Non-alcoholic fatty liver diseases and risk of colorectal neoplasia.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is associated with colorectal neoplasia. Yet, NAFLD ranges from simple steatosis to steatohepatitis with advanced fibrosis. AIM: To investigate the risk of colorectal neoplasia according to the presence and severity of NAFLD. METHODS: A total of 26 540 asymptomatic adults who underwent same day first-time colonoscopy and abdominal ultrasonography as a health check-up programme were analysed. NAFLD was diagnosed by ultrasonography. Advanced colorectal neoplasia was defined as an invasive cancer or adenoma that was at least 10 mm in diameter, had high-grade dysplasia, or had villous histological characteristics or any combination thereof. RESULTS: NAFLD patients had a higher prevalence of any colorectal neoplasia (38.0% vs. 28.9%) and advanced colorectal neoplasia (2.8% vs. 1.9%) compared to those without NAFLD. In a multivariable model adjusted for age, sex, smoking, alcohol, body mass index, first-degree family history of colorectal cancer, aspirin use and metabolic factors, the odd ratios comparing patients with NAFLD to those without were 1.10 [95% confidence interval (CI): 1.03-1.17] for any colorectal neoplasia and 1.21 (95% CI: 0.99-1.47) for advanced colorectal neoplasia. When NAFLD patients were further stratified according to the non-invasive parameters of liver disease severity, the risk of any colorectal neoplasia or advanced colorectal neoplasia was higher for those with severe liver diseases than those with mild liver diseases. CONCLUSIONS: The presence and severity of NAFLD were closely associated with any colorectal neoplasia and advanced colorectal neoplasia, suggesting that clinicians should be aware of the increased risk of colorectal neoplasia in patients with NAFLD.

Renal outcomes after liver transplantation in fulminant hepatitis A with acute kidney injury: comparison with hepatorenal syndrome.

BACKGROUND: Liver transplantation (LT) is the treatment of choice for hepatorenal syndrome (HRS). Recently, acute kidney injury (AKI) due to acute hepatitis A (HA) is increasing, but the outcome of LT is not well established. We investigated the outcomes of LT in patients with AKI due to acute HA compared with those of patients with HRS due to other causes. METHODS: We investigated the outcomes of LT in 20 patients with AKI associated with acute HA (HAV group) compared with 76 patients with hepatorenal syndrome (HRS) due to other causes (HRS group) at 3 Korea centers. RESULTS: Preoperative mean prothrombin time and serum creatinine level were higher in the HAV group than in the HRS group. But mean total bilirubin level was lower in the HAV group. There was no difference in Model for End-Stage Liver Disease scores. Post-transplantation patient and graft survival rates were similar between the 2 groups. More patients in the HAV group needed post-transplantation hemodialysis than in the HRS group (65.0% vs 38.2%; P = .043). However, post-transplantation estimated glomerular filtration rate was significantly higher in the HAV group after post-transplantation month 2 (P < .05). CONCLUSIONS: Peri-transplantation kidney function of the HAV group was poorer than that of HRS group. However, post-transplantation long-term renal outcome could be better in the HAV group.

Influence of hepatitis B virus reactivation on the recurrence of HBV-related hepatocellular carcinoma after curative resection in patients with low viral load.

It is unclear whether the reactivation of hepatitis B virus (HBV) influences the prognosis of hepatocellular carcinoma (HCC) after resection in patients with chronic hepatitis B. The aim of this study was to identify the influence of HBV reactivation on the recurrence of hepatitis B-related HCC after curative resection in patients with low viral load (HBV DNA <2000 IU/mL). We retrospectively analysed a total of 130 patients who underwent curative resection for HBV-related early stage HCC (single nodule; <5 cm/two or three nodules; <3 cm) with pre-operative HBV DNA levels <2000 IU/mL with serial HBV DNA tests. The predictive factors including HBV reactivation for the recurrence of HBV-related HCC after curative resection were investigated. Fifty-three patients (41%) had HBV reactivation after resection among 130 patients. HBV reactivation was observed in 22 of 53 patients with undetectable baseline HBV DNA and in 31 of 77 patients with detectable baseline HBV DNA. Cumulative recurrence rates after resection at 1, 2 and 3 years were 17.0%, 23.3% and 31.4%, respectively. The multivariable analysis demonstrated that the risk factors for the recurrence were the presence of microvascular invasion (hazard ratio (HR) 2.62, P = 0.003), multinodularity (HR 4.61, P = 0.005), HBV reactivation after resection (HR 2.03, P = 0.032) and HBeAg positivity (HR 2.06, P = 0.044). HBV reactivation after curative resection is associated with the recurrence of HBV-related HCC in patients with low viral load.

Proton pump inhibitor use significantly increases the risk of spontaneous bacterial peritonitis in 1965 patients with cirrhosis and ascites: a propensity score matched cohort study.

BACKGROUND: The risk of spontaneous bacterial peritonitis (SBP) associated with proton pump inhibitor (PPI) use has been raised in cirrhotic patients with ascites. However, this is based on case-control studies, often with a small series. AIM: To determine whether PPI use increases the risk of SBP using a large cohort. METHODS: This retrospective cohort study included 1965 cirrhotic patients with ascites diagnosed between January 2005 and December 2009. The SBP incidence rate was compared between the PPI and non-PPI groups before and after propensity score matching to reduce the effect of selection bias and potential confounders. Multivariate analysis was conducted to confirm the association of PPI use with SBP. RESULTS: After excluding 411 patients, 1554 were analysed. Among them, 512 patients (32.9%) were included in the PPI group. The annual SBP incidence rate was higher in the PPI group than in the non-PPI group (10.6% and 5.8%, P = 0.002) before matching. Indications for PPI use and dose of PPI were similar between patients with and without SBP. In the propensity score matched cohort (402 pairs), the SBP incidence rate was also higher in the PPI group than in the non-PPI group (10.8% vs. 6.0%, P = 0.038). Multivariate analysis revealed that PPI use (Hazard ratio 1.396; 95% confidence interval, 1.057-1.843; P = 0.019) was the independent risk factor for SBP. CONCLUSIONS: Proton pump inhibitor use significantly increases the risk of spontaneous bacterial peritonitis in cirrhotic patients with ascites. Proton pump inhibitor use should be undertaken with greater caution and appropriately in patients with cirrhosis.

Prevalence of overt myeloproliferative neoplasms and JAK2 V617F mutation in Korean patients with splanchnic vein thrombosis.

INTRODUCTION: Myeloproliferative neoplasm (MPN) is known to be a major risk factor of splanchnic vein thrombosis (SVT). Recent studies revealed that a significant proportion of patients with SVT harbor a gain-of-function mutation in the JAK2 gene (V617F) with or without MPN. In this study, the authors investigated the prevalence of MPN and JAK2 V617F mutation in Korean patients with SVT. METHODS: The study subjects were 26 patients diagnosed as having SVT based on Doppler ultrasound and/or computed tomography from January 2008 to January 2010 (16 men and 10 women; mean age 44 years, range 15-75 years). The clinical and laboratory data were reviewed. The JAK2 V617F mutation was detected by allele-specific polymerase chain reaction and direct sequencing analyses using DNA from peripheral blood leukocytes. RESULTS: Among 26 study patients, 12 had portal vein thrombosis, five had hepatic vein thrombosis, three had mesenteric, and two had splenic vein thrombosis. Four patients had thrombosis involving more than one splanchnic vein. Two patients (7.7%; 2/26) had overt MPN (essential thrombocythemia). JAK2 V617F was detected in three patients (11.5%) including the two patients with overt MPN. Thus, the prevalence of the JAK2 V617F mutation in patients with SVT but without overt MPN was 4.2% (1/24). CONCLUSION: The prevalence of overt MPN and that of JAK2 V617F were lower in Korean patients with SVT than in previous reports. Data from a larger number of patients with long-term follow-up are needed to reveal the clinical relevancy of JAK2 V617F in Korean patients with SVT.

Prophylactic use of lamivudine for hepatitis B exacerbation in post-operative breast cancer patients receiving anthracycline-based adjuvant chemotherapy.

BACKGROUND: With the increasing incidence of breast cancer worldwide, in particular in southeast Asia (including Korea), and the common use of anthracyclines in the adjuvant and metastatic settings, the occurrence of Hepatitis B virus (HBV) reactivation may develop in this patient population. The use of prophylactic antiviral agents in cancer patients may result in a reduced HBV exacerbation. The purpose of the current study was to assess the efficacy of prophylactic lamivudine in reducing the incidence and severity of HBV reactivation in post-operative breast cancer patients undergoing adjuvant doxorubicin-containing chemotherapy. METHODS: The medical records of patients undergoing anthracycline-based adjuvant chemotherapy at Samsung Medical Center between January 2001 and September 2008 were reviewed. RESULTS: From the database, 1912 breast cancer patients who had received anthracycline-based adjuvant chemotherapy were identified. Of 131 patients who were HBV surface antigen positive, 55 and 76 did and did not receive prophylactic lamivudine, respectively. In all, 30 patients (23%) developed hepatitis during doxorubicin-containing adjuvant chemotherapy. Of the 30 patients, 5 (9%) were in the prophylactic lamivudine group and 25 (33%) in the control group (P=0.001). In the prophylactic lamivudine group, there was significantly less HBV reactivation (1 patient (2%) vs 20 patients (16%); P=0.002), less disruption of chemotherapy (7 vs 14%; P=0.04), and less severe hepatitis (0 vs 17%; P=0.002). CONCLUSION: Prophylactic lamivudine significantly reduced the incidence and severity of HBV reactivation in breast cancer patients undergoing anthracycline-based adjuvant chemotherapy.

The incidence and clinical outcome of YMDD mutants in hepatitis B surface antigen-positive renal allograft recipients after prolonged lamivudine therapy.

Although lamivudine (LAM) is a potent inhibitor of hepatitis B virus (HBV), prolonged therapy may induce the development of LAM-resistant strains, YMDD mutants. Although YMDD mutants have impaired replication that leads to a benign clinical course compared with wild-type virus, some immunosuppressive agents may enhance replication of YMDD mutants, causing a severe hepatitis flare. We retrospectively investigated the incidence and clinical outcomes of YMDD mutants in renal allograft recipients on immunosuppressive treatment. Clinical records of 25 renal allograft recipients, who underwent renal transplantation between December 1997 and February 2006 were hepatitis B surface antigen positive at the time of transplantation, were reviewed. All patients received LAM treatment after renal transplantation. Over 9 to 98 months of follow-up, 16 patients (64.0%) maintained undetectable HBV DNA levels; however, 9 patients (36.0%) showed persistent or increased levels of HBV DNA. Seven were identified as having developed YMDD mutants. Although genotypic analysis was not performed, YMDD mutants were strongly suspected in another two patients, who developed severe hepatic dysfunction combined with high levels of HBV viremia at close to 2 years of LAM therapy. One patient recovered after hepatic transplantation and another patient died of hepatic failure. In conclusion, the incidence of YMDD mutants was similar to that of nonimmunosuppressed individuals; however, the presence of these mutants made it more likely for severe liver disease to develop in renal transplant recipients. Therefore, close monitoring for the development of YMDD mutants should be performed during LAM treatment, especially in this group of patients.

Fatal hepatic failure associated with hepatitis B virus reactivation in a hepatitis B surface antigen-negative patient with rheumatoid arthritis receiving low dose methotrexate.

A 66-year-old female patient with rheumatoid arthritis, who had been HBsAg-negative and anti-HBs-positive, developed hepatic dysfunction following low-dose methotrexate therapy. Serologic testing for HBsAg, HBeAg, IgM HBc and HBV DNA were positive. Despite antiviral therapy with lamivudine, the hepatic condition gradually deteriorated until the patient died. Since HBV replication persists in the liver even in individuals with resolved HBV infection (i.e., HBsAg-negative, anti-HBs-positive), HBV reactivation may occur in these patients with immunosuppression. Therefore, especially in endemic areas, all patients being considered for immunosuppressive therapy should be closely monitored with liver function tests and evaluated for HBV reappearance even when HBsAg-negative.

Lysophosphatidylcholine suppresses apoptotic cell death by inducing cyclooxygenase-2 expression via a Raf-1 dependent mechanism in human cholangiocytes.

PURPOSE: The high incidence of biliary tract carcinoma in patients with anomalous pancreaticobiliary ductal junction (APBDJ) implicates that a compositional alteration in bile may contribute to the genesis of this cancer. Lysophosphatidylcholine (LPC) is generated in the bile of these patients. Given the role of cyclooxygenase-2 (COX-2) in biliary tract carcinogenesis, we postulated that LPC induces COX-2 in cholangiocytes. METHODS: The effect of LPC on COX-2 expression in cholangiocytes was evaluated by immunoblot analysis, real-time PCR and reporter gene assay. Apoptosis was induced by TRAIL treatment, and quantified using DAPI staining. RESULTS: Lysophosphatidylcholine increased COX-2 protein expression in cholangiocytes in a concentration- and time-dependent manner. LPC-induced Raf-1 activation was responsible for this COX-2 induction. Accordingly, LPC increased COX-2 mRNA levels in a Raf-1 dependent manner by stabilizing COX-2 mRNA. Finally, LPC attenuated TRAIL-mediated apoptosis through a COX-2/PgE2 dependent mechanism. CONCLUSIONS: Collectively, these results implicate that LPC inhibits cholangiocyte apoptosis by inducing COX-2 expression via a Raf-1 dependent mechanism. This anti-apoptotic signaling may participate in biliary tract carcinogenesis in APBDJ patients, and therefore, its interruption may be a viable chemopreventative strategy.

Detection of response-predicting mutations in the kinase domain of the epidermal growth factor receptor gene in cholangiocarcinomas.

PURPOSE: Epidermal growth factor receptor (EGFR) signalings have recently been implicated in the genesis and progression of cholangiocarcinomas. Thus, the EGFR kinase inhibitor appears to be promising in the treatment of this cancer. The response-predicting mutations in the tyrosine kinase domain of EGFR gene have recently been detected in non-small cell lung cancers. This study was, therefore, to investigate if these mutations are also found in cholangiocarcinomas. METHODS: Twenty-two consecutive cholangiocarcinoma patients who underwent surgical resection were enrolled. Their resected paraffin-embedded cholangiocarcinoma specimens were used for mutation analysis, which was performed by DNA sequencing of exons 18, 19 and 21 in the EGFR gene. Clinical characteristics were compared between each group according to the presence or absence of mutations. RESULTS: Three patients (13.6%) harbored EGFR mutations. All the mutations found were deletions in exon 19. Mutations were more common in intra-hepatic or poorly differentiated tumors. Differences in age, sex, stage at diagnosis and survival were not observed between mutation-positive and -negative patients. CONCLUSIONS: This study, for the first time, demonstrates that a subset of cholangiocarcinoma patients has response-predicting EGFR mutations. Therefore, a highly selected application of the EGFR kinase inhibitor would be therapeutically effective in these patients.

Augmentation of butyrate-induced differentiation of human hepatocyte by cyclin E over-expression.

In mammalian cells, cellular differentiation into specific cell types is usually preceded by growth arrest. On the other hand, the induced differentiation may also be preceded by an enhanced G1-S transition of the cell cycle prior to the growth arrest. This suggests that an early increase in proliferation is in some way a prerequisite for subsequent differentiation. We therefore attempted to assess whether we could produce human hepatocytes with further differentiated functions by promoting G1-S transition in a butyrate-treated human hepatocyte cell line. A cyclin E-over-expressing cell line was established by transfecting human cyclin E cDNA. Upon butyrate treatment, the cyclin E-over-expressing cells exhibited a significantly increased albumin-secreting and ammonia-detoxifying capacity when compared to the control cells. In particular, the ornithine transcarbamylase activity was increased in these cells. Collectively, these results implicate that the cyclin E over-expression may augment the hepatocyte-specific functions during the butyrate-induced differentiation process of human hepatocytes by enhancing G1-S cell cycle transition.