Hepatocellular and extrahepatic cancers in non-alcoholic fatty liver disease: A systematic review and meta-analysis

Thomas, James A.; Kendall, Bradley J.; Dalais, Christine; Macdonald, Graeme A.; Thrift, Aaron P.

doi:10.1016/j.ejca.2022.06.051

Cited by 45 publications

(28 citation statements)

References 26 publications

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“…Among the weaknesses of the published studies included in this metanalysis, there was no biopsy-proven diagnosis of NAFLD in any of them. A subsequent meta-analytic study published by Thomas et al [19] by comparing 64 studies for analysis of incident HCC (625,984 patients) and extrahepatic cancer (41,027), found that extra-hepatic cancers were over 8-fold more common than HCC in NAFLD and were not associated with the stage of advanced hepatic fibrosis or cirrhosis. This is in striking contrast with HCC where the most advanced stages of liver fibrosis are associated with an increasing risk of disease [20,21].…”

Section: Methods Findings Conclusionmentioning

confidence: 99%

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Extra-hepatic cancers in metabolic fatty liver syndromes

Lonardo

2023

Explor Dig Dis

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The liver operates an array of vital digestive, metabolic, immunological, and purificatory physiological functions including synthesis of albumin, regulation of glucose and lipid homeostasis, detoxification of ammonia and xenobiotics, choleresis and production of hepatokines and hormones [1]. However, in healthy states, it is not involved in the storage of fatty substrates and, whenever the normal liver threshold is exceeded, accumulated triglycerides will impair whole-body insulin sensitivity, trigger sterile low-grade hepatic metaflammation, and promote the progression of the fibrosing process that will eventually conduce to cirrhosis in a subset of individuals [2,3]. While the histopathological cascade described above was first recognized in the 1800s by distinguished liver pathologists, such as Addison, Rokitansky, Pepper, and Bartolow, until the years 1958-1971 the debate, with the contributions by Zelman and Thaler, mainly focused on such hepato-histopathological changes being indistinguishable irrespective of the inciting triggers: alcohol, obesity, and diabetes [4]. From the perspective of clinical nosography, this finding eventually led to coining the innovative definitions of "nonalcoholic steatohepatitis (NASH)" and "nonalcoholic fatty liver disease (NAFLD)" in the 1980s. "Nonalcoholic" is a composite word that, at least in the spelling used by Ludwig et al., and by Schaffner and Thaler; does not require any hyphens [4] at variance with the use that is sometimes encountered in contemporary literature ("non-alcoholic").To convert a "negative" definition (i.e., nonalcoholic) into a positive diagnosis highlighting the pathogenic (dysmetabolic) origin, while also avoiding stigmatizing alcohol consumption, a panel of international experts have proposed renaming NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD). Although endorsed to an unprecedented extent [5], MAFLD retains some elements of ambiguity and amplifies NAFLD's heterogeneity, therefore creating major implications for research arena and clinical practice [6,7].Compared to the history of NAFLD briefly summarized above, the notions that NAFLD and NAFLD-related metabolic conditions could also be a risk factor for the development of primary liver cancer (PLC) in a limited proportion of individuals are more recent (Table 1) [8-13].While it is logical and somewhat foreseeable that PLC may eventually develop in some individuals with NAFLD, more recent observations substantiate the probably unexpected theory that, further to PLCs, NAFLD

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Section: Methods Findings Conclusionmentioning

confidence: 99%

“…Principal modifiers and putative pathomechanisms involved in the association of NAFLD and MAFLD with extra-hepatic cancers. This illustration, based on published studies[18,19,[22][23][24][29][30][31][32], highlights the knowns of this topic. However, our understanding of this complex scenario is far from complete…”

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confidence: 87%

Extra-hepatic cancers in metabolic fatty liver syndromes

Lonardo

2023

Explor Dig Dis

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“…NAFLD patients have an increased risk of developing liver-related morbidity and mortality [ 23 ]. In addition, NAFLD patients are at high risk of developing cardiovascular disease, chronic kidney disease, and extrahepatic malignancies (e.g., colorectal, uterine, and breast cancer), among others [ 24 , 25 ]. For about 30% of the patients affected by NALFD, the disease can progress into the more severe non-alcoholic steatohepatitis (NASH) [ 19 , 26 ].…”

Section: Nash-hcc Is a Global Health Problemmentioning

confidence: 99%

All Roads Lead to Cathepsins: The Role of Cathepsins in Non-Alcoholic Steatohepatitis-Induced Hepatocellular Carcinoma

Mourik

Baumgartner

et al. 2022

Biomedicines

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Cathepsins are lysosomal proteases that are essential to maintain cellular physiological homeostasis and are involved in multiple processes, such as immune and energy regulation. Predominantly, cathepsins reside in the lysosomal compartment; however, they can also be secreted by cells and enter the extracellular space. Extracellular cathepsins have been linked to several pathologies, including non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). NASH is an increasingly important risk factor for the development of HCC, which is the third leading cause of cancer-related deaths and poses a great medical and economic burden. While information regarding the involvement of cathepsins in NASH-induced HCC (NASH-HCC) is limited, data to support the role of cathepsins in either NASH or HCC is accumulating. Since cathepsins play a role in both NASH and HCC, it is likely that the role of cathepsins is more significant in NASH-HCC compared to HCC derived from other etiologies. In the current review, we provide an overview on the available data regarding cathepsins in NASH and HCC, argue that cathepsins play a key role in the transition from NASH to HCC, and shed light on therapeutic options in this context.

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“…As a liver metabolic disorder, NAFLD has been attributed to risk factors including obesity, type 2 diabetes, hyperlipidemia, etc. NFALD is mainly prevalent in the Middle East and South America, affects more than 100 million adults [ 7 ], and its overall pooled HCC incidence rate among NAFLD patients is 1.25 per 1000 person-years [ 8 ]. Despite this, in contrast to NAFLD, HBV and HCV lead to HCC mainly through blood transmission, mother–baby transmission, and sex transmission, which are more prone to spreading.…”

Section: Introductionmentioning

confidence: 99%

Immune Checkpoint Inhibitors in HBV-Caused Hepatocellular Carcinoma Therapy

Zhang

Xie

et al. 2023

Vaccines

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Hepatitis B virus (HBV) infection is the main risk factor for the development of hepatocellular carcinoma (HCC), the most common type of liver cancer, with high incidence and mortality worldwide. Surgery, liver transplantation, and ablation therapies have been used to treat early HBV-caused HCC (HBV-HCC); meanwhile, in the advanced stage, chemoradiotherapy and drug-targeted therapy are regularly considered, but with limited efficacy. Recently, immunotherapies, such as tumor vaccine therapy, adoptive cell transfer therapy, and immune checkpoint inhibitor therapy, have demonstrated promising efficacy in cancer treatment. In particular, immune checkpoint inhibitors can successfully prevent tumors from achieving immune escape and promote an anti-tumor response, thereby boosting the therapeutic effect in HBV-HCC. However, the advantages of immune checkpoint inhibitors in the treatment of HBV-HCC remain to be exploited. Here, we describe the basic characteristics and development of HBV-HCC and introduce current treatment strategies for HBV-HCC. Of note, we review the principles of immune checkpoint molecules, such as programmed cell death protein 1(PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in HBV-HCC, as well as related inhibitors being considered in the clinic. We also discuss the benefits of immune checkpoint inhibitors in the treatment of HBV-HCC and the efficacy of those inhibitors in HCC with various etiologies, aiming to provide insights into the use of immune checkpoint inhibitors for the treatment of HBV-HCC.

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Hepatocellular and extrahepatic cancers in non-alcoholic fatty liver disease: A systematic review and meta-analysis

Cited by 45 publications

References 26 publications

Extra-hepatic cancers in metabolic fatty liver syndromes

Extra-hepatic cancers in metabolic fatty liver syndromes

All Roads Lead to Cathepsins: The Role of Cathepsins in Non-Alcoholic Steatohepatitis-Induced Hepatocellular Carcinoma

Immune Checkpoint Inhibitors in HBV-Caused Hepatocellular Carcinoma Therapy

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