Table 1.

Possible origins of abnormal excretion patterns of urinary organic acids.

Acid/MetaboliteNon-IEM (4)(12)(15)(16)(22)IEM
Aromatic amino acid metabolism (23)
 2-HydroxyphenylacetateUremiaPKU; BH41 deficiency
 4-Hydroxyphenylacetate (24)(25)Bacterial gut metabolism and bacterial contamination (from tyrosine); short bowel syndrome; liver diseasesTyrosinemia; PKU; hawkinsinuria
 4-Hydroxyphenyllactate (24)(25)(26)(27)Bacterial gut metabolism; short bowel syndrome; liver diseases (e.g., secondary to PA, galactosemia, fructosemia); scurvy; lactic acidosisTyrosinemia; PKU; Zellweger; hawkinsinuria; lactic acidosis
 4-HydroxyphenylpyruvateVPA; liver diseases (e.g., secondary to PA, galactosemia, fructosemia)Tyrosinemia; hawkinsinuria
 HomogentisateAlcaptonuria
 Mandelate (28)Preservative in albumin solution for intravenous perfusion; methenamine mandelale; gastrointestinal malabsorption diseasesPKU
N-AcetyltyrosineSome parenteral solutionsTyrosinemia
 PhenylacetateIntestinal bacterial origin (from phenylalanine)PKU; BH4 deficiency
 PhenylacetylglutamineBacterial metabolism (from phenylacetate); hyperammonemia treated with phenylbutyrate or phenylacetate; uremiaPKU
 Phenyllactate (29)Bacterial gut metabolism (d-form); liver diseasesPKU; tyrosinemia (l-form); BH4 deficiency
 PhenylpyruvateBacterial gut metabolism; liver diseasesPKU; BH4 deficiency
 SuccinylacetoacetateTyrosinemia type I
 SuccinylacetoneTyrosinemia type I
Branched-chain amino acid metabolism
 2-Hydroxy-3-methylvalerateMSUD; dihydrolipoyl DH (E3) deficiency
 2-Hydroxyisocaproate (23)Short bowel syndrome (d-form)MSUD; dihydrolipoyl DH (E3) deficiency
 2-HydroxyisovalerateKetosis; lactic acidosisMSUD; dihydrolipoyl DH (E3) deficiency; MAD deficiency; lactic acidosis
 2-Keto-3-methylvalerateLactic acidosis; ketosisMSUD; dihydrolipoyl DH (E3) deficiency; lactic acidosis
 2-KetoisocaproateLactic acidosis; ketosisMSUD; dihydrolipoyl DH (E3) deficiency; lactic acidosis
 2-KetoisovalerateLactic acidosis; ketosisMSUD; dihydrolipoyl DH (E3) deficiency; lactic acidosis
 2-Methyl-acetoacetate (30)Mitochondrial acetoacetyl-CoA-thiolase deficiency
 2-MethylglutaconatePA; MMA (?)2; β-ketothiolase deficiency
 3-Hydroxy-2-ethylyglutaratePA
 3-Hydroxy-2-ethylpropionate (31)(32)Ketosis3-Methylglutaconic aciduria (type II); methylmalonic semialdehyde DH deficiency3; respiratory chain defects (complex I and II)
 3-Hydroxy-2-methylbutyrate (30)(33)(34)(35)KetosisMitochondrial acetoacetyl-CoA-thiolase deficiency; 2-methyl-3-hydroxybutyryl-CoA DH deficiency; PA; Pearson syndrome
 3-Hydroxy-3-methylglutarateKetosisHMG-CoA lyase deficiency
 3-Hydroxyisovalerate (30)(34)Reye & Reye-like syndromes; VPA; ketosisIVA; multicarboxylase deficiency; HMG-CoA lyase deficiency; 3-methylcrotonyl-CoA carboxylase deficiency; 3-methylglutaconyl-CoA hydratase deficiency; succinyl-CoA:3-oxoacid-CoA transferase deficiency; MAD deficiency
 3-Hydroxypropionate (hydracrylate) (33)(34)(36)Bacterial metabolism and contamination; short bowel syndrome; lactic acidosisPA; MMA; multiple carboxylase deficiency; succinic semialdehyde DH deficiency; methylmalonic semialdehyde DH deficiency3; lactic acidosis (with pyruvate carboxylase deficiency)
 3-Keto-2-methylbutyrate (33)PA; MMA (?); β-ketothiolase deficiency
 3-Keto-2-methylvalerate (33)PA; MMA (?); β-ketothiolase deficiency
 3-MethylcrotonylglycineReye & Reye-like syndromes3-Methylcrotonyl-CoA carboxylase deficiency; multiple carboxylase deficiency; HMG-CoA lyase deficiency
 3-Methylglutaconate (37)(38)(39)(40)(41)(42)Uremia; acquired HMG-CoA lyase deficiency; other biochemical origin still unknown; pregnancy3-Methylglutaconyl-CoA hydratase deficiency (methylglutaconic aciduria type I); HMG-CoA lyase deficiency; 3-methylglutaconic aciduria (other than type I); respiratory chain defects (e.g., Pearson syndrome or mitochondrial ATP synthase deficiency); Smith–Lemli–Opitz syndrome; carbamyl phosphate synthetase deficiency
 3-MethylglutarateAs 3-methylglutaconate
 4-HydroxyisovalerateIVA
 Isovalerylglycine (34)VPAIVA; MAD deficiency; EMA aciduria (short-branched chain acyl-CoA DH deficiency; muscle COX deficiency3)
 Methylcitrate (33)(34)(43)MalnutritionPA; MMA; multiple carboxylase deficiency
 Methylmalonate (27)(34)(43)(44)(45)(46)(47)(48)(49)B12 vitamin deficiency, pernicious anemia; bacterial gut metabolism; gastroenteritis in very young infants; short bowel syndrome; apnea; “benign” MMA; decreased GFR (in plasma); malnutritionMMA; transcobalamine II deficiency; malonic aciduria
 Propionylglycine (33)(34)PA; MMA
 Tiglylglycine (30)(31)(33)(34)(35)(50)Reye & Reye-like syndromes; VPAPA; 2-methyl-3-hydroxybutyryl-CoA DH deficiency; mitochondrial acetoacetyl-CoA-thiolase deficiency; multiple carboxylase deficiency; respiratory chain defects (e.g., complex I)
Fatty acid oxidation (16)(51)(52)(53)(54)(55)
 DCA (even, saturated): adipate, suberate, sebacate (17)(26)(43)(56)(57)(58)(59)Seriously ill states: infection, malnutrition, fever, seizures, liver diseases, pulmonary stenosis; MCT administration; ketosis; VPA or acetaminophen; lactic acidosis; hypoglycemia; Reye & Reye-like syndromes; Jamaican vomiting sicknessβ-Oxidation defects (MAD, MCAD, SCAD, VLCAD, SCHAD, LCHAD/TFP); HMG-CoA lyase deficiency; systemic carnitine deficiency; succinic semialdehyde DH deficiency; CPT II deficiency; peroxisomal diseases; glycogen storage disorders I & II; lactic acidosis; fructose intolerance
 Odd DCA (57)(58)As even DCA; from plastic containers; uremiaPeroxisomal diseases
 Unsaturated DCA (59)KetosisVLCAD deficiency; CPT II deficiency
 3-Hydroxy DCA (60)MCT administration; fasting; ketosis; celiac diseaseLCHAD/TFP deficiency; VLCAD deficiency
 2-Hydroxysebacate (58)Peroxisomal diseases
 2-MethylbutyrylglycineVPAMAD deficiency; EMA aciduria (short-branched chain acyl-CoA DH deficiency; muscle COX deficiency3)
 3-Hydroxyadipic (lactone)See 3-hydroxy DCASee 3-hydroxy DCA
 3-Hydroxydo-/tetradecanedioate (61)Hepatocellular disease; ketosis; acetaminophen intoxicationLCHAD/TFP deficiency
 3-Hydroxysebacate (31)(62)See 3-hydroxy DCA; progressive liver disease; acetaminophenSee 3-hydroxy DCA; MCAD deficiency; glycogen storage disorders I & II; secondary to respiratory chain defects
 3-HydroxysuberateSee 3-hydroxy DCASee 3-hydroxy DCA
 4-OctenedioateJamaican vomiting sickness; neonates on fastingMCAD deficiency; MAD deficiency; VLCAD deficiency; LCHAD/TFP deficiency; nonketotic dicarboxyluria; systemic carnitine deficiency; peroxisomal diseases
 5-Hydroxyhexanoate (59)MCT administration; VPA; Reye & Reye-like syndromes; ketosisMAD deficiency; MCAD deficiency; nonketotic dicarboxyluria
 5-HydroxysebacatePeroxisomal diseases
 7-Hydroxyoctanoate (59)MCT administration; VPAMCAD deficiency
 AdipateSee DCA; food additive (Jello®); lithium; neonates on fastingSee DCA
 ButyrylglycineMCT administration; ketosis; Jamaican vomiting sicknessSCAD deficiency; MAD deficiency; EMA aciduria (short-branched chain acyl-CoA DH deficiency; muscle COX deficiency3)
 DecenedioateMCAD deficiency; VLCAD deficiency; LCHAD/TFP deficiency
 Do-/Tetradecanedioate (63)KetosisVLCAD deficiency; LCHAD/TFP deficiency; MAD deficiency; CPT II deficiency
 Ethylmalonate (11)(64)(65)(66)(67)Jamaican vomiting sickness; neonates on fasting; diet (?)SCAD deficiency; MAD deficiency (severe form); MAD deficiency (mild form); acetyl-CoA carboxylase deficiency; EMA aciduria (short-branched chain acyl-CoA DH deficiency; muscle COX deficiency3); respiratory chain defects
 Hexanoylglycine (20)(59)VPA; MCT administration; Jamaican vomiting sicknessMCAD deficiency; MAD deficiency; SCAD deficiency
 IsobutyrylglycineMAD deficiency; EMA aciduria (short-branched chain acyl-CoA DH deficiency, muscle COX deficiency3)
 MethylsuccinateAs EMA
 Octanoate (59)MCT administrationMCAD deficiency
 Phenylpropionylglycine (20)Bacterial gut metabolism and bacterial contaminationIn MCAD deficiency (from phenylalanine bacterial metabolism or after load)
 Suberylglycine (20)(59)MCT administration; ketosis; Reye & Reye-like syndromesMCAD deficiency; MAD deficiency
 TetradecanedioateVLCAD deficiency; LCHAD/TFP deficiency; MAD deficiency
Krebs cycle/respiratory chain (68)(69)(70)(71)
 2-Ketoglutarate (38)(72)Bacterial contamination; lithium; uremia; increase with younger ageAs malate; 2-ketoglutaric DH deficiency; GA I; 2-amino/2-ketoadipate acidemia; dihydrolipoyl DH (E3) deficiency; glycogen storage disorder I; 2-hydroxyglutaric aciduria (d-form); fumarase deficiency
 AconitateRespiratory chain defects (e.g., complex I); Pearson syndrome
 Citrate, isocitrateHigh carbohydrate intake; parathyroid extract; saturnism; citrate intake; fruit juice added to urine; hyperparathyroidism; increase with younger ageDihydrolipoyl DH (E3) deficiency; fumarase deficiency; pyruvate carboxylase deficiency; Pearson syndrome
 FumarateLithium; renal tubular reabsorption defect (fumaric aciduria); increase with younger ageAs malate; fumarase deficiency
 Malate (73)(74)(75)Lithium; uremia; increase with younger ageRespiratory chain defects; pyruvate carboxylase deficiency; PDH complex (E1, E3) deficiency; Pearson syndrome
 Succinate (72)(76)Bacterial (on storage); 2-ketoglutarate degradation; lithium; ketosis; tissue ischemia; increase with younger ageAs malate; malonic aciduria; fumarase deficiency
Lactic acid, ketone bodies (30)(71)(77)
 2-HydroxybutyrateKetosis; lactic acidosisLactic acidosis; GA I; respiratory chain defects
 2-HydroxyisobutyrateLactic acidosisLactic aciduria
 3-Hydroxybutyrate (32)(49)(77)(78)(79)Ketosis (e.g., vomiting, prolonged fasting, diabetic ketoacidosis); B12 vitamin deficiency; Reye & Reye-like syndromes; pulmonary infections; viral gastroenteritis; von Gierke disease; hyperthyroidism; pregnancy; heat stroke; ethanol; protein malnutrition; high-fat dietGluconeogenesis; PHD complex deficiency; respiratory chain defects; IVA; PA; MMA; multiple carboxylase deficiency; 3-methylcrotonyl-CoA carboxylase deficiency; glyceroluria; MSUD; GA I; MAD deficiency; β-ketothiolase deficiencies; 2-amino/2-ketoadipic acidemia; mitochondrial SCHAD; fatty acids oxidation deficiency (inappropriate ketosis)
 Acetoacetate (78)As 3-hydroxybutyrate; acetylsalicylateAs 3-hydroxybutyrate
 Lactate and pyruvate (29)(78)(80)(81)(82)Gut bacteria and bacterial contamination (d-lactate); short bowel syndrome (d-lactate); secondary lactic acidosis (e.g., apnea, septicemia, seizures, respiratory or cardiac insufficiency); diabetic ketoacidosis; Reye & Reye-like syndromes; increase with younger age; saccharose, fructose, lactose; drugs inducing hyperlactemia; dialysis bath; MCT administrationPrimary lactic acidosis; PDH complex (E1, E2, E3) deficiency; oxidative phosphorylation and respiratory chain defects (e.g., MERRF, MELAS, Kearns-Sayre), Krebs acid cycle defects, gluconeogenesis defects (e.g., pyruvate carboxylase, fructose-1, 6-diphosphatase, glycogen storage I disorder); (short-branched chain acyl-CoA DH deficiency; muscle COX deficiency3); MAD deficiency (severe form); VLCAD deficiency; GA I; multiple carboxylase deficiency; some other organic aciduria (MMA, PA, IVA); citrullinemia, glycerol kinase deficiency; HMG-CoA lyase deficiency; EMA aciduria
Lysine, glycine, serine metabolism
 GlutaconateGA I
 GlycerateUremia; increase with younger aged-Glyceric aciduria; hyperoxaluria type II (l-form); succinic semialdehyde DH deficiency
 Glycolate (83)(84)Ethylene glycol poisoningHyperoxaluria type I; succinic semialdehyde DH deficiency; isolated glycolic aciduria3
 GlyoxylateHyperoxaluria type I
 2-Hydroxyadipate (85)2-Amino/2-Ketoadipic aciduria
 3-Hydroxyglutarate (85)GA I
 2-Ketoadipate (85)2-Amino/2-Ketoadipic aciduria
 Glutarate (18)(19)(85)(86)(87)2-Ketoglutarate degradation; bacterial gut metabolism; uremia; ethylene glycol poisoning; lithiumGA I; MAD deficiency (severe form); MAD deficiency (mild form); 2-amino/2-ketoadipic aciduria; malonic aciduria; other mitochondrial dysfunctions
 Oxalate (83)(88)(89)(90)Enteric malabsorption (regional enteritis or ileitis, celiac sprue disease, resection of ileum, Crohn disease); idiopathic stone disease; pyridoxine deficiency; increase with younger age; diet (e.g., beans, leafy vegetables, rhubarb, spinach, tomatoes, strawberries, tea, chocolate); infant formula; ascorbic acid; xylitol; ethylene glycol; methoxyfluraneHyperoxaluria type I and II; hyperoxaluria without known enzyme deficit
Other acids and metabolites
 2-Hydroxyglutarate (82)(85)Bacterial contamination (d-form); lithium; uremia; increase with younger age; 2-ketoglutarate degradation2-Hydroxyglutaric aciduria (l- and d-forms); MAD deficiency, severe (d-form); MAD deficiency, mild (d-form); 2-amino/2-ketoadipic aciduria; malonic aciduria
 3,4-Dihydroxybutyrate (2-deoxytetronate)DietSuccinic semialdehyde DH deficiency
 3-Hydroxyisobutyrate (32)Ketosis3-Hydroxyisobutyric DH deficiency and/or methylmalonic semialdehyde DH deficiency3
 4,5-DihydroxyhexanoateSuccinic semialdehyde DH deficiency
 4-HydroxybutyrateKetosis (?)Succinic semialdehyde DH deficiency
 4-Hydroxycyclohexylacetate (91)Bacterial gut metabolism (?)Hawkinsinuria
 GlycerolContamination (suppository, emollients); uremiaGylcerol kinase deficiency; fructose-1,6-phosphatase deficiency
 Malonate (92)Malonyl-CoA-decarboxylase deficiency; malonic aciduria with normal malonyl-CoA-decarboxylase activity
 Mevalonate and/or its lactoneMevalonate kinase deficiency
N-AcetylaspartateCanavan disease
 Orotate (93)(94)(95)Allopurinol treatment; azauridine; high cell turnover (tissue breakdown, menstruation); folate malabsorptionArgininemia; orotic aciduria; citrullinemia; OCT deficiency; hyperornithinemia-hyperammonemia-homocitrullinuria syndrome; lysinuric protein intolerance; purine nucleoside phosphorylase deficiency; Lesh–Nyhan disease
 Pyroglutamate (l- or d-5-oxoproline) (82)(91)(96)(97)(98)(99)(100)(101)(102)From glutamine of hydrolyzed proteins (infant formula); acetaminophen; vigabatrin; fludoxacillin, netilmicin (?); glutamine degradation (in hyperammonemia, urea cycle defects); vegetarian or low-protein diets, undernutrition; iron oxoprolinate; Steven–Johnson syndrome; burns; premature newborns; transitory (?); glycine deficiency; increase with younger age; renal insufficiency; pregnancy (increased metabolic demand for glycine)Glutathione synthetase deficiency; 5-oxoprolinase deficiency; nephropathic cystinosis; hawkinsinuria; homocystinuria; OCT deficiency; PA
 ThymineCaffeine (?)Dihydropyrimidine DH deficiency
 UracilCaffeine (?)Dihydropyrimidine DH deficiency; OCT deficiency; citrullinemia
 Vanillactate (103)Catecholamine-containing foodstuff (e.g., bananas); l-dopa decarboxylase inhibitors; neuroblastomal-Amino acid decarboxylase deficiency
Nutritional, exogenous, or artifactual compounds (6)
 2,5-Furane dicarboxylate and 5-hydroxymethyl-2-furanoateHeated furanoic sugars (chocolates, fruit juice, intravenous perfusion)
 2-FuroylglycineChocolate; heated fruit juice or parenteral solution; uremia
 3-(3-Hydroxyphenyl)-hydracrylateFrom nutrition
 4-Hydroxycyclohexane-1-carboxylate (104)Diet; bacterial gut metabolism (from tyrosine)
 4-HydroxyhippurateBacterial gut metabolism
 Benzoate (61)(105)Bacterial metabolism (gut, urinary tract) from hippurate or from aromatic amino acids; benzoate treatment; food additive; ethylene glycol poisoning; toluene; hyperammonemia
 Hippurate (106)As benzoate; uremia
 MaleateFluvoxamine maleate
 PalmitateSoap; Jamaican vomiting sickness
p-CresolBacterial metabolism from tyrosine; toluene; uremia
 PhenolBacterial metabolism from tyrosine; exposure to benzene or phenol; malabsorption; uremia
 PivalatePivampicillin or pivmecillinam
 TartarateFood additive; uremia
  • 1 PKU, phenylketonuria; BH4, tetrahydrobiopterin; PA, propionic acidemia; VPA, valproate; MSUD, maple syrup urine disease; DH, dehydrogenase; MMA, methylmalonic acidemia; HMG, 3-hydroxy-3-methylglutarate; IVA, isovaleric acidemia; MAD, multiple acyl-CoA dehydrogenase; EMA, ethylmalonate; COX, cytochrome c oxidase; GFR, glomerular filtration rate; DCA, dicarboxylic acid; MCT, medium-chain triglyceride; MCAD, medium-chain acyl-CoA dehydrogenase; SCAD, short-chain acyl-CoA dehydrogenase; VLCAD, very long-chain acyl-CoA dehydrogenase; SCHAD, short-chain 3-hydroxyacyl-CoA dehydrogenase; LCHAD/TFP, long-chain 3-hydroxyacyl-CoA dehydrogenase/trifunctional protein; CPT, carnitine palmitoyltransferase; GA I, glutaric aciduria type I; PDH, pyruvate dehydrogenase; OCT, ornithine carbamoyltransferase.

  • 2 (?) indicates that this information remains to be confirmed.

  • 3 Enzymatic confirmation not yet established.