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Pathology and Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease-Associated Hepatic Tumors.

ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation in the livers of patients without a history of alcohol abuse. It is classified as either simple steatosis (nonalcoholic fatty liver) or nonalcoholic steatohepatitis (NASH), which can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Recently, it was suggested that the terms "metabolic dysfunction-associated steatotic liver disease (MASLD)" and "metabolic dysfunction-associated steatohepatitis (MASH)" should replace the terms "nonalcoholic fatty liver disease (NAFLD)" and "nonalcoholic steatohepatitis (NASH)", respectively, with small changes in the definitions. MASLD, a hepatic manifestation of metabolic syndrome, is rapidly increasing in incidence globally, and is becoming an increasingly important cause of HCC. Steatohepatitic HCC, a histological variant of HCC, is characterized by its morphological features resembling non-neoplastic steatohepatitis and is closely associated with underlying steatohepatitis and metabolic syndrome. Variations in genes including patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), and membrane-bound O-acyltransferase domain-containing protein 7 (MBOAT7) are associated with the natural history of MASLD, including HCC development. The mechanisms of HCC development in MASLD have not been fully elucidated; however, various factors, including lipotoxicity, inflammation, reactive oxygen species, insulin resistance, and alterations in the gut bacterial flora, are important in the pathogenesis of MASLD-associated HCC. Obesity and MASLD are also recognized as risk factors for hepatocellular adenomas, and recent meta-analyses have shown an association between MASLD and intrahepatic cholangiocarcinoma. In this review, we outline the pathology and pathogenesis of MASLD-associated liver tumors.

SUBMITTER: Takahashi Y

PROVIDER: S-EPMC10604511 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Pathology and Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease-Associated Hepatic Tumors.

Takahashi Yoshihisa Y Dungubat Erdenetsogt E Kusano Hiroyuki H Fukusato Toshio T

Biomedicines 20231012 10

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation in the livers of patients without a history of alcohol abuse. It is classified as either simple steatosis (nonalcoholic fatty liver) or nonalcoholic steatohepatitis (NASH), which can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Recently, it was suggested that the terms "metabolic dysfunction-associated steatotic liver disease (MASLD)" and "metabolic dysfunction-associated steatohepatitis (M ...[more]

PMID: 37893134

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Project description:ImportanceIn the US, hepatocellular carcinoma (HCC) has been the most rapidly increasing cancer since 1980, and metabolic dysfunction-associated steatotic liver disease (MASLD) is expected to soon become the leading cause of HCC.ObjectiveTo develop a prediction model for HCC incidence in a cohort of patients with MASLD.Design, setting, and participantsThis prognostic study was conducted among patients aged at least 18 years with MASLD, identified using diagnosis of MASLD using International Classification of Diseases, Ninth Revision (ICD-9) or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis codes; natural language processing of radiology imaging report text, which identified patients who had imaging evidence of MASLD but had not been formally diagnosed; or the Dallas Steatosis Index, a risk equation that identifies individuals likely to have MASLD with good precision. Patients were enrolled from Kaiser Permanente Northern California, an integrated health delivery system with more than 4.6 million members, with study entry between January 2009 and December 2018, and follow-up until HCC development, death, or study termination on September 30, 2021. Statistical analysis was performed during February 2023 and January 2024.ExposureData were extracted from the electronic health record and included 18 routinely measured factors associated with MASLD.Main outcome and measuresThe cohort was split (70:30) into derivation and internal validation sets; extreme gradient boosting was used to model HCC incidence. HCC risk was divided into 3 categories, with the cumulative estimated probability of HCC 0.05% or less classified as low risk; 0.05% to 0.09%, medium risk; and 0.1% or greater, high risk.ResultsA total of 1 811 461 patients (median age [IQR] at baseline, 52 [41-63] years; 982 300 [54.2%] female) participated in the study. During a median (range) follow-up of 9.3 (5.8-12.4) years, 946 patients developed HCC, for an incidence rate of 0.065 per 1000 person-years. The model achieved an area under the curve of 0.899 (95% CI, 0.882-0.916) in the validation set. At the medium-risk threshold, the model had a sensitivity of 87.5%, specificity of 81.4%, and a number needed to screen of 406. At the high-risk threshold, the model had a sensitivity of 78.4%, a specificity of 90.1%, and a number needed to screen of 241.Conclusions and relevanceThis prognostic study of more than 1.8 million patients with MASLD used electronic health record data to develop a prediction model to discriminate between individuals with and without incident HCC with good precision. This model could serve as a starting point to identify patients with MASLD who may need intervention and/or HCC surveillance.

Project description:Background & aimsThe loss of ovarian functions defining menopause leads to profound metabolic changes and heightens the risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD). Although estrogens primarily act on the female liver through estrogen receptor alpha (ERα), the specific contribution of impaired ERα signaling in triggering MASLD after menopause remains unclear.MethodsTo address this gap in knowledge, we compared the liver transcriptomes of sham-operated (SHAM) and ovariectomized (OVX) control and liver ERα knockout (LERKO) female mice by performing RNA-Seq analysis.ResultsOVX led to 1426 differentially expressed genes (DEGs) in the liver of control mice compared to 245 DEGs in LERKO mice. Gene ontology analysis revealed a distinct ovariectomy-induced modulation of the liver transcriptome in LERKO compared with controls, indicating that hepatic ERα is functional and necessary for the complete reprogramming of liver metabolism in response to estrogen depletion. Additionally, we observed an ovariectomy-dependent induction of male-biased genes, especially in the liver of control females, pointing to hepatic ERα involvement in the masculinization of the liver after estrogen loss. To investigate the translational relevance of such findings, we assessed liver samples from a cohort of 60 severely obese individuals (51 women; 9 men). Notably, a shift of the liver transcriptome toward a male-like profile was also observed only in obese women with MASLD (n = 43), especially in women ≥51 years old (15/15), suggesting that masculinization of the female liver contributes to MASLD development in obese women.ConclusionsThese results highlight the role of hepatic ERα in driving masculinization of the liver transcriptome following menopause, pointing to this receptor as a potential pharmacological target for preventing MASLD in post-menopausal women.Impact and implicationsDespite the increased risk of developing MASLD after menopause, the specific contribution of impaired hepatic estrogen signaling in driving MASLD in females has not been a major research focus, and, thus, has limited the development of tailored strategies that address the specific mechanisms underlying MASLD in post-menopausal women. This study reveals the functional role of hepatic ERα in mediating liver metabolic changes in response to estrogens loss, leading to a shift in the liver transcriptome towards a male-like profile. In women with obesity, this shift is associated with the development of MASLD. These findings underscore the potential of targeting hepatic ERα as a promising approach for developing effective, sex-specific treatments to preserve liver health and prevent or limit the development and progression of MASLD in post-menopausal women.

Dataset Information

Pathology and Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease-Associated Hepatic Tumors.

Publications

Pathology and Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease-Associated Hepatic Tumors.

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