Metabolic management after sustained virologic response in elderly patients with hepatitis C virus: A multicenter study.

AIMS: Hepatocellular carcinoma (HCC) develops even in patients with hepatitis C virus (HCV) eradication by direct-acting antiviral agents. Fatty liver and metabolic dysfunction are becoming major etiologies of HCC. We aimed to evaluate the impact of metabolic dysfunction-associated steatotic liver disease (MASLD), a new definition of steatotic liver disease, on the development of HCC after HCV eradication. METHODS: We enrolled 1280 elderly patients with HCV eradication and no history of HCC. We evaluated α-fetoprotein (AFP), Fibrosis-4 index and MASLD after 24 weeks of sustained virological response. Decision tree analysis was used to investigate factors associated with HCC development after HCV eradication. RESULTS: A total of 86 patients (6.7%) developed HCC during the follow-up period (35.8 ± 23.7 months). On multivariate analysis, serum AFP level (HR 1.08, CI 1.04-1.11, P = 0.0008), Fibrosis-4 index (HR 1.17, CI 1.08-1.26, P = 0.0007), and MASLD (HR 3.04, CI 1.40-6.58, P = 0.0125) at 24 weeks of sustained virological response were independent factors associated with HCC development. In decision tree analysis, the initial classifier for HCC development was AFP ≥7 ng/mL. However, in patients with AFP <7 ng/mL, MASLD, rather than Fibrosis-4 index, was the classifier for HCC development. No significant difference was observed in the cumulative incidence of HCC between patients with AFP ≥7 ng/mL and patients with AFP <7 ng/mL and MASLD. CONCLUSION: MASLD at 24 weeks of sustained virological response is a risk factor for HCC development in elderly patients with HCV eradication. Additionally, decision tree analysis revealed that MASLD was associated with HCC development, even in patients with serum AFP levels <7 ng/mL.

A combination of hepatic encephalopathy and body mass index was associated with the point of no return for improving liver functional reserve after sofosbuvir/velpatasvir treatment in patients with hepatitis C virus-related decompensated cirrhosis.

AIMS: The real-world efficacy of sofosbuvir/velpatasvir treatment for patients with hepatitis C virus-related decompensated cirrhosis is unclear. We aimed to identify factors that improve liver functional reserve after treatment. METHODS: This was a multicenter retrospective study of 12-week sofosbuvir/velpatasvir treatment. A total of 48 patients with Child-Pugh (CP) class B or C were enrolled at 11 institutions. We evaluated changes in liver functional reserve at 24 weeks post-treatment. RESULTS: At baseline, 40 and eight patients were CP class B and C, respectively. The overall rate of sustained virologic response 12 weeks post-treatment was 95.8% (46/48). Serum albumin, alanine aminotransferase and α-fetoprotein levels, and the FIB-4 index were significantly improved post-treatment (P < 0.05). Among patients who achieved sustained virologic response 12 weeks post-treatment, those with CP class A increased from 0 to 24 patients (56%) at 24 weeks post-treatment. In multivariate analysis, body mass index (BMI) ≥25 was an independent factor that inhibited CP class improvement (P < 0.05). In decision tree analysis, after treatment, the initial divergent variable for CP class improvement was hepatic encephalopathy, followed by serum sodium level and BMI. CONCLUSION: Sofosbuvir/velpatasvir treatment improved the liver functional reserve in patients with hepatitis C virus-related decompensated cirrhosis at 24 weeks post-treatment. However, BMI ≥25 inhibited improvement in CP class. Additionally, decision tree analysis revealed that a combination of hepatic encephalopathy, serum sodium levels, and BMI were diversity profiles associated with no improvement in liver functional reserve after the treatment.

Impact of Gut Microbiota on the Pharmacokinetics of Glycyrrhizic Acid in Yokukansan, a Kampo Medicine.

Individual differences in gut microbiota can affect the pharmacokinetics of drugs. Yokukansan is a traditional Japanese kampo medicine used to treat peripheral symptoms of dementia and delirium. A study examining the pharmacokinetics of the components of yokukansan reported large individual differences in the pharmacokinetics of glycyrrhizic acid (GL). It is known that GL is metabolized by intestinal bacteria to glycyrrhetinic acid (GA), which is absorbed in the gastrointestinal tract. Thus, the gut microbiota may affect GL pharmacokinetics. We aimed to clarify the relationship between the gut microbiota composition and pharmacokinetics of GL in yokukansan. Mice were orally administered yokukansan, following the administration of various antibiotics, and the plasma concentration of GA and composition of gut microbiota were measured. The GA plasma concentration was low in mice treated with amoxicillin and vancomycin. The composition of gut microbiota revealed a different pattern from that of the control group. Mice with low plasma levels of GA had lower levels of the phylum Bacteroides and Firmicutes. Additionally, bacteria, such as those belonging to the genera Parabaceroides, Bacteroides, Ruminococcus and an unknown genus in families Lachnospiraceae and Ruminococcaceae, exerted positive correlations between the gene copies and plasma GA levels. These bacteria may contribute to the absorption of GA in the gastrointestinal tract, and multiple bacteria may be involved in GL pharmacokinetics. The pharmacokinetics of GL may be predicted by evaluating the composition of gut bacteria, rather than by evaluating the amount of a single bacterium.

Juzentaihoto Suppresses Muscle Atrophy and Decreased Motor Function in SAMP8 Mice.

Sarcopenia is a disease whose symptoms include decreased muscle mass and weakened muscle strength with age. In sarcopenia, decreased production of insulin-like growth factor-1 (IGF-1) increases ubiquitin ligases, such as Atrogin1 and Muscle RING-Finger Protein-1 (MuRF1), by activating forkhead box O (FOXO), and inflammatory cytokines and oxidative stress increase the expression of ubiquitin ligases by activating the transcription factor nuclear factor-kappa B (NF-κB). In addition, increased levels of ubiquitin ligases cause skeletal muscle atrophy. Conversely, sirtuin 1 (Sirt1) is known to regulate the expression of ubiquitin ligases by suppressing the activities of NF-κB and FOXO. In this study, we evaluated the effect that juzentaihoto hot water extract (JTT) has on skeletal muscle atrophy and motor function by administering it to senescence-accelerated mouse prone-8 (SAMP8). The group treated with JTT displayed larger gastrocnemius muscle (GA) and extensor digitorum longus (EDL) weights, larger GA muscle fiber cross-sectional areas, and motor function decline during rota-rod tests. JTT also increased IGF-1 serum levels, as well as mRNA Sirt1 levels in GA. Serum levels of tumor necrosis factor-α, interleukin-6, and mRNA levels of Atrogin1 and MuRF1 in GA were reduced by JTT. The muscle fiber cross-sectional area of GA was correlated with the mRNA levels of Sirt1 in GA. The results of this study suggested that JTT administration suppresses skeletal muscle atrophy and motor function decline in SAMP8 mice. This effect may be associated with the increased expression levels of Sirt1 and IGF-1 by JTT.

Effect of lubiprostone on vinca alkaloid-induced constipation in patients with hematological malignancies: a propensity score-matched analysis.

Patients receiving vinca alkaloids for hematological malignancies frequently experience constipation that is unresponsive to laxatives. Research on treatment of vinca alkaloid-induced constipation is limited. This study aimed to determine whether the chloride channel activator lubiprostone ameliorates vinca alkaloid-induced constipation in patients with hematological malignancies. In this retrospective cohort study, vinca alkaloid-induced constipation (grade ≥ 3 using the Common Terminology Criteria for Adverse Events) was investigated in patients treated for hematological malignancies between July 2014 and June 2019 who had already been prescribed osmotic laxatives and additionally received either a stimulant laxative or lubiprostone. Univariate and multivariate analyses were performed to identify the risk factors for persistent constipation after introduction of the second laxative. A propensity score model was used to match 67 patients taking a stimulant laxative and 67 treated with lubiprostone, and the occurrence of intractable constipation was compared between groups. Overall, 203 patients were included, among whom 50 (25%) had constipation. On multivariate analysis, body mass index, opioid use, and addition of lubiprostone were independently associated with constipation. Patients treated with lubiprostone were significantly less likely to experience intractable constipation than did those treated with stimulant laxatives (10% vs. 34%, P = 0.002). Moreover, post-constipation diarrhea was significantly less frequent among patients treated with lubiprostone (42% vs. 63%, P = 0.024). Lubiprostone was more effective than stimulant laxatives at treating vinca alkaloid-induced intractable constipation in patients with hematological malignancies, and its use could enable safe vinca alkaloid chemotherapy.

Risk Factors for Pseudoaldosteronism with Yokukansan Use: Analysis Using the Japanese Adverse Drug Report (JADER) Database.

Yokukansan is a Kampo formula that is commonly used by the elderly because it is expected to improve peripheral symptoms of dementia and delirium. However, side effects from its use are frequently reported in the elderly. In particular, pseudoaldosteronism caused by the licorice contained in yokukansan leads to hypertension, hypokalemia, and muscle weakness, which may result in death. This study aimed to identify the risk factors of pseudoaldosteronism with yokukansan use. Using cases reported in the Japanese Adverse Drug Report (JADER) database, the reporting odds ratio (ROR) was calculated and compared to assess the risk of pseudoaldosteronism for each licorice-containing Kampo formula. We also analyzed the risk factors for pseudoaldosteronism in patients taking yokukansan. Yokukansan (ROR 2.4, 95% confidence interval (CI) 1.9-2.8; p < 0.001) had a higher risk of pseudoaldosteronism than that of other licorice-containing Kampo formulas. Furthermore, the results of a logistic regression analysis in patients taking yokukansan showed that the licorice dose (OR 1.5, 95% CI 1.2-2.0; p < 0.01), older age (<70 years, OR 5.9, 95% CI 1.8-20; p < 0.01), dementia (OR 2.8, 95% CI 1.6-4.9; p < 0.001), low body weight (<50 kg, OR 2.2, 95% CI 1.1-3.5; p = 0.034) were risk factors for pseudoaldosteronism, Although not significant, treatment with loop diuretics (OR 1.8, 95% CI 0.98-3.5; p = 0.059) tended to increase the risk of pseudoaldosteronism. In summary, patients must understand the risk factors when considering taking yokukansan and reduce the licorice dose they consume.

Juzentaihoto Suppresses Muscle Atrophy in Streptozotocin-Induced Diabetic Mice.

In diabetic patients, skeletal muscle atrophy occurs due to increased oxidative stress and inflammation. Skeletal muscle atrophy reduces the QOL of patients and worsens life prognosis. Therefore, development of preventive therapy for muscle atrophy in hyperglycemic state is eagerly awaited. Juzentaihoto is a medicinal herb that has a function to supplement physical strength, and it is expected to prevent muscle atrophy. To determine the preventive effect of juzentaihoto on muscle atrophy in hyperglycemic state, streptozotocin (STZ) was administered to induce diabetes in mice and the preventive effect of juzentaihoto was evaluated. Mice that received juzentaihoto extract (JTT) showed that the decrease in muscle fiber cross-sectional area in the gastrocnemius muscle was reversed. Additionally, the expression level of tumor necrosis factor α (TNF-α), an inflammatory cytokine, in serum decreased, and that of ubiquitin ligase (atrogin-1, muscle RING-finger protein-1) mRNA in skeletal muscle decreased. An anti-inflammatory cytokine interleukin-10 showed increased levels in the serum and increased levels in spleen cell culture supernatant collected from mice that received JTT. JTT had no effect on the blood glucose level. These results suggest that prophylactic administration of JTT to STZ-induced diabetic mice affects immune cells such as in spleen, causing an anti-inflammatory effect and inhibiting excessive activation of the ubiquitin-proteasome system, to reverse muscle atrophy.

CD14 expression and Kupffer cell dysfunction in non-alcoholic steatohepatitis: superparamagnetic iron oxide-magnetic resonance image and pathologic correlation.

BACKGROUND AND AIM: Kupffer cell (KC) function and CD14 expression contributes to pathogenesis of non-alcoholic steatohepatitis (NASH). However, these relationships remain unclear. We investigated the relationship of KC function with superparamagnetic iron oxide-enhanced magnetic resonance imaging (SPIO-MRI), histopathological severity of NASH, and number of CD14-positive KCs in NASH. METHODS: This retrospective study included 32 patients (24 with NASH and eight with simple steatosis) who had previously undergone SPIO-MRI with T2-weighted gradient-recalled echo sequence. All subjects were diagnosed pathologically and were evaluated for necroinflammation grade, fibrosis stage, and number of CD14-positive KCs. Patients with NASH and simple steatosis were compared by using the Mann-Whitney test to determine differences in percent reduction of liver-to-muscle signal intensity ratio (reduction-%LMR), as a surrogate parameter of KC function, and number of CD14-positive KCs. Kruskal-Wallis test and Pearson's correlation coefficient were used to analyze relation among reduction-%LMR, histopathological severity and number of CD14-positive KCs. RESULTS: There were statistically significant differences in reduction-%LMR and number of CD14-positive KCs between NASH and simple steatosis patients (Mann-Whitney test, P < 0.001 for all comparisons). Reduction-%LMR decreased with an increase in necroinflammation grade or fibrosis stage. The number of CD14-positive KCs increased with an increase in necroinflammation grade and fibrosis stage (Kruskal-Wallis test, both, P < 0.001). A high correlation was seen between number of CD14-positive KCs and reduction-%LMR (Pearson r = 0.81; P < 0.001). CONCLUSIONS: KC phagocytic function evaluated with SPIO-MRI correlated with histopathological severity and number of CD14-positive KCs. These results support the concept that KC phagocytic dysfunction contributes to the pathogenesis of NASH.

Daptomycin for the successful treatment of postoperative methicillin-resistant Staphylococcus aureus empyema: a case report.

Empyema is typically treated using pleural space drainage and systemic treatment with antimicrobials, and specific antimicrobial agents in the case of methicillin-resistant Staphylococcus aureus (MRSA) infections. A 57-year-old man underwent segmental resection of the left lung owing to multiple lung metastases and developed MRSA-related empyema postoperatively. Although the patient received chest drainage and linezolid, the inflammation caused by the infection persisted. Consequently, linezolid was replaced by daptomycin, and his empyema was accordingly resolved. Our findings indicate that daptomycin could be an effective treatment for postoperative MRSA-related empyema.

Added value of anxiolytic benzodiazepines in predictive models on severe delirium in patients with acute decompensated heart failure: A retrospective analysis.

BACKGROUND: Delirium in patients with acute decompensated heart failure (ADHF) is associated with poor clinical outcomes. Although some medications have been reported as risk factors for delirium, their impact on patients with ADHF is still unclear. This study aimed to determine the association of specific medication use with delirium and their additive predictive value in models based on conventional risk factors. METHODS AND RESULTS: In this single-center, retrospective study, 650 patients treated for ADHF were included. Fifty-nine patients (9.1%) had delirium. In multivariate analysis, anxiolytic benzodiazepines [odds ratio (OR): 6.4, 95% confidence interval (CI): 2.8-15], mechanical ventilation or noninvasive positive pressure ventilation (OR: 6.0, 95% CI: 2.9-12), depression (OR: 3.2, 95% CI: 1.5-6.5), intensive care or high care unit admission (OR: 2.9, 95% CI: 1.5-5.6), male sex (OR: 2.0, 95% CI: 1-3.7), and age (OR: 1.1, 95% CI: 1-1.1) were independently associated with severe delirium. The predictive model that included anxiolytic benzodiazepines had a significantly better discriminatory ability for the incidence of severe delirium than the conventional model. CONCLUSIONS: The use of anxiolytic benzodiazepines was independently correlated with severe delirium, and their use in models based on conventional risk factors had an additive value for predicting delirium in patients with ADHF.

Association of exogenous insulin or sulphonylurea treatment with an increased incidence of hepatoma in patients with hepatitis C virus infection.

BACKGROUND: Diabetes mellitus is frequently seen in hepatitis C patients and is often treated with antidiabetic agents that increase serum insulin levels. Because insulin is a growth-promoting hormone, antidiabetic agents could pose a risk for hepatocellular carcinoma (HCC). AIM: The aim of this study was to investigate an association between antidiabetic therapies and the incidence of HCC in hepatitis C patients with diabetes mellitus. METHODS: A nested case-control study was conducted. Participants were recruited from a cohort study, in which patients with hepatitis C were consecutively registered. Participants were assigned to an HCC group (n=138) or a non-HCC group (n=103). To identify independent factors, variables including use of antidiabetic agents were analysed by logistic regression analysis. RESULTS: Besides ageing, being male, cirrhosis and hypoalbuminaemia, use of exogenous insulin and a second-generation sulphonylurea were significant independent factors associated with an incidence of HCC [odds ratio (OR) 2.969, 95% confidence interval (CI) 1.293-6.819, P<0.0103 and OR 6.831, 95% CI 1.954-23.881, P<0.0026 respectively). In stratified analyses, the impact of these antidiabetic agents was more evident in patients who were non-cirrhotic than in those who were cirrhotic. CONCLUSIONS: Exogenous insulin and a second-generation sulphonylurea were independent variables associated with an incidence of HCC in hepatitis C patients with diabetes mellitus. This association was evident in patients who were non-cirrhotic. To verify a causal relationship between these antidiabetic agents and the development of HCC, a prospective cohort study is required.

The association between chemotherapy-induced febrile neutropenia and breast cancer subtype in Japanese patients.

Background Chemotherapy-induced febrile neutropenia is a common and potentially lethal side effect; therefore, predicting febrile neutropenia development is important. Objective This study examined the risk factors for febrile neutropenia development according to breast cancer subtype among Japanese patients receiving chemotherapy. Methods This single-center retrospective study evaluated 60 outpatients who received chemotherapy for breast cancer (epirubicin plus cyclophosphamide or docetaxel plus cyclophosphamide). Their characteristics were evaluated to identify factors associated with febrile neutropenia development. Results Thirty-three patients developed febrile neutropenia and 27 patients did not. The risk of developing febrile neutropenia was significantly associated with estrogen receptor negativity (p < 0.05). Logistic regression analysis further confirmed that estrogen receptor negativity was an independent risk factor for febrile neutropenia development (odds ratio: 4.35, 95% confidence interval: 1.05-18.0). Moreover, the highest rate of febrile neutropenia was observed in patients with hormone receptor (estrogen and/or progesterone receptor)-negative/human epidermal growth factor receptor 2-positive breast cancer. Conclusion In addition to the known risk factors for febrile neutropenia, our findings revealed that the risk of developing chemotherapy-induced febrile neutropenia is associated with the hormone receptor-negative/human epidermal growth factor receptor 2-positive subtype in Japanese patients with breast cancer.

Severe hypoglycemia caused by a small dose of repaglinide and concurrent use of nilotinib and febuxostat in a patient with type 2 diabetes.

Repaglinide, an oral hypoglycemic agent, is a short-acting insulin secretagogue. We describe a case, in which an extremely low dose of repaglinide caused severe hypoglycemia and novel drug interactions are suggested. A 71-year-old man with type 2 diabetes was taken to the hospital due to consciousness disorder caused by severe hypoglycemia. He was taking repaglinide 0.25 mg once in the morning with nilotinib 400 mg/day and febuxostat 20 mg/day. Endogenous insulin secretion was not suppressed even in hypoglycemia. Detection of plasma repaglinide 10 h after administration in this case indicates delayed elimination of the agent, which might be derived from reduced hepatocyte uptake due to inhibitory effects of nilotinib on OATP1B1 and reduced oxidation of the agents by inhibitory effects of nilotinib, mainly on CYP3A4 activities, and of febuxostat on CYP2C8 activities. Repaglinide is eliminated by the liver, and is a short-acting insulin secretagogue with a good safety profile in patients with type 2 diabetes complicated by renal impairment, including elderly patients; however, its delayed elimination due to drug-drug interactions should be noted.

Correction to: Severe hypoglycemia caused by a small dose of repaglinide and concurrent use of nilotinib and febuxostat in a patient with type 2 diabetes.

[This corrects the article DOI: 10.1007/s13340-020-00434-w.].

Juzentaihoto hot water extract alleviates muscle atrophy and improves motor function in streptozotocin-induced diabetic oxidative stress mice.

A decrease in skeletal muscle mass and motor function occurs in diabetic patients. In type 1 diabetic patients, in particular, fast-type fiber-dominated muscle atrophy occurs due to increased oxidative stress and inflammation. Juzentaihoto is a herbal medicine that has been found to be effective in reducing oxidative stress. In this study, juzentaihoto hot water extract (JTT) was administered prophylactically to mice with diabetic oxidative stress, which was induced by an injection of streptozotocin, and the effects on skeletal muscle mass, motor function, and antioxidant activity were evaluated. In mice that were administered JTT, skeletal muscle atrophy and loss of motor function were suppressed. Additionally, the administration of JTT increased the mRNA expression level of Sirt1 and the activity of superoxide dismutase in the gastrocnemius. In addition to skeletal muscle atrophy, atrophy of the liver, spleen and thymus gland, and kidney hypertrophy were also suppressed. Furthermore, in order to evaluate the antioxidant activity of 10 constituent crude drugs that comprise juzentaihoto, Sirt1 transcriptional activity in C2C12 cells was evaluated. The Sirt1 transcriptional activity was increased by Cinnamomi Cortex, Astragali Radix, and Glycyrrhizae Radix extracts. These three constituent crude drugs play an important function in the antioxidant action of juzentaihoto, suggesting that juzentaihoto can prevent muscle atrophy by decreasing oxidative stress.

Usefulness of serum hepatic fibrosis markers in the diagnosis of nonalcoholic steatohepatitis (NASH).

BACKGROUND/AIMS: In the present study, we examined the usefulness of serum hepatic fibrosis markers for the diagnosis of nonalcoholic steatohepatitis (NASH). METHODOLOGY: The subjects were 16 patients with NASH and 9 patients with fatty liver (FL). All were negative for serum HBsAg, HCVAb, antibodies related with autoimmune diseases, alcohol intake, and drug abuse. We measured the biochemical markers for liver function, hepatic fibrosis markers such as type III procollagen N-peptide (PIIIP), type IV collagen (TyIV), hyaluronic acid (HA) and leptin, and compared these data with histological findings of biopsy specimens. In addition, we examined the diagnostic efficiency of fibrosis markers and leptin for NASH using receiver operating characteristic (ROC) curve. Body mass index (BMI), fasting blood sugar, triglyceride, and degree of fat droplets, inflammation, iron deposition and fibrosis were significantly higher in the NASH group compared with the FL group. RESULTS: The diagnostic efficiencies of NASH% (cut-off value) were 68% (100ng/mL) for TyIV, 68% (10ng/mL) for HA, 64% (0.62U/mL) for PIIIP and 56% (8pg/mL) for leptin. CONCLUSIONS: From these results, it is suggested that the serum hepatic fibrosis markers such as TyIV, in addition to liver biopsy, may be useful for the diagnosis of NASH.

Evaluation of Resistance-Associated Substitutions in NS5A Using Direct Sequence and Cycleave Method and Treatment Outcome with Daclatasvir and Asunaprevir for Chronic Hepatitis C Genotype 1.

BACKGROUND: The aim of this study was to evaluate the efficacy of daclatasvir plus asunaprevir therapy in patients infected with hepatitis C virus and determine its relevance to resistant variants. METHODS: A total of 629 consecutive patients infected with hepatitis C virus genotype 1 were assessed. Daclatasvir (60 mg/day) plus asunaprevir (200 mg/day) was given for 24 weeks. The virological responses and resistance-associated substitutions of hepatitis C virus mutants were examined by the direct sequence and cycleave methods were evaluated. RESULTS: Overall, 89.4% (555/621) of patients exhibited a sustained virological response (SVR). The SVR rates in the patients with wild type, mixed, and mutant type Y93 by direct sequencing were 92.5% (520/562), 70.3% (26/37), and 42.9% (9/21), respectively. The SVR rates in the patients with 100%, 90%, 80%-30%, and 20%-0% Y93 wild by the cycleave method were 93.4% (456/488), 88.2%(30/34), 56.0%(14/25), and 36.8%(7/19), respectively. In contrast, the SVR rates for the wild type and mixed/mutant type L31 by direct sequencing were 90.2% (534/592) and 72.4% (21/29), respectively. In the multivariate analyses, the wild type Y93, no history of simeprevir therapy, the wild type L31, and low HCV RNA level were independent factors of SVR. CONCLUSION: NS5A resistance-associated substitutions, especially Y93H, were major factors predicting the SVR. Although direct sequencing can predict the SVR rate, the cycleave method is considered to be more useful for predicting the SVR when used in combination.

Nateglinide is useful for nonalcoholic steatohepatitis (NASH) patients with type 2 diabetes.

BACKGROUND/AIMS: In the present study we administered nateglinide to nonalcoholic steatohepatitis (NASH) patients with type 2 diabetes who had failed to respond adequately to diet and exercise therapy, and we compared the resulting changes in insulin kinetics and improvements in blood glucose levels, as well as the concomitant changes in hepatic function, diagnostic liver images and liver histology, with the results from a non-treated control group. METHODOLOGY: Subjects for this study consisted of 10 patients with NASH. They all suffered from diabetes and they were all diagnosed with fatty liver by abdominal ultrasonography (US) and computed tomography (CT). Nonalcoholic steatohepatitis was diagnosed as the result of liver biopsy. The subjects were randomly divided into two groups, the nateglinide-treated group and the non-treated control group. Each group contained five patients. The members of the nateglinide-treated group were administered nateglinide every day (270mg/day) before each meal for a period of 20 weeks. Both groups continued to receive diet and exercise therapy. Body mass index (BMI), blood chemistry, plasma glucose and HbAlc, abdominal US and CT were measured before treatment, and every four weeks thereafter. Liver biopsy was performed over again at 16 weeks af terinitiating treatment. RESULTS: The results were compared. Postprandial blood glucose, HbA1c, a 75-g oral glucose tolerance test, liver function, abdominal US and CT imaging tests and liver histological findings were all improved after treatment with nateglinide. CONCLUSIONS: From these results we concluded that nateglinide is useful in the treatment of NASH in patients with type 2 diabetes.

Predictive factors for remission and death in 73 patients with autoimmune hepatitis in Japan.

The prognosis of patients with autoimmune hepatitis (AIH) has not been clearly defined. The aim of this study was to define the prognostic factors of AIH in a population with long-term follow-up in Japan. Seventy-three patients who were diagnosed as having type 1 AIH between January, 1972 - August, 1999 were enrolled in this study. Initial treatment included prednisolone (PSL) (n=62), other drug regimens (n=7), and none (n=4). We examined the relation between several factors obtained at diagnosis in relation to disease activity found at the final observation point (January, 2000 - April, 2000). Multivariate logistic regression and Cox regression were used for statistical analysis. During the observation period, 8 patients died of the following: hepatic failure (n=4), hepatocellular carcinoma (n=1), severe infection (n=1), and unknown causes (n=2). At the end point, the number of patients in complete remission was 13, those with a normal alanine aminotransferase (ALT) level requiring some treatment was 35, and those with an abnormal ALT level despite medication was 17. Factors related to remission were total bilirubin (TB) (Odds ratio, 0.87), and immunoglobulin G (IgG) (Odds ratio, 1.00). Factors related to death were the aspartate aminotransaminase (AST)/ALT ratio (Odds ratio, 11.67) and response to initial PSL regimen (Odds ratio, 0.03). The results of this study show an importance of achieving a good PSL response at onset, and that initial TB, the AST/ALT ratio, and IgG levels are useful for therapeutic strategy.

Interferon-gamma brings additive anti-viral environment when combined with interferon-alpha in patients with chronic hepatitis C.

T-cell hyporesponsiveness may lead to chronicity of hepatitis C virus (HCV) infection. We evaluated whether interferon (IFN)-gamma injection can bring a Th1-dominant environment to patients with chronic hepatitis C. Seventeen patients with genotype 1b received natural IFN-alpha 5MU daily for the first 2 weeks and three times a week for the next 22 weeks followed by natural IFN-gamma 1 MU daily for 2 weeks. In 4 of 17 patients (23.5%), alanine aminotransferase (ALT) was normalized and 3 of these 4 patients (75.0%) cleared HCV RNA. beta2 microglobulin (BMG), neopterin and soluble (s) Fas increased with IFN-alpha and increased more with IFN-gamma. Serum interleukin (IL)-12, CD4 and CD8 remained unchanged with IFN-alpha but increased after IFN-alpha was replaced by IFN-gamma. IL-10 was not changed either with IFN-alpha or gamma. Productions of IL-2, IFN-gamma and tumor necrosis factor (TNF)-alpha by peripheral blood mononuclear cells did not change by IFN-alpha therapy, however, they were enhanced at the end of IFN-gamma therapy. Productions of IL-2 and 4 were unaffected. These results show that some immune parameters become Th1-dominant by additional IFN-gamma in patients with chronic hepatitis C. Combination of these two IFNs should be explored.