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INTRODUCTION:Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC) globally. Prolonged HBV DNA suppression with nucleos(t)ide analogues is known to regress hepatic fibrosis and reduce HCC risk. This is an unusual presentation of a patient with hepatitis B-associated HCC whose liver lesion resolved on antiviral therapy alone.CASE DESCRIPTION/METHODS:Patient is a 64-year-old Chinese male with HBeAg negative chronic hepatitis B with persistent normal serum aminotransferases and was antiviral treatment naïve. He had a positive family history of HCC and was first noted to have asymptomatic elevation of alpha-fetoprotein (AFP) to 648.9 ng/ml 6 months prior to his referral to Hepatology. During his initial Liver Center visit, the AFP increased to 1,900 ng/ml with elevated AFP-L3 at 18.4%. His hepatitis B remained inactive with normal ALT and minimal detectable HBV DNA at 1.6 log IU/ml (Table 1). He was started on entecavir 0.5 mg daily in view of his age and suspicious HCC complication. Initial MRI of the abdomen revealed lesions in segment 4 (2 cm) and segment 7 (2.1 cm) of the liver with arterial enhancement, venous washout and pseudocapsule. Targeted liver biopsy of segment 7 lesion and adjacent liver was performed within 2 weeks on entecavir therapy. The targeted liver specimen revealed a necrotic focus with loss of reticulin with strong immunoreactivity for cytokeratin Hep Par1 and Glypican-3; the findings were highly suspicious for HCC. The adjacent liver had only mild inflammation (grade 0-1) and minimal fibrosis (stage 0-1). Six weeks later, AFP decreased to 19 ng/dl but AFP-L3 remained elevated at 17%. On repeat CT scan, the segment 7 lesion decreased to 1.2 cm and no longer met OPTN HCC criteria. Patient remained clinically stable with optimal HBV DNA suppression. By 7-month follow-up, both AFP and AFP-L3 normalized and the liver lesions remained stable in size (Table 1). He continued to have regular monitoring and the segment 7 liver lesion was no longer visualized on abdominal MRI after 2 years.DISCUSSION:Nucleos(t)ide analogue therapy is known to suppress HBV replication but has not been reported to have direct effect on HCC. This HCC case is unique as the liver lesion regressed and resolved on entecavir therapy alone. While the molecular mechanism leading to the HCC resolution is currently unknown, this case highlights the beneficial role of prolonged HBV DNA suppression with antiviral therapy.Table 1.Changes in AFP, ALT, HBV DNA, and image findings during the course of hepatitis B treatment for this patient

Acute liver injury (ALI) is associated with multiple cellular events such as necrosis, apoptosis, oxidative stress and inflammation, which can lead to liver failure. In this study, we demonstrate a new role of microRNA (miR)‐208a in ALI. ALI was induced in wild‐type (WT) and miR‐208a knockout (KO) mice by CCl4 administration. Increased alanine aminotransferase and decreased hepatic miR‐208a levels were found in WT mice after acute CCl4 treatment. Histopathological evaluations revealed increased necrosis and decreased inflammation in miR‐208a KO compared with WT mice after CCl4 treatment. CCl4 treatment induced a higher alanine aminotransferase elevation and increased numbers of circulating extracellular vesicles (exosomes and microvesicles) in miR‐208a KO compared with WT mice. We found increased CCl4‐induced nuclear factor kappa B activation and tumor necrosis factor‐α induction and decreased monocyte chemoattractant protein 1 levels in miR‐208a KO compared with WT mice. Terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick‐end labeling assay indicated aggravated hepatic apoptosis and necrosis in CCl4‐treated miR‐208a KO compared with WT mice. CCl4 treatment induced a greater increase in cleaved caspase‐8, p18, and caspase‐3 in miR‐208a KO compared with WT mice. p53 is involved in various cell death pathways, including necrosis and apoptosis. Our in silico analysis revealed p53 as a predicted miR‐208a target, and we found enhanced p53 and cyclophilin D protein expressions in miR‐208a KO mice after CCl4 treatment. Increased liver injury in miR‐208a KO mice was further associated with increased Bax (B cell lymphoma 2–associated X protein) and p21 expression. Our in vitro results indicated a role of miR‐208a in cell death. We found that CCl4‐induced cytotoxicity was partially rescued by miR‐208a overexpression in RAW macrophages. Altogether, our results revealed a role of miR‐208a in ALI in mice and suggest a role for miR‐208a in regulating cell death. In this manuscript, we demonstrate a new role of miR‐208a in acute liver injury. Our results revealed a novel role of miR‐208a in acute liver injury in mice and suggest a role for miR‐208a in the regulation of hepatocyte apoptosis and necrosis.

Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous disease driven by genetic and environmental factors. MicroRNAs (miRNAs) serve as pleiotropic post‐transcriptional regulators of cellular pathways. Although several miRNAs have been associated with NAFLD and fibrosis, there are limited studies in humans examining their differential association with pathogenic factors or histological features of NAFLD. We examined the differential relationships of five of the best‐described circulating microRNAs (miR‐34a, miR‐122, miR‐191, miR‐192, and miR‐200a) with histological features and pathogenic factors of NAFLD. A cross‐sectional study was conducted to examine the relationship between relative levels of circulating microRNAs standardized by z‐scores and histological features of NAFLD, common NAFLD genetic polymorphisms, and insulin resistance measured by the enhanced lipoprotein insulin resistance index in 132 subjects with biopsy‐proven NAFLD. We found that miR‐34a, miR‐122, miR‐192, miR‐200a, but not miR‐191, strongly correlate with fibrosis in NAFLD by increases of 0.20 to 0.40 SD (P < 0.005) with each stage of fibrosis. In multivariate analysis, miR‐34a, miR‐122, and miR‐192 levels are independently associated with hepatic steatosis and fibrosis, but not lobular inflammation or ballooning degeneration, whereas miR‐200a is only associated with fibrosis. Among the four miRNAs, miR‐34a, miR‐122, and miR‐192 are associated with pathogenic factors of NAFLD, including insulin resistance measured by eLP‐IR, patatin‐like phospholipase domain containing 3 I148M, and transmembrane 6 superfamily 2 (TM6SF2) E167K polymorphisms. In contrast, miR‐200a is only associated with the TM6SF2 E167K variant. Finally, miR‐34a has the strongest predictive value for various stages of fibrosis, with C‐statistic approximates–combined predictive score for miRNAs. Conclusion: miR‐34a, miR‐122, miR‐192, and miR‐200a demonstrate strong associations with NAFLD severity by histology, but differential associations with pathogenic factors. Although some micro RNAs have been associated with nonalcoholic liver disease, human studies are limited. We provide independent validation of four of the best described miRNA (34a, 122, 192, and 200a) in their association with NAFLD phenotype and fibrosis. We also examine differential association with pathogenesis (insulin resistance and genetics) of the four miRNA.

We compared the pathological diagnoses obtained by anal Papanicolaou (Pap) smear with those obtained by anal biopsy or by surgical excision for 153 men who have sex with men (MSM). Analysis of these paired specimens showed that anal Pap smears were an inaccurate predictor of high-grade anal dysplasia, regardless of human immunodeficiency virus (HIV) serostatus. The presence of any abnormal anal cytological finding indicates a potential for high-grade dysplasia on histological examination of MSM.

Background Accurate assessment of viable HCC on pre-transplant cross sectional imaging is important for correct organ allocation and overall patient outcome following liver transplantation. Purpose Determine accuracy of LI-RADS TRA compared to explant pathology in patients treated with thermal ablation, using contrast enhanced multiphase CT and MRI. Materials and methods Imaging studies for 119 consecutive adult HCC patients treated with thermal ablation and liver transplantation from March 2001 to September 2019 at a single tertiary care hospital were retrospectively studied by three Board-certified radiologists. LI-RADS TRA categories for each tumor were compared with explant pathology. Cohens Kappa test and inter-reader agreement by Fleiss κ test, with 95% confidence intervals obtained with bootstrap technique were used. Results Of the 119 patients (median age 59 years, 95 [80%] male) with 165 HCCs treated with percutaneous thermal ablation, 68% were completely necrotic and 32% were viable on pathologic analysis. Tumors viable on explant were larger on pre-treatment imaging (median 2.4 vs. 2.1 cm; p  = 0.02) with no difference in pre-transplant ablation cavity sizes between groups (4.0 vs. 3.9 cm, respectively; p  = 0.58). NPV of LI-RADS TRA for viable tumor was 71% (68–74); PPV of 62.5% (39–81) ( p  = 0.01) with a sensitivity of 19% (9.4–32), specificity of 95% (89–98), and accuracy of 70% (63–77). On explant, 55 incidental treatment naïve viable tumors, not visible on pre-transplant imaging, were found in 33 patients. Conclusion The “non-viable” category of LI-RADS TRA even when applied to a relatively uniform percutaneous ablation cohort, demonstrated low sensitivity in predicting absence of viable tumor. MRI had more accuracy than CT in predicting tumor viability when compared to explant pathology.

AimsForegut cystic malformations are rare developmental abnormalities, which may involve the hepatopancreaticobiliary tract (HPBT). These cysts are composed of inner ciliated epithelium; subepithelial connective tissue layer; smooth muscle layer; and an outer fibrous layer. While radiopathologic findings are often diagnostic, atypical location and histologic features can pose a diagnostic challenge. We aimed to study ciliated foregut cysts (CFCs) in the HPBT, assess their clinicopathological features with a focus on atypical features.MethodsWe collected cases of CFCs involving the HPBT from three large academic medical centres. H&E-stained slides and immunohistochemical stains (where available) were reviewed for each case. Relevant demographic, clinical and pathological information was collected from the medical records.Results21 cases were identified. The median age was 53 years (range, 3–78 years). 17 cysts were identified within the liver (segment 4 was the most common location, n=10) and 4 in the pancreas. Cysts were mostly identified incidentally (n=13), abdominal pain was a common symptom (n=5). Cyst size ranged from 0.7 to 17.0 cm (median, 2.5 cm). Radiological findings were available in 17 cases. Cilia were identified in all cases. 19 of 21 cases demonstrated the presence of a smooth muscle layer (thickness, <0.1 mm to 3.0 mm). Three cases showed gastric metaplasia, while one case revealed additional low-grade dysplasia, with features similar to intraductal papillary neoplasm of the bile duct.ConclusionsWe highlight clinicopathological features of CFCs in the HPBT. The histomorphology is usually straightforward; however, unusual location and atypical features can pose a diagnostic challenge.

Nonalcoholic fatty liver disease (NAFLD) is a complex disease dictated by both genetic and environmental factors. While insulin resistance (IR) is a key pathogenic driver, two common genetic variants in patatin‐like phospholipase domain containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) also impart significant risk for disease progression. Traditional approaches to NAFLD risk stratification rely on biomarkers of fibrosis, an end result of disease progression. We hypothesized that by combining genetics and a novel measurement for IR we could predict disease progression by the NAFLD activity score (NAS) and histologic presence of significant fibrosis. A total of 177 patients with biopsy‐proven NAFLD were enrolled in this cross‐sectional study. PNPLA3 I148M and TM6SF2 E167K genotypes were determined by TaqMan assays. The enhanced lipoprotein IR index (eLP‐IR) was calculated from serum biomarkers using nuclear magnetic resonance (NMR) spectroscopy. Multivariate regression models were used to study the relationships between genetics, IR, and histologic features of NAFLD. In the multivariate analysis, the eLP‐IR was strongly associated with histologic features of NAFLD activity and hepatic fibrosis (P < 0.001 to 0.02) after adjustment for potential confounders. PNPLA3 148M and TM6SF2 E167K genotypes were significantly associated with steatosis (P = 0.003 and P = 0.02, respectively). A combination of the eLP‐IR and genetic score was able to predict the presence of NAS ≥3 with an area under the receiver operating characteristic curve (AUROC) of 0.74. Adding age to this model predicted stages 3‐4 liver fibrosis with an AUROC of 0.82. Conclusion: This proof‐of‐concept study supports the hypothesis that genetics and IR are major determinants of NAFLD severity and demonstrates the feasibility of a new risk stratification paradigm using exclusively pathogenic factors. Studies in the past two decades demonstrated that genetics and insulin resistance are two major drivers of nonalcoholic fatty liver diseases (NAFLD). This study tested the feasibility of using a novel measurement of insulin resistance and a genetic score to predict NAFLD disease severity. This pathogenesis‐based strategy has many advantages over the conventional liver‐centric approach for risk stratification in the management of NAFLD.

Identification of patients with nonalcoholic fatty liver disease (NAFLD) who have advanced fibrosis is crucial. Vibration controlled transient elastography (VCTE) is an alternative to biopsy, although published experience with VCTE in a US population is limited. We performed a prospective cohort of 164 biopsy-proven NAFLD patients evaluated with VCTE using an M probe and the NAFLD fibrosis score (NFS) at baseline and a repeat VCTE at 6 months. Reliable liver stiffness measurements (LSMs) were defined as 10 valid measurements and interquartile range ≤30% of the median. A total of 120 (73.2%) patients had reliable LSM. The median LSMs for patients with and without F3-F4 (advanced) fibrosis were 6.6 kPA (5.3-8.9) and 14.4 kPA (12.1-24.3), respectively. The optimal LSM cutoff for advanced fibrosis was 9.9 kPA (sensitivity 95% and specificity 77%). In addition, 100% of patients with LSM<7.9 kPA did not have advanced fibrosis. A risk stratification strategy based on VCTE avoids the need for biopsy in at least the 74 (45.1%) patients correctly classified as low risk for advanced fibrosis. For the detection of F3-F4 fibrosis in patients with reliable VCTE, the area under the receiver operating curve (AUROC) is 0.93 (95% CI: 0.86-0.96). This is superior to the AUROC for the NFS (0.77), P=0.01. Patients who achieved a ≥5% weight loss at 6-month follow-up experienced improved LSM (P=0.009), independent of the changes in aminotransferase levels. Reliable VCTE results can rule out advanced fibrosis and avoid the need for biopsy in at least 45% of US patients with NAFLD. However, 1 in 4 patients have uninterpretable studies using the M probe.

ObjectiveAlcohol use in metabolic dysfunction-associated steatohepatitis (MASH) is associated with an increased risk of fibrosis and liver-related death. Here, we aimed to identify a mechanism through which repeated alcohol binges exacerbate liver injury in a high fat-cholesterol-sugar diet (MASH diet)-induced model of MASH.DesignC57BL/6 mice received either chow or the MASH diet for 3 months with or without weekly alcohol binges. Neutrophil infiltration, neutrophil extracellular traps (NETs) and fibrosis were evaluated.ResultsWe found that alcohol binges in MASH increase liver injury and fibrosis. Liver transcriptomic profiling revealed differential expression of genes involved in extracellular matrix reorganisation, neutrophil activation and inflammation compared with alcohol or the MASH diet alone. Alcohol binges specifically increased NET formation in MASH livers in mice, and NETs were also increased in human livers with MASH plus alcohol use. We discovered that cell-free NETs are sensed via Nod-like receptor protein 3 (NLRP3). Furthermore, we show that cell-free NETs in vitro induce a profibrotic phenotype in hepatic stellate cells (HSCs) and proinflammatory monocytes. In vivo, neutrophil depletion using anti-Ly6G antibody or NET disruption with deoxyribonuclease treatment abrogated monocyte and HSC activation and ameliorated liver damage and fibrosis. In vivo, inhibition of NLRP3 using MCC950 or NLRP3 deficiency attenuated NET formation, liver injury and fibrosis in MASH plus alcohol diet-fed mice (graphical abstract).ConclusionAlcohol binges promote liver fibrosis via NET-induced activation of HSCs and monocytes in MASH. Our study highlights the potential of inhibition of NETs and/or NLRP3, as novel therapeutic strategies to combat the profibrotic effects of alcohol in MASH.

To assess outcomes after microcoil embolization for active lower gastrointestinal (GI) bleeding. We retrospectively studied all consecutive patients in whom microcoil embolization was attempted to treat acute lower GI bleeding over 88 months. Baseline, procedural, and outcome parameters were recorded following current Society of Interventional Radiology guidelines. Outcomes included technical success, clinical success (rebleeding within 30 days), delayed rebleeding (>30 days), and major and minor complication rates. Follow-up consisted of clinical, endoscopic, and pathologic data. Nineteen patients (13 men, 6 women; mean age +/- 95% confidence interval = 70 +/- 6 years) requiring blood transfusion (10 +/- 3 units) had angiography-proven bleeding distal to the marginal artery. Main comorbidities were malignancy (42%), coagulopathy (28%), and renal failure (26%). Bleeding was located in the small bowel (n = 5), colon (n = 13) or rectum (n = 1). Technical success was obtained in 17 patients (89%); 2 patients could not be embolized due to vessel tortuosity and stenoses. Clinical follow-up length was 145 +/- 75 days. Clinical success was complete in 13 (68%), partial in 3 (16%), and failed in 2 patients (11%). Delayed rebleeding (3 patients, 27%) was always due to a different lesion in another bowel segment (0 late rebleeding in embolized area). Two patients experienced colonic ischemia (11%) and underwent uneventful colectomy. Two minor complications were noted. Microcoil embolization for active lower GI bleeding is safe and effective in most patients, with high technical and clinical success rates, no procedure-related mortality, and a low risk of bowel ischemia and late rebleeding.