Hepatic iron, liver steatosis and viral genotypes in patients with chronic hepatitis C

Hepatic iron has been described in hepatitis C virus (HCV) infection as an important cofactor of disease outcome. The mechanisms leading to hepatic iron deposits (HIDs) in HCV patients are partially understood. We investigated HIDs in the liver biopsies of a consecutive series of 242 HCV-infected patients with well-compensated liver disease. Serum ferritin was elevated in 20.7% and transferrin saturation in 19.0%, while 38.8% had stainable HIDs indicating that serum markers of systemic iron overload have low sensitivity in predicting HIDs in hepatitis C. A cut-off value of serum ferritin (350 microg/L in females and 450 microg/L in males) had good negative predictive value in excluding presence of mild-moderate HIDs (grade II-III). Hepatic iron deposits correlated by multivariate analysis with serum ferritin [odds ratio (OR) 1.008, 95% confidence interval (CI) 1.005-1.011] and albumin (OR 1.15, 95% CI 1.02-1.297). Hepatic iron deposits were more frequent in HCV-3-infected cases than in other genotypes (P = 0.027) while raised serum iron indices were more frequent in non-HCV-3 genotypes (P = 0.02). Furthermore, advanced fibrosis (F3-F4 by METAVIR) was more frequent in non-HCV-3 genotypes (P = 0.04). In HCV-3 cases there was a close association between HIDs and severe (grade II-III) steatosis (P < 0.00001). These results indicate that in well-compensated chronic hepatitis C HIDs are strongly associated with HCV-3 and viral-induced hepatic steatosis, while in the presence of other genotypes they might merely reflect a more advanced stage of liver disease and/or a systemic iron overload. Serum ferritin could identify a subgroup of patients in which the need of venesection could be excluded without liver biopsy.     

慢性乙肝患者血清铁蛋白与肝组织病理学的关系

探讨慢性乙型肝炎(CHB)血清铁蛋白(serum ferritin,SF)含量与肝功能、肝纤维化指标及肝脏病理的关系。对140例行肝组织活检患者的血清标本进行SF、肝功能、肝纤维化指标检测。结果显示:CHB临床各型SF水平随着病程的进展逐渐升高,与对照组比较有显著差异(P<0.01)。SF与肝组织病理分级、分期、肝纤维化指标及肝功能存在相关性。认为SF可作为肝脏组织病理损害的判断指标之一,检测SF有助于了解肝细胞受损程度。     

Hepatic steatosis in chronic hepatitis B patients is associated with metabolic factors more than viral factors

Background and Aims:  Hepatic steatosis is commonly seen in chronic hepatitis C (CHC) patients. It has been reported to be associated with both metabolic factors and viral factors, and affects the severity of fibrosis in CHC. However, the relationship between hepatic steatosis and chronic hepatitis B (CHB) is unclear. The aims of this study were to investigate the frequency of hepatic steatosis in CHB patients, to identify the factors associated with its presence, and assess the relationship between the stage of steatosis and the severity of fibrosis.
Methods:  Medical records of 153 adult patients with CHB who had undergone a liver biopsy within the past 4 years were included in the study.
Results:  Body mass index (BMI) and age of CHB patients with steatosis was significantly higher than the patients without steatosis ( P  < 0.05), as determined by the univariate analysis. Steatosis was found to correlate with the BMI values and alanine aminotransferase (ALT) levels, and ALT levels were associated with hepatitis B virus (HBV)–DNA levels and histology activity index (HAI) scores, stages of fibrosis were associated with the HAI score and HBV–DNA, as determined by the multivariate analysis. In contrast, there was no significant association between advanced stages of fibrosis and steatosis.
Conclusion:  Our data indicate that hepatic steatosis is more frequently present in CHB patients than in the general population. We hypothesize that steatosis in CHB patients may be due to metabolic factors and the ability of HBV to indirectly facilitate the development of steatosis. In the present study, steatosis in CHB patients was not found to be associated with the severity of fibrosis.     

Serum measures of iron status and HFE gene mutations in patients with hepatitis B virus infection

Aim: We tested associations between HFE mutations and hepatitis B virus (HBV) infection. We also explored measures of total body iron status and their association with chronic HBV infection. Methods: Serum measures of iron status and HFE mutations (C282Y, H63D, and S65C) were assessed in 344 Iranian patients with chronic HBV infection (214 asymptomatic carriers, 130 patients with chronic progressive liver disease [CPLD]) and 302 controls. Results: Frequencies of HFE mutations did not differ between patients with chronic HBV infection and controls (C282Y: P=0.9, H63D: P= 0.8, S65C: P=0.9). By logistic regression, advanced hepatic fibrosis was associated with HFE H63D mutation (OR=13.1, P=0.006; 95% CI=2.0-84.1). Higher levels of serum ferritin and transferrin saturation were observed in patients with CPLD than in healthy controls (P=0.0001 and 0.01, respectively, adjusted for age and sex). None of the serum iron measures was related to liver fibrosis stage or necroinflammatory grade. Conclusion: Serum iron measures are associated with chronic progressive hepatitis B. Carriage of HFE mutations is not associated with the presence of chronic HBV infection or values of serum iron measures in this population, although HFE H63D is associated with more advanced hepatic fibrosis.     

丁型肝炎病毒阳性重型乙型肝炎患者死亡的临床研究

目的探讨丁型肝炎病毒(HDV)在重型乙型肝炎发展中的作用。方法以同期单纯HBV(+)重型肝炎死亡者244例为对照组,76例HDV(+)重型乙型肝炎死亡者进行临床表现、体征、并发症及主要生物化学指标比较。结果HDV(+)死亡组腹水(51.3%)、腹胀(88.2%)、消化道出血(48.7%)与对照组(分别为36.8%,77.1%,33.8%)差异有显著意义(χ2值分别为5.96、4.41和5.97,P＜0.05);肝肾综合征(46.1%)、细菌感染(53.9%)及两种或两种以上并发症发生率(76.3%)与对照组(28.5%、35.7%和53.8%)差异有显著意义(χ2值分别为7.93、8.08和12.27,P＜0.01);生物化学指标总胆红素［(485.45±107.60)μmol/L］、谷丙转氨酶［(38.76±20.15)U/L］、凝血酶原活动度(19.08%±8.09%)与对照组［(407.75±98.54)μmol/L、(56.86±26.75)μmol/L、(23.85±14.07)μmol/L］比较差异有显著意义(u值分别为5.61、7.33和3.67,P＜0.01)。结论HDV对重型乙型肝炎的发展有促进作用。     

HDV重叠感染可增加慢性乙型肝炎患者的肝细胞癌风险

HDV的重叠感染可加速慢性乙型肝炎患者的肝病进程,尤其肝细胞癌(HCC)的发生风险明显增高。但HDV的致癌机制有待进一步探索,治疗方式及效果也亟待突破。综述了HDV相关HCC流行病学新特点、致病机制的新认识和诊疗进展等,对推进研发更精准的HDV检测手段、更有效的治疗药物及减少HDV相关HCC具有重要意义。     

Occult hepatitis B virus infection in Greek patients with chronic hepatitis C and in patients with diverse nonviral hepatic diseases

Occult hepatitis B virus (HBV) infection has been reported in patients with chronic hepatitis C who are negative for HBV surface antigen (HBsAg). However, the significance of 'silent' HBV in hepatitis C virus (HCV) infection is unknown. We investigated 540 subjects for the presence of occult HBV in Greek HCV patients, patients with nonviral liver diseases and healthy donors in an attempt to determine the frequency and importance of this phenomenon. One hundred and eighty-seven anti-HCV(+)/HBsAg(-) patients' sera were investigated for the presence of HBV-DNA by polymerase chain reaction. Two hundred and eighty-two selected blood donors (positive for antibodies to HBV core antigen) and 71 patients with various nonviral hepatic diseases consisted the control groups [both controls were anti-HCV(-)/HBsAg(-)]. HBV-DNA was detected in 26.2% of HCV-infected patients vs 8.5% of patients with nonviral diseases (P = 0.003) and 0/282 of donors (P = 0.0000). HBV-DNA was neither associated with HBV markers, nor with the clinical status of HCV and nonHCV patients. Neither epidemiological, histologic and virologic data nor the response to therapy were associated with the HBV-DNA detection. Hence one quarter of HCV-infected patients had occult HBV infection. Similar findings were not found in both control groups. Occult HBV infection in Greek patients with chronic hepatitis C does not seem to modify the progression of chronic liver disease. Further studies of longer duration are needed in order to clarify the role of 'silent' HBV infection in HCV-infected patients.     

71例血清ALT正常的慢性HBV感染者临床与肝脏病理特征

目的 了解血清ALT正常的慢性HBV感染者的临床及肝脏病理特征.方法 分析71例血清ALT正常,且HBeAg阳性的慢性HBV感染者的年龄、性别、血清HBV DNA水平、肝脏病理改变等.结果 本组病例中＜30岁者61例(85.92%),≥30岁者10例(14.08%).45.07%感染者母亲HBsAg阳性,所有感染者血清HBVDNA为高水平复制,＞107copies/ml者占78.87%.95.77%感染者肝脏有轻度炎症反应,43.66%有不同程度的纤维化,未发现肝硬化.结论 血清ALT正常、HBeAg阳性的慢性HBV感染者多处于免疫耐受期,肝组织病理损害轻微,但部分患者肝脏有一定程度纤维化,显示ALT虽然正常,肝损伤可能在隐匿中进展.因此,对ALT正常的HBV感染者及早进行肝脏病理检查,有利于判断病情和确定治疗方案.     

Quantification of serum markers of hepatitis B (HBV) and Delta virus (HDV) infections in patients with chronic HDV infection

The interplay between hepatitis B (HBV) and delta (HDV) viruses is complex and not always characterized during chronic HDV infection. We assessed the clinical usefulness of new quantitative assays for HBV and HDV serum markers in a retrospective cross‐sectional study. Sera obtained from 122 HDV genotype 1 and HBV genotype D coinfected, anti‐HIV‐negative patients (71 males; median age 49.8 [21.7‐66.9] years), recruited consecutively in two geographical areas (Italy 69 patients, Romania 53 patients) with different HBV and HDV epidemiology, were tested for HBsAg, HBV‐DNA, HBcrAg, total anti‐HBc, HDV‐RNA, IgM and total anti‐HDV using quantitative assays. Cirrhosis, which showed comparable prevalence in the two cohorts, was diagnosed in 97 of 122 (79.5%) patients. At multivariate analysis, cirrhosis was associated with lower total anti‐HBc/IgM anti‐HDV ratio (OR 0.990, 95% CI 0.981‐0.999, P = .038), whereas disease activity was associated with higher total anti‐HDV (OR 10.105, 95% CI 1.671‐61.107, P = .012) and HDV‐RNA levels (OR 2.366, 95% CI 1.456‐3.844, P = .001). HDV‐RNA serum levels showed a positive correlation with HBV‐DNA (ρ = 0.276, P = .005), HBsAg (ρ = 0.404, P < .001) and HBcrAg (ρ = 0.332, P < .001). The combined quantitative profiling of HBV and HDV serum markers identifies specific patterns associated with activity and stage of chronic hepatitis D (CHD). HDV pathogenicity depends on the underlying active HBV infection in spite of the inhibition of its replication. HDV‐RNA, IgM anti‐HDV, total anti‐HDV, total anti‐HBc, HBsAg and HBcrAg serum levels qualify for prospective studies to predict progressive CHD and identify candidates to antiviral therapy.     

慢性HBV/HCV感染人群伴随的免疫相关表现

慢性HBV/HCV感染者常常伴有自身免疫系统紊乱,在丙型肝炎中尤为常见。介绍了慢性丙型肝炎患者免疫状态紊乱的机制,出现非器官特异性自身抗体的比例,以及伴随的免疫相关疾病,如混合型冷球蛋白血症、肾小球肾炎、干燥综合征、甲状腺疾病、2型糖尿病的临床表现、诊断和治疗等。简述了慢性乙型肝炎患者免疫状态紊乱的机制、相关的免疫表现以及抗病毒治疗对其的影响。慢性乙型或丙型肝炎的抗病毒治疗可以减轻伴随的免疫系统疾病,但是不宜采用干扰素治疗,因此,乙型肝炎患者应采用核苷和核苷酸类药物治疗,丙型肝炎患者应采用直接抗病毒药物治疗。     

Hepatic iron accumulation may be associated with insulin resistance in patients with chronic hepatitis C

Background/Aim: Insulin resistance and hepatic iron overload are frequently demonstrated in hepatitis C virus (HCV)-related liver diseases. We investigated the relationship between insulin resistance and hepatic iron deposition in patients with chronic HCV infection. Methods: Insulin resistance was evaluated using the homeostasis model assessments for insulin resistance (HOMA-IR) in 56 non-diabetic non-obese patients with biopsy proven chronic hepatitis C. The relationship between insulin resistance and serum ferritin levels or the grade of hepatic iron deposition was assessed. Results: The levels of plasma immunoreactive insulin (IRI) and HOMA-IR were significantly correlated with serum ferritin levels and the grade of hepatic iron deposition (P = 0.003).Although IRI and HOMA-IR increased in parallel with the development of hepatic fibrosis, insulin resistance (HOMA-IR > 2) was observed in 11 (26.2%) of 42 patients even without severe fibrosis (F0-2). Among patients without severe fibrosis, IRI and HOMA-IR were significantly higher in patients with iron deposits than in those without iron deposits. Conclusion: Hepatic iron overload may be associated with insulin resistance in patients with chronic hepatitis C, especially in patients with mild to moderate fibrosis.     

Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection

BACKGROUND & AIMS: Superinfection in patients with chronic hepatitis B virus (HBV) infection is not uncommon. Acute hepatitis delta virus (HDV) superinfection is associated with severe and/or progressive liver disease. The natural course following acute hepatitis C virus (HCV) superinfection has not been well studied. The aim of this study was to investigate the impact of acute HCV superinfection. METHODS: The clinical features during acute phase and long-term outcomes of acute HCV superinfection were studied and compared with a cohort of acute HDV superinfection and a matched control group of active chronic hepatitis B. RESULTS: Acute HCV superinfection typically occurs as acute icteric hepatitis. The severity is similar to acute HDV superinfection in that hepatic decompensation developed in 34% of patients, hepatitis failure occurred in 11%, and 10% died. During a follow-up period of 1-21 years, patients with acute HCV superinfection had a significantly higher cumulated incidence of cirrhosis (48% at 10 years) and hepatocellular carcinoma (14% at 10 years, 21% at 15 years, and 32% at 20 years) than acute HDV superinfection or active chronic hepatitis B. Hepatitis B surface antigen (HBsAg) seroclearance occurred earlier in HCV superinfected patients. Continuing hepatitis after HBsAg seroclearance was observed only in HCV superinfected patients. CONCLUSIONS: Acute HCV superinfection in patients with chronic HBV infection is clinically severe during its acute phase. The long-term prognosis following acute HCV superinfection is much worse than that following HDV superinfection or active hepatitis B in terms of continuing hepatitis activity after HBsAg loss and the development of cirrhosis or hepatocellular carcinoma.     

Relationship between hepatitis B virus DNA levels and liver histology in patients with chronic hepatitis B

AIM： To study the relationship between hepatitis B virus （HBV） DNA levels and liver histology in patients with chronic hepatitis B （CHB） and to determine the prevalence and characteristics of hepatitis B e antigen （HBeAg） negative patients.
METHODS： A total of 213 patients with CHB were studied, and serum HBV DNA levels were measured by the COBAS Amplicor HBV Monitor test. All patients were divided into two groups according to the HBeAg status.The correlation between serum HBV DNA levels and liver damage （liver histology and biochemistry） was explored.
RESULTS： Of the 213 patients with serum HBV DNA levels higher than 10^5 copies/mL, 178 （83.6%） were HBeAg positive, 35 （16.4%） were HBeAg negative. The serum HBV DNA levels were not correlated to the age,history of CHB, histological grade and stage of liver disease in either HBeAg negative or HBeAg positive patients. There was no correlation between serum levels of HBV DNA and alanine aminotransferanse （ALT）,aspartate aminotrans-ferase （AST） in HBeAg positive patients. In HBeAg negative patients, there was no correlation between serum levels of HBV DNA and AST,while serum DNA levels correlated with ALT （r = 0.351, P = 0.042）. The grade （G） of liver disease correlated with ALT and AST （P 〈 0.05, r = 0.205, 0.327 respectively）in HBeAg positive patients. In HBeAg negative patients,correlations were shown between ALT, AST and the G （P 〈 0.01, and r = 0.862, 0.802 respectively）. HBeAg negative patients were older （35 ± 9 years vs 30 ±9 years, P 〈 0.05 ） and had a longer history of HBV infection （8 ± 4 years vs 6 ± 4 years, P 〈 0.05） and a lower HBV DNA level than HBeAg positive patients （8.4± 1.7 Log HBV DNA vs 9.8 ± 1.3 Log HBV DNA, P 〈0.001）. There were no significant differences in sex ratio,ALT and AST levels and liver histology between the two groups.
CONCLUSION： Serum HBV DNA level is not correlated to histological grade or stage of liver disease in CHB patients with HBV DNA mor     

Hepatic steatosis in chronic hepatitis C virus infection: prevalence and clinical correlation

BACKGROUND AND AIMS: Hepatic steatosis is a histological characteristic in patients with chronic hepatitis C virus (HCV) infection. The aim of this study was to evaluate the prevalence of hepatic steatosis in Chinese patients with chronic hepatitis C, and to look for possible correlation with various histopathological changes and to look for possible correlation with various clinical and pathologic variables. METHODS: One hundred and six patients were enrolled, and patients with alcoholism or diabetes mellitus were excluded. Clinical, biochemical and virologic data, including HCV genotype and serum HCV-RNA titer and histological findings, were compared between patients with and without hepatic steatosis. RESULTS: Fifty-five (52%) of the 106 patients with chronic hepatitis C had hepatic steatosis. Patients with hepatic steatosis had significantly higher mean serum levels of triglyceride and gamma-glutamyl transpeptidase, higher body mass index, and a higher incidence of obesity compared with patients without hepatic steatosis. No significant differences in serum HCV-RNA titer and HCV genotype or the response to interferon therapy were noted between the two groups. Histological analysis showed patients with hepatic steatosis had a significantly higher mean fibrotic score than patients without hepatic steatosis (1.9 +/- 1.2 vs 1.3 +/- 1.0; P = 0.016). There were no significant differences in the severity of necroinflammation, the presence of lymphoid aggregation/follicle or bile duct damage between the two groups. Multivariate logistic regression analysis showed that independent predictors associated with hepatic steatosis were obesity or a histology fibrotic score of > or = 2. CONCLUSION: It was found that 52% of Chinese patients with chronic hepatitis C had hepatic steatosis. Patients with hepatic steatosis were more frequently obese and had more severe hepatic fibrosis.     

Longitudinal evaluation of viral interactions in treated HIV-hepatitis B co-infected patients with additional hepatitis C and D virus

Summary  Virological interactions of hepatitis B (HBV), hepatitis C (HCV) and hepatitis D (HDV) viruses in HIV-infected patients have been poorly characterized especially under treatment influences. Undetection rates of hepatitis viruses were longitudinally analyzed in a 3-year cohort of 308 HIV–HBV co-infected patients and compared using Generalized Estimating Equation models adjusted for age, HIV-RNA, CD4 cell-count and antiviral treatment. Chronic hepatitis co-infection in HIV-infected patients (age years, SD) was: 265 HBV (40.7, 8.2); 19 HBV–HCV (39.7, 4.1); 12 HBV–HDV (35.2, 9.9); 12 HBV–HCV–HDV (39.2, 5.2). At inclusion, treatment with lamivudine/tenofovir was not significantly different between co-infection groups. HBV suppression was significantly associated with HDV (aOR = 3.85, 95%CI 1.13–13.10, P  =   0.03) and HCV tri-infection (aOR = 2.65, 95%CI 1.03–6.81, P  =   0.04), but marginally associated with HIV–HBV–HCV–HDV (aOR = 2.32, 95%CI 0.94–5.74, P  =   0.07). In quad-infection, lower HDV-undetectability ( vs HIV–HBV–HDV, P  =   0.2) and higher HCV-undetectability ( vs HIV–HBV–HCV, P  =   0.1) were demonstrated. The degree of HBV suppression varied between visits and co-infection groups [range of aOR during follow-up ( vs HIV–HBV co-infection): HIV–HBV–HCV = 2.23–5.67, HIV–HBV–HDV = 1.53–15.17]. In treated co-infected patients, HDV expressed continuous suppression over HCV- and HBV-replications. Peaks and rebounds from undetectable hepatitis B, C and/or D viremia warrant closer follow-up in this patient population. HDV-replication was uncontrolled even with antiviral treatment.     

Long-term clinical impact of occult hepatitis B virus infection in chronic hepatitis B patients

BACKGROUND/AIMS: Long-term clinical outcomes of occult hepatitis B virus (HBV) infection were studied. METHODS: Fifteen chronic hepatitis B patients were monitored for a median of 4.4 years (range 0.9-15.3) after hepatitis B surface antigen (HBsAg) seroclearance. Serum HBV DNA was measured by real-time detection polymerase chain reaction. Thirteen patients underwent liver biopsies at the end of follow-up and liver histology was evaluated by Ishak score. Liver HBV DNA was also measured for 12 patients. RESULTS: At the end of follow-up, HBV viremia was absent in 13 (87%) patients, and antibody titers to hepatitis B core antigen showed an inverse correlation with time from HBsAg seroclearance (r=-0.554; P=0.0040). However, all patients retained liver HBV DNA and tested positive for the covalently closed circular HBV DNA replicative intermediate. The hepatic HBV DNA loads had no relation to liver histology. Paired biopsies from 11 patients disclosed that each necroinflammatory score significantly improved after HBsAg seroclearance. Amelioration of liver fibrosis was also evident in eight (73%) patients (P=0.0391 by signed rank test). CONCLUSIONS: A long-standing but strongly suppressed HBV infection may confer histological amelioration after HBsAg seroclearance.     

High viral load is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis B virus infection

BACKGROUND AND AIMS: Hepatitis B virus (HBV) is considered a major risk factor for the progression to liver cirrhosis and hepatocellular carcinoma (HCC). The serum level of HBV-DNA is correlated with progression of the disease. The aim of the present study was to determine the relationship between the level of HBV-DNA and hepatocarcinogenesis in patients with chronic HBV infection. METHODS: The authors studied 73 patients who were diagnosed with chronic HBV infection at Nagasaki University Hospital (Nagasaki, Japan) between January 1980 and December 1999. The significance of age, sex, habitual drinking, serum alanine aminotransferase level, HBV viral load, interferon treatment, hepatic fibrosis and hepatic inflammation on the development of HCC were examined using univariate and multivariate analyses. RESULTS: The cumulative incidence rates of HCC were 14%, 29% and 48% at 5, 10 and 15 years after liver biopsy, respectively. Multivariate analysis identified high viral load, together with age and severe fibrosis, as independent and significant risk factors (P = 0.045, 0.047 and 0.013, respectively) for HCC. CONCLUSIONS: The present findings indicate that high viral load is a risk factor for HCC in patients with chronic HBV infection. Patients with a high HBV viral load should be carefully monitored for HCC.