Hepatic Uroporphyrinogen Decarboxylase Research Articles

Porphyria Cutanea Tarda

A 44-year-old man with human immunodeficiency virus infection, untreated hepatitis C virus infection, and active alcohol abuse presented with bilateral blistering on the dorsal hands of 2 months’ duration (Figure 1). The blisters were pruritic and photoexacerbated and resolved spontaneously with scarring. Examination revealed tense bullae limited to the dorsal hands in various stages of healing, including milia and scarring. Biopsy specimens for histopathologic evaluation and direct immunofluorescence revealed pauci-inflammatory subepidermal clefting and homogeneous deposition along the basement membrane and within walls of superficial dermal vessels with multiple conjugates, consistent with porphyria cutanea tarda (PCT; Figure 2). The patient’s baseline ferritin concentration was found to be higher than 800 ng/dL (to convert to pmol/L, multiply by 0.02247). Serum porphyrins demonstrated increased total porphyrins; fractionation showed increased uroporphyrin, confirming PCT.Figure 2A pauci-inflammatory subepidermal blister on histopathologic examination (hematoxylin and eosin, magnification ×200).View Large Image Figure ViewerDownload Hi-res image Download (PPT) PCT, the most common type of porphyria, is caused by inhibition of hepatic uroporphyrinogen decarboxylase (UROD). Pathogenesis involves cutaneous phototoxicity due to deposition of alternative metabolic products from excess hepatic porphyrinogen accumulation. Approximately 20% of cases are associated with familial UROD mutations,1Badenas C. To-Figueras J. Phillips J.D. Warby C.A. Muñoz C. Herrero C. Identification and characterization of novel uroporphyrinogen decarboxylase gene mutations in a large series of porphyria cutanea tarda patients and relatives.Clin Genet. 2009; 75: 346-353Crossref PubMed Scopus (28) Google Scholar,2Singal A.K. Porphyria cutanea tarda: recent update.Mol Genet Metab. 2019; 128: 271-281Crossref PubMed Scopus (17) Google Scholar whereas 80% of patients present with acquired PCT with absence of UROD mutations. These patients often have liver damage, frequently from alcohol, hepatitis C, human immunodeficiency virus infection, or hemochromatosis.2Singal A.K. Porphyria cutanea tarda: recent update.Mol Genet Metab. 2019; 128: 271-281Crossref PubMed Scopus (17) Google Scholar, 3Jalil S. Grady J.J. Lee C. Anderson K.E. Associations among behavior-related susceptibility factors in porphyria cutanea tarda.Clin Gastroenterol Hepatol. 2010; 8 (302.e1): 297-302Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 4Gisbert J.P. Garcia-Buey L. Pajares J.M. Moreno-Otero R. Prevalence of hepatitis C virus infection in porphyria cutanea tarda: systematic review and meta-analysis.J Hepatol. 2003; 39: 620-627Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 5Ellervik C. Birgens H. Tybjærg-Hansen A. Nordestgaard B.G. Hemochromatosis genotypes and risk of 31 disease endpoints: meta-analyses including 66,000 cases and 226,000 controls.Hepatology. 2007; 46: 1071-1080Crossref PubMed Scopus (113) Google Scholar Typical presenting features include bullae and dyspigmentation of sun-exposed areas. First-line treatment is therapeutic phlebotomy of 450 mL every 2 weeks until ferritin concentration is less than 20 to 25 ng/dL.2Singal A.K. Porphyria cutanea tarda: recent update.Mol Genet Metab. 2019; 128: 271-281Crossref PubMed Scopus (17) Google Scholar Additional management recommendations include broad-spectrum sun protection, alcohol cessation, and hepatitis C treatment. Hydroxychloroquine can be used when phlebotomy is contraindicated.2Singal A.K. Porphyria cutanea tarda: recent update.Mol Genet Metab. 2019; 128: 271-281Crossref PubMed Scopus (17) Google Scholar Although PCT is readily treated and nonfatal, relapses may follow successful treatment.2Singal A.K. Porphyria cutanea tarda: recent update.Mol Genet Metab. 2019; 128: 271-281Crossref PubMed Scopus (17) Google Scholar Thank you to Dr Scott Tuttle for his contributions to this report.

A first report of porphyria cutanea tarda successfully treated with glycyrrhizin.

Porphyria cutanea tarda (PCT) is a condition that affects liver and skin by reduction of hepatic uroporphyrinogen decarboxylase activity. It is characterized by blistering lesions, erosions and crusts on sun-exposed areas. We report a 51-year-old male presenting with recurrent episodes of bullae, erosions, and crust on his neck and dorsum of the hands for 3 months. Aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, lactate dehydrogenase levels, as well as total plasma porphyrin and urinary uroporphyrin levels were elevated. Based on the clinical manifestations, the history and laboratory findings, a diagnosis of PCT was made. The cutaneous and biochemical abnormalities of the patient improved with therapy of glycyrrhizin.

Porphyria cutanea tarda and hepatoerythropoietic porphyria: Identification of 19 novel uroporphyrinogen III decarboxylase mutations

Porphyria Cutanea Tarda (PCT) is a cutaneous porphyria that results from the hepatic inhibition of the heme biosynthetic enzyme uroporphyrinogen decarboxylase (UROD), and can occur either in the absence or presence of an inherited heterozygous UROD mutation (PCT subtypes 1 and 2, respectively). A heterozygous UROD mutation causes half-normal levels of UROD activity systemically, which is a susceptibility factor but is not sufficient alone to cause type 2 PCT. In both Types 1 and 2 PCT, the cutaneous manifestations are precipitated by additional factors that lead to generation of an inhibitor that more profoundly reduces hepatic UROD activity. PCT is an iron-related disorder, and many of its known susceptibility factors, which include infections (e.g. hepatitis C virus, HIV), high alcohol consumption, smoking, estrogens, and genetic traits (e.g. hemochromatosis mutations) can increase hepatic iron accumulation. Hepatoerythropoietic Porphyria (HEP) is a rare autosomal recessive disease that results from homozygosity or compound heterozygosity for UROD mutations and often causes infantile or childhood onset of both erythropoietic and cutaneous manifestations.During the 11-year period from 01/01/2007 through 12/31/2017, the Mount Sinai Porphyrias Diagnostic Laboratory provided molecular diagnostic testing for 387 unrelated patients with PCT and four unrelated patients with HEP. Of the 387 unrelated individuals tested for Type 2 PCT, 79 (20%) were heterozygous for UROD mutations. Among 26 family members of mutation-positive PCT patients, eight (31%) had the respective family mutation. Additionally, of the four unrelated HEP patients referred for UROD mutation analyses, all had homozygosity or compound heterozygosity for UROD mutations, and all eight asymptomatic family members were heterozygotes for UROD mutations. Of the UROD mutations identified, 19 were novel, including nine missense, two nonsense, one consensus splice-site, and seven insertions and deletions. These results expand the molecular heterogeneity of PCT and HEP by adding a total of 19 novel UROD mutations. Moreover, the results document the usefulness of molecular testing to confirm a genetic susceptibility trait in Type 2 PCT, confirm a diagnosis in HEP, and identify heterozygous family members.

Porphyria Cutanea Tarda is a Biochemical and Not Histological Diagnosis

Porphyria cutanea tarda is the most common porphyria, due to acquired deficiency of hepatic uroporphyrinogen decarboxylase (UROD) enzyme, presenting with photosensitivity and blistering skin lesions. Factors making an individual susceptible to PCT include alcohol consumption, smoking, hepatitis C, HIV, estrogen use, and UROD mutation. Diagnosis of PCT is made with typical porphyrin profile of elevated plasma porphyrins (maximum fluorescence at 620 nm) and urine porphyrins (predominant hexa-, penta-, hepta- carboxyporphyrins). Skin biopsy may show features consistent with PCT, however by themselves may not be diagnostic. PCT is readily treatable with either phlebotomy schedule or low dose hydroxychloroquine regimen. We present two cases referred to our centre, all of them diagnosed with PCT based on a skin biopsy. An 81 year old man presented with blistering skin lesions and photosensitivity on dorsal hands and scalp. Skin biopsy from dorsal hand performed by his dermatologist showed dilated blood vessels in dermis with collagen deposition, consistent with PCT. He had no susceptibility factors for PCT. The porphyrin profile was normal with plasma porphyrins of 0.1 mcg/dl (normal <0.9) and urine porphyrins of 35 nmol/L (normal <300). A 28 year old female was diagnosed with PCT based on skin biopsy. She had 4 year history of photosensitivity and plaque like lesions on dorsal hands, which were progressive in spite of being treated with hydroxychloroquine. Except history of smoking, she had no other susceptibility factors of PCT. Biochemical porphyrin profile was normal. She is being treated for pseudoporphyria secondary to doxycycline and is doing well. Conclusions: Biochemical porphyrin profile and not skin histology is the confirmatory test for the diagnosis of PCT

Is Hydroxychloroquine As Effective As Phlebotomy for Porphyria Cutanea Tarda

Porphyria cutanea tarda (PCT) is an iron-related disorder that results from reduced activity of hepatic uroporphyrinogen decarboxylase. Treatment

Low-Dose Hydroxychloroquine Is as Effective as Phlebotomy in Treatment of Patients With Porphyria Cutanea Tarda

Porphyria cutanea tarda (PCT) is an iron-related disorder caused by reduced activity of hepatic uroporphyrinogen decarboxylase; it can be treated by phlebotomy or low doses of hydroxychloroquine. We performed a prospective pilot study to compare the efficacy and safety of these therapies. We analyzed data from 48 consecutive patients with well-documented PCT to characterize susceptibility factors; patients were treated with phlebotomy (450 mL, every 2 weeks until they had serum ferritin levels of 20 ng/mL) or low-dose hydroxychloroquine (100 mg orally, twice weekly, until at least 1 month after they had normal plasma levels of porphyrin). We compared the time required to achieve a normal plasma porphyrin concentration (remission, the primary outcome) for 17 patients treated with phlebotomy and 13 treated with hydroxychloroquine. The time to remission was a median 6.9 months for patients who received phlebotomy and 6.1 months for patients treated with hydroxychloroquine treatment (6.7 and 6.5 mo for randomized patients), a difference that was not significant (log-rank, P = .06 and P = .95, respectively). The sample size was insufficient to confirm noninferiority of hydroxychloroquine treatment (hazard ratio, 2.19; 95% confidence interval, 0.95-5.06) for all patients. Patients who received hydroxychloroquine had substantially better compliance. There were no significant side effects of either treatment. Hydroxychloroquine, 100 mg twice weekly, is as effective and safe as phlebotomy in patients with PCT, although noninferiority was not established. Given these results, higher-dose regimens of hydroxychloroquine, which have more side effects, do not seem justified. Compliance was better and projected costs were lower for hydroxychloroquine than phlebotomy treatment. Long-term studies are needed to compare durability of response. ClinicalTrials.gov number, NCT01573754.

CYP1A2*1F and GSTM1 Alleles Are Associated with Susceptibility to Porphyria Cutanea Tarda

Porphyria cutanea tarda (PCT) is a cutaneous porphyria with sporadic (type 1) and familial (type 2) subtypes, both resulting from decreased hepatic uroporphyrinogen decarboxylase (UROD) activity. Environmental and genetic factors are involved in the development of PCT, and genetic variants in the cytochrome P450 (CYP ) genes, CYP1A1 and CYP1A2, have been implicated. We investigated the association between PCT and variants in CYP1A1, CYP1A2 and CYP2E1, and the glutathione-S-transferase (GST ) genes, GSTM1 and GSTT1. PCT diagnosis was based on urinary or plasma porphyrin profiles. Patients were classified as type 1 or 2 PCT based on UROD mutation analysis. The CYP1A2*1F promoter A allele frequency was significantly higher (P < 0.022) and the A/A genotype frequency marginally higher in PCT patients overall (P < 0.057), with the A/A genotype significantly more common in type 1 PCT (P < 0.043). The presence of the wild-type GSTM1 allele also was associated significantly with PCT (P < 0.019). Neither hemochromatosis (HFE) mutations, tobacco smoking, hepatitis C and HIV infection, ethanol consumption, nor estrogen use were associated with these allelic variants. Age at onset was significantly lower in type 2 PCT patients (P < 0.001), as observed previously. Thus, positive associations between PCT and the CYP1A2*1F promoter A allele and A/A genotype and the wild-type GSTM1 allele indicates that these functional hepatic biotransformation enzymes are risk factors for the development of this disease.

Smoking but not homozygosity for CYP1A2 g‐163A allelic variant leads to earlier disease onset in patients with sporadic porphyria cutanea tarda

Porphyria cutanea tarda (PCT) results from decreased activity of hepatic uroporphyrinogen decarboxylase (UROD). Both sporadic and familial forms are characterised by typical cutaneous lesions triggered by genetic/environmental factors. Studies in rodents showed that cytochrome P4501A2 (CYP1A2) plays a central role in the synthesis of a competitive inhibitor of hepatic UROD, but there is little evidence in humans. The impact of smoking and CYP1A2 g-163C > A allelic variant upon first appearance of clinical signs was investigated in 102 patients (80 sporadic-PCT) and 150 healthy donors from Spain. We found an increase in the frequency of CYP1A2 g-163A allele in patients with PCT when compared with controls, although the more inducible A/A genotype had no effect on the onset age. In sporadic-PCT, smoking leads to earlier onset of clinically overt disease in moderate-to-heavy smokers (>or=10 cigarettes/day). In conclusion, this study provides evidence that smoking hastens the onset of cutaneous symptoms in sporadic-PCT patients.

Complex Gene−Chemical Interactions: Hepatic Uroporphyria As a Paradigm

Many toxicological disorders, in common with numerous human diseases, are probably the consequence of multigene interactions with a variety of chemical and physiological factors. The importance of genetic factors may not be obvious initially from association studies because of their complexity and variable penetrance. The human disease, porphyria cutanea tarda (PCT), is a skin disease caused by the photosensitizing action of porphyrins arising secondary to the decreased activity of an enzyme of heme biosynthesis, uroporphyrinogen decarboxylase (UROD), in the liver. It is triggered by idiosyncratic hepatic interaction between genetic factors and chemicals such as alcohol, estrogenic drugs, and polyhalogenated aromatics. PCT and its animal models are known collectively as the hepatic uroporphyrias. There is strong evidence for the participation of iron in the pathogenesis of these conditions. Mouse models have been used to explore the relative importance of a variety of agents such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), alcohol, and iron in the development of uroporphyria and to elucidate the mechanism of the depression of hepatic UROD activity. Mutations of the UROD and hemochromatosis (HFE) genes are genetic factors in some PCT patients which can be mimicked in mice heterozygous for the Hfe and Urod null genes. Association studies of uroporphyria induced by TCDD or hexachlorobenzene with DNA markers in mouse intercrosses have shown the participation of other, unknown, genetic factors in addition to the strong influence of the Ahr gene. The pathogenesis of hepatic uroporphyrias exemplifies the complexity of the interactions between chemical and genetic factors that can contribute to the hepatotoxicity of chemicals.

A Dialysis Case Presentation and Discussion Edited by Roger A. Rodby: Bullous Skin Lesions in a Patient Undergoing Chronic Hemodialysis

Porphyria cutanea tarda (PCT) is a vesiculobullous skin disorder characterized by a defect in heme biosynthesis. Reduced activity of the hepatic enzyme uroporphyrinogen decarboxylase (URO-D) results in accumulation of photosensitive porphyrins; this ultimately leads to the skin fragility and blistering that is characteristic of this disease. The majority of cases of PCT are associated with acquired deficiencies of the enzyme URO-D, secondary to hepatic injury precipitated by medications or infections. Less commonly, PCT has been documented in patients with end-stage renal disease. The pathogenesis of PCT in long-term hemodialysis (HD) has been attributed to many factors, but the following mechanisms have been implicated: (i) decreased hepatic URO-D activity due to suppressive effects of iron and other hepatotoxins and (ii) poor porphyrin clearance by renal replacement therapies. We report a case of PCT that developed in a patient on maintenance HD for 4 years. He had a history of hepatitis C and evidence of iron overload. However, as the patient was anemic, therapeutic phlebotomy was problematic and therefore erythrocyte-stimulating agents were maximized to mobilize iron stores and allow phlebotomy. With this treatment, the patient's skin lesions improved in conjunction with decreasing ferritin levels.

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.

Porphyria cutanea tarda

A 68-year-old man with relapsed follicular lymphoma developed redness, fragility, recurrent painful blistering and ulcerating lesions on sun-exposed areas of the skin, especially on the back of the hands (Figures). The appearance of the lesions led us to suspect porphyria cutanea tarda (PCT) which was confirmed by elevated urinary excretion of uroporphyrin, hepta-, hexaand pentacarboxylic porphyrins, as well as coproporphyrin. PCT is the most common type of porphyric disorder, triggered by hepatic uroporphyrinogen decarboxylase deficiency. Clinical manifestations include hypertrichosis and a photosensitive bullous dermatosis, predominantly on the hands, forearms, back of the neck and face. PCT may be caused by hepatic siderosis, alcohol abuse, hepatitis C virus infection or oestrogen therapy. During the course of his disease the patient had received several blood transfusions and his serum ferritin concentration was increased (serum ferritin: 2410 lg/l, normal range: 20–290 lg/l). The patient was treated with chloroquine to facilitate urinary elimination of porphyrins and the underlying lymphoma was treated with chemotherapy. Six months later the skin lesions had completely resolved in parallel with lymphoma remission and markedly decreased ferritin levels (serum ferritin: 1130 lg/l).

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.

Hemochromatosis gene sequence deviations in German patients with porphyria cutanea tarda

Patients with porphyria cutanea tarda (PCT) reveal a susceptibility to reversible inactivation of hepatic uroporphyrinogen decarboxylase, which might be triggered by alcohol, hepatitis C virus infection, and iron overload. Inherited factors that may predispose to clinically overt PCT also include sequence deviations in the HFE gene that is mutated in classical hemochromatosis. Here, we studied the prevalence of both common and rare hemochromatosis gene variations in 51 PCT patients and 54 healthy controls of German origin. The frequency of the common HFE gene mutation C282Y was 15.7 % in PCT patients and 2.8 % in healthy control individuals (P < 0.001). By contrast, the frequencies of the common H63D mutation did not differ, and the allele frequencies of the less frequently observed sequence deviations as substitution S65C in the HFE gene and mutation Y250X in the TFR2 gene underlying hemochromatosis type 3 (HFE3) were < 0.02 both in PCT patients and controls. Our results comprise the first molecular studies of both common and rare hemochromatosis gene variants in German PCT patients, indicating a significant role of the C282Y mutation in the pathogenesis of PCT.

Uroporphyria caused by ethanol in Hfe(−/−) mice as a model for porphyria cutanea tarda

Two major risk factors for the development of porphyria cutanea tarda (PCT) are alcohol consumption and homozygosity for the C282Y mutation in the hereditary hemochromatosis gene ( HFE). To develop an animal model, Hfe knockout mice were treated continuously with 10% ethanol in drinking water. By 4 months, uroporphyrin (URO) was detected in the urine. At 6 to 7 months, hepatic URO was increased and hepatic uroporphyrinogen decarboxylase (UROD) activity was decreased. Untreated Hfe(−/−) mice or wild-type mice treated with or without ethanol did not show any of these biochemical changes. Treatment with ethanol increased hepatic nonheme iron and hepatic 5-aminolevulinate synthase activity in Hfe(−/−) but not wild-type mice. The increases in nonheme iron in Hfe(−/−) mice were associated with diffuse increases in iron staining of parenchymal cells but without evidence of significant liver injury. In conclusion, the results of this study suggest that the uroporphyrinogenic effect of ethanol is mediated by its effects on hepatic iron metabolism. Ethanol-treated Hfe(−/−) mice seem to be an excellent model for studies of alcohol-mediated PCT. (H EPATOLOGY 2003;37:351-358.)

Uroporphyria in Hfe mutant mice given 5-aminolevulinate: A new model of Fe-mediated porphyria cutanea tarda

Porphyria cutanea tarda (PCT), a liver disease with skin lesions caused by excess liver production of uroporphyrin (URO), is associated with consumption of alcoholic beverages or estrogens, and moderate iron overload. Recently, it has been shown that many PCT patients carry mutations in the HFE gene, which is responsible for hereditary hemochromatosis. Mice homozygous for either the null mutation in the Hfe gene or the C282Y missense mutation rapidly accumulate hepatic parenchymal iron similar to patients with hemochromatosis. Here we investigated whether disruption of the murine Hfe gene would result in hepatic uroporphyria. Mice homozygous for the Hfe-null mutation accumulated high levels of hepatic URO when fed 5-aminolevulinate (ALA). Hfe (+/-) mice also accumulated hepatic URO when fed ALA, but at a much slower rate. The amount of accumulated URO in the null mutant mice was similar to that in wild-type mice treated with iron carbonyl in the diet, or injected with iron dextran. Iron in both wild-type and Hfe (+/-) mice was mostly in Kupffer cells. In contrast, Hfe (-/-) mice had considerable parenchymal iron deposition as well, in a pattern similar to that observed in wild-type mice treated with iron carbonyl. URO accumulation was accompanied by 84% and 33% decreases in hepatic uroporphyrinogen decarboxylase activities in Hfe (-/-) and Hfe (+/-) mice, respectively. No increases in CYP1A2 or other cytochrome P450s were detected in the Hfe-null mutant mice. We conclude that this experimental model of uroporphyria is a valid model for further investigations into the mechanism of PCT.

Hepatic porphyrin concentration and uroporphyrinogen decarboxylase activity in hepatitis C virus infection

Previous studies have shown a high prevalence of hepatitis C virus (HCV) infection in patients with porphyria cutanea tarda (PCT). The aim of this study was to assess hepatic porphyrin concentrations (HPC) and hepatic uroporphyrinogen decarboxylase (UROD) activity in HCV-infected patients free of PCT. Thirty-two HCV-infected patients (20 M, 12 F, mean age 51 years) and seven control patients (4 M, 3 F, mean age 59 years) free of liver disease, were studied. Knodell's score was determined on liver biopsy by two independent anatomopathologists. Measurement of HPC and hepatic UROD activity levels were carried out on liver biopsy. Relative to controls, HCV-infected patients had high HPC levels (mean +/- SD: 47 +/- 20 vs. 17 +/- 6 pmol/mg protein, P < 0.001) and low hepatic UROD activity levels (514 +/- 95 vs. 619 +/- 125 pmol Copro/h/mg protein, P < 0.05). HPC was not correlated with hepatic UROD activity and the increase was due to coproporphyrin accumulation. No correlation was observed between HPC or hepatic UROD activity values and HCV-RNA concentrations, Knodell's score, hepatic fibrosis, periportal necrosis, periportal inflammation or hepatic iron content in HCV-infected patients. Hepatocellular necrosis was significantly correlated with HPC value (P < 0.005). Hence, in HCV-infected patients, HPC is significantly increased and hepatic UROD activity is very slightly decreased as compared to controls. HPC values and UROD activity are not correlated with HCV-RNA concentrations, hepatic iron content and hepatic fibrosis. The small increase in HPC values in hepatitis C infection is linked with hepatic injury and not with a direct effect on hepatic UROD enzyme.

Hepatic porphyrin concentration and uroporphyrinogen decarboxylase activity in hepatitis C virus infection

Previous studies have shown a high prevalence of hepatitis C virus (HCV) infection in patients with porphyria cutanea tarda (PCT). The aim of this study was to assess hepatic porphyrin concentrations (HPC) and hepatic uroporphyrinogen decarboxylase (UROD) activity in HCV‐infected patients free of PCT. Thirty‐two HCV‐infected patients (20 M, 12 F, mean age 51 years) and seven control patients (4 M, 3 F, mean age 59 years) free of liver disease, were studied. Knodell’s score was determined on liver biopsy by two independent anatomopathologists. Measurement of HPC and hepatic UROD activity levels were carried out on liver biopsy. Relative to controls, HCV‐infected patients had high HPC levels (mean ± SD: 47 ± 20 vs. 17 ± 6 pmol/mg protein, P &lt; 0.001) and low hepatic UROD activity levels (514 ± 95 vs. 619 ± 125 pmol Copro/h/mg protein, P &lt; 0.05). HPC was not correlated with hepatic UROD activity and the increase was due to coproporphyrin accumulation. No correlation was observed between HPC or hepatic UROD activity values and HCV‐RNA concentrations, Knodell’s score, hepatic fibrosis, periportal necrosis, periportal inflammation or hepatic iron content in HCV‐infected patients. Hepatocellular necrosis was significantly correlated with HPC value (P &lt; 0.005). Hence, in HCV‐infected patients, HPC is significantly increased and hepatic UROD activity is very slightly decreased as compared to controls. HPC values and UROD activity are not correlated with HCV‐RNA concentrations, hepatic iron content and hepatic fibrosis. The small increase in HPC values in hepatitis C infection is linked with hepatic injury and not with a direct effect on hepatic UROD enzyme.

A mouse model of familial porphyria cutanea tarda

Approximately one-third of patients with porphyria cutanea tarda (PCT), the most common porphyria in humans, inherit a single mutant allele of the uroporphyrinogen decarboxylase (URO-D) gene. PCT associated with URO-D mutations is designated familial PCT. The phenotype is characterized by a photosensitive dermatosis with hepatic accumulation and urinary excretion of uroporphyrin and hepta-carboxylic porphyrins. Most heterozygotes for URO-D mutations do not express a porphyric phenotype unless hepatic siderosis is present. Hemochromatosis gene (HFE) mutations are frequently found when the phenotype is expressed. We used homologous recombination to disrupt one allele of murine URO-D. URO-D(+/-) mice had half-wild type (wt) URO-D protein and enzymatic activity in all tissues but did not accumulate hepatic porphyrins, indicating that half-normal URO-D activity is not rate limiting. When URO-D(+/-) mice were injected with iron-dextran and given drinking water containing delta-aminolevulinic acid for 21 days, hepatic porphyrins accumulated, and hepatic URO-D activity was reduced to 20% of wt. We bred mice homozygous for an HFE gene disruption (HFE(-/-)) to URO-D(+/-) mice, generating mice with the URO-D(+/-)/HFE(-/-) genotype. These animals developed a porphyric phenotype by 14 weeks of age without ALA supplementation, and URO-D activity was reduced to 14% of wt. These data indicate that iron overload alone is sufficient to reduce URO-D activity to rate-limiting levels in URO-D(+/-) mice. The URO-D(+/-) mouse serves as an excellent model of familial PCT and affords the opportunity to define the mechanism by which iron influences URO-D activity.

Porphyrins, porphyrin metabolism, porphyrias. III. Diagnosis, care and monitoring in porphyria cutanea tarda - suggestions for a handling programme

Deficiency of the fifth enzyme in haem synthesis, uroporphyrinogen decarboxylase (UPGD), may give rise to accumulation and excretion of poly-carboxylated porphyrins, as well as to clinical manifestations in the form of a phototoxic skin reaction and liver engagement leading to cirrhosis and hepatocellular cancer. The cutaneous reaction, presenting as skin fragility and blisters on areas exposed to sun-porphyria cutanea tarda (PCT)-develops only in individuals with a remaining hepatic UPGD activity less than 20% of normal. Experimental results and clinical observation give evidence that PCT is a multifactorial disease. In some individuals a 50% decrease in UPGD activity is a consequence of inheritance of an allele with a mutation in the gene programming for the enzyme, but in these gene carriers, as well as in the other patients with overt PCT, the activity of the hepatic enzyme is reduced below the critical level by the action of specific inhibitors. In the generation of the enzyme inhibitors, iron plays a central role by promoting the formation of reactive oxygen species, a process where a specific class of cytochrome enzymes; cytochrome P450 1A (CYP4501A), participates. The varying individual susceptibility to development of the disease can be discussed in terms of differences in a spectrum of factors that affect the availability of the free form of this element in the liver, or its pathogenic action. In the article the roles of chronic viral infection, alcohol abuse and exposition to polyhalogenated cyclic hydrocarbons are considered in the light of effects on the availability of iron in the liver. Some genetic prerequisites for susceptibility to PCT-inducing agents are included in a tentative model for the disease, i.e. mutations in the UPGD gene and in the HFE gene affected in haemochromatosis, as well as genetically steered inducibilities of the genes programming for CYP4501A and the rate-limiting enzyme in haem synthesis, 5-aminolevulinate synthase. With the pathogenic model as a basis the different therapeutic strategies that can be applied are discussed, and suggestions for a handling programme for the patient presenting with PCT put forward.