Review articleThe syndrome of rhabdomyolysis: Pathophysiology and diagnosis
Introduction
Rhabdomyolysis is a pathological syndrome caused by skeletal muscle cell damage which affects the integrity of the cellular membrane and leads to the release of toxic intracellular constituents into the blood circulation. Its main causes include trauma, ischemia, drugs, toxins, metabolic disorders, and infections [1], [2], [3], [4], [5], [6], [7]. The clinical presentation of rhabdomyolysis varies from an asymptomatic increase in creatine phosphokinase (CPK) to severe acute renal failure and hypovolemic shock [8], [9], [10], [11], [12]. Typically, rhabdomyolysis presents with muscular pain, weakness, and reddish-brown discoloration of urine.
Rhabdomyolysis has been known since ancient times. In the Old Testament, a plague that affected the Israelites after consumption of quails during their exodus from Egypt (Book of Numbers, 11:31–35) is reported [13]. In more recent years, the first report of rhabdomyolysis caused by compression (crush syndrome) was during the earthquake in Sicily in 1908 [5]. Similar reports exist in the German literature during the First World War [5]. The first systematic recording of the syndrome was done by the British investigators Bywaters and Beall, who followed the clinical course of four victims of the bombing of London during the Battle of England in 1940 and realized that these individuals developed acute renal failure [14]. The investigators attributed the acute renal failure to rhabdomyolysis due to compression, without discovering, however, the cause of their observation. A few decades later, it was found that the renal damage had been caused by the nephrotoxic effect of myoglobin, which is released from muscle cells during rhabdomyolysis. The non-traumatic causes of rhabdomyolysis were identified only in the 1970s [5].
In this review, the molecular and cellular mechanisms involved in the pathophysiology of the syndrome of rhabdomyolysis are summarized. The clinical manifestations and the major laboratory findings of the syndrome are also presented.
Section snippets
Homeostasis of intracellular calcium
The concentration of free ionized calcium in the extracellular space [Ca2+]c is 10,000 times higher than that in the intracellular space [15]. Because of this chemical gradient, even minimal changes in the permeability of the cellular membrane for Ca2+ are capable of inducing significant changes in its intracellular concentration with unfavorable consequences for the functional integrity of the cell [16]. Therefore, the cell has to maintain the homeostasis of intracellular calcium with great
Pathophysiological mechanisms of rhabdomyolysis
Despite the fact that the causes of rhabdomyolysis are numerous, the final pathogenetic pathway is common, characterized by an increase in free ionized calcium in the cytoplasm [1]. The increased [Ca2+]c initiates a chain of downstream reactions that eventually lead to the destruction of the muscle cell (Fig. 1).
Clinical presentation
Even though the final diagnosis of rhabdomyolysis is established by laboratory findings, alertness to the syndrome is essential for prompt diagnosis. The clinical spectrum of rhabdomyolysis is rather wide. The typical triad of symptoms involves muscular pain, weakness, and reddish-brown urine [4], [24], [31]. In 50% of the cases, the pain is focused on the central muscle groups (thighs, shoulders). However, more than half of the patients do not report muscular symptoms. The reddish-brown color
Laboratory findings
Due to the muscle cell necrosis and dissolution, several substances are released into the plasma (e.g., myoglobin, CPK, electrolytes, protein and non-protein substances), the detection of which contributes to the early diagnosis of the syndrome.
Conclusions and diagnostic approach
Rhabdomyolysis constitutes a severe medical emergency that requires prompt diagnosis so that its life-threatening complications can be avoided. Although the etiology is multi-factorial, all of the potential causes share the same pathophysiological pathway, which involves an increase in intracellular calcium. Physicians should be aware of all the pathogenetic mechanisms described above as they are strongly linked to the clinical manifestation and laboratory findings of the disease.
With regard to
Learning points
- 1.
Rhabdomyolysis is a pathological condition defined as severe skeletal muscle cell damage leading to the release of toxic intracellular material into the blood circulation.
- 2.
Its major causes include trauma, ischemia, drugs, toxins, metabolic disorders, and infections.
- 3.
The major pathophysiological characteristic of the syndrome is an increase in intracellular free ionized calcium, due to either cellular energy depletion or direct plasma membrane rupture.
- 4.
Clinically, the syndrome presents with severe
Acknowledgement
The authors thank Dr. Nikolaos Tsiampas for his help in the editing of the manuscript.
References (75)
- et al.
Rhabdomyolysis: a review of the literature
Clin Neurol Neurosurg
(1993) Rhabdomyolysis and myohemoglobinuric acute renal failure
Kidney Int
(1996)- et al.
The other medical causes of rhabdomyolysis
Am J Med Sci
(2003) - et al.
Acute renal failure after a meal of quail
Lancet
(1971) - et al.
Exporting calcium from cells
Cell Calcium
(2005) - et al.
Transport mechanism of the sarcoplasmic reticulum Ca2+-ATPase pump
Curr Opin Struct Biol
(2005) Neuromuscular manifestations of electrolyte disorders
Am J Med
(1982)- et al.
Myoplasmic Ca++ concentration during exertional rhabdomyolysis
Lancet
(1995) - et al.
Mitochondrial calcium overload: a general mechanism for cell-necrosis in muscle diseases
Lancet
(1976) - et al.
Rhabdomyolysis as a result of Streptococcus pneumoniae: report of a case and review
Clin Microbiol Infect
(2003)
Malignant hyperthermia
Best Pract Res Clin Anaesthesiol
Malignant hyperthermia and neuromuscular disease
Neuromuscul Disord
Drug-induced and toxic myopathies
Best Pract Res Clin Rheumatol
Intracellular generation of reactive oxygen species by mitochondria
Biochem Pharmacol
Redox modulation of contractile function in respiratory and limb skeletal muscle
Respir Physiol Neurobiol
Membrane structure, toxins and phospholipase A2 activity
Pharmacol Ther
Phospholipase A(2)s and lipid peroxidation
Biochim Biophys Acta
Mitochondrial H(+) leak and ROS generation: an odd couple
Free Radic Biol Med
Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism
Int J Biochem Cell Biol
A century of mitochondrial research: achievements and perspectives
Mitochondrion
Cytosolic Ca2+ increase and cell damage in L6 rat myoblasts by HMG-CoA reductase inhibitors
Biochem Biophys Res Commun
Mitochondria and Ca2+ in cell physiology and pathophysiology
Cell Calcium
Oxidative DNA damage and disease: induction, repair and significance
Mutat Res
Release of cytochrome c from liver mitochondria during permeability transition
Biochem Biophys Res Commun
Crush injury and rhabdomyolysis
Crit Care Clin
Mitochondrial creatine kinase in human health and disease
Biochim Biophys Acta
Mechanisms of rhabdomyolysis
Curr Opin Rheumatol
Drug induced rhabdomyolysis: case report
East Afr Med J
Rhabdomyolysis
J Am Soc Nephrol
Biochemical investigation of suspected rhabdomyolysis
Ann Clin Biochem
Pathogenesis and treatment of renal dysfunction in rhabdomyolysis
Intens Care Med
Pathogenesis of renal failure in rhabdomyolysis: the role of myoglobin
Exp Nephrol
Rhabdomyolysis and myoglobinuria
Nervenarzt
Acute renal failure and rhabdomyolysis
Int J Artif Organs
Rhabdomyolysis: an evaluation of 475 hospitalized patients
Medicine (Baltimore)
Crush injuries with impairment of renal function
BMJ
Intracellular calcium homeostasis
Ánn Rev Biochem
Cited by (213)
Stress biomarker changes following a series of repeated static and dynamic apneas in non-divers
2024, Respiratory Physiology and NeurobiologyDaptomycin-induced rhabdomyolysis complicated with acute gouty arthritis
2023, American Journal of the Medical SciencesPre-operative exercise and pyrexia as modifying factors in malignant hyperthermia (MH)
2022, Neuromuscular DisordersUrate-Lowering Drugs and Muscle Injury: A Systematic Review and Network Meta-Analysis
2024, Journal of Clinical Pharmacology