Hepatocellular adenoma associated with long-term exposure to phenobarbital: a paediatric case report

Cerminara, Caterina; Bagnolo, V.; Leonardis, Francesco De; Coniglio, Antonella; Roberto, Denis; Compagnone, Eliana; Curatolo, Paolo

doi:10.1007/s00381-011-1636-1

Cited by 8 publications

(4 citation statements)

References 24 publications

(29 reference statements)

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“…In one study, PB and/or diphenylhydantoin were reported to produce liver hypertrophy with no evidence of necrosis, inflammation and fibrosis (Aiges et al, 1980), whereas in other studies treatment with PB and/or other anticonvulsant (antiepileptic) drugs hepatotoxicity was reported, suggesting that chronic anticonvulsant therapy may cause liver damage (Di Mizio et al, 2007; Foster et al, 1991). In a paediatric case report from a 13-year-old female subject, Cerminara et al (2012) speculated that treatment with PB for 7 years may have contributed to the development of hepatocellular adenoma observed in this study. A number of epidemiological studies with PB and other anticonvulsant drugs have been performed (Friedman et al, 2009; IARC, 2001; Lamminpää et al, 2002; Olsen et al, 1989, 1995; Selby et al, 1989; White et al, 1979; Whysner et al, 1996) and the data for PB has been recently reviewed by La Vecchia & Negri (2013).…”

Section: Resultsmentioning

confidence: 67%

Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator

Elcombe¹,

Peffer

Wolf

et al. 2013

Critical Reviews in Toxicology

220

219

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The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are important nuclear receptors involved in the regulation of cellular responses from exposure to many xenobiotics and various physiological processes. Phenobarbital (PB) is a non-genotoxic indirect CAR activator, which induces cytochrome P450 (CYP) and other xenobiotic metabolizing enzymes and is known to produce liver foci/tumors in mice and rats. From literature data, a mode of action (MOA) for PB-induced rodent liver tumor formation was developed. A MOA for PXR activators was not established owing to a lack of suitable data. The key events in the PB-induced liver tumor MOA comprise activation of CAR followed by altered gene expression specific to CAR activation, increased cell proliferation, formation of altered hepatic foci and ultimately the development of liver tumors. Associative events in the MOA include altered epigenetic changes, induction of hepatic CYP2B enzymes, liver hypertrophy and decreased apoptosis; with inhibition of gap junctional intercellular communication being an associative event or modulating factor. The MOA was evaluated using the modified Bradford Hill criteria for causality and other possible MOAs were excluded. While PB produces liver tumors in rodents, important species differences were identified including a lack of cell proliferation in cultured human hepatocytes. The MOA for PB-induced rodent liver tumor formation was considered to be qualitatively not plausible for humans. This conclusion is supported by data from a number of epidemiological studies conducted in human populations chronically exposed to PB in which there is no clear evidence for increased liver tumor risk.

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Section: Resultsmentioning

confidence: 67%

Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator

Elcombe¹,

Peffer

Wolf

et al. 2013

Critical Reviews in Toxicology

220

219

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“…112,119 Several associations between HCA and antiepileptic drugs have been reported, but a causative effect remains to be shown. 120,121 However, only a small number of patients using oral contraceptives develop HCA (about 3 per 100,000 in exposed patients). 9 A role for an additional unknown minor allele associated with environmental factors is of concern.…”

Section: Translation In Clinical Carementioning

confidence: 99%

Hepatocellular Benign Tumors—From Molecular Classification to Personalized Clinical Care

2013

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“…In addition, HCAs have been described in other situations, but, so far, without demonstration of a direct link, i.e. antiepileptic drugs 46,47 and haemochromatosis 48 …”

Section: Risk Factorsmentioning

confidence: 99%

Hepatocellular adenoma: what we know, what we do not know, and why it matters

et al. 2022

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Hepatocellular adenoma: what we know, what we do not know, and why it mattersIn the last two decades there has been significant progress in research on and diagnosis of hepatocellular adenoma (HCA), resulting in the establishment of a molecular and immunohistological HCA classification. This review aims to fine-tune the current expertise in order to enhance the histopathological diagnostic possibilities, by refining issues that are already known, addressing diagnostic difficulties, and identifying still unknown aspects of HCA. We discuss novel methods to identify HCA subtypes, in particular the sonic hedgehog HCAs and the interpretation of glutamine synthetase patterns for the recognition of b-cateninmutated HCAs. The major complications of HCAs, i.e. bleeding and malignant transformation, are considered, including the dilemmas of atypical and borderline lesions. HCAs in different clinical and geographical settings, e.g. pregnancy, cirrhosis and non-western countries, are also discussed. The natural history of the different HCA subtypes in relation to age, sex and risk factors is a feature that is still insufficiently investigated. This is also true for the risks of clinical bleeding and malignant transformation in association with HCA subtypes. As HCA is a relatively rare tumour, a multicentre and multidisciplinary approach across geographical boundaries will be the appropriate method to establish prospective programmes with which to identify, classify and manage HCAs, focusing on several aspects, e.g. aetiology, underlying liver disease, complications, regression, and growth. Updating what we know and identifying and addressing what we do not know matters for optimal patient management.

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Hepatocellular adenoma associated with long-term exposure to phenobarbital: a paediatric case report

Cited by 8 publications

References 24 publications

Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator

Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator

Hepatocellular Benign Tumors—From Molecular Classification to Personalized Clinical Care

Hepatocellular adenoma: what we know, what we do not know, and why it matters

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