Review article
The syndrome of rhabdomyolysis: Pathophysiology and diagnosis

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Abstract

Rhabdomyolysis is defined as a pathological condition of skeletal muscle cell damage leading to the release of toxic intracellular material into the blood circulation. Its major causes include trauma, ischemia, drugs, toxins, metabolic disorders, and infections. The pathophysiological hallmark of the syndrome is an increase in intracellular free ionized calcium due to either cellular energy depletion, or direct plasma membrane rupture. The increased intracellular calcium activates several proteases, intensifies skeletal muscle cell contractility, induces mitochondrial dysfunction, and increases the production of reactive oxygen species, ultimately resulting in skeletal muscle cell death. Clinically, the syndrome presents with severe muscular pain, weakness and myoglobinuria. Increased myoglobin and creatine phosphokinase as a consequence of muscular cell death are the major laboratory findings, which, in combination with the clinical presentation, lead the clinician to the final diagnosis of the syndrome.

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.

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