Kamath, Patrick S.

Introduction: Telomere biology disorders (TBD) are multisystemic accelerated aging syndromes due to abnormal telomere length (TL) shortening and increased cancer risk. Pediatric-onset TBD is characterized by severely shortened TL and specific associations with germline pathogenic variants mainly in DKC1, TINF2, PARN genes and characteristic clinical features [bone marrow failure (BMF), abnormal nail/skin/oral mucosa]. Adult-onset TBD is genetically distinct (predominantly, TERT, TERC, and RTEL1 mutations) with varied organ involvement [interstitial lung disease (ILD), BMF, cirrhosis, or bone disease] and heterogenous outcomes. In our previous study of predominantly adult patients with short telomeres, multiple organ involvement (Mangaonkar A et al. Blood Cancer J 2021) predicted poor overall survival (OS). We sought to validate these findings in a larger, well annotated adult cohort of TBD patients. Methods: Patients with suspected TBD underwent comprehensive clinical and molecular evaluation through our TBD-dedicated clinic after regulatory approval. TL was assessed through clinical flow cytometry fluorescence in-situ hybridization (FlowFISH).Clinical and laboratory features, including pulmonary imaging, lung volumes/function testing, hepatic imaging (MR elastography/fibroscan) and bone density assessments were retrospectively abstracted. Germline and somatic genetic testing was performed on peripheral blood through targeted panels for known TBD and myeloid genes respectively. Cox proportional hazard model was used to identify significant variables that also retained independent prognostic impact. Results: Overall, 122 patients met criteria for TBD as defined by lymphocyte TL (LTL) <=10th percentile and/or a presence of a germline-TBD variant; 34 patients LTL <1st percentile, 84 1st and the 10th percentile (27 with TBD-germline variants) and 4 with only TBD-germline variants. Median age at diagnosis was 56 (18-77) years, with 72 (59%) males. Clinical features included presence of ILD (n=81, 66%), BMF (n=39, 32%), cirrhosis/hepatic fibrosis (n=19, 38%), bone disease osteopenia/osteoporosis/fractures, n=53, 70%), MDS/AML (n=11, 9%), non-hematological cancer (n=38, 31%), and head and neck cancer (n=2). Germline pathogenic variants were detected in 22 (18%), most frequently in TERT (n=10), RTEL1 (n=7) and TERC (n=2), while variants of uncertain significance (VUS) were seen in 35 (29%) patients, especially in TERT (n=20), TERC/RTEL1(n=6), NAF1 (n=4). Somatic variants in hematopoietic cells were detected in 37 (30%) patients with frequent alterations seen in DNA damage response and repair (PPM1D/TP53, n=11), and splicing component (U2AF1/SF3B1/ZRSR2, n=9) genes. At last follow-up [median of 3 (0-18) years], there were 26 (21%) deaths (most commonly, progressive ILD-18, cancer of lung/breast/pancreas-3, transplant-related complications-2). After censoring patients at the time of any transplantation (lung transplant-26, liver transplant-5, bone marrow transplant-8), the Kaplan-Meier estimate of median OS was not reached. Univariate survival analysis found adverse OS predicted by older age at diagnosis (P=0.006), presence of ILD (P=0.0002), hepatic fibrosis/cirrhosis (P=0.02), and somatic DNA repair variants (P=0.03). Multivariate model analysis found that only presence of ILD retained independent prognostic impact (HR=2, P=0.02). Among radiographic ILD subtypes, UIP was the most common (51%), followed by NSIP (10%), and others (6%), with median FEV1 of 2L (range: 0.5-4.6), FVC 2.4L (0.7-6.2), and TLC 4L (1.9-7.4). TBD-ILD patients were older (P<0.0001) with a male preponderance (P=0.03), 52 (64%) with multi-organ involvement, and had a less severe hematological phenotype [lower incidence of BMF (P<0.0001) and fetal hemoglobin elevation (P=0.01)], more frequent bone disease (P=0.0009), relatively longer telomeres in lymphocytes (P=0.04), and no particular association with any germline or somatic genetic alterations. Conclusions: Presence of ILD is an independent and significant predictor of adverse survival in adult TBD. Within adult TBD, patients with ILD represent a unique clinical subtype without any obvious genetic or pathologic correlates. Focusing on definitive therapeutic measures in this subgroup of adult TBD has the best chance to alter natural history and improve outcomes.

INTRODUCTION: Perception of the ascites burden and its effects on quality of life may be different between sexes. This study assessed sex differences in perception of ascites burden and its impact on health-related quality of life (HRQoL) in patients with recurrent or refractory ascites. METHODS: The North American Consortium for the Study of End-stage Liver Disease prospectively enrolled outpatients with cirrhosis and large ascites requiring repeat large volume paracenteses. Demographics, laboratory results, comorbidities, medications, frailty measurements, and self-reported questionnaires related to functional status, physical activities, and HRQoL (generic = Short Form 36 and ascites specific = Ascites Questionnaire) were compared between sexes. RESULTS: In total, 392 men (59.6 ± 10.7 years) and 184 women (59.5 ± 11.1 years) with predominantly alcohol-related liver disease (51% and 43%, respectively) and median Model for End-Stage Liver Disease-Na: 13 were enrolled. Both groups had similar comorbidities and cirrhosis complications, ascites duration and severity, and frailty scores ( P = 0.94). Women had more symptoms related to their ascites (Ascites Questionnaire score = 66 ± 21 vs 60 ± 21 in men, P = 0.001) (higher value = feeling worse). 35% of women felt depressed vs 22% of men ( P = 0.0009), with lower mental but not physical functioning components of Short Form 36 ( P = 0.019). Women continued to conduct their daily activities as adequately as men as indicated by Duke Status Activity Index ( P = 0.27) and Godin Leisure Activity Index ( P = 0.47). DISCUSSION: Women with cirrhosis and ascites experienced worse emotional HRQoL than men without difference in daily function. Our analyses underscore the differences in the lived experience of women vs men with cirrhosis and highlight the need for patient-reported metrics to provide patient-centered care.

SummaryBackground and AimsMachine learning (ML) can identify the hidden patterns without hypothesis in heterogeneous diseases like acute‐on‐chronic live failure (ACLF). We employed ML to describe and predict yet unknown clusters in ACLF.MethodsClinical data of 1568 patients with ACLF from a tertiary care centre (2015–2023) were subjected to distance‐, density‐ and model‐based clustering algorithms. Final model was selected on best cluster separation, viz. Silhouette width and Dunn's index (for distance‐ or density‐based algorithms) and minimum BIC (for model‐based algorithms). Cluster assignments, patient trajectories and survival were analysed through inferential statistics. Supervised ML models were trained in 70% data that predicted clusters in remaining 30% data followed by an temporal validation.ResultsThe cohort was male‐predominant (87%), aged 44.3 years, with alcohol‐associated hepatitis (62.9%) and survival of 50.5%. Due to poor performance of distance‐ and density‐based algorithms and better explainability, the latent class model (LCM) was selected for exploration. LCM revealed four clusters with distinct trajectories, reversibility and survival (independent of MELD, CLIF‐C ACLF and AARC scores). Cluster1 had patients with none/one organ failure and highest reversibility. Cluster2 had females with viral hepatitis and two organ failures. More‐than‐one acute precipitant, severity, infections, organ failures and irreversibility escalated from clusters 1 to 4. Circulatory and renal failures critically influenced cluster assignments. Incorporating clusters to CLIF‐C ACLF, infection and ACLF definition improved the discriminative accuracy of CLIF‐C‐ACLF by 11%. Extreme gradient boost and decision trees could predict clusters with AUCs of 0.989 (0.979–0.995) and 0.875 (0.865–0.890). MELD, CLIF‐C‐OF, haemoglobin, lactate, CLIF‐C‐ACLF and ALT were critical variables for cluster prediction. Clusters with distinct survival were documented in a temporal validation cohort.ConclusionsML for the first time could identify clusters with distinct phenotypes, trajectories and outcomes in ACLF. Stratification into clusters can address heterogeneity, guide prognosis, recruitment in trials, resource allocation and liver transplant discussions in ACLF.

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:Alcohol-associated hepatitis (AH) is associated with significant mortality. Model for End-Stage Liver Disease (MELD) score is used to predict short-term mortality and aid in treatment decisions. MELD is frequently updated in the course of AH. However, once the most updated MELD is known, it is uncertain if previous ones still have prognostic value, which might be relevant for transplant allocation and trial design. We aimed to investigate the predictive performance of updated MELDs in a prospectively collected cohort of patients with AH by the InTeam consortium.Methods:Three hundred seven patients (with 859 MELD values within 60 d of admission) fulfilled the inclusion criteria. The main endpoint was time to death or transplant up to 90 days. We used a joint model approach to assess the predictive value of updated MELDs.Results:Updated MELD measurements had a strong prognostic value for death/transplant (HR: 1.20, 95% CI: 1.14–1.27) (p< 0.0001). Previous MELD values did not add predictive value to the most current MELD. We also showed that MELD at day 28 (MELD28) had a significant predictive value for subsequent mortality/transplant in a landmark analysis (HR: 1.18, 95% CI: 1.12–1.23). We show that the use of an ordinal scale including death, transplant, and MELD28 as a trial outcome could substantially reduce the sample size required to demonstrate short-term benefit of an intervention.Conclusion:We show that updated MELDs during the trajectory of AH predict subsequent mortality or the need for transplant. MELD28 inclusion in an ordinal outcome (together with death or transplant) could increase the efficiency of randomized controlled trials.

Abstract Background & Aims: Sarcopenia is common in patients with liver disease and both sarcopenia and short telomeres are associated with mortality, however their relationship in patients with liver disease remains unknown. Methods: A cohort of 16,072 adults from the National Health and Nutrition Examination Survey from 1999-2006 was analyzed. Liver disease was defined by aminotransferases and classified into etiology-based categories. Sarcopenia was defined by dual-energy x-ray absorptiometry. All analyses were conducted separately on each multiple imputation data set and combined via Rubin’s rules. P-values for group comparisons were calculated by testing logistic regression parameter estimates. Cox proportional hazards regression was used for mortality analysis with mortality data available until 2015. Results:Sarcopenia was present in 9.5% of patients with liver disease. Age, race, income, education, physical inactivity, and certain medical comorbidities were associated with sarcopenia. Patients with liver disease and sarcopenia had significantly shorter telomeres than patients with liver disease without sarcopenia when unadjusted for age. The interaction between telomere length and sarcopenia was significantly associated with all-cause mortality. Conclusions: The implications of telomere length on all-cause mortality in patients with liver disease varied by age and sarcopenia status. Shorter telomeres appear to be more highly associated with increased mortality in older patients without sarcopenia.

Background: Remote patient monitoring (RPM) is an emerging focus in health care, and specialized programs may reduce medical costs, supplement in-office visits, and improve patient satisfaction. In this study, we describe the development, feasibility, and early outcomes of an RPM program for patients with decompensated cirrhosis. Methods: Forty-six patients were offered enrollment at the time of hospital discharge in the cirrhosis RPM program (CiRPM), of which 41 completed at least 30 days of monitoring. Participants were mailed remote monitoring equipment and a tablet to be used for patient-reported outcomes. Alerts were continuously monitored by virtual nursing staff who could perform targeted interventions. A cohort of historical controls (n = 74) was created for comparison using inverse probability of treatment weighting. Results: Patients were enrolled in the program for a mean of 83.9 days, with 28 (68%) completing the full 90-day program. Participants uploaded vital signs and responded to symptom-based questionnaires on 93% of the monitored days. On end-of-program surveys, over 75% of patients expressed satisfaction with the program. Gender, age, and MELD-Na were similar between CiRPM and weighted control groups. The 90-day readmission rate was 34% in CiRPM and 47% in weighted controls. In the CiRPM group, 12% of subjects had 2 or more admissions, compared to 37% in the weighted control group. Conclusion: This study demonstrates the feasibility of a cirrhosis-specific RPM program. Overall, patient satisfaction and utilization of the CiRPM was high. Future studies are needed to confirm the impact of RPM on the reduction of hospital readmissions in decompensated cirrhosis.

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.