The Relationship between Nonalcoholic Fatty Liver Disease and Colorectal Cancer: The Future Challenges and Outcomes of the Metabolic Syndrome

Abstract

Nonalcoholic fatty liver disease (NAFLD) is closely related to insulin resistance, metabolic syndrome, obesity, type 2 diabetes, and dyslipidaemia. Obesity and metabolic syndrome are associated with an increased cancer risk, and recent evidence demonstrated an association between NAFLD and colorectal cancer (CRC). The mechanism of how NAFLD can be associated with increased risk of CRC is not fully understood; however, NAFLD represents a condition of profound insulin resistance and a proinflammatory state. Insulin and insulin-like growth factors may promote the development of CRC through their proliferative and antiapoptotic effects. Patients with NAFLD have reduced expression of adiponectin, an adipokine with anti-inflammatory effects. Importantly, hypoadiponectinemia is associated with an increased risk of CRC. Decreased levels of adiponectin lead to increased insulin levels due to marked insulin resistance and in turn increased insulin growth factor-1 (IGF-1). Insulin binds to IGF-1 receptors and plays an important role in cell proliferation, apoptosis, and increased production of vascular endothelial growth factor, an angiogenic factor that supports cancer growth. Further studies are needed to establish (i) the pathophysiology of NAFLD with colorectal cancer, (ii) the benefit of early screening of CRC in NAFLD patients, and (iii) the impact of treatment of NAFLD in the modulation of the risk of colorectal cancer.

Proteomic and genomic studies of non-alcoholic fatty liver disease - clues in the pathogenesis

“…One point to note was that these meta-analyses were not specific to liver aetiology. However, recent evidences demonstrated a correlation between NAFLD and colorectal cancer [134] . The mechanism behind this remains unknown but raises the possibility of Adiponectin's anti-inflammatory effect that suppress TNF-α and other proinflammatory cytokines [38] .…”

“…Possibility of different mechanisms for insulin sensitising in NAFLD Li [20] 2012 Muhidin et al [134] 2012…”

Non-alcoholic fatty liver disease and colorectal cancer

“…The main pathogenic factor in NAFLD development and progression is IR. IR is associated with hepatic steatosis and NASH 11 13 15 16. Currently, there are two main hypotheses regarding how the ‘parts’ should be positioned: the ‘two-hit’ and the ‘multi-hit’ theory 17…”

“…Recent findings established a risk for CRC in patients with T2DM, obesity and MetS. These connections have resulted in recommendations for colonoscopy screening to be performed earlier and more often in those patients 13 22. Given that NAFLD is a liver manifestation of MetS, should we perform a colonoscopy earlier and more frequently in patients with NAFLD?…”

“…One more positive effect of adiponectin is that it inhibits TNF, a cytokine involved in tumour cell proliferation and angiogenesis 25. Furthermore, lower levels of adiponectin lead to increased insulin levels due to marked IR and subsequently increased IGF-1 13 32–35. In contrast to adiponectin, leptin has procarcinogenic influence, mainly via the presence of low adiponectin levels.…”