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.

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.

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.

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 to 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 to those without preoperative visits. CONCLUSION: 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.

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.

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.

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.

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.

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.

Implementing pragmatic clinical trials in hepatology.

Patients with chronic liver disease would benefit from pragmatic trial designs. A pragmatic trial seeks to inform clinical decision-making by providing evidence for the adoption of an intervention into real-world clinical practice. A trial's pragmatism is based on the efficiency by which it identifies, recruits, and follows patients, the degree to which the interventions and design mirror the usual clinical care, and the importance of the outcomes to the patients. We review the promise, trade-offs, and purpose of pragmatic trials in hepatology.

The Rising Costs of Alcohol-Associated Liver Disease in the United States.

INTRODUCTION: Alcohol-associated liver disease (ALD) is rising in the United States because of an increase in high-risk drinking, but population-level ALD cost is unknown. Our aim was to project the direct and indirect costs associated with ALD in the US population through 2040. METHODS: We used a previously validated microsimulation model of alcohol consumption and ALD with model parameters estimated from publicly available data sources, including the National Epidemiologic Survey Alcohol and Related Conditions-III, the Center for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research, the Bureau of Labor Statistics, and published studies informing the impact of alcohol consumption on ALD severity in the United States resident population. The simulated scenario included current and projected ALD-associated costs. RESULTS: From 2022 to 2040, the ALD is projected to cost $880 billion, $355 billion in direct healthcare-related costs, and $525 billion in lost labor and economic consumption. The annual cost of ALD is projected to increase from $31 billion in 2022 to $66 billion (118% increase) in 2040. Although the female population makes up 29% of these costs in 2022, by 2040 on a per annum basis, female costs would be 43% of the total annual expenditure. DISCUSSION: Increased consumption of alcohol in the US population, especially in females, will cause a steep rise in the economic burden of ALD in the United States. These findings highlight the need for planners and policymakers to plan for the increased impact of liver disease in the United States.

An Emulated Clinical Trial of Deprescribing Proton Pump Inhibitors in Patients With Cirrhosis.

INTRODUCTION: Proton pump inhibitors (PPI) are overused and carry harms in cirrhosis. Deprescribing is advocated but has not been trialed. METHODS AND FINDINGS: We emulated a clinical trial using Medicare data. All patients were receiving chronic PPI therapy before a compensated cirrhosis diagnosis. We compared the risk death/decompensation over 3 years between continuous users and deprescribers. We find that PPI deprescription is associated with less ascites and that cumulative PPI use is associated with more ascites and encephalopathy. Ultimately, 71% of deprescribers restart PPIs. DISCUSSION: PPI deprescribing has benefits but requires ongoing support and alternative therapies for gastrointestinal symptoms.

Loneliness and Depressive Symptoms Are High Among Older Adults With Digestive Disease and Associated With Lower Perceived Health.

BACKGROUND & AIMS: Current approaches to managing digestive disease in older adults fail to consider the psychosocial factors contributing to a person's health. We aimed to compare the frequency of loneliness, depression, and social isolation in older adults with and without a digestive disease and to quantify their association with poor health. METHODS: We conducted an analysis of Health and Retirement Study data from 2008 to 2016, a nationally representative panel study of participants 50 years and older and their spouses. Bivariate analyses examined differences in loneliness, depression, and social isolation among patients with and without a digestive disease. We also examined the relationship between these factors and health. RESULTS: We identified 3979 (56.0%) respondents with and 3131 (44.0%) without a digestive disease. Overall, 60.4% and 55.6% of respondents with and without a digestive disease reported loneliness (P < .001), 12.7% and 7.5% reported severe depression (P < .001), and 8.9% and 8.7% reported social isolation (P = NS), respectively. After adjusting for covariates, those with a digestive disease were more likely to report poor or fair health than those without a digestive disease (odds ratio [OR], 1.25; 95% CI, 1.11-1.41). Among patients with a digestive disease, loneliness (OR, 1.43; 95% CI, 1.22-1.69) and moderate and severe depression (OR, 2.93; 95% CI, 2.48-3.47; and OR, 8.96; 95% CI, 6.91-11.63, respectively) were associated with greater odds of poor or fair health. CONCLUSIONS: Older adults with a digestive disease were more likely than those without a digestive disease to endorse loneliness and moderate to severe depression and these conditions are associated with poor or fair health. Gastroenterologists should feel empowered to screen patients for depression and loneliness symptoms and establish care pathways for mental health treatment.