Early detection of hepatocellular carcinoma in patients with chronic type B hepatitis. A prospective study

A prospective surveillance of hepatocellular carcinoma (HCC) using serum alpha-fetoprotein and high-resolution, linear-array, real-time ultrasonography was carried out in 432 patients with clinicopathologically proven chronic type B hepatitis. During a follow-up period of 6-85 mo (median 23, mean 26.9 +/- 16.8 mo), asymptomatic HCC was identified in 8 patients, with a calculated annual incidence of 826/100,000, and 2768/100,000 for patients over age 35 yr. The relative risk of developing HCC in hepatitis B surface antigen-positive chronic hepatitis patients was 2 when compared to those that were hepatitis B surface antigen-negative, and was 5 when compared in patients over age 35 yr. Hepatocellular carcinomas detected by these methods were in a relatively early stage as most tumors were small, only 50% were associated with cirrhosis, 37.5% were positive for hepatitis B e antibody, and most were still resectable. We, therefore, recommend a combination of alpha-fetoprotein and ultrasonography surveillance in patients with chronic hepatitis in order to improve the chance of early HCC detection as well as the chance for successful resection. In addition, the low incidence of cirrhosis and hepatitis B e antibody in these patients with "early" HCCs and the occurrence of hepatitis B e antigen/hepatitis B e antibody seroconversion after HCC had developed suggest that the development of HCC and progression from hepatitis to cirrhosis were two independent (though related) sequelae of chronic hepatitis B virus infection.     

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.     

Thyroxine-binding globulin--not a tumor marker of hepatocellular cancer]

Thyroxin-binding globulin (TBG) is secreted by human hepatoma cell lines and was suggested as a tumor marker of primary hepatocellular carcinoma (HCC). However, the results of several clinical studies are contradictory. Therefore, we decided to investigate whether TBG is a valuable marker for early detection and/or followup of HCC. In 30 patients with HCC we determined TBG, thyroxine (T4), trijodothyronine (T3), alpha-feto-protein, ferritin and the sonographically determined tumor size. Twenty one of these patients had liver cirrhosis. In 19 patients hepatitis B-markers could be detected, 9 of whom with positive HBs antigen. Twenty two patients with liver cirrhosis served as controls. Serum TBG in HCC and liver cirrhosis was not significantly different (21.1 +/- 6.9 vs. 18.7 +/- 5.1 micrograms/ml). T4 (p less than 0.04) and the T4/TBG ratio (p less than 0.0002) were significantly lower in HCC. T3 and ferritin were comparable in both groups. TBG correlated with T4 (r = 0.6), but not with the sonographic tumor size, alpha-fetoprotein or ferritin. In 3 patients alpha-fetoprotein and TBG could be determined 3 to 36 months prior to the primary diagnosis of HCC. In none of these patients an increase of TBG was detected before diagnosis of HCC. In the 4 patients under chemotherapy, TBG decreased after the first course. Three of these patients showed further decreasing TBG values in spite of an increasing tumor size. We conclude that in our patients TBG is no valuable tumor marker for the early diagnosis or follow up of HCC.     

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.     

Hepatocellular carcinoma in hemophilia.

A questionnaire-based survey involving 11,801 hemophiliacs from 54 hemophilia centers in the USA and Europe documented the occurrence of hepatocellular carcinoma (HCC) in 10 patients. The crude rate of HCC was 3.2/100,000 patients/year, at least 30 times higher than the background incidence of this tumor in the countries of origin of the patients. All patients were Caucasians with hemophilia A, 39 to 74 years of age, and had liver cirrhosis. All had one or more risk factor for cirrhosis and HCC: 5 were positive for serum hepatitis B surface antigen, 4 had the antibody to hepatitis C virus, and 4 had histories of alcohol abuse. Serum alpha-fetoprotein, measured in 6 patients, was significantly elevated in 4 (range: 807-1399 ng/ml), and only moderately elevated in 2 (25 and 171 ng/ml). The onset of HCC was asymptomatic in 5 patients, whereas it was accompanied by jaundice, abdominal pain, or ascites in the remaining patients. Thus, HCC seems to be a more important secondary disease for hemophiliacs than formerly recognized. Since HCC is often asymptomatic, screening hemophiliacs with chronic liver disease with periodic ultrasound scans might increase the changes of detecting HCC at a stage amenable to surgical treatment.     

Primary Hepatocellular Carcinoma with Hepatitis B Virus Infection in a 16-Year-Old Noncirrhotic Patient

Primary hepatocellular carcinoma metastasizing to abdominal lymph nodes and to the left lung was observed in a 16-year-old male patient. No clinically apparent chronic liver disease preceded the carcinoma and no signs of cirrhosis were detectable in the nonneoplastic liver. Hepatitis B surface antigen, hepatitis B e antigen and antibody to hepatitis B core antigen were found to be positive in the serum. By immunohistochemistry (peroxidase-antiperoxidase technique) hepatitis B surface antigen could be demonstrated in the nontumorous liver parenchyma, but not in the primary hepatocellular carcinoma itself. Serum alpha-fetoprotein was only moderately elevated (75 ng/ml), but immunohistochemically primary hepatocellular carcinoma revealed a considerable number of alpha-fetoprotein-containing cells, whereas nontumorous parenchyma did not. Carcinoembryonic antigen could be demonstrated immunohistochemically in some tumor cells of a lymph node metastasis, but not in the primary tumor or in the nontumorous liver parenchyma. We propose that primary hepatocellular carcinoma developed in this case in a symptomless hepatitis B virus carrier without preceding cirrhosis, an we exclude a simultaneous acute hepatitis B.     

Long-term effect of interferon therapy on incidence of cirrhosis and hepatocellular carcinoma in Thai patients with chronic hepatitis B

The aim of this study was to assess the long-term effects of interferon (IFN) therapy on the incidence of disease progression to cirrhosis and hepatocellular carcinoma (HCC) in Thai patients with chronic hepatitis B. Sixty-seven patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B who received IFN therapy were retrospectively analyzed. The average duration of follow-up was 59.4+/-30.9 months (ranging from 20 to 119 months). Seventy-two untreated patients with comparable clinical data and mean duration of follow-up served as a control group. During follow-up, 24 (35.8%) treated and 7 (9.7%) untreated patients had a sustained loss of HBeAg. However, none of the treated patients or controls became negative for hepatitis B s antigen (HBsAg). Among treated patients, the response was independent of type and dose of IFN, as well as the presence of steroid priming. In addition, 1 of 24 (4.2%) sustained responders and 6 of 43 (14%) non-responders progressed to cirrhosis whereas 16 of 72 (22.2%) in the control group progressed to such sequelae. The overall incidence of new cirrhosis in sustained responders was significantly lower than in the control group (p=0.04). HCC appeared in 11 cirrhotic patients: 9 (12.5%) in the control group and 2 (4.7%) of the non-responders, whereas none of the sustained responders developed HCC. The average period to detection of HCC was 70.5+/-12.4 months for non-responders and 65.3+/-27.6 months for the control group, with no significant differences between these groups. In conclusion, our data suggest that IFN therapy might prevent the progression of cirrhosis and the development of HCC in patients with chronic hepatitis B. These beneficial effects were particularly observed in those who achieved a sustained virological response to treatment.     

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.     

Growth rate of asymptomatic hepatocellular carcinoma and its clinical implications

The growth rate of 31 asymptomatic hepatocellular carcinomas (diameter less than or equal to 5 cm) discovered in 28 patients by a prospective screening program was determined by real-time ultrasonography over 36-860 days. Except for one tumor that shrank on follow-up, the doubling time ranged from 29 to 398 days, with a median of 117 days, an arithmetic mean of 136 days, and a geometric mean of 110 days. In 17 tumors with more than two measurements, the growth rate remained exponential in nine, declined in growth in seven, and showed an initial lag period in one. Doubling time correlated with initial tumor diameter but was independent of the patient's age, sex, hepatitis B surface antigen status, tumor location, liver function tests, stage of liver cirrhosis, histologic type, or grade of malignancy. Although initial alpha-fetoprotein levels did not correlate well with growth rate, in 14 patients with an exponential increase of serum alpha-fetoprotein, the alpha-fetoprotein doubling time was closely related to the tumor doubling time. Based on the above data, the median detectable subclinical period of hepatocellular carcinoma was deduced to be 3.2 yr, and the suitable screening interval for its early detection in our area was 4-5 mo.     

alpha-Fetoprotein monitoring in Chinese patients with chronic hepatitis B virus infection: role in the early detection of hepatocellular carcinoma

Two hundred ninety patients (203 men, 87 women), age 7 to 74 years (mean: 39.1 years), with chronic hepatitis B virus infection, were prospectively followed for a period of 1 to 4 years to determine the value of alpha-fetoprotein monitoring in the early detection of hepatocellular carcinoma. At presentation, 66% of the patients were asymptomatic, 19% had chronic hepatitis and 15% had established cirrhosis. Forty-four (15%) patients had elevated alpha-fetoprotein levels on one or more occasions during the study period. Twenty patients with normal alpha-fetoprotein levels at presentation developed elevated alpha-fetoprotein levels during the course of follow-up, whereas 24 patients had elevated alpha-fetoprotein levels at presentation. Six (14%) of these 44 patients (five men and one woman), age 23 to 66 years, had persistent or progressive increase in alpha-fetoprotein levels and were confirmed to have hepatocellular carcinoma. In four patients, the alpha-fetoprotein levels were below 500 ng per ml at the time of tumor localization. Only three patients had resectable tumors. All six patients would have been missed if alpha-fetoprotein screening was restricted to men above the age of 40 with cirrhosis and anti-HBe. Of the remaining 38 patients, elevation in alpha-fetoprotein levels in 18 patients was associated with exacerbations of the underlying liver disease and/or significant changes in level of hepatitis B virus replication, but in 20 patients, no apparent cause could be identified. The elevation in AFP levels exceeded 200 ng per ml in 26% and persisted beyond 6 months in 15% of these patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Significant correlation between expression level of HSP gp96 and progression of hepatitis B virus induced diseases

AIM: Gp96, also known as Grp94, is a member of heat shock protein (HSP) family and binds repertoires of peptides thereof eliciting peptide-specific T cell immune responses. It predominantly locates inside the endoplasmic reticulum (ER) with some cell surface expression in certain cancerous cells. Previous studies have shown that gp96 expression level was up-regulated in tumor cells, including hepatocellular carcinoma (HCC). However, relationship between the extent of gp96 expression and disease progression especially HBV-induced chronic infection, cirrhosis and hepatocellular carcinoma, has not been addressed before. As primary HCC can be induced and progressed from chronic hepatitis B virus (HBV) infection and HBV-induced cirrhosis, we designed an immunohistochemical experiment to test the correlation between gp96 expression level and HBV-induced disease progression, from chronic HBV infection, cirrhosis to HCC. METHODS: We chose liver samples from different patients of hepatitis B virus induced diseases, including chronic hepatitis B (77 patients), cirrhosis (27 patients) and primary HCC (30 patients), to test the expression level of gp96 in different affected groups. Formalin-fixed, and paraffin-embedded liver tissues taken from these patients were immuno-stained by using an anti-gp96 monoclonal antibody for the expression level of gp96 protein in the sections. In addition, Western blotting of whole cell lysates derived from established human embryonic liver cell lines and several human HCC cell lines (Huh7, HepG2, SSMC-7721) was compared with the expression of gp96. RESULTS: We found that the extent of elevated gp96 expression was significantly correlated with the disease progression, and was the highest in HCC patients, lowest in chronic HBV infection and was that of the cirrhosis in the middle. CONCLUSION: Increased expression of gp96 might be used as a diagnostic or prognostic bio-marker for the HBV infection and HBV-induced diseases.     

Efficacy of ultrasonography and alpha-fetoprotein on early detection of hepatocellular carcinoma

AIM: To evaluate the effectiveness of ultrasonographic screening for early detection of hepatocellular carcinoma (HCC). METHODS: The data of 14968 patients who had ultrasonography (US) for chronic liver diseases were collected into a database program from June 1995 to June 2005. The risk factors for HCC were also studied. A total of 6089 patients who had repeated US were enrolled, 264 patients were diagnosed with HCC during follow-up (mean, 39 mo). RESULTS: The detection rate of small HCC (≤3 cm in diameter) was 67.7%. The tumor size detected by screening at the intervals of 6 mo was significantly smaller than that at longer intervals. Only 29.3% of HCC patients had an elevated serum alpha fetoprotein (AFP) level above 400 ng/mL. The risk of HCC development during follow-up was higher in patients with liver cirrhosis (10.9%) and hepatitis C (9.0%) than in patients with chronic hepatitis (4.2%), hepatitis B (4.9%) and non-B, non-C hepatitis (NBNC, 3.9%). CONCLUSION: US screening at a interval of 6 mo is beneficial to high-risk patients over 40 years old and the early detection of HCC prolongs survival.     

Dramatic reduction of the alpha-fetoprotein level after lamivudine treatment of patients with chronic hepatitis B virus infection and cirrhosis

Markedly elevated alpha-fetoprotein levels in the range of >1,000 ng/mL are highly suspicious for the presence of hepatocellular carcinoma. This report describes three patients with cirrhosis and replicating hepatitis B virus infection who presented with initial serum alpha-fetoprotein levels of >1,000 ng/mL without clear evidence of hepatocellular carcinoma based on multiple abdominal imaging studies. Initiation of lamivudine treatment led to rapid and dramatic reductions in the alpha-fetoprotein level to the normal range within 12 weeks in one patient and by >1 log at 7 and 16 weeks in the other two patients. One of the three patients previously developed lamivudine resistance, and discontinuation of lamivudine led to a severe flare of hepatitis B before lamivudine treatment was restarted. During a follow-up period of 14 to 36 months, all three patients maintained stable alpha-fetoprotein levels and had no signs of hepatocellular carcinoma demonstrated by serial abdominal imaging studies. The dramatic decrease in the alpha-fetoprotein levels in these patients is unlikely to be a spontaneous event but is possibly due to suppression of viral replication and associated hepatic inflammatory activities by lamivudine. These observations may be helpful in the diagnostic evaluation and management of patients with markedly elevated alpha-fetoprotein levels and chronic hepatitis B-related cirrhosis.     

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.     

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.     

Alpha-fetoprotein changes in the course of chronic hepatitis: relation to bridging hepatic necrosis and hepatocellular carcinoma

To examine the frequency and significance of alpha-fetoprotein (AFP) elevation, radioimmunoassay for AFP was performed every 3-6 months in a prospective follow-up study on 432 hepatitis B surface antigen (HBsAg)-positive and 105 HBsAg-negative patients with clinicopathologically proven chronic hepatitis. In a period of 6-85 months (mean 26.9 +/- 16.8), AFP elevation (greater than 20 ng/ml) was recorded in 45.6% of the HBsAg-positive patients. In addition, 19.4% of the HBsAg-positive patients had AFP levels greater than 100 ng/ml, with a highest level of 2520 ng/ml in the absence of hepatocellular carcinoma (HCC). All these figures were much greater than those for HBsAg-negative patients (P less than 0.001). Most episodes of AFP elevation were transient, with parallel moderate SGPT elevation (greater than 200 IU/L). The AFP levels in such episodes correlated closely with the presence of bridging hepatic necrosis, only weakly with peak SGPT levels, but not with age, sex or hepatitis B e antigen/antibody status. None of the transient episodes was followed by subsequent development of HCC. On the other hand, AFP elevation (greater than 100 ng/ml) without parallel SGPT elevation could predict the presence of HCC with very high specificity (98.7%). However, the sensitivity was not high enough (66.7%) for one to rely solely on AFP for the detection of HCC at its earlier stage.     

Chronic hepatitis B in children after e antigen seroclearance: final report of a 29-year longitudinal study

Chronic hepatitis B is usually a benign disease in Caucasian children; however, the long-term prognosis remains unsettled. This report describes the results of a 29-year longitudinal study including 99 white children with chronic hepatitis B, mainly acquired horizontally: 91 were hepatitis B e antigen (HBeAg) positive (4 had cirrhosis), and 8 were HBeAg negative at presentation. Of the 91 HBeAg-positive children, 89 underwent HBeAg seroconversion after a mean period of 5.2 +/- 4.0 years and were included in the study. Of the 85 children without cirrhosis, one had HBeAg-negative hepatitis and the other 84 became inactive carriers. During a mean follow-up of 14.5 +/- 6.1 years after HBeAg seroclearance, 4 carriers experienced reactivation, and 3 of them had HBeAg-negative hepatitis at the last follow-up. Of the 8 initially HBeAg-negative children, 2 had HBeAg-negative hepatitis, and 6 were inactive carriers. Of the 4 children with cirrhosis, 2 had hepatocellular carcinoma (HCC) and remained alive and 2 lost the histological features of cirrhosis in adulthood. Two patients with HBeAg-negative hepatitis and 1 with cirrhosis had experienced drug abuse. At the end of follow-up, 15 of the 89 initially HBeAg-positive patients and 2 of 8 initially HBeAg-negative children had cleared hepatitis B surface antigen. In conclusion, the overall prognosis for chronic hepatitis B in horizontally infected Caucasian children is favorable; however, some patients progress to HCC and HBeAg-negative hepatitis. Long-term monitoring is important, as is counseling on cofactors of liver damage, such as alcohol and drug abuse.     

Prevention of hepatitis B virus-associated liver diseases by antiviral therapy

Hepatitis B virus (HBV) is a major cause of acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma, particularly in Asia–Pacific countries. The major complications in HBV carriers are hepatocellular carcinoma (HCC), liver failure and esophageal varices following the progression to cirrhosis, while some develop HCC without cirrhosis. The progression to liver fibrosis and these other complications could be prevented by treatment with nucleos(t)ide analogues (NUCs); however, NUCs must be continuously administered for a long time. Peginterferon could lead to HBV surface antigen loss. It is difficult to use peginterferon in HBV-infected patients with decompensated cirrhosis. Acute liver failure due to HBV infection and acute exacerbation of chronic hepatitis B could be treated by NUCs. Universal vaccination programs against HBV could prevent new HBV infections globally. Here, we review the currently available treatments for HBV infection.     

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.     

Hepatitis B antigens and antibodies in serum from 41 cases of primary carcinoma of the liver. A study from Thailand

Thirty-seven patients with hepatocellular carcinoma (HCC), one with cholangiocellular carcinoma (CCC), two with mixed HCC and CCC, and one with an anaplastic primary carcinoma of the liver, all from Bangkok, Thailand, were examined for the presence of hepatitis B virus infection markers in their blood. Of the patients with HCC, 70.6% had macronodular cirrhosis. Their serum was positive for hepatitis B surface antigen (HBsAg) in 64.9%, for hepatitis B core antibody (anti-HBc) in 97.3%, and for hepatitis B e antibody (anti-HBe) in 56.8% of the cases. The serum was positive for hepatitis B surface antibody (anti-HBs) in 53.9% of the HBsAg-negative and positive for hepatitis B e antigen (HBeAg) in 16.7% of the HBsAg-positive patients. The results of the study support the hypothesis of an etiological association between hepatitis B virus infection and HCC in Thailand.