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Metabolic syndrome increases the risk of primary liver cancer in the United States: A study in the SEER-medicare database
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Hepatology August 2011
" Metabolic syndrome is recognized as a risk factor for HCC......results of this population-based study indicate that metabolic syndrome is a significant risk factor for development of both types of primary liver cancer, regardless of the presence of all other major HCC and ICC risk factors. As a result, metabolic syndrome may explain a relevant proportion of idiopathic HCC or ICC in the United States. Consequently, approaches to control the recent worldwide epidemic of metabolic syndrome could contribute to a reduction in the liver cancer burden."
"Among the individual conditions of the metabolic syndrome, impaired fasting glucose/diabetes, dyslipoproteinemia, hypertension, and obesity were each significantly associated with the development of HCC (P < 0.0001). A combination of these conditions revealed that metabolic syndrome was significantly associated with HCC (37.1% versus 17.1%, P < 0.0001)......This is the first large population-based study in the United States that investigated the association between metabolic syndrome and risk for both primary liver cancers: HCC and ICC. The results indicate that preexisting metabolic syndrome, as defined by the 2001 U.S. NCEP-ATP III criteria, confers a statistically significant 2.13- and 1.56-fold increased risk for HCC and ICC that is independent of other risk factors. An indicator of the validity of the findings is that other major and previously defined HCC and ICC risk factors were confirmed in this study population.....metabolic syndrome was present in 15.7% of the HCC cases and 11.6% of the ICC cases. Among the remaining patients who did not have at least three conditions of the metabolic syndrome, 22.4% and 24.2% of the HCC and ICC cases had a diagnosis of at least one metabolic risk factor (impaired fasting glucose/diabetes mellitus, dyslipoproteinemia, hypertension, or obesity). These findings suggest that metabolic syndrome as well as its individual components could possibly explain a relevant proportion of the idiopathic HCC or ICC cases in this study population......The magnitude of the association between metabolic syndrome and both primary liver cancers (HCC, ICC) is similar to the risk for incident cardiovascular disease, coronary heart disease, and all-cause mortality in patients with metabolic syndrome. The relative risks for these outcomes, as reported in three meta-analyses, range from 1.27-1.93.32-34 Given the very high prevalence of metabolic syndrome, even small increases in the absolute risk of HCC may lead to a large number of HCC cases.....The recent increase in metabolic syndrome incidence has turned NAFLD, the hepatic component of metabolic syndrome, into the most frequent liver disease in the United States and in Western countries.6, 7, 19, 20 In particular, NASH, defined as coexistence of hepatic fat accumulation and inflammatory changes, promotes the progression to liver fibrosis, cirrhosis, end-stage liver disease, and HCC.6, 7, 9, 10 Recent studies have reported that 26%-37% of persons with NAFLD and up to 9% of the persons with NASH progress to liver fibrosis and cirrhosis, suggesting that these conditions are important HCC risk factors.7-10 There is evidence that metabolic syndrome-related HCC may also occur in the absence of cirrhotic liver changes.22, 24"
"The pathogenesis of NAFLD and the factors promoting the progression to NASH and end-stage liver disease among patients with metabolic syndrome are complex. Recent research has generated stimulating hypotheses on the roles of oxidative stress and lipotoxicity, cytokine action, and molecular and genetic factors that may promote development and progression of NAFLD.36-39 The frequent co-occurrence of metabolic conditions and their interplay complicates the examination of each individual metabolic factor's contribution to liver disease and hepatocarcinogenesis. For example, it has been acknowledged that the hyperinsulinemia and insulin resistance that frequently co-occur with (central) obesity plays a main role in the development of hepatic steatosis through deposition of free fatty acids and their metabolites in liver tissue.6, 37 However, chronic liver disease may also cause hepatic insulin resistance, favoring de novo lipogenesis and progression of hepatic steatosis, as well as the development of metabolic risk factors such as diabetes mellitus, dyslipoproteinemia, and hypertension.6, 37 In addition, factors that cause necroinflammation (e.g., cytokines, oxidative stress) may also promote hepatic steatosis, which further complicates the delineation of cause and effect.6 Over the last couple of years, several cohort, case-control and population-based studies have reported the association of diabetes mellitus, obesity, and risk for both types of liver cancer (HCC, ICC).40, 41 These findings support an individual contribution of metabolic conditions to the development of NAFLD. Few of these studies, however, investigated the combined effects of all metabolic risk factors as defined by the metabolic syndrome on HCC and ICC risk."
Abstract
Incidence rates of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) have increased in the United States. Metabolic syndrome is recognized as a risk factor for HCC and a postulated one for ICC. The magnitude of risk, however, has not been investigated on a population level in the United States. We therefore examined the association between metabolic syndrome and the development of these cancers. All persons diagnosed with HCC and ICC between 1993 and 2005 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. For comparison, a 5% sample of individuals residing in the same regions as the SEER registries of the cases was selected. The prevalence of metabolic syndrome as defined by the U.S. National Cholesterol Education Program Adult Treatment Panel III criteria, and other risk factors for HCC (hepatitis B virus, hepatitis C virus, alcoholic liver disease, liver cirrhosis, biliary cirrhosis, hemochromatosis, Wilson's disease) and ICC (biliary cirrhosis, cholangitis, cholelithiasis, choledochal cysts, hepatitis B virus, hepatitis C virus, alcoholic liver disease, cirrhosis, inflammatory bowel disease) were compared among persons who developed cancer and those who did not. Logistic regression was used to calculate odds ratios and 95% confidence intervals. The inclusion criteria were met by 3649 HCC cases, 743 ICC cases, and 195,953 comparison persons. Metabolic syndrome was significantly more common among persons who developed HCC (37.1%) and ICC (29.7%) than the comparison group (17.1%, P < 0.0001). In adjusted multiple logistic regression analyses, metabolic syndrome remained significantly associated with increased risk of HCC (odds ratio = 2.13; 95% confidence interval = 1.96-2.31, P < 0.0001) and ICC (odds ratio = 1.56; 95% confidence interval = 1.32-1.83, P < 0.0001). Conclusion: Metabolic syndrome is a significant risk factor for development of HCC and ICC in the general U.S. population.
The incidences of both types of primary liver cancer, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), have increased in the United States.1, 2 Major risk factors for HCC in industrialized countries are chronic infection with hepatitis C virus (HCV), chronic infection with hepatitis B virus (HBV), and excessive alcohol consumption.3 The documented increase in HCV- and HBV-related HCC, however, does not fully explain the recent increase in HCC incidence, because 20%-50% of HCC cases remain idiopathic.3 ICC has been associated with several diseases of the biliary tract or liver, such as primary sclerosing cholangitis, Caroli's disease, cholelithiasis, HCV infection, liver fluke infestation, and inflammatory bowel disease.4 These factors account for only a small proportion of the attributable risk of ICC in the United States, because many ICC cases do not appear to be associated with any of the abovementioned risk factors.5
In recent years, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have received increasing attention for their relationship with end-stage liver disease and HCC.6-11 NAFLD and NASH are clearly associated with the metabolic syndrome, comprising a cluster of interrelated metabolic risk factors such as raised fasting glucose, central obesity, dyslipoproteinemia, and hypertension.12-15 In concert with the recent worldwide epidemic of obesity and metabolic syndrome,16-18 the incidence and prevalence of NAFLD has also increased. It is estimated that up to 37% of the population in industrialized countries exhibit NAFLD, turning it into the most frequent liver disease in these countries.13, 19, 20
The association between metabolic syndrome or NAFLD/NASH and HCC has been documented in case reports, case series, and longitudinal studies7, 8, 11, 21-24; however, larger population-based studies investigating the magnitude of this association in the United States are lacking. Clinical studies investigating the possible impact of metabolic syndrome on ICC risk are very limited,23, 25 because the examination of this association is made difficult by the low incidence of ICC in Western countries. The goal of the current study was to investigate the association between metabolic syndrome and risk of HCC and ICC in the general population of the United States.
Discussion
This is the first large population-based study in the United States that investigated the association between metabolic syndrome and risk for both primary liver cancers: HCC and ICC. The results indicate that preexisting metabolic syndrome, as defined by the 2001 U.S. NCEP-ATP III criteria, confers a statistically significant 2.13- and 1.56-fold increased risk for HCC and ICC that is independent of other risk factors. An indicator of the validity of the findings is that other major and previously defined HCC and ICC risk factors were confirmed in this study population.5
Of the patients included in this study, 42.9% of the patients with HCC and 43.3% of the patients with ICC did not have a history of any previously established risk factor (excluding metabolic conditions). Of the patients with idiopathic disease, metabolic syndrome was present in 15.7% of the HCC cases and 11.6% of the ICC cases. Among the remaining patients who did not have at least three conditions of the metabolic syndrome, 22.4% and 24.2% of the HCC and ICC cases had a diagnosis of at least one metabolic risk factor (impaired fasting glucose/diabetes mellitus, dyslipoproteinemia, hypertension, or obesity). These findings suggest that metabolic syndrome as well as its individual components could possibly explain a relevant proportion of the idiopathic HCC or ICC cases in this study population.
The magnitude of the association between metabolic syndrome and both primary liver cancers (HCC, ICC) is similar to the risk for incident cardiovascular disease, coronary heart disease, and all-cause mortality in patients with metabolic syndrome. The relative risks for these outcomes, as reported in three meta-analyses, range from 1.27-1.93.32-34 Given the very high prevalence of metabolic syndrome, even small increases in the absolute risk of HCC may lead to a large number of HCC cases.
The recent increase in metabolic syndrome incidence has turned NAFLD, the hepatic component of metabolic syndrome, into the most frequent liver disease in the United States and in Western countries.6, 7, 19, 20 In particular, NASH, defined as coexistence of hepatic fat accumulation and inflammatory changes, promotes the progression to liver fibrosis, cirrhosis, end-stage liver disease, and HCC.6, 7, 9, 10 Recent studies have reported that 26%-37% of persons with NAFLD and up to 9% of the persons with NASH progress to liver fibrosis and cirrhosis, suggesting that these conditions are important HCC risk factors.7-10 There is evidence that metabolic syndrome-related HCC may also occur in the absence of cirrhotic liver changes.22, 24
Prospective studies of metabolic syndrome and development and progression of liver disease are hampered by the large number of patients and long duration of follow-up needed to observe a relevant number of cancer outcomes. For ICC, the investigation of this association is even more difficult due to its low incidence. Several longitudinal studies investigating HCC risk in patients with NAFLD or NASH with follow-up periods between 7.6 and 19.5 years reported an incidence of HCC between 0.5%-2.8%.7, 8, 21 A recent prospective study that investigated liver cancer risk in patients with NASH-related cirrhosis found a yearly cumulative HCC incidence of 2.6%, compared to 4% in patients with HCV-related cirrhosis.35 Because most of these studies were single-center studies of referral patients, the generalizability of the reported HCC prevalence rates to the general U.S. population may be limited. In addition, some of these studies were based on small patient numbers and/or limited duration of follow-up, which may have affected their power.
The pathogenesis of NAFLD and the factors promoting the progression to NASH and end-stage liver disease among patients with metabolic syndrome are complex. Recent research has generated stimulating hypotheses on the roles of oxidative stress and lipotoxicity, cytokine action, and molecular and genetic factors that may promote development and progression of NAFLD.36-39 The frequent co-occurrence of metabolic conditions and their interplay complicates the examination of each individual metabolic factor's contribution to liver disease and hepatocarcinogenesis. For example, it has been acknowledged that the hyperinsulinemia and insulin resistance that frequently co-occur with (central) obesity plays a main role in the development of hepatic steatosis through deposition of free fatty acids and their metabolites in liver tissue.6, 37 However, chronic liver disease may also cause hepatic insulin resistance, favoring de novo lipogenesis and progression of hepatic steatosis, as well as the development of metabolic risk factors such as diabetes mellitus, dyslipoproteinemia, and hypertension.6, 37 In addition, factors that cause necroinflammation (e.g., cytokines, oxidative stress) may also promote hepatic steatosis, which further complicates the delineation of cause and effect.6 Over the last couple of years, several cohort, case-control and population-based studies have reported the association of diabetes mellitus, obesity, and risk for both types of liver cancer (HCC, ICC).40, 41 These findings support an individual contribution of metabolic conditions to the development of NAFLD. Few of these studies, however, investigated the combined effects of all metabolic risk factors as defined by the metabolic syndrome on HCC and ICC risk.
Among other HCC and ICC risk factors, HCV infection can cause hepatic steatosis and insulin resistance that is mediated by a genotype-dependent interference of the viral core protein with intracellular insulin signaling.42 Some studies also suggest a synergistic effect of HCV infection, metabolic risk factors, and liver cancer risk.43, 44 In this study, however, no statistically significant interaction was observed between HCV infection and metabolic syndrome (data not shown).
Although the size of the current study (3649 HCC cases, 743 ICC cases) is quite large, the study had several limitations, including the reliance on medical claims data. It should be noted, however, that Medicare files capture 100% of the coverage claims for tests, outpatients visits, and hospitalizations for patients age 65 years and older with continuous enrollment in Medicare part A and part B. To minimize the possibility of missing medical diagnosis information, we restricted all analyses to patients with a minimum of 3 years continuous Medicare enrollment. This led to the exclusion of persons ≤68 years of age, which may limit the generalizability of the study findings. However, the study population is representative of most persons at risk of HCC and ICC, because the median age at diagnosis in SEER registries is 70-74 years. Because Medicare claims are collected for billing rather than research purposes, the prevalences of smoking, overweight, and obesity were almost certainly underestimated. Because of the absence of a specific ICD-9-CM code for central obesity, this study likely missed persons with central adiposity who were not otherwise obese. In addition, the possibility of some misclassification of HCC as ICC at the initial hospital histopathological review can not be excluded. However, a sensitivity analysis that restricted the analyses to well and moderately differentiated tumors confirmed the significant association between metabolic syndrome and risk for both cancers. Furthermore, there is a possibility of diagnostic detection bias, because persons with HCC and ICC are more likely to undergo diagnostic workup and testing than are other persons. Analyses excluding all diagnoses in the year preceding the cancer diagnosis limited the statistical power for some conditions, but did confirm the association between metabolic syndrome and HCC and ICC, respectively.
Detailed information on the use of medications (e.g., statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, sulfonylureas, insulin, biguanides, and thiazolidinediones) that might modify liver cancer risk in patients with diabetes and other metabolic risk factors were not available.39 However, it is likely that the prescription of these drugs was equally distributed among cases and controls with a diagnosis of metabolic conditions preceding the cancer diagnosis, so that this possible bias would be nondifferential. In addition, detailed information on alcohol consumption was not available.
Finally, due to the limited time frame for the risk factor information, the duration-response relationship among metabolic syndrome, liver histologic analysis results, and risk over time could not be estimated in the present study.
Important strengths of the study are related to the data source, as well as the case and control definitions. The SEER registries maintain a 99% completeness rate for case ascertainment, and yearly data quality control checks are conducted. In addition, because SEER registries are selected to be highly representative of the U.S. population, the study findings should be highly generalizable to the U.S. population aged 68 years and older; yet, the predominantly urban population and higher proportion of foreign-born persons included in the SEER registries deserve consideration when generalizing the data to the general U.S. population. To avoid diagnostic misclassification, only patients with histologically confirmed HCC and ICC were included in the study. Although this is a conservative approach, such restriction was necessary to maximize the study's accuracy. Because the liver is a frequent site for metastatic disease, all patients with prior cancer diagnoses in the 5 years preceding the tumor diagnosis were excluded. Finally, the identification of preceding medical conditions using Medicare claims records rather than personal interview data likely avoided recall bias.
In summary, the results of this population-based study indicate that metabolic syndrome is a significant risk factor for development of both types of primary liver cancer, regardless of the presence of all other major HCC and ICC risk factors. As a result, metabolic syndrome may explain a relevant proportion of idiopathic HCC or ICC in the United States. Consequently, approaches to control the recent worldwide epidemic of metabolic syndrome could contribute to a reduction in the liver cancer burden.
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