Liquid Chromatography Tandem-mass Spectrometry (LC-MS/MS) - Technique and Applications in Endocrinology

Abstract

In recent years, liquid chromatography tandem mass spectrometry (LC-MS/MS) has emerged as an innovative analytical technology applicable to a wide number of analyses in the endocrinology laboratory. Compared to the “traditional” technique of gas chromatography-mass spectrometry (GC-MS), LC-MS/MS is easier to use and is applicable for a substantially larger number of relevant analytes. With the development of LC-MS/MS, the widespread application of the proven principle of isotope dilution mass spectrometry is now feasible not only in research but also for routine applications. The aim of this review is to explain the basic technical principles of LC-MS/MS, to describe the general characteristics of analytical LC-MS/MS applications and to comprehensively discuss the application of this technology in the field of endocrinology.

Key words

liquid chromatography-tandem mass spectrometry (LC-MS/MS) - endocrinology

References

• 1 Ackermann BL, Hale JE, Duffin KL. The role of mass spectrometry in biomarker discovery and measurement.  Curr Drug Metab. 2006;  7 525-539
• 2 Azziz R, Dewailly D, Owerbach D. Clinical review 56: nonclassic adrenal hyperplasia: current concepts.  J Clin Endocrinol Metab. 1994;  78 810-815
• 3 Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline.  J Clin Endocrinol Metab. 2006;  91 1995-2010
• 4 Binkley N, Krueger D, Cowgill CS, Plum L, Lake E, Hansen KE, DeLuca HF, Drezner MK. Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization.  J Clin Endocrinol Metab. 2004;  89 3152-3157
• 5 Bjerner J, Bormer OP, Nustad K. The war on heterophilic antibody interference.  Clin Chem. 2005;  51 9-11
• 6 Cabaleiro DR, Stockl D, Kaufman JM, Fiers T, Thienpont LM. Feasibility of standardization of serum C-peptide immunoassays with isotope-dilution liquid chromatography-tandem mass spectrometry.  Clin Chem. 2006;  52 1193-1196
• 7 Cawood ML, Field HP, Ford CG, Gillingwater S, Kicman A, Cowan D, Barth JH. Testosterone measurement by isotope-dilution liquid chromatography-tandem mass spectrometry: validation of a method for routine clinical practice.  Clin Chem. 2005;  51 1472-1479
• 8 Chadwick CA, Owen LJ, Keevil BG. Development of a method for the measurement of dehydroepiandrosterone sulphate by liquid chromatographytandem mass spectrometry.  Ann Clin Biochem. 2005;  42 468-474
• 9 Chan EC, Ho PC. High-performance liquid chromatography/atmospheric pressure chemical ionization mass spectrometric method for the analysis of catecholamines and metanephrines in human urine.  Rapid Commun Mass Spectrom. 2000;  14 1959-1964
• 10 Dettmer K, Aronov PA, Hammock BD. Mass spectrometry-based metabolomics.  Mass Spectrom Rev. 2006;  , [Epub ahead of print]
• 11 Eisenhofer G, Keiser H, Friberg P, Mezey E, Huynh TT, Hiremagalur B, Ellingson T, Duddempudi S, Eijsbouts A, Lenders JW. Plasma metanephrines are markers of pheochromocytoma produced by catechol-O-methyltransferase within tumors.  J Clin Endocrinol Metab. 1998;  83 2175-2185
• 12 Findling JW, Raff H. Screening and diagnosis of Cushing's syndrome.  Endocrinol Metab Clin North Am. 2005;  34 385-402
• 13 Gjerde J, Kisanga ER, Hauglid M, Holm PI, Mellgren G, Lien EA. Identification and quantification of tamoxifen and four metabolites in serum by liquid chromatography-tandem mass spectrometry.  J Chromatogr A. 2005;  1082 6-14
• 14 Glendenning P, Taranto M, Noble JM, Musk AA, Hammond C, Goldswain PR, Fraser WD, Vasikaran SD. Current assays overestimate 25-hydroxyvitamin D3 and underestimate 25-hydroxyvitamin D2 compared with HPLC: need for assay-specific decision limits and metabolite-specific assays.  Ann Clin Biochem. 2006;  43 23-30
• 15 Guo T, Chan M, Soldin SJ. Steroid profiles using liquid chromatographytandem mass spectrometry with atmospheric pressure photoionization source.  Arch Pathol Lab Med. 2004;  128 469-475
• 16 Guo T, Taylor RL, Singh RJ, Soldin SJ. Simultaneous determination of 12 steroids by isotope dilution liquid chromatography-photospray ionization tandem mass spectrometry.  Clin Chim Acta. 2006;  , [Epub ahead of print]
• 17 Holick MF. High prevalence of vitamin D inadequacy and implications for health.  Mayo Clin Proc. 2006;  81 353-373
• 18 Hubbard WC, Moser AB, Tortorelli S, Liu A, Jones D, Moser H. Combined liquid chromatography-tandem mass spectrometry as an analytical method for high throughput screening for X-linked adrenoleukodystrophy and other peroxisomal disorders: preliminary findings.  Mol Genet Metab. 2006;  89 185-187
• 19 Ismail AA. A radical approach is needed to eliminate interference from endogenous antibodies in immunoassays.  Clin Chem. 2005;  51 25-26
• 20 Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J. Calcium plus vitamin D supplementation and the risk of fractures.  N Engl J Med. 2006;  354 669-683
• 21 Jeppsson JO, Kobold U, Barr J, Finke A, Hoelzel W, Hoshino T, Miedema K, Mosca A, Mauri P, Paroni R, Thienpont L, Umemoto M, Weykamp C. International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). Approved IFCC reference method for the measurement of HbA1c in human blood.  Clin Chem Lab Med. 2002;  40 78-89
• 22 Jonsson BA, Malmberg B, Amilon A, Helene Garde A, Orbaek P. Determination of cortisol in human saliva using liquid chromatography-electrospray tandem mass spectrometry.  J Chromatogr B Analyt Technol Biomed Life Sci. 2003;  784 63-68
• 23 Kao PC, Machacek DA, Magera MJ, Lacey JM, Rinaldo P. Diagnosis of adrenal cortical dysfunction by liquid chromatography-tandem mass spectrometry.  Ann Clin Lab Sci. 2001;  31 199-204
• 24 Kool J, Ramautar R, van Liempd SM, Beckman J, de Kanter FJ, Meerman JH, Schenk T, Irth H, Commandeur JN, Vermeulen NP. Rapid on-line profiling of estrogen receptor binding metabolites of tamoxifen.  J Med Chem. 2006;  49 3287-3292
• 25 Kroll CA, Magera MJ, Helgeson JK, Matern D, Rinaldo P. Liquid chromatographic-tandem mass spectrometric method for the determination of 5-hydroxyindole-3-acetic acid in urine.  Clin Chem. 2002;  48 2049-2051
• 26 Kudva YC, Sawka AM, Young Jr WF. Clinical review 164: the laboratory diagnosis of adrenal pheochromocytoma: the Mayo Clinic experience.  J Clin Endocrinol Metab. 2003;  88 4533-4539
• 27 Kushnir MM, Neilson R, Roberts WL, Rockwood AL. Cortisol and cortisone analysis in serum and plasma by atmospheric pressure photoionization tandem mass spectrometry.  Clin Biochem. 2004;  37 357-362
• 28 Kushnir MM, Rockwood AL, Nelson GJ, Terry AH, Meikle AW. Liquid chromatography-tandem mass spectrometry analysis of urinary free cortisol.  Clin Chem. 2003;  49 965-967
• 29 Kushnir MM, Rockwood AL, Roberts WL, Pattison EG, Bunker AM, Fitzgerald RL, Meikle AW. Performance characteristics of a novel tandem mass spectrometry assay for serum testosterone.  Clin Chem. 2006;  52 120-128
• 30 Kushnir MM, Rockwood AL, Roberts WL, Pattison EG, Owen WE, Bunker AM, Meikle AW. Development and performance evaluation of a tandem mass spectrometry assay for 4 adrenal steroids.  Clin Chem. 2006;  52 1559-1567
• 31 Kushnir MM, Urry FM, Frank EL, Roberts WL, Shushan B. Analysis of catecholamines in urine by positive-ion electrospray tandem mass spectrometry.  Clin Chem. 2002;  48 323-331
• 32 Lacey JM, Minutti CZ, Magera MJ, Tauscher AL, Casetta B, McCann M, Lymp J, Hahn SH, Rinaldo P, Matern D. Improved specificity of newborn screening for congenital adrenal hyperplasia by second-tier steroid profiling using tandem mass spectrometry.  Clin Chem. 2004;  50 621-625
• 33 Lagerstedt SA, O'Kane DJ, Singh RJ. Measurement of plasma free metanephrine and normetanephrine by liquid chromatography-tandem mass spectrometry for diagnosis of pheochromocytoma.  Clin Chem. 2004;  50 603-611
• 34 Lembcke J, Ceglarek U, Fiedler GM, Baumann S, Leichtle A, Thiery J. Rapid quantification of free and esterified phytosterols in human serum using APPILC- MS/MS.  J Lipid Res. 2005;  46 21-26
• 35 Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P, Keiser HR, Goldstein DS, Eisenhofer G. Biochemical diagnosis of pheochromocytoma: which test is best?.  JAMA. 2002;  287 1427-1434
• 36 Locati D, Morandi S, Cupisti A, Ghiadoni L, Arnoldi A. Characterization and quantification of soy isoflavone metabolites in serum of renal transplanted patients by high-performance liquid chromatography/electrospray ionization mass spectrometry.  Rapid Commun Mass Spectrom. 2005;  19 3473-3481
• 37 Lopez-Roldan P, Lopez de Alda MJ, Barcelo D. Simultaneous determination of selected endocrine disrupters (pesticides, phenols and phthalates) in water by in-field solid-phase extraction (SPE) using the prototype PROFEXS followed by on-line SPE (PROSPEKT) and analysis by liquid chromatography-atmospheric pressure chemical ionisation-mass spectrometry.  Anal Bioanal Chem. 2004;  378 599-609
• 38 Magnusson MO, Sandstrom R. Quantitative analysis of eight testosterone metabolites using column switching and liquid chromatography/tandem mass spectrometry.  Rapid Commun Mass Spectrom. 2004;  18 1089-1094
• 39 Manini P, Andreoli R, Cavazzini S, Bergamaschi E, Mutti A, Niessen WM. Liquid chromatography-electrospray tandem mass spectrometry of acidic monoamine metabolites.  J Chromatogr B Biomed Sci Appl. 2000;  744 423-431
• 40 Martens-Lobenhoffer J, Krug O, Bode-Boger SM. Determination of arginine and asymmetric dimethylarginine (ADMA) in human plasma by liquid chromatography/mass spectrometry with the isotope dilution technique.  J Mass Spectrom. 2004;  39 1287-1294
• 41 Matsumoto AM, Bremner WJ. Serum testosterone assays - accuracy matters.  J Clin Endocrinol Metab. 2004;  89 520-524
• 42 Maunsell Z, Wright DJ, Rainbow SJ. Routine isotope-dilution liquid chromatography-tandem mass spectrometry assay for simultaneous measurement of the 25-hydroxy metabolites of vitamins D2 and D3.  Clin Chem. 2005;  51 1683-1690
• 43 McCann SJ, Gillingwater S, Keevil BG. Measurement of urinary free cortisol using liquid chromatography-tandem mass spectrometry: comparison with the urine adapted ACS:180 serum cortisol chemiluminescent immunoassay and development of a new reference range.  Ann Clin Biochem. 2005;  42 112-118
• 44 Minutti CZ, Lacey JM, Magera MJ, Hahn SH, McCann M, Schulze A, Cheillan D, Dorche C, Chace DH, Lymp JF, Zimmerman D, Rinaldo P, Matern D. Steroid profiling by tandem mass spectrometry improves the positive predictive value of newborn screening for congenital adrenal hyperplasia.  J Clin Endocrinol Metab. 2004;  89 3687-3693
• 45 Nelson RE, Grebe SK, OKane DJ, Singh RJ. Liquid chromatography-tandem mass spectrometry assay for simultaneous measurement of estradiol and estrone in human plasma.  Clin Chem. 2004;  50 373-384
• 46 Quinkler M, Stewart PM. Hypertension and the cortisol-cortisone shuttle.  J Clin Endocrinol Metab. 2003;  88 2384-2392
• 47 Rashed MS, Bucknall MP, Little D, Awad A, Jacob M, Alamoudi M, Alwattar M, Ozand PT. Screening blood spots for inborn errors of metabolism by electrospray tandem mass spectrometry with a microplate batch process and a computer algorithm for automated flagging of abnormal profiles.  Clin Chem. 1997;  43 1129-1141
• 48 Rauh M, Groschl M, Rascher W, Dorr HG. Automated, fast and sensitive quantification of 17 alpha-hydroxy-progesterone, androstenedione and testosterone by tandem mass spectrometry with on-line extraction.  Steroids. 2006;  71 450-458
• 49 Roda A, Mirasoli M, Michelini E, Magliulo M, Simoni P, Guardigli M, Curini R, Sergi M, Marino A. Analytical approach for monitoring endocrine-disrupting compounds in urban waste water treatment plants.  Anal Bioanal Chem. 2006;  385 742-752
• 50 Rodriguez-Mozaz S, Lopez de Alda MJ, Barcelo D. Picogram per liter level determination of estrogens in natural waters and waterworks by a fully automated on-line solid-phase extraction-liquid chromatography-electrospray tandem mass spectrometry method.  Anal Chem. 2004;  76 6998-7006
• 51 Rogatsky E, Balent B, Goswami G, Tomuta V, Jayatillake H, Cruikshank G, Vele L, Stein DT. Sensitive quantitative analysis of C-peptide in human plasma by 2-dimensional liquid chromatography-mass spectrometry isotope-dilution assay.  Clin Chem. 2006;  52 872-879
• 52 Sabatine MS, Liu E, Morrow DA, Heller E, McCarroll R, Wiegand R, Berriz GF, Roth FP, Gerszten RE. Metabolomic identification of novel biomarkers of myocardial ischemia.  Circulation. 2005;  112 3868-3875
• 53 Serhan CN. Mediator lipidomics.  Prostaglandins & other Lipid Mediators. 2005;  77 4-14
• 54 Sikaris K, McLachlan RI, Kazlauskas R, de Kretser D, Holden CA, Handelsman DJ. Reproductive hormone reference intervals for healthy fertile young men: evaluation of automated platform assays.  J Clin Endocrinol Metab. 2005;  90 5928-5936
• 55 Soldin OP, Guo T, Weiderpass E, Tractenberg RE, Hilakivi-Clarke L, Soldin SJ. Steroid hormone levels in pregnancy and 1 year postpartum using isotope dilution tandem mass spectrometry.  Fertil Steril. 2005;  84 701-710
• 56 Soldin OP, Hilakivi-Clarke L, Weiderpass E, Soldin SJ. Trimester-specific reference intervals for thyroxine and triiodothyronine in pregnancy in iodinesufficient women using isotope dilution tandem mass spectrometry and immunoassays.  Clin Chim Acta. 2004;  349 181-189
• 57 Soldin SJ, Soukhova N, Janicic N, Jonklaas J, Soldin OP. The measurement of free thyroxine by isotope dilution tandem mass spectrometry.  Clin Chim Acta. 2005;  358 113-118
• 58 Souberbielle JC, Fayol V, Sault C, Lawson-Body E, Kahan A, Cormier C. Assay-specific decision limits for two new automated parathyroid hormone and 25-hydroxyvitamin D assays.  Clin Chem. 2005;  51 395-400
• 59 Soukhova N, Soldin OP, Soldin SJ. Isotope dilution tandem mass spectrometric method for T4/T3.  Clin Chim Acta. 2004;  343 185-190
• 60 Stanczyk FZ. Measurement of androgens in women.  Semin Reprod Med. 2006;  24 78-85
• 61 Stowasser M, Gordon RD. Aldosterone assays: an urgent need for improvement.  Clin Chem. 2006;  52 1640-1642
• 62 Tai SS, Sniegoski LT, Welch MJ. Candidate reference method for total thyroxine in human serum: use of isotope-dilution liquid chromatography-mass spectrometry with electrospray ionization.  Clin Chem. 2002;  48 637-642
• 63 Tai SS, Welch MJ. Development and evaluation of a candidate reference method for the determination of total cortisol in human serum using isotope dilution liquid chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry.  Anal Chem. 2004;  76 1008-1014
• 64 Tai SS, Welch MJ. Development and evaluation of a reference measurement procedure for the determination of estradiol-17beta in human serum using isotope-dilution liquid chromatography-tandem mass spectrometry.  Anal Chem. 2005;  77 6359-6363
• 65 Taieb J, Mathian B, Millot F, Patricot MC, Mathieu E, Queyrel N, Lacroix I, Somma-Delpero C, Boudou P. Testosterone measured by 10 immunoassays and by isotope-dilution gas chromatography-mass spectrometry in sera from 116 men, women, and children.  Clin Chem. 2003;  49 1381-1395
• 66 Taylor RL, Grebe SK, Singh RJ. Quantitative, highly sensitive liquid chromatography-tandem mass spectrometry method for detection of synthetic corticosteroids.  Clin Chem. 2004;  50 2345-2352
• 67 Taylor RL, Singh RJ. Validation of liquid chromatography-tandem mass spectrometry method for analysis of urinary conjugated metanephrine and normetanephrine for screening of pheochromocytoma.  Clin Chem. 2002;  48 533-539
• 68 Trakakis E, Laggas D, Salamalekis E, Creatsas. G 21-Hydroxylase deficiency: from molecular genetics to clinical presentation.  J Endocrinol Invest. 2005;  28 187-192
• 69 Vicente FB, Smith FA, Sierra R, Wang S. Measurement of serum testosterone using high-performance liquid chromatography/tandem mass spectrometry.  Clin Chem Lab Med. 2006;  44 70-75
• 70 Vogeser M, Briegel J, Jacob K. Determination of serum cortisol by isotopedilution liquid-chromatography electrospray ionization tandem mass spectrometry with on-line extraction.  Clin Chem Lab Med. 2001;  39 944-947
• 71 Vogeser M, Briegel J, Zachoval R. Dialyzable free cortisol after stimulation with Synacthen.  Clin Biochem. 2002;  35 539-543
• 72 Vogeser M, Groetzner J, Kupper C, Briegel J. Free serum cortisol during the postoperative acute phase response determined by equilibrium dialysis liquid chromatography-tandem mass spectrometry.  Clin Chem Lab Med. 2003;  41 146-151
• 73 Vogeser M, Groetzner J, Kupper C, Briegel J. The serum cortisol: cortisone ratio in the postoperative acute-phase response.  Horm Res. 2003;  59 293-296
• 74 Vogeser M, Hauer D, Azad SC, Huber E, Storr M, Schelling G. Release of anandamide from blood cells.  Clin Chem Lab Med. 2006;  44 488-491
• 75 Vogeser M, Kyriatsoulis A, Huber E, Kobold U. Candidate reference method for the quantification of circulating 25-hydroxyvitamin D3 using liquid chromatography-tandem mass spectrometry.  Clin Chem. 2004;  50 1415-1417
• 76 Vogeser M, Spöhrer U. Automated processing of whole blood samples for the determination of immunosuppressants by LC-MS/MS.  Clin Chem Lab Med. 2006;  44 1126-1130
• 77 Vogeser M, Zachoval R, Jacob K. Serum cortisol/cortisone ratio after Synacthen stimulation.  Clin Biochem. 2001;  34 421-425
• 78 Vogeser M, Zachoval R, Spöhrer U, Jacob K. Potential lack of specificity using electrospray tandem-mass spectrometry for the analysis of mycophenolic acid in serum.  Therapeutic Drug Monitoring. 2001;  23 722-724
• 79 Walker JM, Krey JF, Chen JS, Vefring E, Jahnsen JA, Bradshaw H, Huang SM. Targeted lipidomics: fatty acid amides and pain modulation.  Prostaglandins Other Lipid Mediat. 2005;  77 35-45
• 80 Wang C, Catlin DH, Demers LM, Starcevic B, Swerdloff RS. Measurement of total serum testosterone in adult men: comparison of current laboratory methods versus liquid chromatography-tandem mass spectrometry.  J Clin Endocrinol Metab. 2004;  89 534-543
• 81 Watson AD. Lipidomics: a global approach to lipid analysis in biological systems.  J Lipid Res. 2006;  , [Epub ahead of print]
• 82 Wilcken B, Wiley V, Hammond J, Carpenter K. Screening newborns for inborn errors of metabolism by tandem mass spectrometry.  N Engl J Med. 2003;  348 2304-2312
• 83 Williams LD, Twaddle NC, Churchwell MI, Doerge DR. Quantification of tamoxifen and metabolites and soy isoflavones in human plasma using liquid chromatography with electrospray ionization tandem mass spectrometry.  J AOAC Int. 2006;  89 1168-1173
• 84 Xu CL, Chu XG, Peng CF, Jin ZY, Wang LY. Development of a faster determination of 10 anabolic steroids residues in animal muscle tissues by liquid chromatography tandem mass spectrometry.  J Pharm Biomed Anal. 2006;  41 616-621
• 85 Yin OQ, Lam SS, Lo CM, Chow MS. Rapid determination of five probe drugs and their metabolites in human plasma and urine by liquid chromatography/tandem mass spectrometry: application to cytochrome P450 phenotyping studies.  Rapid Commun Mass Spectrom. 2004;  18 2921-2933
• 86 Zweigenbaum J, Henion J. Bioanalytical high-throughput selected reaction monitoring-LC/MS determination of selected estrogen receptor modulators in human plasma: 2000 samples/day.  Anal Chem. 2000;  72 2446-2454

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