Clin J Gastroenterol (2013) 6:259–263 DOI 10.1007/s12328-013-0410-1
CLINICAL REVIEW
Adiponectin in chronic hepatitis C Toru Arano • Hayato Nakagawa • Hitoshi Ikeda Kazuhiko Koike
•
Received: 21 July 2013 / Accepted: 22 July 2013 / Published online: 14 August 2013 Ó Springer Japan 2013
Abstract White adipose tissue has been increasingly recognized as an important endocrine organ that secretes a number of biologically active adipokines. Adiponectin, one of the major adipokines, possesses anti-inflammatory and insulin-sensitizing properties, and its serum levels typically decline with increasing body weight. Hypoadiponectinemia has been implicated in the development of obesity-related morbidities such as dyslipidemia and cerebrovascular disease. In addition, hypoadiponectinemia has been reported to enhance hepatic steatosis, inflammation, fibrosis, and hepatocarcinogenesis in animal models or clinical liver diseases. Chronic hepatitis C (CHC) has some features which allow it to be recognized not only as a viral disease but also as a metabolic liver disease that encompasses insulin resistance, inflammation, steatosis and fibrosis. CHC is another disease in which adipokines may represent a link between viral infection and steatosis, or metabolic disturbance. In this report, data indicating a possible role of adiponectin in CHC are summarized. Keywords Adiponectin Chronic hepatitis C Hepatocellular carcinoma T. Arano (&) Department of Gastroenterology, Toshiba General Hospital, 6-3-22 Higashi-ooi, Shinagawa-ku, Tokyo 140-8522, Japan e-mail: [email protected] H. Nakagawa K. Koike Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan H. Ikeda Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Introduction The main function of white adipose tissue (WAT) is energy storage and, as such, it plays an important role in energy homeostasis; it stores energy in the form of triglycerides during nutritional abundance and releases it as free fatty acids [1, 2]. While WAT provides an advantage for survival in times of starvation, excess WAT is now linked to obesity-related health problems in the current nutritionally rich environment. Regulated by multiple hormonal signals, nuclear hormone receptors [3, 4], and central nervous systems [5], WAT has been increasingly recognized as an important endocrine organ that secretes a number of biologically active ‘adipokines’ [6–10]. Some of these adipokines have been shown to directly or indirectly affect insulin sensitivity through modulation of insulin signaling and the molecules involved in glucose and lipid metabolism [11]. Of these adipokines, adiponectin has recently attracted attention because of its anti-diabetic and anti-atherogenic effects and is expected to be a novel therapeutic tool for diabetes and the metabolic syndrome [12]. However, obesity-induced dysregulation of adipokines—cytokines secreted by WAT—is considered to play a key role in the context of liver diseases [13, 14]. WAT controls the functions of other organs through the secretion of various adipokines such as leptin, adiponectin, tumor necrosis factor a (TNFa), interleukin-6 (IL-6), and resistin. Obesity with visceral fat accumulation increases the serum levels of leptin, TNFa, IL-6, and resistin, and decreases serum adiponectin levels [13, 14]. These adipokines flow directly into the liver through the portal vein and exert a variety of effects on liver diseases [15]. Adiponectin, one of the major adipokines, possesses anti-inflammatory and insulin-sensitizing properties, and
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its serum levels typically decline with increasing body weight [16]. Hypoadiponectinemia has been implicated in the development of obesity-related morbidities such as dyslipidemia and cerebrovascular disease [17–19]. In addition, hypoadiponectinemia has been reported to enhance hepatic steatosis, inflammation, fibrosis, and hepatocarcinogenesis in animal models of liver diseases [20– 22]. Indeed, reduced adiponectin levels were found in patients with nonalcoholic steatohepatitis (NASH) and were associated with increased steatosis and necroinflammation in the liver. However, the role of adiponectin in hepatitis C virus (HCV)-induced chronic hepatitis is still not understood and the relationship between adiponectin level and disease severity remains controversial. In this paper, we discuss adiponectin and chronic hepatitis C (CHC) based on knowledge gained over recent years.
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Insulin resistance (IR) There have been only a few clinical studies designed to investigate the association between adiponectin and IR. IR is a specific feature of CHC, associated especially with genotypes 1 and 4, and high serum HCV RNA levels [33]. A study by Chen et al. [29] reported that IR, serum visfatin, and adiponectin levels are reportedly associated with metabolic disorders in CHC patients. Liver inflammation and steatosis
CHC has some features which allow it to be recognized not only as a viral disease but also as a metabolic liver disease that encompasses insulin resistance, steatosis, inflammation, and fibrosis. CHC is another disease in which adipokines may represent a link between viral infection and steatosis, or metabolic disturbance [23, 24]. The associations between adiponectin and various parameters in CHC have been reported as follows. There are some studies about the differences in serum adiponectin levels in CHC and healthy controls. Several studies reported that serum adiponectin levels were higher in patients with CHC than in healthy controls in Japan, Egypt and European countries [25–28]. On the other hand, a study by Chen et al. [29] reported that serum adiponectin levels were significantly lower in CHC patients compared with healthy controls.
A study by Cua et al. [34] reported that adiponectin was not associated with histological features of chronic HCV infection except for TNFa which correlated with portal or periportal inflammation. On the other hand, in a study by Jonsson et al. [35], there was a significant increase in serum adiponectin and hepatic adiponectin immunoreactivity with increasing inflammation. A study by Khattab et al. [36] reported that adiponectin correlates with IR and with the different stages of liver injury in patients with HCV-4. A noninterventional multicenter study by Aksu et al. reported that hepatic steatosis was correlated negatively with adiponectin, whereas the increase in age, the presence of IR, and the decrease in adiponectin levels were the significant predictors of hepatic steatosis. These findings indicate a significant relationship between hepatic steatosis and adiponectin level, but not with viral load in Turkish patients with CHC [37]. A study by Petit et al. [38] reported that steatosis was significantly associated with low adiponectin concentration, age, HCV genotype 3, and aspartate aminotransferase level. A study by Zografos et al. [39] reported that lower adiponectin and higher TNFa at baseline were identified as independent predictors of liver steatosis in CHC patients with genotype 3.
Viral load
Fibrosis
A study by Liu et al. [30] reported that high HCV load and genotype 2 were significantly associated with lower serum adiponectin levels, but serum adiponectin levels did not correlate with other clinical or histologic parameters. On the other hand, a study by Khattab et al. [31] reported that neither serum adipocytokines nor homeostasis model assessmentestimated insulin resistance (HOMA-IR) was correlated with viral load. A study by Derbala et al. [32] concluded that adiponectin changes are not related to viral load, insulin resistance or other demographic data, suggesting that this change is histologically related. Similarly, in our report, serum adiponectin levels did not correlate with hepatitis C viral factors, such as viral load or serotype [25].
A study by Korah et al. [27] found serum adiponectin levels were elevated in association with hepatic fibrosis, but decreased in steatosis in male patients with HCV genotype 4. A study by Corbetta et al. [26] reported that patients with none or mild fibrosis showed similar serum adiponectin levels to those in healthy controls, while hyperadiponectinemia was associated with moderate to severe stages of fibrosis. To investigate the localization of adiponectin in the liver, we performed immunohistochemical staining for adiponectin using liver biopsy samples. Adiponectin was stained primarily in hepatocytes, and the staining intensity tended to be higher according to the progression of fibrosis. Additionally, serum adiponectin
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levels were higher in patients with strong staining for adiponectin than in patients with weak staining [23]. Collectively, it remains to be clarified whether serum adiponectin levels would be associated with viral load, genotype, and response to antiviral therapy, insulin resistance, and liver histology such as steatosis, inflammation, and fibrosis in CHC. Hepatocellular carcinoma (HCC) Obesity and metabolic syndrome have been found to be associated with hepatocarcinogenesis in CHC as well as in NASH [15, 40]. In a study by Ohki et al., the risk of HCC in patients with CHC increases in association with body mass index in a wide range of values, from underweight to obesity. Furthermore, a study by Chen et al. showed that extreme obesity was independently associated with a fourfold risk of HCC among CHC patients. Serum levels of adiponectin typically decline with increasing body weight and hypoadiponectinemia is associated with various kinds of medical complications [41]. In addition, adiponectin has been reported to possess a direct tumor suppressive effect on HCC [42, 43]. These results suggest that hypoadiponectinemia in obesity could be a risk factor for HCV-related liver cancer development as well as NASH. However, there have been conflicting results as to the relationship between adiponectin and HCC in CHC patients as discussed in detail below. A prospective study by Nkontchou et al. [44] reported that a higher HOMA-IR index, but not serum adiponectin levels, was a risk factor for HCC development in cirrhotic patients with hepatitis C in univariate and multivariate analyses. Hung et al. [45] also showed that IR measured by HOMA-IR, but not adiponectin, was significantly associated with HCC development in CHC patients. These results suggest that adiponectin may not play a major role in HCVrelated hepatocarcinogenesis. On the other hand, a large scale retrospective study conducted by Arano et al. [25] showed that high serum adiponectin levels were independently associated with higher risk of future HCC development in CHC patients. When compared with the study by Nkontchou et al. [44], correlations between serum adiponectin levels and clinical parameters were similarly observed in the two studies. However, a major difference of each conclusion regarding the association between adiponectin and liver cancer development might be caused by the proportion of cirrhotic patients enrolled in each study. In the study by Nkontchou et al., all patients were diagnosed as cirrhotic by liver biopsy, whereas in the study by Arano et al., about onethird of the patients were clinically diagnosed as cirrhotic. Thus, the different results between the two studies suggest that adiponectin may be a surrogate marker of severity of
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liver disease or play some role in the progression of chronic hepatitis. Furthermore, from the results of these studies, hypoadiponectinemia is not a major reason as to why obesity promotes hepatocarcinogenesis in patients with CHC. Khattab et al. also showed a similar result in that patients with CHC and high serum adiponectin levels may face a higher risk of developing liver cancer. IR, as measured by HOMA-IR, was significantly associated with HCV-related HCC [46]. These findings suggest that adiponectin may be tumorigenic or indicate a liver state independently of other clinical parameters. In fact, a recent report showed that the expression of adiponectin was significantly increased in a large number of HCC patients and adiponectin could increase cell proliferation in a dose-dependent manner in vitro [47]. Some studies assessed a potential association between adiponectin isoforms and HCC. Circulating adiponectin exists in several isoforms, including low- (trimer; LMW), middle- (hexamer; MMW), and high-molecular-weight (12–18-mer; HMW) forms, each of which may exert distinct functions [16]. Recent evidence suggests that HMW adiponectin is more biologically active with regard to insulin sensitivity [48]. In addition, the ratio of HMW adiponectin to total adiponectin (HMWR) was reported to be predictive of insulin resistance, metabolic syndrome, and cardiovascular disease [49, 50]. In this context, Sumie et al. concluded that serum total and HMW adiponectin levels were predictors of liver fibrosis, but not prevalence of HCC in patients with HCV infection. Moreover, low serum adiponectin levels were significantly associated with worse histological grades of HCC [51]. We have also mentioned that both HMW adiponectin and MLMW adiponectin levels were elevated in patients with CHC, and a higher MLMW adiponectin level was an independent risk factor for HCC development. These findings suggest that an elevated MMW or LMW adiponectin level may represent a particular liver disease state independently of other clinical parameters [23]. Thus, the association between adiponectin and HCC should be further elucidated. In conclusion, adiponectin might be one of the important participants in the pathogenesis of CHC. However, the relationship between adiponectin and disease severity of CHC is controversial and complicated. Therefore, many aspects of their action and the influence of adiponectin on genotype, insulin resistance, steatosis, inflammation, fibrosis and hepatocarcinogenesis in CHC need to be further investigated. Conflict of interest of interest.
The authors declare that they have no conflict
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CLINICAL REVIEW
Adiponectin in chronic hepatitis C Toru Arano • Hayato Nakagawa • Hitoshi Ikeda Kazuhiko Koike
•
Received: 21 July 2013 / Accepted: 22 July 2013 / Published online: 14 August 2013 Ó Springer Japan 2013
Abstract White adipose tissue has been increasingly recognized as an important endocrine organ that secretes a number of biologically active adipokines. Adiponectin, one of the major adipokines, possesses anti-inflammatory and insulin-sensitizing properties, and its serum levels typically decline with increasing body weight. Hypoadiponectinemia has been implicated in the development of obesity-related morbidities such as dyslipidemia and cerebrovascular disease. In addition, hypoadiponectinemia has been reported to enhance hepatic steatosis, inflammation, fibrosis, and hepatocarcinogenesis in animal models or clinical liver diseases. Chronic hepatitis C (CHC) has some features which allow it to be recognized not only as a viral disease but also as a metabolic liver disease that encompasses insulin resistance, inflammation, steatosis and fibrosis. CHC is another disease in which adipokines may represent a link between viral infection and steatosis, or metabolic disturbance. In this report, data indicating a possible role of adiponectin in CHC are summarized. Keywords Adiponectin Chronic hepatitis C Hepatocellular carcinoma T. Arano (&) Department of Gastroenterology, Toshiba General Hospital, 6-3-22 Higashi-ooi, Shinagawa-ku, Tokyo 140-8522, Japan e-mail: [email protected] H. Nakagawa K. Koike Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan H. Ikeda Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Introduction The main function of white adipose tissue (WAT) is energy storage and, as such, it plays an important role in energy homeostasis; it stores energy in the form of triglycerides during nutritional abundance and releases it as free fatty acids [1, 2]. While WAT provides an advantage for survival in times of starvation, excess WAT is now linked to obesity-related health problems in the current nutritionally rich environment. Regulated by multiple hormonal signals, nuclear hormone receptors [3, 4], and central nervous systems [5], WAT has been increasingly recognized as an important endocrine organ that secretes a number of biologically active ‘adipokines’ [6–10]. Some of these adipokines have been shown to directly or indirectly affect insulin sensitivity through modulation of insulin signaling and the molecules involved in glucose and lipid metabolism [11]. Of these adipokines, adiponectin has recently attracted attention because of its anti-diabetic and anti-atherogenic effects and is expected to be a novel therapeutic tool for diabetes and the metabolic syndrome [12]. However, obesity-induced dysregulation of adipokines—cytokines secreted by WAT—is considered to play a key role in the context of liver diseases [13, 14]. WAT controls the functions of other organs through the secretion of various adipokines such as leptin, adiponectin, tumor necrosis factor a (TNFa), interleukin-6 (IL-6), and resistin. Obesity with visceral fat accumulation increases the serum levels of leptin, TNFa, IL-6, and resistin, and decreases serum adiponectin levels [13, 14]. These adipokines flow directly into the liver through the portal vein and exert a variety of effects on liver diseases [15]. Adiponectin, one of the major adipokines, possesses anti-inflammatory and insulin-sensitizing properties, and
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its serum levels typically decline with increasing body weight [16]. Hypoadiponectinemia has been implicated in the development of obesity-related morbidities such as dyslipidemia and cerebrovascular disease [17–19]. In addition, hypoadiponectinemia has been reported to enhance hepatic steatosis, inflammation, fibrosis, and hepatocarcinogenesis in animal models of liver diseases [20– 22]. Indeed, reduced adiponectin levels were found in patients with nonalcoholic steatohepatitis (NASH) and were associated with increased steatosis and necroinflammation in the liver. However, the role of adiponectin in hepatitis C virus (HCV)-induced chronic hepatitis is still not understood and the relationship between adiponectin level and disease severity remains controversial. In this paper, we discuss adiponectin and chronic hepatitis C (CHC) based on knowledge gained over recent years.
Clin J Gastroenterol (2013) 6:259–263
Insulin resistance (IR) There have been only a few clinical studies designed to investigate the association between adiponectin and IR. IR is a specific feature of CHC, associated especially with genotypes 1 and 4, and high serum HCV RNA levels [33]. A study by Chen et al. [29] reported that IR, serum visfatin, and adiponectin levels are reportedly associated with metabolic disorders in CHC patients. Liver inflammation and steatosis
CHC has some features which allow it to be recognized not only as a viral disease but also as a metabolic liver disease that encompasses insulin resistance, steatosis, inflammation, and fibrosis. CHC is another disease in which adipokines may represent a link between viral infection and steatosis, or metabolic disturbance [23, 24]. The associations between adiponectin and various parameters in CHC have been reported as follows. There are some studies about the differences in serum adiponectin levels in CHC and healthy controls. Several studies reported that serum adiponectin levels were higher in patients with CHC than in healthy controls in Japan, Egypt and European countries [25–28]. On the other hand, a study by Chen et al. [29] reported that serum adiponectin levels were significantly lower in CHC patients compared with healthy controls.
A study by Cua et al. [34] reported that adiponectin was not associated with histological features of chronic HCV infection except for TNFa which correlated with portal or periportal inflammation. On the other hand, in a study by Jonsson et al. [35], there was a significant increase in serum adiponectin and hepatic adiponectin immunoreactivity with increasing inflammation. A study by Khattab et al. [36] reported that adiponectin correlates with IR and with the different stages of liver injury in patients with HCV-4. A noninterventional multicenter study by Aksu et al. reported that hepatic steatosis was correlated negatively with adiponectin, whereas the increase in age, the presence of IR, and the decrease in adiponectin levels were the significant predictors of hepatic steatosis. These findings indicate a significant relationship between hepatic steatosis and adiponectin level, but not with viral load in Turkish patients with CHC [37]. A study by Petit et al. [38] reported that steatosis was significantly associated with low adiponectin concentration, age, HCV genotype 3, and aspartate aminotransferase level. A study by Zografos et al. [39] reported that lower adiponectin and higher TNFa at baseline were identified as independent predictors of liver steatosis in CHC patients with genotype 3.
Viral load
Fibrosis
A study by Liu et al. [30] reported that high HCV load and genotype 2 were significantly associated with lower serum adiponectin levels, but serum adiponectin levels did not correlate with other clinical or histologic parameters. On the other hand, a study by Khattab et al. [31] reported that neither serum adipocytokines nor homeostasis model assessmentestimated insulin resistance (HOMA-IR) was correlated with viral load. A study by Derbala et al. [32] concluded that adiponectin changes are not related to viral load, insulin resistance or other demographic data, suggesting that this change is histologically related. Similarly, in our report, serum adiponectin levels did not correlate with hepatitis C viral factors, such as viral load or serotype [25].
A study by Korah et al. [27] found serum adiponectin levels were elevated in association with hepatic fibrosis, but decreased in steatosis in male patients with HCV genotype 4. A study by Corbetta et al. [26] reported that patients with none or mild fibrosis showed similar serum adiponectin levels to those in healthy controls, while hyperadiponectinemia was associated with moderate to severe stages of fibrosis. To investigate the localization of adiponectin in the liver, we performed immunohistochemical staining for adiponectin using liver biopsy samples. Adiponectin was stained primarily in hepatocytes, and the staining intensity tended to be higher according to the progression of fibrosis. Additionally, serum adiponectin
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levels were higher in patients with strong staining for adiponectin than in patients with weak staining [23]. Collectively, it remains to be clarified whether serum adiponectin levels would be associated with viral load, genotype, and response to antiviral therapy, insulin resistance, and liver histology such as steatosis, inflammation, and fibrosis in CHC. Hepatocellular carcinoma (HCC) Obesity and metabolic syndrome have been found to be associated with hepatocarcinogenesis in CHC as well as in NASH [15, 40]. In a study by Ohki et al., the risk of HCC in patients with CHC increases in association with body mass index in a wide range of values, from underweight to obesity. Furthermore, a study by Chen et al. showed that extreme obesity was independently associated with a fourfold risk of HCC among CHC patients. Serum levels of adiponectin typically decline with increasing body weight and hypoadiponectinemia is associated with various kinds of medical complications [41]. In addition, adiponectin has been reported to possess a direct tumor suppressive effect on HCC [42, 43]. These results suggest that hypoadiponectinemia in obesity could be a risk factor for HCV-related liver cancer development as well as NASH. However, there have been conflicting results as to the relationship between adiponectin and HCC in CHC patients as discussed in detail below. A prospective study by Nkontchou et al. [44] reported that a higher HOMA-IR index, but not serum adiponectin levels, was a risk factor for HCC development in cirrhotic patients with hepatitis C in univariate and multivariate analyses. Hung et al. [45] also showed that IR measured by HOMA-IR, but not adiponectin, was significantly associated with HCC development in CHC patients. These results suggest that adiponectin may not play a major role in HCVrelated hepatocarcinogenesis. On the other hand, a large scale retrospective study conducted by Arano et al. [25] showed that high serum adiponectin levels were independently associated with higher risk of future HCC development in CHC patients. When compared with the study by Nkontchou et al. [44], correlations between serum adiponectin levels and clinical parameters were similarly observed in the two studies. However, a major difference of each conclusion regarding the association between adiponectin and liver cancer development might be caused by the proportion of cirrhotic patients enrolled in each study. In the study by Nkontchou et al., all patients were diagnosed as cirrhotic by liver biopsy, whereas in the study by Arano et al., about onethird of the patients were clinically diagnosed as cirrhotic. Thus, the different results between the two studies suggest that adiponectin may be a surrogate marker of severity of
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liver disease or play some role in the progression of chronic hepatitis. Furthermore, from the results of these studies, hypoadiponectinemia is not a major reason as to why obesity promotes hepatocarcinogenesis in patients with CHC. Khattab et al. also showed a similar result in that patients with CHC and high serum adiponectin levels may face a higher risk of developing liver cancer. IR, as measured by HOMA-IR, was significantly associated with HCV-related HCC [46]. These findings suggest that adiponectin may be tumorigenic or indicate a liver state independently of other clinical parameters. In fact, a recent report showed that the expression of adiponectin was significantly increased in a large number of HCC patients and adiponectin could increase cell proliferation in a dose-dependent manner in vitro [47]. Some studies assessed a potential association between adiponectin isoforms and HCC. Circulating adiponectin exists in several isoforms, including low- (trimer; LMW), middle- (hexamer; MMW), and high-molecular-weight (12–18-mer; HMW) forms, each of which may exert distinct functions [16]. Recent evidence suggests that HMW adiponectin is more biologically active with regard to insulin sensitivity [48]. In addition, the ratio of HMW adiponectin to total adiponectin (HMWR) was reported to be predictive of insulin resistance, metabolic syndrome, and cardiovascular disease [49, 50]. In this context, Sumie et al. concluded that serum total and HMW adiponectin levels were predictors of liver fibrosis, but not prevalence of HCC in patients with HCV infection. Moreover, low serum adiponectin levels were significantly associated with worse histological grades of HCC [51]. We have also mentioned that both HMW adiponectin and MLMW adiponectin levels were elevated in patients with CHC, and a higher MLMW adiponectin level was an independent risk factor for HCC development. These findings suggest that an elevated MMW or LMW adiponectin level may represent a particular liver disease state independently of other clinical parameters [23]. Thus, the association between adiponectin and HCC should be further elucidated. In conclusion, adiponectin might be one of the important participants in the pathogenesis of CHC. However, the relationship between adiponectin and disease severity of CHC is controversial and complicated. Therefore, many aspects of their action and the influence of adiponectin on genotype, insulin resistance, steatosis, inflammation, fibrosis and hepatocarcinogenesis in CHC need to be further investigated. Conflict of interest of interest.
The authors declare that they have no conflict
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