Extrahepatic Malignancies in Nonalcoholic Fatty Liver Disease

Abstract

Purpose of Review:

Malignancy is the second most common cause of death in individuals with nonalcoholic fatty liver disease (NAFLD). Understanding unique characteristics of malignancy risk beyond hepatocellular carcinoma in NAFLD has significant implications in counseling and personalized preventative measures in this high-risk population. Herein, we systematically review the literature reporting extra-hepatic malignancies in NAFLD and discuss the key biological mechanisms underpinning the association between excess adiposity and cancer risk.

Recent Findings:

Several studies have shown significant associations between NAFLD and extrahepatic malignancies. The strongest association was found with cancers of the gastrointestinal tract and hormone-sensitive cancers. Recent data support sex-specific differences in cancer risk increase in NAFLD: colorectal cancer in men and uterine cancer in women. The risk of cancer development is higher in NAFLD than obesity alone.

Summary:

A growing body of observational evidence over the last decade supports the association between NAFLD and extrahepatic malignancies. This association requires further studies, ideally designed to include more detailed measures of body fat deposition beyond BMI in well-characterized, large cohorts of NAFLD patients, to determine if screening policies should be individualized in this group.

Introduction

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, with an estimated global prevalence of 25% in adults [1–3]. NAFLD is more predominant in those with obesity and metabolic syndrome (MetS)[4]. In North America, the prevalence of NAFLD in the severely obese ranges from 75% to 92%, while the prevalence in patients with type 2 diabetes is estimated to be between 60% and 70% [5–11]. Obesity has become one of the largest public health threats. Strong evidence supports an association between obesity and 11 cancers (esophageal adenocarcinoma, multiple myeloma, gastric cardia, colon, rectum, biliary tract, pancreas, breast, endometrium, ovary and kidney) [12–14]. NAFLD is an established risk factor for hepatocellular carcinoma [15], but emerging evidence supports its association with several extrahepatic cancers. Indeed, malignancy is the second most common cause of death in NAFLD individuals [13, 16].

In this manuscript we systematically review the literature relating extra-hepatic malignancy in NAFLD and discuss the key biological mechanisms underpinning the association between excess adiposity and cancer risk.

Methodology

We searched the PubMed with the help of a professional librarian using the following two search criteria: Search 1: (extrahepatic or extra-hepatic) AND (NAFLD or steatohepatitis or “fatty liver”[ti] or “Fatty Liver”[Mesh] OR “Non-alcoholic Fatty Liver Disease”[Mesh]) AND (malignan* or neoplasm* or cancer* or carcino* or tumor* or tumour* or adenoma* or adenocarcinoma*). Search 2: (colorectal[Title] OR rectal[Title] OR intestin*[Title] OR breast[Title] OR gastrointestinal[Title] OR pancreas*[Title] OR hematologic[Title] OR mammary[Title] OR skin[Title] OR spleen*[Title] OR urogen*[Title]) AND (NAFLD or steatohepatitis or “fatty liver”[ti] or “Fatty Liver”[Mesh] OR “Non-alcoholic Fatty Liver Disease”[Mesh]) AND (malignan* or neoplasm* or cancer* or carcino* or tumor* or tumour* or adenoma* or adenocarcinoma*). The filters used were: language (English) and species (humans). The total articles found from search 1 (97) and search 2 (349) were 446. We reviewed the abstracts and included all studies that described the prevalence or incidence of extrahepatic malignancies in NAFLD patients. We excluded studies focusing on intrahepatic malignancies (i.e. hepatocellular carcinoma and cholangiocarcinoma), studies discussing the reverse relationship (i.e. incidence of NAFLD in cancer patients), review articles, systematic reviews and meta-analysis.

Extrahepatic cancers associated with NAFLD

Significant association was found between NAFLD and several extrahepatic malignancies. The strongest association was found with GI (colorectal, gastric/esophageal, and pancreatic) cancers, in part due to the substantial number of supporting studies. Additional associations were found with hormone-sensitive cancers, such as breast, uterine and prostate, as well as renal and hematologic malignancies. All the studies are summarized in Table 1 (arranged in chronological order).

Table 1:

Extrahepatic malignancies associated with NAFLD. All cancers that had at least one positive association with NAFLD were included.

Cancer Associated with NAFLD	Study	Country	Type of Study	Population Enrolled	Findings
COLORECTAL
Colon	Allen AM, et al. (2019)[27••]	USA	Retrospective cohort	19,163 individuals (24.6% NAFLD) were identified using a medical record linkage system. NAFLD and colorectal cancer were identified using ICD codes. Each NAFLD patient was matched with 3 non-NAFLD subjects. Median follow-up: 8 years	NAFLD patients had higher incidence of colon cancer IRR=1.76 (95%CI 1.08-2.8).
	Cho Y, et al. (2019)[25]	South Korea	Cross-sectional	476 individuals (79.6% NAFLD) underwent screening colonoscopy and liver biopsy	NASH was an independent risk factor for both colorectal polyps (OR 2.08; 95% CI 1.12–3.86) and advanced colorectal neoplasm (OR 2.81; 95% CI 1.01–7.87).
	Kim MC et al., (2019)[24]	South Korea	Cross-sectional	6332 individuals (37.8% NAFLD) underwent screening colonoscopy and abdominal US	NAFLD was an independent risk factor for colorectal adenoma (aOR 1.15; 95% CI 1.02-1.30), advanced adenoma (aOR 1.50; 95% CI 1.12–2.01), and multiple adenomas (aOR 1.32; 95% CI 1.01–1.73).
	Ze EY et al., (2018)[39]	South Korea	Cross-sectional	2976 individuals (50.8% fatty liver) underwent screening colonoscopy and abdominal US	Fatty liver index ≥30 was associated with an increased risk of colorectal adenoma (OR 1.27; 95% CI 1.06–1.49).
	Kim GA, et al. (2017)[26••]	South Korea	Retrospective cohort	25,947 individuals (33.6% NAFLD) underwent screening colonoscopy and abdominal US. Median follow-up: 7.5 years	NAFLD patients had higher incidence of colorectal cancer (69.4 vs. 34.1 per 100,000 person-years; IRR 2.04; 95% CI 1.30–3.19).
	Ahn JS et al., (2017)[23]	South Korea	Cross-sectional	26,540 individuals (36.8% NAFLD) underwent screening colonoscopy and abdominal US	NAFLD patients had a higher prevalence of any colorectal neoplasia (38.0% vs. 28.9%) and advanced colorectal neoplasia (2.8% vs. 1.9%). The aOR in NAFLD patients was 1.10 (95% CI: 1.03–1.17) for any colorectal neoplasia and 1.21 (95% CI: 0.99–1.47) for advanced colorectal neoplasia.
	Chen QF et al., (2017)[28]	China	Cross-sectional	3686 individuals (65.9% males, 13.3% NAFLD) underwent screening colonoscopy and abdominal US	NAFLD was significantly associated with adenomatous polyps (OR = 1.53, 95%CI: 1.18-2.00) and hyperplastic polyps (OR = 1.42, 95%CI: 1.04-1.95) in men, but not in females.
	Pan S et al., (2017)[40]	China	Cross-sectional	1793 individuals (32% NAFLD) underwent screening colonoscopy and abdominal US	NAFLD was independently associated with increased risk of prevalent colorectal cancer (aOR 2.16, 95% CI 1.29–3.22).
	Yang YJ et al., (2017)[41]	South Korea	Retrospective cohort	1023 individuals (43.1% NAFLD) underwent screening colonoscopy and abdominal US or CT. Followed up to 5 years	Cumulative incidence rates of colorectal neoplasm at 3 and 5 years in the NAFLD group were 9.1% and 35.2% vs. 5.0% and 25.3% in non-NAFLD group. NAFLD was associated with increased risk of overall colorectal tumors (aHR 1.31, 95% CI 1.01–1.71), and the development of ≥3 adenomas at the time of surveillance colonoscopy (aHR: 2.49, 95% CI: 1.20-5.20).
	Mahamid M et al., (2017)[42]	Israel	Retrospective cohort	223 individuals (55.2% NASH) underwent screening colonoscopy and liver biopsy	NASH group had higher prevalence of hyperplastic polyps (22.7% vs. 8%). NASH was associated with increased risk for hyperplastic polyps (OR 1.69, 95%CI 1.36–1.98).
	Lee T et al., (2016)[22•]	South Korea	Cross-sectional	44,220 individuals (33.1% NAFLD) underwent screening colonoscopy and abdominal US	aOR for colorectal cancer with varying severity o NAFLD was: 1.13 for mild, 1.12 for moderate, and 1.56 for severe (P for the trend = 0.007).
	Bhatt BD et al., (2015)[43]	USA	Retrospective cohort	591 individuals (12% NAFLD) completed LT evaluation (liver biopsy and colonoscopy)	NAFLD group had higher prevalence of polyps (59% vs. 40%) and adenomas (32% vs. 21%). NAFLD was predictive of finding a polyp on colonoscopy (OR 2.42, P=0.001) and was associated with adenoma (OR 1.95, P=0.02).
	Sun LM et al., (2015)[32]	Taiwan	Retrospective cohort	2109 individuals identified as NAFLD with cirrhosis using ICD codes from the Taiwan National Health Insurance program. Each NAFLD patient was matched to 4 non-cirrhotic individuals. Mean follow-up: 3.62 years	NAFLD with cirrhosis group had higher incidence of colorectal cancer (aHR 2.58, 95% CI 1.59–4.18)
	Aktas E et al., (2014)[44]	Turkey	Case-control	105 patients with CRC were matched with 94 patients without CRC. Abdomnopelvic CT images were compared.	The CT score (liver density) of the CRC group (68.70±18.7) was lower (more fat density) than that of the control group (96.87±11.9) p<0.001.
	Lin XF et al., (2014)[45]	China	Cross-sectional	2315 individuals (11.4% NAFLD) underwent screening colonoscopy and abdominal US	NAFLD group had higher prevalence of colorectal cancer (29.3 % vs. 18.0%). NAFLD was independently associated with increased risk of colorectal cancer (aOR 1.87, 95% CI 1.36–2.57).
	Huang KW et al., (2013)[46]	Taiwan	Retrospective cohort	1522 individuals (40.7% NAFLD) underwent two consecutive colonoscopies (first was negative baseline) and abdominal US. Follow-up: 2.6 years	NAFLD prevalence was 55.6% in the adenoma group and 38.8% in the nonadenoma group. NAFLD was an independent risk factor for colorectal adenoma development (OR = 1.45; 95% CI: 1.07–1.98) after adjusting.
	Lee YI et al., (2012)[29]	South Korea	Retrospective cohort	5517 women (15.1% NAFLD) underwent screening colonoscopy and abdominal US. Mean follow-up: 4.5 years	NAFLD was associated with aRR 1.94 (95% CI 1.11–3.40) for adenomatous polyps, and aRR 3.08 (95% CI 1.02–9.34) for colorectal cancer.
	Wong VW et al., (2011)[21]	China	Cross-sectional	380 individuals (52.4% NAFLD) were recruited for screening colonoscopy from a community-based cohort (had MRS) and a hospital-based cohort (had liver biopsy)	NAFLD group had higher prevalence of colorectal adenomas (34.7% vs 21.5%) and advanced neoplasms (18.6% vs 5.5%) than healthy controls. Among the biopsy group: NASH had higher prevalence of adenomas (51.0% vs 25.6%) and advanced neoplasms (34.7% vs 14.0%) than those with simple steatosis. NASH was also associated with adenomas (aOR 4.89, 95% CI 2.04-11.70) and advanced neoplasms (OR 5.34, 95% CI 1.92-14.84).
	Stadlmayr A et al., (2011)[47]	Austria	Cross-sectional	1211 individuals (45.7% NAFLD) underwent screening colonoscopy and abdominal US	NAFLD was independently associated with increased risk of colorectal adenomas (aOR 1.47, 95% CI 1.08–2.00).
	Hwang ST et al., (2009)[18]	South Korea	Cross-sectional	2917 individuals (32.3% NAFLD) underwent screening colonoscopy and abdominal US	Prevalence of NAFLD was 41.5% in the adenoma group and 30.2% in the nonadenoma group. NAFLD was associated with increased risk of colorectal adenomas (OR 1.28, 95% CI: 1.03–1.60).
	Nonsignificant Association
	Touzin NT et al., (2011)[19]	USA	Retrospective cohort	233 individuals (40.3% NAFLD) underwent screening colonoscopy and abdominal US and liver biopsy	Prevalence of polyps between NAFLD and non-NALFD groups was not significantly different (24.4% vs 25.1%; p=1)
	Sørensen HT et al., (2003)[17]	Denmark	Retrospective cohort	7326 individuals (25% NAFLD) were filtered using the ICD codes for fatty liver disease and colon and rectal cancers	The standardized incidence ratio of colon and rectal cancers in the NAFLD group were: SIR 1.6, 95% CI 0.9-2.9 and SIR 0.5, 95% CI 0.1-1.7, respectively
	Negative Association
	Basyigit S et al., (2015)[20]	Turkey	Cross-sectional	127 individuals (100% NAFLD) underwent screening colonoscopy and abdominal US	The risk for CRC was associated with the absence of NAFLD (OR: 7.38, 95% CI 3.07-7.96).
	GASTRIC AND ESOPHAGEAL
Gastric/Esophageal	Allen MA, et al. (2019)[27••]	USA	Retrospective cohort	Described above	NAFLD patients had higher incidence of gastric cancer (IRR=2.3, 95%CI 1.3-4.1)
	Sun LM et al., (2015)[32]	Taiwan	Retrospective cohort	Described above	NAFLD with cirrhosis group had significantly higher incidence of esophageal cancer (aHR 7.25; 95% CI 2.44–21.6) and gastric cancer (aHR 5.50; 95% CI 2.78–10.9).
	Uzel M et al., (2015)[33]	Turkey	Retrospective cohort	14 individuals diagnosed with distal gastric cancer on EGD, 5 of which were NAFLD (35.7%)	The prevalence of NAFLD was higher in gastric cancer patients compared to that in the Turkish general population.
	Sørensen HT et al., (2003)[17]	Denmark	Retrospective cohort	Described above	The standardized incidence ratio of esophageal cancer in the NAFLD group was: SIR 2.9; 95% CI 0.4-10.3.
PANCREAS
Pancreas	Allen MA, et al. (2019)[27••]	USA	Retrospective cohort	Described above	NAFLD patients had higher incidence of pancreatic cancer (IRR=2.1, 95%CI 1.2-3.3)
	Chang CF et al., (2017)[34]	Taiwan	Case-control	143 (11.9% NAFLD) with and 414 (5.1% NAFLD) without pancreatic cancer underwent abdominal CT	NAFLD prevalence was higher in cancer group (11.9% vs. 5.1%). NAFLD was an independent risk factor for pancreatic cancer (OR 2.63, 95% CI 1.24–5.58).
	Kim GA, et al. (2017)[26••]	South Korea	Retrospective cohort	25,947 individuals (33.6% NAFLD) underwent screening abdominal US. Median follow-up: 7.5 years	NAFLD patients had higher incidence of pancreatic cancer (16.0 vs. 13.8 per 100,000 person-years) but was statistically insignificant (IRR 1.16; 95% CI 0.51-2.65).
	Sun LM et al., (2015)[32]	Taiwan	Retrospective cohort	Described above	NAFLD with cirrhosis group had higher crude and adjusted incidence risk of pancreatic cancer (HR 4.18; 95% CI 1.67–10.4 and aHR 2.72; 95% CI 0.93–7.95, respectively), however the adjusted incidence risk was statically insignificant.
	Sørensen HT et al., (2003)[17]	Denmark	Retrospective cohort	Described above	The standardized incidence ratio of pancreatic cancer in the NAFLD group was: SIR 3.0, 95% CI 1.3-5.8.
BREAST
	Allen MA, et al. (2019)[27••]	USA	Retrospective cohort	Described above	Breast cancer incidence was higher in NAFLD vs. controls, SIR 1.68 (95% CI 1.05-2.76)
Breast	Kwak M-S, et al. (2018)[48]	South Korea	Case-control	270 women diagnosed with breast cancer by screening mammography and breast US (30.0% NAFLD) were matched with 270 with no breast cancer on imaging (20.0% NAFLD). All underwent hepatic US.	NAFLD was independently associated with breast cancer (OR 1.63 95% CI 1.01–2.62; p 0.046), and was significantly associated with breast cancer in the non-obese (OR 3.04, 95% CI 1.37–4.32; p 0.002) but not in the obese group (p 0.163)
	Kim GA, et al. (2017)[26••]	South Korea	Retrospective cohort	11,981 female pts (21% NAFLD) underwent screening abdominal US	NAFLD group had higher incidence of breast cancer (181.6 vs. 102.5 per 100,000 person-years) than non-NAFLD group, with IRR 1.77, 95% CI 1.15–2.74
	Nseir W, et al. (2017)[49]	Israel	Case-control	73 newly diagnosed breast cancer patients (by mammography or US), matched with 73 patients without breast cancer on imaging. Both groups underwent CT abdomen within 1 month (cancer pts) or 3 months (controls) of breast cancer screening	45.2% of cancer pts vs. 16.4% of controls had NAFLD, OR 4.19; 95% CI 1.9-9.1, P = 0.0003
	Bilici A, et al. (2007)[50]	Turkey	Case-control	40 new untreated breast cancer pts (group 1), 45 breast cancer pts treated with systemic therapy (group 2), 40 ovarian cancer pts (group 3), and 40 healthy women (group 4). All evaluated with hepatic US.	Hepatic steatosis in 63%, 72%, 77%, and 48% of pts in groups 1, 2, 3, and 4, respectively. Grade-2 and 3 hepatic steatosis were more prevalent in all breast cancer pts (P = 0.03).
	Chu CH, et al. (2003)[37]	China	Case-control	217 newly diagnosed breast cancer individuals matched with 182 individuals with no breast cancer. All underwent hepatic US	45.2% of cancer patients vs. 20.3% of the controls had NAFLD (OR 3.23; 95% CI 2.1-5.1, P<0.0001).
	Nonsignificant Association
	Lee S, et al. (2017)[38]	South Korea	Cross-sectional	104 pts who underwent surgical treatment for breast cancer also underwent liver MRIs	18.3% of the breast cancer patients were diagnosed with NAFLD, which is insignificantly different from the prevalence of NAFLD in the South Korean general population.
	Sun LM et al., (2015)[32]	Taiwan	Retrospective cohort	Described above	NAFLD with cirrhosis group had higher adjusted incidence risk (aHR 1.23; 95% CI 0.28–5.38) compared to the control group, however this difference was statistically insignificant.
	Sørensen HT et al., (2003)[17]	Denmark	Retrospective cohort	Described above	The standardized incidence ratio of breast cancer in the NAFLD group was: SIR 0.9, 95% CI 0.4-1.7
UTERINE
Uterine	Allen MA, et al. (2019)[27••]	USA	Retrospective cohort	Described above	NAFLD patients had higher incidence of uterine cancer IRR=2.3 (95%CI 1.4-4.1).
	Kim GA, et al. (2017)[26••]	South Korea	Retrospective cohort	11,981 female pts (21% NAFLD) underwent screening abdominal US. Median follow-up: 7.5 years	NAFLD patients had higher incidence of uterine/cervical/ovarian cancers (48.4 vs. 23.5 per 100,000 person-years) but was statistically insignificant (IRR 2.06; 95% CI 0.86-4.91).
	Sun LM et al., (2015)[32]	Taiwan	Retrospective cohort	Described above	NAFLD with cirrhosis group had higher crude and adjusted hazard ratios of uterine cancer (HR 2.11; 95% CI 0.67–6.63; and aHR 2.03; 95% CI 0.60–6.80), however both were statistically insignificant.
PROSTATE
Prostate	Choi YJ et al., (2018)[51•]	South Korea	Cross-sectional	10,516,985 males were filtered from a national database registry. NAFLD was identified using the fatty liver index (FLI, ≥60) or hepatic steatosis index (HIS), and prostate cancer was identified by ICD codes	Prevalence of NAFLD was: 19% FLI and 25% HIS. Each FLI ≥60 and HSI ≥36 was independently associated with the development of prostate cancer (HR 1.09, 95% CI 1.06-1.12 and HR 1.19, 95% CI 1.16-1.23).
	Kim GA, et al. (2017)[26••]	South Korea	Retrospective cohort	13,966 males (44.4% NAFLD) underwent screening abdominal US	NAFLD patients had lower incidence of prostate cancer (126.0 vs. 138.9 per 100,000 person-years) but was statistically insignificant (IRR 0.91; 95% CI 0.63-1.31).
	Sørensen HT et al., (2003)[17]	Denmark	Retrospective cohort	Described above	The standardized incidence ratio of prostate cancer in the NAFLD group was: SIR 1.3, 95% CI 0.5-2.8.
KIDNEY
Kidney	Kim GA, et al. (2017)[26••]	South Korea	Retrospective cohort	25,947 individuals (33.6% NAFLD) underwent screening abdominal US. Median follow-up: 7.5 years	NAFLD patients had higher incidence of renal cancer (35.6 vs. 20.3 per 100,000 person-years) but was statistically insignificant (IRR 1.76; 95% CI 0.96-3.22).
	Sun LM et al., (2015)[32]	Taiwan	Retrospective cohort	Described above	NAFLD with cirrhosis group had higher crude and adjusted hazard ratios of urinary system cancer (HR 1.19; 95% CI 0.53–2.66; and aHR 1.60; 95% CI 0.69–3.72), however both were statistically insignificant.
	Sørensen HT et al., (2003)[17]	Denmark	Retrospective cohort	Described above	The standardized incidence ratio of renal cancer in the NAFLD group was: SIR 2.7, 95% CI 1.1-5.6.
HEMATOLOGIC
Hematologic	Sun LM et al., (2015)[32]	Taiwan	Retrospective cohort	Described above	NAFLD with cirrhosis group had significantly higher adjusted incidence of hematologic cancer (aHR 3.12; 95% CI 1.34–7.25).

A. Gastrointestinal cancers

A1. Colorectal neoplasia

NAFLD is associated with increased incidence and prevalence of colorectal polyps and cancer.

The association between NAFLD and the incidence and prevalence of colorectal lesions (polyps or cancer) has been investigated in 23 observational studies, the vast majority showing a significant association. The relationship was first established in 2003 by Sørensen HT et al., who investigated the incidence of cancers in a Danish cohort (n = 7,326; 25% with NAFLD) and presented the first evidence of higher incidence of colon cancer in NAFLD patients, despite the results being statistically nonsignificant in their study [17]. Next, in 2009, Hwang et al. investigated the incidence of colorectal adenomas in a South Korean population that underwent a routine health checkup, and presented evidence for significant increase in risk of colorectal adenomatous polyps in NAFLD patients [18]. Subsequently, several studies, mostly conducted on Asian populations, confirmed the increased risk of colorectal lesions in NAFLD patients (Table 1).

In contrast, only two small studies suggested an inverse or nonsignificant association between NAFLD and colorectal lesions. In a study that included 233 patients (94 were NAFLD) who underwent screening colonoscopy and abdominal ultrasonography (US) and liver biopsy, the prevalence of colonic adenomas in NAFLD vs. non-NALFD group was not significantly different (24.4% vs 25.1%; p=1). However, the authors found a higher burden of adenomas in the NAFLD vs. non-NAFLD group [19]. Another study included 127 NAFLD patients who underwent screening colonoscopy and abdominal US, to investigate the risk for CRC in NAFLD patients, considering insulin resistance (IR) effects. The study found that the prevalence of CRC was significantly lower in subjects with NAFLD (P = 0.001), and the risk for CRC was significantly higher in non-NAFLD patients (OR: 7.4, 95% CI: 3.07-7.96, P = 0.010), while the prevalence and risk of CRC and adenoma were significantly higher in patients with IR [20]. The obvious common factor between these two studies is the smaller number of study sample compared to the large-sampled studies providing evidence for increased colorectal lesions in NAFLD patients.

NAFLD severity correlates with risk of colorectal neoplasia

The risk of colorectal lesions appears to correlate with disease severity in NAFLD, as assessed by liver biopsy, abdominal US, or noninvasive biomarkers of steatosis or fibrosis. Wong VW et al. first demonstrated higher prevalence of adenomas and advanced neoplasms in nonalcoholic steatohepatitis (NASH) vs. simple steatosis, among patients with biopsy proven NAFLD [21]. Lee T et al. concluded that colorectal neoplasm risk increased with worsening fatty liver severity on abdominal ultrasonography [22•]. Similarly, Ahn JS et al. proved that the risk of any colorectal neoplasia or advanced colorectal neoplasia was higher for those with severe liver diseases than those with mild liver diseases, according to the non-invasive parameters of liver disease severity [23]. Moreover, Kim MC et al. proved that NAFLD subjects with advanced fibrosis had a significantly higher risk for colorectal adenomas than those without advanced fibrosis, using various noninvasive score models [24]. Additionally, Cho Y et al. found that patients with advanced colorectal neoplasm had higher grade of steatosis and higher stage of hepatic fibrosis than those with normal colonoscopic findings or low-grade adenomatous polyp [25]. While Kim GA et al. results showed no significant association between the severity of hepatic steatosis detected on US and any cancer development, they demonstrated evidence for a higher risk of development of all cancers in patients with high NAFLD Fibrosis Score (≥ −1.455) or a high FIB-4 score (≥1.45) among the NAFLD subjects, but this increase in fibrosis severity was not associated with increased colorectal cancer risk in their study [26••].

The colorectal neoplasia risk is high in men but not in women

One unique characteristic of the association between NAFLD and colorectal neoplasia is the sex-related difference in risk. Several studies showed a significant association in men, but not in women. This difference was noted in two large studies of colorectal cancer.

In one study, among the male subjects (n = 13,966), those with NAFLD had significantly higher incidence rates of colorectal cancer (IRR 2.21; 95% CI 1.26–3.87; p = 0.006), while among female subjects (n = 11,981), the incidence rate of colorectal cancer did not differ between the NAFLD and control groups (IRR 1.00; 95% CI 0.37–2.70; p = 0.99) [26••]. Similarly, in a population-based study of over 19,000 subjects NAFLD was associated with higher incidence of colorectal cancer in men (IRR 2.4; 95% CI 1.6-3.9), but not in women (IRR 1.3; 95% CI 0.8-2.1) when compared to age- and sex-matched controls [27••]. The prevalence of colorectal polyps follows a similar sex-specific pattern; OR = 1.40, 95% CI: 1.14-1.71 in men and OR = 0.78, 95% CI: 0.47-1.28 in women [28]. Only one smaller retrospective cohort study conducted exclusively on South Korean women (n = 5517, 15.1% NAFLD) suggested that the risk of colorectal neoplasia is high in women with NAFLD [29].

The reason for the sex-related predisposition to colon cancer in NAFLD remains elusive. Nevertheless, this observational evidence, coupled with similar disparities described in obesity-related colorectal cancer [30] serves as an important framework for future studies that examine whether counseling and screening should be individualized by sex.

A2. Esophageal and gastric cancer

Central adiposity has been linked to esophageal inflammation promoting metaplasia and neoplasia via reflux-dependent and reflux-independent mechanisms. A recent meta-analysis of 6 studies demonstrated that central adiposity, independent of BMI, was associated with increased risk of esophageal adenocarcinoma (aOR, 2.51; 95% CI, 1.54-4.06) in reference to normal body habitus [31]. The association of NAFLD with esophageal or gastric cancer is less clear. In the three large retrospective studies designed to explore the incidence of gastroesophageal cancers in individuals with NAFLD, there were trends in increased risk of both cancer types. However, the results are inconsistent and limited due to small number of cancer outcomes and without sufficient statistical power [17, 27••, 32]. A very small retrospective cohort (n = 14) found higher prevalence of NAFLD in gastric cancer patients than the Turkish general population [33].

A3. Pancreatic cancer

Pancreatic cancer was found to be highly associated with NAFLD. In 4 studies that found higher incidence of pancreatic cancer in NAFLD patients, 3 large retrospective cohort studies were statistically significant [17, 26••, 27••], and one study found significantly higher crude incidence risk but nonsignificant adjusted risk [32]. Further, a smaller case-control study (143 pancreatic cancer patients vs. 414 controls) showed higher prevalence of NAFLD in pancreatic cancer patients [34].

B. Hormone-sensitive cancers

B1. Breast cancer

Several studies have described an association between obesity and breast cancer risk, especially in postmenopausal women who have never used hormone-replacement therapy [35]. The risk of developing breast cancer increases by 11% with each 5 kg of weight gain [36]. A similar association between NAFLD and breast cancer has been found in most retrospective studies, the largest of which estimated a 60-70% increase in incidence [26••, 27••] and 3-fold higher prevalence [37]. A few smaller-size studies failed to show significant association between NAFLD and the incidence [17, 32] or prevalence [38] of breast cancer.

B2. Uterine cancer

Few studies showed evidence of an association between NAFLD and uterine cancer. Three large retrospective cohort studies demonstrated higher incidence of uterine cancer in NAFLD patients [26••, 27••, 32], but only one of them was statistically significant [27••].

B3. Prostate cancer

Large-scale studies have examined the incidence of prostate cancer in NAFLD and showed inconsistent results. There were trends of direct or inverse association, but not statistically significant [33] [42]. The largest study of a South Korean population that included over 10 million males filtered from a national database registry, showed marginally significant higher incidence of prostate cancer in NAFLD patients with fatty liver index ≥60 or hepatic steatosis index ≥36 [51•]. Overall, the evidence does not appear to support prostate cancer as a significant threat in men with NAFLD.

C. Other cancers

C1. Renal cancer

NAFLD was associated with increased incidence of renal cell carcinoma in 3 large retrospective cohort studies [17, 26••, 32], but this risk was statistically significant in only one of them [17].

C2. Hematologic

A single retrospective cohort study that investigated the incidence of cancers in over 2,000 NAFLD patients found statistically significant higher incidence of hematologic cancer [32].

Mechanistic hypotheses in obesity-associated cancers

Several mechanisms by which obesity induces tumorigenesis have been proposed. Chronic hyperinsulinemia may contribute to cancer development through a direct mechanism of growth-promoting signaling and indirectly through insulin-like growth factor 1 which triggers tumorigenic intracellular signaling cascades [33]. Adipokine pathophysiology has been proposed as an additional hormonal pathway to cancer risk. Leptin, which is secreted in excess in obesity, has anti-apoptotic, proliferative, and immunity suppression effects [52, 53]. In contrast, adiponectin, which is decreased in obesity, has opposite effects through pathways that inhibit cell proliferation and inflammation [54]. Excess adipose tissue is accompanied by increased release of inflammatory mediators like C-reactive protein (CRP), tumor necrosis factor (TNF), interleukin-1β (IL-1β), IL-6 and Il-18 [55–57]. This chronic inflammatory state has been linked to increased cancer risk. Hyper-estrogenism may explain the link between obesity and breast, endometrial and ovarian cancers. Excess peripheral adipose tissue accelerates aromatase activity which converts androgen precursors to estrogen (aromatization), which has proliferative effects.

Malignancy risk in NAFLD versus obesity

New paradigms related to systemic versus local effects of excess adiposity on the tumor microenvironments are emerging. Renehan et. al review preclinical and epidemiological research that suggests an effect of local fat in the development of breast cancer, hepatocellular carcinoma and pancreatic cancer via paracrine inflammatory effects [33]. These findings support the hypothesis that assessment of body fat distribution and organ-specific ectopic fat may be more relevant than BMI, which is a crude measure of excess adiposity. In the specific case of NAFLD, the question whether the increased malignancy risk is related to ectopic fat or to obesity in general (as measured by BMI) is highly relevant.

A few observational studies aimed to tease out the association between cancer and obesity, with and without NAFLD. In a large population-based study, Allen et al. found that in reference to non-obese controls, obesity (defined by BMI>30 kg/m², irrespective of NAFLD status) was associated with a trend towards increased malignancy risk: IRR=1.2 (95%CI 0.9, 1.6). However, when analyzed by the presence or absence of NAFLD, in reference to non-obese controls, NAFLD was associated with a higher risk of incident cancers (overall malignancy IRR=2.0, 95% CI 1.5, 2.9, with the largest increase noted among hepatic and gastrointestinal cancers), while obesity alone was not (IRR=1.0, 95%CI 0.8, 1.4) [27••]. Another study by Bhatt el al. concluded that colon polyps had a stronger association with NAFLD than MetS or diabetes [43]. Pan S et al. studied the effect of NAFLD vs. MetS on CRC development by comparing 4 groups with and without NAFLD (N) and MetS (M) (M+N+ vs. M−N+ vs. M+N− vs. M−N−) and found the additive risk effect of NAFLD and MetS to be significantly higher than the other combinations [40].

These studies suggest that NAFLD may be a more important intermediary biomarker of cancer risk than BMI or metabolic syndrome. Whether NAFLD is a predictor of cancer risk or a mediator on the causal pathway remains to be elucidated. Nevertheless, the fact that the largest increase in incident extrahepatic cancers in NAFLD relate to gastrointestinal sites may serve as epidemiological evidence to support the biological plausibility of local tumorigenic effects of ectopic hepatic or visceral fat.

Conclusion

A large body of observational evidence supports an increase in the overall risk of extrahepatic cancers in patients with NAFLD. Noteworthy characteristics of the NAFLD-associated cancers include organ-specificity (gastrointestinal tract) and sex-related differences (increased risk of colorectal cancer in men). Emerging data suggest that the association between NAFLD and malignancy is not explained solely by increased body mass index. This association requires further studies, ideally designed to include more detailed measures of body fat deposition beyond BMI in well-characterized, large cohorts of NAFLD patients, to determine if screening policies should be individualized in this group.

Abbreviations:

aHR

adjusted hazard ratio

aOR

adjusted odds ratio

aRR

adjusted relative risk

BMI

body mass index

CI

confidence interval

CRC

colorectal cancer

CRP

C reactive protein

CT

computed tomography

FIB-4

Fibrosis-4 index

FLI

fatty liver index

GI

gastrointestinal

HIS

hepatic steatosis index

HR

hazard ratio

ICD

international classification of diseases

IL

interleukin

IR

insulin resistance

IRR

incidence rate ratio

LT

liver transplant

MetS

metabolic syndrome

MRI

magnetic resonance imaging

MRS

magnetic resonance spectroscopy

NAFLD

nonalcoholic fatty liver disease

NASH

nonalcoholic steatohepatitis

OR

odds ratio

SIR

standardized incidence ratio

TNF

tumor necrosis factor

US

ultrasound