A Multi-Center, Double-Blind Randomized Controlled Phase III Clinical Trial to Evaluate the Antiviral Activity and Safety of DA-2802 (Tenofovir Disoproxil Orotate) and Viread (Tenofovir Disoproxil Fumarate) in Chronic Hepatitis B Patients

Background@#Tenofovir disoproxil fumarate (TDF, Viread® ) had been used as a standard treatment option of chronic hepatitis B (CHB). This clinical trial was conducted to evaluate the efficacy and safety of DA-2802 (tenofovir disoproxil orotate) compared to TDF. @*Methods@#The present study was a double blind randomized controlled trial. Patients with CHB were recruited from 25 hospitals in Korea and given DA-2802 at a dose of 319 mg once daily or Viread® at a dose of 300 mg once daily for 48 weeks from March 2017 to January 2019. Change in hepatitis B virus (HBV) DNA level at week 48 after dosing compared to baseline was the primary efficacy endpoint. Secondary efficacy endpoints were proportions of subjects with undetectable HBV DNA, those with normal alanine aminotransferase (ALT) levels, and those with loss of hepatitis B envelop antigen (HBeAg), those with loss of hepatitis B surface antigen (HBsAg). Adverse events (AEs) were also investigated. @*Results@#A total of 122 patients (DA-2802 group: n = 61, Viread® group: n = 61) were used as full analysis set for efficacy analysis. Mean age, proportion of males, laboratory results and virologic characteristics were not different between the two groups. The change in HBV DNA level at week 48 from baseline was −5.13 ± 1.40 in the DA-2802 group and −4.97 ± 1.40 log 10 copies/mL in the Viread® group. The analysis of primary endpoint using the nonparametric analysis of covariance showed statistically significant results (P < 0.001), which confirmed non-inferiority of DA-2802 to Viread® by a prespecified noninferiority margin of 1. The proportion of undetectable HBV DNA was 78.7% in the DA-2802 group and 75.4% in the Viread® group (P = 0.698). The proportion of subjects who had normal ALT levels was 75.4% in the DA-2802 group and 73.3% in the Viread® group (P = 0.795). The proportion of those with HBeAg loss was 8.1% in the DA-2802 group and 10.8% in the Viread® group (P = 1.000). No subject showed HBsAg loss. The frequency of AEs during treatment was similar between the two groups. Most AEs were mild to moderate in severity. @*Conclusion@#DA-2802 is considered an effective and safe treatment for patients with CHB.

Effectiveness of Albumin-bilirubin Score as a Predictor of Post-hepatectomy Liver Failure in Patients with Hepatocellular Carcinoma / 대한소화기학회지

Background/Aims@#Post-hepatectomy liver failure (PHLF) is a major concern for patients with hepatocellular carcinoma (HCC) who have undergone liver resection. The albumin-bilirubin (ALBI) score is a novel model for assessing liver function. We aimed to investigate the effectiveness of the ALBI score as a predictor of PHLF in HCC patients who have undergone hepatectomy in South Korea. @*Methods@#Between January 2014 and November 2018, HCC patients who underwent hepatectomy and indocyanine retention rate at 15 min (ICG-R15) test were enrolled in this study. @*Results@#A total of 101 patients diagnosed with HCC underwent hepatectomy. Thirty-two patients (31.7%) experienced PHLF. The ALBI score (OR 2.83; 95% CI 1.22-6.55; p=0.015), ICG-R15 (OR 1.07; 95% CI 1.02-1.12; p=0.007) and ALBI grade (OR 2,86; 95% CI 1.08-7.58; p=0.035) were identified as independent predictors of PHLF by multivariable analysis. The area under the receiver operating characteristic curve of the ALBI score and ICG-R15 were 0.676 (95% CI 0.566-0.785) and 0.632 (95% CI 0.513-0.752), respectively. The optimal cutoff value of the ALBI score in predicting PHLF was -2.62, with a sensitivity of 75.0% and a specificity of 56.5%. @*Conclusions@#The ALBI score is an effective predictor of PHLF in patients with HCC, and its predictive ability is comparable to that of ICG-R15.

Gallbladder Perforation after Transarterial Chemoembolization in a Patient with a Huge Hepatocellular Carcinoma / 대한소화기학회지

Transarterial chemoembolization (TACE) is a common treatment for unresectable hepatocellular carcinoma (HCC). The most common complications after TACE are non-specific symptoms called post-embolization syndrome, such as abdominal pain or fever. Rare complications, such as liver failure, liver abscess, sepsis, pulmonary embolism, cholecystitis, can also occur. On the other hand, gallbladder perforation is quite rare. This paper reports a case of gallbladder perforation following TACE. A 76-year-old male with a single 9-cm-sized HCC underwent TACE. Five days after TACE, he developed persistent right upper quadrant pain and ileus. An abdomen CT scan confirmed gallbladder perforation with bile in the right paracolic gutter and pelvic cavity. Percutaneous transhepatic gallbladder drainage was performed with the intravenous administration of antibiotics. After 1 month, the patient underwent right hemihepatectomy and cholecystectomy. Physicians should consider the possibility of gallbladder perforation, which is a rare complication after TACE, when unexplained abdominal pain persists.

Capsanthin Inhibits both Adipogenesis in 3T3-L1 Preadipocytes and Weight Gain in High-Fat Diet-Induced Obese Mice

Adipogenesis in murine preadipocyte 3T3L-1 has been used as a model system to study anti-obese bioactive molecules. During adipogenesis in 3T3-L1 preadipocytes, we found that capsanthin inhibited adipogenesis (IC₅₀; 2.5 μM) and also showed lipolytic activity in differentiated adipocytes from the preadipocytes (ED₅₀ ; 872 nM). We identified that the pharmacological activity of capsanthin on adipogenesis in 3T3-L1 was mainly due to its adrenoceptor-β2-agonistic activity. In high-fat diet animal model study, capsanthin significantly enhanced spontaneous locomotive activities together with progressive weight-loss. The capsanthin-induced activation of kinetic behavior in mice was associated with the excessive production of ATP initiated by both the enhanced lipolytic activity together with accelerated oxidation of fatty acids due to the adrenoceptor β2-agonistic activity of capsanthin. Capsanthin also dose-dependently increased adiponectin and p-AMPK activity in high fat diet animals, suggesting that capsanthin has both anti-obesity and insulin sensitizing activities.

Barriers to treatment of failed or interferon ineligible patients in the era of DAA: single center study

BACKGROUND/AIMS: Interferon-based treatment is not appropriate for a large number of patients with chronic hepatitis C for various medical and social reasons. Newly developed directly acting antivirals (DAAs) have been used to treat chronic hepatitis C without severe adverse effects and have achieved a sustained viral response (SVR) rate of 80-90% with short treatment duration. We were interested to determine whether all patients who failed to respond to or were ineligible for interferon-based therapy could be treated with DAAs. METHODS: Medical records of patients with positive serum anti-hepatitis C virus (HCV) or HCV RNA between January 2009 and December 2013 were reviewed. Demographic, clinical, and treatment data were collected for analysis. RESULTS: A total of 876 patients were positive for both anti-HCV and HCV RNA. Of these, 244 patients were eligible for interferon, although this was associated with relapse in 39 (16%) of patients. In total, 130 patients stopped interferon therapy (67% adverse effects, 28% non-adherent, 4% malignancy, 1% alcohol abuse) and 502 patients were ineligible (66% medical contraindications, 25% non-adherent, 5% socioeconomic problems). Among 671 patients who were ineligible for or failed to respond to interferon therapy, more than 186 (27.7%) could not be treated with DAA due to financial, social, or cancer-related conditions. CONCLUSIONS: Newly developed DAAs are a promising treatment for patients with chronic hepatitis C who are ineligible for or failed to respond to interferon-based therapy. Nevertheless, not all chronic hepatitis C patients can be treated with DAAs due to various reasons.

A Case of Improved Leukocytoclastic Vasculitis after Successful Treatment of Hepatocellular Carcinoma and Membranous Obstruction of Inferior Vena Cava

Vasculitis is a heterogeneous group of diseases that destroy blood vessel walls by inflammation. Approximately half of vasculitis cases are idiopathic, but sometimes associated with genetic factors, medicines, chronic infection, autoimmune diseases, and malignancies. Although the mechanism remains unclear, vasculitis secondary to malignancy, also known as paraneoplastic vasculitis, has been reported. It is generally associated with hematologic malignancies rather than solid malignancies and commonly presents as leukocytoclastic vasculitis or polyarteritis nodosa. We experienced a case of leukocytoclastic vasculitis in a patient with hepatocellular carcinoma and membranous obstruction of the inferior vena cava. Here, we report this case with a brief review of literature.

Hepatitis C virus (HCV) genotypes and the influence of HCV subtype 1b on the progression of chronic hepatitis C in Korea: a single center experience

BACKGROUND/AIMS: There is some controversy regarding whether or not hepatitis C virus (HCV) subtype 1b is more influential than non-1b subtypes on the progression of chronic hepatitis (CH) C to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). METHODS: We retrospectively analyzed 823 patients with chronic HCV infection, including 443 CH patients, 264 LC patients, and 116 HCC patients, who were HCV RNA positive and HBsAg negative. These patients had not received any prior treatment with either interferon alone or a combination of interferon and ribavirin. RESULTS: HCV subtypes 1b (51.6%) and 2a/2c (39.5%) were the two most common genotypes. The proportions of genotypes 2 (2a/2c, 2b, and 2) and 3 were 45.8% and 1.1%, respectively. One case of genotype 4 was found. HCV subtype 1b (47.3%) was less common than the non-1b subtypes (52.7%) in non-LC patients, but its proportion (56.9%) was higher than that of non-1b subtypes (43.1%) in LC patients (P=0.006). The proportions of patients with HCV subtype 1b did not differ significantly between the LC (55.3%) and HCC (60.3%) groups. Older age, male gender, and the relative progression of liver damage (non-LC vs. compensated LC vs. decompensated LC) were significant risk factors for HCC, with odds ratios of 1.081 (95% confidence interval [CI], 1.056-1.106), 5.749 (95% CI, 3.329-9.930), and 2.895 (95% CI, 2.183-3.840), respectively. HCV subtype 1b was not a significant risk factor for HCC (odds ratio, 1.423; 95% CI, 0.895-2.262). CONCLUSIONS: HCV subtypes 1b and 2a/2c were the two most common HCV genotypes. HCV subtype 1b seemed to be more influential than non-1b subtypes on the progression of CH to LC, but not on the development of HCC from LC.

Mucinous cystadenoma of the liver with ovarian-like stroma: the need for complete resection / 대한외과학회지

Cystadenoma of the liver is a rare neoplasm. Although many cystadenomas are asymptomatic, symptoms can include abdominal pain, postprandial epigastric discomfort, and nausea. Dramatic changes in hepatic imaging techniques have been helpful for diagnosing cystic lesions of the liver, such as simple cyst, hydatid cyst, cystadenoma, cystadenocarcinoma, and metastatic neuroendocrine tumors. However, it remains difficult to differentiate cystadenoma from cystadenocarcinoma for multiseptated cystic hepatic lesions with papillary projection on computed tomography (CT) and magnetic resonance imaging (MRI). Here we report the case of a 47-year-old woman with several months of postprandial discomfort and abdominal fullness. CT and MRI revealed multiseptated cystic lesions with papillary excrescences. A left hemihepatectomy was performed. Histology showed a benign mucinous cystic tumor with ovarian-like stroma.

The Efficacy of Antiviral Agents in Patients with Hepatitis B-related Liver Cirrhosis / 고신대학교의과대학학술지

OBJECTIVES: Improvement of liver synthetic function and the incidence of complication in the patients with hepatitis B-related liver cirrhosis is important. In this study, we study whether antiviral therapy was effective in patients with hepatitis B-related liver cirrhosis. METHODS: 103 patients with hepatitis B-related liver cirrhosis treated with lamivudine 100mg daily over 6 months and followed up over 30 months. 71 patients were positive for serum HBeAg. HBeAg, HBV DNA , CBC, prothrombin time, biochemistry, ultrasonography and endoscopy were tested every 6 months. RESULTS: The medians of ALT, albumin improved after 6 months and then aggravated after 18 months, but they didn't aggravated at 30 months compared with initial test. The median of Child-turcotte-pugh (CTP) score imporved after 6 months and then aggravated after 12 months, but they didn't aggravated at 30 months compared with initial test. The CTP score improved (2 point reduction) in 29 patients. The finding of ultrasonography didn't aggravaed (improved or didn't changed) in 58 patients. The 5 year incidence rate of hepatocelluar carcinoma was 8.3%. CONCLUSIONS: The antiviral therapy in patients with hepatitis B-related liver cirrhosis is improved CTP score and biochmical data. The improvement is more useful in decompensated cirrhosis the compensated cirrhosis. The incidence of hepatocellular carcinoma decreases than other studies. Therefore, the antiviral medication in patients with hepatitis B-related liver cirrhosis is helpful to consider more aggressively.

Two Cases of Autoimmune Hepatitis Accompanied by Connective Tissue Diseases / 대한내과학회지

Autoimmune hepatitis is a generally progressive chronic hepatitis of unknown etiology. Systemic lupus erythematosus (SLE) and Sjogren's syndrome are chronic, multifaceted inflammatory diseases that can affect every organ system, although hepatic involvement is rare. Here, we report two rare cases: autoimmune hepatitis associated with SLE and with primary Sjogren's syndrome. A 52-year-old woman and a 60-year-old woman were admitted our hospital with jaundice and pruritus. They had no history of viral hepatitis, alcohol consumption, or drug use. The pathological findings, clinical manifestations, and laboratory findings satisfied each of the diagnostic criteria for autoimmune hepatitis as well as for SLE and Sjogren's syndrome in the first and second cases, respectively. These patients were treated with prednisolone, and then followed regularly.

A left-sided gallbladder accompanying atrophy of the lateral inferior segment of the liver / 대한내과학회지

A left-sided gallbladder occurring in the absence of situs inversus is a rare anomaly. This anomaly was found in a 50-year-old man without any evidence of pancreatobiliary disease. Epigastric transverse ultrasonography showed a normal gallbladder with its fundus extending past the left lateral end of the liver. Abdominal computed tomography (CT) revealed that the gallbladder was located beneath the quadrate lobe (S4) of the liver to the left of the left branch of the portal vein, and S4 was hypertrophied to compensate for atrophy of the lateral inferior segment (S3) of the liver. Magnetic resonance cholangiopancreatography (MRCP) showed that the gallbladder and pancreatobiliary tree were normal, and that the cystic duct joined the common bile duct from the right side making a characteristic U-shaped hairpin bend.

A Case of Pancreatic Dual Wirsung Ducts in a Patient with von Hippel-Lindau Disease / 대한소화기내시경학회지

Rare autosomal dominant disorders associated with various tumors and cysts, and several kinds of pancreatic lesions have been described in patients with von Hippel- Lindau (VHL) disease, but there have been few studies concerned with the variations of the pancreatic duct. We experienced a case of pancreatic dual Wirsung ducts in a patient with VHL disease. Computed tomography scans showed that multiple cysts had nearly completely replaced the pancreas, there was a solid tumor on the uncinate process of the pancreas and a left renal mass suggested renal cell carcinoma. ERCP shows that the Santorini duct and Wirsung duct were fused in a normal fashion, and another Wirsung duct had shrub-like branches that are commonly seen in pancreatic divisum.

Self-Expandable Polytetrafluoroethylene (PTFE)-covered Nitinol Stent for the Palliative Treatment of Malignant Biliary Obstruction

PURPOSE: We wanted to determine the technical and clinical efficacy of placing a self-expandable PTFE-covered nitinol stent for the management of inoperable malignant biliary obstruction. MATERIALS AND METHODS: Thirty six patients with inoperable malignant biliary obstructions were treated by placement of self-expandable PTFE-covered nitinol stents (S & G Biotech Corporation, Seongnam, Korea). Clinical evaluation was done with assessment of the serum bilirubin and alkaline phosphatase levels, which were measured before and after stent placement within 1 week, at 1 month and at 3 months. The patient survival rate and stent patency rate were calculated with performing Kaplan-Meier survival analysis. RESULTS: Successful stent placement was achieved in all the patients without procedure-related complication. Pancreatitis as an early complication occurred in two cases. The serum bilirubin and alkaline phosphatase levels were significantly decreased after the procedure. During the follow-up, recurrent obstructive jaundice occurred in six cases; stent migration occurred in four cases and tumor overgrowth occurred in two cases. The survival rates were 97%, 80%, 67% and 59% at 1, 3, 6 and 9 months, respectively. The stent patency rates were 96%, 92%, 86% and 86% at 1, 3, 6 and 9 months, respectively. CONCLUSION: Self-expandable PTFE-covered nitinol stent placement seems to be technically feasible and effective for the palliative treatment of malignant biliary obstruction.

A Case of Complete Agenesis of the Dorsal Pancreas / 대한소화기내시경학회지

The pancreas with the complete absence of its body and tail is the result of underdevelopment or agenesis of the dorsal pancreatic bud during embryogenesis, and this is a rare anomaly. We report here on a case of a 38-year-old man who had a pancreas with the total absence of the body and tail. On the abdominal computed tomography (CT), only a pancreatic head portion with speckled calcifications was seen, and the pancreatic body and tail were not visualized at all. Endoscopic retrograde cholangiopancreatography (ERCP) showed only a short major pancreatic duct with smooth tapering and terminal arborization. The Ampulla of Vater had a normal appearance and it was located at the medial side of the second portion of the duodenum. There was no difficulty to perform cannulation. Any minor papilla was not found. On magnetic resonance cholangiopancreatography (MRCP), the duct of Santorini and the duct in the body and tail were not visualized.

The Clinical Meaning of the Emergence of Viral Breakthrough during Lamivudine Treatment in Patients with Hepatitis B Virus Related Chronic Liver Disease / 대한간학회지

BACKGROUND/AIMS: Viral breakthrough has been considered a major limitation of lamivudine in the treatment of hepatitis B virus related chronic liver disease. Its clinical meaning has not been thoroughly assessed. METHODS: 64 patients who showed viral breakthrough during lamivudine treatment were retrospectively reviewed. We evaluated the rate of HBeAg seroconversion and hepatic decompensation after viral breakthrough. RESULTS: After viral breakthrough, serum alanine transaminase (ALT) elevation more than 1.2X upper limit of normal (ULN) was noticed in 40 patients (62.5%). Acute flare (serum ALT elevation >X5 ULN, or serum bilirubin >3 mg/dL) occured in 15 patients (23.4%). During the period of follow up (15.0 +/- 9.7 months; range, 0-31 months) since viral breakthrough, decreased serum HBV-DNA level to below the detection limit and serum ALT normalization was seen in 15 patients (23.4%). HBeAg seroconversion was noticed in 7 (13.7%) of a total of 51 HBeAg positive patients at base line; in 4 (15.4%) of 26 patients with non-hepatic failure (chronic hepatitis or Child-Pugh class A liver cirrhosis) at base line; and in 2 (40.0%) of 5 patients with non-hepatic failure at base line and acute flare after viral breakthrough. During this period, terminal hepatic decompensation (Child-Pugh class C) or death was noticed in 9 (90.0%) of 10 patients who had hepatic decompensation (Child-Pugh class B or C) at baseline and acute flare after viral breakthrough. CONCLUSIONS: Acute flare after viral breakthrough seemed to continue during HBeAg seroconversion and rarely developed into terminal hepatic decompensation or death in patients with non-hepatic decompensation at baseline. Its incidence is not only high but lethal to most patients with hepatic decompensation at baseline.

A Case of Bile Duct Cancer Arising in Choledochal Cyst in a 13-Year-Old Girl / 대한소화기내시경학회지

Choledochal cyst, also referred to as cystic dilatation of the extrahepatic bile duct, is a rare malformation most frequently seen in female. Malignant changes in choledochal cyst have frequently been described, but only one case of malignant change in childhood has been reported till now. Recently, we experienced a case of bile duct cancer arising in choledochal cyst in a 13-year-old girl. She had been complaining of right upper abdominal pain for 15 days. Abdominal CT scan and ERCP showed a cylindrical dilatation of extrahepatic bile duct with irregular cystic wall mass and multiple liver metastasis which was confirmed as adenocarcinoma by ultrasono-guided needle biopsy. Anomalous pancreaticobiliary ductal union was not seen. This patient was the youngest case of bile duct carcinoma arising in choledochal cyst in Korea.

A Case of Obstructive Jaundice Caused by Extrinsic Compresson of Biliary Cystadenoma of the Common Hepatic Duct / 대한소화기내시경학회지

Biliary cystadenoma is a rare tumor that arises in the liver or, less frequently, in the extrahepatic ducts. Jaundice in patients with biliary cyst adenoma is not uncomon, but it is very rare that the jaundice is caused by tumor compression of the bile duct. A 43-year-old woman who had a huge biliary cystadenoma occupying the left liver developed deep jaundice. Endoscopic retrograde cholangiopancreatograpy demontrated that this tumor compressed the common hepatic ducts extrinsically which caused the deep jaundice.

A Case of Isolated-organ Tuberculosis Causing Common Bile Duct Obstruction: Tuberculous periductal lymphadenitis / 대한소화기내시경학회지

The explanation of isolated-organ tuberculosis rests on the assumption that in the course of the lymphatic or hematogenous dissemination of bacilli, organisms may be rapidly destroyed in all other sites save for the particular tissue involved in the isolated tuberculous process. Tuberculosis can arise in all tissues having lymphatics or blood supply, but the disease causing biliary tract obstruction has been known to be rare. Recently, we experi-enced a case of isolated-organ tuberculosis causing common bile duct obstruction and periductal lymph node enlargement in a 46-year-old Korean male. An ultrasonography-guided percutaneous needle biopsy revealed a granulomatous inflammation of the lymph node. After 7 months of anti-tuberculous medication, the common bile duct obstruction and periductal lymph node enlargement disappeared completely in a follow up abdominal CT and ERCP.

Effects of the Sanjoin on the Rat Brain: Focused on Serotonin, Sleeping Time, Sleep EEG and Autonomic Activity

OBJECTS: Sanjoin, the seeds of Zizyphus vulgaris var. spinosus has been used as the most important hypnotic agent in chinese medicine to treat insomnia. This research was performed in order to examine the effect of betulinic acid and sanjoinine-A which are components of Sanjoin. METHOD: Sleeping time, sleep recordings of EEG, serum serotonin level, and locomotor activity were measured in rats which received betulinic acid and sanjoinine-A as sleep induction material extracted from Sanjoin. RESULTS: 1) Groups received betulinic acid, sanjoinine-A, and lorazepam showed increased sleep time than control group with saline. 2) Groups with betulinic acid, sanjoinine-A, lorazepam and saline recorded beta-wave in sleep recording of EEG. In there was no significant difference among all groups. 3) No significant difference in serum serotonin level among all groups was found. 4) In autonomic activity testing, groups of betulinic acid, sanjoinine-A, and lorazepam showed significantly more decreased in activity than saline group. In comparison of groups of betulinic acid and sanjoinine-A with a group of lorazepam, there was no significant difference. CONCLUSION: These results suggests that betulinic acid and sanjoinine-A have the sedative effect like lorazepam rather than sleep effect.

The Double Papilla of Vater / 대한소화기내시경학회지

The common bile duct and the duct of Wirsung cojoin at the level of the duodenum, forming the major. papilla of Vater. Existence of a double major papilla, i.e., two neighboring independent papillary structure:, is infrequent. In our endoscopy unit we have experienced one case of double papilla of Vater wherein canulation of the common bile duct and pancreatic duct could be accom plished through either orifice independently.