Drug-induced liver injury (DILI) is a drug-induced disease that not only complicates the treatment of the primary disease but may also lead to acute liver failure or even death in severe cases. Drugs commonly used in primary care, such as anti-infective agents and nonsteroidal anti-inflammatory drugs, are major causes of DILI. In addition, a large elderly population, comorbidities, and combination therapy with multiple drugs increase the risk of DILI in primary care. Therefore, primary care providers should proactively screen and monitor high-risk patients to identify potential DILI timely. Currently, diagnosis of DILI relies on the exclusion of liver diseases of other etiologies. Collection of detailed medical history of the patients and careful exclusion of other potential liver injury of other etiologies are crucial for accurate diagnosis. This guideline, developed based on evidence-based medicine from the latest research, aimed to provide primary care providers with professional guidance on the timely identification of suspected DILI cases and standardized diagnosis and management in clinical practice.

Neurological complications in acute liver failure are the most common cause of mortality in this group of patients. Almost all neurologic complications arise from underlying increase in intracranial pressure in ALF. In addition to symptomatic management, the treatment relies on measures to bring down ICP. Recently role of renal replacement therapy is gaining a lot of ground in ALF management, primarily due to its ammonia lowering effects indirectly leading to decrease in ICP. In this review we cover the neurologic issues in ALF in detail. We discuss the various non invasive techniques for ICP monitoring & their current application in ALF patients. We also focus on the management protocols in ALF & their role in improving the ICP & hence the outcome.

Acute liver failure (ALF) is defined as the loss of hepatic function in conjunction with hepatic encephalopathy and coagulopathy. There is histological evidence of profound hepatocyte damage. If it is not aggressively managed, ALF can be fatal within a few days. It is a rare disease, often occurring in patients without prior liver disease. Despite numerous causes, ALF usually presents as acute liver necrosis with a clinical picture that includes cognitive dysfunction, increased aminotransferases, and severe coagulopathy. It is essential to distinguish between ALF and acute-on-chronic liver failure (ACLF). Causes for ALF include paracetamol Acute liver failure (ALF) is characterized by acute liver dysfunction associated with overdose, right heart failure (ischemic liver injury), viral hepatitis (A, B, D and E), autoimmune hepatitis and drug-induced liver injury (including some herbal and nutritional supplements). In developed countries, the prevalence of ALF is 1:1,000,000. Survival rates have increased due to improved ICU management.

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.

Acute liver failure (ALF) induces increased energy expenditure and disrupts the metabolism of essential nutrients. Hepatic encephalopathy is a complication of ALF with a poor prognosis and mainly involves the metabolic disturbance of amino acids in its pathogenesis. In this review, we discuss the nutritional management for ALF in consideration of the pathophysiology of ALF with respect to the impairment of hepatocyte function. It is known that enteral nutrition is recommended for patients with ALF, while parenteral nutrition is recommended for patients who cannot tolerate enteral nutrition. As ALF leads to a hypermetabolic state, the energy intake is recommended to cover 1.3 times the resting energy expenditure. Because of the high risk of hypoglycemia associated with disturbances in glucose metabolism, substantial glucose intake is recommended. Along with the deterioration of glucose metabolism, protein metabolism is also disrupted. As patients with ALF have increased systemic protein catabolism together with decreased protein synthesis, appropriate amounts of amino acids or protein under monitoring serum ammonia levels are recommended. In conclusion, nutritional management based on the understanding of nutritional pathophysiology is a pivotal therapeutic approach for patients with ALF. The approach should be individualized in the acute phase, the recovery phase, and the pretransplant phase.

l-Ornithine- l-aspartate (LOLA) reduces toxic ammonium (NH3) plasma levels in hepatic encephalopathy. NH3 detoxification/excretion is achieved by its incorporation into urea and glutamine via activation of carbamoyl phosphate synthetase 1 (CSP1) by l-ornithine and stimulation of arginase by l-aspartate. We aimed at identifying additional molecular targets of LOLA as a potential treatment option for non-alcoholic fatty liver disease (NAFLD). In primary hepatocytes from NAFLD patients, urea cycle enzymes CSP1 and ornithine transcarbamylase (OTC) increase, while the catabolism of branched-chain amino acids (BCAAs) decreases with disease severity. In contrast, LOLA increased the expression rates of the BCAA enzyme transcripts bcat2, bckdha, and bckdk. In untreated HepG2 hepatoblastoma cells and HepG2-based models of steatosis, insulin resistance, and metabolic syndrome (the latter for the first time established herein), LOLA reduced the release of NH3; beneficially modulated the expression of genes related to fatty acid import/transport (cd36, cpt1), synthesis (fasn, scd1, ACC1), and regulation (srbf1); reduced cellular ATP and acetyl-CoA; and favorably modulated the expression of master regulators/genes of energy balance/mitochondrial biogenesis (AMPK-α, pgc1α). Moreover, LOLA reconstituted the depolarized mitochondrial membrane potential, while retaining mitochondrial integrity and avoiding induction of superoxide production. Most effects were concentration-dependent at ≤40 mM LOLA. We demonstrate for l-ornithine-l-aspartate a broad range of reconstituting effects on metabolic carriers and targets of catabolism/energy metabolism impaired in NAFLD. These findings strongly advocate further investigations to establish LOLA as a safe, efficacious, and cost-effective basic medication for preventing and/or alleviating NAFLD.

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.

Drug-induced liver injury (DILI) is an important adverse drug reaction that can lead to acute liver failure or even death in severe cases. Currently, the diagnosis of DILI still follows the strategy of exclusion. Therefore, a detailed history taking and a thorough and careful exclusion of other potential causes of liver injury is the key to correct diagnosis. This guideline was developed based on evidence-based medicine provided by the latest research advances and aims to provide professional guidance to clinicians on how to identify suspected DILI timely and standardize the diagnosis and management in clinical practice. Based on the clinical settings in China, the guideline also specifically focused on DILI in chronic liver disease, drug-induced viral hepatitis reactivation, common causing agents of DILI (herbal and dietary supplements, anti-tuberculosis drugs, and antineoplastic drugs), and signal of DILI in clinical trials and its assessment.

Viral hepatitis-induced acute liver failure (ALF) is a preventable cause for liver-related mortality worldwide. Viruses are the most common cause for ALF in developing nations in contrast to the west, where acetaminophen is largely responsible. Viruses may be hepatotropic or affect the liver secondary to a systemic infection. In tropical countries, infections such as leptospirosis, scrub typhus and malaria can mimic the symptoms of ALF. Differentiating these ALF mimics is crucial because they require etiology-specific therapy. Treatment of viral hepatitis-induced ALF is two-pronged and directed towards providing supportive care to prevent organ failures and antiviral drugs for some viruses. Liver transplantation (LT) is an effective modality for patients deteriorating despite adequate supportive care. Early referral and correct identification of patients who require a transplant are important. Liver support devices and plasma exchange have evolved into "bridging modalities" for LT. Preventive strategies such as hand hygiene, use of clean and potable water and inclusion of vaccines against viral hepatitis in the national program are simple yet very effective methods focusing on the preventive aspect of this disease.

l-Ornithine (Orn) is a core amino acid responsible for ammonia detoxification in the body via the hepatic urea cycle. Clinical studies in Orn therapy have focused on interventions for hyperammonemia-associated diseases, such as hepatic encephalopathy (HE), a life-threatening neurological symptom affecting more than 80% of patients with liver cirrhosis. However, its low molecular weight (LMW) causes Orn to diffuse nonspecifically and be rapidly eliminated from the body after oral administration, resulting in unfavorable therapeutic efficacy. Hence, Orn is constantly supplied by intravenous infusion in many clinical settings; however, this treatment inevitably decreases patient compliance and limits its application in long-term management. To improve the performance of Orn, we designed self-assembling polyOrn-based nanoparticles for oral administration through ring-opening polymerization of Orn-N-carboxy anhydride initiated with amino-ended poly(ethylene glycol), followed by acylation of free amino groups in the main chain of the polyOrn segment. The obtained amphiphilic block copolymers, poly(ethylene glycol)-block-polyOrn(acyl) (PEG-block-POrn(acyl)), enabled the formation of stable nanoparticles (NanoOrn(acyl)) in aqueous media. We employed the isobutyryl (iBu) group for acyl derivatization in this study (NanoOrn(iBu)). In the healthy mice, daily oral administration of NanoOrn(iBu) for one week did not induce any abnormalities. In the mice exhibiting acetaminophen (APAP)-induced acute liver injury, oral pretreatment with NanoOrn(iBu) effectively reduced systemic ammonia and transaminases levels compared to the LMW Orn and untreated groups. The results suggest that the application of NanoOrn(iBu) is of significant clinical value with the feasibility of oral delivery and improvement in APAP-induced hepatic pathogenesis. STATEMENT OF SIGNIFICANCE: Liver injury is often accompanied by hyperammonemia, a life-threatening condition characterized by elevated blood ammonia levels. Current clinical treatments for reducing ammonia typically entail the invasive approach of intravenous infusion, involving the administration of l-ornithine (Orn) or a combination of Orn and L-aspartate. This method is employed due to the poor pharmacokinetics associated with these compounds. In our pursuit of enhancing therapy, we have developed an orally administrable nanomedicine based on Orn-based self-assembling nanoparticle (NanoOrn(iBu)), which provides sustained Orn supply to the injured liver. Oral administration of NanoOrn(iBu) to healthy mice did not cause any toxic effects. In a mouse model of acetaminophen-induced acute liver injury, oral administration of NanoOrn(iBu) surpassed Orn in reducing systemic ammonia levels and liver damage, thereby establishing NanoOrn(iBu) as a safe and effective therapeutic option.

Acute liver failure (ALF) is a rare disease condition with a dynamic clinical course and catastrophic outcomes. Several etiologies are involved in ALF. Hepatitis A and B infections and indiscriminate use of untested herbs or supplemental agents are the most common causes of ALF in Korea. Noninvasive neurological monitoring tools have been used in patients with ALF in recent times. Ongoing improvements in intensive care, including continuous renal replacement therapy, therapeutic plasma exchange, vasopressor, and extracorporeal membrane oxygenation, have reduced the mortality rate of patients with ALF. However, liver transplantation is still the most effective treatment for patients with intractable ALF. There is a need for further research in the areas of better prognostication and precise selection of patients for emergency transplantation.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease in the world. Progression toward non-alcoholic steatohepatitis (NASH) is associated with alterations of skeletal muscle. One plausible mechanism for altered muscle compartment in liver disease is changes in ammonia metabolism. In the present study, we explored the hypothesis that NASH-associated hyperammonemia drives muscle changes as well as liver disease progression.

In Alms1-mutant mice (foz/foz) fed a 60% fat diet (HFD) for 12 weeks; we investigated hepatic and muscular ammonia detoxification efficiency. We then tested the effect of an 8 week-long supplementation with L-ornithine L-aspartate (LOLA), a known ammonia-lowering treatment, given after either 4 or 12 weeks of HFD for a preventive or a curative intervention, respectively. We monitored body composition, liver and muscle state by micro computed tomography (micro-CT) as well as muscle strength by four-limb grip test.

According to previous studies, 12 weeks of HFD induced NASH in all foz/foz mice. Increase of hepatic ammonia production and alterations of urea cycle efficiency were observed, leading to hyperammonemia. Concomitantly mice developed marked myosteatosis. First signs of myopenia occurred after 20 weeks of diet. Early LOLA treatment given during NASH development, but not its administration in a curative regimen, efficiently prevented myosteatosis and muscle quality, but barely impacted liver disease or, surprisingly, ammonia detoxification.

Our study confirms the perturbation of hepatic ammonia detoxification pathways in NASH. Results from the interventional experiments suggest a direct beneficial impact of LOLA on skeletal muscle during NASH development, though it does not improve ammonia metabolism or liver disease.

Ammonia is a neurotoxic compound which is detoxified through liver enzymes from urea cycle. Several inherited or acquired conditions can elevate ammonia concentrations in blood, causing severe damage to the central nervous system due to the toxic effects exerted by ammonia on the astrocytes. Therefore, hyperammonemic patients present potentially life-threatening neuropsychiatric symptoms, whose severity is related with the hyperammonemia magnitude and duration, as well as the brain maturation stage. Inherited metabolic diseases caused by enzymatic defects that compromise directly or indirectly the urea cycle activity are the main cause of hyperammonemia in the neonatal period. These diseases are mainly represented by the congenital defects of urea cycle, classical organic acidurias, and the defects of mitochondrial fatty acids oxidation, with hyperammonemia being more severe and frequent in the first two groups mentioned. An effective and rapid treatment of hyperammonemia is crucial to prevent irreversible neurological damage and it depends on the understanding of the pathophysiology of the diseases, as well as of the available therapeutic approaches. In this review, the mechanisms underlying the hyperammonemia and neurological dysfunction in urea cycle disorders, organic acidurias, and fatty acids oxidation defects, as well as the therapeutic strategies for the ammonia control will be discussed.

Abbreviated pathogenesis and clinical course of the acute liver failure syndrome. The pathogenesis and clinical course of the syndrome of acute liver failure (ALF) differs depending upon the etiology of the primary liver injury. In turn, the severity of the liver injury and resulting synthetic failure is often the primary determinant of whether a patient is referred for emergency liver transplantation. Injuries by viral etiologies trigger the innate immune system via pathogen-associated molecular patterns (PAMPs), while toxin-induced (and presumably ischemia-induced) injuries do so via damage-associated molecular patterns (DAMPs). The course of the clinical syndrome further depends upon the relative intensity and composition of cytokine release, resulting in an early proinflammatory phenotype (SIRS) and later compensatory anti-inflammatory response phenotype (CARS). The outcomes of overwhelming immune activation are the systemic (extrahepatic) features of ALF (cardiovascular collapse, cerebral edema, acute kidney injury, respiratory failure, sepsis) which ultimately determine the likelihood of death.Acute liver failure (ALF) continues to carry a high risk of mortality or the need for transplantation despite recent improvements in overall outcomes over the past two decades. Optimal management begins with identifying that liver failure is indeed present and its etiology, since outcomes and the need for transplantation vary widely across the different etiologies. Most causes of ALF can be divided into hyperacute (ischemia and acetaminophen) and subacute types (other etiologies), based on time of evolution of signs and symptoms of liver failure; the former evolve in 3 to 4 days and the latter typically in 2 to 4 weeks. Both involve intense release of cytokines and hepatocellular contents into the circulation with multiorgan effects/consequences.Management involves optimizing fluid balance and cardiovascular support, including the use of continuous renal replacement therapy, vasopressors, and pulmonary ventilation. Early evaluation for liver transplantation is advised particularly for acetaminophen toxicity, which evolves so rapidly that delay is likely to lead to death.Vasopressor support, high-grade hepatic encephalopathy, and unfavorable (subacute) etiologies heighten the need for urgent listing for liver transplantation. Prognostic scores such as Kings Criteria, Model for End-Stage Liver Disease, and the Acute Liver Failure Group prognostic index take these features into account and provide reasonable but imperfect predictive accuracy. Future treatments may include liver support devices and/or agents that improve hepatocyte regeneration.

Beyond probiotics, the interest in the application of postbiotics to various fields has been growing. We aimed to develop a novel postbiotic complex (PC) with antibacterial and anti-inflammatory properties. Through antibacterial activity testing against Staphylococcus aureus or Cutibacterium acnes, a PC [a mixture of cell-free supernatants (postbiotics) from probiotic Lactobacillus helveticus (HY7801) and Lactococcus lactis (HY449)] was developed. Anti-inflammatory activity of the PC was investigated using HaCaT keratinocytes treated with S. aureus or C. acnes. PC significantly decreased IL-8 levels and increased hyaluronic acid levels in HaCaT cells cultured with S. aureus or C. acnes. GC-MS based metabolic profiling suggested 2-hydroxyisocaproic acid, hypoxanthine, succinic acid, ornithine, and γ-aminobutyric acid as potential contributing metabolites for the antibacterial and anti-inflammatory effects of PC. The PC developed in this study could be utilized in food, cosmetics, and pharmaceutical products as an alternative or complementary resources of probiotics.

The online version contains supplementary material available at 10.1007/s10068-022-01123-x.

Hepatic encephalopathy (HE) is one of the reversible complications of chronic liver disease, associated with a higher mortality rate. In current clinical practice, treatment with rifaximin and lactulose/lactitol is the first line of treatment in HE. With the advance in pathophysiology, a new class of ammonia lowering drugs has been revealed to overcome the hurdle and disease burden. The mechanism of the novel agents differs significantly and includes the alteration in intestinal microbiota, intestinal endothelial integrity, oxidative stress, inflammatory markers, and modulation of neurotoxins. Most of the trials have reported promising results in the treatment and prevention of HE with fecal microbiota transplantation, albumin, probiotics, flumazenil, polyethylene glycol, AST-120, glycerol phenylbutyrate, nitazoxanide, branched-chain amino acid, naloxone, and acetyl-l-carnitine. However, their clinical use is limited due to the presence of major drawbacks in their study design, sample size, safety profile, bias, and heterogenicity. This study will discuss the novel therapeutic targets for HE in liver cirrhosis patients with supporting clinical trial data.

Acute liver failure is a rare syndrome comprising a coagulopathy of liver origin, jaundice and encephalopathy in a patient with no prior history of liver disease. Paracetamol overdose is the leading cause of acute liver failure in the United Kingdom and often presents with extrahepatic organ dysfunction requiring critical care. Presentation: We present the case of a patient with hyper acute liver failure secondary to paracetamol overdose. Management and discussion: Management focused on ensuring the correct diagnosis had been made, administering N-acetyl cysteine, fluid resuscitation and broad spectrum antimicrobials. Early intubation and transfer to a transplant centre were undertaken following development of hepatic encephalopathy. Neuroprotective measures and hypertonic saline were instituted to reduce the risk of intracranial hypertension. High dose haemofiltration was also started to help reduce ammonia levels. Aggressive critical care therapies with specialised input results in good outcomes for patients admitted with paracetamol induced hyper acute liver failure. Liver transplant is reserved for those patients unlikely to survive with medical treatment alone.

Present an outline of acute liver failure, from its definition to its management in critical care, updated with findings of selected newer research.

Survival of patients with acute liver failure has progressively improved. Intracranial hypertension complicating hepatic encephalopathy is now much less frequent than in the past and invasive ICP monitoring is now rarely used. Early renal replacement therapy and possibly therapeutic plasma exchange have consolidated their role in the treatment. Further evidence confirms the low incidence of bleeding in these patients despite striking abnormalities in standard tests of coagulation and new findings of abnormalities on thromboelastographic testing. Specific coagulopathy profiles including an abnormal vWF/ADAMTS13 ratio may be associated with poor outcome and increased bleeding risk. Use of N-acetylcysteine in nonparacetamol-related cases remains unsupported by robust clinical evidence. New microRNA-based prognostic markers to select patients for transplantation are described but are still far from widespread clinical applicability; imaging-based prognostication tools are also promising. The use of extracorporeal artificial liver devices in clinical practice is yet to be supported by evidence.

Medical treatment of patients with acute liver failure is now associated with significantly improved survival. Better prognostication and selection for emergency liver transplant may further improve care for these patients.

The Hepatology Committee of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) aims to educate pediatric gastroenterologists, members of ESPGHAN and professionals from other specialties promoting an exchange of clinical expertise in the field of pediatric hepatology. Herewith we have concentrated on detailing the recent advances in acute liver failure in infants and children.

The 2020 ESPGHAN monothematic three-day conference on pediatric hepatology disease, entitled "acute liver failure" (ALF), was organized in Athens, Greece. ALF is a devastating disease with high mortality and most cases remain undiagnosed. As knowledge in diagnosis and treatment of ALF in infants and children has increased in the past decades, the objective was to update physicians in the field with the latest research and developments in early recognition, curative therapies and intensive care management, imaging techniques and treatment paradigms in these age groups.

In the first session, the definition, epidemiology, various causes of ALF, in neonates and older children and recurrent ALF (RALF) were discussed. The second session was dedicated to new aspects of ALF management including hepatic encephalopathy (HE), coagulopathy, intensive care interventions, acute on chronic liver failure, and the role of imaging in treatment and prognosis. Oral presentations by experts in various fields are summarized highlighting key learning points.

The current report summarizes the major learning points from this meeting. It also identifies areas where there is gap of knowledge, thereby identifying the research agenda for the near future.

Acute liver failure (ALF) is a rare disease with potentially high mortality. We sought to assess the individual approach to ALF by intensive care unit (ICU) professionals.

Cross-sectional survey of ICU professionals. Web-based survey capturing data on respondents' demographics, characteristics of patients with ALF admitted to ICU, and their management.

Among 204 participants from 50 countries, 140 (68.6%) worked in Europe, 146 (71.6%) were intensivists, 142 (69.6%) admitted <25 patients with ALF per year, and 166 (81.8%) reported <25% of patients had paracetamol-related ALF. On patients' outcomes, 126 (75.0%) reported an emergency liver transplantation (ELT) rate <25% and 140 (73.3%) a hospital mortality rate <50%. The approach to ALF in the ICU varied with age, region, level of training, type of hospital, and etiology (prescribing N-acetylcysteine for paracetamol toxicity, triggers for endotracheal intubation, measurement of and strategies for lowering serum ammonia, extracorporeal device deployment, and prophylactic antibiotics).

The management of patients with ALF by ICU professionals differed substantially concerning the relevant clinical measures taken. Further education and high-quality research are warranted.

Pediatric acute liver failure (PALF) is a rare, rapidly progressive clinical syndrome with significant morbidity and mortality. The phenotype of PALF manifests as abrupt onset liver dysfunction, which can be brought via disparate etiology. Management is reliant upon intensive clinical care and support, often provided by the collaborative efforts of hepatologists, critical care specialists, and liver transplant surgeons. The construction of an age-based diagnostic approach, the identification of a potential underlying cause, and the prompt implementation of appropriate therapy can be lifesaving; however, the dynamic and rapidly progressive nature of PALF also demands that diagnostic inquiries be paired with monitoring strategies for the recognition and treatment of common complications of PALF. Although liver transplantation can provide a potential life-saving therapeutic option, the ability to confidently determine the certainness that liver transplant is needed for an individual child has been hampered by a lack of adequately tested clinical decision support tools and accurate predictive models. Given the accelerated progress in understanding PALF, we will provide clinical guidance to pediatric gastroenterologists and other pediatric providers caring for children with PALF by presenting the most recent advances in diagnosis, management, pathophysiology, and associated outcomes.

Hepatic encephalopathy is an often devastating complication of chronic liver disease, associated with high mortality and increased burden on patients and healthcare systems. Current agents (such as nonabsorbable disaccharides and oral antibiotics) are often only partially effective and associated with unpleasant side effects. With our improved understanding of the pathophysiology of hepatic encephalopathy, multiple treatment modalities have emerged with promising results when used alone or as an adjunct to standard medications. The mechanisms of these agents vary greatly, and include the manipulation of gut microbial composition, reduction of oxidative stress, inhibition of inflammatory mediators, protection of endothelial integrity, modulation of neurotransmitter release and function, and other novel methods to reduce blood ammonia and neurotoxins. Despite their promising results, the studies assessing these treatment modalities are often limited by study design, sample size, outcome assessment heterogeneity, and paucity of data regarding their safety profiles. In this article, we discuss these novel agents in depth and provide the best evidence supporting their use, along with a critical look at their limitations and future directions.

Acute liver failure (ALF) is not an uncommon complication of a common disease such as acute hepatitis. Viral hepatitis followed by antituberculosis drug-induced hepatotoxicity are the commonest causes of ALF in India. Clinically, such patients present with appearance of jaundice, encephalopathy, and coagulopathy. Hepatic encephalopathy (HE) and cerebral edema are central and most important clinical event in the course of ALF, followed by superadded infections, and determine the outcome in these patients. The pathogenesis of encephalopathy and cerebral edema in ALF is unique and multifactorial. Ammonia plays a crucial role in the pathogenesis, and several therapies aim to correct this abnormality. The role of newer ammonia-lowering agents is still evolving. These patients are best managed at a tertiary care hospital with facility for liver transplantation (LT). Aggressive intensive medical management has been documented to salvage a substantial proportion of patients. In those with poor prognostic factors, LT is the only effective therapy that has been shown to improve survival. However, recognizing suitable patients with poor prognosis has remained a challenge. Close monitoring, early identification and treatment of complications, and couseling for transplant form the first-line approach to manage such patients. Recent research shows that use of dynamic prognostic models is better for selecting patients undergoing liver transplantation and timely transplant can save life of patients with ALF with poor prognostic factors.

Acute-on-chronic liver failure (ACLF) has a high mortality rate. Metabolic reprogramming is an important mechanism for cell survival. Herein, the metabolic patterns of ACLF patients are analyzed. An in vitro model of ACLF is established using Chang liver cells under hyperammonemia and hypoxia. A randomized clinical trial (ChiCTR-OPC-15006839) is performed with patients receiving L-ornithine and L-aspartate (LOLA) daily intravenously (LOLA group) and trimetazidine (TMZ) tid orally (TMZ group) based on conventional treatment (control group). The primary end point is 90-day overall survival, and overall survival is the secondary end point. By analyzing metabolic profiles in liver tissue samples from hepatitis B virus (HBV)-related ACLF patients and the controls, the metabolic characteristics of HBV-related ACLF patients are identified: inhibited glycolysis, tricarboxylic acid cycle and urea cycle, and enhanced fatty acid oxidation (FAO) and glutamine anaplerosis. These effects are mainly attributed to hyperammonemia and hypoxia. Further in vitro study reveals that switching from FAO to glycolysis could improve hepatocyte survival in the hyperammonemic and hypoxic microenvironment. Importantly, this randomized clinical trial confirms that inhibiting FAO using TMZ improves the prognosis of patients with HBV-related ACLF. In conclusion, this study provides a practical strategy for targeting metabolic reprogramming using TMZ to improve the survival of patients with HBV-related ACLF.

This review describes the current intensive care management of acute liver failure (ALF) and the latest evidence for emerging therapies.

Mortality from ALF continues to improve and in some cases, medical therapy can negate the need for liver transplantation because of protocolized management in specialist centres. Liver transplantation remains the cornerstone of management for poor prognosis ALF. The reduced use of blood products in ALF reflects growing evidence of balanced haemostasis in severe liver disease. Prophylactic therapeutic hypothermia is no longer recommended for neuroprotection. In cases not suitable for liver transplantation, high-volume plasma exchange (HVP) has potential benefit, although further research on the optimal timing and dosing is needed. Although sepsis remains an important complication in ALF, the use of prophylactic antimicrobials is being questioned in the era of emerging bacterial resistance.

ICU management of ALF has improved such that liver transplantation is not required in some cases. HVP has emerged as a potential therapy for patients who may not be good liver transplantation candidates. Nevertheless in suitable patients with poor prognosis liver transplantation remains the optimal therapy.

Acute liver failure (ALF) is defined as severe hepatic dysfunction (marked transaminases elevation, detoxification disorder (jaundice and coagulopathy with international normal ratio (INR) > 1.5), the presence of hepatic encephalopathy, and exclusion of underlying chronic liver disease, and a secondary cause like sepsis or cardiogenic shock. Reasons for ALF include paracetamol and warfarin toxicity, autoimmune and viral (mainly hepatitis B and E) hepatitis, and herbal and dietary supplements. Even in terms of meticulous and careful review of the patient, around 20-30% of the reasons remains unknown. In order of its rarity, a randomized controlled trial could hardly be done. However, because of improved ICU treatment, the mortality, even in the advanced stage of ALF decreased. However, in 5-10% of the cases an emergency transplantation is required. This justifies the treatment of this patient cohort in institutions that can provide this kind of treatment.

L-ornithine, a valuable non-protein amino acid, has a wide range of applications in the pharmaceutical and food industries. Currently, microbial fermentation is a promising, sustainable, and environment-friendly method to produce L-ornithine. However, the industrial production capacity of L-ornithine by microbial fermentation is low and rarely meets the market demands. Various strategies have been employed to improve the L-ornithine production titers in the model strain, Corynebacterium glutamicum, which serves as a major indicator for improving the cost-effectiveness of L-ornithine production by microbial fermentation. This review focuses on the development of high L-ornithine-producing strains by metabolic engineering and reviews the recent advances in breeding strategies, such as reducing by-product formation, improving the supplementation of precursor glutamate, releasing negative regulation and negative feedback inhibition, increasing the supply of intracellular cofactors, modulating the central metabolic pathway, enhancing the transport system, and adaptive evolution for improving L-ornithine production.

Acute liver failure (ALF) is a rare but life-threatening clinical syndrome with a broad range of causes. Significant improvements in outcome have occurred over the last 50 years, resulting not only from incremental improvements in specialist critical care and a step-change following the introduction of transplantation for this indication, but also better and more effective treatment started early at the site of first presentation.1 2 Emergency liver transplantation (LTx) remains an important intervention and the decision regarding the need for LTx remains key to management, though non-transplant therapies now appear effective for many causes of the condition. In this short review, we will outline issues in the recognition and management of ALF and ongoing challenges in its treatment.

Acute liver failure (ALF) is a catastrophic illness, which is associated with high mortality in absence of liver transplantation. ALF is associated with multisystem involvement including acute kidney injury (AKI). AKI worsens the already poor prognosis of ALF. There is limited literature on impact of AKI on outcomes of liver transplantation (LT). The use of continuous renal replacement therapy (CRRT) may have a role in transplant-free survival or bridging to LT. Although results suggest a somewhat lower survival in patients with ALF and AKI, LT is a life-saving option and should not be deferred in absence of other contraindications. In the current review, we discuss impact of AKI on transplant-free survival, possible role of CRRT, and role of LT in patients with ALF associated with AKI.

Neurologic complications are common after solid-organ transplantation, occurring in one-third of patients. Immunosuppression-related neurotoxicity (involving calcineurin inhibitors and corticosteroids), opportunistic central nervous system infections, seizures, and delirium are some of the causes of neurologic symptoms following solid-organ transplantation. An uncommon often missed complication posttransplantation involves buildup of ammonia levels that can lead to rapid clinical deterioration even when treated. Ammonia levels are not routinely checked due to the myriad of other explanations for encephalopathy in a transplant recipient. A treatment of choice for severe hyperammonemia involves renal replacement therapy (RRT), but there are no guidelines on the mode or parameters of RRT for reducing ammonia levels. Hyperammonemia in a transplant recipient poses specific challenges beyond the actual condition because the treatment (RRT) involves significant hemodynamic fluctuations that may affect the graft. In this review, we describe a patient with posttransplantation hyperammonemia and discuss the pathways of ammonia metabolism, potential factors underlying the development of hyperammonemia posttransplantation, and choice of appropriate therapeutic options in these patients.

Hepatic encephalopathy (HE) is a major complication that is closely related to the progression of end-stage liver disease. Metabolic changes in advanced liver failure can promote cognition impairment, attention deficits and motor dysfunction that may result in coma and death. HE can be subdivided according to the type of hepatic injury, namely, type A, which results from acute liver failure, type B, which is associated with a portosystemic shunting without intrinsic liver disease, and type C, which is due to chronic liver disease. Several studies have investigated the pathogenesis of the disease, and most of the mechanisms have been explored using animal models. This article aimed to review the use of preclinical models to investigate HE. The most used animal species are rats and mice. Experimental models of type A HE include surgical procedures and the administration of hepatotoxic medications, whereas models of types B and C HE are generally surgically induced lesions in liver tissue, which evolve to hepatic cirrhosis. Preclinical models have allowed the comprehension of the pathways related to HE.

Pediatric acute liver failure (PALF) is a dynamic, life-threatening condition of disparate etiology. Management of PALF is dependent on intensive collaborative clinical care and support. Proper recognition and treatment of common complications of liver failure are critical to optimizing outcomes. In parallel, investigations to identify underlying cause and the implementation of timely, appropriate treatment can be life-saving. Predicting patient outcome in the era of liver transplantation has been unfulfilling and better predictive models must be developed for proper stewardship of the limited resource of organ availability.

Acute liver failure (ALF) remains a high-risk clinical presentation, and many patients require emergency department (ED) management for complications and stabilization.

This narrative review provides an evidence-based summary of the current data for the emergency medicine evaluation and management of ALF.

While ALF remains a rare clinical presentation, surveillance data suggest an overall incidence between 1 and 6 cases per million people every year, accounting for 6% of liver-related deaths and 7% of orthotopic liver transplants (OLT) in the U.S. The definition of ALF includes neurologic dysfunction, an international normalized ratio ≥ 1.5, no prior evidence of liver disease, and a disease course of ≤26 weeks, and can be further divided into hyperacute, acute, and subacute presentations. There are many underlying etiologies, including acetaminophen toxicity, drug induced liver injury, and hepatitis. Emergency physicians will be faced with several complications, including encephalopathy, coagulopathy, infectious processes, renal injury, and hemodynamic instability. Critical patients should be evaluated in the resuscitation bay, and consultation with the transplant team for appropriate patients improves patient outcomes. This review provides several guiding principles for management of acute complications. Using a pathophysiological-guided approach to the management of ALF associated complications is essential to optimizing patient care.

ALF remains a rare clinical presentation, but has significant morbidity and mortality. Physicians must rapidly diagnose these patients while evaluating for other diseases and complications. Early consultation with a transplantation center is imperative, as is identifying the underlying etiology and initiating symptomatic care.

Acute liver failure (ALF) is a rare condition with fatal outcome. Characteristic is rapid onset of liver damage without preexisting liver diseases, including hepatic encephalopathy and coagulopathy. Early and correct diagnosis is essential for further management of patients, since diagnosis impacts therapy choice. Survival of patients with ALF has improved dramatically due to advances in critical care medicine and the use of liver transplantation.

Ammonia and tumor necrosis factor-alpha (TNF-α) play important roles in the mechanisms of hepatic encephalopathy (HE). Rhesus glycoprotein C (Rhcg) is important for ammonia transport especially in the kidney. The aim of the present study was to investigate the role of Rhcg in the brain in acute liver failure (ALF) and the effect of TNF-α on Rhcg expression.

ALF mouse models were generated by treatment with D-galactosamine (D-GalN) and lipopolysaccharide (LPS), or D-GalN and TNF-α. ALF induction was blocked by pretreatment with anti-TNF-α IgG. The levels of serum TNF-α were determined by ELISA. Blood ammonia and brain ammonia concentrations were detected using an ammonia assay kit. The expression and distribution of Rhcg in the brain tissues of ALF mice were examined by western blotting, real-time PCR, immunohistochemical, and immunofluorescence analyses.

Serum TNF-α levels were increased in the LPS/D-GalN group. Blood and brain ammonia were increased in the LPS/D-GalN- and TNF-α/D-GalN-induced ALF groups. Rhcg mRNA and protein levels were elevated in both ALF groups, consistent with the increase in blood and brain ammonia. Rhcg was mainly expressed in vascular endothelial cells and astrocytes. Pretreatment with anti-TNF-α IgG antibody downregulated Rhcg in brain tissues in the LPS/D-GalN group, prevented the occurrence of ALF, and reduced blood and brain ammonia levels in the LPS/D-GalN group.

TNF-α promoted the transport of ammonia from the blood to brain tissues and exacerbated the toxic effects of ammonia by upregulating Rhcg.

Acute and chronic liver diseases may escalate to hepatic encephalopathy (HE) and multiple organ failure, requiring admission and organ support in Intensive Care Unit (ICU). Hepatic dysfunction in ICU is a broad and complex topic; unfortunately, up to now, the understanding of its underlying pathophysiology is far from complete. HE and cirrhotic cardiomyopathy (CCM) need timely diagnostic and therapeutic measures aiming at the identification and elimination of causative factors, to improve patients' prognosis. Through this short review, we tried to answer the most asked questions about clinical features of HE and CCM at the ICU stage.

Hepatic encephalopathy is a common complication of cirrhosis and has high associated morbidity and mortality. The condition is classified as overt if it is clinically apparent or minimal if only evident though psychometric testing. The exact pathogenesis of this syndrome is unknown although ammonia is thought to play a key role. L-ornithine L-aspartate has ammonia-lowering properties and may, therefore, benefit people with cirrhosis and hepatic encephalopathy.

To evaluate the beneficial and harmful effects of L-ornithine L-aspartate versus placebo, no intervention, or other active interventions in people with cirrhosis and hepatic encephalopathy.

We undertook electronic searches of The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS and Science Citation Index Expanded to December 2017 and manual searches of meetings and conference proceedings; checks of bibliographies; and corresponded with investigators and pharmaceutical companies.

We included randomised clinical trials, irrespective of publication status, language, or blinding. We included participants with cirrhosis who had minimal or overt hepatic encephalopathy or who were at risk for developing hepatic encephalopathy. We compared: L-ornithine L-aspartate versus placebo or no intervention; and L-ornithine L-aspartate versus other active agents such as non-absorbable disaccharides, antibiotics, probiotics, or branched-chain amino acids.

Two review authors, working independently, retrieved data from published reports and correspondence with investigators and pharmaceutical companies. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We undertook meta-analyses and presented the results as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed bias control using the Cochrane Hepato-Biliary Group domains; we evaluated the risk of publication bias and other small trial effects in regression analyses; conducted subgroup and sensitivity analyses; and performed Trial Sequential Analyses. We determined the quality of the evidence using GRADE.

We identified 36 randomised clinical trials, involving at least 2377 registered participants, which fulfilled our inclusion criteria including 10 unpublished randomised clinical trials. However, we were only able to access outcome data from 29 trials involving 1891 participants. Five of the included trials assessed prevention, while 31 trials assessed treatment. Five trials were at low risk of bias in the overall assessment of mortality; one trial was at low risk of bias in the assessment of the remaining outcomes.L-ornithine L-aspartate had a beneficial effect on mortality compared with placebo or no intervention when including all trials (RR 0.42, 95% CI 0.24 to 0.72; I² = 0%; 19 trials; 1489 participants; very low quality evidence), but not when the analysis was restricted to the trials at low risk of bias (RR 0.47, 95% CI 0.06 to 3.58; 4 trials; 244 participants). It had a beneficial effect on hepatic encephalopathy compared with placebo or no intervention when including all trials (RR 0.70, 95% CI 0.59 to 0.83; 22 trials; 1375 participants; I² = 62%; very low quality evidence), but not in the one trial at low risk of bias (RR 0.96, 95% CI 0.85 to 1.07; 63 participants). The analysis of serious adverse events showed a potential benefit of L-ornithine L-aspartate when including all randomised clinical trials (RR 0.63, 95% CI 0.45 to 0.90; 1 trial; 1489 participants; I² = 0%; very low quality evidence), but not in the one trial at low risk of bias for this outcome (RR 0.83, 95% CI 0.15 to 4.65; 63 participants). The Trial Sequential Analyses of mortality, hepatic encephalopathy, and serious adverse events found insufficient evidence to support or refute beneficial effects. Subgroup analyses showed no difference in outcomes in the trials evaluating evaluating the prevention or treatment of either overt or minimal hepatic encephalopathy or trials evaluating oral versus intravenous administration We were unable to undertake a meta-analysis of the three trials involving 288 participants evaluating health-related quality of life. Overall, we found no difference between L-ornithine L-aspartate and placebo or no intervention in non-serious adverse events (RR 1.15, 95% CI 0.75 to 1.77; 14 trials; 1076 participants; I² = 40%). In comparison with lactulose, L-ornithine L-aspartate had no effect on mortality (RR 0.68, 95% CI 0.11 to 4.17; 4 trials; 175 participants; I² = 0%); hepatic encephalopathy (RR 1.13, 95% CI 0.81 to 1.57); serious adverse events (RR 0.69, 95% CI 0.22 to 2.11); or non-serious adverse events (RR 0.05, 95% CI 0.01 to 0.18). In comparison with probiotics, L-ornithine L-aspartate had no effect on mortality (RR 1.01, 95% CI 0.11 to 9.51); serious adverse events (RR 1.07, 95% CI 0.23 to 4.88); or changes in blood ammonia concentrations from baseline (RR -2.30 95% CI -6.08 to 1.48), but it had a possible beneficial effect on hepatic encephalopathy (RR 0.71, 95% CI 0.56 to 0.90). Finally, in comparison with rifaximin, L-ornithine L-aspartate had no effect on mortality (RR 0.33, 95% CI 0.04 to 3.03; 2 trials; 105 participants); hepatic encephalopathy (RR 1.06, 95% CI 0.57 to 1.96); serious adverse events (RR 0.32, 95% CI 0.01 to 7.42), or non-serious adverse events (RR 0.32, 95% CI 0.01 to 7.42).

The results of this review suggest a possible beneficial effect of L-ornithine L-aspartate on mortality, hepatic encephalopathy, and serious adverse events in comparisons with placebo or no-intervention, but, because the quality of the evidence is very low, we are very uncertain about these findings. There was very low quality evidence of a possible beneficial effect of L-ornithine L-aspartate on hepatic encephalopathy, when compared with probiotics, but no other benefits were demonstrated in comparison with other active agents. Additional access to data from completed, but unpublished trials, and new randomised placebo-controlled, double-blind clinical trials are needed.

Cerebral edema remains a significant cause of morbidity and mortality in patients with acute liver failure (ALF) and has been linked to elevated blood ammonia levels. l-ornithine phenylacetate (OPA) may decrease ammonia by promoting its renal excretion as phenylacetylglutamine (PAGN), decreasing the risk of cerebral edema. We evaluated the safety, tolerability, and pharmacokinetics of OPA in patients with ALF and acute liver injury (ALI), including those with renal failure. Forty-seven patients with ALI/ALF and ammonia ≥60 μM were enrolled. Patients received OPA in a dose escalation scheme from 3.3 g every 24 hours to 10 g every 24 hours; 15 patients received 20 g every 24 hours throughout the infusion for up to 120 hours. Plasma phenylacetate (PA) concentrations were uniformly below target (<75 μg/mL) in those receiving 3.3 g every 24 hours (median [interquartile range] 5.0 [5.0] μg/mL), and increased to target levels in all but one who received 20 g every 24 hours (150 [100] μg/mL). Plasma [PAGN] increased, and conversion of PA to PAGN became saturated, with increasing OPA dose. Urinary PAGN clearance and creatinine clearance were linearly related (r = 0.831, P < 0.0001). Mean ammonia concentrations based on the area under the curve decreased to a greater extent in patients who received 20 g of OPA every 24 hours compared with those who received the maximal dose of 3.3 or 6.7 g every 24 hours (P = 0.046 and 0.022, respectively). Of the reported serious adverse events (AEs), which included 11 deaths, none was attributable to study medication. The only nonserious AEs possibly related to study drug were headache and nausea/vomiting.

OPA was well-tolerated in patients with ALI/ALF, and no safety signals were identified. Target [PA] was achieved at infusion rates of 20 g every 24 hours, leading to ammonia excretion in urine as PAGN in proportion to renal function. Randomized, controlled studies of high-dose OPA are needed to determine its use as an ammonia-scavenging agent in patients with ALF. (Hepatology 2018;67:1003-1013).