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The New England Journal of Medicine Apr 2023Erythropoietic protoporphyria and X-linked protoporphyria are inborn errors of heme biosynthesis that cause elevated circulating levels of metal-free protoporphyrin and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Erythropoietic protoporphyria and X-linked protoporphyria are inborn errors of heme biosynthesis that cause elevated circulating levels of metal-free protoporphyrin and phototoxicity. Both disorders are characterized by excruciating phototoxic attacks after exposure to visible light. Dersimelagon is a new, orally administered, selective melanocortin 1 receptor agonist that increases levels of skin eumelanin.
METHODS
We conducted a randomized, placebo-controlled, phase 2 trial to investigate the efficacy and safety of dersimelagon with respect to the time to onset and the severity of symptoms associated with sunlight exposure in patients with erythropoietic protoporphyria or X-linked protoporphyria. Patients 18 to 75 years of age were randomly assigned in a 1:1:1 ratio to receive placebo or dersimelagon at a dose of 100 or 300 mg once daily for 16 weeks. The primary end point was the change from baseline to week 16 in the time to the first prodromal symptom associated with sunlight exposure. Patients recorded daily sunlight exposure and symptom data in an electronic diary. Quality of life and safety were also assessed.
RESULTS
Of the 102 patients (93 with erythropoietic protoporphyria and 9 with X-linked protoporphyria) who underwent randomization, 90% completed the treatment period. The mean daily time to the first prodromal symptom associated with sunlight exposure increased significantly with dersimelagon: the least-squares mean difference from placebo in the change from baseline to week 16 was 53.8 minutes in the 100-mg dersimelagon group (P = 0.008) and 62.5 minutes in the 300-mg dersimelagon group (P = 0.003). The results also suggest that quality of life improved in patients receiving dersimelagon as compared with placebo. The most common adverse events that occurred or worsened during treatment were nausea, freckles, headache, and skin hyperpigmentation.
CONCLUSIONS
At both doses evaluated, dersimelagon significantly increased the duration of symptom-free sunlight exposure in patients with erythropoietic protoporphyria or X-linked protoporphyria. (Funded by Mitsubishi Tanabe Pharma; Endeavor ClinicalTrials.gov number, NCT03520036.).
Topics: Humans; Infant, Newborn; Prodromal Symptoms; Protoporphyria, Erythropoietic; Quality of Life; Skin; Light; Photosensitivity Disorders; Receptor, Melanocortin, Type 1; Administration, Oral; Dermatologic Agents
PubMed: 37043653
DOI: 10.1056/NEJMoa2208754 -
Genetics in Medicine : Official Journal... Sep 2021Patients with erythropoietic protoporphyria (EPP), a severe painful photodermatosis, experience prodromal sensations when exposed to sunlight, which are the "warning...
PURPOSE
Patients with erythropoietic protoporphyria (EPP), a severe painful photodermatosis, experience prodromal sensations when exposed to sunlight, which are the "warning signals" to exit the sun, as prolonged exposure causes an excruciatingly painful phototoxic attack. The unique prodromal cutaneous sensations are reversible and differ from the severe burning pain attack lasting 2-7 days. Previously, afamelanotide treatment was studied using time to pain or time outside as primary outcome measures. Since patients have an ingrained fear of sunlight, these measures did not capture the full treatment effect. We retrospectively characterized and evaluated time to prodrome (TTP) as a safer, patient-reported outcome (PRO) measure in afamelanotide-treated patients.
METHODS
Structured interviews recorded TTP before and during afamelanotide treatment in retrospective US and Dutch cohort studies.
RESULTS
Thirty-one US and 58 Dutch EPP patients participated. Before afamelanotide treatment, 54.8% US and 39.7% Dutch patients reported TTP onset <10 minutes in direct sunlight. In both studies, patients' TTP's were significantly longer during afamelanotide treatment (p < 0.0001). All US patients' TTP increased; no TTP was <10 minutes. Among Dutch patients 81% improved; only 10.3% reported TTPs < 10 minutes.
CONCLUSION
EPP patients reported substantial improvements in TTP during afamelanotide treatment. TTP could provide a safer, PRO-based efficacy endpoint for assessing future EPP treatments.
Topics: Humans; Pain; Patient Reported Outcome Measures; Protoporphyria, Erythropoietic; Retrospective Studies; Sunlight
PubMed: 33941881
DOI: 10.1038/s41436-021-01176-z -
Nihon Shokakibyo Gakkai Zasshi = the... May 2011A 27-year-old man was admitted to our hospital for evaluation and treatment of liver dysfunction with jaundice and hepatosplenomegaly. The patient had severe... (Review)
Review
A 27-year-old man was admitted to our hospital for evaluation and treatment of liver dysfunction with jaundice and hepatosplenomegaly. The patient had severe photosensitivity from childhood. Upper gastrointestinal endoscopy revealed mild esophageal varices. The clinical manifestations, analyses of the urine and blood for porphyrins and skin biopsy led us to a diagnosis of erythropoietic protoporphyria. Because of acute deterioration of liver function, living donor liver transplantation was performed. The resected liver revealed cirrhosis. We report a rare case of erythropoietic protoporphyria with severe liver dysfunction and present a review of the literature.
Topics: Adult; Humans; Liver Diseases; Male; Protoporphyria, Erythropoietic
PubMed: 21558748
DOI: No ID Found -
Annales de Dermatologie Et de... Feb 2019The porphyrias are a group of metabolic disorders resulting from an innate abnormality in haem biosynthesis, and the clinical settings of which vary according to the... (Review)
Review
The porphyrias are a group of metabolic disorders resulting from an innate abnormality in haem biosynthesis, and the clinical settings of which vary according to the genetic enzyme abnormality in question. These are genetic disorders with autosomal dominant or recessive inheritance of varying penetrance, and whose clinical expression differs according to the preferential location of haem precursors. Different classifications have been proposed according to genetic inheritance, the enzyme anomaly at issue, and clinical expression. The clinical classification distinguishes between acute porphyria (acute intermittent porphyria, porphyria variegata, hereditary coproporphyria), bullous cutaneous porphyrias (porphyria cutanea tarda, porphyria variegata and hereditary coproporphyria), painful photosensitive acute cutaneous porphyrias (erythropoietic protoporphyria and X-linked dominant protoporphyria), and rare recessive porphyrias (congenital erythropoietic porphyria, Doss porphyria, hepatoerythropoietic porphyria and harderoporphyria). Treatment depends on the clinical expression of the disorder.
Topics: Biopsy; Coproporphyria, Hereditary; Diagnosis, Differential; Heme; Humans; Photosensitivity Disorders; Porphyria Cutanea Tarda; Porphyria, Erythropoietic; Porphyrias; Protoporphyria, Erythropoietic; Skin; Skin Diseases, Metabolic
PubMed: 30709634
DOI: 10.1016/j.annder.2018.12.005 -
Hepatology (Baltimore, Md.) Mar 2024
Evidence-based consensus guidelines for the diagnosis and management of protoporphyria-related liver dysfunction in erythropoietic protoporphyria and X-linked protoporphyria.
Topics: Humans; Protoporphyria, Erythropoietic; Liver Diseases; Ferrochelatase; Genetic Diseases, X-Linked; 5-Aminolevulinate Synthetase
PubMed: 37505211
DOI: 10.1097/HEP.0000000000000546 -
Histopathology Jul 2021
Topics: Ferrochelatase; Humans; Liver Diseases; Male; Middle Aged; Mutation; Protoporphyria, Erythropoietic; Protoporphyrins; Specimen Handling
PubMed: 33475175
DOI: 10.1111/his.14340 -
Australian Veterinary Journal Jun 1992
Topics: Animals; Breeding; Cattle; Cattle Diseases; Erythrocytes; Female; Male; Pedigree; Photosensitivity Disorders; Porphyrias; Protoporphyria, Erythropoietic; Protoporphyrins
PubMed: 1642600
DOI: 10.1111/j.1751-0813.1992.tb07488.x -
Journal of Hepatology Jan 2007We report the case of a middle-age patient presenting with severe progressive protoporphyric cholestasis. To halt further progression of liver disease, medical treatment... (Review)
Review
We report the case of a middle-age patient presenting with severe progressive protoporphyric cholestasis. To halt further progression of liver disease, medical treatment was given aimed at different mechanisms possibly causing cholestasis in erythropoietic protoporphyria. Within eighty days, liver biochemistry completely normalized and liver histology markedly improved. Bone marrow transplantation was performed to prevent relapse of cholestatic liver disease by correcting the main site of protoporphyrin overproduction. Thirty-three months after cholestatic presentation and ten months after bone marrow transplantation, liver and porphyrin biochemistry remains normal. The patient is in excellent condition and photosensitivity is absent. The theoretical role of each treatment used to successfully reverse cholestasis and the role of bone marrow transplantation in erythropoietic protoporphyria are discussed. Medical treatment can resolve hepatic abnormalities in protoporphyric cholestasis. Bone marrow transplantation achieves phenotypic reversal and may offer protection from future protoporphyric liver disease.
Topics: Bone Marrow Transplantation; Cholestasis; Humans; Liver; Male; Middle Aged; Porphyrins; Protoporphyria, Erythropoietic; Time Factors
PubMed: 17112627
DOI: 10.1016/j.jhep.2006.10.004 -
The British Journal of Dermatology Aug 1976The terminal stages of erythropoietic protoporphyria are recorded. The observations are related to the site of the fundamental lesion and the nature of the biochemical...
The terminal stages of erythropoietic protoporphyria are recorded. The observations are related to the site of the fundamental lesion and the nature of the biochemical defect. The possibly ominous prognosis in this usually mild condition is emphasized. Apart from congenital porphyria, the porphyrias do not usually confer severe cutaneous lesions. These diseases present to dermatologists because of moderate photosensitivity and are not usually regarded as a risk to life. Dangerous central nervous system involvement may occur, however, in acute intermittent, variegate and hereditary coproporphyrias, while in acquired symptomatic porphyria severe underlying liver dysfunction may occur. Probably the most common familial photosensitizing porphyria is erythropoietic protoporphyria. Recently some deaths from severe liver involvement have been reported in this disease.
Topics: Feces; Humans; Liver; Male; Middle Aged; Porphyrias; Protoporphyrins; Sunlight
PubMed: 952751
DOI: 10.1111/j.1365-2133.1976.tb00819.x -
Internal Medicine (Tokyo, Japan) 2018A 27-year-old man bearing an erythropoietic protoporphyria (EPP)-associated ferrochelatase (FECH) mutation was admitted to our hospital for general malaise and marked...
A 27-year-old man bearing an erythropoietic protoporphyria (EPP)-associated ferrochelatase (FECH) mutation was admitted to our hospital for general malaise and marked elevation of the serum levels of hepatobiliary enzymes and bilirubin. Initial treatment with plasma exchange did not reduce the blood protoporphyrin or serum liver enzyme levels, so phlebotomy was started. Surprisingly, weekly phlebotomy normalized the serum levels of liver enzymes, accompanied by a marked reduction in the blood protoporphyrin levels. The clinical course of this case strongly suggests that phlebotomy may be a suitable treatment option for EPP-related hepatopathy.
Topics: Adult; Ferrochelatase; Humans; Liver; Liver Diseases; Male; Mutation; Phlebotomy; Protoporphyria, Erythropoietic; Protoporphyrins
PubMed: 30175727
DOI: 10.2169/internalmedicine.0673-17