Does Nonalcoholic Fatty Liver Disease Increase the Risk for Extrahepatic Malignancies?

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Abbreviations

CRC

colorectal cancer

ICD‐9

International Classification of Diseases, Ninth Revision

IR

insulin resistance

NAFLD

nonalcoholic fatty liver disease

NASH

nonalcoholic steatohepatitis

NAFLD is a clinicopathological entity that encompasses a spectrum of disease severity that ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is now the leading cause of chronic liver disease worldwide, with the highest prevalence in many high‐income countries. ¹ , ² It is strongly associated with the metabolic syndrome. NAFLD is associated with a significantly higher mortality because it increases the risk for end‐stage liver disease, hepatocellular carcinoma (HCC), ³ and non‐liver‐related and all‐cause mortality. ⁴ , ⁵ , ⁶ , ⁷ The majority of deaths among individuals with NAFLD are attributed to cardiovascular disease and malignancy. ² , ⁶ , ⁸ Thus, there has been increasing interest in further investigating the role of NAFLD as a potential important driver of extrahepatic diseases. Extrahepatic malignancy (colon, esophagus, stomach, pancreas, kidney, and breast) is the second most common cause of death in patients with NAFLD (Table 1). ⁹ , ¹⁰ Insulin resistance (IR) with hyperinsulinemia and proinflammatory state with oxidative stress mediate cellular proliferation and risk for malignancy. ¹¹ It has been demonstrated that inflammatory pathways, such as interleukin‐1‐type cytokines, are driving forces of disease processes in NAFLD. ¹² , ¹³ Lipotoxicity and altered gut microbiota are also potential players in disease development. Evidence suggests that visceral adipose tissue and its inflammation can lead to development and progression of NAFLD. ¹⁴ Of particular interest is the relationship between NAFLD and colorectal cancer (CRC). ¹⁵ , ¹⁶ Studies evaluating increased risk for CRC in patients with NAFLD have shown conflicting results. ¹⁷ Most studies have shown a higher prevalence of colorectal lesions in patients with NAFLD compared with patients without. Patients with NAFLD are also more likely to have multiple polyps, ¹⁸ often localized in the right and transverse segments of the colon ¹⁸ , ¹⁹ ; patients with histological diagnosis of NASH are at higher risk for adenomatous polyps with high‐grade dysplasia compared with those with simple fatty liver. ¹⁹ There are limited data on the effect of NAFLD versus obesity on CRC prognosis. A cohort study examining the association between NAFLD and mortality in patients with CRC found that patients with CRC with preexisting NAFLD had a worse prognosis than those without NAFLD, independent of body mass index and prognostic indicators. ²⁰ A meta‐analysis reported that NAFLD was associated with about a 2‐fold risk for colorectal adenoma; highest risk was among the Asian population and patients with NASH. ²¹ However, no association was established between NAFLD and NASH with CRC because of short follow‐up period and retrospective studies that limited the analysis. Hence further large prospective studies are needed to establish the association between NAFLD and CRC. The association of NAFLD with other extrahepatic cancers is less proven. It has been reported that individuals with fatty liver had increased risk for all cancers, ²² and those with NAFLD had a higher risk for pancreatic and kidney cancers, malignant melanoma, and cancer metastases from unspecified primary sites. Another study found that individuals with NAFLD had a higher prevalence of breast cancers compared with healthy control subjects. ²³ However, most studies do not clearly distinguish between the effects of NAFLD versus the background prooncogenic effects of obesity, IR, and type 2 diabetes. There are data to suggest that the carcinogenic effect of NAFLD is linked to visceral obesity. A considerable amount of data recognized the role of visceral obesity in the development of various cancers, including CRC ²⁴ , ²⁵ , ²⁶ , ²⁷ (Fig. 1), esophageal ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ and pancreatic, ³⁵ breast, ³⁶ biliary, ³⁷ , ³⁸ and probably prostate cancer. ³⁹ Low‐grade chronic inflammation and IR create a microenvironment suitable for cancer development through the stimulation of the insulin growth factor‐1 axis by hyperinsulinemia. ⁴⁰ , ⁴¹ The specific types of cancer that patients with NAFLD are at increased risk for or the magnitude of risk compared with those without NAFLD is not known. NAFLD may be a more important intermediary biomarker of cancer risk. It is not clear whether there are particular characteristics of malignancy risk among those with NAFLD that are distinct from those with obesity alone. In a cohort by Allen et al., ⁴² the obesity‐related risk was largely driven by NAFLD, whereas obesity in the absence of NAFLD had minimal association with malignancy risk. The highest increase in the risk was noted for HCC, followed by uterine, gastric, pancreatic, and colon cancer. Moreover, the association between obesity and cancer risk was small in the absence of NAFLD, suggesting that NAFLD may potentiate the obesity‐cancer relationship. ⁴² The same study found an important interaction between sex and the risk for CRC in patients with NAFLD. Whereas the overall risk was significantly higher in NAFLD versus controls, stratification by sex showed that the effect was entirely present in men but insignificant in women, and this was confirmed by formal testing of the sex interaction. ⁴²

TABLE 1.

Examples of Studies for the Association Between NAFLD and Extrahepatic Malignancies

Study	Sample Size	NAFLD Diagnosis	Duration	Study Design	Cancer Type	Cancer Diagnosis
Chen et al. (2018) 44	764	Ultrasonography	2014–2016	Cross sectional	Colorectal	Colonoscopy
Ahn et al. (2017) 45	26,540	Ultrasonography	2003–2012	Cross sectional	Colorectal	Histology
Petrick et al. (2017) 37	328,688	ICD‐9	2000–2011	Case‐control	Cholangiocarcinoma	ICD‐9
Choi et al. (2016) 38	7164	Histology/Imaging	2000–2014	Case‐control	Cholangiocarcinoma	ICD‐9
Allen et al. (2019) 42	676	ICD‐9	1997–2016	Cohort	Breast cancer	ICD‐9
Kwak et al. (2019) 46	540	Ultrasonography	2008–2017	Case‐control	Breast cancer	Ultrasonography

FIG 1.

Pathophysiological mechanisms by which obesity could contribute to development of CRC in humans. (Note: The referenced diet is the Western‐style diet.) Adapted with permission from Gastroenterology. ⁴⁷ Copyright 2014, American Gastroenterological Association.

Overall, a clear understanding of the biological and genetic pathways involved remains lacking because of the close relationships between NAFLD and central obesity, dyslipidemia, and IR. Despite the cumulative evidence that NAFLD is an important risk factor for extrahepatic morbidity and death, current guidelines have yet to include any recommendations for screening these complications. ⁴³ Future studies should aim to rule out obesity because it is the major confounding factor implicated in extrahepatic cancers. Further studies also should use liver biopsy or at least novel noninvasive modalities to stage NAFLD.

Key Points

• Nonalcoholic fatty liver disease (NAFLD) is associated with a nearly 2‐fold increase in the overall risk for incident cancers.

• The highest risk was noted in colorectal, gastroesophageal, pancreatic, biliary, breast, uterine, renal, and prostate cancers.

• The risk for cancer development is higher in NAFLD than in obesity alone.