Malignant hyperthermia: clinical and molecular aspects

Abstracts

CONTEÚDO: A hipertermia maligna (HM) é uma doença farmacogenética potencialmente letal que acomete indivíduos geneticamente predispostos. Manifesta-se em indivíduos susceptíveis em resposta à exposição a anestésicos inalatórios, relaxantes musculares despolarizantes ou atividade física extrema em ambientes quentes. Durante a exposição a esses agentes desencadeadores, há um aumento rápido e sustentado da concentração de cálcio mioplasmático (Ca2+) induzido pela hiperativação dos receptores de rianodina (RYR1) do músculo esquelético, causando uma alteração profunda na homeostase de Ca2+, caracterizando um estado hipermetabólico. RYR1, canais de libertação de Ca2+ do retículo sarcoplasmático, é o principal local de susceptibilidade à HM. Várias mutações no gene que codifica a proteína RYR1 foram identificadas, mas outros genes podem estar envolvidos. Atualmente, o método padrão para o diagnóstico de sensibilidade à HM é o teste de contratura muscular para exposição ao halotano-cafeína (CHCT) e o único tratamento é o uso de dantroleno. No entanto, com os avanços no campo da genética molecular, um pleno entendimento da etiologia da doença pode ser fornecido, favorecendo o desenvolvimento de um diagnóstico preciso, menos invasivo, com o teste de ADN, e também proporcionar o desenvolvimento de novas estratégias terapêuticas para o tratamento da HM. Logo, esta breve revisão tem como objetivo integrar os aspectos clínicos e moleculares da HM, reunindo informações para uma melhor compreensão desta canalopatia.

ANESTÉSICOS, Volátil; BLOQUEADOR MUSCULAR; Cálcio; Hipertermia Maligna; Rianodina

CONTENIDO: La hipertermia maligna (HM) es una enfermedad farmacogenética potencialmente letal que afecta a individuos genéticamente predispuestos. Se manifiesta en los individuos susceptibles en respuesta a la exposición a los anestésicos inhalatorios, relajantes musculares despolarizantes o actividad física extrema en ambientes calientes. Durante la exposición a esos agentes desencadenantes, existe un aumento rápido y constante de la concentración de calcio mioplasmático (Ca2+) inducido por la hiperactivación de los receptores de rianodina (RYR1) del músculo esquelético, causando una alteración profunda en la homeostasa de Ca2+, y caracterizando un estado hipermetabólico. RYR1, canales de liberación de Ca2+ del retículo sarcoplasmático, es la principal región de susceptibilidad a la HM. Varias mutaciones en el gen que codifica la proteína RYR1 han sido identificadas, pero otros genes pueden estar involucrados también. Actualmente, el método estándar para el diagnóstico de la sensibilidad a la HM es el test de contractura muscular para la exposición al halotano-cafeína (CHCT) y el único tratamiento es el uso de dantroleno. Sin embargo, con los avances en el campo de la genética molecular, un pleno entendimiento de la etiología de la enfermedad puede ser suministrado, favoreciendo así el desarrollo de un diagnóstico preciso, menos invasivo, con el test de ADN, y también proporcionar el desarrollo de nuevas estrategias terapéuticas para el tratamiento de la HM. Por eso, esta breve revisión intenta integrar los aspectos clínicos y moleculares de la HM, reuniendo informaciones para lograr una mejor comprensión de esa canalopatía.

ANESTÉSICOS, Volátil; BLOQUEANTE MUSCULAR; Calcio; Hipertermia Maligna; Rianodina

REVIEW ARTICLE

^ILaboratório de Tecnologia Farmacêutica Prof. Delby Fernandes de Medeiros, Universidade Federal da Paraíba, João Pessoa, PB, Brasil

^IIPhD; Student in Pharmacology of Natural and Synthetic Bioactive Products, Universidade Federal da Paraíba. João Pessoa, PB, Brazil

^IIIPhD; Professor, Department of Pharmaceutical Sciences, Center for Health Sciences, Universidade Federal da Paraíba, João Pessoa, PB, Brazil

Correspondence to

SUMMARY

CONTENT: Malignant hyperthermia (MH) is a potentially lethal pharmacogenetic disorder that affects genetically predisposed individuals. It manifests in susceptible individuals in response to exposure to Inhalant anesthetics, depolarizing muscle relaxants or extreme physical activity in hot environments. During exposure to these triggering agents, there is a rapid and sustained increase of myoplasmic calcium (Ca²⁺) concentration induced by hyperactivation of ryanodine receptor of skeletal muscle (RyR1), causing a profound change in Ca²⁺ homeostasis, featuring a hypermetabolic state. RyR1, Ca²⁺ release channels of sarcoplasmic reticulum, is the primary locus for MH susceptibility. Several mutations in the gene encoding the protein RyR1 have been identified; however, other genes may be involved. Actually, the standard method for diagnosing MH susceptibility is the muscle contracture test for exposure to halothane-caffeine (CHCT) and the only treatment is the use of dantrolene. However, with advances in molecular genetics, a full understanding of the disease etiology may be provided, favoring the development of an accurate diagnosis, less invasive, with DNA test, and also will provide the development of new therapeutic strategies for treatment of MH. Thus, this brief review aims to integrate molecular and clinical aspects of MH, gathering input for a better understanding of this channelopathy.

Keywords: Anesthetics, Inhalation; Calcium; Malignant Hyperthermia; Neuromuscular Blocking Agents; Ryanodine.

INTRODUCTION

Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic disorder. During a crisis of MH, inhalational anesthetics, muscle relaxants depolarizing (succinylcholine) or extreme physical activity in hot environments trigger a massive accumulation of calcium (Ca²⁺) in myoplasm, which leads to an accelerated metabolism and skeletal muscle contractile activity. This hypermetabolic state generates heat and leads to hypoxemia, metabolic acidosis, rhabdomyolysis, and rapid increase in body temperature that can be fatal if not recognized and treated early^1,2.

This release of Ca²⁺ in myoplasm occurs due to a membrane depolarization that induces conformational changes in L-type calcium channels (CA_V-L) (or dihydropyridine receptors [DHPRs]), which lead to Ca²⁺ release channels activation from sarcoplasmic reticulum (or ryanodine receptor subtype-1 [RyR1] in skeletal muscle). This functional interaction between DHPRs and RyRs, which transforms the electrical impulse into chemical substance, is commonly referred to as excitation-contraction coupling (E-C)^3,4.

Several mutations in the RyR1 gene have been already identified and implicated in a wide range of channelopathies, and this defect is primarily responsible for susceptibility to MH; however, other genes may be involved². This variation in genes related to susceptibility to MH is the major cause of the syndrome's different manifestations⁵.

Thus, this paper aims to review the molecular and physiological bases of RyRs and outline the pathophysiological and genetic factors involved in malignant hyperthermia, in order to provide a condensed and updated source of scientific information for healthcare professionals and incorporate molecular and clinical aspects for a better understanding of this channelopathy.

RYANODINE RECEPTORS (RYRs)

Classification and location

Ryanodine receptors (RyRs) are high-conductance cation channels, which release Ca²⁺ from intracellular stores such as the endo/sarcoplasmic reticulum (ER/SR)⁶. RyRs are ubiquitous in all cell types and are involved in a variety of cellular processes (E-C coupling, neurotransmission, secretion etc.)⁴. There are three known isoforms of RYRs in mammals that have been classified according to the initially identified tissue: RyR1 is the dominant isoform in skeletal muscle, commonly referred to as skeletal ryanodine receptor; RyR2 is found in the heart muscle, also known as cardiac ryanodine receptor; and RyR3 is expressed at low levels in several tissues, but it is particularly associated with diaphragm and brain^4,7.

Molecular structure

RyRs are homotetramers with a molecular mass of about 560 kDa, characterized by having a bell shape⁸ (Figure 1). It shows ~ 70% homologous amino acid sequence and the higher level of similarity is at the C-terminal region. In all isoforms, the C-terminal portion of the protein contains the transmembrane domains. According to systematic analysis, it is suggestedthat there are between 4 and 12 transmembrane segments per RyR subunit¹⁰ (Figure 2). There is also a large N-terminal cytoplasmic domain containing binding sites for protein and other channel modulators (e.g., Ca²⁺ channels) that control the RyRactivity state¹⁵. Each RyR subunit is closely associated with a 12 kDa protein, FKBP12, which modulates the opening parameters (probability of the channel being open and average time of opening)¹⁶.

Activators and blockers

The various cellular processes, physiological agents, pharmacological substances, and different associated proteins that regulate RyRs receptors are shown in Tables I and ^II.

Role of RyRs in excitation-contraction coupling (E-C)

There is clear evidence that RyRs interact with DHPRs near the T-tubule membrane. This functional interaction between DHPRs and RyRs is commonly referred to as E-C coupling, which is the transformation of an electrical signal into a chemical signal, and these receptors play an important role in this process⁴. The three genetically distinct isoforms of RyR (RyR1, RyR2, and RyR3) show release of Ca²⁺ induced by Ca²⁺ (ICRC), a process by which Ca²⁺ itself activates the channel to release Ca^{2+ 28}. DHFR is an L-type Ca²⁺ channel, also known as CA_V1, and the α-subunit of this channel is the pore-forming unit that functions as a voltage sensor and responds to changes in membrane potential. This α-subunit is the region in which there is binding of dihydropyridines. There are several isoforms of this channel classified according to their location. For example, subtype Ca_V1.1 is present in skeletal muscle and Ca_V1.2 in cardiac muscle¹.

In skeletal muscle, E-C coupling does not require the entry of extracellular Ca²⁺. The release of Ca²⁺ by RyR1 (the predominant isoform in skeletal muscle) is triggered by conformational change in the voltage sensor of DHFR in T-tubule depolarization. This Ca²⁺ release is referred to as depolarization-induced Ca²⁺ release (DICR)²⁹. Structurally, the DHFR-RyR1 complex organization is found in the ratio of 4:1, where RyR1 is physically coupled to four Ca_V1.1⁴ (Figure 3A). In cardiac muscle, however, plasma membrane depolarization activates DHFR (Ca_V1.2) to allow the entry of extracellular Ca²⁺ into cells. The entry of Ca²⁺, in turn, triggers Ca²⁺ release by RyR2 (the predominant isoform in heart) through CICR mechanism (Ca²⁺ release induced by Ca²⁺ itself)³⁰. Structurally, the DHFR-RyR2 complex organization is very different from that found in skeletal muscle, with about one Ca_V1.2 for every 5-10 RyR2 not aligned in a highly ordered manner⁴ (Figure 3B).

Correlated channelopathies

RyRs are encoded by three distinct genes located on human chromosomes19q13.1 (RyR1), 1q42.1-1q43 (RyR2), and 15q14-q15 (RyR3)³¹. Mutations in both RyR1 and RyR2 are correlated with disease¹⁴. To date, over 100 mutations in RyR1 have been identified and grouped into three regions of the protein: N-terminal, Central, and C-terminal⁶. These mutations have been implicated in a wide range of conditions, among them the susceptibility to malignant hyperthermia and various congenital myopathies, including central core disease, multiminicore myopathy with external ophthalmoplegia and, rarely, centronuclear myopathy. Although malignant hyperthermia is predominantly inherited, the central core disease involves both autosomal dominant and recessive inheritance. Multiminicore myopathy with external ophthalmoplegia is associated with recessive inheritance and quantitative defects of RyR1 protein expression³².

RyR2 mutations are associated with two forms of arrhythmia induced by stress, called catecholaminergic polymorphic ventricular tachycardia type 1, and a form of arrhythmogenic right ventricular dysplasia type 2. There are more than 80 mutations related to the RyR2 gene and they are clustered in three regions of the protein, similar to the distribution of changes in RyR1⁶.

MALIGNANT HYPERTHERMIA

Concept

Malignant hyperthermia (MH), also known as malignant hyperpyrexia, is a potentially lethal pharmacogenetic disorder which affects genetically predisposed individuals^2,33.

Etiology

There is clear evidence that individuals susceptible to MH have a skeletal muscle disorder associated with uncontrolled release of Ca²⁺ from sarcoplasmic reticulum³³. Two genes related to susceptibility to MH have been identified and at least four genes are in the process of positive identification⁵ (Table III). Individuals susceptible to MH respond abnormally when exposed to inhalational anesthetics (halothane, enflurane, isoflurane, desflurane, sevoflurane), depolarizing muscle relaxants (e.g. succinylcholine) or extreme physical activity in hot environments¹. During exposure to these triggering agents, there is a rapid and sustained growth of myoplasmic Ca²⁺ concentration due to RyR1 hyperactivation, which causes a profound change in Ca2⁺ homeostasis and characterizes a hypermetabolic state²⁷.

Epidemiology

MH was described in all ethnic groups and its susceptibility occurs equally in both sexes, although seizures are more common in men. The incidence of anesthetic MH in adult patients is 1/50,000 and 1/15,000 in pediatric patients, although cases have been reported in extreme ages. Its true prevalence is difficult to define because some individuals present mild or no reactions and the variable penetrance of the inherited trait^34,35. The incomplete penetrance indicates that, although the individual has the genetic mutation for MH susceptibility, it does not mean that this dysfunction will be expressed during the first or even after the exposure to a triggering agent³⁵.

Pathophysiology

Under normal conditions, the myoplasmatic levels of Ca²⁺ are controlled by RyR1, DHFR, and Ca²⁺-adenosine triphosphatase (Ca²⁺-ATPase) system³⁵. In MH crisis, there is intense change in Ca²⁺ homeostasis in which RyR1 hyperactivation causes an increase in cytoplasmic Ca²⁺ concentration, which results in sustained activation of muscle contraction¹⁸. Sometimes, the first symptom may be the presence of a masseter muscle spasm. This signal is considered by many authors as a sign of suspected syndrome⁵.

The process of muscle contraction and re-absorption of excess Ca²⁺ consume large amounts of ATP and generate excessive heat (hyperthermia), which is the hallmark of disease¹⁸. Depletion of ATP stocks results in disruption of the skeletal muscle membrane and there is leakage of cellular constituents, including potassium, creatine, phosphate, and myoglobin. Loss of potassium from muscle cells results in metabolic acidosis and cardiac arrhythmias³⁷. Decreased concentration of ATP causes muscular rigidity, as the presence of ATP is normally required to allow muscle relaxation, in addition to the combination of actin and myosin to allow muscle rigidity and inextensibility¹⁸.

A potential increase in oxygen consumption through uncontrolled glycolysis and aerobic metabolism leads to cell hypoxia, progressive lactic acidosis, and excessive carbon dioxide generation³⁴. Thus, the most common initial signal of acute malignant hyperthermia is an unexplained increase in values of capnography (EtCO₂), a method that evaluates the gradient of CO₂ present during expiration, in which excess expired CO₂ does not easily decreases with increased minute ventilation. This increased EtCO₂ is associated with the presence of tachycardia (due to sympathetic stimulation by acidosis)⁵.

This hypermetabolic state generates heat and leads to hypoxemia, metabolic acidosis, rhabdomyolysis (breakdown and lysis of muscle cells) and a rapid increase in body temperature, which can be fatal if not recognized and treated early².

Signs and symptoms

The onset of acute malignant hyperthermia is characterized by one or more signals of systemic hypermetabolism during or immediately after administration of a triggering agent³⁴. The first symptoms are tachycardia, hyperventilation, localized muscle stiffness, cyanosis, arrhythmias, excessive sweating and hyperthermia. The crisis of MH can manifest itself later on a recurring basis in up to 20% of cases, even after discontinuation of the triggering agent, and fever above 40ºC, cyanosis, poor cutaneous perfusion, pressure instability, and generalized muscle rigidity may occur³⁵.

Additional and potentially fatal complications include disseminated intravascular coagulation, congestive heart failure, intestinal ischemia, and limb compartment syndrome with a deep muscle edema³⁴.

Diagnosis

Clinical

MH diagnosis is based on clinical and laboratory findings. MH manifestation may be immediately after exposure to the triggering agents or even a few hours after its discontinuation. Without this prior exposure, it is usually impossible to identify a susceptible patient, which makes the clinical diagnosis very difficult^33,35,38.

Crises are classified according to clinical presentation and symptoms may vary from fulminant to abortive conditions, according to its intensity³⁵ (Table IV).

The most common initial symptoms are listed in Table V. Although nonspecific, these initial symptoms associated with exposure to triggering agents in the absence of other apparent cause will be sufficient to establish a preliminary diagnosis of MH and immediately refer the patient to treatment. MH may evolve rapidly, presenting additional clinical and laboratory manifestations (Table V). Between 12 and 24 hours after the crisis onset, the peak plasma levels of creatine kinase (CPK) can be observed. Susceptibility confirmation will depend on caffeine-halothane contracture test (CHCT) outcome, indicated only three months after the crisis' onset³⁵.

Laboratory - Susceptibility to MH

Creatine kinase (CPK) at rest

Increased CPK is found in 50% of relatives of patients with anesthetic malignant hyperthermia. The presence of increased CPK at rest, other than in strenuous exercise or muscle trauma, has relative value only in relatives of susceptible patients. Without additional explanation, high levels of CPK at rest raise the suspicion of myopathy. These changes are common and do not justify plasma CPK measurement in the general population^39.

Contraction test for exposure to caffeine-halothane (CHCT)

Even in classic cases, diagnosis confirmation is mandatory because it will be from the confirmed cases that the investigation planning for relatives of those affected will be made. The standard test adopted for MH diagnosis is the contraction test of exposure to caffeine-halothane (CHCT)³⁵. Through analysis of the contractile response to caffeine-halothane exposure, it is possible to discriminate patients as susceptible (MHS) when the answer to both caffeine and halothane is abnormal; negative (MHN) when the response to caffeine and halothane is normal; and equivocal (MHE) when the response to caffeine or halothane is abnormal. All patients diagnosed as MHE are treated as MHS due to their susceptibility. Clinical diagnosis is considered positive when there is a contracture > 0.5 g for 3% halothane and > 0.3 g at 2 mM of caffeine⁴⁰.

The procedure for muscle biopsy preparation varies depending on the laboratory. Some of them follow the United States' protocol (97% sensitivity, but low specificity, with 22% false positives) while others follow the European protocol - also known as in vitro contracture test - which differs from the American protocol only by including the use of ryanodine or 4-chloro-m-cresol (99% sensitivity, 94% specificity)⁵.

In Brazil, both the Muscle Biopsy Center of the Universidade Federal do Rio de Janeiro and the Study, Diagnosis and Malignant Hyperthermia Research Center (Cedhima) of the Escola Paulista de Medicina, Universidade Federal de São Paulo use the American protocol for the diagnosis of MH⁴¹.

Genetic testing

From the first reported case of MH, it was suspected to be a family inherited disorder⁴⁰. With the demonstration that a mutation in the gene encoding RyR1 in pig muscles was the basis of MH, a simple DNA test in humans to diagnose it increased the expectation. However, this expectation has not yet been achieved because there are many changes in skeletal muscle that may be the cause for the different forms of the syndrome⁴² (Table III).

The mutations associated with the six listed genes correspond to approximately 50% of families surveyed. In other families, the gene involved is still unknown³⁹. Furthermore, despite the MHS1 mutation being the only direct genetic cause for MHS, the additional presence of MHS3, MHS4, or MHS6 mutations may interact and increase the phenotype expression in some individuals⁴⁰.

However, with time, an accuracy test based on DNA and applicable to most patients will be available and, once identified the mutation in a case of MH, all family members may be tested for that specific mutation through a blood sample. A major international effort is underway to clarify the molecular genetic basis of MH⁴².

Treatment

The internationally recommended protocol for treatment of malignant hyperthermia is based on discontinuation of exposure to the triggering agents, administration of specific drug (dantrolene), and support measures or measures aimed at preventing associated complications, such as:

1. Replacing the anesthesia circuit by another circuit uncontaminated by anesthetic agent;

2. Hyperventilating the patient with 100% oxygen;

3. External cooling and, if necessary, internal;

4. Correction of metabolic acidosis;

5. Reduction of hyperkalemia;

6. Correction of cardiac arrhythmias;

7. Maintenance of diuresis^33,35.

Dantrolene

Dantrolene was originally synthesized by Snyder et al. in 1967. It was found to have muscle relaxing properties after intravenous administration in animals. The studies demonstrated that these relaxing properties are due to the depression of excitation-contraction coupling (EC). It was initially used as a muscle relaxant in long-term treatment of skeletal muscle spasticity⁴³. Dantrolene has been used since 1975, but currently its clinical use is restricted to malignant hyperthermia^44,45.

Dantrolene blocks the RyRs, acts directly on RyR1 and RyR3 isoforms, reduces the channel activation by calmodulin, and reduces the channel sensitivity to Ca²⁺. RyR2 is not blocked by dantrolene, which explains its lack of negative inotropic effect on the heart^7,10,46.

The molecular structure of dantrolene, a hydantoin derivative, is planar. It is highly lipophilic and, therefore, poorly water-soluble. This created problems for its introduction into clinical practice until the 1980s. Its widespread use had to wait for a suitable intravenous preparation⁴⁷. Currently, dantrolene is available for intravenous use in vials containing 20 mg of lyophilized sodium dantrolene added to 3 g of mannitol to enhance water solubility. The vial contents should be dissolved in 60 mL of water, which yields a final dantrolene concentration of 0.33 mg.mL^-1 at pH 9.5. The resulting alkaline solution is highly irritating to peripheral veins and must be injected into a large vein or be rapidly infused⁴³.

Rapid preparation and administration of dantrolene are essential. Therapy begins with the administration of 2.5 mg.kg^-1 and must be repeated every five minutes until the hypermetabolic state normalization and disappearance of all MH symptoms⁴⁸. Continuous intravenous infusion of dantrolene at 10 mg.kg^-1 should be given at least 24 hours after successful initial therapy. Support therapy includes body cooling; administration of sodium bicarbonate to treat acidosis; beta-blockers or lidocaine in case of cardiac arrhythmias persistency; and furosemide and glucose-insulin infusion in case of hyperkalemia, hypercalcemia, and myoglobinuria. Thus, early diagnosis generates a successful treatment in most patients⁴³.

Azumolene

Azumolene is 30 times more soluble in water than its analog, dantrolene. This is due to the replacement of the para-nitrophenyl group in dantrolene by the para-bromophenyl group. Compared to dantrolene, azumolene is equipotent for treatment and prevention of MH clinical manifestations during a crisis induced by halothane or succinylcholine. In vitro studies showed azumolene equipotential for relaxing porcine skeletal muscle and, in vivo, it was more potent for inhibiting the gastrocnemius muscle contractions. Therefore, this product may be useful for treating MH in the future. However, for economic reasons, it has not been introduced into clinical practiceyet⁴³.

PERSPECTIVES

The elucidation of the molecular genetic basis of MH has the perspective of making a pre-symptomatic diagnosis, without the need for biopsies, in addition to having a full understanding of the disease etiology. With the advancement in human genome mapping, there is a promising future for characterizing new mutations related to this syndrome and unveiling the genetic heterogeneity of MH, as phenotypic variations may be caused by interactions of several genes, yet unknown, such as the RYR1 gene.

In recent years, a major breakthrough has occurred in understanding the dynamics of Ca²⁺ release via RyR1 from the several modulating proteins of this receptor. Therefore, further studies on these numerous modulating proteins represent potential therapeutic targets. Therefore, studies related to the properties of RyR1 may yield results applicable to clinical practice, such as drugs that increase or disrupt the interaction of these modulating proteins of RyR1, and, thus, provide the development of new therapeutic strategies for treating MH.

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Malignant hyperthermia: clinical and molecular aspects

Ana Carolina de Carvalho Correia^I,II; Polyana Cristina Barros Silva^I,II; Bagnólia Araújo da Silva^I,III

Publication Dates

• Publication in this collection
  06 Dec 2012
• Date of issue
  Dec 2012

History

• Received
  27 Oct 2011
• Accepted
  23 Jan 2012