Management of coagulopathy among patients with cirrhosis undergoing upper endoscopy and paracentesis: Persistent gaps and areas of consensus in a multispecialty Delphi.

Patients with cirrhosis have abnormal coagulation indices such as a high international normalized ratio and low platelet count, but these do not correlate well with periprocedural bleeding risk. We sought to develop a consensus among the multiple stakeholders in cirrhosis care to inform process measures that can help improve the quality of the periprocedural management of coagulopathy in cirrhosis. We identified candidate process measures for periprocedural coagulopathy management in multiple contexts relating to the performance of paracentesis and upper endoscopy. An 11-member panel with content expertise was convened. It included nominees from professional societies for interventional radiology, transfusion medicine, and anesthesia as well as representatives from hematology, emergency medicine, transplant surgery, and community practice. Each measure was evaluated for agreement using a modified Delphi approach (3 rounds of rating) to define the final set of measures. Out of 286 possible measures, 33 measures made the final set. International normalized ratio testing was not required for diagnostic or therapeutic paracentesis as well as diagnostic endoscopy. Plasma transfusion should be avoided for all paracenteses and diagnostic endoscopy. No consensus was achieved for these items in therapeutic intent or emergent endoscopy. The risks of prophylactic platelet transfusions exceed their benefits for outpatient diagnostic paracentesis and diagnostic endosopies. For the other procedures examined, the risks outweigh benefits when platelet count is >20,000/mm 3 . It is uncertain whether risks outweigh benefits below 20,000/mm 3 in other contexts. No consensus was achieved on whether it was permissible to continue or stop systemic anticoagulation. Continuous aspirin was permissible for each procedure. Clopidogrel was permissible for diagnostic and therapeutic paracentesis and diagnostic endoscopy. We found many areas of consensus that may serve as a foundation for a common set of practice metrics for the periprocedural management of coagulopathy in cirrhosis.

Quality measures in pre-liver transplant care by the Practice Metrics Committee of the American Association for the Study of Liver Diseases.

The liver transplantation (LT) evaluation and waitlisting process is subject to variations in care that can impede quality. The American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) developed quality measures and patient-reported experience measures along the continuum of pre-LT care to reduce care variation and guide patient-centered care. Following a systematic literature review, candidate pre-LT measures were grouped into 4 phases of care: referral, evaluation and waitlisting, waitlist management, and organ acceptance. A modified Delphi panel with content expertise in hepatology, transplant surgery, psychiatry, transplant infectious disease, palliative care, and social work selected the final set. Candidate patient-reported experience measures spanned domains of cognitive health, emotional health, social well-being, and understanding the LT process. Of the 71 candidate measures, 41 were selected: 9 for referral; 20 for evaluation and waitlisting; 7 for waitlist management; and 5 for organ acceptance. A total of 14 were related to structure, 17 were process measures, and 10 were outcome measures that focused on elements not typically measured in routine care. Among the patient-reported experience measures, candidates of LT rated items from understanding the LT process domain as the most important. The proposed pre-LT measures provide a framework for quality improvement and care standardization among candidates of LT. Select measures apply to various stakeholders such as referring practitioners in the community and LT centers. Clinically meaningful measures that are distinct from those used for regulatory transplant reporting may facilitate local quality improvement initiatives to improve access and quality of care.

Preoperative Hepatology and Primary Care Visits Improve Postoperative Outcomes in Patients with Cirrhosis Undergoing Surgery.

BACKGROUND AND AIMS: Cirrhosis patients are at increased risk for postoperative complications. It remains unclear whether preoperative nonsurgical clinician visits improve postoperative outcomes. We assessed the impact of preoperative primary care physician (PCP) and/or gastroenterologist/hepatologist (GI/Hep) visits on postoperative mortality in cirrhosis patients undergoing surgery and explored differences in medication changes and paracentesis rates as potential mediators. METHODS: This was a retrospective cohort study of cirrhosis patients in the Veterans Health Administration who underwent surgery between 2008 and 2016. We compared 1982 patients with preoperative PCP and/or GI/Hep visits with 1846 propensity-matched patients without preoperative visits. We used Cox regression and Fine and Gray competing risk regression to evaluate the association between preoperative visit type and postoperative mortality at 6 months. RESULTS: Patients with preoperative GI/Hep and PCP visits had a 45% lower hazard of postoperative mortality compared with those without preoperative visits (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.35-0.87). A smaller effect size was noted with GI/Hep preoperative visit alone (HR, 0.69; 95% CI, 0.48-0.99) or PCP visit alone (HR, 0.70; 95% CI, 0.53-0.93). Patients with preoperative PCP/GI/Hep visits were more likely to have diuretics, spontaneous bacterial peritonitis prophylaxis, and hepatic encephalopathy medications newly initiated and/or dose adjusted and more likely to receive preoperative paracentesis as compared with those without preoperative visits. CONCLUSIONS: Preoperative PCP/GI/Hep visits are associated with a reduced risk of postoperative mortality with the greatest risk reduction observed in those with both PCP and GI/Hep visits. This synergistic effect highlights the importance of a multidisciplinary approach in the preoperative care of cirrhosis patients.

Patients With Cirrhosis Rapidly Review Potentially Abnormal Hepatocellular Carcinoma Surveillance Results Through the Patient Portal.

INTRODUCTION: Test results are immediately released to patients through patient portals. We characterized patient and provider time-to-review of liver imaging results. METHODS: We identified 401 patients with cirrhosis enrolled in the portal with ≥1 liver imaging. We compared result review times for patients and providers and identified factors associated with rapid review. RESULTS: The median time-to-review for patients was shorter than providers (3.7 vs 17.6 hours, P < 0.001), with more than half of results reviewed by patients first. Rapid patient review was inversely associated with older age and Hispanic ethnicity. DISCUSSION: Patients rapidly review imaging results through the portal, often before providers.

The Liver Cirrhosis Network Cohort Study: Cirrhosis Definition, Study Population, and Endpoints.

INTRODUCTION: One of the primary goals of the Liver Cirrhosis Network (LCN) is to develop a cohort study to better understand and predict the risk of hepatic decompensation and other clinical and patient-reported outcomes among patients with Child A cirrhosis. METHODS: The LCN consists of a Scientific Data Coordinating Center and 10 clinical centers whose investigators populate multiple committees. The LCN Definitions and Measurements Committee developed preliminary definitions of cirrhosis and its complications by literature review, expert opinion, and reviewing definition documents developed by other organizations. The Cohort Committee developed the study protocol with the input of the steering committee. RESULTS: The LCN developed a prospective cohort study to describe and predict the rates of incident clinical events pertaining to first decompensation and patient-reported outcomes. The LCN developed a pragmatic definition of compensated cirrhosis incorporating clinical, laboratory, imaging, and histological criteria. Definitions of incident and recompensated ascites, overt hepatic encephalopathy, variceal hemorrhage, bleeding because of portal gastropathy, and hepatocellular carcinoma were also codified. DISCUSSION: The LCN Cohort Study design will inform the natural history of cirrhosis in contemporary patients with compensated cirrhosis. The LCN Definitions and Measures Committee developed criteria for the definition of cirrhosis to standardize entry into this multicenter cohort study and standardized criteria for liver-related outcome measures. This effort has produced definitions intended to be both sensitive and specific as well as easily operationalized by study staff such that outcomes critical to the LCN cohort are identified and reported in an accurate and generalizable fashion. REGISTRATION: NCT05740358.

The RELAX randomized controlled trial: Stretching versus meditation for nocturnal muscle cramps.

BACKGROUND: Muscle cramps are common among persons with cirrhosis and are associated with poor health-related quality of life (HRQOL). Treatment options are limited. We compared stretching or meditation in a randomized-controlled trial (RCT). PATIENTS: We enrolled 98 patients with a history of >4 muscle cramps in the prior month from 7/22-7/23. We randomized patients 1:1 to stretching versus meditation for 35 days. Our primary outcome was the change in cramp severity measured by the visual analogue scale for cramps (VAS-cramps, scaled 0-10). Secondary outcomes included a patient global impression of change (PGIC), change in sleep quality and global HRQOL measured using the EQ-5D and VAS-global HRQOL. RESULTS: Overall, 48% of patients had cirrhosis, 40% had diabetes, 16% the median age was 63, most were women (67%) and 81% were college educated. Both arms experienced a reduction in cramp severity-a median of 1.44 (.58-2.29) points for stretching and 1.97 (1.01-2.93) points for meditation. These changes were significant changes from baseline (p = .001 for stretching, p < .0001 for meditation) but these changes were equivalent between arms (p = .4). The PGIC was improved: 1.33 (1.02-1.65) for stretching, 1.05 (.70-1.41) for meditation, p-difference .2. Sleep was also improved for both. HRQOL did not change according to the Eq5D; according to the VAS, HRQOL rose for meditation by 6 (.1-11.8) points but not for stretching. More patients recommended stretching than meditation (79.2% vs. 55.3%, p = .02). CONCLUSION: In a randomized trial, stretching and meditation both reduced cramp severity and improved sleep quality and global impression of change. While patients preferred stretching, there was no difference in effect between arms.

Racial and Ethnic Disparities in Outcomes After the Development of Ascites: A National Cohort Study.

INTRODUCTION: Ascites, a severe complication of cirrhosis, significantly impacts patient morbidity and mortality especially in Black patients. Access to disease optimizing care has been proposed as a potential driver of this disparity. In this study, we evaluate TIPS utilization across racial and ethnic groups. METHODS: We examined data from a 20% random sample of US Medicare enrollees with continuous Part D coverage. We required 180 days of continuous outpatient enrollment prior to cirrhosis diagnosis and all patients had ≥1 paracentesis within 180 days of their cirrhosis diagnosis. Time zero was the date of the first paracentesis. We assessed the likelihood of TIPS placement. Analyses were conducted to determine the independent associations between each outcome and race/ethnicity. RESULTS: 5915 patients (average age 68.2, 64.4% male) were included in the analysis. 439 (7.4%) patients were identified as Black, 223 (3.8%) as Hispanic, and 4942 (83.6%) as white. When compared to white patients in a multivariable analysis, Black patients were less likely to receive a TIPS procedure (hazard ratio 0.4; 95% confidence interval (CI) 0.2-0.8) and had less days alive outside of the hospital (-100.5; 95% CI -189.4 - -11.6). There were no significant differences in transplant-free survival or number of paracenteses per year between ethnic and racial groups. CONCLUSION: Black patients are less likely to receive a TIPS procedure when controlling for common patient- and disease-specific variables. Access to optimal specialized services may be a significant driver for disparities in outcomes of patients with cirrhosis between racial and ethnic groups.

Food for the Brain: Is Vegan/Vegetarian Diet the Way to Go for Hepatic Encephalopathy?

High-protein diet is the cornerstone of supportive care for patients living with hepatic encephalopathy. Although any protein source is better than protein restriction, there is uncertainty regarding the benefits of specific protein types. Using a randomized trial, Badal et al. evaluate the effect on ammonia levels and metabolomics from 3 protein sources in burgers made from beef, vegan products, and vegetarian products. The vegan and vegetarian burgers did not raise ammonia and may result in favorable metabolomic profiles.

Food Insecurity is Increasing and is More Common Among Persons with Chronic Liver Disease.

Background: Effective interventions for metabolic liver disease include optimized nutritional intake. It is increasingly clear, however, that many patients with metabolic liver disease lack the resources to execute nutritional advice. Data on the trends of food insecurity are needed to prioritize public health strategies to address the burden of liver disease. Methods: Cross-sectional analysis of six waves of data from the 2007-2018, 24,847 subjects aged ≥20 years from the 2017-2018 National Health and Nutrition Examination Survey. Food security was measured using the US Department of Agriculture's Core Food Security Module. Liver disease was defined as elevated liver enzymes and a risk factor: elevated BMI, diabetes, and/or excess alcohol consumption. Models were adjusted using age, sex, race/ethnicity, education, poverty-income ratio, smoking, physical activity, alcohol intake, sugary beverage intake, Healthy Eating Inex-2015 score. Advanced liver disease was estimated using FIB-4 >2.67. Results: The overall prevalence of liver disease was 24.6%, ranging from 21.1% (2017-2018) to 28.3% (2015-2016) (P-trend=0.85). 3.4% of participants had possible advanced liver disease, ranging from 1.9% (2007-2008) to 4.2% (2015-2016)(P-trend=0.07). Among those with liver disease, the prevalence of food insecurity was 13.6% in 2007-2008, which rose steadily to 21.6% in 2015-2016, before declining to 18.0% in 2017-2018 (P-trend=0.0004). Food insecurity rose more sharply for adults aged <50 years (2007-2008: 17.6%, 2015-2016: 28.0%, P-trend=0.004) compared to adults aged ≥50 years (2007-2008: 9.5%, 2015-2016: 16.5%, P-trend<0.0001). Food insecurity was more common among women, those with high BMI, and those with diabetes. Conclusion: Food insecurity is increasingly common among those with liver disease.

FIB-4 and APRI for cirrhosis detection in a privately insured national cohort.

Background and Aims: Non-invasive laboratory-based fibrosis indices have been proposed as a tool for population-based screening for advanced fibrosis. We aimed to examine the performance of fibrosis indices at the time of and prior to cirrhosis diagnosis. Methods: We included adult patients with cirrhosis diagnosis codes in a privately insured database (Optum) from 2010-2018 with 1:4 birth year-matched controls without cirrhosis diagnosis codes. We analyzed aspartate aminotransferase-to-platelet ratio index (APRI), and fibrosis-4 index (FIB-4) up to 30 months prior to the entry of cirrhosis diagnosis codes. Cut-offs of <1 and ≥2 were used for APRI and <1.3 and ≥2.67 were used for FIB-4. Results: We included 10,650 patients with cirrhosis (median age 62 years), who were predominantly white (57.8%) and male (51.9%). The most common etiologies of cirrhosis were non-alcoholic steatohepatitis (23.8%), hepatitis C (23.0%), and alcohol-related liver disease (20.5%). At the time of cirrhosis diagnosis (±3 months), 9.3% of patients with cirrhosis had APRI ≥2 and 41.3% had a FIB-4 ≥2.67 compared to 1.2% and 8.9% in control patients, respectively. In the periods spanning 3-12, 12-21, and 21-30 months prior to cirrhosis diagnosis, APRI was ≥2 in 9.4%, 6.6%, and 6.5% of patients, respectively; FIB-4 was ≥2.67 in 42.1%, 37.1%, and 34.3% of patients, respectively. The sensitivity and specificity of APRI at the time of cirrhosis diagnosis were 9.3% and 98.8%, respectively, while the sensitivity and specificity of FIB-4 were 41.3% and 91.0%, respectively. Lower cut-off values for APRI and FIB-4 showed similar performance. Conclusions: Existing non-invasive fibrosis makers are suboptimal when used for advanced fibrosis identification, missing over half of patients with cirrhosis at the time of and prior to clinical diagnosis. Impact and implications: Commonly available laboratory-based indices, including APRI and FIB-4, have been proposed to rule in or rule out advanced fibrosis in the general population. In a study of a large privately insured cohort from the US, FIB-4 and APRI were not sufficient for screening for advanced fibrosis at the time of or prior to clinical diagnosis. While performance for screening out advanced fibrosis was better, a significant percentage of patients with cirrhosis have lab indices below threshold values. Future studies to develop laboratory-based algorithms to help stratify liver fibrosis for population-based screening are warranted.

Bisphosphonate effectiveness in patients with cirrhosis: An emulated clinical trial.

BACKGROUND: Falls and fractures are common and morbid for patients with cirrhosis. Bisphosphonates are recommended for the prevention of fractures for people with osteoporosis cirrhosis; however, data supporting effectiveness in cirrhosis are lacking. AIM: We sought to emulate a clinical trial of bisphosphonates in cirrhosis. METHODS: We used national Medicare data (2008-2020) to examine the 5-year risk of fractures in patients who did or did not receive bisphosphonates with a new-user design among people diagnosed with cirrhosis and osteoporosis. We balanced treated and untreated with inverse probability of treatment weighting, evaluated intention-to-treat and as-treated effects, and examined both control exposures (statin use) and outcomes (decompensation) to test causal relationships. RESULTS: There were 253 and 20,888 new users and non-users of bisphosphonates, respectively. The median age was 74 years. The most common bisphosphonate used was alendronate (73.6%). Bisphosphonates significantly reduced fractures overall (27.5% vs. 33.0%, p = 0.0004) in the intention-to-treat analysis, particularly for people <65 years (sHR 0.56) old, men (sHR 0.64) and those with non-alcohol related liver disease (sHR 0.85). Though there were fewer arm (20.7% vs. 26.4%, p < 0.0001) and femur (28.9% vs. 31.2%, p = 0.005), there were more spinal (25.8% vs. 19.0%), rib (40.0% vs. 32.2%) and skull (10.1% vs. 8.7%) fractures. In the as-treated analysis, cumulative bisphosphonate exposure significantly reduced fractures, sHR 0.95 95% CI (0.91, 0.98). Treatment was inconsistent; bisphosphonate users spent 29.9% person-years of follow-up on the drug. CONCLUSION: In a nationally representative cohort of elderly patients with cirrhosis, bisphosphonates reduced fractures overall. Efforts to increase uptake and drug continuation are needed.

Symptom burden in chronic liver disease.

Chronic liver disease (CLD) is a significant contributor to global mortality. For people who are living with CLD, however, there is a substantial and often overlooked burden of physical and psychological symptoms that significantly affect health-related quality of life. CLD frequently presents with a multitude of interrelated and intricate symptoms, including fatigue, pruritus, muscle cramps, sexual dysfunction, and falls. Increasingly, there is interest in studying and developing interventional strategies to provide a more global approach to managing these complex patients. Moreover, in addition to established guidelines for the management of conventional complications, such as ascites and hepatic encephalopathy, there have been efforts in developing evidence-based guidance for the treatment of the more subjective yet still problematic elements. This review will address the management of these less "classical" but nonetheless important symptoms.

Medically Tailored Meals for Patients With Cirrhosis and Hepatic Encephalopathy: The BRAINFOOD Proof-of-concept Trial.

Background and aims: Guidelines recommend that patients with hepatic encephalopathy (HE) receive a high-protein diet (roughly 1 g/kg actual body weight). Concommitant sodium restriction, low health literacy, and food insecurity limit patients' ability to meet this goal. We aimed to determine the feasibility of home-delivered high-protein medically tailored meals (MTMs) for patients with a recent episode of overt HE. Methods: We enrolled patients with prior overt HE on active HE therapy in a 6-month trial of MTM. All received 21 home-delivered meals/week with protein snacks (mid-day and bedtime) for 12 weeks. Patients completed follow-up at week 24. The primary outcome was feasibility. Additional outcomes included change in protein and micronutrient intake (measured using 24 h dietary recalls performed by dieticians), cognitive function (Animal Naming Test [ANT]; EncephalApp Stroop), physical function (Liver Frailty Index [LFI]), and quality of life (Short Form-8 Health Survey [SF-8]). Healthcare utilization was also assessed. Results: Ten patients competed the study with >90% of MTM consumed. Protein intake rose from 74.6 ± 25.1 g at baseline to 93.8 ± 24.3 g on MTM (P = 0.04). Branched-chain amino acids also increased-valine 3.73 ± 1.26 g to 5.17 ± 1.28 g, isoleucine 3.32 ± 1.18 to 4.69 ± 1.55, leucine 5.83 ± 2.00 to 7.49 ± 2.07, all P < 0.001. The LFI score improved from 4.42 ± 0.32 to 3.96 ± 0.82 by the end of the MTM phase (P = 0.03). SF-8 quality-of-life scores improved from 55.5 ± 15.5 at baseline to 64.7 ± 18.3 after the MTM phase, to 64.4 ± 19.1 at the end of the study (P = 0.1). EncephalApp Stroop time improved from 227 ± 94 to 194 ± 58s by the end of the MTM phase (P = 0.08). ANT scores were similarly non-significantly improved. Conclusion: Home-delivered MTMs are feasible, increase protein consumption, and may improve patient wellbeing. A randomized trial is needed.

Cardiovascular disease in patients with metabolic dysfunction-associated steatohepatitis compared with metabolic dysfunction-associated steatotic liver disease and other liver diseases: A systematic review.

The burden of cardiovascular disease (CVD) in patients with metabolic dysfunction-associated steatohepatitis (MASH) is poorly characterized, particularly vs other liver diseases including metabolic dysfunction-associated steatotic liver disease (MASLD). To identify available evidence, Embase, MEDLINE, and Cochrane database searches (main search: 2011-September 6, 2021; additional ad hoc search [MEDLINE only]: September 7, 2021-February 15, 2023), plus manual searches (2019-September 2021), were performed. Studies reporting CVD outcomes (angina, coronary artery disease [CAD], heart failure, myocardial infarction, peripheral artery disease, stroke, venous thromboembolic disease, and CV mortality) in adults with histologically confirmed MASH and MASLD or other liver diseases were identified, with studies of MASLD without confirmed MASH excluded. Of 8732 studies, 21 were included. An increased incidence or prevalence of CVD in patients with MASH vs other conditions was reported in 12 studies; odds ratios (OR), where reported, ranged from 3.12 (95 % CI: 1.33-5.32) to 4.12 (95 % CI: 1.91-8.90). The risk of CAD was increased in people with MASH in 6 of 7 studies, while the risk of stroke was increased in 6 of 6 studies, and heart failure in 2 of 4 studies. Three of 6 studies provided evidence of increased CVD-related mortality in patients with MASH vs those without. In conclusion, this literature review suggests that CVD is prevalent in patients with MASH and may contribute to increased mortality. Accordingly, cardiovascular risk factors should be aggressively managed in this population. Whether the CVD burden in patients with MASH is a direct consequence of MASH itself requires further study.

The future of International Classification of Diseases coding in steatotic liver disease: An expert panel Delphi consensus statement.

BACKGROUND: Following the adoption of new nomenclature for steatotic liver disease, we aimed to build consensus on the use of International Classification of Diseases codes and recommendations for future research and advocacy. METHODS: Through a two-stage Delphi process, a core group (n = 20) reviewed draft statements and recommendations (n = 6), indicating levels of agreement. Following revisions, this process was repeated with a large expert panel (n = 243) from 73 countries. RESULTS: Consensus ranged from 88.8% to 96.9% (mean = 92.3%). CONCLUSIONS: This global consensus statement provides guidance on harmonizing the International Classification of Diseases coding for steatotic liver disease and future directions to advance the field.

The Burden of Nonalcoholic Steatohepatitis: A Systematic Review of Epidemiology Studies.

Background and Aims: Nonalcoholic steatohepatitis (NASH) is associated with increased mortality and risk of complications but is often asymptomatic and under-recognized. A systematic review of NASH epidemiology was conducted to provide information on the burden of NASH and highlight important evidence gaps for future research. Methods: Medline, EMBASE, and Cochrane Library databases were searched for English-language publications published from 2010 to January 2022 that reported on natural history, risk factors, comorbidities, and complications of a NASH population or subpopulation. Results: Overall, 173 publications were included. NASH was shown to have a variable disease course and high prevalence of comorbid disease. Although many patients progressed to cirrhosis and end-stage liver disease, disease regression or resolution was reported in up to half of patients in some studies. Reported risk factors for disease progression or resolution included levels of (or changes in) serum fibrosis markers, liver enzymes, and platelets. The presence of NASH increased the risk of liver cirrhosis and other serious diseases such as hepatocellular carcinoma, colorectal cancer, chronic kidney disease, and cardiovascular disease. In 2017, NASH was responsible for ∼118,000 cirrhosis deaths globally, and an increasing proportion of patients are receiving liver transplantation for NASH in Europe and the United States. Consolidation of data was hampered by heterogeneity across the studies in terms of patient populations, follow-up time, and outcomes measured. Conclusion: NASH is associated with significant morbidity and mortality, an increased risk of comorbidities, and imposes an increasing burden among liver transplantation recipients. Longer studies with harmonized study criteria are required to better understand the impact of NASH on patient outcomes.