Search

Bleeding complications from ectopic varices are often difficult to manage. We aimed to study the natural history and outcomes of bleeding ectopic varices to better understand appropriate clinical management. This retrospective cohort study included patients admitted to the hospital with bleeding ectopic or esophageal varices from 2010 through 2019. Study subjects were identified through searching the Medical University of South Carolina's electronic medical record, and complete demographic, clinical, and procedural data were abstracted. 25 patients with gastrointestinal bleeding from ectopic varices and a matched group of 50 patients with bleeding esophageal varices were identified. Bleeding ectopic varices were identified in the following locations: duodenum (n=5), jejunum/ileum (n=5), colon (n=2), rectum (n=6), and anastomotic sites (n=7). Model for End-Stage Liver Disease scores (patients with cirrhosis), need for intensive care unit admission, and administration of octreotide and antibiotics were significantly higher in patients with esophageal variceal bleeding than those with ectopic varices. All-cause 1-year mortality of patients with ectopic varices was significantly lower than those with bleeding esophageal varices (8% vs 35%, p

BACKGROUND: Garcinia cambogia, either alone or with green tea, is commonly promoted for weight loss. Sporadic cases of liver failure from G. cambogia have been reported, but its role in liver injury is controversial. METHODS: Among 1418 patients enrolled in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2018, we identified 22 cases (adjudicated with high confidence) of liver injury from G. cambogia either alone (n=5) or in combination with green tea (n=16) or Ashwagandha (n=1). Control groups consisted of 57 patients with liver injury from herbal and dietary supplements (HDS) containing green tea without G. cambogia and 103 patients from other HDS. RESULTS: Patients who took G. cambogia were between 17 to 54 years, with liver injury arising 13 to 223 days (median = 51) after the start. One patient died, one required liver transplantation, and 91% were hospitalized. The liver injury was hepatocellular with jaundice. Although the peak values of aminotransferases were significantly higher (2001 ± 1386 U/L) in G. cambogia group (p

PURPOSE OF REVIEW: This article discusses the most recent studies regarding the emerging field of endohepatology – the use of diagnostic and therapeutic endoscopic tools for management of patients with liver disease and portal hypertension. RECENT FINDINGS: New research has shown that liver biopsy specimens obtained by each EUS-guidance, the percutaneous approach, and the transjugular approach contained sufficient portal triads to adequately analyzed by experienced pathologists – suggesting that any of these routes of liver biopsy is clinically acceptable; further, all had similar rates of adverse events. An initial prospective study showed that EUS guided portal pressure measurement was safe, effective, and accurate. A recent metanalysis showed that EUS-guided cyanoacrylate injection and coil embolization was statistically more efficacious and with less complications than EUS guided cyanoacrylate injection and EUS guided coil injection alone, suggesting that combination therapy appears to be the preferred approach for GV bleeding. A prospective study evaluating focal liver lesions showed that the use of artificial intelligence had up to 100% sensitivity and 81% specificity for identifying malignant focal liver lesions. SUMMARY: EUS guided liver biopsy is safe and enables accurate diagnosis of underlying liver disease. EUS guided portal pressure measurement is also safe, and is accurate. Combination therapy of EUS guided cyanoacrylate injection and coil embolization is more efficacious and has less complications than injection or coil therapy alone when used for GV bleeding. Artificial intelligence is highly sensitive and specific when used in conjunction with EUS in the diagnosis of malignant focal liver lesions. Endohepatology is a rapidly expanding field with great potential.

Supplementary Appendix 3 from Screening for Colorectal Cancer in a Safety-Net Health Care System: Access to Care Is Critical and Has Implications for Screening Policy

Supplementary Appendix 2 from Screening for Colorectal Cancer in a Safety-Net Health Care System: Access to Care Is Critical and Has Implications for Screening Policy

Background: Data on the number of individuals eligible for screening, and rates of screening, are necessary to assess national colorectal cancer screening efforts. Such data are sparse for safety-net health systems.Methods: A retrospective cohort study of individuals ages 50 to 75 served by a safety-net health system in Tarrant County, TX was conducted to determine (a) the size of the potential screen-eligible population ages 50 to 75, (b) the rate of screening over 5 years among individuals ages 54 to 75, and (c) the potential predictors of screening, including sex, race/ethnicity, insurance status, frequency of outpatient visits, and socioeconomic status.Results: Of 28,708 potential screen-eligible individuals, 20,416 were ages 54 to 75 and analyzed for screening; 22.0% were screened within the preceding 5 years. Female gender, Hispanic ethnicity, ages 65 to 75, insurance status, and two or more outpatient visits were independently associated with screening. Access to care was an important factor: adjusted odds ratio, 2.57 (95% confidence interval, 2.23-2.98) for any insurance; adjusted odds ratio, 3.53 (95% confidence interval, 3.15-3.97) for two or more outpatient visits.Conclusions: The screen-eligible population served by our safety-net health system was large, and the projected deficit in screen rates was substantial. Access to care was the dominant predictor of screening participation. If our results are replicable in similar health systems, the data suggest that screening guidelines and policy efforts must take into account the feasibility of proposed interventions. Strong advocacy for more resources for colorectal cancer screening interventions (including research into the best manner to provide screening for large populations) is needed. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2373–9)

Supplementary Appendix 1 from Screening for Colorectal Cancer in a Safety-Net Health Care System: Access to Care Is Critical and Has Implications for Screening Policy

BACKGROUND AND AIM: Portal hypertensive gastropathy (PHG) most commonly occurs in the setting of increased portal pressure in patients with cirrhosis. Here, we aimed to understand the correlation between hepatic venous pressure gradient (HVPG) and the presence and severity of PHG in patients with cirrhosis. METHODS: We examined patients with cirrhosis who underwent HVPG measurement at the Medical University of South Carolina between 2014 and 2020. Extensive demographic, clinical, laboratory, procedural (including precise grading of PHG severity using standard definitions), and outcome data were abstracted at the time of HVPG measurement. RESULTS: Three hundred and ten patients with HVPG measurements and cirrhosis were identified. Seventy-three patients having endoscopy within 6 months of HVPG measurement were included (mean age 54 ± 11, 44% female). The most common causes of cirrhosis were alcohol (41%) and non-alcoholic steatohepatitis (32%). The average HVPG was 15 mmHg (±6) and 62 patients had clinically significant portal hypertension (CSPH) (HVPG ≥ 10 mmHg). Of the 73 patients with HVPG measured, 45 (62%) had PHG, including 40 (89%) of whom had CSPH. Out of the 45 patients with PHG, 41 and four had mild or severe PHG, respectively. MELD scores were similar in patients with and without PHG [15 ± 9 (SD) and 17 ± 9, respectively; p=.37]. HVPG was higher in patients with PHG (17 ± 7 mmHg) than those without PHG (13 ± 4 mmHg) (p=.01) but did not differ between mild and severe PHG. CONCLUSION: A weak correlation exists between HVPG level and the presence of PHG.

Previous studies in upper gastrointestinal (GI) bleeding have reported inconsistent outcomes about packed red blood cell (PRBC) transfusion practices.To assess whether PRBC transfusion is more likely to be dangerous in variceal bleeding than in non-variceal bleeding due to concern of over-transfusion leading to elevated portal pressure.We used the Nationwide Inpatient Sample (1999-2018). We identified patients with upper GI bleeding using an algorithmic approach, categorising bleeding from non-variceal or variceal sources. Our primary outcome was all-cause inpatient mortality. To control for the severity of bleeding, we performed propensity matching of baseline features, including age, gender, the presence of shock, the need for ICU care and co-morbidities. We also examined PRBC transfusion, inpatient mortality and hospitalisation rates for both populations.We included 10,228,524 upper GI bleeding discharges; 755,135 patients had variceal bleeding. After propensity matching, PRBC transfusion in variceal bleeders was associated with a 22% increase in inpatient mortality, whereas non-variceal bleeders had a 9% increase in inpatient mortality. Compared to non-variceal bleeders receiving blood transfusion, variceal bleeders had nearly four-fold higher odds of inpatient mortality (propensity-matched OR: 3.8; 95% CI: 3.7-3.8; p 0.001). Notably, PRBC transfusion rates in both groups have declined since 2011, although it has remained higher in variceal bleeders. Mortality for upper GI bleeding has been declining since 1999.Although decreased over the last decade, PRBC transfusion rates remain high for variceal bleeders. In addition, PRBC transfusion appears to be more detrimental in variceal bleeders than in non-variceal bleeders.

The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. The aim of this study was to determine whether liver histology impacted causality assessment in suspected DILI using a novel simulation model.Fifty patients enrolled in the DILI Network (DILIN) who had liver biopsies performed within 60 days of DILI onset were randomly selected. All had standard DILIN consensus causality scoring using a 5-point scale (1=definite, 2=highly likely, 3=probable, 4=possible, 5=unlikely) based on 6-month post-injury data. Three experienced hepatologists independently performed a causality assessment using redacted case records, with the biopsy and selected post-biopsy laboratory data removed. The 3 hepatologists also reviewed the liver histology with a hepatopathologist and then repeated causality assessment for each case.Of the 50 cases, there were 42 high causality DILI cases (1, 2 or 3) and 8 low causality cases (4 and 5). The hepatologists judged that liver biopsy was indicated in 62% of patients; after histology review, biopsy was judged to have been helpful in 70% of patients. Histology review changed the causality score in 68% of patients, with an increase in DILI likelihood in 48% and a decrease in 20%. Biopsy results changed diagnostic certainty from less certain (3 or 4) to highly certain (1, 2 or 5) in 38% of patients.Liver histologic findings may help clarify the diagnosis of DILI. Histology appears to be particularly helpful in cholestatic or equivocal cases of DILI (possible or probable), shifting assessment toward a greater or lower certainty of a DILI diagnosis.The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. Herein, we show that, in patients with suspected DILI, a liver biopsy can help physicians diagnose DILI or other causes of liver injury with more certainty.

Hepatic stellate cells (HSCs) are the primary effector cells in liver fibrosis. In the normal liver, HSCs serve as the primary vitamin A storage cells in the body and retain a "quiescent" phenotype. However, after liver injury, they transdifferentiate to an "activated" myofibroblast-like phenotype, which is associated with dramatic upregulation of smooth muscle specific actin and extracellular matrix proteins. The result is a fibrotic, stiff, and dysfunctional liver. Therefore, understanding the molecular mechanisms that govern HSC function is essential for the development of anti-fibrotic medications. The actin cytoskeleton has emerged as a key component of the fibrogenic response in wound healing. Recent data indicate that the cytoskeleton receives signals from the cellular microenvironment and translates them to cellular function-in particular, increased type I collagen expression. Dynamic in nature, the actin cytoskeleton continuously polymerizes and depolymerizes in response to changes in the cellular microenvironment. In this viewpoint, we discuss the recent developments underlying cytoskeletal actin dynamics in liver fibrosis, including how the cellular microenvironment affects HSC function and the molecular mechanisms that regulate the actin-induced increase in collagen expression typical of activated HSCs.

Cirrhosis remains a major burden on the health care system despite substantial advances in therapy and care. Studies simultaneously examining mortality, readmission, and cost of care are not available. Here, we hypothesized that improved patient care in the last decade might have led to improved outcomes and reduced costs in patients with cirrhosis.We identified compensated cirrhosis (CC) and decompensated cirrhosis (DC) patients using carefully chosen ICD-9/ICD-10 codes from the Nationwide Readmission Database (NRD) (years 2010 to 2016). We evaluated trends of 30-day all-cause mortality, 30-day readmission, and inflation-adjusted index hospitalization and readmission costs. Factors associated with mortality and readmission were identified using regression analyses.A total of 3,374,038 patients with cirrhosis were identified, of whom nearly 50% had a decompensating event on initial admission. The 30-day inpatient mortality rate for both CC and DC patients decreased from 2010 to 2016. The 30-day readmission rate remained stable for DC and declined for CC. Over the study period, 30-day readmission costs increased for DC and remained unchanged for CC. The median cost for index hospitalization remained nearly unchanged, but the cost of readmission increased for both CC and DC groups. Gastrointestinal diseases and infections were the leading cause of readmission in CC and DC patient groups.Inpatient mortality has decreased for CC and DC patients. Readmission has declined for CC patients and remained stable for DC patients. However, the economic burden of cirrhosis is rising.

BACKGROUND AND AIMS The hepatic venous pressure gradient (HVPG) is the standard for estimating portal pressure but requires expertise for interpretation. We hypothesized that HVPG could be extrapolated from liver histology using a machine learning (ML) algorithm. APPROACH AND RESULTS Patients with NASH with compensated cirrhosis from a phase 2b trial were included. HVPG and biopsies from baseline and weeks 48 and 96 were reviewed centrally, and biopsies evaluated with a convolutional neural network (PathAI, Boston, MA). Using trichrome-stained biopsies in the training set (n = 130), an ML model was developed to recognize fibrosis patterns associated with HVPG, and the resultant ML HVPG score was validated in a held-out test set (n = 88). Associations between the ML HVPG score with measured HVPG and liver-related events, and performance of the ML HVPG score for clinically significant portal hypertension (CSPH) (HVPG ≥ 10 mm Hg), were determined. The ML-HVPG score was more strongly correlated with HVPG than hepatic collagen by morphometry (ρ = 0.47 vs. ρ = 0.28; P

Introduction The prevalence and significance of acute liver injury in patients with COVID-19 are poorly characterized. Methods Patients with confirmed COVID-19 who were hospitalized in geographically diverse medical centers in North America were included. Demographics, symptoms, laboratory data results, and outcomes were recorded. Linear and logistic regression identified factors associated with liver injury, in-hospital mortality, and length of stay (LOS). Results Among 1555 patients in the cohort, most (74%) had an elevated alanine aminotransferase (ALT) during hospitalization, which was very severe (> 20 × upper limit of normal [ULN]) in 3%. Severe acute liver injury (ALI) was uncommon, occurring in 0.1% on admission and 2% during hospitalization. No patient developed acute liver failure (ALF). Higher ALT was associated with leukocytosis (per mL3) (β 10.0, 95% confidence interval (CI) 6.7–12.6, p 20 × ULN (unadjusted OR 6.0, 95%CI 3.1–11.5, p 3 × ULN (unadjusted OR 4.4, 95%CI 2.5–7.7, p

Treatment of chronic hepatitis C virus with direct-acting antivirals usually eradicates infection, but liver fibrosis does not resolve concurrently. In patients who develop cirrhosis prior to hepatitis C virus treatment, hepatic decompensation and hepatocellular carcinoma can still occur after viral elimination due to residual fibrosis. We hypothesized the liver proteome would exhibit meaningful changes in inflammatory and fibrinogenic pathways change upon hepatitis C virus eradication, which could impact subsequent fibrosis regression. We analysed the liver proteome and phosphoproteome of paired liver biopsies obtained from 8 hepatitis C virus-infected patients before or immediately after treatment with direct-acting antivirals. Proteins in interferon signalling and antiviral pathways decreased concurrent with hepatitis C virus treatment, consistent with prior transcriptomic analyses. Expression of extracellular matrix proteins associated with liver fibrosis did not change with treatment, but the phosphorylation pattern of proteins present within signalling pathways implicated in hepatic fibrinogenesis, including the ERK1/2 pathway, was altered concurrent with hepatitis C virus treatment. Hepatitis C virus treatment leads to reduced expression of hepatic proteins involved in interferon and antiviral signalling. Additionally, changes in fibrosis signalling pathways are detectable before alteration in extracellular matrix proteins, identifying a putative chronology for the dynamic processes involved in fibrosis reversal.

Introduction Ketamine is an effective sedative agent in a variety of settings due to its desirable properties including preservation of laryngeal reflexes and lack of cardiovascular depression. We hypothesized that ketamine is an effective alternative to standard moderate sedation (SMS) regimens for patients undergoing endoscopy. Materials and Methods We conducted a randomized controlled trial comparing ketamine to SMS for outpatient colonoscopy or esophagogastroduodenoscopy at Brooke Army Medical Center. The ketamine group received a 1-mg dose of midazolam along with ketamine, whereas the SMS group received midazolam/fentanyl. The primary outcome was patient satisfaction measured using the Patient Satisfaction in Sedation Instrument, and secondary outcomes included changes in hemodynamics, time to sedation onset and recovery, and total medication doses. Results Thirty-three subjects were enrolled in each group. Baseline characteristics were similar. Endoscopies were performed for both diagnostic and screening purposes. Ketamine was superior in the overall sedation experience and in all analyzed categories compared to the SMS group (P = .0096). Sedation onset times and procedure times were similar among groups. The median ketamine dose was 75 mg. The median fentanyl and midazolam doses were 150 mcg and 5 mg, respectively, in SMS. Vital signs remained significantly closer to the physiological baseline in the ketamine group (P = .004). Recovery times were no different between the groups, and no adverse reactions were encountered. Conclusions Ketamine is preferred by patients, preserves hemodynamics better than SMS, and can be safely administered by endoscopists. Data suggest that ketamine is a safe and effective sedation option for patients undergoing esophagogastroduodenoscopy or colonoscopy (clinicaltrials.gov NCT03461718).

Ongoing liver injury leads to fibrosis and ultimately cirrhosis, a leading cause of death worldwide. The primary mechanism underlying the fibrogenic response is the activation of cells known as hepatic stellate cells (HSCs) which are "quiescent" in the normal liver but become "activated" after injury by transdifferentiating into extracellular matrix-secreting myofibroblasts. Since integrins (extracellular matrix binding receptors) are important mediators of HSC activation and fibrogenesis, we hypothesized that focal adhesion (FA) proteins, which link integrins to the intracellular protein machinery, may be important in the activation process. Therefore, using both an in vitro model of activation in primary rat HSCs and an in vivo model of liver injury, we examined three FA proteins: vinculin, FAK, and talin. All three proteins were significantly upregulated during HSC activation at both the messenger RNA (mRNA) and protein levels. Confocal microscopy demonstrated that the proteins had a widespread expression throughout HSCs with prominent localization at the end of actin filaments. Finally, we stimulated HSCs with the profibrotic ligands endothelin-1 (ET-1) and transforming growth factor beta (TGF-β) and observed an increase in the size of vinculin-containing FAs and the cell area occupied by them. The data indicate that HSCs possess a broad array of FA proteins, and given their upregulation during activation, this raises the possibility that they play a role in the fibrogenic response to injury.

BACKGROUND AND AIMS Herbal supplements, and particularly multi-ingredient products, have become increasingly common causes of acute liver injury. Green tea is a frequent component in implicated products, but its role in liver injury is controversial. The aim of this study was to better characterize the clinical features, outcomes, and pathogenesis of green tea-associated liver injury. APPROACH AND RESULTS Among 1,414 patients enrolled in the U.S. Drug-Induced Liver Injury Network who underwent formal causality assessment, 40 cases (3%) were attributed to green tea, 202 to dietary supplements without green tea, and 1,142 to conventional drugs. The clinical features of green tea cases and representation of human leukocyte antigen (HLA) class I and II alleles in cases and control were analyzed in detail. Patients with green tea-associated liver injury ranged in age from 17 to 69 years (median = 40) and developed symptoms 15-448 days (median = 72) after starting the implicated agent. The liver injury was typically hepatocellular (95%) with marked serum aminotransferase elevations and only modest increases in alkaline phosphatase. Most patients were jaundiced (83%) and symptomatic (88%). The course was judged as severe in 14 patients (35%), necessitating liver transplantation in 3 (8%), but rarely resulting in chronic injury (3%). In three instances, injury recurred upon re-exposure to green tea with similar clinical features, but shorter time to onset. HLA typing revealed a high prevalence of HLA-B*35:01, found in 72% (95% confidence interval [CI], 58-87) of green tea cases, but only 15% (95% CI, 10-20) caused by other supplements and 12% (95% CI, 10-14) attributed to drugs, the latter rate being similar to population controls (11%; 95% CI, 10.5-11.5). CONCLUSIONS Green tea-related liver injury has distinctive clinical features and close association with HLA-B*35:01, suggesting that it is idiosyncratic and immune mediated.

Causality assessment for suspected drug-induced liver injury (DILI) during drug development and following approval is challenging. The IQ DILI Causality Working Group (CWG), in collaboration with academic and regulatory subject matter experts (SMEs), developed this manuscript with the following objectives: (1) understand and describe current practices; (2) evaluate the utility of new tools/methods/practice guidelines; (3) propose a minimal data set needed to assess causality; (4) define best practices; and (5) promote a more structured and universal approach to DILI causality assessment for clinical development. To better understand current practices, the CWG performed a literature review, took a survey of member companies, and collaborated with SMEs. Areas of focus included best practices for causality assessment during clinical development, utility of adjudication committees, and proposals for potential new avenues to improve causality assessment. The survey and literature review provided renewed understanding of the complexity and challenges of DILI causality assessment as well as the use of non-standardized approaches. Potential areas identified for consistency and standardization included role and membership of adjudication committees, standardized minimum dataset, updated assessment tools, and best practices for liver biopsy and rechallenge in the setting of DILI. Adjudication committees comprised of SMEs (i.e., utilizing expert opinion) remain the standard for DILI causality assessment. A variety of working groups continue to make progress in pursuing new tools to assist with DILI causality assessment. The minimum dataset deemed adequate for causality assessment provides a path forward for standardization of data collection in the setting of DILI. Continued progress is necessary to optimize and advance innovative tools necessary for the scientific, pharmaceutical, and regulatory community. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01051-5.

Objectives We aimed to assess the value of liver biopsy in the evaluation of abnormal liver tests. Methods We analyzed consecutive liver biopsy specimens performed for evaluation of unexplained abnormal liver tests from 2014 to 2018. Diagnoses were categorized histologically and clinically. We determined whether histologic examination led to a specific diagnosis and whether prebiopsy laboratory variables predicted the underlying etiology. Results Among the 383 liver biopsy specimens included, chronic hepatitis was the most common histologic (25%) and clinical (17%) diagnosis. Liver biopsy led to a clinical diagnosis in 87% of patients. The most likely clinical diagnoses were autoimmune hepatitis, nonalcoholic fatty liver disease, and drug-induced liver injury (38, 33, and 32 patients, respectively). Using sensitivity, specificity, and positive and negative predictive values, we found that liver tests were not predictive of a specific diagnosis. In patients with no history of liver disease or clinical features of portal hypertension, biopsy specimens revealed histologic cirrhosis in 5% of patients. Conclusions Histopathologic diagnoses were made in 85% of patients undergoing liver biopsy for investigation of unexplained liver tests, leading to a clinical diagnosis in 87% of patients. However, neither liver tests themselves nor their patterns were useful in predicting histologic or clinical diagnoses.

The electron transfer flavoprotein (ETF) complex, made up of the ETF alpha subunit (ETFA), ETF beta subunit (ETFB), and ETF dehydrogenase (ETFDH), regulates fatty acid β‐oxidation activity while scavenging leaked electrons through flavin adenine dinucleotide (FAD)/reduced form FAD (FADH2) redox reactions in mitochondria. Here, we hypothesized that ETF dysfunction‐mediated FAD deficiency may result in increased mitochondrial oxidative stress and steatosis and subsequent liver injury. We report that etfa haploinsufficiency caused hyperlipidemia, hypercholesterolemia, and hepatic steatosis and injury in adult zebrafish. Further, etfa+/ − mutant livers had reduced levels of FAD and glutathione and an increase in reactive oxygen species. Because FAD depletion might be critical in the pathogenesis of the liver lesion identified in etfa+/ − mutants, we used riboflavin to elevate FAD levels in the liver and found that riboflavin supplementation significantly suppressed hepatic steatosis and injury in etfa+/ − mutants through suppression of oxidative stress and de novo lipogenesis in the liver. Additionally, we found that adenosine triphosphate‐linked mitochondrial oxygen consumption and mitochondrial membrane potential were reduced in etfa+/ − primary hepatocytes and that riboflavin supplementation corrected these defects. Conclusion: FAD depletion caused by etfa haploinsufficiency plays a key role in hepatic steatosis and oxidative stress‐mediated hepatic injury in adult zebrafish. This raises the possibility that people with ETFA haploinsufficiency have a high risk for developing liver disease.