Development of hepatocellular carcinoma in patients with chronic hepatitis C who had a sustained virological response to interferon therapy: a multicenter, retrospective cohort study of 1124 patients.

BACKGROUND: Interferon (IFN) improves hepatic inflammation/fibrosis and reduces the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CH-C). However, HCC develops in some patients who have a sustained virological response (SVR) to IFN therapy. We designed this study to establish a follow-up protocol for patients with CH-C who have SVR to IFN therapy. METHODS: We retrospectively studied 1124 patients with CH-C who received IFN. RESULTS: HCC developed in 3.5% of patients with SVR to IFN. As compared with SVR patients without HCC, SVR patients with HCC were predominantly male (P=0.003), older at the initiation of IFN therapy (P=0.002), and at a more advanced histologic stage of disease (P<0.001). However, three of the 13 SVR HCC patients had mild fibrosis. The mean interval from IFN therapy to the detection of HCC in SVR HCC patients was 5.8 years and did not differ significantly from that in non-SVR HCC patients (P=0.304). Although most patients with HCC received curative therapy, the prognosis of some SVR HCC patients was poor, probably because of insufficient follow-up, resulting in delayed detection of HCC. CONCLUSIONS: SVR patients with CH-C who are elderly, male, or have an advanced histologic stage are at a high risk for the development of HCC after IFN therapy. We recommend that SVR patients should be observed carefully for more than 10 years after the completion of IFN therapy, even if they only have early fibrosis.     

Correlation of clinical characteristics with detection of hepatitis B virus X gene in liver tissue in HBsAg-negative,and HCV-negative hepatocellular carcinoma patients

PURPOSE: We studied the clinical features and the etiology of hepatitis B virus surface antigen (HBsAg)-negative and antibody to hepatitis C virus (anti-HCV) negative patients with hepatocellular carcinoma. METHODS: A total of 550 patients, hospitalized with an initial diagnosis of HCC were retrospectively studied. Eighty-one of these patients were HBsAg-positive (HB group), 404 patients were anti-HCV positive (HC group). The other 65 patients were negative for both HBsAg and for anti-HCV (NBNC group). We purified HBV-X gene from HCC or non-tumorous liver tissue of 23 NBNC patients using PCR. RESULTS: Clinical features of NBNC as compared with HB and HC patients were as follows, respectively: non-cirrhosis rate (%): 57,37,15 (P = 0.02 for HB, P < 0.00001 for HC), the proportion of patients with normal ALT concentrations (%): 59,28,10 (P = 0.0002 for HB, P < 0.00001 for HC). Forty of 59 NBNC patients (68%) had anti-HBs and/or anti-HBc (healthy controls: 29%, P < 0.00001) and two of 56 had serum HBV DNA. Twelve of 23 NBNC patients had HBV-X gene in HCC and/or non-cancerous liver tissues (52%). None of 52 had serum HCV RNA. CONCLUSIONS: The NBNC patients with HCC had a higher frequency of non-cirrhotic liver without liver injury. The presence of the HBV-X gene in HCC suggests a possible role of past HBV infection in the development of HCC. About half of NBNC HCC is associated with seronegativity for HBsAg and positivity for the HBV-X gene in liver tissue.     

Long-term clinical and histological outcomes in patients with spontaneous hepatitis B surface antigen seroclearance

BACKGROUND/AIMS: During the natural course of hepatitis B virus (HBV) infection, the long-term clinical and histological outcomes following spontaneous hepatitis B surface antigen (HBsAg) seroclearance remain unclear. METHODS: Between 1984 and 2003, 49 (9.5%) out of 432 inactive HBsAg carriers had no detectable level of circulating HBsAg. Fifteen of 49 patients had undergone paired peritoneoscopic liver biopsies. RESULTS: During a mean follow-up period of 19.6 months after HBsAg seroclearance, 5 of 49 (10.2%) patients were noted to have HCC. Liver cirrhosis (P=0.040), a history of perinatal infection (P=0.005) and long-standing duration (at least 30 years) of HBsAg positivity (P=0.002) were associated with a significantly higher risk of developing HCC. Despite HBsAg seroclearance, HBV DNA was detected in the liver tissues from all 15 patients who underwent paired liver biopsies. Necroinflammation was significantly ameliorated (P<0.0001). On the other hand, amelioration of the fibrosis score did not reach a statistically significant level (P=0.072). Interestingly, aggravation of liver fibrosis was evident in 2 patients (13.3%) including one who had rapidly progressed to overt cirrhosis. CONCLUSIONS: In patients with spontaneous HBsAg seroclearance, necroinflammation was markedly improved and liver fibrosis was unchanged or regressed despite occult HBV infection. However, HCC developed in a minority of cases.     

Treatment of chronic hepatitis C virus infection in patients with cirrhosis

Chronic hepatitis C virus (HCV) infection eventually leads to cirrhosis in 20–30% of patients and to hepatocellular carcinoma (HCC) in 1–5% of patients. Rates of sustained virological response with standard interferon-α (IFN-α) are low in patients without cirrhosis (generally < 20%) and are even lower in those with cirrhosis. Combination therapy with IFN and ribavirin improves response rates in patients with chronic hepatitis C without cirrhosis, and the results from subgroups of HCV-infected patients with advanced fibrosis or cirrhosis are encouraging. Importantly, treatment with IFN slows progression of liver fibrosis, regardless of HCV genotype or early response to therapy, and reduces the risk of HCC by two- to fivefold. The risk of development of HCC is also lower in patients who show at least a partial response to IFN therapy compared with those who show no response. There is a clear need for more definitive studies of treatment in patients with chronic hepatitis C and cirrhosis, ideally using therapies with greater efficacy. Nonetheless, based on the potential to slow the progression of liver fibrosis (regardless of treatment response) and to reduce the risk of HCC, a greater number of HCV-infected patients with cirrhosis should be considered as candidates for IFN treatment. Preliminary data indicate that pegylated IFNs have improved virological response rates and may have additional clinical benefits in the prevention or reduction of fibrosis and retardation of progression of cirrhosis and HCC in these patients.     

Correlation of clinical characteristics with detection of hepatitis B virus X gene in liver tissue in HBsAg-negative,and HCV-negative hepatocellular carcinoma patients

Abstract: Purpose: We studied the clinical features and the etiology of hepatitis B virus surface antigen (HBsAg)-negative and antibody to hepatitis C virus (anti-HCV) negative patients with hepatocellular carcinoma. Methods: A total of 550 patients, hospitalized with an initial diagnosis of HCC were retrospectively studied. Eighty-one of these patients were HBsAg-positive (HB group), 404 patients were anti-HCV positive (HC group). The other 65 patients were negative for both HBsAg and for anti-HCV (NBNC group). We purified HBV-X gene from HCC or non-tumorous liver tissue of 23 NBNC patients using PCR. Results: Clinical features of NBNC as compared with HB and HC patients were as follows, respectively: non-cirrhosis rate (%): 57,37,15 (P = 0.02 for HB, P < 0.00001 for HC), the proportion of patients with normal ALT concentrations (%): 59,28,10 (P = 0.0002 for HB, P < 0.00001 for HC). Forty of 59 NBNC patients (68%) had anti-HBs and/or anti-HBc (healthy controls: 29%, P < 0.00001) and two of 56 had serum HBV DNA. Twelve of 23 NBNC patients had HBV-X gene in HCC and/or non-cancerous liver tissues (52%). None of 52 had serum HCV RNA. Conclusions: The NBNC patients with HCC had a higher frequency of non-cirrhotic liver without liver injury. The presence of the HBV-X gene in HCC suggests a possible role of past HBV infection in the development of HCC. About half of NBNC HCC is associated with seronegativity for HBsAg and positivity for the HBV-X gene in liver tissue.     

Lack of correlation between hepatitis C virus genotypes and clinical course of hepatitis C virus-related cirrhosis

The influence of the hepatitis C virus (HCV)-genotype on liver disease severity was evaluated in 429 consecutive patients with chronic hepatitis C, including 109 with cirrhosis who were followed up prospectively, allowing for the assessment of the role of the HCV-genotype on disease outcome and on the development of hepatocellular carcinoma (HCC). HCV-1 was detected in 147 (46%) patients without cirrhosis and in 47 (43%) with cirrhosis (P: not significant), being mainly HCV-1b. HCV-2 was found in 103 (32%) cases without cirrhosis and in 30 (27.5) with cirrhosis (P: not significant), being mainly HCV-2a. HCV-3 was detected in 32 (10%) patients without cirrhosis and in 2 (2%) with cirrhosis (P < 0.005). Infection with more than one genotype (HCV-1/HCV-2 and HCV-1/HCV-3) was observed only in cirrhotic patients (6 of 109; 5.5%). During a mean follow-up of 67 +/- 22 months, 21 (19%) patients with cirrhosis showed worsening in Child's stage, 5 (4.5%) underwent liver transplantation, 23 (21%) developed HCC, and 24 (22%) died of complication of liver disease; the overall incidence of at least one of these events was 38.5%. By the Kaplan-Meier method and log-rank test, the cumulative probability of developing each or at least one of the above events did not differ in relation to the genotype of infecting HCV, apart from patients with mixed genotype infection who showed a significantly higher incidence of death (P < .05). These data indicate that HCV-genotypes do not have a significant effect on the severity and outcome of liver disease in patients with chronic HCV-infection. Patients with cirrhosis who are also infected by HCV-1 and HCV-2 had a similar prognosis and progression to HCC, while patients infected by more than one genotype showed the most unfavorable course of disease.(Hepatology 1997 Jan;25(1):211-5)     

Plasma tissue inhibitor of metalloproteinases-1 and transforming growth factor beta 1--possible non-invasive biomarkers of hepatic fibrosis in patients with chronic B and C hepatitis

BACKGROUND/AIMS: The role of transforming growth factor-beta 1 (TGF-beta 1) in liver fibrosis is in part related to impairment of extracellular matrix breakdown by stimulation of tissue inhibitor of metalloproteinases-1 (TIMP-1) gene. The aim of the study was to evaluate association between TGF-beta 1 and TIMP-1 in relation to liver injury in chronic viral hepatitis B and C. METHODOLOGY: Association between plasma TGF-beta 1 and TIMP-1 was evaluated in 28 consecutive patients undergoing liver biopsy for chronic viral hepatitis B and C (CH-B, CH-C) and these tests were correlated with hepatic fibrosis, inflammation and liver function tests. Moreover carboxyterminal cross-linked telopeptide of type 1 procollagen (ICTP) and carboxyterminal propeptide of type 1 collagen (PICP) were also measured for assessment of extracellular matrix breakdown or synthesis, respectively. RESULTS: Chronic viral hepatitis B and C resulted in a significant increase in plasma TIMP-1 levels but not TGF-beta 1. Among biochemical markers of liver injury, significant correlation with TGF-beta 1 and TIMP-1 was demonstrated in respect to aminotransferase activities in both groups. TIMP-1 showed significant correlation with ICTP levels in both CH-B (r = 0.59) and CH-C (r = 0.62), whereas TGF-beta 1 was correlated with ICTP only in CH-C patients (r = 0.75). PICP did not demonstrate any correlation with either TGF-beta 1 or TIMP-1. Hepatic fibrosis, but not inflammation, correlated significantly with TGF-beta 1 (CH-B: r = 0.73; CH-C: r = 0.79) and TIMP-1 (CH-B: r = 0.66; CH-C: r = 0.71) in both groups and there was a significant correlation between TIMP-1 and TGF-beta 1 in the CH-B group (r = 0.83) and CH-C group (r = 79). CONCLUSIONS: These results support the role of TIMP-1 in a TGF-beta 1-dependent mechanism for liver fibrosis and suggest their plasma levels can be used as a possible early non-invasive marker of liver fibrosis useful for chronic hepatitis management.     

Common clinicopathological features of the patients with chronic hepatitis B virus infection who developed hepatocellular carcinoma after seroconversion to anti-HBs--a consideration of the pathogenesis of HBV-induced hepatocellular carcinoma and a strategy to inhibit it

BACKGROUND/AIMS: The incidence of hepatocellular carcinoma among patients who have seroconverted to anti-hepatitis B surface antigen (anti-HBs) remains controversial. METHODOLOGY: We report four patients with chronic hepatitis B virus (HBV) infection who had cleared HBsAg and had developed anti-HBs at a later time, but who developed hepatocellular carcinoma (HCC) eventually. RESULTS: The common clinicopathological characteristics of the four patients were: An established diagnosis of precirrhosis or liver cirrhosis more than a decade previously, a long-standing normalization or stabilization at a low level of ALT values due to undetectable HBV DNA by the Amplicore Monitor assay, and a marked reduction of the fibrosis level in the non-tumorous liver obtained at HCC surgery or autopsy compared to the previous histology more than a decade previously. There was no fibrosis in the needle biopsy specimen from one patient. CONCLUSIONS: Our findings suggest that HCC due to HBV can occur in the serologically-cured stage if progression to pre-cirrhosis or cirrhosis already has occurred, where the fibrosis level has improved considerably because of the long-term absence of active HBV viremia and inflammation. Active medical intervention to prevent liver cirrhosis for chronic hepatitis B may have an important role in the inhibition of HCC in patients with chronic hepatitis B.     

Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection

BACKGROUND & AIMS: Spontaneous hepatitis B surface antigen (HBsAg) seroclearance is a rare event in patients with chronic hepatitis B virus infection. The aim of this study was to clarify the controversy on long-term prognosis following spontaneous HBsAg seroclearance using a large series of patients. METHODS: A total of 218 patients (172 men and 46 women) who had undergone spontaneous HBsAg seroclearance were followed up for 12-179 months (median, 61.7 months; mean, 63.4 +/- 38.5 months) with liver biochemistry, serology, measurement of alpha-fetoprotein level, and abdominal ultrasonography every 6 months or every 3 months for the 29 patients who had developed cirrhosis at the time of HBsAg seroclearance. RESULTS: Of the 189 patients who were noncirrhotic at the time of HBsAg clearance, 3 (1.6%) developed cirrhosis, 2 (1.1%) developed hepatocellular carcinoma (HCC), and 1 died of HCC. These complications all developed in patients with concurrent hepatitis C virus or hepatitis delta virus infection (P < 0.001). The prognosis of the noncirrhotic patients without concurrent infection was significantly better than that of the matched control group (elevation of alanine aminotransferase level, 11.6% vs. 0%, P < 0.001; development of cirrhosis/HCC, 4% vs. 0%, P = 0.004). In contrast, of the 29 patients who had developed liver cirrhosis, 4 (13.8%) had hepatic decompensation and one died of HCC. CONCLUSIONS: The prognosis following spontaneous HBsAg seroclearance is excellent, except in patients with cirrhosis or those with concurrent hepatitis C virus or hepatitis delta virus infection.     

National Survey of Hepatocellular Carcinoma in Heavy Drinkers in Japan

Background: The major cause of hepatocellular carcinoma (HCC) in the general Japanese population is an infection related to hepatotropic viruses, especially hepatitis virus C (HCV). Even in heavy drinkers, the major cause of HCC is HCV infection. However, HCC without viral infection has been reported in heavy drinkers. Alcohol has been also reported to be associated with an increased risk of cancer. In this study, we investigated aspects of HCC pathogenesis in heavy drinkers in Japan.
Methods: Questionnaires were sent to 1350 hospitals authorized by the Japanese Society of Gastroenterology. The questionnaires asked about the number of inpatients with the different types of alcoholic liver diseases, admitted to each hospital between 1998 and 2001.
Results: The percentage of heavy drinkers among all admitted patients with liver diseases or liver cirrhosis was approximately 15%. Of the patients with alcoholic liver cirrhosis, the cirrhosis was derived from alcohol alone in 61% and from alcohol plus a virus in 39% of patients. Furthermore, the percentage of patients with alcoholic liver cirrhosis caused by alcohol alone and who did not have HCC was 80%. However, the percentage of HCC patients who tested negative for viral hepatitis serum markers was 27% of the total number of heavy drinkers admitted for HCC. A study mainly on liver cirrhosis performed in the early 1990s demonstrated that the alcohol-alone group accounted for 44% of admitted patients with alcoholic liver cirrhosis and 18% of heavy drinkers admitted for HCC.
Conclusions: Because the consumption of alcohol is increasing in Japan, the frequency and number of cases of alcoholic liver cirrhosis are increasing. Viral hepatitis infection, however, still plays an important role in hepatocarcinogenesis in heavy drinkers. Radiographical examination is recommended even in patients with alcoholic liver cirrhosis who test negative for serum markers of viral hepatitis.     

National Survey of Hepatocellular Carcinoma in Heavy Drinkers in Japan

Background: The major cause of hepatocellular carcinoma (HCC) in the general Japanese population is an infection related to hepatotropic viruses, especially hepatitis virus C (HCV). Even in heavy drinkers, the major cause of HCC is HCV infection. However, HCC without viral infection has been reported in heavy drinkers. Alcohol has been also reported to be associated with an increased risk of cancer. In this study, we investigated aspects of HCC pathogenesis in heavy drinkers in Japan. Methods: Questionnaires were sent to 1350 hospitals authorized by the Japanese Society of Gastroenterology. The questionnaires asked about the number of inpatients with the different types of alcoholic liver diseases, admitted to each hospital between 1998 and 2001. Results: The percentage of heavy drinkers among all admitted patients with liver diseases or liver cirrhosis was approximately 15%. Of the patients with alcoholic liver cirrhosis, the cirrhosis was derived from alcohol alone in 61% and from alcohol plus a virus in 39% of patients. Furthermore, the percentage of patients with alcoholic liver cirrhosis caused by alcohol alone and who did not have HCC was 80%. However, the percentage of HCC patients who tested negative for viral hepatitis serum markers was 27% of the total number of heavy drinkers admitted for HCC. A study mainly on liver cirrhosis performed in the early 1990s demonstrated that the alcohol‐alone group accounted for 44% of admitted patients with alcoholic liver cirrhosis and 18% of heavy drinkers admitted for HCC. Conclusions: Because the consumption of alcohol is increasing in Japan, the frequency and number of cases of alcoholic liver cirrhosis are increasing. Viral hepatitis infection, however, still plays an important role in hepatocarcinogenesis in heavy drinkers. Radiographical examination is recommended even in patients with alcoholic liver cirrhosis who test negative for serum markers of viral hepatitis.     

Hepatic Fas protein expression might be a predictive factor for hepatocellular carcinoma development in patients with chronic hepatitis C undergoing interferon therapy

BACKGROUND: Several studies have revealed that interferon treatment may reduce the incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV). However, even after eradication of HCV, patients remain at risk for developing HCC. STUDY: Of 153 consecutive HCV patients who were treated with interferon and followed up for 5 years, 17 (11.1%) developed HCC. To elucidate predictive factors of HCC development, multivariate analysis was done for the 153 patients, and Fas protein expression in the biopsied specimens of liver before interferon treatment was examined in 17 patients who developed HCC and 17 patients who did not. RESULTS: Among the independent factors (sex, age, HCV genotype, HCV-RNA level, effect of interferon therapy, serum alanine aminotransferase before interferon therapy, and histologic stage and grade) tested by Cox proportional-hazards analysis, histologic stage (hepatic fibrosis) before interferon was significantly associated with HCC development (p = 0.01). In addition, the intensity of Fas protein expression was significantly greater in the liver specimens of the patients who developed HCC than in those who did not (p = 0.015). CONCLUSION: Histologic stage (hepatic fibrosis) and Fas protein expression before interferon treatment might be indicative of the need for intensive follow-up in patients with chronic hepatitis C undergoing interferon therapy.     

Hepatitis B virus DNA integration in hepatocellular carcinoma after interferon-induced disappearance of hepatitis C virus

OBJECTIVES: Hepatocellular carcinoma (HCC) has been reported in patients in whom hepatitis C virus (HCV) was eliminated by interferon (IFN) therapy. We examined the pathogenesis of HCC in patients with sustained viral response. METHODS: Operable HCC developed in 7 of 342 patients cured of HCV infection by IFN monotherapy. No patient abused alcohol or had diabetes mellitus or obesity. Resected specimens of HCC were histologically evaluated. DNA extracted from HCC was examined by polymerase chain reaction (PCR) to locate hepatitis B virus (HBV) DNA. HBV integration sites in human genome were identified by cassette-ligation-mediated PCR. RESULTS: HBV DNA was not amplified in serum samples from any of the seven patients with HCC and was found in liver in four patients. In the latter four patients, HBV DNA was integrated into the human genome of HCC. In two of these patients, covalently closed circular HBV (cccHBV) was also detected. The patients with HBV DNA integration were free of HCV for more than 3 yr. In two of the three patients without HBV DNA integration, the surrounding liver showed cirrhosis. The liver of HCC with HBV DNA integration had not progressed to cirrhosis. Three of the four tumors with HBV integration had one integration site each, located at chromosomes 11q12, 11q22-23, and 22q11, respectively. The other tumor had two integration sites, situated at chromosomes 11q13 and 14q32. At chromosome 11q12, HBV DNA was integrated into protein-coding genome, the function of which remains unclear. CONCLUSION: Integrated HBV DNA may play a role in hepatocarcinogenesis after the clearance of HCV by IFN treatment.     

Progression of fibrosis in chronic hepatitis C

BACKGROUND & AIMS: Fibrosis is the hallmark of hepatic cirrhosis, worsening of which is probably the best surrogate marker for progression of chronic liver disease. We evaluated a large cohort of patients with chronic hepatitis C (CHC) using liver histology to assess the rate and predictors of progression of fibrosis. METHODS: The cohort consisted of 123 patients with CHC who underwent 2 liver biopsies 4-212 months (mean, 44 months) apart without intervening treatment. Liver histology was graded using the histology activity index (score, 0-18) and fibrosis staged using a scoring system of 0 (no fibrosis) to 6 (cirrhosis). RESULTS: Among 123 patients, 48 (39%) showed progression in fibrosis scores, 46 (37%) showed no change, and 29 (24%) showed improvement. Of those with worsening fibrosis, 75% had a 1-point increase and 25% a 2-point or greater increase in scores, and 9% showed progression to cirrhosis. The overall rate of progression was 0.12 fibrosis units per year, a rate that predicts progression to cirrhosis in 50 years if progression was linear. The rate of fibrosis progression was variable, and it was higher among older patients, those with higher serum alanine and aspartate aminotransferase levels, and those with the most extensive periportal necrosis on initial liver biopsy. CONCLUSIONS: The best predictors of fibrosis progression in CHC are the extent of serum aminotransferase elevations and the degree of hepatocellular necrosis and inflammation on liver biopsy. These findings support the recommendation that patients with normal aminotransferase levels and mild liver histology can safely defer treatment.     

Development from simple steatosis to liver cirrhosis and hepatocellular carcinoma: a 27-year follow-up case

Nonalcoholic fatty liver disease (NAFLD) is classified as nonalcoholic steatohepatitis (NASH) or simple steatosis (SS) according to histological findings. It is well recognized that NASH may develop into cirrhosis and hepatocellular carcinoma (HCC), both with unfavorable prognoses. Although the outlook of SS is reported to be better than that of NASH, the long-term prognosis of SS remains unclear. Here, we report the case of a patient who was diagnosed as having SS by a first liver biopsy, and later developed into cirrhosis and HCC over a period of 27 years. In 1980, a 42-year-old Japanese man was admitted because of abnormal liver function tests. He had no history of alcohol intake and was negative for hepatitis virus markers and autoantibodies. A liver biopsy specimen showed macrovesicular steatosis without ballooned hepatocytes, Mallory hyaline, lobular inflammation, or perisinusoidal/perivenular fibrosis, confirming the diagnosis of SS. The patient’s serum aminotransferase levels did not normalize despite repeated dietary instruction, and in 2001, liver histology demonstrated cirrhosis with mild steatosis and hepatocyte ballooning, leading to the diagnosis of NASH-related cirrhosis. HCC appeared in 2007. Overall, this patient progressed to cirrhosis and HCC in 20 and 27 years, respectively, following initial diagnosis. Platelet counts and degree of steatosis, as assessed by periodic ultrasonography, were seen to gradually reduce with progression of fibrosis. This case demonstrates that even a diagnosis of SS does not guarantee non-progression to cirrhosis and HCC, and careful follow-up is needed not only in patients with NASH, but also in those with SS.     

Incidence of HCC in chronic hepatitis C patients with advanced hepatic fibrosis who achieved SVR following DAAs: A prospective study

Liver cirrhosis is an important risk factor for hepatocellular carcinoma. The reported annual incidence of HCC is about 3%‐8% in CHC cirrhotic patients. Based on the Cochrane systematic review, there was no clear evidence, on the long‐term clinical effects of DAAs in patients achieving SVR, as regard liver cirrhosis‐related HCC incidence. The aim of the study was to determine the incidence of HCC in chronic hepatitis C patients genotype IV with liver cirrhosis and advanced liver fibrosis after achieving SVR following DAA treatment in a prospective large cohort of HCV patients with long follow‐up. This was a prospective observational cohort study including 2372 CHC patients with advanced liver fibrosis or cirrhosis receiving DAA therapy in outpatient clinics at the Egyptian Liver Research Institute and Hospital since January 2015. Liver fibrosis was assessed using transient elastography. Abdominal ultrasonography and AFP measurement were done at baseline and follow‐up visits every 6 months, in addition to triphasic abdominal MSCT when needed. Patients were followed up after achieving SVR12 for at least 12 months. HCC developed in 109 cases during the follow‐up period (mean 23.60 ± 8.25 months). Overall HCC incidence was 2.338/100 PY, 95% CI = 1.942‐2.814. In patients with cirrhosis, the incidence of HCC was 2.917/100 PY, 95% CI = 2.407‐3.535, while in patients with advanced liver fibrosis the incidence of HCC was 0.664/100 PY, 95% CI = 0.333‐1.326. In conclusion, the incidence of HCC was reduced in chronic hepatitis C genotype 4 patients with liver cirrhosis (F4) and advanced hepatic fibrosis (F3) who achieved SVR following DAA therapy.     

慢性乙肝病毒感染者血清血管内皮生长因子的研究

目的:检测慢性乙型肝炎病毒感染患者血清中血管内皮生长因子(VEGF)的水平,探讨其临床意义.方法:采用双抗体夹心ELISA法对50例肝细胞癌、40例乙型肝炎肝硬化、36例乙型肝炎肝纤维化、40例慢性乙型肝炎患者血清中VEGF进行检测,并以43例健康者作为对照.同时采用全自动生化分析仪检测所有人员的肝功能常规指标.结果:慢性乙型肝炎、肝纤维化、肝硬化、肝细胞癌组患者血清VEGF浓度明显高于正常对照组(P＜0.01,P＜0.05,P＜0.05,P＜0.05),同时四组患者之间比较,差异均有统计学意义(P＜0.05).四组患者血清VEGF水平与肝功能指标AST、ALT无相关性,与GGT成正相关(r=0.337,P＜0.05).结论:VEGF与慢性乙型肝炎病毒感染者病情密切相关,可作为病情发展动态监测的指标.VEGF与GGT联合检测,可显著提高肝细胞癌的检出率.     

Long-term outcome of chronic hepatitis B based on histological grade and stage

BACKGROUND AND AIM: This study evaluated the long-term outcome and prognostic factors of chronic hepatitis B, based on histological grade and stage. METHODS: A total of 188 patients with chronic hepatitis B were followed for a mean 119.8 months. Ultrasonography and clinical assessment were performed regularly. In addition, liver biopsy specimens were re-evaluated based on histological grade and stage. RESULTS: During follow-up, cirrhosis developed in 62 patients, decompensation in 20 patients, and hepatocellular carcinoma (HCC) in 21 patients. The serum alanine aminotransferase (ALT) level at the time of liver biopsy was significantly correlated with the grades of lobular and porto-periportal activity. The development of cirrhosis correlated well with the grade of porto-periportal activity and stage of fibrosis. The probabilities of developing cirrhosis, decompensation and HCC were significantly higher in patients whose ALT levels were persistently elevated without flares or flared-up without normalization than in patients whose ALT levels flared-up then normalized or were normally sustained. By multivariate analysis, age and biochemical profile during follow-up were independent prognostic factors for chronic hepatitis B. CONCLUSIONS: The results demonstrate that histological grade and stage, and biochemical profile during follow-up in patients with chronic hepatitis B are important prognostic factors. Therefore, effective control of hepatitis activity might improve the long-term outcome of chronic hepatitis B patients.     

Long-term outcome of hepatitis C virus infection after liver transplantation

We analyzed the long-term clinical course of 71 patients with RNA-positive hepatitis C virus (HCV) infection after liver transplantation. Patients with reinfection after transplantation for HCV-related liver disease, or de novo infection at transplantation were followed for up to 12 years. Cumulative survival for patients with HCV infection at 2, 5, and 10 years after transplantation was 67%, 62%, and 62%, respectively. It was not significantly different from that in patients transplanted for other nonmalignant diseases without HCV infection. The main factor determining long-term survival was the presence or absence of hepatocellular carcinoma (HCC) at transplantation. The 5-year survival rate for HCV patients with or without HCC was 35% versus 73%, respectively (P < .05). No deaths because of viral hepatitis of the graft were observed. Deaths in the first year after transplantation were caused by infectious complications, cardiovascular problems, or rejection; deaths after more than 12 months were exclusively because of recurrence of HCC. Biochemical and histological evidence of hepatitis was found in the majority of the patients, only 16% had normal alanine aminotransferase (ALT) values throughout. Twenty-two percent of patients complained of symptoms, with hepatitis C being the cause in 82% of these. Two patients lost their HCV-RNA for prolonged, ongoing periods of time. The severity of the posttransplantation hepatitis was unrelated to age, sex, severity of liver disease before transplantation, cold ischemic time of the graft, duration of the operation, transfusions, the number of rejection episodes, or the long-term immunosuppressive regime. Only initial short-term therapy with interleukin 2 (IL2) receptor antibodies adversely influenced inflammatory activity. Viral genotype did not influence the course of the graft hepatitis in our series. Histology showed inflammation in 88% of the biopsies and signs of fibrosis in 24%. Mean ALT values correlated with inflammation but not with fibrosis in the biopsies. Porto-portal bridging was observed in six patients, one patient developed cirrhosis within 2 years after orthotopic liver transplantation (OLT). We conclude that chronic hepatitis develops in the majority of patients with HCV infection after liver transplantation. Carrier states without significant laboratory abnormalities are observed in approximately 16%, biochemical abnormalities without symptoms are seen in 60%, and symptomatic disease develops in a quarter of the patients. The disease course closely resembles that seen in nontransplanted hepatitis C patients. It is generally mild but little over 10% of patients develop signs of fibrosis of the graft during the first decade.(Hepatology 1997 Jan;25(1):203-10)     

Hepatocellular carcinoma in patients with autoimmune hepatitis

AIM： To evaluate and confirm the low incidence of hepatocellular carcinoma （HCC） in patients with autoimmune hepatitis （AIH）. At present only very few cases of HCC in patients with AIH and definite exclusion of chronic viral hepatitis have been published, suggesting that HCC due to AIH is rare. METHODS： In order to further investigate the incidence of HCC in patients with AIH, we reviewed our large cohort of 278 patients with AIH. RESULTS： Eighty-nine patients （32%） were diagnosed with liver cirrhosis, a preneoplastic condition for HCC. We studied a total of 431 patient years of cirrhosis in these patients, an average 4.8 years per patient. During this period none of the patients of our own study cohort developed HCC. However, three patients with HCC due to AIH associated liver cirrhosis were referred to our department for further treatment of HCC. In all three patients chronic viral hepatitis was excluded. CONCLUSION： We conclude that HCC may under rare circumstances develop due to chronic AIH dependent liver cirrhosis. Compared to other causes of liver cirrhosis such as chronic viral hepatitis, alcohol, or hemochromatosis, the incidence of HCC is significantly lower. Pathophysiological differences between AIH and chronic viral hepatitis responsible for differences in the incidence of HCC are yet to be further characterized and may lead to new therapeutic concepts in prevention and treatment of liver cancer.