Serum zinc levels as predictors of covert hepatic encephalopathy in patients with liver cirrhosis.

BACKGROUND: Covert hepatic encephalopathy (CHE) significantly impacts the quality of life and prognosis in patients with liver cirrhosis. This study aims to analyze the prevalence and risk factors of CHE to identify high-risk patients who would benefit from therapeutic interventions. METHODS: This single-center, retrospective observational study included 126 patients without a history of overt hepatic encephalopathy (OHE). CHE was defined as a score above the age-based cutoff value in the Stroop test. Factors associated with the occurrence of CHE and the subsequent development of OHE were evaluated. RESULTS: CHE was detected in 47 patients (37.3%). A multiple logistic regression analysis identified serum zinc levels (per + 1 µg/dL, odds ratio 0.95, P = 0.0007) as the only risk factor associated with CHE, with a cutoff value of 60 µg/dL (AUC 0.71, P = 0.0001). Neither blood ammonia levels nor liver function were predictive of CHE. During a median observation period of 211 days, OHE developed in 18 patients (14.3%). The administration of more than 20 mg of furosemide was identified as a risk factor for developing OHE (hazard ratio 23.52, P = 0.0207). CONCLUSION: Cirrhotic patients with serum zinc levels below 60 µg/dL exhibit a high risk of developing CHE, regardless of blood ammonia levels. These patients face a significant risk of developing OHE. Therefore, early zinc supplementation is recommended for the prevention of OHE, particularly for those prescribed 20 mg or more of furosemide.

Switching from combination therapy with entecavir hydrate plus tenofovir alafenamide fumarate to tenofovir alafenamide fumarate monotherapy in patients with chronic hepatitis B based on nucleotide sequences of hepatitis B virus pregenome RNA.

AIM: Patients with chronic hepatitis B virus (HBV) infection experiencing viral breakthrough (BTH) or partial response (PR) during lamivudine (LAM) or entecavir hydrate (ETV) administration often took ETV plus tenofovir alafenamide fumarate (TAF) due to the emergence of a drug-resistance mutation. However, in patients lacking drug-resistance mutation against TAF, sufficient antiviral effects may be achievable with TAF monotherapy. We assessed the drug-resistance profile through nucleotide sequences of HBV pregenome RNA, and subsequently changed to TAF monotherapy from ETV plus TAF. METHODS: This prospective study included 25 patients with serum HBV-DNA below 20 IU/mL under ETV plus TAF administration. Pregenome RNA nucleotide sequences of HBV in the sera were analyzed using direct sequencing and deep sequencing. ETV was discontinued in patients without rtA194T and rtS106C + rtH126Y + rtD134E + rtL269I quadruple mutations in direct sequencing. RESULTS: LAM-PR, LAM-BTH, ETV-PR, and ETV-BTH were observed in 1, 16, 7, and 1 patient(s), respectively. Pregenome RNA nucleotide sequences were analyzable in 20 patients. Among the 12 patients classified as LAM-BTH, six patients showed rtL180M + rtM204V/I in direct sequencing, and one patient showed minor clones containing rtL180M + rtM204V + A194T in deep sequencing at a frequency of 0.3%. In the six patients classified as ETV-PR, one patient harbored rtM204I. No clones showing rtS106C + rtH126Y + rtD134E + rtL269I quadruple mutation were detected in deep sequencing. Subsequently, ETV was discontinued, and serum HBV-DNA remained undetectable up to 48 weeks in all patients. CONCLUSION: Patients receiving ETV plus TAF due to partial response or BTH during initial LAM or ETV administration were able to safely transition to TAF monotherapy based on nucleotide sequences of HBV pregenome RNA in the sera.

Safety and effectiveness of SARS-CoV-2 vaccines for patients with intractable hepatobiliary diseases: A multicenter, questionnaire-based, cross-sectional study.

AIM: There are few data regarding the safety and effectiveness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with intractable hepatobiliary diseases. We conducted a multicenter, questionnaire-based, cross-sectional study to determine the safety and effectiveness of the SARS-CoV-2 vaccines in Japanese patients with intractable hepatobiliary disease. METHODS: Patients aged ≥18 years with autoimmune hepatitis (AIH), primary biliary cholangitis, primary sclerosing cholangitis, Budd-Chiari syndrome, idiopathic portal hypertension, and extrahepatic portal vein obstruction at each center were consecutively invited to join the study. Participants were asked to complete a questionnaire regarding their characteristics, vaccination status, post-vaccination adverse effects, and SARS-CoV-2 infection. Additionally, liver disease status, treatment regimens, and liver function test values pre- and post-vaccination were collected. RESULTS: The survey was conducted from September 2021 to May 2022, and 528 patients (220 AIH, 251 primary biliary cholangitis, 6 AIH- primary biliary cholangitis/primary sclerosing cholangitis overlap, 39 primary sclerosing cholangitis, 4 Budd-Chiari syndrome, 5 idiopathic portal hypertension, and 3 extrahepatic portal vein obstruction) participated in the study. Post-vaccination adverse effects were comparable to those observed in the general population. Post-vaccination liver injuries classified as grade 1 or higher were observed in 83 cases (16%), whereas grades 2 and 3 were observed in only six cases (1.1%); AIH-like liver injury requiring treatment was not observed. Overall, 12 patients (2.3%) were infected with SARS-CoV-2, and only one patient was infected 6 months after the second vaccination. CONCLUSION: SARS-CoV-2 vaccines demonstrated satisfactory safety and effectiveness in Japanese patients with intractable hepatobiliary diseases.

Increased expression of TNFRSF14 and LIGHT in biliary epithelial cells of patients with primary sclerosing cholangitis.

BACKGROUND AND AIMS: There is a lack of biliary epithelial molecular markers for primary sclerosing cholangitis (PSC). We analyzed candidates from disease susceptibility genes identified in recent genome-wide association studies (GWAS). METHODS: Expression levels of GWAS genes were analyzed in archival liver tissues of patients with PSC and controls. Immunohistochemical analysis was performed to evaluate expression levels in the biliary epithelia of PSC (N = 45) and controls (N = 12). Samples from patients with primary biliary cholangitis (PBC) were used as disease controls (N = 20). RESULTS: Hepatic expression levels of ATXN2, HHEX, PRDX5, MST1, and TNFRSF14 were significantly altered in the PSC group. We focused on the immune-related receptor, TNFRSF14. Immunohistochemistry revealed that high expression of TNFRSF14 in biliary epithelial cells was observed only in the PSC group. In addition, the expression of LIGHT, which encodes a TNFRSF14-activating ligand, was increased in PSC liver. Immunohistochemistry showed that high expression of LIGHT was more common in PSC biliary epithelia (53%) than in the PBC (15%) or control (0%) groups; moreover, it was positively associated with fibrotic progression, although it was not an independent prognostic factor. CONCLUSIONS: TNFRSF14 and LIGHT are promising candidate markers for PSC.

Retrospective comparative study of new slim-delivery and conventional large-cell stents for stent-in-stent methods for hilar malignant biliary obstruction.

OBJECTIVES: Endoscopic management of unresectable hilar malignant biliary obstruction (HMBO) is technically challenging, and effectiveness of stent-in-stent using large-cell, metal stents was reported. A new, large-cell stent with a 6F tapered delivery system was recently developed. The aim of this study was to compare clinical outcomes of slim-delivery and conventional large-cell stents. METHODS: This was a multicenter retrospective comparative study of stent-in-stent methods using slim-delivery stents (Niti-S Large Cell SR Slim Delivery [LC slim-delivery]) and conventional stents (Niti-S large-cell D-type; LCD) for unresectable HMBO. RESULTS: Eighty-three patients with HMBO were included; 31 LC slim-delivery and 52 LCD. Overall technical and clinical success rates were 100% and 90% in LC slim-delivery group and 98% and 88% in LCD group. Use of the LC slim-delivery was associated with shorter stent placement time in the multiple regression analysis, with a stent placement time of 18 and 23 min in LC slim-delivery and LCD groups, respectively. The early adverse event (AE) rate of LC slim-delivery was 10%, with no cholangitis or cholecystitis as compared to 23% in the LCD group. Recurrent biliary obstruction (RBO) rates and time to RBO were comparable between the two groups: 35% and 44%, and 8.5 and 8.0 months in LC slim-delivery and LCD groups, respectively. The major cause of RBO was tumor ingrowth (82%) in the LC slim-delivery group and sludge (43%) and ingrowth (48%) in LCD group. CONCLUSION: Stent-in-stent methods using LC slim-delivery shortened stent placement time with low early AE rates and comparable time to RBO in patients with HMBO.

Development and external validation of a nomogram for prediction of post-endoscopic retrograde cholangiopancreatography pancreatitis.

BACKGROUND AND AIMS: Endoscopic retrograde cholangiopancreatography (ERCP) is widely performed for management of pancreatobiliary diseases; however, post-ERCP pancreatitis (PEP) remains as an unsolved problem. Although various risk factors for PEP have been reported, the prediction of PEP remains controversial. This study aimed to develop a predictive model for PEP. METHODS: Consecutive patients undergoing ERCP for biliary indications at two centers were retrospectively studied. Using data from a training cohort, we utilized a multivariable model to select five variables to construct a nomogram. The predictive model was internally and externally validated. Based on the nomogram, the patients were categorized into low-, moderate-, and high-risk groups. RESULTS: Using the data of 2224 patients in the training cohort, five variables were selected to generate a nomogram: 1) sex, 2) indication for ERCP, 3) difficult cannulation, 4) guidewire insertion into the pancreatic duct, and 5) endoscopic sphincterotomy or sphincteroplasty. The most significant risk factor was endoscopic papillary balloon dilation such as endoscopic sphincterotomy or sphincteroplasty. The bias-corrected concordance index was 0.72 in the training cohort and 0.72 in the validation cohort. Calibration curves for both cohorts demonstrated good agreement between the predicted and observed frequencies of the actual outcome. In the validation cohort, PEP developed in 5.0% and 14% of patients in the moderate- and high-risk groups, respectively. CONCLUSIONS: We successfully developed a good predictive model for PEP. The prevention of PEP in high risk patients should be investigated further.

Significance of portal venous blood flow as a factor to determine liver function in patients with decompensated cirrhosis due to hepatitis C virus infection following achievement of sustained viral response by sofosbuvir plus velpatasvir.

AIM: To determine the outcomes concerning portal venous blood flow and portosystemic shunts in patients with decompensated cirrhosis due to hepatitis C virus (HCV) infection who achieved sustained viral response (SVR) following antiviral therapy. METHODS: Portal hypertension-related events and liver function were evaluated in 24 patients achieving SVR following sofosbuvir plus velpatasvir therapy. RESULTS: Serum albumin level (median; g/dL) increased from 2.9 at baseline to 3.5 at 12 weeks after the end of treatment (EOT) (p = 0.005), while liver volumes (cm3 ) decreased from 1260 to 1150 (p = 0.0002). Portal hypertension-related events developed in 10 patients (41.7%), and the cumulative occurrence rates after the EOT were 29.2%, 33.3%, and 46.1% at 24, 48, and 96 weeks, respectively. Multivariate logistic regression analysis revealed that the maximal diameter of the shunts (p = 0.0235) was associated with the development of the events, with a cut-off value of 8.3 mm (p = 0.0105). Meanwhile, multiple linear regression analysis revealed that portal venous blood flow, liver volume, serum albumin, and bilirubin levels at baseline were associated with serum albumin levels at 12 weeks after EOT (p = 0.0019, p = 0.0154, p = 0.0010, and p = 0.0350, respectively). CONCLUSION: In patients with decompensated cirrhosis due to HCV infection, the baseline portal venous blood flow and liver volume and function were predictive of liver function following SVR, while the maximal diameter of portosystemic shunts predicted the occurrence of portal hypertension-related events.

Acute pancreatitis as the initial manifestation of acute myeloid leukemia with chromosome 16 rearrangements.

Acute pancreatitis is an acute inflammatory process of the pancreas that is becoming an increasingly common clinical issue. The most frequent underlying etiologies include gallstones and chronic alcohol use, which account for more than two-thirds of cases. We recently experienced a rare case of acute myeloid leukemia (AML) presenting with recurrent acute pancreatitis, which we later discovered was caused by diffusely infiltrating extramedullary sarcoma in the pancreas. Comprehensive analysis of previous cases of AML presenting as acute pancreatitis suggested involvement of cytogenetic alterations in chromosome 16 in its pathogenesis. Further improvement in management of acute pancreatitis is needed, and clinicians should note that this occasionally fatal condition can be the initial and only manifestation of AML. In practice, prompt initiation of intensive chemotherapy is critical for treating such cases of AML-induced acute pancreatitis.

Clinical Outcomes of Intraductal Papillary Mucinous Neoplasms With Dilatation of the Main Pancreatic Duct.

BACKGROUND & AIMS: Dilatation of the main pancreatic duct (MPD) has been a surgical indication for intraductal papillary mucinous neoplasms (IPMNs). Few studies have investigated long-term outcomes of IPMNs with MPD dilatation. METHODS: Among 3610 patients diagnosed with pancreatic cysts between 1994 and 2021, we identified 2829 IPMN patients, including 282 patients with MPD ≥5 mm, and examined short-term (≤6 months) and long-term risks of pancreatic carcinoma. Utilizing competing risks proportional hazards models, we estimated subdistribution hazard ratios for incidence of pancreatic carcinoma with adjustment for potential confounders. RESULTS: In analyses of short-term outcomes of the 282 patients with MPD dilatation, 72 (26%) patients were diagnosed with pancreatic carcinoma based on surgical or nonsurgical exploration. During long-term follow-up of 168 patients, we documented 24 (14%) patients diagnosed with pancreatic carcinoma (18 with IPMN-derived carcinoma and 6 with concomitant ductal adenocarcinoma). The patients with the MPD = 5-9.9 mm had cumulative incidence rates of pancreatic carcinoma diagnosis of 8.1% (95% confidence interval [CI], 4.3%-13.5%) and 10.0% (95% CI, 5.5%-15.9%) at 2 and 5 years, respectively; and the patients with the MPD ≥10 mm had the corresponding rates of 16.0% (95% CI, 3.6-36.5%) and 33.3% (95% CI, 10.3%-58.8%). The multivariable subdistribution hazard ratios were 2.78 (95% CI, 1.57-4.90) and 7.00 (95% CI, 2.58-19.0) for the MPD = 5-9.9 mm and ≥10 mm (vs <5 mm), respectively. CONCLUSIONS: IPMNs with MPD dilatation at baseline were associated with higher prevalence and incidence of pancreatic carcinoma compared with IPMNs with no MPD dilatation.

Comparison of novel large-bore and conventional-bore covered self-expandable metal stents for malignant gastric outlet obstruction: Multicenter, retrospective study.

OBJECTIVES: Covered self-expandable metal stent (cSEMS) for gastric outlet obstruction (GOO) has been developed to overcome tumor ingrowth but is prone to be associated with an increased risk of migration. Clinical impact of the novel large-bore cSEMS for malignant GOO remains unclear. METHODS: A total of 117 patients undergoing endoscopic cSEMS placement for malignant GOO were enrolled in this multicenter retrospective study. Technical and clinical success, adverse events, recurrent GOO, and survival after stent placement were compared between 24 mm-cSEMS (n = 49) and 20 mm-cSEMS (n = 68). RESULTS: Patient characteristics were well-balanced and thus similar survival was observed between the two groups (136 days vs. 89 days, P = 0.60). Technical success rate of 100% and clinical success rate of 96% were achieved both in 24 mm-cSEMS and 20 mm-cSEMS, respectively. The median cumulative time to recurrent GOO was significantly longer in 24 mm-cSEMS than in 20 mm-cSEMS (380 days vs. 138 days, P = 0.01). The incidence of adverse events and recurrent GOO was comparable: 12% vs. 15% (P = 0.91), and 16% vs. 31% (P = 0.11); however, no stent migration was observed in 24 mm-cSEMS. In a subgroup analysis, the superiority of 24 mm-cSEMS to 20 mm-cSEMS was demonstrated in extrinsic cancers (380 days vs. 121 days, P = 0.01) but not in intrinsic cancers (151 days vs. not reached, P = 0.47). CONCLUSIONS: The 24 mm-cSEMS may improve time to recurrent GOO with ensuring acceptable safety in patients with malignant GOO.

Increased risk of biliary infection after biliary stent placement in users of proton pump inhibitors.

Objectives: Proton pump inhibitors (PPIs) are widely prescribed medications for gastric acid-induced diseases. Despite the effectiveness of PPIs, recent evidence suggested an increased risk of various bacterial infections in PPI users. The current study was conducted to evaluate the risk of biliary infection after endoscopic biliary stent placement in regular users of PPIs. Methods: Consecutive patients with a native papilla who underwent endoscopic retrograde cholangiopancreatography and stent placement for biliary stricture between January 2010 and August 2019 were included in this retrospective study. The cumulative incidences of biliary infection were compared between regular and non-regular PPI users. Results: During the study period, 270 regular PPI users and 146 non-regular PPI users were included in the analyses. Age, gender, and indication of endoscopic retrograde cholangiopancreatography were not different between the two groups. The incidences of biliary infection were 43% in regular PPI users and 36% in non-regular PPI users but the time to biliary infection was significantly shorter in regular PPI users than in non-regular users (28 vs. 87 days, p = 0.01). The cumulative incidence of biliary infection was significantly higher in regular PPI users compared with non-regular users (p = 0.008). The multivariable Cox regression analysis also showed a significantly higher hazard ratio of biliary infection in regular PPI users (1.62 [95% confidence interval 1.16-2.26; p = 0.005]). Conclusions: Regular PPI use was associated with a higher risk of biliary infection after endoscopic biliary drainage. Inappropriate PPI use should be avoided.

Endoscopic Bridge-and-Seal of Bile Leaks Using a Fully Covered Self-Expandable Metallic Stent above the Papilla.

BACKGROUND/AIMS: Endoscopic management by endoscopic sphincterotomy with or without plastic stents or fully covered self-expandable metallic stents (FCSEMSs) is widely accepted as the current standard of care for postoperative bile leaks. Biliary stents are placed across the papilla, not above the papilla. We investigated the safety and effectiveness of the bridge-and-seal technique for bile leaks by the placement of FCSEMS above the papilla. METHODS: This was a retrospective study of FCSEMS placement above the papilla for bile leaks between October 2016 and July 2021. FCSEMS was placed above the papilla to bridge and seal the leak. The main outcome measures were the resolution of bile leaks and adverse events. RESULTS: Seven patients with postoperative bile leaks underwent FCSEMS above the papilla. The locations of bile leaks were 1 cystic duct remnant; 2 intrahepatic bile duct; 1 hepatic duct; 2 common bile duct and 1 anastomosis. The technical success rate of FCSEMS placement was 100%, and resolution of bile leaks was achieved in five patients (71.4%). All the adverse events were observed after FCSEMS removal; as follows: 1 moderate cholangitis; 2 mild post-ERCP pancreatitis; and 1 mild remnant cholecystitis. CONCLUSIONS: FCSEMS placement above the papilla can be a treatment option for postoperative bile leaks.

Intra-abdominal hemorrhage as a rare complication of endoscopic ultrasonography: A case report.

Intra-abdominal hemorrhage after endoscopic ultrasonography (EUS) is an uncommon complication, which can lead to potentially fatal outcomes. We describe a case of intra-abdominal hemorrhage due to left gastric arterial bleeding after EUS. The patient developed severe epigastric pain 10 h after diagnostic EUS for pancreatic cysts. Contrast-enhanced computed tomography revealed extravasation from the left gastric artery as well as a hematoma in the lesser omentum, which was confirmed by emergent angiography. Spontaneous hemostasis was obtained without embolization and the patient did not have further episodes of intra-abdominal hemorrhage. Endoscopists should be aware of this rare but serious complication after endoscopic procedures.

Endoscopic ultrasonography-guided tissue acquisition for small solid pancreatic lesions: Does the size matter?

Endoscopic ultrasonography-guided tissue acquisition (EUS-TA) is now an established technique to obtain the pathological diagnosis of solid pancreatic lesions (SPLs), but the diagnosis of small SPLS by EUS-TA can still be difficult. We conducted a literature review and a meta-analysis on the diagnostic yield of EUS-TA according to the tumor size. In a meta-analysis of 33 studies with 6883 cases, a pooled odds ratio (OR) of sensitivity was significantly higher in SPLs of >20 mm (OR 1.64, p = 0.02) and in SPLs of >10 mm (OR 3.05, p = 0.01), but not in SPLs of >30 mm (OR 1.18, p = 0.46). The meta-analysis of accuracy also showed a similar trend: OR of 1.59 in SPLs of >20 mm (p < 0.01) and OR of 3.27 in SPLs of >10 mm (p < 0.01) and OR of 1.03 in SPLs of >30 mm (p = 0.87). The use of a 25-gauge needle tended to improve sensitivity in small SPLs, though not statistically significant: OR of 1.25 and 2.82 in studies with and without a 25-gauge needle (p = 0.08). The use of fine needle biopsy needles, slow pull method, and rapid on-site evaluation did not significantly improve sensitivity in small SPLs. EUS-TA for small SPLs, especially neuroendocrine neoplasms, is reported to have a high risk of adverse events. In summary, the diagnostic yield and safety of EUS-TA for small (<20 mm) SPLs still needs improvement, and the best needle and technique for small SPLs should be further investigated.

MNX1-HNF1B Axis Is Indispensable for Intraductal Papillary Mucinous Neoplasm Lineages.

BACKGROUND & AIMS: Chromatin architecture governs cell lineages by regulating the specific gene expression; however, its role in the diversity of cancer development remains unknown. Among pancreatic cancers, pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMN) with an associated invasive carcinoma (IPMNinv) arise from 2 distinct precursors, and their fundamental differences remain obscure. Here, we aimed to assess the difference of chromatin architecture regulating the transcriptional signatures or biological features in pancreatic cancers. METHODS: We established 28 human organoids from distinct subtypes of pancreatic tumors, including IPMN, IPMNinv, and PDAC. We performed exome sequencing (seq), RNA-seq, assay for transposase-accessible chromatin-seq, chromatin immunoprecipitation-seq, high-throughput chromosome conformation capture, and phenotypic analyses with short hairpin RNA or clustered regularly interspaced short palindromic repeats interference. RESULTS: Established organoids successfully reproduced the histology of primary tumors. IPMN and IPMNinv organoids harbored GNAS, RNF43, or KLF4 mutations and showed the distinct expression profiles compared with PDAC. Chromatin accessibility profiles revealed the gain of stomach-specific open regions in IPMN and the pattern of diverse gastrointestinal tissues in IPMNinv. In contrast, PDAC presented an impressive loss of accessible regions compared with normal pancreatic ducts. Transcription factor footprint analysis and functional assays identified that MNX1 and HNF1B were biologically indispensable for IPMN lineages. The upregulation of MNX1 was specifically marked in the human IPMN lineage tissues. The MNX1-HNF1B axis governed a set of genes, including MYC, SOX9, and OLFM4, which are known to be essential for gastrointestinal stem cells. High-throughput chromosome conformation capture analysis suggested the HNF1B target genes to be 3-dimensionally connected in the genome of IPMNinv. CONCLUSIONS: Our organoid analyses identified the MNX1-HNF1B axis to be biologically significant in IPMN lineages.

Use of proton pump inhibitors and cholangitis complicated with multi-drug resistant bacteria.

BACKGROUND: Multidrug-resistant bacteria (MDRB) has rapidly spread worldwide and become a serious problem. Proton pump inhibitors (PPIs) are a class of commonly prescribed medications, but recent studies have suggested the increased risk of infection with MDRB in PPI users. We evaluated the association between PPI use and incidence of cholangitis with MDRB. METHODS: Consecutive patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) between January 2010 and August 2019 were included in this retrospective study. The incidence of cholangitis with MDRB was compared between regular and non-regular PPI users. RESULTS: A total of 1224 regular PPI users and 1528 non-regular PPI users were identified. There was no clinically significant difference in age and sex between the groups. Indication of ERCP was different between the groups. The number of ERCP sessions during the study periods was higher in regular PPI users. The incidence of cholangitis with MDRB was significantly higher in regular PPI users (3.0% vs 1.1%; P < .001). Multivariable-adjusted odds ratio for cholangitis with MDRB comparing regular PPI users to non-regular users was 2.19 (95% confidence interval 1.20-4.00; P = .01). CONCLUSIONS: Regular PPI use was associated with a higher risk of cholangitis with MDRB.