Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis

Kawada, Natsuko; Imanaka, Kazuho; Kawaguchi, Tetsu; Tamai, Chie; Ishihara, Ryu; Matsunaga, Takashi; Gotoh, Kunihito; Yamada, Terumasa; Tomita, Yoshihiro

doi:10.1007/s00535-009-0112-0

Cited by 197 publications

(140 citation statements)

References 17 publications

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“…Among all patients who underwent curative treatment of HCC, 17.2% had NASH-a volume higher than that noted in other series. 25,31 In agreement with other reports, HCC/NASH patients were more often female, were older at HCC diagnosis, had larger BMI, and more often had components of or the diagnosis of metabolic syndrome compared to HCV/ALD patients. 1,9,[18][19][20]23,24,28,[38][39][40] Similarly, NASH/HCC specimens also had more-severe steatosis, lobular inflammation, and hepatocyte ballooning (Table 1).…”

Section: Discussionsupporting

confidence: 91%

“…Moreover, NASH/HCC patients who underwent hepatic resection and/or ablation were less likely to have histopathologic bridging fibrosis or cirrhosis-a finding corroborated by other studies. 25,32,40 A total of 44.2% of NASH patients in this series had metabolic syndrome. As expected, hypertension, DM, and dyslipidemia were more common in this subgroup relative to other NASH patients.…”

Section: Discussionmentioning

confidence: 70%

“…1,4,12,13,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] Yet, no previous reports have assessed long-term outcomes between patients with NASH and other CLDs within a framework of multimodal curative therapy, including liver transplantation, resection, and ablation. Thus, the aim of this study was to determine the differences in clinical presentation, histopathology, and survival outcomes among patients undergoing any curative therapy for HCC in the setting of NASH compared to hepatitis C (HCV) and/or alcoholic liver disease (ALD).…”

mentioning

confidence: 99%

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Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease

et al. 2012

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Concomitant increasing incidences of hepatocellular carcinoma (HCC) and nonalcoholic steatohepatitis (NASH) suggest that a substantial proportion of HCC arises as a result of hepatocellular injury from NASH. The aim of this study was to determine differences in severity of liver dysfunction at HCC diagnosis and long-term survival outcomes between patients undergoing curative therapy for HCC in the background of NASH compared to hepatitis C virus (HCV) and/or alcoholic liver disease (ALD). Patient demographics and comorbidities, clinicopathologic data, and long-term outcomes among patients who underwent liver transplantation, hepatic resection, or radiofrequency ablation for HCC were reviewed. From 2000 to 2010, 303 patients underwent curative treatment of HCC; 52 (17.2%) and 162 (53.5%) patients had NASH and HCV and/or alcoholic liver disease. At HCC diagnosis, NASH patients were older (median age 65 versus 58 years), were more often female (48.1% versus 16.7%), more often had the metabolic syndrome (45.1% versus 14.8%), and had lower model for end-stage liver disease scores (median 9 versus 10) (all P < 0.05). NASH patients were less likely to have hepatic bridging fibrosis or cirrhosis (73.1% versus 93.8%; P < 0.001). After a median follow-up of 50 months after curative treatment, the most frequent cause of death was liver failure. Though there were no differences in recurrence-free survival after curative therapy (median, 60 versus 56 months; P 5 0.303), NASH patients had longer overall survival (OS) (median not reached versus 52 months; P 5 0.009) independent of other clinicopathologic factors and type of curative treatment. Conclusion: Patients with HCC in the setting of NASH have less severe liver dysfunction at HCC diagnosis and better OS after curative treatment compared to counterparts with HCV and/or alcoholic liver disease. (HEPATOLOGY 2012;55:1809-1819 C oncomitant increases in the incidence of hepatocellular carcinoma (HCC) and prevalence of nonalcoholic fatty liver disease (NAFLD) suggest that a substantial proportion of HCC arises as a result of hepatocellular injury from nonalcoholic steatohepatitis (NASH). As a result, HCC is the most rapidly increasing cause of cancer death in the United States.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 70%

mentioning

confidence: 99%

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Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease

et al. 2012

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“…NAFLD comprises a wide variety of disease criteria ranging from benign simple steatosis to progressive inflammation and fibrosis called nonalcoholic steatohepatitis (NASH), which is a prominent risk factor for the development of hepatocellular carcinoma (HCC) (Hytiroglou et al 2007;Park et al 2010;He & Karin 2011). Interestingly, it has recently become apparent that although HCC develops largely under a cirrhotic background, it often occurs without severe fibrosis/ cirrhosis in patients with NAFLD/NASH (Chagas et al 2009;Kawada et al 2009;Paradis et al 2009;Starley et al 2010;Takuma & Nouso 2010;Ertle et al 2011;Torres & Harrison 2012). However, the mechanistic difference between inflammation-/ fibrosis-dependent and inflammation-/fibrosis-independent HCC development is yet unknown.…”

Section: Introductionmentioning

confidence: 99%

Dietary fructose‐induced hepatocellular carcinoma development manifested in mice lacking apoptosis inhibitor of macrophage (AIM)

et al. 2016

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The consumption of fructose, including the use of high-fructose corn syrup as a sweetener, has increased continuously in recent decades. Although the involvement of fructose in the development of metabolic diseases has been emphasized recently, whether fructose intake increases susceptibility to steatosis-associated hepatocellular carcinoma (HCC) is unclear. Here, we investigated this issue using mice lacking a circulating protein, apoptosis inhibitor of macrophage (AIM, encoded by cd5l). AIM does not induce carcinogenesis of hepatocytes, but provokes necrotic death specifically in AIM-bound cancer cells through complement cascade activation, thereby preventing HCC tumor development in wild-type mice. When subjected to a high-fructose diet (HFrD), AIM-deficient (AIM -/-) mice showed liver steatosis and subsequent liver inflammation as well as fibrosis, but at much milder levels compared with mice fed a high-fat diet. However, AIM -/-mice were markedly susceptible to HCC tumor development, whereas no wild-type mice developed the disease. Systemic metabolic states, including obesity and insulin resistance, were similar in both types of mice after HFrD challenge, indicating no influence of AIM on HFrD-induced metabolic changes. Our results suggest that dietary fructose increases the risk for liver carcinogenesis and that individuals with low blood AIM levels may be susceptible to HCC under chronic fructose intake.

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“…Fatty liver has been recognized as a benign and non-progressive condition (1). However, non-alcoholic steatohepatitis (NASH) is now widely known as a potent liver disease which may progress to liver cirrhosis and finally hepatocellular carcinoma (HCC) (2,3). Patients with NAFLD have frequently presented clinical complications, such as obesity, type 2 diabetes mellitus, and insulin resistance (4).…”

Section: Introductionmentioning

confidence: 99%

Selective aldosterone blocker ameliorates the progression of non-alcoholic steatohepatitis in rats

Noguchi

Yoshiji²,

Ikenaka³

et al. 2010

Int J Mol Med

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Abstract. Although non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma (HCC), no effective therapeutic modalities have been fully established yet. Recent studies have shown that the reninangiotensin-aldosterone-system plays an important role in NASH. The aim of our current study was to elucidate the effects of aldosterone (Ald) inhibition on the progression of NASH. In the choline-deficient L-amino acid-defined dietinduced rat NASH model, the effects of a clinically used selective Ald blocker (SAB) were elucidated in conjunction with the activated hepatic stellate cells (HSC) and neovascularization, which are both known to play important roles in liver fibrosis development and hepatocarcinogenesis, respectively. Liver fibrosis development and the glutathione-S-transferase placental form-positive pre-neoplastic lesions were both markedly attenuated by SAB along with the suppression of the activated HSC and neovascularization. SAB inhibited the hepatic expression of transforming growth factor-ß 1 and also that of the vascular endothelial growth factor. Our in vitro study showed that SAB also inhibited the Ald-induced HSC proliferation and in vitro angiogenesis in a dose-dependent manner. These results indicated that Ald plays a pivotal role in the progression of NASH. Considering that SAB is already widely used in clinical practice, this drug could represent a potential new strategy against NASH in the future.

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Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis

Abstract: This study indicates HCC might arise frequently from non-cirrhotic NASH. While further studies are needed to confirm this observation, both cirrhotic and non-cirrhotic NASH warrant regular screening for HCC.

Cited by 197 publications

References 17 publications

Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease

Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease

Dietary fructose‐induced hepatocellular carcinoma development manifested in mice lacking apoptosis inhibitor of macrophage (AIM)

Selective aldosterone blocker ameliorates the progression of non-alcoholic steatohepatitis in rats

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