There continues to be an ongoing need for fair and equitable organ allocation. The Model for End-Stage Liver Disease (MELD) score has evolved as a calculated framework to evaluate and allocate patients for liver transplantation objectively. The original MELD score has undergone multiple modifications as it is continuously scrutinized for its accuracy in objectively representing the clinical context of patients with liver disease. Several refinements and iterations of the score have been developed, including the widely accepted MELD-Na score. In addition, the most recent updated iteration, MELD 3.0, has been created. The MELD 3.0 calculator incorporates new variables such as patient sex and serum albumin levels and assigns new weights for serum sodium, bilirubin, international normalized ratio, and creatinine levels. It is anticipated that the use of MELD 3.0 scores will reduce overall waitlist mortality and enhance access for female liver transplant candidates. However, despite the emergence of the MELD score as one of the most objective measures for fair organ allocation, various countries and healthcare systems employ alternative methods for stratification and organ allocation. This review article will highlight the origins of the MELD score, its iterations, the current MELD 3.0, and future directions for managing liver transplantation organ allocation. LAY SUMMARY: Organ donation is crucial for the management of patients unwell with liver disease, but organs must be allocated fairly and equitably. One method used for this is the Model for End-Stage Liver Disease (MELD) score, which helps objectively decide which patient is a candidate for liver transplant. Over time, the MELD score has been refined to better reflect patients' needs. For example, the latest version, MELD 3.0, now considers factors like nutrition and gender. This should ensure that more patients, especially females, are candidates and receive appropriate access to liver transplantation. However, not every country uses the MELD score. Some countries have created their own scoring systems based on local research. This review will explain where the MELD score came from, how it has changed, the current characteristics of the MELD 3.0 score, and what the future might hold for organ allocation in liver transplants.

The 2021 American Association for the Study of Liver Disease (AASLD) Practice Guidance recommends albumin infusion when removing ≥5 L of ascites to prevent post-paracentesis circulatory dysfunction. However, the optimal criteria and scenarios for initiating albumin infusion subsequent to therapeutic paracentesis (TP) have been subject to limited scientific inquiry.

We conducted a retrospective cohort study at a US academic healthcare center. Participants received elective, outpatient TP between July 2019 and December 2022. Patients with spontaneous bacterial peritonitis, post-TP clinical adjustments, and/or hospitalization were excluded. The institution strictly followed the AASLD Guidance. We used a sharp regression discontinuity (RD) design to estimate the effect of albumin infusion at the AASLD Guidance-recommended cutoff of 5 L on serum creatinine and sodium trajectory after TP.

Over the study period, 1,457 elective TPs were performed on 235 unique patients. Albumin infusion at the threshold of 5 L of ascites removal reduced serum creatinine levels by 0.046 mg/dL/d (95% confidence interval 0.003-0.116, P = 0.037) and increased serum sodium levels by 0.35 mEq/L/d (95% confidence interval 0.15-0.55, P = 0.001) compared with those who did not receive albumin infusion. The RD plots indicated worsened serum creatine/sodium levels after draining 3 L of fluid, approaching levels similar to or worse than with albumin infusion at 5 L or more.

Our RD models supported the 2021 AASLD Guidance with robust estimation of causal effect sizes at the cutoff level of 5 L. Nevertheless, the findings also highlight the need to further evaluate the efficacy of albumin infusion in patients who undergo elective TP and have 3-5 L of ascites removed.

Over the last 50 years, liver transplantation has evolved into a procedure routinely performed in many countries worldwide. Those able to access this therapy frequently experience a miraculous risk-benefit ratio, particularly if they face the imminently life-threatening disease. Over the decades, the success of liver transplantation, with dramatic improvements in early posttransplant survival, has aggressively driven demand. However, despite the emergence of living donors to augment deceased donors as a source of organs, supply has lagged far behind demand. As a result, rationing has been an unfortunate focus in recent decades. Recent shifts in the epidemiology of liver disease combined with transformative innovations in liver preservation suggest that the underlying premise of organ shortage may erode in the foreseeable future. The focus will sharpen on improving equitable access while mitigating constraints related to workforce training, infrastructure for organ recovery and rehabilitation, and their associated costs. Research efforts in liver preservation will undoubtedly blossom with the aim of optimizing both the timing and conditions of transplantation. Coupled with advances in genetic engineering, regenerative biology, and cellular therapies, the portfolio of innovation, both broad and deep, offers the promise that, in the future, liver transplantation will not only be broadly available to those in need but also represent a highly durable life-saving therapy.

Hepatic recompensation may be achieved in patients with decompensated cirrhosis due to chronic hepatitis B (CHB) upon effective suppression of viral replication by nucleos(t)ide analogues (NAs). However, the optimal timing and predictors of recompensation and the subsequent clinical course of patients with CHB with vs. without recompensation are not well-defined.

This study was a retrospective extension of a multi-centre prospective cohort, focusing on patients with CHB and decompensated cirrhosis treated with entecavir. We followed patients beyond treatment week 120 until a second decompensation event or June 2023. We identified the optimal timing and predictors of recompensation by week 120, evaluated durability of recompensation in patients fulfilling recompensation criteria by week 120 and examined late recompensation in those who did not fulfil it by week 120.

At treatment week 24, serum albumin ≥34 g/L predicted recompensation by week 120. The Brec-PAS model offered good predictive ability for recompensation by week 120. Of the 283 patients who finished 120 weeks of therapy, 175 were followed beyond week 120 (median follow-up: 240 weeks). Among the 106 patients achieving recompensation by week 120, 92 (86.8%) maintained recompensation for another 120 (72-168) weeks. Among the 69 patients without recompensation by week 120, 40.6% attained late recompensation during the subsequent 120 (72-168) weeks. Additionally, hepatocellular carcinoma incidence was lower in the recompensated group (5.0% vs. 16.13%, p = 0.002).

A serum albumin ≥34 g/L at treatment week 24 predicted recompensation by week 120. Recompensation achieved by week 120 of NA treatment is maintained in >80% of patients in the long term. Some patients may achieve recompensation only after >120 weeks of NA treatment. The incidence of hepatocellular carcinoma was reduced but not completely abolished after recompensation.

Our research provides a meaningful contribution to understanding the long-term prognosis of recompensation in patients with chronic hepatitis B and decompensated cirrhosis, as well as to evaluating the predictive value of serum albumin levels, offering a comprehensive view of clinical outcomes after recompensation. The significance of early biomarkers in guiding therapeutic decisions is highlighted, shedding light on the continued benefits and possible risks after recompensation. This enhances the capability for more precise prognostic evaluations and informed therapeutic strategies. For healthcare providers, these insights afford a detailed perspective on patient monitoring and intervention planning, underscoring the need for ongoing assessment past the initial recompensation phase.

Hepatic retransplantation is associated with higher morbidity and mortality when compared to primary transplantation. Given the scarcity of organs and the need for efficient allocation, evaluating parameters that can predict post-retransplant survival is crucial.

This study aimed to analyze prognostic scores and outcomes of hepatic retransplantation.

Data on primary transplants and retransplants carried out in the state of Paraná in 2019 and 2020 were analyzed. The two groups were compared based on 30-day survival and the main prognostic scores of the donor and recipient, namely Model for End-Stage Liver Disease (MELD), MELD-albumin (MELD-a), Donor MELD (D-MELD), Survival Outcomes Following Liver Transplantation (SOFT), Preallocation Score to Predict Survival Outcomes Following Liver Transplantation (P-SOFT), and Balance of Risk (BAR).

A total of 425 primary transplants and 30 retransplants were included in the study. The main etiology of hepatopathy in primary transplantation was ethylism (n=140; 31.0%), and the main reasons for retransplantation were primary graft dysfunction (n=10; 33.3%) and hepatic artery thrombosis (n=8; 26.2%). The 30-day survival rate was higher in primary transplants than in retransplants (80.5% vs. 36.7%, p=0.001). Prognostic scores were higher in retransplants than in primary transplants: MELD 30.6 vs. 20.7 (p=0.001); MELD-a 31.5 vs. 23.5 (p=0.001); D-MELD 1234.4 vs. 834.0 (p=0.034); SOFT 22.3 vs. 8.2 (p=0.001); P-SOFT 22.2 vs. 7.8 (p=0.001); and BAR 15.6 vs. 8.3 (p=0.001). No difference was found in terms of Donor Risk Index (DRI).

Retransplants exhibited lower survival rates at 30 days, as predicted by prognostic scores, but unrelated to the donor's condition.

Prediction of short-term mortality in patients with acute decompensation of liver cirrhosis could be improved. We aimed to develop and validate two machine learning (ML) models for predicting 28-day and 90-day mortality in patients hospitalized with acute decompensated liver cirrhosis. We trained two artificial neural network (ANN)-based ML models using a training sample of 165 out of 290 (56.9%) patients, and then tested their predictive performance against Model of End-stage Liver Disease-Sodium (MELD-Na) and MELD 3.0 scores using a different validation sample of 125 out of 290 (43.1%) patients. The area under the ROC curve (AUC) for predicting 28-day mortality for the ML model was 0.811 (95%CI: 0.714- 0.907; p < 0.001), while the AUC for the MELD-Na score was 0.577 (95%CI: 0.435-0.720; p = 0.226) and for MELD 3.0 was 0.600 (95%CI: 0.462-0.739; p = 0.117). The area under the ROC curve (AUC) for predicting 90-day mortality for the ML model was 0.839 (95%CI: 0.776- 0.884; p < 0.001), while the AUC for the MELD-Na score was 0.682 (95%CI: 0.575-0.790; p = 0.002) and for MELD 3.0 was 0.703 (95%CI: 0.590-0.816; p < 0.001). Our study demonstrates that ML-based models for predicting short-term mortality in patients with acute decompensation of liver cirrhosis perform significantly better than MELD-Na and MELD 3.0 scores in a validation cohort.

This study was performed to examine the possible association of iron overload with infectious complications and survival among liver transplant recipients.

We conducted a systematic review and meta-analysis of studies published in the PubMed, Embase, Web of Science, and Cochrane Library databases up to September 2022. Hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted to estimate the association of iron overload with infectious outcomes and overall survival after liver transplantation.

Eight studies involving 2817 recipients met the inclusion criteria. Iron overload was strongly associated with an increased risk of infection after liver transplantation (HR, 1.66; 95% CI, 1.03-2.68). An increase in the serum ferritin level was associated with an increased risk of infection after liver transplantation (HR, 1.44; 95% CI, 1.09-1.91). Iron overload was a significant predictor of worse overall survival (HR, 1.35; 95% CI, 1.11-1.64). In addition, a high serum ferritin level was significantly associated with an increased risk of death (HR, 1.34; 95% CI, 1.10-1.64).

Iron overload may be associated with a higher risk of infectious complications and a worse prognosis among liver transplant recipients.

Cirrhosis is a major cause of death worldwide, and is associated with significant health care costs. Even if milestones have been recently reached in understanding and managing end-stage liver disease (ESLD), the disease course remains somewhat difficult to prognosticate. These difficulties have already been acknowledged already in the past, when scores instead of single parameters have been proposed as valuable tools for short-term prognosis. These standard scores, like Child Turcotte Pugh (CTP) and model for end-stage liver disease (MELD) score, relying on biochemical and clinical parameters, are still widely used in clinical practice to predict short- and medium-term prognosis. The MELD score, which remains an accurate, easy-to-use, objective predictive score, has received significant modifications over time, in order to improve its performance especially in the liver transplant (LT) setting, where it is widely used as prioritization tool. Although many attempts to improve prognostic accuracy have failed because of lack of replicability or poor benefit with the comparator (often the MELD score or its variants), few scores have been recently proposed and validated especially for subgroups of patients with ESLD, as those with acute-on-chronic liver failure. Artificial intelligence will probably help hepatologists in the near future to fill the current gaps in predicting disease course and long-term prognosis of such patients.

There are few studies on acute-on-chronic liver failure (ACLF) in patients with recompensated cirrhosis. This study was aimed to investigate the clinical features of ACLF patients with recompensated cirrhosis.

A total of 461 ACLF patients were enrolled and divided into three groups: compensated, recompensated, and decompensated cirrhosis with ACLF. The baseline clinical data and 1-year survival rates were compared among the three groups.

Compared with the decompensated group, in the recompensated group, the levels of hemoglobin, albumin, and serum sodium were significantly higher and the white blood cell count, international normalized ratio, and incidence of respiratory failure were significantly lower; there were no evident differences in other organ failures. The proportion of patients with ACLF grade 3 and 1-year survival rates significantly differed between the two groups. Conversely, compared with the compensated group, in the recompensated group, the platelet and total bilirubin levels were significantly lower and the proportion of patients with ACLF grade 1 was significantly higher. However, other clinical indicators or 1-year survival rates did not significantly differ between the two groups.

Compared with patients who developed ACLF with decompensated cirrhosis, those who developed ACLF with recompensated cirrhosis had a less severe condition, lower incidence of respiratory failure, and better 1-year prognosis. However, the baseline clinical features and prognosis were similar between ACLF patients with recompensated and compensated cirrhosis.

Chinese clinical trials registry: ChiCTR1900021539.

Spontaneous bacterial peritonitis (SBP) is a severe complication in cirrhosis patients with ascites, leading to high mortality rates if not promptly treated. However, specific prediction models for SBP are lacking.

This study aimed to compare commonly used cirrhotic prediction models (CTP score, MELD, MELD-Na, iMELD, and MELD 3.0) for short-term mortality prediction and develop a novel model to improve mortality prediction.

Patients with the first episode of SBP were included. Prognostic values for mortality were assessed using AUROC analysis. A novel prediction model was developed and validated.

In total, 327 SBP patients were analyzed, with HBV infection as the main etiologies. MELD 3.0 demonstrated the highest AUROC among the traditional models. The novel model, incorporating HRS, exhibited superior predictive accuracy for in-hospital in all patients and 3-month mortality in HBV-cirrhosis, with AUROC values of 0.827 and 0.813 respectively, surpassing 0.8.

MELD 3.0 score outperformed the CTP score and showed a non-significant improvement compared to other MELD-based scores, while the novel SBP model demonstrated impressive accuracy. Internal validation and an HBV-related cirrhosis subgroup sensitivity analysis supported these findings, highlighting the need for a specific prognostic model for SBP and the importance of preventing HRS development to improve SBP prognosis.

It is still debatable whether serum ferritin is a potential prognostic marker in patients with decompensated cirrhosis. In this meta-analysis, we hope to investigate the relationship between elevated serum ferritin and the risk of death in patients with decompensated cirrhosis. We systematically searched PubMed, Embase, Web of Science, Cochrane Library, CNKI, SinoMed, WAN FANG, and ClinicalTrials.gov without language restrictions from inception to 3 October 2022, and finally identified a total of eight eligible studies with 1829 patients. The pooled prevalence of elevated serum ferritin in decompensated cirrhosis was 40.6% [95% confidence interval (CI) 32.1-49.2%], and it was higher in males, patients with alcohol-associated liver disease, those with Child-Pugh grade C, those with hepatic encephalopathy, and nonsurvivors. Nonsurvivors had significantly higher serum ferritin levels than survivors [mean difference 247.90; 95% CI, 130.97-364.84]. With a pooled unadjusted hazard ratio of 2.38 (95% CI, 1.78-3.18), high serum ferritin was associated with an increased risk of death in patients with decompensated cirrhosis, with low heterogeneity among the included studies. In conclusion, high serum ferritin levels were associated with mortality in patients with decompensated cirrhosis. More prospective and homogeneous clinical studies are required to validate our findings.

Kidney disease is associated with adverse outcomes in patients with cirrhosis including increased post-liver transplantation (LT) mortality. Therefore, diagnosis and staging of kidney disease are critical to timely implementation of treatment and have important implications for transplant eligibility. Serum creatinine (sCr) is a key component of the Model for End-Stage Liver Disease score in LT candidates, and sCr-based estimated glomerular filtration rate (eGFR) values play an important role in determining medical urgency for LT. However, the use of sCr to assess kidney function may be limited in the cirrhotic milieu due to decreased creatinine production, interference of bilirubin with some laboratory assays for sCr, and expansion of the volume of distribution of creatinine. Therefore, conventional eGFR equations perform poorly in patients with cirrhosis and may overestimate kidney function leading to delayed diagnosis of acute kidney injury or lower priority for LT in patients with a truly low glomerular filtration rate. In this review, we will provide an update on the use of sCr for diagnosis and staging of kidney disease in patients with cirrhosis, discuss the limitations of sCr-based eGFR equations, and discuss novel eGFR equations that have been developed in patients with cirrhosis.

Brain manganese (Mn) accumulation is a key feature in patients with acquired hepatocerebral degeneration (AHD). The role of trace elements other than Mn in AHD needs to be clarified. In this study, using inductively coupled plasma mass spectrometry, we aimed to evaluate blood levels of trace elements in patients with AHD before and after liver transplantation (LT). Trace element levels in the AHD group were also compared with those of healthy controls (blood donors, n = 51). Fifty-one AHD patients were included in the study (mean age: 59.2 ± 10.6 years; men: 72.5%). AHD patients had higher levels of Mn, Li, B, Ni, As, Sr, Mo, Cd, Sb, Tl and Pb and a higher Cu/Se ratio, and lower levels of Se and Rb. Six patients (two women; mean age 55 ± 8.7 years) underwent LT, and there was an improvement in neurological symptoms, a significant increase in the Zn, Se and Sr levels, and a decrease in the Cu/Zn and Cu/Se ratios. In summary, several trace element imbalances were identified in AHD patients. Liver transplantation resulted in the improvement of neurological manifestations and the oxidant/inflammatory status. It is possible that observed changes in trace element levels may play a role in the pathophysiology and symptomatology of AHD.

Liver transplantation (LT) is a life-saving and evidence-based intervention for patients with acute liver failure and chronic end-stage liver disease. Significant progress has been made in advancing pre-LT management, transplant techniques, post-LT long-term care, and immunosuppression regimes. However, as rates of DC continue to increase, causes of liver disease and indications for LT continue to be investigated to ensure equity and further improve liver allocation models, waitlist outcomes, and post-LT outcomes for all patient populations.

Nearly 40 y have passed since the 1983 National Institutes of Health Consensus-Development-Conference, which has turned liver transplantation (LT) from a clinical experiment into a routine therapeutic modality. Since' clinical LT has changed substantially. We aimed to comprehensively analyze the publication trends in the most-cited top-notch literature in LT science over a 4-decade period.

A total of 106 523 items were identified between January 1981 and May 2021 from the Web of Science Core Collection. The top 100 articles published were selected using 2 distinct citation-based strategies to minimize bias. Various bibliometric tools were used for data synthesis and visualization.

The citation count for the final dataset of the top 100 articles ranged from 251 to 4721. Most articles were published by US authors (n = 61). The most prolific institution was the University of Pittsburgh (n = 15). The highest number of articles was published in Annals of Surgery, Hepatology, and Transplantation ; however, Hepatology publications resulted in the highest cumulative citation of 9668. Only 10% of the articles were classified as evidence level 1. Over 90% of first/last authors were male. Our data depict the evolution of research focus over 40 y. In part, a disproportional flow of citations was observed toward already well-cited articles. This might also project a slowed canonical progress, which was described in other fields of science.

This study highlights key trends based on a large dataset of the most-cited articles over a 4-decade period. The present analysis not only provides an important cross-sectional and forward-looking guidance to clinicians, funding bodies, and researchers but also draws attention to important socio-academic or demographic aspects in LT.

Liver transplantation is the only curative treatment for end-stage liver disease. Unfortunately, the scarcity of donor organs and the increasing pool of potential recipients limit access to this life-saving procedure. Allocation should account for medical and ethical factors, ensuring equal access to transplantation regardless of recipient's gender, race, religion, or income. Based on their short-term prognosis prediction, model for end-stage liver disease (MELD) and MELD sodium (MELDNa) have been widely used to prioritize patients on the waiting list for liver transplantation resulting in a significant decrease in waiting list mortality/removal. Recent concern has been raised regarding the prognostic accuracy of MELD and MELDNa due, in part, to changes in recipients' profile such as body mass index, comorbidities, and general condition, including nutritional status and cause of liver disease, among others. This review aims to provide a comprehensive view of the current state of MELD and MELDNa advantages and limitations and promising alternatives. Finally, it will explore future options to increase the donor pool and improve donor-recipient matching.

Uromodulin [Tamm-Horsfall protein (THP)] is a glycoprotein uniquely produced in the kidney. It is released by cells of the thick ascending limbs apically in the urine and basolaterally in the renal interstitium and systemic circulation. Processing of mature urinary THP, which polymerizes into supramolecular filaments, requires cleavage of an external hydrophobic patch (EHP) at the COOH-terminus. However, THP in the circulation is not polymerized, and it remains unclear if nonaggregated forms of THP exist natively in the urine. We propose that an alternative processing path, which retains the EHP domain, can lead to a nonpolymerizing form of THP. We generated an antibody that specifically recognizes THP with retained EHP (THP + EHP) and established its presence in the urine in a nonpolymerized native state. Proteomic characterization of urinary THP + EHP revealed its COOH-terminus ending at F617. In the human kidney, THP + EHP was detected in thick ascending limb cells and less strongly in the renal parenchyma. Using immunoprecipitation followed by proteomic sequencing and immunoblot analysis, we then demonstrated that serum THP has also retained EHP. In a small cohort of patients at risk for acute kidney injury, admission urinary THP + EHP was significantly lower in patients who subsequently developed acute kidney injury during hospitalization. Our findings uncover novel insights into uromodulin biology by establishing the presence of an alternative path for cellular processing, which could explain the release of nonpolymerizing THP in the circulation. Larger studies are needed to establish the utility of urinary THP + EHP as a sensitive biomarker of kidney health and susceptibility to injury.NEW & NOTEWORTHY In this work, we discovered and characterized a novel form of uromodulin that does not polymerize because it retains an external hydrophobic patch at the COOH-terminus. These findings establish an alternative form of cellular processing of this protein and elucidate new aspects of its biology. We also provide evidence suggesting that measuring urinary nonpolymerizing uromodulin could be a promising assay to assess the risk of acute kidney injury.

Liver transplant allocation policies in the United States has evolved over 3 decades. The donor liver organs are matched, allocated and procured by the Organ Procurement and Transplantation Network which is administered by the United Network of Organ Sharing (UNOS), a not-for-profit organization governed by the United States human health services. We reviewed the evolution of liver transplant allocation policies. Prior to 2002, UNOS used Child-Turcotte-Pugh score to list and stratify patients for liver transplantation (LT). After 2002, UNOS changed its allocation policy based on model for end-stage liver disease (MELD) score. The serum sodium is the independent indicator of mortality risk in patients with chronic liver disease. The priority assignment of MELD-sodium score resulted in LT and prevented mortality on waitlist. MELD-Sodium score was implemented for liver allocation policy in 2016. Prior to the current and most recent policy, livers from adult donors were matched first to the status 1A/1B patients located within the boundaries of the UNOS regions and donor-service areas (DSA). We reviewed the disadvantages of the DSA-based allocation policies and the advantages of the newest acuity circle allocation model. We then reviewed the standard and non-standard indications for MELD exceptions and the decision-making process of the National Review Liver Review Board. Finally, we reviewed the liver transplant waitlist, donation and survival outcomes in the United States.

Hyponatremia is the most common electrolyte abnormality in patients with decompensated cirrhosis on Liver Transplantation (LT) waiting list. Most of these patients have dilutional or hypervolemic hyponatremia secondary to splanchnic vasodilatation. Excessive secretion of the antidiuretic hormone also plays an important role. Hypervolemic hyponatremia is commonly associated with refractory ascites, spontaneous bacterial peritonitis, and hepatic encephalopathy. Although uncommon, the use of diuretics and laxatives can cause hypovolemic hyponatremia that is characterized by the striking absence of ascites or pedal edema. Clinical features are often nonspecific and depend on the acuity of onset rather than the absolute value of serum sodium. Symptoms may be subtle, including nausea, lethargy, weakness, or anorexia. However, rarely patients may present with confusion, seizures, psychosis, or coma. Treatment includes discontinuation of diuretics, beta-blockers, and albumin infusion. Hypertonic saline (3%) infusion may be used in patients with very low serum sodium (<110 mmol/L) or when patients present with seizures or coma. Short-term use of Vasopressin (V₂) receptor antagonists may also be used to normalize sodium levels prior to LT. However, all these measures may be futile, and LT remains the definite treatment in these patients to improve survival. In this review, we describe the classification, pathogenesis of hyponatremia, and its clinical implications in patients with cirrhosis. Approach to these patients along with management will also be discussed briefly.

The impact of hyponatremia on waitlist and post-transplant outcomes following the implementation of MELD-Na-based liver allocation remains unclear. We investigated waitlist and postliver transplant (LT) outcomes in patients with hyponatremia before and after implementing MELD-Na-based allocation. Adult patients registered for a primary LT between 2009 and 2021 were identified in the OPTN/UNOS database. Two eras were defined; pre-MELD-Na and post-MELD-Na. Extreme hyponatremia was defined as a serum sodium concentration ≤120 mEq/l. Ninety-day waitlist outcomes and post-LT survival were compared using Fine-Gray proportional hazard and mixed-effects Cox proportional hazard models. A total of 118 487 patients were eligible (n = 64 940: pre-MELD-Na; n = 53 547: post-MELD-Na). In the pre-MELD-Na era, extreme hyponatremia at listing was associated with an increased risk of 90-day waitlist mortality ([ref: 135-145] HR: 3.80; 95% CI: 2.97-4.87; P < 0.001) and higher transplant probability (HR: 1.67; 95% CI: 1.38-2.01; P < 0.001). In the post-MELD-Na era, patients with extreme hyponatremia had a proportionally lower relative risk of waitlist mortality (HR: 2.27; 95% CI 1.60-3.23; P < 0.001) and proportionally higher transplant probability (HR: 2.12; 95% CI 1.76-2.55; P < 0.001) as patients with normal serum sodium levels (135-145). Extreme hyponatremia was associated with a higher risk of 90, 180, and 365-day post-LT survival compared to patients with normal serum sodium levels. With the introduction of MELD-Na-based allocation, waitlist outcomes have improved in patients with extreme hyponatremia but they continue to have worse short-term post-LT survival.

Hyponatremia is an important predictor of early death among cirrhotic patients in the orthotopic liver transplantation (OLT) waiting list. Evidence exists that prioritizing OLT waiting list according to the MELD score combined with plasma sodium concentration might prevent pre transplantation death. However, the evolution of plasma sodium concentrations during the perioperative period of OLT is not well known. We aimed to describe the evolution of perioperative sodium concentration during OLT and its relation to perioperative neurohormonal responses.

Twenty-seven consecutive cirrhotic patients who underwent OLT were prospectively included in the study over a period of 27 months. We studied the evolution of plasma sodium levels, the hemodynamics, the neurohormonal response and other biological markers during the perioperative period of OLT.

Among study's population, four patients had hyponatremia before OLT, all with Child cirrhosis. In patients with hyponatremia, plasmatic sodium reached normal levels during surgery, and sodium levels remained within normal ranges 1 day, 7 days, as well as 6 months after surgery for all patients. Creatinine clearance was decreased significantly during the perioperative period, while creatinine and cystatin C levels increased significantly. Neutrophil gelatinase-associated lipocalin (NGAL) and vasopressin levels did not change significantly in this period. Plasma renin activity, concentrations of norepinephrine and brain natriuretic peptide varied significantly during the perioperative period.

In our study, plasmatic sodium concentrations among hyponatremic cirrhotic patients undergoing OLT seem to reach normal levels after OLT and remain stable six months after surgery providing more evidence for the importance of sodium levels in prioritization of liver transplant candidates. Further investigation of rapid correction and stabilization of sodium levels after OLT, as observed in our study, would be of interest in order to fully understand the mechanisms involved in cirrhosis-related hyponatremia, its prognostic value and clinical implications.

Estimates of racial disparity in cirrhosis have been limited by lack of large-scale, longitudinal data, which track patients from diagnosis to death and/or transplant.

We analyzed a large, metropolitan, population-based electronic health record data set from seven large health systems linked to the state death registry and the national transplant database. Multivariate competing risk analyses, adjusted for sex, age, insurance status, Elixhauser score, etiology of cirrhosis, HCC, portal hypertensive complication, and Model for End-Stage Liver Disease-Sodium (MELD-Na), examined the relationship between race, transplant, and cause of death as defined by blinded death certificate review. During the study period, 11,277 patients met inclusion criteria, of whom 2,498 (22.2%) identified as Black. Compared to White patients, Black patients had similar age, sex, MELD-Na, and proportion of alcohol-associated liver disease, but higher comorbidity burden, lower rates of private insurance, and lower rates of portal hypertensive complications. Compared to White patients, Black patients had the highest rate all-cause mortality and non-liver-related death and were less likely to be listed or transplanted (P < 0.001 for all). In multivariate competing risk analysis, Black patients had a 26% increased hazard of liver-related death (subdistribution HR, 1.26; 95% CI, [1.15-1.38]; P < 0.001).

Black patients with cirrhosis have discordant outcomes. Further research is needed to determine how to address these real disparities in the field of hepatology.

Dysnatremias are a rare but significant event in liver transplantation. While recipient pre-transplant hypernatremia has been demonstrated to increase post-transplant mortality, the degree of hypernatremia and the impact of its resolution have been less well characterized. Here, we used multivariate Cox regression with a comprehensive list of donor and recipient factors in order to conduct a robust multivariate retrospective database study of 54,311 United Network for Organ Sharing (UNOS) liver transplant patients to analyze the effect of pre-transplant serum sodium on post-transplant mortality, post-transplant length of hospitalization, and post-transplant graft survival. Mortality and graft failure increased in a stepwise fashion with increasing pre-transplant hypernatremia: 145 -150 mEq/L (HR = 1.118 and HR = 1.113), 150-155 mEq/L (HR = 1.324 and HR = 1.306), and > 155 mEq/L (HR = 1.623 and HR = 1.661). Pre-transplant hypo- and hypernatremia also increased length of post-transplant hospitalization: < 125 mEq/L (HR = 1.098), 125-130 mEq/L (HR = 1.060), 145 -150 mEq/L (HR = 1.140), and 150-155 mEq/L (HR = 1.358). Resolution of hypernatremia showed no significant difference in mortality compared with normonatremia, while unresolved hypernatremia significantly increased mortality (HR = 1.254), including a durable long-term increased mortality risk for patients with creatinine < 2 mg/dL and MELD < 25. Pre-transplant hypernatremia serves as a morbid prognostic indicator for post-transplant morbidity and mortality.

To assess the utility of prognostic scoring systems for adolescents with biliary atresia (BA) surviving with native liver, for predicting the subsequent requirement for liver transplantation (LT).

Single-centre retrospective analysis of 397 BA patients who received Kasai Portoenterostomy (KP) 1980-1996 and survived with the native liver at 16 years. Laboratory and clinical variables at 16 years (timepoint 16 years) were used to calculate (i) LT allocation scores; Model for End-Stage Liver Disease [MELD/MELD-sodium (Na)], and UK End-Stage Liver Disease (UKELD); (ii) Mayo Primary Sclerosing Cholangitis risk score (MayoPSC) and (iii) a modified Paediatric End-Stage Liver Disease (PELD) score. Scores were compared between patients requiring LT after 16 years of age (LT > 16 years), and those who survived with native liver, at the latest follow-up. Additional subgroup analysis for patients with data available at 12 years (timepoint 12 years).

MELD (area under the receiver operating characteristic [AUROC] 0.847) and UKELD (AUROC: 0.815) at 16 years of age predict the need for LT > 16 years. No advantage for MELD-Na over MELD was demonstrated. MELD >8.5 and UKELD >47 predicted LT > 16 years with 84% and 79% sensitivity and 73% and 73% specificity. PELD had a similar performance to MELD, but superiority to UKELD. MayoPSC revealed predictive accuracy for LT >16 years (AUROC 0.859), with a score of >0.87 predicting LT > 16 years with 85% sensitivity and 82% specificity. At timepoint 12 years, MELD and MayoPSC predicted LT >16 years. Change in MELD, PELD and MayoPSC between 12 and 16 years of age, was associated with LT >16 years.

Adult LT allocation scores may help monitor progress in adolescent BA, but the omission of relevant risk factors limits their utility for listing in this cohort. A BA-specific prognostic score would improve the management of adolescent BA.

The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japan Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.

The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japanese Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.

Cirrhosis is frequently complicated by electrolyte disturbances, with prior studies primarily focused on the importance of hyponatremia. Emerging evidence on patients with chronic heart failure and chronic kidney disease has identified hypochloremia as an independent predictor for mortality. This study aimed to investigate the prognostic value of serum chloride and its association with mortality in cirrhotic patients.

Retrospective cohort study.

The medical ICU at Parkland Memorial Hospital, a tertiary care public health system in Dallas, Texas.

Adult patients with confirmed diagnosis of decompensated cirrhosis who were admitted to the ICU between March 2015 and March 2017.

None.

Kaplan-Meier analysis and multivariable Cox proportional hazard ratio models were performed to determine the impact of hypochloremia on 180-day mortality. Of the 389 enrolled patients, 133 (34.2%) died within 180 days of ICU admission. Patients with hypochloremia had higher 180-day mortality than those with normochloremia (45.2% vs 26.7%; p < 0.0001). Cumulative survival via the Kaplan-Meier method was significantly lower in the hypochloremic group. Serum chloride was independently associated with 180-day mortality with multivariable adjustment (hazard ratio, 0.95; 95% CI, 0.93-0.98; p = 0.001) or after adjusting for Model for End-stage Liver Disease or Sequential Organ Failure Assessment. Contrarily, the inverse association between serum sodium and mortality no longer existed in all multivariable models.

Serum chloride is independently and inversely associated with short-term mortality in critically ill cirrhotic patients. Hypochloremia, but not hyponatremia, remained associated with mortality with multivariable analyses, suggesting that hypochloremia may account for the mortality risk previously attributed to hyponatremia. These findings signify the prognostic value of serum chloride and potential inclusion of chloride into future cirrhosis prognostic scores.

The model for end-stage liver disease (MELD) score can be used to predict survival of patients undergoing transjugular intrahepatic portosystemic shunt procedures (TIPS). The effect of hyponatremia on survival resulted in the development of the MELD-Na score. The aim of this study is to compare the prognostic value of MELD and MELD-Na scores in predicting post-TIPS outcomes.

A retrospective chart review was performed on consecutive patients with cirrhosis who underwent TIPS placement from 2012 to 2017. Indications for TIPS were either refractory ascites or variceal bleeding. Primary outcomes analyzed were death or liver transplantation. Follow-up data were censored at 1 year.

Eighty-three patients underwent TIPS. There was no difference in MELD or MELD-Na score between indication groups. However, the delta MELD (MELD-Na subtracted by MELD score) was higher in those with refractory ascites. There was no difference in outcomes of death or liver transplantation between the MELD and MELD-Na at 1 year. (area under the curve 0.79 vs 0.72, respectively, P = 0.119). In patients with a MELD-Na greater than 18, higher delta MELD was protective (hazard ratio 0.74, P < 0.05).

There was no prognostic difference using either score despite a higher delta MELD in those with refractory ascites. The decision to pursue TIPS should utilize the original MELD score, as the MELD-Na score alone may exclude patients with refractory ascites who may benefit from TIPS.

Disorders of tonicity, hyponatraemia and hypernatraemia, are common in neurosurgical patients. Tonicity is sensed by the circumventricular organs while the volume state is sensed by the kidney and peripheral baroreceptors; these two signals are integrated in the hypothalamus. Volume is maintained through the renin-angiotensin-aldosterone axis, while tonicity is defended by arginine vasopressin (antidiuretic hormone) and the thirst response. Edelman found that plasma sodium is dependent on the exchangeable sodium, potassium and free-water in the body. Thus, changes in tonicity must be due to disproportionate flux of these species in and out of the body. Sodium concentration may be measured by flame photometry and indirect, or direct, ion-sensitive electrodes. Only the latter method is not affected by changes in plasma composition. Classification of hyponatraemia by the volume state is imprecise. We compare the tonicity of the urine, given by the sodium potassium sum, to that of the plasma to determine the renal response to the dysnatraemia. We may then assess the activity of the renin-angiotensin-aldosterone axis using urinary sodium and fractional excretion of sodium, urate or urea. Together, with clinical context, these help us determine the aetiology of the dysnatraemia. Symptomatic individuals and those with intracranial catastrophes require prompt treatment and vigilant monitoring. Otherwise, in the absence of hypovolaemia, free-water restriction and correction of any reversible causes should be the mainstay of treatment for hyponatraemia. Hypernatraemia should be corrected with free-water, and concurrent disorders of volume should be addressed. Monitoring for overcorrection of hyponatraemia is necessary to avoid osmotic demyelination.

The MELD score is used in the Eurotransplant (ET) region to allocate liver grafts. Hyponatremia in cirrhotic patients is an important predictor of death but is not incorporated in MELD. This study investigated the performance of the MELD-Na score for the ET region. All adult patients with chronic liver disease on the ET liver transplantation waiting list (WL) allocated through lab MELD scores were included. The MELD-corrected effect of serum sodium (Na) concentration at listing on the 90-day WL mortality was calculated using Cox regression. The MELD-Na performance was assessed with c-indices, calibration per decile and Brier scores. The reclassification from MELD to MELD-Na score was calculated to estimate the impact of MELD-Na-based allocation in the ET region. For the 5223 included patients, the risk of 90-day WL death was 2.9 times higher for hyponatremic patients. The MELD-Na had a significantly higher c-index of 0.847 (SE 0.007) and more accurate 90-day mortality prediction compared to MELD (Brier score of 0.059 vs 0.061). It was estimated that using MELD-Na would reduce WL mortality by 4.9%. The MELD-Na score yielded improved prediction of 90-day WL mortality in the ET region and using MELD-Na for liver allocation will very likely reduce WL mortality.

The current pediatric end-stage liver disease (PELD) score underestimates pediatric waitlist mortality. Children frequently require PELD exception points to achieve appropriate priority ranking. We developed a new PELD score using serum sodium, creatinine, and updated original PELD components to more accurately rank children and equalize children's mortality risk with the age-standardized mortality rate of adults. We included children aged younger than 12 years with chronic liver disease, listed for deceased donor livers January 1, 2005-December 31, 2017. Pediatric candidates (n = 5111) were followed from listing to the earliest of waitlist mortality (death or removal from the list due to being too sick to undergo transplant, n = 339) or 180 days. We incorporated linear splines for the current components of PELD and added sodium and creatinine to the equation. The updated PELD-Na-Cr had a cross-validated AUC ROC of 0.854, vs 0.799 for the original PELD. PELD-Na-Cr required 9.44 additional points to equalize children's mortality risk with the age-standardized mortality rate of adults. PELD-Na-Cr better ordered the sickest children and should better prioritize children relative to adults. As a result, PELD-Na-Cr could increase pediatric transplant rates and reduce pediatric liver transplant waitlist mortality.

Background: B-type natriuretic peptide (BNP) is a well-known predictor for prognosis in patients with cardiac and renal diseases. However, there is a lack of studies in patients with advanced hepatic disease, especially patients who underwent liver transplantation (LT). We evaluated whether BNP could predict the prognosis of patients who underwent LT. Material and Methods: The data from a total of 187 patients who underwent LT were collected retrospectively. The serum levels of BNP were acquired at four time points, the pre-anhepatic (T1), anhepatic (T2), and neohepatic phases (T3), and on postoperative day 1 (T4). The patients were dichotomized into survival and non-survival groups for 1-month mortality after LT. Combined BNP (cBNP) was calculated based on conditional logistic regression analysis of pairwise serum BNP measurements at two time points, T2 and T4. The area under the receiver operating characteristic curve (AUROC) was analyzed to determine the diagnostic accuracy and cut-off value of the predictive models, including cBNP. Results: Fourteen patients (7.5 %) expired within one month after LT. The leading cause of death was sepsis (N = 9, 64.3 %). The MELD and MELD-Na scores had an acceptable predictive ability for 1-month mortality (AUROC = 0.714, and 0.690, respectively). The BNPs at each time point (T1 - T4) showed excellent predictive ability (AUROC = 0.864, 0.962, 0.913, and 0.963, respectively). The cBNP value had an outstanding predictive ability for 1-month mortality after LT (AUROC = 0.976). The optimal cutoff values for cBNP at T2 and T4 were 137 and 187, respectively. Conclusions: The cBNP model showed the improved predictive ability for mortality within 1-month of LT. It could help clinicians stratify mortality risk and be a useful biomarker in patients undergoing LT.

An adequate balance between electrolytes and clear water is of paramount importance to maintaining physiologic homeostasis. Natremia imbalance and, in particular, hyponatremia is the most frequent electrolyte abnormality observed in hospitalized subjects, involving approximately one-fourth of them. Pathological changes occurring during liver cirrhosis predispose patients to an increased risk of sodium imbalance, and hypervolemic hyponatremia has been reported in nearly 50% of subjects with severe liver disease and ascites. Splanchnic vasodilatation, portal-systemic collaterals' opening and increased excretion of vasoactive modulators are all factors impairing clear water handling during liver cirrhosis. Of concern, sodium imbalance has been consistently reported to be associated with increased risk of complications and reduced survival in liver disease patients. In the last decades clinical interest in sodium levels has been also extended in the field of liver transplantation. Evidence that [Na+] in blood is an independent risk factor for in-list mortality led to the incorporation of sodium value in prognostic scores employed for transplant priority, such as model for end-stage liver disease-Na and UKELD. On the other hand, severe hyponatremic cirrhotic patients are frequently delisted by transplant centers due to the elevated risk of mortality after grafting. In this review, we describe in detail the relationship between sodium imbalance and liver cirrhosis, focusing on its impact on peritransplant phases. The possible therapeutic approaches, in order to improve transplant outcome, are also discussed.

Risk scoring for patients with cirrhosis has evolved greatly over the past several decades. However, patients with low Model for End-Stage Liver Disease-Sodium scores still suffer from liver-related morbidity and mortality. Unfortunately, it is not clear which of these low Model for End-Stage Liver Disease-Sodium score patients would benefit from earlier consideration of liver transplantation. This article reviews the literature of risk prediction in patients with cirrhosis, identifies which patients may benefit from earlier interventions, such as transplantation, and proposes directions for future research.