Background and Objectives: Large clinical studies of sodium/glucose cotransporter 2 (SGLT2) inhibitors have shown a significant beneficial effect on heart failure-associated hospitalization and cardiovascular events. As SGLT2 is known to be absent in heart cells, improved cardiovascular outcomes are thought to be accounted for by the indirect effects of the drug. We sought to confirm whether such benefits were mediated through SGLT2 expressed in the heart using myocardial infarction (MI) model. Methods: Mice pre-treated with empagliflozin (EMPA), an SGLT2 inhibitor, showed a significantly reduced infarct size compared with the vehicle group three days post-MI.Interestingly, we confirmed SGLT2 localized in the infarct zone. The sequential changes of SGLT2 expression after MI were also evaluated. Results: One day after MI, SGLT2 transiently appeared in the ischemic areas in the vehicle group and increased until 72 hours. The appearance of SGLT2 was delayed and less in amount compared with the vehicle group. Additionally, there was a significant difference in metabolites, including glucose and amino acids in the 1 H nuclear magnetic resonance analysis between groups. Conclusions Our work demonstrates that SGLT2 is transiently expressed in heart tissue early after MI and EMPA may directly operate on SGLT2 to facilitate metabolic substrates shifts.

Background and Objectives: Large clinical studies of sodium/glucose cotransporter 2 (SGLT2) inhibitors have shown a significant beneficial effect on heart failure-associated hospitalization and cardiovascular events. As SGLT2 is known to be absent in heart cells, improved cardiovascular outcomes are thought to be accounted for by the indirect effects of the drug. We sought to confirm whether such benefits were mediated through SGLT2 expressed in the heart using myocardial infarction (MI) model. Methods: Mice pre-treated with empagliflozin (EMPA), an SGLT2 inhibitor, showed a significantly reduced infarct size compared with the vehicle group three days post-MI.Interestingly, we confirmed SGLT2 localized in the infarct zone. The sequential changes of SGLT2 expression after MI were also evaluated. Results: One day after MI, SGLT2 transiently appeared in the ischemic areas in the vehicle group and increased until 72 hours. The appearance of SGLT2 was delayed and less in amount compared with the vehicle group. Additionally, there was a significant difference in metabolites, including glucose and amino acids in the 1 H nuclear magnetic resonance analysis between groups. Conclusions Our work demonstrates that SGLT2 is transiently expressed in heart tissue early after MI and EMPA may directly operate on SGLT2 to facilitate metabolic substrates shifts.

PURPOSE: The severity of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus (T2DM) population compared with that in normal glucose tolerance (NGT) individuals has not yet been quantitatively assessed. We investigated the prevalence and the severity of NAFLD in a T2DM population using controlled attenuation parameter (CAP). MATERIALS AND METHODS: Subjects who underwent testing for biomarkers related to T2DM and CAP using Fibroscan® during a regular health check-up were enrolled. CAP values of 250 dB/m and 300 dB/m were selected as the cutoffs for the presence of NAFLD and for moderate to severe NAFLD, respectively. Biomarkers related to T2DM included fasting glucose/insulin, fasting C-peptide, hemoglobin A1c (HbA1c), glycoalbumin, and homeostasis model assessment of insulin resistance of insulin resistance (HOMA-IR). RESULTS: Among 340 study participants (T2DM, n=66; pre-diabetes, n=202; NGT, n=72), the proportion of subjects with NAFLD increased according to the glucose tolerance status (31.9% in NGT; 47.0% in pre-diabetes; 57.6% in T2DM). The median CAP value was significantly higher in subjects with T2DM (265 dB/m) than in those with pre-diabetes (245 dB/m) or NGT (231 dB/m) (all p<0.05). Logistic regression analysis showed that subjects with moderate to severe NAFLD had a 2.8-fold (odds ratio) higher risk of having T2DM than those without NAFLD (p=0.02; 95% confidence interval, 1.21-6.64), and positive correlations between the CAP value and HOMA-IR (ρ=0.407) or fasting C-peptide (ρ=0.402) were demonstrated. CONCLUSION: Subjects with T2DM had a higher prevalence of severe NAFLD than those with NGT. Increased hepatic steatosis was significantly associated with the presence of T2DM, and insulin resistance induced by hepatic fat may be an important mechanistic connection.
Adult ; Aged ; Biomarkers/metabolism ; C-Peptide/metabolism ; Case-Control Studies ; Diabetes Mellitus, Type 2/*complications/metabolism ; Female ; Hemoglobin A, Glycosylated/metabolism ; Humans ; Insulin Resistance ; Male ; Middle Aged ; Non-alcoholic Fatty Liver Disease/*epidemiology/metabolism/pathology ; Odds Ratio ; Prevalence

PURPOSE: Due to the seroepidemiological shift in hepatitis A (HA), its severity, mortality, and complications have increased in recent years. Thus, the aim of this study was to identify predictive factors associated with poor prognosis among patients with HA. MATERIALS AND METHODS: A total of 304 patients with HA admitted to our institution between July 2009 and June 2011 were enrolled consecutively. Patients with complications defined as acute liver failure (ALF) were evaluated, and mortality was defined as death or liver transplantation. RESULTS: The mean age of patients (204 males, 100 females) was 32 years. Eighteen (5.9%) patients had progressed to ALF. Of the patients with ALF, 10 patients (3.3%) showed spontaneous survival while 8 (2.6%) died or underwent liver transplantation. Multivariate regression analysis showed that Model for End-Stage Liver Disease (MELD) and systemic inflammatory response syndrome (SIRS) scores were significant predictive factors of ALF. Based on receiver operating characteristics (ROC) analysis, a MELD > or =23.5 was significantly more predictive than a SIRS score > or =3 (area under the ROC: 0.940 vs. 0.742, respectively). In addition, of patients with a MELD score > or =23.5, King's College Hospital criteria (KCC) and SIRS scores were predictive factors associated with death/transplantation in multivariate analysis. CONCLUSION: MELD and SIRS scores > or =23.5 and > or =3, respectively, appeared to be related to ALF development. In addition, KCC and SIRS scores > or =3 were valuable in predicting mortality of patients with a MELD > or =23.5.
Adult ; Female ; Hepatitis A/*complications ; Humans ; Liver Failure, Acute/*etiology/*mortality/pathology ; Male ; Multivariate Analysis ; Prognosis ; Prospective Studies ; ROC Curve ; Systemic Inflammatory Response Syndrome/complications

BACKGROUND/AIMS: Intestinal metaplasia (IM) is a premalignant condition. This study aimed to evaluate the correlation between endoscopic and histological findings of IM. METHODS: The cases of IM were graded by conventional endoscopy, and biopsies were taken from the antrum and body of 1,333 subjects for histological IM diagnosis. Multivariate analyses were performed to identify the factors that affect the sensitivity of endoscopic IM diagnosis. RESULTS: The sensitivity/specificity of endoscopic IM diagnosis based on histology was 24.0%/91.9% for the antrum and 24.2%/88.0% for the body. As indicated by multivariate analysis, the presence of endoscopic atrophic gastritis (AG) (odds ratio [OR], 4.73; 95% confidence interval [CI], 2.07 to 10.79) and the activity of mucosal inflammation (OR, 2.21; 95% CI, 1.08 to 4.54) were associated with the sensitivity of endoscopic IM diagnosis in the antrum, while the presence of endoscopic AG (OR, 8.02; 95% CI, 4.55 to 14.15), dysplasia (OR, 2.40; 95% CI, 1.07 to 5.39), and benign gastric ulcers (OR, 0.35; 95% CI, 0.15 to 0.081) were associated with the sensitivity of endoscopic IM diagnosis in the body. CONCLUSIONS: As the sensitivity of endoscopic IM diagnosis was low, a high index of suspicion for IM is necessary in the presence of atrophy, and confirmation by histology is also necessary.
Atrophy ; Biopsy ; Endoscopy ; Gastritis, Atrophic ; Inflammation ; Metaplasia ; Multivariate Analysis ; Stomach Ulcer

PURPOSE: Refractory ascites (RA) is closely related to a high morbidity and mortality. In this study, we investigated predictors of RA development in patients with hepatitis B virus (HBV)-related cirrhosis who were hospitalized to control ascitic decompensation, and determined predictors for survival in patients who experienced RA. MATERIALS AND METHODS: We analyzed 199 consecutive patients with HBV-related cirrhosis who were hospitalized to control ascitic decompensation between January 1996 and December 2008. RESULTS: Multivariate analyses showed that only serum potassium at admission predicted RA development independently [p=0.013; hazard ratio (HR), 2.800; 95% confidence interval (CI), 1.166-6.722]. During the follow-up period, 16 (8.0%) patients experienced RA within 4.2 (range, 1.0-39.2) months after admission for controlling ascitic decompensation, and they survived a median of 8.7 (range, 3.9-51.3) months. Child-Pugh class and RA type were identified as independent prognostic factors affecting the survival in patients with RA (p=0.045; HR, 8.079; 95% CI, 1.231-67.984 and p=0.013; HR, 14.510; 95% CI, 1.771-118.874, respectively). CONCLUSION: Serum potassium was an independent predictor of RA development in patients with HBV-related cirrhosis who were hospitalized to control ascitic decompensation. After RA development, Child-Pugh class and RA type were independent predictors for survival.
Adult ; Aged ; Ascites/complications/*diagnosis/mortality ; Female ; Hepatitis B, Chronic/complications/mortality/*therapy ; Hospitalization ; Humans ; Liver Cirrhosis/complications/mortality/*therapy ; Liver Transplantation ; Male ; Middle Aged ; Multivariate Analysis ; Potassium/blood ; Prognosis ; Retrospective Studies ; Treatment Outcome

BACKGROUND/AIMS: The incidence of multidrug-resistant (MDR) chronic hepatitis B (CHB) during sequential lamivudine (LAM) and adefovir dipivoxil (ADV) treatment is increasing. We investigated the antiviral efficacies of various rescue regimens in patients who failed sequential LAM-ADV treatment. METHODS: Forty-eight patients (83.3% of whom were HBeAg-positive) who failed sequential LAM-ADV treatment were treated with one of the following regimens: entecavir (ETV) (1 mg) monotherapy (n=16), LAM+ADV combination therapy (n=20), or ETV (1 mg)+ADV combination therapy (n=12). All patients had confirmed genotypic resistance to both LAM and ADV and were evaluated every 12 weeks. RESULTS: The baseline characteristics and treatment duration did not differ significantly among the study groups. During the treatment period (median duration: 100 weeks), the decline of serum HBV DNA from baseline tended to be greatest in the ETV+ADV group at all-time points (week 48: -2.55 log10 IU/mL, week 96: -4.27 log10 IU/mL), but the difference was not statistically significant. The ETV+ADV group also tended to have higher virologic response rates at 96 weeks compared to the ETV monotherapy or LAM+ADV groups (40.0% vs. 20.0% or 20.0%, P=0.656), and less virologic breakthrough was observed compared to the ETV monotherapy or LAM+ADV groups (8.3% vs. 37.5% or 30.0%; P=0.219), but again, the differences were not statistically significant. HBeAg loss occurred in one patient in the ETV+ADV group, in two in the ETV monotherapy group, and in none of the LAM+ADV group. The safety profiles were similar in each arm. CONCLUSIONS: There was a nonsignificant tendency toward better antiviral efficacy with ETV+ADV combination therapy compared to LAM+ADV combination therapy and ETV monotherapy for MDR CHB in Korea, where tenofovir is not yet available.
Adenine/analogs & derivatives/therapeutic use ; Adult ; Aged ; Antiviral Agents/*therapeutic use ; DNA, Viral/blood ; Drug Resistance, Viral ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Genotype ; Guanine/analogs & derivatives/therapeutic use ; Hepatitis B e Antigens/blood ; Hepatitis B virus/genetics ; Hepatitis B, Chronic/*drug therapy ; Humans ; Lamivudine/therapeutic use ; Male ; Middle Aged ; Organophosphonates/therapeutic use ; Treatment Outcome

BACKGROUND/AIMS: To investigate pre-existing hepatitis B virus (HBV) quasispecies and the genotypic evolution of several variants. METHODS: From six patients with lamivudine (LAM) failure, serum samples at pretreatment, 6 months of LAM therapy, and virologic breakthrough were obtained. One hundred clones with HBV inserts in each patient were sequenced at each time point. Pretreatment serum samples were also analyzed from six patients who achieved good responses to LAM therapy. RESULTS: Among the six patients with LAM failure, the analysis of 100 clones from patient 1 revealed the substitutions L180M in 1% of clones and V173L in 2% of clones. Patient 2 had substitutions of L80V, W153Q, and L180M. In patient 3, mutations conferring resistance to adefovir at V84I (5%), I169L (1%), and N236H (7%) and entecavir at S202G (2%) were detected. Patient 4 had mutations at T128N (1%), I169L (1%), V173L (2%), A181V (1%), and Q215H (1%). In patient 5, M204V/I was detected in 1% and 2% of clones, respectively. L80I and V173L were also identified in patient 6. In the six patients who responded to LAM, the degree of overall quasispecies was less than those with LAM failure. CONCLUSIONS: Various HBV quasispecies associated with drug resistance existed before treatment, and the quasispecies dynamically changed through LAM therapy.
Adenine ; Clone Cells ; Drug Resistance ; Guanine ; Hepatitis ; Hepatitis B ; Hepatitis B virus ; Hepatitis B, Chronic ; Hepatitis, Chronic ; Humans ; Lamivudine ; Lipopolysaccharides ; Organophosphonates

PURPOSE: Using FibroScan(R) to obtain a reliable liver stiffness measurement (LSM) may require more than 10 valid measurements (VMs), according to the manufacturer's recommendations. However, this requirement lacks scientific evidence in support thereof. We investigated the minimal number of VMs required to assess liver fibrosis without significant loss of accuracy in patients with chronic hepatitis B (CHB) and C (CHC) and predictors of discordance between LSM and liver biopsy (LB). MATERIALS AND METHODS: Between January 2005 and December 2009, we prospectively enrolled 182 patients with CHB and 68 patients with CHC who were to undergo LB and LSM before starting antiviral treatment. Only LSMs with at least 10 VMs were considered reliable. The Batts and Ludwig scoring system was used for histologic assessment. RESULTS: The mean age and body mass index were 46.0 years and 23.4 kg/m2 in patients with CHB and 49.7 years and 23.1 kg/m2 in those with CHC, respectively. The median elasticity scores from the first 3, first 5, and all VMs taken significantly predicted fibrosis stages > or =F2 and F4 (all p<0.05) without significant differences (all p>0.05 by DeLong's method). Alanine aminotransferase (ALT) was the only predictor of discordance in fibrosis stage as estimated by the median elasticity score from the first 3 VMs and by LB in patients with CHB, whereas no significant predictor was identified in those with CHC. CONCLUSION: After comparison of patients who had more than 10 valid measurements for LSM, three VMs may be enough to assess liver fibrosis using LSM without significant loss of accuracy in patients with CHC and patients with CHB. However, ALT should be considered when interpreting LSM for patients with CHB.
Adult ; Alanine Transaminase/metabolism ; Female ; Hepatitis B, Chronic/*complications/metabolism ; Humans ; Liver/metabolism/pathology ; Liver Cirrhosis/*diagnosis/etiology/metabolism ; Male ; Middle Aged ; Prospective Studies

PURPOSE: Spontaneous bacterial peritonitis (SBP) frequently develops in patients with liver cirrhosis; however, there is little data to suggest whether the acquisition site of infection influences the prognosis. This study compared the bacteriology, clinical characteristics and treatment outcomes of community-acquired SBP (CA-SBP) and nosocomial SBP (N-SBP). MATERIALS AND METHODS: The medical records of 130 patients with hepatitis B virus (HBV)-related liver cirrhosis, who had experienced a first episode of SBP between January 1999 and December 2008, were reviewed. RESULTS: The study population included 111 (85.4%) patients with CA-SBP and 19 (14.6%) patients with N-SBP. Baseline and microbiological characteristics as well as clinical course, including in-hospital mortality, did not differ between patients with CA-SBP and those with N-SBP (all p>0.05). The median survival time was 6.5 months, and 117 (90.0%) patients died during the follow-up period. Patients with CA-SBP and N-SBP survived for median periods of 6.6 and 6.2 months, respectively, without significant difference (p=0.569). Time to recurrence did not differ between patients with CA-SBP and N-SBP (4.7 vs. 3.6 months, p=0.925). CONCLUSION: The acquisition site of infection did not affect clinical outcomes for patients with HBV-related liver cirrhosis who had experienced their first episode of SBP. Third-generation cephalosporins may be effective in empirically treating these patients, regardless of the acquisition site of the infection.
Community-Acquired Infections/etiology/*microbiology/mortality/virology ; Female ; Hepatitis B virus/*pathogenicity ; Humans ; Liver Cirrhosis/complications/mortality/*virology ; Male ; Middle Aged ; Peritonitis/etiology/*microbiology/mortality/*virology ; Retrospective Studies