Hereditary coproporphyria in Germany: clinical-biochemical studies in 53 patients
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.
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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)
- et al.
Coproporphyrinogen-oxidase deficiency in hereditary coproporphyria
Lancet
(1977) - et al.
Biochemical differentiation of the porphyrias
Clin Biochem
(1999) Biochemistry of Porphyria [Review]
Int J Biochem
(1993)- et al.
The occurrence and determination of δ-aminolevulinic acid and porphobilinogen in urine
J Biol Chem
(1956) Enzyme assays and the porphyriaswhich tissues and when indicated
Clin Dermatol
(1998)Advances in understanding and treating “the little imitator”, acute porphyria
Gastroenterology
(1993)The biochemistry of heme synthesis in porphyria and in the porphyrinurias
Clin Dermatol
(1998)- et al.
Harderoporphyrin coproporphyria
Lancet
(1984) - et al.
Hereditary coproporphyria
Q J Med
(1977) - et al.
The porphyrias
Hereditary coproporphyria
Semin Liv Disease
Characterization and expression of cDNA encoding coproporphyrinogen oxidase from a patient with hereditary coproporphyria
Hum Mol Genet
Homozygous hereditary coproporphyria caused by an arginine to tryptophane substitution in coproporphyrinogen oxidase and common intragenic polymorphisms
Hum Mol Genet
The acute porphyrias
Lancet
Fecal coproporphyrin isomers in hereditary coproporphyria
Clin Chem
Hormonal oral contraceptives, urinary porphyrin excretion and porphyrias
Horm Metab Res
A novel missense mutation in exon 4 of the human coproporphyrinogen oxidase gene in two patients with hereditary coproporphyria
Hum Genet
Drug treatment in acute porphyria
Br J Clin Pharmacol
Studies on coproporphyrin isomers in urine and feces in the porphyrias
Clin Chim Acta
Diagnosis and therapy of acute porphyriasstate on the art
Treatment of the porphyrias
Ann Med
Heme in the treatment of porphyrias and hematological disorders
Semin Hematol
Early administration of heme arginate for acute porphyric attacks
Arch Intern Med
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2014, European Journal of Internal MedicineCitation Excerpt :In the rare congenital erythropoietic porphyria (CEP), faecal porphyrin pattern is similar to HCP, but the levels of faecal coproporphyrin are usually much higher and isomer I is prevalent [101]; moreover, in CEP photo cutaneous syndrome is quite more severe and there is no history of acute porphyric attacks. This very rare and severe cutaneous porphyria is also characterized by very high levels of porphyrins in erythrocytes [23,57,102]. Similar to AIP, also in HCP the catalytic capacity of PBGD (HBMS) enzyme may be compromised (probably as a consequence of inhibitory effect of porphyrins produced in excess), and a plasma fluorescence peak positive at 620 nm has been described [23].