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Intractable & Rare Diseases Research Nov 2020Acute intermittent porphyria (AIP) is an autosomal dominant disease caused by mutations in porphobilinogen deaminase (PBGD), the third enzyme of the heme synthesis... (Review)
Review
Acute intermittent porphyria (AIP) is an autosomal dominant disease caused by mutations in porphobilinogen deaminase (PBGD), the third enzyme of the heme synthesis pathway. Symptoms of AIP usually manifest as intermittent acute attacks with occasional neuropsychiatric crises. The management of AIP includes treatment of acute attacks, prevention of attacks, long-term monitoring and treatment of chronic complications. Intravenous injection of heme is the most effective method of treating acute attacks. Carbohydrate loading is used when heme is unavailable or in the event of mild attacks. Symptomatic treatment is also needed during attacks. Prevention of attacks includes eliminating precipitating factors, heme prophylaxis and liver transplantation. New treatment options include givosiran (siRNA) to down-regulate ALA synthase-1 (ALAS1) and the messenger RNA of PBGD (PBGD mRNA) delivered to the liver cells of patients with AIP. Long-term monitoring of chronic complications includes regular liver-kidney function and hepatocellular carcinoma (HCC) screening.
PubMed: 33139979
DOI: 10.5582/irdr.2020.03089 -
Molecular Genetics and Metabolism Nov 2019Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disorder characterized by photosensitivity and by hematologic abnormalities in affected... (Review)
Review
Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disorder characterized by photosensitivity and by hematologic abnormalities in affected individuals. CEP is caused by mutations in the uroporphyrinogen synthase (UROS) gene. In three reported cases, CEP has been associated with a specific X-linked GATA1 mutation. Disease-causing mutations in either gene result in absent or markedly reduced UROS enzymatic activity. This in turn leads to the accumulation of the non-physiologic and photoreactive porphyrinogens, uroporphyrinogen I and coproporphyrinogen I, which damage erythrocytes and elicit a phototoxic reaction upon light exposure. The clinical spectrum of CEP depends on the level of residual UROS activity, which is determined by the underlying pathogenic loss-of-function UROS mutations. Disease severity ranges from non-immune hydrops fetalis in utero to late-onset disease with only mild cutaneous involvement. The clinical characteristics of CEP include exquisite photosensitivity to visible light resulting in bullous vesicular lesions which, when infected lead to progressive photomutilation of sun-exposed areas such as the face and hands. In addition, patients have erythrodontia (brownish discoloration of teeth) and can develop corneal scarring. Chronic transfusion-dependent hemolytic anemia is common and leads to bone marrow hyperplasia, which further increases porphyrin production. Management of CEP consists of strict avoidance of exposure to visible light with sun-protective clothing, sunglasses, and car and home window filters. Adequate care of ruptured vesicles and use of topical antibiotics is indicated to prevent superinfections and osteolysis. In patients with symptomatic hemolytic anemia, frequent erythrocyte cell transfusions may be necessary to suppress hematopoiesis and decrease marrow production of the phototoxic porphyrins. In severe transfection-dependent cases, bone marrow or hematopoietic stem cell transplantation has been performed, which is curative. Therapeutic approaches including gene therapy, proteasome inhibition, and pharmacologic chaperones are under investigation.
Topics: Animals; Biosynthetic Pathways; GATA1 Transcription Factor; Genetic Diseases, Inborn; Genetic Therapy; Heme; Humans; Mice; Mutation; Porphyria, Erythropoietic
PubMed: 30685241
DOI: 10.1016/j.ymgme.2018.12.008 -
Medical Ultrasonography Jun 2024In this series of articles on comments and illustrations of the World Federation for Medicine and Biology (WFUMB) guidelines on contrast-enhanced ultrasound (CEUS), the... (Review)
Review
In this series of articles on comments and illustrations of the World Federation for Medicine and Biology (WFUMB) guidelines on contrast-enhanced ultrasound (CEUS), the topics on very rare focal liver lesions (FLL) are discussed. This article describes the diverse changes of focal liver lesions in peliosis hepatis and the typical changes in porphyria. Although the focus is on the appearance on ultrasound and CEUS, the clinical context is always considered. While peliosis may be a surprising finding on puncture, lesions in porphyria cutanea tarda may be typical visual diagnoses that obviate the need for biopsy. If only you knew. This article aims to sharpen the clinician's eye. It provides knowledge of the clinical presentation and US and CEUS imaging of peliosis hepatis and porphyria.
Topics: Humans; Ultrasonography; Contrast Media; Practice Guidelines as Topic; Peliosis Hepatis; Liver; Porphyrias; Image Enhancement; Diagnosis, Differential
PubMed: 37931015
DOI: 10.11152/mu-4287 -
Australian Family Physician Mar 2017Although venesection was widely applied in the past for the treatment of various ailments and diseases, in modern medical practice, it is indicated in very few... (Review)
Review
BACKGROUND
Although venesection was widely applied in the past for the treatment of various ailments and diseases, in modern medical practice, it is indicated in very few conditions, namely, hereditary haemochromatosis, polycythaemia and porphyria cutanea tarda.
OBJECTIVE
This article briefly reviews the pathophysiology of these conditions, and the rationale and goals of therapeutic venesection as a treatment modality. It also summarises the venesection procedure itself and the considerations for setting up a venesection service in a doctor's surgery.
DISCUSSION
Venesection is generally safe and carries few side effects. Before commencing therapeutic venesection, management goals in terms of laboratory parameters should be set for individual patients. These patients should be monitored regularly so that set targets are met and not overshot as to render them anaemic and acutely symptomatic. Venesections should also be performed by persons familiar with the procedure and management of the attendant complications.
Topics: Clinical Competence; Family Practice; Hemochromatosis; Humans; Phlebotomy; Porphyria Cutanea Tarda
PubMed: 28260267
DOI: No ID Found -
Diagnostics (Basel, Switzerland) Sep 2021The 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... (Review)
Review
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.
PubMed: 34679493
DOI: 10.3390/diagnostics11101795 -
Healthcare (Basel, Switzerland) Jan 2024Porphyrias, as most rare diseases, are characterized by complexity and scarcity of knowledge. A national registry in one of the largest European populations that...
Porphyrias, as most rare diseases, are characterized by complexity and scarcity of knowledge. A national registry in one of the largest European populations that prospectively collects longitudinal clinical and laboratory data are an important and effective tool to close this gap. The German Porphyria Registry (PoReGer) was founded by four centers with longstanding expertise in the field of porphyrias and rare diseases (Charité-Universitätsmedizin Berlin, Porphyria Center Saxony Chemnitz, University Medical Center Hamburg-Eppendorf, University Medical Center Göttingen) and the German reference laboratory for porphyria, and is supported by the largest German porphyria patient organization. A specified data matrix for three subgroups (acute, chronic blistering cutaneous, acute non-blistering cutaneous) includes data on demographics, specific porphyria-related symptoms, clinical course, general medical history, necessary follow-up assessments (including laboratory and imaging results), symptomatic and disease-modifying therapies, and side-effects. Additionally, the registry includes patient-reported outcome measures on quality of life, depression, and fatigue. PoReGer aims to broaden and deepen the understanding on all porphyria-related subjects. We expect these data to significantly improve the management and care of porphyria patients. Additionally, the data can be used for educational purposes to increase awareness, for the planning of healthcare services, and for machine learning algorithms for early detection of porphyrias.
PubMed: 38201016
DOI: 10.3390/healthcare12010111 -
The Israel Medical Association Journal... Apr 2019
Topics: Diagnosis, Differential; Humans; Neglected Diseases; Porphyrias
PubMed: 31032573
DOI: No ID Found -
Cureus Mar 2023Acute intermittent porphyria (AIP) is an autosomal dominant disorder of heme biosynthesis in the liver that is caused by the accumulation of toxic heme metabolites... (Review)
Review
Acute intermittent porphyria (AIP) is an autosomal dominant disorder of heme biosynthesis in the liver that is caused by the accumulation of toxic heme metabolites aminolevulinic acid (ALA) and porphobilinogen (PBG) due to a deficiency in the enzyme hydroxymethylbilane synthase (HMBS). The prevalence of AIP is found to commonly affect females of reproductive age (ages 15-50) and people of Northern European descent. The clinical manifestations of AIP include acute and chronic symptoms that can be outlined into three phases: the prodromal phase, the visceral symptom phase, and the neurological phase. Major clinical symptoms involve severe abdominal pain, peripheral neuropathy, autonomic neuropathies, and psychiatric manifestations. Symptoms are often heterogeneous and vague, which can lead to life-threatening signs if not treated and managed appropriately. Whether treating AIP in its acute or chronic form, the cornerstone of treatment consists of the suppression of the production of ALA and PBG. The mainstay of managing acute attacks continues to comprise discontinuing porphyrogenic agents, adequate caloric support, heme treatment, and the treatment of symptoms. In recurrent attacks and chronic management, prevention is key with the consideration of liver transplantation and/or renal transplantation. In recent years, there has been great interest in emerging treatments that focus on a molecular level such as enzyme replacement therapy, gene inhibition, and even liver gene therapy (GT), which has changed the way of traditionally managing this disease and will pave the way for innovative therapies to come.
PubMed: 37065381
DOI: 10.7759/cureus.36058 -
Metabolites Aug 2022Given its remarkable property to easily switch between different oxidative states, iron is essential in countless cellular functions which involve redox reactions. At... (Review)
Review
Given its remarkable property to easily switch between different oxidative states, iron is essential in countless cellular functions which involve redox reactions. At the same time, uncontrolled interactions between iron and its surrounding milieu may be damaging to cells and tissues. Heme-the iron-chelated form of protoporphyrin IX-is a macrocyclic tetrapyrrole and a coordination complex for diatomic gases, accurately engineered by evolution to exploit the catalytic, oxygen-binding, and oxidoreductive properties of iron while minimizing its damaging effects on tissues. The majority of the body production of heme is ultimately incorporated into hemoglobin within mature erythrocytes; thus, regulation of heme biosynthesis by iron is central in erythropoiesis. Additionally, heme is a cofactor in several metabolic pathways, which can be modulated by iron-dependent signals as well. Impairment in some steps of the pathway of heme biosynthesis is the main pathogenetic mechanism of two groups of diseases collectively known as porphyrias and congenital sideroblastic anemias. In porphyrias, according to the specific enzyme involved, heme precursors accumulate up to the enzyme stop in disease-specific patterns and organs. Therefore, different porphyrias manifest themselves under strikingly different clinical pictures. In congenital sideroblastic anemias, instead, an altered utilization of mitochondrial iron by erythroid precursors leads to mitochondrial iron overload and an accumulation of ring sideroblasts in the bone marrow. In line with the complexity of the processes involved, the role of iron in these conditions is then multifarious. This review aims to summarise the most important lines of evidence concerning the interplay between iron and heme metabolism, as well as the clinical and experimental aspects of the role of iron in inherited conditions of altered heme biosynthesis.
PubMed: 36144223
DOI: 10.3390/metabo12090819 -
Current Opinion in Gastroenterology May 2021Acute hepatic porphyrias (AHP) are a group of rare diseases that are characterized by episodic acute neurovisceral pain episodes caused by abnormal accumulation of the... (Review)
Review
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.
Topics: Humans; Pain; Porphobilinogen Synthase; Porphyria, Acute Intermittent; Porphyrias, Hepatic; Treatment Outcome
PubMed: 33769375
DOI: 10.1097/MOG.0000000000000734