Prognostic significance of serum tyrosine concentration in patients with primary biliary cholangitis under ursodeoxycholic acid therapy.

AIM: Chronic liver insufficiency is often associated with alteration in amino acid metabolism. We evaluated the prognostic value of changes in serum amino acid concentrations in patients with primary biliary cholangitis. METHODS: A total of 75 primary biliary cholangitis patients who started urusodeoxycholic acid therapy were retrospectively enrolled. Baseline serum concentrations of branched-chain amino acids and tyrosine, and branched-chain amino acid-to-tyrosine ratio were determined. The hazard ratios of factors associated with liver-related events were analyzed by Cox proportional hazard analysis. RESULTS: Of the 75 patients enrolled, 12 showed a decrease in serum branched-chain amino acid levels, and 15 showed an increase in serum tyrosine levels. The branched-chain amino acid-to-tyrosine ratio decreased in 16 patients. During a median 5.6-year follow up, liver-related events occurred in 11 patients. Multivariate analysis showed that high serum tyrosine levels at baseline and high alkaline phosphatase levels 48 weeks after starting urusodeoxycholic acid therapy were independent risk factors for event occurrence. From the receiver operator characteristics curve analysis, serum tyrosine concentration >110 µmol/L was identified as a cut-off value with an adjusted hazard ratio of 20.9 (95% confidence interval 4.3-101.5, P < 0.001). Kaplan-Meier analysis showed that the 5-year cumulative incidences of event occurrence in patients with high and low serum tyrosine concentration were 56.5% and 5.5%, respectively (P < 0.001). The 10-year survival probabilities also showed significant differences between patients with high and low serum tyrosine concentration (44.9% vs. 92.0%, P < 0.001). CONCLUSION: Elevation of serum tyrosine concentration indicates a high risk of liver-related events in primary biliary cholangitis patients receiving urusodeoxycholic acid therapy.

On-treatment Serum Mac-2 Binding Protein Glycosylation Isomer (M2BPGi) Level and Risk of Hepatocellular Carcinoma Development in Patients with Chronic Hepatitis B during Nucleot(s)ide Analogue Therapy.

We aimed to analyze the serum level of a novel fibrosis marker, Mac-2-binding protein glycosylation isomer (M2BPGi), and its predictive value for hepatocellular carcinoma (HCC) development in chronic hepatitis B (CHB) under nucleot(s)ide analogue (NA) therapy. Serum M2BPGi levels were quantified in 147 CHB patients at baseline, 48 weeks after starting NA therapy, and at the patients' last visit. The serum M2BPGi level serially decreased at each time point. During the median follow-up time of 6.6 years, 14 of 147 patients developed HCC. Multivariate Cox proportional hazard analysis demonstrated that high serum M2BPGi at 48 weeks was an independent risk factor for HCC development. A cutoff value of M2BPGi at 48 weeks > 1.5 showed an adjusted hazard ratio = 34.9 (95% confidence interval, 4.3-284.9). The 3- and 5-year cumulative incidence of HCC in patients with low M2BPGi were 0.9% and 4.2%, respectively, whereas those in patients with high M2BPGi were 10.1% and 25.6%, respectively (p < 0.001). In conclusion, Serum M2BPGi level at 48 weeks is a useful predictor for HCC development in patients with CHB who receive NA therapy.

Aldo-keto reductase family 1 member B10 is associated with hepatitis B virus-related hepatocellular carcinoma risk.

AIM: Recent reports have indicated that aldo-keto reductase family 1 member B10 (AKR1B10), a cancer-related oxidoreductase, was upregulated in some chronic liver diseases. However, few studies have reported AKR1B10 expression in chronic hepatitis B virus (HBV)-infected patients. The aim of the present study was to analyze AKR1B10 expression and its relevance on hepatocellular carcinoma (HCC) development in patients with chronic HBV infection. METHODS: Expression of AKR1B10 in the liver of 119 chronic HBV-infected patients was assessed and quantified immunohistochemically. A multivariate Cox model was used to estimate the hazard ratios of AKR1B10 expression for HCC development. The cumulative incidences of HCC were evaluated using Kaplan-Meier analysis. RESULTS: Expression of AKR1B10 in the study cohort ranged from 0% to 84%. During the median follow-up time (6.2 years), 13 patients developed HCC. Multivariate analysis revealed that high AKR1B10 expression (≥15%) was an independent risk factor for HCC (hazard ratio, 10.8; 95% confidence interval, 3.0-38.6; P < 0.001). The 5-year cumulative incidences of HCC were 20.6% and 2.6% in patients with high and low AKR1B10 expression, respectively (P < 0.001). Patients with high AKR1B10 expression had significantly higher alanine aminotransferase levels during follow-up than those with low expression, even though antiviral treatment decreased HBV-DNA levels in both groups. CONCLUSION: Chronic HBV-infected patients with high hepatic AKR1B10 expression had an increased risk of HCC development. This suggests that AKR1B10 upregulation might play a role in the early stages of HBV-related hepatocarcinogenesis.

Impact of aldo-keto reductase family 1 member B10 on the risk of hepatitis C virus-related hepatocellular carcinoma.

BACKGROUND AND AIM: Aldo-keto reductase family 1 member B10 (AKR1B10), a cancer-related oxidoreductase, was recently reported to be upregulated in some chronic liver diseases. However, its relevance in hepatocellular carcinoma (HCC) development is not fully assessed, especially in patients with chronic hepatitis C virus (HCV) infection. METHODS: Aldo-keto reductase family 1 member B10 expression in the liver of 550 patients with chronic HCV infection was immunohistochemically assessed and quantified. A multivariate Cox model was used to estimate the hazard ratios (HRs) of AKR1B10 expression for HCC development, and the cumulative incidence of HCC was evaluated using the Kaplan-Meier method. RESULTS: Aldo-keto reductase family 1 member B10 expression in the patients ranged from 0% to 80%. During the median follow-up of 3.2 years, 43 of 550 patients developed HCC. Multivariate analysis demonstrated that high AKR1B10 expression (≥6%) was an independent risk factor for HCC (HR, 6.43; 95% confidence interval, 2.90-14.25; P < 0.001). The 5-year cumulative incidences of HCC were 22.8% and 2.2% in patients with high and low AKR1B10 expression, respectively (P < 0.001). In subgroup analyses, the effects of high AKR1B10 expression on HCC development risk were significant over strata. In particular, HRs attributed to high AKR1B10 expression were significant in the subgroups that had been considered at a lower risk of HCC, such as in patients with younger age and mild hepatic fibrosis or those who achieved sustained virological response after interferon therapy. CONCLUSION: Various degrees of AKR1B10 upregulation in the liver were observed in patients with chronic HCV infection, and high AKR1B10 expression could be a novel predictor of HCC.

Prediction of Hepatocellular Carcinoma Development after Hepatitis C Virus Eradication Using Serum Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein.

We aimed to clarify the association between a novel serum fibrosis marker, Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA⁺-M2BP), and hepatocellular carcinoma (HCC) development in 355 patients with chronic hepatitis C who achieved sustained virologic response (SVR) through interferon-based antiviral therapy. Pretreatment serum WFA⁺-M2BP levels were quantified and the hazard ratios (HRs) for HCC development were retrospectively analyzed by Cox proportional hazard analysis. During the median follow-up time of 2.9 years, 12 patients developed HCC. Multivariate analysis demonstrated that high serum WFA⁺-M2BP (≥2.80 cut off index (COI), HR = 15.20, p = 0.013) and high fibrosis-4 (FIB-4) index (≥3.7, HR = 5.62, p = 0.034) were independent risk factors for HCC development. The three- and five-year cumulative incidence of HCC in patients with low WFA⁺-M2BP were 0.4% and 0.4%, respectively, whereas those of patients with high WFA⁺-M2BP were 7.7% and 17.6%, respectively (p < 0.001). In addition, combination of serum WFA⁺-M2BP and FIB-4 indices successfully stratified the risk of HCC: the five-year cumulative incidences of HCC were 26.9%, 6.8%, and 0.0% in patients with both, either, and none of these risk factors, respectively (p < 0.001). In conclusion, pretreatment serum WFA⁺-M2BP level is a useful predictor for HCC development after achieving SVR.

Prediction of liver stiffness hepatocellular carcinoma in chronic hepatitis C patients on interferon-based anti-viral therapy.

BACKGROUND AND AIM: The purpose of this study was to evaluate the usefulness of liver stiffness measurement (LSM) for assessing the risk of hepatocellular carcinoma (HCC) in chronic hepatitis C (CHC) patients receiving interferon (IFN) therapy. METHODS: One hundred fifty-one CHC patients who underwent LSM and received IFN therapy were included in the estimation cohort, and 56 were included in the validation study. The cumulative HCC incidences were evaluated using Kaplan-Meier plot analysis and the log-rank test. Multivariate Cox proportional hazard analyses were used to estimate the hazard ratios (HRs) of variables for HCC. RESULTS: In the estimation cohort, 9 of 151 patients developed HCC during the median follow-up time of 722 days. Multivariate analysis identified three independent risk factors for HCC: LSM (≥ 14.0 kPa, HR 5.58, P = 0.020), platelet count (< 14.1 × 10(4) /µL, HR 5.59, P = 0.034), and non-sustained virological response (HR 8.28, P = 0.049). The cumulative incidence of HCC development at 3 years was 59.6%, 8.2%, and 0.0% in patients with all three risk factors, one to two risk factors, and none of these risk factors, respectively. The incidence of HCC was significantly different between these groups (P < 0.001). In the validation cohort, HCC incidence was also significantly different with respect to these risk factors (P = 0.037). CONCLUSION: LSM, platelet count, and IFN-therapeutic effect could be used to successfully stratify the risk of HCC in patients receiving IFN therapy and demonstrate the usefulness of LSM before IFN therapy for the management of CHC patients.

Expression of aldo-keto reductase family 1 member b10 in the early stages of human hepatocarcinogenesis.

Aldo-keto reductase family 1, member B10 (AKR1B10), a cancer-related oxidoreductase, is expressed in well-differentiated hepatocellular carcinomas (HCCs). However, AKR1B10 levels are minimal in normal liver tissues (NLs), similar to the 70-kilodalton heat shock protein (HSP70) and glypican-3. Moreover, the role of AKR1B10 in chronic hepatitis or cirrhosis, which are considered preneoplastic conditions for HCC, has not been fully elucidated. The aim of this study was to evaluate the expression of AKR1B10, HSP70, and glypican-3 in 61 HCC tissue samples compared to corresponding non-tumorous liver tissues (NTs), comprising 42 chronic hepatitis and 19 cirrhosis cases to clarify the significance of molecular changes at the preneoplastic stages of HCC. Immunohistochemical analysis demonstrated that the median expression levels of AKR1B10 were higher in HCCs than in NTs (p<0.001) and higher in NTs than NLs (p<0.001) with 54.8%, 2.1%, and 0.3% expression in HCCs, NTs, and NLs, respectively. HSP70 and glypican-3 were expressed in HCCs, but minimally in NTs and NLs with no significant difference between expression in NTs and NLs. Furthermore, a multivariate analysis identified an association between hepatic steatosis and AKR1B10 expression in NTs (p=0.020). Of the three protein expressed in well-differentiated HCCs, only AKR1B10 was upregulated in preneoplastic conditions, and a steatosis-related factor might influence its expression.

Up-regulated aldo-keto reductase family 1 member B10 in chronic hepatitis C: association with serum alpha-fetoprotein and hepatocellular carcinoma.

BACKGROUND: Elevated serum alpha-fetoprotein (AFP) is not only a diagnostic marker for hepatocellular carcinoma (HCC), but is also a risk factor for HCC in chronic hepatitis C patients who do not have HCC. AIM: The aim was to analyse the hepatic gene expression signature in chronic hepatitis C patients with elevated AFP, who were at high risk for HCC. METHODS: Liver tissue samples from 48 chronic hepatitis C patients were stratified by their serum AFP levels and analysed for gene expression profiles. The association between aldo-keto reductase family 1 member B10 (AKR1B10) expression and serum AFP was confirmed by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemical analyses. A matched case-control study was performed to evaluate the risk of AKR1B10 expression for HCC development. RESULTS: Distinct hepatic gene expression patterns were demonstrated in patients with elevated AFP (≥10 ng/mL) and normal AFP (<10 ng/mL). Of the 627 differently expressed genes, the most abundantly expressed gene in patients with elevated AFP was AKR1B10 (fold change, 26.2; P < 0.001), which was originally isolated as an overexpressed gene in human HCC. The qRT-PCR and immunohistochemical studies confirmed a proportional correlation between AKR1B10 expression and serum AFP. A matched case-control study identified that AKR1B10 up-regulation (>6%) was an independent risk factor for HCC development (hazard ratio, 21.4; P = 0.001). CONCLUSION: AKR1B10 was up-regulated in association with serum AFP, and was an independent risk factor for HCC in chronic hepatitis C patients, suggesting its possible involvement at a very early stage of hepatocarcinogenesis.

A case of primary biliary cholangitis overlapping with type 2 autoimmune hepatitis.

A 42-year-old woman was admitted to our hospital with cholestatic liver injury. Serological examination revealed anti-mitochondrial M2 antibody positivity and anti-nuclear antibody and anti-smooth muscle antibody negativity. Histological examination of the first liver biopsy revealed chronic nonsuppurative destructive cholangitis with epithelioid granulomas. Ursodeoxycholic acid therapy successfully treated her cholestasis. Sixteen months later, she developed acute icteric hepatitis with elevation of serum aspartate and alanine aminotransferase levels. Anti-mitochondrial M2 positivity and anti-nuclear antibody and anti-smooth muscle antibody negativity persisted at that time. However, it became clear that anti-liver kidney microsomal type 1 antibody was positive. Histological examination of the second liver biopsy demonstrated scarce interface hepatitis and evident parenchymal inflammation and centrilobular zonal necrosis. Her liver biochemical test results promptly improved with the addition of prednisolone therapy. Considering the findings, she was diagnosed with primary biliary cholangitis-type 2 autoimmune hepatitis overlap syndrome. According to a literature review, this is an extremely rare autoimmune overlap syndrome.

Evaluation of EORTC QLQ-C30 questionnaire in patients undergoing in-hospital chemotherapy for gastrointestinal cancer in Japan.

BACKGROUND AND AIM: There have been few studies in Japan of the utility of quality of life (QOL) questionnaires as an evaluation of chemotherapy for gastrointestinal (GI) cancer. The present study investigated whether QOL can be an indicator of the clinical benefit of chemotherapy, by analyzing the changes in the QOL scores of patients who underwent in-hospital chemotherapy for GI cancer. METHODS: From August 2004 to August 2006, 75 patients with GI cancer who were scheduled to undergo in-hospital chemotherapy were studied. The QOL score was measured with a questionnaire, the European Organization for Research Treatment of Cancer (EORTC) QLQ-C30 (version 3.0, Japanese version), before chemotherapy, and at 2 weeks and 1 month after the initiation of chemotherapy. Patients were divided into three groups according to the clinical response to chemotherapy (partial response [PR], no change [NC], and progressive disease [PD]). RESULTS: In total, 65 patients were included in the analysis. Global QOL and physical functioning scores worsened significantly at 2 weeks. Pain and constipation scores improved significantly at 1 month. Nausea and vomiting, appetite loss, and diarrhea scores worsened significantly at 2 weeks. The global QOL score improved significantly after chemotherapy in the PR group. The pain score improved significantly in the PR and NC groups after chemotherapy. QOL scores improved in the NC group to almost the same level as in the PR group, whereas QOL worsened in the PD group. CONCLUSIONS: Measurement of QOL score is a meaningful marker of the benefit of chemotherapy, other than tumor reduction. The NC group could be considered to have responded with improved QOL.

A case of ischemic gastroduodenal disease in a patient who was receiving hemodialysis treatment that was managed by conservative treatment.

A 69-year-old man was under maintenance dialysis due to diabetic renal failure. He had a drop in blood pressure during dialysis, developed hematemesis, and was transported to our hospital. Emergency upper gastrointestinal endoscopy revealed diffuse erosion, mucosal sloughing, and edematous mucosa in the upper body of the stomach to the posterior wall of the antrum and to the greater curvature, which were considered to be an ischemic change. His underlying diseases included diabetic renal failure, chronic arteriosclerosis obliterans, cerebral infarction, internal carotid artery stenosis, hypertension, and myocardial infarction. Blood evaluation showed only mild inflammation and no fibrinolytic hyperactivity. Contrast-enhanced computed tomography (CECT) showed no occlusion of blood vessels. It was considered that the patient had a transient ischemic change due to blood pressure drop. The patient's condition improved with conservative treatment.

Pretreatment AKR1B10 expression predicts the risk of hepatocellular carcinoma development after hepatitis C virus eradication.

AIM: To clarify the association between aldo-keto reductase family 1 member B10 (AKR1B10) expression and hepatocarcinogenesis after hepatitis C virus eradication. METHODS: In this study, we enrolled 303 chronic hepatitis C patients who had achieved sustained virological response (SVR) through interferon-based antiviral therapy. Pretreatment AKR1B10 expression in the liver was immunohistochemically assessed and quantified as a percentage of positive staining area by using image-analysis software. A multivariate Cox analysis was used to estimate the hazard ratios (HRs) of AKR1B10 expression for hepatocellular carcinoma (HCC) development after achieving SVR. The cumulative incidences of HCC development were evaluated using Kaplan-Meier analysis and the log-rank test. RESULTS: Of the 303 chronic hepatitis C patients, 153 (50.5%) showed scarce hepatic AKR1B10 expression, quantified as 0%, which was similar to the expression in control normal liver tissues. However, the remaining 150 patients (49.5%) exhibited various degrees of AKR1B10 expression in the liver, with a maximal AKR1B10 expression of 73%. During the median follow-up time of 3.6 years (range 1.0-10.0 years), 8/303 patients developed HCC. Multivariate analysis revealed that only high AKR1B10 expression (≥ 8%) was an independent risk factor for HCC development (HR = 15.4, 95%CI: 1.8-132.5, P = 0.012). The 5-year cumulative incidences of HCC development were 13.7% and 0.5% in patients with high and low AKR1B10 expression, respectively (P < 0.001). During the follow-up period after viral eradication, patients expressing high levels of AKR1B10 expressed markedly higher levels of alanine aminotransferase and α-fetoprotein than did patients exhibiting low AKR1B10 expression. CONCLUSION: Chronic hepatitis C patients expressing high levels of hepatic AKR1B10 had an increased risk of HCC development even after SVR.

Second-line treatment for Helicobacter pylori infection in Japan: proton pump inhibitor-based amoxicillin and metronidazole regimen.

BACKGROUND: Recent studies have reported that proton pump inhibitor (PPI)/amoxicillin (A) metronidazole (M) therapy for Helicobacter pylori infection provides a sufficient cure rate in Japan in patients who have failed first-line treatment with PPI/amoxicillin and clarithromycin (AC). To validate the efficacy of this regimen as second-line therapy, our experience with second-line treatment using a PPI/AM regimen was reviewed. METHODS: We analyzed data on 151 patients who had been prescribed a 10-day PPI/AM re-treatment regimen after eradication failure of 1 to 2 weeks' first-line PPI/AC therapy. The PPI/AM regimen was given according to results of susceptibility testing (S+) in 31 patients. The group that had undergone susceptibility testing was further divided into two subgroups according to dosage: standard dose of omeprazole (O)/AM (n = 11) and double dose of lansoprazole (L)/AM (n = 20). The PPI/AM regimen was given without susceptibility testing (S-) to 120 patients. These patients were also divided into two subgroups according to whether they received omeprazole or lansoprazole: OAM (n = 61) and LAM (n = 59). Cure rates and adverse effects in each group were analyzed. RESULTS: The intention-to-treat (ITT)-based cure rate with/without susceptibility testing was 93.5% (95% confidence interval [CI], 79%-99%) and 87.5% (95% CI, 80%-93%), respectively (not significant [NS]). The ITT-based cure rate in S+/S- for OAM and S+/S- for LAM was 90.9% (95% CI, 59%-100%)/82% (95% CI, 70%-91%), and 95% (95% CI, 75%-100%)/93.2% (95% CI, 84%-98%), respectively (NS). Adverse effects were seen in 26.3% and 32.5% of patients in the OAM group and the LAM group, respectively (NS). CONCLUSIONS: The 10-day PPI/AM re-treatment regimen is safe and effective, suggesting its usefulness as second-line treatment in Japan in patients who have failed initial treatment with the PPI/AC regimen.

[GERD and tight junction proteins of the esophageal mucosa].

Recent advancement in the research of GERD has revealed that endoscopy negative GERD may not be a milder form of erosive GERD and may have different pathogenesis. We have previously proven that hypersensitivity to the acid of the esophageal mucosa plays an important role in its pathogenesis. Regarding the mechanisms for the esophageal hypersensitivity, we hypothesized that the tight junction proteins of the esophageal mucosa are fully or partially impaired in GERD patients. Accordingly, we immunohistologically studied the expression of various tight junction proteins using the rat reflux esophagitis model. The results demonstrated that the several kinds of tight junction proteins are expressed differently in the various parts of esophagus and their expression altered according to the development of reflux esophagitis.

Association of visceral obesity with high viral load and histological findings in elderly patients with genotype 1 chronic hepatitis C.

OBJECTIVE: Genotype 1 chronic hepatitis C (G1CHC) is generally accompanied by metabolic disturbances related to visceral obesity, such as insulin resistance, steatosis, or dyslipidemia. Because these abnormalities negatively influence the clinical course of G1CHC, we sought to clarify the effect of visceral obesity on the pathophysiology of G1CHC. METHODS: We evaluated 180G1CHC patients for the presence of visceral obesity on the basis of computed tomography findings. Multivariate analysis was performed to estimate the relationship between visceral obesity and demographic, viral, and biochemical characteristics of patients. The associations of visceral obesity with histological findings and serum adipokine levels were also analyzed. RESULTS: Multiple logistic regression analysis revealed that visceral obesity was independently associated with metabolic syndrome, platelet count, high-density lipoprotein level, and serum viral load in elderly patients (≥65 years). Multiple linear regression analysis confirmed the association between visceral obesity and high viral load. However, visceral obesity was not correlated with viral load in non-elderly patients (<65 years). Histological data (160 patients) demonstrated the significant association between visceral obesity and steatosis. Furthermore, patients with visceral obesity showed increase in the severity of fibrosis with advancing age. However, age-associated fibrosis progression was not evident in patients without visceral obesity. The serum adiponectin level was significantly low in patients with visceral obesity, whereas those of leptin, tumor necrosis factor-α, and interleukin-6 were not affected significantly. CONCLUSION: Visceral obesity was associated with high viral load and histological damage in elderly patients with reduced adiponectin levels.

A study of the effects of saliva stimulation by nizatidine on dry mouth symptoms of primary biliary cirrhosis.

AIM: To elucidate the effect of saliva stimulation by nizatidine on oral symptoms of primary biliary cirrhosis (PBC) by administering it to PBC cases. METHODS: From among 73 cases that had been definitively diagnosed as PBC at our hospital by February 2010, we selected 27 cases of PBC, 4 males and 23 females, as subjects. We obtained subjects' consent after giving them a full explanation of the administration of nizatidine. Nizatidine 150 mg was administered internally twice daily, after morning and evening meals. To observe changes in the quantity of saliva secreted, chewing gum tests were carried out four times: before the initial dose, and after 6 mo, 12 mo and 24 mo of administration. For subjective dry mouth symptoms, a visual analog scale (VAS) method was used to assess their feelings of oral dryness and eating difficulty, five times: before the initial dose, and after 1, 6, 12 and 24 mo of administration in 8 cases. The nutritional condition and the hepatic functional reserve were compared between before and after the nizatidine treatment. RESULTS: The result of a chewing gum test on the subjects before the administration of nizatidine showed that 50% produced less than 10 mL of saliva, i.e., the standard under which cases are considered to have hyposalivation. The results of these tests showed that the quantity of saliva secreted was 10.5 ± 6.8 mL before administration of nizatidine, 10.9 ± 6.0 mL after 6 mo, 10.6 ± 4.9 mL after 12 mo, and 11.8 ± 6.8 mL after 24 mo administration. Thus, there was a slowly increasing trend in the quantity of saliva in the whole group. The percentage of subjects with saliva production above 10 mL was 45.8% after 6 mo administration of nizatidine, that is, only a slight change from before its administration, but it was 64.3% after 12 mo, that is, a significant increase. The saliva secretion by subject patients was examined before the beginning of administration of nizatidine, 12 mo later, and 24 mo later, and Fisher's combined probability test was used to examine the results for increases in saliva secretion. The analysis yielded P values of 0.51 and 0.53 for 12 mo later and 24 mo later, respectively. Thus, although there was no statistically significant increase, it was confirmed that saliva secretion tended to increase. A VAS method was employed to study the intensities of subjective symptoms of oral dryness and eating difficulty. Almost every case indicated some improvement of subjective oral dryness on the VAS early in the administration, i.e., one month after. We also studied the effects of the administration of nizatidine on nutritional condition, hepatic functional reserve, and long-term prognosis of PBC. No significant improvements in cholinesterase (ChE) level, albumin (Alb) level, or Child-Pugh score were found during the period of observation from the beginning to the end of administration of nizatidine, nor in comparison with the non-administration group. A comparative analysis between before administration and 24 mo later yielded P values of 0.41 for Alb, 0.56 for ChE, and 0.59 for the Child-Pugh scores. CONCLUSION: It was confirmed that administering nizatidine to cases of PBC with dry mouth increased the secretion of saliva and improved the symptoms.

Leptin facilitates proliferation of hepatic stellate cells through up-regulation of platelet-derived growth factor receptor.

In the present study, we investigated the effect of leptin on proliferation of hepatic stellate cells (HSCs) in vitro. Proliferation of 3-day cultured rat HSCs was assessed by incorporation of 5-bromo-2'-deoxyuridine (BrdU) into the nuclei. The percentages of BrdU-positive cells were increased in the presence of PDGF-BB (5 ng/ml) for 8h as expected. Co-incubation with leptin (10-100 nM) potentiates this PDGF-dependent increase in BrdU positive cells in a dose-dependent manner. Messenger RNA for PDGF receptor alpha and beta subunits was increased almost 2- to 3-fold by incubation with leptin for 6h. Further, pre-incubation with leptin for 6h enhanced PDGF-induced increases in phospho-p44/42 MAP kinase and phospho-Akt levels in a dose-dependent manner. In the same condition, however, leptin per se did not increase phospho-STAT 3 and phospho-p44/42 MAP kinase levels. Instead, leptin increased phospho-Akt levels in HSCs within 30 min, suggesting that the phosphatidylinositol 3 kinase (PI3K)/Akt pathway is involved in the mechanism by which leptin accelerates the proliferation of HSCs. In conclusion, the present study clearly indicated that leptin potentiates PDGF-dependent proliferative responses of HSCs in vitro.