Relative incidence of primary liver cancer in cirrhosis in Austria. Etiological considerations

ABSTRACT— The incidence of primary liver cancer (PLC) was assessed in 652 patients (429 male, 223 female) with liver cirrhosis. By the end of the study 416 (64%) of all patients had died. The autopsy rate was 65%. PLC developed in 73 patients. Histologically, 67 cases were classified as hepatocellular (HCC), one as mixed hepatocellular-cholangiocellular and five as cholangiocellular carcinoma. In 30 cases, HCC was confirmed within a year of diagnosis of cirrhosis, and in the remaining 37 cases HCC developed 2–13 years later. At autopsy, the frequency of HCC was almost twice as high in males (27%) as in females (15%) (p<0.025). This difference occurred in alcoholic and posthepatitic cirrhosis but not in cryptogenetic cirrhosis. HBsAg was detected in 19.0% of male and 9.2% of female patients (p<0.01). Comparison of patients with and without HCC revealed no significant differences in the prevalence of HBsAg. These data indicate that HCC is common in Austrian patients with cirrhosis, representing 60% of all malignant tumors in this group. In view of the high HBsAg carrier rate and the prevalence of chronic alcoholism in patients with cirrhosis, it is suggested that the two factors together lead to an increased risk of cirrhosis followed by an increased incidence of HCC.     

原发性肝癌合并与不合并肝硬化患者年龄及乙型肝炎病毒血清学特点比较

目的探讨原发性肝癌（PHC）合并肝硬化与无肝硬化患者年龄及HBV血清学特点。方法回顾性分析经影像学检查及甲胎蛋白（AFP）测定诊断为PHC的患者547例,分为有肝硬化和无肝硬化两组,统计分析并比较其年龄分布及HBV血清学标记的特点。结果合并肝硬化与无肝硬化患者分别为265例及282例,两组伴HBV感染者分别为221例、256例。合并肝硬化的肝癌患者男女比例为7.83∶1;60岁以下的男性肝癌患者年龄分布无明显差异,无肝硬化的男性肝癌患者60岁以上比例明显高于有肝硬化者（P〈0.005）。合并肝硬化的男性肝癌患者HBV感染率40岁以下年龄组最高（96.67%）,而HBeAg血清学转换率以40～60岁年龄段最高（89.47%）;无肝硬化者HBV感染率40～60岁年龄段最高（90.43%）,但HBeAg血清学转换率最低（80%）。结论合并肝硬化的PHC患者中,男性占大多数,而且早年HBV感染率高;无肝硬化的PHC患者中,老年人占多数;HBeAg血清学转换率高的人群肝癌发病率相对较高。     

慢性乙型肝炎、乙型肝炎肝硬化及原发性肝癌患者HBV-X基因突变分析

目的研究慢性HBV感染者,如慢性乙型肝炎(CHB)、乙型肝炎肝硬化(LC)、原发性肝癌(PLC)患者血清中HBV-X基因序列的突变与肝癌发生的关系。方法收集2011-2013年间于重庆医科大学附属第二医院就诊的慢性HBV感染者血清共89例,从血清中提取HBV DNA,扩增全长HBV-X基因序列,经测序后与已知HBV-X基因相应序列比较该患者体内HBV-X基因变异位点以及变异形式,并用卡方检验、单因素方差分析处理数据,NCBI的genotype工具测定基因型。结果所有患者均属于B/C基因型,HBeAg阳性患者中B基因型占46.2%,C基因型占53.8%;HBeAg阴性患性中B基因型占81.2%,C基因型占18.8%(P=0.001)。在PLC组中,启动子(BCP)区的突变显著高于CHB、LC(69.2%vs34.4%和61.3%,P0.05),且nt1821位点存在明显的T碱基的缺失(88.5%vs 53.1%和71%,P=0.014)。在CHB、LC中,C基因型BCP的双突变率显著高于B基因型(61.5%vs 15.8%,P=0.007;83.3%vs 47.4%,P=0.045),HBV DNA低病毒载量(≤106拷贝/ml)中BCP的突变率较高病毒载量(106拷贝/ml)更显著(81.3%vs 47.9%,P=0.015)。结论 BCP区的双突变及nt1821位点的缺失可能与PLC的发生密切相关。     

Risk of HBV reinfection after liver transplantation in HBsAg-positive cirrhosis: Primary hepatocellular carcinoma is not a predictor for HBV recurrence

Abstract: Two hundred and twenty-eight patients who underwent orthotopic liver transplantation for hepatitis B-related cirrhosis in 11 European Liver Transplant Centers were collected. The male/female ratio was 184/44, with a median age of 41 years (13–66). In 55 patients (24%) hepatocellular carcinoma was associated with liver disease. All cases were stratified for pre-orthotopic liver transplantation viral characteristics: HBV-DNA neg/HBeAg neg: 106 patients (47%), HBV-DNA neg/Delta pos: 80 (35.5%), HBV-DNA pos/HBeAg pos: 28 (12.5%), other 14 (5%). In 49 patients (21.4%) post-orthotopic liver transplantation passive prophylaxis with anti-HBs immunoglobulins was not followed, while in 179 patients the anti-HBs serum titer was kept above 100–200 mU/ml. Overall 5-year actuarial survival of the series was 54%. One hundred and eighty-five patients were evaluable for HBsAg reappearance in the serum at various intervals after orthotopic liver transplantation. Overall 3-year HBV-free survival of these patients was 55%. There was a significant difference in 3-year HBV-free survival between HBV-DNA neg (52%), HBV-DNA pos (13%) and Delta pos (73%) patients (p: 0.03). Sixty-three percent of patients in the prophylaxis group were HBV-free, compared to only 25% of untreated patients (p>0.001). Three-year HBV-free survival in patients with or without HCC was 44% and 59%, respectively. Cox-multivariate analysis revealed that only post-transplantation prophylaxis (p: 0.003) and pre-transplantation viral activity (p: 0.004) can be considered as independent factors affecting HBV recurrence. Candidates with hepatocellular carcinoma in HBV-cirrhosis should not be excluded from orthotopic liver transplantation, supporting the idea of a higher risk of post-transplantation viral reactivation.     

Changing relative roles of hepatitis B and C viruses in the aetiology of hepatocellular carcinoma in Greece. Epidemiological and clinical observations

Summary. Chronic infection with hepatitis B virus (HBV) has been reported in two-thirds of cases of hepatocellular carcinoma (HCC) in Greece from 1973 to 1995, while chronic hepatitis C virus (HCV) infection in 10% of them. We studied the roles of HBV and HCV in HCC in Greece between 1996 and 2000 compared with the past, and possible differences in clinical and laboratory characteristics of HBV- and HCV-related HCC. Complete clinical and laboratory data from 306 patients with HCC, diagnosed from January 1996 to December 2000, were analyzed. Chronic HBV and HCV infection were detected in 52.3 and 21.6% of the patients, respectively. The ratio of HBV- to HCV-related HCC was 2.42. Compared with the data prior to 1996, there was a 101.8% increase in the relative frequency of HCV ( P  < 0.0001) and an 11.8% decrease in that of HBV ( P  = 0.033), with a −56.3% change in the ratio of HBV- to HCV-related HCC cases. Statistically significant differences in the male/female ratio, median age and frequency of multifocal lesions were found in HBV- vs HCV-related HCC. Although HBV still represents the major aetiological factor of HCC in Greece, its role has significantly decreased in the last 5 years, while a more significant increase has occurred in HCV-related HCC. The two aetiological types of HCC differ in Greece in demographic, epidemiological and other features.     

Potential of laparoscopy in chronic liver disease with hepatitis B and C viruses

Aim: The definitive diagnosis of chronic liver disease is made either by a histological examination of a biopsy specimen or upon visualization of the liver surface at laparoscopy. The aim of this retrospective cohort study is to assess whether histological or laparoscopic findings are associated with hepatocellular carcinoma (HCC) development. Methods: A retrospective review of paired laparoscopy and histology reports was performed on 4124 hepatitis virus-positive patients who underwent laparoscopy: 2804 patients had hepatitis C virus (HCV group) and 1320 patients had hepatitis B virus (HBV group). Based on the irregularities of the liver surface, the laparoscopic findings were classified into three groups in progression order: smooth, irregular, or nodular. The histological findings were classified according to the extent of fibrosis into four stages (stages 1-4) in progression order. Results: The number of patients with HCC development was 565 in the HCV group and 115 in the HBV group. The Coxregression hazard model showed that HCC appearance in the HCV group was independently associated with laparoscopic findings (relative risk based on every progression of one rank [RR], RR = 4.31, P < 0.0001) and histological findings (RR = 2.56, P < 0.0001). In the HBV group, however, HCC appearance in was mainly associated with laparoscopic findings (RR = 2.12, P < 0.0001) compared to histological findings (RR = 1.13, P = 0.403). Conclusion: Our data indicate that laparoscopic findings of the liver are dominant predictors for HCC development compared with histological findings in patients with HBV.     

Profile, spectrum and significance of HBV genotypes in chronic liver disease patients in the Indian subcontinent

BACKGROUND AND AIM: Certain hepatitis B virus (HBV) genotypes have been alleged to be associated with the development of cirrhosis and hepatocellular carcinoma (HCC), and the response to interferon therapy in Taiwanese patients. We undertook to study the prevalence and significance of HBV genotypes in the Indian subcontinent. METHODS: One hundred and thirty histopathologically proven chronic HBV-infected patients, including 52 incidentally detected asymptomatic hepatitis B surface antigen (HBsAg)-positive subjects (IDAHS) with chronic HBV infection (group I), 48 cirrhotics (group II) and 30 hepatocellular carcinoma (HCC; group III) patients were studied. Hepatitis B virus genotypes were determined by using restriction fragment length polymorphism, and direct sequencing of the s gene including the 'a' determinant region. RESULTS: Only genotypes A (46%) and D (48%) were found in the chronic HBV-infected patients. A mixed infection with genotypes A and D was seen in 6% of patients. Genotype A was found in 42, 48 and 50%, and genotype D in 48, 50 and 47% of group I, II and III patients, respectively (P = NS). The patients who had mixed genotypes were significantly younger (P < 0.05). In group I (IDAHS) patients infected with genotype D, none had a histological activity index (HAI) of < four. Genotype D was significantly more common in group I patients with HAI > 4 as compared to genotype A (53 vs 32%, P < 0.05). Similarly, genotype D was associated with more severe liver diseases (61 vs 30%, P < 0.05). Genotype D was more prevalent in HCC patients of < 40 years of age, as compared to IDAHS (63 vs 44%, P = 0.06). CONCLUSIONS: (i) Hepatitis B virus genotypes A and D are prevalent in chronic liver disease patients of Indian origin; and (ii) HBV genotype D is associated with more severe diseases and may predict the occurrence of HCC in young patients.     

Combined hepatocellular and cholangiocellular carcinoma in a non-cirrhotic liver

Combined hepatocellular (HCC) and cholangiocellular carcinoma (CCC) (mixed carcinoma) is a rare subtype of primary hepatic carcinoma. We report a case of mixed carcinoma that developed in a non-cirrhotic liver, in a patient who was serologically negative for both hepatitis B and C viruses. A 65-year-old Japanese woman with a 25-year history of chronic rheumatoid arthritis had been treated with steroids and anti-inflammatory drugs, and was diagnosed by ultrasonography with an asymptomatic solitary tumor in the right lobe of the liver. On computed tomography scan and hepatic arteriography, the tumor was well enhanced by contrast medium in the early phase. Based on the findings of elevated serum alpha-feto protein (AFP, 245 ng/ml) and normal carcino-embryonic antigen (CEA, 2.6 ng/ml) levels, a preoperative diagnosis of hepatocellular carcinoma was made. Right lobectomy of the liver was performed on January 7, 1997. Histological examination showed that the resected tumor consisted of combined CCC cells and HCC cells in an intermingled form, with CCC being far more dominant than HCC. The tumor was therefore determined to be a combined carcinoma, subclassified as intermingled type. This case appears to indicate that mixed type carcinoma developed in a non-cirrhotic liver, with CCC being dominant; such a finding is extremely unusual, based on previously published reports. (Received Sept. 1, 1997; accepted Jan. 23, 1998)     

Hepatitis B virus DNA in patients with hepatitis B‐related liver cirrhosis with or without hepatocellular carcinomas: a matched case‐control study

OBJECTIVE: The relationship between serum viremia and the development of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV)‐related cirrhosis remains unclear. We aimed at calculating odds ratios (OR) for the presence of HCC over a range of HBV DNA levels in these patients. METHODS: Patients were identified retrospectively and 155 pairs of matched, treatment‐naive HBV‐related cirrhotic patients with and without HCC were recruited. Their serum HBV DNA levels were measured at HCC diagnosis, or at the equivalent age in non‐HCC patients, and correlations between the presence of HCC and different DNA levels were calculated using conditional logistic regression. RESULTS: The median HBV DNA level was significantly higher in HCC patients than in non‐HCC patients (5.15 vs 4.83 log₁₀ copies/mL, P = 0.024). The overall OR for HCC in patients with HBV DNA ≥ 3 log₁₀ copies/mL was 2.13, compared with patients with levels <3 log₁₀ copies/mL. Compared with patients with <3 log₁₀ copies/mL, the OR for HCC were 2.39 and 2.61 for patients with 4 to <5 and 5 to <6 log₁₀ copies/mL, respectively, while the OR for DNA levels of ≥6 log₁₀ copies/mL were not significantly different. CONCLUSION: In HBV‐related cirrhosis, a detectable serum HBV DNA was associated with the presence of HCC, but the likelihood of having HCC did not successively increase with increasing serum HBV DNA levels: patients with serum HBV DNA levels between 4 and <6 log₁₀ copies/mL were most likely to present with HCC.     

Changes in hepatitis B virus DNA levels and liver function after transcatheter arterial chemoembolization of hepatocellular carcinoma

Aim: Reports concerning changes in hepatitis B virus (HBV) status and liver function in hepatocellular carcinoma (HCC) during or after transcatheter arterial chemoembolization (TACE) have been rare and the results inconsistent. The objective of this retrospective study was to evaluate these parameters in a large cohort of HBV‐related HCC patients. Methods: One hundred and seventy‐two hepatitis B surface antigen positive HCC patients with Child–Pugh grade A or B liver disease who underwent 228 sessions of TACE were enrolled, and related clinical and laboratory data were analyzed. Results: In total, HBV reactivated in 33 (14.5%), remained stable in 152 (66.7%) and decreased in 43 (18.8%) sessions. Univariate analysis revealed that sex and HBV DNA levels correlated with changes in HBV DNA status after TACE, while hepatitis B e‐antigen (HBeAg), prothrombin time and chemotherapeutic agents were marginally significant factors. Multivariate analysis demonstrated that the major factors that influenced the HBV DNA status were baseline HBV DNA levels(P = 0.0002) and HBeAg (P = 0.0387). A comparison of the post‐TACE (30–90 days) liver function to the baseline revealed no significant differences. The reactivation group has the highest rate of exacerbation (12.1%) compared with the stable group (5.9%) and downregulation group (4.7%). Conclusion: HBV DNA changes after TACE included reactivated, decreased and stable HBV DNA levels. Although HBV reactivation did not necessarily result in exacerbation of liver damage and most HCC patients with Child–Pugh grade A and B tolerated TACE well, careful post‐procedure monitoring and managing is needed.     

Prevalence of hepatitis C virus antibodies in chronic liver disease and hepatocellular carcinoma patients in India

The prevalence of antibodies to hepatitis C virus (HCV) was investigated in 129 patients with chronic liver disease (85 with chronic active hepatitis and 44 with cirrhosis) and 53 patients with hepatocellular carcinoma. The commercially available second generation anti-HCV enzyme immunoassay kit was used. Antibodies to hepatitis C virus were detected in 16.2% of the patients with chronic liver disease and in 15.1% with hepatocellular carcinoma. Of the HCV positive patients in all groups 51.7% were positive for hepatitis B virus (HBV) markers indicating present or past infection. Prevalence of HBV markers in all the three groups (CAH, cirrhosis and HCC) was higher as compared with anti-HCV prevalence. These results suggest that HCV infection may not be a major cause of chronic liver disease and hepatocellular carcinoma in India and indicate the presence of other aetiological agents.     

Remote development of hepatocellular carcinoma in patients with liver cirrhosis type B serologically cured for HBs antigenemia with long-standing normalization of ALT values

In this report, we examine two patients with chronic hepatitis B virus (HBV) infection that had been diagnosed as precirrhosis or liver cirrhosis more than a decade previously. These patients had been cleared of HBsAg and had developed anti-HBs at a later time, yet hepatocellular carcinoma (HCC) eventually occurred. Both patients had been found negative for HBV DNA, using sensitive methods. Interestingly, a nontumor specimen of the liver obtained at surgical resection showed a marked reduction of fibrosis when compared to the histology observed when the patient was diagnosed as precirrhosis. Our findings suggest that the fibrosis from liver cirrhosis had been absorbed to a large extent during the long-term absence of active viremia and the normalization of alanine aminotransferase (ALT) levels. However, the cancer-prone biological characteristics of liver cirrhosis remained. Thus, patients with liver cirrhosis due to past chronic hepatitis B should be monitored carefully for the development of HCC even if HBV infection has been serologically resolved.     

Prognostic significance of liver stiffness for hepatocellular carcinoma and mortality in HBeAg‐negative chronic hepatitis B

Summary. The prognostic value of liver stiffness measurements for chronic hepatitis B (CHB) is not known. The present study aimed to investigate the use of transient elastography in predicting hepatocellular carcinoma (HCC) development and mortality in patients with CHB. Five hundred and twenty‐eight patients with HBeAg‐negative CHB underwent liver stiffness measurements and were prospectively followed up every 3–6 months for a median length of 35 months. The patients were divided into those with liver stiffness <10 kPa (group 1) and ≥10 kPa (group 2). Of the 528 patients, 324 (61%) were men. The median age was 42 years. Compared with group 1, group 2 had a higher percentage of men, with higher median levels of age, liver biochemistry, and viral load. At the third year of follow‐up, the cumulative incidence of HCC was higher in group 2 compared with group 1 (9%vs 0%, respectively, P < 0.001). The cumulative liver‐related mortality was also higher in group 2 compared to group 1 (4%vs 0%, respectively, P < 0.001). After multivariate analysis, only liver stiffness measurement (LSM) was significantly associated with HCC development and mortality. There was also a higher cumulative incidence of hepatitis flares in group 2 compared to group 1 (46%vs 14%, respectively, P = 0.001) in patients with normal ALT, with higher LSM and AST being significantly associated with subsequent flares. In HBeAg‐negative CHB patients, a liver stiffness measurement of ≥10 kPa was associated with a significantly increased risk of subsequent HCC development and mortality.     

Occult hepatitis B virus infection increases hepatocellular carcinogenesis by eight times in patients with non-B, non-C liver cirrhosis: a cohort study

Summary.  An impact of serum hepatitis B virus (HBV) DNA on hepatocarcinogenesis has not been investigated in a cohort of patients with non-B, non-C cirrhosis. Eighty-two consecutive Japanese patients with cirrhosis, who showed negative hepatitis B surface antigen and negative anti-hepatitis C virus, were observed for a median of 5.8 years. Hepatitis B virus core (HBc) region and HBx region were assayed with nested polymerase chain reaction. Both of HBc and HBx DNA were positive in 9 patients (11.0%) and both were negative in 73. Carcinogenesis rates in the whole patients were 13.5% at the end of the 5th year and 24.6% at the 10th year. The carcinogenesis rates in the patients with positive DNA group and negative DNA group were 27.0% and 11.8% at the end of the 5th year, and 100% and 17.6% at the 10th year, respectively ( P  =   0.0078). Multivariate analysis showed that men ( P  =   0.04), presence of HBc and HBx DNA (hazard ratio: 8.25, P  =   0.003), less total alcohol intake ( P  =   0.010), older age ( P  =   0.010), and association of diabetes ( P  =   0.005) were independently associated with hepatocellular carcinogenesis. Existence of serum HBV DNA predicted a high hepatocellular carcinogenesis rate in a cohort of patients with non-B, non-C cirrhosis.     

Hepatitis B and C virus infection as risk factors for liver cirrhosis and cirrhotic hepatocellular carcinoma: a case-control study

To investigate whether hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are risk factors for liver cirrhosis and hepatocellular carcinoma (HCC), a case-control study of 102 cirrhotic HCC patients, 102 sex-matched and age-matched patients with liver cirrhosis, and 102 matched patients with non-hepatic disease controls was performed. The prevalences of hepatitis B surface antigen (HBsAg) and antibody to HCV (anti-HCV) in HCC (70.5%, 39.2%) and liver cirrhosis (74.5%, 27.4%) were higher than controls (16.6%, 10.5%) (P = 0.0001). In HBsAg-negative patients, the prevalence of anti-HCV in cirrhotic HCC (66.6%) and liver cirrhosis (46.1%) was higher than in controls (10.5%; P = 0.0001). There was no such difference in HBsAg-positive patients. Multivariate analysis revealed that both HBsAg and anti-HCV were important risk factors for HCC (odds ratio, 6.52 and 4.59, respectively) and liver cirrhosis (odds ratio, 4.22 and 2.29, respectively). There was no difference in odds ratio when HCC and liver cirrhosis were compared. Our result implies that both HBV and HCV are independent risk factors for cirrhotic HCC and liver cirrhosis in Taiwan.     

Basal core-promoter mutant of hepatitis B virus and progression of liver disease in hepatitis B e antigen-negative chronic hepatitis B.

BACKGROUND/AIMS: The long-term outcomes in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B are distinct from those in HBeAg-positive chronic hepatitis. However, the molecular virological factors that contribute to the progression of liver disease in this special clinical setting remain largely unknown. We thus investigated the association of hepatitis B virus (HBV) genotypes as well as precore/basal core-promoter mutations with the clinical and virological characteristics of patients with HBeAg-negative chronic hepatitis B in Taiwan. METHODS: HBV genotypes and sequences of precore and basal core-promoter regions of the HBV genome were determined in 174 HBeAg-negative chronic HBV infection patients including 62 inactive carriers and 112 with different stages of liver disease. RESULTS: HBV carriers with older age (> 50 years) (odds ratio, 9.09; 95% confidence interval (CI), 3.22-25, P < 0.001) and basal core-promoter mutant of HBV (odds ratio, 4.12; 95% CI, 1.41-12.03, P = 0.01) were associated with the development of liver cirrhosis and hepatocellular carcinoma (HCC). The gender-related risk factors associated with the development of liver cirrhosis and HCC were further analyzed, and basal core-promoter mutant was only associated with the development of liver cirrhosis and HCC in male carriers (odds ratio, 4.35; 95% CI, 1.30-14.52, P = 0.02). CONCLUSIONS: The risk of development of liver cirrhosis and HCC is significantly increased in patients with advanced age as well as with basal core-promoter mutant of HBV. In addition, basal core-promoter mutant might contribute to the gender difference of the progression of liver disease in HBeAg-negative chronic hepatitis B in Taiwan.     

Hepatitis B virus markers and antibodies to hepatitis C virus in Japanese patients with hepatocellular carcinoma

Sera from Japanese patients with chronic liver disease were tested for hepatitis B virus (HBV) markers and antibodies to hepatitis C virus (anti-HCV), and the results were correlated to the presence of hepatocellular carcinoma. In chronic non-A, non-B liver disease, anti-HCV prevalence was high both in patients with hepatocellular carcinoma (78/89, 88%) and without it (66/84, 79%), while previous HBV infection was more common in patients with hepatocellular carcinoma (65/89, 73%) than in those without it (46/84, 55%) (P<0.05). Coexistence of anti-HCV and antibodies to HBV was observed frequently in patients with hepatocellular carcinoma (56/89, 63%) compared with patients without it (39/84, 46%) (P<0.05). In chronic HBV carriers, anti-HCV was more common in patients with hepatocellular carcinoma (12/38, 32%) than in those without it (3/62, 5%) (P<0.01). These results suggest that infection with the two viruses may be a risk factor for more serious liver disease.This work was supported by a Grant-in-Aid from the Ministry of Education, Science and Culture, Japan.