Elsevier

Clinical Biochemistry

Volume 33, Issue 6, August 2000, Pages 465-473
Clinical Biochemistry

Hereditary coproporphyria in Germany: clinical-biochemical studies in 53 patients

https://doi.org/10.1016/S0009-9120(00)00159-4Get rights and content

Abstract

Objectives: To describe the biochemical and clinical features in hereditary coproporphyria (HCP).

Design and method: Within the last 20 years, we investigated 53 patients (male:female = 1:2.5; age = 8–86 years) suffering from HCP. We describe the characteristic levels of urine, and fecal porphyrins and their precursors in hereditary coproporphyria and present the clinical features. Especially, we measured the coproporphyrin isomers I and III.

Results and conclusion: The group of hereditary coproporphyria patients exhibited a significantly higher (p < 0.0001) excretion of urinary porphyrin precursors, δ-aminolevulinic acid (median = 84 μmol/24 h) and porphobilinogen (median = 39 μmol/24 h), as compared to controls (δ-aminolevulinic acid: 22 μmol/24 h, porphobilinogen: 3 μmol/24 h; median, n = 20). The median of coproporphyrin in urine (1315 nmol/24 h) and feces (1855 nmol/g) were enhanced 12- and 168-fold, as compared to healthy subjects (urinary coproporphyrin: 106 nmol/24 h, fecal coproporphyrin: 11 nmol/g; median, n = 20). During therapy on one female patient, with IV application of heme arginate, a considerable decline of porphyrin precursors and porphyrin excretion was observed. The examination of urinary and fecal coproporphyrin isomers I and III revealed an excessive elevation of the coproporphyrin isomer III of 87% in urine and 94% in feces, respectively (normal: urinary isomer III = 69–83% and fecal isomer III = 25–40%). In feces the increase of isomer III caused an inversion of the physiologic coproporphyrin isomer III:I ratio that could be recognized in all various stages in hereditary coproporphyria and in children. Acute attacks of hereditary coproporphyria are accompanied by an acute polysymptomatic clinical syndrome, and this is associated with high levels of urinary porphyrin precursors. On review of our patients, the highest percentage had abdominal pain (89%), followed by neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%).

Introduction

Hereditary coproporphyria (HCP) has been observed in Germany since 1978 as the third most common acute hepatic porphyria in Europe. It is an autosomal dominant inherited disorder characterized by an abnormal hepatic and renal excretion of coproporphyrin and by a deficient activity of the mitochondrial enzyme coproporphyrinogen oxidase 1, 2, 3. In the majority of cases the enzyme activity is reduced to nearly 50% in heterozygotes; in very rare cases of HCP, presumed to be homozygous for the coproporphyrinogen III oxidase defect, it is about 2% 4, 5, 6, 7, 8. Clinical attacks are characterized by an acute polysymptomatic syndrome with abdominal, cardiovascular, neurologic, and psychiatric symptoms 1, 2, 9. Additionally in nearly 20% of cases HCP may be associated with photosensitivity (10). Secondary factors (drugs, most commonly barbiturates, estrogens, sulfonamides, and hormonal oral contraceptives; also alcohol, caloric deprivation, infection, endocrine factors, or stress) can lead to manifestation of HCP in susceptible individuals 11, 12, 13. Thus an early detection of the metabolic disorder is important in the prevention of attacks, so that patients can be advised to avoid the precipitating factors. Enzyme tests are often technically difficult and require tissues such as cultured fibroblasts, lymphocytes, or liver biopsy material and, therefore, they are rarely used (14). Genetic analysis produces a precise diagnosis in some of the porphyrias provided the patient has one of the previously described point mutations, but this technique is currently confined to a few research laboratories (14). For this reason the diagnosis of an acute HCP is based on increased excretion of urinary δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) and a markedly elevation of coproporphyrin in both feces and urine 8, 15, 16. Diagnosis of HCP in carriers of the defective gene, who are in the clinically latent phase; however, is not always possible by the conventional biochemical analyses and, in this case, the determination of fecal coproporphyrin isomers I and III has become a helpful complementary diagnostic method (17).

Treatment of HCP includes the omission of precipitating factors and regulatory treatment by glucose or IV administration of heme 18, 19. Both glucose and heme compounds as hemin and heme arginate have shown to normalise the production of excess heme precursors, as well as to lead to a clinical improvement 19, 20, 21, 22, 23. Early diagnosis and a well-timed administration of carbohydrates together with a withdrawal of dangerous drugs and alcohol cannot be overemphasised for an uncomplicated course of porphyria.

The aim of the study was to show the characteristic biochemical and clinical features obtained from 53 patients suffering from HCP. We specifically wanted to evaluate the diagnostic relevance of fecal coproporphyrin isomer III in patients as well as in asymptomatic gene carriers.

Section snippets

Patients

Investigations were carried out over a period of 20 years on 53 patients suffering from HCP (37 females and 16 males, age: 8–86 years). Most of the patients are not related to each other with exception of two couples and two families. One family with a 10-year-old girl was described previously (24). The second family we described in context with the case report of a 29-year-old female patient, suffering since 1969 from recurrent abdominal complaints. Regarding to the various stages of HCP 6 of

Biochemical investigations

The medians and the ranges of the urinary and fecal heme precursors from 53 patients suffering from HCP are shown in Table 2. Total porphyrin excretions were significantly increased about 15- and 33-fold, and ranged widely from 332 to 35585 nmol/24 h in urine and from 541 to 61317 nmol/g in feces (control group: urine = 135 (85–157) nmol/24 h, feces = 65 (46–209) nmol/g; median (Xmin–Xmax)). In urine this elevation could be explained by a significant rise of the porphyrin precursors, ALA and

Pathobiochemical diagnosis

Diagnosis of overt porphyria requires metabolite studies. Enzyme assays have only a minor part to play in the routine diagnosis and management of the porphyrias 14, 28. The presence of an enzyme defect, most of the time, does not necessarily mean the patient will have clinical manifestations of the associated porphyria. Decreased enzyme activity reflects only that the patient carries an enzyme mutation. As clinical experience shows, only in a minority of genetically affected family members does

Conclusion

Summarizing the main points of our study on hereditary coproporphyria, we conclude that:

1) Diagnosis and differential diagnosis of HCP are based on analysis of urinary porphyrin precursors (ALA and porphobilinogen) and of coproporphyrin in urine and feces.

2) The inversion of the fecal coproporphyrin isomers III:I ratio could be the decisive factor to identify patients in the subclinical (n = 40) and in the latent (n = 7) stage of hereditary coproporphyria.

3) Clinically, hereditary

Acknowledgements

The authors thank Thomas Dietze (Department of Medical Biometrics and Medical Information of the Philipp University, Marburg, Germany) for statistical analysis of the data.

The study was supported by the German Research Association (Grant GR 1363/2-2) and by the Hans-Fischer-Gesellschaft (Munich, Germany).

References (53)

  • P Martásek

    Hereditary coproporphyria

    Semin Liv Disease

    (1998)
  • Nordmann Y, Grandchamp B. Hereditary coproporphyria. Demonstration of a genetic defect in coproporphyrinogen...
  • H Fujita et al.

    Characterization and expression of cDNA encoding coproporphyrinogen oxidase from a patient with hereditary coproporphyria

    Hum Mol Genet

    (1994)
  • P Martásek et al.

    Homozygous hereditary coproporphyria caused by an arginine to tryptophane substitution in coproporphyrinogen oxidase and common intragenic polymorphisms

    Hum Mol Genet

    (1994)
  • Kappas A, Sassa S, Galbraith A, Nordmann Y. The porphyrias. In: Scriver CR, Beaudet AL, Sly WS, Vale D, Eds. The...
  • G.H Elder et al.

    The acute porphyrias

    Lancet

    (1997)
  • D Blake et al.

    Fecal coproporphyrin isomers in hereditary coproporphyria

    Clin Chem

    (1992)
  • U Groβ et al.

    Hormonal oral contraceptives, urinary porphyrin excretion and porphyrias

    Horm Metab Res

    (1995)
  • M Daimon et al.

    A novel missense mutation in exon 4 of the human coproporphyrinogen oxidase gene in two patients with hereditary coproporphyria

    Hum Genet

    (1997)
  • A Gorchein

    Drug treatment in acute porphyria

    Br J Clin Pharmacol

    (1997)
  • Doss M. Hepatic porphyrias. Pathobiochemical, diagnostic, and therapeutic implications. In: Popper H and Schaffner F,...
  • A Kühnel et al.

    Studies on coproporphyrin isomers in urine and feces in the porphyrias

    Clin Chim Acta

    (1998)
  • M.O Doss

    Diagnosis and therapy of acute porphyriasstate on the art

  • R Kauppinen et al.

    Treatment of the porphyrias

    Ann Med

    (1994)
  • P Mustajoki et al.

    Heme in the treatment of porphyrias and hematological disorders

    Semin Hematol

    (1989)
  • P Mustajoki et al.

    Early administration of heme arginate for acute porphyric attacks

    Arch Intern Med

    (1993)
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