-
Diagnostics (Basel, Switzerland) May 2022The 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.... (Review)
Review
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.
PubMed: 35626348
DOI: 10.3390/diagnostics12051193 -
Tidsskrift For Den Norske Laegeforening... Apr 2014Porphyria is an umbrella term for a group of largely hereditary diseases that are due to defective haem synthesis. The diseases have a varied and partly overlapping...
BACKGROUND
Porphyria is an umbrella term for a group of largely hereditary diseases that are due to defective haem synthesis. The diseases have a varied and partly overlapping range of symptoms and presentations. The commonest forms of porphyria are porphyria cutanea tarda, acute intermittent porphyria and erythropoietic protoporphyria. The purpose of this study is to provide an overview of the prevalence and pathological manifestations of porphyrias in Norway.
MATERIAL AND METHOD
Information on all patients registered with the Norwegian Porphyria Centre (NAPOS) up to 2012 was used to estimate the prevalence and incidence of porphyrias in Norway. Figures on symptoms, precipitating factors and follow-up routines were obtained from the Norwegian Porphyria Registry, which includes 70% of Norwegians registered with NAPOS as having porphyria.
RESULTS
The prevalence of porphyria cutanea tarda was approximately 10 : 100,000 and that of acute intermittent porphyria approximately 4 : 100,000. The total incidence of all porphyrias was approximately 0.5-1 : 100,000 per year. Diagnostic delay, i.e. the time passing between the onset of symptoms and diagnosis, varied from 1-17 years depending on the type of porphyria. There was wide variation in the frequency with which patients with the various types of porphyria went for medical check-ups.
INTERPRETATION
The prevalence of acute intermittent porphyria and porphyria cutanea tarda appears to be higher in Norway than in most other countries. Data from the Norwegian Porphyria Registry makes it possible to demonstrate differences in treatment and follow-up of porphyria patients and may be used to initiate necessary measures.
Topics: Adolescent; Adult; Child; Child, Preschool; Humans; Infant; Middle Aged; Norway; Porphyria Cutanea Tarda; Porphyria, Acute Intermittent; Porphyria, Erythropoietic; Porphyrias; Registries
PubMed: 24780981
DOI: 10.4045/tidsskr.13.0649 -
Photodermatology, Photoimmunology &... Mar 2022Erythropoietic protoporphyria (EPP) is a rare disorder of heme biosynthesis hallmarked by early-onset photosensitivity and mainly due to defective ferrochelatase...
Ultraviolet A phototest positivity is associated with higher free erythrocyte protoporphyrin IX concentration and lower transferrin saturation values in erythropoietic protoporphyria.
BACKGROUND
Erythropoietic protoporphyria (EPP) is a rare disorder of heme biosynthesis hallmarked by early-onset photosensitivity and mainly due to defective ferrochelatase activity leading to increased erythrocyte protoporphyrin IX (PPIX) levels. Evidence regarding the relationship between erythrocyte PPIX concentration and photosensitivity is limited.
METHODS
To investigate the relationship between free erythrocyte PPIX (FEP) concentration; routine laboratory tests, particularly iron metabolism biomarkers; and ultraviolet (UV) A/visible light phototesting findings, 20 genetically confirmed EPP and one XLPP treatment-naive patients were included in our study. They underwent UVA and visible light phototesting. On the same day, blood samples were collected for measurement of FEP, serum iron, transferrin, transferrin saturation, and ferritin, 25-hydroxyvitamin D, and liver enzyme levels.
RESULTS
Median FEP concentration at the time of phototesting was 57.50 (IQR: 34.58-102.70) μg/g of Hb. UVA and visible light phototesting were positive in 9 (42.9%) and 8 (38.1%) patients, respectively. Median FEP concentration was significantly higher in UVA phototest-positive patients than in those negative (64.37 [IQR: 57.45-121.82] vs 45.35 [IQR: 24.53-74.61] μg/g of Hb, respectively; P = .04486). Similarly, UVA photosensitive individuals had significantly lower median serum iron levels (61.5 [IQR: 33.5-84] μg/dL vs 109 [IQR: 63.25-154] μg/dL, respectively; P = .01862) and transferrin saturation values (15.005 [IQR: 7.0775-18.41] % vs 29.645 [IQR: 17.8225-34.3575] %; P = .0109) than those negative.
CONCLUSIONS
Our study demonstrates that UVA phototest positivity is associated with higher FEP concentration and lower transferrin saturation and serum iron concentration in EPP.
Topics: Erythrocytes; Humans; Protoporphyria, Erythropoietic; Protoporphyrins; Transferrins
PubMed: 34420239
DOI: 10.1111/phpp.12727 -
Frontiers in Physiology 2022Partial deficiency of the last enzyme of the heme biosynthetic pathway, namely, ferrochelatase (FECH), is responsible for erythropoietic protoporphyria (EPP) in humans....
Partial deficiency of the last enzyme of the heme biosynthetic pathway, namely, ferrochelatase (FECH), is responsible for erythropoietic protoporphyria (EPP) in humans. This disorder is characterized by painful skin photosensitivity, due to excessive protoporphyrin IX (PPIX) production in erythrocytes. Although several papers report the presence of iron deficiency anemia in about 50% of EPP patients, there is still no a conclusive explanation of the why this occurs. In the present work, we explored hematological indices and iron status in 20 unrelated Italian EPP patients in order to propose a new hypothesis. Our data show that microcytosis is present in EPP patients also in the absence of anemia and iron deficiency with a link between PPIX accumulation and reduced MCV, probably indicating an indirect condition of heme deficiency. Patients studied had a downward shift of iron parameters due to increased hepcidin concentrations only in a state of repleted iron stores. Interestingly, hemoglobin synthesis was not limited by iron supply except in cases with further iron loss, in which concomitantly increased soluble transferrin (Tf) receptor (sTfR) levels were detected. The mechanisms involved in the iron uptake downregulation in EPP remain unclear, and the role of PPIX accumulation in microcytosis.
PubMed: 35309058
DOI: 10.3389/fphys.2022.841050 -
Cold Spring Harbor Perspectives in... Apr 2013Heme, which is composed of iron and the small organic molecule protoporphyrin, is an essential component of hemoglobin as well as a variety of physiologically important... (Review)
Review
Heme, which is composed of iron and the small organic molecule protoporphyrin, is an essential component of hemoglobin as well as a variety of physiologically important hemoproteins. During erythropoiesis, heme synthesis is induced before, and is essential for, globin synthesis. Although all cells possess the ability to synthesize heme, there are distinct differences between regulation of the pathway in developing erythroid cells and all other types of cells. Disorders that compromise the ability of the developing red cell to synthesize heme can have profound medical implications. The biosynthetic pathway for heme and key regulatory features are reviewed herein, along with specific human genetic disorders that arise from defective heme synthesis such as X-linked sideroblastic anemia and erythropoietic protoporphyria.
Topics: Coproporphyrinogens; Enzymes; Erythropoiesis; Hematologic Diseases; Heme; Humans; Mitochondria
PubMed: 23471474
DOI: 10.1101/cshperspect.a011676 -
Hematology, Transfusion and Cell Therapy 2018Hemoglobin is an essential biological component of human physiology and its production in red blood cells relies upon proper biosynthesis of heme and globin protein.... (Review)
Review
Hemoglobin is an essential biological component of human physiology and its production in red blood cells relies upon proper biosynthesis of heme and globin protein. Disruption in the synthesis of these precursors accounts for a number of human blood disorders found in patients. Mutations in genes encoding heme biosynthesis enzymes are associated with a broad class of metabolic disorders called porphyrias. In particular, one subtype - erythropoietic protoporphyria - is caused by the accumulation of protoporphyrin IX. Erythropoietic protoporphyria patients suffer from photosensitivity and a higher risk of liver failure, which is the principle cause of morbidity and mortality. Approximately 90% of these patients carry loss-of-function mutations in the enzyme ferrochelatase (), while 5% of cases are associated with activating mutations in the C-terminus of . Recent work has begun to uncover novel mechanisms of heme regulation that may account for the remaining 5% of cases with previously unknown genetic basis. One erythropoietic protoporphyria family has been identified with inherited mutations in the AAA+ protease ClpXP that regulates activity. In this review article, recent findings on the role of ClpXP as both an activating unfoldase and degrading protease and its impact on heme synthesis will be discussed. This review will also highlight the role of ClpX dysfunction in erythropoietic protoporphyria.
PubMed: 30057992
DOI: 10.1016/j.htct.2018.03.001 -
Molecular Genetics and Metabolism... Dec 2022The use of iron supplementation for anemia in erythropoietic protoporphyria (EPP) is controversial with both benefit and deterioration reported in single case reports....
The use of iron supplementation for anemia in erythropoietic protoporphyria (EPP) is controversial with both benefit and deterioration reported in single case reports. There is no systematic study to evaluate the benefits or risks of iron supplementation in these patients. We assessed the potential efficacy of oral iron therapy in decreasing erythrocyte protoporphyrin (ePPIX) levels in patients with EPP or X-linked protoporphyria (XLP) and low ferritin in an open-label, single-arm, interventional study. Sixteen patients (≥18 years) with EPP or XLP confirmed by biochemical and/or genetic testing, and serum ferritin ≤30 ng/mL were enrolled. Baseline testing included iron studies, normal hepatic function, and elevated plasma porphyrins and ePPIX levels. Oral ferrous sulfate 325 mg twice daily was administered for 12 months. The primary efficacy outcome was the relative difference in total ePPIX level between baseline and 12 months after starting treatment with iron. Secondary measures included improvement in serum ferritin, plasma porphyrins, and clinical symptoms. Thirteen patients had EPP (8 females, 5 males) and 3 had XLP (all females) and the mean age of participants was 38.8 years (SD 14.5). Ten patients completed all study visits limiting interpretation of results. In EPP patients, a transient increase in ePPIX levels was observed at 3 months in 9 of 12 (75%) patients. Iron was discontinued in 2 of these patients after meeting the protocol stopping rule of a 35% increase in ePPIX. Seven patients withdrew before study end. Ferritin levels increased on iron replacement indicating an improvement in iron status. A decrease in ePPIX was seen in both XLP patients who completed the study (relative difference of 0.67 and 0.5 respectively). No substantial changes in ePPIX were seen in EPP patients at the end of the study ( = 8; median relative difference: -0.21 (IQR: -0.44, 0.05). The most common side effects of iron treatment were gastrointestinal symptoms. Hepatic function remained normal throughout the study. Our study showed that oral iron therapy repletes iron stores and transiently increases ePPIX in some EPP patients, perhaps due to a transient increase in erythropoiesis, and may decrease ePPIX in XLP patients. Further studies are needed to better define the role of iron repletion in EPP. Trial registration: NCT02979249.
PubMed: 36406817
DOI: 10.1016/j.ymgmr.2022.100939 -
Biomedicine & Pharmacotherapy =... Feb 2023Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by skin photosensitivity caused by accumulation of protoporphyrin IX. We aimed to... (Review)
Review
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by skin photosensitivity caused by accumulation of protoporphyrin IX. We aimed to review the clinical evidence of efficacy and safety of skin photosensitivity treatments in individuals with EPP or XLP. We systematically searched MEDLINE, Embase, the Cochrane Library, and ClinicalTrials.gov. A total of 40 studies with data on 18 treatment modalities were included. Comprehensive treatment safety data were obtained from the European Medicines Agency and the United States Food and Drug Administration. The studies used different outcome measures to evaluate the sensitivity without a generally accepted method to assess treatment effect on skin photosensitivity. Of the included studies, 13 were controlled trials. Gathered, the trials showed moderate positive effect of inorganic sunscreen application and subcutaneous implant of afamelanotide and no effect of organic sunscreen application, or oral treatment with beta-carotene, cysteine, N-acetylcysteine, vitamin C, or warfarin. Studies without control groups suggested treatment effect of foundation cream, dihydroxyacetone/lawsone cream, narrow-band ultraviolet B phototherapy, erythrocyte transfusion, extracorporeal erythrocyte photodynamic therapy, or oral treatment with zinc sulphate, terfenadine, cimetidine, or canthaxanthin, but the real effect is uncertain. Assessment of treatment effect on photosensitivity in patients with EPP or XLP carries a high risk of bias since experienced photosensitivity varies with both weather conditions, exposure pattern, and pigmentation. Controlled trials of promising treatment options are important although challenging in this small patient population.
Topics: United States; Humans; Protoporphyria, Erythropoietic; Sunscreening Agents; Photosensitivity Disorders; Genetic Diseases, X-Linked; Protoporphyrins
PubMed: 36525819
DOI: 10.1016/j.biopha.2022.114132 -
Acta Dermatovenerologica Alpina,... Dec 2008UV irradiation of the skin leads to the induction of free radicals, carcinogenesis, and skin aging, and thus the use of beta-carotene in humans as a chaperoning agent is... (Review)
Review
UV irradiation of the skin leads to the induction of free radicals, carcinogenesis, and skin aging, and thus the use of beta-carotene in humans as a chaperoning agent is discussed. In the photohemolysis model, beta-carotene protects against the phototoxic effects of porphyrins. Beta-carotene should be used in erythropoietic protoporphyria, photosensitive diseases, and to reduce the effects of phototoxic drugs. Its effects on aging skin and on actinic keratosis have not yet been sufficiently studied.
Topics: Dysplastic Nevus Syndrome; Erythema; Food; Food Analysis; Humans; Ultraviolet Rays; Vitamins; beta Carotene
PubMed: 19104740
DOI: No ID Found -
The Journal of Biological Chemistry Mar 2022Heme is a critical biomolecule that is synthesized in vivo by several organisms such as plants, animals, and bacteria. Reflecting the importance of this molecule,... (Review)
Review
Heme is a critical biomolecule that is synthesized in vivo by several organisms such as plants, animals, and bacteria. Reflecting the importance of this molecule, defects in heme biosynthesis underlie several blood disorders in humans. Aminolevulinic acid synthase (ALAS) initiates heme biosynthesis in α-proteobacteria and nonplant eukaryotes. Debilitating and painful diseases such as X-linked sideroblastic anemia and X-linked protoporphyria can result from one of more than 91 genetic mutations in the human erythroid-specific enzyme ALAS2. This review will focus on recent structure-based insights into human ALAS2 function in health and how it dysfunctions in disease. We will also discuss how certain genetic mutations potentially result in disease-causing structural perturbations. Furthermore, we use thermodynamic and structural information to hypothesize how the mutations affect the human ALAS2 structure and categorize some of the unique human ALAS2 mutations that do not respond to typical treatments, that have paradoxical in vitro activity, or that are highly intolerable to changes. Finally, we will examine where future structure-based insights into the family of ALA synthases are needed to develop additional enzyme therapeutics.
Topics: 5-Aminolevulinate Synthetase; Aminolevulinic Acid; Anemia, Sideroblastic; Animals; Genetic Diseases, X-Linked; Heme; Humans; Structure-Activity Relationship
PubMed: 35093382
DOI: 10.1016/j.jbc.2022.101643