Long-term follow-up of chronic hepatitis C in patients diagnosed at a tertiary-care center

BACKGROUND/AIMS: The natural history of chronic hepatitis C (HCV) is not completely understood. This study was aimed to evaluate the long-term outcome of the disease over a prolonged period of time and to identify factors associated with progression. METHODS: One hundred and sixteen patients with non-cirrhotic chronic non-A, non-B hepatitis consecutively diagnosed at a tertiary hospital between 1971 and 1977 were followed until December 1998 or until death. Patients with significant alcohol intake were excluded from the study. Variables obtained at the time of diagnosis, including epidemiological, clinical, laboratory, and histological data were recorded to determine risk factors associated with the development of liver cirrhosis and hepatic decompensation. RESULTS: Based on complete follow-up data, the development of liver cirrhosis and hepatic decompensation was evaluated in 94 and 114 of the 116 patients, respectively. Thirty-seven (39.3%) of 94 patients developed liver cirrhosis; an aspartate aminotransferase (AST) value higher than 70 IU/L was associated with development of cirrhosis (odds ratio (OR) 4.22, 95% CI 1.3-13.8). Hepatic decompensation occurred in 12 (10.5%) of 114 patients, its cumulative probability being 2.8% at 10 years, 5.2% at 15 years and 19.8% at 20 years. The only factor independently associated to the development of hepatic decompensation was the presence of fibrosis (stage 2 or 3) in the initial liver biopsy (OR 4.1, IC 95% 1.22-13.9). Liver-related death occurred only in seven (6%) of 114 patients. In comparison with the 116 patients diagnosed in the 1970's, patients with chronic hepatitis C diagnosed in 1999 were younger, more often asymptomatic, had lower AST and alanine aminotransferase (ALT) values and had significantly lower grade and stage histological scores. CONCLUSIONS: In summary, chronic hepatitis C had a high rate of progression to liver cirrhosis over a prolonged follow-up. However, this might be related to the fact that two decades ago the diagnosis was made at a significantly more advanced stage of the disease. Patients at high risk of progression can be identified by biochemical and histological variables at the time of diagnosis.     

AST/ALT Ratio Predicts Cirrhosis in Patients With Chronic Hepatitis C Virus Infection

Objective: A liver biopsy is necessary to grade and stage chronic hepatitis C virus (HCV) infection. In a previous study of patients with nonalcoholic liver disease, an aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio > 1 suggested cirrhosis. We sought to examine the value of the AST/ALT ratio in distinguishing cirrhotic patients with chronic HCV infection from noncirrhotic patients and to correlate the ratio with the grade and stage of hepatitis and other biochemical indices.
Methods: We retrospectively studied 139 patients with chronic HCV infection. Routine biochemical indices were determined, and the histological grade of necroinflammatory activity and the stage of fibrosis of the liver biopsy specimens were scored.
Results: The mean AST/ALT ratio in the cirrhotic patients (  n = 47  ) was higher than in the noncirrhotic patients (  n = 92  ) (  1.06 ± 0.06 vs 0.60 ± 0.09  ;   p < 0.001  ). A ratio ≥1 had 100% specificity and positive predictive value in distinguishing cirrhotic from noncirrhotic patients, with a 53.2% sensitivity and 80.7% negative predictive value. The ratio correlated positively with the stage of fibrosis but not with the grade of activity or other biochemical indices. Of the cirrhotic patients, 17% had no clinical or biochemical features suggestive of chronic liver disease except for an AST/ALT ratio ≥1.
Conclusion: The AST/ALT ratio is a dependable marker of fibrosis stage and cirrhosis in patients with chronic HCV infection.     

Occurrence of hepatocellular carcinoma and decompensation in Western European patients with cirrhosis type B

To examine the morbidity of compensated cirrhosis type B, a cohort of 349 Western European, white patients (86% men; mean age, 44 years) with biopsy-proven cirrhosis was followed up for a mean period of 73 months and was studied for occurrence of hepatocellular carcinoma (HCC) and decompensation. At entry into the study all patients were tested for hepatitis B e antigen (HBeAg; 34% of patients were HBeAg-positive) and antibody to hepatitis delta virus (anti-HDV; 20% of patients were anti-HDV-positive); 48% of 252 patients tested were hepatitis B virus (HBV)-DNA-positive. During follow-up HCC developed in 32 (9%) of the 349 patients and decompensation was observed in 88 (28%) of 317 tumor-free patients. Five years after diagnosis, the probability of HCC appearance was 6% and the probability of decompensation was 23%. After the first episode of decompensation the probability of survival was 35% at 5 years. Cox's regression analysis identified three variables that independently correlated with HCC: age, serum levels of platelets, and liver firmness on physical examination. HBV (HBeAg or HBV-DNA) and HDV (anti-HDV) markers at presentation had no prognostic value for the development of HCC. In conclusion, a high proportion of patients with HBsAg-positive compensated cirrhosis do not experience worsening of their condition for several years, but once decompensation occurs life expectancy is poor. European, white patients with compensated cirrhosis type B are at consistent risk for HCC. Prognostic factors for HCC reflect an advanced stage of cirrhosis and support the hypothesis that development of a tumor could be the likely consequence of long-standing hepatic disease.     

Laparoscopic findings of reddish markings predict hepatocellular carcinoma in patients with hepatitis B virus-related liver disease

Background

For patients with chronic hepatitis due to hepatitis B virus (HBV), factors predicting hepatocellular carcinoma (HCC) other than high levels of HBV-DNA and alanine aminotransferase (ALT) are needed to prevent HCC development, as many patients with chronic HBV infection fulfill these conditions. The purpose of this study was to clarify factors predictive of HCC development for those patients.

Methods

The study was a systematic cohort analysis of 303 consecutive patients with hepatitis B e-antigen, receiving laparoscopic examination for assessment of liver disease. Laparoscopic, histological, and clinical characteristics were investigated as related to HCC development.

Results

HCC occurred in 27 patients during a mean follow-up of 8.0 ± 5.0 years, at the age of 37–72 years. Significant associations with HCC development were shown for liver cirrhosis, histological activity grade, reddish markings, and older age. Multivariate analysis revealed that HCC development was strongly associated with older age and male gender (P = 0.002 and P = 0.043, respectively). HCC occurred more frequently in patients of age ≥30 years even with early stage than in patients of age <30 years (P = 0.031). Severe reddish markings, a laparoscopic finding of widespread parenchymal destruction, were highly associated with HCC development in patients of age ≥30 years at diagnosis (odds ratio = 1.67, P = 0.034), while histological activity grade and ALT level were not (P = 0.075 and P = 0.69, respectively).

Conclusions

HCC development is associated with older age, male gender, and liver cirrhosis. Reddish markings, rather than histological activity or ALT level, can be useful to predict HCC for HBV patients of age ≥30 years.     

慢性乙型肝炎自然史的研究

目的：对乙型肝炎的自然史进行研究，为其预后判断，药物疗效的分析及药品经济学评估提供佐证。方法：采用回顾性方法随访6－18年前经肝穿病理组织学诊断的183例慢性乙型肝炎的远期转归，影响因素及其抗病毒治疗的远期作用。结果：183例慢性乙型肝炎患者累计死亡20例（10．93％），发生肝硬化22例（12．02％），肝癌12例（6．56％），累计5，10，15年生存率分别为97.27%,91.62%和84.47%。因乙型肝炎及其并发症死亡者占死亡原因的85.00%。累计肝癌5年，10年，15年发生率分别是0，3.19%和11.56%。对照组247例死亡6例（2.43%)，无1例发展为肝硬化和肝癌。慢性乙型肝炎患者的死亡率是普通人群的4．50倍。二者相比，肝硬化，肝癌和死亡的发生率差异有显著性（P＜0．005）。采用Cox回归分析，高龄，病理损害重，HBeAg阳性是肝硬化的危险因素，高龄，病理损害重，男性是死亡的危险因素；未筛选出肝部的危险因素。结论：慢性乙型肝炎的远期预后不良。     

Evaluation of hepatic proliferative activity in chronic liver diseases and hepatocellular carcinomas by proliferating cell nuclear antigen (PCNA) immunohistochemical staining of methanol-fixed tissues

The proliferative activity of chronic liver diseases and hepatoellular carcinomas (HCCs) was studied by PCNA immunohistochemistry. Human liver tissues were obtained by surgical operation or needle biopsy, and PCNA was detected by immunohistochemistry. PCNA-labelling indices (PCNA-LIs) of methanol-fixed tissues corresponded with the incidence of S-phase cells previously reported, whereas paraformaldehyde-fixed tissues showed extremely high PCNA-LIs in all specimens. Therefore, methanol-fixed tissues were used for evaluation. The PCNA-LIs of the methanol-fixed tissues were: normal liver 0.78 ±0.38%, chronic persistent hepatitis 1.06±0.86%, chronic aggressive hepatitis 2A 1.01±0.50%, chronic aggressive hepatitis 2B 4.20±1.79%, inactive cirrhosis 0.81±0.49%, active cirrhosis 1.96±0.93%, HCC of Edmondson's type I 4.83±1.98%, type II 6.65±1.69%, and type III 38.7±30.6%. PCNA-positive cells showed little specific distribution; in periportal areas in chronic hepatitis, at the margins of pseudolobules in cirrhosis, and throughout the tumor in HCC. These findings indicated that proliferative activity increased during the progression of chronic hepatitis, but that it decreased at the stage of cirrhosis. In chronic liver diseases, the PCNA-LIs reflected hepatitis activity. HCC showed higher proliferative activity than liver cirrhosis, and the histological grade was correlated with the PCNA-LI.     

Reversibility of cirrhosis in chronic hepatitis B.

BACKGROUND & AIMS: Hepatic fibrosis and cirrhosis are the consequences of many types of chronic liver disease, and, at its final stage when liver nodule and scarring develop, they are generally considered to be irreversible. METHODS: Here we describe 3 patients with chronic hepatitis B with clinical, biochemical, and histologic evidence of cirrhosis. They underwent treatment with interferon-alpha or lamivudine and had follow-up liver biopsy while in clinical, biochemical, and virologic remission. Biopsy specimens were randomly coded in unpaired manner according to patient, and they were read independently by 2 pathologists using the modified hepatitis activity index (with a maximum stage of 6). The mean interval between biopsies was 5.5 years. RESULTS: The mean ALT level decreased from 113.7 to 28.3 U/L. The mean bilirubin level decreased from 2.4 to 0.9 mg/dL, and the mean prothrombin time decreased from 16.3 to 12.3 seconds. The mean Child-Pugh score decreased from 8 to 5. The mean fibrosis score decreased from 5.8 to 0.5 (P = 0.004), and the mean grading score decreased from 10.8 to 3.2 (P = 0.017). CONCLUSIONS: Cirrhosis due to chronic hepatitis B might be reversible in some patients who respond to antiviral therapy.     

Golgi protein-73: A biomarker for assessing cirrhosis and prognosis of liver disease patients

BACKGROUND Reliable biomarkers of cirrhosis, hepatocellular carcinoma(HCC), or progression of chronic liver diseases are missing. In this context, Golgi protein-73(GP73) also called Golgi phosphoprotein-2, was originally defined as a resident Golgi type II transmembrane protein expressed in epithelial cells. As a result, GP73 expression was found primarily in biliary epithelial cells, with only slight detection in hepatocytes. However, in patients with acute or chronic liver diseases and especially in HCC, the expression of GP73 is significantly up-regulated in hepatocytes. So far, few studies have assessed GP73 as a diagnostic or prognostic marker of liver fibrosis and disease progression.AIM To assess serum GP73 efficacy as a diagnostic marker of cirrhosis and/or HCC or as predictor of liver disease progression.METHODS GP73 serum levels were retrospectively determined by a novel GP73 ELISA (QUANTA Lite~? GP73, Inova Diagnostics, Inc., Research Use Only) in a large cohort of 632 consecutive patients with chronic viral and non-viral liver diseases collected from two tertiary Academic centers in Larissa, Greece(n = 366) and Debrecen, Hungary(n = 266). Aspartate aminotransferase(AST)/Platelets(PLT) ratio index(APRI) was also calculated at the relevant time points in all patients. Two hundred and three patients had chronic hepatitis B, 183 chronic hepatitis C, 198 alcoholic liver disease, 28 autoimmune cholestatic liver diseases, 15 autoimmune hepatitis, and 5 with other liver-related disorders. The duration of follow-up was 50(57) mo [median(interquartile range)]. The development of cirrhosis, liver decompensation and/or HCC during follow-up were assessed according to internationally accepted guidelines. In particular, the surveillance for the development of HCC was performed regularly with ultrasound imaging and alpha-fetoprotein(AFP) determination every 6 mo in cirrhotic and every 12 mo in non-cirrhotic patients.RESULTS Increased serum levels of GP73( 20 units) were detected at initial evaluation in 277 out of 632 patients(43.8%). GP73-seropositivity correlated at baseline with the presence of cirrhosis(96.4% vs 51.5%, P 0.001), decompensation of cirrhosis(60.3% vs 35.5%, P 0.001), presence of HCC(18.4% vs 7.9%, P 0.001) and advanced HCC stage(52.9% vs 14.8%, P = 0.002). GP73 had higher diagnostic accuracy for the presence of cirrhosis compared to APRI score [Area under the curve(AUC)(95%CI): 0.909(0.885-0.934) vs 0.849(0.813-0.886), P = 0.003]. Combination of GP73 with APRI improved further the accuracy(AUC: 0.925) compared to GP73(AUC: 0.909, P = 0.005) or APRI alone(AUC: 0.849, P 0.001). GP73 levels were significantly higher in HCC patients compared to non-HCC [22.5(29.2) vs 16(20.3) units, P 0.001) and positively associated with BCLC stage [stage 0: 13.9(10.8); stage A: 17.1(16.8); stage B: 19.6(22.3); stage C: 32.2(30.8); stage D: 45.3(86.6) units, P 0.001] and tumor dimensions [very early: 13.9(10.8); intermediate: 19.6(18.4); advanced: 29.1(33.6) units, P = 0.004]. However, the discriminative ability for HCC diagnosis was relatively low [AUC(95%CI): 0.623(0.570-0.675)]. Kaplan-Meier analysis showed that the detection of GP73 in patients with compensated cirrhosis at baseline, was prognostic of higher rates of decompensation(P = 0.036), HCC development(P = 0.08), and liver-related deaths(P 0.001) during follow-up.CONCLUSION GP73 alone appears efficient for detecting cirrhosis and superior to APRI determination. In combination with APRI, its diagnostic performance can be further improved. Most importantly, the simple GP73 measurement proved promising for predicting a worse outcome of patients with both viral and nonviral chronic liver diseases.     

Detection of hepatocellular carcinoma during a clinical follow-up of chronic liver disease: observations in 31 patients.

In 31 patients with an initial diagnosis of cirrhosis or chronic hepatitis hepatocellular carcinoma (HCC) was detected after a clinical follow-up of 8 months to 14 years with an average of 59 months. They had had no scintigraphic and biochemical abnormalities suggestive of HCC at the beginning. The follow-up period before the detection of carcinoma was shorter in patients positive for hepatitis B surface antigen compared with those negative for hepatitis B surface antigen. Analyses of clinical data during the follow-up and liver scans made shortly before tumor detection suggested that in most of these patients HCC became discernible relatively early in the course of cirrhosis or long before cirrhosis reached an advanced stage. A sharp rise in serum alpha-fetoprotein level proved highly diagnostic in 11, it remained low throughout in 7, and tumor was already unresectable in the majority. Although continuous and regular check for alpha-fetoprotein is imperative in patients with chronic liver disease, particularly in those with hepatitis B surface antigenemia, additional diagnostic tools are necessary for the detection of small HCC in its resectable stage.     

Natural history of hepatitis C virus carriers with persistently normal aminotransferase levels

BACKGROUND & AIMS: Some patients with serum hepatitis C virus (HCV) have persistently normal aminotransferase (ALT) levels and are affected by cirrhosis. This study prospectively evaluated progression of the disease in a group of anti-HCV-positive patients with persistently normal ALT levels. METHODS: Thirty-seven subjects were studied. Each subject underwent liver biopsy at baseline and after 5 years of follow-up. At baseline, serum samples were tested for genotypes and HCV RNA load. ALT levels and serum HCV RNA were tested every other month and every 6 months, respectively. Patients with increased ALT were discharged from the study and treated with IFN. Five years after the end of IFN therapy, a liver biopsy was performed. RESULTS: Liver biopsy at baseline showed chronic hepatitis in 34 patients and normal histology in 3 patients, 2 of whom were negative for HCV RNA and 1 positive. HCV genotypes were distributed as follows: 2a, 56%; 1b, 41%; and 1a, 3%. At the end of 7-year follow-up, 73% of the patients still had normal ALT values. Liver histology after 5 years was comparable to that observed at entry to study. CONCLUSIONS: Most patients with persistently normal ALT serum levels have very mild chronic hepatitis. However, healthy anti-HCV-positive subjects exist. In patients with HCV-related chronic hepatitis associated with persistently normal ALT levels, the grade of disease activity does not increase over years and progression to cirrhosis is slow or absent.     

慢性乙型肝炎患者血生化指标与肝组织病理的相关性

目的评价慢性乙型肝炎患者血生化指标诊断肝组织炎症活动度与纤维化程度的临床价值。方法对205例慢性乙型肝炎患者活体肝穿刺的病理标本进行组织炎症活动度分级(G)和纤维化程度分期(S),并分别与同期检测的血清肝功能指标比较。结果血清TBIL、ALT、AST、GGT平均值随病理分级和分期的增加而逐渐升高,ALB、PTA则相反;与病理诊断比较,临床诊断的灵敏度分别为:轻度83.5%(81例),中度56.8%(46例),重度51.9%(14例)。结论血清TBIL、ALT、AST、GGT可反映慢性乙型肝炎肝组织炎症活动的程度;ALB、PTA是慢性乙型肝炎病变进展的指标。     

Risk factors for hepatocellular carcinoma in patients with liver cirrhosis.

OBJECTIVE: Although cirrhosis is known to predispose toward hepatocellular carcinoma (HCC), there is no agreement on the factors that can influence the risk for HCC in patients with cirrhosis. This study was designed to identify differences in cirrhosis-related risk factors for developing HCC in relation to epidemiological characteristics, stage of the disease and etiology. METHODS: 512 patients from southwestern Spain with Child-Pugh stage A or B cirrhosis were examined periodically by ultrasonography, and alpha-fetoprotein (AFP) concentration was measured. RESULTS: The average length of follow-up was 37 months. A total of 52 cases of HCC were detected, which represented a risk of 17% after 5 years of follow-up. The Cox model showed that the risk of HCC increased by 8% per year of increasing age. Male sex (relative risk: 3.4), hepatitis C virus infection (relative risk: 4.6), hepatitis B virus infection (relative risk: 2.9) and AFP levels higher than 15 ng/ml (relative risk: 2.5) were also shown to be risk factors. Among alcoholic patients, only age (risk increased by 15% per year), and hepatitis C virus infection (relative risk: 5.4) were risk factors for HCC. However, in patients infected by hepatitis C virus, the main risk factors were age (relative risk increased by 8% per year), male sex (relative risk: 3.9), co-infection with hepatitis B virus (relative risk: 4.9), and increased AFP (relative risk: 2.8). Of the patients with HCC, 71% were infected with hepatitis C virus. Alcoholism, Child-Pugh stage and duration of cirrhosis did not increase the risk of the appearance of HCC. CONCLUSIONS: The risk of HCC increased to 17% after 5 years of follow-up in patients with Child-Pugh stage A or B cirrhosis. Hepatitis C virus infection was the main risk factor in patients with cirrhosis. Other risk factors were age, male sex, hepatitis B virus infection and altered AFP level.     

Anti-HBc positivity was associated with histological cirrhosis in patients with chronic hepatitis C

Introduction. In patients with chronic hepatitis C it is still debated whether previous exposure to the hepatitis B virus, diagnosed from the presence of the anti-HBc antibody, is linked to a greater risk of severe hepatitis. The aim of the study was to evaluate whether the presence of anti-HBc antibodies is associated with cirrhosis in patients with HBsAg-negative chronic hepatitis C.Material and methods. Two hundred twenty-two consecutive HBsAg-negative patients with HCV-related chronic hepatitis were enrolled at their first liver biopsy. Ishak’s scoring system was used to grade necroinflammation and fibrosis and the patients with stage 5 or 6 were considered as having histological cirrhosis.Results. Patients with histological cirrhosis had a higher mean age, AST, ALT, a lower platelet count and prothrombin activity compared to those with milder fibrosis. The presence of anti-HBc was identified in 21 (63.6%) of the 33 patients with fibrosis score 5 or 6 and in 56 (29.6%; p < 0.001) of the 189 with score ≤ 4. Patients with cirrhosis had a significantly higher grading than those without cirrhosis (median = 8, IQR 6-11 vs. Median = 6, IQR = 4-8, respectively, p < 0.001). A multivariate logistic regression analysis showed that age, sex and anti-HBc positivity were independent predictors of histological cirrhosis.Conclusion. Our data support the idea that in patients with chronic hepatitis C the presence in serum of anti-HBc is associated with histological cirrhosis and is therefore a marker of clinical value.     

Long-term benefit of interferon alpha therapy of chronic hepatitis D: regression of advanced hepatic fibrosis

BACKGROUND & AIMS: Little is known about the long-term effects of interferon alpha on clinical outcome and survival of patients with chronic hepatitis D. METHODS: Thirty-six patients with chronic hepatitis D who participated in a randomized controlled trial of a 48-week course of high (9 million units) or low (3 million units) doses of interferon alpha or no treatment were followed for an additional 2 to 14 years. RESULTS: Long-term survival was significantly longer in the high-dose group than in untreated controls (P = 0.003) or in the low-dose group (P = 0.019) but did not differ between patients treated with 3 million units and controls. Among surviving patients at 12 years of follow-up, a biochemical response was present in 7 of 12 treated with 9 million units, in 2 of 4 who received 3 million units, and in none of 3 controls. Long-term alanine aminotransferase (ALT) normalization correlated with improved hepatic function and loss of IgM antibody to hepatitis delta antigen (anti-HD). Patients in the high-dose group had a sustained decrease in HDV replication (P = 0.008), leading to clearance of HDV RNA and, eventually, hepatitis B virus (HBV) in some patients, as well as a dramatic improvement in liver histology with respect to activity grade (P = 0.0004) and fibrosis stage (P = 0.007). Strikingly, we documented an absence of fibrosis in the final biopsy of 4 patients with a long-term biochemical response and an initial diagnosis of active cirrhosis. CONCLUSIONS: High doses of interferon alpha-2a significantly improved the long-term clinical outcome and survival of patients with chronic hepatitis D, even though the majority had active cirrhosis before the onset of therapy.     

Aspartate aminotransferase : alanine aminotransferase ratio in chronic hepatitis C infection: Is it a useful predictor of cirrhosis?

BACKGROUND: The clinical usefulness of the ratio of serum aspartate aminotransferase (AST) to alanine aminotransferase (ALT) has been explored in several liver disorders. It has been suggested that in patients with chronic hepatitis C virus (HCV) infection an AST:ALT > or = 1 has 100% specificity and positive predictive value in distinguishing cirrhotic from non-cirrhotic patients. Such statistical certainty attached to a simple biochemical test merits further evaluation. The present study, therefore, assessed the AST:ALT in patients with chronic HCV infection to determine the validity of the ratio in predicting cirrhosis and to correlate the ratio with the histological grade of necroinflammatory activity and fibrosis. METHODS: A retrospective analysis of 153 patients with chronic HCV infection was conducted. Serum biochemistry had been obtained within a mean of 4 weeks of liver biopsy. The histology was scored in terms of activity and fibrosis as described by Scheuer and correlated with AST:ALT. RESULTS: In 30 patients with cirrhosis, the mean AST:ALT (0.99 +/- 0.06) was higher than in 123 patients without cirrhosis (0.60 +/- 0.02; P < 0.001). A ratio > or = 1 had 95.9% specificity and 73.7% positive predictive value in distinguishing cirrhotic from non-cirrhotic patients, with a 46.7% sensitivity and 88.1% negative predictive value. The ratio also parallelled the Scheuer score with respect to fibrosis but not with respect to inflammation. CONCLUSION: Although relatively insensitive, an AST:ALT > or = 1 is highly specific but not diagnostic for the presence of cirrhosis in patients with chronic HCV infection. The ratio reflects the grade of fibrosis in these patients.     

Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminases

Liver stiffness was measured by transient elastography (FibroScan) in 228 consecutive patients with chronic viral hepatitis, with (115) or without cirrhosis (113), to study its correlations with serum transaminases [alanine aminotransferase (ALT)], fibrosis stage and surrogate noninvasive markers of fibrosis (APRI, FORNS, FibroTest and hyaluronic acid). The dynamic profiles of serum transaminases and liver stiffness were compared by multiple testing in 31 patients during a 6-month follow-up. We identified 8.3 and 14 kPa as the fibrosis >/=F2 and cirrhosis cut-offs, respectively: their sensitivities were 85.2%/78.3%; specificities 90.7%/98.2%; positive predictive values 93.9%/97.8%; negative predictive values 78.8%/81.6%; diagnostic accuracies 87.3%/88.2%. FibroScan performed better than the other surrogate markers of fibrosis (P < 0.001). Other than fibrosis, other factors independently associated with liver stiffness were ALT for all patients and chronic hepatitis patients (P < 0.001), and 12-month persistently normal ALT (biochemical remission, P < 0.001) in cirrhotics. In patients with biochemical remission either spontaneous or after antiviral therapy (48 of 228, 21%), liver stiffness was lower than in patients with identical fibrosis stage, but elevated ALT (P < 0.001). The liver stiffness dynamic profiles paralleled those of ALT, increasing 1.3- to 3-fold during ALT flares in 10 patients with hepatitis exacerbations. Liver stiffness remained unchanged in 21 with stable biochemical activity (P = 0.001). In conclusion, transient elastography is a new liver parameter that behaves as a reliable surrogate marker of fibrosis in chronic viral hepatitis patients, provided that its relationship with major changes of biochemical activity is taken into account.     

Individualized hepatocellular carcinoma risk: The challenges for designing successful chemoprevention strategies

Hepatocellular carcinoma (HCC) develops in the context of environmental risk factors like chronic viral hepatitis, diabetes and alcohol exposure, often associated to an increased risk of cirrhosis. Antiviral treatments that are effective to counteract hepatitis B and C may also attenuate the risk of tumor development. However, since hepatitis B-related carcinogenesis is promoted independently of the onset of cirrhosis, such antiviral treatments as nucleo(t)side analogs can promote regression of cirrhosis, prevent clinical decompensation and variceal bleeding but not HCC. This means that in successfully treated patients with cirrhosis, HCC is often the consequence of their extended survival. In hepatitis C patients, a sustained virological response to interferon-based therapies can reduce the rate of HCC development, even in patients with cirrhosis who experience histological regression of their liver disease. Future therapies aimed at this endpoint in at risk populations should take into consideration pretreatment patient stratification for host, viral and environmental risk factors. In this context the recent discovery of single nucleotide polymorphisms involved in the immune system function and tumorigenesis, might permit enrollment of populations of patients enriched with HCC risk factors for targeted chemopreventive therapies. This could finally pave the way to personalized algorithms, as already seen in the diagnosis and treatment schemes for chemoprevention.     

Diagnosis and treatment of chronic hepatitis B

The diagnosis of chronic hepatitis B virus (HBV) infection is made using a combination of serological, virological, biochemical, and histological markers. The natural history of HBV infection can be divided into 3 phases: immune tolerant, immune active with chronic hepatitis B, and inactive carrier; patients in the immune active phase are candidates for antiviral therapy. The primary goal of therapy for chronic hepatitis B is suppression of viral replication, which has been shown to reduce hepatic necroinflammation and retard progression of hepatic fibrosis. Long-term suppression of serum HBV DNA is likely to reduce progression to cirrhosis and hepatic decompensation and may also decrease the risk of hepatocellular carcinoma. Current antiviral therapy for chronic hepatitis B includes interferon alpha, lamivudine and adefovir, with recent studies demonstrating good safety and efficacy of peginterferon and other nucleoside analogues that will soon become additional treatment options. In patients with HBeAg-positive chronic hepatitis B, antiviral treatment is indicated when the serum HBV DNA level is = or >10(5) copies/mL and the alanine aminotransferase (ALT) level is elevated, particularly greater than 2 times the upper limits of normal. For HBeAg-negative patients, the threshold for initiation of therapy is a HBV DNA level = or >10(4) in association with an elevated ALT level. The presence of at least moderate necroinflammation and the presence of fibrosis on liver biopsy, which is optional and not mandatory before therapy, may be useful in supporting the decision to initiate therapy. While undergoing therapy, patients require monitoring every 3 to 6 months to ensure compliance and to test for the development of resistance if an oral agent is used. Issues that remain controversial or need to be studied further are the necessity of a baseline liver biopsy, the HBV DNA and ALT thresholds for initiation of therapy, the optimal duration of antiviral therapy, selection of one agent over another, and the role of combination therapy.     

Clinical features and survival in Chinese patients with hepatitis B e antigen-negative hepatitis B virus-related cirrhosis

Aim:  To compare the clinical features of hepatitis B e antigen (HBeAg)-negative and HBeAg-positive cirrhosis, and to define the survival and prognostic indicators of Chinese HBeAg-negative hepatitis B virus (HBV)-related cirrhosis.
Methods:  Two hundred and seventeen patients with chronic hepatitis B cirrhosis were studied. Survival was calculated using the Kaplan–Meier method. Proportional hazards Cox regression procedure was used to identify independent predictors of survival. The relationship between HBV-DNA viral load and prognosis was also investigated.
Results:  The mean follow-up time was 35 months (3–47 months). HBeAg-negative liver cirrhosis patients comprised the greatest number of cirrhosis patients. Median alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, median total leukocytes (WBC), hemoglobin (Hb), platelet (Plt) and HBV-DNA levels and the proportion of HBV-DNA > 10⁵ copies/mL were lower in HBeAg-negative patients. There were fewer complications in patients treated with lamivudine than in other patients. Survival rates were significantly reduced in patients with HBeAg-negative cirrhosis ( P  = 0.0024). The baseline Child–Pugh scores and more than one decompensation during follow up were independent variables correlated with survival of HBeAg-negative liver cirrhosis patients ( P  = 0.006 and P  = 0.001, respectively). The HBV-DNA viral load did not correlate with any complications or mortality rates of HBeAg-negative patients.
Conclusions:  The clinical features of HBeAg-negative and -positive liver cirrhosis differ. Survival was significantly reduced for Chinese patients with HBeAg-negative than -positive cirrhosis. Factors contributing to the prognosis were baseline Child–Pugh scores and the presence of more than one decompensation during follow up.