Carbamoyl phosphate synthetase 1 (CPS1) deficiency (OMIM#237300) is a rare inherited disorder due to complete or partial lack of the CPS1 enzyme. Polymyositis is a relatively rare systemic inflammatory autoimmune disease. Here, we report a 59-year-old Japanese woman diagnosed with late-onset CPS1 deficiency during polymyositis treatment. The polymyositis appeared two years before the diagnosis of CPS1 deficiency. Prednisolone (PSL) at 35 mg/day initial dosage, promptly alleviated the symptoms. However, the patient, without apparent cause, suddenly developed confusion progressing to unconsciousness and coma. Upon admission, the patient's plasma ammonia levels were 458 μg/dL (269 μM). Plasma amino acid analysis revealed decreased citrulline levels and elevated glutamine levels. Genetic analysis of CPS1 (OMIM *608307) showed homozygosity for the likely pathogenic variant c.2397G > A (p.Met799Ile), leading to the diagnosis of CPS1 deficiency. The patient responded to pharmacotherapy and continuous hemodialysis. However, the patient experienced hyperammonemia decompensation events while on pharmacotherapy at home, which were successfully managed with emergency treatment and/or hemodialysis. Subsequently, after liver transplantation, the patient's plasma ammonia levels consistently remained at normal. This case illustrates late-onset CPS1 deficiency manifested in an adult treated with PSL for polymyositis, and the cure of its enzyme deficiency by live-donor liver transplantation.

Hepatic encephalopathy (HE) is a mental and neurological complication induced by acute or chronic hepatic failure. Emerging evidence indicates that the farnesoid X receptor (FXR), a multifunctional nuclear receptor and transcription factor, plays a pivotal role in regulating the expression of key genes associated with ammonia metabolism. However, the effect of FXR activation on HE has remained largely uncharted.

We established mouse models of HE by intraperitoneal injection of thioacetamide (TAA) and partial hepatectomy (PHx). Subsequently, we administered obeticholic acid (OCA) to activate FXR and investigated its effects on HE through comprehensive biochemical, biological, histological and behavioral analysis. Additionally, in vitro experiments were conducted to examine the impact of FXR activation on ammonia stress.

In the animal model of HE, activation of FXR upregulated the expression of key enzymes involved in ammonia metabolism pathway within the liver, thereby enhancing urea cycle functionality, reducing plasma ammonia levels, and mitigating liver injury. Furthermore, FXR activation significantly improved behavioral activities in mice and mitigated inflammation in the brain. Finally, our findings demonstrated that activating FXR could enhance ammonia metabolism and ammonia tolerance of C3A cells.

Our data provide novel evidence demonstrating that the activation of FXR by OCA exerts regulatory control over the expression of enzymes involved in ammonia metabolism, thereby effectively alleviating HE. Consequently, FXR could emerge as a promising novel target for HE treatment.

This study was supported by the National Natural Science Foundation of China No: 81970726 (to W-D Chen), and Henan Provincial Key Project of Medical Science and Technology Research No: SBGJ202102215 (to WL Ye).

Acute liver failure (ALF) results in a multitude of complications that result in multi-organ failure. This review focuses on the pathophysiological processes and how to manage with these with artificial liver support and liver transplantation (LT). The pathophysiological sequence of events behind clinical deterioration in ALF comes down to two profound consequences of the failing liver. The first is the development of hyperammonemia, as the liver can no longer synthesize urea. The result is that the splanchnic system instead of removing ammonia becomes an ammonia-producing organ system that causes hepatic encephalopathy (HE) and cerebral oedema. The second complication is caused by the necrotic liver cells that release large molecules that originate from degrading proteins, that is damage associated molecular patterns (DAMPs) which causes inflammatory activation of intrahepatic macrophages and an overflow of DAMPs molecules into the systemic circulation resulting in a clinical picture that resembles septic shock. In this context the combined use of continuous renal replacement therapy (CRRT) and plasma exchange are rational and simple ways to remove ammonia and DAMPS molecules. This combination improve survival for ALF patients deemed not appropriate for LT, despite poor prognostic criteria, but also ensure a better stability of vital organs while awaiting LT. The combination of CRRT with albumin dialysis tends to have a similar effect. Currently, the selection criteria for LT for non-paracetamol cases appear robust while the criteria for paracetamol-intoxicated patients have become more unreliable and now consist of more dynamic prognostic systems. For patients that need LT for survival, a tremendous improvement in the post-LT results has been achieved during the last decade with a survival that now reach merely 90% which is mirroring the results seen after LT for chronic liver disease.

Hyperammonemia is a recognized biochemical abnormality in acute liver failure (ALF). Our aim was to determine a cutoff value for serum ammonia in children with ALF to predict their outcomes while conventional UK liver transplant (LT) listing criteria were applied.

We reviewed and analyzed the data of 68 patients with ALF who presented to our center from January 2014 to December 2018; inherited defects of ammonia metabolism were excluded. Patients were divided into 3 groups: Gr 1, LT (30 patients); Gr2, native liver survival (27 patients); and Gr 3, mortality (11 patients).

Highest ammonia levels during admission before intervention were higher in the LT and mortality group than in the native liver survival group (P = 0.011) with levels of 140 µmol/L showing a specificity of 100% as a predictor for LT/mortality. Sixty-two percent of patients with ALF developed encephalopathy; grades 3 and 4 in almost one-third. Encephalopathy was more common in Gr1 patients, followed by Gr3, whereas Gr2 were the least likely to develop encephalopathy. Ammonia levels were significantly higher in encephalopathic patients than in nonencephalopathic (P = 0.001). Serum ammonia of 80.5 µmol/L predicted encephalopathy with 80% sensitivity and 75% specificity.

Serum ammonia level of >80 µmol/L can be used as an alert to ongoing encephalopathy although encephalopathy signs may be missing or subtle and a surrogate marker for earlier interventions for extracorporeal therapies. Moreover, levels >140 µmol/L predict the need for LT or death.

Neuroglia contribute to the pathophysiology of hepatic encephalopathy (HE) either beneficially or detrimentally. Pathogenesis of HE is linked to damage triggered by blood-derived toxins, with ammonia being the main causative factor. Neuroglial cells, especially astrocytes and microglia, respond to HE-associated systemic and central signals and undergo complex and variable changes in their metabolism, morphology, and function, which include ion and water dyshomeostasis in conjunction with neurotransmission imbalance and neuroinflammation. HE-induced alterations of astrocytes are defined as astrocytopathy, with aberrant astrocytes resulting in either gain or loss of functions. In the chronic HE, the presence of Alzheimer type II cells is a histologic hallmark, with asthenic astrocytes emerging as a newcomer. In acute HE, rapid swelling of astrocytes is a primary cause of cerebral edema and mortality. This chapter reviews the dominant role of astrocytes in the pathogenesis of HE resulting from acute and chronic liver failure, mainly in experimental models. The focus is on the loss of homeostatic function bearing upon the functioning of the glymphatic system, aberrant neurotransmission as a consequence of astrocyte-neuron miscommunication, and the concordant neuroinflammatory response of astrocytes and microglia. The chapter concludes with a delineation of concepts for future research.

Elevated arterial ammonia is associated with several complications of liver disease as it predicts mortality for in-patients and decompensation, hospitalization and death in out-patients with cirrhosis. In this review, our aim was to estimate how the individual organs contribute to arterial ammonia based on published data from human studies. The brain removes ammonia from arterial blood in a concentration-dependent fashion. Ammonia that is released from the gut to portal blood is mainly from metabolism of glutamine in the enterocytes using this as a source of energy. Ammonia produced by bacterial metabolism of urea and proteins only partially reach portal blood and is likely recycled into bacterial proteins. In general, the liver efficiently removes ammonia from arterial or portal blood in proportion to the delivered concentration. As a result,- and in some contrast to conventional wisdom-, the hepato-splanchnic region only contributes marginally to arterial ammonia; even during a simulated upper GI bleed. The only exception is acute liver failure where hepatocyte necrosis allows large quantities of portal ammonia to pass. The kidneys release ammonia from glutamine metabolism into systemic blood. The renal ammonia release increases during a simulated upper GI bleed or hypokalemia where it becomes a major source of elevated arterial ammonia. In the resting state, muscles remove ammonia in a concentration-dependent manner and muscles are the primary ammonia lowering organ in most situations with elevated arterial ammonia. During strenuous exercise, muscles produce large amounts of ammonia into systemic blood. Thus, the complete pattern of ammonia metabolism is very dynamic and illustrates the difficulties in designing ammonia lowering therapies.

Acute liver failure (ALF) is a rare and dynamic syndrome occurring as a sequela of severe acute liver injury (ALI). Its mortality ranges from 50% to 75% based on the aetiology, patients age and severity of encephalopathy at admission. With improvement in intensive care techniques, transplant-free survival in ALF has improved over time. Timely recognition of patients who are unlikely to survive with medical intervention alone is crucial since these individuals may rapidly develop multiorgan failure and render liver transplantation futile. Various predictive models, biomarkers and AI-based models are currently used in clinical practice, each with its fallacies. The King's College Hospital criteria (KCH) were initially established in 1989 to identify patients with acute liver failure (ALF) caused by paracetamol overdose or other causes who are unlikely to improve with conventional treatment and would benefit from a liver transplant. Since then, various models have been developed and validated worldwide. Most models include age, aetiology of liver disease, encephalopathy grade, and liver injury markers like INR, lactate, factor V level, factor VIII/V ratio and serum bilirubin. But none of the currently available models are dynamic and lack accuracy in predicting transplant free survival. There is an increasing interest in developing prognostic serum biomarkers that when used alone or in combination with clinical models enhance the accuracy of predicting outcomes in ALF. Genomics, transcriptomics, proteomics, and metabolomics as well as machine learning and artificial intelligence (AI) algorithms are areas of interest for developing higher-precision predictive models. Overall, the future of prognostic models in ALF is promising, with ongoing research paving the way for more accurate, personalized, and dynamic risk assessment tools that can potentially save lives in this challenging condition. This article summarizes the history of prognostic models in ALF and future trends.

Hepatic encephalopathy (HE) is a syndrome that is associated with both acute and chronic liver injury. It manifests as a wide spectrum of neuropsychological abnormalities, ranging from subtle impairments in executive higher functions observed in cirrhosis, through to coma in acute liver failure. In acute liver failure, the central role of ammonia in the development of brain oedema has remained undisputed for 130 years. It latterly became apparent that infection and inflammation were profound determinants for the development of severe hepatic encephalopathy, associated with the development of cerebral oedema and intracranial hypertension. The relationship of the development of hepatic encephalopathy with blood ammonia levels in cirrhosis is less clear cut and the synergistic interplay of inflammation and infection with ammonia has been identified as being fundamental in the development and progression of hepatic encephalopathy. A perturbed gut microbiome and the presence of an impaired gut epithelial barrier that facilitates translocation of bacteria and bacterial degradation products into the systemic circulation, inducing systemic inflammation and innate and adaptive immune dysfunction, has now become the focus of therapies that treat hepatic encephalopathy in cirrhosis, and may explain why the prebiotic lactulose and rifaximin are efficacious. This review summarises the current clinical perspective on the roles of inflammation and infection in hepatic encephalopathy and presents the evidence base for existing therapies and those in development in the setting of acute and chronic liver failure.

Acute liver failure (ALF) is a rare syndrome where rapid deterioration of liver function occurs after an acute insult in a patient without prior chronic liver disease and leads to jaundice, hepatic encephalopathy (HE), and oftentimes multiorgan failure (MOF). At this time, the only definitive treatment for ALF is LT but some patients, particularly APAP-induced ALF patients, may have ongoing regenerative capacity of the liver and may not require LT with ongoing supportive management. As a result, extracorporeal liver support (ECLS) has been a topic of interest both as a bridge to LT and as a bridge to spontaneous recovery and aims to remove damaging toxins that further aggravate liver failure, stimulate regeneration of the liver, and improve pathophysiologic consequences of liver failure. There are currently two categories of ECLS (artificial and bioartificial). Artificial ECLS does not incorporate active hepatocytes and are based on the principles of filtration and adsorption and includes renal replacement therapy (RRT), plasma adsorption including plasma exchange and Prometheus (Fractionated Plasma Separation and Adsorption), and albumin dialysis including MARS (Molecular Adsorbent Recirculating System) and SPAD (Single Pass Albumin Dialysis). Bioartificial ECLS incorporates active hepatocytes (human or porcine in origin) to improve liver detoxification capacity and to support hepatic synthetic function and includes ELAD (Extracorporeal Liver Assist Device) and HepatAssist.

Patients undergoing solid-organ transplantation (SOT) face a tumultuous journey. Prior to transplant, their medical course is characterized by organ dysfunction, diminished quality of life, and reliance on organ support, all of which are endured in hopes of reaching the haven of organ transplantation. Peritransplant altered mental status may indicate neurologic insults acquired during transplant and may have long-lasting consequences. Even years after transplant, these patients are at heightened risk for neurologic dysfunction from a myriad of metabolic, toxic, and infectious causes. This review provides a comprehensive examination of causes, diagnostic approaches, neuroimaging findings, and management strategies for altered mental status in SOT recipients. Given their complexity and the numerous etiologies for neurologic dysfunction, liver transplant patients are a chief focus in this review; however, we also review lesser-known contributors to neurological injury across various transplant types. From hepatic encephalopathy to cerebral edema, seizures, and infections, this review highlights the importance of recognizing and managing pre- and posttransplant neurological complications to optimize patient outcomes.

Paracetamol (acetaminophen)-induced acute liver failure (ALF) with severe hyperammonemia (ammonia >100 µmol⋅L-1) is a life-threatening condition. A strategy based on high-intensity continuous renal replacement therapy (CRRT) without early (up to day seven) transplantation may enable clinicians to safely identify which patients can recover and survive and which patients require transplantation.

We conducted a single-center, retrospective cohort study of patients with severely hyperammonemic paracetamol-induced ALF. The primary outcome was early transplant-free survival.

We studied 84 patients (median age: 38; female sex: 79 [85%]) over a 12-year period (median ammonia level at ICU admission: 153 µmol⋅L-1; median peak aspartate aminotransferase (AST): 10,029 U⋅L-1; median lactate: 5.0 mmol⋅L-1; and median INR: 4.4) and 55 (65%) with King's College criteria for transplantation. Overall, 87% received high-intensity CRRT (92% in 2020-2023). Median CRRT intensity was 54 mL⋅kg-1⋅hr-1 within the first 48 h and increased by 1.8 mL⋅kg-1⋅hr-1 per year during the study period (p = 0.002). Transplant-free survival to day 7 was 86% in 2011-2023 and 96% in 2020-2023. Overall, only 4 patients were transplanted and only 1 (4%) in 2020-2023. On multivariable Cox analysis, factors independently associated with failure to achieve day seven transplant-free survival were higher APACHE III score (HR = 1.05, 95% CI: 1.02-1.08), higher lactate (HR = 1.27, 95% CI: 1.12-1.44), and lower platelet count at ICU admission (HR = 0.85, 95% CI: 0.78-0.93) and the median effluent dose applied within the first 48 h of ICU admission (HR = 0.67, 95% CI: 0.46-0.98).

Early transplant-free survival is achievable in most patients with paracetamol-induced ALF and severe hyperammonemia with a treatment based on high-intensity CRRT. Such transplant-free survival increased over time together with increased CRRT dose.

Acute liver failure (ALF) is a rare condition leading to morbidity and mortality. Liver transplantation (LT) is often required, but patients are not always listed for LT. There is a lack of data regarding outcomes in these patients. Our aim is to describe outcomes of patients with ALF not listed for LT and to compare this with those listed for LT.

Retrospective analysis of all nonlisted patients with ALF enrolled in the Acute Liver Failure Study Group (ALFSG) registry between 1998 and 2018. The primary outcome was 21-day mortality. Multivariable logistic regression was done to identify factors associated with 21-day mortality. The comparison was then made with patients with ALF listed for LT.

A total of 1672 patients with ALF were not listed for LT. The median age was 41 (IQR: 30-54). Three hundred seventy-one (28.9%) patients were too sick to list. The most common etiology was acetaminophen toxicity (54.8%). Five hundred fifty-eight (35.7%) patients died at 21 days. After adjusting for relevant covariates, King's College Criteria (adjusted odds ratio: 3.17, CI 2.23-4.51), mechanical ventilation (adjusted odds ratio: 1.53, CI: 1.01-2.33), and vasopressors (adjusted odds ratio: 2.10, CI: 1.43-3.08) (p < 0.05 for all) were independently associated with 21-day mortality. Compared to listed patients, nonlisted patients had higher mortality (35.7% vs. 24.3%). Patients deemed not sick enough had greater than 95% survival, while those deemed too sick still had >30% survival.

Despite no LT, the majority of patients were alive at 21 days. Survival was lower in nonlisted patients. Clinicians are more accurate in deeming patients not sick enough to require LT as opposed to deeming patients too sick to survive.

Ammonia levels are orchestrated by a series of complex interrelated pathways in which the urea cycle has a central role. Liver dysfunction leads to an accumulation of ammonia, which is toxic and is strongly associated with disruption of potassium homeostasis, mitochondrial dysfunction, oxidative stress, inflammation, hypoxaemia and dysregulation of neurotransmission. Hyperammonaemia is a hallmark of hepatic encephalopathy and has been strongly associated with liver-related outcomes in patients with cirrhosis and liver failure. In addition to the established role of ammonia as a neurotoxin in the pathogenesis of hepatic encephalopathy, an increasing number of studies suggest that it can lead to hepatic fibrosis progression, sarcopenia, immune dysfunction and cancer. However, elevated systemic ammonia levels are uncommon in patients with metabolic dysfunction-associated steatotic liver disease. A clear causal relationship between ammonia-induced immune dysfunction and risk of infection has not yet been definitively proven. In this Review, we discuss the mechanisms by which ammonia produces its diverse deleterious effects and their clinical relevance in liver diseases, the importance of measuring ammonia levels for the diagnosis of hepatic encephalopathy, the prognosis of patients with cirrhosis and liver failure, and how our knowledge of inter-organ ammonia metabolism is leading to the development of novel therapeutic approaches.

There is an urgent unmet need for a reliable noninvasive tool to detect elevations in intracranial pressure (ICP) above guideline-recommended thresholds for treatment. Gold standard invasive ICP monitoring is unavailable in many settings, including resource-limited environments, and in situations such as liver failure in which coagulopathy increases the risk of invasive monitoring. Although a large number of noninvasive techniques have been evaluated, this article reviews the potential clinical role, if any, of the techniques that have undergone the most extensive evaluation and are already in clinical use. Elevations in ICP transmitted through the subarachnoid space result in distension of the optic nerve sheath. The optic nerve sheath diameter (ONSD) can be measured with ultrasound, and an ONSD threshold can be used to detect elevated ICP. Although many studies suggest this technique accurately detects elevated ICP, there is concern for risk of bias and variations in ONSD thresholds across studies that preclude routine use of this technique in clinical practice. Multiple transcranial Doppler techniques have been used to assess ICP, but the best studied are the pulsatility index and the Czosnyka method to estimate cerebral perfusion pressure and ICP. Although there is inconsistency in the literature, recent prospective studies, including an international multicenter study, suggest the estimated ICP technique has a high negative predictive value (> 95%) but a poor positive predictive value (≤ 30%). Quantitative pupillometry is a sensitive and objective method to assess pupillary size and reactivity. Proprietary indices have been developed to quantify the pupillary light response. Limited data suggest these quantitative measurements may be useful for the early detection of ICP elevation. No current noninvasive technology can replace invasive ICP monitoring. Where ICP monitoring is unavailable, multimodal noninvasive assessment may be useful. Further innovation and research are required to develop a reliable, continuous technique of noninvasive ICP assessment.

Timely diagnosis and management of pediatric acute liver failure (PALF) is of paramount importance to improve survival. The Indian Society of Pediatric Gastroenterology, Hepatology, and Nutrition invited national and international experts to identify and review important management and research questions. These covered the definition, age appropriate stepwise workup for the etiology, non-invasive diagnosis and management of cerebral edema, prognostic scores, criteria for listing for liver transplantation (LT) and bridging therapies in PALF. Statements and recommendations based on evidences assessed using the modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) system were developed, deliberated and critically reappraised by circulation. The final consensus recommendations along with relevant published background information are presented here. We expect that these recommendations would be followed by the pediatric and adult medical fraternity to improve the outcomes of PALF patients.

Ammonia is metabolized into urea in the liver. In acute liver failure (ALF), ammonia has been associated with survival. However, urea variation has been poorly studied.

Observational cohort including ALF patients from Curry Cabral Hospital (Lisbon, Portugal) and Clinic Hospital (Barcelona, Spain) between 10/2010 and 01/2023. The United States ALF Study Group cohort was used for external validation. Primary exposures were serum ammonia and urea on ICU admission. Primary endpoint was 30-day transplant-free survival (TFS). Secondary endpoint was explanted liver weight.

Among 191 ALF patients, median (IQR) age was 46 (32; 57) years and 85 (44.5%) were males. Overall, 86 (45.0%) patients were transplanted and 75 (39.3%) died. Among all ALF patients, following adjustment for age, sex, body weight, and aetiology, higher ammonia or lower urea was independently associated with higher INR on ICU admission (p < .009). Among all ALF patients, following adjustment for sex, aetiology, and lactate, higher ammonia was independently associated with lower TFS (adjusted odds ratio (95% confidence interval [CI]) = 0.991 (0.985; 0.997); p = .004). This model predicted TFS with good discrimination (area under receiver operating curve [95% CI] = 0.78 [0.75; 0.82]) and reasonable calibration (R2 of 0.43 and Brier score of 0.20) after external validation. Among transplanted patients, following adjustment for age, sex, actual body weight, and aetiology, higher ammonia (p = .024) or lower (p < .001) urea was independently associated with lower explanted liver weight.

Among ALF patients, serum ammonia and urea were associated with ALF severity. A score incorporating serum ammonia predicted TFS reasonably well.

Acute liver failure (ALF) is a life-threatening disorder characterised by rapid deterioration of liver function, coagulopathy, and hepatic encephalopathy in the absence of pre-existing liver disease. The cause of ALF varies across the world. Common causes of ALF in adults include drug toxicity, hepatotropic and non-hepatotropic viruses, herbal and dietary supplements, antituberculosis drugs, and autoimmune hepatitis. The cause of liver failure affects the management and prognosis, and therefore extensive investigation for cause is strongly suggested. Sepsis with multiorgan failure and cerebral oedema remain the leading causes of death in patients with ALF and early identification and appropriate management can alter the course of ALF. Liver transplantation is the best current therapy, although the role of artificial liver support systems, particularly therapeutic plasma exchange, can be useful for patients with ALF, especially in non-transplant centres. In this Seminar, we discuss the cause, prognostic models, and management of ALF.

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.

Hyperammonemia and liver disease are closely linked. Most of the ammonia in our body is produced by transamination and deamination activities involving amino acid, purine, pyrimidines, and biogenic amines, and from the intestine by bacterial splitting of urea. The only way of excretion from the body is by hepatic conversion of ammonia to urea. Hyperammonemia is associated with widespread toxicities such as cerebral edema, hepatic encephalopathy, immune dysfunction, promoting fibrosis, and carcinogenesis. Over the past two decades, it has been increasingly utilized for prognostication of cirrhosis, acute liver failure as well as acute on chronic liver failure. The laboratory assessment of hyperammonemia has certain limitations, despite which its value in the assessment of various forms of liver disease cannot be negated. It may soon become an important tool to make therapeutic decisions about the use of prophylactic and definitive treatment in various forms of liver disease.

Acetaminophen (APAP) is a leading cause of acute liver failure. The effect of APAP metabolite's effects in the periphery are well characterized; however, associated consequences in the brain remain poorly understood. Animal studies on this subject are few and reveal that frequent APAP intake can trigger cerebral abnormalities that vary depending on the subject's age. Alarmingly, experimental efforts have yet to examine associated consequences in elderly hosts, who correspond to the highest risk of medication overload, impaired drug clearance, and cognitive deficits. Here, we interrogated the cerebral and peripheral pathology of elderly mice submitted to monthly episodes of APAP intoxication since a young adult age. We found that weeks after the final episode of recurrent APAP exposure, mice exhibited worsened non-spatial memory deficit whereas spatial memory performance was unaltered. Interestingly, one month after the period of APAP intoxication, these mice showed increased glial burden without associated drivers, namely, blood-brain barrier disruption, cholesterol accumulation, and elevation of inflammatory molecules in the brain and/or periphery. Our experimental study reveals how recurrent APAP exposure affects the cognitive performance and cellular events in elderly brains. These data suggest that APAP-containing pharmacological interventions may foreshadow the elevated risk of neuropsychiatric disorders that afflict elderly populations.

Acute liver failure (ALF) or acute-on-chronic liver failure (ACLF) patients have high short-term mortality and morbidity. In the context of liver failure, increased serum ammonia is associated with worse neurological outcomes, including high-grade hepatic encephalopathy (HE), cerebral edema, and intracranial hypertension. Besides its neurotoxicity, hyperammonemia may contribute to immune dysfunction and the risk of infection, a frequent trigger for multi-organ failure in these patients.

We performed a literature-based narrative review. Publications available in PubMed® up to June 2023 were considered.

In the ICU management of liver failure patients, serum ammonia may play an important role. Accordingly, in this review, we focus on recent insights about ammonia metabolism, serum ammonia measurement strategies, hyperammonemia prognostic value, and ammonia-targeted therapeutic strategies.

Serum ammonia may have prognostic value in liver failure. Effective ammonia targeted therapeutic strategies are available, such as laxatives, rifaximin, L-ornithine-l-aspartate, and continuous renal replacement therapy.

Acute liver failure (ALF) is a rare syndrome leading to significant morbidity and mortality. An important cause of mortality is cerebral edema due to hyperammonemia. Different therapies for hyperammonemia have been assessed including continuous renal replacement therapy (CRRT). We conducted a systematic review and meta-analysis to determine the efficacy of CRRT in ALF patients.

We searched MEDLINE, EMBASE, Cochrane Library, and Web of Science. Inclusion criteria included adult patients admitted to an ICU with ALF. Intervention was the use of CRRT for one or more indications with the comparator being standard care without the use of CRRT. Outcomes of interest were overall survival, transplant-free survival (TFS), mortality and changes in serum ammonia levels.

In total, 305 patients underwent CRRT while 1137 patients did not receive CRRT. CRRT was associated with improved overall survival [risk ratio (RR) 0.83, 95% confidence interval (CI) 0.70-0.99, p-value 0.04, I2 = 50%] and improved TFS (RR 0.65, 95% CI 0.49-0.85, p-value 0.002, I2 = 25%). There was a trend towards higher mortality with no CRRT (RR 1.24, 95% CI 0.84-1.81, p-value 0.28, I2 = 37%). Ammonia clearance data was unable to be pooled and was not analyzable.

Use of CRRT in ALF patients is associated with improved overall and transplant-free survival compared to no CRRT.

Hepatic encephalopathy (HE) remains both a clinical diagnosis and one of exclusion. Laboratory testing is largely focused on identifying precipitating factors. Ammonia levels in the blood can be helpful for the diagnosis of HE but are not required for confirmation. More recent literature is lending support to the prognostic capabilities of ammonia in cirrhosis, both in predicting future HE events and in determining outcomes in hospitalized patients. Accurate ammonia testing requires strict protocols to avoid common pitfalls in the measurement of this labile analyte. Future studies investigating the utility of other laboratory testing to diagnose, stage, or predict HE are encouraged.

The 2023 Joint International Congress of the International Liver Transplantation Society (ILTS), the European Liver and Intestine Transplant Association (ELITA), and the Liver Intensive Care Group of Europe (LICAGE) held in Rotterdam, the Netherlands, marked a significant recovery milestone for the liver transplant community after COVID-19. With 1159 participants and a surge in abstract submissions, the event focused on "Liver Disorders and Transplantation: Innovations and Evolving Indications." This conference report provides a comprehensive overview of the key themes discussed during the event, encompassing Hepatology, Anesthesia and Critical Care, Acute Liver Failure, Infectious Disease, Immunosuppression, Pediatric Liver Transplantation, Living Donor Liver Transplantation, Transplant Oncology, Surgical Approaches, and Machine Perfusion. The congress provided a platform for extensive discussions on a wide range of topics, reflecting the continuous advancements and collaborative efforts within the liver transplant community.

The aim of this research was to evaluate the interaction effects of ammonia-N levels and salinity on hematological and serum biochemical parameters in Nile tilapia (Oreochromis niloticus). The fish were randomly divided into 12 treatments including the levels of salinity (0, 4, 8 and 12 ppt) and 0, 50% of LC50-96 h of ammonia-N and 30% of LC50-96 h of ammonia-N in a factorial design (4 salinity levels x 3 ammonia levels). Hemoglobin value in all treatments, except for salinity treatments, namely 2, 3, 4, showed a significant decrease than the control (0 ppt and no poisoning). Also, red blood cells in treatment ammonia-N levels were significantly less than the control. Serum protein concentration, in treatments 9 (50% of LC50-96 h of ammonia-N) and 5 and also with increasing salinity (treatments 2, 3 and 4) had a significant decrease compared to the control. There is a significant increase in serum glucose, cortisol, ammonia and urea levels in 50% and 30% of LC50-96 h of ammonia-N treatments compared to the control, meanwhile these parameters were significantly increased with increasing salinity. Serum thyroid stimulating hormone (TSH), T3 and T4 levels in acute and sub-acute ammonia-N treatments were significantly lower than the control. Moreover, with increasing salinity in 50% and 30% of LC50-96 h of ammonia-N treatments, TSH showed a decreasing pattern. According to the results, fluctuations in blood biochemical factors, increase of stress and decrease of thyroid hormones show that the salinity, ammonia, and their interaction caused adverse effects on fish health during the 96 h of testing.

Pediatric acute liver failure (PALF) is a catastrophic clinical condition with very high morbidity and mortality without early detection and intervention. It is characterized by the acute onset of massive hepatocellular injury that releases circulating inflammatory mediators, resulting in metabolic disturbances, coagulopathy, hepatic encephalopathy and multi-organ failure. The etiological spectrum is dominated by hepatotropic viruses, drug-induced liver injury, metabolic and genetic disorders and immune-mediated diseases. Unlike adults, indeterminate causes for acute liver failure constitute a considerable proportion of cases of acute liver failure in children in the west. The heterogeneity of age and etiology in PALF has led to difficulties in developing prognostic scoring. The recent guidelines emphasize prompt identification of PALF, age-appropriate evaluation for hepatic encephalopathy and laboratory evaluation with careful monitoring. Current therapy focuses on supporting the failing liver and other organs, pending either spontaneous recovery or liver transplantation. Targeted therapy is available for a select group of etiologies. Liver transplantation can be lifesaving and a plan for the same should be organized, whenever indicated. The aim of this review is to define PALF, understand its etiopathogenesis, address the challenges encountered during the management and update the latest advances in liver transplantation and non-transplant treatment options in PALF.

The management of acute liver failure (ALF) in modern hepatology intensive care units (ICU) has improved patient outcomes. Critical care management of hepatic encephalopathy, cerebral edema, fluid and electrolytes; prevention of infections and organ support are central to improved outcomes of ALF. In particular, the pathogenesis of encephalopathy is multifactorial, with ammonia, elevated intra-cranial pressure and systemic inflammation playing a central role. Although ALF remains associated with high mortality, the availability of supportive care, including organ failure support such as plasma exchange, timely mechanical ventilation or continuous renal replacement therapy, either conservatively manages patients with ALF or offers bridging therapy until liver transplantation. Thus, appropriate critical care management has improved the likelihood of patient recovery in ALF. ICU care interventions such as monitoring of cerebral edema, fluid status assessment and interventions for sepsis prevention, nutritional support and management of electrolytes can salvage a substantial proportion of patients. In this review, we discuss the key aspects of critical care management of ALF.

Acute liver failure (ALF) is defined as acute loss of liver function leading to hepatic encephalopathy associated with a high risk of patient death. Brain injury markers in serum and tissue can help detect and monitor ALF-associated brain injury. This study compares different brain injury parameters in plasma and tissue along with the progression of ALF.

ALF was induced by performing an 85% liver resection. Following the resection, animals were recovered and monitored for up to 48 h or until reaching the predefined endpoint of receiving standard medical therapy (SMT). Blood and serum samples were taken at Tbaseline, T24, and upon reaching the endpoint (Tend). Control animals were euthanized by exsanguination following plasma sampling. Postmortem brain tissue samples were collected from the frontal cortex (FCTx) and cerebellum (Cb) of all animals. Glial fibrillary acidic protein (GFAP) and tau protein and mRNA levels were quantified using ELISA and qRT-PCR in all plasma and brain samples. Plasma neurofilament light (NFL) was also measured using ELISA.

All ALF animals (n = 4) were euthanized upon showing signs of brain herniation. Evaluation of brain injury biomarkers revealed that GFAP was elevated in ALF animals at T24h and Tend, while Tau and NFL concentrations were unchanged. Moreover, plasma glial fibrillary acidic protein (GFAP) levels were negatively correlated with total protein and positively correlated with both aspartate transaminase (AST) and alkaline phosphatase (AP). Additionally, lower GFAP and tau RNA expressions were observed in the FCTx of the ALF group but not in the CB tissue.

The current large animal study has identified a strong correlation between GFAP concentration in the blood and markers of ALF. Additionally, the protein and gene expression analyses in the FCTx revealed that this area appears to be susceptible, while the CB is protected from the detrimental impacts of ALF-associated brain swelling. These results warrant further studies to investigate the mechanisms behind this process.

Sepsis is characterized by a dysregulated immune response to an infection. It is a major public health problem owing to its high mortality and morbidity. Sepsis is a medical emergency and requires aggressive and timely management. It can cause multiorgan failure, unmask an existing but undiagnosed disease such as ornithine transcarbamylase deficiency (OTCD), or make a known well-controlled disease worse. We present the case of a 52-year-old male who was brought to the emergency department unresponsive. He was diagnosed with severe sepsis which was associated with multiorgan failure and hyperammonemia crisis. Hyperammonemia was due to a newly diagnosed, late-onset OTCD which was unmasked by severe sepsis. This case will enable physicians to be aware and consider OTCD in a patient presenting with severe sepsis, altered mentation, and seizures, with no obvious cause of hyperammonemia.

Pediatric acute liver failure (PALF) is one of the most demanding emergencies in hepatology, intensive care, and for transplant team. This report describes the clinical pattern, diagnostic and therapeutic modalities in children with ALF considered at risk of death without liver transplantation, basing on a long-term experience of the pediatric transplant center.

Between 1990 and 2022, 104 children aged 7 days-17 years (median 8 years), with body weight 3.1 to 77 kg (median 32 kg), were qualified for LT due to ALF, and finally 81 (78%) of them were transplanted (9% of all 899 LT performed in children in the same period).

A total of 23 children were not transplanted: 15 (14.4%) died while awaiting transplantation. In 8 (7.7%) patients liver function recovered. Before transplantation 45 (43.3%) children developed circulatory failure, in 66 (63.5%) mechanical ventilation was necessary, 18 patients presented acute kidney injury (17.3%), and encephalopathy higher than stage I was present in 60 (57.7%) patients. In 63 children, various kidney/liver assist procedures were performed: CVVHD (continuous veno-venous hemodiafiltration in 22 (21.2%) patients, albumin dialysis (MARS; molecular adsorbent recirculating system) in 39 (37.5%) patients, therapeutic plasma exchange (TPE) in 13 (12.5%) patients. Twenty (24.7%) children died after LT including 15 (18.5%) in the early posttransplant period, and 5 (6.1%) in the late follow-up.

Treatment of children with ALF in the peritransplant period is very difficult and require an experienced, multidisciplinary team. Despite continued advances in the care of children with ALF, patient survival remains lower than for elective indications for liver transplantation, and timely qualification and transplantation still are the most important factors of survival of these children.

Over the past decade, the field of solid organ transplantation has undergone significant changes, with some of the most notable advancements occurring in liver transplantation. Recent years have seen substantial progress in preoperative patient optimization protocols, anesthesia monitoring, coagulation management, and fluid management, among other areas. These improvements have led to excellent perioperative outcomes for all surgical patients, including those undergoing liver transplantation. In the last few decades, there have been numerous publications in the field of liver transplantation, but controversies related to perioperative management of liver transplant recipients persist. In this review article, we address the unresolved issues surrounding the anesthetic management of patients scheduled for liver transplantation.

Hyperammonemia is critical to the development of hepatic encephalopathy (HE) and is associated with mortality in end-stage liver disease. This study investigated the clinical value of ammonia variation in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) patients.

A total of 276 patients with HBV-ACLF were retrospectively recruited. Patients' ammonia levels were serially documented. Baseline ammonia, Peak ammonia (highest level), and Trough ammonia (lowest level) were particularly corrected to the upper limit of normal (AMM-ULN). The primary endpoint was 28-day mortality.

The 28-day, 3-month, and 12-month mortality rates were 19.2, 25.7, and 28.2%, respectively. A total of 51 (18.4%) patients had overt HE (grade 2/3/4). Peak AMM-ULN was significantly higher in patients with overt HE and non-survivors compared with their counterparts (P < 0.001). Following adjustment for significant confounders, high Peak AMM-ULN was an independent predictor of overt HE (hazard ratio, 1.031, P < 0.001) and 28-day mortality (hazard ratio, 1.026, P < 0.001). The cut-off of Peak AMM-ULN was 1.8, determined by using the X-tile. Patients with Peak AMM-ULN appearing on days 1-3 after admission had a higher proportion of overt HE and mortality compared to other groups. Patients with decreased ammonia levels within 7 days had better clinical outcomes than those with increased ammonia.

Serum Peak ammonia was independently associated with overt HE and mortality in HBV-ACLF patients. Serial serum ammonia may have prognostic value.

Non-hepatic hyperammonemia can damage the central nervous system (CNS), and possible prognostic factors are lacking. This study aimed to investigate the prognostic and risk factors for patients admitted to the intensive care unit (ICU).

This prospective, observational, multicenter study was conducted between November and December 2019 at 11 ICUs in the Chinese Heilongjiang province. Changes in blood ammonia level during and after ICU admission were continuously monitored and expressed as the high level (H-), mean level (M-), and initial level (I-) of ammonia. The risk factors of poor prognosis were investigated by conducting univariate and multivariate logistic regression analyses. Receiver operating characteristic (ROC) curve analysis was conducted to compare the predictive ability of Acute Physiologic Assessment and Chronic Health Evaluation II (APACHE-II) score, lactic acid, total bilirubin (TBil), and M-ammonia.

A total of 1060 patients were included in this study, of which 707 (67%) had a favorable prognosis and 353 (33%) had a poor prognosis. As shown by univariate models, a poor prognosis was associated with elevated serum levels of lactic acid, TBil, and ammonia (P < 0.05) and pathologic scores from three assessments: APACHE-II, Glasgow Coma Scale (GCS), and Sequential Organ Failure Assessment (SOFA). Multivariate analysis revealed that circulating mean ammonia levels in ICU patients were independently associated with a poor prognosis (odds ratio [OR] = 1.73, 95% confidence interval [CI]: 1.07-2.80, P = 0.02). However, the APACHE-II score (area under the curve [AUC]: 0.714, sensitivity: 0.86, specificity: 0.68, P < 0.001) remained the most predictive factor for patient prognosis by ROC analysis.

Elevated serum levels of ammonia in the blood were independently prognostic for ICU patients without liver disease.

Hepatic encephalopathy is a confusional state associated with cirrhosis. Serum ammonia levels are neither sensitive nor specific for the diagnosis.

We audited the ordering location and hospital unit whilst assessing the impact on management at a major Australian tertiary centre.

We conducted a single-centre retrospective chart review of the ordering of serum ammonia levels between 1 March 2019 and 29 February 2020 at The Royal Melbourne Hospital, a tertiary-referral centre in Melbourne, Victoria. Demographic, medication and pathology results, including serum ammonia measurements, were collected. The main outcomes assessed were ordering location, sensitivity, specificity and impact on management.

A total of 1007 serum ammonia tests were ordered in 425 patients. Nearly all ammonia ordering was by non-gastroenterologists, 24.2% by the intensive care unit, 23.1% by general medicine and 19.5% by the emergency department (ED). Only 21.6% of patients had a history of cirrhosis, with hepatic encephalopathy diagnosed in 13.6%. On subgroup analysis, 217 ammonia tests were performed in 92 patients with cirrhosis. Cirrhotic patients were older (64 vs 59 years, P = 0.012) and had higher median ammonia levels (64.46 vs 59 μmol/L, P < 0.001) compared with non-cirrhotic patients. In cirrhotic patients, the sensitivity and specificity for serum ammonia and diagnosis of hepatic encephalopathy were 75% and 52.3% respectively.

We affirm the poor utility of serum ammonia levels for guiding management of hepatic encephalopathy within the Australian context. ED and general medical units account for the majority of test ordering within the hospital. Understanding where ordering occurs provides a target for targeted education.

Acute kidney injury (AKI) is a heterogeneous syndrome with multiple etiologies. It occurs frequently in the neurocritical intensive care unit and is associated with greater morbidity and mortality. In this scenario, AKI alters the kidney-brain axis, exposing patients who receive habitual dialytic management to greater injury. Various therapies have been designed to mitigate this risk. Priority has been placed by KDIGO guidelines on the use of continuous over intermittent acute kidney replacement therapies (AKRT). On this background, continuous therapies have a pathophysiological rationale in patients with acute brain injury. A low-efficiency therapy such as PD and CRRT could achieve optimal clearance control and potentially reduce the risk of secondary brain injury. Therefore, this work will review the evidence on peritoneal dialysis as a continuous AKRT in neurocritical patients, describing its benefits and risks so it may be considered as an option when deciding among available therapeutic options.

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.