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 (46). 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 (36):
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(1) The risk of rhabdomyolysis seems to range from 0.1 to 0.2 cases per 1000 person-years (69).
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(2) In a prospective study of statins in 1194 patients, only 2 showed modest elevations of CK (70). Others have expressed skepticism about the value of monitoring CK in patients taking a statin (80; 71).
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(3) A metaanalysis of 21 double-blind randomized clinical trials (n = 48,138) revealed a nonsignificant difference in the incidence of myalgia among participants who received statin or placebo (37).
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(4) A metaanalysis of 4 controlled trials (n = 27,545) comparing intensive and low to moderate statin therapy showed that intensive therapy was associated with a higher risk for CK levels, more than 10 times the upper limit of normal, with or without myalgia (68).
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(5) There is no evidence that asymptomatic hyperCKemia predicts incipient myoglobinuria. One patient had an episode after taking a single dose (33).
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(6) The National Lipid Association (NLA) recommends no change of therapy for patients with CK levels of 3 to 10 times the upper limit of normal (44). Whether baseline CK measurement is needed is controversial but recommended by many experts (85). Pretreatment CK elevation of less than 5 times normal is not a contraindication to statin therapy (31). However, progressively increasing CK or the appearance of progressively more severe myalgia or pigmenturia warrants temporary suspension of the statin or switching to a less myotoxic statin, such as fluvastatin (74) or rosuvastatin (30). Other alternatives include addition of a nonstatin such as ezetimibe or bile acid-binding resin (58). Administration of coenzyme Q10 is of uncertain value. Persistent CK elevation for more than 3 months of discontinuation of the suspected drug warrants investigation for other possible causes or statin-induced necrotizing myopathy.
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(7) Many patients with statin myopathy prove to have hypothyroidism, and replacement therapy is then indicated. Ten percent of patients with statin myopathy have mutations that normally cause rare myopathic syndromes, raising the possibility of genetic susceptibility of statin myopathy (84).
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 (13), hypothyroidism (08), hypoparathyroidism (67), 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 (22). 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 (23). 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 (11).
LGMD2A (calpain mutation). This autosomal recessive disorder is one of the most prevalent forms of limb-girdle muscular dystrophy. HyperCKemia is not invariably present (90).
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 (53). 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 (64).
LGMD 2C, 2D, 2E, and 2F (sarcoglycan mutations). There is a wide spectrum of clinical phenotypes in patients with sarcoglycanopathies. Angelini and colleagues described 2 siblings who had a homozygous mutation of the alpha-sarcoglycan gene (03). 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 (07).
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 (26; 27).
X-linked dystrophies (dystrophinopathies). Female carriers of Duchenne muscular dystrophy may manifest asymptomatic hyperCKemia (79). Roughly 70% of definite carriers of Duchenne muscular dystrophy have raised serum CK activity (20). 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 (62).
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 (45). 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 (25).
Desmin myopathy. Prelle and colleagues described 3 patients (a mother and her 2 sons) with familial asymptomatic hyperCKemia who were found to have abnormal desmin accumulation by muscle biopsy (52).
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 (18).
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 (05). Prevalence of acid maltase deficiency in patients with asymptomatic hyperCKemia was found to be 2.2% (73).
GSD V (myophosphorylase deficiency, McArdle disease). Serum CK levels are invariably elevated with or without symptoms in both adults and children (09).
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 (26; 51).
Asymptomatic hyperCKemia secondary to restless leg syndrome (RLS). Della Marca and colleagues described 7 patients with idiopathic hyperCKemia and RLS with periodic limb movements in sleep (PLMS) (16). 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 RLS 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 RLS (attributed to low serum ferritin values) also received dietary iron supplementation. One patient benefited from gabapentin therapy. Remission of RLS symptoms was obtained in those patients. After 3 months, CK levels fell from 2 to 4 times normal before treatment to normal in 5 patients, and from 6 times normal to 3 times normal in 1 patient.
Asymptomatic hyperCKemia secondary to subclinical myopathy. CK is typically elevated in myopathies. Elevated CK levels may herald the onset of a clinical myopathy (29; 04). Joy and Oh studied 19 patients with asymptomatic hyperCKemia; they found a mild myopathy in 79%, and a specific myopathy was identified in 58% (35). 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 5 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. Genetically proven facioscapulohumeral muscular dystrophy is reported to cause asymptomatic hyperCKemia (91).
High serum CK activity in 3 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 (29).
Okamoto and colleagues reported 9 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) (49).
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 2 of these patients did not complain of myalgia or weakness (82). Asymptomatic hyperCKemia is also reported in association with SRP antibody (72). Triplett and colleagues reported 2 cases of presymptomatic hyperCKemia in association with SRP antibody (81). 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 (47).
Cases of asymptomatic hyperCKemia preceding the onset or recurrence of neuromyelitis optica have been reported (78; 15; 17; 89). EMG was performed in 2 cases, and it was negative; muscle biopsy was negative in one of them (15; 17). 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 (89). A case of AQP-4–associated myopathy with inflammation on muscle biopsy has been reported (32). 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.