Serum Myoglobin


Article Author:
Anoosh Zafar Gondal
Lisa Foris


Article Editor:
John Richards


Editors In Chief:
Lawrence Lee
Michael Firstenberg
Lawrence Greiten


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
7/12/2019 6:59:54 PM

Introduction

Myoglobin is a dark red cytoplasmic hemoprotein found only in cardiac myocytes and oxidative skeletal muscle fibers. It belongs to the super globin family of proteins and is composed of a single polypeptide chain of 154 amino acids as well as 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. Unlike hemoglobin, however, myoglobin has only one binding site for oxygen, the affinity of which is comparatively very high.  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.[1][2][3]

Etiology and Epidemiology

Due to its low molecular weight, myoglobin is released quickly following muscle injury and is the earliest marker of both myocardial infarction and rhabdomyolysis. The release of myoglobin from muscles during such conditions is often also associated with a release of lactate dehydrogenase (LDH) creatine kinase, and serum glutamic-pyruvic transaminase, in addition to other enzymes. [4][5][6]

Secondary complications of rhabdomyolysis include hyperkalemia, hypocalcemia, and acute kidney injury such as caused by myoglobinuria.

Myoglobinuria in adults most often is encountered in cases of trauma or alcohol and drug abuse and generally as a result of muscle necrosis as a result of prolonged immobilization or pressure from the weight of the body.  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.

Contrastingly, rhabdomyolysis or myoglobinuria in children most often is associated with viral myositis as well as trauma, excessive muscular exertion, drug overdose, seizures, connective disuse disease, or metabolic disorders.

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 an epidemic, in certain regions may cause a temporary increase in the incidence of rhabdomyolysis and myoglobinuria. Excessive heat or higher temperatures such as in the summer months or warmer geographic areas which cause heat stroke, especially in those who are more active; or that caused by malignant hyperthermia or neuroleptic malignant syndrome, may additionally increase the incidence of stress or exertion-induced rhabdomyolysis.[7][8]

Pathophysiology

Under normal conditions, myoglobin circulates in the blood bound to plasma globulins which are maintained at a level of 0-0.003 mg/dL. 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.

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

Although myoglobin is normally easily filtered by the glomerulus and quickly excreted in the urine, the presence of large amounts of myoglobin in renal tubules can lead to an interaction of the hemoprotein with Tamm-Horsfall proteins and subsequent precipitation and tubular obstruction. 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 oxidation of ferrous oxide to ferric oxide, a hydroxyl radical. Both tubular obstruction and oxidative damage, as a result of myoglobinuria, can alone or in combination lead to acute kidney injury.

Specimen Requirements and Procedure

Blood and urine samples should be obtained for analysis.

Diagnostic Tests

The diagnosis of rhabdomyolysis requires a high index of suspicion, given that the classic clinical symptoms may not be present. A definitive diagnosis often is made by the presence of elevated serum creatine kinase or urine myoglobin.

Although myoglobin is the first enzyme to be elevated in the setting of rhabdomyolysis, levels often return to normal 24 hours after the onset of symptoms. 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 3 days after the onset of symptoms. Serum creatine kinase is also an important and useful tool for gauging the severity of rhabdomyolysis.  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.

Though myoglobinuria is pathognomonic for rhabdomyolysis, it is important to note that rhabdomyoglobinuria is not always present or visible.

It is important to note that the presence of myoglobin in the blood also lacks cardio specificity, due to its concomitant expression in both cardiac and skeletal muscle cells. Therefore, a more specific indicator, such as troponin or creatine kinase, must be measured to confirm a diagnosis of acute myocardial infarction. 

Testing Procedures

Hematology, as well as blood chemistries, prothrombin time and activated partial thromboplastin time, should be employed to assess serum myoglobin and creatine kinase. Liver and and renal function also may be assessed if complications secondary to rhabdomyolysis are concerning.

Urinalysis should be employed to evaluate for myoglobinuria, such as with acute kidney injury, and assess the severity of renal damage, if present.

Furthermore, if kidney damage is suspected, as a result of rhabdomyolysis, the level of serum creatinine should be assessed, as it 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.

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.

An ECG is necessary to detect cardiac arrhythmias that may result from electrolyte abnormalities due to rhabdomyolysis. An assessment of blood chemistries also may help point towards this, in addition to an arterial blood gas analysis if metabolic acidosis is suspected.   

A thorough history and physical examination are extremely important to form a diagnosis of rhabdomyolysis, though they are not always useful in determining the underlying cause. If infectious causes are suspected, one should assess 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 useful if an underlying endocrine abnormality is suspected. If drugs or toxins are a potential underlying cause, the appropriate screening for toxins should be performed.

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.

The caffeine halothane contracture test can help detect an individual’s risk of developing malignant hypothermia. 

Interfering Factors

A serum creatine kinase level greater than 1000 units/L, which is 5 times the upper limit of normal, is diagnostic for rhabdomyolysis. Levels of serum creatine kinase tend to peak around 3 days following the onset of symptoms and decline gradually over the course of 7 to 10 days.  Persistently elevated levels of creatine kinase in the blood indicate ongoing muscle injury or stress, such as with prolonged exercise or infection, or the development of compartment syndrome.

Creatine kinase levels of 50 times the upper limit of normal often are considered diagnostic for statin-induced rhabdomyolysis, which generally occurs with associated muscle symptoms and darkening of the urine.

Additional enzymes that may be elevated include LDH and aspartate aminotransferase.

Additional electrolyte abnormalities in patients with rhabdomyolysis may release muscle cell contents into the blood, including hyperphosphatemia and hyperkalemia. Furthermore, hypercalcemia may develop as a result of hyperphosphatemia or deposition of calcium in damaged muscle cells.

Serum uric acid may increase, and metabolic acidosis may occur as a result of acute kidney injury secondary to myoglobinuria. Kidney injury also may lead to elevated creatinine and BUN levels along with the increased creatinine already leaking into the blood from the damaged muscle cells themselves.

Urine analysis may reveal myoglobinuria in patients experiencing rhabdomyolysis. Myoglobinuria often is associated with darkened, brown or tea-colored urine in addition to decreased urine output. However, is important to distinguish myoglobinuria from hematuria. Where myoglobinuria produces a more brownish-colored urine and only a few red blood cells per high-power field on urinalysis, hematuria often will cause a more reddish urine and many red blood cells on urinalysis. The level of creatine kinase will be much higher in patients with myoglobinuria, compared to those with hematuria.

Bone scintigraphy in a patient with rhabdomyolysis may demonstrate reaction of Tc99-labeled diphosphate with calcium in muscle tissues due to the destruction of the sarcoplasmic reticulum membrane. Though no imaging modality is considered very specific for rhabdomyolysis, MRI is the most sensitive and may demonstrate either an increased signal on T2 weighted imaging, a decreased signal on T1 weighted imaging, or an obvious contrast on short T1 inversion recovery (STIR, a fat suppression technique) imaging between damaged and healthy tissues. Muscular swelling as a result of edema may be visible as diffuse areas of low attenuation on CT imaging, in addition to the intramuscular foci of hypodensity which is suggestive of necrosis. Ultrasound imaging may similarly reveal hypoechoic areas as a result of edema and inflammation.

When rhabdomyolysis is localized to a specific area, especially when fasciotomy may need to be considered, MRI or bone scintography can prove particularly useful as a tool to avoid any unnecessary intervention.

Clinical Significance

The course and therefore clinical presentation of rhabdomyolysis can vary significantly depending on the cause of the muscle injury.  Symptoms also may be localized to one specific area or may diffusely affect the entire body. Complications may occur at varying stages of muscle injury.

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. Approximately 50% of individuals who experience rhabdomyolysis may present asymptomatically.

Other symptoms seen with rhabdomyolysis include nausea or vomiting, abdominal pain, tachycardia, fever or chills, dehydration, confusion or an altered level of consciousness which may include coma. Serious complications due to rhabdomyolysis are more frequently encountered in patients who are dehydrated.

Elevated potassium in the blood as a result of muscle cell damage may result in cardiac arrhythmias or even cardiac arrest and death.

Although myoglobin is normally easily filtered by the glomerulus and rapidly excreted into the urine, it is important to recognize the presence and severity of myoglobinuria and intervene as early as possible, such as with aggressive hydration or alkalinization of urine, to facilitate the excretion of myoglobin and prevent acute kidney injury. 

It is important to note that compartment syndrome also may result from aggressive fluid resuscitation as a treatment in response to rhabdomyolysis.


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Serum Myoglobin - Questions

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A 10-year-old girl is brought to the emergency department by her parents after her left leg was crushed under the car's wheels. They report she was playing in the garden and ran after a butterfly as her older brother was reversing back into the garage. On examination, she is unconscious, and her left leg is severely bruised. She undergoes immediate resuscitation. IV fluids, analgesics, and antibiotics are initiated, and the patient is stabilized. Labs are drawn, and they show increased levels of myoglobin and creatine kinase in her serum. Which of the following complications need to be watched out for in this patient?



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A 66-year-old male presents with a complaint of chest pain. The pain began three hours ago. It is pressure-like in nature, and it radiates to the chin and left arm. He also reports mild shortness of breath, nausea, and sweating. He has a history of hypertension, and he is not compliant with his medication. Current medications include a low-dose aspirin and lisinopril. He has a 30-year pack history. Vital signs show blood pressure of 160/100 mmHg, heart rate of 92/min, and a respiratory rate of 18/min. His BMI is 35. His physical exam is unremarkable. An ECG performed shows ST-elevations in lead I, II, and aVF. Which of the following enzymes will be detectable the earliest in this patient's serum?



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Which of the following statements about myoglobin is correct?



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After an earthquake, a 10-year-old girl is brought in by her parents. They report she was found with her legs pinned to the floor, by a 200-pound bookshelf. On examination, she is unconscious, and her lower limbs are severely bruised. She undergoes immediate resuscitation. IV fluids, analgesics, and antibiotics are initiated, and the patient is stabilized. On day 2 of hospitalization, her urine output is less than 0.5 mL/kg/hour. Renal function tests are performed and show that the BUN is 50 mg/dl, and creatinine is 3 mg/dl. Which of the following is responsible for this patient's current condition?



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A 60-year-old female presents to the clinic for her yearly evaluation. She has an 8-year history of diabetes mellitus type 2 and migraines. Her current medications include metformin, glyburide, acetaminophen, and atorvastatin. She does not use tobacco, alcohol, or illicit drugs. Her blood pressure is 120/80 mmHg, heart rate 75/min, and her weight is 150 pounds. Routine labs are performed. Fasting lipid profile shows total cholesterol 250 mg/dl, triglycerides 175 mg/dl, HDL 38 mg/dl, LDL 193 mg/dl. Fasting blood glucose is 120 mg/dl. Liver function tests show ALT 30 IU/L, AST 24 IU/L. In light of these lab results, strict diet control is advised, and atorvastatin dose is increased. The patient returns after a month complaining of severe muscle weakness and decreased urine output. She also reports a red-brown discoloration of the urine. A urine dipstick is performed and is positive for heme. Renal function tests reveal a BUN of 40 mg/dl and elevated creatinine levels at 2.6 mg/dl. Which of the following is most likely responsible for the patient's condition?



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A 30-year-old male presents with complaints of pain in the arm and leg muscles, vomiting, and dark-colored urine for one day. He states the symptoms started after he went to the gym after a year. He also reports starting a new high-intensity interval exercise regime and a vegan diet. He had extreme muscle soreness post-exercise and started noticing a reddish-brown discoloration of this urine after a few hours. He has never had similar symptoms in the past. His blood pressure is 110/90 mmHg, the pulse is 110/min, and his respiratory rate is 32/min. On examination, there is tenderness in the abdominal area, which the patient contributes to the crunches he performed during exercise, and passive movement of the upper and lower limbs, illicit pain. On further inquiry, he reports that he has not had to urinate much even though he is drinking large amounts of water. Renal function tests show a significantly raised creatinine and BUN. Creatinine kinase levels are also raised. Urine dipstick is positive for protein, and a urine analysis shows albumin 4+, red blood cell 3-4, pus cells 1-2, and granular casts 6-8/HPF. Which of the following is most likely responsible for the discoloration of this patient’s urine?



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Serum Myoglobin - References

References

Kuzmanovska B,Cvetkovska E,Kuzmanovski I,Jankulovski N,Shosholcheva M,Kartalov A,Spirovska T, Rhabdomyolysis in Critically Ill Surgical Patients. Medical archives (Sarajevo, Bosnia and Herzegovina). 2016 Jul 27;     [PubMed]
Giuliani KTK,Kassianos AJ,Healy H,Gois PHF, Pigment Nephropathy: Novel Insights into Inflammasome-Mediated Pathogenesis. International journal of molecular sciences. 2019 Apr 23;     [PubMed]
Chambers K,Sharma S, Physiology, Hepcidin 2019 Jan;     [PubMed]
Aydin S,Ugur K,Aydin S,Sahin İ,Yardim M, Biomarkers in acute myocardial infarction: current perspectives. Vascular health and risk management. 2019;     [PubMed]
Nilsson A,Alkner B,Wetterlöv P,Wetterstad S,Palm L,Schilcher J, Low compartment pressure and myoglobin levels in tibial fractures with suspected acute compartment syndrome. BMC musculoskeletal disorders. 2019 Jan 5;     [PubMed]
Zhen J,Li L,Yan J, [Advances in biomarkers of myocardial injury in sepsis]. Zhonghua wei zhong bing ji jiu yi xue. 2018 Jul;     [PubMed]
Servonnet A,Dubost C,Martin G,Lefrère B,Fontan E,Ceppa F,Delacour H, Myoglobin: still a useful biomarker in 2017? Annales de biologie clinique. 2018 Apr 1;     [PubMed]
Stopp T,Feichtinger M,Eppel W,Stulnig TM,Husslein P,Göbl C, Pre- and peripartal management of a woman with McArdle disease: a case report. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2018 Sep;     [PubMed]

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