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Clinical Chemistry 48: 708-717, 2002;
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(Clinical Chemistry. 2002;48:708-717.)
© 2002 American Association for Clinical Chemistry, Inc.

Reviews

Metabolic, Nutritional, Iatrogenic, and Artifactual Sources of Urinary Organic Acids: A Comprehensive Table

Alain Kumps1, Pierre Duez1 and Yves Mardensa1

1 Laboratoire de Biochimie Médicale, Institut de Pharmacie, Université Libre de Bruxelles (ULB), Campus Plaine CP 205/3, Boulevard du Triomphe, B-1050 Brussels, Belgium.

aAuthor for correspondence. Fax 32-2-650-5324; e-mail biochmed{at}ulb.ac.be.


   Abstract
Top
 Abstract
Introduction
 Sampling Conditions
 Abnormal Excretion Patterns Not...
 Misleading Normal or Near-Normal...
 Interpretation and...
 References
 
Background: The determination of organic acids and glycine conjugates in urine is key for the diagnosis and follow-up of several inborn errors of metabolism (IEM). However, clinical interpretations may still be hindered by ambiguity in the sources of some urinary organic acids and acylglycines as well as in the relationship between their excretion and IEM.

Approach: Relevant data have been compiled from major books and references on the topic and by exhaustive bibliographic searches through the Medline and Current Contents databases.

Content: A comprehensive table has been designed according to organic acids and conjugates. This table is intended to assist in the interpretation of organic acid profiles because, in addition to IEM, it also refers to other pathologic causes and to physiologic, nutritional, iatrogenic, and artifactual sources. Some preanalytical issues, including possible misinterpretations, are reviewed with regard to IEM.


   Introduction
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 Abstract
 Introduction
Sampling Conditions
 Abnormal Excretion Patterns Not...
 Misleading Normal or Near-Normal...
 Interpretation and...
 References
 
In the field of inborn errors of metabolism (IEM), "organic acids" are low-molecular weight (relative molecular weight less than ~300), water-soluble carboxylic acids that are intermediates or end products of amino acid, carbohydrate, lipid, or biogenic amine metabolism. Amino acids are excluded from this definition, whereas acylglycine conjugates and some decarboxylated derivatives are included because of their common clinical interest.

The analytical procedures for the determination of urinary organic acids usually include oximation, solvent extraction, and silylation followed by gas chromatography with mass detection in scan mode data acquisition. Both the retention time and the mass spectrum allow the identification of the urinary metabolites, with quantification being performed on a specific fragment abundance (1)(2)(3). Analytical considerations can be found in the reports by Jellum (4), Chalmers and Lawson (1), Tuchman and Ulstrom (5), Niwa (6), Sweetman (2), and Duez et al. (3).

More than 250 organic acids and glycine conjugates are either typically present or may possibly be encountered in urine. More than 65 inherited metabolic abnormalities are known to yield a characteristic urinary organic acid pattern, essential for diagnosis and follow-up (1)(2)(5)(7)(8). The interpretation of urinary organic acid profiles can be difficult because of the variability of the compounds excreted. Moreover, there may still be a considerable degree of ambiguity in the origin and/or significance of a given compound. To arrive at a diagnosis, organic acid data can be correlated with, or confirmed by, other analyses, including plasma amino acid determination, plasma and cerebrospinal fluid lactate and pyruvate assays, whole blood acylcarnitine profiling, enzymatic activity determinations in blood cells or other cells, and genome analysis (7)(8)(9)(10)(11).

This report aims to compile information on the origins of the most frequently encountered urinary organic acids. In addition to IEM, our classification (Table 1 )also refers to other pathologic conditions and physiologic, nutritional, iatrogenic, and artifactual causes (1)(2)(4)(5)(6)(7)(8)(10)(11)(12)(13). This review is intended to assist in the interpretation of organic acid profiles and the identification of some preanalytical issues. Table 1 , which is classified by organic compounds, is also proposed as a handy alternative that extends previously published compilations classified by inherited metabolic disorders (2)(5)(6)(7)(13).


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  		Table 1. Possible origins of abnormal excretion patterns of urinary organic acids.


   Sampling Conditions
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 Abstract
 Introduction
 Sampling Conditions
Abnormal Excretion Patterns Not...
 Misleading Normal or Near-Normal...
 Interpretation and...
 References
 
Urine collected over 24 h allows for variations in volume excretion during the day. The practicality of a 24-h collection is, however, such that a random specimen, preferably the first morning voiding, is an acceptable alternative. This specimen usually consists of at least 2 mL and is stored until analysis at below -18 °C without the use of any preservative.

Intraindividual variations will occur with respect to the time of sampling, the patient’s clinical status, eventual diet management, and whether the sample is collected when the patient is fasted or fed. Sampling during fasting or metabolic decompensation is often considered to be most valuable because, in most cases, metabolites of interest are then excreted selectively or at a higher concentration. On the other hand, metabolic decompensation, such as lactic acidosis, ketosis, or liver failure, gives rise to an abnormal excretion of organic acids ({alpha}-keto branched, dicarboxylic, or aromatic acids, respectively) that are otherwise involved in particular IEM; this sometimes renders interpretation even more difficult.

Poor preservation of samples will lead to nonenzymatic conversion of all keto acids to the respective hydroxyacid; for example, acetoacetate is converted to 3-hydroxybutyrate, and 2-ketoglutarate is converted to 2-hydroxyglutarate.


   Abnormal Excretion Patterns Not Attributable to IEM
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 Abstract
 Introduction
 Sampling Conditions
 Abnormal Excretion Patterns Not...
Misleading Normal or Near-Normal...
 Interpretation and...
 References
 
An increase in excretion may be nonspecific because some metabolites are reported to be abnormally excreted in conditions not attributable to IEM (drug therapy, diet, non-IEM diseases, or physiologic conditions), as indicated in Table 1Up .

Two frequent abnormal excretions not necessarily related to IEM are lactic aciduria and ketonuria. Whatever its origin, lactic aciduria is generally accompanied by other compounds; the greater the lactate excretion, the more likely the extent of the excretion of pyruvate, p-hydroxyphenyllactate, 2-hydroxyisovalerate, 2-hydroxybutyrate, and to a lesser extent, branched-chain 2-ketoacids. The abnormal excretion of these branched compounds implies the need for differentiation from dihydrolipoyl dehydrogenase deficiency.

Ketonuria (3-hydroxybutyrate and acetoacetate) is often accompanied by 3-hydroxyisobutyrate, 3-hydroxyisovalerate, 2-hydroxybutyrate, and dicarboxylic acids, particularly their 3-hydroxy derivatives with chain lengths up to C14. In this latter case, the pattern could mimic a long-chain 3-hydroxyacyl-CoA dehydrogenase or a trifunctional protein deficiency profile, except for the very high excretion of ketone bodies [in fatty acid oxidation defects, ketone bodies may appear increased in urine during fasting, but the ketosis remains at an inappropriately low level and the ratio of urinary adipate to 3-hydroxybutyrate is >0.5 (14)].

Another common misinterpretation may arise from bacterial metabolism. Of possible endogenous origin (e.g., intestinal infection) is the abnormal excretion of D-lactate (not chromatographically separated from L-lactate), methylmalonate, p-hydroxyphenylacetate, p-hydroxyphenyllactate, phenylacetylglutamine, phenylpropionylglycine, glutarate, benzoate, and hippurate. Of possible exogenous origin (bacterial growth in urine) are D-lactate, 2-ketoglutarate, D-2-hydroxyglutarate, succinate, 3-hydroxypropionate, and phenol derivatives (phenol, p-cresol, hippurate) (15).

The drug valproic acid may lead to increased excretion of 3-hydroxyisovalerate, 5-hydroxyhexanoate, 7-hydroxyoctanoate, p-hydroxyphenylpyruvate, dicarboxylic acids, and to a lesser extent, hexanoylglycine, tiglylglycine, and isovalerylglycine. The metabolites of this anticonvulsant drug are an important clue to the analyst, however.

The administration of medium-chain triglycerides may yield a pattern resembling fatty acid ß-oxidation defects, with increased saturated even-numbered dicarboxylic acids, mainly sebacate, as well as increased 5-hydroxyhexanoate and 7-hydroxyoctanoate, and the presence of octanoate but the absence or low excretion of glycine derivatives (16)(17).


   Misleading Normal or Near-Normal Excretion
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 Abstract
 Introduction
 Sampling Conditions
 Abnormal Excretion Patterns Not...
 Misleading Normal or Near-Normal...
Interpretation and...
 References
 
The excretion of organic acids in pathologic conditions may be characterized by large variability and thus casts doubt on the clinical sensitivity of the results. Interindividual variations are also possible because, for some diseases, urinary biochemical features may depend on what have been called "excretory" and "non-excretory" patients. Indeed, compounds typically excreted in large amounts may also appear at only slightly increased or even normal concentrations in some IEM. This is particularly true when a patient is clinically well (not in a state of metabolic decompensation) or under suitable dietary control. Among these inborn errors are glutaric aciduria type I (18)(19) (glutarate concentrations may be within reference values, whereas 3-hydroxyglutarate is present); medium-chain acyl-CoA dehydrogenase deficiency (adipate, suberate, and sebacate concentrations may be within reference values, but the presence of suberylglycine and hexanoylglycine will reveal the disorder) (20); multiple acyl-CoA dehydrogenase deficiency, particularly in its mild forms (metabolites suggesting such a disease, including ethylmalonate and glutarate, are quite variable); and 2-ketoglutarate dehydrogenase deficiency (2-ketoglutarate excretion ranges from within reference values to 10 times higher than the upper limit of the reference interval).

Respiratory chain defects give an unpredictable organic acid pattern, but nearly always with marked lactic aciduria; Krebs cycle acids, ethylmalonate, 3-methylglutaconate, and 3-methylglutarate may also be excreted in varying quantities. Urinary orotate may be high but possibly borderline in citrullinemia, ornithine carbamoyltransferase deficiency, lysinuric protein intolerance, and the hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, all disorders for which the biochemical diagnosis, however, is based on plasma ammonium and plasma and urinary amino acid profiles.


   Interpretation and Misinterpretations (7)(8)(10)(11)
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 Interpretation and...
References
 
The relevance of the abnormal excretion of some characteristic metabolites in the diagnosis of IEM has to be emphasized. For example, the presence of succinylacetone and succinylacetoacetate is pathognomonic of tyrosinemia type I (fumarylacetoacetate hydrolase deficiency). Other compounds may also be quite specific, including 3-hydroxyglutarate for glutaric aciduria type I, mevalonic acid for mevalonic aciduria, N-acetylaspartate for Canavan disease, 4-hydroxycyclohexylacetate for hawkinsinuria, and 2-ketoadipate and 2-hydroxyadipate for 2-amino/2-ketoadipate aciduria.

Cooperation between clinical chemists and clinicians is essential for the interpretation of the results. On the one hand, information on diet, drug intake, and clinical symptoms and signs may often be required by the clinical chemist to refine his or her interpretation. The clinical chemist can inform the clinician of pitfalls, the possible origins of abnormal results, and further analyses that can be performed (21). On the other hand, a final diagnosis can be established only in terms of the patient’s history and clinical picture, in addition to results from biochemical and medical examinations.

conclusion
As a practical consequence of possible misinterpretations, urinary organic acid patterns must be interpreted in the context of the complete clinical picture. In this context, both an abnormal organic acid pattern in the urine from an asymptomatic individual and a normal profile from a patient suspected of IEM must be considered as indications for repeated sampling: in the former circumstance, more information on possible drug therapy, diet, non-IEM pathology, and physiologic conditions is mandatory, whereas in the latter case, a period of illness would be preferred for resampling.


   References
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 Abstract
 Introduction
 Sampling Conditions
 Abnormal Excretion Patterns Not...
 Misleading Normal or Near-Normal...
 Interpretation and...
 References
 

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