By Gasper, Mason C; Gilchrist, James M
Measurement of serum enzymes is a widely used screening diagnostic test for suspected muscle disease. Creatine kinase (CK), otherwise known as creatine phosphokinase (CPK), is the preferred screening tool because, unlike other enzymes found in skeletal muscle (e.g., lactate dehydrogenase, aldolase, and transaminases), CK has relative predominance in skeletal muscle, is not falsely elevated by hemolysis, and being unbound in cell cytoplasm is readily released in cellular injury.1,2 Despite these advantages, CK may create diagnostic uncertainty when an elevated level is found in a mildly symptomatic or asymptomatic patient. Not only are myopathy and cardiac disease among possible causes of the elevated CK, but a false positive CK elevation must be considered, such as in transient non-pathological situations (e.g., cramps, post-exercise) or in those with normally high baseline CK levels. To address diagnostic uncertainty in the use of serum CK levels, this paper will describe the structure and function of CK, summarize common reasons for elevated CK levels in normal individuals as well as those with myopathy or neuropathy, and finally develop a diagnostic strategy for mildly symptomatic or asymptomatic patients suspected to have myopathy. Additionally, a strategy for suspected myopathy in statin- treated patients will be addressed.
STRUCTURE AND FUNCTION OF CK
Cytoplasmic CK, a protein-product of chromosome 19, is an 86,000 molecular weight dimer molecule that produces adenosine triphosphate for use in muscle cells by catalyzing the transfer of a high energy phosphate bond from creatine phosphate, the major storage reservoir of energy during muscle at rest, to adenosine diphosphate.3 CK exists in relatively tissue-specific forms called isoenzymes, allowing for greater diagnostic precision. CK-MM makes up over 95% of total CK in skeletal muscle, whereas CK-BB comprises most of the total CK in brain tissue.4,5 Although CK-MB is a useful measure of cardiac muscle infarction, CK-MM is the most abundant isoenzyme (over 60%) in the myocardium.4,5 Total CK content is largely contained in skeletal muscle, exceeding the myocardial concentration by as much as twofold.4 Consequently, serum normally contains CK provided predominantly from skeletal muscle, almost exclusively as the CK-MM isoform.5
Aldolase, present in skeletal muscle, liver, and erythrocytes, is not considered a particularly good screening test for myopathy because the enzyme is not released readily with muscle injury and is often technically compromised by serum sample hemolysis.1,2 However, approximately 10% of active inflammatory myopathies may have normal CKs and elevated aldolase.6 We have had a case in which a patient with isolated persistent elevated serum aldolase levels was found to have florid vasculitis and myositis on muscle biopsy in the face of a normal examination and electromyography, and near-normal CK levels. Therefore, aldolase may be useful in those situations with a high clinical suspicion of myopathy and normal CK levels.
ELEVATED SERUM CK LEVELS IN THE NORMAL POPULATION
Normal values of CK are difficult to estimate due to individual and population variation in serum levels. Persistent high levels of CK may be seen in blacks compared with other races, males compared with females, and in those with large muscle mass.7,8 In one study of normal adults, reported mean total CK was 147 U/L (range of 7 to 284 U/L) for 57 black males, 61 U/L (range 35 to 87 U/L) for 44 white males, 66 U/L (range 16 to 116 U/L) for 90 black females, and 37 U/L (range 19 to 55 U/L) for 99 white females.7 This study highlighted a lack of specificity when laboratory reference values for serum CK do not consider race.
Transient elevations in CK levels are common after reversible causes of muscle injury such as trauma (including injections or needle electromyography), vigorous exertion, or even muscle cramping. A serum sample drawn after electromyography (EMG) in a normal patient will increase up to three fold within the next 24 hours and may show a false positive CK result suggesting myopathy. Therefore, it is important to draw CK levels before EMG studies. In one report, CK levels rose from a mean baseline of 53 U/L in 10 patients to a maximum mean CK of 91 U/L 12 to 24 hours after an EMG; a return to baseline occurred after 48 to 72 hours.9
Vigorous exertion may increase serum CK levels transiently. After a marathon, CK levels in 7 runners were reported to maximally increase 24 hours after the race to a mean of 1404 U/L (range 683 to 2261 U/L).10 In this study, mean CK levels approached baseline after about 1 week. In general, one week of avoidance of exertional activity should be sufficient to ensure accurate measurement of CK levels in a frequently exercising patient. Excessive skeletal muscle exertion resulting in CK elevations can also be seen in certain non- neuromuscular pathological events such as neuroleptic malignant syndrome, convulsive seizures, acute psychosis and violent behavior.2
A single non-pathological cramp can also cause a substantial rise in CK levels. In one published case,11 after a single severe cramp in a gastrocnemius muscle lasting several minutes, serum CK elevated from 117 IU/L (normal
SERUM CK LEVELS IN MUSCLE DISEASE
The degree of CK elevation in muscle disease largely reflects the underlying disease process, and is predominantly due to myonecrosis or membrane defects2, 5 (Figure 1: Serum CK level and time course of various myopathies and Table 1: Expected serum CK levels amongst common myopathies). Highest elevations of CK are seen with conditions causing muscle fiber necrosis as in dystrophinopathies (e.g., Duchenne and Becker muscular dystrophy), rhabdomyolysis, malignant hyperthermia, neuroleptic malignant syndrome, and severe polymyositis. More indolent myopathies, such as fascioscapulohumeral muscular dystrophy, myotonic dystrophy, and inclusion body myositis usually have lesser degrees of CK elevation. Disorders causing muscle atrophy without cell membrane damage often have normal CK levels, as in steroid-induced myopathy, hyperthyroidism, channelopathies and mitochondrial myopathies.
Table 1: Expected serum CK levels amongst common myopathies
Most inflammatory myopathies (i.e., polymyositis, dermatomyositis) will have abnormal CK levels during the disease course, although the extent of CK level elevation can be quite variable.12 In polymyositis and dermatomyositis, CK levels improve on steroids, usually regardless of whether weakness improves and are not particularly useful to monitor success or failure of treatment.12 An acute increase in CK levels in these disorders, however, may be a harbinger of relapse. As patients with chronic myopathies lose muscle mass and strength, CK levels will drop and may approach normal in later stages of muscular dystrophy2, 12 (Figure 2: CK values in a large population of autosomal recessive Limb-girdle muscular dystrophy by duration of disease).
Diagnostic confusion sometimes occurs in destructive myopathies as regenerating fibers may release a larger proportion of the CK-MB fraction compared with mature muscle cells, which primarily release CK-MM when injured.1, 5, 13 In these cases, higher serum levels of CK-MB do not necessarily indicate coexisting cardiac disease in the presence of destructive myopathies.
SERUM CK LEVELS IN NERVE DISEASE
Serum CK levels are not commonly thought to be elevated in neurogenic disease such as mononeurpathy or polyneuropathy, and for the most part, this is true. However, in certain neurogenic diseases, such as amyotrophic lateral sclerosis14, spinal muscular atrophy and Guillan Barre syndrome,15 there may be an elevation of CK, though usually no more than five times normal. One proposed mechanism is damage due to increased work requirement on muscle fibers in weakened muscle,2 though this seems doubtful given that other causes of weakness do not cause elevations of CK. These neuropathies cause denervation of muscle fibers and the ongoing entrophic changes to the muscle fiber membrane may result in leakage of CK. Another possibility would be elevation of CK secondary to frequent cramping, a common symptom in acute neurogenic diseases such as amyotrophic lateral sclerosis and Guillain-Barre syndrome.11
Figure 1: Serum CK level and time course of various myopathies.
COMMONLY ENCOUNTERED PRIMARY CARE SITUATIONS INVOLVING ELEVATED CKs
Three situations commonly confront primary care providers: the patient complaining of myalgias (muscle pain or tenderness) without weakness, the asymptomatic patient found to have elevated CK levels, and suspected myopathy in a patient taking cholesterol-lowering medications. A proposed diagnostic algorithm is presented in Figures 3 and 4.
SITUATION 1: MYALGIAS
Muscle pain is common in normal individuals. One-third to 80% of the population reports muscle pain at some point and many of these patients will have no abnormal test findings.16 Since few cases of myalgia will likely be due to myopathy, screening tests with high specificity are useful to select those few patients in whom more sensitive (and more invasive) testing will be necessary.17 Common screening tests for myopathy include serum CK and erythrocyte \sedimentation rate (ESR), which have been shown to be highly specific (81% and 93%, respectively) for suspected myopathy.17 ESR, while less sensitive than CK in diagnosing myopathy,17 is helpful in evaluating common causes of myalgias that do not cause elevated CKs, e.g., polymyalgia rheumatica. Other potentially useful initial serum testing includes aldolase and thyroid stimulating hormone (TSH). Patients with thyroid disease may show myopathic clinical manifestations that may or may not result in elevated CK levels.
Figure 2: CK values in a large population of autosomal recessive Limb-girdle muscular dystrophy by duration of disease (shows reduced serum CK levels with reduction in muscle mass in limb girdle muscular dystrophy).
If these screening blood tests are abnormal, further investigation should then proceed to EMG testing and possibly, to muscle biopsy as well as other tests (e.g., ischemic exercise testing and DNA evaluation). EMG and muscle biopsy are more invasive tests and typically the second and third line diagnostic tests in screening and confirming muscle disease. Muscle biopsy is the most sensitive diagnostic test for myopathy (81%17) and should be employed in patients with a positive screening test (e.g., confirmed weakness, elevated CK or ESR, abnormal EMG). With normal screening tests, the yield for a significant finding on muscle biopsy is low. One study reported that among 20 patients with modest elevations of CK, a normal neurologic examination and nondiagnostic EMG, only one was found to have a diagnostic muscle biopsy.18
Other tests may also be helpful, including genetic testing for those with a significant family history of myopathy (to test for dystrophinopathy or carrier state, for example) or ischemic exercise testing for those with exercise-related myalgias or weakness, suggesting a possible metabolic myopathy.
SITUATION 2: ASYMPTOMATIC INCREASED LEVELS OF CK
Mild CK elevations are often detected during evaluation of heart disease or routine testing for other medical conditions. Out of 100 consecutive patients seen with elevated CKs after admission to an Austrian medical service,19 the diagnosis was acute myocardial infarction (32%), drug-related (32%), trauma after a fall (24%), hematoma (17%), intramuscular injection (16%), and malignancy (11%). Only 2% of the CK elevations were explainable by neuromuscular disease. Gender, race, age and recent exercise must also be considered in the situation of mildly elevated CK.
A persistent unexplained elevated CK level, usually three- to 10- times above normal, in an otherwise strong healthy asymptomatic individual with a normal EMG and muscle biopsy is termed idiopathic hyperCKemia.2 Numerous studies report the results of detailed neuromuscular evaluation in patients with suspected idiopathic hyperCKemia. After considering common causes of asymptomatic elevated CK levels, such as exertion, thyroid disease or other nonpathological reasons of raised CK levels, identifiable causes for suspected idiopathic hyperCKemia are found in approximately one out of every six cases after extensive testing, including EMG and muscle biopsy.20,21 Neuromuscular diseases subsequently diagnosed in patients with idiopathic hyperCKemia included inflammatory, mitochondrial, and metabolic myopathy among other causes.20,21 The prognosis of idiopathic hyperCKemia is good: a long-term (mean 7 years, range 4-18 years) follow-up study of 31 patients diagnosed with idiopathic hyperCKemia reported no clinical deterioration in 74% of the patients who had a final evaluation.22
For unexplained elevations in CK, we generally perform an EMG. If this is normal, and the patient remains without weakness or significant symptoms, a muscle biopsy is best deferred. The diagnostic yield of muscle biopsy in this setting is low, and even if a diagnosis were made, it would be difficult to make an asymptomatic patient feel better than they already are, thus providing little benefit to the patient. Uncommonly, elevated CK in an asymptomatic individual may be an indicator of either pre- symptomatic or carrier status for an inherited muscle disease, such as muscular dystrophy. The same ethical considerations come into play in this situation as for any asymptomatic patient seeking genetic testing, as for example, Huntington’s disease23 and referral to a center with genetic counseling is appropriate before any genetic testing is done. Continued follow-up of the patient for the development of symptoms or signs suggestive of myopathy is important, though regular testing for CK levels is uncommonly useful as further testing will be predicated not on the already known elevation of CK, but rather on the history and exam.
Figure 3: Diagnostic Algorythm for incidental high CK and myalgias
SITUATION 3: ELEVATED CK WHILE ON A CHOLESTEROL-LOWERING AND OTHER DRUGS
Various medications have been associated with elevated CK levels24, 25 (Table 2: Commonly used medications associated with elevated CK levels). Although most medications that lower cholesterol have been associated with muscle disease, the statins, being the most common cause of cholesterol-lowering agent myopathy (CLAM), will be our primary concern. Statins (HMG CoA reductase inhibitors) are considered first line therapy in reducing low density lipoprotein levels, 26 however, concerns about adverse effects, including CLAM, may be behind reports of underutilization of statins in populations that would benefit from such medications.27 Moreover, concerns of myopathy have led to extensive monitoring of asymptomatic statin-users, leading to increased costs and discontinuation of a medically important therapy.27
CLAM is clinically variable, manifesting in its most acute state as rhabdomyolyisis, or in a more indolent manner as isolated elevations in serum CK levels or subjective complaints of myalgias. The mechanism of statin-induced muscle injury is not completely understood, although a leading theory proposes that statins may create unstable myocytes by reducing the cholesterol content in muscle cell membranes.28
Statin-induced rhabdomyolysis was highlighted by the recent withdrawal of Baycol (cerivastatin) after an association with deaths due to rhabdomyolysis.29 Rhabdomyolysis is a syndrome of myalgias, weakness and muscle swelling associated with acute elevation of CK greater than 10 times the upper limit of normal, usually accompanied by myoglobinuria, hyperkalemia and potentially, acute renal failure.30 The risk of rhabdomyolysis from statins has been extensively studied retrospectively, through voluntary reporting data as well as clinical trials, and is real, although the absolute risk is rare.28,29,30
Table 2: Commonly used medications associated with elevated CK levels
A widely cited analysis summarizing reported adverse events found the incidence of fatal statin-related rhabdomyolysis to be only 0.15 deaths per 1 million prescriptions, although voluntary reports likely underestimate actual occurrences.29 In a review of randomized clinical trials of statin therapy, only 49 cases of myopathy and 7 cases of rhabdomyolysis were noted among the 42,323 patients on statins, numbers virtually identical to the 41,535 control patients.28 One retrospective study of approximately 250,000 patients treated with lipid-lowering medications reported that only 24 required hospitalization for rhabdomyolysis, a risk of 1 in 10,000.31
Statins may also cause low-grade myopathie symptoms, characterized by muscle pain (myalgias) with or without elevated CK levels.32 However, other than individual cases showing a temporal relationship between statins and muscle pain, statin-induced myalgias have been difficult to prove as many studies have shown quite low rates of myalgias in statin-treated patients (in many studies only as high as about 5%) and not significantly different than controls.28,33 Statins do appear to have a real pathological effect on muscle in some cases, however. One report recently documented myopathy by biopsy in four patients with myaglias and normal CK levels while on statin therapy.34
Figure 4: Diagnostic Algorythm for Suspected CLAM
Isolated asymptomatic elevated serum CK associated with statin- use, generally less than 10 times normal, is usually detected incidentally.28 Here again, the incidence has been difficult to determine formally with extremely low rates (
General recommendations30, 33 regarding the use of statins reflect the increased risk of myopathy associated with certain patients and elevated statin serum concentrations. These recommendations include: starting statins at a low dose, especially when used with concomitant medications that affect liver metabolism and using the lowest dose possible to meet cholesterol goals; using statins more cautiously in high risk groups such as the elderly, those with renal insufficiency, liver disease, alcoholism or hypothyroidism, and those on multiple medications; and, possibly withholding statins prior to expected stressful periods such as major surgery. Medications that may be associated with increased risk of CLAM when used concomitantly with a statin include fibrates, cyclosporine, azole antifungals, macrolide antibiotics, protease inhibitors, nefazadone, verapamil, diltiazem, and amiodarone.33 When combination therapy is required, a new inhibitor of intestinal cholesterol absorption, ezetimibe, can be considered which appears to be safe to use in combination with statins without an increased risk of myopathy.28
Routine measurements of CK levels in asymptomatic patients are not required although a baseline CK level is helpful in evaluating subsequent muscle complaints.33 CK levels should be checked for any new muscle complaint while on statins and considerations made to discontinue or lower the dose if myaglias progres\s or CK levels are found to be over 10 times normal.33 Once statins are discontinued, improvement may occur as early as a few days to a week,36 or recovery may be prolonged. In one report, CK returned to normal after 12 days but weakness persisted for over two months.37 Therefore, if myalgias continue to worsen or persist off statins for one to two months, another cause of myopathy is possible.
Serum CK is a useful screening test for suspected myopathy. Diagnostic challenges occur when symptoms are mild (isolated myalgia) or there are no symptoms (isolated rise in serum CK levels). Additionally, statin medications offer many neuromuscular diagnostic challenges. We have briefly reviewed the structure and function of CK, and developed a treatment algorithm for common situations in which CK, as well as follow-up neuromuscular testing, are useful.
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MASON C. GASPER, DO, MPH, AND JAMES M. GILCHRIST, MD
Mason C. Gasper, DO, MPH, formerly a fellow in clinical neurophysiology at Rhode Island Hospital, Brown Medical School, is in practice at the Fallon Clinic in Worcester, Massachusetts.
James M. Gilchrist, MD, is Professor of Neurology, Brown Medical School, and Vice-Chair of Neurology, Rhode Island Hospital.
James M. Gilchrist, MD
593 Eddy Street, APC 689
Providence, RI 02903
Phone: (401) 444-8761
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Copyright Rhode Island Medical Society Nov 2005