Wilson Disease and the COVID-19 pandemic: exploring patients' mental health and vaccination attitudes in a longitudinal study.

Introduction: The COVID-19 pandemic significantly impacted the mental health of individuals with chronic conditions such as Wilson's Disease (WD). This study investigates stress, anxiety, depression, quality of life, cognitive function, vaccination rates, infection rates, and perceptions related to the pandemic and vaccines among WD patients. Methods: The study analyzed COVID-19 perceptions and vaccine attitudes of 62 adult WD patients enrolled in the international multisite WD Registry. A subgroup of 33 participants completed a series of mental health scales. The effect of working essentially, income loss, wellness activity initiation, and infection of COVID-19 during the pandemic was observed. Results: Results indicate that, overall, the pandemic did not exacerbate anxiety or cognitive function in WD patients but did lead to increased depression among essential workers. Patients experiencing income loss exhibited higher levels of stress and anxiety. Despite these challenges, WD patients showed high vaccination rates and positive attitudes towards vaccines. Discussion: The findings underscore the significant impact of the pandemic on the mental health of WD patients.

Taste and smell function in Wilson's disease.

OBJECTIVE: Wilson's disease (WD) is a metabolic disorder associated with abnormal copper metabolism that results in hepatic, psychiatric, and neurologic symptoms. No investigation of taste function has been made in patients with WD, although olfactory dysfunction has been evaluated. METHODS: Quantitative taste and smell test scores of 29 WD patients were compared to those of 790 healthy controls. Taste was measured using the 53-item Waterless Empirical Taste Test (WETT®) and smell using the 40-item revised University of Pennsylvania Smell Identification Test (R-UPSIT®). Multiple linear regression analysis controlled for age and sex. RESULTS: Average WETT® scores did not differ meaningfully between WD and control subjects (respective medians & IQRs = 32 [28-42] & 34 [27-41]); linear regression coefficient = 1.19, 95% CI [-0.81, 3.19], p = 0.242). In contrast, WD was associated with significantly reduced olfactory function [respective median (IQR) R-UPSIT® scores = 35 (33-37) vs. 37 (35-38); adjusted linear regression coefficient = -1.59, 95% CI [-2.34, -0.833]; p < 0.001)]. Neither olfaction nor taste were influenced by WD symptom subtype [23 (79.3%) were hepatic-predominant; 6 (20.7%) neurologic predominant]; R-UPSIT®, p = 0.774; WETT®, p = 0.912). No effects of primary medication or years since diagnosis (R-UPSIT®, p = 0.147; WETT®, p = 0.935) were found. Weak correlations were present between R-UPSIT® and WETT® scores for both control (r=0.187, p < 0.0001) and WD (r=0.237) subjects, although the latter correlation did not reach the 0.05 α level (p = 0.084). CONCLUSION: Although WD negatively impacts smell function, taste is spared. Research is needed to understand the pathophysiologic mechanisms responsible for this divergence.

Effects of trientine and penicillamine on intestinal copper uptake: A mechanistic 64 Cu PET/CT study in healthy humans.

BACKGROUND AND AIMS: Trientine (TRI) and D-penicillamine (PEN) are used to treat copper overload in Wilson disease. Their main mode of action is thought to be through the facilitation of urinary copper excretion. In a recent study, TRI was noninferior to PEN despite lower 24-hour urinary copper excretion than PEN. We tested whether TRI and/or PEN also inhibit intestinal copper absorption. APPROACH AND RESULTS: Sixteen healthy volunteers were examined with positron emission tomography (PET)/CT 1 and 15 hours after an oral Copper-64 ( 64 Cu) dose. They then received 7 days of either PEN or TRI (trientine tetrahydrochloride), after which the 64 Cu PET/CT scans were repeated. Venous blood samples were also collected. Pretreatment to posttreatment changes of the hepatic 64 Cu uptake reflect the effect of drugs on intestinal absorption. 64 Cu activity was normalized to dose and body weight and expressed as the mean standard uptake value. TRI (n=8) reduced hepatic 64 Cu activity 1 hour after 64 Cu dose from 6.17 (4.73) to 1.47 (2.97) standard uptake value, p <0.02, and after 15 hours from 14.24 (3.09) to 6.19 (3.43), p <0.02, indicating strong inhibition of intestinal 64 Cu absorption. PEN (n=8) slightly reduced hepatic standard uptake value at 15 hours, from 16.30 (5.63) to 12.17 (1.44), p <0.04. CONCLUSIONS: In this mechanistic study, we show that TRI inhibits intestinal copper absorption, in addition to its cupriuretic effect. In contrast, PEN has modest effects on the intestinal copper absorption. This may explain why TRI and PEN are equally effective although urinary copper excretion is lower with TRI. The study questions whether the same therapeutic targets for 24-hour urinary excretion apply to both drugs.

Effects of tetrathiomolybdate on copper metabolism in healthy volunteers and in patients with Wilson disease.

BACKGROUND & AIMS: In Wilson disease (WD), copper accumulates in the liver and brain causing disease. Bis-choline tetrathiomolybdate (TTM) is a potent copper chelator that may be associated with a lower risk of inducing paradoxical neurological worsening than conventional therapy for neurologic WD. To better understand the mode of action of TTM, we investigated its effects on copper absorption and biliary excretion. METHODS: In a double-blind randomized setting, hepatic 64Cu activity was examined after orally administered 64Cu by PET/CT in 16 healthy volunteers before and after seven days of TTM treatment (15 mg/d) or placebo. Oral 64Cu was administered one hour after the final TTM dose. Changes in hepatic 64Cu activity reflected changes in intestinal 64Cu uptake. Additionally, in four patients with WD, the distribution of 64Cu in venous blood, liver, gallbladder, kidney, and brain was followed after i.v. 64Cu dosing for up to 68 hours before and after seven days of TTM (15 mg/day), using PET/MRI. Increased gallbladder 64Cu activity was taken as evidence of increased biliary 64Cu excretion. RESULTS: In healthy volunteers, TTM reduced intestinal 64Cu uptake by 82% 15 hours after the oral 64Cu dose. In patients with WD, gallbladder 64Cu activity was negligible before and after TTM, while TTM effectively retained 64Cu in the blood, significantly reduced hepatic 64Cu activity at all time-points and significantly reduced cerebral 64Cu activity two hours after the intravenous 64Cu dose. CONCLUSIONS: While we did not show an increase in biliary excretion of 64Cu following TTM administration, we demonstrated that TTM effectively inhibited most intestinal 64Cu uptake and retained 64Cu in the blood stream, limiting the exposure of organs like the liver and brain to 64Cu. IMPACT AND IMPLICATIONS: Bis-choline tetrathiomolybdate (TTM) is an investigational copper chelator being developed for the treatment of Wilson disease. In animal models of Wilson disease, TTM has been shown to facilitate biliary copper excretion. In the present human study, TTM surprisingly did not facilitate biliary copper excretion but instead reduced intestinal copper uptake to a clinically significant degree. Our study builds on our understanding of human copper metabolism and the mechanism of action of TTM.

Major Depressive Disorder in an International Multisite Wilson Disease Registry.

BACKGROUND AND AIMS: Psychiatric symptoms are frequently reported in Wilson disease (WD); however, systematic assessments with validated measures are lacking. OBJECTIVE: We aim to report the prevalence and clinical correlates for major depressive disorder (MDD) as resulting from a multisite international WD registry. METHODS: All patients enrolled in the WD registry received structured psychiatric evaluations (Mini International Neuropsychiatric Interview, Patient Health Questionnaire-9, Generalized Anxiety Disorder-7 scale, Perceived Stress Scale), laboratory tests, hepatology, and neurological assessments. We present the analysis of the data collected at enrollment for the first 3 years (N = 62). RESULTS: Thirty-seven percent (23) had a lifetime history (MDD), and 6% (4) met the criteria for an active major depressive episode. Depression was self-reported in 30.51% (19) at WD diagnosis. Patients with MDD had worse mental health quality-of-life (QOL) scores (median 43 vs 53.6, P = 0.006), higher severe anxiety (13.04% vs 0), higher perceived stress (median 18 vs 9, P < 0.003), and higher levels of neuroticism (median 8 vs 5.0, P = 0.002). We found no significant difference in physical health QOL and severity of neurological or liver disease. There was no significant difference in copper parameters or liver tests in those with MDD and without. The limitations of our study consist of the small sample size, the cross-sectional report, and the lack of brain copper measurements. CONCLUSIONS: Lifetime MDD is highly prevalent in WD and associated with worse mental health QOL. We did not find a significant association among liver disease, neurological disease laboratory tests, and MDD. Screening for depression should be considered in patients with WD.

Trientine tetrahydrochloride versus penicillamine for maintenance therapy in Wilson disease (CHELATE): a randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: Wilson disease is an inherited disorder of copper transport. Whereas penicillamine is used therapeutically to re-establish copper balance, trientine is indicated for patients with penicillamine intolerance. We aimed to compare penicillamine with trientine tetrahydrochloride (TETA4) for maintenance therapy in patients with Wilson disease. METHODS: We conducted a randomised, open-label, non-inferiority, phase 3 trial at 15 health-care centres across nine countries (patients were recruited from 13 of these health-care centres across Brazil, Europe, and the USA). We enrolled patients aged 18-75 years with stable Wilson disease who were treated for at least 1 year with penicillamine. Patients entered a 12-week period to determine stability through clinical assessment by site investigators and predefined thresholds for serum non-caeruloplasmin-bound copper (NCC; by an exchangeable copper assay; 25-150 µg/L), 24 h urinary copper excretion (100-900 µg/24 h), and alanine aminotransferase (ALT; <2 × upper limit of normal). Stable patients were randomly assigned (1:1) to continue receiving the maintenance twice daily dose of oral penicillamine or switched mg-for-mg to oral TETA4 centrally with a web-based system using minimisation. The primary endpoint, assessed 24 weeks after randomisation, was NCC by speciation assay. The non-inferiority margin of mean difference in NCC by speciation assay was -50 µg/L, as estimated by a general linear model for repeated visits, adjusted for baseline values. Further data on safety and efficacy were collected during a 24-week extension period. Data were analysed using an intention-to-treat approach. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03539952 (active, not recruiting). FINDINGS: Between June 4, 2018, and March 10, 2020, 77 patients were screened. 53 patients were randomly assigned (27 to the penicillamine group and 26 to the TETA4 group). After 24 weeks, the mean difference in serum NCC by speciation assay between the penicillamine group and TETA4 group was -9·1 µg/L (95% CI -24·2 to 6·1), with the lower limit of the 95% CI within the defined non-inferiority margin. At 24 weeks, urinary copper excretion was lower with TETA4 than with penicillamine (mean difference 237·5 µg/24 h (99% CI 115·6 to 359·4). At 48 weeks, TETA4 remained non-inferior to penicillamine in terms of NCC by speciation assay (mean difference NCC -15·5 µg/L [95% CI -34·5 to 3·6]). Urinary copper excretion at 48 weeks remained in the expected range for well treated patients in both study groups, and the mean difference (124·8 µg/24 h [99% CI -37·6 to 287·1]) was not significantly different. At 24 weeks and 48 weeks, masked clinical adjudication of stability assessed by three independent clinicians confirmed clinical stability (100%) of all participants, in agreement with the stability seen with the NCC by speciation assay. There were no notable changes in either the Clinical Global Impression of Change or Unified Wilson Disease Rating Scale (neurological assessment) from baseline (pre-randomisation) at weeks 24 and 48. The mean change in serum total copper from baseline to 24 weeks was 17·6 µg/L (99% CI -9·5 to 44·7) with penicillamine and -6·3 µg/L (-34·7 to 22·1) with TETA4, and the mean change in serum total caeruloplasmin from baseline to 24 weeks was 1·8 mg/L (-19·2 to 22·8) with penicillamine and -2·2 mg/L (-6·1 to 1·7) with TETA4. All liver enzymes were similar at 24 weeks and 48 weeks, with the exception of elevated ALT concentration at 48 weeks for patients in the TETA4 group. Penicillamine was associated with three post-randomisation serious adverse events (leukopenia, cholangiocarcinoma, and hepatocellular cancer); none were reported for TETA4. The most common treatment-emergent adverse events were headache for penicillamine (five [19%] of 27 patients vs two [8%] of 26) and abdominal pain for TETA4 (one [4%] vs four [15%]); all treatment-emergent adverse events resolved and were mild to moderate. One patient developed a rash with TETA4 that resolved on discontinuation of therapy. INTERPRETATION: The efficacy of TETA4 as oral maintenance therapy was non-inferior to penicillamine and well tolerated in adults with Wilson disease. FUNDING: Orphalan.

Defining and characterising a toolkit for the development of a successful European registry for rare liver diseases: a model for building a rare disease registry.

INTRODUCTION: A rare disease is defined by the European Health Commission as a disorder affecting less than 5/10,000 of the population. There are at least 20 rare liver diseases (RLDs) seen frequently in the adult and paediatric liver clinic, signifying that the hepatology community can be influential in developing such patient databases for registering patients with rare hepatic conditions. The aim of this review was, first, to identify registries for RLDs in Europe, and, second, to design a universal blueprint for the development of a registry for RLD by using lessons learnt from the European registries that have already been established. METHODS: We searched PubMed, Google Scholar and clinicaltrials.gov using the MESH terms 'registries', 'database management systems', 'database' and the non-MESH terms 'database$', 'registry', 'repository' and 'repositories'. We only included studies in English from countries/consortia of the European Union (EU). Our literature search was performed in 2020. RESULTS: We identified 37 registries for RLDs in Europe. Using information from the design of these registries we designed a blueprint for the development of a patient registry for an RLD consisting of a theoretical, technical and maintenance phase. DISCUSSION: It is believed that rare diseases may affect as much as 6-8% of the EU population across its 28 member states. Here we have provided a toolkit for designing a registry for an RLD. Our article will complement the efforts of loco-regional, national and international groups seeking to establish robust systems for data collection and analysis for orphan liver diseases.

Sustained Improvement in Patient Experience by Optimizing Patient Flow in Ambulatory Settings.

Patient experience has become a priority for healthcare institutions as it affects clinical quality of care, financial reimbursement, provider, and patient satisfaction. We report our experience of improving patient experience measured by Press Ganey surveys in a busy multidisciplinary clinic over 65 months. We optimized patient flow in the clinic by technology-facilitated communication among the clinic staff and by a modest space redesign. We noted a significant improvement in "clinic visit" scores from baseline of 82.1 to 84.6 at year 1, 86.1 at year 2, 88.7 at year 3, and 88.9 at year 4 (P < .001). In comparison with previous short-term studies, we were able to sustain improvement in patient experience scores over 4 years due to optimized patient flow and monitoring of clinic operations. A similar approach can be implemented in other ambulatory settings and is likely to cause a long-term positive impact on patient experience.

Connecting copper and cancer: from transition metal signalling to metalloplasia.

Copper is an essential nutrient whose redox properties make it both beneficial and toxic to the cell. Recent progress in studying transition metal signalling has forged new links between researchers of different disciplines that can help translate basic research in the chemistry and biology of copper into clinical therapies and diagnostics to exploit copper-dependent disease vulnerabilities. This concept is particularly relevant in cancer, as tumour growth and metastasis have a heightened requirement for this metal nutrient. Indeed, the traditional view of copper as solely an active site metabolic cofactor has been challenged by emerging evidence that copper is also a dynamic signalling metal and metalloallosteric regulator, such as for copper-dependent phosphodiesterase 3B (PDE3B) in lipolysis, mitogen-activated protein kinase kinase 1 (MEK1) and MEK2 in cell growth and proliferation and the kinases ULK1 and ULK2 in autophagy. In this Perspective, we summarize our current understanding of the connection between copper and cancer and explore how challenges in the field could be addressed by using the framework of cuproplasia, which is defined as regulated copper-dependent cell proliferation and is a representative example of a broad range of metalloplasias. Cuproplasia is linked to a diverse array of cellular processes, including mitochondrial respiration, antioxidant defence, redox signalling, kinase signalling, autophagy and protein quality control. Identifying and characterizing new modes of copper-dependent signalling offers translational opportunities that leverage disease vulnerabilities to this metal nutrient.

COVID-19 and the Uncovering of Health Care Disparities in the United States, United Kingdom and Canada: Call to Action.

The coronavirus disease 2019 (COVID-19) pandemic created a crisis that disproportionately affected populations already disadvantaged with respect to access to health care systems and adequate medical care and treatments. Understanding how and where health care disparities are most widespread is an important starting point for exploring opportunities to mitigate such disparities, especially within our patient population with liver disease. In a webinar in LiverLearning, we discussed the impact of the pandemic on the United States, United Kingdom and Canada, highlighting the disproportionate effects on infection rates and death for certain ethnic minorities, those socioeconomically disadvantaged and living in higher density areas, and those working in health care and other essential jobs. We set forth a "call to action" for members of the American Association for the Study of Liver Diseases and the larger community of providers of liver disease care to generate viable solutions to improve access to care and vaccination rates of our patients against COVID-19, and in general help reduce health care disparities and improve the health of disadvantaged populations within their communities. Solutions will likely involve personalized interventions and messaging for communities that honor local leaders and embrace the diverse needs and different cultural sensitivities of our unique patient populations.

Designing Clinical Trials in Wilson's Disease.

BACKGROUND AND AIMS: Wilson's disease (WD) is an autosomal-recessive disorder caused by ATP7B gene mutations leading to pathological accumulation of copper in the liver and brain. Adoption of initial treatments for WD was based on empirical observations. These therapies are effective, but there are still unmet needs for which treatment modalities are being developed. An increase of therapeutical trials is anticipated. APPROACH AND RESULTS: The first Wilson Disease Aarhus Symposium (May 2019) included a workshop on randomized clinical trial design. The authors of the article were organizers or presented during this workshop, and this article presents their consensus on the design of clinical trials for WD, addressing trial population, treatment comparators, inclusion and exclusion criteria, and treatment endpoints. To achieve adequate recruitment of patients with this rare disorder, the study groups should include all clinical phenotypes and treatment-experienced as well as treatment-naïve patients. CONCLUSIONS: The primary study endpoint should be clinical or a composite endpoint until appropriate surrogate endpoints are validated. Standardization of clinical trials will permit pooling of data and allow for better treatment comparisons, as well as reduce the future numbers of patients needed per trial.

The Effect of Mental Health, Neurological Disease, and Liver Disease on Quality of Life in Patients With Wilson Disease.

BACKGROUND: Wilson disease (WD) is a chronic disorder of copper metabolism which may affect patient's quality of life (QOL). OBJECTIVE: Our aim was to assess the relationship between mental QOL (M-QOL) and physical QOL (P-QOL) and severity of the liver, neurological disease and mental health in patients with WD. METHODS: At enrollment into our multisite international WD registry, adults (n = 62) were administered examinations assessing QOL (Short-Form 12-Item Health Survey), cognition, and mood. Patients also underwent hepatology and neurological assessments. RESULTS: Patients had lower M-QOL than P-QOL scores, P = 0.0006. Patients with major depressive disorder (n = 22) had worse M-QOL scores, P = 0.0017 but not P-QOL. We found no association with impaired cognition (n = 37) and QOL. The P-QOL scores have a moderate negative association with neurological disease severity based on the Unified Wilson Disease Rating Scale score (total [r = -0.38, P < 0.003], part 2 [r = -0.50, P < 0.0001], and part 3 [r = -0.37, P = 0.004]). M-QOL was not associated with Unified Wilson Disease Rating Scale scores. Worse P-QOL, but not M-QOL, was found in higher cirrhosis severity indicated by Child-Pugh (r = -0.80, P = 0.002) and Model for End Stage Liver Disease scores (r = -0.64, P = 0.03). CONCLUSIONS: M-QOL was associated with depression but not cognitive impairment, neurological disease, or liver disease severity, suggesting that mental health issues may affect overall QOL independent of the degree of liver or neurological disease. P-QOL was affected by the severity of neurological and liver disease but not mental health but also contributes to overall QOL in WD. An appreciation of the range of problems that affect QOL in adults with WD will help health care providers address issues that could improve overall well-being. The Short-Form 12-Item Health Survey may provide a useful instrument for QOL surveillance in WD.

Recent advances in Wilson disease.

Wilson disease (WD) is rare genetic disorder that presents with varied phenotype that can at times make the diagnosis challenging. Medical treatments are available, but there are still unmet needs for patients. Since life-long therapy is necessary, adherence to medical therapy and best practices for monitoring and individualizing therapy continue to evolve. Studies are ongoing that address some of these issues. In the current review we focused our attention to recent advances in the diagnosis of WD, current medical treatments, future potential therapies and treatment monitoring. We include discussion of new methodology for detection and quantitation of ophthalmologic signs of WD, new brain imaging modalities for early detection of neurologic involvement in patients and potential new diagnostic methodology using blood samples that may be applicable to newborn screening and adult disease diagnosis. In addition, there are new strategies aimed at improving adherence and outcomes with currently available therapies, including once daily chelation dosing and discussion of the efficacy of different zinc salt compounds. With respect to new therapies with different mechanisms of action, we discuss studies on Bis-choline tetrathiomolybdate (TTM) in patients, pre-clinical studies of a novel chelator methanobactin and other animal studies exploring cures for WD with gene therapy using adeno-associated vectors (AAVs) that introduce ATP7B into liver cells. There are also promising advances in the more accurate measurement of non-ceruloplasmin bound copper and exchangeable copper in the circulation which would potentially help with monitoring and individualization of treatment and possibly play a role in future disease diagnosis.

Direct Measurement of ATP7B Peptides Is Highly Effective in the Diagnosis of Wilson Disease.

BACKGROUND & AIMS: Both existing clinical criteria and genetic testing have significant limitations for the diagnosis of Wilson disease (WD), often creating ambiguities in patient identification and leading to delayed diagnosis and ineffective management. ATP7B protein concentration, indicated by direct measurement of surrogate peptides from patient dried blood spot samples, could provide primary evidence of WD. ATP7B concentrations were measured in patient samples from diverse backgrounds, diagnostic potential is determined, and results are compared with biochemical and genetic results from individual patients. METHODS: Two hundred and sixty-four samples from biorepositories at 3 international and 2 domestic academic centers and 150 normal controls were obtained after Institutional Review Board approval. Genetically or clinically confirmed WD patients with a Leipzig score >3 and obligate heterozygote (carriers) from affected family members were included. ATP7B peptide measurements were made by immunoaffinity enrichment mass spectrometry. RESULTS: Two ATP7B peptides were used to measure ATP7B protein concentration. Receiver operating characteristics curve analysis generates an area under the curve of 0.98. ATP7B peptide analysis of the sequence ATP7B 887 was found to have a sensitivity of 91.2%, specificity of 98.1%, positive predictive value of 98.0%, and a negative predictive value of 91.5%. In patients with normal ceruloplasmin concentrations (>20 mg/dL), 14 of 16 (87.5%) were ATP7B-deficient. In patients without clear genetic results, 94% were ATP7B-deficient. CONCLUSIONS: Quantification of ATP7B peptide effectively identified WD patients in 92.1% of presented cases and reduced ambiguities resulting from ceruloplasmin and genetic analysis. Clarity is brought to patients with ambiguous genetic results, significantly aiding in noninvasive diagnosis. A proposed diagnostic score and algorithm incorporating ATP7B peptide concentrations can be rapidly diagnostic and supplemental to current Leipzig scoring systems.

Coagulopathy, Bleeding Events, and Outcome According to Rotational Thromboelastometry in Patients With Acute Liver Injury/Failure.

BACKGROUND AND AIMS: Patients with acute liver injury or failure (ALI/ALF) experience bleeding complications uncommonly despite an abnormal hemostatic profile. Rotational thromboelastometry (ROTEM), which assesses clot formation in whole blood, was used to determine the nature of abnormal hemostasis and whether it contributes to bleeding events, illness severity, or survival. APPROACH AND RESULTS: A total of 200 patients were recruited from sites of the ALF Study Group. Blood collected daily for up to 5 days was analyzed using ROTEM delta devices. Consistent with standard laboratory evidence of hypocoagulability (median international normalized ratio = 2.9 and platelet count = 144 × 109 /L), patients frequently exhibited ROTEM parameters outside the normal range (73% and 62% had abnormalities in clot formation from extrinsic and intrinsic clotting cascades, respectively); however, measures of clot stability were generally normal. Eighteen patients (9%) experienced bleeding events, in whom clot initiation, assembly, and firmness were more severely deranged than patients without bleeding. Abnormal ROTEM parameters were more frequently observed in patients with non-acetaminophen ALI/ALF than those with acetaminophen ALI/ALF (clot initiation [P < 0.001], assembly [P = 0.02], firmness at 10 minutes [P = 0.05], and maximal firmness [P = 0.06]). Patients with more severe systemic complications (high-grade hepatic encephalopathy and need for renal replacement therapy) also had a higher incidence of abnormal ROTEM parameters. Finally, more hypocoagulable ROTEM parameters (clot initiation (P = 0.005), stiffness at 10 minutes (P = 0.05), and maximal stiffness by fibrin assembly (P = 0.004)) were observed in patients who died or underwent liver transplantation than those who survived with their native liver. CONCLUSIONS: In patients with ALI/ALF, abnormal ROTEM parameters are frequent and proportional to disease severity. Whether the increased bleeding risk associated with abnormal ROTEM indicates hemostatic failure or is a proxy for disease severity requires additional study.

American Association for the Study of Liver Diseases Expert Panel Consensus Statement: Vaccines to Prevent Coronavirus Disease 2019 Infection in Patients With Liver Disease.

The aim of this document is to provide a concise scientific review of the currently available COVID-19 vaccines and those in development, including mRNA, adenoviral vectors, and recombinant protein approaches. The anticipated use of COVID-19 vaccines in patients with chronic liver disease (CLD) and liver transplant (LT) recipients is reviewed and practical guidance is provided for health care providers involved in the care of patients with liver disease and LT about vaccine prioritization and administration. The Pfizer and Moderna mRNA COVID-19 vaccines are associated with a 94%-95% vaccine efficacy compared to placebo against COVID-19. Local site reactions of pain and tenderness were reported in 70%-90% of clinical trial participants, and systemic reactions of fever and fatigue were reported in 40%-70% of participants, but these reactions were generally mild and self-limited and occurred more frequently in younger persons. Severe hypersensitivity reactions related to the mRNA COVID-19 vaccines are rare and more commonly observed in women and persons with a history of previous drug reactions for unclear reasons. Because patients with advanced liver disease and immunosuppressed patients were excluded from the vaccine licensing trials, additional data regarding the safety and efficacy of COVID-19 vaccines are eagerly awaited in these and other subgroups. Remarkably safe and highly effective mRNA COVID-19 vaccines are now available for widespread use and should be given to all adult patients with CLD and LT recipients. The online companion document located at https://www.aasld.org/about-aasld/covid-19-resources will be updated as additional data become available regarding the safety and efficacy of other COVID-19 vaccines in development.