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. 2025 Feb 19;9(3):e0657.
doi: 10.1097/HC9.0000000000000657. eCollection 2025 Mar 1.

Liver involvement in a large cohort of patients with erythropoietic protoporphyria or X-linked protoporphyria

Cynthia Levy  1 , Hetanshi Naik  2 , Jessica Overbey  3 , Karli Hedstrom  4 , Kelly Wang  3 , Catherine McDonough  3 , Mary Freeman  4 , Siobán B Keel  5 , Angelika L Erwin  6 , Amy K Dickey  7   8 , Rebecca K Leaf  9 , John Quigley  10 , Marshall Mazepa  11 , Bruce Wang  12 , John Phillips  13 , Charles Parker  13 , Brendan McGuire  14 , Mohamed Kazamel  15 , Herbert Bonkovsky  16 , Sean Rudnick  16 , Karl E Anderson  17 , Akshata Moghe  18 , Manish Thapar  19 , Behnam Saberi  20 , Kristen Wheeden  21 , Robert Desnick  3 , Manisha Balwani  3 ; Porphyrias Consortium of the Rare Diseases Clinical Research Network
Affiliations

Liver involvement in a large cohort of patients with erythropoietic protoporphyria or X-linked protoporphyria

Cynthia Levy et al. Hepatol Commun. .

Abstract

Background: Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by the accumulation of protoporphyrin in the marrow, erythrocytes, plasma, skin, and liver, and present clinically with painful cutaneous phototoxicity. Liver abnormalities have been reported in over 25% of patients with EPP. Further characterization of liver involvement in protoporphyria is needed.

Methods: Patients with EPP or XLP enrolled in the longitudinal studies of the NIH-supported Porphyrias Consortium were included. Medical history, laboratory, and liver histology data were abstracted and described.

Results: A total of 322 patients were enrolled; 28 (8.7%) had XLP, 52% were female, and the median age at enrollment was 33.3 years. Liver chemistries were available for 235 patients, and 132 (56.2%) had abnormalities, mostly mild. Abnormal liver enzymes were associated with higher erythrocyte protoporphyrin levels. Eleven patients had advanced protoporphyric hepatopathy. In total, 54 (16.8%) underwent cholecystectomy, 8 (2.5%) had a liver transplant, 4 (1.2%) had a bone marrow transplant, and 8 (2.5%) died. At least 4 deaths were caused by liver failure due to protoporphyric hepatopathy, 2 were complications of bone marrow transplant, and 1 from HCC, which developed in a patient with EPP without cirrhosis. Patients with XLP were more likely to develop liver-related complications compared to EPP.

Conclusions: Liver abnormalities are common in patients with EPP and XLP. In this national registry, only 3.4% had protoporphyric hepatopathy, with most requiring a transplant. Of the deaths, 62.5% were attributable to liver disease. Further observations are needed for guiding hepatic evaluation and management of patients with protoporphyria with or without initial hepatic abnormalities.

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Conflict of interest statement

Cynthia Levy receives research grants from, and consults for, DISC and Mitsubishi. Siobán B. Keel is a consultant for Disc Medicine. Manisha Balwani receives clinical trial support from Disc, Mitsubishi-Tanabe, and Alnylam Pharma and consults for Disc and Alnylam Pharma. Rebecca K. Leaf receives consulting fees from Alnylam Pharma, and Recordati Pharma and grant support from Disc Medicine. Karl E. Anderson reports grants to the university and consultation fees from Alnylam Pharmaceuticals, Recordati Rare Diseases, Mitsubishi-Tanabe Pharma, and Disc Medicine. Brendan McGuire reports research funding from DISC Medicine and Mitsubishi-Tanabe Pharma. Robert Desnick is a consultant for Disc and Mitsubishi. Bruce Wang is a consultant for Disc and Alnylam. Hetanshi Naik is a consultant for Disc and Alnylam. Herbert Bonkovsky is a consultant to Alnylam Pharma, Disc Medicine, Mitsubishi-Tanabe Pharma North America, and Recordati Rare Chemicals. He has been the site PI of clinical research grants awarded to Atrium Health Wake Forest Baptist for the study of porphyrias from Disc Medicine, Mitsubishi-Tanabe Pharma, NA, and Alnylam Pharma. Herbert Bonkovsky has been the site PI of clinical research grants awarded to Atrium Health Wake Forest Baptist for the study of primary sclerosing cholangitis from Gilead Sciences and for the study of primary biliary cholangitis from Calliditas, SA, Cymabay, now Gilead Sciences, and Kowa Pharma. Amy K. Dickey has received research funding from Disc Medicine and Mitsubishi-Tanabe and is a paid consultant and speaker for Recordati Rare Diseases and Alnylam Pharmaceuticals. Angelika L. Erwin is speaker for Alnylam. The remaining authors have no conflicts to report.

Figures

None
Graphical abstract
FIGURE 1
FIGURE 1
Heme biosynthetic pathway and multisystemic manifestations in EPP and XLP. In EPP, biallelic variants in FECH lead to the deficiency of ferrochelatase, the last enzyme of the heme-biosynthetic pathway, resulting in the accumulation of protoporphyrin IX. In X-linked protoporphyria, gain-of-function variants in ALAS2 result in the accumulation of protoporphyrin despite the normal ferrochelatase activity. Abbreviations: EPP, erythropoietic protoporphyria; FECH, ferrochelatase; XLP, X-linked protoporphyria.
FIGURE 2
FIGURE 2
Liver histopathology in a patient with EPP hepatopathy. A liver biopsy from a 16-year-old male with EPP and liver damage shows features of severe bland cholestasis along with portal inflammation and ductular reaction. Abundant dense brown pigment is seen in the canaliculi as well as kupffer cells and portal macrophages. On polarized microscopy, the brown pigments show birefringence, typical for protoporphyrin IX. Abbreviation: EPP, erythropoietic protoporphyria.
FIGURE 3
FIGURE 3
Protoporphyrin levels in patients with EPP and XLP with normal and abnormal liver chemistries. Abbreviations: EPP, erythropoietic protoporphyria; XLP, X-linked protoporphyria.
See this image and copyright information in PMC

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