Establishment of Reference Ranges and Profile of Urinary Organic Acids in Different Pediatric Age Groups of the Iranian Healthy Population

Document Type : Original Article (s)

Authors

1 MSc Student, Departments of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences AND Student Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran

2 Professor, Departments of Paediatrics, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

3 Associate Professor, Departments of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

4 Pharmacist, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

5 Associate Professor, Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Background: Organic acidurias are a heterogenous group of inherited metabolic disorders characterized by the accumulation and urinary excretion of organic acids. Delay in the detection and treatment of many of these disorders may lead to permanent brain damage or death. Accurate and early diagnosis is therefore paramount. The diagnosis of these disorders is achieved by the analysis of organic acids in the urine using gas chromatography/mass spectrometry (GC/MS). Since genetic and environmental factors and feeding habits can affect the concentration and profile of organic acids, for each population, data should be collected appropriate to that population. Such data did not exist for the Iranian population and thus, needed to be collected.Methods: 140 random urine samples were collected from healthy children in 4 age groups: term neonates (< 30 days), premature neonates, infants (1 month-2 years), and children (> 2 years). In addition, urine samples were collected from 10 children with classical symptoms of inherited metabolic disorders. After extraction and preparation of trimethylsilyl derivatives, organic acids were analyzed using GC/MS.Findings: 61 organic acids in 140 healthy urine samples were measured and the results were reported as the 2.5th-97.5th percentiles. These compounds were normal components of urine and some marker of diseases. In addition, among 10 samples collected from patients suspected of a metabolic disease, 2 patients with methyl malonic academia, 1 patient with propionic acidaemia and 1 patient with glutaric academia type 2 were identified.Conclusion: Urinary organic acid analysis is not currently performed in Iran and samples are sent abroad for investigation. In addition, no reference ranges for urinary organic acids in healthy Iranian children is available. This article, for the first time, reported the urinary organic acid analysis using GC/MS and reference ranges for the Iranian population. Urinary organic acids can now be analysed and results become available within the same day of patient admission in order to initialize early and targeted treatment. This study shows that metabolic disorders do exist in high proportion of patient with clinical signs and it appears that these diseases are prevalent. It also seems that methyl malonic acidemia is the most common disorder in patient with classic symptoms of organic acidemia in Iran.

Keywords

References

  1. Chalmers RA, Lawson AM. Organic acids in man: analytical chemistry, biochemistry, and diagnosis of the organic acidurias: London, UK: Chapman and Hall; 1982.
  2. Seashore M. Metabolic disorders. In: Marcdante K, Kliegman RM, Behrman RE, Hal B. Jenson HB. Nelson essentials of pediatrics. 6th ed. Philadelphia, PA: Saunders; 2010. p. 201.
  3. Pourfarzam M, Barati B. The necessity of screening of individuals with suspected inherited metabolic disorders for early diagnosis and treatment of related diseases. J Isfahan Med Sch 2013; 30(221): 2493-2505. [In Persian].
  4. Rinaldo P, Hahn S, Matern D. Inborn errors of amino acid, organic acid, and fatty acid metabolism. In: Burtis CA, Ashwood ER, Bruns DE, editors. Tietz textbook of clinical chemistry and molecular diagnostic. 4th ed. Philadelphia, PA: Saunders; 2005. p. 2207-47.
  5. Scriver CR, Sly WS, Childs B, Beaudet AL, Valle D, Kinzler KW, et al. The metabolic and molecular bases of inherited disease. New York, NY: McGraw-Hill; 2001.
  6. Hommes FA. Techniques in diagnostic human biochemical genetics: a laboratory manual: London, UK: John Wiley and Sons; 1990.
  7. Kumps A, Duez P, Mardens Y. Metabolic, nutritional, iatrogenic, and artifactual sources of urinary organic acids: a comprehensive table. Clin Chem 2002; 48(5): 708-17.
  8. Tuchman M, Ulstrom RA. Urinary organic acids in health and disease. Adv Pediatr 1985; 32: 469-506.
  9. Sanderson S, Green A, Preece MA, Burton H. The incidence of inherited metabolic disorders in the West Midlands, UK. Arch Dis Child 2006; 91(11): 896-9.
  10. Brustolin S, Souza C, Puga AC, Refosco L, Pires R, Peres R, et al. Assessment of a pioneer metabolic information service in Brazil. Community Genet 2006; 9(2): 127-32.
  11. Mootha VK, Hirschhorn JN. Inborn variation in metabolism. Nat Genet 2010; 42(2): 97-8.
  12. 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(23): 2304-12.
  13. Wasant P, Liammongkolkul S, Kuptanon C, Vatanavicharn N, Sathienkijakanchai A, Shinka T. Organic acid disorders detected by urine organic acid analysis: twelve cases in Thailand over three-year experience. Clin Chim Acta 2008; 392(1-2): 63-8.
  14. Katajamaa M, Oresic M. Data processing for mass spectrometry-based metabolomics. J Chromatogr A 2007; 1158(1-2): 318-28.
  15. Tanaka K, Budd MA, Efron ML, Isselbacher KJ. Isovaleric acidemia: a new genetic defect of leucine metabolism. Proc Natl Acad Sci U S A 1966; 56(1): 236-42.
  16. Fu X, Kimura M, Iga M, Yamaguchi S. Gas chromatographic-mass spectrometric screening for organic acidemias using dried urine filter paper: determination of alpha-ketoacids. J Chromatogr B Biomed Sci Appl 2001; 758(1): 87-94.
  17. Fang-Hoffmann J, Lindner M, Shahbek N, Baric I, Hoffmann GF, Al Thani Gh, et al. Metabolic medicine: new developments in diagnosis and treatment of inborn errors of metabolism. World J Pediatr 2006; 2(3): 169-76.
  18. Guneral F, Bachmann C. Age-related reference values for urinary organic acids in a healthy Turkish pediatric population. Clin Chem 1994; 40(6): 862-6.
  19. Chalmers RA, Healy MJ, Lawson AM, Hart JT, Watts RW. Urinary organic acids in man. III. Quantitative ranges and patterns of excretion in a normal population. Clin Chem 1976; 22(8): 1292-8.
  20. Lawson AM, Chalmers RA, Watts RW. Urinary organic acids in man. I. Normal patterns. Clin Chem 1976; 22(8): 1283-7.
  21. Bjorkman L, McLean C, Steen G. Organic acids in urine from human newborns. Clin Chem 1976; 22(1): 49-52.
  22. Thompson JA, Miles BS, Fennessey PV. Urinary organic acids quantitated by age groups in a healthy pediatric population. Clin Chem 1977; 23(9): 1734-8.
  23. Wittmann G, Karg E, Muhl A, Bodamer OA, Turi S. Comparison of tetrahydrofuran and ethyl acetate as extraction solvents for urinary organic acid analysis. J Inherit Metab Dis 2008; 31(1): 73-80.
  24. Suh JW, Lee SH, Chung BC. GC-MS determination of organic acids with solvent extraction after cation-exchange chromatography. Clin Chem 1997; 43(12): 2256-61.
  25. Hoffmann G, Aramaki S, Blum-Hoffmann E, Nyhan WL, Sweetman L. Quantitative analysis for organic acids in biological samples: batch isolation followed by gas chromatographic-mass spectrometric analysis. Clin Chem 1989; 35(4): 587-95.
  26. Sweetman L. Qualitative and quantitative analysis of organic acids in physiologic fluids for diagnosis of the organic acidurias. In: Nyhan WL, editor. Abnormalities in amino acid metabolism in clinical medicine. Norwalk, CA: Appleton and Lange; 1984. p. 419-53.
  27. Kuhara T. Diagnosis and monitoring of inborn errors of metabolism using urease-pretreatment of urine, isotope dilution, and gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2002; 781(1-2): 497-517.
  28. Kimura M, Yamamoto T, Yamaguchi S. Automated metabolic profiling and interpretation of GC/MS data for organic acidemia screening: a personal computer-based system. Tohoku J Exp Med 1999; 188(4): 317-34.
  29. Shoemaker JD, Elliott WH. Automated screening of urine samples for carbohydrates, organic and amino acids after treatment with urease. J Chromatogr 1991; 562(1-2): 125-38.
  30. Hori D, Hasegawa Y, Kimura M, Yang Y, Verma IC, Yamaguchi S. Clinical onset and prognosis of Asian children with organic acidemias, as detected by analysis of urinary organic acids using GC/MS, instead of mass screening. Brain Dev 2005; 27(1): 39-45.
  31. Chace DH, DiPerna JC, Kalas TA, Johnson RW, Naylor EW. Rapid diagnosis of methylmalonic and propionic acidemias: quantitative tandem mass spectrometric analysis of propionylcarnitine in filter-paper blood specimens obtained from newborns. Clin Chem 2001; 47(11): 2040-4.
Journal of Isfahan Medical School
Volume 32, Issue 280 - Serial Number 280
March and April 2014
Pages 417-431

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History

  • Receive Date: 05 September 2013
  • Revise Date: 01 November 2024
  • Accept Date: 06 April 2022

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