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Blood Nov 2012The inborn errors of heme biosynthesis, the porphyrias, are 8 genetically distinct metabolic disorders that can be classified as "acute hepatic," "hepatic cutaneous,"... (Review)
Review
The inborn errors of heme biosynthesis, the porphyrias, are 8 genetically distinct metabolic disorders that can be classified as "acute hepatic," "hepatic cutaneous," and "erythropoietic cutaneous" diseases. Recent advances in understanding their pathogenesis and molecular genetic heterogeneity have led to improved diagnosis and treatment. These advances include DNA-based diagnoses for all the porphyrias, new understanding of the pathogenesis of the acute hepatic porphyrias, identification of the iron overload-induced inhibitor of hepatic uroporphyrin decarboxylase activity that causes the most common porphyria, porphyria cutanea tarda, the identification of an X-linked form of erythropoietic protoporphyria due to gain-of-function mutations in erythroid-specific 5-aminolevulinate synthase (ALAS2), and new and experimental treatments for the erythropoietic porphyrias. Knowledge of these advances is relevant for hematologists because they administer the hematin infusions to treat the acute attacks in patients with the acute hepatic porphyrias, perform the chronic phlebotomies to reduce the iron overload and clear the dermatologic lesions in porphyria cutanea tarda, and diagnose and treat the erythropoietic porphyrias, including chronic erythrocyte transfusions, bone marrow or hematopoietic stem cell transplants, and experimental pharmacologic chaperone and stem cell gene therapies for congenital erythropoietic protoporphyria. These developments are reviewed to update hematologists on the latest advances in these diverse disorders.
Topics: Biosynthetic Pathways; Genetic Predisposition to Disease; Heme; Humans; Mutation; Porphyrias
PubMed: 22791288
DOI: 10.1182/blood-2012-05-423186 -
The Kaohsiung Journal of Medical... Jul 2012The aim of the present study is to describe recent issues with Yusho disease in Japan, describe the state of dioxin accumulation and the intake of dioxin via food in... (Review)
Review
The aim of the present study is to describe recent issues with Yusho disease in Japan, describe the state of dioxin accumulation and the intake of dioxin via food in Japan, and introduce the Japan Environment and Children's Study. Yusho disease manifested in western Japan in 1968. The causes of Yusho are believed to be dioxin-related compounds, mainly polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs), via the ingestion of rice oil produced in February 1968. As of March 31, 2011, there were 1961 registered Yusho cases, but of these 539 are deceased. A retrospective cohort study on registered Yusho cases reported that the standardized mortality ratios (SMRs) for the major causes of death were not significantly elevated, with the exception of all-cancer (SMR=1.26; 95% confidence interval [CI]: 1.03-1.53) and lung cancer mortality (SMR=1.56; 95% CI: 1.03-2.27) in males. The results of the Yusho mortality study show that the SMR for liver cancer in males tends to decrease over time. In 2011, the Ministry of the Environment of Japan reported that the average concentration of dioxins in the blood (2002-2010) of the Japanese people was 19 pg-TEQ/g-fat, demonstrating a range of 0.10-130 pg-TEQ/g-fat, and that the average dioxin intake from food (2002-2010) was 0.82 pg-TEQ/kg-body weight/day, demonstrating a range of 0.031-6.2 pg-TEQ/kg-body weight/day according to 2006 WHO TEFs. The Japan Environment and Children's Study Project was launched in 2011 and is supported by the Ministry of the Environment of Japan. In this project, 100,000 mother and child pairs will be recruited over 3 years from designated study areas. Follow-up examinations will be carried out from pregnancy until the children are 13 years of age (a so-called birth-cohort study). This project will be implemented by the National Center at the National Institute for Environmental Studies and is supported by the Medical Support Center at the National Center for Child Health and Development. Field operations will be performed at 15 designated regional centers nationwide.
Topics: Animals; Dioxins; Food Contamination; History, 20th Century; History, 21st Century; Humans; Japan; Neoplasms; Porphyrias
PubMed: 22871602
DOI: 10.1016/j.kjms.2012.05.010 -
Cellular and Molecular Gastroenterology... 2019Genetic porphyrias comprise eight diseases caused by defects in the heme biosynthetic pathway that lead to accumulation of heme precursors. Consequences of porphyria... (Review)
Review
Genetic porphyrias comprise eight diseases caused by defects in the heme biosynthetic pathway that lead to accumulation of heme precursors. Consequences of porphyria include photosensitivity, liver damage and increased risk of hepatocellular carcinoma, and neurovisceral involvement, including seizures. Fluorescent porphyrins that include protoporphyrin-IX, uroporphyrin and coproporphyrin, are photo-reactive; they absorb light energy and are excited to high-energy singlet and triplet states. Decay of the porphyrin excited to ground state releases energy and generates singlet oxygen. Porphyrin-induced oxidative stress is thought to be the major mechanism of porphyrin-mediated tissue damage. Although this explains the acute photosensitivity in most porphyrias, light-induced porphyrin-mediated oxidative stress does not account for the effect of porphyrins on internal organs. Recent findings demonstrate the unique role of fluorescent porphyrins in causing subcellular compartment-selective protein aggregation. Porphyrin-mediated protein aggregation associates with nuclear deformation, cytoplasmic vacuole formation and endoplasmic reticulum dilation. Porphyrin-triggered proteotoxicity is compounded by inhibition of the proteasome due to aggregation of some of its subunits. The ensuing disruption in proteostasis also manifests in cell cycle arrest coupled with aggregation of cell proliferation-related proteins, including PCNA, cdk4 and cyclin B1. Porphyrins bind to native proteins and, in presence of light and oxygen, oxidize several amino acids, particularly methionine. Noncovalent interaction of oxidized proteins with porphyrins leads to formation of protein aggregates. In internal organs, particularly the liver, light-independent porphyrin-mediated protein aggregation occurs after secondary triggers of oxidative stress. Thus, porphyrin-induced protein aggregation provides a novel mechanism for external and internal tissue damage in porphyrias that involve fluorescent porphyrin accumulation.
Topics: Animals; Carcinoma, Hepatocellular; Dermatitis, Phototoxic; Heme; Humans; Liver; Liver Neoplasms; Mice; Oxidation-Reduction; Oxidative Stress; Photosensitivity Disorders; Porphyrias; Porphyrins; Protein Aggregates; Protoporphyrins; Uroporphyrins; Zebrafish
PubMed: 31233899
DOI: 10.1016/j.jcmgh.2019.06.006 -
Journal of Postgraduate Medicine 2023Porphyrias are a rare group of inborn errors of metabolism due to defects in the heme biosynthetic pathway. The biochemical hallmark is the overproduction of porphyrin...
Porphyrias are a rare group of inborn errors of metabolism due to defects in the heme biosynthetic pathway. The biochemical hallmark is the overproduction of porphyrin precursors and porphyrin species. Afflicted patients present with a myriad of symptoms causing a diagnostic odyssey. Symptoms often overlap with those of common diseases and may be overlooked unless there is heightened clinical suspicion. We are reporting clinical features and diagnostic challenges in four pediatric patients having variegate porphyria, congenital erythropoietic porphyria, acute intermittent porphyria, and erythropoietic protoporphyria (EPP), who presented with diverse multisystem manifestations. This case series illustrates a logical analysis of symptoms and judicious selection of investigations and the role of genotyping in successfully diagnosing porphyrias.
Topics: Child; Humans; Porphyrias; Porphyria, Acute Intermittent; Porphyrins
PubMed: 37082991
DOI: 10.4103/jpgm.jpgm_698_22 -
Anesthesiology 1966
Topics: Humans; Porphyrias; Thiopental
PubMed: 5919017
DOI: 10.1097/00000542-196609000-00031 -
British Medical Journal Sep 1948
Topics: Animals; Humans; Porifera; Porphyria, Acute Intermittent; Porphyrias
PubMed: 18881289
DOI: 10.1136/bmj.2.4575.531-b -
Hepatology (Baltimore, Md.) Oct 2017The acute hepatic porphyrias are a group of four inherited disorders, each resulting from a deficiency in the activity of a specific enzyme in the heme biosynthetic... (Review)
Review
The acute hepatic porphyrias are a group of four inherited disorders, each resulting from a deficiency in the activity of a specific enzyme in the heme biosynthetic pathway. These disorders present clinically with acute neurovisceral symptoms which may be sporadic or recurrent and, when severe, can be life-threatening. The diagnosis is often missed or delayed as the clinical features resemble other more common medical conditions. There are four major subgroups: symptomatic patients with sporadic attacks (<4 attacks/year) or recurrent acute attacks (≥4 attacks/year), asymptomatic high porphyrin precursor excretors, and asymptomatic latent patients without symptoms or porphyrin precursor elevations. Given their clinical heterogeneity and potential for significant morbidity with suboptimal management, comprehensive clinical guidelines for initial evaluation, follow-up, and long-term management are needed, particularly because no guidelines exist for monitoring disease progression or response to treatment. The Porphyrias Consortium of the National Institutes of Health's Rare Diseases Clinical Research Network, which consists of expert centers in the clinical management of these disorders, has formulated these recommendations. These recommendations are based on the literature, ongoing natural history studies, and extensive clinical experience. Initial assessments should include diagnostic confirmation by biochemical testing, subsequent genetic testing to determine the specific acute hepatic porphyria, and a complete medical history and physical examination. Newly diagnosed patients should be counseled about avoiding known precipitating factors. The frequency of follow-up depends on the clinical subgroup, with close monitoring of patients with recurrent attacks who may require treatment modifications as well as those with clinical complications. Comprehensive care should include subspecialist referrals when needed. Annual assessments include biochemical testing and monitoring for long-term complications. These guidelines provide a framework for monitoring patients with acute hepatic porphyrias to ensure optimal outcomes. (Hepatology 2017;66:1314-1322).
Topics: Disease Management; Humans; Porphyrias, Hepatic
PubMed: 28605040
DOI: 10.1002/hep.29313 -
Advances in Clinical and Experimental... 2016Porphyrias are diverse disorders that arise from various inherited enzyme defects in the heme biosynthesis pathway, except for porphyria cutanea tarda (PCT), in which... (Review)
Review
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.
Topics: Animals; Enzymes; Gene Expression Regulation, Enzymologic; Genetic Predisposition to Disease; Heme; Heredity; Humans; Mutation; Pedigree; Phenotype; Porphyrias; Prognosis
PubMed: 27627571
DOI: 10.17219/acem/58955 -
Fukuoka Igaku Zasshi = Hukuoka Acta... May 2015Yusho incident is an unprecedented mass food poisoning that occurred in the western area of Japan in 1968. It was caused by the ingestion of rice bran oil contaminated... (Review)
Review
Yusho incident is an unprecedented mass food poisoning that occurred in the western area of Japan in 1968. It was caused by the ingestion of rice bran oil contaminated with polychlorinated biphenyls (PCBs) and various dioxins and dioxin-like compounds, such as polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). The victims of Yusho have suffered from characteristic skin manifestations in company with systemic, ophthalmological, and mucosal symptoms for a long period. Since the outbreak of Yusho, the Study Group of Yusho has been conducting annual medical check-ups on Yusho victims. We describe here the latest research findings of chronic dioxin-induced toxicity to Yusho patients and the mechanisms of toxicities of dioxins through the aryl hydrocarbon receptor (AhR) pathway. High amounts of PCBs and PCDFs are still present in a number of patients with Yusho. The patients have persistent various symptoms, some of which were significantly associated with blood levels of PCBs, dioxins, or dioxin-like compounds. The adverse effects on the next generation are also found. According to the findings of recent basic studies, the biological and toxicological effects mediated by the AhR system have been becoming clear; therefore, the therapeutic interventions may be found in the near future.
Topics: Female; Humans; Male; Porphyrias
PubMed: 26226682
DOI: No ID Found -
Orphanet Journal of Rare Diseases Apr 2021This study used quantitative and qualitative research methods to analyze how acute hepatic porphyria (AHP) affects patients with varying annualized porphyria attack...
BACKGROUND
This study used quantitative and qualitative research methods to analyze how acute hepatic porphyria (AHP) affects patients with varying annualized porphyria attack rates. The overall impact of AHP on patients and caregivers, including their quality of life, was explored. The nature and treatment of acute attacks, experiences of long-term heme arginate treatment and access to other appropriate treatment, and the extent of and treatment for chronic symptoms were also investigated within this study.
METHODS
Patient and caregiver data were collected via an online survey of members of the British Porphyria Association, followed by an optional 1-h telephone interview.
RESULTS
Thirty-eight patients and 10 caregivers responded to the survey. Of those, 10 patients and three caregivers completed follow-up interviews. Overall, 19 patients (50%) had experienced an acute attack within the previous 2 years, and the severity and types of symptoms experienced during or between acute attacks varied considerably. There were no clear definitions among patients for 'mild' or 'severe' attacks. Treatments and treatment settings used to manage attacks also varied. Following unsatisfactory care experiences at hospitals, some patients reported avoiding further hospital services for later attacks. Therefore, using settings of care as a measure of attack severity should be avoided. Ninety-four percent of patients also experienced chronic symptoms, which were as varied as acute attacks. Pain was the predominant chronic symptom and was managed with opioids in severe cases. Regardless of AAR, porphyria heavily impacted the daily lives of patients and caregivers. Although patients experiencing frequent attacks generally endured a greater impact on their daily life, patients with less frequent attacks also experienced impacts on all domains (social, leisure activities, relationship with family, relationships, psychological wellbeing, finances, employment, and study). Caregivers were most affected in the finance, relationships with family, and employment domains, and just over half of the caregivers reported a moderate impact on their psychological wellbeing.
CONCLUSIONS/IMPLICATIONS
The burden of illness with AHP is high across all patients, regardless of frequency of attacks, and AHP negatively affects patients and caregivers alike.
Topics: Caregivers; Humans; Porphobilinogen Synthase; Porphyrias, Hepatic; Quality of Life; United Kingdom
PubMed: 33902669
DOI: 10.1186/s13023-021-01816-2