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Advances in Diagnosis and Treatment of Porphyrias
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Advances in Diagnosis and Treatment of Porphyrias

A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 27558

Special Issue Editor

Dr. Paolo Ventura

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Guest Editor
Internal Medicine Unit, Department of Medical and Surgical Science for Children and Adults, Regional Reference Center for Diagnosing and Management of Porphyrias, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria Policlinico of Modena, Largo del Pozzo 71, 41124 Modena, Italy
Interests: porphyrias; homocysteine; liver cirrhosis; portal hypertension; hepatocellular carcinoma; liver transplantation; portal vein thrombosis

Special Issue Information

Dear Colleagues,

Porphyrias are a complex group of rare and mostly inherited metabolic disorders of heme biosynthesis. They are characterized by confusing or easily misleading clinical features, mostly requiring appropriate knowledge to be correctly diagnosed and treated in order to avoid possible severe progression to fatal events.

The aim of this Special Issue is to provide the readers with the latest advances in the diagnosis and treatment of porphyrias. The volume will be intended for clinicians working in emergency, internal and general medicine, laboratory, gastroenterology, hematology, dermatology, medical genetics, neurology, neurology and psychology/psychiatric units. Among the topics, we will consider biochemical and/or genetic diagnosis of porphyrias, covering from classical to the latest laboratory techniques, including the quality control schemes, such as algorithms for differential diagnosis, available for porphyrias. Clinical and/or genetic epidemiology and natural history data of these diseases will be included as well. The treatment of porphyrias, including the latest novel approaches and clinical trial results, will be another topic of the Issue. Special attention will be also given to the molecular basis of diseases and the molecular targets of the most recently available treatments. Psychosocial aspects related to porphyrias are also an emerging issue in this field, and thus these aspects could also be covered, even considering their great interest in the future. Mini-reviews, short reports and original articles covering these aspects will be considered for this Special Issue.

Dr. Paolo Ventura
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Diagnostics is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Porphyrias 
  • Acute hepatic porphyrias 
  • Erythropoietic protoporphyria 
  • Porphyria cutanea tarda 
  • Congenital erythropoietic porphyria 
  • Genetic diagnosis 
  • Biochemical analysis 
  • Quality control 
  • Delta-aminolevulinic acid (ALA) 
  • Neurotoxicity 
  • Photodermatoses 
  • Enzymatic therapy 
  • Molecular therapy 
  • Psychological aspects 
  • Quality of life (QoL) assessment 
  • Liver and renal failure 
  • Neurological complications 
  • Hepatocellular carcinoma

Published Papers (7 papers)

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Research

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13 pages, 1834 KiB  
Communication
α-Lipoic Acid Improves Hepatic Metabolic Dysfunctions in Acute Intermittent Porphyria: A Proof-of-Concept Study
by Miriam Longo, Erika Paolini, Marica Meroni, Lorena Duca, Irene Motta, Anna Ludovica Fracanzani, Elena Di Pierro and Paola Dongiovanni
Diagnostics 2021, 11(9), 1628; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11091628 - 06 Sep 2021
Cited by 8 | Viewed by 2521
Abstract
Background: Acute intermittent porphyria (AIP) is caused by the haploinsufficiency of porphobilinogen deaminase (PBGD) enzymatic activity. Acute attacks occur in response to fasting, and alterations in glucose metabolism, insulin resistance, and mitochondrial turnover may be involved in AIP pathophysiology. Therefore, we investigated the [...] Read more.
Background: Acute intermittent porphyria (AIP) is caused by the haploinsufficiency of porphobilinogen deaminase (PBGD) enzymatic activity. Acute attacks occur in response to fasting, and alterations in glucose metabolism, insulin resistance, and mitochondrial turnover may be involved in AIP pathophysiology. Therefore, we investigated the metabolic pathways in PBGD-silenced hepatocytes and assessed the efficacy of an insulin mimic, α-lipoic acid (α-LA), as a potential therapeutic strategy. Methods: HepG2 cells were transfected with siRNA-targeting PBGD (siPBGD). Cells were cultured with low glucose concentration to mimic fasting and exposed to α-LA alone or with glucose. Results: At baseline, siPBGD cells showed a lower expression of genes involved in glycolysis and mitochondrial dynamics along with reduced total ATP levels. Fasting further unbalanced glycolysis by inducing ATP shortage in siPBGD cells and activated DRP1, which mediates mitochondrial separation. Consistently, siPBGD cells in the fasted state showed the lowest protein levels of Complex IV, which belongs to the oxidative phosphorylation (OXPHOS) machinery. α-LA upregulated glycolysis and prompted ATP synthesis and triglyceride secretion, thus possibly providing energy fuels to siPBGD cells by improving glucose utilization. Finally, siPBGD exposed to α-LA plus glucose raised mitochondrial dynamics, OXPHOS activity, and energy production. Conclusions: α-LA-based therapy may ameliorate glucose metabolism and mitochondrial dysfunctions in siPBGD hepatocytes. Full article
(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Porphyrias)
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Review

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20 pages, 1823 KiB  
Review
Therapy Follows Diagnosis: Old and New Approaches for the Treatment of Acute Porphyrias, What We Know and What We Should Know
by Petro E. Petrides
Diagnostics 2022, 12(7), 1618; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics12071618 - 03 Jul 2022
Cited by 7 | Viewed by 2119
Abstract
Heme, iron protoporphyrin IX, is one of life’s most central molecules. Hence, availability of the enzymatic machinery necessary for its synthesis is crucial for every cell. Consequently, inborn errors of porphyrin metabolism that compromise normal synthesis, namely the family of porphyrias, undermine normal [...] Read more.
Heme, iron protoporphyrin IX, is one of life’s most central molecules. Hence, availability of the enzymatic machinery necessary for its synthesis is crucial for every cell. Consequently, inborn errors of porphyrin metabolism that compromise normal synthesis, namely the family of porphyrias, undermine normal cellular metabolism given that heme has functions in catalytic centers, signal transduction and functional regulation and its synthesis is fully integrated into the center of intermediary metabolism. Very often, diagnosis of porphyrias is difficult and therefore delayed. Therapy can be as complicated. Over the last 50 years, several strategies have been developed: because of its integration with other parts of intermediary metabolism, the infusion of glucose (glucose effect) was one of the first attempts to counterbalance the dysregulation of porphyrin synthesis in porphyrias. Since heme synthesis is impaired, infusional replacement of heme was the next important therapeutic step. Recently, siRNA technology has been introduced in order to downregulate 5-ALA-synthase 1, which contributes to the patho-physiology of these diseases. Moreover, other novel therapies using enzyme protein replacement, mRNA techniques or proteostasis regulators are being developed. Full article
(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Porphyrias)
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16 pages, 819 KiB  
Review
Psychological Aspect and Quality of Life in Porphyrias: A Review
by Granata Francesca, Annamaria Nicolli, Alessia Colaiocco, Elena Di Pierro and Giovanna Graziadei
Diagnostics 2022, 12(5), 1193; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics12051193 - 10 May 2022
Cited by 3 | Viewed by 2199
Abstract
The World Health Organization (WHO) describes “health” as a state of physical, mental, and social well-being and not merely the absence of disease or infirmity. Therefore, a biopsychosocial approach should be considered as an integral part of patients’ management. In this review, we [...] Read more.
The World Health Organization (WHO) describes “health” as a state of physical, mental, and social well-being and not merely the absence of disease or infirmity. Therefore, a biopsychosocial approach should be considered as an integral part of patients’ management. In this review, we summarize the available data starting from 1986 on the biological, psychological, and social aspects of porphyrias in order to provide a useful tool for clinicians about the missing knowledge within this field. Porphyrias are a group of rare metabolic disorders affecting the heme biosynthetic pathway and can be categorized into hepatic and erythropoietic. Here, a total of 20 articles reporting the psychological and the quality of life (QoL) data of porphyria patients affected by acute hepatic porphyrias (AHPs), Porphyria Cutanea Tarda (PCT), and Erythropoietic Protoporphyria (EPP) were analyzed. These 13 articles include reported quantitative methods using questionnaires, while the reaming articles employed qualitative descriptive approaches through direct interviews with patients by psychology professionals. We conclude that the use of questionnaires limits the complete description of all areas of a patient’s life compared to a direct interview with specialists. However, only a combined use of these methods could be the best approach for the correct disorder management. Full article
(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Porphyrias)
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13 pages, 1075 KiB  
Review
Kidney Involvement in Acute Hepatic Porphyrias: Pathophysiology and Diagnostic Implications
by Andrea Ricci, Claudio Carmine Guida, Paola Manzini, Chiara Cuoghi and Paolo Ventura
Diagnostics 2021, 11(12), 2324; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11122324 - 10 Dec 2021
Cited by 11 | Viewed by 2844
Abstract
Porphyrias are a group of rare disorders originating from an enzyme dysfunction in the pathway of heme biosynthesis. Depending on the specific enzyme involved, porphyrias manifest under drastically different clinical pictures. The most dramatic presentation of the four congenital acute hepatic porphyrias (AHPs: [...] Read more.
Porphyrias are a group of rare disorders originating from an enzyme dysfunction in the pathway of heme biosynthesis. Depending on the specific enzyme involved, porphyrias manifest under drastically different clinical pictures. The most dramatic presentation of the four congenital acute hepatic porphyrias (AHPs: acute intermittent porphyria—AIP, ALAD deficiency, hereditary coproporphyria—HCP, and porphyria variegata—VP) consists of potentially life-threatening neurovisceral attacks, for which givosiran, a novel and effective siRNA-based therapeutic, has recently been licensed. Nonetheless, the clinical manifestations of acute porphyrias are multifaceted and do not limit themselves to acute attacks. In particular, porphyria-associated kidney disease (PAKD) is a distinct, long-term degenerating condition with specific pathological and clinical features, for which a satisfactory treatment is not available yet. In PAKD, chronic tubule-interstitial damage has been most commonly reported, though other pathologic features (e.g., chronic fibrous intimal hyperplasia) are consistent findings. Given the relevant role of the kidney in porphyrin metabolism, the mechanisms possibly intervening in causing renal damage in AHPs are different: among others, δ-aminolevulinic acid (ALA)-induced oxidative damage on mitochondria, intracellular toxic aggregation of porphyrins in proximal tubular cells, and derangements in the delicate microcirculatory balances of the kidney might be implicated. The presence of a variant of the human peptide transporter 2 (PEPT2), with a greater affinity to its substrates (including ALA), might confer a greater susceptibility to kidney damage in patients with AHPs. Furthermore, a possible effect of givosiran in worsening kidney function has been observed. In sum, the diagnostic workup of AHPs should always include a baseline evaluation of renal function, and periodic monitoring of the progression of kidney disease in patients with AHPs is strongly recommended. This review outlines the role of the kidney in porphyrin metabolism, the available evidence in support of the current etiologic and pathogenetic hypotheses, and the known clinical features of renal involvement in acute hepatic porphyrias. Full article
(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Porphyrias)
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17 pages, 932 KiB  
Review
Mechanisms of Neuronal Damage in Acute Hepatic Porphyrias
by Andrea Ricci, Elena Di Pierro, Matteo Marcacci and Paolo Ventura
Diagnostics 2021, 11(12), 2205; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11122205 - 26 Nov 2021
Cited by 10 | Viewed by 2422
Abstract
Porphyrias are a group of congenital and acquired diseases caused by an enzymatic impairment in the biosynthesis of heme. Depending on the specific enzyme involved, different types of porphyrias (i.e., chronic vs. acute, cutaneous vs. neurovisceral, hepatic vs. erythropoietic) are described, with different [...] Read more.
Porphyrias are a group of congenital and acquired diseases caused by an enzymatic impairment in the biosynthesis of heme. Depending on the specific enzyme involved, different types of porphyrias (i.e., chronic vs. acute, cutaneous vs. neurovisceral, hepatic vs. erythropoietic) are described, with different clinical presentations. Acute hepatic porphyrias (AHPs) are characterized by life-threatening acute neuro-visceral crises (acute porphyric attacks, APAs), featuring a wide range of neuropathic (central, peripheral, autonomic) manifestations. APAs are usually unleashed by external “porphyrinogenic” triggers, which are thought to cause an increased metabolic demand for heme. During APAs, the heme precursors δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) accumulate in the bloodstream and urine. Even though several hypotheses have been developed to explain the protean clinical picture of APAs, the exact mechanism of neuronal damage in AHPs is still a matter of debate. In recent decades, a role has been proposed for oxidative damage caused by ALA, mitochondrial and synaptic ALA toxicity, dysfunction induced by relative heme deficiency on cytochromes and other hemeproteins (i.e., nitric oxide synthases), pyridoxal phosphate functional deficiency, derangements in the metabolic pathways of tryptophan, and other factors. Since the pathway leading to the biosynthesis of heme is inscribed into a complex network of interactions, which also includes some fundamental processes of basal metabolism, a disruption in any of the steps of this pathway is likely to have multiple pathogenic effects. Here, we aim to provide a comprehensive review of the current evidence regarding the mechanisms of neuronal damage in AHPs. Full article
(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Porphyrias)
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18 pages, 512 KiB  
Review
Porphyrias in the Age of Targeted Therapies
by Angelika L. Erwin and Manisha Balwani
Diagnostics 2021, 11(10), 1795; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11101795 - 29 Sep 2021
Cited by 9 | Viewed by 3061
Abstract
The porphyrias are a group of eight rare genetic disorders, each caused by the deficiency of one of the enzymes in the heme biosynthetic pathway, resulting in the excess accumulation of heme precursors and porphyrins. Depending on the tissue site as well as [...] Read more.
The porphyrias are a group of eight rare genetic disorders, each caused by the deficiency of one of the enzymes in the heme biosynthetic pathway, resulting in the excess accumulation of heme precursors and porphyrins. Depending on the tissue site as well as the chemical characteristics of the accumulating substances, the clinical features of different porphyrias vary substantially. Heme precursors are neurotoxic, and their accumulation results in acute hepatic porphyria, while porphyrins are photoactive, and excess amounts cause cutaneous porphyrias, which present with photosensitivity. These disorders are clinically heterogeneous but can result in severe clinical manifestations, long-term complications and a significantly diminished quality of life. Medical management consists mostly of the avoidance of triggering factors and symptomatic treatment. With an improved understanding of the underlying pathophysiology and disease mechanisms, new treatment approaches have become available, which address the underlying defects at a molecular or cellular level, and promise significant improvement, symptom prevention and more effective treatment of acute and chronic disease manifestations. Full article
(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Porphyrias)
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24 pages, 2952 KiB  
Review
Laboratory Diagnosis of Porphyria
by Elena Di Pierro, Michele De Canio, Rosa Mercadante, Maria Savino, Francesca Granata, Dario Tavazzi, Anna Maria Nicolli, Andrea Trevisan, Stefano Marchini and Silvia Fustinoni
Diagnostics 2021, 11(8), 1343; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11081343 - 26 Jul 2021
Cited by 20 | Viewed by 9903
Abstract
Porphyrias are a group of diseases that are clinically and genetically heterogeneous and originate mostly from inherited dysfunctions of specific enzymes involved in heme biosynthesis. Such dysfunctions result in the excessive production and excretion of the intermediates of the heme biosynthesis pathway in [...] Read more.
Porphyrias are a group of diseases that are clinically and genetically heterogeneous and originate mostly from inherited dysfunctions of specific enzymes involved in heme biosynthesis. Such dysfunctions result in the excessive production and excretion of the intermediates of the heme biosynthesis pathway in the blood, urine, or feces, and these intermediates are responsible for specific clinical presentations. Porphyrias continue to be underdiagnosed, although laboratory diagnosis based on the measurement of metabolites could be utilized to support clinical suspicion in all symptomatic patients. Moreover, the measurement of enzymatic activities along with a molecular analysis may confirm the diagnosis and are, therefore, crucial for identifying pre-symptomatic carriers. The present review provides an overview of the laboratory assays used most commonly for establishing the diagnosis of porphyria. This would assist the clinicians in prescribing appropriate diagnostic testing and interpreting the testing results. Full article
(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Porphyrias)
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