Introduction:
Nonalcoholic fatty liver disease (NAFLD), characterized by significant liver damage, affects approximately 25% of the global population, presenting a significant global public health challenge. NAFLD is closely linked to type 2 diabetes and metabolic syndromes, and its incidence mirrors the increasing prevalence of diabetes and obesity. As NAFLD progresses, its detrimental effects escalate. Complications such as nonalcoholic steatohepatitis (NASH) and cirrhosis not only impair liver function but also contribute to other systemic diseases like cardiovascular disease and chronic kidney disease.
Moreover, various large-scale studies have highlighted the association between NAFLD and cancer risk. Research indicates that individuals with NAFLD face a heightened risk, ranging from 1.2- to 15-fold, of developing liver cancer, gastrointestinal cancers, and other cancer types. Notably, NAFLD-induced NASH has become a leading cause of liver cancer-related deaths, surpassing those caused by hepatitis B and C viruses. Consequently, the persistent increase in NAFLD incidence raises significant new concerns regarding public health and necessitates proactive intervention strategies.
What Is Fatty Liver?
Non-alcoholic fatty liver disease (NAFLD), also known as fatty liver, is characterized by the accumulation of fat in the liver without significant alcohol consumption. It comprises two main subtypes: NAFL (non-alcoholic fatty liver) or steatosis, and NASH (non-alcoholic steatohepatitis).
NAFL is defined as the presence of hepatic fat buildup without signs of hepatocyte injury, such as hepatocyte ballooning. On the other hand, NASH involves both hepatic fat accumulation and inflammation, accompanied by hepatocyte injury, Mallory bodies, and inflammatory infiltrates in the liver. It is crucial to recognize that NAFLD exists on a spectrum, with NAFL representing the milder end and NASH and cirrhosis at the more severe end. Distinguishing between NAFL and NASH requires histological analysis and a liver biopsy. NAFLD is commonly linked with Metabolic Syndrome, obesity, diabetes, and high cholesterol levels. Roughly 80% of individuals diagnosed with Metabolic Syndrome also have NAFLD.
Fatty liver disease (FLD) is characterized by fat accumulation in liver cells. It can be classified into two main types:
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Non-Alcoholic Fatty Liver Disease (NAFLD): This occurs in individuals who drink little to no alcohol and is often associated with obesity, type 2 diabetes, and metabolic syndrome.
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Alcoholic Fatty Liver Disease (AFLD): It is caused by heavy alcohol consumption.
Is There a Connection Between Fatty Liver Disease and Cancer?
Hepatocellular cancer (HCC) is a swiftly rising, highly lethal form of cancer. The primary risk factors for HCC consist of hepatitis C virus (HCV) infection, heavy alcohol consumption, and hepatitis B virus (HBV) infection. However, recent investigations have noted that many HCC patients lack these well-known risk factors. Speculation suggests that non-alcoholic fatty liver disease (NAFLD) could be the underlying cause in some, if not all, of these cases.
NAFLD has emerged as the leading cause of chronic liver disease, believed to be the hepatic manifestation of metabolic syndrome, closely linked with diabetes and obesity. As the prevalence of metabolic syndrome has surged, so has the incidence of NAFLD, doubling in the general population over the past two decades, with estimates as high as 30%.
While NAFLD often presents as non-progressive hepatic steatosis with minimal complications, approximately 20–30% of individuals with NAFLD progress to more severe liver disease characterized by inflammation and fibrosis, potentially leading to cirrhosis in 10–20% of cases. This makes NAFLD the fastest-growing cause of cirrhosis, raising concerns due to its possible association with HCC. Notably, HCC has been observed in patients with NAFLD, even in the absence of cirrhosis.
NAFLD often goes unnoticed due to its asymptomatic nature, potentially contributing to the onset of other metabolic disorders like hyperlipidemia and type 2 diabetes. Left untreated or undiagnosed, NAFLD can progress to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC).
Research indicates that NAFLD isn't solely linked to HCC but also to various gastrointestinal cancers, including colorectal cancer (CRC). Numerous independent studies encompassing diverse demographics consistently demonstrate a clear association between NAFLD and the development of adenomatous polyps and poorer survival rates for CRC. NAFLD significantly correlates with the occurrence of colon adenomatous polyps and advanced colon neoplasms in both genders. Individuals with NAFLD risk adenomatous polyps, compared to those without NAFLD.
Extrahepatic Association:
Over recent decades, the rise in obesity and type 2 diabetes (T2D) has paralleled an increase in non-alcoholic fatty liver disease (NAFLD), with a global prevalence estimated at around 24%. This surge has drawn attention to both hepatic complications (like cirrhosis and hepatocellular carcinoma (HCC)) and extrahepatic consequences (such as T2D, cardiovascular disease, and extrahepatic cancers) associated with NAFLD. Several studies have consistently highlighted an elevated risk of HCC in NAFLD patients, and cancer has emerged as a significant cause of mortality among those with biopsy-proven NAFLD.
However, the absolute risk of HCC in NAFLD patients without cirrhosis appears to be relatively low. In a cohort study with NAFLD but no cirrhosis, elevated cancer risk was observed compared to NAFLD-free controls. A higher cancer risk in NAFLD-diagnosed patients was noted compared to non-NAFLD controls, with no increased risk observed in obese patients without NAFLD. While some studies have demonstrated an increased risk of colorectal cancer in males with NAFLD but not females, a meta-analysis found an elevated risk of colorectal cancer in NAFLD patients independent of gender.
Breast cancer risk has been shown to rise in individuals with NAFLD, although specific studies suggest this increase may be limited to non-obese or post-menopausal women with NAFLD. Results regarding other cancers like lung, esophageal, prostate, and bladder cancer have been inconsistent and lack reproducibility.
How Does Fatty Liver Progress to Cancer?
The involvement of cancer stem cell (CSC)-like properties in tumor initiation, progression, and therapy resistance is well-established. However, the role of stem cells in the onset and advancement of NAFLD is currently being investigated. The development of hepatocellular carcinoma (HCC) from NAFLD is a complex process, with excess hepatic lipid deposition being one of the underlying factors.
Research indicates that saturated fatty acids can induce cancer stem cell-like properties in hepatoma cells. Recent findings suggest that these properties in hepatocytes are associated with the malignant transformation of normal hepatocytes in fatty liver conditions. Notably, the CSC marker CD44 remains highly expressed in rat hepatocytes throughout NAFLD and HCC progression, with elevated serum CD44 levels observed in late-stage NAFLD and HCC. High CD44 expression is linked to aggressive forms of HCC, and CD44-positive HCC cells exhibit self-renewal capabilities that facilitate tumor growth and metastasis. Inhibiting CD44 and TGF-β1 simultaneously diminishes epithelial-mesenchymal transition (EMT) phenotypes and the migration of HCC cells through an AKT/GSK-3β/β-catenin dependent mechanism. These findings suggest that inducing CSC-like properties in hepatocytes may be one mechanism by which NAFLD promotes HCC development.
On another front, it has been proposed that normal intestinal stem cells can transform into CSC-like progenitor cells through the stabilization of β-catenin, persistent activation of the Wnt-β-catenin pathway, and loss of p53 and Apc genes. These progenitor cells acquire self-renewal and pro-survival capacities by activating various oncogenic signaling pathways like PI3K/Akt/mTOR and RAS/RAF/MAPK. CRC CSCs exhibit chemoresistance through efficient DNA damage repair, high expression of ABC transporters, and anti-apoptotic genes, and they are implicated in liver metastasis. It's conceivable that NAFLD may promote CRC liver metastasis by maintaining or enhancing the CSC properties of CRC cells.
Conclusion:
Accumulating evidence suggests a significant connection between fatty liver disease (NAFLD) and various cancers. While NAFLD is primarily recognized for its hepatic complications, such as cirrhosis and hepatocellular carcinoma (HCC), studies increasingly highlight its association with extrahepatic cancers, including colorectal, breast, and potentially others. The complex interplay between NAFLD, obesity, diabetes, and cancer risk underscores the importance of comprehensive monitoring and early intervention strategies to mitigate both hepatic and extrahepatic cancer burdens in affected populations. Further research is warranted to elucidate the underlying mechanisms and optimize preventative measures and therapeutic interventions.
