Safety, Tolerability, and Outcomes of Tafamidis for the Treatment of Acquired Amyloid Neuropathy in Domino Liver Transplant Recipients.

INTRODUCTION: Acquired amyloid neuropathy is an iatrogenic disease that appears years after a domino liver transplant. The objectives of our study are to analyze the efficacy and tolerability of tafamidis for the treatment of acquired amyloid neuropathy in domino liver transplant recipients. This post-authorization, prospective, longitudinal study included seven domino liver transplant recipients with acquired amyloid neuropathy who received treatment with tafamidis for 18 months. METHODS: The primary endpoints were the response rate, defined as those patients with an increase of < 2 points on the Neurological Impairment Score (NIS) from baseline, and the change in the NIS score from baseline. Secondary endpoints included the Quantitative Sensory Test, 10-m walk test, quality of life (Norfolk), and disability (Rasch-built Overall Disability Scale). As safety parameters, the evidence of graft rejection, changes in immunosuppressive trough levels and changes in antiviral and allogeneic cellular immunity before and 12 months after tafamidis treatment were also assessed. RESULTS: Six patients (85.7%) had responded at 18-months. Compared to baseline, we observed non-statistically significant improvement in mean NIS score at 6 months (- 2.54 points, CI - 5.92 to 0.84), 12 months (- 3.25 points; CI - 6.63 to 0.13), and 18 months (- 2.35 points; CI - 5.74 to 1.02). Changes in the Quantitative Sensory Test, 10-m walk tests and the quality of life and disability questionnaires were not statistically significant. The use of tafamidis did not induce relevant side effects or drug interactions. Also, no acute rejections events nor changes in functional adaptive immunity were observed. CONCLUSION: Our study supports the safety and tolerability of tafamidis for the treatment of acquired amyloid neuropathy in domino liver transplant recipients. Tafamidis shows promise as a useful treatment in the clinical management of these patients. Future randomized placebo-controlled clinical trials with longer follow-up durations are needed.

Use of Fluorescence Imaging in Liver Transplant Surgery.

Liver transplant surgery is a complex procedure that demands high knowledge of surgical anatomy and the precise recognition and preservation of structures. To address this, the use of fluorescence imaging has facilitated the identification of anatomical structures such as biliary ducts, arteries, and liver segmentation. Indocyanine green is among the most commonly utilized fluorescent agents, not just during surgery but also in the pre- and postoperative phases, where it is used to assess graft failure by measuring the plasma disappearance rate. New advancements such as artificial intelligence paired with fluorescence imaging have the potential to enhance patient outcomes. Additionally, technologies such as augmented reality and mixed reality could be integrated into surgical procedures, broadening the scope of possibilities for improving patient safety.

Biguanides and glucagon like peptide 1 receptor agonists in the amelioration of post liver transplant weight gain; a scoping review of the mechanism of action, safety and efficacy.

Weight gain post-liver transplant can lead to adverse patient outcomes in the post-transplant period. Pharmacotherapy and other measures can be utilised to reduce the burden and occurrence of weight gain in this population. We explored the mechanism of action, safety, and efficacy of these medications, specifically GLP-1 receptor agonists and metformin, focusing on liver transplant patients. This scoping review was conducted in line with the scoping review structure as outlined by the PRISMA guidelines. Metformin and GLP-1 receptor agonists have been observed to be safe and effective in liver transplant patients. Experimental models have found liver-centric weight loss mechanisms in this drug cohort. There is a paucity of evidence about the use of antihyperglycemics in a post-transplant population for weight loss purposes. However, some small studies have shown strong safety and efficacy data. The evidence in relation to using these medications in patients with metabolic syndrome for weight loss warrants further study in a transplant population.

Successful pregnancy after 10 consecutive failures in a liver transplant patient with advanced kidney failure.

We report a successful, albeit complicated pregnancy with a live-born healthy baby at 28 weeks' gestation, after 10 pregnancy failures, in a 39-year-old patient with a history of liver transplantation and chronic kidney disease with hypertension and proteinuria. Multidisciplinary management (obstetrician, nephrologist and hepatology transplant specialist) allowed close monitoring, adaptation of immunosuppressive treatments and strict control of fetal growth. The onset of preeclampsia at 28 weeks' gestation led to a cesarean section, resulting in the birth of a healthy 830 g boy, with subsequent normal development. Following pregnancy, the patient experienced liver transplant rejection, which resolved after adapting immunosuppressive drugs. No deterioration in kidney function was observed in the year following delivery.

Epidemiology and Management of Infections in Liver Transplant Recipients.

Background: Improvements in liver transplant (LT) outcomes are attributed to advances in surgical techniques, use of potent immunosuppressants, and rigorous pre-LT testing. Despite these improvements, post-LT infections remain the most common complication in this population. Bacteria constitute the most common infectious agents, while fungal and viral infections are also frequently encountered. Multi-drug-resistant bacterial infections develop because of polymicrobial overuse and prolonged hospital stays. Immediate post-LT infections are commonly caused by viruses. Conclusions: Appropriate vaccination, screening of both donor and recipients before LT and antiviral prophylaxis in high-risk individuals are recommended. Antimicrobial drug resistance is common in high-risk LT and associated with poor outcomes; epidemiology and management of these cases is discussed. Additionally, we also discuss the effect of coronavirus disease 2019 (COVID-19) infection and monkeypox in the LT population.

A case study of a liver transplant-treated patient with glycogen storage disease type Ia presenting with multiple inflammatory hepatic adenomas: an analysis of clinicopathologic and genetic data.

BACKGROUND: Glycogen storage disease (GSD) is a disease caused by excessive deposition of glycogen in tissues due to genetic disorders in glycogen metabolism. Glycogen storage disease type I (GSD-I) is also known as VonGeirk disease and glucose-6-phosphatase deficiency. This disease is inherited in an autosomal recessive manner, and both sexes can be affected. The main symptoms include hypoglycaemia, hepatomegaly, acidosis, hyperlipidaemia, hyperuricaemia, hyperlactataemia, coagulopathy and developmental delay. CASE PRESENTATION: Here, we present the case of a 13-year-old female patient with GSD Ia complicated with multiple inflammatory hepatic adenomas. She presented to the hospital with hepatomegaly, hypoglycaemia, and epistaxis. By clinical manifestations and imaging and laboratory examinations, we suspected that the patient suffered from GSD I. Finally, the diagnosis was confirmed by liver pathology and whole-exome sequencing (WES). WES revealed a synonymous mutation, c.648 G > T (p.L216 = , NM_000151.4), in exon 5 and a frameshift mutation, c.262delG (p.Val88Phefs*14, NM_000151.4), in exon 2 of the G6PC gene. According to the pedigree analysis results of first-generation sequencing, heterozygous mutations of c.648 G > T and c.262delG were obtained from the patient's father and mother. Liver pathology revealed that the solid nodules were hepatocellular hyperplastic lesions, and immunohistochemical (IHC) results revealed positive expression of CD34 (incomplete vascularization), liver fatty acid binding protein (L-FABP) and C-reactive protein (CRP) in nodule hepatocytes and negative expression of ß-catenin and glutamine synthetase (GS). These findings suggest multiple inflammatory hepatocellular adenomas. PAS-stained peripheral hepatocytes that were mostly digested by PAS-D were strongly positive. This patient was finally diagnosed with GSD-Ia complicated with multiple inflammatory hepatic adenomas, briefly treated with nutritional therapy after diagnosis and then underwent living-donor liver allotransplantation. After 14 months of follow-up, the patient recovered well, liver function and blood glucose levels remained normal, and no complications occurred. CONCLUSION: The patient was diagnosed with GSD-Ia combined with multiple inflammatory hepatic adenomas and received liver transplant treatment. For childhood patients who present with hepatomegaly, growth retardation, and laboratory test abnormalities, including hypoglycaemia, hyperuricaemia, and hyperlipidaemia, a diagnosis of GSD should be considered. Gene sequencing and liver pathology play important roles in the diagnosis and typing of GSD.

Individualized management of immunosuppressants in liver transplant recipients by using a novel immune score system.

BACKGROUND: There is no reliable means to evaluate the immune status of liver transplant recipients. We proposed a novel score model, namely Mingdao immune cell analysis and Mingdao immune score system, to quantify the immunity. METHODS: Data from those who underwent a single liver transplant between January 2017 and June 2020 at Beijing Chaoyang Hospital, were collected. In addition, healthy volunteers were also enrolled. The score model was based on the immune cell populations determined by flow cytometry. RESULTS: There were a total of 376 healthy controls with 376 tests and 148 liver transplant recipients with 284 tests in this study. Evaluated by Mingdao immune cell analysis and Mingdao immune score system, the mean scores of healthy controls were near zero suggesting a balanced immune system. In contrast, the mean scores of liver transplant recipients were negative both before and after surgery indicating a compromised immune system. When liver transplant recipients were given a reduced or routine first dose according to their preoperative score, they had similar recovery of liver function. Moreover, liver transplant recipients with increased scores ≥ 5 were associated with elevated aspartate transaminase and alanine amiotransferase. Finally, on multivariate analysis the score model was the only significant independent risk factor for clinical acute rejection (P = 0.021; Odds ratio, 0.913; 95% confidence interval, 0.845-0.987). CONCLUSION: The novel score model could be used as an indicator to reflect immunity and to regulate immunosuppressants in liver transplant recipients after surgery.

Women Are Also Disadvantaged in Accessing Transplant Outside the United States: Analysis of the Spanish Liver Transplantation Registry.

Sex inequities in liver transplantation (LT) have been documented in several, mostly US-based, studies. Our aim was to describe sex-related differences in access to LT in a system with short waiting times. All adult patients registered in the RETH-Spanish Liver Transplant Registry (2000-2022) for LT were included. Baseline demographics, presence of hepatocellular carcinoma, cause and severity of liver disease, time on the waiting list (WL), access to transplantation, and reasons for removal from the WL were assessed. 14,385 patients were analysed (77% men, 56.2 ± 8.7 years). Model for end-stage liver disease (MELD) score was reported for 5,475 patients (mean value: 16.6 ± 5.7). Women were less likely to receive a transplant than men (OR 0.78, 95% CI 0.63, 0.97) with a trend to a higher risk of exclusion for deterioration (HR 1.17, 95% CI 0.99, 1.38), despite similar disease severity. Women waited longer on the WL (198.6 ± 338.9 vs. 173.3 ± 285.5 days, p < 0.001). Recently, women's risk of dropout has reduced, concomitantly with shorter WL times. Even in countries with short waiting times, women are disadvantaged in LT. Policies directed at optimizing the whole LT network should be encouraged to guarantee a fair and equal access of all patients to this life saving resource.

The Role of Frequent Screening or Diagnostic Testing of Serum Cryptococcal Antigen in Liver Transplant Recipients: A Descriptive Epidemiology.

Background: Cryptococcosis is a notable infectious complication of liver transplantation. Currently, there is no recommendation for screening serum cryptococcal antigen (CrAg) levels in solid organ transplant recipients. We aimed to explore the role of serum CrAg in liver transplant recipients at an institution where posttransplant serum CrAg has been widely tested. Methods: This retrospective study was conducted at a tertiary care center in Japan. All liver transplant recipients with serum CrAg measured either for screening or for diagnostic testing at least once after transplantation between April 2005 and March 2022 were included. For participants with either a positive CrAg test result or positive culture for Cryptococcus, we manually reviewed clinical manifestations, management, and prognosis from the medical records. Results: During the study period, 12 885 serum CrAg tests (median, 16 tests per patient) were performed in 468 liver transplant recipients. The 1-year posttransplant incidence of positive serum CrAg test results and culture-proven cryptococcosis was 1.9% (9/468) and 0.6% (3/468), respectively. No patient with persistently negative serum CrAg test results showed growth of Cryptococcus in culture. Four patients had clinical manifestations consistent with cryptococcosis, of whom 2 (50.0%) started antifungal therapy promptly based on a positive serum CrAg test result. In contrast, 5 patients had no clinical manifestations. Three of the 5 (60.0%) patients did not receive antifungal therapy and remained free of clinical manifestations. Conclusions: Serum CrAg test was more sensitive than culture among liver transplant recipients and prompted early diagnosis and antifungal therapy in symptomatic patients. However, serial screening of serum CrAg in asymptomatic patients may be of little value, with the potential for false-positive results.

Dietary inflammatory index after liver transplantation: Associated effects and long-term outcomes.

BACKGROUND & AIMS: We examined the dietary inflammatory potential in patients who underwent liver transplantation (LTx), associated factors and its relationship with clinical outcomes ten years after the initial evaluation. METHODS: Dietary Inflammatory Index (DII®) scores were generated from data derived from the 24-h recall in 108 patients. RESULTS: Patients with higher DII scores (highest tertile), indicating a pro-inflammatory diet, had significantly higher serum LDL cholesterol (108.0 vs 78.2 mg/dL, p = <0.01) at the initial evaluation. However, DII scores did not significantly predict the occurrence of clinical outcomes after ten years of follow-up. Patient age was predictive of neoplasia (OR:1.05 95% CI:1.00-1.11; p = 0.03). Higher BMI at the initial evaluation was associated with steatosis (OR:1.51; 95% CI:1.29-1.77; p < 0.01), and smoking history was associated with the occurrence of cardiovascular events (OR:7.71; 95% CI:1.53-38.79; p = 0.01). CONCLUSIONS: A pro-inflammatory diet was associated with higher serum LDL cholesterol in the initial evaluation but may not be strongly related to clinical outcomes during long-term follow-up.

H2FPEF Scores Are Increased in Patients with NASH Cirrhosis and Are Associated with Post-liver Transplant Heart Failure.

INTRODUCTION: Patients with cirrhosis are at risk for cardiac complications such as heart failure, particularly heart failure with preserved ejection fraction (HFpEF) due to left ventricular diastolic dysfunction (LVDD). The H2FPEF score is a predictive model used to identify patients with HFpEF. Our primary aim was to assess the H2FPEF score in patients with cirrhosis and determine its potential to identify patients at risk for heart failure after liver transplant. METHODS: This was a cohort study of patients undergoing liver transplant for cirrhosis from January 2010 and October 2018 who had a pre-transplant transthoracic echocardiogram. RESULTS: 166 cirrhosis subjects were included in the study. The majority were men (65%) and Caucasian (85%); NASH was the most common cause of cirrhosis (41%) followed by alcohol (34%). The median H2FPEF score was 2.0 (1.0-4.0). Patients with NASH cirrhosis had higher H2FPEF scores (3.22, 2.79-3.64) than those with alcohol induced cirrhosis (1.89, 1.5-2.29, p < 0.001) and other causes of cirrhosis (1.73, 1.28-2.18, p < 0.001). All subjects with a H2FPEF score > 6 had NASH cirrhosis. There was no association between the H2FPEF scores and measures of severity of liver disease (bilirubin, INR, or MELD score). Patients with heart failure after liver transplant had higher H2FPEF scores than those without heart failure (4.0, 3.1-4.9 vs. 2.3, 2.1-2.6, respectively; p = 0.015), but the score did not predict post-transplant mortality. CONCLUSION: H2FPEF scores are higher in cirrhosis patients with NASH and appear to be associated with post-transplant heart failure, but not death.

Continuous renal replacement therapy and therapeutic plasma exchange in pediatric liver failure.

Patients with acute liver failure (ALF) and acute on chronic liver failure (ACLF) have significant morbidity and mortality. They require extracorporeal blood purification modalities like continuous renal replacement therapy (CRRT) and therapeutic plasma exchange (TPE) as a bridge to recovery or liver transplantation. Limited data are available on the outcomes of patients treated with these therapies. This is a retrospective single-center study of 23 patients from 2015 to 2022 with ALF/ACLF who underwent CRRT and TPE. We aimed to describe the clinical characteristics and outcomes of these patients. Median (IQR) age was 0.93 years (0.57, 9.88), range 16 days to 20 years. Ten (43%) had ALF and 13 (57%) ACLF. Most (n = 19, 82%) started CRRT for hyperammonemia and/or hepatic encephalopathy and all received TPE for refractory coagulopathy. CRRT was started at a median of 2 days from ICU admission, and TPE started on the same day in most. The liver transplant was done in 17 (74%), and 2 recovered native liver function. Four patients, all with ACLF, died prior to ICU discharge without a liver transplant. The median peak ammonia pre-CRRT was 131 µmol/L for the whole cohort. The mean (SD) drop in ammonia after 48 h of CRRT was 95.45 (43.72) µmol/L in those who survived and 69.50 (21.70) µmol/L in those who did not (p 0.26). Those who survived had 0 median co-morbidities compared to 2.5 in non-survivors (aOR (95% CI) for mortality risk of 2.5 (1.1-5.7), p 0.028). Conclusion: In this cohort of 23 pediatric patients with ALF or ACLF who received CRRT and TPE, 83% survived with a liver transplant or recovered with their native liver. Survival was worse in those who had ACLF and those with co-morbid conditions. What is Known: •  Pediatric acute liver failure is associated with high mortality. •  Patients may require extracorporeal liver assist therapies (like CRRT, TPE, MARS, SPAD) to bridge them over to a transplant or recovery of native liver function. What is New: • Standard volume plasma exhange has not been evaluated against high volume plasma exchange for ALF. • The role, dose, and duration of therapeutic plasma exchange in patients with acute on chronic liver failure is not well described.

Harnessing Metabolites as Serum Biomarkers for Liver Graft Pathology Prediction Using Machine Learning.

Graft injury affects over 50% of liver transplant (LT) recipients, but non-invasive biomarkers to diagnose and guide treatment are currently limited. We aimed to develop a biomarker of graft injury by integrating serum metabolomic profiles with clinical variables. Serum from 55 LT recipients with biopsy confirmed metabolic dysfunction-associated steatohepatitis (MASH), T-cell mediated rejection (TCMR) and biliary complications was collected and processed using a combination of LC-MS/MS assay. The metabolomic profiles were integrated with clinical information using a multi-class Machine Learning (ML) classifier. The model's efficacy was assessed through the Out-of-Bag (OOB) error estimate evaluation. Our ML model yielded an overall accuracy of 79.66% with an OOB estimate of the error rate at 19.75%. The model exhibited a maximum ability to distinguish MASH, with an OOB error estimate of 7.4% compared to 22.2% for biliary and 29.6% for TCMR. The metabolites serine and serotonin emerged as the topmost predictors. When predicting binary outcomes using three models: Biliary (biliary vs. rest), MASH (MASH vs. rest) and TCMR (TCMR vs. rest); the AUCs were 0.882, 0.972 and 0.896, respectively. Our ML tool integrating serum metabolites with clinical variables shows promise as a non-invasive, multi-class serum biomarker of graft pathology.

Establishing Neonate-specific Prognostic Markers in Acute Liver Failure: Admission Alpha Fetoprotein and Novel nALF Scores Predict Patient Outcomes.

OBJECTIVES: To develop neonate-specific prediction models for survival with native liver (SNL) in neonatal acute liver failure (ALF) and to determine if these prediction models have superior accuracy to existing models for older children with ALF. STUDY DESIGN: A single-center, retrospective chart review was conducted on neonates ≤ 30 days of life between 2005 and 2022 with ALF (INR ≥ 2 or prothrombin time [PT] ≥ 20s and liver dysfunction). Statistical analysis included comparison of patients by outcome of SNL and generalized linear modeling to derive prediction models. The predictive accuracy of variables was evaluated by receiver operating characteristic (ROC) analysis and Kaplan-Meier survival analysis. RESULTS: 51 patients met inclusion criteria. The most common causes of neonatal ALF included ischemia (22%), infection (20%), and gestational alloimmune liver disease (GALD) (16%). Overall SNL rate was 43% (n=22). AFP levels were higher in SNL patients (p=0.034) and differed more significantly by SNL status among non-GALD patients (n=21, p=0.001). An AFP < 4775 ng/mL had 75% sensitivity and 100% specificity to predict death or transplant in non-GALD patients with an area under the ROC curve (AUROC) of 0.81. A neonate-specific admission model (INR and ammonia) and peak model (PT and ammonia) also predicted SNL with good accuracy (AUROC = 0.73 and 0.82 respectively). CONCLUSIONS: We identified neonate-specific prognostic variables for SNL in ALF. Findings from our study may help early risk stratification to guide medical decision-making and consideration for liver transplantation.

External validation of population pharmacokinetic models of tacrolimus in Thai adult liver transplant recipients.

OBJECTIVE: Several population pharmacokinetic models of tacrolimus in liver transplant patients were built, and their predictability was evaluated in their settings. However, the extrapolation in the prediction was unclear. This study aimed to evaluate the predictive performance of published tacrolimus models in adult liver transplant recipients using data from the Thai population as an external dataset. METHODS: The selected published models were systematically searched and evaluated for their quality. The external dataset of patients who underwent the first liver transplant and received immediate-release tacrolimus was used to assess the predictive performance of each selected model. Trough concentrations between 3 and 6 months were retrospectively collected to evaluate the predictability of each model using prediction-based diagnostics, simulation-based diagnostics, and Bayesian forecasting. RESULTS: Sixty-seven patients with 360 trough concentrations and eight selected published models were included in this study. None of the models met the predictive precision criteria in prediction-based diagnostics. Meanwhile, four published population pharmacokinetic models showed a normal distribution in NPDE testing. Regarding Bayesian forecasting, all models improved their forecasts with at least one prior information data point. CONCLUSION: Bayesian forecasting is more accurate and precise than other testing methods for predicting drug concentrations. However, none of the evaluated models provides satisfactory predictive performance for generalization to Thai liver transplant patients. This underscores the need for future research to develop population PK models tailored to the Thai population. Such efforts should consider the inclusion of nonlinear pharmacokinetics and region-specific factors, including genetic variability, to improve model accuracy and applicability.

Optimizing pediatric liver transplantation: Evaluating the impact of donor age and graft type on patient survival outcome.

BACKGROUND: We examined the combined effects of donor age and graft type on pediatric liver transplantation outcomes with an aim to offer insights into the strategic utilization of these donor and graft options. METHODS: A retrospective analysis was conducted using a national database on 0-2-year-old (N = 2714) and 3-17-year-old (N = 2263) pediatric recipients. These recipients were categorized based on donor age (≥40 vs <40 years) and graft type. Survival outcomes were analyzed using the Kaplan-Meier and Cox proportional hazards models, followed by an intention-to-treat (ITT) analysis to examine overall patient survival. RESULTS: Living and younger donors generally resulted in better outcomes compared to deceased and older donors, respectively. This difference was more significant among younger recipients (0-2 years compared to 3-17 years). Despite this finding, ITT survival analysis showed that donor age and graft type did not impact survival with the exception of 0-2-year-old recipients who had an improved survival with a younger living donor graft. CONCLUSIONS: Timely transplantation has the largest impact on survival in pediatric recipients. Improving waitlist mortality requires uniform surgical expertise at many transplant centers to provide technical variant graft (TVG) options and shed the conservative mindset of seeking only the "best" graft for pediatric recipients.

Deoxyguanosine kinase deficiency: natural history and liver transplant outcome.

Autosomal recessive pathogenetic variants in the DGUOK gene cause deficiency of deoxyguanosine kinase activity and mitochondrial deoxynucleotides pool imbalance, consequently, leading to quantitative and/or qualitative impairment of mitochondrial DNA synthesis. Typically, patients present early-onset liver failure with or without neurological involvement and a clinical course rapidly progressing to death. This is an international multicentre study aiming to provide a retrospective natural history of deoxyguanosine kinase deficient patients. A systematic literature review from January 2001 to June 2023 was conducted. Physicians of research centres or clinicians all around the world caring for previously reported patients were contacted to provide followup information or additional clinical, biochemical, histological/histochemical, and molecular genetics data for unreported cases with a confirmed molecular diagnosis of deoxyguanosine kinase deficiency. A cohort of 202 genetically confirmed patients, 36 unreported, and 166 from a systematic literature review, were analyzed. Patients had a neonatal onset (≤ 1 month) in 55.7% of cases, infantile (>1 month and ≤ 1 year) in 32.3%, pediatric (>1 year and ≤18 years) in 2.5% and adult (>18 years) in 9.5%. Kaplan-Meier analysis showed statistically different survival rates (P < 0.0001) among the four age groups with the highest mortality for neonatal onset. Based on the clinical phenotype, we defined four different clinical subtypes: hepatocerebral (58.8%), isolated hepatopathy (21.9%), hepatomyoencephalopathy (9.6%), and isolated myopathy (9.6%). Muscle involvement was predominant in adult-onset cases whereas liver dysfunction causes morbidity and mortality in early-onset patients with a median survival of less than 1 year. No genotype-phenotype correlation was identified. Liver transplant significantly modified the survival rate in 26 treated patients when compared with untreated. Only six patients had additional mild neurological signs after liver transplant. In conclusion, deoxyguanosine kinase deficiency is a disease spectrum with a prevalent liver and brain tissue specificity in neonatal and infantile-onset patients and muscle tissue specificity in adult-onset cases. Our study provides clinical, molecular genetics and biochemical data for early diagnosis, clinical trial planning and immediate intervention with liver transplant and/or nucleoside supplementation.

Prognostic Markers in Pediatric Acute Liver Failure.

Introduction: Acute liver failure (ALF), although rare in children, is a complex progressive pathology, with multisystem involvement and high mortality. Isolated variables or those included in prognostic scores have been studied, to optimize organ allocation. However, its validation is challenging. This study aimed to assess the accuracy of several biomarkers and scores as predictors of prognosis in pediatric ALF (PALF). Methods: An observational study with retrospective data collection, including all cases of ALF, was defined according to the criteria of the Pediatric Acute Liver Failure Study Group, admitted to a pediatric intensive care unit (PICU) for 28 years. Two groups were defined: spontaneous recovery (SR) and non-SR (NSR) - submitted to liver transplantation (LT) or death at PICU discharge. Results: Fifty-nine patients were included, with a median age of 24 months, and 54% were female. The most frequent etiologies were metabolic (25.4%) and infectious (18.6%); 32.2% were undetermined. SR occurred in 21 patients (35.6%). In NSR group (N = 38, 64.4%), 25 required LT (42.4%) and 19 died (32.2%), 6 (15.7%) of whom after LT. The accuracy to predict NSR was acceptable for lactate at admission (AUC 0.72; 95% CI: 0.57-0.86; p = 0.006), ammonia peak (AUC 0.72; 95% CI: 0.58-0.86; p = 0.006), and INR peak (AUC 0.70; 95% CI: 0.56-0.85; p = 0.01). The cut-off value for lactate at admission was 1.95 mmol/L (sensitivity 78.4% and specificity 61.9%), ammonia peak was 64 µmol/L (sensitivity 100% and specificity 38.1%), and INR peak was 4.8 (sensitivity 61.1% and specificity 76.2%). Lactate on admission was shown to be an independent predictor of NSR on logistic regression model. Two prognostic scores had acceptable discrimination for NSR, LIU (AUC 0.73; 95% CI: 0.59-0.87; p = 0.004) and PRISM (AUC 0.71; 95% CI: 0.56-0.86; p = 0.03). In our study, the PALF delta score (PALF-ds) had lower discrimination capacity (AUC 0.63; 95% CI: 0.47-0.78; p = 0.11). Conclusions: The lactate at admission, an easily obtained parameter, had a similar capacity than the more complex scores, LIU and PRISM, to predict NSR. The prognostic value in our population of the promising dynamic score, PALF-ds, was lower than expected.

Introdução: A falência hepática aguda (FHA), apesar de rara em pediatria, é uma patologia complexa, com envolvimento multissistémico e elevada mortalidade. Têm sido estudadas variáveis isoladas ou incluídas em scores de prognóstico, com o objetivo de otimizar a alocação de órgãos. No entanto, a sua validação apresenta alguns desafios. O presente estudo tem como objetivo avaliar a precisão de vários biomarcadores e scores, como preditores de prognóstico na FHA. Métodos: Estudo observacional com método de colheita de dados retrospetivo, tendo como critérios de inclusão os casos de FHA, definida de acordo com os critérios da Pediatric Acute Liver Failure Study Group, admitidos numa Unidade de Cuidados Intensivos Pediátricos (UCIP) num período de 28 anos. Definiram-se 2 grupos: recuperação espontânea (RE) e sem recuperação espontânea (SRE) ­ doentes submetidos a transplante hepático (TRH) ou morte na alta da UCIP. Resultados: Incluíram-se 59 doentes, com mediana de idade de 24 meses, 54% do sexo feminino. As etiologias mais frequentes foram a metabólica (25.4%) e a infeciosa (18.6%); em 32.2% foi indeterminada. Apresentaram RE 21 doentes (35.6%). No grupo SRE (N = 38, 64.4%), 25 necessitaram de TRH (42.4%) e 19 faleceram (32.2%), dos quais 6 (15.7%) tinham sido submetidos a TRH. A precisão prognóstica para a ausência de recuperação espontânea foi aceitável para o lactato na admissão (AUC 0.72; IC 95%: 0.57­0.86; p = 0.006), amónia máxima (AUC 0.72; IC 95%: 0.58­0.86; p = 0.006) e INR máximo (AUC 0.70; IC 95%: 0.56­0.85; p = 0.01). O valor de cut-off do lactato na admissão foi de 1.95 mmol/L (sensibilidade 78.4% e especificidade 61.9%) e da amónia máxima foi de 64 umol/L (sensibilidade 100% e especificidade 38.1%). O lactato à admissão mostrou ser um fator independente para NSR, no modelo de regressão logística. Os scores LIU e PRISM apresentaram curvas ROC com aceitável capacidade de discriminação para a ausência de recuperação espontânea, com AUC de 0.73 (IC 95%: 0.59­0.87; p = 0.004) e 0.71 (IC 95%: 0.56­0.86; p = 0.03), respetivamente. No nosso estudo, o score PALF-Delta (PALF-ds) teve uma menor capacidade de discriminação (AUC 0.63; IC 95%: 0.47­0.78; p = 0.11). Conclusões: O lactato na admissão, um parâmetro de fácil obtenção, teve uma capacidade semelhante aos scores mais complexos, LIU e PRISM, para predizer a ausência de recuperação espontânea. O valor prognóstico nesta série, do promissor score dinâmico PALF-ds, foi inferior ao esperado.

Hepatolithiasis: Epidemiology, presentation, classification and management of a complex disease.

The term hepatolithiasis describes the presence of biliary stones within the intrahepatic bile ducts, above the hilar confluence of the hepatic ducts. The disease is more prevalent in Asia, mainly owing to socioeconomic and dietary factors, as well as the prevalence of biliary parasites. In the last century, owing to migration, its global incidence has increased. The main pathophysiological mechanisms involve cholangitis, bile infection and biliary strictures, creating a self-sustaining cycle that perpetuates the disease, frequently characterised by recurrent episodes of bacterial infection referred to as syndrome of "recurrent pyogenic cholangitis". Furthermore, long-standing hepatolithiasis is a known risk factor for development of intrahepatic cholangiocarcinoma. Various classifications have aimed at providing useful insight of clinically relevant aspects and guidance for treatment. The management of symptomatic patients and those with complications can be complex, and relies upon a multidisciplinary team of hepatologists, endoscopists, interventional radiologists and hepatobiliary surgeons, with the main goal being to offer relief from the clinical presentations and prevent the development of more serious complications. This comprehensive review provides insight on various aspects of hepatolithiasis, with a focus on epidemiology, new evidence on pathophysiology, most important clinical aspects, different classification systems and contemporary management.

Upadacitinib-Induced Hepatitis B Reactivation Leading to Liver Transplant.

Hepatitis B virus (HBV) reactivation can occur with the use of immunosuppressive therapy used to treat autoimmune conditions, such as rheumatoid arthritis. Janus kinase inhibitors, such as upadacitinib, have been approved for the treatment of rheumatoid arthritis. This is the first case report of a patient who used upadacitinib without antiviral prophylaxis against HBV and developed HBV reactivation, leading to fulminant hepatic failure necessitating emergent liver transplantation.