Nonalcoholic Fatty Liver Disease (NAFLD) and Extra Hepatic Malignancies

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, its prevalence reaches 25 % in adults and about 10% in children (1-3). The prevalence of nonobese NAFLD ranged from 25% or less in some countries to higher than 50% in others (4). NAFLD’s disease spectrum varies from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), the most dangerous form with its complications of hepatic fibrosis, cirrhosis, and hepatocellular carcinoma (5,6). The existence of steatohepatitis and severe fibrosis are considered indicators of undesirable outcomes in patients with NAFLD and are associated with an increased risk for morbi-mortality by hepatic and extra hepatic complications (7,8). In decreasing order, mortality in NAFLD patients is due, first, to cardiovascular events and, second, to gastrointestinal (liver, intestine, esophagus, stomach, and pancreas) and extraintestinal (kidney in men and breast in women) malignancies, while end-stage liver disease represents the third cause of death (8,9). The hepatic manifestation of metabolic syndrome (Mets) is generally considered the NAFLD, and a remarkable body of literature shows an enhanced cancer risk in Mets subjects, especially in the gastrointestinal tract. In this environment, NAFLD may either express similar risk factors (i.e., obesity and millets diabetes). The frequency, prevalence, and severity of these complications are related to the histological severity of liver injury, signifying that NAFLD, but especially NASH, may also lead to low-grade inflammatory status by releasing multiple markers of inflammation, oxidative stress, and procoagulant factors (10,11). The aim of this narrative analysis was to synthesize recent evidence of NAFLD extrahepatic malignancies, based on the predominant prevalent incident/risk of such diseases in NAFLD patients. To date, an effective screening approach for extrahepatic malignancies has not yet been established. For patient management, collaborative care with relevant experts seems to be required because extrahepatic cancers can emerge across various organs (12).


Introduction
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, its prevalence reaches 25 % in adults and about 10% in children (1)(2)(3). The prevalence of nonobese NAFLD ranged from 25% or less in some countries to higher than 50% in others (4). NAFLD's disease spectrum varies from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), the most dangerous form with its complications of hepatic fibrosis, cirrhosis, and hepatocellular carcinoma (5,6).
The existence of steatohepatitis and severe fibrosis are considered indicators of undesirable outcomes in patients with NAFLD and are associated with an increased risk for morbi-mortality by hepatic and extra hepatic complications (7,8). In decreasing order, mortality in NAFLD patients is due, first, to cardiovascular events and, second, to gastrointestinal (liver, intestine, esophagus, stomach, and pancreas) and extraintestinal (kidney in men and breast in women) malignancies, while end-stage liver disease represents the third cause of death (8,9). The hepatic manifestation of metabolic syndrome (Mets) is generally considered the NAFLD, and a remarkable body of literature shows an enhanced cancer risk in Mets subjects, especially in the gastrointestinal tract. In this environment, NAFLD may either express similar risk factors (i.e., obesity and millets diabetes). The frequency, prevalence, and severity of these complications are related to the histological severity of liver injury, signifying that NAFLD, but especially NASH, may also lead to low-grade inflammatory status by releasing multiple markers of inflammation, oxidative stress, and procoagulant factors (10, 11). The aim of this narrative analysis was to synthesize recent evidence of NAFLD extrahepatic malignancies, based on the predominant prevalent incident/risk of such diseases in NAFLD patients. To date, an effective screening approach for extrahepatic malignancies has not yet been established. For patient management, collaborative care with relevant experts seems to be required because extrahepatic cancers can emerge across various organs (12).
lesions of NASH is a high-risk factor of for CRC. Patients with NAFLD diagnosed by both proton magnetic resonance spectroscopy and liver biopsy in a cross-sectional study had a substantially higher incidence of colorectal adenomas (34.7% vs. 21.5%) and advanced neoplasms (18.6% vs. 5.5%) than control subjects. CRC has been observed more commonly in NASH patients than in those with simple steatosis (51.0 % vs. 25.6 % and 34.7% vs. 14.0 %). NASH was associated with increased risk for both adenomas ( (20).
On the other hand, only two studies have failed to show an increased occurrence of colorectal adenomas in NAFLD patients compared with controls. The first was found to have a higher adenoma incidence in NAFLD patients, but the results did not meet statistical significance. The second revealed a significantly lower prevalence of CRC in NAFLD patients but an increased risk of CRC in the presence of insulin resistance, but it is well known that both increased levels of alanine aminotransferase (ALT) and ultrasound will underestimate the diagnosis of NAFLD (21,22). A wellknown risk factor for CCR is the existence of metabolic syndrome, including diabetes mellitus and obesity (23,24). Nevertheless, it is unclear if NAFLD is associated with an increased risk of CCR simply because of shared metabolic disorders or whether NAFLD itself could contribute to CCR growth. As for the current possibility, insulin resistance-induced hyperinsulinemia causes carcinogenesis by activating the process of proliferation via its effect on insulin receptors on tumor cells. Moreover, hyperinsulinemia raises insulin-like growth factor (IGF)-1 expression, which has more effective mitogenic and anti-apoptotic properties than insulin and can serve as a trigger for preneoplastic and neoplastic cell growth (12,23). Following the above possibility, adiponectin, which has anti-carcinogenic effects, has decreased blood levels in NAFLD patients. This process is due to the capacity of adiponectin to interrupt proliferation of colon cancer cells by the Amp-activated protein kinase (AMPK) and to cause a caspase dependent pathway that results in apoptosis of endothelial cells (11).

Esophageal and Gastric Cancer
Esophageal and gastric cancers are the 7 th and 5 th most prevalent cancers worldwide, with an estimated 572,000 and 1,000,000 cases in 2018 (25). In males, both cancer forms are more frequent than in females. Obesity may contribute to metabolic disorders, such as higher levels of pro-inflammatory cytokines (such as tumor necrosis factor-alpha and interleukin-6), adipokines (such as glucose, insulin, and leptin), and endogenous sex steroids, which could increase the risk of cancer (26,36,37). There is significant evidence

Pancreatic Cancer
With more than 50,000 reported new cases in the United States in 2016, the incidence of pancreatic cancer is rising.

Renal Cancer
Some of the elements of Mets, have been identified as risk factors in addition to smoking and alimentary habits, whose correlation with renal cancer is well recognized, and men-  3.5% in HCV patients, and the incidence of prostate malignance in NAFLD was higher than in the general population (11).

The Presumed Role of Insulin Resistance and Gut Microbiota in NAFLD in Extra-Hepatic Cancers Development
Even though data on the pro-inflammatory and procarcinogenic implications of insulin resistance (IR) are generally the most substantial evidence of a potential mechanistic between NAFLD and extra-hepatic oncogenesis, gut microbiota has recently been described as a new and fascinating striker in the development of obesity, NAFLD and many types of cancer. Dysbiosis is described in NAFLD patients, and the liver remains at the intersection of a complex relationship between modifications of microbiota, IR, inflammation, and carcinogenesis (66)(67)(68)(69). Patients with colon cancer have been shown to have dysbiosis (70). Qualitative and quantitative changes of gut microbiota, through several pathways, contribute to increased intestinal permeability, including the control of tight junctions such as zonulin-1 and the occlusion in the ileum of toll-like receptor 2 (TLR2) (71)(72)(73). It is well established that the host diet has a profound effect on the microbial composition of the gut. The myeloid differentiation factor 88 (MyD88)dependent pathway can mediate diet-induced NAFLD (74). This

American Journal of Biomedical Science & Research
Copy@ Amalou khellaf factor is a converter molecule that is important for TLR signaling.
It is mobilized after interaction between microorganism-associated molecular patterns (MAMPs) and TLRs (particularly TLR4) and stimulates the transcription by activation of NF-B or c-Jun NH2terminal kinase (JNK) contributing to IR initiation of many proinflammatory cytokines. Failure of mutation or knockout mice in TLR4 prevent obesity-induced IRs that underlie the essential role of this receptor in the regulation of the innate immune system (74).
The key element of the axis of central obesity contains NAFLD and visceral adipose tissue. Low-grade chronic inflammation and insulin resistance (IR) establish a microenvironment appropriate for the cancer development in this environment by stimulating the insulin growth factor-1 (IGF-1) axis via hyperinsulinemia (75)(76)(77). Extra hepatic cancers have been associated with enhanced serum levels of IGF-1. Pertinently, the risk of Barrett's esophagus and esophageal adenocarcinoma may be affected by the insulin/IGF system (78)(79)(80)(81)(82)(83)(84), but this is not entirely agreed upon (85). In carcinogenic processes, multiple adipokines, implicated in the control of metabolism, inflammation and fibrogenesis, may also be involved. The pro-carcinogenic implications of leptin have been thoroughly explored, particularly in the presence of low rates of adiponectin (86,87). Leptin can promote motility and intrusiveness in human colon cancer cells through mitogen-activated protein kinase (MAPK) process induction. A case-cohort analysis in postmenopausal CRC women found that elevated plasma leptin levels were associated with an increased risk of CRC (88,89). The combination of high leptin and low adiponectin rates can also raise the risk of Barrett's esophagus and esophageal adenocarcinoma in obese patients by increasing cell proliferation and decreasing apoptosis through extracellular signal-regulated kinase (90)(91)(92)(93). After that, resisting could also be related to malignancies associated with obesity by triggering the nuclear factor-B (NF-B) pathway and amplifying the procardiogenic actions of interleukin (IL)-1, IL-6 and TNF-ἀ, respectively. To present, in breast cancer, non-small cell lung cancer and in digestive tumors, a presumed role of resisting has been reported (94)(95)(96). IR-associated low-grade chronic inflammation also promotes the activation of macrophages and the large secretion into the systemic circulation of many proinflammatory cytokines, such as IL-6 and TNFἀ. Animal models have shown a correlation between TNF ἀ and various malignancies, like CCR (97)(98)(99). IL-6 has been related to carcinoma of renal cells, gastric cancer and CCR. By modulating many genes involved in proliferation, survival, and angiogenesis, cancer (100)(101)(102)(103)(104)(105).

Conclusion
NAFLD is a complex and multifactorial disorder that is closely linked to obesity and type 2 diabetes and shares a substantially elevated risk of several cancer forms. Further than HCC risk, obviously induced by NASH, there is a clear epidemiological and biological argument, with the strongest support for colorectal tumors, for the correlation between NAFLD and certain extrahepatic cancers. However, before clear screening guidelines for cancer in NAFLD patients can be given, further studies are required, but we advise health care professionals who care for patients with NAFLD to be cautious about any signs and symptoms of malignancies, especially CCR, and to refer patients for further evaluation and management.