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(Journal of Nutrition. 2001;131:1615S-1620S.)
© 2001 The American Society for Nutritional Sciences

Supplement

Mass Spectrometry Methods for Metabolic and Health Assessment1

Dietrich Matern2 and Mark J. Magera

Biochemical Genetics Laboratory, Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905

2To whom correspondence should be addressed. E-mail: matern{at}mayo.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 Recent clinical applications of...
 Future MS applications
 Nano-ESI-MS
 Matrix-assisted laser desorption...
 REFERENCES
 
Beginning in the mid 1960s, mass spectrometry was introduced in a few academic laboratories for the analysis of organic acids by gas chromatography-mass spectrometry. Since then, multiple-stage mass spectrometers have become available and many new applications have been developed. Major advantages of these new techniques include their ability to rapidly determine many different compounds in complex biological matrices with high sensitivity and in sample volumes of usually < 100 µL. A high sample throughput is further realized because extensive sample preparations are often not necessary. However, because the technical know-how is not yet widely available and significant experience is required for correct interpretation of results, these methods are being implemented slowly in routine clinical laboratories as opposed to research laboratories. Several of these new applications are considered with regard to clinical medicine.

KEY WORDS: • mass spectrometry • tandem mass spectrometry • inborn errors of metabolism • vitamin deficiencies


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
Recent clinical applications of...
 Future MS applications
 Nano-ESI-MS
 Matrix-assisted laser desorption...
 REFERENCES
 
Mass spectrometry (MS)3 is an analytical technique that allows the measurement of molecules in a variety of matrices (gas, liquid, solid) after their conversion into ions. Once a sample containing the molecule of interest has been introduced into the mass spectrometer either directly or after some kind of sample preparation or separation, the sample is ionized, positively or negatively charged fragment ions are generated, sorted by their mass-to-charge (m/z) ratio and recorded. The result is generated by a computer system in the form of a mass spectrum, which is a graphic representation of the ions separated according to their m/z ratio and normalized as the percentage of the most abundant species in the sample (Fig. 1Citation ).



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  		Figure 1. Basic scheme of a tandem mass spectrometer. A sample is introduced into the mass spectrometer via the source either straight or after some form of manual or automatic sample preparation along with or without additional sample separation. For example, a chromatography technique can be connected to the mass spectrometer in series (e.g., GC-MS, liquid chromatography-MS).

 
Over the last decades, MS has gained a prominent position among analytical methods due to its versatility, unmatched sensitivity and the commercial availability of instruments that are relatively affordable, robust, computer-driven and increasingly user friendly. Initially, MS was used primarily in physics and chemistry research laboratories as well as in petroleum and pharmaceutical industries. Clinical MS applications were developed in the 1960s, when Tanaka first used gas chromatography MS (GC-MS) for the identification of organic acidurias in children (Tanaka et al. 1966Citation ). During the 1980s, tandem MS (MS/MS) was introduced into clinical laboratories, again first applied to the evaluation of children at risk of inborn errors of metabolism (Gaskell et al. 1986Citation , Millington et al. 1986Citation , Millington et al. 1989Citation , Roe et al. 1986Citation ). This development was further enhanced by the availability of stable isotope-labeled internal standards. These compounds are identical to their native analytes except that they differ slightly in their masses, because their nuclei contain different numbers of neutrons. The addition of these isotopes at known concentrations to the sample before mass analysis enables positive identification and quantification of the analytes. These compounds can be obtained from various commercial sources, but in some cases, as with acylglycines and some acylcarnitines, custom synthesis is necessary.

In the following article, we outline our experience with newer in vitro MS applications in a biochemical genetics laboratory that analyzes in excess of 100,000 samples per year. Established methods, such as GC-MS used for organic acid and acylglycine analysis, are not considered here (Lehotay and Clarke 1995Citation , Rinaldo 2001Citation ) but are listed in Table 1Citation along with other mass spectrometric applications currently used in clinical laboratories for the determination of endogenous metabolites. The role of MS for in vivo stable isotope studies is also reviewed elsewhere (Klein 2001Citation , de Meer et al. 1999Citation ).


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  		Table 1. MS and its current use in the analysis of endogenous metabolites

 

   Recent clinical applications of MS
TOP
 ABSTRACT
 INTRODUCTION
 Recent clinical applications of...
Future MS applications
 Nano-ESI-MS
 Matrix-assisted laser desorption...
 REFERENCES
 
Tandem mass spectrometers allow the analysis of compounds in complex mixtures and are characterized by the coupling of two mass analyzers separated by a fragmentation chamber, all within one instrument. In general, the first (MS1) or second analyzer (MS2) can be set either to scan a mass range or to select one or more individual ions. The fragmentation chamber is used to further breakdown the ions by use of a collision gas (e.g., nitrogen) and to transmit them to MS2.

The most widely used instruments are triple quadrupole analyzers combined with electrospray ionization (ESI) sources. A liquid sample is introduced into the source through a capillary tube and exposed to a strong electric field and a counter flow of nitrogen gas, which in combination produce the electrospray. This causes evaporation of the solvent and eventually desorption of charged ions into the mass analyzer. ESI occurs under atmospheric pressure allowing efficient ionization, whereas the mass analyzers operate at very low pressure. The combination is possible by introducing the ions into the analyzers through a very small orifice (< 1 mm) and using powerful vacuum pumps. Quadrupole mass analyzers consist of four rods with a circular or hyperbolic cross section. Each pair of opposing rods is either positively or negatively charged (Fig. 2Citation ). The ions entering the analyzer are separated according to their mass-to-charge ratio based on their trajectories when exposed to the electric field in the space between the rods. Although, the mass range (up to 4,000 Da) and resolving power of quadrupole mass analyzers are not as good as that of magnetic sector and time-of-flight (TOF) instruments, they are widely used due to their sensitivity, analytical speed and relatively simple operation.



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  		Figure 2. Basic scheme of a quadrupole mass analyzer. Charged species, whether a single atom or molecule, are caused to oscillate in an electric field (the quadrupole field) between the paired rods of the quadrupole. For a given complex pattern of voltages, molecules with a specific m/z ratio (molecule A+) will oscillate with a harmonic ion trajectory creating an ion beam that traverses the quadrupole. All other ions (molecule B+) are filtered out of the ion beam. This transmission mode can be converted to a scanning mode by changing the voltages per unit time to selectively pass m/z one at a time.

 
Four different scan modes can be used for sample analysis by MS/MS. When MS1 is set to transmit exclusively ions with specific m/z values, scanning of MS2 gives only a spectrum of the product ions arising from the primary, collision-activated fragmentation (product ion scan). This scanning method is reversed in the precursor ion mode, where MS1 scans a defined mass range and MS2 is set to transmit only fragment ions with a specific m/z value. In this mode, the data system then correlates each detected ion to its respective precursor scanned in MS1. Clinically, this precursor or parent ion scan is used for the analysis of acylcarnitines in plasma, blood spots dried on filter paper, bile, amniotic fluid and fibroblast culture medium, relevant for the diagnosis of mitochondrial fatty acid ß-oxidation disorders (e.g., medium-chain acyl-CoA dehydrogenase deficiency) and some organic acidurias (e.g., isovaleryl-CoA dehydrogenase deficiency) (Chace et al. 1997Citation , Matern et al. 1999Citation , Millington et al. 1992Citation , Rashed et al. 1995Citation , Shen et al. 2000Citation , Van Hove et al. 1993aCitation , Van Hove et al. 1993bCitation ). Acylcarnitine analysis also plays a role in the follow-up of patients affected with such disorders, because treatment effectiveness and metabolic homeostasis can be assessed (Van Hove et al. 2000Citation ). As an example, acylcarnitine profiles and values from a patient with isovaleryl-CoA dehydrogenase deficiency [isovaleric acidemia (IVA)] before and after initiation of treatment are shown in Figure 3Citation and Table 2Citation .



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  		Figure 3. Profiles of short- and medium-chain acylcarnitine species in blood spots from a newborn with isovaleryl-coenzyme A dehydrogenase deficiency (isovaleric acidemia, IVA) before and during treatment with L-carnitine and a protein-restricted diet. Note the normalization of the acetylcarnitine (C2) concentration and the mild decrease of the combined isovaleryl-/2-methylbutyryl-carnitine (C5) concentration in relation to the stable isotope-labeled internal standards (IS) and the normal control blood spot, documenting metabolic improvement (precursor of m/z 99 scan).

 

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  		Table 2. Quantitative comparison of short-chain acylcarnitines in a patient with isovaleryl-CoA dehydrogenase deficiency (isovaleric acidemia; fig. 3Citation ) before and after initiation of treatment1

 
IVA is an autosomal recessively inherited disorder of leucine metabolism. Most children present acutely in the neonatal period with severe metabolic acidosis, pancytopenia, vomiting and a characteristic smell of sweaty feet. This disorder can be diagnosed by urine organic acid and acylglycine analyses by GC-MS or acylcarnitine analysis in plasma and blood spots by MS/MS, because isovaleryl-CoA and its metabolites are excessively elevated during an acute metabolic decompensation. Treatment consists of avoidance of fasting with a diet low in leucine, in addition to supplementation with L-carnitine and/or glycine. Treatment can be evaluated by metabolite studies as demonstrated in Figure 3Citation and Table 2Citation . Unless metabolic decompensations caused permanent neurological damage, successfully treated patients have a favorable prognosis.

In the precursor ion mode, a spectrum of all parent ions that produce a characteristic fragment (or daughter) ion is generated, whereas in a neutral loss experiment MS1 and MS2 are both scanned at the same rate with a constant m/z difference. The resulting spectrum includes only those compounds among precursor ions that fragment with a common neutral loss, a behavior indicating that they belong to a family of structurally related compounds. The primary clinical use of the neutral loss scan currently lies in the analysis of amino acids in blood spots dried on filter paper in the setting of newborn screening for inborn errors of amino acid metabolism (Chace et al. 1996Citation , Chace et al. 1995Citation , Chace et al. 1998Citation ). This application is likely to facilitate the follow-up care of patients with disorders like phenylketonuria as well. It can be envisioned that parents of pediatric patients and older patients collect a drop of blood on filter paper at home using lancet devices for capillary blood collection (as in diabetes care). A significant number of routine clinic visits would become obsolete because the dried blood spots could be sent by mail to the laboratory and possible treatment changes discussed with the physician by telephone. This approach would not only simplify the lives of patients and their families but should also significantly reduce the overall costs of follow-up care for the families and providers of medical insurance.

Tandem mass spectrometric analyses can be further enhanced in the selected reaction monitoring mode, where the selection of a parent ion in MS1 is followed by a similar process for a specific fragment ion in MS2. The resulting signal corresponds exclusively to the transition from parent to product ion, a process virtually free of any interference even when complex biological matrices such as blood and urine are analyzed. Several applications making use of this scanning mode have recently been developed (Bonafe et al. 2000Citation , Casetta et al. 2000Citation , Ito et al. 2000Citation , Johnson 2000Citation , Magera et al. 2000Citation , Magera et al. 1999Citation ). The technique has already proven its potential and value in the conversion of several high performance liquid chromatography (HPLC) methods. For example, the assessment of homocysteine in plasma has received major attention in the last years due to its role as a cardiovascular risk factor and an indicator of nutritional deficiencies (folic acid, cobalamin) (Bostom et al. 1999Citation , McCully 1996Citation , Selhub et al. 1999Citation ). The surge of interest in this amino acid, which in the past was primarily considered a biochemical marker for several rare inborn errors of metabolism and was measured using either time-consuming HPLC methods or an expensive immunoassay, has made the development of a fast, less-expensive and robust method desirable that accommodates high volume testing. Magera et al. (1999Citation ) established a stable isotope dilution liquid chromatography MS/MS method that met all these requirements by enabling the preparation of > 200 samples in 6 h. The coupling of an autosampler with the instrument further allows for the overnight analysis of the samples.

The same approach was used in our laboratory for the development of assays measuring homovanillic acid (HVA), vanillylmandelic acid, and methylmalonic acid. HVA and vanillylmandelic acid, both catecholamine metabolites, are used to identify patients at risk for catecholamine producing tumors. Again a cumbersome HPLC method that yielded poorly resolved results could be replaced and significantly improved in all aspects (Fig. 4Citation ). The determination of methylmalonic acid is likely to become an important factor in the diagnosis of cobalamin deficiency, because it is considered a more reliable marker for this acquired disorder than the difficult to measure cobalamin itself (Holleland et al. 1999Citation ). This has also translated into an increased number of requests for testing of samples than the current analytical method (GC-MS) is able to accommodate unless more instruments are used simultaneously. Again, the application of liquid chromatography MS/MS for measurement of these metabolites proved to be a rational, time and cost-saving solution (Magera et al. 2000Citation ).



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  		Figure 4. Comparison of chromatograms obtained by a HPLC method (A) and a newly developed liquid chromatography MS/MS method (B) for the determination of HVA in urine. Note the inaccurate peak identification by the HPLC method (A). The unequivocal identification of HVA is illustrated by the addition of stable isotope-labeled HVA [13C6,18O-HVA (B)].

 
All of these scanning modes can be used in the analysis of a single sample. The foremost clinical example of this approach has been the application of MS/MS to newborn screening. In contrast to conventional screening methods, MS/MS does not measure single analytes (one test for one disorder) but acquires metabolite profiles that enable the biochemical diagnosis of > 20 different inborn disorders affecting fatty acid and amino acid metabolism (Chace and Naylor 1999Citation ). A 4.8-mm blood spot dried on filter paper requires brief preparation (addition of internal standards, extraction and conversion of analytes to butylesters) followed by MS/MS analysis, which takes only ~2 min. During this time several different analyses are performed: a precursor ion scan for most acylcarnitines, a neutral loss scan for most amino acids and various analyses by selected reaction monitoring for free carnitine and individual amino acids. The result consists of metabolite profiles that can be computerized into ~60 metabolite concentrations and concentration ratios. This type of result is unique in today’s clinical laboratory setting and poses a potential drawback to this analytical method because the correct result interpretation requires significant experience and is not yet fully automatable.

An application using single stage MS coupled with immunoaffinity chromatography was recently developed by Lacey et al. (2001Citation ) that aims at the identification of transferrin isoforms primarily for the diagnosis of pediatric patients with one of the congenital disorders of glycosylation (formerly known as carbohydrate deficient glycoprotein syndromes). At the current time, carbohydrate-deficient transferrins are primarily analyzed using isoelectric focusing (IEF) techniques, which are time-consuming, laborious, expensive and require relatively large sample volumes (1 ml of serum in our laboratory). The new assay using an immunoaffinity liquid chromatography MS setup can also be automated to a high degree and improves the current IEF approach with respect to: 1) required sample volume (5 µl vs. 1 ml for IEF); 2) turn around time (24 samples in 4 h vs. 72 h for IEF); and 3) supply costs. Additional studies will have to reveal whether this analysis may become a tool in the follow-up of patients with chronic alcoholism, because chronic and substantial alcohol consumption alters the glycosylation of transferrin (Lieber 1999Citation , Salaspuro 1999Citation ).


   Future MS applications
TOP
 ABSTRACT
 INTRODUCTION
 Recent clinical applications of...
 Future MS applications
Nano-ESI-MS
 Matrix-assisted laser desorption...
 REFERENCES
 
In recent years, modified ESI interfaces and other than quadrupole mass spectrometers have been introduced into biotechnology industry and research laboratories. Broader use of these technologies in routine clinical laboratories will probably not occur in the very near future because their use is more difficult and expensive.


   Nano-ESI-MS
TOP
 ABSTRACT
 INTRODUCTION
 Recent clinical applications of...
 Future MS applications
 Nano-ESI-MS
Matrix-assisted laser desorption...
 REFERENCES
 
Nano-ESI-MS was developed in the 1990s. Using this technique, the sample is delivered to the mass spectrometer through capillaries with diameters of only 1 to 10 µm. These capillaries are positioned under microscopic control near the orifice of the mass spectrometer with the distance between the capillary and MS orifice typically < 2 mm. The advantage over conventional ES ionization is primarily the ability to analyze minute volumes with as little as 0.5 µl and analyte concentrations as low as 10-8 mol/L. Furthermore, the droplets released from the nano-ESI capillaries are much smaller than those using ESI. This enables, for example, the detection of compounds that are not surface active, such as carbohydrates. Nano-ESI can be coupled with single or multistage mass spectrometers (e.g., nano-ESI-MS/MS). However, the capillaries can only be used for one sample, which translates into high costs if high sample throughput is considered. This and the tedious positioning of the capillaries in front of the MS orifice so far prohibit the use of this technique outside research laboratories (Karas et al. 2000Citation ).


   Matrix-assisted laser desorption-ionization (MALDI)-TOF MS
TOP
 ABSTRACT
 INTRODUCTION
 Recent clinical applications of...
 Future MS applications
 Nano-ESI-MS
 Matrix-assisted laser desorption...
REFERENCES
 
MALDI-TOF MS was first described in 1988 for the analysis of large molecules, such as proteins (Karas and Hillenkamp 1988Citation ). The ionization principle of MALDI is similar to that of fast atom bombardment (FAB) ionization. FAB-MS and FAB-MS/MS with quadrupole analyzers were primarily used for clinical purposes before the advent of ESI (Millington et al. 1986Citation , Millington et al. 1989Citation , Millington et al. 1984Citation ). In both techniques, MALDI and FAB, the sample is added to a matrix, applied to a stationary probe and then exposed to high energy for desorption and ionization of the analytes. Differences between MALDI and FAB are the type of matrix used (ultraviolet-absorbing crystals for MALDI vs. glycerol or thioglycerol for FAB) and the source of energy applied to the sample (high power ultraviolet laser pulses for MALDI vs. bombardment of the sample with cesium or xenon ions for FAB). The pulsed release of ionized analyte makes MALDI the preferred ionization method in conjunction with TOF mass analyzers. In MALDI-TOF MS, the sample is added to a matrix, dried until this mixture crystallizes and then brought into the path of the laser beam within a vacuum. The desorbed ions are accelerated and travel through a flight tube in the MS to the detector. The time needed for this journey to the detector depends on the individual ion’s m/z value. Automation of MALDI-TOF is feasible using multiwell plates when the plate is moved so that one well after the other is exposed to the laser pulse. This technique can be applied to the analysis of biomolecules with masses up to 1,000 kDa. Currently, MALDI-TOF mass analysis receives most attention for its use in molecular genetics, recently reviewed elsewhere (Griffin and Smith 2000Citation , Guo 1999Citation , Jackson et al. 2000Citation ).

In summary, MS methods in particular those using MS/MS enable rapid, highly sensitive and specific determination of many different classes of diagnostic metabolites with minimal sample volumes and sample preparation. This allows for testing of single analytes but also groups of related metabolites in large numbers of samples. However, two issues should not be overlooked before investing in this technology. First, although MS technology has become more user friendly than ever, the availability of easy to maintain instruments is not at hand. Personnel have to be thoroughly trained to become proficient in the use, troubleshooting and maintenance of the mass spectrometers. Ready-to-use, hands-off instruments or analytical kits are not available. Second, the interpretation of complex metabolite profiles is difficult and requires significant experience. A beginner user may find the interpretation process more time consuming than the analysis itself, in part, because step-by-step interpretation guidelines are not available.


   FOOTNOTES
 
1 Presented at the symposium "Non- or Minimally-Invasive Technologies for Monitoring Health and Nutritional Status in Mothers and Young Children" held August 7–8, 2000 at the Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX. This symposium was sponsored by Baylor College of Medicine Office of Analysis, Nutrition and Evaluation of the Food and Nutrition Service of the U.S. Department of Agriculture. The proceedings of this symposium are published as a supplement to The Journal of Nutrition. Guest editors for the supplement publication were Dennis M. Bier, Baylor College of Medicine, Houston, TX and D’Ann Finley, University of California, Davis, CA. Back

3 Abbreviations used: MS, mass spectrometry; m/z, mass-to-charge; GC-MS, gas chromatography mass spectrometry; MS/MS, tandem mass spectrometry; ESI, electrospray ionization; TOF, time-of-flight; IVA, isovaleric acidemia; HPLC, high performance liquid chromatography; HVA, homovanillic acid; IEF, isoelectric focusing; MALDI, matrix-assisted laser desorption-ionization; FAB, fast atom bombardment. Back


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 Recent clinical applications of...
 Future MS applications
 Nano-ESI-MS
 Matrix-assisted laser desorption...
 REFERENCES
 

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