Sofosbuvir plus ribavirin for the treatment of hepatitis C virus genotype 2 in Korea: What's the optimal dosage of ribavirin in real-world setting?

OBJECTIVE: This study aimed to investigate the efficacy and safety of sofosbuvir plus ribavirin for the treatment of hepatitis C virus (HCV) genotype 2 infection and to determine the optimal ribavirin dosage. METHODS: From May 2016 to March 2017, 199 patients received sofosbuvir plus ribavirin treatment for HCV genotype 2 infection at four centers in Jeollanam-do Province, Korea. After excluding patients lost to follow-up and those with insufficient data, we retrospectively assessed the data for 194 patients. The treatment efficacy and safety of sofosbuvir plus ribavirin were evaluated. RESULTS: A sustained virological response was achieved in 189 patients (intention-to-treat [ITT] 97.4%; per protocol [PP]: 99.5%, both at 12 and 24 weeks) whose average ribavirin dosage was 937.1 mg/day. The most frequent adverse event was anemia (17.5%), and its incidence significantly increased (P < 0.001) with a higher ribavirin dosage per body weight. Discontinuation of ribavirin or dosage reduction occurred in 27 (14.2%). The ribavirin dosage reduction rate increased at a dosage of >15 mg/kg (area under the receiver operating characteristic curve 0.652, 95% confidence interval [CI] 0.54-0.76, P = 0.01). Multivariate analysis showed that age ≥70 years, with liver cirrhosis, and female gender were associated with ribavirin dosage reduction. CONCLUSIONS: Remarkable outcomes were attained in patients with HCV genotype 2 infection treated with sofosbuvir plus ribavirin. Age ≥70 years, with liver cirrhosis, and female gender were associated with ribavirin dosage reduction. Thus, sustained virological response can be achieved with <1000 mg of ribavirin, with an optimal dosage of 15 mg/kg.

Chronic Hepatitis B Infection Is Significantly Associated with Chronic Kidney Disease: a Population-based, Matched Case-control Study.

BACKGROUND: Hepatitis B virus (HBV) infection leads to hepatic and extrahepatic manifestations including chronic kidney disease (CKD). However, the association between HBV and CKD is not clear. This study investigated the association between chronic HBV infection and CKD in a nationwide multicenter study. METHODS: A total of 265,086 subjects who underwent health-check examinations in 33 hospitals from January 2015 to December 2015 were enrolled. HBV surface antigen (HBsAg) positive cases (n = 10,048), and age- and gender-matched HBsAg negative controls (n = 40,192) were identified. CKD was defined as a glomerular filtration rate (GFR) < 60 mL/min/1.73 m2 or proteinuria as at least grade 2+ of urine protein. RESULTS: HBsAg positive cases showed a significantly higher prevalence of GFR < 60 mL/min/1.73 m2 (3.3%), and proteinuria (18.9%) than that of the controls (2.6%, P < 0.001, and 14.1%, P < 0.001, respectively). In the multivariate analysis, HBsAg positivity was an independent factor associated with GFR < 60 mL/min/1.73 m2 along with age, blood levels of albumin, bilirubin, anemia, and hemoglobin A1c (HbA1c). Likewise, HBsAg positivity was an independent factor for proteinuria along with age, male, blood levels of bilirubin, protein, albumin, and HbA1c. A subgroup analysis showed that HBsAg positive men but not women had a significantly increased risk for GFR < 60 mL/min/1.73 m2. CONCLUSION: Chronic HBV infection was significantly associated with a GFR < 60 mL/min/1.73 m2 and proteinuria (≥ 2+). Therefore, clinical concern about CKD in chronic HBV infected patients, especially in male, is warranted.

Comparison of efficacy and safety between endoscopic submucosal dissection and transanal endoscopic microsurgery for the treatment of rectal tumor.

Background/Aim: To compare the treatment efficacy and safety between endoscopic submucosal dissection (ESD) and transanal endoscopic microsurgery (TEM) for the treatment of rectal epithelial tumors, including large adenoma, cancer, and subepithelial tumors (SET). Patients and Methods: We conducted a retrospective analysis of the medical records of 71 patients with rectal tumors who were treated with ESD (48 patients) or TEM (23 patients) from January 2013 to December 2015. The patient group comprised 56 patients with epithelial tumors and 15 patients with SET. Treatment efficacy such as en bloc resection, procedure time, local recurrence, hospital stay, additional procedure rate, and safety between the treatment groups were evaluated and analyzed. Results: There were no significant differences in tumor size, location, macroscopic appearance, and histological depth between ESD and TEM groups. For ESD compared to TEM in rectal epithelial tumors, en bloc resection rates were 95% vs. 93.7% and R0 resection rates were 92.5% vs. 87.5% (P = 0.617); in rectal SET, en bloc resection rates were 100% vs. 100% and R0 resection rates were 87% vs. 85% (P = 0.91). The procedure time was 71.5 ± 51.3 min vs. 105.6 ± 28.2 min (P = 0.016) for epithelial tumors and 32.13 ± 13.4 min vs. 80.71 ± 18.35 min (P = 0.00) for SET, respectively. Hospital stay was 4.3 ± 1.2 days vs. 5.8 ± 1.8 days (P = 0.001) for epithelial tumors and 4.1 ± 4.1 days vs. 5.5 ± 2 days (P = 0.42) for rectal SET, respectively. There were no significant differences between recurrence rates, additional procedure rates, and complications in the two groups. Conclusions: ESD and TEM are both effective and safe for the treatment of rectal epithelial tumors and SET because of favorable R0 resection rates and recurrence rates. However, the ESD group showed shorter procedure times and hospital stays than the TEM group. Therefore, ESD should be considered more preferentially than TEM in the treatment of large rectal epithelial tumors and SET.

Prostanoid EP3 receptor agonist sulprostone enhances pacemaker activity of colonic interstitial cells of Cajal.

EP receptor activation by PGE2 regulates gastrointestinal motility by modulating smooth muscle contractility. Interstitial cells of Cajal (ICCs) are pacemaker cells that regulate smooth muscle activity. We aimed to determine effects of the EP3 receptor agonist sulprostone on pacemaker potentials in colonic ICCs. We performed a whole cell patch clamp, RT-PCR, and Ca2+ imaging in cultured ICCs from mouse colon. Sulprostone depolarized the membrane and increased pacemaker frequency. EP3 receptor antagonist blocked these sulprostone-induced effects. EP3 receptors were expressed in ANO1-positive ICCs. Phospholipase C inhibitor or Ca2+-ATPase inhibitor from the endoplasmic reticulum blocked the sulprostone-induced effects and sulprostone increased intracellular Ca2+ ([Ca2+]i) oscillations. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blockers also suppressed the sulprostone-induced effects. Sulprostone enhanced pacemaker activity through EP3 receptors by activating HCN channels via the [Ca2+]i release pathway. Therefore, EP3 receptor activation in ICCs may modulate colonic motility and could be a therapeutic target for enhancing colonic GI motility.

ATP-sensitive K+ channels maintain resting membrane potential in interstitial cells of Cajal from the mouse colon.

To investigate the role of ATP-sensitive K+(KATP) channels on pacemaker activity in interstitial cells of Cajal (ICC), whole-cell patch clamping, RT-PCR, and intracellular Ca2+([Ca2+]i) imaging were performed in cultured colonic ICC. Pinacidil (a K+ channel opener) hyperpolarized the membrane and inhibited the generation of pacemaker potential, and this effect was reversed by glibenclamide (a KATP channel blocker). RT-PCR showed that Kir 6.1 and SUR2B were expressed in Ano-1 positive colonic ICC. Glibenclamide depolarized the membrane and increased pacemaker potential frequency. However, 5-hydroxydecanoic acid (a mitochondrial KATP channel blocker) had no effects on pacemaker potentials. Phorbol 12-myristate 13-acetate (PMA; a protein kinase C activator) blocked the pinacidil-induced effects, and PMA alone depolarized the membrane and increased pacemaker potential frequency. Cell-permeable 8-bromo-cyclic AMP also increased pacemaker potential frequency. Recordings of spontaneous intracellular Ca2+([Ca2+]i) oscillations showed that glibenclamide increased the frequency of [Ca2+]i oscillations. In small intestinal ICC, glibenclamide alone did not alter the generation of pacemaker potentials, and Kir 6.2 and SUR2B were expressed in Ano-1 positive ICC. Therefore, KATP channels in colonic ICC are activated in resting state and play an important role in maintaining resting membrane potential.

Coffee consumption is associated with lower serum aminotransferases in the general Korean population and in those at high risk for hepatic disease.

BACKGROUND AND OBJECTIVES: The favourable effects of coffee on liver enzymes have been reported worldwide. This study investigated the association between coffee consumption and serum aminotransferase concentration in Korean adults. METHODS AND STUDY DESIGN: Data were obtained from the fourth and fifth Korea National Health and Nutrition Examination Surveys. Elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentration were defined as >30 IU/L for men and >19 IU/L for women. The risk of elevated ALT and AST according to general characteristics and frequency of coffee consumption were tested by chi-square tests and multiple logistic regression analyses. RESULTS: The prevalence of elevated ALT was 27.4%, 27.8%, and 26.9% in subjects who drank <1, 1, and >=2 times/day, respectively. The proportions of individuals with elevated AST were 32.5%, 33.1%, and 26.7% in subjects who drank <1, 1, and >=2 times/day, respectively. The aORs for elevated ALT and AST were significantly lower in subjects who drank >=2 times of coffee/day than in those who drank <1 time/day (ALT: aOR=0.86, 95% CI=0.79-0.94; AST: aOR=0.83, 95% CI=0.76-0.91). In subgroup analysis, consumption of >=2 times/day was associated with lower ORs for elevated ALT in the high-risk group overall and in the viral hepatitis and obesity subgroups, respectively. In sensitivity analysis, reduced frequency of coffee consumption was associated with an increased risk for elevated liver enzymes, although an association between coffee consumption and elevated ALT was not observed in women or current smokers. CONCLUSIONS: Higher coffee consumption was associated with lower risk of elevated aminotransferase concentration in Korean adults.

Regulation of the Pacemaker Activity of Colonic Interstitial Cells of Cajal by Protease-Activated Receptors: Involvement of Hyperpolarization-Activated Cyclic Nucleotide Channels.

BACKGROUND AND PURPOSE: The exact mechanism of protease-activated receptors (PARs) on pacemaker activity of interstitial cells of Cajal (ICCs) has not been reported. We investigated the effects on pacemaker activity by the activation of PARs and its signal mechanisms in colonic ICCs. METHODS: The whole-cell patch-clamp technique, RT-PCR and Ca2+ imaging were used in cultured ICCs from mouse colon. RESULTS: PAR-1 and PAR-2 were expressed in Ano-1 positive ICCs. TFLLR-NH2 (a PAR-1 agonist) and trypsin (a PAR-2 agonist) depolarized the membrane and increased the pacemaker potential frequency. U-73122 (a phospholipase C (PLC) inhibitor) and thapsigargin (a Ca2+ ATPase inhibitor) suppressed the TFLLR-NH2- and trypsin-induced effects on pacemaker potential. TFLLR-NH2 and trypsin also increased intracellular Ca2+ ([Ca2+]i) intensity with increasing of Ca2+ oscillations. Genistein (a tyrosine kinase inhibitor), SP600125 (a JNK inhibitor), CsCl, ZD7288, clonidine (hyperpolarization-activated cyclic nucleotide (HCN) channel blockers), SQ-22536 and dideoxyadenosine (adenylate cyclase inhibitors) suppressed the increased pacemaker potential frequency without effects on depolarization of the membrane induced by TFLLR-NH2 and trypsin. CONCLUSION: These results suggest that activation of PAR-1 and PAR-2 modulates the pacemaker activity of colonic ICCs through the PLC-dependent [Ca2+]i release pathway. The increased pacemaker potential frequency by PAR-1 and PAR-2 was also dependent on tyrosine kinase, JNK, and HCN activation.

The Correlation of Endoscopic Findings and Clinical Features in Korean Patients with Scrub Typhus: A Cohort Study.

Scrub typhus is an infectious disease caused by Orientia tsutsugamushi-induced systemic vasculitis, but the involvement of the gastrointestinal tract and the endoscopic findings associated with scrub typhus are not well understood. We performed a prospective study and recommend performing esophagogastroduodenoscopy (EGD) for all possible scrub typhus patients, regardless of gastrointestinal symptoms. Gastrointestinal symptoms, endoscopic findings and clinical severity based on organ involvement and ICU admission were analyzed. Gastrointestinal symptoms occurred in up to 76.4% of scrub typhus patients. The major endoscopic findings were ulcers (43/127, 33.9%). Interestingly, 7.1% (9/127) of the patients presented with esophageal candidiasis. There was no correlation between the presence or absence of gastrointestinal symptoms and the endoscopic grade (P = 0.995). However, there was a positive correlation between the clinical severity and the endoscopic findings (P = 0.001). Sixty-three percent of the patients presented with erosion or ulcers on prospectively performed endoscopic evaluations, irrespective of gastrointestinal symptoms. Gastrointestinal symptoms did not reflect the need for endoscopy. Scrub typhus patients could have significant endoscopic abnormalities even in the absence of gastrointestinal symptoms.

Regulatory Roles of Endogenous Mitogen-Activated Protein Kinases and Tyrosine Kinases in the Pacemaker Activity of Colonic Interstitial Cells of Cajal.

BACKGROUND AND PURPOSE: Mitogen-activated protein (MAP) and tyrosine kinases play an important role in regulating smooth muscle contraction of the gastrointestinal (GI) tract. Interstitial cells of Cajal (ICCs) are pacemaker cells that regulate GI smooth muscle activity. Thus, the role of MAP and tyrosine kinases on the pacemaker potentials of colonic ICCs was investigated. METHODS: Cultured ICCs were prepared from mice colons, and their pacemaker potentials were recorded using whole-cell patch clamping. RESULTS: In current-clamping mode, colonic ICCs displayed spontaneous pacemaker potentials. SB203580 (a p38 MAP kinase inhibitor), SP600125 (a c-jun NH2-terminal kinase (JNK) inhibitor), genistein and herbimycin A (tyrosine kinase inhibitors) blocked the generation of pacemaker potentials. However, PD98059 (a p42/44 MAP kinase inhibitor) had no effects on pacemaker potentials. LY-294002 (phosphoinositide 3-kinase inhibitor) also reduced the pacemaker potential frequency but calphostin C and chelerythrine (protein kinase C inhibitors) had no effects. However, PD98059, SB203589, SP600125, genistein, herbimycin A, LY-294002, and calphostin C had no effect on normal pacemaker activity in small intestinal ICCs. CONCLUSIONS: Endogenous p38 MAP kinases, JNKs, tyrosine kinases, and PI3-kinases participate in the generation of pacemaker potentials in colonic ICCs but not in ICCs of the small intestine.

Double primary hepatic cancer (sarcomatoid carcinoma and hepatocellular carcinoma): A case report.

Primary liver sarcomatoid carcinoma (SC) is a rare and aggressive tumor exhibiting rapid growth and a high recurrence rate following resection. To date, there have been no reports of primary liver SC occurring simultaneously with hepatocellular carcinoma (HCC). This is the case report of a 54-year-old man with liver cirrhosis due to hepatitis B virus (HBV) infection and alcoholic hepatitis. The abdominal computed tomography and magnetic resonance imaging revealed two distinct hepatic masses in a background of hepatic cirrhosis and esophageal varices. Following a clinical diagnosis of two HCCs, a right hepatic lobectomy was performed. Grossly, two distinct lesions were identified: the larger mass was gray to white and well-demarcated, sized 2.5×2.0 cm, located in S5-6, whereas the other was a gray to whitish nodule, sized 1.3×1.0 cm, located in S8. The microscopic analysis revealed that the larger mass was a primary liver SC, which was immunoreactive for cytokeratin (CK) and vimentin (VMT) and negative for hepatocyte-specific antigen (HSA). The other nodule was histologically diagnosed as HCC, which was positive for HSA and CK and negative for HSA, VMT, CK7 and CK19. There was no transition or intermingling lesion between the two tumors. To the best of our knowledge, this is the first case report of double primary liver cancer comprising an SC and a HCC.

Peritonsillar Involvement in Pyoderma Gangrenosum associated with Ulcerative Colitis.

Peritonsillar abscess is a common deep throat infection. Early diagnosis and prompt, appropriate management of a peritonsillar abscess prevents mortality. A 45-year-old woman on steroids for an ulcerative colitis (UC) exacerbation presented with sore throat and multiple skin ulcers on her left forearm and right foot. Computed tomography of the neck revealed a peritonsillar abscess. Gram staining and culture of the abscess were negative, and a skin biopsy suggested pyoderma gangrenosum (PG). The final diagnosis was peritonsillar involvement of steroid-refractory PG-associated UC. The patient showed a complete response to infliximab. Here, we report a case of successful infliximab treatment for peritonsillar involvement of steroid-refractory PG-associated UC.

A nationwide seroepidemiology of hepatitis C virus infection in South Korea.

BACKGROUND & AIMS: The aim of this study was to reveal nationwide seroprevalence of HCV infection in South Korea by a large-scale survey. METHODS: From January to December 2009, a total of 291 314 adults underwent health check-up in 29 centres nationwide. The data concerning anti-HCV antibody and biochemical tests were obtained from all participants. Among subjects with positive anti-HCV, such data as HCV RNA, genotypes and treatment detail were additionally analysed. RESULTS: Using an estimated 2009 population of Korea, the age, sex and area-adjusted anti-HCV positive rate was 0.78%. Anti-HCV prevalence in female patients (0.83%) was higher than that in male patients (0.75%). Gradual increase in anti-HCV positivity was observed, from 0.34% in those aged 20-29 years to 2.31% in those >70 years. The age- and sex-adjusted anti-HCV prevalence varied in different areas, being higher in Busan and Jeonnam (1.53-2.07%), mid-level in Seoul and surrounding districts (0.50-0.61%) and lower in Jeju (0.23%). The comparative analysis of laboratory variables between anti-HCV (+) and anti-HCV (-) group revealed significantly higher levels of alanine aminotransferase and lower levels of serum lipids in anti-HCV (+) group. Among 1 718 anti-HCV positive subjects, serum HCV RNA was measured only in 478 people, of whom 268 (56.1%) patients had detectable HCV RNA in serum. Among 50 patients for whom assessment of response to antiviral therapy was feasible, overall sustained virological response was achieved in 84% of patients. CONCLUSION: The prevalence of HCV infection is low in South Korea. Studies to analyse risk factors are warranted to reduce HCV infection.

A comparative study of hepatitis caused by scrub typhus and viral hepatitis A in South Korea.

We compared clinical features and laboratory findings of 104 patients with hepatitis A and 197 patients with scrub typhus. Nausea, vomiting, abdominal pain, hepatomegaly, and jaundice were common in patient with hepatitis A, and fever and headache were significantly more common in patients with scrub typhus. At presentation, an alanine aminotransferase (ALT) level ≥ 500 U/L was observed in 1% of scrub typhus patients and in 87.5% of hepatitis A patients (P < 0.001). A bilirubin level ≥ 1.3 mg/dL was observed in 16.8% of scrub typhus patients and 90.4% of hepatitis A patients. The ALT:lactate dehydrogenase ratio was ≤ 5 in 97.4% of the patients with scrub typhus and > 5 in 95.2% of those with hepatitis A (P < 0.001). Fever, headache, rash, and eschar are findings that indicate scrub typhus. An ALT level ≥ 500 U/L (adjusted odds ratio = 0.011) a bilirubin level ≥ 1.3 (adjusted odds ratio = 0.024), an ALT:lactate dehydrogenase ratio > 5, and hepatomegaly are indications of viral hepatitis A.

[The effect of proton pump inhibitor on healing of post-esophageal variceal ligation ulcers].

BACKGROUND/AIMS: Esophageal variceal ligation (EVL) is the most preferable method for controlling variceal bleeding. However, EVL is associated with complications such as hemorrhage, chest pain, dysphagia, and odynophagia due to post-EVL ulcers in the esophageal mucosa. The aim of this study was to assess the effect of proton pump inhibitor (PPI), pantoprazole on the healing of post-EVL ulcers. METHODS: Forty seven patients were randomly allocated into PPI group and control group. Patients in PPI group received 40 mg of pantoprazole intravenously for 3 days after EVL, then 40 mg of oral pantoprazole for 11 days consecutively. Control patients received intravenous and oral placebo. Endoscopic examinations were performed twice at 7+/-2 days and 14+/-2 days after EVL respectively. Clinical outcomes include the size of ulcers, symptoms reported by patients; chest pain, dysphagia, and odynophagia. RESULTS: Forty seven patients completed the 7 days protocol (PPI/control; 25/22), and twenty six patients completed the 14 days protocol (PPI/control; 16/10). Post-EVL ulcers in PPI group were significantly smaller than those in control group (7 days; 98.7 mm2/119.4 m2, 14 days; 32.3 m2/43.8 m2, p<0.01). No difference was observed between two the groups with respect to summations of symptom scores (p> 0.05). Nineteen patients (PPI/control; 9/10) did not complete the 14 days protocol due to patients' refusal and adverse outcomes, such as hepatic failure and sepsis with bleeding from post-EVL ulcer occurred in two patients of control group. CONCLUSIONS: PPI treatment following EVL may be effective in healing post-EVL ulcer.

[Effects of tamoxifen on the voltage-dependent ionic currents in mouse colonic smooth muscle cells].

BACKGROUND/AIMS: Tamoxifen is a widely used anticancer drug for breast cancer with frequent gastrointestinal side effects. Changes in gastrointestinal motility is associated with altered activities of membrane ion channels. Ion channels have important role in regulating membrane potential and cell excitability. This study was performed to investigate the effects of tamoxifen on the membrane ionic currents in colonic smooth muscle cells. METHODS: Murine colonic smooth muscle cells were isolated from the proximal colon using collagenase, and the membrane currents were recorded using a whole-cell patch clamp technique. RESULTS: Two types of voltage-dependent K(+) currents were recorded (A-type and delayed rectifier K(+) currents). Tamoxifen inhibited both types of voltage-dependent K(+) currents in a dose-dependent manner. However, tamoxifen did not change the half-inactivation potential and the recovery time of voltage-dependent K(+) currents. Chelerythrine, a protein kinase C inhibitor or phorbol 12, 13-dibutyrate, a protein kinase C activator did not affect the voltage-dependent K(+) currents. Guanosine 5'-O-(2-thio-diphosphate) did not affect the tamoxifen-induced inhibition of voltage-dependent K(+) currents. Tamoxifen inhibited voltage-dependent Ca(2+) currents completely in whole-test ranges. CONCLUSIONS: These results suggest that tamoxifen can alter various membrane ionic currents in smooth muscle cells and cause some adverse effects on the gastrointestinal motility.

[Characterization of pacemaking currents in cultured interstitial cells of Cajal from mice small intestine].

BACKGROUND/AIMS: Gastrointestinal motility is initiated by the periodic generation of slow waves. Interstitial cells of Cajal (ICC) are pacemaker cells that generate slow waves and drive spontaneous mechanical contractions of the gastrointestinal smooth muscle. Slow waves generate the periodic activation of spontaneous inward currents (pacemaker currents). The aim of this study was to investigate the characterization of pacemaker currents of ICC. METHODS: The ICC in mice small intestine were cultured with stem cell factor for 2 days, and then we recorded pacemaker currents and slow waves using a whole-cell patch clamp technique. RESULTS: Under voltage clamp at -80 mV of holding potential, ICC generated pacemaker currents. Tetrodotoxin and nifedipine did not affect on the pacemaker currents. In addition, tetraethylammonium, 4-aminopyridine and glibenclamide did not affect on the pacemaker currents. The reduction of external Na+ concentrations inhibited pacemaker currents. Moreover, these currents were completely abolished in the external Ca2+-free condition. Gadolinium and flufenamic acid, inhibitors of non-selective cationic currents, inhibited pacemaker currents. Thapsigargin and cyclopiazoic acid, inhibitors of Ca2+-ATPase in endoplasmic reticulum, abolished pacemaker currents. Carbachol depolarized membrane potential and increased inward currents. CONCLUSIONS: These results suggest that pacemaker currents are mediated by the activation of non-selective cation channel and become a target of neurotransmitters in regulation of intestinal motility.