Effects of branched-chain amino acid granules on serum albumin level and prognosis are dependent on treatment adherence in patients with liver cirrhosis.

AIM: To test if the treatment adherence to branched-chain amino acid (BCAA) granules influences the serum albumin level and prognosis in prospective 2984 patients with decompensated liver cirrhosis who were prescribed BCAA granules containing 952 mg of L-isoleucine, 1904 mg of L-leucine and 1144 mg of L-valine at 4.15 g/sachet three times a day after meals. METHODS: The primary end-point was the time to the event defined as "hospital admission due to progression of hepatic failure", and factors affecting this outcome were explored. Changes in serum albumin level were evaluated as the secondary end-point. RESULTS: Patients were divided into the good adherence group (those who reported to have taken "nearly all" prescribed doses) and the poor adherence group (those who reported to have taken "approximately half" or "less" doses), because such stratification was validated by treatment responses in plasma BCAA/tyrosine ratio. Factors related to the primary end-point were age, drug adherence during 6 months of study treatment, previous hepatic cancer, current clinical manifestations, previous clinical manifestations, baseline serum albumin level, platelet count and total bilirubin level. The cumulative event-free survival was significantly higher in the good adherence group. Increase in the serum albumin level was also greater in the good adherence group. CONCLUSION: Higher BCAA treatment adherence better raised the serum albumin level, leading to improvement of event-free survival. These results indicate the importance of patient instruction for the adequate use of BCAA granules.

Long-term outcomes of add-on adefovir dipivoxil therapy to ongoing lamivudine in patients with lamivudine-resistant chronic hepatitis B.

AIM: Add-on adefovir dipivoxil (ADV) therapy has been a standard rescue treatment for patients with lamivudine (LAM)-resistant chronic hepatitis B, but the overall benefits of long-term add-on ADV therapy are still limited. The aim of this study was to evaluate the long-term efficiency of add-on ADV treatment and to explore predictive factors associated with it. METHODS: A total of 158 patients with LAM-resistant chronic hepatitis B were included in this retrospective, multicenter, nationwide study in Japan. After confirming LAM resistance, ADV was added to LAM treatment. Three types of events were considered as outcomes: virological response, hepatitis B e antigen (HBeAg) clearance and alanine aminotransferase (ALT) normalization. Virological response was defined as serum hepatitis B virus (HBV) DNA levels of less than 3 log copies/mL. Baseline factors contributing to these outcomes were examined by univariate and multivariate analyses. RESULTS: The median total duration of ADV treatment was 41 months (range, 6-84). The rate of virological response was 90.8% at 4 years of treatment; HBeAg clearance and ALT normalization were achieved by 34.0% and 82.7%, respectively, at the end of follow up. Each outcome had different predictive factors: baseline HBV DNA and albumin level were predictive factors for virological response, history of interferon therapy and ALT level for HBeAg clearance, and sex and baseline albumin level for ALT normalization. CONCLUSION: Long-term add-on ADV treatment was highly effective in LAM-resistant chronic hepatitis B patients in terms of virological and biochemical responses. Lower HBV replication and lower albumin level at baseline led to better outcomes.

Hepatocellular carcinoma and survival in patients with autoimmune hepatitis (Japanese National Hospital Organization-autoimmune hepatitis prospective study).

BACKGROUND/AIMS: Although the outcome of autoimmune hepatitis (AIH) is generally good, the natural course and likelihood of progression to cirrhosis or hepatocellular carcinoma (HCC) remain undefined, and may vary by region and population structure. Our aims were to evaluate risk factors that contribute to poor outcome and particularly development of HCC in a prospective multicentric cohort study of AIH. METHODS: The study group comprised 193 Japanese patients with AIH who were prospectively followed up at annual intervals between 1995 and 2008. The mean follow-up period was 8.0 ± 4.5 years. RESULTS: Twenty-one (10.9%) patients had cirrhosis at presentation and a further 15 (7.8%) developed cirrhosis during the follow-up period. Survival rates were 94.2% at 10 years and 89.3% at 15 years. HCC was diagnosed in seven of the 193 patients. The presence of cirrhosis at presentation was a risk factor for HCC according to a Cox proportional hazard model, and the HCC-free survival rate was significantly lower in those with cirrhosis compared to those without cirrhosis according to Kaplan-Meier analysis. CONCLUSIONS: Although the outcome of AIH is as good if not better among Japanese than for other populations, there was an increased risk of HCC in these patients. Cirrhosis at presentation was predictive of development of HCC in AIH in Japan.

Genetic polymorphisms in CTLA4 and SLC4A2 are differentially associated with the pathogenesis of primary biliary cirrhosis in Japanese patients.

BACKGROUND: Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis (PBC). In order to dissect the genetic basis for the production of these autoantibodies, as well as the development and progression of PBC in Japanese patients, we examined single nucleotide polymorphisms (SNPs) in cytotoxic T-lymphocyte antigen 4 (CTLA4) and solute carrier family 4 anion exchanger, member 2 (SLC4A2), which have been associated with the pathogenesis of PBC in Caucasian patients. METHODS: Four SNPs for both CTLA4 and SLC4A2 were genotyped, using the polymerase chain reaction-restriction fragment length polymorphism method and TaqMan assay, in 450 Japanese PBC patients and 371 sex-matched healthy controls. RESULTS: The CTLA4 rs231775, rs3087243, and rs231725 SNPs were significantly associated with PBC susceptibility. The CTLA4 rs231725 SNP was significantly associated with progression to late-stage disease. The CTLA-4 haplotype 1 (rs231775 G, rs231777 C, rs3087243 G, rs231725 A; GCGA) was a risk factor for PBC susceptibility but a protective factor for PBC progression. Conversely, the CTLA-4 haplotype 2 (ACAG) was a protective and risk factor, respectively, for PBC susceptibility and progression. In addition, the CTLA4 rs231777 SNP and haplotype 3 (ATGG) was significantly associated with anti-gp210 antibody production, while SLC4A2 haplotype 4 (rs2069443 A, rs2303933 G, rs2303937 A, rs2303941 T; AGAT) and haplotype 3 (AAGC) were significantly associated with PBC susceptibility and anti-centromere antibody production, respectively. CONCLUSIONS: CTLA4 and SLC4A2 genetic polymorphisms are differentially associated with PBC development and progression, as well as anti-gp210 or anti-centromere antibody production, in Japanese PBC patients.

Evaluation of risk factors for the development of cirrhosis in autoimmune hepatitis: Japanese NHO-AIH prospective study.

Autoimmune hepatitis (AIH) is a chronic and progressive liver disease characterized by histological interface hepatitis and circulating autoantibodies. Our aims were to evaluate risk factors that contribute to the outcome and, particularly, the development of liver cirrhosis in a prospective multicenter cohort study of AIH. One hundred and seventy-four patients were enrolled. Histologically 21 (12.1%) had cirrhosis at the initial observation and the remaining 153 showed chronic or acute hepatitis at presentation. Among the latter 153 patients, 14 developed cirrhosis during the follow-up period (mean 8.0 years). Demographic, clinical, and laboratory indices associated with the development of cirrhosis were identified. Patients who developed cirrhosis differed in mean levels of alanine aminotransferase (ALT; 158 ± 182 vs. 441 ± 423 IU/ml) and platelet counts (14.7 ± 5.5 vs. 19.4 ± 6.9 × 10(4)/µl) at presentation and received lower doses of corticosteroid (13.9 ± 15.8 vs. 31.8 ± 85.5 mg/day). In a multivariate analysis, an independent predictor for progression to cirrhosis was an older age of onset (≥ 60 years). AIH patients with cirrhosis, or those who developed cirrhosis, had a worse survival. AIH patients with an older age of onset were likely to develop cirrhosis, and careful observation and aggressive treatments are necessary for such patients.

Re-evaluation of the serum alanine aminotransferase upper normal limit in chronic hepatitis C patients.

OBJECTIVE: The aim of this study was to re-evaluate the upper limit of normal range (ULN) for serum alanine aminotransferase (ALT) in chronic hepatitis C (CH-C) patients who achieved sustained virological response (SVR) to interferon therapy. METHODS: Enrolled in this study were 136 consecutive patients, 84 males and 52 females, mean age 52.1+/-14.8 years, with CH-C who received interferon therapy during 1992 to 2008 and achieved SVR. AST and ALT levels (3 serial measurements) were measured every 3 to 4 months over one year after termination of interferon therapy and then the measurements were averaged for each patient. RESULTS: The distribution of AST and ALT showed normal distribution. Overall, AST levels were 19.7+/-3 IU/L and ALT levels were 13.8+/-3.1 IU/L in all patients, AST levels were 19.8+/-3 IU/L and 12.9+/-2.9 IU/L and ALT levels were 14.4+/-3.2 IU/L and 9.9+/-3.5 IU/L in male and female patients, respectively. AST level was the highest in the 6th decade and ALT level was in the 5th decade. CONCLUSION: In this study on CH-C patients with SVR to interferon therapy, ULN of serum ALT and AST were far lower than the current accepted value. We propose that a suitable ULN of serum AST is <25 IU/L and ALT is <20 IU/L in CH-C patients.

Heterogeneity of hepatitis B virus genotype D in Japan.

OBJECTIVE: Hepatitis B virus (HBV) genotypes B and C are predominant in Japan. Previously, we reported that approximately 9% of HBV carriers in the Ehime area of western Japan were infected with genotype D (HBV/D) and their sequences closely related. Recently, serum samples from 3 patients with chronic HBV/D infections living in Tokyo and the surrounding area became available for testing. The purpose of this study was to determine whether the HBV/D isolates from these different areas of Japan are closely related. METHODS: Of the 3 Tokyo area patients infected with HBV/D, 2 had chronic hepatitis, and 1 had hemophilia with a history of frequent coagulation factor injections. The complete HBV/D genome sequences of each were determined, and compared with those of subjects from the Ehime area. RESULTS: All 3 HBV/D sequences had a genomic length of 3,182 bases, and the hepatitis B surface antigen subtype was ayw3. Phylogenetic analysis revealed that the 1 of the HBV/D isolates was closely related to the isolates from Ehime Prefecture, while 1 was similar and 1 was clearly distinct. CONCLUSION: Our results indicate that HBV/D infections in Japan are heterogeneous.

Factors regarding increase of platelet counts in chronic hepatitis C patients with sustained virological response to interferon-Relation to serum thrombopoietin levels.

UNLABELLED: Thrombocytopenia is frequently found in patients with chronic liver disease, and associated with advanced fibrosis stage and with decreased liver function. Serum thrombopoietin (TPO) levels also decrease as the disease progresses from mild fibrosis to cirrhosis. On the other hand, platelet counts increase associated with improvement of fibrosis in chronic hepatitis C (CH-C) patients with sustained virological response (SVR) to interferon (IFN) therapy. Then, we studied if the increase of platelet counts in SVR associate with elevated TPO production or a reduction of spleen size. Liver fibrosis, spleen size, serum TPO levels, albumin, zinc turbidity test (ZTT), platelet counts were compared in fifteen CH-C patients with SVR before and after IFN therapy. RESULTS: Albumin increased from 4.2+/-0.3 to 4.3+/-0.3g/dl (p=0.067), ZTT decreased from 17.7+/-5.9 to 8.9+/-3.9K-U (p<0.001), platelet counts increased from 15.5+/-6.8x10(4) to 19.9+/-5.8x10(4)/mul (p<0.01) and serum TPO levels increased from 1.65+/-0.94 to 2.06+/-1.22fmol/ml (p=0.073). Spleen size was measured by ultrasonography, and the spleen index was calculated by multiplication of the long and short axes from hilus, which decreased from 14.6+/-5.0 to 10+/-3.1 (p<0.001) after IFN therapy. In conclusion, increase of platelet counts in SVR may be related to the reduction of spleen size and increased serum TPO levels associated with improvement of fibrosis after IFN therapy.

Risk factors for the development of hepatocellular carcinoma among patients with chronic hepatitis C who achieved a sustained virological response to interferon therapy.

BACKGROUND AND AIM: Hepatitis C virus (HCV)-infected patients who responded to interferon (IFN) treatment with clearance of serum HCV RNA may rarely develop hepatocellular carcinoma (HCC). The aim of the present study was to elucidate the risk factors for liver carcinogenesis among such patients. METHODS: In total, 126 patients with chronic hepatitis C (CHC) who achieved a sustained virological response (SVR) to IFN monotherapy, which was defined as the absence of detectable HCV RNA in the serum at 6 months after completion of treatment, were enrolled and possible risk factors for HCC were analyzed. RESULTS: During the observation period of 66 +/- 36 months after cessation of IFN treatment, five (4.0%) of the 126 patients developed HCC. The cumulative incidence of HCC at 3, 5 and 10 years was estimated to be 0.9, 4.7 and 7.5%, respectively. The cumulative incidence of HCC was significantly higher among patients with severe fibrosis (F3 or F4) than among patients with no or mild fibrosis (F0 to F2) in the liver before treatment (P = 0.007); among patients with alcohol intake of > or = 27 g/day than among patients with that of < 27 g/day (P = 0.015); and among patients who were > or = 65 years old than among patients who were < 65 years old at the start of treatment (P = 0.026). CONCLUSIONS: Patients with CHC who had severe fibrosis, who had regularly taken moderate amounts of alcohol, or who were > or = 65 years at the start of IFN treatment should be carefully followed to detect small and controllable HCC, even after eradication of HCV.

Late liver-related mortality from complications of transfusion-acquired hepatitis C.

Although several cohort studies have been reported in individuals with chronic hepatitis C virus (HCV) infection, little is known about liver-related mortality among the elderly. We conducted a cohort study in 302 patients with tuberculosis sequelae who had received a blood transfusion at a young age and had subsequently been treated at a chest clinic. The cohort consisted of 147 patients with antibody to HCV (anti-HCV), of whom 81% were positive for HCV RNA, and 155 without anti-HCV. The cohort was followed for a mean duration of 5.7 years. There were no differences between the two groups in the mean age of the patients at the time of transfusion (31 vs. 34 years) or at the time of entry into the study (65 vs. 66 years). The outcome of 143 patients with, and 145 without, anti-HCV could be traced; 92 (64%) and 82 (57%) had died, respectively. The main cause of death was tuberculosis sequelae in 61 (42%) and 66 (46%) patients, respectively. Eight (6%) of the 143 patients with anti-HCV died of liver disease (hepatocellular carcinoma: seven; rupture of varices: one). The average annual mortality from liver disease from study entry in the patients with anti-HCV was 9.8 per 1,000 person-years. The patients with anti-HCV had a significantly lower cause-specific survival probability for liver disease (92% vs. 100% at 10 years, P < .005). In conclusion, in our study, liver-related mortality appeared to be high among elderly HCV-infected individuals.

Circulating KL-6 level at baseline is a predictive indicator for the occurrence of interstitial pneumonia during interferon treatment for chronic hepatitis C.

Interstitial pneumonia (IP) is a serious adverse event of interferon alpha (IFNalpha) treatment for chronic hepatitis C (CH-C). Among 558 CH-C patients who received IFNalpha treatment with or without ribavirin between January 1992 and June 2002, six patients (1.1%) developed IP, including one patient who developed IP in 1993 and again in 2002. Among the seven cases who contracted IP, at the onset of IP, seven (100%), five (71%), and two cases (29%) had elevated serum levels of KL-6, surfactant protein A (SP-A), and surfactant protein D (SP-D), respectively. Prior to starting IFN treatment (baseline), the serum SP-A and SP-D levels were within the normal range in all seven cases, but the serum KL-6 level was elevated in five of the seven cases, contrasting with that in three of 48 age-adjusted CH-C patients who did not develop IP during IFN treatment (71 vs. 6%; P=0.0003). Furthermore, the circulating KL-6 level at baseline was significantly higher among the seven cases than among the controls (543+/-105 vs. 304+/-98 U/ml, P=0.0001). These results indicate that measurement of the circulating KL-6 level in CH-C patients before IFN treatment may be useful for predicting the occurrence of IP during IFN treatment.

High TT virus load as an independent factor associated with the occurrence of hepatocellular carcinoma among patients with hepatitis C virus-related chronic liver disease.

The TT virus (TTV) load was estimated in sera obtained from 237 patients with hepatitis C virus (HCV)-related chronic liver disease including 42 patients with hepatocellular carcinoma (HCC), by real-time detection PCR using primers and a probe derived from the well-conserved untranslated region of the TTV genome, which can detect all known TTV genotypes. Of the 237 patients studied, 18 (8%) were negative for TTV DNA, 87 (37%) had low TTV viremia (1.3 x 10(2)-9.9 x 10(3) copies/ml), and 132 (56%) had high TTV viremia (1.0 x 10(4)-2.1 x 10(6) copies/ml). Various features were compared between the patients with high TTV load (n = 132) and those with no TTV viremia or low viral load (n = 105). High TTV viremia (> or =10(4) copies/ml) was significantly associated with higher age (P < 0.05), past history of blood transfusion (P < 0.001), complication of cirrhosis (P < 0.05) or HCC (P < 0.0005), lower HCV RNA titer (P < 0.05), and lower platelet count (P < 0.01). On multivariate logistic regression analysis, high TTV viral load was a significant risk factor for HCC (P < 0.05), independent from known risk factors such as complication of liver cirrhosis (P < 0.0001) and high age (> or =65 years, P < 0.05), among all 237 patients. Furthermore, high TTV viral load was an independent risk factor for HCC among the 90 cirrhotic patients (P < 0.05). These results suggest that a high TTV viral load is associated independently with the complication of HCC and may have prognostic significance in patients with HCV-related chronic liver disease, although whether high TTV viremia mediates the progression of HCV-related chronic liver disease remains to be defined.

TT virus of certain genotypes may reduce the platelet count in patients who achieve a sustained virologic response to interferon treatment for chronic hepatitis C.

The platelet count increases after a sustained response to interferon (IFN) treatment for chronic hepatitis C (CH-C). However, the extent of the increase differs by patient. We investigated whether concurrent TT virus (TTV) infection interferes with the improvement of thrombocytopenia. Serial serum samples were obtained from 85 noncirrhotic CH-C patients who achieved a sustained virologic response for hepatitis C virus (HCV) upon IFN treatment, and tested for TTV DNA by three polymerase chain reaction (PCR) methods (UTR, N22 and TTV genotype-1). UTR PCR can detect essentially all TTV genotypes, whereas N22 PCR primarily detects four major TTV genotypes (1-4). Eighty-four patients (84/85, 99%) were positive for TTV DNA by UTR PCR, 27 (32%) by N22 PCR and 18 (21%) by TTV genotype-1 PCR just before IFN treatment was started (baseline). A sustained virologic response for TTV was observed in 6% (5/84) by UTR PCR, 52% (14/27) by N22 PCR and 56% (10/18) by TTV genotype-1 PCR. The platelet count was significantly lower in the N22 PCR-positive group than in the N22 PCR-negative group not only at baseline (14.9+/-3.8 vs. 18.1+/-6.4x10(4)/&mgr;l, P<0.05), but also at the non-HCV-viremic state one year after the completion of IFN treatment (15.5+/-2.8 vs. 18.6+/-5.5x10(4)/&mgr;l, P<0.05), the differences also being statistically significant by TTV genotype-1 PCR, but not by UTR PCR. These results suggest that certain TTV genotypes including genotype 1 may play a role in aggravating the thrombocytopenia of CH-C patients, either alone or in concert with HCV.