Impact of ammonia levels on outcome in clinically stable outpatients with advanced chronic liver disease.

Background & Aims: Ammonia levels predicted hospitalisation in a recent landmark study not accounting for portal hypertension and systemic inflammation severity. We investigated (i) the prognostic value of venous ammonia levels (outcome cohort) for liver-related outcomes while accounting for these factors and (ii) its correlation with key disease-driving mechanisms (biomarker cohort). Methods: (i) The outcome cohort included 549 clinically stable outpatients with evidence of advanced chronic liver disease. (ii) The partly overlapping biomarker cohort comprised 193 individuals, recruited from the prospective Vienna Cirrhosis Study (VICIS: NCT03267615). Results: (i) In the outcome cohort, ammonia increased across clinical stages as well as hepatic venous pressure gradient and United Network for Organ Sharing model for end-stage liver disease (2016) strata and were independently linked with diabetes. Ammonia was associated with liver-related death, even after multivariable adjustment (adjusted hazard ratio [aHR]: 1.05 [95% CI: 1.00-1.10]; p = 0.044). The recently proposed cut-off (≥1.4 × upper limit of normal) was independently predictive of hepatic decompensation (aHR: 2.08 [95% CI: 1.35-3.22]; p <0.001), non-elective liver-related hospitalisation (aHR: 1.86 [95% CI: 1.17-2.95]; p = 0.008), and - in those with decompensated advanced chronic liver disease - acute-on-chronic liver failure (aHR: 1.71 [95% CI: 1.05-2.80]; p = 0.031). (ii) Besides hepatic venous pressure gradient, venous ammonia was correlated with markers of endothelial dysfunction and liver fibrogenesis/matrix remodelling in the biomarker cohort. Conclusions: Venous ammonia predicts hepatic decompensation, non-elective liver-related hospitalisation, acute-on-chronic liver failure, and liver-related death, independently of established prognostic indicators including C-reactive protein and hepatic venous pressure gradient. Although venous ammonia is linked with several key disease-driving mechanisms, its prognostic value is not explained by associated hepatic dysfunction, systemic inflammation, or portal hypertension severity, suggesting direct toxicity. Impact and implications: A recent landmark study linked ammonia levels (a simple blood test) with hospitalisation/death in individuals with clinically stable cirrhosis. Our study extends the prognostic value of venous ammonia to other important liver-related complications. Although venous ammonia is linked with several key disease-driving mechanisms, they do not fully explain its prognostic value. This supports the concept of direct ammonia toxicity and ammonia-lowering drugs as disease-modifying treatment.

Incidence, Clinical Correlates, and Prognostic Impact of Dementia in Heart Failure: A Population-Based Cohort Study.

Background: Heart failure (HF) may increase the risk of dementia via shared risk factors. Objectives: The authors investigated the incidence, types, clinical correlates, and prognostic impact of dementia in a population-based cohort of patients with index HF. Methods: The previously territory-wide database was interrogated to identify eligible patients with HF (N = 202,121) from 1995 to 2018. Clinical correlates of incident dementia and their associations with all-cause mortality were assessed using multivariable Cox/competing risk regression models where appropriate. Results: Among a total cohort aged ≥18 years with HF (mean age 75.3 ± 13.0 years, 51.3% women, median follow-up 4.1 [IQR: 1.2-10.2] years), new-onset dementia occurred in 22,145 (11.0%), with age-standardized incidence rate of 1,297 (95% CI: 1,276-1,318) per 10,000 in women and 744 (723-765) per 10,000 in men. Types of dementia were Alzheimer's disease (26.8%), vascular dementia (18.1%), and unspecified dementia (55.1%). Independent predictors of dementia included: older age (≥75 years, subdistribution hazard ratio [SHR]: 2.22), female sex (SHR: 1.31), Parkinson's disease (SHR: 1.28), peripheral vascular disease (SHR: 1.46), stroke (SHR: 1.24), anemia (SHR: 1.11), and hypertension (SHR: 1.21). The population attributable risk was highest for age ≥75 years (17.4%) and female sex (10.2%). New-onset dementia was independently associated with increased risk of all-cause mortality (adjusted SHR: 4.51; P < 0.001). Conclusions: New-onset dementia affected more than 1 in 10 patients with index HF over the follow-up, and portended a worse prognosis in these patients. Older women were at highest risk and should be targeted for screening and preventive strategies.

Risk of further decompensation/mortality in patients with cirrhosis and ascites as the first single decompensation event.

Background & Aims: Although ascites is the most frequent first decompensating event in cirrhosis, the clinical course after ascites as the single index decompensation is not well defined. The aim of this multicentre study was thus to systematically investigate the incidence and type of further decompensation after ascites as the first decompensating event and to assess risk factors for mortality. Methods: A total of 622 patients with cirrhosis presenting with grade 2/3 ascites as the single index decompensating event at 2 university hospitals (Padova and Vienna) between 2003 and 2021 were included. Events of further decompensation, liver transplantation, and death were recorded. Results: The mean age was 57 ± 11 years, and most patients were male (n = 423, 68%) with alcohol-related (n = 366, 59%) and viral (n = 200,32%) liver disease as the main aetiologies. In total, 323 (52%) patients presented with grade 2 and 299 (48%) with grade 3 ascites. The median Child-Pugh score at presentation was 8 (IQR 7-9), and the mean model for end-stage liver disease (MELD) was 15 ± 6. During a median follow-up period of 49 months, 350 (56%) patients experienced further decompensation: refractory ascites (n = 130, 21%), hepatic encephalopathy (n = 112, 18%), spontaneous bacterial peritonitis (n = 32, 5%), hepatorenal syndrome-acute kidney injury (n = 29, 5%). Variceal bleeding as an isolated further decompensation event was rare (n = 18, 3%), whereas non-bleeding further decompensation (n = 161, 26%) and ≥2 concomitant further decompensation events (n = 171, 27%) were frequent. Transjugular intrahepatic portosystemic shunt was used in only 81 (13%) patients. In patients presenting with grade 2 ascites, MELD ≥15 indicated a considerable risk for further decompensation (subdistribution hazard ratio [SHR] 2.18; p <0.001; 1-year incidences: <10: 10% vs. 10-14: 13% vs. ≥15: 28%) and of mortality (SHR 1.89; p = 0.004; 1-year incidences: <10: 3% vs. 10-14: 6% vs. ≥15: 14%). Importantly, mortality was similarly high throughout MELD strata in grade 3 ascites (p = n.s. for different MELD strata; 1-year incidences: <10: 14% vs. 10-14: 15% vs. ≥15: 20%). Conclusions: Further decompensation is frequent in patients with ascites as a single index decompensation event and only rarely owing to bleeding. Although patients with grade 2 ascites and MELD <15 seem to have a favourable prognosis, those with grade 3 ascites are at a high risk of mortality across all MELD strata. Lay summary: Decompensation (the development of symptoms as a result of worsening liver function) marks a turning point in the disease course for patients with cirrhosis. Ascites (i.e. , the accumulation of fluid in the abdomen) is the most common first decompensating event, yet little is known about the clinical course of patients who develop ascites as a single first decompensating event. Herein, we show that the severity of ascites is associated with mortality and that in patients with moderate ascites, the widely used prognostic MELD score can predict patient outcomes.

Deprescribing zolpidem reduces falls and fractures in patients with cirrhosis.

Background & Aims: Benzodiazepines are associated with an increased risk of harm in patients with cirrhosis. However, stopping benzodiazepines must be done with care to avoid withdrawal or other unintended consequences. The impact of deprescribing on patients with cirrhosis is unknown. Methods: We emulated a hypothetical 3-year trial of benzodiazepine deprescription among Medicare enrollees with compensated cirrhosis who lacked other life-limiting diagnoses. All received continuous benzodiazepine prescriptions for the 6-months prior to their diagnosis of cirrhosis. During a 90-day landmark period following their diagnosis of cirrhosis, patients were classified as complete deprescribers (no benzodiazepines dispensed), continuous users, or partial deprescribers. We used inverse probability treatment weighting to compare complete deprescribers to continuous users of traditional benzodiazepines and zolpidem. Outcomes accounted for competing risk of mortality and included incident decompensation (hepatic encephalopathy, ascites, or variceal bleeding), fractures, falls, and alcohol-related hospitalizations. Results: There were 1,651 and 1,463 continuous users of traditional benzodiazepines and zolpidem, respectively, and 728 complete deprescribers. Patients were aged a median of 68 years, 24% had alcohol-related cirrhosis. There was no difference in the risk of death or decompensation for continuous users and deprescribers. Among deprescribers of traditional benzodiazepines, there was no improvement in the risk of falls or fractures. However, compared to continuous zolpidem users, deprescribers had a lower risk of falls (23.2% vs. 31%, p = 0.04) and fractures (21% vs. 29%, p = 0.02). Conclusions: Deprescribing zolpidem reduces the risk of falls and fractures. However, deprescribing benzodiazepines does not improve the risk of decompensation. Efforts to safely address the indications for benzodiazepines such as insomnia and anxiety are urgently needed. Lay summary: Many people with cirrhosis have anxiety, depression, and sleep disorders. Increasingly, patients with cirrhosis are treated with sedating medications called benzodiazepines, including valium, alprazolam ('Xanax'), clonopin, and the sleep-aid zolpidem ('Ambien'), which can cause falls, broken bones, and maybe other brain disorders. For this reason, many researchers are interested in trials of 'deprescribing' (stopping) benzodiazepines. However, no trials have been performed. We used health record data to simulate a trial of deprescribing. We found that stopping benzodiazepines may reduce the chance of falls or broken bones, but it does not improve survival or liver health.

Early hepatocellular carcinoma detection using magnetic resonance imaging is cost-effective in high-risk patients with cirrhosis.

BACKGROUND & AIMS: Reinforced hepatocellular carcinoma (HCC) surveillance using magnetic resonance imaging (MRI) could increase early tumour detection but faces cost-effectiveness issues. In this study, we aimed to evaluate the cost-effectiveness of MRI for the detection of very early HCC (Barcelona Clinic Liver Cancer [BCLC] 0) in patients with an annual HCC risk >3%. METHODS: French patients with compensated cirrhosis included in 4 multicentre prospective cohorts were considered. A scoring system was constructed to identify patients with an annual risk >3%. Using a Markov model, the economic evaluation estimated the costs and life years (LYs) gained with MRI vs. ultrasound (US) monitoring over a 20-year period. The incremental cost-effectiveness ratio (ICER) was calculated by dividing the incremental costs by the incremental LYs. RESULTS: Among 2,513 patients with non-viral causes of cirrhosis (n = 840) and/or cured HCV (n = 1,489)/controlled HBV infection (n = 184), 206 cases of HCC were detected after a 37-month follow-up. When applied to training (n = 1,658) and validation (n = 855) sets, the construction of a scoring system identified 33.4% and 37.5% of patients with an annual HCC risk >3% (3-year C-Indexes 75 and 76, respectively). In patients with a 3% annual risk, the incremental LY gained with MRI was 0.4 for an additional cost of €6,134, resulting in an ICER of €15,447 per LY. Compared to US monitoring, MRI detected 5x more BCLC 0 HCC. The deterministic sensitivity analysis confirmed the impact of HCC incidence. At a willingness to pay of €50,000/LY, MRI screening had a 100% probability of being cost-effective. CONCLUSIONS: In the era of HCV eradication/HBV control, patients with annual HCC risk >3% represent one-third of French patients with cirrhosis. MRI is cost-effective in this population and could favour early HCC detection. LAY SUMMARY: The early identification of hepatocellular carcinoma in patients with cirrhosis is important to improve patient outcomes. Magnetic resonance imaging could increase early tumour detection but is more expensive and less accessible than ultrasound (the standard modality for surveillance). Herein, using a simple score, we identified a subgroup of patients with cirrhosis (accounting for >one-third), who were at increased risk of hepatocellular carcinoma and for whom the increased expense of magnetic resonance imaging would be justified by the potential improvement in outcomes.

International study on the outcome of locoregional therapy for liver transplant in hepatocellular carcinoma beyond Milan criteria.

BACKGROUND & AIMS: Good outcomes after liver transplantation (LT) have been reported after successfully downstaging to Milan criteria in more advanced hepatocellular carcinoma (HCC). We aimed to compare post-LT outcomes in patients receiving locoregional therapies (LRT) before LT according to Milan criteria and University of California San Francisco downstaging (UCSF-DS) protocol and 'all-comers'. METHODS: This multicentre cohort study included patients who received any LRT before LT from Europe and Latin America (2000-2018). We excluded patients with alpha-foetoprotein (AFP) above 1,000 ng/ml. Competing risk regression analysis for HCC recurrence was conducted, estimating subdistribution hazard ratios (SHRs) and corresponding 95% CIs. RESULTS: From 2,441 LT patients, 70.1% received LRT before LT (n = 1,711). Of these, 80.6% were within Milan, 12.0% within UCSF-DS, and 7.4% all-comers. Successful downstaging was achieved in 45.2% (CI 34.8-55.8) and 38.2% (CI 25.4-52.3) of the UCSF-DS group and all-comers, respectively. The risk of recurrence was higher for all-comers (SHR 6.01 [p <0.0001]) and not significantly higher for the UCSF-DS group (SHR 1.60 [p = 0.32]), compared with patients remaining within Milan. The all-comers presented more frequent features of aggressive HCC and higher tumour burden at explant. Among the UCSF-DS group, an AFP value of ≤20 ng/ml at listing was associated with lower recurrence (SHR 2.01 [p = 0.006]) and better survival. However, recurrence was still significantly high irrespective of AFP ≤20 ng/ml in all-comers. CONCLUSIONS: Patients within the UCSF-DS protocol at listing have similar post-transplant outcomes compared with those within Milan when successfully downstaged. Meanwhile, all-comers have a higher recurrence and inferior survival irrespective of response to LRT. Additionally, in the UCSF-DS group, an ALP of ≤20 ng/ml might be a novel tool to optimise selection of candidates for LT. CLINICAL TRIAL NUMBER: This study was registered as part of an open public registry (NCT03775863). LAY SUMMARY: Patients with more extended HCC (within the UCSF-DS protocol) successfully downstaged to the conventional Milan criteria do not have a higher recurrence rate after LT compared with the group remaining in the Milan criteria from listing to transplantation. Moreover, in the UCSF-DS patient group, an ALP value equal to or below 20 ng/ml at listing might be a novel tool to further optimise selection of candidates for LT.

Arterial Thromboembolism in Cancer Patients: A Danish Population-Based Cohort Study.

BACKGROUND: The relation between cancer and arterial thromboembolism (ATE) remains unclear. OBJECTIVES: The purpose of this study was to evaluate ATE risk in cancer patients. METHODS: Danish registries were used to identify all cancer patients between 1997 and 2017, each matched to three cancer-free comparator individuals. ATE was defined as the composite of myocardial infarction, ischemic/unspecified stroke, and peripheral arterial occlusion. A competing risk approach was used to compute cumulative incidences and subdistribution hazard ratios (SHRs). Cause-specific hazard ratios (HRs) were calculated using Cox regression. Among cancer patients, mortality risk was estimated in Cox regression analysis by treating ATE as a time-varying exposure. Patients were followed for 12 months. RESULTS: The study included 458,462 cancer patients and 1,375,386 comparator individuals. In the 6-month period following cancer diagnosis/index date, the cumulative incidence for ATE was 1.50% (95% confidence interval [CI]: 1.47% to 1.54%) in cancer patients and 0.76% (95% CI: 0.75% to 0.77%) in comparator individuals (HR: 2.36; 95% CI: 2.28 to 2.44). Among cancer patients age <65 years, 65 to 75 years, and >75 years, this was 0.79% (95% CI: 0.74% to 0.83%), 1.61% (95% CI: 1.55% to 1.67%), and 2.30% (95% CI: 2.22% to 2.38%), respectively. Other predictors for ATE among cancer patients were prior ATE (SHR: 2.96; 95% CI: 2.77 to 3.17), distant metastasis (adjusted SHR: 1.21; 95% CI: 1.12 to 1.30), and chemotherapy (SHR: 1.47; 95% CI: 1.33 to 1.61). Among cancer patients, ATE was associated with an increased risk of mortality (HR: 3.28; 95% CI: 3.18 to 3.38). CONCLUSIONS: Cancer patients are at increased risk of ATE. Clinicians should be aware of this risk, which is associated with mortality.

Balance between macrophage migration inhibitory factor and sCD74 predicts outcome in patients with acute decompensation of cirrhosis.

BACKGROUND & AIMS: Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine and an important regulator of innate immune responses. We hypothesised that serum concentrations of MIF are associated with disease severity and outcome in patients with decompensated cirrhosis and acute-on-chronic liver failure (ACLF). METHODS: Circulating concentrations of MIF and its soluble receptor CD74 (sCD74) were determined in sera from 292 patients with acute decompensation of cirrhosis defined as new onset or worsening of ascites requiring hospitalisation. Of those, 78 (27%) had ACLF. Short-term mortality was assessed 90 days after inclusion. RESULTS: Although serum concentrations of MIF and sCD74 did not correlate with liver function parameters or ACLF, higher MIF (optimum cut-off >2.3 ng/ml) and lower concentrations of sCD74 (optimum cut-off <66.5 ng/ml) both indicated poorer 90-day transplant-free survival in univariate analyses (unadjusted hazard ratio [HR] 2.01 [1.26-3.22]; p = 0.004 for MIF; HR 0.59 [0.38-0.92]; p = 0.02 for sCD74) and after adjustment in multivariable models. Higher MIF concentrations correlated with surrogates of systemic inflammation (white blood cells, p = 0.005; C-reactive protein, p = 0.05) and were independent of genetic MIF promoter polymorphisms. Assessment of MIF plasma concentrations in portal venous blood and matched blood samples from the right atrium in a second cohort of patients undergoing transjugular intrahepatic portosystemic shunt insertion revealed a transhepatic MIF gradient with higher concentrations in the right atrial blood. CONCLUSIONS: Serum concentrations of MIF and its soluble receptor CD74 predict 90-day transplant-free survival in patients with acute decompensation of cirrhosis. This effect was independent of liver function and genetic predispositions, but rather reflected systemic inflammation. Therefore, MIF and sCD74 represent promising prognostic markers beyond classical scoring systems in patients at risk of ACLF. LAY SUMMARY: Inflammatory processes contribute to the increased risk of death in patients with cirrhosis and ascites. We show that patients with high serum levels of the inflammatory cytokine macrophage migration inhibitory factor (MIF) alongside low levels of its binding receptor sCD74 in blood indicate an increased mortality risk in patients with ascites. The cirrhotic liver is a relevant source of elevated circulating MIF levels.

Sex disparities in waitlisting and liver transplant for acute liver failure.

BACKGROUND & AIMS: Sex disparities in liver transplantation (LT) for chronic liver disease have been described. It is unclear if similar disparities exist for acute liver failure (ALF). METHODS: Adults waitlisted for LT from 2002 to 2016 with ALF were investigated using the United Network of Organ Sharing database. Clinical characteristics and causative aetiologies were compared between men and women who were waitlisted Status-1. Differences in LT, waitlist removal, and 1-year post-transplant survival were explored. RESULTS: Of 8,408 patients waitlisted for LT with ALF, 41.3% of men and 63.9% of women were waitlisted Status-1 (p <0.001). Women had significantly higher international normalised ratio, higher frequency of grade 3-4 hepatic encephalopathy, and different aetiologies of ALF than men. On univariable analysis, women were less likely to undergo LT (subdistribution hazard ratio [SHR] 0.90; 95% CI 0.84-0.97) and were more likely to die or be removed from the waitlist as a result of clinical deterioration (SHR 1.14; 95% CI 1.002-1.30) than men. The disparities in LT (HR 0.95; 95% CI 0.87-1.03) and death/clinical deterioration (SHR 1.13; 95% CI 0.99-1.29) were no longer significant on multivariable analysis. On multivariable analysis, there was no difference in 1-year post-transplant survival between men and women. CONCLUSIONS: Women with ALF are more likely to be waitlisted Status-1 than men. There were no clear disparities in LT or waitlist removal. Sex differences in LT and waitlist removal were attenuated on fully adjusted models, suggesting that these disparities may in part be mitigated by Status-1 listing. LAY SUMMARY: Women with acute liver failure appear to be sicker than men and more often require urgent Status-1 waitlisting. There were no sex disparities in waitlist removal because of clinical deterioration or liver transplantation. This is in contrast to chronic liver disease, where sex disparities exist. The Status-1 waitlisting that women with acute liver failure receive may in part mitigate sex disparities in liver transplantation.