Are Muscles That Preveslly Had Rabdo Milos Cis More Likley to Get It Again
CMAJ. 2012 Mar 6; 184(4): 426–430.
Recurrent exercise-induced rhabdomyolysis
Apreviously healthy white 29-twelvemonth-former man presented to the emergency department with a one-twenty-four hours history of diffuse muscle aches and dark urine post-obit a four-hour hockey game. He had no symptoms to suggest intercurrent infection and was taking no medications. His medical history was notable for similar episodes occurring most once per year since he was 13 years old, which were never brought to medical attention. His first episode had occurred at a rigorous hockey training camp. He described triggers for muscle aches including a long delay between meals, intake of alcohol, exposure to common cold temperature, slumber deprivation and prolonged intense practise, although he was able to tolerate up to one.5 hours of moderate exercise without symptoms. With near episodes of musculus aches, his symptoms would resolve afterwards a short period of remainder and adequate nutrition. He had no previous admissions to hospital and no exposure to anesthetics. His parents were nonconsanguineous, and there was no history of like symptoms in his family unit.
When seen in the emergency department, the patient's blood pressure was 138/88 mm Hg, heart rate was seventy beats/min and regular, temperature was 36.eight°C, respiratory charge per unit was 17 breaths/min and his full general physical test was normal. Bulk, power and tone of muscles were normal in all muscle groups, but mild lengthened tenderness of muscles was noted on palpation. Reflexes were reduced merely symmetric. He had findings suggestive of peripheral neuropathy with decreased vibration sense in the upper and lower extremities, and decreased sensation to pinprick in the lower extremities.
Laboratory investigations were consistent with rhabdomyolysis (creatine kinase level 110 190 [normal 35–250] U/L) with renal impairment (creatinine level 271 [normal 60–115] μmol/Fifty). Urine tested positive for myoglobin. Screening blood tests to look for acquired causes of rhabdomyolysis such equally hypothyroidism, diabetic ketoacidosis, hypokalemia, hyponatremia and hypophosphatemia were normal. He was given intravenous fluids and was discharged from hospital 5 days later with normal renal function and creatine kinase level.
Given his history of recurrent muscle aches triggered past situations in which muscles were using fat every bit an energy source and physical findings of peripheral neuropathy, he was referred for evaluation of possible metabolic myopathy. Because the triggers he listed for his symptoms suggested a disorder of fatty acid β-oxidation, an acylcarnitine contour was performed, which was suggestive of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. The diagnosis was then confirmed through mutation analysis (heterozygous for the common mutation 1528C>Thousand). His siblings were screened for this autosomal recessive disorder and found to be unaffected.
Discussion
Nosotros present a example of a defect in fat acrid β-oxidation in which the patient presented to the emergency department with rhabdomyolysis. Rhabdomyolysis is the breakdown of muscle tissue and leakage of its toxic content in the claret secondary to disruption of cell homeostasis. About 26 000 instances of rhabdomyolysis are reported annually in the United States.1 Several ions take been implicated in the pathogenesis of this disorder with increased intracellular calcium existence the final common pathway and trigger of apoptosis (jail cell decease).ii The archetype triad of presentation, muscle aches, weakness and dark urine, is seen in less than ten% of patients.3 Although get-go described in World War II victims of crush injury, rhabdomyolysis can likewise occur in healthy individuals following strenuous exercise.4
Causes of rhabdomyolysis
The causes of rhabdomyolysis differ in patients with single episodes versus those with recurrent disease. In a review of 97 adult patients who presented to the emergency department with single episodes of rhabdomyolysis, the almost common triggers were cocaine apply, exercise and immobilization.5 Other causes are outlined in Box 1. Alcohol has been implicated in up to 20% of single episodes secondary to its direct toxic effect on the muscle sarcolemma or the ascertainment that intoxicated patients lying unconscious on a difficult surface may cause straight injury to muscles from the ongoing external pressure to the tissue.1 , 4 It is non known why some patients develop rhabdomyolysis while others who are exposed to the same triggers do not.
Astute episodes
In an acute episode of rhabdomyolysis, clinical evaluation and uncomplicated laboratory tests will confirm the diagnosis. The most sensitive measurement for diagnosis is plasma creatine kinase level, which is usually elevated in the thousands. Serial tests for creatine kinase levels should be done every 6–12 hours, with a usual superlative in 24 hours and a gradual decline thereafter. If creatine kinase levels remain elevated, compartment syndrome should be considered.2 Although nonspecific, a urine dipstick test for myoglobinuria tin can exist indicative of the early stages of rhabdomyolysis in 50% of instances.2 More specific skeletal musculus measurements that are not readily available are carbonic anhydrase III and myosin heavy-chain fragments.2 , 3 Other tests that are used to diagnose complications of rhabdomyolysis such as acute kidney injury or disseminated intravascular coagulopathy include claret urea nitrogen, creatinine, platelet count, prothrombin and activated fractional thromboplastin fourth dimension. An interesting finding is transient hypocalcemia early in the course of the disorder (from the influx of calcium into the injured myocyte), corrected by secondary hyperparathyroidism in the later stages of disease.ii
Once the diagnosis of rhabdomyolysis has been confirmed, a history of trauma, drug utilize and exposure to anesthetic agents should be elicited.2 , iii Patients should be asked near progressive musculus weakness between episodes of rhabdomyolysis, articulation inflammation and peel rash, which may exist clues to the presence of inflammatory myopathies such as polymyositis. Constitutional symptoms may suggest an infectious etiology. Simple blood tests such every bit electrolytes, glucose and thyroid-stimulating hormone tin can exist used to dominion out other acquired causes of the disorder.2
Acute handling
Guidelines on acute treatment of rhabdomyolysis indicate that supportive therapy with isotonic crystalloids helps to maintain renal office, with a goal of urine output of 200–300 mL/h.six The guidelines also address abstention of triggers, correction of electrolyte abnormalities, such every bit hyperkalemia, and diverse diuretics (e.g., mannitol) as well as bicarbonate therapy to alkalinize urine for the prevention of myoglobin cast precipitation in the kidney tubules.6
Recurrent episodes
All patients with recurrent rhabdomyolysis should undergo investigation for an underlying crusade, although in many of these patients, no cause volition exist identified. Recurrent rhabdomyolysis may be caused by acquired myopathies such as polymyositis, congenital muscle disorders such as muscular dystrophy7 or by metabolic myopathies. There are three main groups of metabolic myopathies: disorders of fat metabolism, disorders of carbohydrate metabolism and disorders of mitochondrial part.viii , 9 Tabular array 1 describes features on history and physical examination that tin can be used to distinguish these 3 wide classes of metabolic myopathies.
Table i:
Metabolic myopathies causing recurrent-episode rhabdomyolysis
| Feature | Disorders of fatty acrid β-oxidation | Muscle glycogenoses | Mitochondrial diseases |
|---|---|---|---|
| Prevalence | Varies with type MCAD 1/x 0008,9 Others less common except in certain populations | Varies with type McArdle disease 1/100 0008,9 Others less common | 1/8000eight,9 |
| Inheritance pattern | Nearly are autosomal recessive8,ix | Most are autosomal recessive8,9 | Any pattern of inheritance is possible: maternally inherited through mitochondrial DNA or inherited through nuclear DNA in autosomal dominant or recessive or X-linked fashion8,9 |
| Duration of do needed to trigger symptoms | Longer elapsing (> 30 min) 8,9 | Shorter duration (< 30 min) 8,9 | Variable8,9 |
| History of second-wind miracle* | No | Often presentviii,9 | Not normally presenteight,9 |
| Creatine kinase levels | Normal betwixt episodes of symptoms8,ix | Elevated even between episodes of symptoms8,9 | Variable; may be normalviii,9 |
| Other organ systems involved | Depends on type Adult often present only with rhabdomyolysis Other symptoms may include encephalopathy, cardiomyopathy, peripheral neuropathy or hypoketotic hypoglycemia8,9 | Depends on type May take hepatomegaly and history of hypoglycemia; some types have cardiac involvement8,ix | Other organ systems frequently involved, with cardiac, endocrine and central nervous systemic involvement mutual8,9 |
| Investigations leading to diagnosis | Acylcarnitine profile will suggest diagnosis, which can be confirmed by mutation assay or fibroblast culture to appraise specific enzymes in fatty acrid β-oxidation pathwayviii,9 | Diagnosis often establish on muscle biopsy showing increased glycogen stores; subtyping of the type of glycogen storage disease may require further enzyme or DNA analysis8,ix | Muscle biopsy with assay for defects in mitochondrial DNA or nuclear DNA8,9 |
Simple points on history such as duration of exercise needed to bring on symptoms, second-wind phenomenon and the presence of symptoms in other organ systems will assist clinicians make up one's mind which of the three main groups of metabolic myopathies (disorders of fatty acrid β-oxidation, muscle glycogenoses and mitochondrial diseases) should be considered. Also, a family unit history of consanguinity or sudden infant decease syndrome may be suggestive of a metabolic cause.
When patients are presenting with symptoms of a disorder of fat acid β-oxidation, creatine kinase levels are usually elevated (> 100 000 U/L) and then return to normal when energy demand is met. It is this normalization of creatine kinase levels between episodes that is a clue to the presence of a disorder of fatty acid β-oxidation, as creatine kinase levels remain elevated in other causes of muscle pain such as inflammatory myopathy and muscle glycogenosis.eight , 9
Information technology is important to identify patients with a possible disorder of fat acid β-oxidation with clues on history and concrete examination, because this diagnosis can be confirmed with blood testing, whereas the other causes of metabolic myopathies frequently crave muscle biopsy for confirmation.
Disorders of fatty acrid β-oxidation
The most common cause of recurrent exercise-induced rhabdomyolysis is a disorder of fat acid β-oxidation,8,9 and the pathway of fatty acid β-oxidation is summarized in Figure 1. In patients with disorders of fatty acid β-oxidation, provision of free energy from fat is not sufficient to encompass demand, especially for organs such as the eye and skeletal muscles with high energy requirements during exposure to cold, infection or fasting.x The power to perform short-elapsing, intense practice is non impaired in people with disorders of fat acid β-oxidation because glycogen is the primary substrate used for free energy production during the outset 10–30 minutes of practise.eight , ix
Simplified illustration of fatty acrid β-oxidation. Fat acids enter cells through specialized receptors. Once in the cytoplasm, fat acids are activated through esterification (i.eastward., joined to coenzyme A [CoA] to form acyl-CoA). The acyl-CoA is then linked to a carnitine molecule and this acylcarnitine is shuttled by two enzymes (CPT1 and CPT2) through the outer and inner mitochondrial membranes. The carnitine molecule is removed, leaving the acyl-CoA, which is metabolized by a series of enzymes including very-long-concatenation acyl-CoA dehydrogenase (VLCAD) and mitochondrial trifunctional protein (mTFP) that consists of hydratase, long-chain 3-hydroxylacyl CoA dehydrogenase (LCHAD) and thiolase action, into smaller fatty acid chains, which are ultimately converted into adenosine triphosphate (ATP) within the mitochondrion. In our patient, deficiency of LCHAD pb to a fill-in of long-chain acyl-CoA species that could not be metabolized, and the resultant deficiency of ATP lead to rhabdomyolysis. These long-chain species are converted to acylcarnitine, which is readily permeable to cross the cell membrane and can be detected with a simple blood test. For details about the biochemical pathways of fat acrid β-oxidation, see The Online Metabolic and Molecular Bases of Inherited Disease 8 and Online Mendelian Inheritance in Man.9 CPT = carnitine palmitoyltransferase.
Iii disorders of fatty acid β-oxidation are specially mutual: medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency and carnitine palmitoyltransferase II (CPT2) deficiency, which are pan-indigenous,8 , nine and carnitine palmitoyltransferase I (CPT1) deficiency in Canadian Aboriginal populations.
Medium-chain acyl-coenzyme A dehydrogenase deficiency, one of the inborn errors of metabolism that can nowadays with sudden infant death syndrome, was the first disorder of fat acid β-oxidation to be added to newborn screening panels effectually the earth.eleven , 12 Once newborn screening for MCAD was in identify, data were published showing that the prevalence of MCAD deficiency of roughly 1/ten 000 ascertained through newborn screening was three to 4 times college than that ascertained through clinical presentation.11 , 12 This discrepancy suggests that a large number of patients with MCAD deficiency may non receive diagnoses in babyhood. A recent publication that reviewed instances of MCAD deficiency diagnosed in adults found that rhabdomyolysis tin exist the presenting symptom; other presentations included encephalopathy, cardiomyopathy and hypoglycemia.12 The mortality rate of these newly diagnosed instances of MCAD deficiency in adults was high (29%).12 Thus, it is clear that the first presentation of a disorder of fatty acrid β-oxidation may occur in developed patients.
Carnitine palmitoyltransferase II deficiency is the virtually common metabolic myopathy presenting with rhabdomyolysis in adults.8 , 9 These patients primarily present with myopathic symptoms: muscle aches, cramps, muscle stiffness and weakness, beginning in the first or second decade of life. The severity of attacks range from mild musculus aches to life-threatening rhabdomyolysis. The triggers include situations in which lipid metabolism is used for free energy product equally seen in illness, fasting, diet with loftier intake of fat, drugs (e.g., ibuprofen, acetaminophen, anesthetics) and prolonged exercise,8 , 9 equally in our patient.
A third cistron defect in disorders of fatty acid β-oxidation involving CPT1 has recently been shown to exist very common in Canadian Ancient populations. A recent public symposium in British Columbia on disorders of fatty acid β-oxidation in First Nations showed evidence that upward to 25% of the Canadian Aboriginal population living on Vancouver Island are homozygous for a mutation in CPT1 (P479L), which is also highly prevalent in other Canadian Aboriginal populations, including those in some regions of Nunavut.13 , 14 The prevalence of this defect is related to infant expiry in one study from Alaska.xv Information technology is non yet articulate if adults with this disorder are at risk of symptoms, so further data are needed to define the clinical impact of the CPT1 mutation in the Canadian Ancient population.
If a clinician suspects that rhabdomyolysis is acquired by a disorder of fatty acid β-oxidation, investigations should begin with testing of fasting blood glucose and lactate levels, as well as a unproblematic screening exam known as the acylcarnitine contour.8 , nine The contour is measured using tandem mass spectrometry and can identify more than than 20 dissimilar metabolic defects of fatty acid and organic acid metabolism.8 , 9 The acylcarnitine profile can be measured in a bloodspot (in which a pocket-size amount of blood is spotted into filter paper, similar to the technique used to perform screening in newborns) or measured in serum.eight , 9 This test can be washed at all laboratories that perform screening in newborns, and therefore clinicians everywhere in the land tin admission this simple and cheap test. The diagnosis is confirmed with mutation analysis and fibroblast cultures of enzyme activity.8 , 9 Mitochondrial and glycogen storage diseases require a musculus biopsy for diagnosis.eight , 9
Prevention of recurrent episodes
All patients with recurrent episodes of rhabdomyolysis, regardless of cause, should be taught to avert triggers and ensure adequate hydration, and encouraged to warm up before exercise. Patients with disorders of fat acrid β-oxidation tin can also prefer a low-fat diet to reduce the frequency of rhabdomyolysis.16 Other modalities of handling for disorders of fatty acrid β-oxidation include replacement of essential fatty acids in the diet using supplemental walnut or soy oils. Carnitine supplementation is ofttimes used, although there is no testify that this will bear on outcome.17 Although these therapies for disorders of fatty acid β-oxidation may reduce the frequency of episodes of rhabdomyolysis, other long-term complications, such every bit cardiomyopathy, retinopathy and neuropathy, continue to occur.16 A contempo trial of bezafibrate was shown to restore the capacity for normal fatty acid β-oxidation in muscle cells from patients with a mild form of CPT2 deficiency, an approach which may exist useful for other disorders of fatty acid β-oxidation.18
Key points
-
The most common causes of unmarried episodes of rhabdomyolysis are drugs, exercise and immobility.
-
Defects in fatty acid β-oxidation are the nearly mutual metabolic myopathy to cause recurrent exercise-induced rhabdomyolysis.
-
Some defects of fatty acid β-oxidation are common particularly in Canadian Aboriginal populations, although the clinical significance of this finding is not yet clear.
-
The acylcarnitine profile is a widely bachelor and uncomplicated method used for initial screening for these defects.
Acknowledgement
The authors thank Dr. Graham Sinclair for performing the acylcarnitine assay.
Footnotes
Competing interests: None declared by Fady Hannah-Shmouni or Kevin McLeod. Sandra Sirrs has received payment for lectures from Shire Human Genetics Therapies, Genzyme Canada and Actelion Pharmaceuticals, and is an investigator for the Canadian Fabry Affliction Initiative, which is funded jointly by the x provincial governments, Genzyme Canada and Shire Human Genetics Therapies.
This article has been peer reviewed.
Contributors: Each writer contributed equally to the conception, blueprint, assay, data collection, interpretation, writing, critical revision and final approval of the article. Sandra Sirrs guarantees the scientific integrity of the work as a whole.
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291671/
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