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The Tohoku Journal of Experimental... Oct 2023Erythropoietic protoporphyria (EPP) is a very rare disease with an estimated prevalence of 1 in 200,000 individuals. Decreased ferrochelatase activity causes the... (Review)
Review
Erythropoietic protoporphyria (EPP) is a very rare disease with an estimated prevalence of 1 in 200,000 individuals. Decreased ferrochelatase activity causes the accumulation of protoporphyrin in the body, and light exposure results in the generation of active oxygen, causing photosensitivity. Liver damage has the greatest influence on the prognosis, and liver transplantation is the only treatment option for patients with decompensated liver cirrhosis. We report a case of living-donor liver transplantation for decompensated liver cirrhosis associated with EPP. The patient was a 52-year-old male who led a normal life except for mild photosensitivity. When the patient was 37-year-old, hepatic dysfunction was noticed. At 48-year-old, high erythrocyte protoporphyrin levels, skin biopsy, and genetic tests resulted in a diagnosis of EPP. The patient underwent living- donor liver transplantation because of decompensated liver cirrhosis. In the operating room and intensive care unit, a special light-shielding film was applied to all light sources to block light with harmful wavelengths during treatment. Due to the need for special measures, a lecture on patients with EPP was given before surgery to deepen understanding among all medical professionals involved in the treatment. As a result, no adverse events occurred during the perioperative period, and the patient was discharged on the 46th post-operative day. Currently, the transplanted liver is functioning extremely well, and the patient is alive 3 years post-transplant. Herein, we describe a case of living donor liver transplantation for EPP with a brief literature review.
Topics: Male; Humans; Middle Aged; Adult; Protoporphyria, Erythropoietic; Liver Transplantation; Living Donors; Protoporphyrins; Ferrochelatase; Liver Diseases; Liver Cirrhosis
PubMed: 37495523
DOI: 10.1620/tjem.2023.J061 -
Cureus Apr 2023Erythropoietic protoporphyria (EPP) is a rare inherited disorder of porphyrin metabolism that can cause liver damage and cholestatic hepatocellular failure. We report a...
Erythropoietic protoporphyria (EPP) is a rare inherited disorder of porphyrin metabolism that can cause liver damage and cholestatic hepatocellular failure. We report a case of EPP in a teenaged male who underwent liver biopsy for investigation of liver dysfunction of unknown cause. The diagnosis was not made until a re-biopsy approximately three years later, when the patient presented with recurrent skin lesions and elevated blood and urinary protoporphyrin levels. The liver biopsies contained brownish deposits that exhibited birefringence under polarized light and porphyrin fluorescence under fluorescence spectroscopy. EPP should be considered in young patients with unexplained liver dysfunction, skin symptoms, and seasonal changes in symptoms. Fluorescence spectroscopy of liver biopsy tissue can be a useful tool in the diagnosis of EPP.
PubMed: 37228562
DOI: 10.7759/cureus.38017 -
Life (Basel, Switzerland) Apr 2023In animal models, melanocyte-stimulating hormones (MSHs) protect the liver from various injuries. Erythropoietic protoporphyria (EPP), a metabolic disorder, leads to the...
UNLABELLED
In animal models, melanocyte-stimulating hormones (MSHs) protect the liver from various injuries. Erythropoietic protoporphyria (EPP), a metabolic disorder, leads to the accumulation of protoporphyrin (PPIX). In addition to the most prominent symptom of incapacitating phototoxic skin reactions, 20% of EPP patients exhibit disturbed liver functioning and 4% experience terminal liver failure caused by the hepatobiliary elimination of excess PPIX. Skin symptoms are mitigated through the application of the controlled-release implant afamelanotide, an α-MSH analog, every sixty days. Recently, we showed that liver function tests (LFTs) improved during afamelanotide treatment when compared to before treatment. The present study investigated whether this effect is dose-dependent, as the evidence of dose dependency would support a beneficial influence of afamelanotide.
METHODS
In this retrospective observational study, we included 2933 liver-function tests, 1186 PPIX concentrations and 1659 afamelanotide implant applications in 70 EPP patients. We investigated whether the number of days since the preceding afamelanotide dose or the number of doses during the preceding 365 days had an effect on LFTs and PPIX levels. In addition, we assessed the effect of global radiation.
RESULTS
Inter-patient differences exerted the most prominent effect on PPIX and LFTs. In addition, PPIX increased significantly with an increase in the number of days since the last afamelanotide implant ( < 0.0001). ALAT and bilirubin decreased significantly with an increasing number of afamelanotide doses in the preceding 365 days ( = 0.012, = 0.0299, respectively). Global radiation only influenced PPIX ( = 0.0113).
CONCLUSIONS
These findings suggest that afamelanotide ameliorates both PPIX concentrations and LFTs in EPP in a dose-dependent manner.
PubMed: 37109595
DOI: 10.3390/life13041066 -
Journal of Postgraduate Medicine 2023Porphyrias are a rare group of inborn errors of metabolism due to defects in the heme biosynthetic pathway. The biochemical hallmark is the overproduction of porphyrin...
Porphyrias are a rare group of inborn errors of metabolism due to defects in the heme biosynthetic pathway. The biochemical hallmark is the overproduction of porphyrin precursors and porphyrin species. Afflicted patients present with a myriad of symptoms causing a diagnostic odyssey. Symptoms often overlap with those of common diseases and may be overlooked unless there is heightened clinical suspicion. We are reporting clinical features and diagnostic challenges in four pediatric patients having variegate porphyria, congenital erythropoietic porphyria, acute intermittent porphyria, and erythropoietic protoporphyria (EPP), who presented with diverse multisystem manifestations. This case series illustrates a logical analysis of symptoms and judicious selection of investigations and the role of genotyping in successfully diagnosing porphyrias.
Topics: Child; Humans; Porphyrias; Porphyria, Acute Intermittent; Porphyrins
PubMed: 37082991
DOI: 10.4103/jpgm.jpgm_698_22 -
Pharmacology Research & Perspectives Jun 2023Dersimelagon (formerly MT-7117) is a novel, orally administered nonpeptide small molecule selective agonist for melanocortin 1 receptor currently being investigated for...
Absorption, metabolism, and excretion of [ C]dersimelagon, an investigational oral selective melanocortin 1 receptor agonist, in preclinical species and healthy volunteers.
Dersimelagon (formerly MT-7117) is a novel, orally administered nonpeptide small molecule selective agonist for melanocortin 1 receptor currently being investigated for the treatment of erythropoietic protoporphyria, X-linked protoporphyria, and diffuse cutaneous systemic sclerosis (dcSSc). Findings of studies evaluating the absorption, distribution, metabolism, and excretion (ADME) of dersimelagon following a single dose of [ C]dersimelagon in healthy adult volunteers (N = 6) who participated in phase 1, single-center, open-label, mass balance study (NCT03503266), and in preclinical animal models are presented. Rapid absorption and elimination were observed following oral administration of [ C]dersimelagon in clinical and nonclinical studies, with a mean T of 30 min in rats and 1.5 h in monkeys, and a median T of 2 h in humans. In rats, there was a widespread distribution of [ C]dersimelagon-related material, but little or no radioactivity was detected in the brain or fetal tissues. In humans, elimination of radioactivity in urine was negligible (excretion of radioactivity into the urine: 0.31% of dose), and the primary route of excretion was feces, with more than 90% of the radioactivity recovered through 5 days postdose. Based on these findings, dersimelagon is not retained in the human body. Findings from humans and animals suggest dersimelagon is extensively metabolized to the glucuronide in the liver, which is eliminated in bile, and hydrolyzed to unchanged dersimelagon in the gut. The results to date for this orally administered agent elucidate the ADME of dersimelagon in human and animal species and support its continued development for the treatment of photosensitive porphyrias and dcSSc.
Topics: Adult; Animals; Humans; Rats; Bile; Feces; Healthy Volunteers; Liver; Receptor, Melanocortin, Type 1
PubMed: 37078227
DOI: 10.1002/prp2.1084 -
Results from a first-in-human study of dersimelagon, an investigational oral selective MC1R agonist.European Journal of Clinical... Jun 2023To describe outcomes from the first-in-human study of dersimelagon, an investigational oral selective MC1R agonist, under development for the treatment of erythropoietic... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To describe outcomes from the first-in-human study of dersimelagon, an investigational oral selective MC1R agonist, under development for the treatment of erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP).
METHODS
In this double-blind, placebo-controlled phase 1 study, the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending oral doses of dersimelagon in healthy participants were evaluated.
RESULTS
Dersimelagon was generally well tolerated in healthy participants, with the most common TEAEs being lentigo (52.8%) and skin hyperpigmentation (50.0%) after multiple doses. Systemic exposure to dersimelagon in plasma (based on AUC and C) increased in a slightly more than dose-proportional manner over the 1- to 600-mg single-dose range. Following multiple doses, dersimelagon was rapidly absorbed (median T ranging from 4 to 5 h postdose on days 1 and 14). Mean t ranged from 10.56 to 18.97 h on day 14, and the steady state of plasma concentration was generally reached by 5 days of multiple dosing. There were no observable effects of age or race on the PK profile of dersimelagon or its metabolite dersimelagon glucuronide. No treatment-related effects on melanin density (MD) were observed following single doses of dersimelagon; however, after multiple doses, increases in MD were observed in participants receiving 150 and 300 mg dersimelagon.
CONCLUSION
Our study results indicate that dersimelagon is generally well tolerated and demonstrates a generally consistent PK profile across diverse subgroups. Treatment-related increases in MD warrant further investigation in a larger study population and in patients with EPP and XLP.
TRIAL REGISTRATION
A Study to Investigate the Safety, Tolerability and Pharmacokinetics of MT-7117 in Healthy Subjects, NCT02834442, https://clinicaltrials.gov/ct2/show/NCT02834442 , registration began July 2016.
Topics: Humans; Area Under Curve; Double-Blind Method; Healthy Volunteers; Dose-Response Relationship, Drug; Administration, Oral
PubMed: 37060458
DOI: 10.1007/s00228-023-03476-6 -
International Journal of Environmental... Mar 2023Erythropoietic protoporphyria (EPP) is an ultra-rare inborn error of metabolism characterised by painful phototoxic burn injuries after short exposure times to visible...
Erythropoietic protoporphyria (EPP) is an ultra-rare inborn error of metabolism characterised by painful phototoxic burn injuries after short exposure times to visible light. Patients with EPP are highly adapted to their condition which makes the quantification of their health-related quality of life (QoL) challenging. In the presented patient-initiated feasibility study, we describe a new approach to assess treatment benefits in EPP by measuring QoL with the generic EQ-5D instrument in five patients under long-term (≥two years) treatment with afamelanotide, the first approved therapy for EPP. For the study, we selected patients with EPP who in addition were affected by an involuntary treatment interruption (caused by a temporary reimbursement suspension) because we hypothesized that individuals who had previously unlearned their adaptation are better able to assess their life without treatment than treatment-naïve patients. QoL under treatment was comparable to the age-matched population norm, and retrospective results for a treatment interruption and phototoxic reaction time point were comparable to the QoL of patients with chronic neuropathic pain and acute burn injuries, respectively. The results were accepted by the National Institute for Health and Care Excellence in England for their evaluation of the cost-effectiveness of afamelanotide, i.e., the calculation of quality-adjusted life years.
Topics: Humans; Protoporphyria, Erythropoietic; Quality of Life; Retrospective Studies; Quality-Adjusted Life Years; Rare Diseases; Feasibility Studies
PubMed: 37047912
DOI: 10.3390/ijerph20075296 -
Blood Jun 2023Erythropoietic protoporphyria (EPP) is an inherited cutaneous porphyria caused by reduced expression of ferrochelatase, the enzyme that catalyzes the final step in heme...
Erythropoietic protoporphyria (EPP) is an inherited cutaneous porphyria caused by reduced expression of ferrochelatase, the enzyme that catalyzes the final step in heme biosynthesis. The resultant accumulation of protoporphyrin IX leads to severe, painful cutaneous photosensitivity, as well as potentially life-threatening liver disease in a small percentage of patients. X-linked protoporphyria (XLP) is clinically similar to EPP but results from increased activity of δ-aminolevulinic acid synthase 2, the first step in heme biosynthesis in the bone marrow, and also causes protoporphyrin accumulation. Although historically the management of EPP and XLP (collectively termed protoporphyria) centered around avoidance of sunlight, novel therapies have recently been approved or are in development, which will alter the therapeutic landscape for these conditions. We present 3 patient cases, highlighting key treatment considerations in patients with protoporphyria, including (1) approach to photosensitivity, (2) managing iron deficiency in protoporphyria, and (3) understanding hepatic failure in protoporphyria.
Topics: Humans; Protoporphyria, Erythropoietic; Ferrochelatase; Liver Diseases; Photosensitivity Disorders; Protoporphyrins; Heme
PubMed: 36898083
DOI: 10.1182/blood.2022018688 -
ACG Case Reports Journal Feb 2023Erythropoietic protoporphyria (EPP) presents with nonblistering photosensitivity. Hepatobiliary manifestations are seen in around 5% cases and include cholelithiasis,...
Erythropoietic protoporphyria (EPP) presents with nonblistering photosensitivity. Hepatobiliary manifestations are seen in around 5% cases and include cholelithiasis, elevations in liver enzymes, progressive jaundice, and end-stage liver disease. The diagnosis is suspected based on clinical features and elevated erythrocyte metal-free protoporphyrin and confirmed by genetic analysis showing loss-of-function mutations in the ferrochelatase (FECH) gene. We present an adolescent boy who presented with jaundice and photosensitivity with the liver biopsy showing deposition of brown pigments within the canaliculi and hepatocytes. This pigment showed Maltese cross birefringence on polarizing microscopy and Medusa-head appearance on electron microscopy. Genetic analysis revealed loss-of-function mutations in FECH. Introduction of EPP is an inborn error of heme biosynthesis caused by mutations in FECH with a prevalence of 1:75,000 to 1:200,000. We present a case of a 16-year-old adolescent boy with photosensitivity, abdominal pain, and jaundice with protoporphyrin deposition in the liver who was ultimately diagnosed with EPP based on genetic analysis.
PubMed: 36891180
DOI: 10.14309/crj.0000000000000996