Hepatocellular Carcinoma Surveillance Patterns and Outcomes in Patients With Cirrhosis.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) surveillance is associated with improved early detection and reduced mortality, although practice patterns and effectiveness vary in clinical practice. We aimed to characterize HCC surveillance patterns in a large, diverse cohort of patients with HCC. METHODS: We conducted a retrospective cohort study of patients diagnosed with HCC between January 2008 and December 2022 at 2 large US health systems. We recorded imaging receipt in the year before HCC diagnosis: ultrasound plus α-fetoprotein (AFP), ultrasound alone, multiphasic contrast-enhanced computed tomography (CT)/magnetic resonance imaging (MRI), and no liver imaging. We used multivariable logistic and Cox regression analysis to compare early tumor detection, curative treatment receipt, and overall survival between surveillance strategies. RESULTS: Among 2028 patients with HCC (46.7% Barcelona Clinic Liver Cancer stage A), 703 (34.7%) had ultrasound plus AFP, 293 (14.5%) had ultrasound alone, 326 (16.1%) had multiphasic CT/MRI, and 706 (34.8%) had no imaging in the year before HCC diagnosis. Over the study period, proportions without imaging were stable, whereas use of CT/MRI increased. Compared with no imaging, CT/MRI and ultrasound plus AFP, but not ultrasound alone, were associated with early stage HCC detection and curative treatment. Compared with ultrasound alone, CT/MRI and ultrasound plus AFP were associated with increased early stage detection. CONCLUSIONS: HCC surveillance patterns vary in clinical practice and are associated with differing clinical outcomes. While awaiting data to determine if CT or MRI surveillance can be performed in a cost-effective manner in selected patients, AFP has a complementary role to ultrasound-based surveillance, supporting its adoption in practice guidelines.

Association between bridging therapy and posttransplant outcomes in patients with HCC within Milan criteria: A systematic review and meta-analysis.

Liver transplantation is the curative therapy of choice for patients with early-stage HCC. Locoregional therapies are often employed as a bridge to reduce the risk of waitlist dropout; however, their association with posttransplant outcomes is unclear. We conducted a systematic review using Ovid MEDLINE and EMBASE to identify studies published between database inception and August 2, 2023, which reported posttransplant recurrence-free survival and overall survival among patients transplanted for HCC within Milan criteria, stratified by receipt of bridging therapy. Pooled HRs were calculated for each outcome using the DerSimonian and Laird method for a random-effects model. We identified 38 studies, including 19,671 patients who received and 20,148 patients who did not receive bridging therapy. Bridging therapy was not associated with significant differences in recurrence-free survival (pooled HR: 0.91, 95% CI: 0.77-1.08; I2 =39%) or overall survival (pooled HR: 1.09, 95% CI: 0.95-1.24; I2 =47%). Results were relatively consistent across subgroups, including geographic location and study period. Studies were discordant regarding the differential strength of association by pretreatment tumor burden and pathologic response, but potential benefits of locoregional therapy were mitigated in those who received 3 or more treatments. Adverse events were reported in a minority of studies, but when reported occurred in 6%-15% of the patients. Few studies reported loss to follow-up and most had a risk of residual confounding. Bridging therapy is not associated with improvements in posttransplant recurrence-free or overall survival among patients with HCC within Milan criteria. The risk-benefit ratio of bridging therapy likely differs based on the risk of waitlist dropout.

Biliary atresia and liver transplantation in the United States: A contemporary analysis.

BACKGROUND: Biliary atresia (BA) remains the number one indication for paediatric liver transplantation (LT) worldwide but is an uncommon indication for older LT recipients. The impact of recent donor allocation changes, pervasive organ shortage and evolving LT practices on the BA LT population is unknown. METHODS: We identified patients who underwent LT between January 2010 and December 2021 using the UNOS database. We compared clinical outcomes between patients with BA and those with non-BA cholestatic liver disease. Groups were stratified by age, <12 years (allocated via PELD system) and ≥12 years (allocated via MELD system). Waitlist outcomes were compared using competing-risk regression analysis, graft survival rates were compared using Kaplan-Meier time-to-event analysis and Cox proportional hazards modelling provided adjusted estimates. RESULTS: There were 2754 BA LT waitlist additions and 2206 BA LTs (1937 <12 years [younger], 269 ≥12 years [older]). There were no differences in waitlist mortality between BA and non-BA cholestatic patients. Among BA LT recipients, there were 441 (20.0%) living-donor liver transplantations (LDLT) and 611 (27.7%) split deceased-donor LTs. Five-year graft survival was significantly higher among BA versus non-BA cholestatic patients in the older group (88.3% vs. 79.5%, p < .01) but not younger group (89.3% vs. 89.5%). Among BA LT recipients, improved graft outcomes were associated with LDLT (vs. split LT: HR: 2, 95% CI: 1.03-3.91) and higher transplant volume (volume >100 vs. <40 BA LTs: HR: 3.41, 95% CI: 1.87-6.2). CONCLUSION: Liver transplant outcomes among BA patients are excellent, with LDLT and higher transplant centre volume associated with optimal graft outcomes.

Biomarkers for the Prediction and Diagnosis of Fibrostenosing Crohn's Disease: A Systematic Review.

BACKGROUND AND AIMS: Intestinal strictures are a common complication of Crohn's disease (CD). Biomarkers of intestinal strictures would assist in their prediction, diagnosis, and monitoring. Herein we provide a comprehensive systematic review of studies assessing biomarkers that may predict or diagnose CD-associated strictures. METHODS: We performed a systematic review of PubMed, EMBASE, ISI Web of Science, Cochrane Library, and Scopus to identify citations pertaining to biomarkers of intestinal fibrosis through July 6, 2020, that used a reference standard of full-thickness histopathology or cross-sectional imaging or endoscopy. Studies were categorized based on the type of biomarker they evaluated (serum, genetic, histopathologic, or fecal). RESULTS: Thirty-five distinct biomarkers from 3 major groups were identified: serum (20 markers), genetic (9 markers), and histopathology (6 markers). Promising markers include cartilage oligomeric matrix protein, hepatocyte growth factor activator, and lower levels of microRNA-19-3p (area under the curves were 0.805, 0.738, and 0.67, respectively), and multiple anti-flagellin antibodies (A4-Fla2 [odds ratio, 3.41], anti Fla-X [odds ratio, 2.95], and anti-CBir1 [multiple]). Substantial heterogeneity was observed and none of the markers had undergone formal validation. Specific limitations to acceptance of these markers included failure to use a standardized definition of stricturing disease, lack of specificity, and insufficient relevance to the pathogenesis of intestinal strictures or incomplete knowledge regarding their operating properties. CONCLUSIONS: There is a lack of well-defined studies on biomarkers of intestinal stricture. Development of reliable and accurate biomarkers of stricture is a research priority. Biomarkers can support the clinical management of CD patients and aid in the stratification and monitoring of patients during clinical trials of future antifibrotic drug candidates.

Rural-Urban Disparities in Mortality From Cirrhosis in the United States From 1999 to 2019.

INTRODUCTION: We examined trends in rural-urban cirrhosis mortality disparities in the United States from decedents aged 25 years and older from 1999 to 2019. METHODS: We calculated cirrhosis age-adjusted mortality rates across 3 population categories: large metropolitan (≥1 million), medium/small metropolitan (50,000-999,999), and rural (<50,000) areas using the US Centers for Disease Control and Prevention Wide-ranging ONline Data for Epidemiologic Research database. RESULTS: We found an almost 20-fold increase in the absolute difference in cirrhosis age-adjusted mortality rates between rural and large metropolitan areas between 1999 and 2019. DISCUSSION: Future research is needed to investigate reasons for this widening rural-urban disparity to improve rural cirrhosis care.

An Electronic Decision Support Intervention Reduces Readmissions for Patients With Cirrhosis.

INTRODUCTION: Rifaximin use in combination with lactulose is associated with a decreased risk of overt hepatic encephalopathy (HE). METHODS: We prospectively evaluated the impact of an interruptive electronic medical record alert to indicate rifaximin for patients with cirrhosis and HE on lactulose. RESULTS: The intervention was associated increased rifaximin utilization, particularly for nongastroenterology and hospitalist services odds ratio 1.20 95% confidence interval (1.09-1.31). For patients with HE, the intervention was associated with a lower readmission risk-adjusted subdistribution hazard ratio 0.63 95% confidence interval (0.48-0.82). DISCUSSION: An interruptive alert in the electronic ordering system was associated with a lower risk of readmissions.

Rate of Successful Extubation in Mechanically Ventilated Patients with Cirrhosis and Hepatic Coma.

BACKGROUND: The prognosis of critically ill patients with cirrhosis who require mechanical ventilation is guarded. Data are lacking for the optimal therapeutic approach to hepatic encephalopathy (HE) in the ventilated patient. METHODS: Retrospective cohort analysis of 314 encounters (298 patients) with cirrhosis who underwent mechanical ventilation in a medical ICU and were ordered at least 1 dose of lactulose. Hazard of extubation alive was determined using a competing risk model. Primary exposures were HE therapy (lactulose and rifaximin) which were adjusted for the indication for ventilation (HE, procedures, respiratory failure), age, MELD-Na, and compensation status. RESULTS: Indications for ventilation were 22.3% for grade 4 HE, 29.9% for procedures, and 47.8% for respiratory or cardiovascular failure. Median length of intubation was 2.63 days; death rate on ventilator was 31.2%. Relative to intubation for procedure, hazard of extubation for intubation for HE was 0.34 (95% confidence interval (CI): 0.22-0.52) and 0.33 (CI: 0.23-0.47) for respiratory failure. Hazard of extubation for rifaximin administration within 24-h after intubation was significant at 1.74 (1.21-2.50). Lactulose dosing was not significant for hazard of extubation. DISCUSSION: Mortality is high for all patients with cirrhosis requiring mechanical ventilation, including those intubated for grade 4 HE. Efforts to optimize the odds of successful extubation are urgently needed. Our findings suggest improved incidence of extubation associated with rifaximin administration in the first 24-h after intubation. Prospective, multi-center data to confirm these findings in this vulnerable population are warranted.

Viscoelastic Testing Prior to Non-surgical Procedures Reduces Blood Product Use Without Increasing Bleeding Risk in Cirrhosis.

BACKGROUND/AIMS: Thromboelastography (TEG) and Rotational Thromboelastometry (ROTEM) analyze hemostatic function in patients with coagulopathy. We sought to quantify the impact of TEG and ROTEM-guided transfusion algorithms on blood product utilization in patients with cirrhosis undergoing non-surgical procedures. METHODS: We performed a systematic review and meta-analysis on the utility of viscoelastic testing prior to non-surgical procedures to determine their impact on pre-procedural blood product use and post-procedural bleeding events. Studies comparing TEG or ROTEM-guided transfusions with standard-of-care (SOC) prior to non-surgical procedures in adult patients with cirrhosis were included. Primary outcomes were fresh frozen plasma (FFP) and platelet transfusion and secondary outcomes of post-procedure bleeding, transfusion-related complications, and mortality; and were reported as standardized mean differences (SMD) and risk ratios (RR). RESULTS: Six studies (five randomized controlled trials and one cohort study) involving 367 patients met inclusion criteria. Compared with SOC, TEG/ROTEM-guided transfusions led to an overall decreased number of patients who received FFP transfusions (SMD = -0.93, 95% CI [-1.54, -0.33], p < 0.001) and platelets transfusions (SMD = -1.50, CI [-1.85, -1.15], p < 0.001). Total amount of FFP (SMD-0.86, p < 0.001) and platelet (SMD = -0.99, p < 0.001) transfused in the TEG/ROTEM group were also lower. Decreased pre-procedure transfusion in the TEG/ROTEM group did not result in increased post-procedure bleeding (RR = 0.61, p = 0.09) or in mortality (RR = 0.91, p = 0.93). CONCLUSION: In patients with cirrhosis, TEG or ROTEM significantly reduces blood product utilization prior to non-surgical procedures, with no increase in post-procedure bleeding or mortality. TEG and ROTEM utilization can promote high-value care and improve transfusion stewardship in this population.

Combining K-72 Hepatic Failure with 15 Individual T-Codes to Identify Patients with Idiosyncratic Drug-Induced Liver Injury in the Electronic Medical Record.

BACKGROUND: The aim of this study was to determine the utility of combining three K72 codes (hepatic failure) with 15 individual T-Codes (drug toxicity/poisoning) to identify potential DILI cases. METHODS: The EMR was searched for encounters that had a K72 code combined with a T-code that also met minimal liver injury laboratory criteria between 10/1/15 and 9/30/18. After manual chart review, a DILIN expert opinion causality score (1-5) was assigned to each case. RESULTS: Among the 345 patient encounters identified, mean age was 57 years, 53% were male, and 89% Caucasian. Thirty-seven cases (10.7%) were adjudicated as probable DILI with antibiotics being the most frequently identified suspect drugs. Of the 308 non-DILI cases, liver injury was most commonly due to congestive hepatopathy (38%) and hepatic metastases (15%). The probable-DILI cases were significantly more likely to have hepatocellular liver injury (57% vs 32.5%, p = 0.01), higher total bilirubin levels (7.7 vs 4.6 mg/dl, p = 0.03), and more severe liver injury scores (p < 0.01). The K72.0 (acute/ subacute hepatic failure) yielded the most DILI cases (29) compared to K72.9 (13) and K72.1 (0). The positive predictive value of the searching algorithm was 10.7% and improved to 15% when using only the K72.0 codes. CONCLUSIONS: K72 codes combined with drug poisoning T-codes had a low positive predictive value in identifying patients with idiosyncratic DILI. These data support further refinement of ICD-10-based algorithms to detect DILI cases in the EMR.

Impact of Prior Drug Allergies on the Risk, Clinical Features, and Outcomes of Idiosyncratic Drug-Induced Liver Injury in Adults.

BACKGROUND: Prior drug allergies are common and may increase susceptibility to adverse medication effects. The aim of this study was to compare the frequency, clinical features, and outcomes of DILI among patients with and without a history of prior drug allergy. METHODS: The EMR at a large liver referral center was searched for all DILI encounters using ICD-10 T-codes for drug poisoning/toxicity and K-71 codes for toxic liver injury between 10/1/2015 and 9/30/2019. Clinically significant liver injury was identified using predefined laboratory criteria, and cases were adjudicated using a 5-point expert opinion scale: 1/2/3 = probable DILI and 4/5 = non-DILI. Drug allergy was defined as a history of anaphylaxis, hives, rash, or pruritus after drug exposure. RESULTS: Among 766,930 patient encounters, 127 unique patients met inclusion criteria with 72 (56.7%) cases adjudicated as probable DILI and 55 (43.3%) as non-DILI. In the probable DILI group, the most frequent suspect drug classes were: antimicrobials (41.9%), herbal and dietary supplements (9.5%), and antineoplastics (8.1%). Twenty-three of the 72 DILI patients (31.9%) had a history of drug allergy before the DILI episode compared to 16 (29.1%) of the 55 non-DILI cases (p = 0.89). However, none of the allergy drugs and suspect DILI drugs were the same although many were in the same drug class. DILI patients with a prior drug allergy were more likely to be female (73.9% vs. 44.9%, p = 0.04) and have lower serum bilirubin (4.0 vs. 7.8, p = 0.08) and INR (1.1 vs. 1.6, p = 0.043) levels at presentation. The likelihood of death or liver transplantation among probable DILI cases with prior drug allergy was lower than those without prior drug allergy (0% vs. 8.2%, p = 0.35). The suspect drug was subsequently documented in the "Drug Allergy" section of the EMR in only 23 (31.9%) of the 72 probable DILI patients, and these patients were more likely to present with a rash (7% vs. 2%, p = 0.006) and higher serum bilirubin levels (10.5 vs. 4.7, p = 0.008) compared to those in whom the suspect drug was not listed as "drug allergy." CONCLUSION: A prior drug allergy history was not associated with a greater likelihood of developing DILI compared to other causes of acute liver injury. However, the probable DILI patients with a history of prior drug allergy tended to have less severe liver injury and clinical outcomes. The low rate of suspect drug documentation in the "Drug Allergy" section of EMR after a DILI episode is of concern and could lead to avoidable harm from inadvertent suspect drug re-challenge.

Applying Administrative Data-Based Coding Algorithms for Frailty in Patients With Cirrhosis.

Frailty is a powerful prognostic tool in cirrhosis. Claims-based frailty scores estimate the presence of frailty without the need for in-person evaluation. These algorithms have not been validated in cirrhosis. Whether they measure true frailty or perform as well as frailty in outcome prediction is unknown. We evaluated 2 claims-based frailty scores-Hospital Frailty Risk Score (HFRS) and Claims-Based Frailty Index (CFI)-in 3 prospective cohorts comprising 1100 patients with cirrhosis. We assessed differences in neuromuscular/neurocognitive capabilities in those classified as frail or nonfrail based on each score. We assessed the ability of the indexes to discriminate frailty based on the Fried Frailty Index (FFI), chair stands, activities of daily living (ADL), and falls. Finally, we compared the performance of claims-based frailty measures and physical frailty measures to predict transplant-free survival using competing risk regression and patient-reported outcomes. The CFI identified neuromuscular deficits (balance, chair stands, hip strength), whereas the HFRS only identified poor chair-stand performance. The CFI had areas under the receiver operating characteristic curve (AUROCs) for identifying frailty as measured by the FFI, ADL, and falls of 0.57, 0.60, and 0.68, respectively; similarly, the AUROCs were 0.66, 0.63, and 0.67, respectively, for the HFRS. Claims-based frailty scores were associated with poor quality of life and sleep but were outperformed by the FFI and chair stands. The HFRS, per 10-point increase (but not the CFI) predicted survival of patients in the liver transplantation (subdistribution hazard ratio [SHR], 1.08; 95% confidence interval [CI], 1.03-1.12) and non-liver transplantation cohorts (SHR, 1.13; 95% CI, 1.05-1.22). Claims-based frailty scores do not adequately associate with physical frailty but are associated with important cirrhosis-related outcomes.

Social Support Does Not Modify the Risk of Readmission for Patients with Decompensated Cirrhosis.

BACKGROUND: Patients with decompensated cirrhosis are at high risk of frequent hospitalizations. Whether the level of perceived social support impacts this risk is unknown. We sought to determine the relationship between social support and burden of hospitalization in patients with decompensated cirrhosis. METHODS: A total of 73 patients, all with decompensated cirrhosis and an index cirrhosis-related admission between 7/1/2017 and 7/1/2019, completed the modified medical outcomes study social support (mMOS-SS) survey. We retrospectively assessed the relationship between mMOS-SS scores and probability of readmission 90-days after the index admission. Additionally, we prospectively analyzed the association between mMOS-SS scores at enrollment and risk of 90-day hospitalization. RESULTS: At enrollment, 50.7% were female, median age 61 years, and median mMOS-SS score was 87.5. Median model for end-stage liver disease sodium (MELD-Na) at the time of the index admission was 15 and was 13 at the time of enrollment. The mMOS-SS score did not modify the rate of readmission 90 days after the index admission date (adjusted HR 1.01, 95%CI 0.98-1.03) nor was it associated with the rate of admission 90 days after enrollment prospectively (adjusted HR 0.99, 95%CI 0.96-1.02). The MELD-Na score at enrollment was the only significant predictor of hospitalization during prospective follow-up (adjusted HR 1.18, 95%CI 1.09-1.27). CONCLUSIONS: Social support, as measured by the mMOS-SS survey, in patients with decompensated cirrhosis was high. However, this did not modify the risk of cirrhosis-related hospitalizations. Future investigation to define the specific components of social support that could modify readmission risk is needed.

Hepatic Steatosis Is Associated with Increased Disease Severity and Liver Injury in Coronavirus Disease-19.

BACKGROUND: Coronavirus disease-2019 (COVID-19) is a global pandemic. Obesity has been associated with increased disease severity in COVID-19, and obesity is strongly associated with hepatic steatosis (HS). However, how HS alters the natural history of COVID-19 is not well characterized, especially in Western populations. AIMS: To characterize the impact of HS on disease severity and liver injury in COVID-19. METHODS: We examined the association between HS and disease severity in a single-center cohort study of hospitalized COVID-19 patients at Michigan Medicine. HS was defined by either hepatic steatosis index > 36 (for Asians) or > 39 (for non-Asians) or liver imaging demonstrating steatosis > 30 days before onset of COVID-19. The primary predictor was HS. The primary outcomes were severity of cardiopulmonary disease, transaminitis, jaundice, and portal hypertensive complications. RESULTS: In a cohort of 342 patients, metabolic disease was highly prevalent including nearly 90% overweight. HS was associated with increased transaminitis and need for intubation, dialysis, and vasopressors. There was no association between HS and jaundice or portal hypertensive complications. In a sensitivity analysis including only patients with liver imaging > 30 days before onset of COVID-19, imaging evidence of hepatic steatosis remained associated with disease severity and risk of transaminitis. CONCLUSIONS: HS was associated with increased disease severity and transaminitis in COVID-19. HS may be relevant in predicting risk of complications related to COVID-19.

Acceptance and use of a smartphone application in cirrhosis.

BACKGROUND AND AIMS: The development of cirrhosis-related smartphone applications for remote monitoring is increasing. Whether patients with cirrhosis will welcome such new technology, however, is uncertain. METHODS: We prospectively enrolled patients with cirrhosis (N = 102) to determine predictors of acceptance and utilization of a smartphone application for cirrhosis management using a 12-item Technology Acceptance Model (TAM) survey. Patients were then shown the EncephalApp© and evaluated for their willingness to download and use the application. RESULTS: Patients had a median age of 61.3 years and 63.7% had a history of hepatic decompensation. Intention to use the hypothetical application was associated with perceived usefulness (ß: 0.4, 95% CI: 0.3-0.5) and the presence of a caregiver (ß: 1.1, 95% CI: 0.2-2.0). Of the eligible participants, 71% agreed to download the EncephalApp© and the decision was influenced by computer anxiety, behavioural intent, caregiver presence and disease state factors. Actual usage was 32% and not associated with baseline characteristics or the technology acceptance model. CONCLUSIONS: Patient acceptance of smartphone applications for the management of cirrhosis is high and related to their attitudes towards technology and the presence of a caregiver. However, usage was low. Future research must employ behavioural interventions to optimize uptake and utilization of remote monitoring technology.