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Serum Myoglobin

Editor: John R. Richards Updated: 4/13/2023 6:04:00 PM

Introduction

Myoglobin is a dark red cytoplasmic hemoprotein found only in cardiac myocytes and oxidative skeletal muscle fibers.[1] It belongs to the super globin family of proteins. It comprises a single polypeptide chain of 154 amino acids and a porphyrin ring containing a central ferrous iron molecule. Similar to hemoglobin, myoglobin functions to reversibly bind oxygen and can form oxymyoglobin, carboxy myoglobin, or metmyoglobin.[2] Unlike hemoglobin, however, myoglobin has only one binding site for oxygen, the affinity of which is comparatively very high.[3] As a result, myoglobin can receive oxygen from hemoglobin at the tissue level via the Bohr effect and either store oxygen or deliver it to muscle cells during periods of hypoxia, anoxia, or increased metabolic activity.[4]

Etiology and Epidemiology

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Etiology and Epidemiology

Due to its low molecular weight, myoglobin is released quickly following muscle injury; it is the earliest marker of myocardial infarction and rhabdomyolysis.[5] The release of myoglobin from muscles during such conditions is often also associated with the release of lactate dehydrogenase (LDH), creatine kinase, and serum glutamic-pyruvic transaminase, in addition to other enzymes.[6] Secondary complications of rhabdomyolysis include hyperkalemia, hypocalcemia, and acute kidney injury; myoglobin in the urine is toxic to the nephron.[7]

Myoglobinuria in adults is most often encountered in cases of alcohol and drug abuse or trauma; muscle necrosis with subsequent myoglobin release also commonly occurs due to prolonged immobilization or pressure from the weight of the body.[8] Furthermore, excessive physical activity; metabolic disorders; viral infections, such as influenza, HIV, or herpes simplex; toxin-producing bacterial infections; connective tissue disease; seizures; electrical shock injury, including lightning strikes; third-degree burns; venom from a snake or insect bite; certain medications, such as statins or antipsychotics; or prolonged alcohol or drug use, as with heroin, cocaine, or amphetamines all can create an imbalance in muscle energy production and consumption which result in muscle damage and destruction.[9]

Contrastingly, rhabdomyolysis or myoglobinuria in children is often associated with viral myositis, trauma, excessive muscular exertion, drug overdose, seizures, connective tissue disease, or metabolic disorders.[10]

The incidence of myoglobinuria in the United States varies depending on the incidence of traumas or natural disasters. An increased incidence of viral myositis, such as that caused by a regional epidemic, may cause a temporary increase in the incidence of rhabdomyolysis and myoglobinuria.[11] The excessive heat or higher temperatures seen in the summer months or warmer geographic areas may cause heat stroke, especially in those who are more active; malignant hyperthermia or neuroleptic malignant syndrome may additionally increase the incidence of stress or exertion-induced rhabdomyolysis.[12]

Pathophysiology

Under normal conditions, myoglobin circulates in the blood bound to plasma globulins which are maintained between 0 to 0.003 mg/dL.[7] Once serum myoglobin levels reach a level above 0.5 to 1.5 mg/dL, the rate of metabolism, endocytosis, and serum protein binding capacity is overwhelmed, and myoglobin is rapidly excreted in the urine.[13]

Myoglobin release from muscle tissues occurs due to damage to muscle cells and a change in skeletal muscle cell membrane permeability.[14] Damage to muscle cells results in dysregulation of sodium-calcium channel functioning, ultimately elevating intracellular free ionized calcium.[15] This causes a resultant activation of calcium-dependent enzymes, which further metabolize and destroy the muscle cell membrane and allow for the release of intracellular contents, including myoglobin and creatine kinase.[16]

In health, myoglobin is easily filtered by the glomerulus and quickly excreted in the urine. However, large amounts of myoglobin in renal tubules can lead to an interaction of the hemoprotein with Tamm-Horsfall proteins, subsequent precipitation, and tubular obstruction.[17] This process occurs most favorably in conditions where acidic urine is present. In addition, damage to both muscle tissues and kidney epithelial cells promotes the production of reactive oxygen species, which can, in turn, lead to the oxidation of ferrous oxide to ferric oxide, a hydroxyl radical.[18] Myoglobinuria-induced tubular obstruction and oxidative damage can, either alone or in combination, lead to acute kidney injury.[19]

Specimen Requirements and Procedure

The preferred specimen is non-hemolyzed, non-lipemic serum. One study found no significant difference between heparinized plasma and serum, although results from EDTA plasma samples were significantly lower than serum samples.[20] Another study found that different anticoagulants can substantially interfere with myoglobin assays.[21] Each method should be investigated concerning the differences observed between serum and the use of various anticoagulants. Specimens are stable at 4^oC for one week and up to four weeks at −20^oC.[22]

Urine samples should be collected without preservatives and assayed within 24 hours of sample collection. If the test is not performed immediately after sample collection, the urine sample should be kept at 2^oC to 8^oC and centrifuged to remove any debris before the assay.[23] Myoglobin in urine is stable under alkaline conditions (pH 9.0) for many days at 2^oC, −20^oC, and −70^oC; sodium hydroxide can be added if long-term storage is needed.[24]

Diagnostic Tests

The diagnosis of rhabdomyolysis requires a high index of suspicion, given that the classic clinical symptoms may not be present.[7] A definitive diagnosis is often made by elevated serum creatine kinase or urine myoglobin.[25] Liver and renal function may be assessed if complications secondary to rhabdomyolysis are concerning.[26] 

Although myoglobin is the first enzyme to be elevated in rhabdomyolysis, levels often return to normal within 24 hours after the onset of symptoms.[27] Serum creatine kinase levels, on the other hand, begin to rise approximately 2 to 12 hours after the onset of symptoms and remain elevated for 7 to 10 days, with levels peaking around three days after the onset of symptoms.[28] Serum creatine kinase is also an important and useful tool for gauging the severity of rhabdomyolysis.[29] Elevated serum creatine kinase suggests a possible delay of clearance from the plasma by the kidneys, indicating complications such as acute kidney damage or injury.[30]

Though myoglobinuria is pathognomonic for rhabdomyolysis, it is important to note that rhabdomyoglobinuria is not always present or visible.[31] The presence of myoglobin in the blood also lacks cardiac specificity due to its concomitant expression in both cardiac and skeletal muscle cells.[32] Therefore, a more specific indicator, such as troponin or creatine kinase, must be measured to confirm a diagnosis of acute myocardial infarction.[33] 

Urinalysis should be employed to evaluate for myoglobinuria and assess the presence or severity of renal damage or acute kidney injury.[34] Furthermore, if kidney injury due to rhabdomyolysis is suspected, the serum creatinine level should be assessed; creatinine is often quickly elevated during rhabdomyolysis when compared to other causes of kidney injury. In addition to this, the blood urea nitrogen to creatinine ratio is also generally low.[35]

A thorough history and physical examination are critical to diagnosing rhabdomyolysis, though they are not always helpful in determining the underlying cause.[25] If infectious causes are suspected, one should assess the complete blood count, appropriate cultures, and any additional serologic studies that may help confirm or point toward a diagnosis. Blood chemistries and endocrine assays may be helpful if an underlying endocrine abnormality is suspected.[26] If drugs or toxins are a potential underlying cause, the appropriate screening for toxins should be performed.[36] In patients with repeated instances of rhabdomyolysis, genetic testing, a muscle biopsy, or the forearm ischemic exercise test may reveal an underlying myopathy or metabolic disorder.[28]

Though imaging is not generally indicated in cases of rhabdomyolysis, given that it is a clinical syndrome often diagnosed with supportive laboratory tests, MRI, bone scintigraphy, ultrasound, or CT can be used to demonstrate some changes in muscle tissue.[37] An ECG is necessary to detect cardiac arrhythmias from electrolyte abnormalities due to rhabdomyolysis.[38] An assessment of blood chemistries also may help point towards this, in addition to an arterial blood gas analysis if metabolic acidosis is suspected.[25]

Testing Procedures

Qualitative and semiquantitative immunological methods have been used for the detection of myoglobin.[24] With the simplicity of the agar gel precipitin techniques and the speed of electrophoresis, counter immunoelectrophoresis has been used to detect myoglobin in both serum and urine.[39] It is a qualitative procedure with a sensitivity of only 2 mg/L. Thus, it is unsuitable for detecting acute myocardial infarction (AMI).[40]

A rapid, qualitative latex agglutination test for detecting increased concentrations of myoglobin in serum has been reported.[41] In this test procedure, any interfering rheumatoid factor present in the sample is removed when 50 μL of test serum is mixed with 5 μL of rheumatoid factor absorption medium on a dark slide. About 50 μL of a suspension of latex particles with bound anti-myoglobin antibodies is added and mixed with the serum by gentle tilting for 5 minutes. Agglutination of the particles occurs in the presence of myoglobin. A negative exponential relationship has been found between the time of agglutination and myoglobin concentrations.[42] Myoglobin concentration was considered to be greater than 400 mg/L if agglutination occurred within 1 minute, 150 to 400 mg/L if agglutination time was between 1 and 2 minutes, 80 to 150 mg/L if agglutination time was between 2 and 3 minutes, and less than 80 mg/L (upper limit of reference interval) if more than 3 minutes were required for agglutination.[43]

Red blood cell agglutination techniques are reported to be sensitive in the 50 to 100 mg/L range. A disadvantage of this technique is that some sera containing a high concentration of rheumatoid factor gave positive agglutination reactions.[44] The latex agglutination procedure is, at best semiquantitative and is somewhat subjective, requiring visual observation to establish an endpoint. The sensitivity of the latex test may not be adequate.[45] The advantage of the latex test is its simplicity.[42]

A quantitative microcomplement fixation assay has been developed to detect myoglobin in the serum and urine of patients with acute coronary syndrome or myopathies.[46] This technique is based on consuming a fixed amount of hemolytic complement by myoglobin-antimyoglobin complexes.[47] The amount of myoglobin present in the sample is inversely proportional to the extent of hemolysis of the hemolysin-sensitized sheep cells used as the indicator system.[48] Quantitative microcomplement fixation is an extremely time-consuming and laborious technique.[47] 

Currently, the determination of serum myoglobin for diagnosing AMI and other muscle disorders is performed almost exclusively by immunoassay techniques because of their high analytical sensitivity, specificity, precision, and rapid turnaround time.[49] Radioimmunoassay (RIA) procedures have also been described for quantitative measurement of serum myoglobin. However, in clinical laboratories, RIA has largely been replaced by automated 2-site non-isotopic immunoassays.[50] The capture antibody is linked to a bead or paramagnetic particle. The detecting antibody is linked to a tag that can produce a nephelometric, turbidimetric, fluorometric, or chemiluminescence signal.[49] Automated immunoassay analyzers perform a separation between bound and free labels to produce a quantitative result.[51] 

Qualitative and quantitative methods for serum myoglobin have also been developed for point-of-care (POC) use.[52] One POC method utilizes a self-calibrating immunoassay system whereby whole blood is separated from plasma that reacts with fluorescent antibody conjugates within a reaction chamber. Following an incubation step, the reaction mixture flows down a detection lane by capillary action. The myoglobin–fluorescent antibody complex is captured by a second antibody in a discrete measuring zone. The intensity of the label (visual or fluorescence) is related to myoglobin concentration. The procedure takes approximately 15 minutes to complete.[53] Since myoglobin measurements are most commonly used in diagnosing and excluding AMI, several POC devices have combined myoglobin with other cardiac markers, such as CK-MB and cardiac troponin, into a single cartridge or slide.[54]

International guidelines such as those from the National Academy of Clinical Biochemistry have suggested that results of cardiac markers should be reported within one hour of blood collection.[55] Other groups, such as the American Heart Association, have suggested an optimal turnaround time of under 30 minutes.[56] These POC devices are designed for use at the patient bedside or emergency department satellite laboratories to produce results that meet these recommended 30- to 60-minute turnaround time goals for reporting test results.[57]

Interfering Factors

The use of collection tubes with separator gels has been reported to both increase and decrease myoglobin results.[21]  Bilirubin has been found not to interfere.[58] Rheumatoid factor (RF) has been found to affect results in some assays, with a lack of concordance between concentrations of RF and the magnitude of interference.[49] As with any 2-site immunoassays that use monoclonal antibodies, the presence of human anti-mouse antibodies can potentially cause a false-positive result.[59]

Clinical Significance

Myoglobin is a relatively small globular protein composed of a single polypeptide chain of 154 amino acids and an iron-containing heme prosthetic group identical to that of hemoglobin.[11] It can reversibly bind oxygen molecules and speed up the diffusion of oxygen into skeletal and cardiac muscle cells, where it is present.[1] Myoglobin is an oxygen carrier in the cytoplasm and appears responsible for transporting oxygen from the muscle cell membrane to the mitochondrion.[60] Immunological techniques cannot discriminate between myoglobins from skeletal and cardiac muscles since they are immunologically identical.[46]

Due to its relatively low molecular mass, myoglobin may leak from muscle tissue into the bloodstream due to skeletal or cardiac muscle injury and then show up in the urine.[8] Myoglobinemia and myoglobinuria have been used in the diagnosis of myopathies and cardiomyopathies.[28] A pronounced increase in serum myoglobin is an early quantitative indicator of AMI.[5] It has been reported that myoglobinuria is a more sensitive clinical indicator of AMI than increased activities or concentrations of serum creatine kinase-MB (CK-MB) isoenzyme, especially when blood samples are drawn in the early stage of the disease (e.g., within 3 hours after onset).[61] However, these assays are less specific because no assay can differentiate myocardial from skeletal muscle myoglobin.[62] Increased serum myoglobin concentrations return to normal sooner than total CK and the CK-MB isoenzyme in AMI.[63] The faster elimination of myoglobin from the blood may be advantageous in the assessment of reinfarctions occurring during the period of increased enzyme activities.[64] Recurrent increases in serum myoglobin are thus suggestive of an extension of the original infarction.[65]

Since myoglobin is also present in skeletal muscle and is cleared almost exclusively through glomerular filtration, myoglobin will increase after acute muscle trauma, acute or chronic kidney injury, severe heart failure, prolonged shock, and in patients with myopathies of a variety of causes.[11] Therefore, using serum myoglobin levels to furnish early, quantitative documentation of AMI should be limited to patients who do not have these underlying or associated problems and who are within the first 18 hours of the clinical onset of infarction.

In addition, serum myoglobin levels have been used to evaluate neuromuscular diseases such as muscular dystrophy, muscular atrophy, and polymyositis.[66] Percy et al. reported that the combination of CK, hemopexin, and myoglobin measurements provided significantly better detection of Duchenne muscular dystrophy carriers than when these three tests were used alone or as a combination of CK and hemopexin without myoglobin.[67]

In studies conducted on myopathies in children, serum myoglobin concentrations for subjects 0.6 to 20 years were lower than in adults, so using assays with a high sensitivity of 2 µg/L or less is necessary.[68] Mean myoglobin concentrations of 17.1 and 12.5 µg/L were obtained from 37 males and 29 females, respectively, and were statistically different.

Investigations in children with muscle diseases, however, have been somewhat disappointing. Only 2 out of 14 patients studied had increased serum myoglobin concentrations. The patients evaluated in this study were relatively young, ranging from 0.3 to 16 years of age, and were presumably in the relatively early stages of the disease.[66] This might have contributed to the low rate of hypermyoglobinemia in this group of patients. Edwards et al. also found that measurement of myoglobin offered no advantage over CK for investigating any aspect of Duchenne muscular dystrophy. However, serum myoglobin measurements were helpful in detecting Duchenne muscular dystrophy carriers when used with CK and hemopexin.[69]

Myoglobin measurements are also used for the diagnosis of patients with rhabdomyolysis.[7] The course and clinical presentation of rhabdomyolysis can vary significantly depending on the cause of the muscle injury. Symptoms may be localized to one specific area or diffusely affect the entire body. Complications may occur at varying stages of muscle injury.[26] The classic triad of symptoms associated with rhabdomyolysis includes muscle pain, especially in the shoulders, lower back, or thighs; muscle weakness; and darkened brownish urine or decreased urine output.[25] Approximately 50% of individuals who experience rhabdomyolysis may present asymptomatically.[27]

Other symptoms seen with rhabdomyolysis include nausea, vomiting, abdominal pain, tachycardia, fever or chills, dehydration, confusion, or an altered level of consciousness which may present as a coma.[70] Severe complications due to rhabdomyolysis are more frequently encountered in patients who are dehydrated.[71] Elevated potassium in the blood due to muscle cell damage may result in cardiac arrhythmias or even cardiac arrest and death.[28] Serum uric acid may increase, and metabolic acidosis may occur due to acute kidney injury secondary to myoglobinuria. Kidney injury may lead to elevated creatinine and blood urea nitrogen levels, in addition to an increase in creatinine leaking into the blood from the damaged muscle cells themselves.[30]

Although myoglobin is easily filtered by the glomerulus and rapidly excreted into the urine in health, it is important to recognize the presence and severity of myoglobinuria and intervene as early as possible. Aggressive hydration or alkalinization of urine may facilitate the excretion of myoglobin and prevent acute kidney injury.[72] Myoglobinuria is often associated with darkened, brown, or tea-colored urine and decreased urine output.[8] However, it is essential to distinguish myoglobinuria from hematuria. Where myoglobinuria produces more brownish-colored urine and only a few red blood cells per high-power field on urinalysis, hematuria often will cause reddish urine and many red blood cells on urinalysis.[9] The creatine kinase level will be much higher in patients with myoglobinuria than in those with hematuria.[71]

Quality Control and Lab Safety

For non-waived tests, laboratory regulations require, at the minimum, analysis of at least two levels of control materials once every 24 hours.[73] Laboratories can assay QC samples more frequently to ensure accurate results. Quality control samples should be assayed after calibration or maintenance of an analyzer to verify the correct method performance.[74] To minimize QC when performing tests for which manufacturers’ recommendations are less than those required by the regulatory agency (such as once per month), the labs can develop an individualized quality control plan (IQCP) that involves performing a risk assessment of potential sources of error in all phases of testing and putting in place a QC plan to reduce the likelihood of errors.[75] Westgard multi-rules are used to evaluate the quality control runs. In case of any rule violation, proper corrective and preventive action should be taken before patient testing is performed.[76]

The laboratory must participate in the external quality control or proficiency testing (PT) program because it is a regulatory requirement published by the Centers for Medicare and Medicaid Services (CMS) in the Clinical Laboratory Improvement Amendments (CLIA) regulations.[77] It is helpful to ensure the accuracy and reliability of the laboratory with regard to other laboratories performing the same or comparable assays. Required participation and scored results are monitored by CMS and voluntary accreditation organizations.[78] The PT plan should be included as an aspect of the quality assessment (QA) plan and the overall quality program of the laboratory.[79]

Consider all specimens, control materials, and calibrator materials as potentially infectious. Exercise the normal precautions required for handling all laboratory reagents. Disposal of all waste material should be in accordance with local guidelines.[80] Wear gloves, a lab coat, and safety glasses when handling human blood specimens. Place all plastic tips, sample cups, and gloves that come into contact with blood in a biohazard waste container. Discard all disposable glassware into sharps waste containers.[81] Protect all work surfaces with disposable absorbent bench top paper, discarded into biohazard waste containers weekly or whenever blood contamination occurs. Wipe all work surfaces weekly.[82]

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