blockers, and rosiglitazone have all been implicated in acquired hyperCKemia.

A prospective study on 155 patients treated with tyrosine kinase inhibitors for solid tumors found elevated CK in one third of the patients, including 3% of patients with CK as high as 2.5 to 5 times the upper limit normal (01).

Statin myopathy. Fatal attacks of myoglobinuria brought statins to the front pages and resulted in the withdrawal of cerivastatin (Baycol) from the market. In the United States alone, 13 million patients receive statins. Moreover, more than 40% of patients eligible for statin use are not currently receiving them (47). Accordingly, statin myopathy may be the most common cause of asymptomatic hyperCKemia. Statin myotoxicity may be responsible for asymptomatic hyperCKemia, myalgia with normal CK, myopathy, or myoglobinuria (rhabdomyolysis). In this regard, the following comments seem reasonable but only after understanding that most of the clinical studies on statin myotoxicity are troubled by the lack of unified definition of terms and the exclusion of patients with history of statin intolerance (37):

Asymptomatic hyperCKemia secondary to muscle injury. Heavy exercise (including manual labor occupations), intramuscular injections, infections (eg, bacterial, viral, or parasitic myositis; sepsis), and trauma (including intraoperative muscle injury) may all raise serum CK levels.

Asymptomatic hyperCKemia secondary to metabolic conditions. Fever (14), hypothyroidism (09), hypoparathyroidism (68), or large muscle mass can all lead to asymptomatic elevations in CK levels.

Asymptomatic hyperCKemia secondary to muscular dystrophies. The modern classification of muscular dystrophies relies on molecular rather than descriptive terms. Description of each form of muscular dystrophy is beyond the scope of this article.

Asymptomatic persistent elevation of CK to variable degrees is common in patients and carriers alike in most muscular dystrophies at one stage or another of the disease. Considering the clinical and genetic heterogeneity of muscular dystrophies, it is difficult to draw a unified concept for the CK elevation in these diseases. In general, autosomal recessive limb-girdle muscular dystrophies are more likely to cause elevation of serum CK values. Among 69 relatives of patients with different forms of recessive limb-girdle muscular dystrophy (LGMD2A, 2B, 2C, 2D, 2E), 36% of the heterozygotes had asymptomatic hyperCKemia, with CK values 2 to 50 times normal (23). The following points seem to be appropriate in regard to CK elevation in muscular dystrophies:

Limb-girdle muscular dystrophies:

LGMD1C (CAV3 gene mutation). This is generally an autosomal dominant disorder, but a sporadic mutation in this gene can cause partial deficiency of caveolin-3 in skeletal muscle. These patients demonstrate asymptomatic, persistently elevated serum levels of CK. This mutation is also reported to cause rippling muscle disease (24). Based on that, immunochemical evaluation of caveolin-3 protein expression and muscular genetic analysis of the CAV3 gene should be considered in patients with unexplained hyperCKemia (12).

LGMD2A (calpain mutation). This autosomal recessive disorder is one of the most prevalent forms of limb-girdle muscular dystrophy. HyperCKemia is not invariably present (91).

LGMD2B (dysferlin mutation). This autosomal recessive disorder may be manifested as posterior compartment distal myopathy (Miyoshi type) or as a limb-girdle muscular dystrophy. Asymptomatic hyperCKemia is reported in some cases before the weakness appears (54). Similarly, anoctamin 5 gene mutation, which can also cause Miyoshi type muscular dystrophy or limb-girdle muscular dystrophy (LGMD2L), was found to cause asymptomatic hyperCKemia (65).

LGMD 2C, 2D, 2E, and 2F (sarcoglycan mutations). There is a wide spectrum of clinical phenotypes in patients with sarcoglycanopathies. Angelini and colleagues described two siblings who had a homozygous mutation of the alpha-sarcoglycan gene (04). The brother was asymptomatic and had only mild scoliosis on examination; the sister had mild limb-girdle muscular dystrophy.

LGMD2I (fukutin-related protein gene, FKRP, mutation). This is an autosomal recessive disease. Asymptomatic FKRP mutation carriers may have mild elevated serum CK levels and severely affected siblings (08).

LGMD2M (fukutin gene, FKTN, mutation). This mutation causes classic Fukuyama congenital muscular dystrophy with cobblestone lissencephaly. Milder forms include limb girdle muscular dystrophy and cardiomyopathy without brain involvement. A case of asymptomatic hyperCKemia was reported in a 12-year-old boy with mutations in this gene (27; 28).

X-linked dystrophies (dystrophinopathies). Female carriers of Duchenne muscular dystrophy may manifest asymptomatic hyperCKemia (80). Roughly 70% of definite carriers of Duchenne muscular dystrophy have raised serum CK activity (21). Immunocytochemical analysis of muscle by antidystrophin antibody in these patients shows the random presence of both normal and dystrophin-deficient fibers. Asymptomatic dystrophinopathy with hyperCKemia was found in brothers aged 7 and 8 and also in their 67-year-old grandfather (63).

Myotonic dystrophy. Most often, patients with myotonic dystrophy have distal limb weakness with myotonia, with little or no CK elevation. However, a patient with type 2 myotonic dystrophy was reported to have persistently asymptomatic hyperCKemia with no clinical or electromyographic myotonia (46). Finsterer and colleagues reported a case of a 55-year-old female with myotonic dystrophy type 1 who presented with hyperCKemia, syncope, and palpitation. This presentation was thought to be secondary to short CTG expansion of 70 repeats (26).

Desmin myopathy. Prelle and colleagues described three patients (a mother and her two sons) with familial asymptomatic hyperCKemia who were found to have abnormal desmin accumulation by muscle biopsy (53).

Dystroglycanopathy. Defects in glycosylation of alpha dystroglycan lead to muscular dystrophy and brain and eye malformation. A patient with mutation in dystroglycan 1 (dystrophin-associated glycoprotein or DAG1) was reported to have asymptomatic hyperCKemia (19).

Asymptomatic hyperCKemia secondary to metabolic myopathies. Although CK elevation occurs during or after exercise and usually is associated with muscle cramps, persistent, low-grade CK elevation is not unusual in metabolic myopathies.

Glycogen-storage diseases (GSD). At least 14 GSDs have been linked to specific enzyme deficiencies, and all can affect skeletal muscle except for type 1 (glucose-6-phosphatase (G6Pase) deficiency) and type 6 (Hers disease, hepatic phosphorylase deficiency), which involve hepatic enzymes.

GSD II (acid alpha-glucosidase or acid maltase deficiency). This is an autosomal recessive disorder that can cause asymptomatic elevation of serum CK (06). Prevalence of acid maltase deficiency in patients with asymptomatic hyperCKemia was found to be 2.2% (74).

GSD V (myophosphorylase deficiency, McArdle disease). Serum CK levels are invariably elevated with or without symptoms in both adults and children (10).

Lipid-storage diseases. In carnitine palmitoyltransferase 2 (CPT2 deficiency), serum CK levels are usually normal except after strenuous activity.

In carnitine deficiency, the most common disorder of lipid metabolism, serum CK levels are normal in about 50% of cases. Asymptomatic CK elevation is also reported in some cases.

Two cases of asymptomatic hyperCKemia in childhood were reported in association with mutation in the gene PNPLA2, which encodes adipose triglyceride lipase and is responsible for neutral lipid storage disease with myopathy, a disease diagnosed mostly in adulthood (27; 52).

Asymptomatic hyperCKemia secondary to restless leg syndrome. Della Marca and colleagues described seven patients with idiopathic hyperCKemia and restless leg syndrome with periodic limb movements in sleep (17). Neuromuscular diseases were excluded in all patients after extensive diagnostic workup, including neurologic examinations, blood essays, thyroid function, basal and postexercise lactate, needle EMG, and neurography. Three patients had an open biopsy of the vastus lateralis, processed for histologic, immunohistochemical, and biochemical studies. Six patients had MRI studies of leg muscles. The diagnostic protocol for restless leg syndrome included clinical evaluation, International Restless Legs Syndrome Study Group Rating Scale 2, Suggested Immobilization Test, and video-polysomnography. Six patients were treated with pramipexole; those with secondary restless leg syndrome (attributed to low serum ferritin values) also received dietary iron supplementation. One patient benefited from gabapentin therapy. Remission of restless leg syndrome symptoms was obtained in those patients. After 3 months, CK levels fell from two to four times normal before treatment to normal in five patients, and from six times normal to three times normal in one patient.

Asymptomatic hyperCKemia secondary to subclinical myopathy. CK is typically elevated in myopathies. Elevated CK levels may herald the onset of a clinical myopathy (30; 05). Joy and Oh studied 19 patients with asymptomatic hyperCKemia; they found a mild myopathy in 79%, and a specific myopathy was identified in 58% (36). The diagnoses (number of patients) were polymyositis (5), mitochondrial myopathy (2), sarcoid myopathy (1), McArdle disease (1), central core disease (1), multicore disease (1), and inclusion body myopathy (1). In the 4-year follow-up, however, only five of these patients eventually developed symptomatic limb weakness. The authors concluded that persistent asymptomatic hyperCKemia is caused by subclinical myopathy in most cases and that vigilant follow-up is important.

Alamr and colleagues performed a retrospective review of patients with inclusion body myositis (IBM). Although most of the 357 inclusion body myositis patients in the cohort had typical presentation, 50 patients (14%) had atypical presentation. Among the patients with atypical presentations, 12 of them (24%) presented with either asymptomatic hyperCKemia (7 patients) or minimally symptomatic hyperCKemia (fatigue or myalgia in five patients) (03).

Genetically proven facioscapulohumeral muscular dystrophy is reported to cause asymptomatic hyperCKemia (92).

High serum CK activity in three patients with asymptomatic distal myopathy was reported by Galassi and colleagues who noted that a proximal muscle biopsy could miss myopathic changes in cases of asymptomatic hyperCKemia caused by a distal myopathy (30).

Okamoto and colleagues reported nine patients with mild myopathy and episodic hyperCKemia associated with 16 mtDNA alterations. Muscle biopsy showed ragged-red fibers, highly expressed succinate dehydrogenase staining fibers, and cytochrome c oxidase-deficient fibers. They reported these cases as possible novel mitochondrial disease and they suggested naming it: mitochondrial myopathy with episodic hyper-CK-emia (MIMECK) (50).

There have been reports of asymptomatic or presymptomatic hyperCKemia in cases of autoimmune necrotizing myopathy. Typically, such myopathy is associated with significant proximal weakness. Troyanov and colleagues reported 12 cases of statin induced HMGCR antibody positive necrotizing myopathy and two of these patients did not complain of myalgia or weakness (83). Asymptomatic hyperCKemia is also reported in association with SRP antibody (73). Triplett and colleagues reported two cases of presymptomatic hyperCKemia in association with SRP antibody (82). The patients developed muscular symptoms 3 and 4 months after the identification of CK elevation. In some cases of autoimmune necrotizing myopathy, CK elevation preceded the onset of muscle weakness by more than 10 years (48).

Cases of asymptomatic hyperCKemia preceding the onset or recurrence of neuromyelitis optica have been reported (79; 16; 18; 90). EMG was performed in two cases, and it was negative; muscle biopsy was negative in one of them (16; 18). The prevalence and mechanism of hyperCKemia in neuromyelitis optica are unknown. Water channel aquaporin-4 (AQP-4), the target antigen for antibodies in neuromyelitis optica, is present in the muscles. This suggests that the development of AQP-4 antibody might be associated with hyperCKemia and lead to the onset of neuromyelitis optica spectrum disorder (90). A case of AQP-4–associated myopathy with inflammation on muscle biopsy has been reported (33). The patient had relapsing optic neuritis and transverse myelitis, and the muscle biopsy showed loss of AQP-4 and deposition of IgG and complement activation product in addition to inflammatory exudates.

Diagnostic workup

Some authorities recommend measuring CK activity more than once (eg, three measurements at monthly intervals) and after a period of rest (eg, no heavy exercise for 1 week prior to testing). A retrospective analysis by Capasso and colleagues included patients with asymptomatic hyperCKemia, with no family history of neurologic disorders, were not taking drugs known to cause hyperCKemia, were euthyroid, and had normal EMG and normal findings or minimal nonspecific changes on muscle biopsy. They found familial asymptomatic hyperCKemia in almost half of the cases. The inheritance pattern suggested autosomal dominant with higher penetrance in men. The authors suggested serum CK measurements in family members of the index case (11).

In a retrospective study of 114 asymptomatic or minimally symptomatic patients with persistent hyperCKemia, Prelle and colleagues found that after clinical examination, blood tests, EMG, and muscle biopsy, a neuromuscular disorder was identified in 18%, and 50% had nondiagnostic but pathological findings in EMG or muscle biopsy (55). Thirty-two percent had completely normal findings. Muscle biopsy was the best test for diagnosis; EMG was helpful but rarely diagnostic except for the presence of myotonia or myopathy. Other ancillary tests (lactate responses to exercise, urine amino acid and organic acid levels) were not helpful (55).

Another retrospective study of 104 asymptomatic or minimally symptomatic (myalgia, cramps, fatigue) patients with hyperCKemia and muscle biopsy found a definite or probable diagnosis in 55% of cases (25). The probability of achieving a diagnosis was significantly higher if the patient was younger than 15 years old or had a CK level higher than 2000 UI/L. The authors included glycogen storage diseases, inflammatory myopathies, and muscular dystrophies, which are outside the original concept of asymptomatic hyperCKemia and are not often asymptomatic.

For patients with persistent hyperCKemia with neuromuscular symptoms, Reijneveld and colleagues recommended that the diagnostic workup should include measurement of acid alpha-glucosidase activity in leukocytes to evaluate possible Pompe disease (56). For patients with symptoms, muscle biopsy provides tissue for immunocytochemical evaluation of the many limb girdle muscular dystrophies.

Similarly, for statin-associated hyperCKemia, those with symptoms should have an EMG and then a muscle biopsy if EMG shows evidence of myopathy or myotonia. TSH determination is recommended in all patients taking a statin.

Lentini and colleagues reported an association between obstructive sleep apnea syndrome and high serum CK levels (43). With continuous positive airway pressure treatment, CK levels declined significantly. However, the mean CK value in these patients was less than 200 UI/L, a mild elevation. In otherwise healthy people with minimally elevated CK levels and a high body mass index, obstructive sleep apnea syndrome can be considered.

The European Federation of Neurological Societies task force provided evidence-based guidelines for the assessment of patients with paucisymptomatic or asymptomatic hyperCKemia (39). Electronic databases, including Medline, the Cochrane Library, and the American Academy of Neurology, were searched for existing guidelines and articles dealing with series of patients investigated for asymptomatic or paucisymptomatic hyperCKemia. The task force also reviewed articles dealing with diverse myopathies that might cause asymptomatic hyperCKemia.

These European recommendations were based on the limited number of class IV studies and the expert opinion of the panel members. They recommended repeating the CK assay after seven days of abstinence from strenuous exercises. At least two samples 1 month apart should be taken to confirm the hyperCKemia.

According to the guidelines, muscle biopsy may be performed if one or more of the following applies:

Shaibani and colleagues studied the yield of muscle biopsy (the probability of finding specific diagnosis) depending on pre-test variables (hyperCKemia, EMG, and strength) (67). This probability was less than 15% for isolated hyperCKemia (in the absence of myopathic EMG and weakness). The probability increases to more than 50% if the patient has myopathic EMG and proximal weakness.

In women with hyperCKemia but a CK value less than three times normal, DNA analysis for dystrophin mutation is recommended to rule out a Duchenne or Becker mutation carrier state before doing a biopsy.

The presence of proximal limb weakness even with only mild CK elevation is another indication for muscle biopsy.

Of note, a study showed that a significant number of patients with hyperCKemia (12 of 19 subjects) have had abnormal single fiber EMG study (increased fiber density), which suggested that single fiber EMG could detect the presence of muscle disease while it was in the subclinical phase (58). Muscle biopsy was abnormal in all 12 of these subjects, whereas it was normal in the rest.

Next-generation sequencing may be considered as an alternative to muscle biopsy. Wu and colleagues examined the yield of a next-generation sequencing panel of muscular dystrophy–associated genes in screening patients who presented with muscle weakness, recurrent rhabdomyolysis, or idiopathic hyperCKemia (89). Pathogenic and likely pathogenic variants were identified in 36.09% of patients (61/169). The detection rate was 37.04% for patients with muscle weakness, 33.33% for patients with rhabdomyolysis, and 31.25% for patients with idiopathic hyperCKemia. A larger genetic panel or whole exome sequencing can also be considered. Of note, the gene sequencing has its own limitations, including missing triplet repeat expansion, deletions, polyploidy, and others. In addition, some of the metabolic panels may not include the RYR1 gene, which is an important gene in hyperCKemia workup. In light of these limitations, genetic testing is likely to be more productive if clinically directed using personal and family history, physical examination, and laboratory and electrodiagnostic findings.

Management

As indicated above, we do not think that asymptomatic hyperCKemia is a medical emergency. Patients and their primary care physicians can be reassured on this point and can live as normally as possible. For those with myalgia or objective limb weakness, diagnostic studies may be indicated. For those taking statins, the dosage might be lowered or even eliminated, depending on the hazards of hypercholesterolemia. Hypothyroidism should be treated. Muscle biopsy and evaluation of hereditary myopathies may be needed for genetic counseling.

Special considerations

Pregnancy

A reduction of serum CK levels during pregnancy has been reported in asymptomatic people and also in carriers of the Duchenne dystrophy gene (07; 22). In one patient with idiopathic hyperCKemia, enzyme activity became normal during several pregnancies in 10 years (29); the authors suggested that estrogens stabilized muscle membrane.

Anesthesia

Malignant hyperthermia is an autosomal dominant myopathy, manifest by a catastrophic reaction to a combination of general anesthesia and neuromuscular blocking drugs. It has been suggested that people with high CK values might be at risk for anesthetic reactions. However, in the absence of a clinical or family history of anesthetic complications, the relationship of idiopathic hyperCKemia to malignant hyperthermia remains unclear. Serum CK activity has not been found to be a useful screening test for malignant hyperthermia in this group of patients (87); however, anesthesiologists should be alerted to the possibility of malignant hyperthermia susceptibility. Weglinski and colleagues recommended that patients with idiopathic hyperCKemia receive a neurologic examination (87); if muscle biopsy is advised for diagnosis of myopathy, tests for malignant hyperthermia susceptibility with the in vitro halothane caffeine contracture test can be done too. A positive contracture test warrants anesthetic precautions, though the test itself has a low specificity. After analyzing 37 subjects with persistent hyperCKemia and no definite weakness or other neurologic symptoms, Malandrini and colleagues concluded that the in vitro contracture test is not sufficiently reliable as a predictor of malignant hyperthermia for subjects with hyperCKemia, and the incidence of hyperthermia in these people is still not known (44). In vitro contracture testing detected one malignant hyperthermia-susceptible and one malignant hyperthermia-equivocal subject. A less invasive diagnostic test was proposed using microdialysis technique. After intramuscular injection of halothane or caffeine, a significant local increase in lactate was found only in malignant hyperthermia–susceptible individuals. Those individuals were determined using the in vitro contracture test as a gold standard (35).