Bryce A. Heese
Roberto T. Zori
The Human Genome Project (HGP), initiated in 1990 and completed in 2001, promised to revolutionize the practice of medicine with cheap and efficient technology. Traditionally, genetic testing has consisted of broad genome screening studies (e.g. chromosome karyotype, comparative genomics hybridization) or DNA-based techniques for a select number of single gene disorders. However, the HGP has provided a wealth of information for scientific discovery and has led to development of new and more efficient methods for genetic analysis. Both the number of disease-causing genes being discovered and the number of applicable gene tests being developed are increasing exponentially. The future of genomics promises personalized health management, such as selection of specific therapies and drugs based on individualized genetic information from whole genome screening. However, for many nongenetic clinicians, the promised revolution is not yet obvious, and the use of genetic information in daily clinical practice can be confusing and difficult to manage.
The complexity of the human genome is highlighted by the knowledge that the set of human proteins (several million) is significantly greater than the relatively small number of genes (estimated to be only about 25,000). This underscores the importance of epigenetics, such as alternate splicing (alternate coding sequence) within the same gene, or posttranslational modification of the coded protein to create innumerable gene products. Proteomics is the study of the physiologic composition of proteins (or the proteome) as affected by different biologic processes. Of note, the use of certain protein biomarkers, such as C-reactive protein and creatine kinase isoforms, have been commonly used in clinical practice for decades in disease profiling. More recently, the FDA has emphasized the role of protein biomarkers in drug development and clinical analysis, which is also helping to spur research in the field. Proteomics shows great promise in critical care, since drugs typically target proteins and not genes. However, the complexity and massive expanse of human proteins and gene expression are added barriers to proteomic research, often causing difficulty in producing reliable results. The future promise of proteomics, similar to genomics, is to provide revolutionary information for the managing clinician. Like genomics, however, its clinical applicability is presently limited.
Population screening for genetic disease is another current topic in clinical genetics that proposes to change clinical medicine. The purpose of population screening is to reduce morbidity and mortality by detecting an individual's risk prior to manifesting clinical disease. The original principles for population screening by the World Health Organization have been adapted to fit the construct of a new genomics era (1). The key feature of any population screen is to weigh relative costs, ethics, and other considered risks compared to the benefits, particularly the ability to treat based on early detection (2). Prenatal screening for genetic diseases is steadily increasing, as is the promise of population genetic screening in adults and children for common genetic diseases. In reality, population genetic screening has been implemented for decades. A particular example is the mass newborn screening primarily used to detect inherited metabolic diseases, as well as genetic disorders such as sickle cell anemia. The early detection and management of genetic disorders has increased survival of these previously unrecognized and devastating diseases. Such detection and management also provides a significant clinical problem for the future, as there will be a deficiency in metabolic specialists, typically pediatric trained, to care for long-term surviving children who achieve adulthood with inherited metabolic disorders. This will place a burden on intensivists due to the added risk of surgery and illness for these individuals.
This chapter will concentrate primarily on genetic conditions that may present in a catastrophic fashion and frequently require attendance in a critical care unit. The purpose is to alert the critical care physician to the presence of genetic or inherited metabolic diseases, as well as to provide some guidance for emergency therapy in unique situations, in particular, those involving patients in acute metabolic crises. This section is not intended to be a comprehensive list of genetic diseases encountered, as such information is far too detailed for this chapter and, additionally, will likely be outdated shortly after publication. Instead, the reader is encouraged to use the information summarized herein as a starting point to find up-to-date, peer-reviewed, Web-based information for the proper management of genetic conditions.
Fundamentals of Genomics/Genetics
The term genome refers to the complete set of DNA (deoxyribonucleic acid) within an organism. In humans, the nuclear genome consists of 46 chromosomes (or 23 pairs of chromosomes), half of which are maternally inherited (from the egg) and half inherited paternally (from sperm). The nucleus of most cells within the body contain a single copy of the human genome. A distinction should be made between the 46 chromosomes found within the cell's nucleus and the mitochondrial genome, which is found within each mitochondria of the cell.
Mitochondria, and thus, mitochondrial DNA, is inherited only maternally (the sperm does not contribute mitochondria to the zygote). Mitochondrial disorders will be discussed again in the following mitochondrial disease section.
A single nuclear chromosome consists of a continuous chain of double-stranded DNA, which if stretched from end to end would measure about 1 yard in length. Each strand contains a sequence of nucleotides (adenine, thymine, cytosine, or guanine) in various combinations. The order of the nucleotides contributes to the genetic information and is, essentially, the organism's blueprint. When two complementary strands of DNA are in a dormant stage, they are bonded together as a double strand, forming the chromosome. During replication or gene expression (transcription and translation; see below), parts of the double strand must be separated by a complex molecular process to expose the genes.
Genes are regions of DNA that contain a sequence of nucleotides coding for a single strand of RNA (ribonucleic acid), a process called transcription. RNA, in turn, exits the nucleus and serves as the template from which amino acids are combined to form a protein, a process referred to as translation. Depending on its structure, shape, and a complex process of posttranslational modifications, a protein may have any number of functions, such as a structural component (the cell membrane or extracellular matrix), cellular receptors, plasma transporters, enzymes, or numerous other functions within the body. Each gene is about 10,000 base pairs in length, but can range from a few hundred to several thousands of base pairs, and they are located on various sites throughout the genome. Genes also contain promoter regions, introns, and other nontranscribed sequences that are important regulatory factors for efficient and timely gene expression. The Human Genome Project described about 25,000 genes, accounting for only about 10% of the full genome. Much of the remainder of the genome consists of vast expansions of highly conserved repeat sequences, the function of which is not presently understood.
Individual humans share over 99.9% of this sequence with one another. However, given the size of the human genome, about 3 billion base pairs, this allows for significant differences between individuals. An individual's genotype refers to the structural makeup of DNA. Genotype is typically used in reference to a single gene of interest; however, it may also be used in the context of a set of genes and gene modifiers, or even the entire genome. An individual's phenotype is a term used to describe the physical manifestations, which are typically determined by both gene expression and environmental influences. Genetic variations, or mutations, can be in the form of a single nucleotide substitution, or small insertions or deletions of nucleotides within a DNA sequence. If a mutation occurs within the translational region of a gene, it may potentially change the transcription or translation of that gene, causing an alteration in the gene product, and therefore changing an individual's phenotype. A mutation may also occur within a regulatory region of a gene, which may alter the expression of a gene, causing decreased or increased translation. Alternatively, mutations may occur within the translated segment of a gene but have little or no affect on the gene product or clinical phenotype. In many cases, mutations occur outside of the gene sequence or within untranslated regions of a gene (e.g., introns) where there would not be an affect on gene expression.
Traditionally, genetics has focused on monogenetic and/or Mendelian disorders in which an identifiable change in DNA material, such as a mutation in a gene or chromosomal anomaly, results in an identifiable genetic disorder. More and more, genetics research is involving polygenic diseases such as cardiovascular disease, hyperlipidemia, or asthma, where genetics likely plays a role in disease susceptibility; in most cases, there is not an identifiable single gene defect, but rather multiple genetic variations. Single-nucleotide polymorphisms (SNPs) are a method of looking at DNA sequence variation. SNPs may occur within or outside of a coding region, and may or may not cause a change in an amino acid and/or protein structure. The HapMap project is an offshoot of the Human Genome Project that is working on cataloging haplotypes, or variations of SNPs, within the population. This information can then be used in research and eventually medicine to identify genetic variants that lead to increased susceptibility to complex (or polygenic) diseases.
Genetic Testing
The promise of genomics is to provide a cheap and efficient personalized genomic profile for every person. Today's reality, however, is sporadic testing for several well-characterized genetic disorders. However, the number of genetic tests available has increased tenfold within the past decade, and technology and discovery are rapidly evolving. The breadth of genetic testing will likely continue to grow exponentially (3). For the nongeneticist, deciding on how to proceed with genetic testing can be cumbersome and confusing. Because of scientific discovery and the continued expansion of genetic testing, it would be overwhelming to list all of the genetic testing available, particularly as the information quickly becomes outdated. The clinician, thus, must be able to use updated, often Web-based, materials to aid in this decision process.
Genetic testing may consist of whole chromosome screening (e.g., chromosomal karyotype or comparative genomic hybridization arrays) and FISH (fluorescence in situ hybridization). These tests look for large deletions or duplications, often associated with specific syndromes, within the genome. This section will primarily discuss DNA-based gene tests that typically identify single gene disorders.
Common gene testing includes sequence analysis, targeted mutation analysis, and mutation scanning. DNA sequence analysis identifies a given nucleotide sequence in an individual and compares it to the known normal sequence to look for alterations. This method of testing has traditionally been time-consuming and costly. It can be particularly burdensome for large gene regions. However, as technology becomes more efficient, more gene tests will likely turn to sequencing, as it has a slightly higher rate of detection. Targeted mutation analysis is used as a diagnostic tool when a small number of mutations within a single gene are known to cause a disease. Often, when a mutation is not detected by this method, gene sequencing is performed to look for a possible mutation not included in the targeted analysis. Finally, mutation scanning, a screening tool using various methods to detect variations in DNA segments, is used when other methods are too time consuming or costly because several mutations are distributed along large segments of DNA. Each method has benefits and deficiencies for detecting mutations, depending on the specific situation. It is, therefore, important to keep in mind that there are multiple detection techniques available when making the decision to proceed with genetic testing.
Several factors must be taken into account when considering genetic testing:
1. The clinician should, first, establish a clinical basis for suspecting a particular genetic disease. Today, genetic testing is relatively expensive and can be time-intensive, depending on the study. A personal and family history, physical exam, screening laboratory and radiographic tests, as well as any supporting studies can provide evidence pointing to a specific diagnosis and should be used when deciding whether to proceed with genetic testing. In the circumstance of inherited metabolic diseases, screening metabolic laboratory tests and enzyme assays may also be used to eliminate the need for specific genetic studies (discussed in inherited metabolic diseases section below).
2. The clinician must weigh the necessity of genetic testing, particularly taking into account whether management or treatment options will change as a result of testing. Although in some cases, test results may not alter the management of a patient, the genetic results may be useful for screening family members who are at risk of inheriting the condition.
3. No genetic test is perfect. False-positive and -negative results, test sensitivity, and other measures must be evaluated when deciding the utility of testing. This information can often be found in sources such as GeneTests (discussed below), or should be available from the testing laboratory itself.
4. Both the clinician and the patient should understand the purpose and utility of genetic testing. A common pitfall is for a clinician to evaluate genetic results as strictly positive or negative when, in fact, there is a certain level of uncertainty in almost every test. Genetic testing is rarely 100% sensitive. False-negative results are possible when a mutation occurs in a region of the gene that is not evaluated, such as a regulatory sequence or intron. Additionally, many diseases exhibit locus heterogeneity (more than one gene may be responsible); therefore, a genetic test may miss a significant portion of affected individuals. At the same time, it is not uncommon to find an abnormality in a gene that is predicted (or known) to be completely benign. A common pitfall is to interpret these benign variant results as a positive test. Furthermore, genetic testing is commonly performed without discussing options with the patient or patient's family. As genetic testing may have consequences (e.g., ethical, insurance, or familial inheritance factors) beyond the patient's acute setting, many—but not all—genetic centers require consent prior to testing, but it is always appropriate to keep the patient informed regardless of the laboratory's procedures. Careful consideration of each component is essential, and assistance from a genetic counselor or geneticist can be useful in the decision process and interpretation of genetic tests.
Clinical genetic testing is constantly evolving. Along with current journal articles and reviews, Web-based information is becoming essential for the proper evaluation and management of genetic diseases. A commonly used site for comprehensive literature review of DNA-based diseases is the Online Mendelian Inheritance in Man. OMIM* also provides links to MEDLINE and many related databases. Another helpful resource for updated genetic testing is GeneTests† (4). GeneTests encompasses several hundred current, peer-reviewed articles of common genetic disorders. The site includes information on specific tests offered from both clinical and strictly research laboratories as well as estimates of mutation detection rates, alternate genes, and differential diagnostic considerations. GeneTests provides suggestions for management and counseling, as well as links to educational resources for many of these diseases.
Inherited Disorders of Metabolism
Inherited disorders of metabolism comprise a heterogeneous group of genetic diseases, several of which present in acute metabolic distress, which require emergency management and critical care monitoring. Each disorder involves a defective enzyme or transport protein that normally contributes to proper biochemical process within the body. As a group, the clinical manifestations of metabolic disorders can be extremely variable depending on the affected biochemical pathway, severity of the molecular defect (e.g., the amount of residual enzyme activity), and environmental factors (e.g., illness, fasting, or dietary intake). Although there are approximately 1,000 metabolic disorders described, each disorder is relatively rare; collectively, however, there is an estimated incidence of about 1:4,000.
Increased awareness and detection in all ages, as well as advances in our understanding and management of metabolic diseases, has decreased morbidity and increased survival in children with metabolic disorders, even into adulthood (5,6). For example, expanded newborn screening identifies more infants with metabolic disorders. In addition to improved early detection of presymptomatic infants with metabolic disorders, newborn screening has secondarily identified affected siblings and family members of all ages. Furthermore, case reports of adult-onset metabolic disease are not uncommon, typically described in the setting of an acute metabolic stressor such as a prolonged presurgical fast or an illness with vomiting and dehydration (7,8). It is essential for the intensivist to be knowledgeable about the possible presentation, initial evaluation, and emergency management for patients of all ages with this group of disorders.
Metabolism refers to the sum of the process of biochemical synthesis (anabolism) and breakdown (catabolism) of compounds, such as proteins, carbohydrates, and lipids from the diet or stored within the body. Inherited metabolic disorders are genetic defects that affect an enzyme or a transport protein important to normal metabolism. Clinically, inherited metabolic disorders manifest with a wide range of symptoms, from chronic progressive disease to acute metabolic crises, following an apparently asymptomatic interval. Depending on the severity and type of disorder, any number of organ systems may be involved. Hepatic failure may present in tyrosinemia type I, Wilson disease, and Gaucher disease. Cardiomyopathy may be a feature in infantile and juvenile Pompe disease, very-long-chain acyl-CoA dehydrogenase deficiency, and various lysosomal storage diseases. Muscle disease, either myopathy and/or rhabdomyolysis, may occur in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), very-long-chain acyl-CoA dehydrogenase deficiency, and McArdle disease. Acute encephalopathy is a concern in many organic acidurias, urea cycle defects, and fatty acid oxidation defects.
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Figure 51.1. Most inborn errors of metabolism are due to an enzyme defect within a metabolic pathway. The defect may lead to toxic accumulation of substrate, or metabolic by-products, or to deficiency of an essential product within that pathway. |
Often, the acute presentation of an inherited metabolic disorder may mimic a more common, systemic disease such as sepsis or intoxication; however, swift recognition and management of a metabolic disorder is important for improving the overall morbidity and mortality. Saudubray et al. (9) loosely classified these disorders into three groups:
1. Metabolic disorders of intermediary metabolism that cause toxic accumulation of metabolites. This may be conceptualized as a road block in the normal metabolic pathway causing a traffic jam and the buildup of potentially toxic intermediary metabolites. Some of these metabolites will be directed to alternative pathways, which may lead to the accumulation of toxic byproducts (Fig. 51.1). Examples of this group include organic acidurias, aminoacidopathies, fatty acid oxidation defects, urea cycle defects, disorders of metal transport (e.g., Wilson disease), and carbohydrate defects. In critical care, many of these diseases present in acute metabolic crises with some combination of encephalopathy, liver disease, multisystem failure, metabolic acidosis, ketoacidosis, lactic acidosis, or hyperammonemia.
2. Metabolic defects that affect cellular respiration or mitochondrial energy production. This group includes enzyme defects of the mitochondrial respiratory chain itself. It also includes enzymes in glycolysis (the breakdown of glucose, for energy), glycogenosis (utilization of glycogen stores for energy), gluconeogenesis (glucose synthesis for transport to other organs), and the tricarboxylic acid (TCA or Kreb) cycles. Fatty acid oxidation disorders, which cause toxic accumulation of fatty acids and other byproducts (group 1), are also considered here, as the products of these reactions are an essential energy source for the TCA cycle and mitochondrial respiratory chain, particularly during fasting stress.
3. Disorders involving the synthesis or breakdown of complex (large) molecules. This group includes lysosomal storage disorders, peroxisomal disorders (e.g., X-linked adrenoleukodystrophy), disorders of glycosylation, and cholesterol synthesis defects. In general, these disorders are chronic progressive disease, and though they may rapidly worsen during illness or stress, they rarely present in acute metabolic crises.
For an exhaustive discussion of all known metabolic disorders, the reader is referred to comprehensive reviews (10,11). Herein, we focus on metabolic disorders and associated scenarios that may present to the critical care unit.
Fatty Acid Oxidation Disorders
Fatty acid oxidation disorders encompass a group of metabolic defects of mitochondrial beta-oxidation. Beta-oxidation is the process of breaking down fatty acids to aid in energy production, as adenosine triphosphate (ATP), via the respiratory chain complex. Several 2-carbon molecules (acetyl-CoA) are also produced by beta-oxidation of each fatty acid. Acetyl-CoA can be utilized in the tricarboxylic acid cycle for aerobic respiration or as a precursor for the production of ketone bodies. Therefore, the beta-oxidation cycle is essential for the normal physiologic response to fasting after typical energy sources, such as glucose and glycogen, are depleted. In the fasting state, vital organs, in particular the brain, require an alternate source of energy in the form of ketone bodies.
Several enzymes are essential in the beta-oxidation of fatty acids. Carnitine palmitoyltransferase 1 (CPT1), carnitine palmitoyltransferase 2 (CPT2), and carnitine acylcarnitine carrier protein are important for the transfer of fatty acids into the mitochondria. Long-chain fatty acids (12–18 carbon-length molecules) are acted on by the enzyme's very long-chain acyl-CoA dehydrogenase (VLCAD), mitochondrial trifunctional protein, and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD). Medium-chain fatty acids (6–12 carbon-length molecules) are broken down by the enzyme medium-chain acyl-CoA dehydrogenase (MCAD) (Fig. 51.2).
Disease manifestation, age of onset, and severity vary greatly, depending on the enzyme defect. The most common of these conditions, MCAD deficiency, with an estimated incidence of 1 in 15,000, can present at any age, with fasting intolerance, metabolic encephalopathy, and hypoketotic hypoglycemia. Often, the acute presentation is a result of an illness with vomiting and dehydration. This condition may also cause liver disease with significant hyperammonemia, referred to as Reye-like syndrome. Of note, myopathy and cardiomyopathy are rare in MCAD deficiency. Individuals with MCAD deficiency are essentially completely asymptomatic between acute episodes. Long-chain fatty acid defects (VLCADD, LCHADD, or TFP [trifunctional protein] deficiency) and CPT2 deficiency may also present early in childhood with similar fasting intolerance and hypoketotic hypoglycemia, along with cardiomyopathy. However, milder forms of these diseases may not present until adolescence or early adulthood, typically with only muscle disease associated with rhabdomyolysis and/or cardiomyopathy.
Organic Acidurias and Aminoacidopathies
Organic acidurias are caused by defects in the normal cellular breakdown of amino acids or odd-chain fatty acids. Examples include propionic aciduria and methylmalonic aciduria, which are disorders of the breakdown of the amino acids isoleucine and valine. Other disorders include isovaleric aciduria, 3-methylglutaconic aciduria, glutaric aciduria type I, multiple carboxylase deficiency, and biotinidase deficiency.
Aminoacidopathies, disorders marked by the abnormal accumulation of specific amino acids, can be included within this group, as there is clinical overlap in many of these conditions. Amino acids are organic acids (which include a carboxylic group) that are unique in that they have an amino group (containing nitrogen). As a group, aminoacidopathies can have much more variability in clinical presentation. Examples may include maple syrup urine disease (MSUD), a defect involving the catabolism of the branched chain amino acids leucine, isoleucine, and valine, or tyrosinemia type I, which can cause accumulation of the by-product succinylacetone, a metabolite toxic to liver cells.
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Figure 51.2. Fatty acid oxidation occurs primarily in the mitochondria. Carnitine plays an important role in transport of long-chain fatty acids into the mitochondria. Each fatty acid molecule is broken down by several enzymatic cycles (beta-oxidation) in which each cycle produces a 2 carbon molecule (acetyl-CoA). Beta-oxidation enzymes are fatty acid chain-length specific (i.e. medium-chain acyl-CoA dehydrogenase breaks down fatty acids that are of medium chain length, 6–10 carbons). Acetyl-CoA is important for ketogenesis, energy production, and other essential biochemical roles. |
In the ICU, it is important to be aware of this group of disorders, many of which present with acute metabolic crises that may mimic or accompany more typical scenarios such as sepsis or drug overdose.
Urea Cycle Disorders
Defects of the urea cycle affect the normal detoxification of ammonia (Fig. 51.3). Ammonia primarily results from nitrogen waste accumulated from excess intake of protein or the endogenous catabolism of protein. The most common urea cycle disorder, X-linked ornithine transcarbamylase (OTC) deficiency, severely affects neonatal males shortly after birth. This often presents as significant encephalopathy and respiratory alkalosis at a few days of life, after significant protein intake.
Females who are carriers for OTC deficiency are essentially heterozygous for the condition but may also be symptomatic, with significant recurrent episodes of hyperammonemia, depending on the extent of X-inactivation. It is not uncommon for females with OTC deficiency to present in later childhood or as adults. Additional urea cycle disorders include citrullinemia, carbamylphospate synthase-1 deficiency, and argininosuccinic aciduria. Acute hyperammonemia in urea cycle defects may manifest at any age. Thus, an individual with poorly explained encephalopathy, including lethargy or coma, should have an ammonia level evaluated.
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Figure 51.3. Removal of excess nitrogen (ammonium, NH4+) waste from dietary intake and catabolism of protein is facilitated by several enzyme steps in the urea cycle. The end product is a water soluble compound, urea, which is readily excreted by the kidneys. N-acetylglutamate (NAG) is an important positive activator of carbamyl phosphate synthetase, the first enzyme in the urea cycle. The formation of NAG is inhibited by accumulation of organic acid metabolites from the breakdown of organic acids, amino acids, fatty acids and other organic compounds, thus potentially leading to secondary hyperammonemia. |
Mitochondrial Disease
Mitochondrial disorders consist of disorders of oxidative phosphorylation, including pyruvate dehydrogenase deficiency, disorders of the tricarboxylic acid cycle, and respiratory chain defects. These are a heterogeneous group of metabolic defects and should be considered whenever unrelated organ systems are affected without a reasonable explanation. Mitochondrial disorders can be caused by gene defects within the nuclear DNA, which have a typical Mendelian inheritance pattern. In general, these conditions are inherited autosomal recessive and have a clinically more severe onset, usually in infancy and early childhood. Mitochondrial disorders that are inherited from genes within mitochondrial DNA itself are more commonly progressive and present later in life (12).
Defects involving mitochondrial DNA are only maternally inherited, because only the egg—not the sperm—donates mitochondria to the zygote. Another consideration in mitochondrial (maternal) inherited disorders is that each cell in the body contains multiple sets of mitochondria; therefore, the same cell—and thus an individual—may have a mixture of both mutated and normal mitochondrial DNA. This is referred to as heteroplasmy and contributes to the phenotypic heterogeneity observed in patients with maternally inherited mitochondrial disorders. The clinician should be aware of mitochondrial disorders, such as the more common mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), which may present to the ICU with multisystem disease. Of particular concern in these disorders is metabolic stroke and lactic acidosis (see respective sections below).
Although understanding and awareness of mitochondrial disorders is improving, treatment remains limited. In the acute setting, supportive management including ventilatory support, treatment of lactic acidosis, fluid and nutritional support (i.e., limiting glucose intake to 3–5 g/kg/min and supplementing with lipids), and management of seizures is important. Specific therapies, such as a “mitochondrial cocktail” of vitamins and cofactors, are predicted to aid in ATP production, and are used by most specialists who treat mitochondrial disorders. Although considered safe, the efficacy of these vitamins and cofactors in treating these conditions is not well established. This generally includes CoQ10, L-carnitine, vitamin B1 (thiamine), and vitamin B2 (riboflavin) (13,14). Particular attention should be given to mitochondrial patients requiring anesthetics. These individuals are inherently at risk due to the mitochondria's inability to deal with added oxidative stress from surgery and anesthesia. Additionally, most anesthetic agents affect mitochondrial function in some fashion, such as depressing carbohydrate metabolism or inhibiting certain components of the mitochondrial respiratory chain. These risks are primarily based on scientific reasoning and in vitro studies; clinical evidence is lacking. However, given the risk, all anesthetics should be used with caution in individuals with this group of disorders (15). Particular drugs of concern include barbiturates, propofol, nitroprusside, theophylline, valproate, and phenobarbital (16).
Inherited Metabolic Disorders Testing
Routine laboratory studies—blood glucose, electrolytes, bicarbonate, urea nitrogen, creatinine, ammonia, lactate, blood gases, liver transaminases, complete blood count, creatine kinase, uric acid and plasma or urine ketones—must be considered in the emergency department or ICU, particularly when a metabolic disease is suspected. A rapid and accurate plasma lactic acid level should be available to evaluate for anion gap metabolic acidosis, and a rapid and accurate ammonia level should also be available to evaluate any patient with encephalopathy. Of note, a common pitfall in practice is to neglect an ammonia level during the initial evaluation of a critically ill patient, particularly in the case of unusual or unexplained encephalopathy. The above tests, along with clinical signs, are helpful in establishing evidence for an inborn error of metabolism. This information is often sufficient to initiate appropriate empiric therapy for metabolic diseases while diagnostic and confirmatory studies are performed. Please refer to Table 51.1 for a list of routine laboratory studies which can aid in the workup of a suspected metabolic disorder.
Specialized Metabolic Laboratories
The basic laboratory studies, as noted above, are important in the initial evaluation of any critically ill patient, particularly if an etiologic explanation for the observed symptom complex is not readily apparent. When a metabolic disease is suspected, special laboratory investigations are warranted (Table 51.2). These include plasma amino acids, plasma acylcarnitines, and urine organic acids. The relative pattern of accumulated and deficient metabolites is useful in suggesting, or even diagnosing, specific inherited metabolic disorders. These studies are typically performed at only a handful of specialized clinical laboratories by laboratorians trained in the appropriate interpretation of metabolic profiles. Therefore, samples most likely will have to be sent away, preferably by overnight courier, while empiric management is initiated. It is, however, important to make every attempt to obtain these samples prior to initiating therapy. In certain situations, the typical treatment for a metabolic disorder, such as the correction of blood glucose in hypoglycemia, may also correct the accumulation of diagnostic metabolites that are seen in metabolic screening tests, thus creating difficulty in interpretation (12). Realizing the urgency in swiftly treating a critically ill patient, empiric management clinicians should not wait for results; however, laboratory samples may be drawn and placed aside until the acute crisis is over. At the very least, plasma (5 mL) and urine (at least 5 mL) should be obtained and stored frozen until the appropriate investigations can be considered. Blood spots dropped onto filter paper (such as newborn screening cards available in any laboratory affiliated with a nursery), completely dried and stored with a desiccant, may also be saved for further analysis such as an acylcarnitine profile and, in some cases, molecular gene testing (17).
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Table 51.1 Routine Laboratory Studies in Known/Suspected Metabolic Disorders |
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Plasma Acylcarnitines
Plasma acylcarnitines aid in diagnoses of fatty acid oxidation disorders and certain organic acidurias. This is the same technology used in expanded newborn screening programs due to the ability to screen for several metabolites—and, thus, several different disorders—by a single technique. A common pitfall in the hospital setting is to mistakenly order total and free carnitine levels in place of a plasma acylcarnitine profile. Although carnitine levels are useful in the workup of primary carnitine deficiency, caused by a defective carnitine uptake transporter protein, which is manifested by muscle myopathy and cardiomyopathy, carnitine levels also evaluate specifically for carnitine deficiency, which may accompany several metabolic disorders. Although the carnitine levels are of significance in the management of a suspected metabolic disorder, plasma acylcarnitines will likely be more useful when the diagnosis of a metabolic disease is in question.
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Table 51.2 Specialized Metabolic Laboratory Studies for Suspected Metabolic Disorders |
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Quantitative Plasma Amino Acids
Quantitative plasma amino acids aid in the diagnoses of urea cycle disorders, certain organic acidurias, and primary lactic acidoses (i.e., an elevated alanine is indirect evidence of chronic lactic acidosis). This test is also essential for the safe monitoring of patients who are on a protein-restricted diet or specific amino acid–restricted diet. Another common pitfall in the hospital is to mistakenly order a urine amino acid profile. Aside from evaluating for renal tubular disease and a handful of inherited disorders of amino acid transport (e.g., cystinuria), urine amino acids have little value in the workup of metabolic disorders, particularly in the setting of an acute metabolic crisis.
Urine Organic Acids
Urine organic acids aid in the diagnoses of organic acidurias, primary lactic acidemias (e.g., respiratory chain disorders and pyruvate dehydrogenase deficiency), as well as certain fatty acid oxidation disorders. This test is also essential in establishing a specific diagnosis in devastating disorders such as tyrosinemia type I (by the presence of the metabolite succinylacetone) and glutaric aciduria type I (by the presence of 3-hydroxyglutaric acid).
Endocrine studies, such as an insulin level, a random cortisol level, C-peptide, thyroid function studies, or growth hormone levels, are also important in the workup of individuals with atypical acute presentations, particularly in unusual fasting hypoglycemia, but will not be described in detail within the realm of genetic diseases. Additionally, there are several other metabolic screening studies, such as a very long-chain fatty acid panel (to identify peroxisomal disorders such as X-linked adrenoleukodystrophy), urine glycosaminoglycans and oligosaccharides (to identify various lysosomal storage disorders), or plasma sterols (to identify cholesterol biosynthesis disorders). These studies may be helpful in the workup of certain, often chronic, progressive disorders. However, they are not typically useful in evaluating a patient in acute metabolic crises.
Confirmatory Studies
When a specific metabolic disorder is suggested by the screening laboratory studies discussed above, confirmatory studies are typically performed to ensure proper diagnosis and management. This may include specific enzyme studies performed on leukocytes or biopsied samples, such as hepatocytes, myocytes, or other tissues, depending on the disorder in question. Increasingly, specific DNA-based gene studies are being used for diagnostic testing in metabolic disorders. This level of testing is typically performed only in selected laboratories with an interest in the specific disorder. Such studies can be time-consuming and often costly, and are generally not useful for management of a patient in the emergency department or ICU.
Postmortem Evaluation for Metabolic Disorders
When a metabolic disease is suspected in a patient who has died, several key samples must be taken for follow-up testing. Plasma (5 mL, stored frozen) and urine (any amount, stored frozen) should be drawn, preferably prior to death. Additionally, when a metabolic disease is in question, the ICU should be prepared to obtain proper consent for retrieving and storing tissue for future metabolic studies. Fresh tissues from biopsied liver, muscle, and skin (fibroblasts) should be obtained as quickly and efficiently as possible after death. Obviously, this can be a very stressful situation for medical staff and for family members; therefore, the hospital and ICU should establish a postmortem metabolic protocol in anticipation of such an event to help the process flow as smoothly as possible. When it is not feasible to retrieve the above samples, a blood spot, dried on filter paper as described above, should be obtained for possible metabolic or genetic testing. Ideally, this would also include dried bile spots on filter paper for a more thorough analysis. However, this, too, requires a postmortem examination (18).
Genetic Scenarios in Critical Care
Emergency Protocol
Patients with a previously diagnosed metabolic disorder, prone to acute metabolic crisis, often possess an emergency protocol letter that has been drafted by a treating genetic or metabolic specialist. The protocol should contain general information about the condition and how it affects the particular patient. It should also provide important recommendations for management during an acute metabolic episode. Depending on the disorder, emergency therapies may include one or more of the following components:
1. Management of the acute insult (e.g., dehydration, infection, and trauma) with supportive care
2. Detoxification of accumulated metabolites (e.g., with hydration, bicarbonate, scavenger therapy, or hemodialysis)
3. Reversing the catabolic process (typically by increasing caloric intake).
Hypoglycemia in Metabolic Disease
Hypoglycemia is a serious concern in critical care. It is typically defined by a blood glucose level less than 40 mg/dL in all ages. However, the American Diabetes Association describes hypoglycemia in nondiabetic individuals as a blood glucose less than 70 mg/dL due to normal physiologic triggers that occur below this level (19). In any event, tight control of blood sugars—in most centers to a level between 80 and 110 mg/dL—is ideal in the management of critically ill patients (20). In the critical care setting, hypoglycemia can be a normal physiologic response to severe systemic illness, multiple organ failure, or liver damage. More commonly, it is the result of drugs such as insulin or alcohol, although rare causes of hypoglycemia include endocrine and metabolic disorders.
Postprandial hypoglycemia—that occurring within four to six hours of a meal—may indicate an endocrine disorder such as hyperinsulinism. Hyperinsulinism also presents with low or no ketone production, which is contrary to a normal physiologic response to low blood sugar. Postprandial hypoglycemia may also be observed in glycogen storage disease type I, which typically presents in the neonatal or infant stage, and is often accompanied by hepatomegaly.
Atypical hypoglycemic response to prolonged fasting, defined as six to 24 hours, may indicate a metabolic defect of fatty acid oxidation. Fatty acid oxidation is the normal physiologic response to fasting in which fatty acids are broken down into ketone bodies for energy. Due to the inability to produce ketones from fatty acids, these disorders may present as hypoketotic hypoglycemia, as well as acute encephalopathy from accumulation of toxic metabolites combined with low ketones and glucose. For example, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is believed to have an incidence of 1 in 15,000. Acute metabolic attacks in MCAD deficiency can be severe, often presenting in infancy or childhood after an inciting illness or fast. However, between attacks, individuals with this disorder may be completely asymptomatic, and some individuals potentially reach adulthood undiagnosed and without symptoms. In critical care, it is important to be aware of these conditions when working up patients with an atypical response to illness, stress, or prolonged fasting, such as a routine surgical procedure (8).
Other metabolic disorders may include hypoglycemia in their presentation. Elevated ketones with low blood sugar may be observed as secondary effects of acute decompensation in individuals with an organic aciduria, such as propionic aciduria. In this case, accumulated toxic metabolites may also manifest with encephalopathy and metabolic acidosis. Hypoglycemia that accompanies lactic acidosis can be a sign of a respiratory chain disorder or a defect in mitochondrial energy metabolism. Depending on the severity and cause of the respiratory chain dysfunction, other signs and symptoms may accompany a respiratory chain defect, such as encephalopathy, myopathy, stroke-like episodes, and various other organ diseases.
Laboratory Investigations for Metabolic Causes of Hypoglycemia
When suspecting a metabolic disorder, the basic metabolic laboratory studies, including accurate blood glucose, electrolytes, bicarbonate, blood urea nitrogen, creatinine, ammonia, blood gas analysis, lactic acid, liver transaminases, complete blood count, creatine kinase, and uric acid, should be obtained. Blood for insulin, cortisol, and C-peptide levels should be obtained while an individual is hypoglycemic to evaluate for a potential endocrine disorder. The normal physiologic response to fasting hypoglycemia is to produce ketone bodies. Thus, abnormally low plasma and/or urine ketone levels may indicate either inappropriate insulin production or a disorder of fatty acid oxidation. Elevated plasma-free fatty acids may also be indicative of a fatty acid oxidation defect. Plasma acylcarnitines, urine organic acids, and plasma amino acids are important screening studies when suspecting a metabolic disorder. It is essential that these studies—including the above-cited endocrine laboratories—be obtained prior to initiating management for hypoglycemia. Correction of the blood glucose will cause difficulty in the interpretation of many laboratory results—for example, a normal or elevated insulin level in the setting of a corrected blood glucose level would not be useful. In certain cases, correction of hypoglycemia may also correct the accumulation of diagnostic metabolites that are seen in metabolic screening tests (12).
Management of Hypoglycemia
When oral correction of hypoglycemia is not possible, an initial intravenous bolus of 25 g of dextrose—50 mL of a 50% solution (for children: 1 mg/kg glucose of a 20% solution)—may be used, followed by continuous infusion of a 10% dextrose solution with appropriate electrolytes. Management of a suspected metabolic disorder may require 7 to 10 mg/kg/min to maintain appropriate glucose levels, or even greater in certain cases of hyperinsulinism. Although glucagon may be administered for transient correction of hypoglycemia, it will be ineffective in conditions where glycogen reserves are not available, as in certain glycogen storage diseases or where glycogen reserves are depleted as in a fatty acid oxidation defect, organic aciduria, as well as alcohol ingestion.
Glucose, lactic acid, and acid-base status must be closely monitored due to the high glucose concentration administered. In many cases, hypoglycemia is accompanied by significant dehydration requiring fluid correction. With high fluids and glucose administration, electrolytes —particularly sodium—must be carefully monitored, and sodium levels should be maintained above 135 mMol/L to avoid complications of cerebral edema (21). If a fatty acid oxidation defect or organic aciduria is suspected, carnitine (100 mg/kg per day; maximum 5 g per day may be given IV or orally) should be initiated empirically until a more definitive diagnosis is made. Carnitine will aid by conjugating and facilitating the excretion of accumulated toxic fatty acid and organic acid metabolites.
Ketoacidosis in Metabolic Disease
Ketone bodies, including 3-hydroxybutyrate, acetoacetate, and acetate, are derived from excess acetyl-CoA and generally formed in the mitochondria of liver cells from fatty acid breakdown. Ketogenesis is a physiologic response to the depletion of carbohydrates, such as glucose and glycogen, as seen in prolonged fasting. Vital tissues, particularly the brain, can convert ketone bodies back into acetyl-CoA for use in the tricarboxylic cycle and use acetyl-CoA as an alternate energy source when glucose is not available.
Ketoacidosis is the abnormal accumulation of these acidic ketone bodies, causing significantly low pH. Exhaled acetone, the “fruity” breath odor can be a sign of ketoacidosis. Diabetic ketoacidosis (discussed elsewhere in this textbook) is a common problem in critical care due to absence of insulin, which normally suppresses fatty acid breakdown into ketone bodies. Ketoacidosis is also observed in individuals on a ketogenic diet, a possible treatment for certain refractory seizure disorders. Alcoholic ketoacidosis may occur in chronic alcoholics following abrupt withdrawal of ethanol along with depletion of carbohydrates. Several metabolic disorders, including organic acidurias (e.g., propionic aciduria, methylmalonic aciduria), aminoacidopathies (e.g., maple syrup urine disease) and respiratory chain defects, may be associated with profound ketoacidosis as a secondary effect during acute metabolic decompensation. A neonate, child, or adult presenting with any combination of ketoacidosis, metabolic acidosis, lactic acidosis, hypoglycemia, hyperammonemia, systemic disease, liver disease, lethargy, encephalopathy, or coma should be evaluated for a metabolic disease, particularly if a reasonable explanation for the presentation cannot be found.
Laboratory Investigation for Metabolic Ketoacidosis
Evaluation for ketoacidosis, particularly when a metabolic disorder is suspected, should include initial basic laboratory studies including blood glucose, electrolytes, bicarbonate, blood urea nitrogen, creatinine, ammonia, blood gas analysis, lactic acid, liver transaminases, complete blood count, creatine kinase, and uric acid. An ammonia level should be obtained, as secondary hyperammonemia may be suggestive of a metabolic disease such as an organic aciduria. A complete blood count may show neutropenia or pancytopenia in certain organic acidurias, respiratory chain abnormalities, or glycogen storage diseases. Specialized laboratory tests to screen for a suspected metabolic disorder include plasma acylcarnitines, plasma amino acids, and urine organic acids.
Management of Metabolic Ketoacidosis
Management strategies for ketoacidosis, in the context of a known or suspected metabolic disease, begins with treatment of the underlying stress, such as infection or fever, followed by careful improvement of metabolic acidosis and prevention of further protein catabolism. Intake of protein and fatty acids should be discontinued, and administration of fluids up to 1.5 times maintenance and dextrose as a 10% solution, up to 10 mg/kg/min with appropriate electrolytes will also help to reverse the catabolic state, which, if left unchecked, will worsen the acute metabolic crisis (17,21). High volumes of fluid may be important, as metabolic decompensation often follows an inciting stressor such as vomiting and dehydration. Intravenous sodium bicarbonate can be used, but the goal should be to raise and maintain arterial blood pH to 7.2 and keep plasma bicarbonate levels greater than 10 mMol/L—and not to correct the acidosis to normal. Electrolyte, fluid, and acid-base status and frequent neurologic assessment must be monitored closely. Serum sodium levels should be maintained above 135 mMol/L to prevent cerebral edema. However, the administration of sodium bicarbonate can also lead to hypernatremia. Hypokalemia may occur as a response to rising pH and should be closely monitored throughout therapy.
A specific example of a disease that may present with profound ketoacidosis during metabolic crises is maple syrup urine disease (MSUD). These individuals, particularly older children and adults who are no longer growing, can be very difficult to manage. In cases of severe ketoacidosis with MSUD, the administration of IV insulin in combination with a steady supply of high glucose has been shown to enhance anabolism in addition to preventing hyperglycemia from excess carbohydrate infusion (17,22). Obviously, careful and frequent monitoring of blood glucose is necessary when using high concentrations of glucose, particularly with the use of insulin. Another important factor in managing metabolic defects with profound ketoacidosis is that prolonged (greater than 48 hours) restriction of protein will cause the body to become deficient in certain essential amino acids and therefore resume breakdown of endogenous protein stores, thus worsening the ketoacidosis (23). Consultation with a metabolic specialist and/or metabolic nutritionist familiar with these disorders is essential in both short- and long-term management.
Hyperammonemia in Metabolic Disease
An ammonia level should be standard in any critical care situation involving an obtunded patient, particularly if the cause is not readily apparent. A normal ammonia level in a healthy adult is typically less than 50 µM/L and slightly higher in healthy neonates, up to 80 µM/L. Elevated ammonia is toxic to brain cells and can result in lethargy with plasma ammonia levels as low as 100 to 200 µM/L; severe encephalopathy and coma may result from higher levels (24). Respiratory alkalosis from hyperventilation is caused by ammonia's effect on the brain's respiratory drive. Regardless of the cause, hyperammonemia should be managed quickly and efficiently to reduce significant morbidity.
Plasma ammonia may be artificially elevated as a result of sample handling and/or difficult blood draw—for example, with the use of a tourniquet during phlebotomy. Severe liver disease and overproduction of ammonia by colonized urease-producing bacteria are possible causes of hyperammonemia (25). Several inherited metabolic disorders should be considered in patients of all ages presenting with hyperammonemia. Severe urea cycle disorders may present in the neonatal period shortly after birth, with ammonia levels well above 1,000 µM/L; however, milder cases may not present until adolescence or adulthood (7,26). The urea cycle is essential in the disposal of excess nitrogen wastes, including ammonia, by forming soluble urea which is more readily excreted by the kidneys. Thus, the physiologic process of protein catabolism (e.g., in the case of fasting or illness) leads to toxic accumulation of ammonia in patients with urea cycle defects. Other metabolic disorders that cause the accumulation of toxic organic acid, amino acid, or fatty acid metabolites may also cause a prominent elevation in ammonia by secondarily inhibiting the enzyme N-acetylglutamate synthase, a component in the urea cycle (Fig. 51.3). Therefore, a thorough investigation into metabolic causes of hyperammonemia may be warranted.
Laboratory Investigations for Metabolic Causes of Hyperammonemia
When suspecting a metabolic cause of hyperammonemia, the clinician should obtain basic metabolic laboratory investigations, as described above. Of note, an abnormally low blood urea nitrogen in the context of elevated ammonia may be further evidence of an underlying urea cycle defect (25). Further laboratory investigation for a suspected urea cycle defect includes plasma quantitative amino acids to measure levels of the urea cycle intermediates, particularly citrulline and arginine. These compounds, in addition to urine orotic acid measurement, will be useful in differentiating the specific defect within the urea cycle. As mentioned above, certain organic acidurias and fatty acid oxidation disorders may present with hyperammonemia. Therefore, plasma acylcarnitines and urine organic acids should also be obtained.
Management of Hyperammonemia
Hyperammonemia should be aggressively managed, as it can be toxic to the brain. Excess nitrogen must be reduced by halting the protein intake. If a diagnosis is not immediately known, fat must also be restricted until a disorder of fatty acid oxidation has been formally ruled out. In addition, administration of high glucose, 10 mg/kg/min, will provide extra calories and prevent further protein catabolism, and thus the accumulation of excess nitrogen. It will be difficult to achieve this level of glucose infusion in adult patients. Typically, a safe place to start is a 10% dextrose solution with appropriate electrolytes to run at 1.5 times maintenance. Glucose, lactate, and acid-base levels must be closely monitored while the patient is receiving high glucose concentrations. The increased fluid intake—again, up to 1.5 times maintenance—will assist in the excretion of ammonium. Electrolytes, particularly sodium, must be carefully monitored and kept above 135 mMol/L. Additional diuresis may be necessary to avoid complications of fluid overload and cerebral edema (21). The nitrogen scavenging drugs—sodium benzoate, 5.5 g/m2 (250 mg/kg in children) and sodium phenylacetate, also 5.5 g/m2 (250 mg/kg in children)—should be readily available to aid in the removal of excess ammonia by allowing an alternate pathway for nitrogen excretion (17). These medications can be diluted in 10% dextrose and administered intravenously as a loading dose over 90 minutes, and then this same dose given continuously over 24 hours. Sodium benzoate and sodium phenylacetate are now FDA-approved for the management of hyperammonemia, and dosage and administration should comply with the manufacturer's recommendations. Additionally, the essential amino acid, arginine, is an intermediate in the urea cycle found downstream from most of the common defects, and it is often deficient in urea cycle defects. Intravenous infusion of L-arginine, 4 g/m2 (300 mg/kg in children), may be administered with sodium benzoate and sodium phenylacetate as a loading dose over 90 minutes, followed by a continuous infusion over 24 hours (27). Alternatively, arginine may be given orally if the patient is able to take it. If the diagnosis is uncertain, carnitine, 100 mg/kg/day, IV or orally, should be given for empiric treatment of a potential organic aciduria or fatty acid oxidation defect (21). Dialysis should be readily available for refractory cases or for severe hyperammonemia—that is, with levels greater than 400 µM/L. This can be in the form of hemodialysis, hemofiltration, or peritoneal dialysis, although obviously the former are more efficient in the removal of toxic metabolites.
Lactic Acidosis in Metabolic Disease
Lactic acidosis is a common problem in intensive care and is typically a secondary effect from inadequate oxygen supply or tissue hypoperfusion as seen in respiratory failure, systemic shock, or tissue infarction. Signs and symptoms indicative of lactic acidosis include metabolic acidosis (pH <7.3, bicarbonate <15 mEq/L) with hyperventilation, and an abnormal anion gap (>15 mEq/L). Drugs such as ethanol, ethylene glycol, and salicylates may cause secondary lactic acidosis (28). A related isoform, D-lactate, is produced by bacteria colonized primarily in the gut and may contribute to significant metabolic acidosis. D-lactic acidosis should be considered in a patient who presents with encephalopathy, metabolic acidosis with a high serum anion gap, and symptoms of short bowel syndrome or gastric malabsorption (29,30). Plasma and/or urine D-lactate levels must be determined separately, as the regular assay for plasma lactic acid may be normal and miss the isoform.
Any metabolic disorder that presents with acute decompensation, such as certain organic acidurias, urea cycle defects, and fatty acid oxidation defects, may also develop significant lactic acidosis secondary to systemic disease. Because acute metabolic attacks are often triggered by an inciting stressor, such as illness with vomiting and dehydration, the clinician should consider metabolic disorders in patients with atypical presentations of lactic acidosis or unusual response to therapy.
Defects that affect glycogen metabolism (e.g., certain glycogen storage disorders), gluconeogenesis (e.g., fructose diphosphatase deficiency), and disorders of cellular aerobic respiration (e.g., pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency, and disorders of the respiratory chain complex) constitute a group of metabolic disorders referred to as primary lactic acidoses. In these cases, lactic acid is the accumulated byproduct from the metabolic defect itself rather than a secondary effect from systemic disease. Timing in relation to a carbohydrate load may be useful in the evaluation of lactic acidosis. For example, the lactic acid level in disorders of gluconeogenesis generally improves after the fed state with normal glucose levels, and lactic acidosis worsens with fasting hypoglycemia. In contrast, certain glycogen storage disorders and disorders of cellular aerobic respiration respond with a paradoxical elevation of lactic acid following a carbohydrate load due to the inherent block in carbohydrate utilization (31). Mitochondrial disorders will also be discussed in this section, as well as metabolic stroke.
Laboratory Investigations for Metabolic Causes of Lactic Acidosis
When the presentation of lactic acidosis suggests a possible metabolic disorder, basic metabolic laboratory investigations, as noted above, should be obtained immediately. As with serum ammonia levels, lactic acid levels may be artificially elevated as a result of sample handling and/or difficult blood draw—for example, with use of a tourniquet during phlebotomy. Additional screening laboratory tests for a suspected metabolic disease should include a plasma acylcarnitine profile, urine organic acids, and plasma amino acids. An abnormal elevated alanine seen in plasma amino acids may be an indirect measurement of pyruvate and lactate but is not affected by a tourniquet lab draw (12). Abnormal ketosis, particularly paradoxical postprandial ketosis, may be indicative of a primary lactic acidosis defect. An elevated cerebrospinal fluid (CSF) lactate may be helpful in the evaluation of a suspected primary lactic acidosis. As noted above, a d-lactic acid level should be considered in a patient who presents with encephalopathy, metabolic acidosis with a high serum anion gap, and symptoms of short bowel syndrome or gastric malabsorption.
A pyruvate level and differential measurements of the two serum ketones—3-hydroxybutyrate and acetoacetate—can be helpful in distinguishing between the different primary lactic acidoses. For example, an elevated lactate-to-pyruvate ratio with an elevated 3-hydroxybutyrate-to-acetoacetate ratio, in the setting of paradoxical postprandial ketosis and lactic acidosis, would highly suggest a respiratory chain disorder. These ratios act as an indirect method of measuring cellular oxidation/reduction status (31). However, due to the difficulty in collection, handling, and interpretation of these studies, this level of analysis is generally not feasible nor necessary for the acute management of patients with a primary lactic acidosis.
Management of Lactic Acidosis
Managing the underlying cause of lactic acidosis is the mainstay of treatment in most cases. For example, adequate ventilation and oxygenation, tissue perfusion, antimicrobial coverage, and other strategies common to the critical care setting should be continually monitored and adjusted. Intravenous sodium bicarbonate to correct anion gap acidosis caused by excess lactic acid can be used, but the goal should be to raise and maintain arterial blood pH to 7.2 and keep plasma bicarbonate levels greater than 10 mMol/L rather than correct the acidosis to normal. Large amounts of sodium bicarbonate may be necessary to achieve this goal. Therefore, sodium should be closely monitored for the risk of developing hypernatremia from large amounts of sodium bicarbonate. Potassium should also be monitored for the risk of hypokalemic response to rising pH. Diuretics such as furosemide, with adequate potassium supplementation, can be considered in this case. Other considerations might include the use of tris-hydroxymethyl aminomethane (THAM) or dialysis for cases refractory to typical treatment (17).
If a primary lactic acidosis is confirmed or highly suspected, glucose should be limited to between 3 and 5 mg/kg/min, as carbohydrates may worsen the accumulation of lactic acid (21).
Alternative calories—for example, lipids—should be sought. Before restricting glucose, however, note that disorders of fatty acid oxidation cannot handle excess lipids efficiently, and organic acidurias require high caloric loads to prevent acute protein catabolism. Both of these conditions should be reasonably ruled out. The diagnosis of a primary versus secondary causes of lactic acidosis is tricky, and consultation with a metabolic specialist familiar with the diagnosis and management of these disorders is recommended.
Genetic Considerations in Rhabdomyolysis
Rhabdomyolysis, or myonecrosis, refers to skeletal muscle destruction and release of toxic substances in the circulatory system. Laboratory markers for rhabdomyolysis include elevated serum creatine kinase (CK) and the presence of myoglobinuria, or red-brown, cola-colored urine. Rapid identification and management is important to decrease morbidity, particularly the development of acute renal failure.
Rhabdomyolysis most commonly results from direct muscle trauma, particularly crush injury. Excessive muscle exertion such as in status epilepticus may cause a significant elevation of CK. It has also been described in an unconditioned otherwise healthy individual, although this would be a rare circumstance (32). Drug exposure may be the most common cause of rhabdomyolysis, particularly in critical care. Common medications that have been associated include diuretics, statins, clofibrate, narcotics, theophylline, corticosteroids, benzodiazepines, phenothiazines, and tricyclic antidepressants, as well as recreational drugs of abuse including alcohol, cocaine, amphetamines, heroin, phencyclidine, and lysergic acid diethylamide (33). Late-onset muscular dystrophies—for example, X-linked Becker muscular dystrophy—may present with exertional rhabdomyolysis; however, these individuals are often limited by weakness (31).
Recurrent rhabdomyolysis, or severe disease for which there is not a reasonable cause, may indicate an underlying metabolic disorder. These disorders may present at any age, and it is not uncommon for onset to occur in early adulthood despite a typical active childhood. Active muscle has a high energy demand for adenosine triphosphate (ATP), generated primarily from stored glycogen during the initial part of exercise and free fatty acids during prolonged exercise. Defects in these metabolic processes may lead to exercise intolerance and potentially rhabdomyolysis. McArdle disease (myophosphorylase deficiency, or glycogen storage disease type V) is a defect in glycolysis and often presents in late childhood to early adulthood with muscle fatigue and cramps. Certain long-chain fatty acid oxidation defects—such as long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency (LCHAD), very long-chain acyl-CoA dehydrogenase deficiency (VLCAD), carnitine palmitoyltransferase deficiency type II (CPT2), and primary carnitine deficiency—can present with exercise intolerance and rhabdomyolysis in older children and adults. In addition, myoadenylate deaminase deficiency, a defect in the recycling of purines—and hence ATP—can have a similar presentation. Finally, respiratory chain disorders (see mitochondrial diseases, below) should be considered in recurrent myoglobinuria when accompanied by multisystemic involvement and lactic acidosis (31).
Laboratory Investigation for Metabolic Causes of Rhabdomyolysis
Laboratory investigations important in the management and workup of rhabdomyolysis include basic laboratory investigations, as noted above. Lactic acidosis can acutely accompany muscle damage or hypoperfusion, but a history of chronic lactic acidosis may be an indicator of an underlying mitochondrial respiratory chain disorder. A plasma acylcarnitine analysis should be drawn to evaluate for a possible fatty acid oxidation defect (e.g., LCHAD, VLCAD, CPT2). Further diagnostic workup for metabolic causes of rhabdomyolysis may require an open muscle biopsy for muscle enzyme studies, such as CPT2, myophosphorylase, and myoadenylate deaminase. This is important to consider; however, time-intensive specialized enzyme studies are not likely helpful in the acute management of rhabdomyolysis.
Management of Rhabdomyolysis
Management of rhabdomyolysis involves preventing further muscle damage and providing supportive care to prevent significant morbidity from acute renal failure, hypovolemia, metabolic acidosis, hyperkalemia, disseminated intravascular coagulation, and respiratory and hepatic insufficiency. Early and aggressive fluid management with normal saline, at the rate of 1.5 L per hour, is the only therapy that has been proven beneficial. However, many centers also use the administration of bicarbonate to alkalinize urine, as well as mannitol for theoretical benefit in minimizing kidney damage (34,35). In disorders of fatty acid oxidation, rhabdomyolysis is caused by muscle tissue damage due to lack of energy from fatty acid metabolism. Consider the administration of dextrose (up to a 10% solution) for known or highly suspected metabolic disorders to minimize continued muscle breakdown in these conditions.
Genetic Considerations in Stroke
Stroke is a heterogeneous neurologic condition that refers to the presentation of focal cerebral damage. A strong familial predilection suggests a genetic component (36,37). However, with rare exception (e.g., CADISIL, see below), single genes have a relatively low impact on the overall stroke risk (38). Therefore, it is well established that stroke is multifactorial, or influenced by environmental factors with a certain genetic predisposition. Well-known modifiable risk factors, including smoking, hypertension, hyperlipidemia, and diabetes mellitus, have a significant environmental component. However, these risk factors, particularly hypertension, hyperlipidemia, and diabetes, also have a familial predisposition and thus contribute to the genetic susceptibility of stroke as well.
Single gene disorders that cause isolated stroke, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy or (CADISIL), are rare. Alternatively, most genes (and/or genetic disorders) associated with stroke are part of a multisystem disease in which stroke is a secondary manifestation of the disorder. This includes multifactorial disorders such as hyperlipidemia, hypertension, and diabetes mellitus, as noted above, as well as single-gene disorders that affect cerebral vascular structure (e.g., connective tissue disorders) or hematologic conditions that increase the risk for thromboembolism (e.g., antithrombin III deficiency). Certain inherited metabolic disorders are also associated with a secondary risk of stroke. We will present several defined genetic disorders that either cause or predispose to stroke. The reader is referred to more comprehensive reviews on stroke (37,39); nonetheless, caution should be used, as there is ever-increasing knowledge and discovery of new genes in stroke, as is the case in any multigenic disorder.
Causative Gene Disorders in Stroke
Single-gene disorders that cause familial, isolated stroke are rare. An example is CADISIL, which typically presents in midadult life with clinical manifestations of migraines, transient ischemic attacks, lacunar infarcts, and multi-infarct dementia. The condition is diagnosed by clinical findings, distinct MRI studies showing subcortical white matter lesions, and traditionally by skin biopsy showing electron dense granules within smooth muscle cells. The gene for CADISIL (Notch3) has been identified and is clinically available for diagnostic testing (40). Clinical genetic testing should be considered in any unusual presentation of isolated stroke, particularly in adults younger than 50 years of age with clinical and radiographic evidence of CADISIL (37). Although the specific pathophysiology of CADISIL is still unknown, it is believed to be due to the increased fragility of cerebral microvessels. An autosomal recessive counterpart, CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy), and other candidate genes causing isolated stroke are under investigation. However, currently, only CADISIL gene testing appears to have clinical applicability.
Genetic Susceptibility to Stroke
Connective tissue disorders that affect cervical and intracranial arteries can cause the formation of aneurysms and/or arterial dissection and lead to ischemic stroke. Disorders such as vascular type (or type IV) Ehlers-Danlos syndrome (EDS) and Marfan syndrome are well-known connective disorders affecting large vessels; both are inherited autosomal dominant. This underscores the importance of obtaining a personal or family history, particularly when there is a presentation of recurrent arterial dissection or aneurysm. Individuals with Marfan syndrome and vascular type EDS typically have an identifiable physical phenotype, and clinical diagnostic criteria exist for these conditions. Genetic and molecular testing is available for these disorders and can be helpful, not only to confirm the diagnosis, but also for family screening. Of note, vascular involvement in Marfan syndrome typically affects the larger arteries, particularly the aortic root; however, several related connective tissue diseases, such as the Marfanlike Loeys-Dietz syndrome, have recently been described with a possible predisposition to arterial involvement (41). Genetic and molecular testing is available for some of these disorders. Furthermore, there are likely several, yet undiscovered, connective tissue genes that predispose to abnormalities in the vascular wall. Additionally, many of these conditions are likely multifactorial, and many investigators are looking for candidate susceptibility genes (42,43). Finally, autosomal dominant polycystic kidney disease has also been described with intracranial aneurysms and should be considered in the workup for stroke (44).
Vascular disease may predispose to vessel occlusion and ischemic disease, and thus stroke. Genetic disorders that can lead to cerebrovascular disease include fibromuscular dysplasia (more commonly affecting renal arteries) and Moyamoya disease (cerebrovascular disease of arteries near basal ganglia, typically seen in children). Another vascular defect, Fabry disease, is an X-linked lysosomal storage disorder affecting the breakdown of specific glycosphingolipids. The disorder typically manifests in male adolescents or adults with recurrent pain crises, and leads to renal failure and cardiovascular disease if left untreated. Accumulated deposition of glycosphingolipids in small arteries, particularly vertebrobasilar arteries, leads to occlusion and infarcts (45).
Thromboembolism contributes to about 30% of ischemic stroke. Therefore, coagulation studies should be obtained to rule out common causes of thrombotic disease. Genetic predisposition to coagulopathy leading to thrombosis may include protein C deficiency, protein S deficiency, factor V Leiden mutation, antiphospholipid antibody syndromes, homocystinemia, and sickle cell anemia.
Inherited Metabolic Disorders and Susceptibility to Stroke
Homocystinuria is a metabolic disorder associated with a significant risk for thromboembolism. Clinical features of homocystinuria can be quite variable; many individuals have low IQ, psychiatric problems, and extrapyramidal signs. A tall, marfanoid body habitus has also been described. Similarly, mild to moderate homocystinemia can be caused by acquired nutritional deficiency of folic acid, vitamin B12 or vitamin B6, or by a congenital defect in the gene coding for 5, 10-methylenetetrahydrofolate reductase (MTHFR). In any case of thromboembolic stroke, a plasma homocystine level should be obtained (39).
Methylmalonic aciduria (MMA) is a metabolic defect in the breakdown of certain amino acids. MMA also has been described with MRI and/or CT findings involving bilateral lesions of the globus pallidus and cortical atrophy, along with clinical findings of dystonia and choreoathetosis. The rare onset of stroke in these patients is generally not isolated. Rather, it is typically observed in the setting of acute metabolic decompensation, such as profound anion gap metabolic acidosis and ketoacidosis (46) (See the section on ketoacidosis, above).
Metabolic Stroke in Mitochondrial Disorders
Metabolic stroke, or stroke-like episodes observed in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), as well as other inherited mitochondrial disorders, can be devastating. However, the etiology of these strokes is not well understood (14,47). Of note, stroke-like episodes have also been described in children with certain congenital disorders of glycosylation, a diverse group of disorders often presenting with dysmorphic features and multisystem involvement (48). Stroke-like episodes typically present with infarcts within the posterior temporal, parietal, and occipital lobes on imaging. The infarcts are atypical in that they are localized in regions near large vessels as opposed to watershed regions (49,50). Aside from supportive care, no definitive therapy has been established for treating metabolic stroke. Koga et al. (51) administered L-arginine, 0.5 g/kg per dose, intravenously during acute metabolic stroke in a few patients with MELAS with positive results. The rationale behind using arginine in mitochondrial patients is that stroke-like episodes may, in part, be due to poor vasodilatation of cerebral arteries, and arginine, a precursor to nitric oxide, may improve vascular tone. Caution must be observed with use of intravenous L-arginine. Hypotension may be a side effect of IV infusion, and acid-base status should be monitored carefully due to the common preparation of IV arginine hydrochloride. Arginine is not considered standard therapy in this situation, and therefore consultation with a metabolic specialist is recommended for determining the appropriate therapy for metabolic stroke (14).
Genetic Considerations in Cardiomyopathy and Sudden Cardiac Death
Cardiomyopathies encompass a heterogeneous group of disorders with multiple clinical, molecular, and histiologic presentations. Traditionally, these have been categorized according to various pathophysiologic manifestations, such as hypertrophic (increased myocardial tissue thickness; e.g., increased myocyte size, fibrosis, or storage material), dilated (enlarged cardiac chamber volume), restrictive (inhibited ventricular filling), and mixed disorders (52). Definitions and classification schemes can be confusing due to the marked variability of causes and presentation. In particular, many traditional schemes do not account for the increasingly updated genetic and molecular discoveries. Furthermore, ion channelopathies, or dysrhythmic disorders, such as long QT syndrome (LQTS), present with a structurally normal heart, distinct from cardiomyopathies. It is well known that most forms of familial hypertrophic cardiomyopathy and long QT syndrome are inherited autosomal dominant. Both conditions predispose the affected individual to sudden cardiac death, often with little or no warning. This underscores the importance of not only properly diagnosing and managing the affected individual, but also screening and monitoring family members at risk for inheriting the condition (53,54,55). DNA-based genetic testing is available for several genes responsible for both hypertrophic cardiomyopathy and LQTS. Genetic testing should be considered in any patient presenting with a significant clinical picture suspicious for either condition, in particular young individuals presenting with sudden cardiac death. Finally, several metabolic disorders are at risk for developing cardiomyopathy—for example, fatty acid oxidation defects affecting mitochondrial energy (ATP) production or lysosomal storage diseases leading to cardiac tissue infiltration of storage material. This section is an overview of the genetic considerations in cardiomyopathies and causes of sudden cardiac death.
Ion Channelopathies
The most common congenital arrhythmia, long QT syndrome (LQTS), is inherited either autosomal dominant (Romano-Ward syndrome) or autosomal recessive (Jervell, Lange-Nielsen). About half of the individuals with these conditions are symptomatic, commonly with tachydysrhythmias resulting in syncopal events. However, some individuals remain asymptomatic (56). The autosomal dominant conditions, Andersen-Tawil syndrome and Timothy syndrome, are also associated with dysmorphic findings. The autosomal recessive forms of LQTS are typically associated with sensorineural deafness. Traditionally, these disorders are diagnosed clinically by history and rate-corrected QT interval. However, today, several genes responsible for this condition have been found, and genetic testing for many of these genes is clinically available. This is an example that genetic testing is not only beneficial for confirming the diagnosis but also for potential screening of first-degree relatives who may be asymptomatic and at risk for inheriting the condition. Family members who inherit the condition can have early and appropriate management to prevent complications, particularly death. All individuals who have a known mutation causing LQTS, and all first-degree relatives at risk for LQTS in whom a causative mutation is not found, are recommended to have at least a 12-lead ECG performed, followed by an exercise ECG, the latter particularly to evaluate a borderline resting ECG (57). Other less common ion channelopathies include Brugada syndrome (autosomal dominant sodium channelopathy causing a distinctive ECG pattern), catecholaminergic polymorphic ventricular tachycardia (autosomal dominant with normal resting ECG), and short QT syndrome (linked to mutations seen in ion channel genes of LQTS) (55).
Hypertrophic Cardiomyopathy
Familial hypertrophic cardiomyopathy (HCM), commonly autosomal dominant, is the most common cause of sudden cardiac death in young individuals. This condition is inherited as autosomal dominant, and therefore, a thorough family history is important in the workup. As with LQTS, many individuals with HCM may be completely asymptomatic. Clinically, HCM may be diagnosed by standard imaging, such as an echocardiogram showing left ventricular wall thickening. Several causative genes, typically coding for contractile proteins within the muscle cell, have been identified. Many of these genes are clinically available for genetic testing. As with LQTS, genetic testing for HCM may be useful not only for confirmatory diagnosis, but also for screening first-degree relatives at risk to inherit the condition. Recommendations for asymptomatic individuals at risk for HCM due to either a known mutation or a first-degree relative with HCM include a yearly physical exam, 12-lead ECG, and echocardiogram until the age of 18 years (58). Beyond 18 years of age, it is generally recommended to continue screening at least every 5 years, although management strategies may differ (58,59,60).
Dysrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), caused by abnormal fibrofatty infiltration and tissue replacement within the right ventricle, is another cause of sudden cardiac death in young individuals. It has an autosomal dominant inheritance and is clinically difficult to diagnose. Several genes have been determined to have a role in this condition (55).
Several storage diseases lead to the infiltration of large molecules within the cardiac tissue. Although the pathophysiology is significantly different, clinically, these disorders may mimic hypertrophic cardiomyopathy. Dominant mutations in the gene PRKAG2 have been shown to cause glycogen accumulation in vacuoles within myocytes, clinically manifesting as HCM (61). Another condition, Danon disease, is an X-linked glycogen storage disease that presents with cardiomyopathy and typically skeletal myopathy, primarily in adolescent males. Mental retardation has also been seen in Danon disease. Glycogen storage disease type II has been shown to cause significant hypertrophic cardiomyopathy, with severe hypotonia in the infantile-onset form. However, adolescents and adults with milder forms of Pompe disease present later with proximal muscle weakness and do not typically have the cardiac manifestations. Other inherited metabolic disorders causing infiltrative hypertrophic cardiomyopathy typically accompany other significant clinical manifestations. Examples include Hunter syndrome (X-linked), Hurler (autosomal recessive), and Fabry disease (X-linked).
Dilated Cardiomyopathy
Dilated cardiomyopathy (DCM), or ventricular enlargement with systolic dysfunction, leads to progressive failure and is a common reason for heart transplant. The causes of DCM are variable, typically from acquired disorders such as infection, toxic exposures, and nutritional deficiencies (such as carnitine deficiency). Duchenne and Becker muscular dystrophy, as well as other diseases of the heart muscle, may lead to progressive cardiac failure and a dilated cardiomyopathy presentation. In addition, inherited metabolic disorders, such as organic acidurias, fatty acid oxidation defects, and respiratory chain disorders, may manifest with cardiomyopathy. Although potential carnitine deficiency or defects in mitochondrial aerobic respiration have been implicated as a cause of cardiomyopathy in metabolic acute metabolic disease, the specific pathophysiologic mechanism is not readily known. A cardiac evaluation is generally recommended in individuals with metabolic defects presenting in acute metabolic crises.
Familial DCM has been suggested in about 20% to 35% of cases by autosomal dominant, autosomal recessive or X-linked inheritance patterns. Several genes have been implicated in these conditions; however, clinical testing is not yet feasible for most cases of DCM. A particular exception is tafazzin, a mitochondrial protein responsible for the X-linked Barth syndrome typically seen in young males. As with HCM, family screening and monitoring is recommended, particularly in at-risk first-degree relatives (62).
Anesthesia Risks in Genetic and Metabolic Disorders
Certain genetic, and particularly metabolic, diseases have an increased anesthesia risk. This not only includes an increased risk via the anesthetics themselves but also increased risks due to specific structural abnormalities that accompany some genetic disorders.
Individuals with metabolic disorders, such as fatty acid oxidation defects, organic acidurias, and urea cycle disorders, are predisposed to metabolic decompensation from physical and catabolic tissue breakdown from the stress of surgery and anesthetics. Preventative measures, such as high glucose infusion (typically 10% dextrose solution) and hydration (generally 1.5 times maintenance fluids with appropriate electrolyte) before, during, and after surgery are necessary to avoid a catabolic state (17). Consultation with a specialist familiar with metabolic disorders will aid in determining the appropriate management of these patients.
Particular attention should be given to mitochondrial patients requiring anesthetics. These individuals are inherently at risk due to the mitochondria's inability to deal with added oxidative stress from surgery and anesthesia. Additionally, most anesthetics affect mitochondrial function in some fashion, such as depressing carbohydrate metabolism or inhibiting certain components of the mitochondrial respiratory chain. These risks are primarily based on scientific reasoning and in vitro studies, resulting in inadequate or nonexistent clinical evidence. However, given the inherent risk, all anesthetics should be used with caution in this group of disorders (15). Drugs that should be used with particular caution in mitochondrial disorders include barbiturates, propofol, nitroprusside, theophylline, valproate, and phenobarbital (16).
Presedation evaluations should include an assessment for the presence of a genetic condition that carries a heightened risk of anesthesia. Well-described risks in genetic conditions include airway difficulty from structural and functional defects, abnormal respiratory mechanics, gastric reflux, cardiovascular disease, neuromuscular problems, liver disease, and renal disease, as well as risk for hyperthermia. Butler et al. (63) recently published an extensive review encompassing 163 single-gene, chromosomal, and multifactorial genetic conditions with anesthesia risks. Examples of airway management problems in genetic conditions include Down syndrome and certain skeletal dysplasias in which there is a risk of cervical cord compression due to atlantoaxial instability or kyphoscoliosis, respectively (17,64). In these patients, recent cervical spine radiographs should be reviewed prior to intubation and head positioning.
Pharmacogenetics and Pharmacogenomics
Personalized medicine is not a new concept. Many drugs and therapies are adjusted according to age, weight, body mass, and even gender and ethnicity. In many cases, treatment is modified depending on individual drug response. The preoperative evaluation includes personal and family history, including medications and drug use, and history of drug reactions, and anesthetic and bleeding complications, all of which may affect the management of a patient. The era of genomics has promised to personalize medicine according to an individual's specific genotype. The Human Genome Project has accelerated academic and pharmaceutical research in this field; however, in practical terms, the use of genetic- or genomic-based drug therapy is currently used only in specific situations. Pharmacogenetics refers to a drug's response according to differences in a single gene (e.g., CYP2D6, which codes for a specific enzyme responsible for metabolizing several drugs). Pharmacogenomics refers to a drug's response according to the effects of multiple genes and environmental factors. Although these terms have slightly different meanings, they are often used synonymously. Currently, there are few examples of clinically applicable genetic tests that influence drug therapy. Current pharmacogenetic testing relies on single-gene mutation studies, even though it is clear that most drug response is influenced by multigenic (multiple genes affecting the metabolism of a drug) and multifactorial (combination of genetic and environmental) factors.
Drugs—and other foreign chemicals (e.g., pollutants, carcinogens, or food additives)—are typically subject to extensive metabolism by cellular enzymes and transporters. This is the body's natural mechanism for detoxifying and eliminating potentially harmful compounds. Pharmaceutical drugs are formulated and dosed accordingly with this process in mind. Many drugs are administered as an inactive compound (prodrug) that relies on cellular metabolism to convert it to an active metabolite (65).
Early observations relevant to pharmacogenetics occurred over 50 years ago. For example, during World War II, African American soldiers given the antimalarial drug, primaquine, were noted to develop hemolytic anemia much more commonly than Caucasians (66). It is now recognized that the susceptibility to hemolytic anemia is related to an inherited defect in the enzyme, glucose-6-phosphate dehydrogenase, which is more common in certain ethnicities. Similarly, in the 1950s, Kalow and Gunn (67) noted an atypical response to the muscle relaxant, succinylcholine, in a small subset of Caucasians, which is now known to be caused by differences in the enzyme pseudocholinesterase, responsible for the metabolism of this drug.
A handful of examples of genetic testing are relevant to individualized drug therapy. 6-Mercaptopurine (6-MP) and its prodrug, azathioprine, are commonly used in treating certain forms of leukemia or rheumatologic disorders, respectively. This drug is metabolized, in part, by an enzyme called thiopurine methyltransferase (TPMT). It is recognized that about 1 in 300 individuals have a deficiency in TPMT and are unable to effectively metabolize these drugs, thus leading to toxic accumulation of thiopurine metabolites, which can be fatal (68). Many centers typically screen for TPMT genotype and dose these drugs accordingly to avoid adverse effects, while at the same time optimizing therapeutic response. A second example of pharmacogenetics entering the field of medicine is testing for polymorphisms (or genetic variants) in the CYP2D6 gene. CYP2D6 is a member of a superfamily of genes that code for cytochrome P450 enzymes responsible for metabolizing many commonly used drugs. CYP2D6 is one of the most studied enzymes within this group and is responsible for metabolizing a diverse group of drugs such as codeine, dextromethorphan, metoprolol, and nortriptyline (69). Polymorphisms within this gene or gene deletions are believed to be responsible for ‘slow metabolism’ of some commonly used drugs. An example is codeine, which has little or no affect in about 10% of the population due to poor metabolism of this prodrug to active metabolites, such as morphine. It is conceivable that genetic testing, comprising a panel of susceptible genes and their related polymorphisms such as in CYP2D6, could be invaluable in optimizing drug doses in patients; indeed, clinical genotyping has recently become clinically available (70). The efficacy, as well as practical clinical application, particularly in a critical scenario, of this type of testing (pharmacogenomic) has yet to be realized. For more information about pharmacogenomics and its potential application in clinical practice, the reader is referred to more in-depth reviews on this subject (71,72,73,74).
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