Soluble CD163 is a predictor of fibrosis and hepatocellular carcinoma development in nonalcoholic steatohepatitis.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. The serum level of soluble CD163 (sCD163), a macrophage activation marker, is associated with liver tissue changes; however, its prognostic value is unknown. Here, we determined the utility of sCD163 as a marker for hepatocellular carcinoma (HCC) and prognostic marker for NAFLD. METHODS: This retrospective study obtained data regarding serum sCD163 levels, liver histology, and background factors associated with NAFLD in 287 patients (men/women, 140/147; average age, 53 ± 14 years) with NAFLD who underwent liver biopsy. Repeated liver biopsies of 287 patients with NAFLD (5.0 ± 2.7 years) were compared regarding serum sCD163 levels and liver tissue changes (stage, grade, steatosis, and NAFLD activity score). RESULTS: Serum sCD163 levels increased with the progression of liver fibrosis and inflammation (both P < 0.05) and were particularly helpful in distinguishing cases of Grade 4 fibrosis (P < 0.001). Levels of sCD163 significantly decreased in patients with NAFLD exhibiting alleviated fibrosis and inflammation (P < 0.05). We could also predict the development of HCC and associated mortality based on serum sCD163 levels at the time of NAFLD diagnosis. Serum sCD163 levels were higher in patients with HCC than in patients without HCC (1074 ± 379 ng/ml vs. 669 ± 261 ng/ml; P < 0.0001), and the same trend was observed for mortality. CONCLUSIONS: The serum sCD163 level reflects the progression of fibrosis and inflammation in liver tissues, showing much promise as a noninvasive biomarker for nonalcoholic steatohepatitis and NAFLD as well as a possible predictor of HCC development and patient prognosis.

Lean nonalcoholic fatty liver disease: Age-dependent differences in pathology, prognosis, and liver-related events.

AIM: This study aimed to evaluate the age-specific characteristics, prognosis, and complications of patients with lean nonalcoholic fatty liver disease (NAFLD). METHODS: Background factors (age, sex, diabetes, dyslipidemia, hypertension, and PNPLA3 gene polymorphism), blood test results, liver histology findings, muscle mass, and grip strength were investigated in 782 patients with NAFLD who underwent liver biopsy. Prognosis and complications were compared among 549 patients with nonlean or lean NAFLD who were followed up for 6.5 years. Additionally, background factors, blood test results, liver histology findings, prognosis, and complications were compared according to age (≥60 years vs. <60 years) in patients with lean NAFLD. RESULTS: Lean NAFLD patients showed lower aspartate aminotransferase, alanine aminotransferase, homeostasis model assessment-insulin resistance, high-sensitivity C-reactive protein, ferritin, and leptin but higher adiponectin and hemoglobin A1c (HbA1c) levels than patients with nonlean NAFLD. Furthermore, lean NAFLD patients showed less liver fibrosis, inflammation, steatosis, and ballooning. Among lean NAFLD patients, those aged 60 years and older were more frequently female, showed higher rates of hypertension, diabetes, and dyslipidemia, had higher HbA1c and type IV collagen 7S levels, lower platelet count, higher liver fibrosis and inflammation grades, and lower muscle mass and grip strength. Lean NAFLD was associated with a worse prognosis in patients aged 60 years and over than in those younger than 60 years of age and with a higher incidence of liver-related disease, cerebrocardiovascular events, and nonliver cancer. CONCLUSIONS: Age is an important consideration in patients with lean NAFLD. Compared with nonlean NAFLD, lean NAFLD was associated with a worse prognosis and higher risk of complications in patients aged 60 years and older.

Differences between patients with inpatient-onset and outpatient-onset acute lower gastrointestinal bleeding: An observational study.

BACKGROUND AND AIM: The clinical severity and course of acute lower gastrointestinal bleeding (ALGIB) are believed to differ between inpatient-onset and outpatient-onset cases, but no reports have investigated these issues in detail. We aimed to evaluate the clinical differences between inpatient-onset and outpatient-onset ALGIB. METHODS: Medical records of patients who had undergone emergency colonoscopy for ALGIB were retrospectively reviewed. The severity was evaluated using the NOBLADS score. Patients with obvious ALGIB relapse and/or persistent iron-deficiency anemia after emergency colonoscopy were considered to exhibit a poor clinical course. RESULTS: We reviewed 723 patients with ALGIB and divided them into the inpatient-onset cohort (172 patients) and outpatient-onset cohort (551 patients). Compared with the outpatient-onset cohort, the inpatient-onset cohort had a significantly higher proportion of patients with a poor clinical course (51.2% vs 21.6%; P < 0.001) and a significantly higher mean NOBLADS score (3.6 ± 1.1 vs 2.5 ± 1.0; P < 0.001). The most common bleeding source was acute hemorrhagic rectal ulcer (52.3%) in the inpatient-onset cohort and colonic diverticular bleeding (29.4%) in the outpatient-onset cohort. Multivariate analysis showed that a platelet count < 15 × 104 /µL and albumin concentration < 3 g/dL were significantly associated with a poor clinical course in the inpatient-onset cohort. CONCLUSIONS: The clinical course was significantly worse in the inpatient-onset cohort than in the outpatient-onset cohort. The bleeding source, clinical characteristics, and clinical course differed between the inpatient-onset and outpatient-onset cohorts. The clinical course in the inpatient-onset cohort may depend on the patient's condition at ALGIB onset.

Two Cases of Acute Gastric Mucosal Lesions Due to Helicobacter pylori Infection Confirmed to be Transient Infection.

Two adult cases of acute gastric mucosal lesions (AGML) caused by Helicobacter pylori infection were confirmed by spontaneous eradication during the follow-up period. The clinical course of the initial infection by H. pylori in adults with AGML remains unclear, whether it is transient or progresses to a persistent infection. In these two reported cases, gastric biopsies at the time of the onset revealed the presence of H. pylori; however, serum H. pylori antibodies performed at the same time were negative. Retesting for H. pylori serum antibody, after six months in one and after two months in the other, was negative, confirming spontaneous eradication.

[Evacuation of tissue and blood biomarkers of progression to NASH cirrhosis by six liver biopsies: a case report].

We present a 56-year-old female patient diagnosed with stage 2/grade 3 non-alcoholic steatohepatitis (NASH) via liver biopsy. Over the next 14 years, six liver biopsies were performed, and the patient was followed up clinically. This was a valuable case wherein we were able to investigate the histology of the liver and the timing of changes in the AST/ALT ratio, platelets, albumin, FIB4-Index, and liver fibrosis markers.

Severe grade of melanosis coli is associated with a higher detection rate of colorectal adenoma.

The severity and distribution of melanosis coli differ among individuals, and the related factors remain unknown. Additionally, their clinical implications have not been sufficiently demon-strated. Thus, we aimed to detect clinical factors related to the severity and range of melanosis coli and elucidate the associations between the grade, location, and detection rate of colorectal neoplasms. Colonoscopy cases performed at our institution from January 2011 to February 2021 were included. Melanosis coli was classified into mild and severe grades. Clinical characteristics and neoplasm detection rates were compared between the mild and severe MC groups and between the right-sided and whole-colon melanosis coli groups. Overall, 236 MC (mild, n = 143; severe, n = 93) cases, of which 50 were right-sided, 5 were left-sided, and 181 were whole-colon melanosis coli cases, were enrolled. The proportion of anthranoid users was higher in the severe melanosis coli group than in the mild melanosis coli group. The adenoma detection rate was higher in the severe melanosis coli and whole-colon melanosis coli groups. The prevalence of neoplasms measuring 5-9 mm and >9 mm was higher in the severe melanosis coli group (p<0.01 and p = 0.04). Severe melanosis coli due to anthranoid usage is associated with colorectal adenoma development.

Treatment of ectopic variceal bleeding at choledochojejunostomy by endoscopic glue injection therapy with cyanoacrylate: Report of three cases including long-term outcomes.

Ectopic varices around the choledochojejunostomy site after pancreatoduodenectomy are rare. Diagnosing ectopic varices is difficult but, if untreated or misdiagnosed, the resulting mortality is high. This report describes three cases of ectopic variceal bleeding at the choledochojejunostomy site that were improved by endoscopic glue injection therapy (EGIT) with cyanoacrylate (CA). Case 1 was a 68-year-old man admitted to the hospital with hematemesis and melena. Six years prior, the patient underwent a total pancreatectomy for intraductal papillary mucinous adenocarcinoma. We diagnosed ectopic variceal rupture at the choledochojejunostomy site and controlled bleeding by EGIT with alpha-CA (αCA). Two recurrences of bleeding were improved by EGIT. Case 2 was a 71-year-old man admitted to the hospital with melena. Two and a half years prior, the patient underwent pancreatoduodenectomy for pancreatic head adenocarcinoma. We found the red plug on the ectopic varices at the choledochojejunostomy site through endoscopic observation and performed EGIT with αCA. He had no recurrence. Case 3 was a 77-year-old woman admitted to the hospital with melena. Eleven years prior, the patient underwent pancreatoduodenectomy for chronic pancreatitis at the pancreatic head. We controlled ectopic variceal bleeding at the choledochojejunostomy site by EGIT with αCA. Seven years after EGIT, ectopic varices could not be identified with an endoscope and there was no recurrence of ectopic bleeding.

Asymptomatic gangrenous cholecystitis diagnosed using contrast-enhanced ultrasonography in a patient with pancreatic cancer.

A 72-year-old female without abdominal symptoms visited our hospital for routine follow-up while undergoing pancreatic cancer treatment (using TS-1). Her vital signs were normal, and her abdomen was soft and non-tender. Blood test revealed elevated C-reactive protein levels with normal white blood cell count. Computed tomography was performed for follow-up of pancreatic cancer. Contrast-enhanced computed tomography showed partial discontinuity and irregular thickness of the gallbladder wall; however, a definitive diagnosis was not obtained due to unclear imaging. Contrast-enhanced transabdominal ultrasonography revealed intraluminal membranes in the gallbladder and a perfusion defect at the bottom, indicating gangrenous cholecystitis. Surgical resection was performed, and pathological examination showed severe necrosis of the gallbladder wall, consistent with the findings of contrast-enhanced transabdominal ultrasonography.

Afferent-Loop Syndrome Treated with Endoscopic Ultrasound-Guided Drainage of the Afferent Loop with a Plastic Stent.

Afferent-loop syndrome (ALS) is known as a rare complication of partial or total gastrectomy and also occurs after pancreatoduodenectomy. The symptoms of ALS vary with the location of the mechanical obstruction, and the choice of therapeutic method should reflect the patient's condition and disease state. Herein, we report the use of endoscopic ultrasound (EUS)-guided afferent loop drainage with a plastic stent and its reintervention for malignant ALS. An 80-year-old man was admitted to our hospital with abdominal pain. Thirty-two months before, the patient underwent left hepatectomy with choledochojejunostomy and Roux-en-Y reconstruction for hilar biliary adenocarcinoma. An abdominal CT scan showed a dilated afferent loop and a low-density lesion in the peritoneum that suggested recurrence of hilar biliary adenocarcinoma and malignant ALS due to mechanical obstruction of the afferent loop caused by peritoneal dissemination. The recurrence site did not include the choledochojejunostomy anastomosis and was far distal to it. We employed a convex EUS scope and directly punctured the afferent loop from the stomach. We inserted one double pig-tail stent, and the ALS immediately improved. Five months later, ALS recurred, and we exchanged a plastic stent through the fistula. After reintervention, ALS did not recur before the patient's death due to cancer progression.

Efficacy of primary drainage by endoscopic ultrasound-guided biliary drainage for unresectable pancreatic adenocarcinoma.

Background and Aim: Obstructive jaundice induced by pancreatic adenocarcinoma is typically treated with biliary drainage with endoscopic retrograde cholangiopancreatography (ERCP)-guided biliary drainage (ERCP-BD). Recently, endoscopic ultrasonography-guided biliary drainage (EUS-BD) was employed as an alternative method after ERCP-BD failed. We aimed to determine the efficacy and safety of EUS-BD for primary biliary drainage. Methods: Between December 2011 and February 2019, at Kawasaki General Medical Center, we retrospectively enrolled 33 patients who had undergone endoscopic biliary drainage with a metal stent, in a first attempt to relieve obstructive jaundice caused by unresectable pancreatic adenocarcinoma. We compared the technical and clinical outcomes between ERCP-BD and EUS-BD. Results: Twenty-three patients underwent ERCP-BD and 10 underwent EUS-BD. Both groups achieved 100% technical success. The clinical success rates were similar between the groups: 91% (21/23 patients) for ERCP-BD and 100% (10/10 patients) for EUS-BD (P = 0.48). Biliary obstruction recurred in 6/23 patients (26%) treated with ERCP-BD and 1/10 patients (10%) treated with EUS-BD (P = 0.40). Other adverse events occurred in 4/23 patients (17%) in the ERCP-BD group and 1/10 patients (10%) in the EUS-BD group (P = 0.99). Conclusion: We suggest that EUS-BD could be employed for primary biliary drainage in patients with obstructive jaundice caused by unresectable pancreatic adenocarcinoma.

Increased Colonic Fluorodeoxyglucose Uptake in Melanosis Coli-A Case Series of Three Patients.

We report 3 Japanese cases with increased colonic 18-fluorodeoxyglucose (FDG) uptake in association with melanosis coli. Case 1: A 56-year-old woman received 18-FDG positron emission tomography (PET) for comprehensive medical checkup. Case 2: A 79-year-old man received FDG-PET for follow-up evaluation for intestinal cancer. Case 3: A 51-year-old woman received FDG-PET for medical checkup. Each showed increased cecal and/or ascending colonic uptake without any colonic wall changes. Colonoscopy detected melanosis coli where FDG uptake was demonstrably increased. Neither malignancy nor inflammatory response was confirmed. Succeeding follow-ups showed neither malignant nor inflammatory lesions in any of the patients.

Combination of type IV collagen 7S, albumin concentrations, and platelet count predicts prognosis of non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and affects approximately 25% of the general global adult population. The prognosis of NAFLD patients with advanced liver fibrosis is known to be poor. It is difficult to assess disease progression in all patients with NAFLD; thus, it is necessary to identify patients who will show poor prognosis. AIM: To investigate the efficacy of non-invasive biomarkers for predicting disease progression in patients with NAFLD. METHODS: We investigated biomarkers associated with mortality in patients with NAFLD who visited the Kawasaki Medical School General Medical Center from 1996 to 2018 and underwent liver biopsy and had been followed-up for > 1 year. Cumulative overall mortality and liver-related events during follow-up were calculated using the Kaplan-Meier analysis and compared using log-rank testing. We calculated the odds ratio and performed receiver operating characteristic curve analysis with logistic regression analysis to determine the optimal cut-off value with the highest prognostic ability. RESULTS: We enrolled 489 patients who were followed-up for a period of 1-22.2 years. In total, 13 patients died (2.7% of total patients enrolled); 7 patients died due to liver-related causes. Poor prognosis was associated with liver fibrosis on histological examination but not with inflammation or steatosis. Blood biomarkers associated with mortality were platelet counts, albumin levels, and type IV collagen 7S levels. The optimal cutoff index for predicting total mortality was a platelet count of 15 × 104/µL, albumin level of 3.5 g/dL, and type IV collagen 7S level of 5 mg/dL. In particular, only one-factor patients with NAFLD presenting with platelet counts ≤ 15 × 104/µL, albumin levels ≤ 3.5 g/dL, or type IV collagen 7S ≥ 5 mg/dL showed 5-year, 10-year, and 15-year survival rates of 99.7%, 98.3%, and 94%, respectively. However, patients with two factors had lower 5-year and 10-year survival rates of 98% and 43%, respectively. Similarly, patients with all three factors showed the lowest 5-year and 10-year survival rates of 53% and 26%, respectively. CONCLUSION: A combination of the three non-invasive biomarkers is a useful predictor of NAFLD prognosis and can help identify patients with NAFLD who are at a high risk of all-cause mortality.

Disappearance of Gastric Hyperplastic Polyps after the Discontinuation of Proton Pump Inhibitor in a Patient with Liver Cirrhosis.

Here, we report on a rare case of gastric hyperplastic polyps which disappeared after the discontinuation of proton pump inhibitor (PPI). The patient was an 83-year-old woman with liver cirrhosis and portal hypertension, along with gastroesophageal reflux disease treated by PPI. An initial upper gastrointestinal endoscopy showed unique polypoid lesions in the greater curvature of the stomach. Biopsy specimens of the lesions were diagnosed as hyperplastic polyps and she was followed. One year later, a second endoscopy showed that the lesions had increased in number and size, and an endoscopic mucosal resection (EMR) was performed for the main polyps. The resected specimens indicated a proliferation of foveolar epithelium cells with an increase of capillary ectasia and parietal cell hyperplasia, which was thought to be induced by hypergastrinemia from the PPI. Three months after the EMR, she was admitted because of bleeding from the remaining polyps along with an increase in new polyps. After conservative treatment, PPI was stopped and rebamipide was used. One year and 6 months later, an endoscopy showed the complete disappearance of all gastric polyps.

Progression from Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis Cirrhosis Confirmed by Liver Histology after 14 Years.

A 44-year-old patient progressed from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) cirrhosis. She was diagnosed with NAFL via a liver biopsy. At 56 years old, she was diagnosed with NASH stage 3 via a second liver biopsy. One year later, she was diagnosed with NASH cirrhosis via a third liver biopsy. This is the first study to report the gradual deterioration of liver histology shown via three liver biopsies and fibrosis markers in a patient who progressed from NAFL to NASH cirrhosis. Following menopause, it is necessary to be aware of the rapid development of liver fibrosis.

Differences in emergency endoscopy outcomes according to gastrointestinal bleeding location.

BACKGROUND AND AIM: With recent technological advances in the field of endoscopic hemostasis, the prognosis of patients with gastrointestinal (GI) bleeding has improved. However, few studies have reported on the clinical course of patients with GI bleeding. This study aimed to evaluate the differences in clinical outcomes of patients with lower GI bleeding (LGIB) compared with upper GI bleeding (UGIB) and the factors related to their prognosis. METHODS: Patients who had undergone emergency endoscopy for GI bleeding were retrospectively reviewed. The severity of GI bleeding was evaluated using the Glasgow-Blatchford (GB), AIMS65, and NOBLADS scores. Patients in whom obvious GI bleeding relapsed and/or iron deficiency anemia persisted after emergency endoscopy were considered to exhibit rebleeding. RESULTS: We reviewed 1697 consecutive patients and divided them into UGIB (1054 patients) and LGIB (643 patients) groups. The proportion of patients with rebleeding was significantly greater in the UGIB group than in the LGIB group; the mortality rate was significantly higher in the UGIB group than in the LGIB group. Multivariate analysis showed that a GB score ≥12 and an AIMS65 score ≥2 were significantly associated with rebleeding in the UGIB group, whereas a NOBLADS score ≥4 was significantly associated with rebleeding in the LGIB group. Notably, the influence of emergency endoscopy differed according to GI bleeding location. CONCLUSIONS: The clinical course was significantly worse in patients with UGIB than in patients with LGIB. The influence of emergency endoscopy differed according to GI bleeding location.

High Prevalence of Autoimmune Gastritis in Patients with Nonalcoholic Steatohepatitis.

Objective To evaluate the prevalence of autoimmune gastritis in patients with histologically proven nonalcoholic steatohepatitis (NASH). Methods A total of 33 patients with NASH and 143 patients with chronic liver disease (66, 24, 22, 10, 1, and 21 patients with hepatitis C, hepatitis B, autoimmune hepatitis/primary biliary cholangitis, non-B/non-C hepatitis, fatty liver, and alcoholic disease, respectively) who underwent upper gastrointestinal endoscopy between January 2013 and August 2016 were retrospectively assessed to determine the prevalence of autoimmune gastritis. The clinical characteristics of these patients with NASH and autoimmune gastritis were examined, and the clinical characteristic and biomarkers were compared between patients with NASH with and without autoimmune gastritis. Results Six of the 33 patients with NASH (19.4%) were diagnosed with autoimmune gastritis. The prevalence of autoimmune gastritis was higher in patients with NASH than in those with other chronic liver diseases [4/143 (2.8%), p=0.002]. All six patients with NASH and autoimmune gastritis exhibited high serum gastrin levels; five of the patients were positive for anti-parietal cell antibodies, and one was negative for anti-parietal cell antibodies but positive for intrinsic factor antibody. Furthermore, 1 patient presented with iron-deficiency anemia (hemoglobin <11 g/dL), but none developed pernicious anemia. Endocrine cell micronests were found in four patients. Patients with NASH and autoimmune gastritis tended to be older with lower ferritin levels than the other patients. Conclusion The prevalence of NASH with concomitant autoimmune gastritis was high, highlighting the need for upper endoscopy for the diagnosis of autoimmune gastritis and gastric malignancies.

Herpetic esophagitis following bendamustine-containing regimen.

A 76-year-old Japanese woman presented to our hospital with anorexia. Two years before, she was diagnosed with non-Hodgkin's lymphoma and had received ten cycles of systemic chemotherapy. After salvage chemotherapy with bendamustine and rituximab (B-R), bone marrow suppression had lasted >3 months. Esophagogastroscopy revealed polynesic white protrusions in the mid-esophagus. These lesions were diagnosed as herpetic esophagitis. To the best of our knowledge, there is no other report in which herpetic esophagitis has been documented as an adverse event of B-R regimen. Because the complication could cause symptomatic gastrointestinal discomfort, physicians should be aware of this disease.

Gliostatin/thymidine phosphorylase-regulated vascular endothelial growth-factor production in human fibroblast-like synoviocytes.

Gliostatin/thymidine phosphorylase (GLS/TP) is known to have angiogenic and arthritogenic activities. The purpose of this study was to elucidate whether GLS/TP is involved in the regulation of the angiogenic cytokine vascular endothelial growth factor (VEGF) in rheumatoid arthritis (RA). Fibroblast-like synoviocytes (FLSs) from patients with RA were cultured and stimulated with recombinant human GLS (rHuGLS) and interleukin (IL)-1beta. Immunohistochemistry showed that GLS/TP and VEGF were detectable in the synovial lining cells. In cultured FLSs, both VEGF mRNA and protein levels were markedly increased by rHuIL-1beta treatment. rHuGLS increased VEGF mRNA expression in a dose-dependent manner. We detected high concentrations of VEGF165 protein in culture supernatants from FLSs treated with rHuGLS (300 ng/ml), which were comparable to GLS levels found in synovial fluid of RA patients. These findings indicate that GLS/TP and VEGF have synergistic effects on angiogenesis in rheumatoid synovitis, and that GLS/TP has a role in regulating VEGF.

The inhibitory effect of disease-modifying anti-rheumatic drugs and steroids on gliostatin/platelet-derived endothelial cell growth factor production in human fibroblast-like synoviocytes.

Gliostatin/platelet-derived endothelial cell growth factor (GLS/PD-ECGF) is known to have both angiogenic and arthritogenic activities. The purpose of this study was to investigate whether disease-modifying anti-rheumatic drugs (DMARDs) and steroids are involved in the regulation of GLS expression. Fibroblast-like synoviocytes (FLSs) obtained from patients with rheumatoid arthritis (RA) were cultured and stimulated by interleukin (IL)-1beta with or without DMARDs and steroids. The expression levels of GLS were determined using the reverse transcription-polymerase chain reaction and an ELISA. In cultured rheumatoid FLSs, the expression of GLS mRNA was significantly increased by stimulation with IL-1beta. By contrast, GLS mRNA levels in IL-1beta-stimulated FLSs were reduced by treatment with aurothioglucose (AuTG) and dexamethasone (DEX). These findings indicate that AuTG and DEX have anti-rheumatic activity, which is mediated via the suppression of GLS production. Neither methotrexate (MTX) nor sulfasalazine (SSZ) had a significant influence on GLS levels in our study.