Tools
Serum Myoglobin
Introduction
Myoglobin is a dark red cytoplasmic hemoprotein found only in cardiac myocytes and oxidative skeletal muscle fibers.[1] This protein belongs to the globin superfamily and consists of a single polypeptide chain of 154 amino acids and a porphyrin ring containing a central ferrous iron molecule. Similar to hemoglobin, myoglobin reversibly binds oxygen, forming oxymyoglobin, carboxy myoglobin, or metmyoglobin.[2] However, unlike hemoglobin, 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 through 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, making it one of the earliest markers of myocardial infarction and rhabdomyolysis.[5] The release of myoglobin from muscles during such conditions is often 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 most commonly occurs 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 body's weight.[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 between muscle energy production and consumption, leading to muscle damage and destruction.[9]
In contrast, 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 temporarily increase the incidence of rhabdomyolysis and myoglobinuria.[11] The excessive heat or higher temperatures observed in the summer months or warmer geographic areas may cause heat stroke, especially in individuals 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, with levels maintained between 0 and 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 the dysregulation of sodium-calcium channel functioning, ultimately leading to elevated intracellular free ionized calcium levels.[15] This increase activates calcium-dependent enzymes, which further metabolize and destroy the muscle cell membrane, allowing the release of intracellular contents, including myoglobin and creatine kinase.[16]
Under normal physiological conditions, 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. A study found no significant difference between heparinized plasma and serum samples, although results from EDTA plasma samples were significantly lower compared to those from 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 for 1 week at 4 °C and up to 4 weeks at −20 °C.[22]
Urine samples should be collected without preservatives and assayed within 24 hours of collection. If the test is not performed immediately after sample collection, the urine sample should be kept at 2 to 8 °C 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, −20, and −70 °C; sodium hydroxide can be added if long-term storage is required.[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] In contrast, serum creatine kinase levels 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 3 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 levels suggest a possible delay of clearance from the plasma by the kidneys, indicating complications such as acute kidney damage or injury.[30]
Although 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 is essential for evaluating myoglobinuria and assessing the presence or severity of renal damage or acute kidney injury.[34] If kidney injury due to rhabdomyolysis is suspected, the serum creatinine level should be assessed; creatinine is often quickly elevated during rhabdomyolysis compared to other causes of kidney injury. In addition, the blood urea nitrogen-to-creatinine ratio is also generally low.[35]
A detailed history and a thorough physical examination are crucial for diagnosing rhabdomyolysis, although they are not always helpful in determining the underlying cause.[25] If infectious causes are suspected, a complete blood count, appropriate cultures, and additional serologic studies should be performed. 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]
Although imaging is not generally indicated in cases of rhabdomyolysis, given that it is a clinical syndrome often diagnosed with supportive laboratory tests, magnetic resonance imaging, bone scintigraphy, ultrasound, or computed tomography can be used to demonstrate changes in muscle tissue.[37] An electrocardiogram is essential for detecting cardiac arrhythmias caused by electrolyte abnormalities due to rhabdomyolysis.[38] An assessment of blood chemistries can provide critical insights, and arterial blood gas analysis is recommended if metabolic acidosis is suspected.[25]
Testing Procedures
Qualitative and semiquantitative immunological methods have been used to detect myoglobin.[24] With the simplicity of the agar gel precipitin techniques and the speed of electrophoresis, counterimmunoelectrophoresis has been used to detect myoglobin in both serum and urine.[39] This qualitative procedure has a sensitivity of only 2 mg/L, making it unsuitable for detecting acute myocardial infarction.[40]
A rapid, qualitative latex agglutination test has been reported to detect elevated concentrations of myoglobin in serum.[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 agglutination time and myoglobin concentration.[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 have been reported to be sensitive within the range of 50 to 100 mg/L. 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–anti-myoglobin 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 acute myocardial infarction 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 procedures have also been described for quantitative measurement of serum myoglobin. However, in clinical laboratories, radioimmunoassay has largely been replaced by automated two-site non-isotopic immunoassays.[50] The capture antibody is linked to a bead or paramagnetic particle, and the detecting antibody is linked to a tag that can produce a nephelometric, turbidimetric, fluorometric, or chemiluminescence signal.[49] Automated immunoassay analyzers separate 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] A POC method uses a self-calibrating immunoassay system in which 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] As myoglobin measurements are most commonly used in diagnosing and excluding acute myocardial infarction, several POC devices have combined myoglobin with other cardiac markers, such as creatine kinase-MB (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 1 hour of blood collection.[55] Other groups, such as the American Heart Association, have suggested an optimal turnaround time of less than 30 minutes.[56] These POC devices are designed for use at the bedside of patients 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 shown not to interfere with these results.[58] Rheumatoid factor has been found to affect results in some assays, with a lack of concordance between concentrations of rheumatoid factor and the magnitude of interference.[49] As with any two-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 small, globular protein consisting of a single polypeptide chain of 154 amino acids and an iron-containing heme prosthetic group, which is identical to that found in hemoglobin.[11] Myoglobin 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 weight, myoglobin can leak from muscle tissue into the bloodstream following a skeletal or cardiac muscle injury, subsequently appearing 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 acute myocardial infarction.[5] Myoglobinuria has been reported as a more sensitive clinical indicator of acute myocardial infarction compared to increased activities or concentrations of serum CK-MB isoenzyme, especially when blood samples are drawn in the early stage of the disease, such as 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 compared to total creatine kinase and the CK-MB isoenzyme in acute myocardial infarction.[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]
Myoglobin present in skeletal muscle is cleared almost exclusively through glomerular filtration. The release of myoglobin increases following acute muscle trauma, acute or chronic kidney injury, severe heart failure, prolonged shock, and in patients with various myopathies.[11] Therefore, using serum myoglobin levels to furnish early, quantitative documentation of acute myocardial infarction should be limited to patients who do not have these underlying or associated conditions 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 combining creatine kinase, hemopexin, and myoglobin measurements significantly enhanced the detection of Duchenne muscular dystrophy carriers compared to using creatine kinase and hemopexin alone or any of these tests individually.[67]
Studies conducted on myopathies showed that serum myoglobin concentrations for patients aged 0.6 to 20 were lower compared to those observed in adults; therefore, assays with a high sensitivity of 2 µg/L or less are 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 have yielded limited findings regarding elevated serum myoglobin concentrations. Only 2 out of 14 patients studied showed increased levels of serum myoglobin. The patients in this study were relatively young, aged 0.3 to 16, and were presumably in the early stages of the disease, which might have contributed to the low rate of hypermyoglobinemia in this group of patients.[66] Edwards et al also found that the measurement of myoglobin offered no advantage over creatine kinase in evaluating Duchenne muscular dystrophy. However, when combined with creatine kinase and hemopexin, serum myoglobin measurements were useful for identifying Duchenne muscular dystrophy carriers.[69]
Myoglobin measurements are also used to diagnose patients with rhabdomyolysis.[7] The course and clinical presentation of rhabdomyolysis can vary significantly depending on the cause of muscle injury. Symptoms may be localized to a 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 observed 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 dehydrated patients.[71] Elevated levels of 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 levels of creatinine and blood urea nitrogen. In addition, damaged muscle cells contribute to creatinine leakage into the bloodstream, exacerbating the renal burden.[30]
Although myoglobin is easily filtered by the glomerulus and rapidly excreted into the urine under normal conditions, early recognition and management of myoglobinuria are critical to preventing complications. Aggressive hydration or alkalinization of urine may facilitate the excretion of myoglobin and prevent acute kidney injury.[72] Myoglobinuria is commonly associated with dark, brown, or tea-colored urine and decreased urine output.[8] However, distinguishing myoglobinuria from hematuria is essential. Myoglobinuria produces more brownish-colored urine and only a few red blood cells per high-power field on urinalysis. In contrast, hematuria often causes reddish urine and many red blood cells on urinalysis.[9] The creatine kinase level is much higher in patients with myoglobinuria compared to those with hematuria.[71]
Quality Control and Lab Safety
For non-waived tests, laboratory regulations require analyzing at least two levels of control materials at least every 24 hours.[73] Laboratories can more frequently assay quality control (QC) samples to ensure accurate results. QC 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 compared to those required by the regulatory agency, such as once per month, the laboratories can develop an individualized quality control plan 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 proceeding with patient testing.[76]
The laboratories must participate in the external quality control or proficiency testing program as mandated by the Centers for Medicare and Medicaid Services (CMS) under the Clinical Laboratory Improvement Amendments regulations.[77] Participation helps ensure accuracy and reliability by comparing laboratory results with those from other laboratories performing similar assays. CMS and voluntary accreditation organizations monitor participation and scored results.[78] The proficiency testing plan should be included as an aspect of the quality assessment plan and the laboratory's overall quality program.[79]
All specimens, control materials, and calibrator materials should be treated as potentially infectious, and standard precautions for handling laboratory reagents must be followed. All waste materials should be disposed of in accordance with local guidelines.[80] Laboratory personnel should wear gloves, a lab coat, and safety glasses when handling human blood specimens. All materials in contact with blood, such as plastic tips, sample cups, and gloves, should be disposed of in a biohazard waste container. Disposable glassware should be discarded into sharps waste containers.[81] Work surfaces should be protected with disposable absorbent bench top paper, discarded into biohazard waste containers weekly or whenever blood contamination occurs, and wiped down regularly.[82]
Enhancing Healthcare Team Outcomes
Effective management of conditions associated with elevated serum myoglobin, such as rhabdomyolysis and myocardial infarction, requires a coordinated interprofessional approach. Clinicians and advanced practitioners diagnose the underlying condition and initiate treatment, whereas laboratory technicians ensure accurate and timely results through optimized sample handling and advanced diagnostic methods. Pharmacists contribute by advising on medication management to mitigate risks, such as avoiding nephrotoxic drugs in vulnerable patients. Nurses monitor patient symptoms and administer hydration therapy to prevent complications such as acute kidney injury.
Effective communication among healthcare team members is vital for sharing critical findings, adjusting treatment strategies, and delivering comprehensive patient education. By implementing streamlined workflows, such as POC testing protocols in emergency settings, the team ensures rapid diagnostic turnaround and enables prompt clinical decision-making. This collaborative effort enhances patient safety and improves clinical outcomes by addressing potential complications early and tailoring interventions to each patient’s unique needs.
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