Changes in Clinical Characteristics of Non-B, Non-C Hepatocellular Carcinoma

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1 293 Original Article St. Marianna Med J. Vol. 36, pp , 2008 Changes in Clinical Characteristics of Non-B, Non-C Hepatocellular Carcinoma Toshiya Ishii 1, Michihiro Suzuki 1, Nobuyuki Matsumoto 1, Norie Yamada 1, Masaru Okamoto 1, Hiroki Ikeda 1, Minoru Kobayashi 1, Hideaki Takahashi 1, Yoshiki Katakura 1, Kotaro Matsunaga 1, Chiaki Okuse 1, Jyunki Koike 2, Hiroshi Yotsuyanagi 3, Shiro Maeyama 4,andFumio Ito 1 Received for Publication: August 19, 2008 Abstract The aim of this study is to describe changes in clinical characteristics associated with the rising trend in the incidence of non-b non-c HCC NBNC-HCC in patients who are negative for both serum HBs antigen and HCV antibody in St. Marianna University Hospital. A total of 59 patients with NBNC-HCC diagnosed during the 6-year period from 2001 to 2006 recent period were divided into 4 groups according to history of excessive alcohol abuse AL-HCC, primary biliary cirrhosis PBC-HCC, autoimmune hepatitis AIH- HCC, and unknown cause Cryptogenic-HCC. We investigated the clinical characteristics at the age of diagnosis of HCC in the recent period compared with the 6-year period between 1995 and 2000 prior period. The incidence of NBNC-HCC patients in all HCC patients ranged 19, it was significantly increased from the 10 seen during the prior period P0.01. AL-HCC were seen in 48, Cryptogenic- HCC in 48, those account for the majority of NBNC-HCC. Comparison with the prior period, the incidence of both AL-HCC and Cryptogenic-HCC patients in NBNC-HCC patients showed no change, but the numbers of patients showed a 2.6-fold increase in both HCC. Women accounting for 27 of NBNC- HCC cases, significantly increased from the prior period 4 P0.05. It is caused by the number of women patients in Cryptogenic-HCC. In Cryptogenic-HCC, the mean BMI was significantly higher in the recent period 27.4 kgm 2 than in the prior period P0.05. About half of the patients had diabetes andor hypertension, 32 had coexisting another sites of cancer and 80 were obese. Six patients had developed HCC from non-alcoholic steatohepatitis NASH, the mean age at initial diagnosis was 69.7 years, and all were obese. Two patients with NASH-HCC showed disease originating in noncirrhotic liver. The incidence of NBNC-HCC has recently increased. This may be related to the change of lifestyles, including increased alcohol consumption and the increased incidence of metabolic syndrome, which results in the development of chronic liver disease. Lifestyle-related chronic liver disease should be carefully followed and monitored to detect HCC. Key Words: Non-B non-c hepatocellular carcinoma NBNC-HCC, Non-alcoholic steatohepatitis NASH, Lifestyle-related chronic liver disease 1 Department of Internal Medicine, Division of Gastroenterology and Hepatology, St. Marianna University School of Medicine. 2 Department of Diagnositic Pathology, St. Marianna University School of Medicine. 3 Department of Internal Medicine, Division of Infectious Diseases, University of Tokyo. 4 Kita-kashiwa General Rehabilitation Hospital. 11

2 294 Ishii T Suzuki M et al Introduction It is generally considered that more than 90 of hepatocellular carcinoma HCC in Japan occur in patients with chronic liver disease due to hepatitis B virus HBV andor hepatitis C virus HCV 1, 2. However, the incidence of non-b, non-c HCC NBNC-HCC in patients who are negative for both serum HBs antigen and HCV antibody has recently increased. According to the 17th nationwide followup survey of primary liver cancer in Japan 3, NBNC-HCC accounts for up to 15 of all HCC patients. Although the reason for this increase has yet to be clarified, two diseases are suggested as contributing factors. The first one is chronic alcoholic liver disease. The estimated annual ethanol intake per person is about 9 liters, representing a 4.5-fold increase from 60 years ago 4. When considering the fact that alcoholic liver disease is one of the most common causes of chronic liver disease in developed countries 5, this suggests that chronic alcoholic liver disease associated with increased alcohol consumption may be one of the causes for increases in NBNC-HCC. The other is non-alcoholic steatohepatitis NASH. Non-alcoholic simple fatty liver steatosis has been regarded as a reversible benign disease. However, simple fatty liver progresses to NASH in some cases. And a subset of these cases undergo further progression to cirrhosis and they sometimes develop HCC 6, 7. Recently, some cases of HCC developed in NASH have been reported in Japan 810. These reports raised an interest, which was focused on NASH not only as a progressive chronic liver disease but also as a cause of NBNC-HCC not associated with alcohol or autoimmunity. Since St. Marianna University Hospital plays a central role in Kawasaki area, socioeconomical andor sociocultural changes of Kawasaki area may a#ect characteristics of our patients. As it is important to clearly recognize the current epidemiologic feature of HCC in clinical practice, we planed this study to investigate changes in clinical characteristics associated with the rising trend in the incidence of NBNC-HCC in St. Marianna University Hospital. Patients and Methods 1. Patients Our study involved a total of 316 patients with HCC treated as inpatients during the 6-year period from 2001 to 2006 recent period at St. Marianna University Hospital. The diagnosis of HCC was made by the following: increase of serum tumor markers such as a-fetoprotein AFP and protein induced by vitamin K PIVKA-II, and positive finding at ultrasonography, CT, MRI. Pathological diagnosis was made based on liver biopsy. All patiens were divided into type C HCC HCV antibody -positive, type B HCC HBs antigen-positive, type BC HCC both positive and NBNC-HCC both negative. NBNC-HCC patients were further subdivided into 4 groups, according to: history of daily alcohol consumption 0.54 liters for 10 years AL-HCC; primary biliary cirrhosis PBC-HCC; autoimmune hepatitis AIH-HCC; and unidentified cause Cryptogenic-HCC. 2. Clinical characteristics Clinical data were collected from the patient and hospital medical records. Clinical characteristics including gender, age at initial diagnosis, Child- Pugh classification, HCC stage, body-mass index BMI, coexisting diseases: diabetes mellitus; hypertension; hyperlipidemia, HBc antibody HBc Ab positivity, and coexisting di#erent cancer at another site were compared with the 6-year period between 1995 and 2000 prior period. Considering clinical practice for NASH, we consider the year 2001 as a turning point, since the concept of NASH was focused as a theme of the annual meeting of the Japan Society of Hepatology of 2001, and after this meeting, NASH was widely recognized. Thus, we divided the recent period and prior period at Ethics This study was approved by the Bioethics Committee of St. Marianna University School of Medicine Approval No Statistical analysis Results are shown as the mean SD. The clinical factors were analyzed using the Student[s t-test, the c 2 test and the Mann-Whitney U-test P 0.05 was considered statistically significant Results 1. Clinical characteristics of NBNC-HCC In the recent period, NBNC-HCCs accounted for patients of 316 HCC patients. This frequency is significantly higher than that in the prior period 10 P0.01. The rate of type B was similar about 10 in both periods, whereas type C decreased significantly from 78 to 71 P0.05 Fig Gender, age at initial diagnosis, Child-Pugh 12

3 Changes of NBNC-HCC 295 Fig. 1. Compared the epidemiology of hepatocellular carcinoma HCC between the two periods, non-b non-c HCC NBNC-HCC patients were 59 patients 19 in recent period, 23 patients 10 in prior period. The frequency of NBNC-HCC was significantly higher in recent period than in prior period P0.05. C : HCV, B : HBV, BC :HBVHCV, NBNC : non HBV and non HCV. Table 1. Background of NBNC-HCC Recent Period vs Prior Period Table 2. BMI and Complications of NBNC-HCC Recent Period vs Prior Period classification, and HCC stage Table 1 Women accounted for 27 of NBNC-HCC cases. This ratio increased significantly from the prior period P0.05. There were no significant changes in the two periods in the mean age at initial diagnosis, the frequency of the patients with relatively good liver function Child-Pugh A and the frequency of advanced HCC stage III or IV. 2 BMI, coexisting diseases, HBc Ab positivity and coexisting di#erent cancer at another site Table 2 In NBNC-HCC patients, the mean BMI was 25.3 kgm 2 and more than 40 had coexisting diabetes andor hypertension. No significant change was observed from the prior period. The incidence of HBcAb positivity was 34, no change was seen from the prior period. Coexisting di#erent cancer at another site was present in 17 of NBNC-HCC patients, an increase from the prior period. Also 80 of NBNC-HCC patients with coexisting di#erent cancer at another site were obese BMI25 kg 13

4 296 Ishii T Suzuki M et al Fig. 2. Compared the epidemiology of NBNC-HCC between the two periods, the frequency of AL-HCC and Cryptogenic-HCC showed no change. AL: alcohol, PBC: primary biliary cirrhosis, AIH: autoimmune hepatitis, Cryptogenic: unknown cause. Table 3. Background of Cryptogenic-HCC and Al-HCC Recent Period vs Prior Period m 2. 3 Etiology Fig. 2 Among patients with NBNC-HCC, forty eight percent 28 patients had AL-HCC, 1 1 patient had PBC-HCC, 3 2 patients had AIH-HCC, and patients had Cryptogenic-HCC. Equal percentages of patients had AL-HCC and Cryptogenic-HCC. Actual numbers of AL-HCC and Cryptogenic-HCC showed a 2.6-fold increase in comparison with the prior period. 2. Comparison between Cryptogenic-HCC and AL- HCC Since most of the NBNC-HCC patients were assigned to AL-HCC or Cryptogenic-HCC, we analyzed their clinical characteristics, and compared the di#erence between these two groups. 1 Gender, age at initial diagnosis, Child-Pugh classification, and HCC stage Table 3 Thirty nine percent of the patients with Cryptogenic-HCC were female, and there was a significant 14

5 Changes of NBNC-HCC 297 Table 4. BMI and Complications of Cryptogenic-HCC and AL-HCC Recent Period vs Prior Period increase compared to the prior period. No significant change of the gender ratio was observed in AL-HCC. Age at initial diagnosis did not significantly di#er from the prior period. Child-Pugh classification and HCC stage were not significantly changed from the prior period in both groups. 2 BMI, coexisting diseases, HBc Ab positivity and coexisting di#erent cancer at another site Table 4 In Cryptogenic-HCC, the mean BMI was significantly higher in the recent period 27.4 kgm 2 than in the prior period 23.5 kgm 2 P0.05. The percentage of obese patients increased significantly from 27 to 64 P0.05. About half of the patients had diabetes andor hypertension, but no significant increase was apparent. The incidence of HBc Ab positivity in Cryptogenic-HCC and AL- HCC was about 30 through both periods. However, thirty two percent 9 patients of patients with Cryptogenic-HCC had coexisting di#erent cancer at another site 4 gastric cancers, 3 colon cancers, breast cancer and uterine cancer, and 89 of these patients 8 patients were obese. In AL-HCC, BMI and coexisting disease di#erent cancer at another site rates were unchanged from the prior period. 3. HCC originating from NASH Table 5 We could obtain noncancerous tissue samples 17 patients among 39Cryptogenic-HCC patients. Thirty five percent of patiens 6 patients showed histological findings typical of NASH NASH- HCC. Mean age at initial diagnosis was 69.7 years Table 5. Background, BMI and Complications of NASH-HCC in Recent Period and all were obese. Two patients with NASH-HCC showed disease originating in noncirrhotic livers 11, 12. Of the patients with NASH-HCC, 50 3 patients had diabetes, 33 2 patients had hypertension, and 33 2 patients had coexisting di#erent cancer at another site uterine and colon cancer. In the prior period, NASH-HCC was only seen in 1 patient. 15

6 298 Ishii T Suzuki M et al Discussion According to Vital Statistics of Japan by the Ministry of Health, Labor, and Welfare 13, 33,662 patients died from HCC in This represents 36.7 deaths per 100,000 men and 17.2 deaths per 100,000 women. This frequency ranks 3rd after lung and stomach cancer in men, and 5th after stomach, lung, colon, and breast cancer in women. This clearly makes HCC an important malignant tumor. The peak number of HCC-related deaths was 34,637 in 2002 and decreased in This was attributed to decreases in hepatitis virus-positive patients as a result of prevention with screening of blood and blood-component products and use of disposable syringes. In addition, hepatitis B vaccine and interferon treatment for hepatitis C infection have contributed to reductions in hepatitis patients with virus infection. However, the number of HCCrelated deaths has plateaued since This suggests that a decline in hepatitis virus infection is no longer necessarily decreasing the incidence of HCC. Identification of pathogenic factors associated with the increasing incidence of NBNC-HCC is thus important. Our findings show that NBNC-HCC accounted for 19 of all HCC cases between 2001 and 2006 recent period, a significant increase from the 10 seen between 1995 and 2000 prior period. A similar result has been reported by Hatanaka et al. 14, supporting generalization of our result. To investigate the causes of increases in NBNC-HCC, we extracted AL-HCC and Cryptogenic-HCC patients, since most of the NBNC-HCC patients were assigned to these two etiological groups. And we compared the di#erence of the features between the recent period and the prior period. Frequencies of AL-HCC and Cryptogenic- HCC were not significantly changed, but the number of each HCC was increased indicating increases of both group patients. Since HCC is supposed to arise from a liver su#ering from chronic liver disease, this increase should be explained by increases of chronic liver disease. Concerning AL-HCC group, alcoholic liver disease is attributed to alcohol consumption. Total alcohol consumption has recently been increasing in Japan 5. This suggests that the increasing incidence of HCC is due to an increase in patients with alcoholic hepatic fibrosis and cirrhosis. On the other hand, concerning Cryptogenic-HCC in the recent study, about two-thirds of patients were obese, a significant increase from the prior period. The number of women increased and age at initial diagnosis was higher. This tendency clearly di#ers from that for AL-HCC, and these findings points to the involvement of NASH in these patients. Calle et al. 15 reported that the risk of HCC in severely obese persons compared to non-obese controls was 4.52-fold higher in men and 1.68-fold higher in women. In addition, in patients with cirrhosis who underwent liver transplant, Nair et al. found that obesity significantly increased the risk of HCC 16. These reports strongly suggests that obesity is a risk factor for HCC in spite of existence of virus. On the other hand, about half of the patients with Cryptogenic-HCC also had diabetes. El-Serag et al. 17 reported that in diabetic patients, a 3-fold increase in HCC incidence occurred even in the absence of chronic liver disease. In another study from Japan, Inoue et al. 18 reported that the risk of HCC in diabetics compared to nondiabetics was 2.42-fold higher in men and 1.94-fold higher in women. Combinding, these findings suggest that diabetes is also a risk factor for HCC. We thought that obesity may be a stronger risk factor than diabetes for HCC in Cryptogenic-HCC, because the mean BMI was significantly higher in the recent period than in the prior period. Obesity and diabetes are closely linked to and included as diagnostic criteria for metabolic syndrome. NASH is considered to be a hepatic phenotype of metabolic syndrome. Recent interest has focused on NASH as a progressive chronic liver disease, in some patients with metabolic syndrome 610. Our findings of NASH-HCC seen in 35 of Cryptogenic-HCC patients, suggest the importance of treatment for NASH to prevent HCC. The term NASH was coined by Ludwig et al. in , representing a liver disease that resembles alcoholic liver disease, but occurs with no known history of alcohol abuse. NASH often progresses to cirrhosis, and even HCC may develop in some cases. However, in suspected NASH patients, whether diabetes, obesity or both are directly associated with progression to NASH-HCC remains an issue for further investigation. In 2 of the 6 patients, NASH-HCC originated in noncirrhotic livers. In previous reports, NASH-HCCs were seen in patients with higher age, male and advanced fibrosis, in addition to obesity and diabetes. The proposed mechanism is DNA damage due to oxidative stress 16

7 Changes of NBNC-HCC 299 in the setting of insulin resistance 20. Considering the reports about increased oxidative stress is also often reported in obesity and diabetes 21, 22, it seems to be an applicable mechanism for NASH. However, the mechanisms of NASH progression to cancer are yet to be elucidated. In this study, obese patients with Cryptogenic- HCC displayed a high rate of coexisting another site of cancer, and two-thirds of those patients had diabetes. Obese patients with Cryptogenic-HCC had coexisting di#erent cancer at another site: 4 gastric cancers and 2 colon cancers in males, breast cancer and uterine cancer in females. Calle et al. 15 reported that obese patients also displayed higher risk of pancreatic and stomach cancer in males and uterine and kidney cancer in females, compared to nonobese patients. On the other hand, diabetes also conferred a higher risk of kidney and pancreatic cancer in men and ovarian cancer in women 18. These findings suggest that obesity may be stronger risk factors than diabetes for coexisting di#erent cancers at another site. When NBNC-HCC is diagnosed along with obesity and or diabetes, careful evaluation for another site of cancer is important. HBcAb positivity was about 30 in NBNC- HCC. There were no di#erences between AL-HCC and Cryptogenic-HCC. And no patient with HBcAb positivity was obtained in NASH-HCC. These findings suggested that HBcAb positivity was not a clear explanation for hepatocarcinogenesis in NBNC-HCC. The risks of HCC in chronic liver disease due to hepatitis B and C infections are well understood and evaluated. However, screening for NBNC- HCC remains inadequate, with many patients having advanced stage of HCC when first diagnosed. Our data suggest that an increase in NBNC-HCC is likely in the future. Screening for AL-HCC and NASH-HCC should be established in chronic liver disease without hepatitis virus infections. Conclusions The incidence of NBNC-HCC has recently increased. This may be related to the change of lifestyle, including increased alcohol consumption and the increased incidence of metabolic syndrome, which results in the development of chronic liver disease. Lifestyle-related chronic liver disease should be carefully followed and monitored to detect chronic liver disease which may result in HCC. References 1 Johnson PJ and Williams R. Cirrhosis and the etiology of hepatocellular carcinoma. J Hepatol 1987; 4: Ikeda K, Saitoh S, Koida I, Arase Y, Tsubota A, Chayama K, Kumada H and Kawanishi M. A multivariate analysis of risk factors for hepatocellular carcinoma: a prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 1993; 18: The Liver Cancer Study Group of Japan: Report of the 17th follow-up survey of primary liver cancer Acta Hepatologica Jpn 2007; 48: in Japanese. 4 Schuppan D and Afdhal NH. Liver cirrhosis. Lancet 2008; 371: National Tax Agency: The 131th National Tax Agency Annual Statistics Report 2005: 1719 in Japanese. 6 Matteoni CA, Younnossi ZM, Gramlich T, Boparai N, Liu YC and McCullough AJ. A spectrum of clinical and pathological severity. Gastroenterology 1999; 116: Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM and Lok AS. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology 2002; 36: Shimada M, Hashimoto E, Taniai M, Hasegawa K, Okuda H, Hayashi N, Takasaki K and Ludwig J. Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J Hepatol 2002; 37: Baba S, Suzuki M, Kobayashi M, Ikeda H, Takahashi H, Nakazawa M, Fukuda Y, Nagase Y, Katakura Y, Matsunaga K, Ishii T, Okuse N, Matsumoto N, Okuse C, Koike J, Maeyama S and Itoh F. A case of Hepatocellular Carcinoma HCC Originating from Long Term Observation for Non-alcoholic Steatohepatitis NASH. St. Marianna Med J 2006; 34: in Japanese. 10 Ikeda H, Suzuki M, Takahashi H, Kobayashi M, Okuse N, Moriya H, Koike J, Maeyama S, Yotsuyanagi H and Itoh F. Hepatocellular carcinoma with silent and cirrhotic non-alcoholic steatohepatitis, accompanying ectopic liver tissue attached to gallbladder. Pathol Int 2006; 56: Brunt EM, Janney CG, Di Bisceglic A, Neush- 17

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9 Changes of NBNC-HCC 301 B C recent period B C NBNC-HCC 59 AL-HCC PBC-HCC AIH-HCC Cryptogenic-HCC prior period NBNC-HCC HCC NBNC-HCC 19 prior period 10 P0.01 AL-HCC Cryptogenic-HCC 48 prior period 2.6 Cryptogenic-HCC BMI 27.4 kgm 2 prior period P NASH 6 NBNC-HCC HCC