Liver Transplantation Failure Research Articles

The Impact of Perioperative Bilirubin and Albumin Levels on Postoperative Early Complications in Adult Liver Transplantation.

Postoperative complications persist as a significant cause of graft failure in liver transplantation. Identifying circulatory markers that predict such complications holds excellent clinical value. This study aimed to investigate serological indicators that can indicate early complications in adult liver transplantation. This study included 436 patients who underwent liver transplantation at our hospital, along with corresponding monitoring protocols. The differences and interactions of circulating indicators at various time points were analyzed using repeated measures analysis of variance. Post-hoc multiple comparisons were adjusted using the Bonferroni method. Restricted cubic spline regression models assessed non-linear associations between circulating markers, complications, and mortality. This study demonstrated significant time effects for all related markers, with substantial differences in complications and mortality for direct bilirubin and albumin. The restricted cubic spline model revealed a significant positive association between direct bilirubin and complications across three postoperative phases (p postoperative phase 1 = 0.0011, p postoperative phase 2 = 0.0001, p postoperative phase 3 = 0.0020). Conversely, albumin showed a significant negative association with complications in phases 1 and 2 (p postoperative phase 1 = 0.0001, p postoperative phase 2 = 0.0009). Furthermore, direct bilirubin was significant associated with increased mortality of postoperative phase 2 and phase 3 (p postoperative phase 2 < 0.0001, p postoperative phase 3 < 0.0001), while albumin showed a significant negative association with mortality (p postoperative phase 1 = 0.0306). Direct bilirubin and albumin are potential critical factors affecting early complications after liver transplantation. Close monitoring of these markers within 24-72 postoperative hours may help predict the occurrence of complications.

Exercise Preconditioning of the Donor Liver Decreases Cold Ischemia/Reperfusion Injury in a Mouse Model.

Liver transplantation stands as the primary treatment for end-stage liver disease, with demand surging in recent decades because of expanded indications. However, hepatic ischemia/reperfusion injury can lead to liver transplant failure in both deceased donor and living donor transplantation. This study explored whether preconditioning donor livers through exercise training (ExT) could mitigate cold ischemic injury posttransplantation. Donor C57BL/6 mice underwent ExT via treadmill running or remained sedentary. After 4 wk, the donor liver underwent cold storage and subsequent orthotopic liver transplantation or ex vivo warm reperfusion. Donor liver from mice subjected to ExT showed significantly decreased hepatic injury on reperfusion. Tissue histology revealed decreased sinusoidal congestion, vacuolization, and hepatocellular necrosis in livers from ExT mice, and immunofluorescence staining further revealed a decreased number of apoptotic cells in ExT grafts. Livers from ExT donors expressed decreased intragraft inflammatory cytokines cascade, decreased neutrophil infiltration and neutrophil extracellular traps, and increased M2 phenotype of recipient macrophages compared with grafts from sedentary mice. After cold storage, liver grafts from ExT donors showed decreased accumulation of reactive oxygen species and decreased levels of cytochrome c and high mobility group box 1 released in the liver effluent. In addition, ExT grafts showed upregulated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and higher levels of mitochondrial content. Similar effects of decreased hepatic injury were observed in wild-type mice when pretreated with a PGC-1α stimulator ZLN005 instead of ExT. These findings suggest that augmenting hepatocytic mitochondrial content through donor exercise or PGC-1α stimulation may offer therapeutic avenues to mitigate postreperfusion inflammation and improve transplant outcomes.

Multi-omics analysis reveals a crosstalk between ferroptosis and peroxisomes on steatotic graft failure after liver transplantation.

To identify the mechanism underlying macrosteatosis (MaS)-related graft failure (GF) in liver transplantation (LT) by multi-omics network analysis. The transcriptome and metabolome were assayed in graft and recipient plasma in discovery (n=68) and validation (n=89) cohorts. Differentially expressed molecules were identified by MaS and GF status. Transcriptional regulatory networks were generated to explore the mechanism for MaS-related inferior post-transplant prognosis. The differentially expressed molecules associated with MaS and GF were enriched in ferroptosis and peroxisome-related pathways. Core features of MaS-related GF were presented on decreased transferrin and impaired anti-oxidative capacity dependent upon dysregulation of transcription factors hepatocytenuclear factor 4A (HNF4A) and hypoxia-inducible factor 1A (HIF1A). Furthermore, miR-362-3p and miR-299-5p inhibited transferrin and HIF1A expression, respectively. Lower M2 macrophages but higher memory CD4 T cells were observed in MaS-related GF cases. These results were validated in clinical specimens and cellular models. Systemic analysis of multi-omics data depicted a panorama of biological pathways deregulated in MaS-related GF. Transcriptional regulatory networks centered on transferrin and anti-oxidant responses were associated with poor MaS graft quality, qualifying as potential targets to improve prognosis of patients after LT.

JCAD deficiency delayed liver regenerative repair through the Hippo-YAP signalling pathway.

Liver regeneration retardation post partial hepatectomy (PH) is a common clinical problem after liver transplantation. Identification of key regulators in liver regeneration post PH may be beneficial for clinically improving the prognosis of patients after liver transplantation. This study aimed to clarify the function of junctional protein-associated with coronary artery disease (JCAD) in liver regeneration post PH and to reveal the underlying mechanisms. JCAD knockout (JCAD-KO), liver-specific JCAD-KO (Jcad△Hep) mice and their control group were subjected to 70% PH. RNA sequencing was conducted to unravel the related signalling pathways. Primary hepatocytes from KO mice were treated with epidermal growth factor (EGF) to evaluate DNA replication. Fluorescent ubiquitination-based cell cycle indicator (FUCCI) live-imaging system was used to visualise the phases of cell cycle. Both global and liver-specific JCAD deficiency postponed liver regeneration after PH as indicated by reduced gene expression of cell cycle transition and DNA replication. Prolonged retention in G1 phase and failure to transition over the cell cycle checkpoint in JCAD-KO cell line was indicated by a FUCCI live-imaging system as well as pharmacologic blockage. JCAD replenishment by adenovirus reversed the impaired DNA synthesis in JCAD-KO primary hepatocyte in exposure to EGF, which was abrogated by a Yes-associated protein (YAP) inhibitor, verteporfin. Mechanistically, JCAD competed with large tumour suppressor 2 (LATS2) for WWC1 interaction, leading to LATS2 inhibition and thereafter YAP activation, and enhanced expression of cell cycle-associated genes. JCAD deficiency led to delayed regeneration after PH as a result of blockage in cell cycle progression through the Hippo-YAP signalling pathway. These findings uncovered novel functions of JCAD and suggested a potential strategy for improving graft growth and function post liver transplantation. JCAD deficiency leads to an impaired liver growth after PH due to cell division blockage. JCAD competes with LATS2 for WWC1 interaction, resulting in LATS2 inhibition, YAP activation and enhanced expression of cell cycle-associated genes. Delineation of JCADHippoYAP signalling pathway would facilitate to improve prognosis of acute liver failure and graft growth in living-donor liver transplantation.

Good outcomes after repeated pediatric liver retransplantations: A justified procedure even in times of organ shortage.

Pediatric liver transplantations generally represent advanced surgery for selected patients. In case of acute or chronic graft failure, biliary or vessel complications, a retransplantation (reLT) can be necessary. In these situations massive adhesions, critical patient condition or lack of good vessels for anastomosis often are problematic. Between 2008 and 2021, 208 pediatric patients received a liver transplantation at our center. Retrospectively, all cases with at least one retransplantation were identified and stored in a database. Indication, intra- and postoperative course and overall survival (OS) were analyzed. Altogether 31 patients (14.9%) received a reLT. In 22 cases only one reLT was done, 8 patients received 2 reLTs and 1 patient needed a fourth graft. Median age for primary transplantation, first, second and third reLT was 14 (range: 1-192 months), 60.5 (range: 1-215 months), 58.5 (range: 14-131 months) and 67 months, respectively. Although biliary atresia (42%) and acute liver failure (23%) represented the main indications for the primary liver transplantation, acute and chronic graft failure (1st reLT: 36%, 2nd reLT: 38%), hepatic artery thrombosis (1st reLT: 29%, 2nd reLT: 25%, 3rd reLT: 100%) and biliary complications (1st reLT: 26%, 2nd reLT: 37%) were the most frequent indications for reLT. OS was 81.8% for patients with 1 reLT, 87.5% with 2 reLTs and 100% with 3 reLTs. Pediatric liver retransplantation is possible with a good outcome even after multiple retransplantations in specialized centers. Nevertheless, careful patient and graft selection, as well as good preoperative conditioning, are essential.

Bioactive Indole Alkaloid from Aspergillus amoenus TJ507 That Ameliorates Hepatic Ischemia/Reperfusion Injury.

Hepatic ischemia/reperfusion injury (IRI) is a major factor contributing to the failure of hepatic resection and liver transplantation. As part of our ongoing investigation into bioactive compounds derived from fungi, we isolated eight indole alkaloids (1-8) from the endophytic fungus Aspergillus amoenus TJ507. Among these alkaloids, one previously undescribed compound, amoenamide D (1), was identified. The planar structure of 1 was elucidated by extensive spectroscopic analysis, including HRESIMS and NMR spectra. The absolute configuration of 1 was elucidated by using electronic circular dichroism calculations. Notably, in the CoCl2-induced hepatocyte damage model, notoamide Q (3) exhibited significant anti-hypoxia injury activity. Furthermore, in a murine hepatic ischemia/reperfusion injury model, treatment with 3 prevents IRI-induced liver damage and hepatocellular apoptosis. Consequently, 3 might serve as a potential lead compound to prevent hepatic ischemia/reperfusion injury.

NO-IL-6/10-IL-1β axis: a new pathway in steatotic and non-steatotic liver grafts from brain-dead donor rats.

Brain death (BD) and steatosis are both risk factors for organ dysfunction or failure in liver transplantation (LT). Here, we examine the role of interleukin 6 (IL- 6) and IL-10 in LT of both non-steatotic and steatotic liver recovered from donors after brain death (DBDs), as well as the molecular signaling pathways underlying the effects of such cytokines. BD reduced IL-6 levels only in nonsteatotic grafts, and diminished IL-10 levels only in steatotic ones. In both graft types, BD increased IL-1β, which was associated with hepatic inflammation and damage. IL-6 administration reduced IL-1β only in non-steatotic grafts and protected them against damage and inflammation. Concordantly, IL-1β inhibition via treatment with an IL-1 receptor antagonist caused the same benefits in non-steatotic grafts. Treatment with IL-10 decreased IL-1β only in steatotic grafts and reduced injury and inflammation specifically in this graft type. Blockading the IL-1β effects also reduced damage and inflammation in steatotic grafts. Also, blockade of IL-1β action diminished hepatic cAMP in both types of livers, and this was associated with a reduction in liver injury and inflammation, then pointing to IL-1β regulating cAMP generation under LT and BD conditions. Additionally, the involvement of nitric oxide (NO) in the effects of interleukins was evaluated. Pharmacological inhibition of NO in LT from DBDs prompted even more evident reductions of IL-6 or IL-10 in non-steatotic and steatotic grafts, respectively. This exacerbated the already high levels of IL-1β seen in LT from DBDs, causing worse damage and inflammation in both graft types. The administration of NO donors to non-steatotic grafts potentiated the beneficial effects of endogenous NO, since it increased IL-6 levels, and reduced IL-1β, inflammation, and damage. However, treatment with NO donors in steatotic grafts did not modify IL-10 or IL-1β levels, but induced more injurious effects tan the induction of BD alone, characterized by increased nitrotyrosine, lipid peroxidation, inflammation, and hepatic damage. Our study thus highlights the specificity of new signaling pathways in LT from DBDs: NO-IL-6-IL-1β in non-steatotic livers and NO-IL-10-IL-1β in steatotic ones. This opens up new therapeutic targets that could be useful in clinical LT.

Low socio-economic status is associated with increased graft failure in liver transplantation

Background: Low socio-economic status (SES) has been shown to be associated with inferior liver graft outcomes. We aimed to characterize SES and liver graft survival in our Institution.

Acute liver failure and unique challenges of pediatric liver transplantation amidst a worldwide cluster of adenovirus-associated hepatitis

Investigation into a recent cluster of acute hepatitis in children from the southeastern United States identified human adenovirus (HAdV) DNAemia in all 9 cases. Molecular genotyping in 5 of 9 (56%) children identified HAdV type 41 in all cases (100%). Importantly, 2 children from this cluster progressed rapidly to pediatric acute liver failure (PALF) and required liver transplantation. HAdV type 41, a known cause of self-limited gastroenteritis, has not previously been associated with severe cholestatic hepatitis and liver failure in healthy children. Adenovirus polymerase chain reaction assay and sequencing of amplicons performed on DNA extracted from formalin-fixed, paraffin-embedded liver tissue also identified adenovirus species F (HAdV type 40 or 41) in these 2 children with PALF. Transplant considerations and successful liver transplantation in such situations remain scarce. In this report, we describe the clinical course, laboratory results, liver pathology, and treatment of 2 children with PALF associated with HAdV type 41, one of whom developed secondary hemophagocytic lymphohistiocytosis. Their successful posttransplant outcomes demonstrate the importance of early multidisciplinary medical management and the feasibility of liver transplantation in some children with PALF and HAdV DNAemia.

Predicting graft failure in pediatric liver transplantation based on early biomarkers using machine learning models

The early detection of graft failure in pediatric liver transplantation is crucial for appropriate intervention. Graft failure is associated with numerous perioperative risk factors. This study aimed to develop an individualized predictive model for 90-days graft failure in pediatric liver transplantation using machine learning methods. We conducted a single-center retrospective cohort study. A total of 87 liver transplantation cases performed in patients aged < 12 years at the Severance Hospital between January 2010 and September 2020 were included as data samples. Preoperative conditions of recipients and donors, intraoperative care, postoperative serial laboratory parameters, and events observed within seven days of surgery were collected as features. A least absolute shrinkage and selection operator (LASSO) -based method was used for feature selection to overcome the high dimensionality and collinearity of variables. Among 146 features, four variables were selected as the resultant features, namely, preoperative hepatic encephalopathy, sodium level at the end of surgery, hepatic artery thrombosis, and total bilirubin level on postoperative day 7. These features were selected from different times and represent distinct clinical aspects. The model with logistic regression demonstrated the best prediction performance among various machine learning methods tested (area under the receiver operating characteristic curve (AUROC) = 0.898 and area under the precision–recall curve (AUPR) = 0.882). The risk scoring system developed based on the logistic regression model showed an AUROC of 0.910 and an AUPR of 0.830. Together, the prediction of graft failure in pediatric liver transplantation using the proposed machine learning model exhibited superior discrimination power and, therefore, can provide valuable information to clinicians for their decision making during the postoperative management of the patients.

Absence of indoleamine 2,3‑dioxygenase 2 promotes liver regeneration after partial hepatectomy in mice.

The partial loss of liver due to liver transplantation or acute liver failure induces rapid liver regeneration. Recently, we reported that the selective inhibition of indoleamine 2,3‑dioxygenase (Ido) 1 promotes early liver regeneration. However, the role of Ido2 in liver regeneration remains unclear. Wild‑type (WT) and Ido2‑deficient (Ido2‑KO) mice were subjected to 70% partial hepatectomy (PHx). Hepatocyte growth was measured using immunostaining. The mRNA expression of inflammatory cytokines and production of kynurenine in intrahepatic mononuclear cells (MNCs) were analyzed using reverse transcription‑quantitative PCR and high‑performance liquid chromatography. The activation of NF‑κB was determined by both immunocytochemistry and western blotting analysis. The ratio of liver to body weight and the frequency of proliferation cells after PHx were significantly higher in Ido2‑KO mice compared with in WT mice. The expression of IL‑6 and TNF‑α in MNCs were transiently increased in Ido2‑KO mice. The nuclear transport of NF‑κB was significantly higher in peritoneal macrophages of Ido2‑KO mice compared with WT mice. These results suggested that Ido2 deficiency resulted in transiently increased production of inflammatory cytokines through the activation of NF‑kB, thereby promoting liver regeneration. Therefore, the regulation of Ido2 expression in MNCs may play a therapeutic role in liver regeneration under injury and disease conditions.

Indocyanine green clearance test in liver transplantation: defining cut-off levels for graft viability assessment during organ retrieval and for the prediction of post-transplant graft function recovery - the Liver Indocyanine Green (LivInG) Trial Study Protocol

IntroductionViability assessment of the graft is essential to lower the risk of liver transplantation (LT) failure and need for emergency retransplantation, however, this still relies mainly on surgeon’s experience. Post-LT...

Human Amnion-Derived Mesenchymal Stromal/Stem Cells Pre-Conditioning Inhibits Inflammation and Apoptosis of Immune and Parenchymal Cells in an In Vitro Model of Liver Ischemia/Reperfusion.

Ischemia/reperfusion injury (IRI) represents one of the leading causes of primary non-function acute liver transplantation failure. IRI, generated by an interruption of organ blood flow and the subsequent restoration upon transplant, i.e., reperfusion, generates the activation of an inflammatory cascade from the resident Kupffer cells, leading first to neutrophils recruitment and second to apoptosis of the parenchyma. Recently, human mesenchymal stromal/stem cells (hMSCs) and derivatives have been implemented for reducing the damage induced by IRI. Interestingly, sparse data in the literature have described the use of human amnion-derived MSCs (hAMSCs) and, more importantly, no evidence regarding hMSCs priming on liver IRI have been described yet. Thus, our study focused on the definition of an in vitro model of liver IRI to test the effect of primed hAMSCs to reduce IRI damage on immune and hepatic cells. We found that the IFNγ pre-treatment and 3D culture of hAMSCs strongly reduced inflammation induced by M1-differentiated macrophages. Furthermore, primed hAMSCs significantly inhibited parenchymal apoptosis at early timepoints of reperfusion by blocking the activation of caspase 3/7. All together, these data demonstrate that hAMSCs priming significantly overcomes IRI effects in vitro by engaging the possibility of defining the molecular pathways involved in this process.

The use of pre-trained deep learning models for the photographic assessment of donor livers for transplantation

Aim: Hepatic steatosis is a recognised major risk factor for primary graft failure in liver transplantation. In general, the global fat burden is measured by the surgeon using a visual assessment. However, this can be augmented by a histological assessment, although there is often inter-observer variation in this regard as well. In many situations the assessment of the liver relies heavily on the experience of the observer and more experienced surgeons will accept organs that more junior surgeons feel are unsuitable for transplantation. Often surgeons will err on the side of caution and not accept a liver for fear of exposing recipients to excessive risk of death. Methods: In this study, we present the use of deep learning for the non-invasive evaluation of donor liver organs. Transfer learning, using deep learning models such as the Visual Geometry Group (VGG) Face, VGG16, Residual Neural Network 50 (ResNet50), Dense Convolutional Network 121 (DenseNet121) and MobileNet are utilised for effective pattern extraction from partial and whole liver. Classification algorithms such as Support Vector Machines, k-Nearest Neighbour, Logistic Regression, Decision Tree and Linear Discriminant Analysis are then used for the final classification to identify between acceptable or non-acceptable donor liver organs. Results: The proposed method is distinct in that we make use of image information both from partial and whole liver. We show that common pre-trained deep learning models can be used to quantify the donor liver steatosis with an accuracy of over 92%. Conclusion: Machine learning algorithms offer the tantalising prospect of standardising the assessment and the possibility of using more donor organs for transplantation.

Doppler ultrasonography is a useful tool for the diagnosis of hemodynamics in congestive graft injury due to heart failure after liver transplantation: A case report

IntroductionPatients with end-stage liver disease often have cardiac dysfunction, which can be worsened by hemodynamic instability in liver transplantation, causing congestive graft injury.Presentation of caseA 28-year-old male with Wilson's disease underwent liver transplantation. The patient's history included cirrhotic cardiomyopathy and a preoperative ejection fraction of 37% on echocardiography. After liver transplantation, massive transfusion and acute renal failure led to increased central venous pressure. Doppler ultrasonography (US) showed an increase in positive components of the hepatic vein triphasic wave, followed by pulsatile changes in the portal vein waveforms and an eventual to-and-fro pattern. Laboratory data showed severe elevations of hepatocellular transaminase levels. Based on Doppler US findings, we determined liver damage was due to passive congestion caused by heart failure. Immediate initiation of continuous hemodiafiltration (CHDF) and intra-aortic balloon pumping (IABP) led to the patient's recovery from severe heart failure and graft injury.DiscussionIn our case, changes in the hepatic and portal vein waveforms and marked elevation of hepatocellular transaminases implied exacerbation of heart failure caused by hepatic congestion and injury. Worsening heart failure, in turn, led to progressive liver damage as the result of hepatic passive congestion. The patient's condition was successfully managed with early initiation of CHDF and IABP.ConclusionDoppler US can help diagnose congestive graft injury due to heart failure in liver transplant patients and should be performed during post-transplant management of patients with cardiac dysfunction.

Management of Acute Portal Vein Thrombosis With Serial Mechanical Thrombectomy and tPA in a Pediatric Liver Transplant Recipient: A Case Report

Acute portal vein thrombosis is a major cause of fulminant allograft failure in pediatric liver transplantation. Timely intervention is critical to save the graft and patient. Serial interventional radiologic management of this condition is scarcely reported in the literature. A recently transplanted 17-year-old male presented to the emergency department with abdominal pain. Rising liver enzymes prompted discovery of a diffuse portal thrombus, which precipitated fulminant liver failure. The adolescent developed respiratory failure, vasodilatory shock, acute kidney injury, and hepatic encephalopathy, complicating treatment. Multiple interventions attempted to clear the thrombus, including interventional radiologic and medical therapies. Uniquely, a continuous infusion catheter was placed at the thrombosis, delivering local tissue plasminogen activator during a 5-day period. Upon thrombus clearance, the patient made a full recovery with no complications during 12 months of follow-up. When used as a component of multidisciplinary management, continuous locally directed tissue plasminogen activator may be a useful tool for clearance of persistent portal vein thrombosis.

Research advances in the risk factors for infection after liver transplantation

With the continuous development of surgical techniques, liver transplantation has gradually become mature, but postoperative infection remains one of the major causes of failure in liver transplantation. By exploring the risk factors associated with postoperative infection, researchers have found that in addition to the previously reported risk factors, several risk factors which are not discovered or emphasized should be taken seriously. From the aspects of donor-related factors, recipient-related factors, and other factors, this article summarizes the risk factors associated with infection after liver transplantation with reference to the latest advances, so as to provide a theoretical basis for effective prevention and treatment of infection after liver transplantation.

Role of FGF15 in Hepatic Surgery in the Presence of Tumorigenesis: Dr. Jekyll or Mr. Hyde?

The pro-tumorigenic activity of fibroblast growth factor (FGF) 19 (FGF15 in its rodent orthologue) in hepatocellular carcinoma (HCC), as well as the unsolved problem that ischemia-reperfusion (IR) injury supposes in liver surgeries, are well known. However, it has been shown that FGF15 administration protects against liver damage and regenerative failure in liver transplantation (LT) from brain-dead donors without tumor signals, providing a benefit in avoiding IR injury. The protection provided by FGF15/19 is due to its anti-apoptotic and pro-regenerative properties, which make this molecule a potentially beneficial or harmful factor, depending on the disease. In the present review, we describe the preclinical models currently available to understand the signaling pathways responsible for the apparent controversial effects of FGF15/19 in the liver (to repair a damaged liver or to promote tumorigenesis). As well, we study the potential pharmacological use that has the activation or inhibition of FGF15/19 pathways depending on the disease to be treated. We also discuss whether FGF15/19 non-pro-tumorigenic variants, which have been developed for the treatment of liver diseases, might be promising approaches in the surgery of hepatic resections and LT using healthy livers and livers from extended-criteria donors.

Prognosis of primary sclerosing cholangitis according to age of onset.

Liver failure and biliary tract cancer (BTC) are major life-threatening events in the clinical course of primary sclerosing cholangitis (PSC). Although these are competing events, they are typically evaluated as a composite prognostic endpoint. In Japan, the clinical characteristics and prognosis of PSC reportedly differ according to age of onset. We compared the prognosis of younger- versus older-onset PSC by competing risk analysis. This was a retrospective analysis of 144 patients with PSC who were followed up for a median of 6.7years. The patients were divided into two groups according to a cutoff age of onset of 44years. We compared the prognosis of younger-onset PSC (n=91) and older-onset PSC (n=53) by competing risk analysis, incorporating mortality related and that unrelated to BTC as competing events. There was no difference in BTC-related mortality between patients with younger-onset and those with older-onset PSC (subdistribution hazard ratio [SHR], 0.89; 95% confidence interval [CI], 0.17-4.56, P=.888). The cumulative incidence of mortality due to other causes, including liver transplantation and liver failure, was non-significantly higher in patients with older-onset PSC (SHR, 1.58; 95% CI, 0.88-2.84; P=.129). Although we did not find a significant difference in prognosis by onset age, patients with older-onset PSC had worse liver-transplantation-free survival than those with younger-onset PSC. A large cohort study is needed to evaluate the clinical outcomes of older- and younger-onset PSC.

Artificial intelligence in precision medicine in hepatology.

The advancement of investigation tools and electronic health records (EHR) enables a paradigm shift from guideline-specific therapy toward patient-specific precision medicine. The multiparametric and large detailed information necessitates novel analyses to explore the insight of diseases and to aid the diagnosis, monitoring, and outcome prediction. Artificial intelligence (AI), machine learning, and deep learning (DL) provide various models of supervised, or unsupervised algorithms, and sophisticated neural networks to generate predictive models more precisely than conventional ones. The data, application tasks, and algorithms are three key components in AI. Various data formats are available in daily clinical practice of hepatology, including radiological imaging, EHR, liver pathology, data from wearable devices, and multi-omics measurements. The images of abdominal ultrasonography, computed tomography, and magnetic resonance imaging can be used to predict liver fibrosis, cirrhosis, non-alcoholic fatty liver disease (NAFLD), and differentiation of benign tumors from hepatocellular carcinoma (HCC). Using EHR, the AI algorithms help predict the diagnosis and outcomes of liver cirrhosis, HCC, NAFLD, portal hypertension, varices, liver transplantation, and acute liver failure. AI helps to predict severity and patterns of fibrosis, steatosis, activity of NAFLD, and survival of HCC by using pathological data. Despite of these high potentials of AI application, data preparation, collection, quality, labeling, and sampling biases of data are major concerns. The selection, evaluation, and validation of algorithms, as well as real-world application of these AI models, are also challenging. Nevertheless, AI opens the new era of precision medicine in hepatology, which will change our future practice.