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Composition of Urinary Coproporphyrin Isomers I —IV in Human Porphyrias1)

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Composition of Urinary Coproporphyrin Isomers I —IV in Human Porphyrias1) Jacob and Doss: Coproporphyrin isomers in porphyrias 617 Eur. J. Clin. Chem. Clin. Biochem. Vol. 31, 1993, pp. 617-624 © 1993 Walter de Gruyter & Co. Berlin · New York Composition of Urinary Coproporphyrin Isomers I —IV in Human Porphyrias1) By K. Jacob1 and M. O. Doss2 1 Institut jur Klinische Chemie am Klinikum Gro hadern der Universit t M nchen, Germany 2 Abteilung Klinische Biochemie, Fachbereich Humanmedizin, Philipps-Universit t, Marburg, Germany (Received March 19/June 24, 1993) Dedicated to Professor Claude Rimington in honour of his 90th birthday Summary: The urinary distribution and relative proportions of the four Coproporphyrin isomers I—IV were investigated in 50 patients suffering from hepatic and erythropoietic types of hereditary porphyrias. A highly efficient sample preparation method was applied to isolate urinary coproporphyrins, the isomer ratios of which were quantitated by isocratic ion-pair high-performance liquid chromatography. Results showed a significant decrease (p < 0.001) of the proportion of Coproporphyrin I in acute hepatic porphyria (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, porphobilinogen synthase deficiency porphyria) as compared with chronic hepatic porphyria (porphyria cutanea tarda, chronic hepatic porphyria type B and C) (13.2 ± 5.3%, χ ± S.D., vs. 31.4 ± 11.5%). Conversely, the proportion of isomer III was significantly higher (p < 0.001) in acute hepatic porphyria than in chronic hepatic porphyria (80.9 + 5.2% vs. 62.2 + 10.9%). As expected, the highest level of Coproporphyrin I (90.0 ± 1.9%) was found in congenital erythropoietic porphyria. The atypical coproporphyrins II and IV were detected in all types of porphyria analysed and ranged from 0.2 to 9.0%; no significant differences were seen between acute and chronic hepatic porphyrias. The diagnostic importance of the isomer ratios of coproporphyrins I and III has been confirmed in our study, while the significance of the atypical Coproporphyrin isomers II and IV is still unclear at present. the haem biosynthetic enzymes in blood cells help to Porphyrias are caused by deficiencies of haem bio- identify the nature of the hereditary defect (1, 2). synthetic enzymes (fig. 1). Characteristic excretion Additional diagnostic information can be obtained patterns of porphyrins and pprphyriri precursors — for some porphyrias when the ratios of the naturally reflecting the respective enzymatic defect — are ob- occurring isomers of series I and III are determined served in these conditions. (3). Alterations of the normal ratios of copropor- ^._ . , ,. , . , . phyrin isomers I and III are found in cases of both Differential diagnosis orf porphyrias requires analysis à ,.^ j* · u · é j · · . 6 . à F J .1 « j .· hereditary and toxic porphyrias, e.g. lead poisoning of haem precursors m unne,r feces, blood and tissues ,- \ τ/ · * ^ π é Ë *· f ff * * · * /„ nx ^ é χ / j· r (3"~*) c · For instance, the well-known overproduction of affected patients (1,2). Complementary studies of - . T . , . * \ > / t- j Of type j lsomers m congenital erythropoietic por- phyria (4, 6) or the preponderance of heptacarboxy- ^~I 77 . ,*, . τ, é . porphyrin III in porphyria cutanea tarda (3) greatly !) Presented in part at th e M"InternationaY l Meeting on Porphyrin £ .!.' . é_· é_ · é j· - r.V Metabolism and Iron Metabolism", April 30-May 4; 1992, facilitate s thA e biochemical diagnosis of these por- Papendal, The Netherlands. phyrias. On the other hand, secondary copropor- Eur. J. Clin. Chem. Clin. Biochem. / Vol. 31,1993 / No. 10 618 Jacob and Doss: Coproporphyrin isomers in porphyrias Porphyria Substrate Enzyme EC Glycine + Succinyl CoA 5- AminolaevuUnate synthase 2.3.1.37 • r 5-Aminolaevulinic acid Doss 1 Aminolaevulinate porphyria τ dehydratase 4. 2.1.24 Porphobilinogen Acute intermittent Porphobilinogen porphyria 1 deaminase 4. 3. 1. 8 Hydroxymethylbilanτ e Congenital erythro- 1 Uroporphyrinogen poietic porphyria τ cosynthase k. 2. 1.75 Uroporphyrinogen Porphyria cutanea 1 Uroporphyrinogen tarda t decarboxylase A. 1. 1.37 Coproporphyrinogen Hereditary 1 Coproporphyrinogen coproporphyria t oxidase 1. 3. 3. 3 Protoporphyrinogen Variegate 1 Protoporphyrinogen porphyria τ oxidase 1. 3.3. Protoporphyrin Erythropoietic 1 Ferrochelatase 4.99.1. 1 protoporphyria τ Haem Fig. 1. Inherited enzyme blocks in the porphyrias. (Slightly modified from I.e. (28)). phyrinurias often show characteristic isomer ratios urine of patients suffering from the common types of which may originate from lead intoxication (5), some hereditary porphyria. The individual isomer ratios liver diseases, like alcohol- and protoporphyrin-in- were determined in order to clarify their potential in duced cholestasis (7, 8) or hereditary hyperbilirubin- the differential diagnosis of porphyrias. aemias such as Rotor's syndrome and Dubin-Johnson syndrome (9). Thus, the respective isomer ratios are valuable tools for the differential diagnosis of these disorders (10). Materials and Methods The development of enhanced high-performance liq- Patients uid Chromatographie (HPLC) methods enabled the We analysed the isomer ratios of coproporphyrins I—IV in simultaneous resolution of the naturally occurring urine of patients suffering from acute intermittent porphyria (N = 20), hereditary coproporphyria (N = 6), variegate por- type I and type III isomers in the series from uro- to phyria (N = 3), porphobilinogen synthase (synonym: 5-ami- coproporphyrin in a single Chromatographie run (11, nolaevuiinic acid dehydratase) deficiency porphyria (N = 1), 12). In addition, complete resolution of the four co- porphyria cutanea tarda (N = 10), chronic hepatic porphyria (type B and C, N = 5), congenital erythropoietic porphyria proporphyrin isomers I —IV was achieved under iso- (N = 3), and protoporphyria (N = 2). Diagnosis of the re- cratic conditions (12, 13). However, the atypical iso- spective porphyrias was based on the characteristic biochemical mers of the series II and IV were previously thought constellations (1 — 3,8) in connection with the clinical symptoms to be non-existent in biological materials (14). Re- in overt cases. cently, we were able to detect small amounts of co- Table 1 shows the excretion of urinary porphyrin precursors and porphyrins of four porphyria patients. The patients with proporphyrin II and IV in human urine (15) and feces acute intermittent porphyria, porphobilinogen synthase defi- (16). These symmetrically substituted isomers are ciency porphyria and congenital erythropoietic porphyria were mainly formed by non-enzymatic isomerization of in a non-acute phase at the time of investigation, whereas the patient with porphyria cutanea tarda was in a clinically manifest porphyrinogens in relatively acidic urines (17). phase. Due to the homozygous status of the patients with porphobilinogen synthase deficiency 'jJorphyria and congenital In this study, we investigated for the first time the erythropoietic porphyria, their metabolite excretion is exces- isomeric composition of coproporphyrins I— IV in sively increased (tab. 1). Eur. J. Clin. Chem. Clin. Biochem. / Vol. 31,1993 / No. 10 Jacob and Doss: Coproporphyrin isomers in porphyrias 619 Tab. 1. Urinary porphyrin precursors and porphyrins in four patients with various types of porphyria. Porphyria Acute intermittent Porphyria cutanea PBG synthase defi- Congenital erythro- Controls, pofphyria, female, tarda, female, 43 ciency porphyria, poietic porphyria, upper 38 years old, non- years old, manifest male, 33 years old, male, 26 years old, reference acute phase phase non-acute phase non-acute phase limit* (fig. 3a) (fig. 3b) (fig. 3c) (fig. 3d) Porphyrin precursors (μηοΙ/24 h) δ-Aminolaevulinic acid 175 40 1018 21 49 Porphobilinogen 315 3 8 2 8 Porphyrins (nmol/24 h) Uroporphyrin 950 2180 49 4918 29 Heptacarboxylic 45 1290 25 543 4 porphyrin Hexacarboxylic 33 24 11 279 3 porphyrin Pentacarboxylic 70 265 122 1256 6 porphyrin Coproporphyrin 285 205 2834 6878 119 According to Doss (29) Urines Briefly, urine samples (5 to 10 ml) were oxidized with iodine, 24 h-urine samples were collected in dark brown bottles and and porphyrins were then adsorbed on talc, esterified with kept frozen until analysis. methanol/conc. sulphuric acid, and the porphyrin methyl esters separated by TLC (see above). After hydrolysis, the free copro- porphyrins were further purified by adsorption on Sep-Pak Qg Sample preparation cartridges (Waters, Eschborn, Germany) and eluted with meth- anol/acetone (1 + 1, by vol.). Urinary total coproporphyrins were isolated by the method described previously (18) with the following modification: the TLC separation of the individual porphyrin methyl esters was performed on Kieselgel 60 (Merck, Darmstadt, Germany) using High-performance liquid Chromatographie analysis n-hexane/dichloromethaiie/acetone (41 +41 -f 18, by vol.) as the solvent (19). Coproporphyrins I —IV were separated by isocratic ion-pair HPLC on a 5 μπι-LiChrosorb RJP-18 column (Merck) using tetrabutylammonium phosphate as the ion-pairing reagent (18). Coproporphyrins Percentages of Coproporphyrin isomers were calculated from peak area ratios of the individual isomers. Statistical analysis The Kolmogorov-Smirnov test (20) was used to assess statistical significance between different variable classes. á> Results and Discussion á> er High-performance liquid Chromatographie separation and quantitation of Start coproporphyrins I —IV Simultaneous separation of all four Coproporphyrin isomers was achieved by means of isocratic ion-pair 0
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