Obesity and Hepatocellular Carcinoma: Hype and Reality See Article on Page 858
I
t has been suggested that the rising prevalence of obesity and its associated metabolic consequences, including diabetes mellitus, have contributed considerably to the overall as well the increasing burden of hepatocellular carcinoma (HCC) in several Western societies. This statement depends on interpretation of the association between obesity and HCC, the burden (measured by attributable fraction) of obesity-related HCC, and the temporal trends of obesity-related HCC. We will review the veracity of this statement based on the available epidemiological and mechanistic evidence, and place the findings of the study by Aleksandrova et al. in context.1 The association between obesity and HCC has been examined in several epidemiological studies. Most—but not all—of these studies are suggestive of a modest increase in the relative risk of HCC in obese persons. For example, a systematic review2 of 10 cohort studies found a positive association between obesity, measured as body mass index (BMI), and risk of HCC in seven studies (relative risks ranging from 1.4 to 4.1), no association in two, and an inverse association in one study. Many of these studies were limited by a small number of cases with HCC, possibility of misclassification, and inconsistent adjustment for potential confounders. The contribution of obesity to the overall HCC burden is driven to a large extent by the prevalence of obesity in the general population. However, the interpretation of available data is limited by the relative risk estimates as well as overreliance on BMI as a meaAbbreviations: BMI, body mass index; EPIC, European Prospective Investigation into Cancer and Nutrition; HCC, hepatocellular carcinoma; IGF-1, insulin-like growth factor 1; NASH, nonalcoholic steatohepatitis; PAF, population attributable fraction. Address reprint requests to: Hashem B. El-Serag, M.D., MPH, Section of Gastroenterology and Hepatology, Michael E DeBakey VA Medical Center and Baylor College of Medicine, and Houston VA HSR&D Center for Innovations in Quality, Effectiveness and Safety, Houston TX 77030. E-mail: hasheme@ bcm.edu; fax: 713-748-7359. Published 2014. This article is a US Government work and is in the public domain in the USA. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27172 Potential conflict of interest: Nothing to report.
sure of obesity in most published studies. In contrast to the relative risk ratios (as described in the systematic review and meta-analysis described above), population attributable fraction (PAF) accounts for both an estimate of prevalence as well as the relative risk, and thus describes the proportional reduction in disease that would occur if exposure to a risk factor were to be eliminated. Using this parameter, obesity is likely to have the greatest PAF of any HCC risk factors in the U.S. and several other regions in Europe and North America. For example, a report based on the European Prospective Investigation into Cancer and Nutrition (EPIC) indicated that obesity might account for 16% of HCC3 cases in Europe (EPIC is a population-based cohort from several European countries). Similarly, data from U.S. SEER Medicare estimated that diabetes and/or obesity may be attributed to 36.6% of HCC in the U.S. Medicare population.4 However, these studies make certain assumptions in calculating attributable risk that may not be true. First, there are differences between excess fraction (differences between HCC risk in obese and nonobese irrespective of the presence of other cofactors such as viral hepatitis or alcoholic liver disease) which is used in the PAF calculation, and etiological fraction (differences between the groups limited to cases caused solely by obesity) which may be much smaller.5 The magnitude of the difference between excess fraction and etiological fraction related to obesity is unknown. Second, the PAF calculations do not account for the considerable time lag between acquiring the risk factor (obesity) and developing the disease (HCC), and therefore the applicability of PAF to current HCC burden is very doubtful. In the available cross-sectional studies of HCC, viral hepatitis still accounts for most cases and there have been no convincing studies of temporal trends of obesity-related HCC. Thus, the available obesity-related PAF data may represent, if at all, the upper bound of the HCC risk associated with obesity (i.e., the worst-case scenario). Lastly, the factors that increase or attenuate the risk of HCC among obese persons are only partly understood. We believe that thoughtful modeling studies that incorporate natural history estimates of disease progression are needed for a better understanding of the burden of obesity-related HCC. 779
780
EL-SERAG AND KANWAL
Most studies used BMI to classify patients as obese versus nonobese. BMI is a rather gross and likely distal operator in explaining the link between obesity and HCC. Moving beyond BMI and into more proximal features in the association between BMI and HCC, a previous publication from the EPIC cohort found that a high waist-to-hip ratio conferred a 3fold higher HCC risk to subjects in the upper tertile of waist hip ratio6 than those in the lowest tertile. These findings suggest a role for abdominal visceral fat as a source of imbalance for cytokines and adipokines.7 There is a clear need for studies to examine more proximal—and likely mechanistic—links that either jointly or independently explain the association between obesity and HCC. Examining these mechanistic associations is particularly important in obesity-related HCC. This is because the conventional assumption that most HCC develops in patients with underlying cirrhosis may be violated in the case of obesity-related HCC. While nonalcoholic steatohepatitis (NASH) arising from fatty liver disease seems to be an underlying lesion for some HCC cases,8 the extent to which the presence or the severity of NASH explains obesity-related HCC remains unclear. For example, HCC was reported in a French surgical series to have developed in a background liver without significant fibrosis in approximately two-thirds of 31 cases with metabolic syndrome (a strong correlate of obesity) as the only risk factor for liver disease, compared with less than one-third in 97 with an overt cause of liver disease.9 Another Japanese study reported that approximately half of the 87 cases of HCC occurring in patients with histologically confirmed NASH had no established cirrhosis.10 These findings are supportive of the possibility that HCC arises in these traditionally nonhigh-risk groups by completely bypassing cirrhosis and possibly through mechanisms other than NASH. There are several potential mediators of obesityrelated HCC that were discussed in previous reviews11,12; these include lipotoxicity, changes in the gut microbiome,13 an imbalance in proinflammatory/ antiinflammatory cytokines, stimulation of the insulinlike growth factor 1 (IGF-1) axis by hyperinsulinemia, reduced adiponectin secretion, and increased leptin.14 These biomarkers may also explain the joint effect of obesity with traditional risk factors toward further increasing the risk of HCC. However, only a few prospective epidemiological studies examined the association between inflammatory or metabolic biomarkers and risk of HCC in a general population. Having this information is important because evidence of the relation between obesity-related biomarkers and risk of
HEPATOLOGY, September 2014
liver cancer may provide clues for understanding the underlying etiological mechanisms. In this issue of HEPATOLOGY, Aleksandrova et al. reported the findings of a nested case-control study in the EPIC cohort. A total of 125 HCC cases were compared to controls matched on the recruitment center, age, sex, fasting serum status, and time of specimen collection. Higher baseline serum levels of C-reactive protein, interleukin 6, C peptide, and high molecular weight adiponectin were associated with an increased risk of developing HCC in the general population. The risk ratios were modest and ranged between 1.22 and 2.25 for doubling of each of the significant biomarkers. Other biomarkers of interest that were not significantly associated with HCC included leptin. The study has multiple strengths, including a populationbased cohort, longitudinal design, and careful characterization of study subjects. Some of the limitations include the relatively small number of HCC cases and the absence of main risk factors among HCC cases (only 30% had either hepatitis C virus [HCV] or HBV), which, while possible, invokes likely misclassification bias. Lastly, the finding that high adiponectin was associated with higher HCC risk goes against the proposed biological rationale (adiponectin, a protective factor, is reduced in obesity). Despite these limitations, as the authors mention, there are two broad potential implications for their findings. First, the study provides a mechanistic link between obesity and HCC by demonstrating an association with obesity using measures that are more “proximal” than BMI and anthropometric measures. Second, the study provides potential biomarkers for HCC. With regard to the first implication, we believe that the study findings represent a significant advance. However, this may not be the case with the latter implication. There the potential use of proposed biomarkers is considerably limited by biological (the markers have been implicated with several other conditions including nonliver cancer) and test performance (although the relative risk of HCC was elevated modestly with some of the markers, the absolute risk of HCC in this mostly low-risk population is exceedingly small, and hence increasing this risk by 2 to 3-fold is still not meaningful personal predictive value) factors. In summary, the relative risk of HCC is modestly elevated in obese persons but the absolute risk is likely very low. The factors that influence HCC risk among obese person are unclear. Obesity-related inflammatory mechanisms are possibly operative in mediating obesity-related HCC (as shown in this longitudinal study), but the factors that further increase or
HEPATOLOGY, Vol. 60, No. 3, 2014
attenuate HCC risk among obese persons are unclear. The obesity-related increase in HCC risk has not translated yet into a large burden, but its future impact is possible and needs to be studied. The possibility of obesity-related HCC developing in noncirrhotic liver is real and needs to be further examined because of its potential to disrupt the current algorithms for defining high-risk groups (with implications for prevention and surveillance).
HASHEM B. EL-SERAG, M.D., MPH FASIHA KANWAL, M.D., MSHS
Section of Gastroenterology and Hepatology Michael E DeBakey VA Medical Center and Baylor College of Medicine Houston VA HSR&D Center for Innovations in Quality, Effectiveness and Safety Houston, TX
References 1. Aleksandrova K, Boeing H, Nothlings U, Jenab M, Fedirko V, Kaaks R, et al. Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer. HEPATOLOGY 2014;60:858-871. 2. Saunders D, Seidel D, Allison M, Lyratzopoulos G. Systematic review: the association between obesity and hepatocellular carcinoma — epidemiological evidence. Aliment Pharmacol Ther 2010;31:1051-1063.
EL-SERAG AND KANWAL
781
3. Schlesinger S, Aleksandrova K, Pischon T, Jenab M, Fedirko V, Trepo E, et al. Diabetes mellitus, insulin treatment, diabetes duration, and risk of biliary tract cancer and hepatocellular carcinoma in a European cohort. Ann Oncol 2013;24:2449-2455. 4. Welzel TM, Graubard BI, Quraishi S, Zeuzem S, Davilla JA, El-Serah HB, et al. Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States. Am J Gastroenterol 2013;108:1314-1321. 5. Greenland S, Robins JM. Conceptual problems in the definition and interpretation of attributable fractions. Am J Epidemiol 1988;128:1185-1197. 6. Schlesinger S, Aleksandrova K, Pischon T, Jenab M, Fedirko V, Trepo E, et al. Abdominal obesity, weight gain during adulthood and risk of liver and biliary tract cancer in a European cohort. Int J Cancer 2013; 132:645-657. 7. Zhao J, Lawless MW. Stop feeding cancer: pro-inflammatory role of visceral adiposity in liver cancer. Cytokine 2013;64:626-637. 8. White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 2012;10:1342-1359. 9. Paradis V, Zalinski S, Chelbi E, Guedj N, Degos F, Vigrain V, et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. HEPATOLOGY 2009;49:851-859. 10. Yasui K, Hashimoto E, Komorizono Y, Koike J, Arii S, Imai Y, et al. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol 2011;9:428-433. 11. Vanni E, Bugianesi E. Obesity and liver cancer. Clin Liver Dis 2014; 18:191-203. 12. Esposito K, Capuano A, Giugliano D. Metabolic syndrome and cancer: holistic or reductionist? Endocrine 2013. 13. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013;499:97-101. 14. Farrell G. Insulin resistance, obesity, and liver cancer. Clin Gastroenterol Hepatol 2014;12:117-119.
I
t has been suggested that the rising prevalence of obesity and its associated metabolic consequences, including diabetes mellitus, have contributed considerably to the overall as well the increasing burden of hepatocellular carcinoma (HCC) in several Western societies. This statement depends on interpretation of the association between obesity and HCC, the burden (measured by attributable fraction) of obesity-related HCC, and the temporal trends of obesity-related HCC. We will review the veracity of this statement based on the available epidemiological and mechanistic evidence, and place the findings of the study by Aleksandrova et al. in context.1 The association between obesity and HCC has been examined in several epidemiological studies. Most—but not all—of these studies are suggestive of a modest increase in the relative risk of HCC in obese persons. For example, a systematic review2 of 10 cohort studies found a positive association between obesity, measured as body mass index (BMI), and risk of HCC in seven studies (relative risks ranging from 1.4 to 4.1), no association in two, and an inverse association in one study. Many of these studies were limited by a small number of cases with HCC, possibility of misclassification, and inconsistent adjustment for potential confounders. The contribution of obesity to the overall HCC burden is driven to a large extent by the prevalence of obesity in the general population. However, the interpretation of available data is limited by the relative risk estimates as well as overreliance on BMI as a meaAbbreviations: BMI, body mass index; EPIC, European Prospective Investigation into Cancer and Nutrition; HCC, hepatocellular carcinoma; IGF-1, insulin-like growth factor 1; NASH, nonalcoholic steatohepatitis; PAF, population attributable fraction. Address reprint requests to: Hashem B. El-Serag, M.D., MPH, Section of Gastroenterology and Hepatology, Michael E DeBakey VA Medical Center and Baylor College of Medicine, and Houston VA HSR&D Center for Innovations in Quality, Effectiveness and Safety, Houston TX 77030. E-mail: hasheme@ bcm.edu; fax: 713-748-7359. Published 2014. This article is a US Government work and is in the public domain in the USA. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27172 Potential conflict of interest: Nothing to report.
sure of obesity in most published studies. In contrast to the relative risk ratios (as described in the systematic review and meta-analysis described above), population attributable fraction (PAF) accounts for both an estimate of prevalence as well as the relative risk, and thus describes the proportional reduction in disease that would occur if exposure to a risk factor were to be eliminated. Using this parameter, obesity is likely to have the greatest PAF of any HCC risk factors in the U.S. and several other regions in Europe and North America. For example, a report based on the European Prospective Investigation into Cancer and Nutrition (EPIC) indicated that obesity might account for 16% of HCC3 cases in Europe (EPIC is a population-based cohort from several European countries). Similarly, data from U.S. SEER Medicare estimated that diabetes and/or obesity may be attributed to 36.6% of HCC in the U.S. Medicare population.4 However, these studies make certain assumptions in calculating attributable risk that may not be true. First, there are differences between excess fraction (differences between HCC risk in obese and nonobese irrespective of the presence of other cofactors such as viral hepatitis or alcoholic liver disease) which is used in the PAF calculation, and etiological fraction (differences between the groups limited to cases caused solely by obesity) which may be much smaller.5 The magnitude of the difference between excess fraction and etiological fraction related to obesity is unknown. Second, the PAF calculations do not account for the considerable time lag between acquiring the risk factor (obesity) and developing the disease (HCC), and therefore the applicability of PAF to current HCC burden is very doubtful. In the available cross-sectional studies of HCC, viral hepatitis still accounts for most cases and there have been no convincing studies of temporal trends of obesity-related HCC. Thus, the available obesity-related PAF data may represent, if at all, the upper bound of the HCC risk associated with obesity (i.e., the worst-case scenario). Lastly, the factors that increase or attenuate the risk of HCC among obese persons are only partly understood. We believe that thoughtful modeling studies that incorporate natural history estimates of disease progression are needed for a better understanding of the burden of obesity-related HCC. 779
780
EL-SERAG AND KANWAL
Most studies used BMI to classify patients as obese versus nonobese. BMI is a rather gross and likely distal operator in explaining the link between obesity and HCC. Moving beyond BMI and into more proximal features in the association between BMI and HCC, a previous publication from the EPIC cohort found that a high waist-to-hip ratio conferred a 3fold higher HCC risk to subjects in the upper tertile of waist hip ratio6 than those in the lowest tertile. These findings suggest a role for abdominal visceral fat as a source of imbalance for cytokines and adipokines.7 There is a clear need for studies to examine more proximal—and likely mechanistic—links that either jointly or independently explain the association between obesity and HCC. Examining these mechanistic associations is particularly important in obesity-related HCC. This is because the conventional assumption that most HCC develops in patients with underlying cirrhosis may be violated in the case of obesity-related HCC. While nonalcoholic steatohepatitis (NASH) arising from fatty liver disease seems to be an underlying lesion for some HCC cases,8 the extent to which the presence or the severity of NASH explains obesity-related HCC remains unclear. For example, HCC was reported in a French surgical series to have developed in a background liver without significant fibrosis in approximately two-thirds of 31 cases with metabolic syndrome (a strong correlate of obesity) as the only risk factor for liver disease, compared with less than one-third in 97 with an overt cause of liver disease.9 Another Japanese study reported that approximately half of the 87 cases of HCC occurring in patients with histologically confirmed NASH had no established cirrhosis.10 These findings are supportive of the possibility that HCC arises in these traditionally nonhigh-risk groups by completely bypassing cirrhosis and possibly through mechanisms other than NASH. There are several potential mediators of obesityrelated HCC that were discussed in previous reviews11,12; these include lipotoxicity, changes in the gut microbiome,13 an imbalance in proinflammatory/ antiinflammatory cytokines, stimulation of the insulinlike growth factor 1 (IGF-1) axis by hyperinsulinemia, reduced adiponectin secretion, and increased leptin.14 These biomarkers may also explain the joint effect of obesity with traditional risk factors toward further increasing the risk of HCC. However, only a few prospective epidemiological studies examined the association between inflammatory or metabolic biomarkers and risk of HCC in a general population. Having this information is important because evidence of the relation between obesity-related biomarkers and risk of
HEPATOLOGY, September 2014
liver cancer may provide clues for understanding the underlying etiological mechanisms. In this issue of HEPATOLOGY, Aleksandrova et al. reported the findings of a nested case-control study in the EPIC cohort. A total of 125 HCC cases were compared to controls matched on the recruitment center, age, sex, fasting serum status, and time of specimen collection. Higher baseline serum levels of C-reactive protein, interleukin 6, C peptide, and high molecular weight adiponectin were associated with an increased risk of developing HCC in the general population. The risk ratios were modest and ranged between 1.22 and 2.25 for doubling of each of the significant biomarkers. Other biomarkers of interest that were not significantly associated with HCC included leptin. The study has multiple strengths, including a populationbased cohort, longitudinal design, and careful characterization of study subjects. Some of the limitations include the relatively small number of HCC cases and the absence of main risk factors among HCC cases (only 30% had either hepatitis C virus [HCV] or HBV), which, while possible, invokes likely misclassification bias. Lastly, the finding that high adiponectin was associated with higher HCC risk goes against the proposed biological rationale (adiponectin, a protective factor, is reduced in obesity). Despite these limitations, as the authors mention, there are two broad potential implications for their findings. First, the study provides a mechanistic link between obesity and HCC by demonstrating an association with obesity using measures that are more “proximal” than BMI and anthropometric measures. Second, the study provides potential biomarkers for HCC. With regard to the first implication, we believe that the study findings represent a significant advance. However, this may not be the case with the latter implication. There the potential use of proposed biomarkers is considerably limited by biological (the markers have been implicated with several other conditions including nonliver cancer) and test performance (although the relative risk of HCC was elevated modestly with some of the markers, the absolute risk of HCC in this mostly low-risk population is exceedingly small, and hence increasing this risk by 2 to 3-fold is still not meaningful personal predictive value) factors. In summary, the relative risk of HCC is modestly elevated in obese persons but the absolute risk is likely very low. The factors that influence HCC risk among obese person are unclear. Obesity-related inflammatory mechanisms are possibly operative in mediating obesity-related HCC (as shown in this longitudinal study), but the factors that further increase or
HEPATOLOGY, Vol. 60, No. 3, 2014
attenuate HCC risk among obese persons are unclear. The obesity-related increase in HCC risk has not translated yet into a large burden, but its future impact is possible and needs to be studied. The possibility of obesity-related HCC developing in noncirrhotic liver is real and needs to be further examined because of its potential to disrupt the current algorithms for defining high-risk groups (with implications for prevention and surveillance).
HASHEM B. EL-SERAG, M.D., MPH FASIHA KANWAL, M.D., MSHS
Section of Gastroenterology and Hepatology Michael E DeBakey VA Medical Center and Baylor College of Medicine Houston VA HSR&D Center for Innovations in Quality, Effectiveness and Safety Houston, TX
References 1. Aleksandrova K, Boeing H, Nothlings U, Jenab M, Fedirko V, Kaaks R, et al. Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer. HEPATOLOGY 2014;60:858-871. 2. Saunders D, Seidel D, Allison M, Lyratzopoulos G. Systematic review: the association between obesity and hepatocellular carcinoma — epidemiological evidence. Aliment Pharmacol Ther 2010;31:1051-1063.
EL-SERAG AND KANWAL
781
3. Schlesinger S, Aleksandrova K, Pischon T, Jenab M, Fedirko V, Trepo E, et al. Diabetes mellitus, insulin treatment, diabetes duration, and risk of biliary tract cancer and hepatocellular carcinoma in a European cohort. Ann Oncol 2013;24:2449-2455. 4. Welzel TM, Graubard BI, Quraishi S, Zeuzem S, Davilla JA, El-Serah HB, et al. Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States. Am J Gastroenterol 2013;108:1314-1321. 5. Greenland S, Robins JM. Conceptual problems in the definition and interpretation of attributable fractions. Am J Epidemiol 1988;128:1185-1197. 6. Schlesinger S, Aleksandrova K, Pischon T, Jenab M, Fedirko V, Trepo E, et al. Abdominal obesity, weight gain during adulthood and risk of liver and biliary tract cancer in a European cohort. Int J Cancer 2013; 132:645-657. 7. Zhao J, Lawless MW. Stop feeding cancer: pro-inflammatory role of visceral adiposity in liver cancer. Cytokine 2013;64:626-637. 8. White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 2012;10:1342-1359. 9. Paradis V, Zalinski S, Chelbi E, Guedj N, Degos F, Vigrain V, et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. HEPATOLOGY 2009;49:851-859. 10. Yasui K, Hashimoto E, Komorizono Y, Koike J, Arii S, Imai Y, et al. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol 2011;9:428-433. 11. Vanni E, Bugianesi E. Obesity and liver cancer. Clin Liver Dis 2014; 18:191-203. 12. Esposito K, Capuano A, Giugliano D. Metabolic syndrome and cancer: holistic or reductionist? Endocrine 2013. 13. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013;499:97-101. 14. Farrell G. Insulin resistance, obesity, and liver cancer. Clin Gastroenterol Hepatol 2014;12:117-119.
