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(a) Three years before cholestasis, liver histology revealed focal, minor macrovesicular steatosis and focal cholestasis but no inflammation and scarce protoporphyrin deposition. Fibrosis was minimal (not shown). (b) Before treatment, liver architecture was severely disturbed with hepatocyte ballooning (filled arrow), prominent nucleoli and marked nuclear polymorphism with some binucleated hepatocytes. Rich inflammatory infiltrates composed by lymphocytes and granulocytes infiltrated surrounding parenchyma in portal regions. There was pronounced intraand extracellular cholestasis, focal cholangitis (open arrow) and several protoporphyrin deposits surrounded by inflammatory cells (thin arrow). Fibrosis had progressed to stage 2 (Batts and Ludwig). Protoporphyrin deposits displayed birefringence, at some places with the classic Maltese cross interference pattern, when viewed with polarizing filter (small picture). (c) After 131 days, liver architecture was markedly improved. There was still some nuclear polymorphism and some hepatocytes had rich cytoplasm. Only focal portal inflammation lingered, but no infiltration of surrounding parenchyma. Focal, extracellular cholestasis and rare periportal deposits of protoporphyrin in Kupffer cells remained, but no cholangitis. Fibrosis was still stage 2 (Batts and Ludwig). c
Source publication
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 histol...
Contexts in source publication
Context 1
... allele. Erythrocyte protoporphyrin concentration has constantly been above 100 (normal <1.2 lmol/L), faecal porphyrin excretion markedly elevated but urinary excretion normal. Liver biopsy in 1997 revealed mild abnormalities with protoporphyrin deposits and in 2001 minimal fibrosis was the only sign of histopathologic progression over four years (Fig. 2a). In the following three years, serum liver function tests remained normal and the porphyrin metabolic state ...
Context 2
... markers for autoimmune, viral and other metabolic diseases. Candesartan, amlodipine and hydrochlorthiazide, his anti-hypertensive medications since three years, were not likely causative factors and his alcohol intake was negligible. In the previous months, he had voluntarily lost roughly five kilograms on a glycemic index diet. Liver biopsy (Fig. 2b) now revealed marked progress of histological features characteristic for protoporphyrin parenchymal damage and progress of fibrosis. The cholestasis was considered to be caused by EPP. No exogenous factor was regarded causative although caloric restriction affects hepatic haem biosynthesis [5], suggesting a possible connection with ...
Citations
... 11 Since then, other centers successfully accomplished HSCT for EPP. 12 ...
... Hepatopulmonary syndrome is a severe complication in patients with end-stage liver disease and portal 8 Wahlin et al 12 Windon et al 18 Smiers et al 19 Cheung et al 20 Hashmi et al 21 hypertension. Busulfan may induce direct toxicity to the epithelial lining cells of the lungs, contributing to the higher risk. ...
... Wahlin et al12 Windon et al 18 Smiers et al19 Cheung et al20 Hashmi et al21 Wang et al 22 In years. aGvHD indicates acute graft versus host disease; AML, acute myeloid leukemia; ATG, thymoglobulin; AZA, azathioprine; BK, polyomavirus; BM, bone marrow; BMT, bone marrow transplant; BSX, basiliximab; BuCy, busulfan and cyclophosphamide; BuFluCy, busulfan, fludarabine and cyclophosphamide; cGvHD, chronic graft versus host disease; CMV, cytomegalovirus; CsA, cyclosporine; EBV, Epstein-barr virus; EP, erythrocyte protoporphyrin; FECH, mitochondrial enzyme ferrochelatase; FluMEL, fludarabine and melphalan; GvHD, grfat versus host disease; HAPLO, haploidentical; HbOV, human bocavirus; HSCT, hematopoietic stem cell transplantation; HSV, herpes simplex virus; IST, immunosuppression; JC, John Cunningham virus; KPC, Klebsiella pneumoniae carbapenemase producing; LT, liver transplant; MELD, model for end-stage liver disease; MET, methylprednisone; MMF, mycophenolate; MRD, matched related donor; MRSA, methicillin-resistant Staphylococcus aureus; MTX, methotrexate; MURD, matched unrelated donor; NE, neutrophil engraftment; NE, not specified; PBSC, peripheral blood stem cell; PP, plasma protoporphyrin; PRED, prednisone; PTLD, post-transplant lymphoproliferative disease; RBC, red blood cells; RITUX, rituximab; RV, reference value; SIRO, sirolimus; TAC, tacrolimus; TBI, total body irradiation; TR, therapy-related; USA, United states of America;VOD, veno-occlusive disease; VZV, varicella zoster virus. ...
Background:
Erythropoietic protoporphyria (EPP) is a rare inherited disease of heme biosynthesis resulting in the accumulation of protoporphyrin, characterized by liver failure in a minority of cases. Although liver transplant (LT) is the therapeutic strategy for advanced hepatic disease, it does not correct the primary defect, which leads to recurrence in liver graft. Thus, hematopoietic stem cell transplantation (HSCT) is an approach for treating EPP.
Methods:
We aim to describe the first sequential LT and HSCT for EPP performed in Latin America, besides reviewing the present-day literature.
Results:
The patient, a 13-year-old female with a history of photosensitivity, presented with symptoms of cholestatic and hepatopulmonary syndrome and was diagnosed with EPP. Liver biopsy demonstrated cirrhosis. She was submitted to a successful LT and showed improvement of respiratory symptoms. However, she had disease recurrence on the liver graft. She underwent a myeloablative HSCT using a matched unrelated donor, conditioning with BuCy (busulfan and cyclophosphamide), and GvHD (graft vs. host disease) prophylaxis with ATG (thymoglobulin), tacrolimus and methotrexate. Neutrophil engraftment occurred on D+18. She has presented mixed chimerism, but normalization of PP levels, being 300 days after HSCT, in good state of health and normal liver function.
Conclusions:
Consecutive LT and HSCT for EPP is a procedure that has been described in 10 cases in the literature and, even though these patients are a highly diversified population, studies have shown favorable results. This concept of treatment should be considered in patients with established liver disease.
... HSCT corrects the defect in heme biosynthesis in the bone marrow but should only be considered in patients with significant liver complications, particularly in young patients after successful OLT in order to preserve graft function, in patients with progressive liver disease who do not yet meet criteria for OLT, and after improvement of liver failure without advanced liver fibrosis. [96][97][98][99][100][101][102] Most published cases of HSCT for protoporphyria are from matched-unrelated donors with a non-myeloablative, reducedintensity conditioning (RIC) regimen, though reports are emerging of haploidentical transplants. 102 Similar to HSCT approaches in other nonmalignant diseases, in patients with protoporphyria, we How I treat protoporphyria Page 16 recommend RIC, use of bone marrow as the stem cell source, and either ex-vivo graft manipulation (such as alphabeta T-cell receptor and CD19+ depletion) or post-transplant cyclophosphamide for graft-versus-host disease prevention especially if a haploidentical donor is selected. ...
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 similar to EPP clinically, but results from increased activity of δ-aminolevulinic acid synthase 2 (ALAS2), 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 three patient vignettes 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.
... Csontvelő-transzplantációt végeztek a kolesztatikus májbetegség visszaesésének megelőzésére a protoporfirin túltermelés fő helyének korrigálásával. Harminchárom hónappal a kolesztatikus megjelenés és tíz hónappal a csontvelő-transzplantáció után a máj és a porfirin biokémiája normális maradt (83). ...
Sunlight has many biological effects. If the average or low dose of light produces more pronounced, intense, or unusual acute or chronic skin symptoms, it is called photosensitivity. Rarely, photosensitivity is due to a genetic abnormality. Genophotodermatoses result in photosensitivity due to mutations in proteins with a protective function against light, while porphyrias result in the accumulation of phototoxic metabolites. Most of them also have a genetic background. The present report describes these diseases in the light of the latest literature data but does not cover diseases associated with melanin synthesis, which also results in photosensitivity.
... Although liver transplantation is effective in restoring liver function in patients with PP, it does not cure the FECH deficit in erythroid cells and does not abate liver exposure to plasma protoporphyrin molecules; therefore, there is a real risk of the recurrence of PP-liver disease after transplantation. The risk can be minimized only through hematopoietic cell transplantation [122], which issometimes performed in a sequential approach after liver transplantation [123]. Probably due to the persistence of biliary excretion of protoporphyrin, patients with PP are more susceptible to biliary complications compared to other liver transplant recipients. ...
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are inherited disorders resulting from defects in two different enzymes of the heme biosynthetic pathway, i.e., ferrochelatase (FECH) and delta-aminolevulinic acid synthase-2 (ALAS2), respectively. The ubiquitous FECH catalyzes the insertion of iron into the protoporphyrin ring to generate the final product, heme. After hemoglobinization, FECH can utilize other metals like zinc to bind the remainder of the protoporphyrin molecules, leading to the formation of zinc protoporphyrin. Therefore, FECH deficiency in EPP limits the formation of both heme and zinc protoporphyrin molecules. The erythroid-specific ALAS2 catalyses the synthesis of delta-aminolevulinic acid (ALA), from the union of glycine and succinyl-coenzyme A, in the first step of the pathway in the erythron. In XLP, ALAS2 activity increases, resulting in the amplified formation of ALA, and iron becomes the rate-limiting factor for heme synthesis in the erythroid tissue. Both EPP and XLP lead to the systemic accumulation of protoporphyrin IX (PPIX) in blood, erythrocytes, and tissues causing the major symptom of cutaneous photosensitivity and several other less recognized signs that need to be considered. Although significant advances have been made in our understanding of EPP and XLP in recent years, a complete understanding of the factors governing the variability in clinical expression and the severity (progression) of the disease remains elusive. The present review provides an overview of both well-established facts and the latest findings regarding these rare diseases.
... As PPIX is produced mainly by the bone marrow and because hepatopathy may recur, a subsequent bone marrow transplantation should be considered. [75][76] An acute cholestatic hepatitis can be precipitated by other causes of liver disease, including 77 As a preventive measure, all EPP patients are urged to refrain from alcohol and hepatotoxic medication, and immunisation against hepatitis A and B is advised. Caution should be taken for EPP patients requiring surgery, since prolonged exposure (> 3 hours) to bright surgical lights can induce phototoxic tissue injury, which can be prevented by using yellow filters that block blue light. ...
Porphyrias are rare metabolic disorders. Lack of awareness and knowledge about the clinical features of porphyrias results in diagnostic and therapeutic delays for many patients. Delays in diagnosing and treating porphyrias can result in severe, progressive morbidity (and mortality) and psychological distress for patients. This review discusses the pathophysiology, diagnosis, treatment, and follow-up of the most prevalent porphyrias: acute intermittent porphyria, porphyria cutanea tarda, and erythropoietic protoporphyria.
... The patients who progress to liver cirrhosis and develop liver failure can be rescued by liver transplantation. However, liver transplantation does not alter the excessive production of PP in the bone marrow [6,13,19], and the recipients are at risk of disease recurrence in the grafted liver. Windon et al [16] reported that in 31 cases of EPP treated with liver transplantation, approximately 70% of the patients developed liver damage in the graft [20], and 4 cases required a second liver transplantation because of progressive liver damage in the transplanted organ. ...
Background:
Erythropoietic protoporphyria is a rare disease of heme biosynthesis resulting in excessive accumulation of protoporphyrin in various organs. The most typical symptom is photosensitivity caused by activated protoporphyrins (wavelength ~400 nm). Accumulated protoporphyrin in the liver also causes liver failure, and liver transplantation is the only life-saving treatment. Phototoxic injury to abdominal organs has been reported during liver transplantation. Thus, to avoid phototoxic injury during liver transplantation, it has previously been conducted with only shadowless lights and ceiling lights off in the operating theater. Here, we report a case of a safe and successful liver transplantation in a patient with erythropoietic protoporphyria where the operating theater lights were covered with polyimide film.
Case presentation:
A 50-year-old man presented with hepatic failure owing to erythropoietic protoporphyria. Before liver transplantation, the shadowless lights and ceiling lights in the operating theater were covered entirely with polyimide film. This filter completely blocked the harmful wavelength of light (400-470 nm). Orthotopic liver transplantation was safely and successfully performed with adequate illumination and patient monitoring. The patient followed a normal postoperative course without phototoxic injuries or protoporphyrin re-accumulation.
Conclusion:
Covering not only shadowless lights but also all ceiling lights in the operating theater with the polyimide film allowed safe surgery, safe anesthesia, and safe monitoring of the patient who underwent liver transplantation for severe liver failure owing to erythropoietic protoporphyria.
... The results of only a handful of AlloSCT for EPP have been published: 2 in the pediatric population and 2 in the adult population. (2,(38)(39)(40)(41) In the pediatric literature, there are 2 reported cases of sequential OLT and AlloSCT. The first, from an HLA-matched sister, resulted in graft rejection, but using a more aggressive myeloablative conditioning regimen in the second attempt resulted in successful engraftment. ...
... The first case was complicated with graft failure that was overcome in the second attempt with more aggressive myeloablation. (41) The second case, which was a sequential OLT and AlloSCT, was successful using a reduced-intensity conditioning regimen consisting of fludarabine, busulfan, and total body irradiation without T cell depletion. (40) In our patients, both allograft attempts resulted in initial graft failure that was overcome successfully in one by more aggressive conditioning with melphalan and omission of T cell depletion. ...
Erythropoietic protoporphyria (EPP) is an inherited metabolic disorder of heme synthesis resulting from overproduction of protoporphyrin IX (PPIX) which can lead to progressive liver disease characterized by recurrent EPP crisis and end stage liver disease. We utilized the Australian Transplant Registry to identify five patients referred for liver transplantation between 2008 and 2017. Four patients had EPP secondary to ferrochelatase (FECH) deficiency and one had X‐Linked EPP (XLP). No patient had specialist follow‐up prior to the diagnosis of progressive liver disease. Three patients underwent orthotopic liver transplant (OLT), while two died while on the transplant waiting list. Parenteral PPIX‐lowering therapy was utilized in four patients and was effective in three patients although two of these had rebound porphyria and worsening liver function following decreasing the intensity of therapy. Early disease recurrence in the allograft following transplantation occurred in two patients requiring red cell exchange (RCE) to successfully attain and maintain low PPIX levels, but RCE was associated with hemosiderosis in one case. Allogeneic stem cell transplantation (AlloSCT) was performed in two patients. One failed engraftment twice while the second rejected their first graft but achieved full donor chimerism with a second graft and increased immunosuppression. Conclusion: Our observations suggest that progressive liver disease needs parenteral PPIX‐lowering treatment with the intensity adjusted to achieve a target Erc‐PPIX level. Since recurrent EPP liver disease is the rule, AlloSCT should be considered in all patients with adequate immunosuppression to facilitate engraftment. RCE appears effective for recurrent EPP liver disease but is associated with an increased risk of iron overload. This article is protected by copyright. All rights reserved.
... However, a PPIX reduction of up to 85% and a resolution of inflammatory liver damage have been reported after allogeneic hematopoietic stem cell transplantation, even when performed before or after liver transplantation. 125,126 Drug restriction, as required for AHP, is not required for patients with EPP or XLP. Interestingly, iron substitution can decrease protoporphyrin concentrations and improve symptoms in patients with XLP-sufficient iron as second substrate promotes conversion of toxic PPIX to heme by FECH. ...
... Excess PPIX is excreted through the liver and cause damages to hepatocytes and cholangioles. In 2-5% of the patients, the cholestatic liver damage is so severe that liver transplantation -preferentially together with bone marrow transplantation to prevent relapse by ongoing PPIX overproduction in the native erythropoietic tissue -is needed to save patients' lives 3,4 . ...
Erythropoietic protoporphyria consists of two different genetic diseases, erythropoietic protoporphyria (EPP) and X-linked erythropoietic protoporphyria (XLEPP). Both of them are often accompanied by iron deficiency. Iron supplementation appears to be beneficial in XLEPP, although the clinical experience until to date is limited. In EPP, iron supplementation is discussed ambiguously and may cause harm in the majority of cases.
This minireview summarizes the limited knowledge on the connections of iron metabolism to regulation of porphyrin and heme synthesis and the influence these regulations may have on disease severity in the protoporphyrias. Further, we propose clinical guidelines, how to manage iron deficiency in both XLEPP and EPP.
... A causative treatment and eventually a cure for EPP can be achieved by bone marrow transplantation. However, because of inherent severe immunological risks, experts recommend this procedure only in cases of recurrent life-threatening liver complications (Anstey and Hift, 2007; Minder et al., 2016; Wahlin et al., 2007). A gene therapy using a FECH cDNA expression construct has been proven to work experimentally in mice (Pawliuk et al., 1999; Richard et al., 2001), but has not been advanced to the clinical stage. ...
Erythropoietic Protoporphyria (EPP) is caused by deficiency of ferrochelatase (FECH) which incorporates iron into protoporphyrin IX (PPIX) to form heme. Excitation of accumulated PPIX by light generates oxygen radicals which evoke excessive pain and, after longer light exposure, ulcerations in exposed skin areas of EPP patients. Moreover, ∼5% of the patients develop a liver dysfunction due to PPIX accumulation. Most patients (∼97%) have a severe FECH mutation (Mut) in trans to an intronic polymorphism (c.315-48C) which reduces ferrochelatase synthesis by stimulating the use of an aberrant 3' splice site 63 nt upstream of the normal site for exon 4. In contrast, with the predominant c.315-48T allele, the correct splice site is mostly used, and individuals with a T/Mut genotype do not develop EPP symptoms. Thus, the C allele is a potential target for therapeutic approaches that modify this splicing decision. To provide a model for pre-clinical studies of such approaches, we engineered a mouse containing a partly humanized Fech gene with the c.315-48C polymorphism. F1 hybrids obtained by crossing these mice with another inbred line carrying a severe Fech mutation (named m1Pas), show a very strong EPP phenotype which includes elevated PPIX in the blood, enlargement of liver and spleen, anemia, as well as strong pain reactions and skin lesions after short light exposure. In addition to the expected use of the aberrant splice site, the mice also show a strong skipping of the partly humanized exon 3. This will limit the use of this model for certain applications and illustrates that engineering of a hybrid gene may have unforeseeable consequences on its splicing.
