Non‐alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis

Ertle, Judith; Dechêne, Alexander; Sowa, Jan-Peter; Penndorf, Volker; Herzer, Kerstin; Kaiser, Gernot; Schlaak, Joerg F.; Gerken, Guido; Syn, Wing–Kin; Canbay, Ali

doi:10.1002/ijc.25797

Cited by 455 publications

(363 citation statements)

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“…Moreover, several reports suggest that HCC may arise in histologically confirmed NAFLD without cirrhosis. [11][12][13] Improving our understanding of the molecular mechanisms determining HCC development and progression, in particular in the context of NAFLD, is integral to the development of novel therapeutic strategies for this disease. Therefore, the blocking of hepatocyte death pathways, especially apoptotic cell death, presents itself as a logical treatment point of chronic liver disease and, concomitantly, as a preventive measure for liver cancer.…”

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confidence: 99%

Hepatocyte-specific Bid depletion reduces tumor development by suppressing inflammation-related compensatory proliferation

et al. 2015

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Liver cancer is a major health-care concern and its oncogenic mechanisms are still largely unclear. Persistent hepatocyte cell death is a common feature among various chronic liver diseases, the blocking of which presents as logical treatment. Therefore, we aimed at investigating tumor development in mice with hepatocyte-specific Bid depletion -a BH3-only Bcl-2 family member that amplifies apoptotic death signals. Hepatocyte-specific conditional Bid-knockout mice (Bid Δhep ) were injected with 25 mg/kg diethylnitrosamine (DEN) at 14 days of age, and liver tumorigenesis was investigated 9 months later. Additionally, different models of acute liver injury were used including: acute high-dose DEN challenge, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet and carbon tetrachloride (CCL4) injection. Bid Δhep mice developed significantly fewer tumors, showed smaller maximal and average tumor size and reduced tumor incidence. In the acute DEN model, 48 h post injection we observed a significant reduction in liver injury in Bid Δhep animals, assessed via serum transaminases and liver histopathology. Furthermore, TNF-α, IL-1ß, cJUN and IL-6 mRNA expression was reduced. These findings were accompanied by reduced compensatory hepatocyte proliferation in Bid Δhep mice when compared with controls by immunohistochemistry for Ki67 and proliferating cell nuclear antigen 48 h after DEN injection. In the acute CCL4 model, Bid Δhep mice displayed reductions in liver injury and inflammation when compared with controls. No differences in liver injury and serum bilirubin levels were detected in Bid Δhep and Bid flo/flo mice fed with DDC, which induces bile duct injury and a ductular reaction. Our study demonstrates that in DEN-induced hepatocellular carcinoma, the inhibition of hepatocyte death pathways through Bid deletion protects animals from tumorigenesis. These results suggest that reducing hepatocyte cell death, liver inflammation and compensatory proliferation has a stronger beneficial effect than the potential side effect of enhancing tumor cell survival.

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Hepatocyte-specific Bid depletion reduces tumor development by suppressing inflammation-related compensatory proliferation

et al. 2015

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“…In another retrospective study, cirrhosis was detected in only 53% of NASH-related HCC patients, which was significantly less than in the group with non-NASH HCC (90%). Therefore, though cirrhosis is a crucial risk factor, NASH is likely a significant independent risk factor for HCC [18] . Future prospective, large population-based studies with longer durations of follow-up are needed to determine the validity of this potentially important observation.…”

Section: Risk Factors For Nash-related Hccmentioning

confidence: 99%

Advances in hepatocellular carcinoma: Nonalcoholic steatohepatitis-related hepatocellular carcinoma

Khan

Perumpail

Wong

et al. 2015

WJH

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An increase in the prevalence of obesity and diabetes mellitus has been associated with the rise in non alcoholic fatty liver disease (NAFLD). Twothirds of the obese and diabetic populations are estimated to develop NAFLD. Currently, NAFLD is the most common etiology for chronic liver disease globally. The clinical spectrum of NAFLD ranges from simple steatosis, an accumulation of fat greater than 5% of liver weight, to nonalcoholic steatohepatitis (NASH), a more aggressive form with necroinflammation and fibrosis. Among the patients who develop NASH, up to 20% may advance to cirrhosis and are at risk for complications of endstage liver disease. One of the major complications observed in patients with NASHrelated cirrhosis is hepatocellular carcinoma (HCC), which has emerged as the sixth most common cancer and second leading etiology of cancerrelated deaths worldwide. The incidence of HCC in the United States alone has tripled over the last three decades. In addition, emerging data are suggesting that a small proportion of patients with NAFLD may be at higher risk for HCC in the absence of cirrhosis implicating obesity and diabetes mellitus as potential risk factors for HCC. Core tip: The worldwide rise in overweight and obesity has been associated with increasing rates of nonalcoholic fatty liver disease (NAFLD), which is now the most common etiology of chronic liver disease.

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“…Of particular interest is the emergence of HCC during chronic liver disease in absence of liver cirrhosis, that is known as the major risk factor for HCC development [5,6] . HCC development requires decades and is characterized by a gradual transition through a dysplastic to transformed liver tissue [7] .…”

Section: Introductionmentioning

confidence: 99%

Fat and hepatocellular carcinoma

Balsano¹,

Porcu²,

Sideri³

et al. 2018

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Obesity and diabetes are associated with the onset of hepatocellular carcinoma (HCC). These two illnesses correlate also with the development of non-alcoholic fatty liver disease (NAFLD). Currently, NAFL is considered the leading form of chronic liver disease in the Western industrialized countries. Insulin resistance is the common pathogenic factor among these three pathologies. NAFL is characterized by fat accumulation in the liver that involves greater than 5% of the liver parenchyma with no evidence of hepatocyte injury. However, NAFL may progress toward non-alcoholic steatohepatitis that in turn may lead to advanced fibrosis, cirrhosis and HCC. It is alarming that NAFLD related HCC has been, at present, considered as a growing burden worldwide, and its prevalence is tending to further increase together with the increasing incidence of obesity and diabetes. Worthy of note is that in the presence of chronic accumulation of fat in the liver it has been reported the emergence of HCC during chronic liver disease in absence of liver cirrhosis, usually the major risk factor for the development of HCC. Thus, in the future NAFLD related HCCs will place a growing strain on health-care systems from the need for their management. Unfortunately, most of the NAFLD related HCC patients are diagnosed at advanced stages and are characterized by a poor prognosis, because they are ineligible to radical treatments. Thus, it is urgent to boost up new screening policies to make early diagnoses, as well as to develop preventive-therapeutic strategies.

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Non‐alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis

Cited by 455 publications

References 50 publications

Hepatocyte-specific Bid depletion reduces tumor development by suppressing inflammation-related compensatory proliferation

Hepatocyte-specific Bid depletion reduces tumor development by suppressing inflammation-related compensatory proliferation

Advances in hepatocellular carcinoma: Nonalcoholic steatohepatitis-related hepatocellular carcinoma

Fat and hepatocellular carcinoma

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