Diabetes is associated with advanced fibrosis and fibrosis progression in non-genotype 3 chronic hepatitis C patients

Background

Diabetes is a risk factor of fibrosis progression in chronic hepatitis C (CHC). However, only one longitudinal study exploring whether diabetes is associated with progression from non-cirrhotic liver to cirrhosis in CHC patients has been conducted.

应用寡核苷酸芯片对乙型肝炎病毒转染HepG2细胞基因表达谱的研究

HBV与肝细胞之间相互作用的分子机制还不清楚，对HBV蛋白调控宿主细胞基因表达情况也了解甚少。本实验选用基因芯片进行HBV基因表达谱改变的研究，筛选HBV感染应答基因，探讨HBV感染的分子致病机制，寻找预防和治疗HBV感染的靶点。     

HBV X基因-HCV C基因cDNA融合基因真核表达载体的构建及其表达

目的：构建HBV X-HCV C融合基因真核表达载体，并获得稳定表达该基因的HepG2细胞株。方法：双酶切质粒pXT1-X，得到完整的HBV X基因片段后，将其插入到质粒PBK-CMV和PBK-HCVC的相应酶切位点，得到重组质粒PBK-X和PBK-X-C；再将质粒RBK-CMV、PBK-X、PBK-HCV C和PBK-X-C分别导入肝癌细胞株HepG2中，G418筛选，RT-PCR、蛋白印迹鉴定HBV X和HCV C蛋白表达。结果：质粒PBK-CMV、PBK-X、PBK-HCV C和PBK-X-C在HepG2细胞中有稳定表达。结论：成功构建HBV X-HCVC融合基因真核表达载体，并获得稳定表达该基因的HepG2细胞株。     

Disease progression in chronic hepatitis C patients with normal alanine aminotransferase levels

AIM:To investigate whether the disease progression of chronic hepatitis C patients with normal alanine aminotransferase(ALT) levels differs by ALT levels.METHODS:A total of 232 chronic hepatitis C patients with normal ALT(< 40 IU/L) were analyzed.The patients were divided into "high-normal" and "low-normal" ALT groups after determining the best predictive cutoff level associated with disease progression for each gender.The incidence of disease progression,as defined by the occurrence of an increase of ≥ 2 points in the Child-Pugh score,spontaneous bacterial peritonitis,bleeding gastric or esophageal varices,hepatic encephalopathy,the development of hepatocellular carcinoma,or death related to liver disease,were compared between the two groups.RESULTS:Baseline serum ALT levels were associatedwith disease progression for both genders.The best predictive cutoff baseline serum ALT level for disease progression was 26 IU/L in males and 23 IU/L in females.The mean annual disease progression rate was 1.2% and 3.9% for male patients with baseline ALT levels ≤ 25 IU/L(low-normal) and > 26 IU/L(highnormal),respectively(P = 0.043),and it was 1.4% and 4.8% for female patients with baseline ALT levels ≤ 22 IU/L(low-normal) and > 23 IU/L(high-normal),respectively(P = 0.023).ALT levels fluctuated during the follow-up period.During the follow-up,more patients with "high-normal" ALT levels at baseline experienced ALT elevation(> 41 IU/L) than did patients with "lownormal" ALT levels at baseline(47.7% vs 27.9%,P = 0.002).The 5 year cumulative incidence of disease progression was significantly lower in patients with persistently "low-normal" ALT levels than "high-normal" ALT levels or those who exhibited an ALT elevation > 41 U/L during the follow-up period(0%,8.3% and 34.3%,P < 0.001).CONCLUSION:A "high normal" ALT level in chronic hepatitis C patients was associated with disease progression,suggesting that the currently accepted normal threshold of serum ALT should be lowered.     

Dermatomyositis associated with hepatocellular carcinoma in an elderly female patient with hepatitis C virus-related liver cirrhosis

A 79-year-old female patient with hepatitis C virus-related liver cirrhosis was diagnosed as having hepatocellular carcinoma (HCC) with a diameter of 2.0 cm. She refused therapy for HCC. Nine months after the diagnosis, she developed dermatomyositis when the HCC enlarged to a diameter of 6.0 cm. She underwent therapy for dermatomyositis, and then transcatheter arterial chemoembolization for HCC. Although the manifestations of dermatomyositis improved and entire tumor necrosis was achieved, she died of pneumonia 2 mo after the treatment of HCC. HCC and/or chronic hepatitis C virus infection might be involved in the pathogenesis of dermatomyositis.     

Chemoprevention of hepatocellular carcinoma in patients with hepatitis C virus related cirrhosis

Interferon(IFN) therapy has been reported to decrease the risk of hepatocellular carcinoma(HCC) and improve survival by preventing liver-related deaths in patients with chronic hepatitis C virus(HCV) infection, while the role of IFN therapy on the natural history of hepatitis C related cirrhosis is still under debate. The ideal goal of therapy is to prevent the progression into end-stage disease. The use of IFN in patients with HCV compensated cirrhosis reduces the negative clinical evolution independently of the type of laboratoristic and virological response. In our experience, IFN therapy in HCV compensated cirrhosis is barely useful in prevention of HCC, as cirrhosis itself represents a risk of cancer.Some authors noted that IFN treatment reduces the risk of HCC independently of the virological response. It would probably be interesting to evaluate the efficacy of weekly low-dose pegylated(PEG)-IFN therapy in patients with HCV cirrhosis and to assess potential benefits of long-term PEG-IFN plus Ribavirin treatment.     

Hepatocellular carcinoma in patients with chronic hepatitis C virus infection without cirrhosis

AIM:To investigate and characterise patients with chronic hepatitis C virus(HCV) infection presenting with hepatocellular carcinoma(HCC) in the absence of cirrhosis.METHODS:Patients with chronic hepatitis C infection without cirrhosis presenting with HCC over a 2-year period were identified.The clinical case notes,blood test results and histological specimens were reviewed to identify whether additional risk factors for the development of HCC were present.RESULTS:Six patients(five male,one female) with chro...     

肝癌和慢性肝炎患者丙型肝炎病毒核心蛋白基因表达及其核苷酸序列分析

目的：为探讨丙型肝炎病毒（HCV）感染在肝癌发生中的作用。方法：从HCV第二代抗体阳性的肝癌和慢性肝炎患者血清中提取HCV-RNA，经随机引物逆转录合成cDNA，再以病毒5’-末端至E1区间的多对引物进行巢式PCR扩增，其最终产物（425bp和621bp）分别连接p-GEM－T载体，在大肠杆菌中表达后进行测序。结果：所有患者均为HCV－Ⅱ型感染，完整的核心蛋白基因（573bp）与已报道的其它株比较，其核苷酸同源性为：慢性肝炎株89．0％～95.5％，肝癌株88．7％～92.3％；氨基酸同源性为：前者91.1％～96.6％，后者87．4％～92．1％。且发现该段基因中核苷酸置换肝癌患者较明显地高于慢性肝炎患者。结论：本文资料提示核心蛋白基因的变异，可能与HCV的慢性持续感染及肝癌的发生有关。     

Prediction model of hepatocarcinogenesis for patients with hepatitis C virus-related cirrhosis. Validation with internal and external cohorts

BACKGROUND/AIMS: To estimate hepatocarcinogenesis rates in patients with hepatitis C virus (HCV)-related cirrhosis, an accurate prediction table was created. METHODS: A total of 183 patients between 1974 and 1990 were assessed for carcinogenesis rate and risk factors. Predicted carcinogenesis rates were validated using a cohort from the same hospital between 1991 and 2003 (n=302) and an external cohort from Tokyo National Hospital between 1975 and 2002 (n=205). RESULTS: The carcinogenesis rates in the primary cohort were 28.9% at the 5th year and 54.0% at the 10th year. A proportional hazard model identified alpha-fetoprotein (>or=20 ng/ml, hazard ratio 2.30, 95% confidence interval 1.55-3.42), age (>or=55 years, 2.02, 95% CI 1.32-3.08), gender (male, 1.58, 95% CI 1.05-2.38), and platelet count (<100,000 counts/mm3, 1.54, 95% CI 1.04-2.28) as independently associated with carcinogenesis. When carcinogenesis rates were simulated in 16 conditions according to four binary variables, the 5th- and 10th-year rates varied from 9 to 64%, and 21-93%, respectively. Actual carcinogenesis rates in the internal and external validation cohorts were similar to those of the simulated curves. CONCLUSIONS: Simulated carcinogenesis rates were applicable to patients with HCV-related cirrhosis. Since, hepatocarcinogenesis rates markedly varied among patients depending on background features, we should consider stratifying them for cancer screening and cancer prevention programs.     

Insulin resistance is associated with hepatocellular carcinoma in chronic hepatitis C infection

AIM:To elucidate the role of insulin resistance(IR) and serum adiponectin level in hepatocellular carcinoma(HCC) associated with chronic hepatitis C.METHODS:Clinical and biochemical characteristics were collected from 165 consecutive patients with newly diagnosed HCC.Homeostasis model assessment of IR(HOMA-IR) and serum adiponectin level were investigated in 188 patients with different stages of hepatitis C virus(HCV) infection.RESULTS:Among HCC patients,type 2 diabetics(DM) was more prevalent in HCV subjec...     

Hepatocellular carcinoma in patients co-infected with hepatitis C virus and human immunodeficiency virus

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) share a common route of transmission so that about one third of HIV infected individuals show HCV co-infection. Highly active antiretroviral therapy has offered a longer and better life to infected patients. While has removed AIDS-related diseases from the list of most common causes of death their place has been taken by complications of HCV infection, such as cirrhosis, end stage liver disease and hepatocellular carcinoma (HCC). HIV/HCV co-infection requires complex management, especially when HCC is present. Co-infected patients with HCC undergo the same therapeutic protocol as their mono-infected counterparts, but special issues such as interaction between regimens, withdrawal of therapy and choice of immunosuppressive agents, demand a careful approach by specialists. All these issues are analyzed in this minireview.     

Latent hepatitis B is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C

AIM:To study the potential association between hepatocellular carcinoma(HCC)in patients with chronic hepatitis C(CHC),cirrhosis and latent hepatitis B(LHB)infection,defined as the absence of detectable serum hepatitis B surface antigen(HBsAg)and the presence of hepatitis B core antibody(HBcAb).METHODS:This retrospective analysis is comprised of 185 cirrhotic patients with HCC who were hepatitis C virus antibody(HCV Ab)(+)and HBsAg(-)at Wayne State University between 1999 and 2008.From these,108 patients had HCV polymerase chain reaction confirmation of viremia while the remaining(77)were considered to have CHC on the basis of a positive HCV Ab and the absence of any other cause of liver disease.Controls were drawn from our institutional database from the same time period and consisted of 356 HBsAg(-)age,race and gender matched patients with HCV RNA-confirmed CHC and without evidence of HCC.A subgroup of controls included 118matched patients with liver cirrhosis.χ2test and t test were used for data analysis.RESULTS:Seventy-seven percent of patients in all3 groups were African Americans.Patients with HCC had a significantly higher body mass index(P=0.03),a higher rate of co-infection with human immunodeficiency virus(HIV)(P=0.05)and a higher prevalence of alcohol abuse(P=0.03)than the controls.More patients with HCC had LHB than controls(78%vs39%,P=0.01).Sixty three percent of patients with HCC were both hepatitis B surface antigen(HBsAb)(-)and HBcAb(+)compared to 23%of controls(P<0.01).When compared to cirrhotic controls,the frequency of HBcAb(+)remained higher in patients with HCC(78%vs 45%,P=0.02).Patients with HCC were more likely to be both HBsAb(-)and HBcAb(+)than the cirrhotic controls(63%vs 28%,P=0.01).Although not statistically significant,100%of CHC and HIV coinfected patients with HCC(n=11)were HBcAb(+)when compared to controls(44%;n=9).CONCLUSION:These data suggest that LHB occurs at a significantly increased frequency in patients with CHC and HCC than in patients with CHC without HCC.     

Natural interferon-beta treatment for patients with chronic hepatitis C in Japan

Chronic hepatitis C virus(HCV) infection can cause liver cirrhosis and hepatocellular carcinoma(HCC). Several studies have demonstrated that the eradication of HCV reduces the occurrence of HCC. In Japan, as many people live to an advanced age, HCV-infected patients are also getting older, and the age at HCC diagnosis has also increased. Although older HCV-infected patients have a risk of developing HCC, the treatment response to peginterferon-alpha plus ribavirin therapy is relatively poor in these patients because of drop-out or discontinuation of this treatment due to adverse events. It is established that the mechanism of action between interferon-alpha and interferon-beta is slightly different. Short-term natural interferon-beta monotherapy is effective for patients with acute hepatitis C and patients infected with HCV genotype 2 and low viral loads. Natural interferon-beta plus ribavirin for 48 wk or for 24 wk are also effective for some patients with HCV genotype 1 or HCV genotype 2. Natural interferon-beta plus ribavirin has been used for certain "difficult-totreat" HCV-infected patients. In the era of direct-acting anti-virals, natural interferon-beta plus ribavirin may be one of the therapeutic options for special groups of HCV-infected patients. In the near future, signal transduction pathways of interferon-beta will inform further directions.     

Liver stiffness measurement in the primary care setting detects high rates of advanced fibrosis and predicts liver-related events in hepatitis C

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Association of interferon lambda-4 rs12979860 polymorphism with hepatocellular carcinoma in patients with chronic hepatitis C infection

BACKGROUND Hepatitis C virus(HCV) infection is a public health concern worldwide.Several factors,including genetic polymorphisms,may be evolved in the progression of HCV infection to liver diseases.Interferon lambdas(IFNLs) modulate the immune response during viral infections.IFNLs induce antiviral activity,interfering in the viral replication by promoting the expression of several genes that regulate immunological functions.The interferon lambda-4(IFNL4) rs12979860 polymorphism,which is characterized by a C to T transition in intron 1,is associated with spontaneous and treatment-induced clearance of HCV infection and may play a role in the development of HCV-associated liver diseases,including hepatocellular carcinoma(HCC).AIM To investigate the association of IFNL4 rs12979860 polymorphism with fibrosis,cirrhosis,and HCC in patients with chronic HCV infection.METHODS This study was comprised of 305 chronic HCV-infected patients(53 fibrosis,154 cirrhosis,and 98 HCC cases).The control group was comprised of 260 HCVnegative healthy individuals.The IFNL4 rs12979860 polymorphism was genotyped using the TaqMan assay.Fibrosis was diagnosed based on liver biopsy findings,while cirrhosis was diagnosed through clinical,laboratory,anatomopathological,and/or imaging data.HCC was diagnosed through imaging tests,tumor,and/or anatomopathological markers.RESULTS The T allele was observed in the three groups of patients(fibrosis,cirrhosis,and HCC) at a significantly higher frequency when compared with the control group(P=0.047,P 0.001,and P=0.01,respectively).Also,genotype frequencies presented significant differences between the control group and cirrhosis patients(P 0.001) as well as HCC patients(P=0.002).The risk analysis was performed using the codominant and dominant T allele models.In the codominant model,it was observed that the CT genotype showed an increased risk of developing cirrhosis in comparison with the CC genotype [odds ratio(OR)=2.53;95%confidence interval(CI):1.55-4.15;P 0.001] as well as with HCC(OR=2.54;95%CI:1.44-4.56;P=0.001).A similar result was observed in the comparison of the TT vs CC genotype between the control group and cirrhosis group(OR=2.88;95 % CI:1.44-5.77;P=0.001) but not for HCC patients.In the dominant T allele model,the CT+TT genotypes were associated with an increased risk for progression to cirrhosis(OR=2.60;95%CI:1.63-4.19;P 0.001) and HCC(OR=2.45;95%CI:1.42-4.31;P=0.001).CONCLUSION These findings suggest that the T allele of IFNL4 rs12979860 polymorphism is associated with the development of cirrhosis and HCC in chronic HCV-infected patients.     

Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis: a prospective observation of 2215 patients

Background/Aims/Methods: The aim of this study was to elucidate the rate of development to cirrhosis and the rate of development to cirrhosis and the rate of appearance of hepatocellular carcinoma in chronic viral hepatitis and to assess the risk factors for the development of disease in 2215 consecutive patients with viral hepatitis who were prospectively studied for a median observation period of 4.1 years.Results: The rates of development to cirrhosis were 7.6%, 21.7%, and 32.2%, at the 5th, 10th, and 15th year, respectively. The carcinogenesis rates were 3.4%, 10.5%, and 22.4% at the 5th, 10th, and 15th year, respectively. The appearance rates of cancer in 645 patients with only hepatitis B surface antigen and in 1500 patients with only anti-hepatitis C virus antibodies were 2.1% and 4.8% at the 5th year, 4.9% and 13.6% at the 10th year, and 18.8% and 26.0% at the 15th year, respectively. The proportional hazard model identified that the amount of alcohol intake (p=0.0002) and the indocyanine green retention rate (p=0.022) were independently associated with carcinogenesis in hepatitis type B; and stage of hepatitis (p<0.0001), gamma-glutamyl transpeptidase (p=0.0046), history of blood transfusion (p=0.0093), albumin (p=0.012), and amount of alcohol intake (p=0.031) were independently associated with the carcinogenesis rate in hepatitis type C. Although the severity of portal fibrosis was closely correlated with the future disease development and carcinogenesis in chronic hepatitis C, it was not a good predictor in chronic hepatitis B.Conclusion: These epidemiological results suggest that there are some differences in the activity and modes of disease progression and cancer promotion between hepatitis B virus infection and hepatitis C virus infection.     

Diabetes enhances hepatocarcinogenesis in noncirrhotic, interferon-treated hepatitis C patients

Background

This retrospective cohort study assessed the impact of diabetes mellitus on hepatocarcinogenesis and determined the predictors of hepatocarcinogenesis in noncirrhotic, interferon-treated patients with hepatitis C virus infection.

Methods

A total of 2058 hepatitis C virus-positive, noncirrhotic patients treated with interferon were enrolled. The median follow-up period was 6.7 years. The primary end point was the onset of hepatocellular carcinoma. The cumulative rate of new hepatocellular carcinoma cases was computed by the Kaplan-Meier method and Cox proportional hazard analysis according to diabetic state and response to interferon therapy.

Results

The cumulative rates of hepatocellular carcinoma in diabetic patients (3.2% at 4 years, 8.5% at 8 years, and 24.4% at 12 years) were significantly higher than those of nondiabetic patients (1.3% at 4 years, 2.2% at 8 years, and 5.6% at 12 years, P <.001). In patients with a sustained virologic response, diabetes had no significant effect on the rate of hepatocarcinogenesis. In contrast, the rate in patients with a nonsustained virologic response was significantly higher in diabetic than in nondiabetic patients. Multivariate analysis identified lack of sustained virologic response (hazard ratio [HR] 7.28; 95% confidence interval [CI], 3.28-16.15; P <.001) and diabetes as independent risk factors for hepatocarcinogenesis (HR 2.00; 95% CI, 1.05-3.84; P = .036).

Conclusions

Our results highlight the enhancing effect of diabetes mellitus on hepatocarcinogenesis in noncirrhotic, interferon-treated patients with hepatitis C virus. The sustained virologic response induced by interferon therapy eliminates the influence of diabetes and markedly reduces the rate of hepatocarcinogenesis in such patients.     

Hepatic steatosis as a possible risk factor for the development of hepatocellular carcinoma after eradication of hepatitis C virus with antiviral therapy in patients with chronic hepatitis C

AIM: To elucidate risk factors contributing to the development of hepatocellular carcinoma (HCC) among patients with sustained viral response (SVR) after interferon (IFN) treatment and to examine whether HCV-RNA still remained in the liver of SVR patients who developed HCC. METHODS: Two-hundred and sixty-six patients, who achieved SVR, were enrolled in this study. We retrospectively reviewed clinical, viral and histological features of the patients, and examined whether the development of HCC depends on several clinical variables using Kaplan-Meier Method. RT-PCR was used to seek HCV-RNA in 3 out of 7 patients in whom liver tissue was available for molecular analysis. RESULTS: Among the enrolled 266 patients with SVR, HCC developed in 7 patients (7/266; 2.6%). We failed to detect HCV-RNA both in cancer and non-cancerous liver tissue in all three patients. The cumulative incidence for HCC was significantly different depending on hepatic fibrosis (F3-4) (P = 0.0028), hepatic steatosis (Grade 2-3) (P = 0.0002) and age (≥ 55) (P = 0.021) at the pre-interferon treatment. CONCLUSION: The current study demonstrated that age, hepatic fibrosis, and hepatic steatosis at pre- interferon treatment might be risk factors for developing HCC after SVR.