Living-Donor Liver Transplantation for Erythropoietic Protoporphyria: A Case Report and Literature 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.

Evidence-based consensus guidelines for the diagnosis and management of erythropoietic protoporphyria and X-linked protoporphyria.

Erythropoietic protoporphyria and X-linked protoporphyria are rare genetic photodermatoses. Limited expertise with these disorders among physicians leads to diagnostic delays. Here, we present evidence-based consensus guidelines for the diagnosis, monitoring, and management of erythropoietic protoporphyria and X-linked protoporphyria. A systematic literature review was conducted, and reviewed among subcommittees of experts, divided by topic. Consensus on guidelines was reached within each subcommittee and then among all members of the committee. The appropriate biochemical and genetic testing to establish the diagnosis is reviewed in addition to the interpretation of results. Prevention of symptoms, management of acute phototoxicity, and pharmacologic and nonpharmacologic treatment options are discussed. The importance of ongoing monitoring for liver disease, iron deficiency, and vitamin D deficiency is discussed with management guidance. Finally, management of pregnancy and surgery and the safety of other therapies are summarized. We emphasize that these are multisystemic disorders that require longitudinal monitoring. These guidelines provide a structure for evidence-based diagnosis and management for practicing physicians. Early diagnosis and management of these disorders are essential, particularly given the availability of new and emerging therapies.

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Erythropoietic protoporphyria (EPP) is an inherited metabolic disease caused by the deficiency in ferrochelatase (FECH) encoded by the FECH gene, and it is inherited in an autosomal recessive manner. EPP usually produces acute pain photosensitivity after exposure to sunlight in infancy or early childhood, and liver failure is the most serious associated complication. This article reported an adult female case of EPP complicated with thyrotoxicosis and liver dysfunction which is a rare condition. The patient's liver function improved after liver protection treatment, her thyroid function returned to normal, and her EPP symptoms improved significantly. Moreover, the c.286C>T gene mutation may be the pathogenic locus of EPP. For patients with abnormal liver function, the possibility of EPP should be considered after the common causes are excluded, and FECH gene detection should be done to confirm the diagnosis in time. When EPP is associated with thyrotoxicosis and liver dysfunction, priority may be given to hepatoprotective therapy.

ABCB6 polymorphisms are not overly represented in patients with porphyria.

The Mendelian inheritance pattern of acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria is autosomal dominant, but the clinical phenotype is heterogeneous. Within the general population, penetrance is low, but among first-degree relatives of a symptomatic proband, penetrance is higher. These observations suggest that genetic factors, in addition to mutation of the specific enzyme of the biosynthetic pathway of heme, contribute to the clinical phenotype. Recent studies by others suggested that the genotype of the transporter protein ABCB6 contribute to the porphyria phenotype. Identifying the molecule(s) that are transported by ABCB6 has been problematic and has led to uncertainty with respect to how or if variants/mutants contribute to phenotypic heterogeneity. Knockout mouse models of Abcb6 have not provided a direction for investigation as homozygous knockout animals do not have a discrete phenotype. To address the proposed link between ABC6 genotype and porphyria phenotype, a large cohort of patients with acute hepatic porphyria and erythropoietic protoporphyria was analyzed. Our studies showed that ABCB6 genotype did not correlate with disease severity. Therefore, genotyping of ABCB6 in patients with acute hepatic porphyria and erythropoietic protoporphyria is not warranted.

Liver involvement in patients with erythropoietic protoporphyria: retrospective analysis of clinicopathological features of 5 cases.

Erythropoietic protoporphyria (EPP) is a rare inherited disease whose morbidity is about 1:75,000 to 1:200,000. It is caused by the deficiency of porphyrin ferrochelatase (FECH). Liver involvement in EPP is even rarer. The diagnosis of EPP with liver involvement mainly relies on clinical manifestations, laboratory examinations, histopathological examinations and genetic testing, which is still a huge challenge for both clinicians and pathologists. Here, 5 cases of EPP with liver injury were collected, and the clinicopathological features of these patients were analyzed. The clinical manifestations and laboratory examinations varied from person to person, whereas the liver biopsies showed that there were dark brown deposits within the hepatocytes, Kupffer cells, bile canaliculi and the lumen of bile ducts, which was a constant finding by histopathological examination. Gene tests were conducted in two of the five cases, and the results confirmed the diagnosis. Fully understanding of the diseases can help us reduce the rate of missed diagnosis and provide proper treatment as early as possible.

Distribution of protoporphyrin IX in erythrocytes in a case of acquired erythropoietic protoporphyria.

BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare genetic photodermatosis caused by loss-of-function mutations in the gene for ferrochelatase leading to accumulation of the fluorescent protoporphyrin IX (PpIX) in erythrocytes. The mutations are most often inherited mutations present in all cells causing inherited EPP. In very rare cases EPP are acquired in association with myelodysplastic syndromes or myeloproliferative neoplasms, conditions with genetic instability. CASE REPORT: We report a case of acquired EPP in association with hematological disease. We followed erythrocyte PpIX concentration over a year and measured PpIX fluorescence in individual erythrocytes in a blood sample from the case using flow cytometry. The major proportion of erythrocytes did not fluoresce (84%), whereas 13% contained low PpIX fluorescence, 1% contained medium fluorescence, and 2% contained high fluorescence. DISCUSSION: Our observation of the very skewed PpIX distribution in erythrocytes supports the description that acquired EPP is caused by a somatic mutation effecting a clone of hematopoietic cells.

Inherited genetic late-onset erythropoietic protoporphyria: A systematic review of the literature.

BACKGROUND: Inherited genetic erythropoietic protoporphyria (EPP) is characterized by a photosensitive rash that emerges during infancy or early childhood. Acquired EPP can erupt at any age, even during adulthood, and is associated with hematological disorders. A third, less-studied type of EPP is also inherited but appears later in life (during adulthood). PURPOSE: To evaluate the characteristics of inherited genetic late-onset (IGLO) EPP. METHODS: A systematic comprehensive search of the literature was conducted using PubMed, Google Scholar, ScienceDirect, and clinicaltrials.gov databases. Studies describing patients with IGLO EPP were included. Additionally, we present an index case of a patient, treated at our clinic in whom inherited genetic EPP was diagnosed at age 21 years. RESULTS: The search yielded 1514 citations. Five publications were eligible for review. Along with our case, 7 patients (4 males) were included in the analysis. Mean age at disease onset was 34.2 years (range 18-69, median 30). Most patients presented with mild pruritus and rash in a photosensitive distribution. Mean level of free erythrocyte protoporphyrin IX (FEP) was 8.6 µmol/L. A mutant ferrochelatase gene (FECH) in trans to a hypomorphic FECH allele was found in 3 of the 4 patients who underwent genetic testing. CONCLUSION: We describe the distinct features of IGLO EPP. This work emphasizes that a diagnosis of inherited genetic EPP should not be ruled out in adults with new-onset photosensitive manifestations.

Hematopoietic cell transplant for reversal of liver fibrosis in a pediatric patient with erythropoietic protoporphyria.

BACKGROUND: EPP is a rare disorder of heme biosynthesis in which patients present with disabling photosensitivity. A subset of patients develop severe liver disease with progressive liver failure necessitating an OLT. A HCT can potentially cure EPP by replacing the native bone marrow, which is the primary site of heme synthesis. However, due to concerns for inherent risks of treatment-related toxicities, the use of HCT has been reserved for patients undergoing an OLT to avoid disease recurrence in the hepatic graft. Data for HCT in EPP are lacking, particularly in the pediatric population. CASE (METHODS/RESULTS): We present the case of a 12-year-old patient with EPP photosensitivity and cirrhosis, whom we successfully treated with pre-emptive allogeneic HCT, significantly improving the patient's quality of life. We used a matched-unrelated donor bone marrow-derived graft. Our patient achieved full donor peripheral blood chimerism and has not had any evidence of GVHD. In addition to resolution of photosensitivity, our patient had reversal of liver fibrosis which we feel was largely due to intervention at an early stage of compensated cirrhosis. CONCLUSION: Our case highlights the successful application of a known RIC regimen to this rare disorder that was well tolerated with sustained donor engraftment. It also emphasizes the importance of timing for HCT in patients with EPP and liver fibrosis. HCT should be considered early in pediatric patients with EPP-hepatopathy to prevent progression to liver failure and need for OLT with lifelong immunosuppression.

Evidence in the UK Biobank for the underdiagnosis of erythropoietic protoporphyria.

PURPOSE: Erythropoietic protoporphyria (EPP), characterized by painful cutaneous photosensitivity, results from pathogenic variants in ferrochelatase (FECH). For 96% of patients, EPP results from coinheriting a rare pathogenic variant in trans of a common hypomorphic variant c.315-48T>C (minor allele frequency 0.05). The estimated prevalence of EPP derived from the number of diagnosed individuals in Europe is 0.00092%, but this may be conservative due to underdiagnosis. No study has estimated EPP prevalence using large genetic data sets. METHODS: Disease-associated FECH variants were identified in the UK Biobank, a data set of 500,953 individuals including 49,960 exome sequences. EPP prevalence was then estimated. The association of FECH variants with EPP-related traits was assessed. RESULTS: Analysis of pathogenic FECH variants in the UK Biobank provides evidence that EPP prevalence is 0.0059% (95% confidence interval [CI]: 0.0042-0.0076%), 1.7-3.0 times more common than previously thought in the UK. In homozygotes for the common c.315-48T>C FECH variant, there was a novel decrement in both erythrocyte mean corpuscular volume (MCV) and hemoglobin. CONCLUSION: The prevalence of EPP has been underestimated secondary to underdiagnosis. The common c.315-48T>C allele is associated with both MCV and hemoglobin, an association that could be important both for those with and without EPP.

Updates on the diagnosis and management of the most common hereditary porphyrias: AIP and EPP.

The porphyrias are a family of metabolic disorders caused by defects in the activity of one of the enzymes in the heme biosynthetic pathway. Acute intermittent porphyria (AIP), caused by autosomal dominant mutations in the gene encoding hydroxymethylbilane synthase, can lead to hepatocyte overaccumulation and systemic distribution of the proximal porphyrin precursors, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). ALA and PBG are toxic to neurons and extrahepatic tissue and cause the neurovisceral clinical manifestations of AIP. Management of AIP includes awareness and avoidance of triggering factors, infusions of hemin for severe acute attacks, and, if indicated for chronic suppressive therapy, maintenance treatment with hemin or givosiran, a small interfering RNA molecule that antagonizes ALA synthase 1 transcripts. Erythropoietic protoporphyria (EPP) is most commonly caused by autosomal recessive mutations in the gene encoding ferrochelatase (FECH), the heme pathway terminal enzyme. FECH deficiency leads to erythrocyte overaccumulation and high plasma levels of lipophilic protoporphyrins that photoactivate in the skin, causing burning pain and erythema. Protoporphyrins excreted in the bile can cause gallstones, cholestasis, fibrosis, and ultimately liver failure. Management of EPP includes skin protection and afamelanotide, an α-melanocyte stimulating hormone analog that increases melanin pigment and reduces photoactivation. Liver transplantation may be necessary for severe EPP-induced liver complications. Because AIP and EPP arise from defects in the heme biosynthetic pathway, hematologists are often consulted to evaluate and manage suspected or proven porphyrias. A working knowledge of these disorders increases our confidence and effectiveness as consultants and medical providers.

Clinical and molecular epidemiology of erythropoietic protoporphyria in Italy.

BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare inherited disease associated with heme metabolism, characterized by severe life-long photosensitivity and liver involvement. OBJECTIVE: To provide epidemiological data of EPP in Italy. MATERIALS & METHODS: Prospective/retrospective data of EPP patients were collected by an Italian network of porphyria specialist centres (Gruppo Italiano Porfiria, GrIP) over a 20-year period (1996-2017). RESULTS: In total, 179 patients (79 females) with a clinical and biochemical diagnosis of EPP were assessed, revealing a prevalence of 3.15 cases per million persons and an incidence of 0.13 cases per million persons/year. Incidence significantly increased after 2009 (due to the availability of alfa-melanotide, which effectively limits skin photosensitivity). Mean age at diagnosis was 28 years, with only 22 patients (12.2%) diagnosed ≤10 years old. Gene mutations were assessed in 173 (96.6%) patients; most (164; 91.3%) were FECH mutations on one allele in association with the hypomorphic variant, c.315-48C, on the other (classic EPP), and nine (5.2%) were ALAS2 mutations (X-linked EPP). Only one case of autosomal recessive EPP was observed. Of the 42 different FECH mutations, 15 are novel, three mutations collectively accounted for 45.9% (75/164) of the mutations (c.215dupT [27.2%], c.901_902delTG [11.5%] and c.67 + 5G > A [7.2%]), and frameshift mutations were prevalent (33.3%). A form of light protection was used by 109/179 (60.8%) patients, and 100 (56%) had at least one α-melanotide implant. Three cases of severe acute liver involvement, requiring OLT, were observed. CONCLUSION: These data define, for the first time, the clinical and molecular epidemiology of EPP in Italy.

Human aminolevulinate synthase structure reveals a eukaryotic-specific autoinhibitory loop regulating substrate binding and product release.

5'-aminolevulinate synthase (ALAS) catalyzes the first step in heme biosynthesis, generating 5'-aminolevulinate from glycine and succinyl-CoA. Inherited frameshift indel mutations of human erythroid-specific isozyme ALAS2, within a C-terminal (Ct) extension of its catalytic core that is only present in higher eukaryotes, lead to gain-of-function X-linked protoporphyria (XLP). Here, we report the human ALAS2 crystal structure, revealing that its Ct-extension folds onto the catalytic core, sits atop the active site, and precludes binding of substrate succinyl-CoA. The Ct-extension is therefore an autoinhibitory element that must re-orient during catalysis, as supported by molecular dynamics simulations. Our data explain how Ct deletions in XLP alleviate autoinhibition and increase enzyme activity. Crystallography-based fragment screening reveals a binding hotspot around the Ct-extension, where fragments interfere with the Ct conformational dynamics and inhibit ALAS2 activity. These fragments represent a starting point to develop ALAS2 inhibitors as substrate reduction therapy for porphyria disorders that accumulate toxic heme intermediates.

Delivery of oligonucleotides to bone marrow to modulate ferrochelatase splicing in a mouse model of erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP) is a rare genetic disease in which patients experience acute phototoxic reactions after sunlight exposure. It is caused by a deficiency in ferrochelatase (FECH) in the heme biosynthesis pathway. Most patients exhibit a loss-of-function mutation in trans to an allele bearing a SNP that favors aberrant splicing of transcripts. One viable strategy for EPP is to deploy splice-switching oligonucleotides (SSOs) to increase FECH synthesis, whereby an increase of a few percent would provide therapeutic benefit. However, successful application of SSOs in bone marrow cells is not described. Here, we show that SSOs comprising methoxyethyl-chemistry increase FECH levels in cells. We conjugated one SSO to three prototypical targeting groups and administered them to a mouse model of EPP in order to study their biodistribution, their metabolic stability and their FECH splice-switching ability. The SSOs exhibited distinct distribution profiles, with increased accumulation in liver, kidney, bone marrow and lung. However, they also underwent substantial metabolism, mainly at their linker groups. An SSO bearing a cholesteryl group increased levels of correctly spliced FECH transcript by 80% in the bone marrow. The results provide a promising approach to treat EPP and other disorders originating from splicing dysregulation in the bone marrow.