Definition:
Malignant hyperthermia is a rare life-threatening condition that is triggered by exposure to certain drugs used for general anesthesia (specifically all volatile anesthetics), nearly all gas anesthetics, and the neuromuscular blocking agent succinylcholine.
Physiopathology
In susceptible individuals, these drugs can induce a drastic and uncontrolled increase in skeletal muscle oxidative metabolism which overwhelms the body's capacity to supply oxygen, remove carbon dioxide, and regulate body temperature, eventually leading to circulatory collapse and death if not treated quickly.
Susceptibility to MH:
It is often inherited as an autosomal dominant disorder, for which there are at least 6 genetic loci of interest, most prominently the ryanodine receptor gene (RYR1). MH susceptibility is phenotypically and genetically related to central core disease (CCD), an autosomal dominant disorder characterized both by MH symptoms and myopathy.
MH is usually unmasked by anesthesia, or when a family member develops the symptoms. There is no simple, straightforward test to diagnose the condition.
The protein RYR1
Signs and symptoms:
Malignant hyperthermia develops during or after receiving a general anaesthetic, and symptoms are generally identified by operating department staff.
Characteristic signs are:
-muscular rigidity
-hypermetabolic state with increased oxygen consumption
-increased carbon dioxide production (hypercapnia, usually measured by capnography)
-tachycardia (fast heart rate)
-increase in body temperature (hyperthermia) at a rate of up to ~2°C per hour;
-temperatures up to 42°C are not uncommon.
-Rhabdomyolysis (breakdown of muscle tissue) may develop, as evidenced by red-brown decoloration of the urine and cardiological or neurological evidence of electrolyte disturbances
Disease mechanism:
The potential for malignant hyperthermia is caused in a large proportion (50-70%) of cases by a mutation of the ryanodine receptor (type 1), located on the sarcoplasmic reticulum (SR), the organelle within skeletal muscle cells that stores calcium.
RYR1 opens in response to increases in intracellular Ca2+ level mediated by L-type calcium channels, thereby resulting in a drastic increase in intracellular calcium levels and muscle contraction.
RYR1 has two sites believed to be important for reacting to changing Ca2+ concentrations: the A-site and the I-site.
The A-site is a high affinity Ca2+ binding site that mediates RYR1 opening.
The I-site is a lower affinity site that mediates the protein's closing.
Caffeine, Halothane, and other triggering agents act by drastically increasing the affinity of the A-site for Ca2+ and concomitantly decreasing the affinity of the I-site in mutant proteins. Mg2+ also affect RYR1 activity, causing the protein to close by acting at either the A- or I-sites.
In MH mutant proteins, the affinity for Mg2+ at either one of these sites is greatly reduced.
The end result of these alterations is greatly increased Ca2+ release due to a lowered activation and heightened deactivation threshold.
The process of reabsorbing this excess Ca2+ consumes large amounts of ATP (adenosine triphosphate), the main cellular energy carrier, and generates the excessive heat (hyperthermia) that is the hallmark of the disease.
The muscle cell is damaged by the depletion of ATP and possibly the high temperatures, and cellular constituents "leak" into the circulation, including potassium, myoglobin, creatine, phosphate and creatine kinase.
The other known causative gene for MH is CACNA1S, which encodes and L-type voltage-gated calcium channel α-subunit. There are two known mutations in this protein, both affecting the same residue, R1086.
This residue is located in the large intracellular loop connecting domains 3 and 4, a domain possibly involved in negatively regulating RYR1 activity.
Cells expressing these channels have an increased basal cytosolic Ca2+ concentration. As these channels interact with and activate RYR1, h3{color:blue}. these alterations result in a drastic increase of intracellular Ca2+, and, thereby, muscle excitability.
Treatment:
The current treatment of choice is the intravenous administration of dantrolene, the only knon antidote, discontinuation of triggering agents, and supportive therapy directed at correcting hyperthermia, acidosis, and organ dysfunction.
Treatment must be instituted rapidly on clinical suspicion of the onset of malignant hyperthermia.
Dantrolene is a muscle relaxant that appears to work directly on the ryanodine receptor to prevent the release of calcium. . Dantrolene remains as the only drug known to be effective in the treatment of MH.
