`Erythropoietic' protoporphyria and cirrhosis in sisters

Thompson, R. P. H.; Molland, E. A.; Nicholson, D. C.; Gray, C. H.

doi:10.1136/gut.14.12.934

Cited by 40 publications

(10 citation statements)

References 19 publications

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“…In agreement with observations in patients with EPP‐induced liver disease 28–31, variable amounts of PP deposition were present in hepatocytes, bile canaliculi, and lobular and portal macrophages, and in the lumen of small bile ducts of fch/fch mouse livers. Small bile ducts containing PP deposits had a flattened and damaged epithelium.…”

Section: Discussionsupporting

confidence: 89%

“…Hepatocellular damage and loss of variable severity were noted in the lobules of fch/fch mouse livers and correlated with the amount of intralobular PP deposition, which supports the hypothesis that toxic dark effects of PP cause hepatocellular damage 35–38. In contrast with the other morphological manifestations of hepatocellular damage, Mallory bodies have never been described in patients with EPP 28, 29, 39, 40. Mallory bodies represent a peculiar sign of hepatocellular injury 41 and have also been described in the griseofulvin‐induced mouse model of EPP 42, 43.…”

Section: Discussionsupporting

confidence: 63%

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Liver pathology and hepatocarcinogenesis in a long‐term mouse model of erythropoietic protoporphyria

Libbrecht

Meerman

Kuipers³

et al. 2002

The Journal of Pathology

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Erythropoietic protoporphyria (EPP) is an inherited disease of haem synthesis caused by a mutation in one of the alleles of the enzyme ferrochelatase. This mutation leads to partial deficiency of the enzyme, resulting in increased concentrations of protoporphyrin (PP) in blood, liver, and faeces. Five to ten per cent of patients with EPP develop severe liver disease characterized by the presence of PP deposits. This study used histochemistry and immunohistochemistry to investigate the histopathological features present in the livers of 44 mice with a heterozygous or homozygous point mutation in the ferrochelatase gene (fch/+ and fch/fch mice, respectively). Some fch/+ mouse livers showed mixed steatosis and large cell dysplasia. The livers of fch/fch mice showed periportal or septal fibrosis accompanied by an atypical ductular reaction. These findings suggest that the obstruction and damage of a proportion of large and small bile ducts by PP deposits cause an accumulation of PP in the parenchyma, which leads to damage and loss of hepatocytes due to the toxic effects of PP. The classical stages of hepatocarcinogenesis were observed and hepatic progenitor cells appear to be involved in this process. PP acts as the promoting agent and is probably also the initiating agent.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 63%

Liver pathology and hepatocarcinogenesis in a long‐term mouse model of erythropoietic protoporphyria

Libbrecht

Meerman

Kuipers³

et al. 2002

The Journal of Pathology

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“…These deposits were birefringent under polarized light, yielding Maltese crosses (Fig. 1 B ) that are characteristic of porphyrin deposits in liver biopsy samples of patients with EPP (2, 39).…”

Section: Resultsmentioning

confidence: 95%

A precursor‐inducible zebrafish model of acute protoporphyria with hepatic protein aggregation and multiorganelle stress

et al. 2016

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Protoporphyria is a metabolic disease that causes excess production of protoporphyrin IX (PP-IX), the final biosynthetic precursor to heme. Hepatic PP-IX accumulation may lead to end-stage liver disease. We tested the hypothesis that systemic administration of porphyrin precursors to zebrafish larvae results in protoporphyrin accumulation and a reproducible nongenetic porphyria model. Retro-orbital infusion of PP-IX or the iron chelator deferoxamine mesylate (DFO), with the first committed heme precursor α-aminolevulinic acid (ALA), generates high levels of PP-IX in zebrafish larvae. Exogenously infused or endogenously produced PP-IX accumulates preferentially in the liver of zebrafish larvae and peaks 1 to 3 d after infusion. Similar to patients with protoporphyria, PP-IX is excreted through the biliary system. Porphyrin accumulation in zebrafish liver causes multiorganelle protein aggregation as determined by mass spectrometry and immunoblotting. Endoplasmic reticulum stress and induction of autophagy were noted in zebrafish larvae and corroborated in 2 mouse models of protoporphyria. Furthermore, electron microscopy of zebrafish livers from larvae administered ALA + DFO showed hepatocyte autophagosomes, nuclear membrane ruffling, and porphyrin-containing vacuoles with endoplasmic reticulum distortion. In conclusion, systemic administration of the heme precursors PP-IX or ALA + DFO into zebrafish larvae provides a new model of acute protoporphyria with consequent hepatocyte protein aggregation and proteotoxic multiorganelle alterations and stress.-Elenbaas, J. S., Maitra, D., Liu, Y., Lentz, S. I., Nelson, B., Hoenerhoff, M. J., Shavit, J. A., Omary, M. B. A precursor-inducible zebrafish model of acute protoporphyria with hepatic protein aggregation and multiorganelle stress.

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“…The site of the principal lesion is not yet known but present evidence suggests the existence of a hepatic as well as an erythropoietic lesion. Following reports of intrahepatic deposits of protoporphyrin in erythropoietic protoporphyria by Cripps and Scheuer (1965), cases of cirrhosis and liver cell failure have been described (Barnes, Hurworth, and Millar, 1968;Donaldson, McCall, Magnus, Simpson, Caldwell, and Hargreaves, 1971;Schmidt and Stich, 1971; Thompson, Molland, Nicholson, and Gray, 1973), and the term 'erythrohepatic protoporphyria' has been suggested (Donaldson et al, 1971) as a more comprehensive description of the disease.…”

mentioning

confidence: 99%

“…Nicholson, and Gray, 1973), and the term 'erythrohepatic protoporphyria' has been suggested (Donaldson et al, 1971) as a more comprehensive description of the disease.…”

mentioning

confidence: 99%

A light and electron microscopic study of the liver in case of erythrohepatic protoporphyria and in griseofulvin-induced porphyria in mice

Matilla

Molland

1974

J Clin Pathol

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`Erythropoietic' protoporphyria and cirrhosis in sisters

Cited by 40 publications

References 19 publications

Liver pathology and hepatocarcinogenesis in a long‐term mouse model of erythropoietic protoporphyria

Liver pathology and hepatocarcinogenesis in a long‐term mouse model of erythropoietic protoporphyria

A precursor‐inducible zebrafish model of acute protoporphyria with hepatic protein aggregation and multiorganelle stress

A light and electron microscopic study of the liver in case of erythrohepatic protoporphyria and in griseofulvin-induced porphyria in mice

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