Mol Biol Rep (2014) 41:2989–2997 DOI 10.1007/s11033-014-3157-y

Increased risk of colorectal malignant neoplasm in patients with nonalcoholic fatty liver disease: a large study Xian-Feng Lin • Ke-Qing Shi • Jie You • Wen-Yue Liu • Ying-Wan Luo • Fa-Ling Wu • Yong-Ping Chen • Danny Ka-Ho Wong • Man-Fung Yuen • Ming-Hua Zheng

Received: 7 May 2013 / Accepted: 13 January 2014 / Published online: 22 January 2014 Ó Springer Science+Business Media Dordrecht 2014

Abstract Nonalcoholic fatty liver disease (NAFLD) has been suggested to be a strong risk factor of colorectal benign adenomas and advanced neoplasms. The aim of this large cohort study was to further investigate the prevalence of colorectal malignant neoplasm (CRMN) in patients with NAFLD and determine whether association between NAFLD and CRMN exists. 2,315 community subjects (1,370 males and 945 females) who underwent a routine colonoscopy according to international colorectal cancer screening guideline were recruited. Nature of colorectal lesions determined by biopsy and NAFLD was diagnosed by ultrasound. Binary logistic regression analysis was applied to explore the related associations. Prevalence of CRMN was 29.3 % (77/263) in patients with NAFLD, which was significantly higher than 18.0 % (369/ 2,052) in the control group (P \ 0.05). In addition, malignant neoplasm in NAFLD group occurred more frequently at

Xian-Feng Lin, Ke-Qing Shi and Wen-Yue Liu are co-first authors.

Electronic supplementary material The online version of this article (doi:10.1007/s11033-014-3157-y) contains supplementary material, which is available to authorized users. X.-F. Lin  K.-Q. Shi  W.-Y. Liu  Y.-W. Luo  F.-L. Wu  Y.-P. Chen  M.-H. Zheng (&) Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou 325000, China e-mail: [email protected]

sigmoid colon than in control group (14.3 vs. 11.9 %). The incidence of highly-differentiated colorectal adenocarcinoma in NAFLD group was significantly higher than control group (62.3 vs. 9.8 %). Univariate analysis showed that NAFLD had strong association with CRMN (OR 2.043; 95 % CI 1.512–2.761; P \ 0.05). After adjusting for metabolic and other confounding factors, NAFLD remained as an independent risk factor for CRMN (OR 1.868; 95 % CI 1.360–2.567; P \ 0.05). NAFLD was an independent risk factor for CRMN. Sigmoid carcinoma and highly differentiated colorectal adenocarcinoma were more commonly found in NAFLD. (ClinicalTrials.gov number, NCT01657773, website: http://clinicaltrials.gov/ct2/show/ NCT01657773?term=zheng?minghua&rank=1). Keywords Neoplasm  Colorectal malignant neoplasm  Nonalcoholic fatty liver disease  Risk factor  Metabolic syndrome Abbreviations BP Blood pressure BMI Body mass index CRMN Colorectal malignant neoplasm J. You Department of Oncological Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China W.-Y. Liu  Y.-W. Luo School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China

X.-F. Lin Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, China

D. K.-H. Wong  M.-F. Yuen Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong

K.-Q. Shi  F.-L. Wu  Y.-P. Chen  M.-H. Zheng Institute of Hepatology, Wenzhou Medical University, Wenzhou, China

D. K.-H. Wong  M.-F. Yuen State Key Laboratory for Liver Research, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong

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CI Hb HDL LDL MS NCEP-ATP III NAFLD OR STROBE

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Confidence interval Hemoglobin High density lipoprotein Low density lipoprotein Metabolic syndrome National cholesterol education program adult treatment panel phase III Nonalcoholic fatty liver disease Odds ratio Strengthening the reporting of observational studies in epidemiology

Introduction As one of the most common cancers worldwide, colorectal cancer is a major cause of cancer death in Asian countries [1, 2]. It accounts for an estimated 1.2 million new cancer cases and more than sixty-three thousand cancer deaths per year [3]. During the past three decades, the incidence of colorectal malignant neoplasm (CRMN) had been increased rapidly in China [4–6]. It is believed that colonoscopy is the most accurate technique for early detection of CRMN and can contribute to decreased mortality [7]. Identifying risk factors for colorectal cancer and performing colonoscopy to high-risk populations are one of the most effective measures to lower CRMN incidence and mortality [8]. However, there are quite a number of people lacking the knowledge of colorectal cancer symptoms and risk factors [9]. Therefore, improved risk stratification knowledge of the target population is necessary to improve colorectal cancer patients’ prognosis. Inflammatory bowel disease (i.e. ulcerative colitis and Crohn’s disease) and genetic factors (i.e. hereditary nonpolyposis and Gardner syndrome) have been ascertained for leading to colorectal cancer. There are now some evidence that more than 75–95 % of colorectal cancer occurs in people with little or no genetic risk, and are linked with several dietary and lifestyle factors (i.e. physical inactivity, excess body weight, and a central deposition of adiposity) [10–12]. However, the explicit mechanisms and potential risk factors for colorectal cancer are still undefined [12]. Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide, affecting up to 46 % the community populations, and it is considered as a liver manifestation of metabolic syndrome (MS) [13–15]. In recent years, MS and its individual components were considered as the risk factors of colorectal neoplasm [16– 18]. However, all these studies failed to separate certain diseases (i.e. NAFLD, viral hepatitis and other liver diseases) which were frequently coexisted with MS and probably as the potential risk factors for CRMN. Mechanistically, insulin resistances were associated with

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hyperinsulinemia, increased levels of growth factors including IGF-1, and alterations in NF-kappaB and peroxisome proliferator-activated receptor signaling, which may promote CRMN through their effects on colonocyte kinetics [19]. In addition, adipokines and chronic inflammation, often associated with NAFLD, are also thought to promote the initiation and progression of cancers [20]. Recent studies have demonstrated that NAFLD was a risk factor of colorectal adenomas and advanced neoplasms [21–23]. However, there was a paucity of research concerning the direct relationship between NAFLD and CRMN and the direct confirmation of this association was required. Therefore, we aimed to investigate the prevalence of CRMN in patients with NAFLD and evaluate whether NAFLD is an independent risk factor of CRMN.

Methods Study population We performed a retrospective and consecutive cohort study from October 2007 to December 2011 in the First Affiliated Hospital of Wenzhou Medical University. The study population consisted entirely of community patients. Patients were classified into with and without NAFLD. A single blind design was used. All of the variables were collected when patients were advised to perform the colonoscopy. The patients who had following symptoms and signs, including abdominal pain, melena, hematochezia, change in bowel habit, diarrhea, constipation, iron deficiency anemia, weight loss (unintentional loss of more than 10 % of body weight) and abdominal mass, were regarded as the indications for colonoscopy and their data were collected. Besides, patients with positive fecal occult blood test, abnormal barium enema and intestinal obstruction were also offered to perform colonoscopy and enrolled in this study. Based on blood tests and abdomen ultrasonography, patients without NAFLD were regarded as control group and those with NAFLD constituted the NAFLD group. Patients were included only if they had colonoscopy and conventional inspections (blood routine, liver function test and abdomen ultrasonography). Patients with history of colorectal cancer, adenoma and polyp; history of other extraintestinal malignancies (prostate, lung, ovarin, breast cancer) and contraindications to colonoscopy were excluded. Besides, we excluded patients who had viral hepatitis (hepatitis B and hepatitis C), cirrhosis, liver cancer or other liver diseases. Males who drank more than 30 g alcohol per day and females who drank more than 20 g alcohol per day were also excluded. The research protocol was approved by the Ethics Committee of the First Affiliated Hospital of Wenzhou

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Medical University and informed consent was obtained from every patient. The study procedure was conformed to the Helsinki Declaration and Strengthening the reporting of observational studies in epidemiology (STROBE) statement [24]. All authors had access to the study data and had reviewed and approved the final manuscript.

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underwent colonoscopy examination. The liver function tests included alanine aminotransferase, aspartate aminotransferase, albumin, serum sodium, serum chloride and creatinine. Complete blood count was made up of platelet and hemoglobin (Hb). Blood lipids test contains, total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and triglycerides.

Patients’ baseline characteristics Ultrasound examination Three days prior to colonoscopy examination, patients’ baseline characteristics were collected. Smoking, alcohol consumption, past medical history, and family history were all recorded using a standardized questionnaire. The height and weight were measured by trained nurses with patients wearing a light gown and body mass index (BMI) was calculated for all patients. Blood pressure (BP) was measured in rest state with a standard mercury sphygmomanometer. Colonoscopy examination Colonoscopy was performed in all participants by three experienced endoscopists, who had at least 5 years’ experience in colonoscopy examination at the First Affiliated Hospital of Wenzhou Medical University. Prior to colonoscopy examination, all patients were given 4 L polyethylene glycol lavage solution for bowel preparation. Judged by intestinal residual contents and surface seen, the quality of bowel preparation, based on residues and percentages of surface seen, was graded as good, fair and poor. Complete examination was noted only if an endoscope reached the caecum; otherwise it was regarded as incomplete examination, which was excluded from analysis. The colonoscopy features include the types, location, size, number of lesions and differentiation of neoplasm. All the patients’ lesions were proven by biopsy and were classified into three types: enteritis, benign neoplasm and malignant neoplasm. Pathologic diagnosis was performed by two experienced pathologists, who were blinded to the clinical and laboratory data throughout the study. The location of neoplasm was divided into ascending colon, transverse colon, descending colon, sigmoid colon and rectum. The size of the neoplasm was classified into those less than 5, 5–9 and 10 mm or more. The number of neoplasm was classified into single and multiple lesions. The differentiation of neoplasm was graded as low-grade adenomatoid polyp, high-grade adenomatoid polyp, high-differentiated colorectal adenocarcinoma, middle-differentiated colorectal adenocarcinoma and low-differentiated colorectal adenocarcinoma [2]. Laboratory assay and measurement Complete blood count, liver function, blood glucose, blood lipids and other related tests were performed for patient who

Hepatic ultrasonography scanning (Siemens, Germany) was performed on all patients by three experienced sonographers who were blinded clinical details of the patients. The diagnosis of NAFLD was based on specific ultrasonographic features including hepatomegaly, diffusely increased echogenicity of liver parenchyma, and blurring of vasculature [25] and after exclusion of viral hepatitis, cirrhosis, liver cancer or other liver disease and excess alcohol consumption. Definitions Colorectal neoplasm includes benign neoplasm (inflammatory polyp, low-grade and high-grade adenomatoid polyp) and malignant neoplasm (high-differentiated, middle-differentiated and low-differentiated colorectal adenocarcinoma). MS was defined based on modified National Cholesterol Education Program Adult Treatment Panel Phase III (NCEP-ATP III) criteria [26, 27]. Patients who met the following criteria (C3 criteria) were diagnosed to have MS: hypertriglyceridemia (1.7 mmol/L), low HDL-C (\1.03 mmol/L for men and \1.29 mmol/L for women), impaired FPG (C5.6 mmol/L), elevated blood pressure (C130/85 mmHg), or hyperuricemia ([420 lmol/L for men and [360 lmol/L for women). Statistical analysis Statistical analysis was performed using SPSS 13.0 software (SPSS Inc, Chicago, IL, United States). The statistical results were presented as the mean ± standard deviation or percentages. Continuous variables were compared using Wilcoxon signed rank test or Mann–Whitney U test as appropriate. Categorical variables were compared using proportions v2 test or the Fisher’s exact test as appropriate. The binary logistic regression analysis was applied to determine the correlation between NAFLD and CRMN after adjustment for independent factors, including BMI, history of hypertension, triglycerides, uric acid, alamine aminotransferase, haemoglobin, platelet, albumin. In addition, odds ratio (OR) and corresponding 95 % confidence interval (CI) were calculated. P \ 0.05 was considered statistically significant.

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Fig. 1 Study participant flow

Results Baseline characteristic A total of 2,858 patients were enrolled. According to exclusion criteria, 321 males and 222 females were eliminated. 2,315 patients (1,370 males and 945 females) were included in the analysis (Fig. 1). NAFLD was diagnosed in 151 of 1,370 (11.0 %) males and 112 of 945 (11.9 %) females. Baseline characteristics of the study patients with and without NAFLD were summarized in Table 1. Compared to the patients without NAFLD, the NAFLD group had significantly higher BMI in both male and female (P = 0.001 and 0.001 for male and female patients, respectively), systolic blood pressure (P = 0.002 and 0.006, respectively), total cholesterol (P = 0.001 and 0.004, respectively), LDL cholesterol (P = 0.005 and 0.015, respectively), triglycerides (P = 0.001 and 0.001, respectively), uric acid (P = 0.001 and 0.001, respectively), fasting glucose (P = 0.029 and 0.046, respectively), albumin (P = 0.001 and 0.001, respectively) and total protein (P = 0.001 and 0.004, respectively). The NAFLD patients also had lower HDL cholesterol (P = 0.041 and 0.016 for male and female patients, respectively). Prevalence of NAFLD and MS in patients with neoplasm The presence of NAFLD, MS and individual components of MS, benign neoplasm and malignant neoplasm patients were shown in Table 2. The percent of NAFLD in male was found to be higher in malignant neoplasm patients than in benign neoplasm patients (19.2 vs. 8.2 %, respectively;

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P = 0.001). However, this relationship did not exist in female (14.1 vs. 10.9 %, respectively; P = 0.278). We also found that the scale of overweight, hypertension and high plasma triglycerides were also increased both in male and female malignant neoplasm patients. Prevalence of colorectal lesions in patients with and without NAFLD As shown in Table 3 and supplementary Table 1, the prevalence of colorectal lesions was 90.9 % in the NAFLD group and 93.3 % in the control group. NAFLD group had higher prevalence of malignant neoplasm than control group (29.3 vs. 18.0 %, respectively; P = 0.001). Furthermore, 35.1 and 21.4 % of the male and female NAFLD patients, respectively, were complicated with malignant neoplasm, while the occurrence of complications in the control group was lower. In addition, neoplasm and malignant neoplasm in NAFLD group were more frequently found at transverse colon, descending colon, and sigmoid colon. Compared with control group, NAFLD group had higher multiple neoplasm (10.2 vs. 7.6 %); nevertheless, single malignant neoplasm was more frequently observed in NAFLD patients (51.9 vs. 48.2 %). Moreover, the incidence of highly-differentiated colorectal adenocarcinoma in NAFLD group was significant higher than control group (62.3 vs. 9.8 %). Assessment of the relationship between NAFLD and malignant neoplasm Univariate and multivariate analyses of the risk factors of colorectal neoplasm and malignant neoplasm were shown

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Table 1 Clinical and biochemical characteristics of the study cohort grouped as subjects with and without NAFLD Male (n = 1,370) NAFLD group (n = 151)

Female (n = 945) Control group (n = 1,219)

P value

NAFLD group (n = 112)

Control group (n = 833)

P value

Age (years)

63.1 ± 12.8

65.4 ± 13.8

0.056

64.8 ± 11.5

63.4 ± 14.3

0.304

BMI (kg/m2)

24.3 ± 2.9

21.8 ± 3.1

0.001

23.9 ± 3.6

21.2 ± 3.3

0.001

SBP (mmHg) DBP (mmHg)

133.7 ± 19.8 80.9 ± 11.4

128.3 ± 20.1 77.2 ± 11.7

0.002 0.001

133.7 ± 19.8 77.7 ± 12.4

128.1 ± 20.3 76.6 ± 11.1

0.006 0.344

4.9 ± 1.4

4.3 ± 1.2

0.001

5.0 ± 1.1

4.6 ± 1.2

0.004

Total cholesterol (mmol/L) LDL cholesterol (mmol/L)

2.9 ± 1.7

2.6 ± 1.1

0.005

2.9 ± 1.1

2.7 ± 1.0

0.015

HDL cholesterol (mmol/L)

1.0 ± 0.27

1.1 ± 0.38

0.041

1.1 ± 0.3

1.2 ± 0.4

0.016

Triglycerides (mmol/L) Uric acid (mmol/L)

2.6 ± 3.2

1.5 ± 1.1

0.001

2.0 ± 1.3

1.4 ± 0.9

0.001

347.8 ± 100.5

311.3 ± 101.8

0.001

287.0 ± 79.1

250.8 ± 83.8

0.001

AST (U/L)

29.4 ± 22.6

32.1 ± 50.7

0.507

31.6 ± 53.0

40.5 ± 374.3

0.802

ALT (U/L)

38.0 ± 46.3

29.4 ± 52.7

0.037

36.8 ± 67.0

28.0 ± 144.2

0.522 0.046

6.1 ± 2.40

0.029

6.5 ± 1.9

6.1 ± 2.3

Haemoglobin (g/L)

Fasting glucose (mmol/L)

129.1 ± 34.2

6.5 ± 2.9

114.2 ± 37.0

0.001

116.8 ± 29.8

104.6 ± 31.8

0.001

Platelet (g/L)

225.6 ± 85.6

225.5 ± 89.2

0.986

258.3 ± 75.2

244.4 ± 97.1

0.146

Albumin (g/L)

151 ± 41.6

39.4 ± 6.0

0.001

42.3 ± 5.3

39.5 ± 5.9

0.001

Alkaline phosphatase (U/L)

80.4 ± 43.1

92.5 ± 111.0

0.011

85.1 ± 63.1

87.7 ± 92.1

0.770

Gamma glutamyltransferase (U/L)

71.0 ± 146.4

67.9 ± 167.9

0.828

69.6 ± 284.3

49.7 ± 150.1

0.248

Erythrocyte count (91012/L) Creatinine (lmol/L)

4.4 ± 0.58 79.9 ± 58.4

4.0 ± 0.65 79.4 ± 67.4

0.001 0.924

4.2 ± 2.0 53.2 ± 13.2

3.8 ± 0.54 56.0 ± 26.0

0.001 0.257

NAFLD nonalcoholic fatty liver disease, BMI body mass index, SBP systolic blood pressure, DBP diastolic blood pressure, LDL low density lipoprotein, HDL high density lipoprotein, AST aspartate aminotransferase, ALT alanine aminotransferase

in Table 4. The prevalence rates for malignant neoplasm were 29.3 % in NAFLD group and 18.0 % in the control group (Fig. 2). Univariate analysis showed that patients with NAFLD had higher prevalence of CRMN than patients without NAFLD (OR 2.043; 95 % CI 1.512–2.761; P = 0.001). After adjusting for metabolic and other confounding factors, NAFLD still remained as an independent risk factor for CRMN (OR 1.868; 95 % CI 1.360–2.567; P = 0.001). Moreover, we found that through multivariate analysis the relationships between neoplasm and smoking history (OR 1.510; 95 % CI 1.132–2.014; P = 0.005), age (OR 1.038; 95 % CI 1.029–1.046; P = 0.001), HDL cholesterol (OR 1.754; 95 % CI 1.222–2.518; P = 0.002), albumin (OR 1.068; 95 % CI 1.045–1.093; P = 0.001) and gamma glutamyltransferase (OR 0.999; 95 % CI 0.998–0.999; P = 0.001) were statistically significant.

Discussion This study is a large cohort study to investigate the relationship between ultrasound-diagnosed NAFLD and CRMN in the community patients. In this study, NAFLD was proved to be an independent risk factor for CRMN (OR 1.868; 95 % CI 1.360–2.567; P = 0.001).

It had been well established that colorectal neoplasm and malignant neoplasm are most commonly developed at sigmoid colon and rectum [28, 29]. In the current study, the percentage of neoplasm and malignant neoplasm in NAFLD group occurred at above locations were quite high (58.4 and 42.9 %, respectively). Because of perceived health, psychological, perceived access barriers and other reasons, the population who should have been undergone full colonoscopy was performed less frequently [9, 30, 31]. Compared with full colonoscopy, sigmoidoscopy had more solid evidence of decreasing both colorectal cancer incidence and mortality and was much easier to be carried out [7, 31]. Therefore, we recommended that if full colonoscopy cannot be used to screen NAFLD patients, sigmoidoscopy can be applied as alternative to screen out approximately half of NAFLD patients with neoplasm or malignant neoplasm. In addition, another new discovery was that CRMN happened in NAFLD patients was mostly of highly-differentiated colorectal adenocarcinoma, which indicated that full colonoscopy or sigmoidoscopy to NAFLD patients has important meaning for improving outcomes of these patients. Recently, Hwang et al. [23] first proposed the evidence for an association of NAFLD with an increased rate of colorectal adenomatous polyps. The prevalence of colorectal

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358 (15.5 %)

891 (38.5 %)

1. Elevated fasting glucose

2. Overweight and (or) obesity

3. Low plasma HDL

126 (10.8 %)

698 (59.7 %) 331 (28.3 %)

377 (32.2 %)

194 (16.6 %)

612 (52.3 %)

321 (27.4 %)

25 (12.5 %)

104 (52.0 %) 49 (24.5 %)

92 (46.0 %)

29 (14.5 %)

99 (49.5 %)

59 (29.5 %)

73 (8.2 %)

517 (57.8 %) 233 (26.1 %)

283 (31.7 %)

138 (15.4 %)

465 (52.0 %)

230 (25.7 %)

181 (65.6 %) 98 (35.6 %)

94 (34.1 %)

56 (20.3 %)

147 (53.3 %)

91 (33.0 %)

53 (19.2 %)

Malignant neoplasm (n = 276)

463 (59.7 %) 224 (28.9 %)

326 (42.0 %)

122 (15.7 %)

464 (59.8 %)

277 (35.7 %)

90 (11.6 %)

With neoplasm (n = 776)

Benign neoplasm (n = 894)

With neoplasm (n = 1,170) Without neoplasm (n = 200)

Female (n = 945)

Male (n = 1,370)

83 (49.1 %) 45 (26.6 %)

96 (56.8 %)

13 (7.7 %)

80 (47.3 %)

48 (28.4 %)

22 (13.0 %)

Without neoplasm (n = 169)

353 (58.3 %) 170 (28.1 %)

257 (42.4 %)

94 (15.5 %)

323 (53.3 %)

199 (32.8 %)

66 (10.9 %)

Benign neoplasm (n = 606)

110 (64.7 %) 54 (31.8 %)

69 (40.6 %)

28 (16.5 %)

141 (82.9 %)

78 (45.9 %)

24 (14.1 %)

Malignant n neoplasm (n = 170)

117 (44.5 %) 77 (29.3 %)

Adenomatoid polyp Malignant neoplasm

NAFLD nonalcoholic fatty liver disease

22 (8.4 %)

139 (52.9 %)

Benign neoplasm

Inflammatory polyp

23 (8.7 %) 216 (82.1 %)

Neoplasm

1,143 (55.7 %) 369 (18.0 %)

218 (10.6 %)

1,361 (66.3 %)

1,730 (84.3 %)

184 (9.0 %)

1,914 (93.3 %)

(n = 2,052)

(n = 263) 239 (90.9 %)

Control group

NAFLD group

Enteritis

Types of colorectal lesions

Number of patients with colorectal lesions

Colorectal lesions n, %

Table 3 Prevalence and types of colorectal lesions in with and without NAFLD patients

56 (37.1 %) 53 (35.1 %)

17 (11.3 %)

73 (48.3 %)

126 (83.4 %)

12 (7.9 %)

138 (91.4 %)

Male (n = 151)

NAFLD group

61 (54.5 %) 24 (21.4 %)

5 (4.5 %)

66 (58.9 %)

90 (80.4 %)

11 (9.8 %)

101 (90.2 %)

Female (n = 112)

699 (57.3 %) 223 (18.3 %)

122 (10.0 %)

821 (67.4 %)

1,044 (85.6 %)

99 (8.1 %)

1,143 (93.8 %)

Male (n = 1,219)

Control group

444 (50.3 %) 146 (16.5 %)

96 (10.9 %)

540 (61.2 %)

686 (77.7 %)

85 (9.6 %)

771 (87.3 %)

Female (n = 883)

1. Elevated fasting glucose: blood sugar C5.6 mmol/L; 2. Overweight and (or) obesity: BMI C25.0 kg/m2; low plasma HDL: plasma HDL in males\0.9 mmol/L and in females\1.1 mmol/L; 3. Hypertension: SBP C130 mmHg and (or) DBP C85 mmHg; 4. High plasma triglycerides: plasma triglycerides [1.7 mmol/L; MS, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease; SBP, systolic blood pressure; DBP, diastolic blood pressure

1,348 (58.2 %) 649 (28.0 %)

1,255 (54.2 %)

MS (C3/5 criteria)

4. Hypertension 5. High plasma triglycerides

263 (11.4 %)

705 (30.5 %)

NAFLD

All patients (n = 2,315)

Table 2 Components of NAFLD and MS in all patients with and without neoplasm and benign or malignant neoplasm

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1.274 (1.018–1.594) 1.027 (1.019–1.035)

Gender

Age (years)

1.004 (0.957–1.053)

Fasting glucose (mmol/L)

1.000 (0.998–1.002) 1.056 (0.825–1.351) 1.161 (0.797–1.691) 1.280 (0.980–1.670) 1.209 (0.917–1.595)

Gamma glutamyltransferase (U/L)

Creatinine (lmol/L)

History of hypertension History of diabetes

Smoking history

Drinking history

0.179

0.070

0.668 0.438

0.809

0.001

0.001

0.001

0.233

0.465

0.873

0.001

0.005

0.001

0.241

0.001

0.518

0.100

0.002 0.013

0.001

0.001

0.034

0.364

1.510 (1.132–2.014)

0.999 (0.998–0.999)

1.068 (1.045–1.093)

1.754 (1.222–2.518)

1.038 (1.029–1.046)

0.005

0.001

0.001

0.002

0.001

1.043 (0.812–1.338)

1.045 (0.824–1.326)

1.321 (1.053–1.656) 1.246 (0.900–1.726)

1.002 (1.000–1.003)

1.000 (1.000–1.001)

1.000 (0.999–1.001)

1.022 (1.003–1.042)

0.997 (0.996–0.998)

1.006 (1.003–1.009)

0.982 (0.937–1.030)

1.002 (1.000–1.004)

1.001 (0.999–1.003)

1.002 (1.001–1.003)

1.184 (1.088–1.288)

1.083 (0.820–1.432)

0.970 (0.878–1.072)

1.029 (0.940–1.126)

1.003 (0.998–1.009) 1.012 (1.003–1.022)

1.043 (1.010–1.077)

0.996 (0.988–1.004)

1.101 (0.886–1.367)

2.043 (1.512–2.761)

0.743

0.717

0.016 0.186

0.081

0.230

0.879

0.022

0.001

0.001

0.455

0.027

0.199

0.001

0.001

0.573

0.547

0.538

0.212 0.010

0.009

0.366

0.387

0.001

P value

0.997 (0.996–0.999)

1.001 (1.000–1.002)

1.132 (1.037–1.235)

1.868 (1.360–2.567)

OR (95 % CI)

Multivariate analysis

0.001

0.031

0.006

0.001

P value

NAFLD nonalcoholic fatty liver disease, SBP systolic blood pressure, DBP diastolic blood pressure, LDL low density lipoprotein, HDL high density lipoprotein, AST aspartate aminotransferase, ALT alanine aminotransferase, BMI body mass index, OR odds ratio, CI confidence interval

0.998 (0.997–0.999) 0.999 (0.998–0.999)

Alkaline phosphatase (U/L)

1.062 (1.042–1.081)

0.997 (0.995–0.999)

ALT (U/L)

Albumin (g/L)

0.997 (0.995–0.999)

AST (U/L)

1.001 (0.998–1.004)

1.002 (1.001–1.003)

Uric acid (mmol/L)

1.001 (1.000–1.002)

1.063 (0.960–1.178)

Triglycerides (mmol/L)

Platelet (g/L)

2.334 (1.690–3.224)

HDL cholesterol (mmol/L)

Haemoglobin (g/L)

1.081 (0.985–1.187) 1.034 (0.933–1.146)

LDL cholesterol (mmol/L)

1.009 (1.003–1.015) 1.013 (1.003–1.023)

Total cholesterol (mmol/L)

1.066 (1.029–1.105)

BMI (kg/m )

SBP (mmHg) DBP (mmHg)

2

0.855 (0.611–1.198)

NAFLD

OR (95 % CI)

OR (95 % CI)

OR (95 % CI)

P value

Univariate analysis

Multivariate analysis

Univariate analysis P value

Malignant neoplasm (n = 446)

Neoplasm (n = 1,946)

Table 4 Univariate and multivariate analysis of the risk for colorectal neoplasm and malignant neoplasm

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Fig. 2 Prevalence of colorectal malignant neoplasm by gender in non-alcoholic fatty liver disease and control group

adenomatous polyps in NAFLD and control group was 41.5 and 30.2 %, respectively. Wong et al. [21] presented further evidence that colorectal adenomas and advanced colorectal neoplasm were more prevalent in NAFLD subjects and recommended these patients should be underwent colonoscopy. However, it was worth noting that all these studies had not offered enough and direct evidences to demonstrate that NAFLD was an independent risk factor of CRMN. Moreover, they failed to describe the degrees of pathological differentiation of CRMN in detail. Our study provided plenteous data and confirmed the correlation between NAFLD and CRMN. The mechanistic links between NAFLD and CRMN is still unclear. It was likely that NAFLD was the hepatic manifestation of MS and insulin resistance played a key factor in disease pathogenesis [32, 33]. A large amount of research indicated that insulin resistance and its associated conditions, including increased insulin and insulin-like growth factor can promote the occurrence and the development of CRMN [12, 18, 19, 34]. NAFLD patients also had adipocytokines metabolism disorders. Adiponectin and leptin serum levels were significantly decreased and increased respectively in NAFLD patients [35, 36]. Adiponectin and leptin secreted by adipocytes were believed to be the critical mediators in the above mechanistic links [37]. Accumulating data from experimental and observational studies suggested that lowlevel adiponectin and high-level leptin may be an important factor in the increased incidence of CRMN [38–40]. In addition, inflammatory may also play a role in CRMN and can exert cancer-promoting effects, with deregulated inflammation pathways and cell proliferation, apoptosis, angiogenesis, and metastasis [41–43]. Increased adipose tissue can contribute to augmented secretion of proinflammatory adipokines, especially tumor necrosis factor-alpha [44]. Many guidelines for colorectal cancer screening had regarded cigarette smoking, obesity and drinking as factors

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for an increased risk of colorectal cancer and these populations were recommended to undergo colonoscopy at an earlier age [2, 8, 45]. In this study, we found an increased prevalence of CRMN in patients with NAFLD. This finding suggested that physicians should give a proper attention to perform colorectal cancer screening in patients with NAFLD. There are a few limitations of this study. First, this is a cross-sectional study which made it difficult to conclude the causal relationship between NAFLD and CRMN. The follow-up for patients with malignant neoplasm is more important and meaningful. Second, our study population only came from a single center and a multi-centered research is needed to further corroborate the association in the next step. Third, fatty liver was diagnosed based on ultrasound. However, liver biopsy, as the gold-standard for NAFLD and can distinguish non-alcoholic steatohepatitis from simple steatosis, is invasive and is performed less infrequently. In summary, NAFLD was associated with an increased risk of CRMN. Further studies are needed to elucidate the exact mechanisms how NAFLD contributes to CRMN. Acknowledgments This work was supported by Grants from Scientific Research Foundation of Wenzhou, Zhejiang Province, China (H20090014, Y20090269), Health Bureau of Zhejiang Province (2010KYB070), Research Foundation of Education Bureau of Zhejiang Province (Y201009942), Fresh Talent Program for Science and Technology Department of Zhejiang Province (2013R413018, 2013R413035 and 2013R413015), Research Funds for Tian Qing Liver Diseases (TQGB20120057) and Project of New Century 551 Talent Nurturing in Wenzhou. Conflict of interest All authors declare that they do not have anything to disclose regarding funding from industries with respect to this manuscript.

References 1. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300 2. Sung JJ, Lau JY, Young GP, Sano Y, Chiu HM, Byeon JS, Yeoh KG, Goh KL, Sollano J, Rerknimitr R et al (2008) Asia Pacific consensus recommendations for colorectal cancer screening. Gut 57:1166–1176 3. Kamangar F, Dores GM, Anderson WF (2006) Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 24:2137–2150 4. Ji BT, Devesa SS, Chow WH, Jin F, Gao YT (1998) Colorectal cancer incidence trends by subsite in urban Shanghai, 1972–1994. Cancer Epidemiol Biomarkers Prev 7:661–666 5. Lu JB, Sun XB, Dai DX, Zhu SK, Chang QL, Liu SZ, Duan WJ (2003) Epidemiology of gastroenterologic cancer in Henan Province, China. World J Gastroenterol 9:2400–2403 6. Yang L, Parkin DM, Li LD, Chen YD, Bray F (2004) Estimation and projection of the national profile of cancer mortality in China: 1991–2005. Br J Cancer 90:2157–2166 7. Schoen RE, Pinsky PF, Weissfeld JL, Yokochi LA, Church T, Laiyemo AO, Bresalier R, Andriole GL, Buys SS, Crawford ED

Mol Biol Rep (2014) 41:2989–2997

8.

9.

10. 11. 12. 13.

14.

15.

16.

17.

18. 19.

20.

21.

22.

23.

24.

25. 26.

et al (2012) Colorectal-cancer incidence and mortality with screening flexible sigmoidoscopy. N Engl J Med 366:2345–2357 Dominic OG, McGarrity T, Dignan M, Lengerich EJ (2009) American college of gastroenterology guidelines for colorectal cancer screening 2008. Am J Gastroenterol 104:2626–2627 Sung JJ, Choi SY, Chan FK, Ching JY, Lau JT, Griffiths S (2008) Obstacles to colorectal cancer screening in Chinese: a study based on the health belief model. Am J Gastroenterol 103:974–981 Watson AJ, Collins PD (2011) Colon cancer: a civilization disorder. Dig Dis 29:222–228 Fujita T (2010) Colorectal cancer. Lancet 376:331 Giovannucci E (2002) Modifiable risk factors for colon cancer. Gastroenterol Clin North Am 31:925–943 Marchesini G, Forlani G (2002) NASH: from liver diseases to metabolic disorders and back to clinical hepatology. Hepatology 35:497–499 Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G, Melchionda N (2001) Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 50:1844–1850 Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA (2011) Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140:124–131 Ahmed RL, Schmitz KH, Anderson KE, Rosamond WD, Folsom AR (2006) The metabolic syndrome and risk of incident colorectal cancer. Cancer 107:28–36 Murphy TK, Calle EE, Rodriguez C, Kahn HS, Thun MJ (2000) Body mass index and colon cancer mortality in a large prospective study. Am J Epidemiol 152:847–854 Giovannucci E (2007) Metabolic syndrome, hyperinsulinemia, and colon cancer: a review. Am J Clin Nutr 86:s836–s842 Komninou D, Ayonote A, Richie JP Jr, Rigas B (2003) Insulin resistance and its contribution to colon carcinogenesis. Exp Biol Med (Maywood) 228:396–405 Siegel AB, Zhu AX (2009) Metabolic syndrome and hepatocellular carcinoma: two growing epidemics with a potential link. Cancer 115:5651–5661 Wong VW, Wong GL, Tsang SW, Fan T, Chu WC, Woo J, Chan AW, Choi PC, Chim AM, Lau JY et al (2011) High prevalence of colorectal neoplasm in patients with non-alcoholic steatohepatitis. Gut 60:829–836 Stadlmayr A, Aigner E, Steger B, Scharinger L, Lederer D, Mayr A, Strasser M, Brunner E, Heuberger A, Hohla F et al (2011) Nonalcoholic fatty liver disease: an independent risk factor for colorectal neoplasia. J Intern Med 270:41–49 Hwang ST, Cho YK, Park JH, Kim HJ, Park DI, Sohn CI, Jeon WK, Kim BI, Won KH, Jin W (2010) Relationship of nonalcoholic fatty liver disease to colorectal adenomatous polyps. J Gastroenterol Hepatol 25:562–567 Vandenbroucke JP, Von Elm E, Altman DG, Gotzsche PC, Mulrow CD, Pocock SJ, Poole C, Schlesselman JJ, Egger M (2009) Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration. Gac Sanit 23:158 Obika M, Noguchi H (2012) Diagnosis and evaluation of nonalcoholic fatty liver disease. Exp Diabetes Res 2012:145754 Zimmet P, Magliano D, Matsuzawa Y, Alberti G, Shaw J (2005) The metabolic syndrome: a global public health problem and a new definition. J Atheroscler Thromb 12:295–300

2997 27. Fan JG, Saibara T, Chitturi S, Kim BI, Sung JJ, Chutaputti A (2007) What are the risk factors and settings for non-alcoholic fatty liver disease in Asia-Pacific? J Gastroenterol Hepatol 22: 794–800 28. Wu X, Cokkinides V, Chen VW, Nadel M, Ren Y, Martin J, Ellison GL (2006) Associations of subsite-specific colorectal cancer incidence rates and stage of disease at diagnosis with county-level poverty, by race and sex. Cancer 107:1121–1127 29. Larsen IK, Bray F (2010) Trends in colorectal cancer incidence in Norway 1962–2006: an interpretation of the temporal patterns by anatomic subsite. Int J Cancer 126:721–732 30. Gluecker TM, Johnson CD, Harmsen WS, Offord KP, Harris AM, Wilson LA, Ahlquist DA (2003) Colorectal cancer screening with CT colonography, colonoscopy, and double-contrast barium enema examination: prospective assessment of patient perceptions and preferences. Radiology 227:378–384 31. Ioannou GN, Chapko MK, Dominitz JA (2003) Predictors of colorectal cancer screening participation in the United States. Am J Gastroenterol 98:2082–2091 32. Marignani M, Angeletti S (2002) Nonalcoholic fatty liver disease. N Engl J Med 347:768–769 33. Williams R (2006) Global challenges in liver disease. Hepatology 44:521–526 34. Giovannucci E (2001) Insulin, insulin-like growth factors and colon cancer: a review of the evidence. J Nutr 131:3109S–3120S 35. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J (2004) Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 40:46–54 36. Procaccini C, Galgani M, De Rosa V, Carbone F, La Rocca C, Ranucci G, Iorio R, Matarese G (2010) Leptin: the prototypic adipocytokine and its role in NAFLD. Curr Pharm Des 16: 1902–1912 37. Tilg H, Diehl AM (2011) NAFLD and extrahepatic cancers: have a look at the colon. Gut 60:745–746 38. An W, Bai Y, Deng SX, Gao J, Ben QW, Cai QC, Zhang HG, Li ZS (2012) Adiponectin levels in patients with colorectal cancer and adenoma: a meta-analysis. Eur J Cancer Prev 21:126–133 39. Saxena A, Chumanevich A, Fletcher E, Larsen B, Lattwein K, Kaur K, Fayad R (2012) Adiponectin deficiency: role in chronic inflammation induced colon cancer. Biochim Biophys Acta 1822:527–536 40. Ogunwobi OO, Beales IL (2007) The anti-apoptotic and growth stimulatory actions of leptin in human colon cancer cells involves activation of JNK mitogen activated protein kinase, JAK2 and PI3 kinase/Akt. Int J Colorectal Dis 22:401–409 41. Cowey S, Hardy RW (2006) The metabolic syndrome: a high-risk state for cancer? Am J Pathol 169:1505–1522 42. Aggarwal BB, Gehlot P (2009) Inflammation and cancer: how friendly is the relationship for cancer patients? Curr Opin Pharmacol 9:351–369 43. Ono M (2008) Molecular links between tumor angiogenesis and inflammation: inflammatory stimuli of macrophages and cancer cells as targets for therapeutic strategy. Cancer Sci 99:1501–1506 44. Sonnenberg GE, Krakower GR, Kissebah AH (2004) A novel pathway to the manifestations of metabolic syndrome. Obes Res 12:180–186 45. Anderson JC, Alpern Z, Sethi G, Messina CR, Martin C, Hubbard PM, Grimson R, Ells PF, Shaw RD (2005) Prevalence and risk of colorectal neoplasia in consumers of alcohol in a screening population. Am J Gastroenterol 100:2049–2055

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Increased risk of colorectal malignant neoplasm in patients with nonalcoholic fatty liver disease: a large study.

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