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Lissing M, Wang B, Wahlin S. Liver transplantation and primary liver cancer in porphyria. Liver Int 2025; 45:e15894. [PMID: 38456621 PMCID: PMC11815609 DOI: 10.1111/liv.15894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 02/22/2024] [Accepted: 02/28/2024] [Indexed: 03/09/2024]
Abstract
The porphyrias are a heterogeneous group of metabolic disorders that result from defects in heme synthesis. The metabolic defects are present in all cells, but symptoms are mainly cutaneous or related to neuropathy. The porphyrias are highly relevant to hepatologists since patients can present with symptoms and complications that require liver transplantation (LT), and some porphyrias are associated with a high risk for primary liver cancer (PLC). Among the cutaneous porphyrias, erythropoietic protoporphyria (EPP) can lead to cholestatic liver failure where LT cures the liver disease but not the porphyria. In acute porphyria (AP), neurotoxic porphyrin precursors are produced in the liver and LT is a curative treatment option in patients with recurrent severe neuropathic attacks. Patients with AP, mainly acute intermittent porphyria, have a significantly increased risk for PLC that warrants surveillance and adequate follow-up of high-risk groups. LT is well established in both EPP with liver failure and AP with recurrent attacks, but most transplant centres have little porphyria experience and cooperation between transplant hepatologists, and porphyria experts is important in the often-difficult decisions on timing and management of comorbid conditions.
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Affiliation(s)
- Mattias Lissing
- Hepatology Division, Department of Upper GI DiseasesKarolinska University HospitalStockholmSweden
- Department of Medicine, HuddingeKarolinska InstitutetStockholmSweden
| | - Bruce Wang
- Department of Medicine and Division of GastroenterologyUniversity of California San FranciscoSan FranciscoCaliforniaUSA
| | - Staffan Wahlin
- Hepatology Division, Department of Upper GI DiseasesKarolinska University HospitalStockholmSweden
- Department of Medicine, HuddingeKarolinska InstitutetStockholmSweden
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2
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Naik H, Brown M, Meninger S, Lombardelli S. Patient experience with acute hepatic porphyria before and after long-term givosiran treatment in a qualitative interview study. Mol Genet Metab Rep 2025; 42:101174. [PMID: 39811158 PMCID: PMC11731774 DOI: 10.1016/j.ymgmr.2024.101174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 11/21/2024] [Accepted: 12/02/2024] [Indexed: 01/16/2025] Open
Abstract
Background Acute hepatic porphyria (AHP) is characterized by debilitating and potentially life-threatening neurovisceral attacks, possible chronic symptoms, and long-term complications. In a phase 1/2 open-label extension (OLE) study and the phase 3 ENVISION study, givosiran led to sustained improvement in annualized attack rate and quality of life (QOL) measures. To capture the patient experience of symptoms and impacts of AHP, and any changes experienced during treatment with givosiran, qualitative interviews were conducted with study participants. Methods Participants who continued givosiran treatment after completing the phase 1/2 OLE study and the phase 3 ENVISION study participated in semi-structured interviews (i.e., loosely structured interviews on a predetermined topic without strict adherence to wording or order of questions) in 2022 that were developed and executed by RTI Health Solutions. Transcripts were assessed using thematic analysis methods. Authors/investigators categorized symptoms as likely acute attack-related or chronic based on the participants' descriptions. Select clinical trial results (baseline characteristics and QOL scores from the phase 1/2 and ENVISION studies) from interview participants were compiled. Results Duration of givosiran treatment in the 21 participants at the time of interview was approximately 4-5 years (mean [SD], 51.8 [7.9] months; median [range], 49.7 [41.4, 69.1] months). Participants reported experiencing AHP symptoms prior to the phase 1/2 OLE or phase 3 studies, including abdominal pain (n = 20/21 [95 %]) and fatigue (n = 20/21 [95 %]), with impacts including work/school (n = 21/21 [100 %]) and family and intimate relationships (n = 20/21 [95 %]). Post-treatment, participants reported improvements in symptoms including abdominal pain (n = 20/20 [100 %] participants), fatigue (n = 20/20 [100 %]), and nausea (n = 19/19 [100 %]), and in impacts, including family and intimate relationships (n = 20/20 [100 %]) and work/school (n = 19/21 [90 %]). Most participants (n = 19/21 [90 %]) used opioids prior to the trials, and many reported stopping opioids (n = 10/17 [59 %]) or using a lower dose (n = 4/17 [24 %]). Participants reported complete relief of certain symptoms, including vomiting (n = 8/11 [73 %]), nausea (n = 10/15 [67 %]), and abdominal pain (n = 8/19 [42 %]). Participants with complete relief of pain or cessation of opioid use tended to be younger and more recently diagnosed, with higher baseline EuroQOL visual analog scale scores during the clinical trials. Participants with prior hemin prophylaxis at entry into the clinical trials were more likely to have experienced abdominal pain, neuropathic pain/paresthesia, and gastrointestinal symptoms before the study, and were generally more or as likely to have complete relief of these symptoms (e.g., n = 6/8 [75 %] participants with prior hemin prophylaxis reported complete relief of abdominal pain vs n = 2/11 [18 %] participants without prior hemin prophylaxis). All participants reported being "very satisfied" with givosiran. Conclusions Participants reported meaningful improvements in AHP symptoms, increased QOL, and reduced opioid use with long-term monthly givosiran treatment.
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Affiliation(s)
- Hetanshi Naik
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
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3
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Ramanujam VMS, Moghe A, Huda R, Turner SB, Anderson KE. Porphyria Diagnostics Part 2: Essential Biochemical Testing for Diagnosis of the Porphyrias. Curr Protoc 2025; 5:e70092. [PMID: 39927625 DOI: 10.1002/cpz1.70092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2025]
Abstract
Porphyrins and porphyrin precursors are normally detected in small amounts in healthy individuals but are found in large quantities in the urine, feces, blood, plasma, bone marrow, and liver in patients with various types of porphyrias. These are intermediates, or are derived from intermediates, in the pathway for heme biosynthesis. Heme is synthesized in all body tissues but in the largest amounts in the bone marrow and liver. Accurately measuring these compounds is important for diagnosis and monitoring of porphyrias. In addition, measurement of enzyme activities and mutation analyses by DNA sequencing enables confirmation of a porphyria diagnosis and genetic counseling. Biochemical approaches described here include measurements of porphyrin precursors and porphyrins in the urine, feces, plasma, erythrocytes, and liver, and determination of specific enzyme activities in erythrocytes and other cells. © 2025 Wiley Periodicals LLC.
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Affiliation(s)
| | - Akshata Moghe
- Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Texas Health Science Center at Houston, Houston, Texas
| | - Ruksana Huda
- Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas
| | - Shalonda B Turner
- Department of Internal Medicine, Galveston Porphyria Laboratory, The University of Texas Medical Branch, Galveston, Texas
| | - Karl E Anderson
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, The University of Texas Medical Branch, Galveston, Texas
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4
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Francisco Idiaquez J, Khandelwal A, Nassar BA, Thoni AJ, Mann A, Prasad C, O'Brien A, Sholzberg M, Colantonio DA, Bril V. Canadian guidance for diagnosis and management of acute hepatic porphyrias. Clin Biochem 2024; 131-132:110792. [PMID: 38992557 DOI: 10.1016/j.clinbiochem.2024.110792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 07/04/2024] [Accepted: 07/08/2024] [Indexed: 07/13/2024]
Abstract
Acute hepatic porphyrias (AHP) comprise four rare monogenic autosomal conditions. Each is linked to a deficiency of heme metabolizing enzymes. Common manifestations include severe abdominal pain, nausea, confusion, hyponatremia, hypertension, tachycardia, and neuropathy. Diagnosis is challenging due to a non-specific, variable presentation with symptoms mimicking other common conditions. Initial diagnosis of AHP can be made with a test for urinary porphobilinogen, δ-aminolevulinic acid and porphyrins using a single random (spot) sample. However, many patients have complications due to delays in diagnosis and management. A novel small interfering RNA-based agent, givosiran, has demonstrated efficacy in reducing acute attacks in a recent Phase III trial, leading to its approval for the management of AHP. Early diagnosis is crucial for the timely introduction of disease-modifying treatments that reduce impairments, enhance quality of life, and extend survival. In this guidance, we aim to improve awareness and outcomes of AHP by making recommendations about diagnosis, monitoring, and treatment in Canada.
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Affiliation(s)
- Juan Francisco Idiaquez
- Ellen and Martin Prosserman Centre for Neuromuscular Diseases, Division of Neurology, Department of Medicine, University Health Network, University of Toronto, Toronto, Canada
| | - Aditi Khandelwal
- Adult Hematology, Transfusion Medicine and Apheresis, St Michael's Hospital, UnityHealth Toronto, Canada
| | - Bassam A Nassar
- Departments of Pathology and Laboratory Medicine, Nova Scotia Health-Central Zone and Dalhousie University, Halifax, Nova Scotia, Canada; Professor of Pathology, Medicine and Urology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Andrea J Thoni
- Departments of Pathology and Laboratory Medicine, Nova Scotia Health-Central Zone and Dalhousie University, Halifax, Nova Scotia, Canada
| | - Anna Mann
- Canadian Association for Porphyria, Canada
| | - Chitra Prasad
- Paediatrics (Section of Genetics and Metabolism) Clinical and Metabolic Geneticist Director of Metabolic Clinic London Health Sciences Centre London Ontario N6C2V5, Canada
| | - Alan O'Brien
- Service de Médecine Génique, Département de Médecine, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada
| | - Michelle Sholzberg
- Departments of Medicine, and Laboratory Medicine and Pathobiology, St. Michael's Hospital, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, Canada
| | - David A Colantonio
- Pathology and Laboratory Medicine, University of Ottawa and Clinical Biochemist, The Ottawa Hospital/EORLA, Canada
| | - Vera Bril
- Ellen and Martin Prosserman Centre for Neuromuscular Diseases, Division of Neurology, Department of Medicine, University Health Network, University of Toronto, Toronto, Canada.
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Duarte TL, Viveiros N, Godinho C, Duarte D. Heme (dys)homeostasis and liver disease. Front Physiol 2024; 15:1436897. [PMID: 39135705 PMCID: PMC11317413 DOI: 10.3389/fphys.2024.1436897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 07/15/2024] [Indexed: 08/15/2024] Open
Abstract
Heme is essential for a variety of proteins involved in vital physiological functions in the body, such as oxygen transport, drug metabolism, biosynthesis of steroids, signal transduction, antioxidant defense and mitochondrial respiration. However, free heme is potentially cytotoxic due to the capacity of heme iron to promote the oxidation of cellular molecules. The liver plays a central role in heme metabolism by significantly contributing to heme synthesis, heme detoxification, and recycling of heme iron. Conversely, enzymatic defects in the heme biosynthetic pathway originate multisystemic diseases (porphyrias) that are highly associated with liver damage. In addition, there is growing evidence that heme contributes to the outcomes of inflammatory, metabolic and malignant liver diseases. In this review, we summarize the contribution of the liver to heme metabolism and the association of heme dyshomeostasis with liver disease.
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Affiliation(s)
- Tiago L. Duarte
- i3S–Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- IBMC–Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
| | - Nicole Viveiros
- i3S–Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Catarina Godinho
- i3S–Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Faculdade de Medicina da Universidade do Porto (FMUP), Porto, Portugal
| | - Delfim Duarte
- i3S–Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Serviço de Hematologia e Transplantação da Medula Óssea, Instituto Português de Oncologia do Porto Francisco Gentil, E.P.E. (IPO Porto), Porto, Portugal
- Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto (FMUP), Porto, Portugal
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Balogun O, Nejak-Bowen K. The Hepatic Porphyrias: Revealing the Complexities of a Rare Disease. Semin Liver Dis 2023; 43:446-459. [PMID: 37973028 PMCID: PMC11256094 DOI: 10.1055/s-0043-1776760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2023]
Abstract
The porphyrias are a group of metabolic disorders that are caused by defects in heme biosynthesis pathway enzymes. The result is accumulation of heme precursors, which can cause neurovisceral and/or cutaneous photosensitivity. Liver is commonly either a source or target of excess porphyrins, and porphyria-associated hepatic dysfunction ranges from minor abnormalities to liver failure. In this review, the first of a three-part series, we describe the defects commonly found in each of the eight enzymes involved in heme biosynthesis. We also discuss the pathophysiology of the hepatic porphyrias in detail, covering epidemiology, histopathology, diagnosis, and complications. Cellular consequences of porphyrin accumulation are discussed, with an emphasis on oxidative stress, protein aggregation, hepatocellular cancer, and endothelial dysfunction. Finally, we review current therapies to treat and manage symptoms of hepatic porphyria.
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Affiliation(s)
- Oluwashanu Balogun
- Department of Experimental Pathology, University of Pittsburgh, Pittsburgh, PA
| | - Kari Nejak-Bowen
- Department of Experimental Pathology, University of Pittsburgh, Pittsburgh, PA
- Pittsburgh Liver Institute, University of Pittsburgh, Pittsburgh, PA
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Lissing M, Wester A, Vassiliou D, Floderus Y, Harper P, Sardh E, Wahlin S. Porphyrin precursors and risk of primary liver cancer in acute intermittent porphyria: A case-control study of 188 patients. J Inherit Metab Dis 2023; 46:1186-1194. [PMID: 37650859 DOI: 10.1002/jimd.12676] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 08/24/2023] [Accepted: 08/29/2023] [Indexed: 09/01/2023]
Abstract
Acute intermittent porphyria (AIP) is a rare hereditary metabolic disease characterized by acute attacks and accumulation of the porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Patients with AIP have a high risk of primary liver cancer (PLC). We aimed to assess the association between porphyrin precursor excretion and the risk for PLC in patients with AIP. We studied 48 patients with AIP who developed PLC between 1987 and 2015 and 140 age and sex matched controls with AIP but no PLC. Data on all available urinary PBG and ALA samples collected from 1975 until 1 year before PLC diagnosis were analyzed and compared between cases and controls using logistic regression. Porphyrin precursor excretion was higher in patients with PLC (PBG median 7.9 [IQR 4.4-21.9] mmol/mol creatinine) than in controls (3.8 [1.2-9.8]) (adjusted odds ratio 1.07, 95% confidence interval: 1.02-1.12). None of the 28 patients with all registered samples below the upper limit of normal (ULN) developed PLC, and only one of the 45 patients with all samples <2× ULN developed PLC. Among non-PLC controls, ALA and PBG levels decreased after age 50-60 while an increasing trend was observed after age 65 among those who developed PLC. Increased urinary porphyrin precursors are associated with a high risk of developing PLC. Patients with normal levels appear to have a low risk while high or increasing ALA and PBG after age 65 indicates high risk, which should be considered in surveillance decisions.
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Affiliation(s)
- Mattias Lissing
- Hepatology Division, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Axel Wester
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Daphne Vassiliou
- Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden
- Centre for Inherited Metabolic Diseases (CMMS), Porphyria Centre Sweden, Karolinska University Hospital, Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Ylva Floderus
- Centre for Inherited Metabolic Diseases (CMMS), Porphyria Centre Sweden, Karolinska University Hospital, Stockholm, Sweden
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Pauline Harper
- Centre for Inherited Metabolic Diseases (CMMS), Porphyria Centre Sweden, Karolinska University Hospital, Stockholm, Sweden
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Eliane Sardh
- Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden
- Centre for Inherited Metabolic Diseases (CMMS), Porphyria Centre Sweden, Karolinska University Hospital, Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Staffan Wahlin
- Hepatology Division, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
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8
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Belosevic A, Minder AE, Gueuning M, van Breemen F, Thun GA, Mattle-Greminger MP, Meyer S, Baumer A, Minder EI, Schneider-Yin X, Barman-Aksözen J. First Report of a Low-Frequency Mosaic Mutation in the Hydroxymethylbilane Synthase Gene Causing Acute Intermittent Porphyria. Life (Basel) 2023; 13:1889. [PMID: 37763293 PMCID: PMC10533070 DOI: 10.3390/life13091889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 09/04/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
Acute porphyrias are a group of monogenetic inborn errors of heme biosynthesis, characterized by acute and potentially life-threatening neurovisceral attacks upon exposure to certain triggering factors. Biochemical analyses can determine the type of acute porphyria, and subsequent genetic analysis allows for the identification of pathogenic variants in the specific gene, which provides information for family counselling. In 2017, a male Swiss patient was diagnosed with an acute porphyria while suffering from an acute attack. The pattern of porphyrin metabolite excretion in urine, faeces, and plasma was typical for an acute intermittent porphyria (AIP), which is caused by inherited autosomal dominant mutations in the gene for hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway. However, the measurement of HMBS enzymatic activity in the erythrocytes was within the normal range and Sanger sequencing of the HMBS gene failed to detect any pathogenic variants. To explore the molecular basis of the apparent AIP in this patient, we performed third-generation long-read single-molecule sequencing (nanopore sequencing) on a PCR product spanning the entire HMBS gene, including the intronic sequences. We identified a known pathogenic variant, c.77G>A, p.(Arg26His), in exon 3 at an allelic frequency of ~22% in the patient's blood. The absence of the pathogenic variant in the DNA of the parents and the results of additional confirmatory studies supported the presence of a de novo mosaic mutation. To our knowledge, such a mutation has not been previously described in any acute porphyria. Therefore, de novo mosaic mutations should be considered as potential causes of acute porphyrias when no pathogenic genetic variant can be identified through routine molecular diagnostics.
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Affiliation(s)
- Adrian Belosevic
- Institute of Laboratory Medicine, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
| | - Anna-Elisabeth Minder
- Division of Endocrinology, Diabetology, Porphyria and Clinical Nutrition, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
- Swiss Reference Centre for Porphyrias, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
| | - Morgan Gueuning
- Department of Research and Development, Blood Transfusion Service Zurich, Swiss Red Cross, 8952 Schlieren, Switzerland
| | - Franziska van Breemen
- Institute of Laboratory Medicine, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
- Swiss Reference Centre for Porphyrias, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
| | - Gian Andri Thun
- Department of Research and Development, Blood Transfusion Service Zurich, Swiss Red Cross, 8952 Schlieren, Switzerland
| | - Maja P. Mattle-Greminger
- Department of Research and Development, Blood Transfusion Service Zurich, Swiss Red Cross, 8952 Schlieren, Switzerland
| | - Stefan Meyer
- Department of Molecular Diagnostics and Cytometry, Blood Transfusion Service Zurich, Swiss Red Cross, 8952 Schlieren, Switzerland
| | - Alessandra Baumer
- Institute of Medical Genetics, University of Zürich, 8952 Schlieren, Switzerland
| | - Elisabeth I. Minder
- Division of Endocrinology, Diabetology, Porphyria and Clinical Nutrition, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
- Swiss Reference Centre for Porphyrias, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
| | - Xiaoye Schneider-Yin
- Institute of Laboratory Medicine, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
- Swiss Reference Centre for Porphyrias, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
| | - Jasmin Barman-Aksözen
- Institute of Laboratory Medicine, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
- Swiss Reference Centre for Porphyrias, Stadtspital Zürich, Triemli, 8063 Zurich, Switzerland
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9
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Guida CC, Nardella M, Fiorentino L, Latiano T, Napolitano F, Ferrara G, Crisetti A, Mazzoccoli G, Aucella F, Aucella F. Intrahepatic Cholangiocarcinoma and Acute Intermittent Porphyria: A Case Report. J Clin Med 2023; 12:jcm12093091. [PMID: 37176532 PMCID: PMC10178950 DOI: 10.3390/jcm12093091] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 04/19/2023] [Accepted: 04/22/2023] [Indexed: 05/15/2023] Open
Abstract
Patients suffering from different forms of acute hepatic porphyria present a high risk of primary liver cancer, specifically hepatocellular carcinoma and cholangiocarcinoma, determined by the activity of the disease even though an exact mechanism of carcinogenesis has not been recognized yet. Here, we present the clinical case of a 72-year-old woman who, approximately 29 years after the diagnosis of acute intermittent porphyria, presented with intrahepatic cholangiocarcinoma with a histological diagnosis of adenocarcinoma starting from the biliary-pancreatic ducts, which was diagnosed during the clinical and anatomopathological evaluation of a pathological fracture of the femur.
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Affiliation(s)
- Claudio Carmine Guida
- Interregional Reference Center for Porphyria, 71013 San Giovanni Rotondo, Italy
- Department of Medical Sciences, Division of Nephrology, Fondazione IRCCS "Casa Sollievo della Sofferenza", 71013 San Giovanni Rotondo, Italy
| | - Maria Nardella
- Interregional Reference Center for Porphyria, 71013 San Giovanni Rotondo, Italy
- Department of Medical Sciences, Division of Nephrology, Fondazione IRCCS "Casa Sollievo della Sofferenza", 71013 San Giovanni Rotondo, Italy
| | | | - Tiziana Latiano
- Division of Oncology, Fondazione IRCCS "Casa Sollievo della Sofferenza", 71013 San Giovanni Rotondo, Italy
| | - Francesco Napolitano
- Interregional Reference Center for Porphyria, 71013 San Giovanni Rotondo, Italy
- Department of Medical Sciences, Division of Nephrology, Fondazione IRCCS "Casa Sollievo della Sofferenza", 71013 San Giovanni Rotondo, Italy
| | - Gaetano Ferrara
- Interregional Reference Center for Porphyria, 71013 San Giovanni Rotondo, Italy
- Department of Medical Sciences, Division of Nephrology, Fondazione IRCCS "Casa Sollievo della Sofferenza", 71013 San Giovanni Rotondo, Italy
| | - Annalisa Crisetti
- Interregional Reference Center for Porphyria, 71013 San Giovanni Rotondo, Italy
- Department of Medical Sciences, Division of Nephrology, Fondazione IRCCS "Casa Sollievo della Sofferenza", 71013 San Giovanni Rotondo, Italy
| | - Gianluigi Mazzoccoli
- Division of Internal Medicine and Chronobiology Laboratory, Department of Medical Sciences, Fondazione IRCCS "Casa Sollievo della Sofferenza", 71013 San Giovanni Rotondo, Italy
| | - Francesco Aucella
- Interregional Reference Center for Porphyria, 71013 San Giovanni Rotondo, Italy
- Department of Medical Sciences, Division of Nephrology, Fondazione IRCCS "Casa Sollievo della Sofferenza", 71013 San Giovanni Rotondo, Italy
| | - Filippo Aucella
- Interregional Reference Center for Porphyria, 71013 San Giovanni Rotondo, Italy
- Department of Medical Sciences, Division of Nephrology, Fondazione IRCCS "Casa Sollievo della Sofferenza", 71013 San Giovanni Rotondo, Italy
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10
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Menezes PR, Trufen CEM, Lichtenstein F, Pellegrina DVDS, Reis EM, Onuki J. Transcriptome profile analysis reveals putative molecular mechanisms of 5-aminolevulinic acid toxicity. Arch Biochem Biophys 2023; 738:109540. [PMID: 36746260 DOI: 10.1016/j.abb.2023.109540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 12/23/2022] [Accepted: 02/03/2023] [Indexed: 02/05/2023]
Abstract
5-aminolevulinic acid (5-ALA) is the first precursor of the heme biosynthesis pathway, accumulated in acute intermittent porphyria (AIP), an inherited metabolic disease characterized by porphobilinogen deaminase deficiency. An increased incidence of hepatocellular carcinoma (HCC) has been reported as a long-term manifestation in symptomatic AIP patients. 5-ALA is an α-aminoketone prone to oxidation, yielding reactive oxygen species and 4,5-dioxovaleric acid. A high concentration of 5-ALA presents deleterious pro-oxidant potential. It can induce apoptosis, DNA damage, mitochondrial dysfunction, and altered expression of carcinogenesis-related proteins. Several hypotheses of the increased risk of HCC rely on the harmful effect of elevated 5-ALA in the liver of AIP patients, which could promote a pro-carcinogenic environment. We investigated the global transcriptional changes and perturbed molecular pathways in HepG2 cells following exposure to 5-ALA 25 mM for 2 h and 24 h using DNA microarray. Distinct transcriptome profiles were observed. 5-ALA '25 mM-2h' upregulated 10 genes associated with oxidative stress response and carcinogenesis. Enrichment analysis of differentially expressed genes by KEGG, Reactome, MetaCore™, and Gene Ontology, showed that 5-ALA '25 mM-24h' enriched pathways involved in drug detoxification, oxidative stress, DNA damage, cell death/survival, cell cycle, and mitochondria dysfunction corroborating the pro-oxidant properties of 5-ALA. Furthermore, our results disclosed other possible processes such as senescence, immune responses, endoplasmic reticulum stress, and also some putative effectors, such as sequestosome, osteopontin, and lon peptidase 1. This study provided additional knowledge about molecular mechanisms of 5-ALA toxicity which is essential to a deeper understanding of AIP and HCC pathophysiology. Furthermore, our findings can contribute to improving the efficacy of current therapies and the development of novel biomarkers and targets for diagnosis, prognosis, and therapeutic strategies for AHP/AIP and associated HCC.
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Affiliation(s)
- Patricia Regina Menezes
- Laboratório de Desenvolvimento e Inovação, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900, São Paulo, SP, Brazil
| | - Carlos Eduardo Madureira Trufen
- Laboratório de Desenvolvimento e Inovação, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900, São Paulo, SP, Brazil; Centro de Excelência para Descoberta de Novos Alvos Moleculares, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900, São Paulo, SP, Brazil; Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Průmyslová 595, 252 50, Vestec, Czech Republic
| | - Flavio Lichtenstein
- Laboratório de Desenvolvimento e Inovação, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900, São Paulo, SP, Brazil; Centro de Excelência para Descoberta de Novos Alvos Moleculares, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900, São Paulo, SP, Brazil
| | | | - Eduardo Moraes Reis
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, 05508-900, São Paulo, SP, Brazil
| | - Janice Onuki
- Laboratório de Desenvolvimento e Inovação, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900, São Paulo, SP, Brazil; Centro de Excelência para Descoberta de Novos Alvos Moleculares, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900, São Paulo, SP, Brazil; Laboratório de Herpetologia, Instituto Butantan, Av. Vital Brazil, 1500, 05503-900, São Paulo, SP, Brazil.
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11
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Wang B, Bonkovsky HL, Lim JK, Balwani M. AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review. Gastroenterology 2023; 164:484-491. [PMID: 36642627 PMCID: PMC10335308 DOI: 10.1053/j.gastro.2022.11.034] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/28/2022] [Accepted: 11/20/2022] [Indexed: 01/17/2023]
Abstract
DESCRIPTION The acute hepatic porphyrias (AHP) are rare, inborn errors of heme-metabolism and include acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and porphyria due to severe deficiency of 5-aminolevulinic acid dehydratase. Acute intermittent porphyria is the most common type of AHP, with an estimated prevalence of patients with symptoms of approximately 1 in 100,000. The major clinical presentation involves attacks of severe pain, usually abdominal and generalized, without peritoneal signs or abnormalities on cross-sectional imaging. Acute attacks occur mainly in women in their childbearing years. AHP should be considered in the evaluation of all patients, and especially women aged 15-50 years with recurrent severe abdominal pain not ascribable to common causes. The screening tests of choice include random urine porphobilinogen and δ-aminolevulinic acid corrected to creatinine. All patients with elevations in urinary porphobilinogen and/or δ-aminolevulinic acid should initially be presumed to have AHP. The cornerstones of management include discontinuation of porphyrinogenic drugs and chemicals, administration of oral or intravenous dextrose and intravenous hemin, and use of analgesics and antiemetics. Diagnosis of AHP type can be confirmed after initial treatment by genetic testing for pathogenic variants in HMBS, CPOX, PPOX, and ALAD genes. AHP is also associated with chronic symptoms and long-term risk of systemic arterial hypertension, chronic renal and liver disease, and hepatocellular carcinoma. Patients who have recurrent acute attacks (4 or more per year) should be considered for prophylactic therapy with intravenous hemin or subcutaneous givosiran. Liver transplantation is curative and reserved for patients with intractable symptoms who have failed other treatment options. METHODS This expert review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these BPA statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Women aged 15-50 years with unexplained, recurrent severe abdominal pain without a clear etiology after an initial workup should be considered for screening for an AHP. BEST PRACTICE ADVICE 2: Initial diagnosis of AHP should be made by biochemical testing measuring δ-aminolevulinic acid, porphobilinogen, and creatinine on a random urine sample. BEST PRACTICE ADVICE 3: Genetic testing should be used to confirm the diagnosis of AHP in patients with positive biochemical testing. BEST PRACTICE ADVICE 4: Acute attacks of AHP that are severe enough to require hospital admission should be treated with intravenous hemin, given daily, preferably into a high-flow central vein. BEST PRACTICE ADVICE 5: In addition to intravenous hemin, management of acute attacks of AHP should include pain control, antiemetics, management of systemic arterial hypertension, tachycardia, and hyponatremia, and hypomagnesemia, if present. BEST PRACTICE ADVICE 6: Patients should be counseled to avoid identifiable triggers that may precipitate acute attacks, such as alcohol and porphyrinogenic medications. BEST PRACTICE ADVICE 7: Prophylactic heme therapy or givosiran, administered in an outpatient setting, should be considered in patients with recurrent attacks (4 or more per year). BEST PRACTICE ADVICE 8: Liver transplantation for AHP should be limited to patients with intractable symptoms and significantly decreased quality of life who are refractory to pharmacotherapy. BEST PRACTICE ADVICE 9: Patients with AHP should be monitored annually for liver disease. BEST PRACTICE ADVICE 10: Patients with AHP, regardless of the severity of symptoms, should undergo surveillance for hepatocellular carcinoma, beginning at age 50 years, with liver ultrasound every 6 months. BEST PRACTICE ADVICE 11: Patients with AHP on treatment should undergo surveillance for chronic kidney disease annually with serum creatinine and estimated glomerular filtration rate. BEST PRACTICE ADVICE 12: Patients should be counseled on the chronic and long-term complications of AHP, including neuropathy, chronic kidney disease, hypertension, and hepatocellular carcinoma, and need for long-term monitoring.
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Affiliation(s)
- Bruce Wang
- Department of Medicine and Division of Gastroenterology, University of California San Francisco, San Francisco, California.
| | - Herbert L Bonkovsky
- Section of Gastroenterology and Hepatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Joseph K Lim
- Section of Digestive Diseases and Yale Liver Center, Yale University School of Medicine, New Haven, Connecticut
| | - Manisha Balwani
- Departments of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
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12
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Brenner DM, Brandt LJ, Fenster M, Hamilton MJ, Kamboj AK, Oxentenko AS, Wang B, Chey WD. Rare, Overlooked, or Underappreciated Causes of Recurrent Abdominal Pain: A Primer for Gastroenterologists. Clin Gastroenterol Hepatol 2023; 21:264-279. [PMID: 36180010 DOI: 10.1016/j.cgh.2022.09.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 09/07/2022] [Accepted: 09/08/2022] [Indexed: 01/28/2023]
Abstract
Recurrent abdominal pain is a common reason for repeated visits to outpatient clinics and emergency departments, reflecting a substantial unmet need for timely and accurate diagnosis. A lack of awareness of some of the rarer causes of recurrent abdominal pain may impede diagnosis and delay effective management. This article identifies some of the key rare but diagnosable causes that are frequently missed by gastroenterologists and provides expert recommendations to support recognition, diagnosis, and management with the ultimate aim of improving patient outcomes.
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Affiliation(s)
- Darren M Brenner
- Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
| | - Lawrence J Brandt
- Division of Gastroenterology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York
| | - Marc Fenster
- Division of Gastroenterology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York
| | - Matthew J Hamilton
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts
| | - Amrit K Kamboj
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Amy S Oxentenko
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona
| | - Bruce Wang
- Department of Medicine, University of California, San Francisco, San Francisco, California
| | - William D Chey
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, Ann Arbor, Michigan
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13
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Lissing M, Vassiliou D, Harper P, Sardh E, Wahlin S. Comment on Ramai et al. Risk of Hepatocellular Carcinoma in Patients with Porphyria: A Systematic Review. Cancers 2022, 14, 2947. Cancers (Basel) 2023; 15:795. [PMID: 36765753 PMCID: PMC9913564 DOI: 10.3390/cancers15030795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 01/17/2023] [Indexed: 01/31/2023] Open
Abstract
We read with interest this review by Ramai et al. [...].
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Affiliation(s)
- Mattias Lissing
- Hepatology Division, Department of Upper GI Diseases, Karolinska University Hospital, 17164 Stockholm, Sweden
- Department of Medicine, Huddinge, Karolinska Institutet, 14186 Stockholm, Sweden
| | - Daphne Vassiliou
- Department of Endocrinology, Karolinska University Hospital, 17164 Stockholm, Sweden
- Centre for Inherited Metabolic Diseases (CMMS), Porphyria Centre Sweden, Karolinska University Hospital, 17164 Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 14186 Stockholm, Sweden
| | - Pauline Harper
- Centre for Inherited Metabolic Diseases (CMMS), Porphyria Centre Sweden, Karolinska University Hospital, 17164 Stockholm, Sweden
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 14186 Stockholm, Sweden
| | - Eliane Sardh
- Department of Endocrinology, Karolinska University Hospital, 17164 Stockholm, Sweden
- Centre for Inherited Metabolic Diseases (CMMS), Porphyria Centre Sweden, Karolinska University Hospital, 17164 Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 14186 Stockholm, Sweden
| | - Staffan Wahlin
- Hepatology Division, Department of Upper GI Diseases, Karolinska University Hospital, 17164 Stockholm, Sweden
- Department of Medicine, Huddinge, Karolinska Institutet, 14186 Stockholm, Sweden
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14
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Recent Insights into the Pathogenesis of Acute Porphyria Attacks and Increasing Hepatic PBGD as an Etiological Treatment. LIFE (BASEL, SWITZERLAND) 2022; 12:life12111858. [PMID: 36430993 PMCID: PMC9694773 DOI: 10.3390/life12111858] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/03/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022]
Abstract
Rare diseases, especially monogenic diseases, which usually affect a single target protein, have attracted growing interest in drug research by encouraging pharmaceutical companies to design and develop therapeutic products to be tested in the clinical arena. Acute intermittent porphyria (AIP) is one of these rare diseases. AIP is characterized by haploinsufficiency in the third enzyme of the heme biosynthesis pathway. Identification of the liver as the target organ and a detailed molecular characterization have enabled the development and approval of several therapies to manage this disease, such as glucose infusions, heme replenishment, and, more recently, an siRNA strategy that aims to down-regulate the key limiting enzyme of heme synthesis. Given the involvement of hepatic hemoproteins in essential metabolic functions, important questions regarding energy supply, antioxidant and detoxifying responses, and glucose homeostasis remain to be elucidated. This review reports recent insights into the pathogenesis of acute attacks and provides an update on emerging treatments aimed at increasing the activity of the deficient enzyme in the liver and restoring the physiological regulation of the pathway. While further studies are needed to optimize gene therapy vectors or large-scale production of liver-targeted PBGD proteins, effective protection of PBGD mRNA against the acute attacks has already been successfully confirmed in mice and large animals, and mRNA transfer technology is being tested in several clinical trials for metabolic diseases.
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15
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Molina L, Zhu J, Trépo E, Bayard Q, Amaddeo G, Blanc JF, Calderaro J, Ma X, Zucman-Rossi J, Letouzé E, Chiche L, Bioulac-Sage P, Balabaud C, Possenti L, Decraecker M, Paradis V, Laurent A. Bi-allelic hydroxymethylbilane synthase inactivation defines a homogenous clinico-molecular subtype of hepatocellular carcinoma. J Hepatol 2022; 77:1038-1046. [PMID: 35636578 PMCID: PMC10061578 DOI: 10.1016/j.jhep.2022.05.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 04/22/2022] [Accepted: 05/10/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Acute intermittent porphyria (AIP), caused by heterozygous germline mutations of the heme synthesis pathway enzyme HMBS (hydroxymethylbilane synthase), confers a high risk of hepatocellular carcinoma (HCC) development. Yet, the role of HMBS in liver tumorigenesis remains unclear. METHODS Herein, we explore HMBS alterations in a large series of 758 HCC cases, including 4 patients with AIP. We quantify the impact of HMBS mutations on heme biosynthesis pathway intermediates and we investigate the molecular and clinical features of HMBS-mutated tumors. RESULTS We identify recurrent bi-allelic HMBS inactivation, both in patients with AIP acquiring a second somatic HMBS mutation and in sporadic HCC with 2 somatic hits. HMBS alterations are enriched in truncating mutations, in particular in splice regions, leading to abnormal transcript structures. Bi-allelic HMBS inactivation results in a massive accumulation of its toxic substrate porphobilinogen and synergizes with CTNNB1-activating mutations, leading to the development of well-differentiated tumors with a transcriptomic signature of Wnt/β-catenin pathway activation and a DNA methylation signature related to ageing. HMBS-inactivated HCC mostly affects females, in the absence of fibrosis and classical HCC risk factors. CONCLUSIONS These data identify HMBS as a tumor suppressor gene whose bi-allelic inactivation defines a homogenous clinical and molecular HCC subtype. LAY SUMMARY Heme (the precursor to hemoglobin, which plays a key role in oxygen transport around the body) synthesis occurs in the liver and involves several enzymes including hydroxymethylbilane synthase (HMBS). HMBS mutations cause acute intermittent porphyria, a disease caused by the accumulation of toxic porphyrin precursors. Herein, we show that HMBS inactivation is also involved in the development of liver cancers with distinct clinical and molecular characteristics.
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Affiliation(s)
- Laura Molina
- Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris, France; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
| | - Junjie Zhu
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Eric Trépo
- Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris, France; Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
| | - Quentin Bayard
- Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris, France
| | - Giuliana Amaddeo
- Université Paris Est Créteil, INSERM, IMRB, Créteil, France; INSERM, U955, Equipe 18 "Physiopathologie et Thérapeutiques des Hépatites Virales Chroniques et des cancers liés", Créteil, France; Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Service d'Hépatologie, Créteil, France
| | | | - Jean-Frédéric Blanc
- Department of Hepato-Gastroenterology and Digestive Oncology, CHU de Bordeaux, Haut-Lévêque Hospital, Bordeaux, Aquitaine, France; Department of Pathology, CHU de Bordeaux, Pellegrin Hospital, Bordeaux, Aquitaine, France; Bordeaux Research in Translational Oncology, Université Bordeaux, Bordeaux, Aquitaine, France
| | - Julien Calderaro
- Université Paris Est Créteil, INSERM, IMRB, Créteil, France; INSERM, U955, Equipe 18 "Physiopathologie et Thérapeutiques des Hépatites Virales Chroniques et des cancers liés", Créteil, France; Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Département de Pathologie, Créteil, France
| | - Xiaochao Ma
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris, France; Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.
| | - Eric Letouzé
- Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris, France; Nantes Université, Inserm UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, Nantes, France.
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16
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Wang B, Ventura P, Takase KI, Thapar M, Cassiman D, Kubisch I, Liu S, Sweetser MT, Balwani M. Disease burden in patients with acute hepatic porphyria: experience from the phase 3 ENVISION study. Orphanet J Rare Dis 2022; 17:327. [PMID: 36028858 PMCID: PMC9419398 DOI: 10.1186/s13023-022-02463-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 07/24/2022] [Indexed: 11/29/2022] Open
Abstract
Background Acute hepatic porphyria (AHP) is a family of four rare genetic diseases, each involving deficiency in a hepatic heme biosynthetic enzyme. Resultant overproduction of the neurotoxic intermediates δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) leads to disabling acute neurovisceral attacks and progressive neuropathy. We evaluated the AHP disease burden in patients aged ≥ 12 years in a post hoc analysis of the Phase 3, randomized, double-blind, placebo-controlled ENVISION trial of givosiran (NCT03338816), an RNA interference (RNAi) therapeutic that targets the enzyme ALAS1 to decrease ALA and PBG production. We analyzed baseline AHP severity via chronic symptoms between attacks, comorbidities, concomitant medications, hemin-associated complications, and quality of life (QOL) and evaluated givosiran (2.5 mg/kg monthly) in patients with and without prior hemin prophylaxis on number and severity of attacks and pain scores during and between attacks. Results Participants (placebo, n = 46; givosiran, n = 48) included patients with low and high annualized attack rates (AARs; range 0–46). At baseline, patients reported chronic symptoms (52%), including nausea, fatigue, and pain; comorbidities, including neuropathy (38%) and psychiatric disorders (47%); concomitant medications, including chronic opioids (29%); hemin-associated complications (eg, iron overload); and poor QOL (low SF-12 and EuroQol visual analog scale scores). A linear relationship between time since diagnosis and AAR with placebo suggested worsening of disease over time without effective treatment. Givosiran reduced the number and severity of attacks, days with worst pain scores above baseline, and opioid use versus placebo. Conclusions Patients with AHP, regardless of annualized attack rates, have considerable disease burden that may partly be alleviated with givosiran.
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Affiliation(s)
- Bruce Wang
- Division of Gastroenterology, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA.
| | - Paolo Ventura
- University of Modena and Reggio Emilia, Modena, Italy
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17
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Jerves T, Blau N, Ferreira CR. Clinical and biochemical footprints of inherited metabolic diseases. VIII. Neoplasias. Mol Genet Metab 2022; 136:118-124. [PMID: 35422340 PMCID: PMC9189061 DOI: 10.1016/j.ymgme.2022.03.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/23/2022] [Accepted: 03/24/2022] [Indexed: 12/21/2022]
Abstract
Cancer, caused by multiple cumulative pathogenic variants in tumor suppressor genes and proto-oncogenes, is a leading cause of mortality worldwide. The uncontrolled and rapid cell growth of the tumors requires a reprogramming of the complex cellular metabolic network to favor anabolism. Adequate management and treatment of certain inherited metabolic diseases might prevent the development of certain neoplasias, such as hepatocellular carcinoma in tyrosinemia type 1 or hepatocellular adenomas in glycogen storage disorder type 1a. We reviewed and updated the list of known metabolic etiologies associated with various types of benign and malignant neoplasias, finding 64 relevant inborn errors of metabolism. This is the eighth article of the series attempting to create a comprehensive list of clinical and metabolic differential diagnosis by system involvement.
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Affiliation(s)
- Teodoro Jerves
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Nenad Blau
- Division of Metabolism, University Children's Hospital, Zürich, Switzerland.
| | - Carlos R Ferreira
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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18
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Lissing M, Vassiliou D, Floderus Y, Harper P, Bottai M, Kotopouli M, Hagström H, Sardh E, Wahlin S. Risk of primary liver cancer in acute hepatic porphyria patients: A matched cohort study of 1244 individuals. J Intern Med 2022; 291:824-836. [PMID: 35112415 PMCID: PMC9311710 DOI: 10.1111/joim.13463] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND The acute hepatic porphyrias (AHP) are associated with a risk of primary liver cancer (PLC), but risk estimates are unclear, and what AHP characteristics that predict PLC risk are unknown. In this register-based, matched cohort study, we assessed the PLC risk in relation to biochemical and clinical porphyria severity, genotype, age, and sex. METHODS All patients in the Swedish porphyria register with acute intermittent porphyria (AIP), variegate porphyria (VP), or hereditary coproporphyria (HCP) during 1987-2015 were included. This AHP cohort was compared with age-, sex-, and county-matched reference individuals from the general population. National register-based hospital admissions for AHP were used to indicate the clinical severity. For AIP, the most common AHP type, patients were stratified by genotype and urinary porphobilinogen (U-PBG). Incident PLC data were collected from national health registers. RESULTS We identified 1244 individuals with AHP (1063 [85%] AIP). During a median follow-up of 19.5 years, we identified 108 incident PLC cases, including 83 AHP patients (6.7%) and 25 of 12,333 reference individuals (0.2%). The adjusted hazard ratio for AHP-PLC was 38.0 (95% confidence interval: 24.3-59.3). Previously elevated U-PBG and hospitalizations for porphyria, but not AIP genotype or sex, were associated with increased PLC risk. Patients aged >50 years with previously elevated U-PBG (n = 157) had an annual PLC incidence of 1.8%. CONCLUSION This study confirmed a high PLC risk and identified a strong association with clinical and biochemical AIP activity. Regular PLC surveillance is motivated in patients older than 50 years with a history of active AIP.
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Affiliation(s)
- Mattias Lissing
- Hepatology Division, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden.,Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Daphne Vassiliou
- Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden.,Centre for Inherited Metabolic Diseases (CMMS), Porphyria Centre Sweden, Karolinska University Hospital, Stockholm, Sweden.,Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Ylva Floderus
- Centre for Inherited Metabolic Diseases (CMMS), Porphyria Centre Sweden, Karolinska University Hospital, Stockholm, Sweden.,Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Pauline Harper
- Centre for Inherited Metabolic Diseases (CMMS), Porphyria Centre Sweden, Karolinska University Hospital, Stockholm, Sweden.,Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Matteo Bottai
- Division of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Marianna Kotopouli
- Division of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Hannes Hagström
- Hepatology Division, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden.,Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.,Unit for Clinical Epidemiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Eliane Sardh
- Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden.,Centre for Inherited Metabolic Diseases (CMMS), Porphyria Centre Sweden, Karolinska University Hospital, Stockholm, Sweden.,Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Staffan Wahlin
- Hepatology Division, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden.,Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
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19
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Córdoba KM, Jericó D, Sampedro A, Jiang L, Iraburu MJ, Martini PGV, Berraondo P, Avila MA, Fontanellas A. Messenger RNA as a personalized therapy: The moment of truth for rare metabolic diseases. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 372:55-96. [PMID: 36064267 DOI: 10.1016/bs.ircmb.2022.03.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Inborn errors of metabolism (IEM) encompass a group of monogenic diseases affecting both pediatric and adult populations and currently lack effective treatments. Some IEM such as familial hypercholesterolemia or X-linked protoporphyria are caused by gain of function mutations, while others are characterized by an impaired protein function, causing a metabolic pathway blockage. Pathophysiology classification includes intoxication, storage and energy-related metabolic disorders. Factors specific to each disease trigger acute metabolic decompensations. IEM require prompt and effective care, since therapeutic delay has been associated with the development of fatal events including severe metabolic acidosis, hyperammonemia, cerebral edema, and death. Rapid expression of therapeutic proteins can be achieved hours after the administration of messenger RNAs (mRNA), representing an etiological solution for acute decompensations. mRNA-based therapy relies on modified RNAs with enhanced stability and translatability into therapeutic proteins. The proteins produced in the ribosomes can be targeted to specific intracellular compartments, the cell membrane, or be secreted. Non-immunogenic lipid nanoparticle formulations have been optimized to prevent RNA degradation and to allow safe repetitive administrations depending on the disease physiopathology and clinical status of the patients, thus, mRNA could be also an effective chronic treatment for IEM. Given that the liver plays a key role in most of metabolic pathways or can be used as bioreactor for excretable proteins, this review focuses on the preclinical and clinical evidence that supports the implementation of mRNA technology as a promising personalized strategy for liver metabolic disorders such as acute intermittent porphyria, ornithine transcarbamylase deficiency or glycogen storage disease.
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Affiliation(s)
- Karol M Córdoba
- Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Daniel Jericó
- Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Ana Sampedro
- Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Lei Jiang
- Moderna Inc, Cambridge, MA, United States
| | - María J Iraburu
- Department of Biochemistry and Genetics. School of Sciences, University of Navarra, Pamplona, Spain
| | | | - Pedro Berraondo
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Program of Immunology and Immunotherapy, CIMA-University of Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Matías A Avila
- Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Antonio Fontanellas
- Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
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20
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Sirch C, Khanna N, Frassetto L, Bianco F, Artero ML. Diagnosis of acute intermittent porphyria in a renal transplant patient: A case report. World J Transplant 2022; 12:8-14. [PMID: 35096552 PMCID: PMC8771597 DOI: 10.5500/wjt.v12.i1.8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 11/16/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute intermittent porphyria (AIP) is an inherited disorder of porphyrin metabolism with a worldwide distribution and a prevalence ranging from 1 to 9 per million population. AIP is caused by an autosomal dominant-inherited mutation of low penetrance resulting in a deficiency of porphobilinogen deaminase (PBGD) activity. Acute attacks are provoked by stressors such as certain medications, alcohol, and infection. We herein present the first case report of AIP detected in a post-renal transplant patient. CASE SUMMARY The patient was a 65-year-old man who underwent transplantation 2 years previously for suspected nephroangiosclerosis and chronic interstitial nephro-pathy. He subsequently developed diabetes mellitus which required insulin therapy. He had been treated in the recent past with local mesalamine for proctitis. He presented with classic but common symptoms of AIP including intense abdominal pain, hypertension, and anxiety. He had multiple visits to the emergency room over a 6-mo period for these same symptoms before the diagnosis of AIP was entertained. His urinary postprandial blood glucose level was 60 mg/24 h (normal, < 2 mg/24 h). He was placed on a high carbohydrate diet, and his symptoms slowly improved. CONCLUSION This case report describes a common presentation of an uncommon disease, in which post-transplant complications and medications may have contributed to precipitating the previously undiagnosed AIP. We hypothesize that the low-carbohydrate diet and insulin with which our patient was treated may have led to the attacks of AIP. Alternatively, our patient's mesalamine treatment for proctitis may have led to an acute AIP crisis. A high index of suspicion is needed to consider the diagnosis of a heme synthesis disorder, which presents with the common symptoms of abdominal pain, high blood pressure, and anxiety.
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Affiliation(s)
- Cristina Sirch
- Nefrologia e Dialisi, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste 34100, Italy
| | - Niloufar Khanna
- Medicine, California Northstate University, Elk Grove, CA 95757, United States
| | - Lynda Frassetto
- Internal Medicine, Division of Nephrology, University of California San Francisco, San Francisco, CA 94193, United States
| | - Francesco Bianco
- Nefrologia e Dialisi, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste 34100, Italy
| | - Mary Louise Artero
- Nefrologia e Dialisi, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste 34100, Italy
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21
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Abstract
PURPOSE OF REVIEW Acute hepatic porphyrias (AHP) are a group of rare diseases that are characterized by episodic acute neurovisceral pain episodes caused by abnormal accumulation of the neurotoxic porphyrin precursor delta-aminolevulinic acid (ALA). Patient with frequent recurrent acute attacks have been difficult to treat and these patients sometimes require liver transplantation. Recent developments in small interfering RNA (siRNA)-based therapy led to the development of an effective prophylactic treatment for patients with frequent recurrent attacks. This review will describe treatment options for AHP and highlight management in light of new treatment option. RECENT FINDINGS Givosiran is a novel siRNA-based therapy targeted specifically to hepatocytes to inhibit ALA synthase 1, the first and rate-limiting step in heme biosynthesis. Patients with frequent recurrent attacks treated with givosiran had durable normalization of ALA and significantly reduced numbers of acute attacks and need for hemin treatment. The overall safety profile for givosiran was comparable with placebo and the drug was recently approved by the Food and Drug Administration for treatment of AHP patients. SUMMARY Givosiran is an effective treatment for prevention of acute porphyria attacks in AHP patients with frequent recurrent attacks.
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Affiliation(s)
- Bruce Wang
- Department of Medicine, University of California, San Francisco, San Francisco, California, USA
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22
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Saberi B, Naik H, Overbey JR, Erwin AL, Anderson KE, Bissell DM, Bonkovsky HL, Phillips JD, Wang B, K Singal A, M McGuire B, Desnick RJ, Balwani M. Hepatocellular Carcinoma in Acute Hepatic Porphyrias: Results from the Longitudinal Study of the U.S. Porphyrias Consortium. Hepatology 2021; 73:1736-1746. [PMID: 32681675 DOI: 10.1002/hep.31460] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 06/26/2020] [Accepted: 07/01/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS The risk for hepatocellular carcinoma (HCC) is increased in acute hepatic porphyrias (AHP). The aim of this study was to explore the clinicopathologic characteristics, outcomes, and frequency of HCC in patients with AHP in the United States. APPROACH AND RESULTS This cross-sectional analysis evaluated patients with HCC in a multicenter, longitudinal study of AHP. Among 327 patients with AHP, 5 (1.5%) were diagnosed with HCC. Of the 5 HCC cases, 4 had acute intermittent porphyria and 1 had variegate porphyria, confirmed by biochemical and/or genetic testing. All patients were white females, with a median age of 27 years (range 21-75) at diagnosis. The median age at HCC diagnosis was 69 years (range 61-74). AHP was asymptomatic in 2 patients; 2 reported sporadic attacks; and 1 reported recurrent attacks (>4 attacks/year). All patients had a single HCC lesion on liver imaging that was 1.8-6.5 centimeters in diameter. Serum alpha fetoprotein levels were below 10 ng/mL in all 4 patients with available results. Four patients underwent liver resection, and 1 was treated with radioembolization. No significant inflammation or fibrosis was found in adjacent liver tissues of 3 patients who underwent liver resection. Two patients developed recurrence of HCC at 22 and 26 months following liver resection. All patients are alive with survival times from HCC diagnosis ranging from 26-153 months. CONCLUSION In this U.S. study, 1.5% of patients with AHP had HCC. HCC in AHP occurred in the absence of cirrhosis, which contrasts with other chronic liver diseases. Patients with AHP, regardless of clinical attacks, should be screened for HCC, beginning at age 50. The pathogenesis of hepatocarcinogenesis in AHP is unknown and needs further investigation.
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Affiliation(s)
- Behnam Saberi
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Hetanshi Naik
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Jessica R Overbey
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY
| | | | - Karl E Anderson
- Department of Preventive Medicine and Population Health, University of Texas Medical Branch, Galveston, TX
| | | | - Herbert L Bonkovsky
- Section on Gastroenterology and Hepatology, Department of Internal Medicine, Wake Forest/NC Baptist Medical Center, Winston-Salem, NC
| | - John D Phillips
- Department of Internal Medicine, University of Utah, Salt Lake City, UT
| | - Bruce Wang
- Department of Medicine, University of California, San Francisco, CA
| | - Ashwani K Singal
- Department of Internal Medicine, University of South Dakota, Sioux Falls, SD.,Division of Hepatology, Avera Transplant Institute, Sioux Falls, SD
| | | | - Robert J Desnick
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Manisha Balwani
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
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23
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Anderson KE, Lobo R, Salazar D, Schloetter M, Spitzer G, White AL, Young RM, Bonkovsky HL, Frank EL, Mora J, Tortorelli S. Biochemical Diagnosis of Acute Hepatic Porphyria: Updated Expert Recommendations for Primary Care Physicians. Am J Med Sci 2021; 362:113-121. [PMID: 33865828 DOI: 10.1016/j.amjms.2021.03.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 02/05/2021] [Accepted: 03/10/2021] [Indexed: 01/06/2023]
Abstract
Acute hepatic porphyria (AHP) is a group of rare, metabolic diseases where patients can experience acute neurovisceral attacks, chronic symptoms, and long-term complications. Diagnostic biochemical testing is widely available and effective, but a substantial time from symptom onset to diagnosis often delays treatment and increases morbidity. A panel of laboratory scientists and clinical AHP specialists collaborated to produce recommendations on how to enhance biochemical diagnosis of AHP in the USA. AHP should be considered in the differential diagnosis of unexplained abdominal pain, the most common symptom, soon after excluding common causes. Measurement of porphobilinogen (PBG) and porphyrins in a random urine sample, with results normalized to creatinine, is recommended as an effective and cost-efficient initial test for AHP. Delta-aminolevulinic acid testing may be included but is not essential. The optimal time to collect a urine sample is during an attack. Substantial PBG elevation confirms an AHP diagnosis and allows for prompt treatment initiation. Additional testing can determine AHP subtype and identify at-risk family members. Increased awareness of AHP and correct diagnostic methods will reduce diagnostic delay and improve patient outcomes.
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Affiliation(s)
| | - Raynah Lobo
- Quest Diagnostics, Nichols Institute, San Juan Capistrano, CA, USA
| | - Denise Salazar
- Quest Diagnostics, Nichols Institute, San Juan Capistrano, CA, USA
| | | | - Gary Spitzer
- Strategic Medical Testing Services, Greenville, SC, USA
| | - Amy L White
- Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Randolph M Young
- Special Chemistry Department, LabCorp Center for Esoteric Testing, Burlington, NC, USA
| | | | - Elizabeth L Frank
- Department of Pathology and ARUP Laboratories, University of Utah, Salt Lake City, UT, USA
| | | | - Silvia Tortorelli
- Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
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24
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Lissing M, Nowak G, Adam R, Karam V, Boyd A, Gouya L, Meersseman W, Melum E, Ołdakowska‐Jedynak U, Reiter FP, Colmenero J, Sanchez R, Herden U, Langendonk J, Ventura P, Isoniemi H, Boillot O, Braun F, Perrodin S, Mowlem E, Wahlin S, European Liver and Intestine Transplant Association. Liver Transplantation for Acute Intermittent Porphyria. Liver Transpl 2021; 27:491-501. [PMID: 37160035 PMCID: PMC8248103 DOI: 10.1002/lt.25959] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 10/19/2020] [Accepted: 11/03/2020] [Indexed: 12/14/2022]
Abstract
Recurrent attacks of acute intermittent porphyria (AIP) result in poor quality of life and significant risks of morbidity and mortality. Liver transplantation (LT) offers a cure, but published data on outcomes after LT are limited. We assessed the pretransplant characteristics, complications, and outcomes for patients with AIP who received a transplant. Data were collected retrospectively from the European Liver Transplant Registry and from questionnaires sent to identified transplant and porphyria centers. We studied 38 patients who received transplants in 12 countries from 2002 to 2019. Median age at LT was 37 years (range, 18-58), and 34 (89%) of the patients were women. A total of 9 patients died during follow-up, and 2 patients were retransplanted. The 1-year and 5-year overall survival rates were 92% and 82%, which are comparable with other metabolic diseases transplanted during the same period. Advanced pretransplant neurological impairment was associated with increased mortality. The 5-year survival rate was 94% among 19 patients with moderate or no neuropathy at LT and 83% among 10 patients with severe neuropathy (P = 0.04). Pretransplant renal impairment was common. A total of 19 (51%) patients had a GFR < 60 mL/minute. Although few patients improved their renal function after LT, neurological impairments improved, and no worsening of neurological symptoms was recorded. No patient had AIP attacks after LT, except for a patient who received an auxiliary graft. LT is a curative treatment option for patients with recurrent attacks of AIP. Severe neuropathy and impaired renal function are common and increase the risk for poor outcomes. If other treatment options fail, an evaluation for LT should be performed early.
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Affiliation(s)
- Mattias Lissing
- Hepatology DivisionDepartment of Upper GI DiseasesPorphyria Centre SwedenKarolinska Institutet and Karolinska University HospitalStockholmSweden
| | - Greg Nowak
- Department of Clinical Science, Intervention and Technology (CLINTEC)Karolinska Institutet and Karolinska University HospitalStockholmSweden
| | - René Adam
- Paul Brousse HospitalUniversity Paris‐SudInserm U935VillejuifFrance
| | - Vincent Karam
- Paul Brousse HospitalUniversity Paris‐SudInserm U935VillejuifFrance
| | | | - Laurent Gouya
- Centre Francais des PorphyriesHôpital Louis MourierAssistance Publique‐Hôpitaux de ParisParisFrance
| | - Wouter Meersseman
- Department of General Internal MedicineUniversitair Ziekenhuis (UZ) LeuvenLeuvenBelgium
| | - Espen Melum
- Section for GastroenterologyNorwegian Primary Sclerosing Cholangitis (PSC) Research CenterDepartment of Transplantation MedicineResearch Institute of Internal MedicineDivision of SurgeryInflammatory Diseases and TransplantationOslo University Hospital RikshospitaletHybrid Technology Hub‐Centre of ExcellenceInstitute of Basic Medical SciencesInstitute of Clinical MedicineFaculty of MedicineUniversity of OsloOsloNorway
| | | | - Florian P. Reiter
- Liver Center MunichDepartment of Medicine IIUniversity HospitalLudwig Maximilian University (LMU) MunichMunichGermany
| | - Jordi Colmenero
- Liver Transplant UnitHospital Clínic de BarcelonaInstitut d'Investigacions Biomèdiques August Pi i SunyerCentro de Investigación Biomédica en Red en Enfermedades Hepáticas y DigestivasUniversitat de BarcelonaBarcelonaSpain
| | - Rosario Sanchez
- Institute of Sanitary and Biomedical Investigation of AlicanteAlicanteSpain
| | - Uta Herden
- Department of Visceral Transplant SurgeryUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Janneke Langendonk
- Erasmus MCUniversity Medical Center RotterdamPorphyria Center RotterdamRotterdamThe Netherlands
| | - Paolo Ventura
- Department of Medical and Surgical Sciences for Children and AdultsUniversity of Modena and Reggio EmiliaUnit of Internal MedicinePoliclinico Hospital of ModenaModenaItaly
| | - Helena Isoniemi
- Department of Transplantation and Liver SurgeryHelsinki University HospitalHelsinkiFinland
| | | | - Felix Braun
- Department of General, Visceral, Thoracic, Transplantation and Pediatric SurgeryUniversitätsklinikum Schleswig‐Holstein (UKSH)Campus KielKielGermany
| | - Stéphanie Perrodin
- Department of Visceral Surgery and MedicineInselspital University Hospital of BernBernSwitzerland
| | - Elizabeth Mowlem
- The Liver UnitAddenbrooke's HospitalCambridge University HospitalsCambridgeUK
| | - Staffan Wahlin
- Hepatology DivisionDepartment of Upper GI DiseasesPorphyria Centre SwedenKarolinska Institutet and Karolinska University HospitalStockholmSweden
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25
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PPO-Inhibiting Herbicides and Structurally Relevant Schiff Bases: Evaluation of Inhibitory Activities against Human Protoporphyrinogen Oxidase. Processes (Basel) 2021. [DOI: 10.3390/pr9020383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The study of human protoporphyrinogen oxidase (hPPO) inhibition can contribute significantly to a better understanding of some pathogeneses (e.g., porphyria, herbicide exposure) and the development of anticancer agents. Therefore, we prepared new potential inhibitors with Schiff base structural motifs (2-hydroxybenzaldehyde-based Schiff bases 9–13 and chromanone derivatives 17–19) as structurally relevant to PPO herbicides. The inhibitory activities (represented by the half maximal inhibitory concentration (IC50) values) and enzymatic interactions (represented by the hPPO melting temperatures) of these synthetic compounds and commercial PPO herbicides used against hPPO were studied by a protoporphyrin IX fluorescence assay. In the case of PPO herbicides, significant hPPO inhibition and changes in melting temperature were observed for oxyfluorten, oxadiazon, lactofen, butafenacil, saflufenacil, oxadiargyl, chlornitrofen, and especially fomesafen. Nevertheless, the prepared compounds did not display significant inhibitory activity or changes in the hPPO melting temperature. However, a designed model of hPPO inhibitors based on the determined IC50 values and a docking study (by using AutoDock) found important parts of the herbicide structural motif for hPPO inhibition. This model could be used to better predict PPO herbicidal toxicity and improve the design of synthetic inhibitors.
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26
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Linenberger M, Fertrin KY. Updates on the diagnosis and management of the most common hereditary porphyrias: AIP and EPP. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2020; 2020:400-410. [PMID: 33275677 PMCID: PMC7727547 DOI: 10.1182/hematology.2020000124] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/02/2023]
Abstract
The porphyrias are a family of metabolic disorders caused by defects in the activity of one of the enzymes in the heme biosynthetic pathway. Acute intermittent porphyria (AIP), caused by autosomal dominant mutations in the gene encoding hydroxymethylbilane synthase, can lead to hepatocyte overaccumulation and systemic distribution of the proximal porphyrin precursors, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). ALA and PBG are toxic to neurons and extrahepatic tissue and cause the neurovisceral clinical manifestations of AIP. Management of AIP includes awareness and avoidance of triggering factors, infusions of hemin for severe acute attacks, and, if indicated for chronic suppressive therapy, maintenance treatment with hemin or givosiran, a small interfering RNA molecule that antagonizes ALA synthase 1 transcripts. Erythropoietic protoporphyria (EPP) is most commonly caused by autosomal recessive mutations in the gene encoding ferrochelatase (FECH), the heme pathway terminal enzyme. FECH deficiency leads to erythrocyte overaccumulation and high plasma levels of lipophilic protoporphyrins that photoactivate in the skin, causing burning pain and erythema. Protoporphyrins excreted in the bile can cause gallstones, cholestasis, fibrosis, and ultimately liver failure. Management of EPP includes skin protection and afamelanotide, an α-melanocyte stimulating hormone analog that increases melanin pigment and reduces photoactivation. Liver transplantation may be necessary for severe EPP-induced liver complications. Because AIP and EPP arise from defects in the heme biosynthetic pathway, hematologists are often consulted to evaluate and manage suspected or proven porphyrias. A working knowledge of these disorders increases our confidence and effectiveness as consultants and medical providers.
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27
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Chidambaranathan-Reghupaty S, Fisher PB, Sarkar D. Hepatocellular carcinoma (HCC): Epidemiology, etiology and molecular classification. Adv Cancer Res 2020; 149:1-61. [PMID: 33579421 PMCID: PMC8796122 DOI: 10.1016/bs.acr.2020.10.001] [Citation(s) in RCA: 505] [Impact Index Per Article: 101.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC), the primary malignancy of hepatocytes, is a diagnosis with bleak outcome. According to National Cancer Institute's SEER database, the average five-year survival rate of HCC patients in the US is 19.6% but can be as low as 2.5% for advanced, metastatic disease. When diagnosed at early stages, it is treatable with locoregional treatments including surgical resection, Radio-Frequency Ablation, Trans-Arterial Chemoembolization or liver transplantation. However, HCC is usually diagnosed at advanced stages when the tumor is unresectable, making these treatments ineffective. In such instances, systemic therapy with tyrosine kinase inhibitors (TKIs) becomes the only viable option, even though it benefits only 30% of patients, provides only a modest (~3months) increase in overall survival and causes drug resistance within 6months. HCC, like many other cancers, is highly heterogeneous making a one-size fits all option problematic. The selection of liver transplantation, locoregional treatment, TKIs or immune checkpoint inhibitors as a treatment strategy depends on the disease stage and underlying condition(s). Additionally, patients with similar disease phenotype can have different molecular etiology making treatment responses different. Stratification of patients at the molecular level would facilitate development of the most effective treatment option. With the increase in efficiency and affordability of "omics"-level analysis, considerable effort has been expended in classifying HCC at the molecular, metabolic and immunologic levels. This review examines the results of these efforts and the ways they can be leveraged to develop targeted treatment options for HCC.
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Affiliation(s)
- Saranya Chidambaranathan-Reghupaty
- C. Kenneth and Dianne Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA, United States
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States.
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28
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de Oliveira Neves AC, Galván I. 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. Bioessays 2020; 42:e2000155. [PMID: 33155299 DOI: 10.1002/bies.202000155] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 08/27/2020] [Indexed: 11/06/2022]
Abstract
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.
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Affiliation(s)
| | - Ismael Galván
- Department of Evolutionary Ecology, Doñana Biological Station, CSIC, Sevilla, 41092, Spain
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29
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Gouya L, Ventura P, Balwani M, Bissell DM, Rees DC, Stölzel U, Phillips JD, Kauppinen R, Langendonk JG, Desnick RJ, Deybach J, Bonkovsky HL, Parker C, Naik H, Badminton M, Stein PE, Minder E, Windyga J, Bruha R, Cappellini MD, Sardh E, Harper P, Sandberg S, Aarsand AK, Andersen J, Alegre F, Ivanova A, Talbi N, Chan A, Querbes W, Ko J, Penz C, Liu S, Lin T, Simon A, Anderson KE. EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks. Hepatology 2020; 71:1546-1558. [PMID: 31512765 PMCID: PMC7255459 DOI: 10.1002/hep.30936] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 09/04/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. APPROACH AND RESULTS EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. CONCLUSIONS Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies.
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Affiliation(s)
- Laurent Gouya
- Centre de Référence Maladies Rares PorphyriesColombesFrance
- University of ParisParisFrance
- Laboratory of Excellence GR‐ExParisFrance
| | - Paolo Ventura
- Università degli Studi di Modena e Reggio EmiliaEmilia‐RomagnaItaly
| | | | | | - David C. Rees
- King’s College HospitalKing’s College LondonLondonUK
| | | | | | | | - Janneke G. Langendonk
- Porphyria CenterCenter for Lysosomal and Metabolic DiseaseDepartment of Internal MedicineErasmus MCUniversity Medical Center Rotterdamthe Netherlands
| | | | - Jean‐Charles Deybach
- Centre de Référence Maladies Rares PorphyriesColombesFrance
- University of ParisParisFrance
- Laboratory of Excellence GR‐ExParisFrance
| | - Herbert L. Bonkovsky
- Section on Gastroenterology & HepatologyWake Forest University/NC Baptist Medical CenterWinston‐SalemNC
| | | | | | | | | | | | - Jerzy Windyga
- Department of Hemostatic Disorders and Internal MedicineInstitute of Hematology and Transfusion MedicineWarsawPoland
| | - Radan Bruha
- 4th Internal ClinicGeneral University HospitalCharles UniversityPragueCzech Republic
| | | | - Eliane Sardh
- Porphyria Centre Sweden, Centre for Inherited Metabolic DiseasesKarolinska Institutet, Karolinska University HospitalStockholmSweden
| | - Pauline Harper
- Porphyria Centre Sweden, Centre for Inherited Metabolic DiseasesKarolinska Institutet, Karolinska University HospitalStockholmSweden
| | - Sverre Sandberg
- Norwegian Porphyria CentreHaukeland University HospitalBergenNorway
| | - Aasne K. Aarsand
- Norwegian Porphyria CentreHaukeland University HospitalBergenNorway
| | - Janice Andersen
- Norwegian Porphyria CentreHaukeland University HospitalBergenNorway
| | | | | | - Neila Talbi
- Centre de Référence Maladies Rares PorphyriesColombesFrance
- University of ParisParisFrance
- Laboratory of Excellence GR‐ExParisFrance
| | - Amy Chan
- Alnylam PharmaceuticalsCambridgeMA
| | | | - John Ko
- Alnylam PharmaceuticalsCambridgeMA
| | | | | | - Tim Lin
- Alnylam PharmaceuticalsCambridgeMA
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30
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Fontanellas A, Ávila MA, Anderson KE, Deybach JC. Current and innovative emerging therapies for porphyrias with hepatic involvement. J Hepatol 2019; 71:422-433. [PMID: 31102718 DOI: 10.1016/j.jhep.2019.05.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 04/24/2019] [Accepted: 05/03/2019] [Indexed: 01/19/2023]
Abstract
Porphyrias are rare inherited disorders caused by specific enzyme dysfunctions in the haem synthesis pathway, which result in abnormal accumulation of specific pathway intermediates. The symptoms depend upon the chemical characteristics of these substances. Porphyrins are photoreactive and cause photocutaneous lesions on sunlight-exposed areas, whereas accumulation of porphyrin precursors is related to acute neurovisceral attacks. Current therapies are suboptimal and mostly address symptoms rather than underlying disease mechanisms. Advances in the understanding of the molecular bases and pathogenesis of porphyrias have paved the way for the development of new therapeutic strategies. In this Clinical Trial Watch we summarise the basic principles of these emerging approaches and what is currently known about their application to porphyrias of hepatic origin or with hepatic involvement.
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Affiliation(s)
- Antonio Fontanellas
- Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain. Instituto de Salud Carlos III, Spain.
| | - Matías A Ávila
- Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain. Instituto de Salud Carlos III, Spain
| | - Karl E Anderson
- Porphyria Laboratory & Center, Departments of Preventive Medicine and Community Health, and Internal Medicine (Division of Gastroenterology), University of Texas Medical Branch, Galveston, TX, USA
| | - Jean-Charles Deybach
- CRMR Porphyries France, Assistance Publique-Hôpitaux de Paris (AP-HP), University Denis Diderot Paris 7, France; European Porphyria Network (EPNET)
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Martini PGV, Guey LT. A New Era for Rare Genetic Diseases: Messenger RNA Therapy. Hum Gene Ther 2019; 30:1180-1189. [PMID: 31179759 DOI: 10.1089/hum.2019.090] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Exogenous delivery of messenger RNA (mRNA) is emerging as a new class of medicine with broad applicability including the potential to treat rare monogenic disorders. Recent advances in mRNA technology, including modifications to the mRNA itself along with improvements to the delivery vehicle, have transformed the utility of mRNA as a potential therapy to restore or replace different types of therapeutic proteins. Preclinical proof-of-concept has been demonstrated for mRNA therapy for three different rare metabolic disorders: methylmalonic acidemia, acute intermittent porphyria, and Fabry disease. Herein, we review those preclinical efficacy and safety studies in multiple animal models. For all three disorders, mRNA therapy restored functional protein to therapeutically relevant levels in target organs, led to sustained and reproducible pharmacology following each dose administration of mRNA, and was well tolerated as supported by liver function tests evaluated in animal models including nonhuman primates. These data provide compelling support for the clinical development of mRNA therapy as a treatment for various rare metabolic disorders.
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Affiliation(s)
| | - Lin T Guey
- Rare Diseases, Moderna, Inc., Cambridge, Massachusetts
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Berraondo P, Martini PGV, Avila MA, Fontanellas A. Messenger RNA therapy for rare genetic metabolic diseases. Gut 2019; 68:1323-1330. [PMID: 30796097 DOI: 10.1136/gutjnl-2019-318269] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 02/04/2019] [Accepted: 02/05/2019] [Indexed: 12/12/2022]
Abstract
Decades of intense research in molecular biology and biochemistry are fructifying in the emergence of therapeutic messenger RNAs (mRNA) as a new class of drugs. Synthetic mRNAs can be sequence optimised to improve translatability into proteins, as well as chemically modified to reduce immunogenicity and increase chemical stability using naturally occurring uridine modifications. These structural improvements, together with the development of safe and efficient vehicles that preserve mRNA integrity in circulation and allow targeted intracellular delivery, have paved the way for mRNA-based therapeutics. Indeed, mRNAs formulated into biodegradable lipid nanoparticles are currently being tested in preclinical and clinical studies for multiple diseases including cancer immunotherapy and vaccination for infectious diseases. An emerging application of mRNAs is the supplementation of proteins that are not expressed or are not functional in a regulated and tissue-specific manner. This so-called 'protein replacement therapy' could represent a solution for genetic metabolic diseases currently lacking effective treatments. Here we summarise this new class of drugs and discuss the preclinical evidence supporting the potential of liver-mediated mRNA therapy for three rare genetic conditions: methylmalonic acidaemia, acute intermittent porphyria and ornithine transcarbamylase deficiency.
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Affiliation(s)
- Pedro Berraondo
- Immunology and Immunotherapy Program, Centro de Investigación Médica Aplicada (Cima), University of Navarra, Pamplona, Navarra, Spain.,Centro de Investigación Biomédica en Red de Cáncer, CIBERonc, Instituto de Salud Carlos III, Madrid, Spain.,Instituto de Investigación Sanitaria de Navarra IdiSNA, Pamplona, Spain
| | | | - Matias A Avila
- Instituto de Investigación Sanitaria de Navarra IdiSNA, Pamplona, Spain.,Hepatology Program, CIMA, University of Navarra, Pamplona, Navarra, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Antonio Fontanellas
- Instituto de Investigación Sanitaria de Navarra IdiSNA, Pamplona, Spain.,Hepatology Program, CIMA, University of Navarra, Pamplona, Navarra, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
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