Erythrocyte Uroporphyrinogen Decarboxylase Research Articles

The D519G Polymorphism of Glyceronephosphate O-Acyltransferase Is a Risk Factor for Familial Porphyria Cutanea Tarda.

Both familial and sporadic porphyria cutanea tarda (PCT) are iron dependent diseases. Symptoms of PCT resolve when iron stores are depleted by phlebotomy, and a sequence variant of HFE (C282Y, c.843G>A, rs1800562) that enhances iron aborption by reducing hepcidin expression is a risk factor for PCT. Recently, a polymorphic variant (D519G, c.1556A>G, rs11558492) of glyceronephosphate O-acyltransferase (GNPAT) was shown to be enriched in male patients with type I hereditary hemochromatosis (HFE C282Y homozygotes) who presented with a high iron phenotype, suggesting that GNPAT D519G, like HFE C282Y, is a modifier of iron homeostasis that favors iron absorption. To challenge this hypothesis, we investigated the frequency of GNPAT D519G in patients with both familial and sporadic PCT. Patients were screened for GNPAT D519G and allelic variants of HFE (both C282Y and H63D). Nucleotide sequencing of uroporphyrinogen decarboxylase (URO-D) identified mutant alleles. Patients with low erythrocyte URO-D activity or a damaging URO-D variant were classified as familial PCT (fPCT) and those with wild-type URO-D were classified as sporadic PCT (sPCT). GNPAT D519G was significantly enriched in the fPCT patient population (p = 0.0014) but not in the sPCT population (p = 0.4477). Both HFE C282Y and H63D (c.187C>G, rs1799945) were enriched in both PCT patient populations (p<0.0001) but showed no greater association with fPCT than with sPCT. Conclusion: GNPAT D519G is a risk factor for fPCT, but not for sPCT.

Familial and Sporadic Porphyria Cutanea Tarda

Porphyria cutanea tarda is the most frequent porphyria and occurs in both sporadic and familial forms. We conducted the current study in a series of 152 consecutive patients with porphyria cutanea tarda attending the Porphyria Unit of the Hospital Clinic of Barcelona, Spain, to update the clinical manifestations of the disease and to study the sex differences, the proportion of familial forms, and the role of different risk factors in this population. Patients were classified as familial and sporadic cases according to erythrocyte uroporphyrinogen-decarboxylase activity and uroporphyrinogen-decarboxylase genotyping. In our cohort, skin fragility and blisters on the hands were the most frequent clinical manifestations. Women more frequently had facial hypertrichosis (84.8%; p = 0.004), affected areas other than the hands and face (33.3%; p = 0.008), and pruritus (27.3%; p = 0.041) compared with men. Of our patients, 11.8% did not present the typical clinical onset of the disease, with facial hypertrichosis and hyperpigmentation the more frequent complaints in these cases. Analysis of risk factors showed a high prevalence of hepatitis C virus infection (65.8%) and alcohol abuse (59.9%), both being more frequent in men (p < 0.001). Hepatitis C virus infection was the only risk factor that showed differences between the sporadic and familial forms in the logistic regression model (odds ratio, 0.05; 95% confidence interval, 0.006-0.46). In conclusion, atypical forms of presentation of porphyria cutanea tarda should be considered in order to prevent delayed diagnosis. We note the sustained role of hepatitis C virus infection in the precipitation of sporadic porphyria cutanea tarda. Therefore, in countries with a high prevalence of hepatitis C virus infection, the absence of such infection in a patient with porphyria cutanea tarda may suggest a possible familial case.

Associations Among Behavior-Related Susceptibility Factors in Porphyria Cutanea Tarda

Porphyria cutanea tarda (PCT) is the most common of the human porphyrias and results from an acquired deficiency of hepatic uroporphyrinogen decarboxylase (UROD). Some susceptibility factors have been identified; we examined associations among multiple factors in a large cohort of patients. Multiple known or suspected susceptibility factors and demographic and clinical features of 143 patients (mean age 52 years, 66% male, 88% Caucasian) with documented PCT (mean onset at 41 +/- 8.8 years) were tabulated; associations were examined by contingency tables, classification and regression tree (CART) analysis, and logistic regression. The most common susceptibility factors for PCT were ethanol use (87%), smoking (81%), chronic hepatitis C virus (HCV) infection (69%), and HFE mutations (53%; 6% C282Y/C282Y and 8% C282Y/H63D). Of those who underwent hepatic biopsy or ultrasound, 56% had evidence of hepatic steatosis. Of those with PCT, 66% of females took estrogen, 8% were diabetic, 13% had human immunodeficiency virus (HIV) infection, and 17% had inherited uroporphyrinogen decarboxylase (UROD) deficiency (determined by low erythrocyte UROD activity). Three or more susceptibility factors were identified in 70% of patients. HCV infection in patients with PCT was significantly associated with other behavior-related factors such as ethanol use (odds ratio [OR], 6.3) and smoking (OR, 11.9). Susceptibility factors for PCT were similar to previous studies; most patients had 3 or more susceptibility factors. Associations between PCT and HCV, ethanol or smoking could be accounted for by a history of multiple substance abuse; other factors are distributed more randomly among patients.

A Pilot Study Investigating the Safety and Efficacy of Injectable Hemin (Panhematin®) in Patients with Low to Intermediate-1 Risk Myelodysplastic Syndrome.

Abstract 4859 Authors J. M. Shammo1, K. Shell1, D. Rhoades1, A. Rizman1, K. E. Anderson2, M. Holmay3, I. Miller1, S. Gregory1 Institutions 1Rush University Medical Center, Chicago, IL, 2University of Texas Medical Branch, Galveston, TX, 3Director CNS Medical Liaisons, Lundbeck, Inc. Background Injectable hemin (Panhematin) is an iron-containing metalloporphyrin that is approved for the treatment of acute intermittent porphyria. Preclinical data indicate that hemin administration has the potential to stimulate progenitor cell growth and gamma globin chain synthesis. Clinical trial data from Europe on the use of hemin in myelodysplastic syndrome (MDS) suggest it can result in hematologic improvements in a subset of patients (Volin 1988, Timonen 1992). Objective This was an investigator initiated study aimed at evaluating the safety and efficacy of Panhematin in patients with low or intermediate-1 risk MDS. Response assessments were done at week 8, as defined by the International Working Group. Secondary endpoints included the alterations of ferritin, porphyrin, and hemoglobin F levels from baseline with treatment Patients and Methods Between 6/2007 and 10/2008, 6 patients (median age 73.5, range 64-80, men = 5, women = 1) were treated. All patients had a diagnosis of low or intermediate-1 risk MDS (International Prognostic Scoring (IPSS) score of 0-1), were transfusion-dependent or had hemoglobin values of ' 10 g/dL, had ' 10% blasts in bone marrow and peripheral blood, had platelet counts &gt; 50,000/ microL and absolute neutrophil counts (ANC) &gt; 500/microL. Patients received daily doses of Panhematin® at 3 mg/kg IV on days 1 through 4 of week 1, and weekly on day 1 of weeks 2 through 8. Efficacy and safety assessments, including bone marrow biopsies, were performed on Week 8. Partial and complete responders in any of the three cell lines were allowed to continue treatment for as long as they benefit. Patients who did not demonstrate a response or those whose disease had progressed at Week 8 were withdrawn from the study. Results Five of 6 patients completed 8 weeks of treatment and were evaluable for response assessment. One patient withdrew his consent. One patient received an additional 4 weekly doses after achieving an erythroid response and was later retreated for an additional 16 weeks. All other patients had stable disease and four of them remained transfusion dependent. Only 1 (with RARS) out of 5 evaluable patients met criteria for hematologic response. His baseline hemoglobin (Hb) of 7.3g/dL increased to 8.5g/dL at week 8, and peaked at 8.7g/dL at week 9. His bone marrow biopsy at week 8 revealed a decrease in ringed sideroblasts from 73% to 51%. Once off treatment, this patient's Hb dropped back to a near baseline level of 7.0g/dL. Approximately a year later (after protocol amendment allowed for re-treatment), he was retreated and his Hb again increased to 8.2 g/dL at week 8, peaking at 8.8 g/dL. In two patients with RARS (the responder and another patient), it was noted that the erythrocyte protoporphyrin level was initially elevated and rose even higher at week 8. Similarly, erythrocyte porphobilinogen deaminase (PBGD) and uroporphyrinogen decarboxylase (UROD) activities increased with treatment, especially in the one patient who responded. In that patient, these activities decreased again after treatment ended. The reticulocyte count increased from 0.0294 to 0.0411 × 10 6/mcL only in this patient. There was no correlation observed between response to panhematin and HbF levels. Treatment was well tolerated in all patients and no major toxicities were observed. Conclusions In this small study of hemin treatment of patients with low to Int-1 risk MDS, one patient responded with increases in hemoglobin and in reticulocytes. The increases in reticulocytes and in erythrocyte PBGD and UROD in the responder may indicate an increase in erythropoeisis resulting in a larger proportion of young erythrocytes in peripheral circulation after treatment. Clearly, such observations need validation in larger studies, which may result in better understanding of MDS disease biology. Disclosures Shammo: ovation pharmaceutical: Research Funding. Off Label Use: the use of Panhematin in MDS.

Identification and characterization of novel uroporphyrinogen decarboxylase gene mutations in a large series of porphyria cutanea tarda patients and relatives

Porphyria cutanea tarda (PCT) arises from decreased hepatic activity of uroporphyrinogen decarboxylase (UROD). Both genetic and environmental factors interplay in the precipitation of clinically overt PCT, but these factors may vary between different geographic areas. Decreased activity of UROD in erythrocytes was used to identify patients with UROD mutations among a group of 130 Spanish PCT patients. Nineteen patients (14.6%) were found to harbor a mutation in the UROD gene. Eight mutations were novel: M1I, 5del10, A22V, D79N, F84I, Q116X, T141I and Y182C. Five others were previously described: F46L, V134Q, R142Q, P150L and E218G. The new missense mutations and P150L were expressed in Escherichia coli. D79N and P150L resulted in proteins that were localized to inclusion bodies. The other mutations produced recombinant proteins that were purified and showed reduced activity (range: 2.3-73.2% of wild type). These single amino acid changes were predicted to produce complex structural alterations and/or reduced stability of the enzyme. Screening of relatives of the probands showed that 37.5% of mutation carriers demonstrated increased urinary porphyrins. This study emphasizes the role of UROD mutations as a strong risk factor for PCT even in areas where environmental factors (hepatitis C virus) have been shown to be highly associated with the disease.

Familial and Sporadic Porphyria Cutanea Tarda: Characterization and Diagnostic Strategies

Porphyria cutanea tarda (PCT) occurs in sporadic (sPCT) and familial (fPCT) forms, which are generally clinically indistinguishable and have traditionally been differentiated by erythrocyte uroporphyrinogen decarboxylase (UROD, EC 4.1.1.37) activity. We used UROD gene sequencing as the reference standard in assessing the diagnostic accuracy of UROD activity, evaluating the mutation spectrum of the UROD gene, determining the frequency and disease attributes of PCT and its subtypes in Norway, and developing diagnostic models that use clinical and laboratory characteristics for differentiating fPCT and sPCT. All consecutive patients with PCT diagnosed within a 6-year period were used for incidence calculations. UROD activity analysis, UROD gene sequencing, analysis of hemochromatosis mutations, and registration of clinical and laboratory data were carried out for 253 patients. Fifty-three percent of the patients had disease-relevant mutations, 74% of which were c.578G>C or c.636+1G>C. The UROD activity at the optimal cutoff had a likelihood ratio (LR) of 9.2 for fPCT, whereas a positive family history had an LR of 19. A logistic regression model indicated that low UROD activity, a high uroporphyrin-heptaporphyrin ratio, a young age at diagnosis, male sex, and low alcohol consumption were predictors of fPCT. The incidence of PCT was 1 in 100 000. Two commonly occurring mutations are responsible for the high frequency of fPCT in Norway. UROD activity has a high diagnostic accuracy for differentiating the 2 PCT types, and a model that takes into account both clinical information and laboratory test results can be used to predict fPCT.

Molecular heterogeneity of familial porphyria cutanea tarda in Spain: characterization of 10 novel mutations in the UROD gene

Porphyria cutanea tarda (PCT) results from decreased hepatic uroporphyrinogen decarboxylase (UROD) activity. In the majority of patients, the disease is sporadic (S-PCT or type I) and the enzyme deficiency is limited to the liver. Familial PCT (F-PCT or type II) is observed in 20-30% of patients in whom mutations on one allele of the UROD gene reduce UROD activity by approximately 50% in all tissues. Another variant of PCT (type III) is characterized by family history of the disease although it is biochemically indistinguishable from S-PCT. To investigate the molecular basis of PCT in Spain and to compare enzymatic and molecular analysis for the identification of patients with F-PCT. Erythrocyte UROD activity measurement and mutation analysis of the UROD gene were carried out in a cohort of 61 unrelated Spanish patients with PCT and 50 control individuals. Furthermore, each novel missense mutation identified was characterized by prokaryotic expression studies. Of these 61 patients, 40 (66%) were classified as having S-PCT, 16 (26%) as having F-PCT and five (8%) as having type III PCT. Discordant results between enzymatic and molecular analysis were observed in two patients with F-PCT. In total, 14 distinct mutations were found, including 10 novel mutations: five missense, one nonsense, three deletions and an insertion. Prokaryotic expression of the novel missense mutations demonstrated that each results in decreased enzyme activity or stability. These results confirm the high degree of molecular heterogeneity of F-PCT in Spain and emphasize the usefulness of molecular genetic analysis to distinguish between F-PCT and S-PCT.

The role of inherited and acquired factors in the development of porphyria cutanea tarda in the Argentinean population

Inherited and environmental factors are implicated in the expression of porphyria cutanea tarda (PCT); the contribution of each factor depends on the population. To provide a review of PCT cases diagnosed in Argentina over 24 years and evaluate the role of different precipitating factors in its pathogenesis. Methods Plasma and urinary porphyrin levels and erythrocyte uroporphyrinogen decarboxylase (URO-D) activity were determined. Potential precipitating factors were identified in each patient. Additional tests for hepatitis C virus (HCV) and hemochromatosis gene mutations were carried out. Several factors (mainly alcohol abuse in men and estrogen ingestion in women), alone or combined were identified in our patients. Prevalence of HCV infection was 35.2%. Inherited URO-D deficiency occurs in 25.0% of cases. H63D was the most common hemochromatosis gene mutation. High incidence of PCT associated with HIV infection was found. PCT is multifactorial. Therefore, knowledge of all risk factors in each patient is important for the management of the disease.

Familial and sporadic porphyria cutanea tarda: clinical, biochemical and genetic features with emphasis on iron status.

The manifestation of porphyria cutanea tarda reflects genetic and environmental factors. Mutations in the uroporphyrinogen decarboxylase gene, located at chromosome 1p34, discriminate familial porphyria cutanea tarda from sporadic cases. Furthermore, mutations in the haemochromatosis gene may be involved in the aetiology. In this study 53 unrelated Danish patients with porphyria cutanea tarda were classified according to uroporphyrinogen decarboxylase and haemochromatosis gene mutations and the genotype related to the clinical and biochemical data. Thirteen patients (25%) had familial porphyria cutanea tarda. The results signify the advantage of DNA diagnostics for identification of familial cases, as anamnestic data are doubtful and erythrocyte uroporphyrinogen decarboxylase activity measurements insufficient for correct classification. Eight patients with porphyria cutanea tarda (15%) were homozygous for the haemochromatosis gene C282Y mutation and 8 patients were heterozygous. Patients homozygous for the haemochromatosis related mutation showed biochemical evidence of excessive iron storage as well as increased urine porphyrin excretion levels. This seems to confirm a relationship between porphyria cutanea tarda and haemochromatosis. No differences were found between patients with sporadic and familial porphyria cutanea tarda regarding age of onset, clinical severity, sex distribution, liver function tests and iron storage parameters. However, daily alcohol intake and use of oestrogens were reported more frequently in the group of sporadic patients. It was found that women were over-represented in our study.

010������Late onset congenital erythropoietic porphyria (G��nther's disease)

Congenital erythropoietic porphyria is a rare autosomal recessive disease due to the deficient activity of uroporphyrinogen III synthase, the fourth enzyme in the porphyrin-heme synthetic pathway. Of the porphyrias, it is the most mutilating type, usually presenting early in life. We present a patient who developed skin fragility of sun-exposed skin and red urine at the age of 72 years. Porphyrin profile showed plasma maximum fluorescence at neutral pH of 617 nm. In plasma, urine and erythrocytes, the predominant porphyrins were uroporphyrin and coproporphyrin. In all specimens, isomer I predominated. Urine δ-aminolevulinic acid and porphobilinogen, and erythrocyte uroporphyrinogen decarboxylase levels were within nomal limits. These finding were consistent with congenital erythropoietic porphyria. Thrombocytopenia and myelodysplasia with bone-marrow sideroblasts were also incidentally discovered. Including our patient, only 12 cases of late onset congenital erythropoietic porphyria have been reported worldwide, with our patient being the oldest. Patients who develop late onset congenital erythropoietic porphyria develop less severe manifestations, possibly due to heterogeneous mutations in the defective enzyme. Of the 12 reported cases, seven had thrombocytopenia, six of which also had myelodysplasia.

Porphyria cutanea tarda: multiplicity of risk factors including HFE mutations, hepatitis C, and inherited uroporphyrinogen decarboxylase deficiency.

The coexistence of factors considered to contribute to development of porphyria cutanea tarda was studied in 39 consecutive patients. Highly prevalent factors were alcohol intake in 79%, smoking in 86%, hepatitis C virus infection in 74%, estrogen use in 73% of 11 females, and at least one mutation in the HFE (hereditary hemochromatosis) gene in 65%. The C282Y mutation was found in 29%, H63D in 47%, and S65C in 0%. HFE genotypes included C282Y/C282Y in 9%, H63D/H63D in 9%, C282Y/H63D in 12%, C282Y/wild type in 9%, and H63D/wild type in 26%. Less prevalent were HIV infection in 15% (or 25% of those tested, N = 24) and erythrocyte uroporphyrinogen decarboxylase deficiency, which distinguishes familial (type 2) from "sporadic" (type 1) porphyria cutanea tarda, in 19%. Multiple contributing factors coexisted in both types 1 and 2, with 92% of all patients having three or more factors. These observations indicate that this porphyria is multifactorial in the individual patient, and therefore is seldom attributable to a single identifiable cause. Profiling for all potentially contributing factors is important for individualizing management.

Erythrocyte uroporphyrinogen decarboxylase activity and therapeutic phlebotomy in porphyria cutanea tarda

On the basis of the uroporphyrinogen decarboxylase ( UD ) activity in the erythrocytes, and the family history of the disease, different types of porphyria cutanea tarda ( PCT ) can be distinguished. In some cases, however, the distinction may involve some uncertainty (overlapping of subgroups). The question arises of whether the current erythrocyte UD activities in the different types of PCT are determined merely genetically. The erythrocyte UD activities in 72 unrelated patients with different forms of PCT (62 with type I PCT and 10 with type II PCT ), in different stages of the disease, were measured in order to test whether the activity exhibits any change during the long period of recovery. In both types the activities were faintly but significantly increased, from 94.9% (in PCT I) or 54.3% (in PCT II) up to 98.4% or 56.1% respectively. In both types the lower activity in the untreated condition can be attributed to a combination of several factors, including oxidative damage to UD , which results in a minor additional inhibition of the genetically determined enzyme activities.

Porphyrin status in aluminum foundry workers exposed to hexachlorobenzene and octachlorostyrene.

The possible interference of hexachlorobenzene and octachlorostyrene (i.e., thermal byproducts from hexachloroethane in aluminum degassing) with porphyrin metabolism was investigated in exposed workers. Urine specimens from 9 male aluminum foundry workers (i.e., smelters) at 6 different companies and from 18 controls-matched for sex, age, residence, and socioeconomic status-were analyzed for total porphyrins and porphyrin isomers. Workers exposed to hexachlorobenzene and octachlorostyrene had a statistically significant increase in urinary total porphyrins, compared with controls (mean +/- standard deviation: 13.63 +/- 11.13 micromol/mol creatinine and 6.24 +/- 3.84 micromol/mol creatinine, respectively; p = .02). The authors attributed the results mainly to differences in excretion of coproporphyrins-notably coproporphyrin III. Erythrocyte uroporphyrinogen decarboxylase activity was similar in both groups. There was a high correlation between levels of hexachlorobenzene and octachlorostyrene, respectively, in plasma and urinary excretion of porphyrins; these findings, however, relied heavily on 1 subject for whom extreme values were obtained. The results indicated that occupational exposure to hexachlorobenzene and octachlorostyrene in aluminum degassing with hexachloroethane may affect porphyrin metabolism in a manner consistent with early secondary coproporphyrinuria-the first recognized step in the development of chronic hepatic porphyria. It was also noted that changes remained detectable some years after exposure ceased.

Purification and properties of uroporphyrinogen decarboxylase from human erythrocytes

Publisher Summary Uroporphyrinogen decarboxylase (UROD) is a cytosolic enzyme of the heme biosynthetic pathway. This chapter discusses the purification and properties of uroporphyrinogen decarboxylase from human erythrocytes. Erythrocytes are, therefore, a convenient source from which homogeneous preparations of UROD can be obtained in relatively good yield. The enzyme has also been purified to homogeneity from chicken erythrocytes, bovine liver, yeast, and Rhodobacter spheroides . All stages of the purification procedure are carried out at 4°. Dithiothreitol (DTT) is added to all buffers immediately before the use to a final concentration of 0.5 m M . Uroporphyrinogen decarboxylase activity is monitored at each stage of the purification procedure by measuring the conversion of pentacarboxylate porphyrinogen III to coproporphyrinogen III or by a modification in which porphyrins are not converted to their methyl esters but separated directly by reversed-phase high-performance liquid chromatography. For some preparations, UROD concentration is measured by electroimmunoassay, using a rabbit polyclonal antiserum to purified human erythrocyte UROD.

Five New Mutations in the Uroporphyrinogen Decarboxylase Gene Identified in Families With Cutaneous Porphyria

We describe five new mutations in the uroporphyrinogen decarboxylase (UROD) gene. All mutations were observed in conjunction with decreased erythrocyte UROD and clinical familial porphyria cutanea tarda (fPCT), (four families) or hepatoerythropoietic porphyria (HEP), (one family). The fPCT mutations included three point mutations that resulted in amino acid substitutions: a lysine to glutamine at amino acid position 253 (exon 7); a glycine to arginine at position 318 (exon 10); an isoleucine to threonine at position 334 (exon 10). The lysine to glutamine at amino acid position 253 was found in conjunction with a single C nucleotide deletion in exon 8 on the same allele of the UROD gene in the same family. This deletion resulted in a shift in the reading frame and the introduction of a premature stop codon 8 amino acids downstream. In the fourth family, a 31-bp deletion (nucleotides 828-858: exon 8) of the coding region, resulted in a frameshift and the introduction of a stop codon 19 amino acids downstream. A point mutation was observed in an individual diagnosed with HEP, resulting in an alanine to glycine change at amino acid position 80 and was present on both alleles. All mutations were confirmed in at least one other family member. The impact of these mutations on the function of the UROD protein was examined using in vitro protein expression and with activity assessed using pentacarboxylic acid porphyrinogen I as a substrate for UROD. Although three mutations reduced UROD activity to < 15% of normal, one resulted in a UROD protein with 50% functional activity and the other had near normal activity. These results indicate that many different genetic lesions of the UROD gene are associated with fPCT.

Dual porphyria of coexisting variegata and cutanea tarda.

While porphyria cutanea tarda and porphyria variegata are independent diseases, we report on seven rare cases with a coincidence of these two different porphyrias in one individuum. The mutual clinical symptom was a cutaneous photosensitivity, which is a major symptom in porphyria cutanea tarda and a facultative one in porphyria variegata. Additionally, five patients had also experienced episodes of acute abdominal pain, which were in three cases accompanied by neurological symptoms, thus offering evidence for an acute hepatic porphyria, such as porphyria variegata. Determination of urinary porphyrin metabolites revealed a porphyria cutanea tarda-like excretion pattern with an elevation of uroporphyrin (mean 1134 nmol/24 h, range 563-4052, normal < or = 30) and heptacarboxyporphyrin (mean 389 nmol/24 h, range 64-830, normal < or = 4). In all patients, however, urinary coproporphyrin was also increased, reaching levels too high for porphyria cutanea tarda but typical for porphyria variegata (mean 1788 nmol/24 h, range 142-4168, normal < or = 120). Fecal porphyrin excretion also resembled the variegate-type with a high concentration especially of protoporphyrin (mean 628 nmol/g dry weight, range 401-1018, normal < or = 151), accompanied by an increase of coproporphyrin (mean 194 nmol/g dry weight, range 75-409, normal < or = 37). The urinary porphyrin precursors 5-aminolaevulinic acid and porphobilinogen were markedly elevated only in one patient, who was in an acute porphyric phase at the time of investigation. The activity of uroporphyrinogen decarboxylase in erythrocytes was considerably decreased in six of our cases (33-64%) and slightly diminished in the other one (83% of normal activity).(ABSTRACT TRUNCATED AT 250 WORDS)

Decreased Uroporphyrinogen Decarboxylase Activity in Patients with End-Stage Renal Disease Undergoing Hemodialysis

Raised plasma uroporphyrin levels were found in all the 14 patients with end-stage renal disease studied, 7 of whom were on continuous ambulatory peritoneal dialysis (CAPD) and 7 on hemodialysis (HD). The elevation observed in the HD group was higher than that noted in the CAPD group; 18-fold in the former and 13-fold in the latter. The difference in uroporphyrin plasma levels between the two dialysis populations might be explained, at least partially, by the reduced activity of uroporphyrinogen decarboxylase (UROD), the enzyme which converts uroporphyrinogen to coproporphyrinogen. A decrease of 48% was noted in the HD group, whereas no change was observed in the CAPD group. A significant negative correlation (r = -0.37, p < 0.01) was found between the concentration of uroporphyrin in plasma and the activity of UROD. In view of the data shown, it is suggested that erythrocyte UROD activity should be interpreted with caution in HD patients suspected of having porphyria cutanea tarda.

Order of uroporphyrinogen III decarboxylation on incubation of porphobilinogen and uroporphyrinogen III with erythrocyte uroporphyrinogen decarboxylase

The isomeric compositions of the heptacarboxylic, hexacarboxylic and pentacarboxylic porphyrinogens formed by incubation of porphobilinogen with human red-cell haemolysates have been analysed and compared with those derived from incubation with chemically prepared uroporphyrinogen III as substrate. The results indicated that when supplied with an excess (3.7 microM) of exogenous uroporphyrinogen III, uroporphyrinogen decarboxylase utilized the substrate at random and a mixture of isomers was produced; whereas with uroporphyrinogen III generated enzymically from porphobilinogen as substrate a clockwise decarboxylation sequence was observed, resulting in the formation of intermediates mainly with the ring-D, rings-AD and rings-ABD acetate groups decarboxylated. Using [14C]uroporphyrinogen III as substrate at low concentrations (0.01-0.5 microM) also led to preferential decarboxylation of the ring-D acetate group. It was concluded that the order of uroporphyrinogen III decarboxylation is substrate-concentration-dependent, and under normal physiological conditions enzymic decarboxylation is most probably orderly and clockwise, starting at the ring-D acetate group.

Porphyria cutanea tarda and peptic ulcer

A high incidence of peptic ulcer was found in a retrospective study of 199 Bulgarians with porphyria cutanea tarda. Ulcers were found in 35 patients (17.59%), while its incidence in Bulgaria varies between 2.52 and 3.7%. The site of the ulcer was duodenal in 29 porphyriacs, gastric in three, both duodenal and gastric in two and pyloric in one. The pattern of localization was similar to that seen in the general population. Peptic ulcers became symptomatic before the appearance of porphyria in 30 cases. Six (17.1%) of the patients had perforations, while the frequency of this complication in the general population was 1.7-8.5%. Two porphyriacs with perforations died of peritonitis. Ulcers were found in 21 (24.4%) of 86 patients with normal activity of erythrocyte uroporphyrinogen decarboxylase, i.e. they had sporadic (acquired) porphyria cutanea tarda. Two (10%) of 20 patients suffering from the familial form of the disease (with low erythrocyte uroporphyrinogen decarboxylase activity) had ulcers. The examination of 105 unselected porphyriacs showed a significantly higher incidence of blood group B in comparison with the general population (23.8% vs. 16.6%). The association between the porphyriacs with ulcers and blood group B (8 of 21 examined persons) and the rare occurrence of group O (only 4 of 21) was unexpected. An association between porphyria and some of the haptoglobin types could not be established in 98 unselected patients (including those with and without ulcer). More studies are needed to substantiate the validity of blood groups and uroporphyrinogen decarboxylase as genetic markers for porphyria cutanea tarda combined with peptic ulcer.(ABSTRACT TRUNCATED AT 250 WORDS)

Is porphyria cutanea tarda a paraneoplastic disorder?

T he term porphyria cutanea tarda (PCZ’) encompasses a group of inherited or acquired metabolic disorders of the heme biosynthetic pathway characterized by deficient activity of the enzyme uroporphyrinogen decarboxylase (URO-D). The resultant excess accumulation and excretion of several polycarboxylated porphyrin by-products of the pathway, most prominently uroporphyrin (B-COOH), heptacarboxylic porphyrin, and isocoproporphyrin (4-COOH), biochemically characterize these disorders. In acquired, or sporadic, PCT (type I) reduced activity of URO-D can be detected in liver tissue.’ In familial PCT (type II), heterozygous inheritance of a gene defect encoding altered URO-D protein results in reduced enzyme activity that can be detected in erythrocytes as well as in liver.2 Heterozygous familial PCT in which erythrocyte URO-D activity is normal (type III) has also been described.3,4 Hepatoerythropoietic porphyria (HEP) is a disorder resulting from inheritance of two mutant genes, each encoding defective URO-D, typically yielding a profoundly reduced residual enzyme activity.5*6 Epidemic forms of PCT resulting from exposure to hepatotoxic polychlorinated aromatic hydrocarbons compounds such as hexachlorobenzene’ and dioxin8 have also been described.