The incidence and risk factors for the development of hepatocellular carcinoma after peginterferon plus ribavirin therapy for chronic hepatitis C.

BACKGROUND/AIMS: Although the incidence of hepatocellular carcinoma (HCC) has been shown to be reduced after pegylated glycol-interferon plus ribavirin (Peg-IFN/RBV) therapy in patients with chronic hepatitis C, the risk factors for the development of HCC are not fully understood. The aim of this study was to clarify the incidence and the risk factors for the development of HCC after Peg-IFN/RBV therapy in patients with chronic hepatitis C. METHODOLOGY: A total of 474 patients with chronic hepatitis C who received Peg-IFN/RBV therapy between December 2004 and August 2010 were enrolled and followed in a multicenter trial. The patients were assessed for HCC by either ultrasound or computed tomography every 6 months. The incidence and risk factors for the development of HCC were identified. RESULTS: Of the 474 patients, 23 developed HCC during a median follow-up of 4 years and 8 months (range 1-6 years and 3 months) after completion of Peg-IFN/RBV therapy. According to a univariate analysis, higher age, low platelet counts, a low level of serum albumin, a high level of alpha-fetoprotein (AFP) and a sustained viral response (SVR) to Peg-IFN/RBV therapy were independent factors associated with the occurrence of HCC. The multivariate analysis using the Cox proportional hazard model revealed the risk factors for HCC were the platelet count, AFP level and the outcome of Peg-IFN/RBV therapy. CONCLUSIONS: To reduce the incidence of HCC in chronic hepatitis C, attainment of a sustained response rate is an essential issue. For patients with low platelet counts and/or a high AFP level, strict surveillance should be continued even after eradication of HCV because the risk of HCC was found to be higher for these patients.

Hepatic peribiliary cysts with rapidly progressive refractory obstructive jaundice and esophageal varices.

A 54-year-old man with decompensated alcoholic liver cirrhosis presented with acute cholangitis. Although no localized lesions were detected in the liver on contrast-enhanced computed tomography and no risky varices were noted on endoscopy, hepatic peribiliary cysts (HPBCs) developed along the intrahepatic portal vein in the course of only 40 days. Moreover, esophageal varices with the red color sign grew rapidly during the same period, and the patient ultimately died due to rupture. HPBC formation is a rare complication of liver disease, including cirrhosis. Although HPBCs are generally harmless, on rare occasions they may induce the rapid progression of esophageal varices.

Clinical outcomes of hepatitis B virus (HBV) genotypes B and C in Japanese patients with chronic HBV infection.

The aims of this retrospective survey were to determine the epidemiologic distribution of hepatitis B virus (HBV) genotypes and analyze the genotype-related clinical differences among Japanese patients with chronic HBV infection. The 158 surveyed patients with chronic HBV infection lived in Fukuoka and Okinawa were serially tested for serum alanine aminotransferase (ALT) and hepatitis B e antigen (HBeAg). Follow-up was for a period of 10.8 +/- 6.4 years (mean +/- SD). The HBV genotypes were determined in sera by an enzyme-linked immunosorbent assay and detection of HBV DNA in serum was done by the transcription-mediated amplification-hybridization protection assay. Genotypes B and C were found in 58 (36.7%) and 100 (63.3%) of the patients, respectively. Genotype B was predominant in Okinawa (B = 86.9%, C = 13.1%), whereas genotype C was predominant in Fukuoka (B = 5.2%, C = 94.8%). The HBeAg positivity and ALT abnormality rates at the start of the observation period were significantly higher in patients with genotype C (66.0% and 84.0%) than in patients with genotype B (34.5% and 22.4%) (P < 0.05, respectively). The annual rate of spontaneous HBeAg disappearance in patients with genotype B was much higher than in patients with genotype C (8.38% versus 2.34%, respectively). Patients with genotype C who were continuously HBeAg negative from entry had a significantly higher ALT abnormality (58.8%) than those with genotype B (19.2%) (P < 0.05). Interestingly, patients with genotype C who became HBeAg negative after treatment with interferon had a high ALT abnormality (58.8%). All patients with an ALT abnormality were positive for HBV DNA in their serum. These findings indicate that patients with HBV genotype C have more severe liver deterioration because of the delay of HBeAg disappearance and continued HBV replication after HBeAg disappearance.

[Living donor liver transplantation for fulminant hepatic failure--medical treatment organization in Kyushu University].

Liver transplantation has been recognized as an effective therapeutic method for end-stage liver disease in Japan. Fulminant hepatic failure is also an indication for liver transplantation, and the number of patients undergoing liver transplantation has been increasing. Reversibility and urgency are characteristics of fulminant hepatitis. If given appropriate critical support, many patients recover spontaneously. However, many patients develop cerebral edema or multiorgan failure before the liver can regenerate. From October 1996 to July 2002, living donor liver transplantation (LDLT) was performed to 84 end stage liver disease patients in Kyushu University. Twenty-four (28.6%) of 84 LDLTs were for fulminant hepatic failure. In Kyushu University, LDLT candidates including urgent cases were discussed with indication in the liver transplantation committee (the medical professions division and an outside-the-university committee are included) and then the coordinator committee performs informed consent. LDLT can be performed only by cooperation of each section concerned such as Transfusion part, Medicine part, Radiation part, Operation part, Intensive Care Unit and so on. In this paper, we outline about fulminant hepatic failure and living donor liver transplantation, and describe the fulminant hepatitis medical treatment organization in Kyushu University.

Refractory primary hepatic actinomycosis with direct infiltration to the diaphragm and thorax: the usefulness of contrast-enhanced ultrasonography.

An 80-year-old man was admitted to our hospital with a diagnosis of primary hepatic actinomycosis determined based on a percutaneous aspiration biopsy. The abscesses and state of liquefaction were easily and effectively visualized on contrast-enhanced ultrasonography. Ampicillin/sulbactam was administered; however, lesions of hepatic actinomycosis suddenly infiltrated the diaphragm and right thorax six months later. A drainage tube was inserted into the right thoracic space, and the pleural effusion gradually decreased. The patient received continuous antibiotic therapy for nearly two years and remained free of hepatic actinomycosis on follow-up more than one year later.

Pretreatment prediction of interferon-alfa efficacy in chronic hepatitis C patients.

BACKGROUND & AIMS: Interferon has been used widely to treat patients with chronic hepatitis C infections. Prediction of interferon efficacy before treatment has been performed mainly by using viral information, such as viral load and genotype. This information has allowed the successful prediction of sustained responders (SR) and non-SRs, which includes transient responders (TR) and nonresponders (NR). In the current study we examined whether liver messenger RNA expression profiles also can be used to predict interferon efficacy. METHODS: RNA was isolated from 69 liver biopsy samples from patients receiving interferon monotherapy and was analyzed on a complementary DNA microarray. Of these 69 samples, 31 were used to develop an algorithm for predicting interferon efficacy, and 38 were used to validate the precision of the algorithm. We also applied our methodology to the prediction of the efficacy of interferon/ribavirin combination therapy using an additional 56 biopsy samples. RESULTS: Our microarray analysis combined with the algorithm was 94% successful at predicting SR/TR and NR patients. A validation study confirmed that this algorithm can predict interferon efficacy with 95% accuracy and a P value of less than .00001. Similarly, we obtained a 93% prediction efficacy and a P value of less than .0001 for patients receiving combination therapy. CONCLUSIONS: By using only host data from the complementary DNA microarray we are able to successfully predict SR/TR and NR patients for interferon therapy. Therefore, this technique can help determine the appropriate treatment for hepatitis C patients.

High-density lipoprotein binding rate differs greatly between genotypes 1b and 2a/2b of hepatitis C virus.

The hepatitis C virus (HCV) virion is associated with lipoproteins and immunoglobulins in the sera of patients with chronic hepatitis C; however, an accurate binding rate of HCV to lipoproteins or immunoglobulins has not yet been elucidated. Therefore, the accurate binding rate of HCV to low-density lipoproteins (LDL), high-density lipoproteins (HDL), and immunoglobulins was measured quantitatively by a real-time PCR assay. The immunoglobulin binding rate of HCV was found to be greater than 97.5% in most patients, as compared with an LDL binding rate of greater than 80% in most patients. In contrast, the HDL binding rate was greater than 98% in the genotype 2a/2b patients, while it varied in the genotype 1b patients. The genotype 2a/2b HCV not only had a higher LDL binding rate but also had a strikingly higher HDL binding rate than that of the genotype 1b HCV. These lipoprotein binding rates correlated neither to any patient's variables, including the serum apolipoprotein levels, nor to the viral load or the hypervariable region 1 (HVR 1) amino acid sequences. Most of the HCV virions in the sera of such patients have been shown to be associated simultaneously with immunoglobulins and LDL and/or HDL, but not exclusively.

Antisense RNAs transcribed from the upstream region of the precore/core promoter of hepatitis B virus.

The bidirectional activity of the precore/core promoter of hepatitis B virus (HBV) has been demonstrated in cultured cell lines. However, HBV antisense transcripts (asRNAs) have not been demonstrated in vivo. In the present study using liver tissue from patients with chronic hepatitis, an anchored 5'RACE mapping the 5' ends at position 1680/1681, 1655 or 1609/1602 was carried out. In limited cases, RLM-3'RACE detected asRNAs to terminate at four or five consecutive dT residues in the 0.7 kb downstream region. PCR of oligo(dT)-primed cDNA did not amplify a typical polyadenylated asRNA. RT-PCR using various primers did not detect any spliced forms. Competitive RT-PCR estimated the copy numbers of the asRNAs to be 0.05-0.4 % of total sense RNAs. All sequenced asRNAs had ORF6 but, in one patient, the asRNA initiating at position 1680/1681 had additional initiation and termination codons in front of ORF6. Therefore, asRNAs are transcribed by RNA polymerase III at a low level, encompass a dispensable ORF6 gene and might be retained in the nucleus. The endogenous asRNAs complementary to the common ends of all sense RNAs suggest antisense-mediated self-regulation of hepadnavirus.

Correlation between histopathological findings of the liver and IgA class antibodies to 2-oxo-acid dehydrogenase complex in primary biliary cirrhosis.

Although anti-mitochondrial antibody (AMA) is the characteristic serological feature of primary biliary cirrhosis (PBC), its pathogenetic role remains unclear. We tested sera from 72 Japanese patients with histologically confirmed PBC for AMA by indirect immunofluorescence, anti-pyruvate dehydrogenase complex (PDC) by enzyme inhibition assay, immunoglobulin (Ig) G class anti-PDC by ELISA, and IgG, IgM, and IgA class anti-2-oxo-acid dehydrogenase complex (2-OADC) by immunoblotting. Of the 72 sera, 60 (83%), 50 (69%), 42 (58%), and 71 (99%) were positive for AMA by immunofluorescence, enzyme inhibition assay, ELISA, and immunoblotting, respectively. There was no significant correlation between histological stages and AMA by immunofluorescence, PDC inhibitory antibodies by enzyme inhibition assay, IgG class anti-PDC antibodies by ELISA, or IgG and IgM class anti-2-OADC by immunoblotting. IgA class anti-2-OADC by immunoblotting was more frequent in stages 2-4 than in stage 1 (P = 0.0083). Of the IgA class anti-2-OADC, anti-PDC-E2 (74 kDa) and anti-E3BP (52 kDa) were more frequent in stages 2-4 than in stage 1 (P = 0.0253 and 0.0042, respectively). Further examination of histopathological findings in 53 of 72 liver biopsy specimens showed that IgA class anti-PDC-E2 and IgA class anti-E3BP were associated with bile duct loss, and IgA class anti-PDC-E2 was also associated with interface hepatitis and atypical ductular proliferation. IgA is known to be secreted into the bile through biliary epithelial cells, implying that IgA class anti-PDC-E2 and E3BP may have a specific pathogenetic role during their transport into the bile by binding to their target antigen(s) in biliary epithelial cells, and this may be followed by dysfunction and finally destruction of biliary epithelial cells. Our present results suggest that these autoantibodies against 2-OADC detected by immunoblotting may be associated with the pathogenesis and pathologic progression of PBC.

A low-density cDNA microarray with a unique reference RNA: pattern recognition analysis for IFN efficacy prediction to HCV as a model.

We have designed and established a low-density (295 genes) cDNA microarray for the prediction of IFN efficacy in hepatitis C patients. To obtain a precise and consistent microarray data, we collected a data set from three spots for each gene (mRNA) and using three different scanning conditions. We also established an artificial reference RNA representing pseudo-inflammatory conditions from established hepatocyte cell lines supplemented with synthetic RNAs to 48 inflammatory genes. We also developed a novel algorithm that replaces the standard hierarchical-clustering method and allows handling of the large data set with ease. This algorithm utilizes a standard space database (SSDB) as a key scale to calculate the Mahalanobis distance (MD) from the center of gravity in the SSDB. We further utilized sMD (divided by parameter k: MD/k) to reduce MD number as a predictive value. The efficacy prediction of conventional IFN mono-therapy was 100% for non-responder (NR) vs. transient responder (TR)/sustained responder (SR) (P < 0.0005). Finally, we show that this method is acceptable for clinical application.