Magnetic resonance imaging-based risk factors of hepatocellular carcinoma after direct-acting antiviral therapy: A multicenter observational study.

AIM: To determine risk factors associated with hepatocellular carcinoma (HCC) development following direct-acting antiviral (DAA) therapy. METHODS: We enrolled patients with chronic hepatitis C who underwent direct-acting antiviral therapy and achieved sustained virologic response at 12 weeks between 2012 and 2018. Subsequently, patients were followed up. The primary endpoint was the development of HCC or the date of the last follow up when the absence of HCC was confirmed. Uni- and multivariate Cox proportional hazards models were used to identify factors contributing to HCC development, including gadoxetic acid-enhanced magnetic resonance imaging findings. The cumulative incidence rates of HCC development were calculated using the Kaplan-Meier method, and differences between groups were assessed using the log-rank test. RESULTS: The final study cohort comprised 482 patients (median age 70.5 years; 242 men). The median follow-up period was 36.8 months. Among 482 patients, 96 developed HCC (19.9%). The 1-, 3-, and 5-year cumulative rates of HCC development were 4.9%, 18.6%, and 30.5%, respectively. Multivariate analysis revealed that age, male sex, history of HCC, and hepatobiliary phase hypointense nodules without arterial phase hyperenhancement were independent risk factors significantly associated with HCC development (p < 0.001-0.04). The highest risk group included patients with both a history of HCC and the presence of hepatobiliary phase hypointense nodules without arterial phase hyperenhancement (the 1- and 3-year cumulative HCC development rates were 14.2% and 62.2%, respectively). CONCLUSION: History of HCC and presence of hepatobiliary phase hypointense nodules without arterial phase hyperenhancement were strong risk factors for HCC development following direct-acting antiviral therapy.

Early-phase prothrombin time-international normalized ratio in acute liver injury indicates the timing of therapeutic intervention and predicts prognostic improvement.

AIM: We investigated whether an early-phase prothrombin time-international normalized ratio (PT-INR) is an interventional prognostic indicator for patients with acute liver injury, including acute liver failure. METHODS: This was a multicenter retrospective observational study. We included 595 patients with alanine aminotransferase levels ≥300 U/L due to acute liver injury who were admitted to Kagoshima University Hospital or other collaborative investigation organizations between January 1, 2010, and December 31, 2015. Patients with alanine aminotransferase levels ≥300 U/L and no previous liver disease were defined as having an acute liver injury. Acute liver failure was defined by PT-INR ≥1.5 with or without hepatic encephalopathy in acute liver injury patients. Data were obtained retrospectively from case reports and analyzed. RESULTS: The PT-INR on day 1 was the most accurate independent prognosis predictor in patients with acute liver injury and acute liver failure. On day 1, the transplant-free survival rates were significantly lower in patients with PT-INR ≥1.3. The transplant-free survival rates were also significantly higher in patients with acute liver injury and acute liver failure, in whom the PT-INR had recovered from ≥1.3 on day 1 to <1.3 by day 8. CONCLUSION: Early-phase changes in the PT-INR can predict the prognosis of patients with acute liver injury and acute liver failure. Furthermore, PT-INR ≥1.3 could be an interventional marker, whereas PT-INR <1.3 after 1 week could reflect prognostic improvement.

Usefulness of the aldehyde breath test for predicting metachronous recurrence in patients with esophageal squamous cell carcinoma and hypopharyngeal squamous cell carcinoma.

BACKGROUND: The rate of metachronous recurrence after endoscopic submucosal dissection for early-stage esophageal squamous cell carcinoma and hypopharynx squamous cell carcinoma is as high (10-15%). The acetaldehyde breath test may detect acetaldehyde dehydrogenase 2 gene polymorphisms. Therefore, we evaluated its usefulness in assessing metachronous recurrence in patients with esophageal squamous cell carcinoma and hypopharynx squamous cell carcinoma. METHODS: A total of 76 patients underwent endoscopic submucosal dissection for esophageal squamous cell carcinoma and hypopharynx squamous cell carcinoma and were followed up for at least 3 years (non-recurrence group: 52 patients; recurrence group: 24 patients). The risk factors for carcinogenesis were compared between the recurrence and non-recurrence groups, and the acetaldehyde-to-ethanol ratio was assessed. The cutoff acetaldehyde-to-ethanol ratio that correlated with recurrence was established, and the cumulative recurrence rate was evaluated. RESULTS: The recurrence group had a higher acetaldehyde-to-ethanol ratio, daily alcohol consumption, and Lugol-voiding lesion grade than the non-recurrence group in the univariate analysis. The cutoff acetaldehyde-to-ethanol ratio for recurrence was 28.1 based on the receiver operating characteristic curve. The multivariate analysis revealed an acetaldehyde-to-ethanol ratio of > 28.1 and a Lugol-voiding lesion grade associated with carcinogenesis. Patients with an acetaldehyde-to-ethanol ratio of ≥ 28.1 had a significantly high recurrence rate using the Kaplan-Meier method. CONCLUSIONS: The acetaldehyde-to-ethanol ratio detected using the acetaldehyde breath test could be a novel biomarker of metachronous recurrence after endoscopic submucosal dissection in patients with esophageal squamous cell carcinoma and hypopharynx squamous cell carcinoma. TRIAL REGISTRATION NUMBER: UMIN000040615.

Efficacy of rifaximin, a poorly absorbed rifamycin antimicrobial agent, for hepatic encephalopathy in Japanese patients.

AIM: Rifaximin is recommended as treatment for hepatic encephalopathy (HE) that targets intestinal bacterial flora. Although combined use with synthetic disaccharides is the standard of care worldwide, the therapeutic effects of rifaximin for overt encephalopathy (OHE) in Japanese patients have not been examined sufficiently. We examined the therapeutic effects of rifaximin for OHE in Japanese patients. METHODS: A total of 76 patients who developed OHE of West Haven grade II or higher at least once within the 12 months before starting rifaximin were included. Blood ammonia levels and the incidence of OHE during the 12 months before and after starting rifaximin therapy were compared in a before-and-after study. Rifaximin efficacy and predictors of efficacy were also examined. RESULTS: Post-treatment blood ammonia levels were significantly lower than pretreatment levels. The mean annual number of OHE incidents and intravenous branched-chain amino acid preparations used per patient were significantly lower after starting rifaximin therapy (2.51 vs. 0.76 times/year, p < 0.001; and 71.9 vs. 20.7 preparations/year, p = 0.003, respectively). The cumulative incidence of hospitalizations associated with HE significantly decreased after rifaximin therapy (hazard ratio 0.187; p < 0.001). The efficacy rate, defined as the proportion of patients without OHE during the administration of rifaximin for 1 year after starting rifaximin therapy, was 65.8%. Serum albumin ≥2.7 g/dl was an independent predictor of efficacy. CONCLUSION: Rifaximin was associated with decreased blood ammonia levels, lower incidence of OHE, and fewer hospitalizations in Japanese patients with HE. In addition, serum albumin level was an important predictor on efficacy of rifaximin.

Changes in body composition and low blood urea nitrogen level related to an increase in the prevalence of fatty liver over 20 years: A cross-sectional study.

AIM: Qualitative body composition (BC) change, characterized by the combination of visceral fat gain and muscle loss, is drawing attention as a risk factor for fatty liver (FL). The present study aimed to describe trends in BC change and its association with FL in the Japanese population. METHODS: Data from medical checkups carried out on 56 639 Japanese participants every 5 years from 1997 to 2017 were analyzed. Fat mass index (FMI) and fat-free mass index (FFMI) were calculated using body mass index and body fat percentage. Subjects were divided into two groups according to deviations from the correlation line of FMI and FFMI as the reference: FMI-predominant BC and FFM-dominant BC. Fatty liver was determined using abdominal ultrasonography. RESULTS: The prevalence of FL significantly increased from 27.3% to 42.7% in men and from 18.0% to 25.5% in women. The prevalence of FMI predominance significantly increased from 33.6% to 43.9% in men and from 29.1% to 47.0% in women. Fat mass index predominance was independently associated with FL in men and women (odds ratio: 1.96 and 1.94, respectively). Serum blood urea nitrogen level was inversely associated with FL in men and women (0.958 and 0.961, respectively) and significantly decreased from 15.8 to 14.9 mg/dl in men and from 15.1 to 14.0 mg/dl in women. CONCLUSIONS: Increasing FMI-predominant BC and decreasing serum blood urea nitrogen level could account for the increase in the prevalence of FL over 20 years. We believe that these factors stem from current lifestyle habits in Japan.

Viral and host factors are associated with retreatment failure in hepatitis C patients receiving all-oral direct antiviral therapy.

AIM: Direct-acting antiviral (DAA) therapy for hepatitis C virus is associated with high sustained virologic response rates. However, patients for whom DAA therapy fails acquire resistance-associated substitutions (RASs). We therefore evaluated the efficacy of DAA retreatment and factors associated with retreatment failure. METHODS: Non-structural 5A RASs were investigated at the start of DAA therapy and at treatment failure in 64 patients with hepatitis C virus genotype 1b for whom DAA combination therapy had failed. A total of 59 patients were introduced to DAA retreatment. The factors associated with retreatment failure were investigated. RESULTS: A total of 20 of 43 (46.5%) daclatasvir + asunaprevir-treated patients with virologic failure had no RASs at baseline, and three (15%) acquired P32 deletion RASs. Four of seven sofosbuvir/ledipasvir-treated patients with virologic failure had more than two RASs of NS5A at baseline. The sustained virologic response rates on retreatment were as follows: sofosbuvir/ledipasvir, 81.8%; with elbasvir + grazoprevir, 0%; and glecaprevir/pibrentasvir, 87.5%. Patients for whom sofosbuvir/ledipasvir or elbasvir + grazoprevir failed achieved sustained virologic response with glecaprevir/pibrentasvir. Two of three patients for whom glecaprevir/pibrentasvir retreatment failed had Q24/L28/R30 and A92K RASs; the other had P32 deletion RAS at baseline. Interestingly, 10 of 11 patients with retreatment failure had the interleukin (IL)-28B single-nucleotide polymorphism (SNP) minor allele. A multivariate analysis showed that the IL28B SNP minor allele (P = 0.005, odds ratio 28.291) was an independent risk factor for retreatment failure. CONCLUSIONS: In addition to viral factors (e.g. Q24, L28, R30, and A92 or P32 deletion RASs), host factors (e.g. IL28B SNP) are associated with DAA retreatment failure.

Sustained virologic response after eight weeks of treatment with sofosbuvir, ledipasvir, and ribavirin in a decompensated cirrhotic patient with hepatitis C virus genotype 1b.

A 68-year-old Japanese man with decompensated cirrhosis due to hepatitis C virus (HCV) genotype 1b infection was treated with sofosbuvir (SOF; 400 mg/day), ledipasvir (LDV; 90 mg/day), and ribavirin (RBV; 400 mg/day). Before treatment, his Child-Pugh and Model for End-Stage Liver Disease (MELD) scores were 10 (class C) and 13 points, respectively. Although RBV was initially given at two-thirds the normal dose due to anemia, his hemoglobin level gradually declined, and RBV was reduced to 200 mg daily on day 11, and 200 mg every other day on day 14. His alanine aminotransferase level gradually decreased during combination therapy; and HCV-RNA was undetectable on day 28. He complained of fatigue from day 49, and RBV was ceased. On day 56, he asked to discontinue treatment because of strong fatigue and insomnia. As hepatic encephalopathy occurred just after the cessation of direct-acting antivirals, diuretics were discontinued, and treatment with synthetic disaccharides and intractable antibiotics were given, after which his consciousness returned to normal. Ascites gradually disappeared, and a sustained virologic response (SVR) was achieved. At 1.5 years after treatment, his Child-Pugh and MELD scores had improved to 6 (class A) and 10 points, respectively. Although he did not experience hepatic encephalopathy during the observation period, his blood ammonia concentration persistently increased. We reported a case of decompensated cirrhosis in a patient who achieved SVR with SOF/LDV plus RBV for 8 weeks. Although his liver function improved after treatment, careful long-term observation is required for complications of liver cirrhosis, even after HCV elimination.

Effect of tolvaptan on the prognosis of patients with hepatic ascites.

AIM: Despite accumulating evidence concerning the efficacy of tolvaptan in the treatment of body fluid retention or hyponatremia, the effect of tolvaptan on the prognosis of patients with hepatic ascites has not been fully investigated. METHODS: A total of 628 patients with hepatic ascites who were treated with diuretics (furosemide, spironolactone, or tolvaptan) between 2007 and 2017 were enrolled and divided into two groups: those who received tolvaptan (original tolvaptan group, n = 278) and those who did not (original control group, n = 350). The cumulative survival rates between the groups were compared and the factors associated with survival in patients with hepatic ascites were identified using a Cox regression analysis. In addition, propensity score matching was applied in patients who started conventional diuretics for new-onset hepatic ascites after September 2013 (pre-matching tolvaptan group, n = 177; pre-matching control group, n = 63), and the cumulative survival rates were compared between the post-matching tolvaptan and control groups. RESULTS: The survival rate was significantly higher in the tolvaptan group than the control group (P = 0.005), and tolvaptan therapy was identified as an independent factor associated with survival (hazard ratio 0.721 for death relative to control, P < 0.001). The propensity score-matched comparison also showed a significantly higher survival rate in the tolvaptan group (n = 51) than in the control group (n = 51) (P = 0.009). CONCLUSIONS: This study suggests that tolvaptan might improve the prognosis of patients with hepatic ascites.

Hepatocyte Growth Factor Facilitates Esophageal Mucosal Repair and Inhibits the Submucosal Fibrosis in a Rat Model of Esophageal Ulcer.

BACKGROUND/AIMS: Esophageal mucosal damage often causes scar tissue, leading to refractory stricture. The aim of this study was to clarify the effect of hepatocyte growth factor (HGF) on esophageal mucosal repair and fibrosis leading to stricture in a rat model of esophageal ulcer. METHODS: Esophageal ulcers were induced in rats by topical exposure of the lower esophageal serosa to acetic acid, followed by intraperitoneal administration of HGF (200 µg/day) using an osmotic pump for 7 days. The effect of HGF on esophageal mucosal injury was investigated macroscopically and microscopically. The effect of HGF on epithelial cell proliferation and the expression of genes closely associated with the development of fibrosis were also examined. RESULTS: The administration of HGF for 7 days led to a significant reduction in the ulcerative area and enhanced the proliferation of esophageal epithelial cells. HGF treatment significantly decreased the fibrosis, and subsequently attenuated not only the foreshortening but also the narrowing of the esophagus. The expression levels of tissue inhibitor of metalloproteinase (TIMP)-1, -2, and matrix metalloproteinase (MMP)-2, -9 were significantly decreased among rats treated with HGF. CONCLUSION: HGF facilitates the repair of esophageal mucosal injury and may also ameliorate the esophageal fibrosis, possibly through enhanced re-epithelization.

Reduction effect of the quantity of radiation exposure and contrast media by image support system in transarterial chemoembolization for the treatment of hepatocellular carcinoma.

BACKGROUND AND AIM: We confirmed the clinical utility of a three-dimensional navigation system during transarterial chemoembolization. METHODS: We evaluated 128 tumors in 91 patients enrolled between May 2015 and August 2016. We evaluated the accuracy of the three-dimensional navigation imaging system for all tumors. We compared the patients who were able to undergo route detection using three-dimensional navigation with previously treated patients who underwent transarterial chemoembolization without using three-dimensional navigation (n = 21). For 38 patients who underwent super-selective microcatheter insertion after a feeding artery was identified by three-dimensional navigation, we confirmed the relationship between the tumors and contrasted liver parenchyma and divided the computed tomography hepatic arteriography findings into four grades. Grade 1: an overlap of > 5 mm, grade 2: an overlap between 0 and 5 mm, grade 3: the borders of the tumor within the liver parenchyma but in contact with the edges, and grade 4: a tumor outside the borders of the liver parenchyma. RESULTS: Using the three-dimensional navigation system, we identified a tumor-feeding artery in 125/128 tumors (97.6%). Furthermore, this system allowed us to significantly reduce the volume of contrast media and the radiation exposure dose in patients undergoing an evaluation. We identified 15 grade 1 tumors (39.5%), 3 grade 2 tumors (7.9%), 11 grade 3 tumors (28.9%), and 9 grade 4 tumors (23.7%) according to our definitions. CONCLUSION: The three-dimensional navigation is useful not only for patients but also for surgeons who have relatively little experience.

Efficacy of vasopressin V2 receptor antagonist tolvaptan in treatment of hepatic edema.

AIM: Tolvaptan, an oral active vasopressin V2 receptor antagonist, is widely used for hepatic edema in Japan, but its clinical benefits have yet to be fully clarified. The present study evaluated the efficacy of tolvaptan in hepatic edema. METHODS: The efficacy and treatment regimen of tolvaptan were evaluated in 150 patients with hepatic edema by analyzing the initial (day 14) and long-term (day 90) responses to the drug and their predictive factors. All patients were divided into good (Child-Pugh classification B, and absent of advanced hepatocellular carcinoma) and poor hepatic condition groups, and the response rates were compared between the two groups. RESULTS: The initial response rate was 62%, and the long-term response rate was 47%. The assessment of predictive factors for response to tolvaptan showed that serum creatinine and C-reactive protein levels were important predictors of initial response, and that hepatic conditions, such as the Child-Pugh score or presence of hepatocellular carcinoma, as well as initial response, were significant predictors of long-term response. In addition, both the initial and long-term response rates and the cumulative survival rate were found to be higher in the good hepatic condition group than in the poor hepatic condition group, respectively (71% vs. 57%, P = 0.113; 62% vs. 39%, P = 0.009; log-rank test, P < 0.001). CONCLUSION: These results suggest that tolvaptan may provide high response rates when used early in the course of hepatic edema, or when both hepatic and renal functions are still retained, leading to an improved disease prognosis.

Horizontal transmission of de novo hepatitis B between spouses: A case report.

We report a female patient with acute hepatitis B due to horizontal transmission of hepatitis B virus from her husband, who suffered from de novo hepatitis B. A 48-year-old man underwent peripheral blood stem cell transplantation (PBSCT) for adult T-cell leukemia/lymphoma. Nine months after the initial treatment, he was referred to our hospital because of jaundice. Laboratory data showed elevated serum aminotransferase levels and hepatitis B surface antigen (HBsAg) positivity. We diagnosed de novo hepatitis B because a pre-PBSCT serum sample was negative for HBsAg and positive for anti-hepatitis B core antibody (HBcAb). His liver function improved with entecavir therapy. Two months after his diagnosis of hepatitis B, his 31-year-old wife was admitted with fever and appetite loss. She was diagnosed with acute hepatitis B because of increased serum aminotransferase levels and HBsAg and immunoglobulin M HBcAb positivity. Sequencing of HBV DNA in the serum obtained from both patients showed 99.9% homology. Therefore, we diagnosed her acute hepatitis B as due to horizontal transmission of de novo hepatitis B from her husband. HBV derived from de novo hepatitis B should be considered a potential source of infection, although intrafamilial transmission of de novo hepatitis B is rare.

Serum levels of apoptosis inhibitor of macrophage are associated with hepatic fibrosis in patients with chronic hepatitis C.

BACKGROUND: Apoptosis inhibitor of macrophage (AIM) and adipocytokines are involved in the metabolic syndrome, which has been putatively associated with the progression of chronic hepatitis C (CHC). However, the association between these cytokines and CHC is not fully elucidated. The aim of this study is to test whether serum levels of AIM and adipocytokines are associated with histological features, homeostasis model assessment-insulin resistance index (HOMA-IR), or whole body insulin sensitivity index (WBISI) in CHC patients. METHODS: Serum samples were obtained from 77 patients with biopsy-proven CHC. In 39 patients without overt diabetes mellitus, a 75 g oral glucose tolerance test (OGTT) was performed and HOMA-IR and WBISI were calculated. RESULTS: A serum AIM level of ≥ 1.2 µg/ml was independently associated with advanced hepatic fibrosis (F2 or F3) (odds ratio [OR], 5.612; 95% confidence interval [CI], 1.103-28.563; P = 0.038) based on a multivariate analysis, but there was no significant association between AIM and hepatic steatosis or inflammation. Furthermore, a serum leptin level of ≥ 8.6 ng/ml was independently associated with the presence of hepatic steatosis (≥ 5%) (OR, 6.195; 95% CI, 1.409-27.240; P = 0.016), but not hepatic fibrosis or inflammation. No relationship was observed between levels of adiponectin or resistin and hepatic histological parameters based on a multivariate analysis. Although serum levels of leptin, resistin, and adiponectin were significantly correlated with HOMA-IR and WBISI, there was no significant relationship between serum AIM levels and HOMA-IR or WBISI, respectively. CONCLUSION: High serum levels of AIM in CHC patients are potentially related to advanced hepatic fibrosis. AIM and adipocytokines are possibly associated with pathological changes via a different mechanism.

Analysis of the susceptibility of refractory hepatitis C virus resistant to nonstructural 5A inhibitors.

Resistance-associated substitutions (RASs) of hepatitis C virus (HCV) affect the efficacy of direct-acting antivirals (DAAs). In this study, we aimed to clarify the susceptibility of the coexistence of nonstructural (NS) 5A Q24K/L28M/R30Q (or R30E)/A92K RASs, which were observed in patients with DAAs re-treatment failure and to consider new therapeutic agents. We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir. The Q24K/L28M/R30E/A92K RASs was 816.3 times more resistant to pibrentasvir than the Q24K/L28M/R30Q/A92K RASs. Furthermore, a combination of pibrentasvir and sofosbuvir showed therapeutic efficacy against these RASs. Combination regimens may eradicate HCV with NS5A Q24K/L28M/R30E/A92K RASs.

Skill Proficiency, Efficacy, and Safety of the Transradial Approach in Transarterial Treatments for Hepatocellular Carcinoma.

Introduction Abdominal angiography procedures such as transarterial chemoembolization (TACE) are essential for hepatocellular carcinoma treatment. One method commonly used is transfemoral access (TFA). However, issues associated with this method, which include postoperative compression of the puncture site and long periods of bed rest, can affect patient satisfaction. Thus, transradial access (TRA), a minimally invasive treatment method that improves treatment quality, was developed for TACE. This retrospective, multicenter study aimed to investigate the efficacy and safety of abdominal angiography using the radial artery approach. Methods In total, 1,601 patients underwent abdominal angiography using TRA and received treatment (radial access for visceral intervention (RAVI)) at 14 institutions in Japan. The treatment time, procedure completion rate, patient satisfaction, and complications were investigated. Results The success rate of RAVI was 99.4%, and the complication rate was 1.2%. Approximately 98.2% of the patients requested the radial artery approach again. There were no significant differences in the success rate of RAVI and the incidence of complications based on the operator's years of experience or the patient's age. Some patients developed minor complications such as puncture site bleeding, hematoma, vascular pain, and vasospasm. Further, serious complications (cerebral infarction (n = 1), cerebellar infarction (n = 1), and aortic dissection (n = 1)) were observed. Conclusion Similar to the conventional TFA, RAVI helped in facilitating peritoneal angiography safely. In abdominal angiography, this method can reduce patient burden and can be widely used in the future from the perspective of clinical benefit.

Transgenic expression of human neutrophil peptide-1 enhances hepatic fibrosis in mice fed a choline-deficient, L-amino acid-defined diet.

BACKGROUND: Neutrophils infiltrate the livers of patients with nonalcoholic steatohepatitis (NASH). Human neutrophil peptides (HNPs) induce cytokine and chemokine production under inflammatory conditions, which may contribute to the progression of NASH. In this study, we focused on the effects of HNP-1 on hepatic steatosis and fibrosis in a mouse model of NASH induced by a choline-deficient, L-amino acid-defined (CDAA) diet. MATERIALS & METHODS: We generated transgenic mice expressing HNP-1 under the control of a ß-actin-based promoter. HNP-1 transgenic and wild-type C57BL/6N mice were fed a CDAA diet for 16 weeks to induce hepatic steatosis and fibrosis. Serological and histological features were examined, and the effects of HNP-1 on hepatic stellate cell lines were assessed. RESULTS: HNP-1 transgenic and wild-type mice fed the CDAA diet showed no significant differences in serum alanine aminotransferase levels or the degree of hepatic steatosis based on Oil red O staining and hepatic triglyceride content. In contrast, Sirius Red and Azan staining showed significantly more severe hepatic fibrosis in HNP-1 transgenic mice compared with wild-type mice. In addition, significantly more α-smooth muscle actin-positive hepatic stellate cells were observed in the transgenic mice than in the wild-type mice. Finally, the proliferation of the LI90 hepatic stellate cell line increased in response to HNP-1. CONCLUSION: Our data indicate that HNP-1 enhances hepatic fibrosis in fatty liver by inducing hepatic stellate cell proliferation. Thus, neutrophil-derived HNP-1 may contribute to the progression of NASH.

A case of acute liver failure due to aggressive natural killer-cell leukemia with a rapid course.

An 87-year-old man consulted a former doctor with a complaint of black stool and was admitted to hospital because of anemia and multiple gastric ulcers. The laboratory findings showed that his hepatobiliary enzyme levels and inflammatory response were elevated. Computed tomography showed hepatosplenomegaly and enlarged intra-abdominal lymph nodes. Two days later, he was transferred to our hospital due to deterioration of his liver function. Since he had low level of consciousness and his ammonia level was high, we diagnosed him with acute liver failure (ALF) with hepatic coma, and started on-line hemodiafiltration. As the cause of ALF, we suspected hepatic involvement of a hematologic tumor because of high lactate dehydrogenase and soluble interleukin-2 receptor levels and large abnormal lymphocyte-like cells in the peripheral blood. Because of his poor general condition, bone marrow and other histological examinations were difficult, and he died on the third day of hospitalization. Pathological autopsy showed marked hepatosplenomegaly and the proliferation of large abnormal lymphocyte-like cells in the bone marrow, liver, spleen, and lymph nodes. Immunostaining revealed aggressive natural killer-cell leukemia (ANKL).We herein report a rare case of the development of ALF with coma due to ANKL with a review of the relevant literature.

Successful Percutaneous Transhepatic Obliteration Plus Sengstaken-Blakemore Tube Combination Therapy for Recurrent Gastroesophageal Variceal Bleeding.

We treated a case of gastroesophageal varices due to decompensated liver cirrhosis associated with Wilson's disease. The varicose veins penetrated the paraesophageal vein. We performed endoscopic variceal ligation (EVL) on the perforating vein and endoscopic injection sclerotherapy distally. However, 5 days after treatment, the patient vomited blood. Esophagogastroduodenoscopy showed bleeding from the ulcer after EVL at the perforating vein. We performed EVL and stopped the bleeding. However, the next day, she vomited blood again and developed hemorrhagic shock. We were able to achieve hemostasis and save the patient's life with combination therapy consisting of percutaneous transhepatic obliteration and Sengstaken-Blakemore tube placement.

Development of a risk prediction score and equation for chronic kidney disease: a retrospective cohort study.

Chronic kidney disease (CKD) is a risk factor for end-stage renal disease and contributes to increased risk of cardiovascular disease morbidity and mortality. We aimed to develop a risk prediction score and equation for future CKD using health checkup data. This study included 58,423 Japanese participants aged 30-69 years, who were randomly assigned to derivation and validation cohorts at a ratio of 2:1. The predictors were anthropometric indices, life style, and blood sampling data. In derivation cohort, we performed multivariable logistic regression analysis and obtained the standardized beta coefficient of each factor that was significantly associated with new-onset CKD and assigned scores to each factor. We created a score and an equation to predict CKD after 5 years and applied them to validation cohort to assess their reproducibility. The risk score ranged 0-16, consisting of age, sex, hypertension, dyslipidemia, diabetes, hyperuricemia, and estimated glomerular filtration rate (eGFR), with area under the curve (AUC) of 0.78 for the derivation cohort and 0.79 for the validation cohort. The CKD incidence gradually and constantly increased as the score increased from ≤ 6 to ≥ 14. The equation consisted of the seven indices described above, with AUC of 0.88 for the derivation cohort and 0.89 for the validation cohort. We developed a risk score and equation to predict CKD incidence after 5 years in Japanese population under 70 years of age. These models had reasonably high predictivity, and their reproducibility was confirmed through internal validation.