Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma: Natural History?

Cotrim, Helma Pinchemel; Paraná, Raymundo; Lyra, Luiz Guilherme Costa

doi:10.1111/j.1572-0241.2000.03241.x

Cited by 107 publications

(55 citation statements)

References 6 publications

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“…There is some evidence that HCC may develop as the last step in the natural history of progressive NASH, based on case reports of HCC in patients with NASH-related cirrhosis from various parts of the world, including Southern Europe (Cotrim et al, 2000;Zen et al, 2001;Shimada et al, 2002;Cuadrado et al, 2005). Almost all the HCC cases had obesity and/or type II diabetes, and they were all negative for HBsAg and anti-HCV, with biopsy-based diagnosis of NASH-related cirrhosis.…”

Section: Non-alcoholic Steatohepatitis and Hepatocellular Carcinomamentioning

confidence: 99%

Southern Europe as an example of interaction between various environmental factors: a systematic review of the epidemiologic evidence

et al. 2006

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Hepatitis B virus (HBV), hepatitis C virus (HCV) and alcohol consumption are major causes of hepatocellular carcinoma (HCC) worldwide. We performed a systematic review of epidemiologic studies carried out on HCC aetiology in Southern Europe, an area with an intermediatehigh prevalence of these agents as well as of putative risk factors such as tobacco smoking, diabetes and obesity. To retrieve the articles, we performed a Medline search for titles and abstracts of articles. After the Medline search, we reviewed the papers and reference lists to identify additional articles. A synergism between HCV infection and HBV infection, overt (hepatitis B virus antigen (HbsAg) positivity) or occult (HBsAg negativity with presence of HBV DNA in liver or serum), is suggested by the results of some studies. The pattern of the risk for HCC due to alcohol intake shows a continuous dose-effect curve without a definite threshold, although most studies found that HCC risk increased only for alcohol consumption above 40-60 g of ethanol per day. Some evidence supports a positive interaction of alcohol intake probably with HCV infection and possibly with HBV infection. A few studies found that coffee has a protective effect on HCC risk due to various risk factors. Some data also support a role of tobacco smoking, diabetes and obesity as single agents or preferably cofactors in causing HCC. In countries with a relatively high alcohol consumption and intermediate levels of HCV and HBV infections (1-3% of population infected by each virus), such as Mediterranean countries, the three main risk factors together account for about 85% of the total HCC cases, leaving little space to other known risk factors, such as haemochromatosis, and to new, still unrecognised, factors as independent causes of HCC.

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Section: Non-alcoholic Steatohepatitis and Hepatocellular Carcinomamentioning

confidence: 99%

Southern Europe as an example of interaction between various environmental factors: a systematic review of the epidemiologic evidence

et al. 2006

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“…8,52,57,[93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109] Male patients make up the majority of cases with a mean age at diagnosis of 66.7 (range ¼ 45-82). The patients are typically older at presentation than patients with HCC related to other chronic liver diseases.…”

Section: Case Reports and Case Series Of Nash And Hccmentioning

confidence: 99%

Nonalcoholic fatty liver disease and hepatocellular carcinoma: A weighty connection

2010

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Hepatocellular carcinoma (HCC) is a common and deadly malignancy that is increasing in incidence in developed countries. The emergence of hepatitis C virus (HCV) accounts for about half of this increase in HCC, although the etiology of HCC in 15%-50% of new HCC cases remains unclear. The most common form of chronic liver disease in developed countries is nonalcoholic fatty liver disease (NAFLD), which encompasses a broad spectrum of histopathology. The prevalence of NAFLD, including the more aggressive nonalcoholic steatohepatitis (NASH), is increasing with the growing epidemics of diabetes and obesity. NASH can progress to cirrhosis and its related complications. Growing evidence suggests that NASH accounts for a large proportion of idiopathic or cryptogenic cirrhosis, which is associated with the typical risk factors for NASH. HCC is a rare, although important complication of NAFLD. Diabetes and obesity have been established as independent risk factors for the development of HCC. New evidence also suggests that hepatic iron deposition increases the risk of HCC in NASH-derived cirrhosis. Multiple case reports and case reviews of HCC in the setting of NASH support the associations of diabetes and obesity with the risk of HCC, as well as suggest age and advanced fibrosis as significant risks. Insulin resistance and its subsequent inflammatory cascade that is associated with the development of NASH appear to play a significant role in the carcinogenesis of HCC. The complications of NASH, including cirrhosis and HCC, are expected to increase with the growing epidemic of diabetes and obesity.

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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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Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma: Natural History?

Cited by 107 publications

References 6 publications

Southern Europe as an example of interaction between various environmental factors: a systematic review of the epidemiologic evidence

Southern Europe as an example of interaction between various environmental factors: a systematic review of the epidemiologic evidence

Nonalcoholic fatty liver disease and hepatocellular carcinoma: A weighty connection

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

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