Cotter, Thomas G.

Abstract Objectives Hepatic steatosis impacts the quality of grafts, affecting transplant outcomes. Rising obesity rates and subsequent donor graft steatosis further influence the organ shortage crisis in pediatric liver transplantation (LT). Our study aimed to evaluate how donor steatosis modulates the outcomes of pediatric LT. Methods We analyzed the United Network of Organ Sharing database for transplanted donor grafts from January 01, 2004, to April 30, 2024. We stratified pediatric (≤18 years) LT recipients into steatotic grafts, subdivided into <30% and ≥30%. Graft failure was assessed using Kaplan–Meier curves, and Cox proportional hazards models, with Lasso regression identifying key predictive variables. Gradient‐boosting decision tree was used to assess the level of likelihood importance for post‐LT survival. Results Five hundred and ninety‐five pediatric LT recipients were included; 62 (10.4%) received donors with steatosis levels ≥30%. Survival rates for steatotic grafts ≥30% were 93.5% at 1 year, 89.9% at 5 years, and 84.4% at 10 years, compared to 94.7%, 89.5%, and 85.2% respectively, among steatotic grafts <30% ( p = 0.72, p = 0.92, and p = 0.92). Donor age (adjusted hazard ratio [aHR]: 1.01, 95% confidence interval [CI]: 1.01–1.03), donation after cardiac death (DCD) (aHR: 10.68, 95% CI: 3.27–34.86), and recipient life support (aHR: 1.95, 95% CI: 1.19–3.20) were associated with an increased risk of mortality. Conclusion Steatotic grafts in pediatric patients had acceptable outcomes. Predictors of mortality in steatotic grafts, including donor age, DCD, and recipient life support, underscore the complex interplay of multiple factors in post‐LT outcomes.

Background & Aims: The clinical course and outcomes of alcohol-associated hepatitis (AH) remain poorly understood. Major adverse liver outcomes do not capture the added risk of return to drinking. We examined the natural history of AH and developed a composite endpoint using a contemporary observational cohort of AH. Approach & Results: A cohort of 1127 participants: 712 AH patients, 256 heavy drinking controls without clinically evident liver disease, and 159 healthy controls, were prospectively followed for 6 months at 8 United States centers as part of the Alcoholic Hepatitis Network (AlcHepNet) consortium. Outcomes included mortality and a composite endpoint (AlcHepNet composite index) that included death, liver transplantation, hepatic decompensation (new onset/worsening ascites, HE, variceal bleeding), liver-related hospital admission, MELD increase ≥5, and return to drinking. Of 712 AH patients (age 45±10.7 y; 59.1% male), 558 (79.0%) had severe and 148 (21.0%) had moderate AH, 232 (32.5%) died, and 86 (12.1%) underwent liver transplantation. Mortality rates in moderate AH and severe AH were 0.7% versus 17.2% (30 d), 3.4% versus 26.5% (90 d), and 8.8% versus 30.5% (180 d), respectively (all p <0.001). Composite liver/alcohol use events were noted in 459 (64.5%) AH patients. Higher MELD score, lower mean arterial pressure, and baseline leukocytosis were associated with higher 90-day mortality in AH (all p <0.05). College education and higher ALP were associated with lower mortality. Heavy drinking controls had low mortality (n=3; 1.2%). Conclusions: This large observational study showed a high incidence of composite liver and alcohol-use events within 6 months, reiterating the need for early interventions.

Goals: Our aim was to perform a national survey of provider attitudes, practices, and knowledge regarding weight loss and MASLD medications in patients with MASLD. Background: While weight loss is a cornerstone in the management of metabolic dysfunction-associated steatotic liver disease (MASLD), FDA-approved medications for weight loss remain underutilized. Results: We conducted a survey before resmetirom approval of hepatology and gastroenterology providers practicing in 44 states. Surveys were sent to 747 providers with 304 complete responses (41%), of whom 260 (86%) work at a liver transplant center. While nearly all respondents (96%) believed that weight loss medications could benefit patients with MASLD, 77% have never/rarely prescribed them due to low comfort (81%). Among weight loss medication prescribers, glucagon-like peptide-1 (GLP-1) receptor agonists were preferred (66%). In contrast, 63% had prescribed off-label medications for MASLD in the past 12 months, most commonly vitamin E (30%) and GLP-1 receptor agonists (25%). The top reported barriers to prescribing weight loss medications were lack of training/unfamiliarity, cost/insurance coverage, and side-effects, which may be explained by low formal obesity education and lack of knowledge (only 33% of FDA-approved medications for weight loss were correctly identified by >50% of providers). Overall, there was reasonable provider-reported adherence to the 2023 AASLD practice guidance for MASLD. Conclusions: This nationwide survey of hepatology and gastroenterology providers before resmetirom demonstrates that while off-label prescribing for MASLD was common, weight loss medication prescription rates remain very low due to low comfort possibly from insufficient education despite strong beliefs that they can benefit patients with MASLD.

Abstract Background Outcomes in alcohol‐associated liver disease (ALD) are influenced by several race and ethnic factors, yet its natural history across the continuum of patients in different stages of the disease is unknown. Methods We conducted a retrospective cohort study of U.S. adults from 2011 to 2018, using three nationally representative databases to examine potential disparities in relevant outcomes among racial and ethnic groups. Our analysis included logistic and linear regressions, along with competing risk analysis. Results Black individuals had the highest daily alcohol consumption (12.6 g/day) while Hispanic participants had the largest prevalence of heavy episodic drinking (33.5%). In a multivariable‐adjusted model, Hispanic and Asian participants were independently associated with a higher ALD prevalence compared to Non‐Hispanic White interviewees (OR: 1.4, 95% CI: 1.1–1.8 and OR: 1.5 95% CI:1.1–2.0, respectively), while Blacks participants had a lower ALD prevalence (OR: .7 95% CI: .6–.9), and a lower risk of mortality during hospitalization due to ALD (OR: .83 95% CI: .73–.94). Finally, a multivariate competing‐risk analysis showed that Hispanic ethnicity had a decreased probability of liver transplantation if waitlisted for ALD (SHR: .7, 95% CI: .6–.8) along with female Asian population (HR: .40, 95% CI: .26–.62). Conclusions After accounting for key social and biological health determinants, the Hispanic population showed an increased risk of ALD prevalence, even with lower alcohol consumption. Additionally, Hispanic and Asian female patients had reduced access to liver transplantation compared to other enlisted patients.

Background and Aims: In a recent trial, patients with severe alcohol-associated hepatitis treated with anakinra plus zinc (A+Z) had lower survival and higher acute kidney injury (AKI) rates versus prednisone (PRED). We characterize the clinical factors and potential mechanisms associated with AKI development in that trial. Approach and Results: Data from 147 participants in a multicenter randomized clinical trial (74 A+Z, 73 PRED) were analyzed. AKI, AKI phenotypes, and kidney injury biomarkers were compared between participants who did/did not develop AKI in the 2 treatment arms. Multivariable competing risk analyses were performed to identify baseline risk factors for incident AKI, with death treated as a competing event. Risk factors considered were age, sex, mean arterial pressure, white blood cell count, albumin, MELD, ascites, HE, and treatment arm. At baseline, no participants had AKI; 33% (n=49) developed AKI during follow-up. AKI incidence was higher in A+Z than in PRED (45% [n=33] versus 22% [n=16], p=0.001). AKI phenotypes were similar between the 2 treatment arms (p=0.361), but peak AKI severity was greater in A+Z than PRED (stage 3 n=21 [63.6%] vs. n=8 [50.0%], p=0.035). At baseline, urine-neutrophil-gelatinase–associated lipocalin levels were similar between participants who developed AKI in both treatment arms (p=0.319). However, day 7 and 14 urine-neutrophil-gelatinase–associated lipocalin levels were significantly elevated in participants treated with A+Z who developed AKI versus participants treated with PRED who developed AKI (p=0.002 and 0.032, respectively). On multivariable competing risk analysis, only A+Z was independently associated with incident AKI (subdistribution hazard ratio 2.35, p=0.005). Conclusions: AKI occurred more frequently and was more severe in participants treated with A+Z. A+Z–treated participants with AKI had higher urine-neutrophil-gelatinase–associated lipocalin, suggesting that A+Z maybe nephrotoxic in patients with severe alcohol-associated hepatitis.

Linked ContentThis article is linked to Cotter et al and Fernández‐Bañares and Gisbert papers. To view these articles visit https://doi.org/10.1111/apt.14133 and https://doi.org/10.1111/apt.14220.

SummaryBackgroundMicroscopic colitis (MC) is a common cause of chronic diarrhoea. Various treatment options have been described, but there are limited data describing outcomes of corticosteroid‐sparing treatments.AimTo evaluate the outcomes of patients with active MC treated with immune modulators.MethodsAll patients seen at Mayo Clinic, Rochester between January 1, 1997 and November 30, 2016 with a histological diagnosis of MC were identified. Patients treated with an immune modulator of interest were selected and clinical outcomes recorded.ResultsSeventy‐three MC patients (50 collagenous colitis and 23 lymphocytic colitis) with a median disease duration of 24 months (range, 7‐60) were included. The indications for treatment were budesonide‐refractoriness in 66%, budesonide dependence in 29%, and budesonide intolerance in 5%. Median age was 51.8 years (range, 43.4‐63.1) and 61 (84%) were female. Thiopurines were used in 49 patients (67%) for a median of 4 months (range, 1.5‐15). Complete and partial response occurred in 43% and 22% respectively. Adverse effects resulting in therapy cessation occurred in 17 patients (35%). Twelve patients (16%) were treated with methotrexate for a median of 14 months (3‐18.8). Complete and partial response occurred in 58% and 17%, respectively. Anti‐TNF therapy was used in 10 patients (14%) for a median of 4 months (range, 2.3‐5.5). Complete response occurred in four patients and partial response in four patients.ConclusionsThe majority of patients with active MC responded to thiopurines, methotrexate, or anti‐TNF therapy. Larger controlled studies are required to confirm the efficacy and safety of these medications in MC.

Abstract Background: Studies of colorectal cancer screening by multitarget stool DNA (MT-sDNA) show false-positive (FP) rates of 7% to 13%. It is unclear whether FP patients are at increased long-term risk of adverse outcomes. Methods: We compared subsequent clinical events among patients with apparent FP MT-sDNA with those in patients reported as true negative (TN). This was a retrospective cohort study of participants in pre-FDA approval MT-sDNA studies having nonadvanced or negative baseline colonoscopy findings from a single referral center. Per-protocol and calibrated cutoffs defined FP and TN groups. From the time of stool collection, we measured differences between FP and TN groups in time to death, subsequent cancer diagnosis, and onset of alarm symptoms. Results: Of 1,050 eligible patients, only 6 were lost to follow-up. Median age was 65.6 years [interquartile range (IQR), 56.8–72.3]; 54% were female. Median follow-up time was 4 years (IQR, 3.5–5.3). Eight aerodigestive (lung and gastrointestinal tract) cancers occurred. FP status by calibrated, but not per-protocol, cutoffs was associated with subsequent aerodigestive cancer; however, cumulative incidence did not exceed SEER expectations from the general population. By any cutoff method, FP status was not associated with mortality or alarm symptoms. Conclusions: Although FP status was associated with long-term aerodigestive cancers, new cases were not temporally related and did not exceed incidence estimates from general population. Impact: These observations do not justify aggressive follow-up evaluation for patients with FP MT-sDNA at this time. Larger studies are needed to confirm these early findings. Cancer Epidemiol Biomarkers Prev; 26(4); 614–21. ©2016 AACR.

Objective Microscopic colitis (MC) is a common cause of chronic diarrhoea, often with additional symptoms. No validated instruments exist to assess disease activity in MC, making it difficult to compare efficacy of treatments between clinical trials. We aimed to identify clinical features that independently predicted disease severity and create a Microscopic Colitis Disease Activity Index (MCDAI). Design Patients with MC were prospectively administered a survey assessing their GI symptoms and the IBD Questionnaire (IBDQ). A single investigator also scored a physician global assessment (PGA) of disease severity on a 10-point scale. Multiple linear regression identified which symptoms best predicted the PGA. These symptoms were then combined in a weighted formula to create the MCDAI. The relationship between MCDAI and the IBDQ was investigated. Results Of the 175 patients enrolled, 13 (7.4%) did not complete the survey. The remaining 162 had a median age of 66 years (range, 57–73) and 74% were female. Several clinical features were independently associated with PGA (number of unformed stools daily, presence of nocturnal stools, abdominal pain, weight loss, faecal urgency and faecal incontinence). These parameters were combined to create the MCDAI, which strongly predicted the PGA (R 2 =0.80). A 1-unit decrease in disease activity (ΔMCDAI) was associated with a 9-unit increase in quality of life (ΔIBDQ). Conclusions The MCDAI strongly predicted the PGA and correlated with a validated measure of quality of life. Several symptoms in addition to diarrhoea are associated with disease severity in MC.