Potential of PALBI-T score as a prognostic model for hepatocellular carcinoma in alcoholic liver disease.

BACKGROUND AND AIM: With the control of viral hepatitis, alcoholic hepatocellular carcinoma (HCC) is becoming increasingly important in Japan. In alcoholic cirrhosis, the impact of portal hypertension is significant. Thus, it may be difficult to predict prognosis accurately with the reported prognostic scores. Here we propose the platelet-albumin-bilirubin tumor nodes metastasis (TNM) score (PALBI-T score) as a prognostic model for HCC in alcoholic liver disease, and investigate its usefulness. The PALBI-T score is an integrated score based on the TNM stage and PALBI grade including platelets, reflecting portal hypertension. METHODS: This study included 163 patients with alcoholic HCC treated at our Center from 1997 to 2018. We compared the prognostic prediction abilities of the Japan Integrated Staging (JIS) score, ALBI-T score, and PALBI-T score. The PALBI-T score was calculated similarly to the JIS and ALBI-T scores. Areas under the receiver operating characteristic curve (AUC) were calculated for predicting overall survival (OS). RESULTS: In predicting the 1-year survival, the JIS score had a larger AUC (AUC = 0.925) than the ALBI-T score (AUC = 0.895) and PALBI-T score (AUC = 0.891). On the other hand, there was no significant difference in predicting OS among the integrated scores. The PALBI-T score (AUC = 0.740) had the largest AUC, and the JIS score (AUC = 0.729) and ALBI-T score (AUC = 0.717) were not significantly different from the PALBI grade (AUC = 0.634). The PALBI grade reflected the degree of portal hypertension. CONCLUSION: In patients with alcoholic HCC, the Japan Integrated Staging score is useful for predicting short-term prognosis. The PALBI-T score, which reflects portal hypertension, appears to be a more valid prognostic score for predicting long-term prognosis.

IFN-λ3 as a host immune response in acute hepatitis E virus infection.

BACKGROUND AND AIM: Hepatitis E virus (HEV) is mainly transmitted orally, either waterborne or zoonotic foodborne. Intestinal viruses such as rotavirus are known to induce type III interferon (IFN) in the gastrointestinal (GI) tract where type III IFN dominantly functions in comparison with type I IFN. Therefore, the aim of this study is to investigate the significance of type III IFN (IFN-λ3) in acute hepatitis E. METHODS: IFN-λ3 and HEV RNA levels in the sera of patients with acute HEV infection and in the supernatant of HEV-inoculated cells were measured, using an in-house high-sensitivity method and reverse transcription-polymerase chain reaction, respectively. RESULTS: High serum IFN-λ3 levels were found in the early phase of acute HEV infection, which normalized after resolution. Interestingly, serum IFN-λ3 levels correlated well with serum HEV RNA titers in the same sera, both of which showed the peak before the robust increase of transaminases. In vitro experiments demonstrated that HEV replicated well in the cells with little IFN-λ3 induction (Caco-2, A549) and recombinant IFN-λ3 inhibited HEV replication in a dose-dependent manner. In contrast, in HT-29 cells, a colon cancer cell line, HEV poorly replicated and induced IFN-λ3 in a titer-dependent manner. CONCLUSIONS: These clinical and experimental observations suggest that HEV induced IFN-λ3 as a host innate immune response, which may play a protective role against HEV.

TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus by interferon-free therapy.

BACKGROUND: The aim of this study is to ascertain whether the TLL1 variant at rs17047200 is associated with the development of HCC after achieving sustained virological response (SVR) by interferon (IFN)-free therapy for chronic hepatitis C (CHC). METHODS: A total of 1029 Japanese CHC patients with the following inclusion criteria were enrolled: (i) achieved SVR by IFN-free therapy, (ii) followed up at least 1 year from the end of treatment (EOT) (median 104 weeks), (iii) no history of hepatocellular carcinoma (HCC) by 1 year from the EOT. RESULTS: Nineteen patients developed HCC (HCC group) and 1010 did not (non-HCC group). The proportion of rs17047200 AT/TT was significantly higher in the HCC group than the non-HCC group (47.4% vs. 20.1%, P = 0.008). Multivariate analysis showed that higher levels of α-fetoprotein, FIB-4 and rs17047200 AT/TT were independent risk factors for developing HCC (HR = 3.22, P = 0.021 for α-fetoprotein > 4.6 ng/ml; HR = 3.89, P = 0.036 for FIB-4 > 2.67; HR = 2.80, P = 0.026 for rs17047200 AT/TT). Cumulative incidence of HCC was significantly higher in patients with rs17047200 AT/TT than in those with AA (P = 0.006). Comparing clinical characteristics according to the TLL1 genotypes, patients with rs17047200 AT/TT had significantly lower platelet counts and higher levels of FIB-4 than those with AA (P = 0.011 and 0.032, respectively). CONCLUSIONS: The TLL1 variant was independently associated with HCC development after HCV eradication by IFN-free regimen. It might be involved in hepatic fibrogenesis and thereby carcinogenesis.

Non-alcoholic fatty liver disease in patients with autoimmune hepatitis.

BACKGROUND AND AIM: The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing all over the world. NAFLD develops in patients with liver disease, including patients with autoimmune hepatitis (AIH). NAFLD and AIH have some similar laboratory and histological findings. The aim of this study was to elucidate the characteristics of AIH patients with NAFLD. METHODS: We re-evaluated the nationwide survey performed in Japan in 2015 of AIH patients diagnosed between 2009 and 2013. RESULTS: A total of 1151 subjects (144 men and 1007 women) were enrolled in the present study. The overall prevalence of NAFLD was 17.0%. Compared to AIH without NAFLD, AIH patients with NAFLD had the following characteristics: (i) low female-to-male ratio, (ii) older age, (iii) mild elevation in hepatobiliary enzymes, (iv) histologically progressive fibrosis and mild plasma cell infiltration or mild lobular hepatitis, (v) lower prevalence of prednisolone administration and higher prevalence of ursodeoxycholic acid administration, (vi) higher levels of hepatic enzymes and immunoglobulin G after treatment, and (vii) similar prevalence of autoimmune and malignant complications. CONCLUSION: AIH patients with NAFLD have many features that are different from AIH patients without NAFLD. Understanding these differences is essential for the proper diagnosis and treatment of AIH patients with NAFLD.

Dysregulation of miRNA in chronic hepatitis B is associated with hepatocellular carcinoma risk after nucleos(t)ide analogue treatment.

Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC). Nucleos(t)ide analogue (NA) therapy effectively reduces the incidence of HCC, but it does not completely prevent the disease. Here, we show that dysregulation of microRNAs (miRNAs) is involved in post-NA HCC development. We divided chronic hepatitis B (CHB) patients who received NA therapy into two groups: 1) those who did not develop HCC during the follow-up period after NA therapy (no-HCC group) and 2) those who did (HCC group). miRNA expression profiles were significantly altered in CHB tissues as compared to normal liver, and the HCC group showed greater alteration than the no-HCC group. NA treatment restored the miRNA expression profiles to near-normal in the no-HCC group, but it was less effective in the HCC group. A number of miRNAs implicated in HCC, including miR-101, miR-140, miR-152, miR-199a-3p, and let-7g, were downregulated in CHB. Moreover, we identified CDK7 and TACC2 as novel target genes of miR-199a-3p. Our results suggest that altered miRNA expression in CHB contributes to HCC development, and that improvement of miRNA expression after NA treatment is associated with reduced HCC risk.

Genome-wide association study identified new susceptible genetic variants in HLA class I region for hepatitis B virus-related hepatocellular carcinoma.

We have performed a genome-wide association study (GWAS) including 473 Japanese HBV (hepatitis B virus)-positive HCC (hepatocellular carcinoma) patients and 516 HBV carriers including chronic hepatitis and asymptomatic carrier individuals to identify new host genetic factors associated with HBV-derived HCC in Japanese and other East Asian populations. We identified 65 SNPs with P values < 10-4 located within the HLA class I region and three SNPs were genotyped in three independent population-based replication sets. Meta-analysis confirmed the association of the three SNPs (rs2523961: OR = 1.73, P = 7.50 × 10-12; rs1110446: OR = 1.79, P = 1.66 × 10-13; and rs3094137: OR = 1.73, P = 7.09 × 10-9). We then performed two-field HLA genotype imputation for six HLA loci using genotyping data to investigate the association between HLA alleles and HCC. HLA allele association testing revealed that HLA-A * 33:03 (OR = 1.97, P = 4.58 × 10-4) was significantly associated with disease progression to HCC. Conditioning analysis of each of the three SNPs on the HLA class I region abolished the association of HLA-A*33:03 with disease progression to HCC. However, conditioning the HLA allele could not eliminate the association of the three SNPs, suggesting that additional genetic factors may exist in the HLA class I region.

Acute presentation of autoimmune hepatitis: a multicentre study with detailed histological evaluation in a large cohort of patients.

AIMS: Although liver biopsy is crucial to diagnose and guide treatment decisions, a detailed histological analysis of autoimmune hepatitis (AIH) with clinically acute presentations has not yet been performed. This study aimed to characterise the histological features and explore potential histological hallmarks to diagnose the acute presentation of AIH. METHODS: We systematically evaluated liver specimens of 87 adult patients with acute presentation of AIH retrospectively enrolled from Japanese multicentre facilities. Each histological feature was predefined by consensus based on the diagnostic criteria. RESULTS: Key findings were that acute presentation of AIH revealed histological features of both acute hepatitis and chronic hepatitis accompanying various degrees of fibrosis. The prominent features were lobular necrosis/inflammation (97.7%), plasma cell infiltration (96.4%), emperipolesis (89.3%), pigmented macrophages (84.5%), cobblestone appearance of hepatocytes (82.6%) and perivenular necroinflammatory activity, including centrilobular necrosis (81.4%). CONCLUSIONS: The acute presentation of AIH represents the entire histological spectrum of acute hepatitis and chronic hepatitis with various activity grades and fibrosis stages that clinically correspond to acute-onset AIH and acute exacerbation of classic AIH, respectively. Although there are no pathognomonic features for the pathological diagnosis, the prominent presence of lobular and perivenular necroinflammatory activity, pigmented macrophages and cobblestone appearance of hepatocytes in addition to the classic AIH features, such as plasma cell infiltration and emperipolesis, are useful for the pathological diagnosis of the acute presentation of AIH.

A case of extrahepatic growth-type hepatocellular carcinoma presenting with bleeding from colonic metastasis.

A 60-year-old woman visited our hospital due to hematochezia. Colonoscopy revealed a 50-mm-diameter submucosal tumor with ulceration of the left side of the transverse colon, and magnetic resonance imaging (MRI) demonstrated the presence of small hepatic nodules. Submucosal tumor of the colon with liver metastasis was therefore diagnosed. To prevent tumor bleeding, we performed partial transverse colectomy. The histopathological diagnosis was moderately differentiated hepatocellular carcinoma presenting as a submucosal tumor with a high frequency of vascular invasion. Computed tomography (CT) angiography revealed a 40-mm-diameter confluent multinodular-type hepatocellular carcinoma with outward spread from segment II and multiple intrahepatic metastases. Our final diagnosis was hepatocellular carcinoma with hematogenous colon metastasis.

Association of serum IFN-λ3 with inflammatory and fibrosis markers in patients with chronic hepatitis C virus infection.

BACKGROUND: Hepatitis C virus (HCV) is one of the major causes of liver cancer. The single nucleotide polymorphisms within the IFNL3 gene, which encodes interferon (IFN)-λ(3), are strongly associated with the response to pegylated IFN-α (PEG-IFN-α) plus ribavirin (RBV) therapy in chronic hepatitis C (C-CH) patients. However, the roles of IFN-λ(3) in chronic HCV infection are still elusive. In this study, we aimed to identify clinical and immunological factors influencing IFN-λ(3) and evaluated whether serum IFN-λ(3) levels are involved or not involved in the response to PEG-IFN-α plus RBV therapy. METHODS: We enrolled 119 C-CH patients with HCV genotype 1 infection who underwent 48 weeks of PEG-IFN-α plus RBV therapy. As controls, 23 healthy subjects and 56 patients with non-HCV viral hepatitis were examined. Serum IFN-λ(3) was quantified by chemiluminescence enzyme immunoassay, and 27 cytokines or chemokines were assayed by the multiplexed BioPlex system. RESULTS: Serum IFN-λ(3) levels were higher in C-CH patients or acute hepatitis E patients than in healthy volunteers. Such levels did not differ between the IFNL3 genotypes. In C-CH patients, serum IFN-λ(3) was positively correlated with aspartate aminotransferase, alanine aminotransferase, α-fetoprotein, histological activity, fibrosis index, IFN-γ-inducible protein 10, and platelet-derived growth factor. Multivariate analysis showed that IFNL3 single nucleotide polymorphisms, fibrosis score, and macrophage inflammatory protein 1α were involved in the sustained viral clearance in PEG-IFN-α plus RBV therapy; however, serum IFN-λ(3) levels were not involved. CONCLUSION: Serum IFN-λ(3) levels are increased in C-CH patients regardless of the IFNL3 genotype. IFN-λ(3) is a biomarker reflecting the activity and fibrosis of liver disease, but is not correlated with the responsiveness to PEG-IFN-α plus RBV therapy.

New susceptibility and resistance HLA-DP alleles to HBV-related diseases identified by a trans-ethnic association study in Asia.

Previous studies have revealed the association between SNPs located on human leukocyte antigen (HLA) class II genes, including HLA-DP and HLA-DQ, and chronic hepatitis B virus (HBV) infection, mainly in Asian populations. HLA-DP alleles or haplotypes associated with chronic HBV infection or disease progression have not been fully identified in Asian populations. We performed trans-ethnic association analyses of HLA-DPA1, HLA-DPB1 alleles and haplotypes with hepatitis B virus infection and disease progression among Asian populations comprising Japanese, Korean, Hong Kong, and Thai subjects. To assess the association between HLA-DP and chronic HBV infection and disease progression, we conducted high-resolution (4-digit) HLA-DPA1 and HLA-DPB1 genotyping in a total of 3,167 samples, including HBV patients, HBV-resolved individuals and healthy controls. Trans-ethnic association analyses among Asian populations identified a new risk allele HLA-DPB1*09 ∶ 01 (P = 1.36 × 10(-6); OR= 1.97; 95% CI, 1.50-2.59) and a new protective allele DPB1*02 ∶ 01 (P = 5.22 × 10(-6); OR = 0.68; 95% CI, 0.58-0.81) to chronic HBV infection, in addition to the previously reported alleles. Moreover, DPB1*02 ∶ 01 was also associated with a decreased risk of disease progression in chronic HBV patients among Asian populations (P = 1.55 × 10(-7); OR = 0.50; 95% CI, 0.39-0.65). Trans-ethnic association analyses identified Asian-specific associations of HLA-DP alleles and haplotypes with HBV infection or disease progression. The present findings will serve as a base for future functional studies of HLA-DP molecules in order to understand the pathogenesis of HBV infection and the development of hepatocellular carcinoma.

Efficacy and long-term outcomes of radiofrequency ablation in the elderly with hepatocellular carcinoma.

AIM: The use of radiofrequency ablation (RFA) in elderly patients is increasing in those with hepatocellular carcinoma (HCC). This study compares the elderly (≥75 years old) to non-elderly patients (<75 years old) in the outcomes of the efficacy and safety of RFA. METHODS: Three hundred and thirty-five patients, 103 elderly and 232 non-elderly, with naive HCC who were treated with RFA from 1999 to 2012 were enrolled. Patient characteristics, complications, length of hospital stay, overall survival (OS), median survival time (MST), recurrence-free survival (RFS) and factors related to OS were analyzed. RESULTS: Median age was 79 years (range, 75-88) in the elderly group and 65 years (38-74) in the non-elderly group. The proportion of women (45.6% and 28.0%), hepatitis C virus infection (63.1% and 50.4%) and comorbidities (78.6% and 44.0%) in the elderly group compared to the non-elderly group, respectively, was significantly higher. No difference existed in the complications and length of hospital stay. The 5-year OS rates and MST were 67.3% and 90.5 months in the elderly group and 60.9% and 86.4 months in the non-elderly group, respectively (P = 0.486). The median RFS time was 20 months in the elderly group and 18.7 months in the non-elderly group (P = 0.429). In multivariate analysis, the Child-Pugh grade and tumor-node-metastasis stage were significantly associated with OS (P < 0.001, =0.003); age was not (P = 0.355). CONCLUSION: RFA in elderly patients is as effective and safe as in non-elderly patients for the treatment of HCC.

Reactivation of hepatitis B virus in patients with undetectable HBsAg undergoing chemotherapy for malignant lymphoma or multiple myeloma.

Despite increasing reports of hepatitis B virus (HBV) reactivation in hematological malignancies, its incidence, and risk factors are still obscure. The aim of this study was to clarify the frequency and risk factors of HBV reactivation in hepatitis B surface antigen (HBsAg) undetectable patients with malignant lymphoma or multiple myeloma, during or after chemotherapy. A total of 109 patients with undetectable HBsAg undergoing chemotherapy for malignant lymphoma or multiple myeloma were enrolled in this study. Anti-hepatitis B surface (anti-HBs) and anti-hepatitis B core (anti-HBc) were checked before treatment, and HBV DNA in sera was quantified monthly during and after chemotherapy. Out of 109 patients, 42 (38.5%) had anti-HBs and 59 (54.1%) had anti-HBc. Among the 59 anti-HBc positive patients, four patients (4/59, 6.8%) showed HBV reactivation during 20.5 median follow-up months. In all four patients with HBV reactivation, peripheral lymphocyte counts before chemotherapy were lower than those without HBV reactivation (P=0.033). HBV reactivation occurred during and after chemotherapy containing rituximab for non-Hodgkin lymphoma. Four patients, who had HBV reactivation, did not develop de novo hepatitis due to HBV reactivation and were able to undergo chemotherapy against malignant lymphoma as scheduled. Monitoring of HBV DNA in sera is useful for the early diagnosis of HBV reactivation, and preemptive therapy is an useful alternative to prevent hepatitis due to HBV reactivation. Patients must be monitored periodically for HBV-DNA levels during and after chemotherapy.

Implantable arterial port-related bloodstream infection in patients with primary or metastatic hepatic malignancies.

The incidence of implantable arterial post-related bloodstream infections (IAP-RBSI) among patients with unresectable hepatic malignancies is not well defined. We reviewed the 9-year incidence of implantable arterial post-related bloodstream infections in patients with hepatic malignancies, at a tertiary care center in Japan. The incidence was 1.9 infections per 10,000 catheter-days.

Feasibility of the virtual needle tracking system for percutaneous radiofrequency ablation of hepatocellular carcinoma.

AIM: To evaluate the feasibility of the real-time virtual needle tracking system for percutaneous radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). METHODS: An electromagnetic field created by an ultrasound (US) machine detected the tracking bracket mounted onto the RFA needle. When the needle tip was confirmed to be in the accurate plane extracorporeally, the needle was inserted into the liver using the virtual navigation US system, and RFA was performed. Eight patients with eight liver lesions underwent percutaneous RFA under ultrasound for HCC from October to November 2012 using the real-time electromagnetic virtual needle tracking system (VirtuTRAX). RESULTS: The average size of the tumors was 11.5 mm with one lesion in S4, two in S5, two in S7 and three in S8. Sufficient margins were obtained in a single session in all cases. Using only B-mode, the needle tip was obscured due to the condition of the surrounding liver or subcutaneous fat tissue, but it was identifiable with the use of the virtual needle tracking device in all cases. In one case where the lesion was large, the needle was placed twice deliberately, but the second puncture was made difficult by the ablation artifact of the first puncture. With the tracking device, however, it was possible to perform the second puncture accurately. CONCLUSION: The virtual tracking system is useful in cases where the needle tip is obscured due to surrounding liver conditions or when multiple punctures are necessary due to the ablation artifact's obscuring the needle tip. Freehand puncturing may be possible in the future using this technique with further improvements in the system.

Feasibility of fused imaging for the evaluation of radiofrequency ablative margin for hepatocellular carcinoma.

AIM: To evaluate the feasibility of fusion of conventional imaging modalities to facilitate assessment of ablative margin of radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). METHODS: Two hundred and thirty-nine liver lesions in 109 patients underwent percutaneous RFA under ultrasound for HCC from January 2008 to December 2010. Within these patients, 13 lesions in 12 patients who developed local tumor progression in the follow-up period of at least 8 months were retrospectively reviewed. Imaging obtained before and after RFA was used for creating fused images on a workstation. Ablative margins were assessed using only axial images, and with fused images. RESULTS: The ablative margin was assessed as sufficient in all 13 lesions using side-by-side axial images; however, all lesions were assessed as insufficient with fused imaging evaluation. The reason for the discrepancy of the assessment results were differences in the respiratory dislocation of the liver in the pre- and post-RFA images in eight lesions (61.5%), and rotational displacement of the liver and the torso in five (38.5%). The site of local tumor recurrence relative to the HCC lesion was craniocaudal in 12 lesions, dorsoventral in seven and lateral in seven. In all lesions, the site of local tumor recurrence was congruent with the area of the thinnest ablative margin. CONCLUSION: Assessment of ablative margin with fused imaging revealed insufficiency of ablation previously evaluated as sufficient with conventional axial imaging. Fused imaging evaluation has proved to be an accurate and useful tool for the assessment of RFA margins.

Genome-wide association study confirming association of HLA-DP with protection against chronic hepatitis B and viral clearance in Japanese and Korean.

Hepatitis B virus (HBV) infection can lead to serious liver diseases, including liver cirrhosis (LC) and hepatocellular carcinoma (HCC); however, about 85-90% of infected individuals become inactive carriers with sustained biochemical remission and very low risk of LC or HCC. To identify host genetic factors contributing to HBV clearance, we conducted genome-wide association studies (GWAS) and replication analysis using samples from HBV carriers and spontaneously HBV-resolved Japanese and Korean individuals. Association analysis in the Japanese and Korean data identified the HLA-DPA1 and HLA-DPB1 genes with P(meta) = 1.89×10⁻¹² for rs3077 and P(meta) = 9.69×10⁻¹° for rs9277542. We also found that the HLA-DPA1 and HLA-DPB1 genes were significantly associated with protective effects against chronic hepatitis B (CHB) in Japanese, Korean and other Asian populations, including Chinese and Thai individuals (P(meta) = 4.40×10⁻¹9 for rs3077 and P(meta) = 1.28×10⁻¹5 for rs9277542). These results suggest that the associations between the HLA-DP locus and the protective effects against persistent HBV infection and with clearance of HBV were replicated widely in East Asian populations; however, there are no reports of GWAS in Caucasian or African populations. Based on the GWAS in this study, there were no significant SNPs associated with HCC development. To clarify the pathogenesis of CHB and the mechanisms of HBV clearance, further studies are necessary, including functional analyses of the HLA-DP molecule.

No association for Chinese HBV-related hepatocellular carcinoma susceptibility SNP in other East Asian populations.

BACKGROUND: A recent genome-wide association study (GWAS) using chronic HBV (hepatitis B virus) carriers with and without hepatocellular carcinoma (HCC) in five independent Chinese populations found that one SNP (rs17401966) in KIF1B was associated with susceptibility to HCC. In the present study, a total of 580 HBV-derived HCC cases and 1351 individuals with chronic hepatitis B (CHB) or asymptomatic carrier (ASC) were used for replication studies in order to evaluate the reported association with HBV-derived HCC in other East Asian populations. RESULTS: We did not detect any associations between rs17401966 and HCC in the Japanese cohorts (replication 1: OR = 1.09, 95 % CI = 0.82-1.43; replication 2: OR = 0.79, 95 % CI = 0.54-1.15), in the Korean cohort (replication 3: OR = 0.95, 95 % CI = 0.66-1.36), or in the Hong Kong Chinese cohort (replication 4: OR = 1.17, 95 % CI = 0.79-1.75). Meta-analysis using these cohorts also did not show any associations with P = 0.97. CONCLUSIONS: None of the replication cohorts showed associations between rs17401966 and HBV-derived HCC. This may be due to differences in the genetic diversity among the Japanese, Korean and Chinese populations. Other reasons could be the high complexity of multivariate interactions between the genomic information and the phenotype that is manifesting. A much wider range of investigations is needed in order to elucidate the differences in HCC susceptibility among these Asian populations.

[Sarcomatoid carcinoma of the liver: a case report and review of the literature].

A 66-year-old woman presented to our outpatient clinic with abdominal discomfort in April, 2008. Ultrasound revealed a hypo-echoic 10cm mass in the right hepatic lobe but no indication of chronic liver disease, with similar results in her history, on physical exam, and imaging. Serum testing did not identify any systemic disease. The mass was suspected to be intrahepatic cholangiocarcinoma and right hepatic lobectomy was performed. Histologic examination of the specimen revealed numerous spindle cells, and immunostaining confirmed a definitive diagnosis of sarcomatoid carcinoma of the liver. On subsequent review of the case, an abdominal CT performed 2.5 years earlier for unrelated symptoms had shown a 1cm faint low density area in the same location as the mass. The doubling time of this tumor was about 95 days.

Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection.

The outcome of acute hepatitis B virus (HBV) infection is variable, influenced by host and viral factors. From 1982 through 2004, 301 patients with acute HBV infection entered a multi-center cross-sectional study in Japan. Patients with fulminant hepatitis (n = 40) were older (44.7 +/- 16.3 vs. 36.0 +/- 14.3 years, P < .0017), less predominantly male (43% vs. 71%, P = .0005), less positive for hepatitis B e antigen (HBeAg) (23% vs. 60%, P < .0001), less infected with subgenotype Ae (0% vs. 13%, P < .05), and more frequently with Bj (30% vs. 4%, P < .0001) than those with acute self-limited hepatitis (n = 261). Precore (G1896A) and core-promoter (A1762T/G1764A) mutations were more frequent in patients with fulminant than acute self-limited hepatitis (53% vs. 9% and 50% vs. 17%, P < .0001 for both). HBV infection persisted in only three (1%) patients, and they represented 2 of the 23 infected with Ae and 1 of the 187 with the other subgenotypes (9% vs. 0.5%, P = .032); none of them received antiviral therapy. In multivariate analysis, age 34 years or older, Bj, HBeAg-negative, total bilirubin 10.0 mg/dL or greater, and G1896A mutation were independently associated with the fulminant outcome. In in vitro transfection experiments, the replication of Bj clone was markedly enhanced by introducing either G1896A or A1762T/G1764A mutation. In conclusion, persistence of HBV was rare (1%) and associated with Ae, whereas fulminant hepatitis was frequent (13%) and associated with Bj and lack of HBeAg as well as high replication due to precore mutation in patients with acute HBV infection.