Setting Of Acute Liver Failure Research Articles

Multimodal decoding of human liver regeneration

The liver has a unique ability to regenerate1,2; however, in the setting of acute liver failure (ALF), this regenerative capacity is often overwhelmed, leaving emergency liver transplantation as the only curative option3–5. Here, to advance understanding of human liver regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling of healthy and ALF explant human livers to generate a single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+ migratory hepatocyte subpopulation, which emerges during human liver regeneration, and a corollary subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. Four-dimensional intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 reduces hepatocyte growth factor-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation that mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut–liver barrier may advance new areas of therapeutic discovery in regenerative medicine.

The Role of Carbamoyl Phosphate Synthetase 1 as a Prognostic Biomarker in Patients With Acetaminophen-induced Acute Liver Failure

Carbamoyl phosphate synthetase 1 (CPS1) is a highly abundant mitochondrial urea cycle enzyme that is expressed primarily in hepatocytes. CPS1 is constitutively and physiologically secreted into bile but is released into the bloodstream upon acute liver injury (ALI). Given its abundance and known short half-life, we tested the hypothesis that it may serve as a prognostic serum biomarker in the setting of acute liver failure (ALF). CPS1 levels were determined using enzyme-linked immunosorbent assay and immunoblotting of sera collected by the ALF Study Group (ALFSG) from patients with ALI and ALF (103 patients with acetaminophen and 167 non-acetaminophen ALF etiologies). A total of 764 serum samples were examined. The inclusion of CPS1 was compared with the original ALFSG Prognostic Index by area under the receiver operating characteristic curve analysis. CPS1 values for acetaminophen-related patients were significantly higher than for non-acetaminophen patients (P < .0001). Acetaminophen-related patients who received a liver transplant or died within 21 days of hospitalization exhibited higher CPS1 levels than patients who spontaneously survived (P= .01). Logistic regression and area under the receiver operating characteristic analysis of CPS1 enzyme-linked immunosorbent assay values improved the accuracy of the ALFSG Prognostic Index, which performed better than the Model for End-Stage Liver Disease, in predicting 21-day transplant-free survival for acetaminophen- but not non-acetaminophen-related ALF. An increase of CPS1 but not alanine transaminase or aspartate transaminase, when comparing day 3 with day 1 levels was found in a higher percentage of acetaminophen transplanted/dead patients (P < .05). Serum CPS1 determination provides a new potential prognostic biomarker to assess patients with acetaminophen-induced ALF.

Kidney injury and status 1 liver transplantation: Outcomes, kidney function, and listing for kidney transplantation.

Effects of kidney injury (KI) at the time of liver transplantation (LT) for acute liver failure (ALF) remain poorly described. We hypothesized that patients with ALF and KI who undergo LT have persistent post-transplant KI, inferior survival, and increased rate of kidney transplantation (KT). The US Scientific Registry of Transplant Recipients database was queried for patients transplanted with status 1 listing for LT between 2002 and 2021. KI was defined as estimated glomerular filtration rate (eGFR)≤30mL/min/1.73m2 or dialysis in the week prior to LT. Outcomes evaluated were post-LT eGFR, listing for subsequent KT, and overall survival (OS) after LT. A total of 2984 patients underwent LT for ALF with 1241 (41.6%) having KI. KI patients had lower eGFR at 6months post-LT (57.8 vs. 68.7, p<.001) that persisted out to 5years (59.9 vs. 69.7, p<.001). KI patients were more likely to be listed for KT (4.3% vs. 1.9%, p<.001) and undergo listing sooner after LT (.8 vs. 3.7years, p<.001). Patients without KI had higher adjusted post-transplant OS compared to those with KI (HR .75, p<.001). KI in the setting of ALF portends a worse prognosis for both kidney recovery and OS.

The potential liver donor with tuberculosis: A fresh look at international recommendations based on a survey of practice in Indian liver transplant centres.

Background The western recommendations for the use of organs from liver donors with tuberculosis (TB) come from an environment where the burden of disease is low and cadaveric organ donation rates are high-in complete contrast to the Indian scenario, where these recommendations may be too restrictive. Methods A questionnaire relating to current practice on the use of organs from liver donors with TB was sent to all liver transplant centres in India. Results Responses were obtained from 94% of centres. Two-thirds accepted organs from deceased donors with TB in the elective setting, especially for recipients with a high MELD (Model for end-stage liver disease) score. The proportion rose by 1.5 times in the setting of acute liver failure. Two-thirds advised anti-TB treatment (ATT) for corresponding recipients, and the remaining advised isonicotinic acid hydrazide (INH) prophylaxis. Untreated living donors with TB were not accepted. Half the respondents accepted living donors after completion of ATT, and did not treat recipients postoperatively. The remainder accepted them after 8 weeks of treatment and advised INH prophylaxis or ATT for recipients. Conclusions That this practice has not impacted recipient outcomes suggests that the guidelines for management of liver donors and recipients may need to be altered for populations endemic for TB.

Wilson Disease: What Does Copper Have to Do With It?

The purpose of this article is to educate and provide practice implications to advanced practice providers caring for patients with Wilson disease. The pathogenesis, risk factors/genetics, screening, diagnosis, clinical presentations, and predictors of mortality are discussed, along with treatment options, including supportive care, nutritional needs, pharmacotherapy, and liver transplantation. Special considerations in the setting of acute liver failure, pregnancy, and malignancy risks are also addressed. Research and future directions for treatment and management are considered. Finally, practice implications for advanced practice providers to better address this population’s unique needs using a multidisciplinary approach are discussed.

PCRRT Expert Committee ICONIC Position Paper on Prescribing Kidney Replacement Therapy in Critically Sick Children With Acute Liver Failure.

Management of acute liver failure (ALF) and acute on chronic liver failure (ACLF) in the pediatric population can be challenging. Kidney manifestations of liver failure, such as hepatorenal syndrome (HRS) and acute kidney injury (AKI), are increasingly prevalent and may portend a poor prognosis. The overall incidence of AKI in children with ALF has not been well-established, partially due to the difficulty of precisely estimating kidney function in these patients. The true incidence of AKI in pediatric patients may still be underestimated due to decreased creatinine production in patients with advanced liver dysfunction and those with critical conditions including shock and cardiovascular compromise with poor kidney perfusion. Current treatment for kidney dysfunction secondary to liver failure include conservative management, intravenous fluids, and kidney replacement therapy (KRT). Despite the paucity of evidence-based recommendations concerning the application of KRT in children with kidney dysfunction in the setting of ALF, expert clinical opinions have been evaluated regarding the optimal modalities and timing of KRT, dialysis/replacement solutions, blood and dialysate flow rates and dialysis dose, and anticoagulation methods.

The current pediatric perspective on type B and C hepatic encephalopathy

That children present with hepatic encephalopathy (HE) in the setting of acute liver failure (ALF) is accepted and a recognized prognostic factor for survival [1,2]. What is less understood is the impact of chronic liver disease (CLD) on the neuro-cognitive and –psychiatric development and outcomes of children with chronic liver disease early in life. Much is extrapolated from the adult literature or from work in experimental models. But what distinguishes children is that central nervous system development, characterized by massive brain growth, is ongoing at the time of liver disease, arguably exposing them to unique risks, something which cannot be extrapolated from adults. The purpose of this brief review is to summarize what is distinctive about the neurocognition of children with CLD or having presented CLD or portosystemic bypass in childhood.

Perturbation of astroglial Slc38 glutamine transporters by NH4+ contributes to neurophysiologic manifestations in acute liver failure.

Ammonia is considered the main pathogenic toxin in hepatic encephalopathy (HE). However, the molecular mechanisms involved have been disputed. As altered glutamatergic and GABAergic neurotransmission has been reported in HE, we investigated whether four members of the solute carrier 38 (Slc38) family of amino acid transporters-involved in the replenishment of glutamate and GABA-contribute to ammonia neurotoxicity in HE. We show that ammonium ion exerts multiple actions on the Slc38 transporters: It competes with glutamine for the binding to the system N transporters Slc38a3 and Slc38a5, consequently inhibiting bidirectional astroglial glutamine transport. It also competes with H+ , Na+ , and K+ for uncoupled permeation through the same transporters, which may perturb astroglial intracellular pH, membrane potential, and K+ -buffering. Knockdown of Slc38a3 in mice results in cerebral cortical edema and disrupted neurotransmitter synthesis mimicking events contributing to HE development. Finally, in a mouse model of acute liver failure (ALF), we demonstrate the downregulation of Slc38a3 protein, impeded astroglial glutamine release, and cytotoxic edema. Altogether, we demonstrate contribution of Slc38 transporters to the ammonia-induced impairment of glutamine recycling between astrocytes and neurons, a phenomenon underlying acute ammonia neurotoxicity in the setting of ALF.

The Modulating Effect of Ursodeoxycholic Acid on Liver Tissue Cyclooxygenase-2 Expression Following Extended Hepatectomy.

Introduction: Hepatic regeneration is a complex process involving a multitude of well-timed molecular operations. Ursodeoxycholic acid (UDCA) is postulated to exert a protective effect against oxidative stress and enzymatic degradation of the extracellular matrix, in turn potentiating the regenerative response. The aim of the present animal study is to evaluate the impact of UDCA administration in liver tissue expression of cyclooxygenase-2 (COX-2) in a setting of acute liver failure achieved by 80% hepatectomy.Materials and methods: Twenty-four adult male Sprague-Dawley rats were randomly assigned to an experimental (UDCA) and a control group. Animals in the UDCA received oral pretreatment with UDCA for 14 days via feeding tube, while animals in the control group received saline. All animals underwent resection of approximately 80% of the liver parenchyma. Tissue and blood sample collection were performed 48 hours postoperatively.Results: The postoperative mitotic index and Ki-67 levels were found to be elevated in the UDCA group (43±11.4 and 13.7±24.7 versus 31±16.7 and 7.6±5.7), albeit without any statistical significance. Pretreatment with UDCA significantly decreased COX-2 expression levels (p=0.28) as well as serum tumor necrosis factor α (TNFα) levels (37.3±10.9 pg/mL versus 75.4±14.4 pg/mL, p=0.004). COX-2 expression score was observed to be weakly correlated to Ki-67 levels in both groups. Although COX-2 expression score was not correlated with serum TNFα levels in the control group, animals pretreated with UDCA exhibited moderate correlation (r=0.45).Conclusion: Preoperative administration of UDCA exerts a suppressive effect on tissue expression of COX-2 following 80% hepatectomy and enforces a positive correlation between COX-2 and serum TNFα levels, suggesting that UDCA preconditions liver tissue to display an enhanced regenerative response to circulating cytokines, most notably TNFα. The weak association of COX-2 with Ki-67 expression levels suggests that COX-2 may be of secondary importance during the early phases of liver regeneration.

Warfarin-Induced Skin Necrosis in the Presence of Acute Hepatic Injury and May-Thurner Syndrome.

Purpose: The purpose of the report is to describe a patient with warfarin-induced skin necrosis in the presence of acute hepatic injury and significant risk factors for venous thromboembolism, including protein C deficiency and May-Thurner syndrome. Summary: A 44-year-old female with multiple comorbidities presented to the emergency department with a significantly elevated international normalized ratio (INR > 15.9) rapidly reversed with vitamin K and fresh frozen plasma. Due to the findings of bilateral acute on chronic deep vein thromboses (DVTs) and suspected warfarin-induced skin necrosis, a heparin infusion was initiated but later discontinued due to endogenous partial thromboplastin times (PTT) elevations despite dose reductions. Although the necrosis encompassed large areas of the fatty tissue, the depth of necrosis remained mostly superficial. Supportive care and wound management were provided following warfarin reversal; no skin grafts or amputations were performed. Conclusion: A 44-year-old female developed a complicated probable warfarin-induced skin necrosis in the setting of acute liver failure, septic shock, May-Thurner syndrome, previously failed anticoagulation, and acute deep vein thrombosis.

Acute Liver Failure and Concomitant Severe Acute Pancreatitis Due to Hepatitis B: Successful Management with Liver Transplantation

Acute pancreatitis in the setting of acute liver failure is an uncommon but challenging clinical entity. Although the presence of acute pancreatitis in acute liver failure has important prognostic implications, it should not be considered a contraindication to liver transplantation. Here we present a case of successful liver transplantation in a patient with acute hepatitis B virus acute liver failure with concurrent necrotising pancreatitis and multiple organ dysfunctions.

Fulminant Hepatic Failure Secondary to Herpes Hepatitis in a Patient With Myasthenia Crisis: An Elusive Diagnosis

Herpes hepatitis is a rare cause of fulminant hepatic failure contributing to less than 1% of all cases. It is most often seen in persons who are immunosuppressed and in pregnant women. The presentation is usually non-specific and rapidly progressive, thus making antemortem diagnosis of this condition rare. We present a patient who was on chronic immunosuppressive therapy for systemic lupus erythematosus and subsequently developed multi-organ failure with anicteric transaminitis as a result of disseminated herpes infection. The diagnosis was only made post-mortem. A confounding factor in this case was the fact that the patient underwent plasmapheresis, which skewed the interpretation of liver function tests in the setting of acute liver failure.

Brain edema in acute liver failure: mechanisms and concepts

Brain edema and associated increase in intracranial pressure continue to be lethal complications of acute liver failure (ALF). Abundant evidence suggests that the edema in ALF is largely cytotoxic brought about by swelling of astrocytes. Elevated blood and brain ammonia levels have been strongly implicated in the development of the brain edema. Additionally, inflammation and sepsis have been shown to contribute to the astrocyte swelling/brain edema in the setting of ALF. We posit that ammonia initiates a number of signaling events, including oxidative/nitrative stress (ONS), the mitochondrial permeability transition (mPT), activation of the transcription factor (NF-κB) and signaling kinases, all of which have been shown to contribute to the mechanism of astrocyte swelling. All of these factors also impact ion-transporters, including Na(+), K(+), Cl(-) cotransporter and the sulfonylurea receptor 1, as well as the water channel protein aquaporin-4 resulting in a perturbation of cellular ion and water homeostasis, ultimately resulting in astrocyte swelling/brain edema. All of these events are also potentiated by inflammation. This article reviews contemporary knowledge regarding mechanisms of astrocyte swelling/brain edema formation which hopefully will facilitate the identification of therapeutic targets capable of mitigating the brain edema associated with ALF.

Analysis of Serum Inflammatory Mediators Identifies Unique Dynamic Networks Associated with Death and Spontaneous Survival in Pediatric Acute Liver Failure

BackgroundTools to predict death or spontaneous survival are necessary to inform liver transplantation (LTx) decisions in pediatric acute liver failure (PALF), but such tools are not available. Recent data suggest that immune/inflammatory dysregulation occurs in the setting of acute liver failure. We hypothesized that specific, dynamic, and measurable patterns of immune/inflammatory dysregulation will correlate with outcomes in PALF.MethodsWe assayed 26 inflammatory mediators on stored serum samples obtained from a convenience sample of 49 children in the PALF study group (PALFSG) collected within 7 days after enrollment. Outcomes were assessed within 21 days of enrollment consisting of spontaneous survivors, non-survivors, and LTx recipients. Data were subjected to statistical analysis, patient-specific Principal Component Analysis (PCA), and Dynamic Bayesian Network (DBN) inference.FindingsRaw inflammatory mediator levels assessed over time did not distinguish among PALF outcomes. However, DBN analysis did reveal distinct interferon-gamma-related networks that distinguished spontaneous survivors from those who died. The network identified in LTx patients pre-transplant was more like that seen in spontaneous survivors than in those who died, a finding supported by PCA.InterpretationThe application of DBN analysis of inflammatory mediators in this small patient sample appears to differentiate survivors from non-survivors in PALF. Patterns associated with LTx pre-transplant were more like those seen in spontaneous survivors than in those who died. DBN-based analyses might lead to a better prediction of outcome in PALF, and could also have more general utility in other complex diseases with an inflammatory etiology.

Brain edema in acute liver failure: Role of neurosteroids

Brain edema is a major neurological complication of acute liver failure (ALF) and swelling of astrocytes (cytotoxic brain edema) is the most prominent neuropathological abnormality in this condition. Elevated brain ammonia level has been strongly implicated as an important factor in the mechanism of astrocyte swelling/brain edema in ALF. Recent studies, however, have suggested the possibility of a vasogenic component in the mechanism in ALF. We therefore examined the effect of ammonia on blood–brain barrier (BBB) integrity in an in vitro co-culture model of the BBB (consisting of primary cultures of rat brain endothelial cells and astrocytes). We found a minor degree of endothelial permeability to dextran fluorescein (16.2%) when the co-culture BBB model was exposed to a pathophysiological concentration of ammonia (5mM). By contrast, lipopolysaccharide (LPS), a molecule well-known to disrupt the BBB, resulted in an 87% increase in permeability. Since increased neurosteroid biosynthesis has been reported to occur in brain in ALF, and since neurosteroids are known to protect against BBB breakdown, we examined whether neurosteroids exerted any protective effect on the slight permeability of the BBB after exposure to ammonia. We found that a nanomolar concentration (10nM) of the neurosteroids allopregnanolone (THP) and tetrahydrodeoxycorticosterone (THDOC) significantly reduced the ammonia-induced increase in BBB permeability (69.13 and 58.64%, respectively). On the other hand, we found a marked disruption of the BBB when the co-culture model was exposed to the hepatotoxin azoxymethane (218.4%), but not with other liver toxins commonly used as models of ALF (thioacetamide and galactosamine, showed a 29.3 and 30.67% increase in permeability, respectively). Additionally, THP and THDOC reduced the effect of TAA and galactosamine on BBB permeability, while no BBB protective effect was observed following treatment with azoxymethane. These findings suggest that ammonia does not cause a significant BBB disruption, and that the BBB is intact in the TAA or galactosamine-induced animal models of ALF, likely due to the protective effect of neurosteroids that are synthesized in brain in the setting of ALF. However, caution should be exercised when using azoxymethane as an experimental model of ALF as it caused a severe breakdown of the BBB, and neurosteriods failed to protect against this breakdown.

Analysis of Evaluation of Potentail Donors for Living Donor Liver Transplantation

Introduction: Living Donor Liver Transplantation (LDLT) is the commonest form of Liver Transplantation in India. The key to the success of a LDLT program is the safety of the donor. A thorough donor evaluation encompasses all aspects from social to medical and this determines the number of donors who actually donate from the entire group of potential donors who are evaluated.AIMTo analyse the entire number of potential donors evaluated for LDLT and to assess the rate of actual donation from the evaluated group of donors. Method: A retrospective analysis of the recipients and donors evaluated at our center from August 2009 to January 2012 was done. Recipients were given the option of Deceased donor or Living Related Liver Transplantation. If a suitable and voluntarily consenting donor came forward from the relatives of the recipient, they underwent the evaluation process which involved psycho- social counseling and medical evaluation. Results:TableTable: [Results in ALF]Conclusion: A very thorough donor evaluation is imperative to the success and safety of a Living Donor Liver Transplant program. When both the psycho social and medical aspects are evaluated, only about 40% of potential donors who underwent evaluation actually donated. The rate for donation was higher in the setting of Acute Liver Failure in a pediatric patient.

Akutes Leberversagen

Acute liver failure is a multisystem disease with predominantly sudden and severe hepatic injury and hepatic encephalopathy caused by apoptotic or necrotic hepatocyte damage. The clinical challenge in patients with acute liver failure is to promptly identify those with poor prognosis and refer them for emergency liver transplantation. This review article highlights the main aspects of decision making in the setting of acute liver failure, summarizes new aspects of its critical care management and gives an overview of sclerosing cholangitis in the critically ill patient, an under-recognized disease entity that can progress to acute liver failure.

Early myocardial injury is an integral component of experimental acute liver failure - a study in two porcine models.

IntroductionThere is accumulating clinical evidence that acute liver failure may be regularly associated with myocardial injury. To test this hypothesis in a standardized experimental setting, we used two porcine models of ALF.Material and methodsIn 14 domestic pigs ALF was induced by either a) surgical devascularization of the liver (DV group, n = 7), or b) partial (70-75%) hepatectomy and ischaemia/reperfusion of the liver remnant for 150 min (I/R group, n = 7). Four additional animals constituted the sham operation group. All animals were monitored for a 12-h period, at the end of which their hearts were harvested. Plasma troponin I (cTnI) and malondialdehyde (MDA) were measured before the operation (baseline) and at 6 h and 12 h postoperatively. The harvested hearts were histologically analysed, appointing a score from 0 (no injury) to 3 (maximum injury) to selected injury indicators.ResultsIn the sham group, all cTnI measurements and total myocardial injury score were zero in all animals. In both ALF groups, plasma cTnI levels increased by the 6th and remained elevated up to the 12th postoperative hour (p < 0.01 vs. sham animals). Total myocardial injury score and total histological score revealed some extent of myocardial injury. The rise of MDA levels suggests an underlying oxidative mechanism.ConclusionsOur study provides direct evidence of early myocardial injury in the setting of acute liver failure in pigs. The mechanism of injury remains to be elucidated.

Primary Hepatic Burkitt Lymphoma Presenting with Acute Liver Failure

We report the first case of immunophenotypically confirmed primary hepatic Burkitt lymphoma presenting with acute liver failure. The patient survived following an aggressive diagnostic approach followed by emergent chemotherapy. Data from the primary hepatic non-Hodgkin lymphoma literature show a survival rate of 87% at 5 years with combination regimens of chemotherapy. However, mortality rate in this population is 85% in patients with acute liver failure. Primary hepatic Burkitt lymphoma may respond well to emergent chemotherapy even in the setting of acute liver failure.

When the heart kills the liver: acute liver failure in congestive heart failure

Congestive heart failure as a cause of acute liver failure is rarely documented with only a few cases.Although the pathophysiology is poorly understood, there is rising evidence, that low cardiac output with consecutive reduction in hepatic blood flow is a main causing factor, rather than hypotension. In the setting of acute liver failure due to congestive heart failure, clinical signs of the latter can be absent, which requires an appropriate diagnostic approach.As a reference center for acute liver failure and liver transplantation we recorded from May 2003 to December 2007 202 admissions with the primary diagnoses acute liver failure. 13/202 was due to congestive heart failure, which was associated with a mortality rate of 54%. Leading cause of death was the underlying heart failure. Asparagine transaminase (AST), bilirubin, and international normalized ratio (INR) did not differ significantly in surviving and deceased patients at admission. Despite both groups had signs of cardiogenic shock, the cardiac index (CI) was significantly higher in the survival group on admission as compared with non-survivors (2.1 L/min/m2 vs. 1.6 L/min/m2, p = 0.04). Central venous - and pulmonary wedge pressure did not differ significantly. Remarkable improvement of liver function was recorded in the group, who recovered from cardiogenic shock.In conclusion, patients with acute liver failure require an appropriate diagnostic approach. Congestive heart failure should always be considered as a possible cause of acute liver failure.