Non-Alcoholic Steatohepatitis, Liver Cirrhosis and Hepatocellular Carcinoma: The Molecular Pathways

Abstract

Non-alcoholic steatohepatitis (NASH) is growing into global problem, mainly due to NASH-induced cirrhosis and hepatocellular carcinoma (HCC), that can develop either subsequently to cirrhosis or preceding it. In addition, NASH-induced cirrhosis constitutes a significant fraction of cases diagnosed as cryptogenic cirrhosis. Thus, there is a need for deeper understanding of the molecular basis, leading to liver steatosis, then-to the associated inflammation seen in NASH, loss of liver architecture and cirrhosis, followed or paralleled by carcinogenesis and HCC. Insulin resistance, increased hepatic iron level, and certain cytokines, including TNF-α and IL-6 derived from extrahepatic adipose tissues, can trigger the chain of events. The imbalance between leptin and adiponectin is important as well. These markers remain important during the whole course from NASH through liver cirrhosis to HCC. The molecular pathogenesis substantiates treatment: hypertriglyceridemia can be lowered by low calorie diet; mTOR complex can become inhibited by physical activity and metformin; cholesterol synthesis, RAF/ MAPK1/ERK and p21 pathway by statins; inflammation by pentoxyfillin, and kinases (in HCC) by sorafenib. Bidirectional regulation of telomere attrition, senescence and p21 pathway, restoration of wild-type p53 activity and regulation of miRNA network represent attractive future treatment options. Focusing on relevant molecular pathways allows deeper understanding of NASH pathogenesis, leading to identification of predictive markers and treatment targets.[10] and other Western industrialised countries, facing high occurrence of the major risk factors for NAFLD, namely, central obesity, type 2 diabetes mellitus, dyslipidemia and metabolic syndrome [11]. In a recent meta-analysis of 86 studies, comprising 8,515,431 persons from 22 countries, the global prevalence of NAFLD was 25.24% (95% confidence interval [CI], showing the highest occurrence in the Middle East and South America and the lowest in Africa [5].Liver Cirrhosis -Update and Current Challenges 2 Thus, 90% of patients suffering from morbid obesity (defined as having body mass index 40 kg/m 2 or higher) and 74% patients affected by diabetes mellitus develop NAFLD. In addition, NAFLD has been observed even in non-obese, non-diabetic patients who have increased insulin levels in blood and resistance to insulin action. Consequently, NAFLD affects up to 20-30% of adults in Europe and 46% in the USA: a tremendously high prevalence for a condition that can cause any significant complications [9, 10]. Non-Alcoholic Steatohepatitis, Liver Cirrhosis and Hepatocellular Carcinoma: The Molecular Pathways http://dx.doi.org/10.5772/intechopen.68771 3Most patients are diagnosed with NAFLD in their 40s or 50s. Studies vary in regard to the gender distribution of NAFLD, with some suggesting that it is more common in women and others suggesting more frequent occurrence in men [11,12].Since 1998, non-alcoholic fatty liver disease has been considered a condition with a "two-hit" course of...

Update in global trends and aetiology of hepatocellular carcinoma

“…Risk factors such as morbid obesity (body mass index 40 kg/m 2 or higher) and diabetes mellitus are known to cause NAFLD, but it has also been observed in the non-obese and in non-diabetics with insulin resistance [ 61 ]. Several mechanisms such as increased levels of TNF-α and IL-6, and increased levels of leptin, an iron compound deposition that predisposes to oxidative DNA damage, have been implicated in carcinogenesis in NASH [ 62 ].…”

Perilipin 5 Deletion in Hepatocytes Remodels Lipid Metabolism and Causes Hepatic Insulin Resistance in Mice

“…Dysregulation of one or more of these processes can lead to hepatic steatosis, which is excessive accumulation of intracellular lipids and is the defining component of nonalcoholic fatty liver disease (NAFLD). NAFLD is of clinical importance because it is closely linked to metabolic abnormalities such as insulin resistance and dyslipidemia (2) and is a risk factor for life-threatening complications, including steatohepatitis, cirrhosis, and hepatocellular carcinoma (3).…”

Hepatokines and adipokines in NASH-related hepatocellular carcinoma

“…In 77 non-viral-associated HCC patients 30% of NAFLD-HCC cases developed in no or minimal fibrosis [6,11]. Collectively, these results suggest that HCC in NAFLD can develop in any stage of hepatic fibrosis [6,10,11], with 20-50% of NAFLD-related HCC occurring in non-cirrhotic cases. This wide range could be explained by heterogeneous methods and protocols to assure or exclude liver cirrhosis.…”

“…The pathogenic mechanisms linking NAFLD/NASH to HCC remain poorly understood (Figure 1). Although liver cirrhosis is the major risk factor for HCC development [4,5], a significant portion of NASH-associated HCC develops in livers with no or minimal liver fibrosis [6]. Among individuals without liver cirrhosis, those with NASH are at a higher risk of HCC when compared with other etiologies [7].…”

“…The risk to develop HCC in a non-cirrhotic liver was 5.4-fold in NAFLD and 5-fold for metabolic syndrome (MetS) compared to HCV-related HCC [10]. In 77 non-viral-associated HCC patients 30% of NAFLD-HCC cases developed in no or minimal fibrosis [6,11]. Collectively, these results suggest that HCC in NAFLD can develop in any stage of hepatic fibrosis [6,10,11], with 20-50% of NAFLD-related HCC occurring in non-cirrhotic cases.…”