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Myoglobinuria

Myoglobinurias

Myoglobinuria is a condition in which myoglobin, a marker of degenerated or necrosed muscle, is excreted in the urine. There are numerous events and illnesses involving muscle tissue which cause myoglobinuria.


Presentation

Myoglobinuria is usually a consequence of rhabdomyolysis. The clinical presentation of the latter is the classical triad of myalgia, muscle weakness, and dark urine. Nonspecific symptoms may include fever or nausea. Elderly individuals may also experience delirium.

The patient's background typically involves trauma, strenuous exercise, alcohol, and/or substance abuse, coma, or one of the etiologies discussed previously.

Myopathy
  • Of six individuals who developed statin-induced myopathy, one was a carrier for Glu769Gly, a pathogenic mutation in the LPIN1 gene.[ncbi.nlm.nih.gov]
  • The diuretics-induced hypokalemic myopathy is rare in the literature.[ncbi.nlm.nih.gov]
  • We report on a 23-year-old man in whom recurrent myoglobinuria was observed due to necrotizing vacuolar myopathy confirmed on muscle biopsy.[ncbi.nlm.nih.gov]
  • On electron microscopy, the mitochondria showed abnormalities typical of mitochondrial myopathy.[ncbi.nlm.nih.gov]
  • ; Metabolic and mitochondrial myopathies; Sporadic inclusion body myositis; Toxic myopathies; Idiopathic Inflammatory myopathies; Approach to muscle disease.[books.google.ro]
Increased Muscle Mass
  • Persons who exercise and have increased muscle mass have an increased intracellular myoglobin content.[emedicine.com]
Osteoporosis
  • Abstract It is now well established that strenuous engagement in aerobic endurance sports may cause menstrual problems and hypoestrogenemia-related phenomena, such as osteoporosis.[ncbi.nlm.nih.gov]
Thigh Pain
  • A 20-year-old male police recruit was admitted to a psychiatric hospital because of complaints about black urine and severe thigh pain. Serum creatinine kinase (CK) was significantly elevated at 87,335 U/l.[ncbi.nlm.nih.gov]
Withdrawn
  • They are associated with muscle aches and pains and can cause myositis and rhabdomyolysis which can be fatal. [ 11, 12, 13 ] Cerivastatin was the most frequently used statin with associated rhabdomyolysis and was subsequently withdrawn. [ 14, 15 ] The[patient.info]
Dark Urine
  • Dark urine was identified promptly intraoperatively and treated aggressively. All of these patients required intensive care unit (ICU) admission and had a prolonged hospital stay.[ncbi.nlm.nih.gov]
  • The boy presented an episode of dark urine, identified as presence of blood by a urine dipstick, occurred 10 days after an episode of fever and sore throat treated with antibiotics.[ncbi.nlm.nih.gov]
  • Symptoms such as dark urine, myalgia, and muscle weakness should immediately arouse suspicion of rhabdomyolysis. Especially dark-colored urine should always be investigated for the occurrence of rhabdomyolysis.[ncbi.nlm.nih.gov]
  • Therefore, among the possible signs and symptoms to look for would be: Swollen and painful muscles Fever, nausea Delirium (elderly individuals) Myalgia Dark urine Calcium ions (decrease) Trauma, vascular problems, malignant hyperthermia, certain drugs[en.wikipedia.org]
  • The clinical presentation of the latter is the classical triad of myalgia, muscle weakness, and dark urine. Nonspecific symptoms may include fever or nausea. Elderly individuals may also experience delirium.[symptoma.com]
Kidney Failure
  • This syndrome can lead to complications such as electrolyte imbalances in the body, kidney failure, and cardiac arrest.[justanswer.com]
  • International Acute kidney injury due to rhabdomyolysis was first described by Bywaters and Beall during World War II; they noted the hypovolemic shock, dark urine, and kidney failure that developed in survivors from the rubbles of the London bombings[emedicine.com]
  • But if the CPK ever exceeds 50 times normal, or if kidney failure develops, alternative lipid-lowering strategies like low-density lipoprotein (LDL) apheresis or red yeast rice should be considered.[clevelandclinicmeded.com]
Red Urine
  • A few thoughts from a layman, based on literature that may be totally out of date by now: As you probably know, red urine is pretty common among runners.[letsrun.com]
  • Trauma Crush injury, excess/prolonged physical exertion–eg, marathon running, severe muscle injury, crush injury Etcetera Hyperthermia, infarction due to vascular occlusion, seizures The diagnosis is based on clinical suspicion–especially with bright red[medical-dictionary.thefreedictionary.com]
Oliguria
  • Each child had oliguria, elevated muscle enzymes, and pigmented urine positive for blood, but without red cells on microscopic examination. These findings are suggestive of myoglobinuria.[ncbi.nlm.nih.gov]
  • Indications: Low Urine pH in Rhabdomyolysis Theory: Myoglobin is less nephrotoxic in a more alkaline environment Protocol Saline 0.45% (1/2 NS) with Sodium Bicarbonate 40 meq (1 to 2 ampules) and Mannitol 10 grams per liter Contraindications Persistent Oliguria[fpnotebook.com]

Workup

When a patient presents with muscle pain, muscle weakness, and tea-colored urine, the clinician should obtain a thorough history and ask pertinent questions to ascertain the cause. Additionally, a full physical exam and laboratory tests should be performed.

Laboratory tests

The most beneficial study is the assessment of CK, which is used to test for rhabdomyolysis. CK will usually peak 3 days after symptoms begin and continue to be elevated for 3 days. Due to its delayed clearance, CK levels remains high after myoglobin (serum and urine) disappears since CK has delayed clearance. In contrast, myoglobin, which is pathognomonic for rhabdomyolysis, is rapidly cleared and hence returns to a normal concentration within the 24 hours despite being the first protein to increase. Additionally, results of the radioimmunoassays for myoglobin take several days and hence is not helpful for prompt evaluation.

In rhabdomyolysis patients, a CK measurement greater than 1000 U/L is typical [7] [8]. There are other muscle enzymes that also rise. These are aldolase, lactate dehydrogenase (LDH), and glutamic-oxaloacetic transaminase (SGOT).

Further useful tests are electrolyte measurements since hyperkalemia and hyperphosphatemia are consequences of damaged muscle. Additionally, hypercalcemia or hypocalcemia and hyperuricemia may be observed. These imbalances occur in response to spillage of intracellular contents into the plasma.

Since acute kidney injury is very likely to ensue, renal function tests are crucial. Typically in these patients, creatinine may be increased and out of proportion to blood urea nitrogen (BUN) levels.

These patients are at risk for acid-base disorders such as metabolic acidosis. Therefore, appropriate tests may be warranted.

The urine dipstick test accurately detects hematuria but provides a false positive result for myoglobinuria. Therefore, it is important to consider their distinct appearances in order to correctly differentiate between them. For example, brown colored urine containing a few red blood cells (RBCs) is indicative of myoglobinuria while hematuria is characterized by a reddish color and a proportionately high quantity of RBCs [9]. Moreover, centrifuged urine yields red sediment in hematuria but shows a clear serum color in myoglobinuria.

Other

When evaluating the etiology, the clinician will carefully assess the patient and then order the relevant studies to determine the cause of this metabolic disorder.

For individuals suspected to have autoimmune polymyositis or similar conditions, antinuclear antibodies and complement tests will be performed. Furthermore, patients with sickle cell disease may undergo additional testing. Finally, those with a history suggestive of drug use should be evaluated with a toxicology screen.

T Wave Inversion
  • We report a case of a 34-year-old woman with ST segment depression and T-wave inversion in the inferolateral leads during the acute episode of myoglobinuria.[ncbi.nlm.nih.gov]

Treatment

The therapeutic plan for this metabolic condition is hospital admission followed by urgent treatment with IV fluids and the management of sequelae. Moreover, aggressive IV hydration is initiated for patients with a CK level greater than 5000 U/L in order to promote diuresis and to prevent the precipitation of myoglobin and the development of acute kidney injury. Specifically, the recommended urine output is 2 to 3 mL/kg/h.

The recommended treatment is isotonic saline of 20mL/kg with further boluses if needed. Once adequate hydration is achieved, the patient is placed on maintenance fluid that is double or triple the rate [10]. Once the CK measurement is persistently below 1000 U/L and the urine becomes clear, then the patient can be switched to oral fluids.

Some suggest that mannitol in addition to the IV fluid can be used to facilitate the diuresis. This drug can reduce the deposition of myoglobin in the tubules. Moreover, it is a renal vasodilator. While some advocate the use of this medicine, studies have shown that saline alone can prevent acute renal failure [11].

A questionable practice is the supplementation of sodium bicarbonate with the IV saline in order to increase the pH of the urine. However, its use is not supported by studies.

Surgical intervention

Any patient with crush injuries should be assessed for the destruction of soft tissue and bones. Surgical debridement of necrosed muscle may be necessary and fasciotomy is required for compartment compression syndrome.

Other

Electrolyte imbalances should be corrected. For example, hyperkalemia and hypocalcemia warrant prompt attention.

Prognosis

Prognosis is good for patients with uncomplicated cases of myoglobinuria.

Etiology

There are numerous causes for myoglobinuria which include any scenario or condition that leads to muscle destruction and necrosis. Patients may have a history of fever, viral illnesses, crush injuries, burns, or other trauma. Another common etiology is the participation in athletic events such as bicycle races or running. Snake and spider bites are other causes as well.

Additionally, errors in metabolism may also contribute to myoglobinuria. Examples include lactate dehydrogenase deficiency, phosphofructokinase deficiency [2], carnitine palmitoyltransferase II deficiency, and McArdle's disease.

Autoimmune dermatomyositis and polymyositis can affect muscle tissue and lead to myoglobinuria. Also, there is a reported case of a 14-year-old female with Becker muscular dystrophy who suffered from recurrent episodes of myoglobinuria [3].

Medications such as azidothymidine (AZT), lovastatin, diazepam, amphotericin-B, phencyclidine, codeine, barbiturates, amphetamines, and certain dietary supplements can predispose the individual to myoglobinuria. Additionally, the chemical known as ethylene glycol and illicit drugs like heroin may cause myoglobinuria.

Epidemiology

Epidemiologic studies have reported that the median age of individuals with myoglobinuria is 11 years [4]. Also, the most predominant etiology of rhabdomyolysis in children between ages of 0 and 9 years is viral myositis while trauma is the most common cause in the ages between 9 and 18 years.

It is important to note that the prevalence of myoglobinuria depends on the environment. For example, urban communities with heavy alcohol and drug abuse are associated with myoglobinuria and frequent visits to the emergency department. Also, elevated temperatures contribute to the development of rhabdomyolysis, particularly in athletes.

With regards to trauma, global reports have stated that natural disasters such as earthquakes have resulted in crush injuries. Survivors should be suspected to have myoglobinuria, rhabdomyolysis, and acute renal failure.

Sex distribution
Age distribution

Pathophysiology

Following trauma and crush injuries, the damaged muscle tissue releases myoglobin [5], a dark red monomeric heme that carries ferrous iron [6]. This protein can be filtered and excreted into the urine rather easily. However, when elevated concentrations of this protein enter the renal tubules, it precipitates and causes obstruction in the distal tubule. Adding further insult, free radicals produced by the damaged muscle and renal epithelial cells will contribute to the toxic injury in the proximal tubule. The consequences of these mechanisms lead to acute kidney injury.

Furthermore, damage to myocytes disrupts the sodium-potassium ATPase pump and the sodium-calcium channel. Therefore, the skeletal muscle cell membrane becomes permeable and calcium flows into the cytoplasm. The abnormally high intracellular calcium concentration will further degrade the cell membrane by activating calcium-facilitated enzymes. This results in the extrusion of myoglobin and creatine kinase (CK) into the plasma.

Prevention

Individuals performing strenuous activities should hydrate adequately and avoid heavy activities in hot weather if possible.

All individuals are encouraged to partake in healthy lifestyles and avoid/cease alcohol abuse and illicit drug use.

Also, those with metabolic muscle disorders should be cautious about overexertion, trauma, and injuries.

Summary

Myoglobinuria occurs as a consequence of rhabdomyolysis, which is the destruction of muscle. There are numerous conditions and scenarios that can produce this metabolic disorder. For example, trauma, viral myositis, and excessive physical activity are chief causes of rhabdomyolysis in the pediatric population [1]. Additionally, crush and burn injuries, metabolic and connective tissue disorders, malignant hyperthermia, substance abuse, and even certain medications can result in severe muscle injury.

Pathologically, the damaged muscle facilitates the release of intracellular proteins such as myoglobin into the plasma. This large amount of myoglobin travels to the renal system, gets deposited in the renal tubules, obstructs the lumen and leads to acute kidney injury.

The clinical presentation of rhabdomyolysis consists of muscle pain, weakness, and dark urine. The typical patient history will feature trauma, participation in strenuous sporting events, or one of the other likely causes. In addition to obtaining a full history and performing a physical exam, appropriate diagnostic tools such as measurement of creatinine kinase (CK) levels are important. This is one of the enzymes that increases in conjunction with the discharge of myoglobin from myocytes.

Once myoglobinuria or rhabdomyolysis is suspected, the patient should be admitted and vigorous intravenous (IV) hydration initiated to promote diuresis and thereby prevent acute kidney injury. Also, electrolyte imbalances should be promptly addressed. Moreover, once the underlying cause is established, this will warrant further treatment. Typically, these patients recover completely without sequelae.

Patient Information

What is myoglobinuria?

Myoglobin is a large protein that is contained inside cells. If present in urine, this is due to muscle destruction in a condition known as rhabdomyolysis.

What causes this condition?

There are many causes such as the following:

Conditions and scenarios such as the above destroy muscle tissue and therefore the myoglobin is released from cells into the bloodstream. Once the myoglobin proteins reach the kidneys, there is such a large amount that it cannot all be filtered out into the urine. Therefore, it causes injury to the kidneys and leads to acute renal failure.

What are the symptoms?

There are 3 classical signs of rhabdomyolysis, which are:

Patients may also have symptoms such as:

How is myoglobinuria diagnosed?

The most useful diagnostic test is the creatinine kinase (CK) level, which is a marker for rhabdomyolysis. CK levels usually increase 3 days after the symptoms begin and continue to be elevated for a few days afterward. The myoglobin test is not always helpful because this protein is excreted into the urine and therefore the levels become normal.

How is this condition treated?

A patient who is suspected to have rhabdomyolysis or myoglobinuria should be hospitalized and treated with intravenous fluids. The key is to provide the patients with aggressive hydration in order to promote diuresis and excretion of the myoglobin before it accumulates and deposits in the tubules of the kidneys.

Note that these patients will have abnormalities such as elevated potassion, phosphate, and uric acid. Additionally, calcium levels in the blood may be increased or decreased. All of these abnormal values should be corrected.

What is the prognosis?

Patients do well after hydration. There are usually no long-lasting effects.

How can it be prevented?

Trauma and other injuries should be avoided if possible. Athletes participating in strenuous activities and competitions should hydrate adequately and be careful when practicing in high temperatures.

References

Article

  1. Clarke W, Frost SJ, Kraus E, et al. Renal function testing. Laboratory medicine practice guidelines: evidence-based practice for point-of-care testing. National Academy of Clinical Biochemistry (NACB). 2006.
  2. Toscano A, Musumeci O. Tarui disease and distal glycogenoses: clinical and genetic update. Acta Myol. 2007; 26(2):105–7.
  3. Fujii K, Minami N, Hayashi Y, et al. Homozygous female Becker muscular dystrophy. Am J Med Genet A. 2009; 149A(5):1052-5.
  4. Mannix R, Tan ML, Wright R, Baskin M. Acute pediatric rhabdomyolysis: causes and rates of renal failure. Pediatrics. 2006; 118(5):2119-25.
  5. Chatzizisis YS, Misirli G, Hatzitolios AI, Giannoglou GD. The syndrome of rhabdomyolysis: complications and treatment. Eur J of Intern Med. 2008; 19(8):568-74.
  6. Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. New Engl J Med. 2009; 361(1):62-72.
  7. Luck RP, Verbin S. Rhabdomyolysis: a review of clinical presentation, etiology, diagnosis, and management. Pediatr Emerg Care. 2008; 24(4):262-8.
  8. Mannix R, Tan ML, Wright R, Baskin M. Acute pediatric rhabdomyolysis: causes and rates of renal failure. Pediatrics. 2006; 118(5):2119-25.
  9. Veerreddy P. Hemoglobinuria Misidentified as Hematuria: Review of Discolored Urine and Paroxysmal Nocturnal Hemoglobinuria. Clin Med Insights Blood Disord.. 2013;6:7-17.
  10. Scharman EJ, Troutman WG. Prevention of kidney injury following rhabdomyolysis: a systematic review. Ann Pharmacother. 2013; 47(1):90-105.
  11. Brown CV, Rhee P, Chan L, et al. Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference? J Trauma. 2004; 56(6):1191-6.

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Last updated: 2019-07-11 22:09