Serum lactate and mean arterial pressure thresholds in patients with cirrhosis and septic shock.

BACKGROUND: The Sepsis-3 guidelines have incorporated serum lactate levels of >2 mmol/L in septic shock definition to account for higher observed mortality. Further evidence is needed to support this threshold in cirrhosis, as well as target mean arterial pressure (MAP) during resuscitation. METHODS: This observational cohort study investigated the association between initial serum lactate and resuscitation MAP levels on in-hospital mortality in patients with and without cirrhosis. Patients admitted to the intensive care unit for the treatment of septic shock between 2006 and 2021 in a quaternary academic center were included. Patients with cirrhosis documented on imaging and International Classification of Disease codes (n=595) were compared to patients without cirrhosis (n=575). The association of intensive care unit admission lactate levels and median 2-hour MAP with in-hospital mortality and the need for continuous renal replacement therapy was assessed. The association between median 24-hour MAP and in-hospital mortality was analyzed post hoc. RESULTS: Within the cirrhosis group, admission lactate levels of 2-4 and >4 mmol/L were associated with increased in-hospital mortality compared to lactate <2 mmol/L [adjusted odds ratio (aOR): 1.69, CI: 1.03-2.81, aOR: 4.02, CI: 2.53-6.52]. Median 24-hour MAP 60-65 and <60 mm Hg were also associated with increased in-hospital mortality compared with MAP >65 mm Hg (aOR: 2.84, CI: 1.64-4.92 and aOR: 7.34, CI: 3.17-18.76). In the noncirrhosis group, associations with in-hospital mortality were weaker for lactate 2-4 and >4 mmol/L (aOR: 1.32, CI: 0.77-2.27 and aOR: 2.25, CI: 1.40-3.67) and median 24-hour MAP 60-65 and <60 mm Hg (aOR: 1.70, CI: 0.65-4.14 and aOR: 4.41, CI: 0.79-29.38). CONCLUSIONS: These findings support utilizing lactate >2 mmol/L in the definition of septic shock, as well as a target MAP of >65 mm Hg during resuscitation in patients with cirrhosis.

Large-scale identification of undiagnosed hepatic steatosis using natural language processing.

Background: Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity in people with and without diabetes, but it is underdiagnosed, posing challenges for research and clinical management. Here, we determine if natural language processing (NLP) of data in the electronic health record (EHR) could identify undiagnosed patients with hepatic steatosis based on pathology and radiology reports. Methods: A rule-based NLP algorithm was built using a Linguamatics literature text mining tool to search 2.15 million pathology report and 2.7 million imaging reports in the Penn Medicine EHR from November 2014, through December 2020, for evidence of hepatic steatosis. For quality control, two independent physicians manually reviewed randomly chosen biopsy and imaging reports (n = 353, PPV 99.7%). Findings: After exclusion of individuals with other causes of hepatic steatosis, 3007 patients with biopsy-proven NAFLD and 42,083 patients with imaging-proven NAFLD were identified. Interestingly, elevated ALT was not a sensitive predictor of the presence of steatosis, and only half of the biopsied patients with steatosis ever received an ICD diagnosis code for the presence of NAFLD/NASH. There was a robust association for PNPLA3 and TM6SF2 risk alleles and steatosis identified by NLP. We identified 234 disorders that were significantly over- or underrepresented in all subjects with steatosis and identified changes in serum markers (e.g., GGT) associated with presence of steatosis. Interpretation: This study demonstrates clear feasibility of NLP-based approaches to identify patients whose steatosis was indicated in imaging and pathology reports within a large healthcare system and uncovers undercoding of NAFLD in the general population. Identification of patients at risk could link them to improved care and outcomes. Funding: The study was funded by US and German funding sources that did provide financial support only and had no influence or control over the research process.

Chylous Ascites: Reassessment of Diagnostic Criteria in Patients With Portal Hypertension.

INTRODUCTION: The triglyceride (TG) threshold for diagnosis of chylous ascites in patients with portal hypertension remains uncertain. METHODS: Retrospective analysis of lipoprotein electrophoresis was conducted in 286 consecutive ascites samples. RESULTS: Ascitic TG ≥ 81 mg/dL is 95.4% sensitive and 94.6% specific for chylous ascites diagnosed by the presence of significant chylomicron population. DISCUSSION: The cutoff for chylous ascites diagnosis should be TG ≥ 81 mg/dL.

Acute Esophageal Necrosis: A Retrospective Cohort Study Highlighting the Mayo Clinic Experience.

OBJECTIVE: To describe the clinical, endoscopic, and histologic features in patients with acute esophageal necrosis (AEN). PATIENTS AND METHODS: In this retrospective cohort study, patients who were diagnosed as having AEN at Mayo Clinic sites in Minnesota, Florida, and Arizona between January 1, 1996, and January 31, 2021, were included. Data were collected on patient clinical characteristics and endoscopic and pathologic findings. RESULTS: The study included 79 patients with AEN with a median (range) age of 64 years (12 to 91 years); 53 (67.1%) were men. Predominant presenting symptoms were hematemesis (49 of 79 [62.0%]), abdominal pain (29 [36.7%]), and melena (20 [25.3%]). Shock was the triggering event for AEN in 49 (62.0%). The 30- and 90-day mortality were 24.0% (19 of 79) and 31.6% (25), respectively. The presence of coexisting infection or bacteremia was significantly associated with 90-day mortality (P<.01). Endoscopically, involvement of the distal third only, distal two-thirds only, and entire esophagus was observed in 31.6% (24 of 76), 39.5% (30), and 29.0% (22), respectively. The length of esophageal involvement correlated with duration of hospitalization (P=.05). The endoscopic appearance of the esophageal mucosa ranged from predominantly white (21 of 44 [47.7%]) to mixed white and black (13 [29.6%]) to predominantly black (10 [22.7%]), and sloughing was present in 18 (40.9%). In the 26 patients with histopathologic findings available for review, 25 (96.1%) had necrosis and/or ulceration with abundant pigmentation. Among the 79 patients, 39 (49.4%) had a follow-up esophagogastroduodenoscopy; 26 of these 39 patients (66.7%) had resolution while 5 had persistent AEN, 4 of whom had improvement. Esophageal strictures developed in 7 of the 39 patients (18.0%). CONCLUSION: Acute esophageal necrosis is a serious condition observed in critically ill patients. Its endoscopic appearance can be highly variable. In patients with an unclear diagnosis, esophageal biopsies may be helpful given the characteristic histologic findings.

Machine Learning Techniques Differentiate Alcohol-Associated Hepatitis From Acute Cholangitis in Patients With Systemic Inflammation and Elevated Liver Enzymes.

OBJECTIVE: To develop machine learning algorithms (MLAs) that can differentiate patients with acute cholangitis (AC) and alcohol-associated hepatitis (AH) using simple laboratory variables. METHODS: A study was conducted of 459 adult patients admitted to Mayo Clinic, Rochester, with AH (n=265) or AC (n=194) from January 1, 2010, to December 31, 2019. Ten laboratory variables (white blood cell count, hemoglobin, mean corpuscular volume, platelet count, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, direct bilirubin, albumin) were collected as input variables. Eight supervised MLAs (decision tree, naive Bayes, logistic regression, k-nearest neighbor, support vector machine, artificial neural networks, random forest, gradient boosting) were trained and tested for classification of AC vs AH. External validation was performed with patients with AC (n=213) and AH (n=92) from the MIMIC-III database. A feature selection strategy was used to choose the best 5-variable combination. There were 143 physicians who took an online quiz to distinguish AC from AH using the same 10 laboratory variables alone. RESULTS: The MLAs demonstrated excellent performances with accuracies up to 0.932 and area under the curve (AUC) up to 0.986. In external validation, the MLAs showed comparable accuracy up to 0.909 and AUC up to 0.970. Feature selection in terms of information-theoretic measures was effective, and the choice of the best 5-variable subset produced high performance with an AUC up to 0.994. Physicians did worse, with mean accuracy of 0.790. CONCLUSION: Using a few routine laboratory variables, MLAs can differentiate patients with AC and AH and may serve valuable adjunctive roles in cases of diagnostic uncertainty.

Review article: current and emerging therapies for acute alcohol-associated hepatitis.

BACKGROUND: Alcohol-associated hepatitis is an acute manifestation of alcohol-associated liver disease (ALD) and is associated with 30%-40% mortality at 28 days. Abstinence and corticosteroids are the mainstays of treatment, but the latter only improves short-term mortality, so new and improved therapies remain an unmet need. AIMS: The aim was to review the pathophysiology of alcohol-associated hepatitis and how various targets can be used by current and emerging therapies as treatment. METHODS: A thorough literature review was conducted on acute alcohol-associated hepatitis, current therapies and therapies under investigation. RESULTS: With the increasing prevalence of alcohol use disorder and ALD, the burden of alcohol-associated hepatitis is also expected to rise. The current understanding of alcohol-associated hepatitis pathophysiology has led to clinical trials of several therapies involving IL-1 antagonism, modification of the gut microbiome and liver regeneration. CONCLUSIONS: Corticosteroid therapy for alcohol-associated hepatitis is restricted in its applicability and has limited efficacy. Developing multidisciplinary, patient-centred care models based on digital health technologies, in combination with continued discovery of novel therapies using multiomics data and computational biology techniques will be necessary to tackle the increasing burden of alcohol-associated hepatitis.

Development of the AI-Cirrhosis-ECG Score: An Electrocardiogram-Based Deep Learning Model in Cirrhosis.

INTRODUCTION: Cirrhosis is associated with cardiac dysfunction and distinct electrocardiogram (ECG) abnormalities. This study aimed to develop a proof-of-concept deep learning-based artificial intelligence (AI) model that could detect cirrhosis-related signals on ECG and generate an AI-Cirrhosis-ECG (ACE) score that would correlate with disease severity. METHODS: A review of Mayo Clinic's electronic health records identified 5,212 patients with advanced cirrhosis ≥18 years who underwent liver transplantation at the 3 Mayo Clinic transplant centers between 1988 and 2019. The patients were matched by age and sex in a 1:4 ratio to controls without liver disease and then divided into training, validation, and test sets using a 70%-10%-20% split. The primary outcome was the performance of the model in distinguishing patients with cirrhosis from controls using their ECGs. In addition, the association between the ACE score and the severity of patients' liver disease was assessed. RESULTS: The model's area under the curve in the test set was 0.908 with 84.9% sensitivity and 83.2% specificity, and this performance remained consistent after additional matching for medical comorbidities. Significant elevations in the ACE scores were seen with increasing model for end-stage liver disease-sodium score. Longitudinal trends in the ACE scores before and after liver transplantation mirrored the progression and resolution of liver disease. DISCUSSION: The ACE score, a deep learning model, can accurately discriminate ECGs from patients with and without cirrhosis. This novel relationship between AI-enabled ECG analysis and cirrhosis holds promise as the basis for future low-cost tools and applications in the care of patients with liver disease.

Inverse Association of Telomere Length With Liver Disease and Mortality in the US Population.

Physiologic aging leads to attrition of telomeres and replicative senescence. An acceleration of this process has been hypothesized in the progression of chronic liver disease. We sought to examine the association of telomere length (TL) with liver disease and its impact on mortality risk. A cohort of 7,072 adults with leukocyte TL measurements from the National Health and Nutrition Examination Survey 1999-2002 with mortality follow-up through 2015 was analyzed. Liver disease was defined by aminotransferase levels and classified into etiology-based and advanced fibrosis categories. Multivariable-adjusted linear regression models estimated effect sizes, with 95% confidence intervals (CIs), of the presence of liver disease on TL. Cox regression models evaluated associations between TL and all-cause mortality risk using adjusted hazard ratios (HRs). The cohort was representative of the US population with mean age 46.1 years and mean TL 5.79 kilobase pairs. No overall association between TL and liver disease was found; however, there was a significant negative association of TL and advanced liver fibrosis in individuals aged 65 and above. The liver disease cohort (HR 1.22, 95% CI 0.99-1.51) and those with metabolic syndrome (HR 1.26, 95% CI 0.96-1.67) had increased mortality risk with shorter TL. The relationship between TL and all-cause mortality was stronger in women (HR 1.51, 95% CI 1.02-2.23) and in non-Hispanic Whites (HR 1.37, 95% CI 1.02-1.84). Conclusion: Shortened leukocyte TL is independently associated with advanced liver disease at older ages, and with a higher risk of all-cause mortality in those with liver disease. These associations reaffirm the need to better understand the role of telomeres in the progression of liver disease.

A comparison of 9-min colonoscopy withdrawal time and 6-min colonoscopy withdrawal time: A systematic review and meta-analysis.

INTRODUCTION: The optimal colonoscopy withdrawal time is still a controversial topic. While several studies demonstrate that longer withdrawal time improves adenoma detection rate, others have contradicted these findings. METHODS: Three independent reviewers performed a comprehensive review of all original articles published from inception to January 2021 and included studies reporting comparison of the two cohorts-(i) ≥ 6 but less than 9 min of colonoscopy withdrawal time (CWT) and (ii) ≥ 9 min of CWT. The outcome measures were the following: (i) adenoma detection rate (ADR), (ii) advanced ADR, and (iii) sessile serrated adenoma detection rate (SDR). The meta-analysis was performed, and the statistics were two-tailed. RESULTS: A total of seven studies met the inclusion criteria after a thorough search of the literature was completed. The analysis revealed that ≥ 9 min of CWT had significantly higher odds of adenoma detection as compared with 6-9 min of CWT (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.30-1.82; I2  = 93.7). Additionally, a significantly higher odds of sessile serrated adenoma detection (OR 1.68, 95% CI 1.28-2.22; I2  = 0) and a trend towards higher odds of advanced adenoma detection (OR 1.38, 95% CI 0.98-1.95, I2  = 90) were seen with CWT of at least 9 min when compared with 6-9 min of CWT. CONCLUSION: This systematic review and meta-analysis analysis provides further evidence that at least 9 min of CWT cohort had significantly higher ADR and SDR as compared with the at least 6 min but less than 9 min of cohort.

Evaluation of Charcot Triad, Reynolds Pentad, and Tokyo Guidelines for Diagnosis of Cholangitis Secondary to Choledocholithiasis Across Patient Age Groups.

OBJECTIVE: To determine the prevalence of Charcot triad, Reynolds pentad, and Tokyo Guidelines criteria and clinical outcomes among patients with cholangitis across different age groups. PATIENTS AND METHODS: We conducted a retrospective analysis of 257 consecutive hospitalized adult patients with acute cholangitis due to endoscopic retrograde cholangiopancreatography-confirmed choledocholithiasis between January 1, 2015, and December 31, 2019. Patients were divided into 3 age groups: less than 65 years, 65 to 79 years, and 80 years or older. Symptoms, vital signs, and laboratory data on admission were collected. Outcomes included length of hospitalization, intensive care unit stay, and 3-month mortality. Nominal variables were tested with the Pearson χ2 test, and continuous variables were tested with the Wilcoxon rank sum test. RESULTS: Charcot triad decreased with older ages. In the group that was age 80 years or older, malaise was the most common symptom; 33.6% (37 of 110) presented with altered sensorium, 9.1% (10 of 110) had no pain, fever, or jaundice, and positive blood culture results were more frequent. Tokyo cholestasis criterion was present in 96.0% (247 of 257), while inflammation (considered essential for diagnosis) was present in 75.9% (195 of 257). Patients 80 years or older had significantly higher mean length of hospital stay (P<.001) and mean length of intensive care unit stay (P=.021). CONCLUSION: Compared with patients in younger age groups, patients with cholangitis who are 80 years or older are less likely to have Charcot triad, are more likely to have features of Reynolds pentad, or present with unexplained malaise. Within the Tokyo Guidelines, cholestasis should replace inflammation as an essential diagnostic criterion.

Inverse Association of Coffee with Liver Cancer Development: An Updated Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Coffee consumption has been suggested to reduce the risk for hepatocellular carcinoma (HCC). While several studies report inverse correlation with coffee drinking, others have suggested more than 2 cups of coffee every day decrease the risk of liver cancer or HCC. However, controversy exists about the exact dose that would provide protective benefit. Therefore, we aimed to carry out a systematic review and meta-analysis of all studies that investigated the association of coffee consumption and risk of HCC and/or liver cancer. Our outcomes were the evaluation of the association of coffee with HCC or liver cancer development along with the amount of coffee needed to prevent HCC or liver cancer. METHODS: We performed a PubMed/MEDLINE/EMBASE/Ovid/Google Scholar search of original articles published in English from 1996 to June 2019, on case-control or cohort or prospective studies that associated coffee with liver cancer or HCC. We calculated the relative risk (RR) of the two conditions for coffee drinking and then stratified this into increments of one cup of coffee per day. Twenty studies were identified. The analysis was performed using random effects models from the methods of DerSimonian and Laird with inverse variance weighting. The Cochrane Q and the I 2 statistics were calculated to assess heterogeneity between studies. A p<0.10 value for chi-square test and I 2 <20% were interpreted as low-level heterogeneity. Probability of publication bias was assessed using funnel plots and with the Egger's test. RESULTS: The overall RR was 0.69 (95%CI 0.56-0.85; p<0.001) with significant heterogeneity between the studies. We performed subgroup analysis over the increments of 1 cup of coffee. Higher doses of coffee consumption were associated with a significant decrease in the risk of developing HCC or liver cancer. The funnel plot did not show significant publication bias. CONCLUSIONS: Our systematic review and meta-analysis suggests that drinking coffee provides benefits with a reduction in the risk of HCC or liver cancer. Higher doses of coffee have higher benefits in terms of risk reduction. However, further biological and epidemiological studies are required to determine the exact mechanism and to study specific subgroups such as viral hepatitis B or C related HCC.

Portal Hypertension and Chronic Kidney Disease Significantly Increase the Risk of Early Unplanned Readmissions in GAVE- Related Admissions.

BACKGROUND AND AIMS: Gastric antral vascular ectasia (GAVE) is an uncommon cause of non-variceal upper gastrointestinal bleeding that is characterized by dilation of blood vessels in the antrum of the stomach. Various co-morbidities are associated with the development of GAVE, but the impact of co-morbidities on unplanned GAVE readmissions is unclear. The aim of this study was to assess the national incidence, 30-day mortality rate, and 30-day readmissions related to GAVE. Secondary outcomes were evaluation of predictors of early readmission, hospital length of stay (LOS) and total hospitalization charges. METHODS: Using the 2016 National Readmission Database, we analyzed discharges for GAVE. ICD-10 CM codes were utilized to identify associated comorbidities and inpatient procedures during the index admission. 30-day readmissions were identified for GAVE. Secondary measures of outcomes including LOS and hospitalization charges were also calculated. Risk factors for early readmission were also evaluated using multivariate analysis to adjust for confounders. RESULTS: A total of 18,375 index admissions for GAVE were identified. 20.49% (n=3,720) of the discharged patients were readmitted within 30 days. 30-day mortality of GAVE-related admissions was 1.82% (n=335). Early readmissions accounted for 20,157 hospital days along with $189 million in hospitalization costs. Multivariate analysis revealed that the presence of portal hypertension (OR 1.63; 95% CI 1.37-1.93; p=0.0001) and chronic kidney disease (CKD) (OR 1.62, 95% CI 1.44-1.82; p<0.0001) significantly increased the odds of early readmission. CONCLUSIONS: Our analysis demonstrates that the overall 30-day mortality rate of GAVE-related admissions is relatively low, but the 30-day readmission rate is significantly high. Patients with comorbid CKD and portal hypertension have a significantly higher risk of readmission. Further studies are required to determine if therapeutic interventions such as argon plasma coagulation or radiofrequency ablation during the index admission may prevent readmissions in these specific subgroups.

The Microbiome and Hepatocellular Carcinoma.

The human microbiome is a vast and complex system encompassing all of the microbes and their genes that occupy the environmentally exposed surfaces of the human body. The gut microbiota and its associated microbiome play an integral role in mammalian metabolism and immune tolerance as well as in immunocompetence. Disruptions in the human gut microbiome are associated with a cycle of hepatocyte injury and regeneration characteristic of chronic liver disease. The persistence of this inflammation has been shown to induce the accumulation of genetic and epigenetic changes leading to hepatocellular carcinoma (HCC). Therefore, the importance and prognostic influence of the gut microbiome on hepatocarcinogenesis has been increasingly studied in recent years. This review discusses the mechanisms by which imbalances in the gut microbiome disturb the gut-liver axis to impact hepatocarcinogenesis, including disruption of the intestinal barrier, changes in bile acid metabolism, and reduction in tumor-suppressing microRNA. Furthermore, this review summarizes recent advances in potential microbiome-based therapeutic opportunities in HCC.