Porphyrin Excretion Research Articles

Current status of photodynamic technology for urothelial cancer.

5‐Aminolevulinic acid is a new‐generation photosensitizer with high tumor specificity. It has been used successfully in the diagnosis, treatment, and screening of urological cancers including bladder cancer; specifically, it has been used in photodynamic diagnosis to detect tumors by illuminating the lesion with a specific wavelength of light to produce fluorescence in the lesion after administration of 5‐aminolevulinic acid, in photodynamic therapy, which induces tumor cell death via production of cytotoxic reactive oxygen species, and in photodynamic screening, in which porphyrin excretion in the blood and urine is used as a tumor biomarker after administration of 5‐aminolevulinic acid. In addition to these applications in urological cancers, 5‐aminolevulinic acid–based photodynamic technology is expected to be used as a novel strategy for a large number of cancer types because it is based on a property of cancer cells known as the Warburg effect, which is a basic biological property that is common across all cancers.

Direct composite resin fillings versus amalgam fillings for permanent posterior teeth.

Direct composite resin fillings versus amalgam fillings for permanent posterior teeth.

Acute intermittent porphyria: familial disease cases (clinical observation)

Acute intermittent porphyria is a rare autosomal dominant disorder characterized by excessive accumulation and excretion of porphyrins and their precursors, repeated attacks of neurological and mental symptoms. Due to the rarity of this pathology and the atypical course in the onset, certain difficulties often arise during the initial diagnosis. The main pathogenetic drug is gemin (Normosang), which allows obtaining a stable clinical response and preventing the development of severe changes in the nervous system. This article presents an analysis of a clinical case of acute intermittent porphyria among blood relatives and discusses the effectiveness of targeted therapy.

Models for human porphyrias: Have animals in the wild been overlooked?: Some birds and mammals accumulate significant amounts of porphyrins in the body without showing the injurious symptoms observed in human porphyrias.

Humans accumulate porphyrins in the body mostly during the course of porphyrias, diseases caused by defects in the enzymes of the heme biosynthesis pathway and that produce acute attacks, skin lesions and liver cancer. In contrast, some wild mammals and birds are adapted to accumulate porphyrins without injurious consequences. Here we propose viewing such physiological adaptations as potential solutions to human porphyrias, and suggest certain wild animals as models. Given the enzymatic activity and/or the patterns of porphyrin excretion and accumulation, the fox squirrel, the great bustard and the Eurasian eagle owl may constitute overlooked models for different porphyrias. The Harderian gland of rodents, where large amounts of porphyrins are synthesized, presents an underexplored potential for understanding the carcinogenic/toxic effect of porphyrin accumulation. Investigating how these animals avoid porphyrin pathogenicity may complement the use of laboratory models for porphyrias and provide new insights into the treatment of these disorders.

Effects of early and recent mercury and lead exposure on the neurodevelopment of children with elevated mercury and/or developmental delays during lactation: A follow-up study.

This follow-up study of 82 children investigated the potential impact of early and recent exposure to mercury and lead on their neurodevelopmental performance at 5-8 years of age (2017-2018). Early exposure of these children to mercury, methylmercury, and lead was assessed during lactation at 3-12 months old, as well as their mother's exposure using measurements from a cross-sectional study (2011-2013). Only infants who failed to pass the neurodevelopment screening tools and/or had elevated mercury were included in this study. Urine and hair were sampled during the follow-up study to assess the children's recent exposure to mercury, methylmercury, and lead. Their cognitive performance and visual-motor integration were also measured using the Test of Non-Verbal Intelligence (TONI) and the Beery-Visual-Motor Integration (Beery VMI), respectively. The association between alterations in urinary porphyrins excretion and exposure to metals was analyzed and their influence on the children's neurodevelopment was explored. Linear regression models revealed a significant negative association between the infants' mercury exposure during lactation and the TONI Quotient (β=-0.298, 95%CI=-4.677, -0.414) and Beery VMI Age Equivalent scores at age 5-8 (β=-0.437, 95%CI=-6.383, -1.844). The mothers' blood methylmercury was inversely and significantly associated with their children's TONI Quotient (β=-0.231, 95%CI=-8.184, -0.331). In contrast, the children's Beery VMI Age Equivalent scores were positively and significantly associated with the hair methylmercury of the mothers (β=0.214, 95%CI=0.088, 3.899) and their infants (β=0.256, 95%CI=0.396, 4.488). These relationships suggest the presence of negative confounding that we did not take into account. Unlike mercury, there was some evidence that lead in breast milk had an inverse relationship with the children's visual-motor coordination skills. Our study did not show a clear association between children's recent exposure to metals and neurodevelopment. However, a significant inverse association was observed between the TONI Quotient and the interaction of hair methylmercury×∑porphyrins (ß=-0.224, 95%CI=-0.86, -0.049), implying that porphyrins are a sensitive measure of low body-mercury burden. Although lead induced higher ∑porphyrins excretion in urine (β=0.347, 95%CI=0.107, 0.525), their interaction did not influence children's neurodevelopmental scores. The interactions between metals and porphyrins might provide insights into their potential contributory role in the pathogenesis associated with neurological disorders or other diseases. Despite the small sample size of the present study, its findings about the association between toxic metal exposure and the high risk of poor neurodevelopmental performance are worrying, particularly at an early age, and additional research is needed using larger sample sizes.

2306 Hydroxychloroquine-Induced Acute Liver Injury

INTRODUCTION: Hydroxychloroquine is a commonly prescribed medication with antimalarial and anti-inflammatory properties. A very rarely reported side effect of this medication is drug induced acute liver injury. CASE DESCRIPTION/METHODS: A 62-year old female with a history of rheumatoid arthritis, on long term prednisone, presented to the emergency department with two day history of arthralgias, generalized weakness, and fever of 104 F. She had no history of alcohol use or any risk factors for viral hepatitis. Clinical exam was unremarkable. Laboratory data showed Aspartate aminotransferase (AST) or 798 IU/L and Alanine aminotransferase (ALT) of 1254 IU/L, with normal serum bilirubin, alkaline phosphatase and coagulation profile. Serologic tests for viral etiology including Hepatitis A, Hepatitis B, Hepatitis C, Cytomegalovirus, Epstein-Barr virus, and Human immunodeficiency virus were non-reactive. Anti-nuclear antibody, smooth muscle antibody, and anti-double-stranded DNA antibody were unremarkable. Her urine and blood cultures showed no growth. Abdominal ultrasound showed an echogenic liver consistent with hepatic steatosis and no evidence of biliary obstruction. Chest X-ray was normal. Upon review of her medications, patient had started hydroxychloroquine two weeks prior to admission. The medication was discontinued upon admission, after which she continued to improve. At follow up ten days later, she remained asymptomatic and her liver function tests continued to improve with AST of 46 and ALT of 161. DISCUSSION: Acute transaminitis due to hydroxychloroquine is rare. Only four reported cases have been noted per literature review. Mechanism of injury to hepatic cells is unknown however the drug is metabolized in the liver and may alter the metabolism of other drugs. Porphyria cutanea tarda is a disease that may be treated with low doses of hydroxychloroquine. It is known that higher doses of hydroxychloroquine usually greater than 100 mg twice a week can trigger acute liver injury in patients with history of Porphyria cutana tarda. These patients present with sudden onset of fever and marked serum enzyme elevations with increased excretion of porphyrins and photosensitivity. The presented patient in the case report did not have underlying Porphyria cutanea tarda.

Abstract 1285A: Erythropoietin can cancelchemo-resistances viadown regulation of ABC transporters

Abstract Introduction: Erythropoietin (EPO) is a glycoprotein cytokine which stimulates red blood cell production (erythropoiesis) in the bone marrow. The receptor of it (EPOR) was reported to exist on the cancer cellular membrane: more than 85% cancer cell expresses EPOR. Several reports suggested to play an important role for cancer cellular growth, however, the role of EPOR in cancer cells is not confirmed. The authors have studied the cancer cellular porphyrin accumulation, metabolism and excretion to clear the pathogenetic mechanism which involved the high concentration of porphyrins. The authors found that reactive oxygen species (ROS) accelerate both the cancer cellular porphyrin accumulation and the effect of photodynamic therapy. However, we cannot confirm which substrate is a key of signal transduction. EPO has been known used to be up-regulated at the metabolic acidosis via the stabilization of HIF-1α, a nuclear factor. Since HIF-1α can be stabilized by not only acidosis but also the high concentration of nitric oxide (NO), NO rich cancer cells may involve EPOR. Moreover, the purpose of EPO-EPOR system is likely to survive the hypoxic condition, it may keep intracellular heme/ porphyrins. The authors’ hypothesis is EPO-EPOR system in cancer cells may down-regulate ABCG2 which excretes heme/ porphyrins, and several anti-cancer drugs. Moreover, if so, the excretion of several anti-cancer chemo reagents should be inhibited to involve more effective chemotherapy. Methods: To prove these possibilities, the authors carry out following experiments with gastric and colorectal cancer cells. The existence of EPOR, the amount of ABC transporters (B1, C5, G2) after the recombinant EPO (rEPO) exposure (dose dependency and time dependency) were analyzed by western blotting. Cytotoxicity of anti-cancer drugs with or without rEPO was measured with the Cell Counting Kit-8. Result: (1) EPOR existed in each cell line used in this study. (2) rEPO treatment involved down regulation of ABC transporters (B1, C5, G2) in dose dependently. (3) ABCG2 expression decreased until 24 hours after rEPO treatment. However, its expression re-increased 48 hours after treatment. (4) The 24 hours pretreatment of EPO significantly increased the effect of doxorubicin, paclitaxel, irrinotecan, cisplatin, 5-FU and oxaliplatin even in chemo-resistant cells. Conclusions: rEPO accelerates the effect of anti-cancer drugs via the down regulation of ABC transporters. Citation Format: Hirofumi Matsui, Hiromi Kurokawa. Erythropoietin can cancelchemo-resistances viadown regulation of ABC transporters [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1285A.

Erythropoietin Accelerates a Cancer Specific Porphyrins' Accumulation

Introduction: Erythropoietin (EPO) is a glycoprotein cytokine which stimulates red blood cell production (erythropoiesis) in the bone marrow. The receptor of it (EPOR) was reported to exist on the cancer cellular membrane: more than 85% cancer cell expresses EPOR. Several reports suggested to play an important role for cancer cellular growth, however, the role of EPOR in cancer cells is not confirmed. The authors have studied the cancer cellular porphyrin accumulation, metabolism and excretion to clear the pathogenic mechanism which involved the high concentration of porphyrins. The authors found that reactive oxygen species (ROS) accelerate both the cancer cellular porphyrin accumulation and the effect of photodynamic therapy. However, we cannot confirm which substrate is a key of signal transduction. EPO has been known used to be up-regulated at the metabolic acidosis via the stabilization of HIF-1α, a nuclear factor. Since HIF-1α can be stabilized by not only acidosis but also the high concentration of nitric oxide (NO), NO rich cancer cells may involve EPOR. Moreover, the purpose of EPO-EPOR system is likely to survive the hypoxic condition, it may keep intracellular heme/ porphyrins. The authors’ hypothesis is EPO-EPOR system in cancer cells may down-regulate ABCG2 which excretes heme/ porphyrins, and several anti-cancer drugs. Moreover, if so, the excretion of both porphyrins and several anti-cancer chemo reagents should be inhibited to involve more effective PDT and chemotherapy. Methods: To prove these possibilities, the authors carry out following experiments with gastric and colorectal cancer cells. The existence of EPOR, the amount of ABC transporters (B1, C5, G2) after the recombinant EPO (rEPO) exposure (dose dependency and time dependency) were analyzed by western blotting. Cytotoxicity of both PDT and anti-cancer drugs with or without rEPO was measured with the Cell Counting Kit-8.Result: (1) EPOR existed in each cell line used in this study. (2) rEPO treatment involved down regulation of ABC transporters (B1, C5, G2) in dose dependently. (3) ABCG2 expression decreased until 24 hours after rEPO treatment. However, its expression re-increased 48 hours after treatment. (4) The 24 hours pretreatment of EPO significantly increased the effect of PDT, doxorubicin, paclitaxel, irrinotecan, cisplatin, 5-FU and oxaliplatin even in chemo-resistant cells.Conclusions: rEPO accelerates the effect of PDT and anti-cancer drugs via the down regulation of ABC transporters.

Computational disease model of phenobarbital-induced acute attacks in an acute intermittent porphyria mouse model

IntroductionAcute intermittent porphyria (AIP) is characterized by hepatic over-production of the heme precursors when aminolevulinic acid (ALA)-synthase 1 is induced by endogenous or environmental factors. The aim of this study was to develop a semi-mechanistic computational model to characterize urine accumulation of heme precursors during acute attacks based on experimental pharmacodynamics data and support the development of new therapeutic strategies. MethodsMale AIP mice received recurrent phenobarbital challenge starting on days 1, 9, 16 and 30. 24-h urine excretion of ALA, porphobilinogen (PBG) and porphyrins from challenges D1, D9 and D30 constituted the training data set to build the mechanistic model using the population approach. In a second study, porphyrin and porphyrin precursor excretion from challenge D16 were used as a validation data set. ResultsThe computational model presented the following features: (i) urinary excretion of ALA, PBG and porphyrins was governed by unmeasured circulating heme precursor amounts, (ii) the circulating amounts of ALA and PBG were the precursors of circulating amounts of PBG and porphyrins, respectively, and (iii) the phenobarbital effect linearly increased the synthesis of circulating ALA and PBG levels. The model displayed good parameter precision (coefficient of variation below 32% in all parameters), and adequately described the experimental data. Finally, a theoretical hemin effect was implemented to illustrate the applicability of the model to dosage optimization in drug therapies. ConclusionsA semi-mechanistic disease model was successfully developed to describe the temporal evolution of urinary heme precursor excretion during recurrent biochemical-induced acute attacks in AIP mice. This model represents the first computational approach to explore and optimize current and new therapies.

Nrf2 Activation Ameliorates Hepatotoxicity Induced by a Heme Synthesis Inhibitor.

Transcription factor Nrf2 protects hepatocytes against various toxicants by upregulating cytoprotective genes. The heme synthesis inhibitor 3, 5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC) leads to liver injury around the portal vein, unlike other groups of toxicants that cause hemorrhage and necrosis in the centrilobular area. To examine whether and how Nrf2 protects livers from the injury, we fed DDC to Nrf2 knockout (Nrf2KO), wild-type (WT), Keap1flox/flox (Keap1-knockdown; Keap1KD), and liver-specific Keap1 knockout (Keap1-Alb) mice, as these lines of mice exhibit stepwise increases in Nrf2 protein expression levels. Liver-specific Keap1::Nrf2 double-knockout (Keap1::Nrf2-Alb) mice were also exploited to examine the contribution of Nrf2. Two weeks after DDC feeding, Keap1-Alb mice were fully recovered from body weight loss, but the WT and Nrf2KO mice were not. The liver-to-body-weight ratio of Keap1-Alb mice was significantly larger than that of WT and Nrf2KO mice. Two indicators of hepatotoxicity, alanine aminotransferase and bilirubin in plasma, were both elevated in WT mice, but downregulated in Keap1-Alb mice after the DDC-feeding. DDC-induced porphyrin accumulation was reduced in the livers of Keap1-Alb and Keap1KD mice compared with that of WT mice. When assessed by the Nqo1 level, Nrf2 expression was further enhanced by DDC in Keap1-Alb mice, suggesting that DDC may have a Keap1 independent potential to activate Nrf2. Genetic activation of Nrf2 in Keap1-Alb mice increased the extracellular excretion of porphyrins, but contrary to our expectation, hepatic damages in Nrf2KO mice appeared to be similar to that of WT mice. Based on these observations, we conclude that Nrf2 activation protects livers against DDC-elicited hepatotoxicity.

Assessment of occupational exposures to multiple metals with urinary porphyrin profiles.

Chronic occupational exposures to low levels of metal mixtures necessitates biomonitoring of exposed workers. However, a single biomarker (BM) is rarely sufficient to ascertain the exposure of an individual to a complex mixture, with multiparameter analysis of the same sample considered recently as a preferred approach. Porphyrins are formed as intermediates of heme biosynthesis and different metals can exert their effects at different points of this metabolic pathway, leading to changed urinary porphyrins excretion profiles. The aim of this work was to develop a model that could serve to identify, on an individual basis, multiple metal exposure resulting from mining work, by using urinary porphyrin profiles. Urine samples of workers were obtained from a Portuguese mining company and a non-occupationally exposed group was used as control. The levels of uro-, hepta-, hexa-, penta-, copro- and protoporphyrins were determined by HPLC. It was observed that only heptaporphyrin levels in miners were significantly (p<0.05) different from controls. However, when the concentrations of all porphyrins were combined by binary logistic regression, their ability to discriminate between miners and controls was higher than each one of the porphyrins alone, as indicated by a greater curve' area under a ROC curve. Moreover, when the combined porphyrins were used to calculate the probability of each subject fit in the occupationally exposed group, 83% of 47 individuals were correctly identified with respect to their type of exposure. These results suggest that the integration of the urinary porphyrin profile is a promising tool for the detection of subjects exhibiting biochemical modifications due to occupational exposure to metals in mines.

Hepatitis C virus core protein triggers abnormal porphyrin metabolism in human hepatocellular carcinoma cells.

Porphyria cutanea tarda (PCT), the most common of the human porphyrias, arises from a deficiency of uroporphyrinogen decarboxylase. Studies have shown a high prevalence of hepatitis C virus (HCV) infection in patients with PCT. While these observations implicate HCV infection as a risk factor for PCT pathogenesis, the mechanism of interaction between the virus and porphyrin metabolism is unknown. This study aimed to assess the effect of HCV core protein on intracellular porphyrin metabolism to elucidate the link between HCV infection and PCT. The accumulation and excretion of porphyrins after treatment with 5-aminolevulinic acid, a porphyrin precursor, were compared between cells stably expressing HCV core protein and controls. Cells expressing HCV core protein had lower amounts of intracellular protoporphyrin IX and heme and had higher amounts of excreted coproporphyrin III, the oxidized form of coproporphyrinogen III, compared with controls. These observations suggest that HCV core protein affects porphyrin metabolism and facilitates the export of excess coproporphyrinogen III and/or coproporphyrin III, possibly via porphyrin transporters. Real-time PCR analysis revealed that the presence of HCV core protein increased the mRNA expression of porphyrin exporters ABCG2 and FLVCR1. Western blot analysis showed a higher expression level of FLVCR1, but not ABCG2, as well as a higher expression level of mature ALAS1, which is the rate-limiting enzyme in the heme synthesis pathway, in HCV core protein-expressing cells compared with controls. The data indicate that HCV core protein induced abnormal intracellular porphyrin metabolism, with an over-excretion of coproporphyrin III. These findings may partially account for the susceptibility of HCV-infected individuals to PCT development.

Best practice guidelines on first-line laboratory testing for porphyria.

The porphyrias are disorders of haem biosynthesis which present with acute neurovisceral attacks or disorders of sun-exposed skin. Acute attacks occur mainly in adults and comprise severe abdominal pain, nausea, vomiting, autonomic disturbance, central nervous system involvement and peripheral motor neuropathy. Cutaneous porphyrias can be acute or chronic presenting at various ages. Timely diagnosis depends on clinical suspicion leading to referral of appropriate samples for screening by reliable biochemical methods. All samples should be protected from light. Investigation for an acute attack: • Porphobilinogen (PBG) quantitation in a random urine sample collected during symptoms. Urine concentration must be assessed by measuring creatinine, and a repeat requested if urine creatinine <2 mmol/L. • Urgent porphobilinogen testing should be available within 24 h of sample receipt at the local laboratory. Urine porphyrin excretion (TUP) should subsequently be measured on this urine. • Urine porphobilinogen should be measured using a validated quantitative ion-exchange resin-based method or LC-MS. • Increased urine porphobilinogen excretion requires confirmatory testing and clinical advice from the National Acute Porphyria Service. • Identification of individual acute porphyrias requires analysis of urine, plasma and faecal porphyrins. Investigation for cutaneous porphyria: • An EDTA blood sample for plasma porphyrin fluorescence emission spectroscopy and random urine sample for TUP. • Whole blood for porphyrin analysis is essential to identify protoporphyria. • Faeces need only be collected, if first-line tests are positive or if clinical symptoms persist. Investigation for latent porphyria or family history: • Contact a specialist porphyria laboratory for advice. Clinical, family details are usually required.

Hydroxychloroquine Induced Liver Injury

Introduction: Hydroxychloroquine is a commonly prescribed medication with antimalarial and anti-inflammatory properties. Drug induced liver injury is a very rarely reported side effect of this medication. Case Report: 62 year old female with history of rheumatoid arthritis, on long term prednisone, presented to the ER with 2 days of arthralgia, generalized weakness, sweats and fever up to 104F. Chest x-ray and CT of the head showed no acute abnormalities. Upon laboratory evaluation, elevated liver function tests with AST 331 and ALT 379 were noted. Bilirubin and ALP were normal. Prothrombin time not elevated. She was admitted for possible sepsis from an unknown source and placed on empiric antibiotics. Upon review of her medications it became apparent that she had started hydroxychloroquine 16 days prior to admission. Hydroxychloroquine was stopped on hospital day 2 due to concern for drug induced liver injury. Her AST and ALT peaked at 798 and 1254, respectively on hospital day 3 and represent a 17 and 20 fold increase above the ULN. Serology tests for HAV, HBV, HCV, CMV, EBV, and HIV were nonreactive. ANA titer had increased from < 1:40 four months ago to 1:80. Anti-histone antibody, ASMA, and anti ds-DNA antibody were unremarkable. There was an increase in urine porphyrin excretion. Abdominal ultrasound showed an echogenic liver consistent with hepatic steatosis and no evidence of biliary obstruction. No growth was seen on blood cultures and antibiotics were de-escalated. AST and ALT began to trend downward on hospital day 4. Her fever had abated by hospital day 6. AST and ALT were down to 228 and 487 respectively at the time of discharge on hospital day 7. She had remained afebrile without any arthralgia at follow up appointment 10 days after discharge. AST and ALT had improved to 46 and 161 respectively. Discussion: We present this case of apparent hydroxychloroquine induced liver injury to add to the fund of knowledge of drug induced liver injuries. Based on our literature review there appears to be four previously reported cases of hydroxychloroquine induced liver injury. Hydroxychloroquine may trigger an acute worsening of porphyria cutanea tarda in susceptible individuals which could present with sudden onset of fever and marked serum enzyme elevations with increased excretion of porphyrins.

Late-onset cutaneous porphyria in a patient heterozygous for a uroporphyrinogen III synthase gene mutation

Deficiency of uroporphyrinogen III synthase (UROS) causes congenital erythropoietic porphyria (CEP). The disease, originating from the inheritance of mutations within the UROS gene, presents a recessive form of transmission. In a few patients, a late-onset CEP-like phenotype without UROS mutations appears to be associated with a myelodysplastic syndrome. We report a 60-year-old man with late-onset signs of cutaneous porphyria and accumulation in urine, plasma and faeces of type I porphyrin isomers characteristic of CEP. Analysis of DNA from peripheral leucocytes, skin and bone marrow aspirate showed that he was a heterozygous carrier of a Cys73Arg (c.217 T>C) mutation within UROS. Sequencing of cDNA from peripheral blood confirmed heterozygosity and expression of the normal allele. Measurement of UROS enzymatic activity in erythrocytes showed values ~70% of normal, indirectly indicating expression of the normal allele. Differently from other cases of late-onset uroporphyria, the patient did not present thrombocytopenia or any evidence of a myelodysplastic syndrome. Five years of clinical follow-up showed persistence of skin signs and increased excretion of porphyrins, independently of lifestyle factors or changes in medication regimes. We hypothesize acquired mosaicism (in the bone marrow) affecting the UROS gene. Thus, unstable cellular clones initiated overproduction of isomer I porphyrins leading to a CEP phenotype. This could be explained either by a clonal expansion of the porphyric (Cys73Arg) allele or by loss of function of the normal allele. Cellular turnover would facilitate release of uroporphyrins into circulation and subsequent skin lesions. This is the first case of a CEP heterozygous carrier presenting clinical manifestations.

Clinical, Biochemical and Molecular Characteristics of the Main Types of Porphyria.

Porphyrias are diverse disorders that arise from various inherited enzyme defects in the heme biosynthesis pathway, except for porphyria cutanea tarda (PCT), in which the enzyme deficiency in most cases is acquired. The biosynthetic blocks resulting from the defective enzymes are largely expressed either in the liver or bone marrow, the sites where the majority of heme is produced. Although the pathophysiologic mechanisms of the clinical manifestations of the porphyrias are not fully understood, two cardinal features prevail: skin photosensitivity and neurologic symptoms of intermittent autonomic neuropathy, acute neurovisceral attacks, and disorders of the nervous system. The primary diagnosis of the proband is based on biochemical testing, which is not always able to identify acute porphyrias, especially in asymptomatic family carriers when heme precursors and porphyrins excretion is normal, low-normal and high-reduced values of enzyme activity overlap, and hematological diseases responsible for abnormal blood cells distribution coexist. Molecular analysis of gene mutations responsible for each type of porphyria is the best diagnostic approach for symptomatic as well as presymptomatic gene carriers.

Porphyria Diagnostics-Part 1: A Brief Overview of the Porphyrias.

Porphyria diseases are a group of metabolic disorders caused by abnormal functioning of heme biosynthesis enzymes and characterized by excessive accumulation and excretion of porphyrins and their precursors. Precisely which of these chemicals builds up depends on the type of porphyria. Porphyria is not a single disease but a group of nine disorders: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), δ-aminolevulinic acid dehydratase deficiency porphyria (ADP), porphyria cutanea tarda (PCT), hepatoerythropoietic porphyria (HEP), congenital erythropoietic porphyria (CEP), erythropoietic protoporphyria (EPP), and X-linked protoporphyria (XLP). Each porphyria results from overproduction of heme precursors secondary to partial deficiency or, in XLP, increased activity of one of the enzymes of heme biosynthesis. Taken together, all forms of porphyria afflict fewer than 200,000 people in the United States. Based on European studies, the most common porphyria, PCT, has a prevalence of 1 in 10,000, the most common acute porphyria, AlP, has a prevalence of ∼1 in 20,000, and the most common erythropoietic porphyria, EPP, is estimated at 1 in 50,000 to 75,000. CEP is extremely rare, with prevalence estimates of 1 in 1,000,000 or less. Only six cases of ADP are documented. The current porphyria literature is very exhaustive and a brief overview of porphyria diseases is essential in order for the reader to better appreciate the relevance of this area of research prior to undertaking biochemical diagnostics procedures. This unit summarizes the current knowledge on the classification, clinical features, etiology, pathogenesis, and genetics of porphyria diseases.

Experimental protoporphyria: effect of bile acids on liver damage induced by griseofulvin.

The effect of bile acids administration to an experimental mice model of Protoporphyria produced by griseofulvin (Gris) was investigated. The aim was to assess whether porphyrin excretion could be accelerated by bile acids treatment in an attempt to diminish liver damage induced by Gris. Liver damage markers, heme metabolism, and oxidative stress parameters were analyzed in mice treated with Gris and deoxycholic (DXA), dehydrocholic (DHA), chenodeoxycholic, or ursodeoxycholic (URSO). The administration of Gris alone increased the activities of glutathione reductase (GRed), superoxide dismutase (SOD), alkaline phosphatase (AP), gamma glutamyl transpeptidase (GGT), and glutathione-S-transferase (GST), as well as total porphyrins, glutathione (GSH), and cytochrome P450 (CYP) levels in liver. Among the bile acids studied, DXA and DHA increased PROTO IX excretion, DXA also abolished the action of Gris, reducing lipid peroxidation and hepatic GSH and CYP levels, and the activities of GGT, AP, SOD, and GST returned to control values. However, porphyrin accumulation was not prevented by URSO; instead this bile acid reduced ALA-S and the antioxidant defense enzymes system activities. In conclusion, we postulate that DXA acid would be more effective to prevent liver damage induced by Gris.

A skin disease, a blood disease or something in between? An exploratory focus group study of patients' experiences with porphyria cutanea tarda.

BackgroundPorphyria cutanea tarda (PCT) is characterized by fragile skin with blistering on sun-exposed areas. Symptoms typically develop in late adulthood and can be triggered by iron overload, alcohol intake, oestrogens and various liver diseases. Treatment consists of phlebotomy to reduce iron, or increasing urinary porphyrin excretion by administering chlorochin. To optimize patient care, health personnel need to understand the subjective experiences of PCT.ObjectivesTo explore the experiences of persons with PCT with regard to symptoms, treatment, follow-up and prevention of the disease.MethodsInterpretive description was used as a qualitative approach. Twenty-one participants attended three focus groups. All participants had experienced PCT symptoms during the last 5 years.ResultsParticipants' experiences varied from trivializing symptoms and fragile skin to what was described as a desperate situation, with huge blisters, skin falling off and feeling as if one was in a ‘horror movie’. For some, itching was very troublesome, preventing sleep and delaying skin healing. In managing PCT a shift in focus from skin to blood was described. PCT was perceived as a chronic and systemic disease causing a range of health problems. Strategies for preventing symptoms ranged from doing nothing to frequent controls and check-ups.ConclusionsParticipants had a systemic perception of PCT, and a tendency to attribute a range of health problems to the condition. This study adds insight into the experiences patients have with PCT.

Urinary excretion of porphyrins, porphobilinogen and δ-aminolaevulinic acid following an attack of acute intermittent porphyria

Background and objectivesThe porphyrias are a group of rare, mainly inherited, diseases caused by a deficiency of one of the enzymes of the haem biosynthesis pathway. The biochemical hallmark of...