Liver Disease In Erythropoietic Protoporphyria Research Articles

Liver involvement in patients with erythropoietic protoporphyria.

In erythropoietic protoporphyria (EPP), which presents with severe painful phototoxicity, progressive deposition of protoporphyrins in hepatocytes and bile canaliculi may result in liver disease. Clinically EPP related liver disease ranges from mildly elevated liver enzymes to cirrhosis and acute cholestatic hepatic failure. The prevalence of liver disease in EPP, and factors predicting the risk of developing liver disease, have not been defined in a large series of unselected EPP patients. To determine the prevalence of liver disease in EPP-patients. A single-center prospective unselected cohort study of 114 adult EPP patients, who underwent routine laboratory testing, abdominal ultrasonography and transient elastography to assess the presence of steatosis (controlled attenuation parameter,dB/m) and liver stiffness (kPa). 114 adult EPP patients were included. Elevated liver enzymes were found in 6.2% of the patients. Liver steatosis was detected in 29.0%, and significant fibrosis as assessed with liver stiffness measurements was present in 9.6% of patients. BMI positively predicted CAP-values (p=0.026); and protoporphyrin IX levels (p=0.043) positively predicted liver stiffness. This study demonstrates a prevalence of hepatic steatosis and fibrosis in adult EPP-patients comparable to that found in the general population. Protoporphyrin IX levels correlate with increased liver stiffness in EPP.

Management of Patients With Erythropoietic Protoporphyria-Related Progressive Liver Disease.

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 crises and end-stage liver disease. We used the Australian Transplant Registry to identify 5 patients referred for liver transplantation between 2008 and 2017. A total of 4 patients had EPP secondary to ferrochelatase deficiency, and 1 patient had X-linked EPP. No patient had follow-up with a specialist prior to the diagnosis of progressive liver disease. There were 3 patients who underwent orthotopic liver transplantation, whereas 2 died while on the transplant waiting list. Parenteral PPIX-lowering therapy was used in 4 patients and was effective in 3 patients, although 2 of these had rebound porphyria and worsening liver function following a decrease in the intensity of therapy. Early disease recurrence in the allograft following transplantation occurred in 2 patients requiring red cell exchange (RCE) to successfully attain and maintain low PPIX levels, but RCE was associated with hemosiderosis in 1 patient. Allogeneic stem cell transplantation (AlloSCT) was performed in 2 patients. One failed engraftment twice, whereas the second rejected the first graft but achieved full donor chimerism with a second graft and increased immunosuppression. In conclusion, our observations suggest that progressive liver disease needs parenteral PPIX-lowering treatment with the intensity adjusted to achieve a target Erc-PPIX level. Because EPP liver disease is universally recurrent, AlloSCT should be considered in all patients with adequate immunosuppression to facilitate engraftment. RCE appears to be effective for recurrent EPP liver disease but is associated with an increased risk of iron overload.

Liver transplantation in the management of porphyria

Porphyrias are a group of eight metabolic disorders, each resulting from a mutation that affects an enzyme of the heme biosynthetic pathway. Porphyrias are classified as hepatic or erythropoietic, depending upon the site where the gene defect is predominantly expressed. Clinical phenotypes are classified as follows: (1) acute porphyrias with neurovisceral symptoms: acute intermittent porphyria; delta amino-levulinic acid hydratase deficiency porphyria; hereditary coproporphyria; and variegate porphyria and (2) cutaneous porphyrias with skin blistering and photosensitivity: porphyria cutanea tarda; congenital erythropoietic porphyria; hepatoerythropoietic porphyria and both erythropoietic protoporphyrias: autosomal dominant and X-linked. Liver transplantation (LT) may be needed for recurrent and/or life-threatening acute attack in acute intermittent porphyria or acute liver failure or end-stage chronic liver disease in erythropoietic protoporphyria. LT in acute intermittent porphyria is curative. Erythropoietic protoporphyria patients needing LT should be considered for bone marrow transplantation to achieve cure. This article provides an overview of porphyria with diagnostic approaches and management strategies for specific porphyrias and recommendations for LT with indications, pretransplant evaluation, and posttransplant management.

UK experience of liver transplantation for erythropoietic protoporphyria

Erythropoietic protoporphyria (EPP) is characterised by excess production of free protoporphyrin from the bone marrow, most commonly due to deficiency of the enzyme ferrochelatase. Excess protoporphyrin gives rise to the cutaneous photosensitivity characteristic of the disease, and in a minority of patients leads to end-stage liver disease necessitating liver transplantation (LT). There is limited information regarding the timing, impact and long-term outcome of LT in such patients, thus we aimed to identify the indications and outcomes of all transplants performed for EPP in the UK using data from the UK Transplant Registry. Between 1987 and 2009, five patients underwent LT for EPP liver disease. Median follow-up was 60 months, and there were two deaths at 44 and 95 months from causes unrelated to liver disease. The remaining recipients are alive at 22.4 years, 61 months and 55 months after transplant. A high rate of postoperative biliary stricturing requiring multiple biliary interventions was observed. Recurrent EPP-liver disease occurred in 4/5 (80%) of patients but graft failure has not been observed. Given the role of biliary obstruction in inducing EPP-mediated liver damage, we suggest that consideration should be given for construction of a Roux loop at the time of transplant. Thus we demonstrate that although EPP liver transplant recipients have a good long-term survival, comparable to patients undergoing LT for other indications, biliary complications and disease recurrence are almost universal, and bone marrow transplantation should be considered where possible.

Erythropoietic Protoporphyria

A 34-year-old woman with a history of photosensitivity reaction was admitted to our hospital for epigastralgia and jaundice, which had persisted for 1 month. She had no history of alcohol consumption, and had regularly been taking ferric oxide for the treatment of anemia. Physical examination revealed that the skin and conjunctiva were icteric; abdominal tenderness and palpable liver and spleen were noted. Blood examination revealed anemia (hemoglobin 9.2 g/dL), and liver dysfunction (international normalized ratio, 1.54; total bilirubin, 4.4 mg/dL; alanine aminotransferase, 90 IU/L; y-glutamyltransferase, 159 IU/L). The results of serologic examination for hepatitis B and C virus were negative. An abdominal computed tomography scan showed hepatosplenomegaly. For further investigation, needle biopsy of the liver was performed.On hematoxylin-eosin staining (Figure A), the liver specimen showed slightly distorted lobular architecture. It contained deposits of dark reddish-brown pigment localized in the cytoplasm of the hepatocytes and Kupffer cells in the lumen of the dilated canaliculi and/or interlobular ducts. All the deposits exhibited striking birefringence on polarization microscopic examination (Figure B). Characteristically, some globular deposits appeared bright red and had a centrally-located Maltese cross (arrow). Further, a significant increase was noted in the protoporphyrin levels in the patient's red blood cell count (8578 μg/dL). These findings led to the diagnosis of erythropoietic protoporphyria (EPP).EPP is an inborn error of haem biosynthesis caused by mutations in the gene encoding the mitochondrial enzyme ferrochelatase, which is the final enzyme in the haem biosynthetic pathway. Defects in ferrochelatase lead to an excess of protoporphyrin in the plasma, which in turn induces photosensitivity. Liver damage occurs due to cholestasis caused by excess protoporphyrin and/or exposure to protoporphyrin itself. Protoporphyrin-induced hepatotoxicity is a rare condition occurring in 1%–5% of EPP patients1Anstey A.V. Hift R.J. Liver disease in erythropoietic protoporphyria: insights and implications for management.Gut. 2007; 56: 1009-1018PubMed Google Scholar; however, in patients with deteriorating liver disease, EPP may be irreversible, and such patients require liver transplantation.2McGuire B.M. Bonkovsky H.L. Carithers R.L. et al.Liver transplantation for erythropoietic protoporphyria liver disease.Liver Transpl. 2005; 11: 1590-1596Crossref PubMed Scopus (111) Google Scholar A 34-year-old woman with a history of photosensitivity reaction was admitted to our hospital for epigastralgia and jaundice, which had persisted for 1 month. She had no history of alcohol consumption, and had regularly been taking ferric oxide for the treatment of anemia. Physical examination revealed that the skin and conjunctiva were icteric; abdominal tenderness and palpable liver and spleen were noted. Blood examination revealed anemia (hemoglobin 9.2 g/dL), and liver dysfunction (international normalized ratio, 1.54; total bilirubin, 4.4 mg/dL; alanine aminotransferase, 90 IU/L; y-glutamyltransferase, 159 IU/L). The results of serologic examination for hepatitis B and C virus were negative. An abdominal computed tomography scan showed hepatosplenomegaly. For further investigation, needle biopsy of the liver was performed. On hematoxylin-eosin staining (Figure A), the liver specimen showed slightly distorted lobular architecture. It contained deposits of dark reddish-brown pigment localized in the cytoplasm of the hepatocytes and Kupffer cells in the lumen of the dilated canaliculi and/or interlobular ducts. All the deposits exhibited striking birefringence on polarization microscopic examination (Figure B). Characteristically, some globular deposits appeared bright red and had a centrally-located Maltese cross (arrow). Further, a significant increase was noted in the protoporphyrin levels in the patient's red blood cell count (8578 μg/dL). These findings led to the diagnosis of erythropoietic protoporphyria (EPP). EPP is an inborn error of haem biosynthesis caused by mutations in the gene encoding the mitochondrial enzyme ferrochelatase, which is the final enzyme in the haem biosynthetic pathway. Defects in ferrochelatase lead to an excess of protoporphyrin in the plasma, which in turn induces photosensitivity. Liver damage occurs due to cholestasis caused by excess protoporphyrin and/or exposure to protoporphyrin itself. Protoporphyrin-induced hepatotoxicity is a rare condition occurring in 1%–5% of EPP patients1Anstey A.V. Hift R.J. Liver disease in erythropoietic protoporphyria: insights and implications for management.Gut. 2007; 56: 1009-1018PubMed Google Scholar; however, in patients with deteriorating liver disease, EPP may be irreversible, and such patients require liver transplantation.2McGuire B.M. Bonkovsky H.L. Carithers R.L. et al.Liver transplantation for erythropoietic protoporphyria liver disease.Liver Transpl. 2005; 11: 1590-1596Crossref PubMed Scopus (111) Google Scholar

Biochemical Abnormality in Erythropoietic Protoporphyria

Erythropoietic protoporphyria (EPP) is a genetic disorder in which deficient ferrochelatase (FECH) activity causes the excessive production and excretion of protoporphyrin. This in turn causes the major clinical manifestation of EPP, photosensitivity and, in some patients, hepatobiliary disease that may be severe. The objective of this study was to define genotypic determinants of phenotype in EPP. FECH activity was measured in 30 tissue samples from 26 patients with symptomatic EPP to determine the degree of deficient activity. FECH DNA analysis was also done in 26 families with EPP to identify mutations and examine for the presence of a polymorphism (IVS3-48c) that causes low gene expression. The level of residual FECH activity that was measured in tissue samples of patients with symptomatic EPP was <or=30% of the mean normal level in all patients except one. Lowest levels (4-20% normal) were in patients with advanced EPP liver disease. Heterozygous FECH mutations were found in 45 individuals from 26 families with EPP. In 94% of the 32 symptomatic individuals, 15 of whom had liver disease, the polymorphism was present in the nonmutant allele. In 13 asymptomatic patients, the polymorphism was absent. Patients with symptomatic EPP (photosensitivity with/without hepatobiliary disease) usually have a mutation in 1 FECH allele that alters enzyme structure/function, together with a polymorphism in the nonmutant allele that causes low gene expression. This leads to a significant reduction in FECH activity that causes symptomatic disease to develop because of the excess protoporphyrin produced.

Molecular Studies of Liver Disease in Erythropoietic Protoporphyria

The goal of this study was to define molecular determinants of liver disease in erythropoietic protoporphyria (EPP). EPP is a genetic disorder in which deficient ferrochelatase activity causes excessive production of protoporphyrin, which is excreted in bile. Some patients develop liver disease that necessitates transplantation. Ferrochelatase gene analysis was done in 25 families with EPP to identify mutations and a polymorphism (IVS3-48c) that causes low gene expression. Expression of multiple hepatic genes was also examined by DNA microarray analysis in patients who had liver transplantation to identify genes with altered regulation. Heterozygous ferrochelatase mutations were found in 43 individuals. In 94% of 31 symptomatic patients, 15 of whom had liver disease, the polymorphism was also present in the nonmutant allele. Explanted liver of patients who had transplantation showed significant change in expression of several genes involved in wound healing, organic anion transport, and oxidative stress. Patients with EPP who develop liver disease usually have a mutation in one ferrochelatase allele that alters enzyme function, together with a polymorphism in the nonmutant allele that causes low gene expression. This results in significant increase in the hepatobiliary excretion of protoporphyrin, which can damage the liver through both cholestatic injury and oxidative stress.

Liver transplantation for erythropoietic protoporphyria liver disease

In erythropoietic protoporphyria (EPP), there is excessive production of protoporphyrin, primarily in the bone marrow, resulting in increased biliary excretion of this heme precursor. Some patients will develop progressive liver disease that may ultimately require liver transplantation. However, excessive production of protoporphyrin by the bone marrow continues after transplantation, which may cause recurrent disease in the allograft. This study was performed to define post-transplant survival, the risk of recurrent disease, and specific management issues in patients transplanted for EPP liver disease. The patients studied consisted of twelve males and eight females, with an average age of 31 (range, 13-56) years at the time of transplantation. The estimated maximum MELD score prior to transplant was 21 (range, 15-29). Unique complications in the perioperative period were light induced tissue damage in four patients and neuropathy in six, requiring prolonged mechanical ventilation in four. Patient and graft survival rates were 85% at 1 year, 69% at 5 years, and 47% at 10 years. Recurrent EPP liver disease occurred in 11 of 17 patients (65%) who survived more than 2 months. Three patients were retransplanted at 1.8, 12.6, and 14.5 years after the initial transplant for recurrent EPP liver disease. In conclusion, the 5-year patient survival rate in patients transplanted for EPP liver disease is good, but the recurrence of EPP liver disease appears to diminish long term graft and patient survival.

A “null allele” mutation is responsible for erythropoietic protoporphyria in an Israeli patient who underwent liver transplantation: relationships among biochemical, clinical, and genetic parameters

Mutations in the human ferrochelatase gene ( FECH) are the primary cause of the inborn disorder erythropoietic protoporphyria (EPP). While the majority of the EPP patients exhibit only photosensitivity, a small percentage of patients (∼2%) develop liver complications in addition to the cutaneous symptoms. In this study, the FECH gene of an Israeli EPP patient who suffered from EPP-related liver complications was sequenced. A splicing defect IVS10+1, g→t, which is known to cause the deletion of exon 10, was identified in the index patient as well as in his symptomatic older sister and his asymptomatic mother. Like the other 12 known FECH mutations associated with liver complications, IVS10+1, g→t is a “null-allele” mutation. Although the two siblings with overt EPP share an identical genotype with respect to both the mutation on one FECH allele and three intragenic single nucleotide polymorphisms, −251G, IVS1-23T, and IVS3-48C on the other allele, the sister of the index patient has so far shown no signs of liver involvement, suggesting that additional factors might account for the liver disease in EPP.

882 Familial intrahepatic cholestasis: mutation detection in the Saudi Arabian and Israeli populations

Mutations in the human ferrochelatase gene (FECH) are the primary cause of the inborn disorder erythropoietic protoporphyria (EPP). While the majority of the EPP patients exhibit only photosensitivity, a small percentage of patients (∼2%) develop liver complications in addition to the cutaneous symptoms. In this study, the FECH gene of an Israeli EPP patient who suffered from EPP-related liver complications was sequenced. A splicing defect IVS10+1, g→t, which is known to cause the deletion of exon 10, was identified in the index patient as well as in his symptomatic older sister and his asymptomatic mother. Like the other 12 known FECH mutations associated with liver complications, IVS10+1, g→t is a “null-allele” mutation. Although the two siblings with overt EPP share an identical genotype with respect to both the mutation on one FECH allele and three intragenic single nucleotide polymorphisms, −251G, IVS1-23T, and IVS3-48C on the other allele, the sister of the index patient has so far shown no signs of liver involvement, suggesting that additional factors might account for the liver disease in EPP.

Hepatic complications of erythropoietic protoporphyria.

A quarter of patients with erythropoietic protoporphyria develop mild to severe cholestatic liver disease. The determination of early indicators of hepatobiliary involvement are of pivotal importance to select patients for choleretic therapy. Porphyrin parameters were studied during ursodeoxycholic acid treatment in eight patients with protoporphyrin-associated liver disease and eight patients with liver failure before and after liver transplantation. The patients with intrahepatic cholestasis exhibited excessive protoporphyrinemia (27 mumol/l) compared with controls (normal < 0.64 mumol/l). Fecal protoporphyrin excretion decreased in patients with deterioration of liver function, whereas urinary coproporphyrin increased up to 2290 nmol/24 h (normal < 119 nmol/24 h). Coproporphyrin isomer I proportion increased to 71 +/- 10% (mean +/- SD, n = 8) in patients with terminal liver failure (normal < 31%). During therapy with ursodeoxycholic acid biochemical improvement occurred but without clinical remission in most cases. Eight patients underwent liver transplantation between 1987 and 1997. One patient died of liver failure. Two transplant recipients are in a good condition since 8 and 9 years, respectively. All explanted livers revealed micronodular cirrhosis and high protoporphyrin levels of about 25,000-fold (mean, n = 3). Immediately after liver transplantation protoporphyrin in erythrocytes decreased to 46-96% of pre-operative values. Coproporphyrin remained moderately elevated due to post-operative cholestasis. A post-operative rise in fecal protoporphyrin elimination reflected sufficient biliary clearence of protoporphyrin by the transplant. In conclusion, moderate coproporphyrinuria with isomer I is the earliest sign of liver complications in erythropoietic protoporphyria. Progression of protoporphyrin induced toxic liver injury is indicated by excessive protoporphyrinemia and coproporphyrinuria with an isomer I proportion > 71 +/- 10%, and reduction of fecal protoporphyrin excretion. Results suggest that therapy of intrahepatic cholestasis with ursodeoxycholic acid is only effective in the initial stages of liver disease in erythropoietic protoporphyria. In patients with severe cholestatic hepatic failure, liver transplantation is the treatment of choice.

Terminal hepatic failure in erythropoietic protoporphyria

Erythropoietic protoporphyria is an inherited disorder characterized biochemically by a deficiency of ferrochelatase, the enzyme that catalyzes the incorporation of ferrous iron into protoporphyrin to form heme. We describe a patient who illustrates the unpredictability of the course of liver disease in erythropoietic protoporphyria. She remained stable for several years after her first evidence of liver function abnormalities. Then, in a period of weeks, hepatic failure developed and she died. Findings of serial liver biopsy specimens showed extensive hepatocellular degeneration and inflammation that appeared in a 10-day period. The factors that cause this rapid deterioration in hepatic function remain unknown. Reported cases of fatal hepatic failure in patients with erythropoietic protoporphyria are reviewed.