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Opposite Association Between Diabetes,Dyslipidemia, and Hepatocellular Carcinoma Mortality in the Middle-Aged and Elderly

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Diabetes and dyslipidemia are oppositely associated with liver cancer mortality in middle-aged and elderly adults

Chien-Hsieh Chiang, MD, MPH1,2; Shou-Hung Hung, MD1,2; Wen-Yuan Lin, MD, PhD1,3,4,5; Long-Teng Lee, MD, PhD1; Pei-Kun Sung, MD6; Kuo-Chin Huang, MD, PhD1,5

1 Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan

2 Department of Community and Family Medicine, National Taiwan University Hospital Yun-Lin Branch, Yunlin, Taiwan

3 Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan 4 School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan 5 Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan 6 MJ Health Screening Center, Taipei, Taiwan

Correspondence: Prof. Kuo-Chin Huang, MD, PhD, Head, Department of Family Medicine, National Taiwan University Hospital, 7, Chung Shan South Road, Taipei 100, Taiwan. Tel.: +886-2-23123456 Ext. 66081; fax: +886-2-23118674; e-mail: bretthuang@ntu.edu.tw.

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Abstract

Importance The association between diabetes and liver cancer has appealed growing concern. However, questions remain regarding the metabolic risk factors for liver cancer mortality in aging individuals without chronic viral hepatitis.

Objective This study aimed to investigate the association between diabetes, dyslipidemia and liver cancer mortality in middle-aged and elderly adults without hepatitis B or C virus infection.

Design, Setting and Participants A Taiwan nationwide screening units-based prospective cohort of 50,080 participants, aged 40 years or more, without preexisting hepatitis B or C virus infection, cirrhosis, or cancer of any types entered into our analysis. We used multivariate Cox regression analyses to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) of diabetes and dyslipidemia for deaths of liver cancer during a 10-year follow-up period.

Main Outcome Measure Liver cancer mortality from 1998-1999 through December 31, 2008. Results There were 235 deaths due to liver cancer during the follow-up period. Diabetes (HR, 3.25; 95% CI, 2.26-4.67; P <0.0001) was positively associated with liver cancer mortality. However, hypertriglyceridemia (HR, 0.39; 95% CI, 0.27-0.56; P <0.0001) and hypercholesterolemia (HR, 0.49; 95% CI, 0.36-0.65; P <0.0001) were inversely associated with liver cancer mortality. Metabolic syndrome defined by the American Heart Association/National Heart Lung Blood Institute criteria (HR, 0.64; 95% CI, 0.47-0.86; P <0.005) or by the International Diabetes Federation criteria (HR, 0.60; 95% CI, 0.42-0.87; P <0.01) were inversely associated with liver cancer mortality, especially in men. Furthermore, participants with diabetes, no

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95% CI, 10.4-44.0; P <0.0001) compared with those without diabetes, but with hypertriglyceridemia and hypercholesterolemia.

Conclusions and Relevance Liver cancer mortality was positively associated with preexisting diabetes, but was inversely associated with dyslipidemia in a middle-aged and elderly cohort without hepatitis B or C virus infection during a 10-year follow-up period. The mMiddle-aged and elderly diabetics, although without chronic hepatitis B or C, may be considered a high-risk group deserving liver cancer surveillance. More research should focus on the underlying metabolic mechanism of metabolic factors like diabetes and dyslipidemia for liver cancer mortality.

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Introduction

Liver cancer is one of the most prevalent cancer types with high incidence and mortality globally, especially in Asia-Pacific regions. It is ranked second as the second leading cancer cause of cancer death of 2011 in Taiwan (www.doh.gov.tw) in 2011. Chronic viral hepatitis, alcoholic liver disease, and nonalcoholic fatty liver disease have been considered as major risk factors for liver cancer, mainly hepatocellular carcinoma (HCC) in Taiwan.1-6 In recent years, the association between diabetes mellitus (DM) and HCC has appealed much concern.7-13 A systematic review and meta-analysis of 17 case-control studies and 32 cohort studies showed that DM was associated with moderately increased risk of HCC prevalence, as well as HCC mortality.14

However, there were only a few reports investigating the relationship between dyslipidemia and liver cancer;8 very few studies trying to exclude the interference from chronic viral hepatitis;8,9 and much less evidence primarily targeting the population bearing highest greater risk of cancer death, such as middle-aged and elderly adults. Therefore in this study, we aimed to investigate the association between diabetes, dyslipidemia and liver cancer mortality in middle-aged and elderly adults without hepatitis B or C virus (HBCV) infection.

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Designs and Methods

Participants

A total of 63,712 participants, aged 40 years or more were recruited from a nationwide heath screening center between 1998 and 1999 in Taiwan.15,16 Excluded were 12,033 participants (18.9%) with HBCV infection, 1,375 participants (2.2%) who had preexisting cancer of any types and 233 participants (0.4%) with cirrhosis at entry. Finally 50,080 participants entered into our analysis. The history of diabetes, hypertension, dyslipidemia, cigarette smoking and alcohol consumption was collected by patient self-reported questionnaire. For example, pSubjectsatients who reported

physician-diagnosed diabetes and took anti-diabetes diabetic medications were classified as “history of diabetes”. Similarly, those who reported physician-diagnosed hypertension and took

anti-hypertension medications were classified as “history of anti-hypertension”. The age and gender structure in this cohort was similar to the national data of adults (Taiwan Public Health Report 2000 at goo.gl/vSugl). The vital status of the cohort members was determined from 1998-1999 through December 31, 2008. Deaths were ascertained by computer linkage to the national death registry (death certificates created by the Department of Health, Taiwan) using ID numbers. This death certificates had been validated. The overall agreement rates between the reviewers and coders were above 80% with good agreement for malignant neoplasms (kappa = 0.94).17 All deaths that occurred between study entry and December 2008 were included. Deaths with the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes 155 were classified as liver cancer-related deaths. All participants provided informed consent. The study complies with the

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Declaration of Helsinki that ethic committee approval for patient recruitment and data analyses was obtained from the MJ Research Foundation Review Committee in Taiwan.

Anthropometric indices and laboratory measurements

Body heights and weights were measured using an auto-anthropometer (KN-5000A, Nakamura, Tokyo, Japan), and body mass index (BMI) was calculated. The participants were classified as extreme obesity if their BMI is ≥30 kg/m2 according to the potential public health action points for Asian populations recommended by World Health Organization.18 Waist

circumference (WC) was taken at the end of exhalation in the horizontal plane at the midway point between the inferior margin of the lowest rib and the iliac crest. Central obesity was defined as a waist circumference ≥90 cm for men or ≥80 cm for women according to the criteria for metabolic syndrome used in Taiwan (www.bhp.doh.gov.tw). Blood pressure (BP) was measured in the right arm with a standard mercury sphygmomanometer with the patient seated after resting for at least ten minutes. Each participant underwent laboratory testing after fasting for at least 12 hours. Serum hepatitis B surface antigen (HBsAg) and serum antibody to hepatitis C virus (anti-HCV) were tested by an auto-immunoassay (Abbot Laboratories, North Chicago, IL, USA). Serum Plasma glucose, lipid, alanine aminotransferase (ALT), and creatinine levelswas were measured using a Hitachi 7150 Automated analyzer (Hitachi, Tokyo, Japan). Estimated glomerular filtration rate (eGFR) was calculated using the four-variable version of the Modification of Diet in Renal Disease Study equation for Chinese Patients.19 Briefly, eGFR (ml/min per 1.73 m2) = 175 × (serum creatinine –1.234) × (age –0.179) × 0.79 (if female). A high fasting plasma glucose was defined as fasting glucose levels

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≥100 mg/dL (5.56 mmol/L) or having current drugs for hyperglycemia. The hypertriglyceridemia was defined as serum plasma triglycerides levels ≥150 mg/dL (1.70 mmol/L); and the

hypercholesterolemia was defined as serum plasma total cholesterol levels ≥200 mg/dL (5.18 mmol/L). The low high-density lipoprotein cholesterol (HDL-C) was defined as serum plasma HDL-C levels <40 mg/dL (1.04 mmol/L) in men and <50 mg/dL (1.29 mmol/L) in women.

Metabolic syndrome was defined clinically, based on the presence of three or more of the American Heart Association/National Heart Lung Blood Institute (AHA/NHLBI) criteria: (i) central obesity; (ii) hypertriglyceridemia or on drugs for elevated triglycerides; (iii) a low HDL-C level or on drugs for reduced HDL-C; (iv) high BP (≥130/85 mm Hg) or on antihypertensive drugs; and (v) a high fasting plasma glucose or having anti-diabetic drugs for hyperglycemia.20 The International Diabetes Federation (IDF) criteria were also applied to define metabolic syndrome, if participants had central obesity plus any two of the other four components.21

Statistical analysis

For descriptive analyses, values were presented as either a number (percent) or mean ± standard deviation (SD). For univariate analyses, categorical data were compared by the means of the chiChi-square test or Fisher exact test. Continuous variables were compared using the two-sample Student’s t-test. Statistical significance levels were determined by two-tailed tests (P value < 0.05). Crude hazard ratios (HRs) and 95% confidence intervals (95% CIs) of selected metabolic factors and metabolic syndrome for liver cancer-related deaths during a 10-year follow-up period were estimated. Multivariate Cox regression models were then applied to estimate the adjusted HRs

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and 95% CIs of diabetes, dyslipidemia, and metabolic syndrome for liver cancer-related deaths after controlling age, gender, other significant metabolic factors in crude analysis, serum plasma alanine aminotransferaseALT level, eGFRestimated glomerular filtration rate, smoking, and alcohol drinking. Furthermore, the interaction between diabetes, hypertriglyceridemia, and

hypercholesterolemia on liver cancer-related mortality was examined. The unadjusted Kaplain-Meier survival curves of liver cancer for diabetic subjects versus non-diabetic counterparts were drawn. All of the abovementioned statistical analyses were performed with SAS software version 9.1.3 SP4 (SAS Institute Inc., Cary, NC, USA).

Results

Baseline characteristics of female and male participants

There were 2,686 deaths during the 10 years of follow-up; 235 deaths were due to liver cancer. At the baseline, a total of 26,596 (53.1%) female participants and 23,484 (46.9%) male participants entered into our analysis. As shown in Table 1, male individuals were older and had higher ALT levels (P <0.0001), BMI (P <0.0001), and waist circumferenceWC (P <0.0001); but lower eGFR (P <0.0001). Male subjects also had higher prevalence of high fasting glucose, diabetes history (P =0.014), high blood pressureBP (P =0.001), hypertension history (P =0.040), hypertriglyceridemia (P <0.0001), hypercholesterolemia (P <0.0001), low HDL-C level (P <0.0001), current smoking (P <0.0001), current alcohol drinking (P <0.0001) and metabolic syndrome using the AHA/NHLBI criteria (P =0.001); but lower prevalence of metabolic syndrome using the IDF criteria (P <0.0001).

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Metabolic risk factors of liver cancer-related deaths

Using univariate Cox regression analyses (Table 2), high fasting glucose (HR, 1.64; 95% CI, 1.27-2.11; P <0.001), history of diabetes (HR, 3.64; 95% CI, 2.59-5.12; P <0.0001), high blood pressure (HR, 1.73; 95% CI, 1.33-2.25; P <0.0001), and history of hypertension (HR, 2.03; 95% CI, 1.53-2.70; P <0.0001) were positively associated with risk of liver cancer-related deaths during a 10-year follow-up period for all participants. Conversely, hypertriglyceridemia (HR, 0.48; 95% CI, 0.34-0.67; P <0.0001) and hypercholesterolemia (HR, 0.46; 95% CI, 0.36-0.60; P <0.0001) were inversely associated with risk of liver cancer-related deaths. There was no significant association between metabolic syndrome using whether the AHA/NHLBI or the IDF criteria and liver cancer mortality.

In the multivariate Cox regression analyses (Table 3), history of diabetes and dyslipidemia were oppositely associated with risk of liver cancer-related deaths. History of diabetes (HR, 3.25; 95% CI, 2.26-4.67; P <0.0001) was positively associated with liver cancer mortality. The Kaplain-Meier survival curves revealed significant lower survival probability for subjects with preexisting diabetes (P <0.0001) (Figure 1A). However, hypertriglyceridemia (HR, 0.39; 95% CI, 0.27-0.56; P <0.0001) and hypercholesterolemia (HR, 0.49; 95% CI, 0.36-0.65; P <0.0001) were inversely associated with liver cancer mortality. Metabolic syndrome using whether the AHA/NHLBI criteria (HR, 0.64; 95% CI, 0.47-0.86; P <0.005) or the IDF criteria (HR, 0.60; 95% CI, 0.42-0.87; P <0.01) was also inversely associated with liver cancer mortality.

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2, Table 3), history of diabetes remained positively associated with risk of liver cancer-related deaths, especially in women. The Kaplain-Meier survival curves also revealed significant results (P <0.0001) (Figure 1B, Figure 1C). Hypertriglyceridemia was inversely associated with liver cancer mortality among both female and male subjects, but non-significantly in the univariate analysis for women. Hypercholesterolemia had consistently inverse association with risk of liver cancer-related deaths among both female and male subjects, whether using univariate or multivariate analyses. Extreme obesity was positively related to risk of liver cancer-related deaths only in female subjects (adjusted HR, 2.46; 95% CI, 1.17-5.21; P <0.05); while central obesity was inversely related to risk of liver cancer-related deaths only in male subjects (adjusted HR, 0.61; 95% CI, 0.40-0.92; P <0.05). For the females, metabolic syndrome using whether the AHA/NHLBI or the IDF criteria was only positively associated with liver cancer mortality in the univariate analyses. For the males, on the other hand, metabolic syndrome using whether the AHA/NHLBI or the IDF criteria was inversely associated with liver cancer mortality in both the univariate and multivariate analyses.

In the further analysis for the interaction between diabetes, hypertriglyceridemia, and hypercholesterolemia on liver cancer-related mortality (Table 4), participants with history of diabetes, no hypertriglyceridemia nor hypercholesterolemia had an extraordinarily increased risk of liver cancer mortality (HR, 21.3; 95% CI, 10.4-44.0; P <0.0001) compared with those without history of diabetes, but with hypertriglyceridemia and hypercholesterolemia. The Log-Rank test was significant (P <0.0001) using the Kaplain-Meier survival curves (Figure 2).

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Discussion

Middle-aged and elderly adults are the population bearing higher risk of liver cancer

incidence.3 According to a recent causal-pie study,6 unknown risk factors of HCC other than viral hepatitis and alcohol drinking were estimated to be be 27% of HCC etiology. However, surveillance for liver cancer was suggested exclusively for those with chronic viral hepatitis, cirrhosis, or

advanced hepatic fibrosis in most countries.3,22-25 Previously, we tried to elucidate the association between viral factors and host metabolic factors,26-28 which could be earlier detected in the outpatient care settings than the former. Our aforementioned studies inferred that obesity and hypertriglyceridemia contribute to liver damage through oxidative stress, insulin resistance, hepatic inflammation and hepatic steatosis, instead of inducing HBV replication.27,29 We need more

evidence primarily investigating the relationship between common metabolic factors and liver cancer mortality for the early detection of high-risk middle-aged and elderly adults without chronic viral hepatitis. This cohort study excluded cirrhotic participants to avoid the interference of ascites with BMI and waist circumferenceWC. Our results set out to reveal that preexisting diabetes history was positively associated with liver cancer mortality. Oppositely, baseline hypertriglyceridemia and hypercholesterolemia were inversely associated with liver cancer mortality. Metabolic syndrome was inversely associated with liver cancer mortality, especially in men.

The positive association between DM and liver cancer incidence might somewhat be explained by the increased surveillance for liver cancer early after the diagnosis of DM, the reverse causation that undiagnosed liver cancer increased the probability of DM diagnosis, the common underlying

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mechanisms for DM and liver cancer occurrence, and the carcinogenetic effects of insulin or some oral anti-diabetes agents.30 Similarly, metabolic syndrome, DM or insulin resistance, obesity, hypertension and dyslipidemia were linked to worsened liver cancer outcomes and mortality.31,32 Intriguingly, we found an inverse association between dyslipidemia, metabolic syndrome and liver cancer mortality in subjects aged over 40 years without chronic viral hepatitis (Table 3, Table 4). Reasons for this contradictory finding remained unclear and may involve comorbidities. For example, malnutrition-related low serum levels of total cholesterol and triglycerides hastened the deaths of liver cancer patient who had underwent anti-cancer therapies. Extremely obese female subjects tended to have accompanying cardiovascular disorders and accelerated liver cancer deaths; on the other hand, centrally obese male participants might have lower prevalence of malnutrition and fewer liver cancer deaths.

The potential confounding of nonalcoholic fatty liver disease deserves further testing. A total of 20,895 participants in our cohort underwent ultrasonography and 10,994 (52.6%) had hepatic steatosis. Participants with baseline hepatic steatosis had higher adjusted risk of liver cancer

mortality (HR, 2.41; 95% CI, 1.39-4.19; P =0.002) adjusted for the same covariates in Table 3. The particular significant association between diabetes (HR, 3.73), hypertriglyceridemia (HR, 0.33) and hypercholesterolemia (HR, 0.43), and liver cancer mortality remained similar after controlling hepatic steatosis (data not shown). Another concern is the competing risks.33 Patients with untreated dyslipidemia might have early cardiovascular events impeding the occurrence and mortality of liver cancer. But we did the competing-risks regression and there was still an inversely significant

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association between dyslipidemia, and liver cancer mortality (data not shown).

This study has some limitations to be addressed. The occult hepatitis B and C virus infection could not be completely excluded although thebut its clinical impact is unclear with bias is toward the null.34 The definition of DM in our baseline cohort was by patient-reported questionnaire and the prevalence of DM could be underestimated. If the fasting plasma glucose levels had been repeatedly checked based on the current diagnostic criteria,35 we would have less bias toward the null. Besides, the disease duration and the glycated hemoglobin were not recorded and may cause some residual confounding. A total of 2,128 (75.5%) DM participants in this cohort had regular anti-diabetes agents. Diabetic participants with anti-diabetes agents had much higher risk of liver cancer mortality than all diabetic participants (HR, 3.37 vs 3.25) compared to non-diabetics adjusted for the same covariates in Table 3. It would be better if we could collect the details of all anti-diabetes medications and did a confirmatory testing for their class effects on cancer outcome as on cancer risks.36 In contrast, only 572 (3.7%) participants with hypertriglyceridemia in this cohort had regular lipid-lowering agents. Participants with hypertriglyceridemia taking lipid-lowering agents had higher but non-significant risk of liver cancer mortality (HR, 0.50; 95% CI, 0.12-2.05; P =0.338) than participants with hypertriglyceridemia taking no lipid-lowering agents (HR, 0.40; 95% CI, 0.28-0.59; P <0.0001) compared to participants without hypertriglyceridemia adjusted for the same covariates in Table 3. This result seems to be inconsistent with the fibrates-induced anti-proliferative effects from cultured human HCC cells,37 and to the protective effects of statins on HCC incidence from recent human studies.38,39 But the above reports of fibrates and statins were on

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cancer risk, rather than cancer death. They were also not verified for middle-aged and elderly adults without chronic viral hepatitis. If we had recorded the kinds of lipid-lowering agents, the dates of liver cancer diagnosis, we would conduct a confirmatory testing for their class effects of lipid-lowering agents on liver cancer incidence and mortality.

Metabolic syndrome is a well-known risk factor of cardiovascular disease incidence and mortality.40,41 But according to our results, metabolic syndrome using whether either the

AHA/NHLBI or the IDF criteria turns to be inversely associated with liver cancer mortality. This may be owing to the inverse contributions of dyslipidemia (all) and central obesity (male) (Table 2, Table 3). Diabetic dyslipidemia is not necessarily related to the worst outcome for all diseases (Table 4). In conclusion, from this screening units-based follow-up cohort of 50,080 participants, aged 40 years or more, without preexisting cancer or cirrhosis in Taiwan, we demonstrated that diabetes was positively associated with liver cancer mortality; however, hypertriglyceridemia and hypercholesterolemia was inversely associated with liver cancer mortality in middle-aged and elderly adults. For the clinical implications, we consider middle-aged and elderly diabetics,

although without HBCV, to be a potential high-risk group deserving liver cancer surveillance. More research should focus on elucidating the underlying metabolic mechanism of low serum plasma levels of triglycerides or total cholesterol in the middle-aged and elderly for liver cancer mortality.

Acknowledgements

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Author contributions: Chiang and Huang had have full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Chiang, and Huang. Data acquisition: Chiang, Sung, and Huang. Statistical analysis: Chiang. Data analysis, interpretation, and drafting of the manuscript: Chiang, Hung, Lin, Lee, Sung and Huang. Critical revision of the manuscript for important intellectual content: Chiang, Lin and Huang. All authors have approved the final draft submitted.

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Figure legends

Figure 1A. Kaplan-Meier survival curves for all diabetic subjects (age ≥ 40) (red line) versus non-diabetic counterparts (blue line). The Log-Rank test is significant with P < 0.0001.

Figure 1B. Kaplan-Meier survival curves for female diabetic female subjects (age ≥ 40) (red line) versus non-diabetic counterparts (blue line). The Log-Rank test is significant with P < 0.0001.

Figure 1C. Kaplan-Meier survival curves for male diabetic male subjects (age ≥ 40) (red line) versus non-diabetic counterparts (blue line). The Log-Rank test is significant with P < 0.0001.

Figure 2. Kaplan-Meier survival curves for diabetic subjects (age ≥ 40) with normal triglycerides (TG) and normal total cholesterol (TCHO) levels (red line) versus other their counterparts (blue line). The Log-Rank test is significant with P < 0.0001.

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