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. 2024 Mar 1;79(3):731-743.
doi: 10.1097/HEP.0000000000000546. Epub 2023 Jul 27.

Evidence-based consensus guidelines for the diagnosis and management of protoporphyria-related liver dysfunction in erythropoietic protoporphyria and X-linked protoporphyria

Cynthia Levy  1 , Amy K Dickey  2   3 , Bruce Wang  4 , Manish Thapar  5 , Hetanshi Naik  6 , Siobán B Keel  7 , Behnam Saberi  8 , Simon W Beaven  9 , Sean R Rudnick  10 , Sarina B Elmariah  11 , Angelika L Erwin  12 , Robert J Goddu  13 , Karli Hedstrom  14 , Rebecca Karp Leaf  3   15 , Mohamed Kazamel  16 , Marshall Mazepa  17 , Lisa Liang Philpotts  18 , John Quigley  19 , Haya Raef  2   7   11 , Jonathan Ungar  20 , Karl E Anderson  21 , Manisha Balwani  14 ; Porphyrias Consortium of the Rare Diseases Clinical Network
Affiliations

Evidence-based consensus guidelines for the diagnosis and management of protoporphyria-related liver dysfunction in erythropoietic protoporphyria and X-linked protoporphyria

Cynthia Levy et al. Hepatology. .
No abstract available

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Conflict of interest statement

Cynthia Levy consults and received grants from Disc Medicine and Mitsubishi Tanabe. She received grants from Alnylam. Amy K. Dickey consults for Alnylam and Recordati Rare Diseases. She received grants from Disc Medicine. Bruce Wang consults and received grants from Disc Medicine. He advises and received grants from Alnylam and Mitsubishi Tanabe. He advises Recordati Rare Diseases. Manish Thapar consults and advises Alnylam and Recordati Rare Diseases. He consults for Mitsubishi Tanabe and Disc Medicine. Hetanshi Naik consults and advises Alnylam, Disc Medicine, and Mitsubishi Tanabe. She consults for Recordati Rare Diseases. Siobán B. Keel consults for Disc Medicine. She grants from Alnylam and Mitsubishi Tanabe. Sean R. Rudnick consults for Alnylam. Sarina B. Elmariah consults, advises, and is on the speakers’ bureau for Bellus Health, Galderma, Incyte, Menlo Therapeutics, Regeneron, Sanofi-Genzyme, and Trevi Therapeutics. Angelika L. Erwin consults and advises Disc Medicine and Mitsubishi Tanabe. Karli Hedstrom is employed by Icahn School of Medicine at Mount Sinai. Rebecca Karp Leaf consults for Alnylam, Mitsubishi Tanabe, and Recordati Rare Diseases. Mohamed Kazamel consults for Alnylam Pharmaceuticals. John Quigley consults and is on the speakers’ bureau for Alnylam. He advises Recordati Rare Diseases. Jonathan Ungar advises AbbVie, Castle Biosciences, Demavant Sciences, Janssen Biotech, Menlo Therapeutics, Mitsubishi Tanabe, and UCB. Karl E. Anderson consults, advises, and received grants from Mitsubishi Tanabe and Recordati Rare Diseases. He consults and received grants from Alnylam and Disc Medicine. Manisha Balwani consults, advises, and received grants from Alnylam, Disc Medicine and Mitsubishi Tanabe. She consults and advises Recordati Rare Diseases. The remaining authors have no conflicts to report.

Figures

Figure 1 –
Figure 1 –
Proposed mechanisms for development of protoporphyric hepatopathy: 1-metal-free protoporphyrin (PPIX) accumulates in bone marrow reticulocytes in both erythropoietic protoporphyria (EPP), which is due to ferrochelatase deficiency, and X-linked protoporphyria (XLP), due to ALAS2 gain-of-function. 2- PPIX is also markedly increased in circulating erythrocytes, and is gradually transported from erythroid cells into plasma through the transporter ABCG2, where it binds to plasma proteins, and then into hepatocytes and bile, which is the only route for its removal from the body. 3- Large amounts of PPIX transported into liver and bile may undergo enterohepatic circulation. 4- PPIX accumulates in hepatocytes and Kupffer cells near bile ducts, and at some point, especially in the setting of higher circulating levels, it is transported into bile through the ABCG2 efflux transporter. PPIX-rich bile is associated with gallstone formation and also with injury to cholangiocytes. Subsequent hepatocyte damage may be mediated by formation of reactive oxygen species and lipid peroxidation; this vicious cycle of declining hepatic uptake and increased excretion of PPIX into bile while plasma levels continue to rise results in advanced liver disease, namely protoporphyric hepatopathy.
Figure 2-
Figure 2-
Liver biopsy in protoporphyric hepatopathy illustrating brown pigment deposition in hepatocytes that displays classic birefringence and a centrally located Maltese cross. Also shown are rare hepatocyte ballooning and admixed cholestasis. Photograph courtesy of Dr. Monica Garcia-Buitrago.
Figure 3-
Figure 3-
PRISMA diagram detailing literature search methodology utilized in this consensus development
Figure 4-
Figure 4-
Algorithm for diagnosis of EPP and XLP and screening recommendations for liver involvement.
Figure 5 –
Figure 5 –
Management algorithm for protoporphyric hepatopathy
See this image and copyright information in PMC

References

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