Native Liver Function Research Articles

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 48h 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.

CT Volumetry Can Be Used for Monitoring Liver Function Recovery in Auxiliary Partial Orthotopic Liver Transplantation.

Scintigraphy with a 99m TC-trimethyl-Br-IDA tracer (TBIDA) is used to monitor liver function regeneration after auxiliary partial orthotopic liver transplantation (APOLT) for acute liver failure (ALF). As computed tomography (CT) is also regularly performed during patient follow-up, CT volumetry could be used as an alternative to monitor native liver recovery after APOLT for ALF. This was a retrospective cohort study of all patients who underwent APOLT (October 2006-July 2019). Collected data included liver graft and native liver CT volumetry measurements (expressed as fractions), TBIDA scintigraphy results, and biological and clinical data including immunosuppression therapy after APOLT. Four follow-up time points were defined (baseline, discontinuation of mycophenolate mofetil, beginning of tacrolimus reduction, and tacrolimus discontinuation) for analysis. Twenty-four patients (7 men; median age 28.5 y old) were included. The main etiologies of ALF were acetaminophen intoxication (n = 12), hepatitis B virus (n = 5), and amanita phalloides intoxication (n = 3). The median native liver function fractions on scintigraphy at baseline, at discontinuation of mycophenolate mofetil, at tacrolimus reduction, and at tacrolimus discontinuation were 22.0% (interquartile range 14.0-30.8), 30.5% (21.5-49.0), 32.0% (28.0-62.0), and 93.0% (77.0-100.0), respectively. The corresponding median native liver volume fractions on CT were 12.8% (10.4-17.3), 20.5% (14.2-27.3), 24.7% (21.3-48.4), and 77.9% (62.5-96.9), respectively. Volume and function were strongly correlated (r = 0.918; 95% confidence interval, 0.878-0.945; P < 0.01). Median time-to-immunosuppression discontinuation was 25.0 (17.0-35.0) mo. Estimated time-to-immunosuppression discontinuation was shorter in patients with acetaminophen-induced ALF (22 versus 35 mo; P = 0.035). In patients who receive APOLT for ALF, CT-based liver volumetry closely parallels native liver function recovery evaluated on TBIDA scintigraphy.

Treatment of Hepatitis E.

Hepatitis E virus (HEV) infections are the most common cause of acute hepatitis, but they can also take a chronic course. There is no specific therapy for acute hepatitis, and current treatment is supportive. Choosing ribavirin as the first-line therapy for chronic HEV is advisable, especially immunosuppressed individuals. Moreover, ribavirin therapy in the acute phase of infection provides major benefits for those at high risk of acute liver failure (ALF)/acute-on-chronic liver failure (ACLF). Pegylated interferon α has been used successfully for treatment of hepatitis E but is associated with major side effects. Cholestasis is one of the most common, but devastating, manifestations in hepatitis E. Current therapy for HEV aims to treat symptoms. Therapy generally involves several measures, such as vitamins, albumin, and plasma for supporting treatment, symptomatic treatment for cutaneous pruritus, ursodeoxycholic acid, Obeticholic acid, S-adenosylmethionine, etc. for removing jaundice. HEV infection during pregnancy and patients with underlying liver disease may develop liver failure. For these patients, active monitoring, standard care, and supportive treatment are the foundations. Ribavirin has successfully been used to prevent liver transplantation (LT). Prevention and treatment of complications are important for treatment of liver failure. Liver support devices are intended to support liver function until such time as native liver function recovers, or until LT. LT is widely considered as irreplaceable and definitive treatment for liver failure, particularly for patients who do not improve with supportive measures to sustain life.

1277: USE OF MOLECULAR ADSORBENT RECIRCULATING SYSTEM LEADING TO IMPROVED TRANSPLANT-FREE SURVIVAL

Introduction: Acute liver failure (ALF) has many different etiologies and carries significant morbidity and mortality. Hepatic encephalopathy (HE) is a main cause of mortality in these patients and is associated with cerebral edema and risk for progression to brainstem herniation. Albumin dialysis, mainly utilizing the Molecular Adsorbent Recirculating System (MARS) has been demonstrated in the past to improve HE, although data on mortality benefit has been inconsistent. The Children’s Hospital at Montefiore is a children’s hospital within a larger adult healthcare system. We report our single center experience utilizing extracorporeal liver support via the MARS device on pediatric and adult patients over our inaugural year. Methods: This is a retrospective report of all patients who underwent MARS therapy during the first year of our program. As per our institutional guidelines, all patients were eligible for MARS due to having grade 3+ HE or grade 2 HE with an additional failing organ system. All patients, despite their age, were treated by the pediatric MARS team. Results: Four pediatric and two adult patients underwent MARS therapy. The underlying etiologies of the acute liver failure were: acetaminophen overdose in one, indeterminate in three, disseminated varicella in one, and acute fatty liver of pregnancy with hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome and atypical hemolytic uremic syndrome in one. Survival was 100%. Of the two adults, one had severe Grade 4 HE with loss of multiple brainstem reflexes upon initiation of MARS support. Her neurologic exam demonstrated improvement during her first MARS treatment cycle, and she was successfully transplanted later that night. The second adult, as well as all four pediatric patients were able to achieve full recovery of their native liver function without need for transplantation. Conclusions: The use of MARS therapy appears in this cohort to allow for liver recovery and improved transplant free survival.

Liver-on-a-chip: Considerations, advances, and beyond.

The liver is the largest internal organ in the human body with largest mass of glandular tissue. Modeling the liver has been challenging due to its variety of major functions, including processing nutrients and vitamins, detoxification, and regulating body metabolism. The intrinsic shortfalls of conventional two-dimensional (2D) cell culture methods for studying pharmacokinetics in parenchymal cells (hepatocytes) have contributed to suboptimal outcomes in clinical trials and drug development. This prompts the development of highly automated, biomimetic liver-on-a-chip (LOC) devices to simulate native liver structure and function, with the aid of recent progress in microfluidics. LOC offers a cost-effective and accurate model for pharmacokinetics, pharmacodynamics, and toxicity studies. This review provides a critical update on recent developments in designing LOCs and fabrication strategies. We highlight biomimetic design approaches for LOCs, including mimicking liver structure and function, and their diverse applications in areas such as drug screening, toxicity assessment, and real-time biosensing. We capture the newest ideas in the field to advance the field of LOCs and address current challenges.

A non-human primate model of acute liver failure suitable for testing liver support systems.

Acute hepatic failure is associated with high morbidity and mortality for which the only definitive therapy is liver transplantation. Some fraction of those who undergo emergency transplantation have been shown to recover native liver function when transplanted with an auxiliary hepatic graft that leaves part of the native liver intact. Thus, transplantation could have been averted with the development and use of some form of hepatic support. The costs of developing and testing liver support systems could be dramatically reduced by the availability of a reliable large animal model of hepatic failure with a large therapeutic window that allows the assessment of efficacy and timing of intervention. Non-lethal forms of hepatic injury were examined in combination with liver-directed radiation in non-human primates (NHPs) to develop a model of acute hepatic failure that mimics the human condition. Porcine hepatocyte transplantation was then tested as a potential therapy for acute hepatic failure. After liver-directed radiation therapy, delivery of a non-lethal hepatic ischemia-reperfusion injury reliably and rapidly generated liver failure providing conditions that can enable pre-clinical testing of liver support or replacement therapies. Unfortunately, in preliminary studies, low hepatocyte engraftment and over-immune suppression interfered with the ability to assess the efficacy of transplanted porcine hepatocytes in the model. A model of acute liver failure in NHPs was created that recapitulates the pathophysiology and pathology of the clinical condition, does so with reasonably predictable kinetics, and results in 100% mortality. The model allowed preliminary testing of xenogeneic hepatocyte transplantation as a potential therapy.

Volumetric Bioprinting of Organoids and Optically Tuned Hydrogels to Build Liver‐Like Metabolic Biofactories (Adv. Mater. 15/2022)

Volumetric Bioprinting Volumetric bioprinting shapes organoid-laden constructs into centimeter-scale assemblies that mimic native liver function. In article number 2110054, Riccardo Levato and co-workers report the development of a hydrogel-based bioresin with tunable optical properties to minimize scattering in light-based printing and ensure high resolution. Organoid viability and maturation is preserved by the shear-stress-free printing, and salient liver functions mature in response to the 3D bioprinted architecture.

Plasma Exchange in Acute and Acute on Chronic Liver Failure.

Liver failure in the context of acute (ALF) and acute on chronic liver failure (ACLF) is associated with high mortality in the absence of a liver transplant. For decades, therapeutic plasma exchange (TPE) is performed for the management of immune-mediated diseases. TPE has emerged as an attractive extracorporeal blood purification technique in patients with ALF and ACLF. The basic premise of using TPE is to remove the toxic substances which would allow recovery of native liver functions by facilitating liver regeneration. In recent years, encouraging data have emerged, suggesting the benefits of TPE in patients with liver failure. TPE has emerged as an attractive liver support device for the failing liver until liver transplantation or clinical recovery. The data in patients with ALF suggest routine use of high-volume TPE, while the data for such a strategy are less robust for patients with ACLF.

Auxiliary liver transplantation for acute liver failure

Contents 1. What is auxiliary LT (ALT)? 2. When does ALT need? 3. What are issues of ALT for acute liver failure (ALF)? 4. Who can be a good candidate for ALT? 5. How to carve out a niche of technical challenges 6. How to manage Post-ALT patients 7. A SNUH case: A video clip 8. Reappraisal of ALT for ALF for Expanding Organ Utility. An APOLT (auxiliary partial orthtopic liver transplantation) for ALF has a benefit of immunosuppressant discontinuation in 60%-100% without compromising patients' survival outcome. This can also provide to expand the donor pool in some aspect. However, it's technically challenging as well as graft function and native liver regeneration is usually unpredictable. Thus, selection of good candidates (young, biopsy guided, hemodyenamically stable) and delicate surgical modification are important to lead a successful APOLT for ALF. In addition, this should be supported by careful postoperative monitoring and slow/steady immunosuppressant withdrawal after confirmation of native liver function restoration.

Gene Regulatory Network Analysis and Engineering Directs Development and Vascularization of Multilineage Human Liver Organoids.

SUMMARYPluripotent stem cell (PSC)-derived organoids have emerged as novel multicellular models of human tissue development but display immature phenotypes, aberrant tissue fates, and a limited subset of cells. Here, we demonstrate that integrated analysis and engineering of gene regulatory networks (GRNs) in PSC-derived multilineage human liver organoids direct maturation and vascular morphogenesis in vitro. Overexpression of PROX1 and ATF5, combined with targeted CRISPR-based transcriptional activation of endogenous CYP3A4, reprograms tissue GRNs and improves native liver functions, such as FXR signaling, CYP3A4 enzymatic activity, and stromal cell reactivity. The engineered tissues possess superior liver identity when compared with other PSC-derived liver organoids and show the presence of hepatocyte, biliary, endothelial, and stellate-like cell populations in single-cell RNA-seq analysis. Finally, they show hepatic functions when studied in vivo. Collectively, our approach provides an experimental framework to direct organogenesis in vitro by systematically probing molecular pathways and transcriptional networks that promote tissue development.

Liver transplantation for deterioration in native liver function after portoenterostomy for biliary atresia in Japan: Short- versus long-term survivors

PurposeWe reviewed our post-Kasai portoenterostomy biliary atresia (BA) patients who required liver transplantation (LTx) for deterioration in native liver (NL) function to investigate mortality in relation to age at LTx. MethodsBA patients indicated for LTx when less than 18years old (U18; n=17) and when 18 or older (18+; n=13) were compared. All achieved jaundice clearance postoperatively (TBil ≤1.2mg/dL (≈20μmol/L)). ResultsIn U18, living-donor (LD) LTxs were performed at a median of 6.1years (range: 0.5–16.7; n=14) and cadaveric (CD) LTxs at a median of 1.3years (1.1–1.5; n=3). In 18+, LDLTxs were performed at a median of 28years (18–37; n=8), and 1 case died from graft versus host disease. CDLTxs were indicated in 5, but 4 died at a median of 30years (26–32), a mean of 1.4years (0.7–1.8) after NL deterioration commenced. One case is awaiting CDLTx. At the time of review, all U18 and 7 LDLTx cases in 18+ were clinically stable. Mortality rates were 0% in U18 and 38% in 18+ (P=.006). ConclusionOur results highlight the extremely grave prognosis for long-term BA patients requiring LTx when 18 or older because of poor donor availability in Japan. Level of evidenceLevel III.

Assembly of Hepatocyte Spheroids Using Magnetic 3D Cell Culture for CYP450 Inhibition/Induction.

There is a significant need for in vitro methods to study drug-induced liver injury that are rapid, reproducible, and scalable for existing high-throughput systems. However, traditional monolayer and suspension cultures of hepatocytes are difficult to handle and risk the loss of phenotype. Generally, three-dimensional (3D) cell culture platforms help recapitulate native liver tissue phenotype, but suffer from technical limitations for high-throughput screening, including scalability, speed, and handling. Here, we developed a novel assay for cytochrome P450 (CYP450) induction/inhibition using magnetic 3D cell culture that overcomes the limitations of other platforms by aggregating magnetized cells with magnetic forces. With this platform, spheroids can be rapidly assembled and easily handled, while replicating native liver function. We assembled spheroids of primary human hepatocytes in a 384-well format and maintained this culture over five days, including a 72 h induction period with known CYP450 inducers/inhibitors. CYP450 activity and viability in the spheroids were assessed and compared in parallel with monolayers. CYP450 activity was induced/inhibited in spheroids as expected, separate from any toxic response. Spheroids showed a significantly higher baseline level of CYP450 activity and induction over monolayers. Positive staining in spheroids for albumin and multidrug resistance-associated protein (MRP2) indicates the preservation of hepatocyte function within spheroids. The study presents a proof-of-concept for the use of magnetic 3D cell culture for the assembly and handling of novel hepatic tissue models.

Treatment of Hepatitis E.

Hepatitis E virus (HEV) infections are the most common cause of acute hepatitis, but they can also take a chronic course. There is no specific therapy for acute hepatitis, and current treatment is supportive. Choosing ribavirin as the first-line therapy for chronic HEV is advisable, especially in solid organ transplant patients. Pegylated interferon-α has been used successfully for treatment of hepatitis E but is associated with major side effects. Cholestasis is one of the most common, but devastating, manifestations in hepatitis E. Current therapy for HEV aims to treat symptoms. Therapy generally involves several measures, such as vitamins for adequate nutrition, albumin and plasma for supporting treatment, symptomatic treatment for cutaneous pruritus, and ursodeoxycholic acid and S-adenosylmethionine, and Traditional Chinese medicine for removing jaundice. Patients with underlying liver disease may develop liver failure. For these patients, supportive treatment is the foundation. Ribavirin has successfully been used to prevent liver transplantation. Prevention and treatment of complications are important for treatment of liver failure. Liver support devices are intended to support liver function until such time as native liver function recovers or until liver transplantation. Liver transplantation is widely considered as irreplaceable and definitive treatment for acute-on-chronic liver failure, particularly for patients who do not improve with supportive measures to sustain life.

Artificial liver support systems: a patient‐device model

ABSTRACTMany efforts have been carried out for over 40 years in the attempt to design liver support devices suitable for a temporary clinical use, either to bridge the patients to liver transplantation or to help to keep them alive until the recovery of native liver function. Really, a deeper knowledge of the physicochemical basis of their functioning is essential to ‘engineer’ these devices, that is, to design new artificial liver devices, to optimize the existing ones and to taylor the patient treatment on his clinical state. In this framework, this work has been finalized to obtain a mathematical model of the whole patient‐artificial device system as useful tool for a chemical engineering point of view analysis. © 2014 Curtin University of Technology and John Wiley &amp; Sons, Ltd.

A bio-artificial liver reactor evaluation method

This study reports a method for evaluating the risk and safety associated with a Bio-Artificial Liver (BAL). The methods of making Fuzzy Analytic Hierarchy Process (FAHP) have been developed in order to deal with the uncertainty. AHP has been frequently used to quantify preference relationships and aid decision making. The use of preference relationships in decision-making processes is a standard technique. Here, the use of FAHP is proposed as an evaluation method for the selection of reactors in a type of medical device known as BAL. Six BAL-support system reactors are evaluated using five criteria: safety, scalability, cell growth environment, handling and the ability to mimic native liver function. The six different BAL bio-reactor types were evaluated by three separate stakeholders. FAHP method is used to combine the different stakeholder’s evaluations and rank the BAL systems for use as a temporary liver function replacement device for patients awaiting liver transplant.

Native Portal Vein Embolization for Persistent Hyperoxaluria Following Kidney and Auxiliary Partial Liver Transplantation

Type 1 primary hyperoxaluria (PH1) causes renal failure, for which isolated kidney transplantation (KT) is usually unsuccessful treatment due to early oxalate stone recurrence. Although hepatectomy and liver transplantation (LT) corrects PH1 enzymatic defect, simultaneous auxiliary partial liver transplantation (APLT) and KT have been suggested as an alternative approach. APLT advantages include preservation of the donor pool and retention of native liver function in the event of liver graft loss. However, APLT relative mass may be inadequate to correct the defect. We here report the first case of native portal vein embolization (PVE) to increase APLT to native liver mass ratio (APLT/NLM-R). Following initial combined APLT-KT, both allografts functioned well, but oxalate plasma levels did not normalize. We postulated the inadequate APLT/NLM-R could be corrected by trans-hepatic native PVE. The resulting increased APLT/NLM-R decreased serum oxalate to normal levels within 1 month following PVE. We conclude that persistently elevated oxalate levels after combined APLT-KT for PH1 treatment, results from inadequate relative functional capacity. This can be reversed by partial native PVE to decrease portal flow to the native liver. This approach might be applicable to other scenarios where partial grafts have been transplanted to replace native liver function.

Native Liver Function Prevents Coagulopathy and Bleeding Associated With Pig to Baboon Liver Xenotransplantation

Native Liver Function Prevents Coagulopathy and Bleeding Associated With Pig to Baboon Liver Xenotransplantation

Extracorporeal liver support-albumin dialysis with the Molecular Adsorbent Recirculating System (MARS)

Extracorporeal liver support has been a much studied topic throughout the last 50 years. Albumin dialysis as a therapeutic option for patients with acute liver failure or acute decompensation of chronic liver disease was introduced in the mid-nineties. The Molecular Adsorbent Recirculating System (MARS) is based on the concept of albumin dialysis and allows for the removal of protein-bound as well as water-soluble toxins. Besides its role as a sufficient volume expander human serum albumin is an important scavenger for molecules with pathophysiological relevance in liver failure. Albumin dialysis enables the selective regeneration of patient’s albumin resulting in an increase of albumin binding capacity. Clinically, an improvement of central and local hemodynamics as well as liver-, brain-, and kidney-functions were observed. Thus, the treatment can contribute to liver regeneration and stabilization of vital organ functions and thus help to bridge patients to liver transplantation or to recovery of native liver function. Proper patient selection is critical for clinical success. Aggressive treatment of infections and sepsis seems to be a decisive pre-requisite for its safe and efficient use. Cautious anticoagulation with heparin is the common standard. Citrate use is recommended for patients prone to bleeding. Today, albumin dialysis MARS is among the best studied liver support methods. It appears as a valuable therapeutic tool for the treatment of various complications of of liver failure, especially hemodynamic instability and hepatic encephalopathy. Further studies will need to help defining the optimal patient selection and technical process parameters such as session-length and frequency of treatment.

La scintigraphie hépatobiliaire : aspects et applications d’une technique sous-exploitée

We present two clinical cases illustrating two indications of cholescintigraphy that are purposely very dissimilar to illustrate the panel of application of this technique. The first reported case is a young man who received an auxiliary-liver transplantation for the treatment of fulminant hepatitis, in whom cholescintigraphy enabled to follow the evolution of the graft and the native-liver function and to determine the appropriate time to (gradually) reduce and then cease the antirejection-drug treatment. The second case is a middle-aged man with incapacitating abdominal pain. Cholescintigraphy related pain to a dysfunction of the sphincter of Oddi.

Acetaminophen-Induced Acute Liver Failure Treated with Single-Pass Albumin Dialysis: Report of a Case

Acetaminophen (paracetamol) overdose is a leading cause of acute liver failure (ALF). When patients fulfill the King's College criteria for acetaminophen-induced ALF (AALF), they have a poor prognosis for survival without liver transplantation. Recent advances in artificial liver support have used albumin as a binding and scavenging molecule in ALF. One method, single-pass albumin dialysis (SPAD), involves dialyzing blood against an albumin-containing solution across a high-flux membrane to remove albumin-bound toxins. Herein, we describe our protocol for SPAD and report its use in a case of AALF as a bridge to native liver recovery. A 41-year-old female with no documented history of liver disease presented with acute acetaminophen toxicity and developed hepatic encephalopathy, coagulopathy and lactic acidosis. The patient met King's College criteria for liver transplantation, based on pH and INR, but was deemed not suitable as a candidate due to psychosocial comorbidities. On day 3 of her ICU admission, she received the first of five consecutive daily runs (total ~77 hours) of SPAD. The patient's course was complicated by cerebral edema requiring mannitol. She was extubated on day 11 and transferred to the ward by day 13. At ICU discharge, her liver function (INR 1.9, bilirubin 435 mmol/L) and kidney function were recovering. She did not have any long-term neurological sequelae. By hospital discharge (day 46) her native liver function had recovered with a bilirubin <100mmol/L. We describe a case of a patient with acetaminophen-induced acute liver failure who was successfully bridged to spontaneous native liver recovery as a result of SPAD treatment. In patients with ALF, SPAD may be an additional intervention for temporary extracorporeal support. Further investigation in larger prospective studies is warranted.