Application of TSPO-Specific Positron Emission Tomography Radiotracer as an Early Indicator of Acute Liver Failure Induced by Propacetamol, a Prodrug of Paracetamol.

Acetaminophen overdose is a leading cause of acute liver failure (ALF), and effective treatment depends on early prediction of disease progression. ALF diagnosis currently requires blood collection 24-72 h after APAP ingestion, necessitating repeated tests and hospitalization. Here, we assessed earlier ALF diagnosis using positron emission tomography (PET) imaging of translocator proteins (TSPOs), which are involved in molecular transport, oxidative stress, apoptosis, and energy metabolism, with the radiotracer [18F]GE180. We intraperitoneally administered propacetamol hydrochloride to male C57BL/6 mice to induce ALF. We performed in vivo PET/CT imaging 3 h later using the TSPO-specific radiotracer [18F]GE180 and quantitatively analyzed the PET images by determining the averaged standardized uptake value (SUVav) in the liver parenchyma. We assessed liver TSPO expression levels via real-time polymerase chain reaction, Western blotting, and immunohistochemistry. [18F]GE180 PET imaging 3 h after propacetamol administration (1500 mg/kg) significantly increased liver SUVav compared to controls (p = 0.001). Analyses showed a 10-fold and 4-fold increase in TSPO gene and protein expression, respectively, in the liver, 3 h after propacetamol induction compared to controls. [18F]GE180 PET visualized and quantified propacetamol-induced ALF through TSPO overexpression. These findings highlight TSPO PET's potential as a non-invasive imaging biomarker for early-stage ALF.

Amyloidosis: a rare cause of severe acute liver failure.

Gastrointestinal amyloidosis can be primary, more associated with monoclonal plasma cell dyscrasia, or secondary, usually secondary to a tissue-destructive, chronic inflammatory process (such as inflammatory bowel disease, for example) and long-term dialysis. The rare presentation of severe acute liver failure in systemic amyloidosis can make this diagnosis/ management more difficult. Hepatomegaly with signs of diffuse infiltrative disease and periportal involvement associated with thoracic and other abdominal radiological findings in the appropriate clinical context may constitute a diagnostic imaging clue in this challenge.

Label-Free Imaging Techniques to Evaluate Metabolic Changes Caused by Toxic Liver Injury in PCLS.

Abuse with hepatotoxic agents is a major cause of acute liver failure. The search for new criteria indicating the acute or chronic pathological processes is still a challenging issue that requires the selection of effective tools and research models. Multiphoton microscopy with second harmonic generation (SHG) and fluorescence lifetime imaging microscopy (FLIM) are modern label-free methods of optical biomedical imaging for assessing the metabolic state of hepatocytes, therefore reflecting the functional state of the liver tissue. The aim of this work was to identify characteristic changes in the metabolic state of hepatocytes in precision-cut liver slices (PCLSs) under toxic damage by some of the most common toxins: ethanol, carbon tetrachloride (CCl4) and acetaminophen (APAP), commonly known as paracetamol. We have determined characteristic optical criteria for toxic liver damage, and these turn out to be specific for each toxic agent, reflecting the underlying pathological mechanisms of toxicity. The results obtained are consistent with standard methods of molecular and morphological analysis. Thus, our approach, based on optical biomedical imaging, is effective for intravital monitoring of the state of liver tissue in the case of toxic damage or even in cases of acute liver injury.

Novel radiological technique to recognize acute liver failure caused by yellow phosphorous containing rodenticides.

Yellow phosphorous rodenticide (YPR) poisoning is the commonest cause for acute liver failure (ALF) in southern and western India. Due to medicolegal issues, history of YPR ingestion may not be available. As early recognition of YPR poisoning is important and there are no specific biochemical assays, other early predictors to identify this entity is necessary. We evaluated the diagnostic role of plain computed tomography (CT) in identifying YPR-induced ALF. All patients admitted to the liver unit with a diagnosis of ALF underwent a plain CT scan abdomen. Demographic details, clinical history, laboratory parameters, liver attenuation index (LAI) calculated on CT scan, treatment details, need for liver transplantation and clinical outcome were analyzed. Parameters for YPR-induced ALF (ALF-YPR) and other causes (ALF-OTH) were compared. Ability of LAI to distinguish ALF-YPR and ALF-OTH was analyzed using receiver operating characteristic (ROC) curve analysis. Twenty-four patients (15 female [62.5%]) were included in the study. Thirteen patients (54%) had YPR poisoning, while the rest formed the ALF-OTH group (11,46%). ALF-YPR patients had higher transaminase levels, lower peak serum bilirubin levels. ALF-YPR livers had significantly lower LAI as compared to ALF-OTH (- 30 vs. - 8, p = 0.001). On ROC curve analysis, an LAI greater than - 18 ruled out YPR as the cause for ALF with 91% sensitivity and 85% specificity. On regression analysis, LAI was the only independent factor predicting ALF-YPR (odds ratio - 0.86, [0.76, 0.96] p = 0.008). Our data shows that LAI on plain abdominal CT scan can be used to quickly recognize ALF-YPR in unclear cases so that necessary treatment protocol can be activated, or patient transfer arranged. Our analysis shows that an LAI greater than - 18 can reliably rule out YPR ingestion as the cause for ALF.

Performance of the Liver Maximum Function Capacity Test, Fibrinogen, and Transient Elastography in Patients with Acute Liver Injury.

BACKGROUND: Acute liver failure (ALF) occurs as a rare, sudden, extensive loss of liver function in a previously healthy liver. In advanced cases, ALF may require liver transplantation (LT). Available prognostic parameters have limited accuracy to decide, which patient to consider for LT. The liver maximum function capacity test (LiMAx) can accurately determine liver function and was assessed as predictor of survival, along with coagulation parameters and liver stiffness in nonacetaminophen-induced ALF. METHODS: Various liver function tests, including LiMAx measurements, coagulation factors, and transient elastography (TE), were analyzed retrospectively for associations with clinical outcome in 34 patients with ALF or acute hepatitis (AH). Data were compared between patients with spontaneous recovery (SR) and non-SR (3-month mortality/LT; NSR). RESULTS: The analysis included 34 patients (22 ALF, 12 AH; 19 males, 15 females; age 36.7 ± 14.6 years) with drug-induced liver injury (DILI) (n = 12), autoimmune hepatitis (AIH; n = 13), AIH-DILI overlap (n = 1), viral (n = 9), or cryptogenic liver failure (n = 1). Thirty-one patients recovered spontaneously, 2 patients died, and 1 patient underwent LT. The LiMAx was 197.6 (±68.4) for SR versus 92.33 (±65.0) for NSR (p = 0.0157). Fibrinogen was significantly lower in patients with NSR than in SR patients (209.0 vs. 106.3; p = 0.02). Mean liver stiffness measured by TE was 39.3 for NSR and 17.3 for SR (p = 0.26). KCC was fulfilled in only 4 patients (3 SR, 1 NSR). LiMAx results correlated positively with serum fibrinogen and antithrombin III concentrations and correlated negatively with liver stiffness. No other analyzed factor could differentiate between SR and NSR. CONCLUSION: Decision-making in ALF remains challenging. LiMAx and fibrinogen might predict the prognosis in patients with nonacetaminophen-induced ALF and in combination could be feasible tools to decide if LT is necessary.

Transcranial Doppler Ultrasonography in Children With Acute Liver Failure and Severe Hepatic Encephalopathy.

OBJECTIVES: To report our single-center use of transcranial Doppler (TCD) for noninvasive neuromonitoring in pediatric patients with acute liver failure (ALF). DESIGN: Retrospective cohort from January 2016 to June 2019. SETTING: PICU in Bicêtre Hospital, Assistance Publique- Hôpitaux de Paris (AP-HP), a national referral center for pediatric liver transplantation. PATIENTS: Pediatric patients with severe ALF (prothrombin time < 30% and Hepatic Encephalopathy score ≥ 3), on continuous venovenous high-flow hemofiltration. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Ten children were identified, six were transplanted (1/6 died) and four were not (3/4 died). TCD was performed several times per patient and the evolution of cerebral perfusion parameters was followed. Of interest, zero of six patients who survived lost end-diastolic velocity (EDV), whereas four of four patients who died did (difference, 100%; 95% CI, 37-100%; χ 2 , 9; degrees of freedom, 1; p = 0.0027). We failed to identify an association between pulsatility index (PI) or EDV, and severity of hepatic encephalopathy. CONCLUSIONS: TCD was a noninvasive and bedside available tool to detect and screen for presence of abnormal cerebral flow in children with ALF, according to age-related reference values. TCD detected reduced EDV and elevated PI in children with ALF awaiting transplant who died compared with those who survived.

The magnetic resonance imaging assessment of optic nerve sheath diameter in pediatric acute liver failure patients.

OBJECTIVE: To evaluate the diagnostic value of optic nerve sheath diameter (ONSD) using brain MRI in the pretransplantation period in the pediatric acute liver failure patients, and correlate the ONSD with clinical grade of hepatic encephalopathy (HE) and MRI findings. PATIENTS AND METHODS: Forty acute liver failure patients and 40 control group patients were retrospectively analyzed. The high signal intensities in T2W (T2-weighted image), FLAIR (Fluid Attenuated Inversion Recovery) and DWI (diffusion-weighted imaging) sequences were evaluated and ONSD was measured. The patients were grouped first into 5 according to their West Haven score, and HE grade 0 and grade 1 were accepted as low grade HE, HE grade 2, 3 and 4 were accepted as high grade HE. The patients were grouped to 2 according to the MRI findings as low grade and high grade MRI group. RESULTS: The mean value of ONSD was 6.0 ± 1.80 and 4.94 ± 1.27 in the all patients and in the control group, respectively. There was statistically significant difference between both the ONSD and the low grade-high grade HE groups (p=0.01), and between the ONSD and the low grade-high grade MRI groups (p<0.001). CONCLUSIONS: Although high ONSD values do not make the diagnosis of cerebral edema, it may cause suspicion in the early period. MRI can be helpful in the diagnoses of increased intracranial pressure like ultrasound. Our study is the first study to compare ONSD and MRI findings in addition to HE grades. The widespread use of MRI in children in recent years may help determine the normal range of ONSD values.

A ROS-Sensitive Nanozyme-Augmented Photoacoustic Nanoprobe for Early Diagnosis and Therapy of Acute Liver Failure.

Early diagnosis of acute liver failure (ALF) is critical for curable treatment of patients, because most existing ALF therapies have narrow therapeutic time windows after disease onset. Reactive oxygen species (ROS), which lead to the sequential occurrences of hepatocyte necrosis and the leakage of alanine aminotransferase (ALT), represent early biomarkers of ALF. Photoacoustic imaging is emerging as a powerful tool for in vivo imaging of ROS. However, high-performance imaging probes that can boost the photoacoustic signals of the short-lived ROS of ALF are yet to be developed, and there remains a great challenge for ROS-based imaging of ALF. Herein, a ROS-sensitive nanozyme-augmented photoacoustic nanoprobe for successful in vivo imaging of ALF is presented. The deep-penetrating photoacoustic signals of the nanoprobe can be activated by the overexpressed ROS in ALF due to the synergy between nanocatalytic bubbles generation and thermoelastic expansion. Impressively, the nanozyme-augmented ROS imaging enables earlier diagnosis of ALF than the clinical ALT method, and the ROS-activated catalytic activity of nanoprobe permits timely nanocatalytic therapy of ALF.

Acute liver failure due to herpes simplex virus: diagnostic clues and potential role of plasmapheresis: A case report.

INTRODUCTION: Acute liver failure (ALF) is a life-threatening condition that remains challenging for physicians despite several advances in supportive care. Etiologies vary worldwide, with herpes simplex virus (HSV) hepatitis representing less than 1% of cases. Despite its low incidence, ALF is a lethal cause of acute necrotizing hepatitis and has a high mortality. Early antiviral treatment is beneficial for survival and decreased liver transplantation necessity. However, plasmapheresis, despite its theoretical potential benefit, is scarcely reported. PATIENT CONCERNS: A 25-year-old woman with no known disease presented with painful pharynx ulcers, increased transaminases and impaired liver function. DIAGNOSIS: ALF due to a disseminated HSV-2 primary infection was diagnosed with a positive polymerase chain reaction for HSV-2 in the biopsied liver tissue and blood. INTERVENTIONS: Empiric antiviral treatment was initiated. After clinical deterioration, plasmapheresis was also initiated. OUTCOMES: After 6 cycles of plasmapheresis and supportive care, the patient's condition improved without undergoing liver transplantation. CONCLUSIONS: ALF is a life-threatening condition, and HSV as an etiology must be suspected based on background, clinical manifestation, and laboratory information. The potential role of plasmapheresis in HSV hepatitis should be considered.

Site-Specific Biomimicry of Antioxidative Melanin Formation and Its Application for Acute Liver Injury Therapy and Imaging.

Biocompatible nano-antioxidants composed of natural molecules/materials, such as dopamine and melanin, are of great interest for diverse biomedical applications. However, the lack of understanding of the precise structure of these biomaterials and thus the actual dose of effective components impedes their advancement to translation. Herein, a strategy to mimic in situ melanin formation and explore its antioxidative applications is reported, by developing a PEGylated, phenylboronic-acid-protected L-DOPA precursor (PAD) that can self-assemble into well-defined nanoparticles (PADN). Exposure to oxidative species leads to deprotection of phenylboronic acids, transforming PADN to PEG-L-DOPA, which, similar to the biosynthetic pathway of melanin, can be oxidized and polymerized into an antioxidative melanin-like structure. With ultrahigh stability and superior antioxidative activity, the PADN shows remarkable efficacy in prevention and treatment of acute liver injury/failure. Moreover, the in situ structure transformation enables PADN to visualize damaged tissue noninvasively by photoacoustic imaging. Overall, a bioinspired antioxidant with precise structure and site-specific biological activity for theranostics of oxidative stress-related diseases is described.

Tc-99m GSA scintigraphy within the first 3 days after admission as an early predictor of outcome in severe acute liver injury.

Patients with severe acute liver injury (SLI) usually recover spontaneously. However, some SLI patients progress to acute liver failure with varying degrees of hepatic encephalopathy. Acute liver failure is associated with high mortality and can be substantially reduced by liver transplantation. Therefore, distinguishing SLI patients who might progress to acute liver failure and are at a risk of death is important when evaluating patients needing liver transplantation. The present study aimed to determine whether technetium-99m-diethylenetriaminepentaacetic acid galactosyl human serum albumin (Tc-99m GSA) scintigraphy can predict the prognosis of patients with SLI. This prospective observational study included 69 SLI patients. The accuracy of Tc-99m GSA for predicting death or liver transplantation for 6 months was assessed. Between the two groups of patients stratified based on the cut-off values from the receiver operating characteristic curves, 6-month transplant-free survival was compared. Sixteen (23.2%) patients died or underwent liver transplantation from admission (poor outcome). The hepatic accumulation index was calculated by dividing the radioactivity of the liver region of interest by that of the liver-plus-heart region of interest at 15 min (i.e., LHL15). The LHL15 in the 16 patients (0.686) was significantly lower than that in survivors (0.836; P < 0.0001). The optimal LHL15 cut-off for distinguishing poor outcome and survival was 0.737 with a sensitivity of 81.3%, specificity of 88.7%, and area under the curve of 0.907 (95% CI, 0.832-0.981). When patients were divided into two groups based on the LHL15 cut-off value, the 6-month transplant-free survival was significantly lower in patients with an LHL15 level ≤ 0.737. Tc-99m GSA scintigraphy may help predict the prognosis of patients with SLI.

Characterization of a complex phenotype (fever-dependent recurrent acute liver failure and osteogenesis imperfecta) due to NBAS and P4HB variants.

We report the clinical, biochemical and genetic findings from a Spanish boy of Caucasian origin who presented with fever-dependent RALF (recurrent acute liver failure) and osteogenesis imperfecta (OI). Whole-exome sequencing (WES) uncovered two compound heterozygous variants in NBAS (c.[1265 T > C];[1549C > T]:p.[(Leu422Pro)];[(Arg517Cys)]), and a heterozygous variant in P4HB (c.[194A > G];[194=]:p.[(Lys65Arg)];[(Lys65=)]) that was transmitted from the clinically unaffected mother who was mosaic carrier of the variant. Variants in NBAS protein have been associated with ILFS2 (infantile liver failure syndrome-2), SOPH syndrome (short stature, optic nerve atrophy, and Pelger-Huët anomaly syndrome), and multisystem diseases. Several patients showed clinical manifestations affecting the skeletal system, such as osteoporosis, pathologic fractures and OI. Experiments in the patient's fibroblasts demonstrated that mutated NBAS protein is overexpressed and thermally unstable, and reduces the expression of MGP, a regulator of bone homeostasis. Variant in PDI (protein encoded by P4HB) has been associated with CLCRP1 (Cole-Carpenter syndrome-1), a type of severe OI. An increase of COL1A2 protein retention was observed in the patient's fibroblasts. In order to study if the variant in P4HB was involved in the alteration in collagen trafficking, overexpression experiments of PDI were carried out. These experiments showed that overexpression of mutated PDI protein produces an increase in COL1A2 retention. In conclusion, these results corroborate that the variants in NBAS are responsible for the liver phenotype, and demonstrate that the variant in P4HB is involved in the bone phenotype, probably in synergy with NBAS variants.

Acute (fulminant) liver failure: a clinical and imaging review.

Acute liver failure (ALF) is a rare clinical entity with high morbidity and mortality frequently requiring liver transplantation for survival. Imaging, particularly with ultrasound, plays an important role, especially to distinguish patients with underlying chronic liver disease who have lower transplant priority. We discuss the clinical and imaging findings in the three subtypes of ALF using a multi-modality approach with an emphasis on ultrasound.

Luminescence Imaging of Acute Liver Injury by Biodegradable and Biocompatible Nanoprobes.

Liver injury can result in different hepatic diseases such as fatty liver, liver fibrosis, hepatitis, and liver failure, which are mainly responsible for global mortality and morbidity. Early diagnosis is critical for the treatment of liver diseases. Herein we report luminescence imaging of neutrophil-mediated acute liver injury, including alcoholic liver injury (ALI) and acute liver failure (ALF). To this purpose, a biodegradable luminescent material was developed by chemical functionalization of a cyclic oligosaccharide, which can be produced into nanoprobes (defined as LaCD NPs). Luminescence of LaCD NPs was dependent on the level of reactive oxygen species and myeloperoxidase (MPO). Correspondingly, activated neutrophils could be specifically imaged by LaCD NPs, and the luminescent signal was positively associated with the neutrophil count. In mouse models of ALI and ALF, LaCD NPs enabled precise quantification and tracking of neutrophils in livers. In both cases, changes in the luminescence intensity are consistent with time-dependent profiles of neutrophils, MPO, and other parameters relevant to the pathogenesis of liver injury. Moreover, the luminescence imaging capacity of LaCD NPs can be additionally improved by surface functionalization with a neutrophil-targeting peptide. In addition, preliminary in vitro and in vivo studies demonstrated good safety of LaCD NPs. Consequently, LaCD NPs can be further developed as an effective and biocompatible luminescent nanoprobe for in vivo dynamic detection of the development of neutrophil-mediated acute liver injury. It is also promising for diagnosis of other neutrophil-associated liver diseases.

Hydrogen peroxide-activatable polymeric prodrug of curcumin for ultrasound imaging and therapy of acute liver failure.

Curcumin is a major active phenolic component of turmeric and has gained great attention in pharmaceutics due to its potent antioxidant, anti-inflammatory and anticancer activity. Here, we developed poly(oxalate-co-curcumin) (POC) as a hydrogen peroxide (H2O2)-activatable polymeric prodrug of curcumin by incorporating curcumin in the backbone of H2O2-responsive polyoxalate. POC particles effectively scavenged H2O2 and released curcumin in a H2O2-triggered manner. POC particles exhibited excellent antioxidant and anti-inflammatory activity in activated cells. POC particles intravenously administrated into acetaminophen-intoxicated mice remarkably suppressed the level of alanine transaminase and inhibited apoptotic cell death in liver. Interestingly, POC particles could also enhance the ultrasound contrast in the intoxicated liver due to CO2 bubble generation through H2O2-triggered oxidation of peroxalate esters. Given their H2O2-responsiveness and highly potent antioxidant activity, POC particles hold great translational potential as theranostic agents for H2O2-associated diseases.

Acid-triggered echogenic nanoparticles for contrast-enhanced ultrasound imaging and therapy of acute liver failure.

There has been increasing interest in the development of pathological stimulus-activatable nanoplatforms with theranostic functions. Here, we report ketalized maltodextrin (KMD) nanoparticles which are able to deliver therapeutic and imaging functions to the acidic conditions simultaneously, as may be found in the site of inflammation. KMD was synthesized as a platform of the theranostic nanoparticles by conjugating acid-cleavable hydrophobic moieties to maltodextrin through carbonate bonds. KMD nanoparticles could undergo acid-triggered hydrolytic degradation to generate carbon dioxide (CO2) bubbles, amplifying the ultrasound signal. The potential of KMD nanoparticles as a drug carrier was evaluated using silymarin as a model drug. KMD nanoparticles displayed significantly enhanced ultrasound contrast at acidic pH and released drug payloads in acid-triggered manners. The translational potential of silymarin-loaded KMD (s-KMD) nanoparticles as ultrasound contrast agents and therapeutic agents was thoroughly evaluated using cell culture models and mouse models of acetaminophen (APAP)-induced acute liver failure. s-KMD nanoparticles exhibited significantly enhanced ultrasound contrast in the APAP-intoxicated liver and also remarkably suppressed the hepatic damages by inhibiting the expression of pro-inflammatory cytokines. These results suggest that KMD nanoparticles hold tremendous potential as theranostic agents for various inflammatory diseases.

Cerebrovascular reactivity and cerebral perfusion of rats with acute liver failure: role of L-glutamine and asymmetric dimethylarginine in L-arginine-induced response.

Cerebral blood flow (CBF) is impaired in acute liver failure (ALF), however, the complexity of the underlying mechanisms has often led to inconclusive interpretations. Regulation of CBF depends at least partially on variations in the local brain L-arginine concentration and/or its metabolic rate. In ALF, other factors, like an increased concentration of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor and elevated level of L-glutamine, may contribute to CBF alteration. This study demonstrated strong differences in the reactivity of the middle cerebral arteries and their response to extravascular L-arginine application between vessels isolated from rats with thioacetamide (TAA)-induced ALF and control animals. Our results also showed the decrease in the cerebral perfusion in TAA rats measured by arterial spin labeling perfusion magnetic resonance. Subsequently, we aimed to investigate the importance of balance between the concentration of ADMA and L-arginine in the CBF regulation. In vivo, intraperitoneal L-arginine administration in TAA rats corrected: (i) decrease in cerebral perfusion, (ii) decrease in brain extracellular L-arginine/ADMA ratio and (iii) increase in brain L-glutamine concentration. Our study implicates that impaired vascular tone of cerebral arteries is most likely associated with exposure to high ADMA and L-glutamine levels resulting in limited availability of L-arginine and might be responsible for reduced cerebral perfusion observed in ALF.

Performance-Enhancing Drugs Abuse Caused Cardiomyopathy and Acute Hepatic Injury in a Young Bodybuilder.

A number of performance-enhancing drugs (PEDs) are used illicitly to improve muscle strength by the bodybuilders. The misuse of these drugs is associated with serious adverse effects to different organs. A previously healthy 22-year-old male bodybuilder after taking stanozolol, clenbuterol, and triiodothyronine for 10 days presented to the hospital with symptoms of icteric sclera, progressive dyspnea, intermittent cough, and bloody sputum. He was diagnosed with dilated cardiomyopathy and acute hepatic injury. Rapidly progressive dilated cardiomyopathy and acute hepatic injury among bodybuilders in such a short period of time have not been reported. People using these drugs must monitor liver and cardiac functions regularly, and they should discontinue using PEDs after diagnosis of liver or cardiac abnormalities. Physicians should always consider the possibility of the PED abuse in the context of a young athlete suffering cardiomyopathy or hepatic injury.

Clinical and prognostic associations of liver volume determined by computed tomography in acute liver failure.

BACKGROUND: Liver volume (LV) can be non-invasively determined from the analysis of computed tomography (CT) images, and in patients with acute liver injury (ALI) or failure (ALF), it can reflect the balance of structural collapse with hepatic regeneration. We examined its relation to cause of liver injury, measures of liver function and histopathological findings, and utility in prediction of complications and mortality. METHODS: Two hundred and seventy-three patients with ALF/ALI admitted to a specialist intensive care unit were studied. One hundred and ninety-nine patients (73%) had non-acetaminophen (NA) aetiologies and 74 (27%) had acetaminophen-induced disease. LV and proportion of predicted LV (PLV%) were determined from admission CT imaging. RESULTS: LV and PLV% showed marked variation when aetiologic groups were compared (P < .0001), including loss in cases with indeterminate cause (LV 939 cm3 [IQR 680-1259], PLV% 56% [42-84]) and increase in Budd-Chiari syndrome (1891 cm3 [1601-2094], 121% [111-131]). Progression to high-grade encephalopathy was more common with smaller LV and PLV. A < 1000 cm3 threshold identified NA patients who later developed it with 93% (95%CI 83-98) specificity and odds ratio 10.6 (3.3-34.5) at median 5 days prior to onset, and risk of death in those with NA-drug-induced (DILI) or indeterminate disease with 91% (71-99) specificity and 63% (50-75) sensitivity. CONCLUSION: In patients with ALF/ALI, LV shows marked variation by the cause of disease, and in prognostic importance. In indeterminate and DILI cases, loss of volume to <1000 cm3 may indicate irreversible liver injury and regenerative failure and serve as an early clinical predictor for the development of high-grade encephalopathy and death.