Muscle enzymes in the evaluation of neuromuscular diseases

INTRODUCTION — The measurement of serum levels of muscle enzymes is a critical part of the evaluation of patients presenting with weakness or myalgias, and it is important in monitoring the course and response to therapy of certain muscular disorders. Creatine kinase (CK), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and aldolase are the serum enzymes that are measured in clinical practice.

This topic will review the biochemistry of muscle enzymes and their use in clinical practice. The biochemistry and use of serum enzymes in patients with renal failure are discussed separately. (See "Serum enzymes in patients with kidney failure" and "Cardiac troponins in patients with kidney disease".)

PHYSIOLOGY OF MUSCLE ENZYMES

Creatine kinase — Creatine kinase (CK) is the most widely used enzyme to diagnose and follow muscle disease. It is present in the highest concentrations in serum in response to muscle injury, is the most sensitive indicator of muscle injury, and is the best measure of the course of muscle injury [1].

CK is located on the inner mitochondrial membrane, on myofibrils, and in the muscle cytoplasm [2]. It is involved in cellular energy storage and transfer via two major effects:

●It catalyzes the production of high-energy adenosine triphosphate (ATP) via transfer of a phosphate from creatine phosphate, which is the major storage reservoir of energy during muscle rest, to adenosine diphosphate (ADP).

●It participates in the transfer of high-energy phosphate from its site of production in the mitochondria into the muscle cell cytoplasm where it is used during muscle contraction.

CK is a dimer molecule and occurs in three distinct isoenzyme forms (termed MM, MB, and BB), which can be distinguished electrophoretically. Skeletal muscle has the highest concentration of CK of any tissue. Normal skeletal muscle CK is more than 99 percent MM with small amounts of MB. By comparison, cardiac tissue has the highest concentration of CK-MB, which accounts for approximately 20 percent of cardiac CK [3].

The concentration of MB in skeletal muscle increases in individuals with inflammatory myopathy or muscular dystrophy, in the resting muscles of well-trained elite athletes, and in many individuals after extreme exercise such as marathon running. This change is probably due to the increased number of regenerating muscle fibers in these conditions. Regenerating muscle fibers revert to the fetal state of increased MB production [4]. An increased ratio of serum CK-MB measured in inflammatory myopathies [5] or in athletes after extreme exertion may be confused with myocardial infarction [6]. Troponin I is a more specific marker for myocardial damage than CK-MB since it does not appear to be present in either normal or damaged skeletal muscle [7-9], while Troponin T may be present in inflamed or regenerating skeletal muscle paralleling the elevation of CK-MB [10]. (See "Troponin testing: Clinical use".)

Brain tissue CK consists of 90 percent CK-BB with the remainder CK-MM. Smaller amounts of CK are also found in the intestine, lung, and bladder [3].

Macro CK is a term used to refer to CK that has an increased molecular weight. Complexes of CK and immunoglobulin (type 1 macro CK) and CK and an undetermined protein (type 2 macro CK) are more slowly cleared from the circulation than normal CK, leading to elevated levels. Macro CK can be detected by CK isoenzyme electrophoresis, which is usually available in reference clinical laboratories. The two types of macro CK can then be distinguished by protein G affinity chromatography. In those laboratories reporting CK isoenzymes, macro CK will be reported as an increased CK-MB fraction, which may cause diagnostic confusion suggesting cardiac injury [11]. (See "Use of creatine kinase to detect myocardial injury" and "Use of creatine kinase to detect myocardial injury", section on 'CK-MB fraction for diagnosis of acute MI'.)

CK levels are elevated in some patients with end stage renal disease on dialysis. Serum cardiac enzymes in patients with renal failure are discussed separately. (See "Cardiac troponins in patients with kidney disease".)

Aldolase — Aldolase is another glycolytic pathway enzyme that is found in all tissues but predominantly in skeletal muscle, liver, and brain. While increased aldolase levels are not as specific or sensitive for muscle disease as CK levels, aldolase concentrations are occasionally elevated in patients with myositis who have normal CK levels [1].

Lactate dehydrogenase — Lactate dehydrogenase (LDH) catalyzes the final step of glycolysis, converting pyruvate to lactate [12]. It is found in nearly every tissue of the body; as a result, increased serum levels are found in a great variety of disease states. There are five LDH isoenzymes, each consisting of tetrameric combinations of M and H chains. The LD1 isoenzyme is more common in cardiac tissue, and, in the setting of cardiac injury, the usual LD2 greater than LD1 ratio is reversed. LD5 predominates in skeletal muscle, but increased LD5 is also seen in hepatic disease [1].

Aminotransferases — The aminotransferases (transaminases) catalyze the conversion of the amino acids alanine and aspartate to alpha-ketoglutarate, providing a source of nitrogen for the urea cycle [13]. Both enzymes are found widely in many tissues, and increased serum levels are a nonspecific indicator of disease. Serum concentrations are highest in various hepatic disorders, but increased values are also seen in skeletal muscle, myocardial disease, and hemolysis. (See "Approach to the patient with abnormal liver biochemical and function tests", section on 'Elevated serum aminotransferases'.)

Rate of enzyme clearance — In patients with an acute myocardial infarction, the increase in serum CK is short-lived while that of LDH persists. Thus, a patient seen a few days after the event may have elevations in LDH and in troponin but no elevation in the serum CK. It is uncertain if this distinction occurs with skeletal muscle injury. Limited data following exercise suggest that the time course of elevation in muscle enzymes is similar for CK, LDH, and the aminotransferases. Why the response to skeletal and cardiac muscle injury might be different is not known. (See 'Exercise' below.)

MUSCLE ENZYMES IN THE DIAGNOSIS OF NEUROMUSCULAR DISORDERS — In clinical practice, the measurement of serum muscle enzymes is most commonly used in the evaluation of the patient presenting with muscle weakness or myalgias in whom myopathy is suspected. In general, marked elevation of serum muscle enzymes is seen in myopathies. Thus, serum creatine kinase (CK) activity >1000 units/L helps to distinguish muscle disease from neurogenic causes of weakness and muscle atrophy. More modest elevation of CK may occur in some primary neurologic disorders, particularly motor neuron disease. (See "Approach to the patient with muscle weakness" and 'Motor neuron disease' below.)

This section will review the disorders in which serum muscle enzyme concentrations are elevated either chronically (as in most myopathies) or acutely (as in reversible causes of rhabdomyolysis) (table 1). This will be followed by a discussion of settings in which muscle enzymes can be used to follow the course of the disease and the response to therapy.

Inflammatory myopathies — In Bohan's original series of 153 patients with inflammatory myopathy (polymyositis and dermatomyositis), only two patients had persistently normal muscle enzymes throughout their clinical course [14]. Subsequent reports have confirmed the nearly universal elevation of at least one of the muscle enzymes at some time during the course of active myositis [15,16]. CK is the most commonly measured muscle enzyme, although at times aldolase, lactate dehydrogenase (LDH), or the aminotransferases will be elevated in the absence of an elevated CK [1,14]. It is not known why this occurs.

Rarely, clinical muscle disease with weakness and abnormal electromyography (EMG) and muscle biopsy findings occurs in the absence of muscle enzyme elevation. It has been suggested in these cases that an inhibitor of CK is present causing a false negative CK level [17]. Slight elevation or normal levels of serum CK activity may be present in patients with inclusion body myositis.

In other patients, the rash of dermatomyositis is present without clinical muscle disease or elevated muscle enzymes, termed "amyopathic dermatomyositis" or "dermatomyositis sine myositis" [18]. (See "Clinical manifestations and diagnosis of inclusion body myositis" and "Clinical manifestations of dermatomyositis and polymyositis in adults", section on 'Muscle enzymes'.)

The degree of CK elevation in dermatomyositis and polymyositis varies greatly, reaching as high as 100 times normal. One report noted a correlation between the height of CK elevation at diagnosis and the severity of disease [19], but this relationship has not been confirmed by others [16].

Patients with myopathy presenting with nonspecific arthralgias, myalgias, or constitutional symptoms that may overshadow the presence of muscle weakness are commonly evaluated with a multichannel chemical analyzer in which elevated LDH and aminotransferases may first suggest the presence of liver disease. In this setting, a careful assessment of muscle strength and measurement of CK and aldolase should lead to the correct diagnosis of muscle disease and avoidance of an unnecessary liver biopsy [20].

Similarly, in juvenile dermatomyositis, at least one of the serum muscle enzymes is elevated at some time in the course of almost all cases [21]. There are rare patients who have normal enzymes in the presence of muscle weakness. (See "Juvenile dermatomyositis and other idiopathic inflammatory myopathies: Epidemiology, pathogenesis, and clinical manifestations".)

Other exceptions include:

●Very early disease in which children present with rash and fever, but before muscle weakness and enzyme elevation occur

●Very advanced disease in which there are marked muscle atrophy and normalization of enzymes

Muscle enzyme elevation in patients with other connective diseases including rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, and scleroderma suggests an associated myositis which may be subclinical or marked by mild muscle weakness [22,23]. The enzyme elevations in these disorders are usually mild [22] and, in a patient with systemic lupus or scleroderma, are suggestive of mixed connective tissue disease [24] or scleroderma/polymyositis overlap [25]; these disorders are associated with the specific autoantibodies anti-U1 RNP and anti-PM/Scl, respectively. (See "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes" and "Mixed connective tissue disease".)

There are a number of other myopathies that are associated with elevated serum muscle enzyme concentrations:

●A group of disorders classified as localized myositis presents with focal muscle involvement and variable degrees of muscle enzyme elevation [26]. Etiologies include infections, focal presentations of polymyositis, insect bites, and idiopathic cases.

●Serum CK elevations occur in about 80 percent of patients with inclusion body myositis. The elevations are mild, less than 10 times the normal range [27]. (See "Clinical manifestations and diagnosis of inclusion body myositis".)

●Other inflammatory conditions associated with myositis and elevated muscle enzymes include the systemic vasculitides (polyarteritis nodosa [28], Churg-Strauss vasculitis [29], and granulomatosis with polyangiitis [30]), polymyositis associated with chronic graft-versus-host disease [31], Behçet syndrome [32], and sarcoidosis [33].

Infectious myopathies — Infectious myopathies with elevated serum enzyme concentrations can follow viral, bacterial [34], spirochetal [35,36], mycobacterial [37], fungal [38], and parasitic [39] infections. Muscle involvement in these infections may be either localized or generalized. CK elevations in viral myositis may reach levels greater than 1000 times normal [40]. (See "Overview of viral myositis".)

Dystrophinopathies — Elevated serum muscle enzyme concentrations occur in the sex-linked recessive muscular dystrophies (Duchenne's and Becker's), the limb-girdle dystrophies, facioscapulohumeral dystrophy, and myotonic dystrophy. CK levels are elevated in patients with Duchenne and Becker muscular dystrophy from the newborn period, before any clinical signs of the disease appear. CK levels peak by age two and then progressively fall, often to the normal range, as more and more muscle is replaced by fat and fibrosis [41]. (See appropriate topic reviews on the muscular dystrophies.)

CK levels are increased in approximately 70 and 50 percent of Duchenne and Becker female carriers, respectively [41]. The elevations are usually mild, up to three times the upper limit of normal.

Rhabdomyolysis — Acute, massive muscle injury due to trauma, prolonged muscle compression, seizures, electrolyte imbalances, infections or drugs is associated with marked elevations of muscle enzymes [42]. The degree of CK elevation correlates with the risk of acute renal failure [43]. Unlike chronic myopathies, however, the levels decrease rapidly to normal after the offending stimulus is removed. (See "Rhabdomyolysis: Clinical manifestations and diagnosis".)

Drugs — Muscle enzymes are elevated in various drug-induced myopathies including those due to colchicine, antimalarials, cholesterol-lowering drugs (statins, gemfibrozil, nicotinic acid, and clofibrate), cocaine, and alcohol [44,45] (see "Drug-induced myopathies" and "Statin muscle-related adverse events"). Serum CK concentrations range from mild elevations of three to four times normal with antimalarial neuromyopathy to 10- to 20-fold elevations in colchicine neuromyopathy and to massive elevations and rhabdomyolysis with cocaine use or acute alcoholic myopathy. Massive elevations of CK have also been reported in patients on mechanical ventilators treated with nondepolarizing muscle blocking agents and high dose glucocorticoids [46].

Neuroleptic malignant syndrome — Neuroleptic malignant syndrome (NMS) is a drug-induced disorder characterized by a change in mental status and the presence of rigidity, fever, and dysautonomia. Elevation of CK is a variable feature, and otherwise typical cases of NMS have occurred in the absence of CK elevation. This syndrome is most often seen with either traditional or "atypical" neuroleptic agents (eg, haloperidol, fluphenazine, and chlorpromazine; clozapine, risperidone, and olanzapine) and has also occurred in the setting of use of antiemetic drugs (eg, metoclopramide and promethazine); NMS is discussed in more detail elsewhere. (See "Neuroleptic malignant syndrome".)

Metabolic myopathies — Inherited disorders of carbohydrate, lipid, and purine metabolism are associated with episodic muscle damage ranging from myalgias and mild muscle enzyme elevation to frank rhabdomyolysis. While these conditions represent a very small percentage of cases of rhabdomyolysis, they should be suspected in cases where no obvious precipitating factors are present, particularly when there is a history of recurrent episodes. The heritable metabolic myopathies are discussed in more detail elsewhere. (See "Metabolic myopathies caused by disorders of lipid and purine metabolism".)

Carnitine palmitoyltransferase (CPT) and muscle phosphorylase deficiency are the most common metabolic myopathies [47].

Muscle phosphorylase deficiency, or McArdle's Disease, is inherited in an autosomal recessive pattern. Affected individuals typically have a history of exercise intolerance in childhood followed by recurrent cramps, fatigue, and myoglobinuria in adolescence or early adulthood. CK levels do not completely return to normal between episodes of rhabdomyolysis.

In contrast, individuals with CPT deficiency have normal CK levels during interictal periods. Thus, serum muscle levels should be measured when the individual is symptomatic.

Protein aggregate myopathies — These conditions, which can occur in childhood or in later life, are related to the abnormal aggregation of intrinsic muscle proteins leading to mild muscle symptoms or a slowly progressive myopathy with muscle fiber vacuolization and inclusions observed on muscle biopsy. The genetic basis for some of these conditions has been identified [48,49].

Malignant hyperthermia — Malignant hyperthermia is characterized by fever, generalized muscular contraction and rigidity, metabolic acidosis, and rhabdomyolysis, most commonly occurring after the use of inhalational anesthetic agents in susceptible individuals. CK levels may rise several hundred times greater than normal during an episode and may remain persistently elevated in those individuals who recover.

Malignant hyperthermia may occur sporadically or may be familial. Affected family members may have an elevated CK when asymptomatic, but muscle enzyme measurement has insufficient sensitivity to be useful as a screening test. Approaches to diagnosis and screening of possibly affected or at-risk family members are discussed in more detail elsewhere. (See "Susceptibility to malignant hyperthermia: Evaluation and management" and "Malignant hyperthermia: Diagnosis and management of acute crisis".)

Endocrine myopathies — Hypothyroidism is frequently accompanied by myalgias, stiffness, mild muscle weakness, and mild to moderate elevations of CK and other muscle enzymes. Rarely, rhabdomyolysis and myoglobinuria occur after vigorous exercise. Muscle enzymes return to normal levels after one to two months of thyroid replacement therapy. (See "Hypothyroid myopathy".)

Muscle enzymes are typically normal in patients with hyperthyroidism. However, rhabdomyolysis and acute renal failure have rarely been reported in association with hyperthyroidism [50,51].

Gradually progressive proximal muscle weakness with or without muscle wasting occurs in some patients with acromegaly. Mild myopathic changes may be seen on muscle biopsy, and mild elevation of muscle enzymes has been reported [52]. However, weakness may be a manifestation of peripheral neuropathy. (See "Causes and clinical manifestations of acromegaly", section on 'Soft tissue and skin'.)

Cushing's syndrome, glucocorticoid-induced myopathy, and hyperparathyroidism may all be associated with muscle weakness. However, muscle enzyme levels remain normal in these conditions. (See "Epidemiology and clinical manifestations of Cushing syndrome" and "Glucocorticoid-induced myopathy" and "Primary hyperparathyroidism: Clinical manifestations", section on 'Symptomatic primary hyperparathyroidism'.)

Diabetic muscle infarction is a rare complication of diabetes mellitus. Patients with poorly controlled type I disease appear to be at highest risk of developing this otherwise rare disorder. The sudden onset of pain and localized swelling in the thigh or calf muscles that characterize muscle infarction must be distinguished from pyomyositis or other causes of localized myositis. The serum CK level may be normal or elevated. The erythrocyte sedimentation rate (ESR) is usually increased. Gradual resolution of pain and swelling is expected over several weeks to months, but recurrences may occur. (See "Diabetic muscle infarction".)

Periodic paralyses — The periodic paralyses are characterized by unpredictable recurrent episodes of muscle weakness lasting generally from a few hours to a few days and then spontaneously resolving. The periodic paralyses have been classified as primary or secondary depending upon whether there is a family history or an underlying condition such as thyrotoxicosis and, on the basis of serum potassium levels during an attack, as hypokalemic, hyperkalemic, or normokalemic. The common mechanism of these conditions appears to be an intermittent unexcitability of the muscle fiber membrane related to electrolyte shifts across the membrane. (See "Hypokalemic periodic paralysis" and "Hyperkalemic periodic paralysis" and "Thyrotoxic periodic paralysis".)

Muscle enzyme levels rise rapidly during an attack and may remain slightly elevated between attacks. The degree of enzyme elevation varies widely among patients with these disorders [53].

ELEVATED MUSCLE ENZYMES IN THE ABSENCE OF MUSCLE DISEASE — Serum muscle enzyme concentrations can be increased in the absence of muscle disease with exercise, muscle trauma, and motor neuron disease.

Exercise — Serum creatine kinase (CK) concentrations reach peak levels at 8 to 24 hours after exercise, begin to decrease at 24 to 48 hours, and return to baseline levels by 72 hours [54]. The increase in CK levels is related to the intensity and duration of exercise and is greater in untrained than trained individuals [54-56]. In an exercise laboratory setting, for example, repetitive sets of leg extension against resistance for 30 minutes resulted in a greater than threefold increase in CK at 8 to 24 hours [54]. Serum lactate dehydrogenase (LDH) and transaminase levels follow a similar pattern after exercise, although the increase is not as great as with CK [54,57]. Postexercise elevations in muscle enzymes may be asymptomatic or accompanied by muscle soreness.

Iatrogenic muscle injury — CK levels follow the same temporal pattern after an intramuscular injection, major surgery, electromyography (EMG), or muscle biopsy. The muscle enzyme elevations in the last two settings may confuse serum muscle enzyme measurements in the evaluation of myopathy [1]. Major surgical procedures, particularly orthopedic and spinal surgery, cause serum enzyme elevation due to direct muscle trauma and to ischemic compression of muscle due to positioning during the procedure [58,59].

Motor neuron disease — In one study of 94 patients with motor neuron disease (amyotrophic lateral sclerosis), mild elevations in serum muscle enzymes were found in 75 percent of cases, particularly in the early phases of the disease and more commonly in men [60]. The highest measured CK concentration was 11 times normal, and the mean CK for the entire group was about twofold greater than normal, possibly leading to misdiagnosis of an inflammatory myopathy or inclusion body myositis.

Mild elevations of CK, usually less than twice the upper limit of normal, may occur in the various childhood motor neuron disorders also known as the spinal muscular atrophies. These disorders include Werdnig-Hoffmann disease and Kugelberg-Welander disease. Children with the chronic form of spinal muscular atrophy may present some diagnostic difficulty in distinguishing cases from juvenile polymyositis. However, marked elevations of CK in young children presenting with proximal muscle weakness would exclude the diagnosis of spinal muscular atrophy [61]. (See "Spinal muscular atrophy".)

Asymptomatic elevations in creatine kinase — Individuals with persistently elevated CK but with no or minimal muscle symptoms and no weakness present a diagnostic dilemma.

Muscle biopsies in these individuals are infrequently diagnostic, and in those patients in whom a specific diagnosis can be made, it is usually a disorder for which there is no treatment, such as a dystrophy or a metabolic myopathy with a benign outcome. The following studies are illustrative:

●In one report including 114 individuals with elevated CK and no or minimal muscle symptoms, 50 percent of individuals had abnormalities on EMG or muscle biopsy, but a specific diagnosis could only be made in 18.4 percent [62]. These diagnoses included metabolic myopathies, dystrophies, malignant hyperthermia susceptibility, and congenital myopathy. Approximately 32 percent of individuals had normal muscle findings on biopsy and EMG.

●Long-term follow-up of 55 asymptomatic individuals from the aforementioned study revealed that a specific diagnosis could be made in only three of these individuals after an average of 7.5 years [63].

●In other studies, the frequency of a diagnostic muscle biopsy has ranged from 0 to 78 percent with an average of 23 percent, although an abnormal muscle biopsy was present in 67 percent [64].

An approach to evaluating an asymptomatic patient with an unexplained elevated CK includes:

●Determine if the elevated CK is high enough to be of clinical significance based on age, gender, and race. CK levels decrease with age, so elevated levels are more likely to be due to an identifiable cause in children and adolescents. Serum CK levels vary between racial groups, being higher in Black Americans compared with White, Hispanic, or Asian Americans [65]. Within racial groups, CK levels are correlated with body size and composition, including body mass index (BMI) and fat mass, and are higher in males than females. The racial differences in serum CK levels cannot be completely explained, however, by differences in body composition [66,67]. A large population-based cohort study showed that the upper limit of normal CK levels vary by race and gender, and these levels are higher than the reference levels provided by the assay manufacturers [68]. CK levels 1.5 times the upper limit of normal should be considered abnormal; these equate to >1200 for Black men, >650 for Black women, >500 for White men, and >325 for White women.

●Repeat the CK after the patient has refrained from intense exercise for at least three days if there is any question that the elevation could be due to overexertion. Exclude recent intramuscular injections.

●Review the medication list and inquire about recent drug exposures that could lead to a drug-induced CK elevation, particularly if the patient is treated with a statin drug. (See "Drug-induced myopathies" and "Statin muscle-related adverse events".)

●Consider the possibility of macro CK, particularly if there is an unexpected increase in the MB isoenzyme, which can be identified by CK electrophoresis [11,69]. (See 'Creatine kinase' above.)

●EMG can be performed to exclude motor neuron disease. EMG is not, however, adequately specific or sensitive to exclude myopathy with certainty.

●A muscle biopsy can be performed only after a discussion with the patient that the likelihood of making a definite diagnosis of a treatable condition is extremely low and that the prognosis of an isolated unexplained CK is very good.

●If there is concern for malignant hyperthermia susceptibility based on the patient’s family history or a previous reaction to an inhaled anesthetic agent, a muscle biopsy may be done for a contracture test. (See "Susceptibility to malignant hyperthermia: Evaluation and management", section on 'Contracture test'.)

Renal disease — The effects of renal failure on creatine kinase, aminotransferases, and other serum enzymes are discussed in detail separately. (See "Cardiac troponins in patients with kidney disease" and "Serum enzymes in patients with kidney failure".)

MUSCLE ENZYMES IN MONITORING THE COURSE OF DISEASE — Monitoring the serum concentration of muscle enzymes can be used to monitor the course of patients with dermatomyositis/polymyositis or those with rhabdomyolysis.

Dermatomyositis or polymyositis — In adults with dermatomyositis or polymyositis, serum levels of creatine kinase typically decrease by about 50 percent during the first month of high-dose therapy with glucocorticoids, and normalization of muscle enzymes may take up to four months [14,19,70]. Muscle enzyme levels generally decrease before improvement in muscle strength occurs; normalization of muscle enzymes with therapy is predictive of recovery of strength. In one study, for example, good clinical outcomes accompanied 17 of 17 myositis episodes in which muscle enzymes normalized but only 8 of 25 episodes in which muscle enzymes did not normalize [71]. Failure to normalize muscle enzymes after two months should prompt consideration of alternative diagnoses such as inclusion body myositis, muscular dystrophy, or hypothyroidism.

However, in some cases of severe disease, serum enzymes will fail to normalize even with aggressive glucocorticoid and immunosuppressive therapy. (See "Initial treatment of dermatomyositis and polymyositis in adults" and "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults".)

Disease exacerbations are usually preceded by an increase in muscle enzymes. Thus, serial enzyme measurements are generally useful in assessing the disease course in an individual patient. In some cases, the elevations in serum creatine kinase (CK) or aminotransferase concentrations are within the normal range but are still a harbinger of increased clinical disease activity. If glucocorticoids are tapered at the time of a mild increase in CK, a further increase in CK to outside the normal range and relapse of muscle weakness is likely [71]. By contrast, recurrence of weakness during glucocorticoid treatment with no increase in serum enzymes is more likely to represent steroid myopathy than increased disease activity.

Muscle enzymes also tend to parallel disease activity in juvenile dermatomyositis. In one study, aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were found to be better predictors of disease flares than CK [72]. However, this observation must be confirmed before the general practice of monitoring the serum CK concentration is changed.

Rhabdomyolysis — The degree of serum muscle enzyme elevation does not always predict the development of acute renal failure in rhabdomyolysis, although there is a general correlation. In one study, for example, 58 percent of patients developing acute renal failure had peak CK levels greater than 16,000 units/L compared with only 11 percent in those who did not develop acute renal failure [43]. The peak CK elevation is usually reached quickly, occurring within the first day after the muscle insult. It then falls rapidly back to the normal range over several days to one week, depending on the maximum peak level. This rapid decline helps to distinguish rhabdomyolysis from more chronic disorders of myopathy such as polymyositis. (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury".)

SUMMARY AND RECOMMENDATIONS — The measurement of serum levels of muscle enzymes is a critical part of the evaluation of patients presenting with weakness or myalgias and is important in monitoring the course and response to therapy of certain muscular disorders. Creatine kinase (CK), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and aldolase are the serum enzymes that are measured in clinical practice.

●CK is the most widely used enzyme to diagnose and follow muscle disease. It is present in the highest concentrations in serum with muscle injury, is the most sensitive indicator of muscle injury, and is the best measure of the course of muscle injury. CK is located on the inner mitochondrial membrane, on myofibrils, and in the muscle cytoplasm, and it is involved in cellular energy storage and transfer. (See 'Creatine kinase' above.)

●CK is a dimer, which occurs in three distinct isoenzyme forms (termed MM, MB, and BB), which can be distinguished electrophoretically. Normal skeletal muscle CK is over 99 percent MM with small amounts of MB. The concentration of MB in skeletal muscle increases in individuals with inflammatory myopathy or muscular dystrophy, in the resting muscles of elite athletes, and in many individuals after extreme exercise. An increased ratio of serum CK-MB measured in inflammatory myopathies or in athletes after extreme exertion may be confused with myocardial infarction. (See 'Creatine kinase' above.)

●Serum aldolase concentrations are occasionally elevated in patients with myositis who have normal CK levels, but increased aldolase levels are not as specific or sensitive for muscle disease as CK levels. LDH and the aminotransferases are present in many tissues and are often elevated with skeletal muscle injury. (See 'Aldolase' above and 'Lactate dehydrogenase' above and 'Aminotransferases' above.)

●In general, marked elevation of serum muscle enzymes is seen in myopathies. Thus, serum CK activity greater than 1000 units/L helps to distinguish muscle disease from neurogenic causes of weakness and muscle atrophy. More modest elevation of CK may occur in some primary neurologic disorders, particularly lower motor neuron disease. (See 'Muscle enzymes in the diagnosis of neuromuscular disorders' above.)

●Serum levels of muscle enzymes may be elevated in a number of conditions. These include:

•Inflammatory myopathies (see 'Inflammatory myopathies' above)

•Infectious myopathies (see 'Infectious myopathies' above)

•Dystrophinopathies (see 'Dystrophinopathies' above)

•Rhabdomyolysis (see 'Rhabdomyolysis' above)

•Use of certain medications (see 'Drugs' above)

•Metabolic myopathies (see 'Metabolic myopathies' above)

•Malignant hyperthermia (see 'Malignant hyperthermia' above)

•Endocrine myopathies (see 'Endocrine myopathies' above)

•Periodic paralyses (see 'Periodic paralyses' above)

●Muscle enzymes may be elevated in the absence of muscle disease under certain conditions, including following exercise, in patients with iatrogenic muscle injury or motor neuron disease, and in several other situations without obvious neuromuscular disease. (See 'Elevated muscle enzymes in the absence of muscle disease' above.)

●The serum concentration of muscle enzymes can be used to monitor the course of patients with dermatomyositis/polymyositis or of those with rhabdomyolysis. (See 'Muscle enzymes in monitoring the course of disease' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marc L Miller, MD, who contributed to an earlier version of this topic review.