- Email: [email protected]
Extreme clinical chemistry
Clinica Chimica Acta 448 (2015) 48–49
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Letter to the Editor Extreme clinical chemistry
Dear editor There has always been a fascination with extremes, e.g., the largest, or the smallest or the tallest or the smallest, as evidenced by the popularity of the annual Guinness World Records™ book [1] (Fig. 1). A similar formal and regularly updated compilation does not exist for laboratory medicine, yet the circumstances surrounding the highest or lowest ever reported values for different analytes in a body fluid, such as blood, serum or plasma, often provide interesting diagnostic insights or valuable practice points [2]. A definitive lowest value can be established for some analytes based on genetic abnormalities, such as analbuminemia [3] or undetectable serum HDL in Tangier disease [4]. In contrast, establishing the highest ever reported value for an analyte is a moving target and complicated by methodological differences. Some notable highest ever reported values include a serum sodium of 255 mmol/l, that was seen in a woman who had ingested 1 kg of salt dissolved in one liter of water as part of an exorcism [5]. The highest serum potassium (45.6 mmol/l) is not associated with disease, but instead with a pre-analytical error, namely using a K2EDTA collection tube [6]. However, there is also a report of a patient with a hyperkalemia of 10.1 mmol/l that survived [7]. Tumor lysis is the underlying cause of the highest ever reported value for serum uric acid (71.3 mg/dl) [8]. Excessive consumption can also underlie record extreme values, as exemplified by the highest blood alcohol ever recorded, 1480 mg/dl (1.48%; 325.6 mmol/l), that was found in a road traffic accident victim. The victim was alive at the scene of the accident but died later from injuries sustained in the accident [9–11]. For other analytes, an inherited metabolic disorder is the basis for an extreme increase, as in the case of a plasma ammonia of 1693 μmol/l/l seen in a patient with arginase deficiency [12], and a blood sugar of 2656 mg/dl (147.6 mmol/l) in a diabetic [13]. Combinations of factors can contribute to extreme elevations of an analyte as in the case of the highest ever reported value for serum carbohydrate antigen 19-9 at 19,516,020 U/ml (ref range 0–37 U/ml) which was attributed to CA 19-9 from the primary tumor (adenocarcinoma of the tail of the pancreas), liver metastases, and intrahepatic cholestasis [14]. While a collection of extremely elevated or decreased laboratory values may seem to be an exercise in laboratory quality or a frivolous hobby, observations in biomarker outliers have yielded important discoveries. A genomic examination of patients with very low LDL cholesterol concentrations [e.g., 14 mg/dl (0.36 mmol/l)] resulted in the discovery of loss-of-function variants in PCSK9 (proprotein convertase subtilisin/kexin type 9) [15,16]. Patients with loss in function of PCSK9 were found to be healthy and have an 88% lower risk of cardiovascular disease. This discovery has led to late stage clinical trials of PCSK9 targeting agents to decrease serum lipid levels [15,16].
http://dx.doi.org/10.1016/j.cca.2015.06.014 0009-8981/© 2015 Elsevier B.V. All rights reserved.
Fig. 1. Extremes of human phenotypes — Angus MacAskill and Tom Thumb (from Gillis, JD, “The Cape Breton Giant,” Halifax; TC Allen & Co, 1919, frontispiece. Courtesy of the Library and Archives Canada/C-018686.).
The integration of extremes in biomarker levels with genomic approaches has created a new field of extreme phenotype study design [17,18]. Biomarkers can be used to quantify extreme phenotypes and improve the efficiency of gene discovery [17,18]. Recent studies have applied this gene discovery approach by using extremes in various biomarkers such as: HDL [19,20]; apoA-I [19]; TNF-alpha [21]; CK-MB [22]; and CD4 cell count [23]. Similar to novel PCSK9 therapeutics, the identification of rare genetic variants coupled with extreme changes in biomarkers may result in the discovery of other novel targeted therapeutics. The routine practice of clinical chemistry involves the study of analytes that are typically, by definition, within a normal distributed reference range. By training, we are skeptical of extremes in analytical measurement and suspect analytical or pre-analytical error. However, when coupled with genomic techniques, observations in extremes of serum biomarkers may present new opportunities in drug discovery.
Letter to the Editor
References [1] B. Watson, World's unlikeliest bestseller (50th anniversary of Guinness world records), Smithsonian 36 (2005) 76–81. [2] The Happy Hospitalist. Extreme Lab Values: Medical High and Low Findings in the Hospital, http://thehappyhospitalist.blogspot.com/2008/11/another-personalmedical-record.html [Accessed June 2015]. [3] S. Watkins, J. Madison, M. Galliano, L. Minchiotti, F.W. Putnam, Analbuminemia: three Cases resulting from different point mutations in the albumin gene, Proc Natl Acad Sci U S A 91 (1994) 9417–9421. [4] J. Gell, C. van Heyningen, Homozygous Tangier disease with undetectable serum high density lipoprotein cholesterol levels and no clinical features, OA Case Rep 2 (2013) 126. [5] Y. Ofran, D. Lavi, D. Opher, T.A. Weiss, E. Elinav, Fatal voluntary salt intake resulting in the highest ever documented sodium plasma level in adults (255 mmol l−1): a disorder linked to female gender and psychiatric disorders, J Intern Med 256 (2004) 525–528. [6] M.P. Cornes, C. Ford, R. Gama, Spurious hyperkalaemia due to EDTA contamination: common and not always easy to identify, Ann Clin Biochem 45 (2008) 601–603. [7] P.M. Muck, S. Letterer, U. Lindner, H. Lehnert, C.S. Haas, Beating the odds—surviving extreme hyperkalemia, Am J Emerg Med 30 (250) (2012) e1–e4. [8] S. Mehringer, T. Vogt, H.C. Jabusch, et al., Treatment of panniculitis in chronic pancreatitis by interventional endoscopy following extracorporeal lithotripsy, Gastrointest Endosc 53 (2001) 104–107. [9] The 5 highest blood alcohol levels ever recorded, http://coed.com/2011/04/25/the5-highest-b-a-c-s-ever-recorded/ [Accessed June 2015]. [10] Blood alcohol content, http://en.wikipedia.org/wiki/Blood_alcohol_content#Highest_ recorded_blood_alcohol_level.2Fcontent [Accessed June 2015]. [11] Śmiertelny rekord: Kierowca z powiatu ostrołęckiego miał 22 promile alkoholu! Zginął w wypadku [ZDJĘCIA], http://www.eostroleka.pl/smiertelny-rekordkierowca-z-powiatu-ostroleckiego-mial-22-promile-alkoholu-zginal-w-wypadkuzdjecia,art31892.html [Accessed June 2015]. [12] W.W. Grody, R.M. Kern, D. Klein, et al., Arginase deficiency manifesting delayed clinical sequelae and induction of a kidney arginase isozyme, Hum Genet 91 (1993) 1–5. [13] Highest blood sugar level. Guinness World Records, http://www.guinnessworldrecords. com/world-records/highest-blood-sugar-level/ (Accessed June 2015). [14] H. Al-Khallaf, P.J. Monaghan, A. Ourfali, et al., The highest ever reported level of carbohydrate antigen 19-9: a case report, J Med Cases 2 (2011) 71–75. [15] M.A.V. Willrich, L.M. Baudhuin, PCSK9 and the road less traveled: how an unconventional approach led to a major discovery, Clin Chem 59 (2013) 1283–1284. [16] J.C. Cohen, H.H. Hobbs, Simple genetics for a complex disease, Science 340 (6133) (2013). http://dx.doi.org/10.1126/scince.1239101.
49
[17] D.D. O'Rielly, G. Zhai, P. Rahman, Powered for success: considerations for using the candidate gene approach in rheumatic diseases in the post-genomics era, J Rheumatol 41 (2014) 1573–1575. [18] J.L. Perez-Garcia, M. Gloria Ruiz-Ilundain, I. Garcia-Ribas, E. Maria Carrasco, The role of extreme phenotype selection studies in the identification of clinically relevant genotypes in cancer research, Cancer 95 (2002) 1605–1610. [19] C.L. Haase, R. Frikke-Schmidt, B.G. Nordestgaard, A. Tybjaerg-Hansen, Populationbased resequencing of APOA1 in 10,330 individuals: spectrum of genetic variation, phenotype, and comparison with extreme phenotype approach, PLoS Genet 8 (2012) e1003063. http://dx.doi.org/10.1371/journal.pgen.1003063. [20] M.M. Motazacker, J. Peter, M. Treskes, C.C. Shoulders, J.A. Kuivenhoven, G.K. Hovingh, Evidence of a polygenic origin of extreme high-density lipoprotein cholesterol levels, Arterioscler Thromb Vasc Biol 33 (2013) 1521–1528. [21] J.C. Nossent, S. Sagen-Johnsen, G. Bakland, Tumor necrosis factor-alpha promoter308/238 polymorphism association with less severe disease in ankylosing spondylitis is unrelated to serum TNF-alpha and does not predict TNG inhibitor response, J Rheumatol 41 (2014) 1675–1682. [22] M.D. Kertai, Y.J. Li, Y.W. Li, et al., BMJ Open 6 (2015) e006920. http://dx.doi.org/10. 1136/bmjopen-2014-006920. [23] A.D. Olson, M. Guiguet, R. Zangerle, et al., Evaluation of rapid progressors in HIV infection as an extreme phenotype, J Acquir Immune Defic Syndr 67 (2014) 15–21.
Jason Y. Park Department of Pathology and the Eugene McDermott Center for Human Growth and Development, Children's Medical Center and University of Texas Southwestern Medical School, 1935 Medical District Drive, Dallas, TX 75235, USA E-mail address: [email protected]. Larry J. Kricka Department of Pathology & Laboratory Medicine, 7.103 Founders Pavilion, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, PA 19104, USA Corresponding author. E-mail address: [email protected]. 2 June 2015 Available online 24 June 2015
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Letter to the Editor Extreme clinical chemistry
Dear editor There has always been a fascination with extremes, e.g., the largest, or the smallest or the tallest or the smallest, as evidenced by the popularity of the annual Guinness World Records™ book [1] (Fig. 1). A similar formal and regularly updated compilation does not exist for laboratory medicine, yet the circumstances surrounding the highest or lowest ever reported values for different analytes in a body fluid, such as blood, serum or plasma, often provide interesting diagnostic insights or valuable practice points [2]. A definitive lowest value can be established for some analytes based on genetic abnormalities, such as analbuminemia [3] or undetectable serum HDL in Tangier disease [4]. In contrast, establishing the highest ever reported value for an analyte is a moving target and complicated by methodological differences. Some notable highest ever reported values include a serum sodium of 255 mmol/l, that was seen in a woman who had ingested 1 kg of salt dissolved in one liter of water as part of an exorcism [5]. The highest serum potassium (45.6 mmol/l) is not associated with disease, but instead with a pre-analytical error, namely using a K2EDTA collection tube [6]. However, there is also a report of a patient with a hyperkalemia of 10.1 mmol/l that survived [7]. Tumor lysis is the underlying cause of the highest ever reported value for serum uric acid (71.3 mg/dl) [8]. Excessive consumption can also underlie record extreme values, as exemplified by the highest blood alcohol ever recorded, 1480 mg/dl (1.48%; 325.6 mmol/l), that was found in a road traffic accident victim. The victim was alive at the scene of the accident but died later from injuries sustained in the accident [9–11]. For other analytes, an inherited metabolic disorder is the basis for an extreme increase, as in the case of a plasma ammonia of 1693 μmol/l/l seen in a patient with arginase deficiency [12], and a blood sugar of 2656 mg/dl (147.6 mmol/l) in a diabetic [13]. Combinations of factors can contribute to extreme elevations of an analyte as in the case of the highest ever reported value for serum carbohydrate antigen 19-9 at 19,516,020 U/ml (ref range 0–37 U/ml) which was attributed to CA 19-9 from the primary tumor (adenocarcinoma of the tail of the pancreas), liver metastases, and intrahepatic cholestasis [14]. While a collection of extremely elevated or decreased laboratory values may seem to be an exercise in laboratory quality or a frivolous hobby, observations in biomarker outliers have yielded important discoveries. A genomic examination of patients with very low LDL cholesterol concentrations [e.g., 14 mg/dl (0.36 mmol/l)] resulted in the discovery of loss-of-function variants in PCSK9 (proprotein convertase subtilisin/kexin type 9) [15,16]. Patients with loss in function of PCSK9 were found to be healthy and have an 88% lower risk of cardiovascular disease. This discovery has led to late stage clinical trials of PCSK9 targeting agents to decrease serum lipid levels [15,16].
http://dx.doi.org/10.1016/j.cca.2015.06.014 0009-8981/© 2015 Elsevier B.V. All rights reserved.
Fig. 1. Extremes of human phenotypes — Angus MacAskill and Tom Thumb (from Gillis, JD, “The Cape Breton Giant,” Halifax; TC Allen & Co, 1919, frontispiece. Courtesy of the Library and Archives Canada/C-018686.).
The integration of extremes in biomarker levels with genomic approaches has created a new field of extreme phenotype study design [17,18]. Biomarkers can be used to quantify extreme phenotypes and improve the efficiency of gene discovery [17,18]. Recent studies have applied this gene discovery approach by using extremes in various biomarkers such as: HDL [19,20]; apoA-I [19]; TNF-alpha [21]; CK-MB [22]; and CD4 cell count [23]. Similar to novel PCSK9 therapeutics, the identification of rare genetic variants coupled with extreme changes in biomarkers may result in the discovery of other novel targeted therapeutics. The routine practice of clinical chemistry involves the study of analytes that are typically, by definition, within a normal distributed reference range. By training, we are skeptical of extremes in analytical measurement and suspect analytical or pre-analytical error. However, when coupled with genomic techniques, observations in extremes of serum biomarkers may present new opportunities in drug discovery.
Letter to the Editor
References [1] B. Watson, World's unlikeliest bestseller (50th anniversary of Guinness world records), Smithsonian 36 (2005) 76–81. [2] The Happy Hospitalist. Extreme Lab Values: Medical High and Low Findings in the Hospital, http://thehappyhospitalist.blogspot.com/2008/11/another-personalmedical-record.html [Accessed June 2015]. [3] S. Watkins, J. Madison, M. Galliano, L. Minchiotti, F.W. Putnam, Analbuminemia: three Cases resulting from different point mutations in the albumin gene, Proc Natl Acad Sci U S A 91 (1994) 9417–9421. [4] J. Gell, C. van Heyningen, Homozygous Tangier disease with undetectable serum high density lipoprotein cholesterol levels and no clinical features, OA Case Rep 2 (2013) 126. [5] Y. Ofran, D. Lavi, D. Opher, T.A. Weiss, E. Elinav, Fatal voluntary salt intake resulting in the highest ever documented sodium plasma level in adults (255 mmol l−1): a disorder linked to female gender and psychiatric disorders, J Intern Med 256 (2004) 525–528. [6] M.P. Cornes, C. Ford, R. Gama, Spurious hyperkalaemia due to EDTA contamination: common and not always easy to identify, Ann Clin Biochem 45 (2008) 601–603. [7] P.M. Muck, S. Letterer, U. Lindner, H. Lehnert, C.S. Haas, Beating the odds—surviving extreme hyperkalemia, Am J Emerg Med 30 (250) (2012) e1–e4. [8] S. Mehringer, T. Vogt, H.C. Jabusch, et al., Treatment of panniculitis in chronic pancreatitis by interventional endoscopy following extracorporeal lithotripsy, Gastrointest Endosc 53 (2001) 104–107. [9] The 5 highest blood alcohol levels ever recorded, http://coed.com/2011/04/25/the5-highest-b-a-c-s-ever-recorded/ [Accessed June 2015]. [10] Blood alcohol content, http://en.wikipedia.org/wiki/Blood_alcohol_content#Highest_ recorded_blood_alcohol_level.2Fcontent [Accessed June 2015]. [11] Śmiertelny rekord: Kierowca z powiatu ostrołęckiego miał 22 promile alkoholu! Zginął w wypadku [ZDJĘCIA], http://www.eostroleka.pl/smiertelny-rekordkierowca-z-powiatu-ostroleckiego-mial-22-promile-alkoholu-zginal-w-wypadkuzdjecia,art31892.html [Accessed June 2015]. [12] W.W. Grody, R.M. Kern, D. Klein, et al., Arginase deficiency manifesting delayed clinical sequelae and induction of a kidney arginase isozyme, Hum Genet 91 (1993) 1–5. [13] Highest blood sugar level. Guinness World Records, http://www.guinnessworldrecords. com/world-records/highest-blood-sugar-level/ (Accessed June 2015). [14] H. Al-Khallaf, P.J. Monaghan, A. Ourfali, et al., The highest ever reported level of carbohydrate antigen 19-9: a case report, J Med Cases 2 (2011) 71–75. [15] M.A.V. Willrich, L.M. Baudhuin, PCSK9 and the road less traveled: how an unconventional approach led to a major discovery, Clin Chem 59 (2013) 1283–1284. [16] J.C. Cohen, H.H. Hobbs, Simple genetics for a complex disease, Science 340 (6133) (2013). http://dx.doi.org/10.1126/scince.1239101.
49
[17] D.D. O'Rielly, G. Zhai, P. Rahman, Powered for success: considerations for using the candidate gene approach in rheumatic diseases in the post-genomics era, J Rheumatol 41 (2014) 1573–1575. [18] J.L. Perez-Garcia, M. Gloria Ruiz-Ilundain, I. Garcia-Ribas, E. Maria Carrasco, The role of extreme phenotype selection studies in the identification of clinically relevant genotypes in cancer research, Cancer 95 (2002) 1605–1610. [19] C.L. Haase, R. Frikke-Schmidt, B.G. Nordestgaard, A. Tybjaerg-Hansen, Populationbased resequencing of APOA1 in 10,330 individuals: spectrum of genetic variation, phenotype, and comparison with extreme phenotype approach, PLoS Genet 8 (2012) e1003063. http://dx.doi.org/10.1371/journal.pgen.1003063. [20] M.M. Motazacker, J. Peter, M. Treskes, C.C. Shoulders, J.A. Kuivenhoven, G.K. Hovingh, Evidence of a polygenic origin of extreme high-density lipoprotein cholesterol levels, Arterioscler Thromb Vasc Biol 33 (2013) 1521–1528. [21] J.C. Nossent, S. Sagen-Johnsen, G. Bakland, Tumor necrosis factor-alpha promoter308/238 polymorphism association with less severe disease in ankylosing spondylitis is unrelated to serum TNF-alpha and does not predict TNG inhibitor response, J Rheumatol 41 (2014) 1675–1682. [22] M.D. Kertai, Y.J. Li, Y.W. Li, et al., BMJ Open 6 (2015) e006920. http://dx.doi.org/10. 1136/bmjopen-2014-006920. [23] A.D. Olson, M. Guiguet, R. Zangerle, et al., Evaluation of rapid progressors in HIV infection as an extreme phenotype, J Acquir Immune Defic Syndr 67 (2014) 15–21.
Jason Y. Park Department of Pathology and the Eugene McDermott Center for Human Growth and Development, Children's Medical Center and University of Texas Southwestern Medical School, 1935 Medical District Drive, Dallas, TX 75235, USA E-mail address: [email protected]. Larry J. Kricka Department of Pathology & Laboratory Medicine, 7.103 Founders Pavilion, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, PA 19104, USA Corresponding author. E-mail address: [email protected]. 2 June 2015 Available online 24 June 2015