Complication Of Acute Liver Failure Research Articles

Neurological recovery in rats with portocaval anastomosis-induced hepatic encephalopathy treated with leuprolide acetate, a GnRH agonist.

Hepatic encephalopathy (HE) is a neuropsychiatric complication of acute liver failure or chronic liver injury. Liver dysfunction impairs ammonia detoxification, allowing it to cross the blood-brain barrier (BBB) and disrupt brain function. The hippocampus becomes a crucial target during elevated ammonia levels, causing spatial memory impairment and decreased learning ability. Leuprolide acetate (LA), a GnRH agonist, has been implicated in neuroprotection and neuroregeneration in several regions of the central nervous system (CNS) including hippocampus. In this study, we aim to evaluate the effects of LA treatment on hippocampus of rats with HE induced by portocaval anastomosis (PCA) trough cognitive tests, histology analysis and expression of neuronal recovery marker proteins, such as neurofilament (NF200) and neurabin II, and astrocyte marker glial fibrillary acidic protein (GFAP). Rats were divided into three groups: SHAM, portocaval anastomosis with saline solution (PCA + SS) and portocaval anastomosis treated with LA (PCA + LA). To evaluate learning and spatial memory elevated T-maze (ETM) and Y-maze test (YMT) were respectively used. Results indicated that LA-treated rats performed significantly better in ETM and YMT than untreated rats. Histological analysis of hippocampus showed increased neuron density, nuclear area, and layer thickness in dentate gyrus of PCA + LA group compared to PCA + SS. Additionally, neurabin II and NF200 expression were higher in LA-treated rats, while GFAP expression was elevated in the PCA + SS group compared to control and PCA + LA groups. In conclusion, LA enhances hippocampal neuron recovery and reduces astrogliosis, suggesting its potential as a therapeutic intervention for attenuating hippocampal damage during HE.

Nutritional management for acute liver failure.

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.

Low liver reserve is a risk factor for acute pancreatitis in patients with acute liver failure.

Acute pancreatitis is a complication of acute liver failure (ALF). This study aimed to investigate the prevalence of and clinical features associated with acute pancreatitis in patients with ALF. We retrospectively analyzed a cohort of ALF patients without hepatic encephalopathy diagnosed during a period 2011-2018, and compared clinical features between patients with acute pancreatitis and those without. Acute pancreatitis was diagnosed according to the Acute Pancreatitis Clinical Practice Guidelines 2021. A multivariate analysis was carried out to identify factors associated with acute pancreatitis. There were 83 ALF patients without hepatic encephalopathy (34 men; 11 deaths; 6 liver transplants; median age, 63years). Acute pancreatitis occurred in nine patients (10.8%). The median time duration from ALF to the onset of acute pancreatitis was 8days. The survival rate was lower in patients with than those without acute pancreatitis (22% vs. 86%). The model for end-stage liver disease score (hazard ratio 1.10, 95% confidence interval 1.03-1.18) was found to be a significant factor associated with acute pancreatitis, whereas triglyceride, age, and sex were not. A high model for end-stage liver disease score may be a marker to stratify patients with ALF at a risk of acute pancreatitis.

Acute kidney injury in acute liver failure: A narrative review.

Acute kidney injury (AKI) is a frequent complication of acute liver failure (ALF) and it worsens the already worse prognoses of ALF. ALF is an uncommon disease, with varying etiologies and varying definitions in different parts of the world. There is limited literature on the impact of AKI on the outcome of ALF with or without transplantation. The multifaceted etiology of AKI in ALF encompasses factors such as hemodynamic instability, systemic inflammation, sepsis and direct nephrotoxicity. Indications of renal replacement therapy (RRT) for AKI in ALF patients extend beyond the conventional criteria for dialysis and continuous renal replacement therapy (CRRT) may have a role in transplant-free survival or bridge to liver transplantation (LT). LT is a life-saving option for ALF, so despite somewhat lower survival rates of LT in ALF patients with AKI, LT is not usually deferred. In this review, we will discuss the guidelines' recommended definition and classification of AKI in ALF, the impact of AKI in ALF, the pathophysiology of AKI and the role of CRRT and LT in ALF patients with AKI.

Association between proton pump inhibitors and risk of hepatic encephalopathy in patients undergoing transjugular intrahepatic portosystemic shunt: a protocol for a systematic review and meta-analysis

IntroductionHepatic encephalopathy (HE) is a major complication of acute liver failure, cirrhosis and transjugular intrahepatic portosystemic shunt (TIPS) placement. Its clinical manifestations range from mild cognitive deficits to coma. Furthermore,...

A study of mortality frequency and clinical course of postoperative renal and abdominal visceral complications following open aortic surgery for abdominal aortic aneurysm requiring supra renal aortic cross-clamp

ABSTRACT Background: Endovascular interventions for abdominal aortic aneurysms (AAAs) are fast evolving; however, due to higher rates of reintervention and no survival benefits after 2 years, open surgical procedures are pivotal. Here, we present mortality and morbidity analysis of open surgical procedures requiring suprarenal cross clamping for AAA repair. Materials and Methods: The present study is a retrospective hospital record-based study selecting 34 cases that required suprarenal cross-clamping out of 200 abdominal aortic aneurysm surgeries. Out of the total 34 patients, 22 (64.7%) were males and 12 (35.3%) were females. The mean age of all participants was 58.05 years (with an 8.1 standard deviation). Out of 34 cases, 20 cases (58.8%) were classified as suprarenal and pararenal aneurysms and 14 cases were juxtarenal aneurysms (41.2%). Out of the 14 juxtrarenal aneurysm cases, 7 (50%) were atherosclerotic and 2 (14.3%) were Marfan’s Syndrome, while inflammatory were 2 (14.3%) and infected were 2 (14.3%) and 1 was a case of Takayasu’s arteritis (7.1%). Mortality and morbidity, including renal function decline, need for hemodialysis, acute pancreatitis, and hepatic and gastrointestinal (GI) complications, were recorded as early (up to 30 days) and late (up to 1 year). The results were recorded separately for suprarenal, pararenal, and juxtarenal aneurysm types and presented in that way, which is the highlight of our study. Results: Early mortality occurred in 3/34 (8.8%) cases, where late mortality happened in 2/34 (5.9%) cases, which are exclusive of early mortality cases. Considering the early mortality and complications, 2 out of 4 cases (50.0%) of the suprarenal group died early, renal dysfunction happened in 4/34 cases (11.8%), of which 3 (8.8%) required dialysis. No cases of pancreatitis, while acute liver failure complicated 3 out of 34 (8.8%) cases. GI bleed and mesentric ischemia each complicated 2 out of 34 cases (5.9%). Prolonged ileus was noticed as the most common GI complication complication. Early mortality was highest in the suprarenal group with renal dysfunction. Considering late mortality and complications, 1 out of 16 cases (6.3%) of the pararenal group died late, and 1 out of 14 cases (7.1%) of the juxta renal cases died late. There was no late mortality in the suprarenal group. Renal dysfunction happened in 2/34 cases (5.9%), of which none required dialysis. Complete data have been presented as per the aneurysm type. Conclusions: Patients requiring suprarenal aortic cross-clamping for open surgical repair of abdominal aorta aneurysm are usually high-risk surgical candidates, considering both early and late mortality and morbidity. Early mortality was maximum in the suprarenal group (50.0%), as were postoperative renal dysfunction and hemodialysis requirements. Visceral complications (acute liver failure and GI complications) were also maximum with the suprarenal group. Late mortality was recorded in the pararenal and juxtarenal groups, with renal dysfunction being recorded in the suprarenal and juxtarenal groups. Visceral complications were recorded in both pararenal and juxtarenal groups. One confounding factor could be the high early mortality in the suprarenal group, resulting in less number of survivors for late postoperative recording. Overall, we conclude that suprarenal aortic aneurysms carry the highest burden of early mortality with renal and visceral complications postoperative.

Acute kidney injury is an unfavorable prognostic factor in acute liver failure and is associated with tumor necrosis factor-alpha.

Acute kidney injury (AKI) is a common complication of acute liver failure (ALF); but its pathogenesis is unknown. ALF was divided into 2 subgroups; ALF with hepatic coma, which corresponds to ALF in the US and Europe, and ALF without hepatic coma. AKI has been shown to worsen the prognosis of ALF patients with hepatic coma; however, its prognostic significance in ALF without hepatic coma remains unknown. A single-center retrospective study of 174 patients with ALF was performed. AKI was defined according to KDIGO criteria. AKI developed in 29 (66.0%) of 44 ALF patients with hepatic coma and 27 (38.5%) of 130 ALF patients without hepatic coma. Systemic inflammatory response syndrome (SIRS) was found to be significantly associated with AKI incidence in ALF patients (P < .001). Tumor necrosis factor-alpha (TNF-α) was found to be significantly associated with the presence and severity of AKI (P = .0039 and P = .0140, respectively). On multivariate analysis, TNF-α was an independent risk factor linked with AKI (P = .0103). Even in the absence of hepatic coma, the transplant-free survival rate of ALF was significantly associated with the presence and severity of AKI. Even when hepatic coma is absent, AKI complicated in ALF is strongly associated with TNF-α and worsens the transplant-free survival rate. Before the onset of hepatic coma, plasma exchange, or extracorporeal blood purification to remove inflammatory cytokines should be considered in ALF patients.

Association of giant cell hepatitis and autoimmune hemolytic anemia in infancy

Giant cell hepatitis associated with autoimmune hemolytic anemia (GCH-AIHA) is a rare disorder with unfavorable prognosis, affecting infants and young children. The mortality rate is high, complications of acute liver failure, sepsis, or liver transplantation can be responsible for fatal outcomes. An 18-month-old child who was diagnosed previously with autoimmune hemolytic anemia, developed acute hepatitis and acute liver failure concomitant to the relapse of the disease. GCH-AIHA is characterized by Coombs positive hemolytic anemia and progressive liver injury, histologically defined by widespread giant cell transformation. Liver biopsy was performed to establish the diagnosis, histological examination confirmed the presence of multinuclear, giant cell hepatocytes. Corticosteroid and azathioprine treatment were started. As a result of subsequent rituximab treatment and intravenous immunoglobulin therapy, acute liver failure and anemia gradually resolved. The exact background of the association of the two entities is still unknown, an autoimmune mechanism is suspected. Conventional immunosuppressive treatment with corticosteroid and azathioprine seems to be ineffective in most cases, therefore second- and third-line therapies are required. Since the introduction of the anti-CD20 rituximab therapy, the prognosis of GCH-AIHA has improved significantly. Orv Hetil. 2023; 164(36): 1432-1436.

Variations of dengue shock syndrome cases and their management: report of three cases

Background: Dengue hemorrhagic fever (DHF) occurs due to plasma leakage due to increased vascular permeability, which is also supported by an active complement system, which makes DHF fall into complications such as shock or dengue shock syndrome (DSS). The comprehensive management of DSS could prevent morbidity and mortality in patients. We aimed to report three variations of dengue shock syndrome cases and their management. Case presentation: Three cases of DSS from our hospital. Two case reports with clinical dengue fever patients with shock and one case report with clinical dengue patients with shock and complications of acute liver failure. The first case was a 24 years olds male patient with classic signs of dengue fever plus spontaneous bleeding in the form of nosebleeds accompanied by hemodynamic disturbances. Laboratory examination revealed severe thrombocytopenia. In the second case, a male patient with dengue shock syndrome accompanied acute liver failure. The patient complains of heartburn and nausea accompanied by tea-like urine. Dengue patients with abdominal pain typical of liver disorders, nausea, vomiting and anorexia, and hepatomegaly with or without jaundice are typical of liver disorders. The third case, a male patient with dengue shock syndrome, accompanied the suspicion of ascites. The main treatment is the administration of isotonic crystalloid fluids according to body weight. While in cases of acute liver failure, NAC can be given. Conclusion: We found three cases of DSS with some complications. It is important to know the right treatment immediately so that complications do not occur.

Assessing the effect of N-acetylcysteine in the survival of subjects having acute liver failure

Background: Acute liver failure (ALF) is a rare syndrome, characterized by acute derangement of liver function and carries a high mortality. Indeterminate ALF still forms a significant number of cases in India as well as in the world. A prospective case-control study was carried to determine the effect of N-Acetylcysteine (NAC) on the survival of indeterminate ALF patients. Methods: A total of 30 patients with a diagnosis of indeterminate ALF were included in the study. 14 patients received NAC infusion for 72hrs whereas 16 patients in the control group received placebo. The parameters evaluated were demographic, clinical, biochemical, outcome, and length of hospital stay.Results: The two groups were comparable for the various baseline characteristics (demographic, clinical, biochemical, etc.). A total of 18 of 30 (60%) patients died with ALF complications; 6 (42.8%) patients belonged to NAC group and 12 (75%) patients to Control group (P = 0.077). The overall survival was not improved by NAC in indeterminate ALF. The use of NAC also did not reduce the duration of hospital stay of surviving patients (P = 0.409). Conclusion: The overall survival was not improved by NAC in indeterminate ALF. NAC administration did not reduce the dura­tion of hospital stay.

Clinical characteristics of acute liver failure associated with hepatitis A infection in children in Mogadishu, Somalia: a hospital-based retrospective study

BackgroundHepatitis A is one of the most common infectious causes of acute hepatitis, and currently, a neglected global public health problem necessitating an urgent response in Somalia. Hepatitis A infection and its rare complication of acute liver failure in children are largely based on very limited data. The aim of the study was therefore to investigate the Hepatitis A infection and its rare complication of acute liver failure in children in Somalia.MethodsThis retrospective study was conducted on children aged 0–18 years who were admitted to the pediatric departments of the Somalia Mogadishu-Turkey Training and Research Hospital, Somali, from June 2019 and December 2019. Patients who were tested for hepatitis A infection during the study period and had complete data were included. Children with chronic disease, primary or secondary immunodeficiency, blood transfusion history, and missing data were excluded. ed data including patients' demographics, clinical presentation, laboratory results, ultrasonographic findings, length of hospital stay, clinical course and outcome were retrieved from the hospital database system.ResultsOf the 13,047 children, 219 were analyzed. Of the 219 Hepatitis A cases, 25 (11%) were diagnosed with pediatric acute liver failure (PALF). The mean age of children with Hepatitis A was 6.7 years. The majority of cases were reported in the 5–9 (39.7%) year age range. Hepatic encephalopathy, length of hospital stay, levels of albumin, and values of PT, aPPT, and INR were significantly higher in children with acute live failure. The presence of cholecystitis and cholecystitis with ascites in the sonographic evaluation were poor prognostic markers for acute liver failure.ConclusionsThis study revealed hepatitis A virus infection and its related acute liver failure among hospitalized children in Somalia of which 11% had PALF. Hence, the introduction of Hepatitis A vaccination, which is the main public health tool, into the national immunization program, the improvement of hygiene conditions, raising awareness of the disease, and increasing health literacy are necessary to prevent the consequence of the Hepatitis A virus in children.

Hypophosphatemia in acute liver failure of a broad range of etiologies is associated with phosphaturia without kidney damage or phosphatonin elevation

Hypophosphatemia is a common and dangerous complication of acute liver failure (ALF) of various etiologies. While various mechanisms for ALF-associated hypophosphatemia have been proposed including high phosphate uptake into regenerating hepatocytes, acetaminophen (APAP)-associated hypophosphatemia was linked to renal phosphate wasting, and APAP-induced renal tubular injury was proposed as underlying mechanism. We studied 30 normophosphatemic and 46 hypophosphatemic (serum phosphate < 2.5 mg/dL) patients from the Acute Liver Failure Study Group registry with APAP- or non-APAP-induced ALF. Since kidney injury affects phosphate excretion, patients with elevated serum creatinine (>1.2 mg/dL) were excluded. Maximal amount of renal tubular phosphate reabsorption per filtered volume (TmP/GFR) was calculated from simultaneous serum and urine phosphate and creatinine levels to assess renal phosphate handling. Instead of enhanced renal phosphate reabsorption as would be expected during hypophosphatemia of non-renal causes, serum phosphate was positively correlated with TmP/GFR in both APAP- and non-APAP-induced ALF patients (R2=0.66 and 0.46, respectively; both P < 0.0001), indicating renal phosphate wasting. Surprisingly, there was no evidence of kidney damage based on urinary markers including neutrophil gelatinase-associated lipocalin and cystatin C even in the APAP group. Additionally, there was no evidence that the known serum phosphatonins parathyroid hormone, fibroblast growth factor 23, and α-Klotho contribute to the observed hypophosphatemia. We conclude that the observed hypophosphatemia with renal phosphate wasting in both APAP- and non-APAP-mediated ALF is likely the result of renal tubular phosphate leak from yet-to-be identified factor(s) with no evidence for proximal tubular damage or contribution of known phosphatonins.

Effects of caffeine on brain antioxidant status and mitochondrial respiration in acetaminophen-intoxicated mice.

Hepatic encephalopathy is a pathophysiological complication of acute liver failure, which may be triggered by hepatotoxic drugs such as acetaminophen (APAP). Although APAP is safe in therapeutic concentration, APAP overdose may induce neurotoxicity, which is mainly associated with oxidative stress. Caffeine is a compound widely found in numerous natural beverages. However, the neuroprotective effect of caffeine remains unclear during APAP intoxication. The present study aimed to investigate the possible modulatory effects of caffeine on brain after APAP intoxication. Mice received intraperitoneal injections of APAP (250mg/kg) and/or caffeine (20mg/kg) and, 4h after APAP administration, samples of brain and blood were collected for the biochemical analysis. APAP enhanced the transaminase activity levels in plasma, increased oxidative stress biomarkers (lipid peroxidation and reactive oxygen species), promoted an imbalance in endogenous antioxidant system in brain homogenate and increased the mortality. In contrast, APAP did not induce dysfunction of the mitochondrial bioenergetics. Co-treatment with caffeine modulated the biomarkers of oxidative stress as well as antioxidant system in brain. Besides, survival assays demonstrated that caffeine protective effects could be dose- and time-dependent. In addition, caffeine promoted an increase of mitochondrial bioenergetics response in brain by the enhancement of the oxidative phosphorylation, which could promote a better energy supply necessary for brain recovery. In conclusion, caffeine prevented APAP-induced biochemical alterations in brain and reduced lethality in APAP-intoxicated mice, these effects may relate to the preservation of the cellular antioxidant status, and these therapeutic properties could be useful in the treatment of hepatic encephalopathy induced by APAP intoxication.

Extracorporeal renal and liver support in pediatric acute liver failure.

The liver is the only organ which can regenerate and, thus, potentially negate the need for transplantation in acute liver failure (ALF). Cerebral edema and sepsis are leading causes of mortality in ALF. Both water-soluble and protein-bound toxins have been implicated in pathogenesis of various ALF complications. Ammonia is a surrogate marker of water-soluble toxin accumulation in ALF and high levels are associated with higher grades of hepatic encephalopathy, raised intracranial pressure, and mortality. Therefore, extracorporeal therapies aim to lower ammonia and maintain fluid balance and cytokine homeostasis. The most common and easily available modality is continuous kidney replacement therapy (CKRT). Early initiation of high-volume CKRT utilizing an anticoagulation regimen minimizing treatment downtime and delivering the prescribed dose is highly desirable. Ideally, extracorporeal liver-assist devices (ECLAD) should perform both synthetic and detoxification functions of the liver. ECLAD may temporarily replace lost liver function and serve as a bridge, either to spontaneous recovery or liver transplantation. Various bioartificial and biologic liver-assist devices are described in specialty literature, including molecular adsorbent recirculating system (MARS), single pass albumin dialysis (SPAD), and total plasma exchange (TPE); however, clinicians commonly use modalities easily available in intensive care units. There is a lack of standardization of indications for ECLAD, availability of different extracorporeal devices with varied technical approaches, and, of note, the differences in doses of ECLAD provided in clinical practice. We review the practicalities and evidence regarding these four artificial liver support devices in pediatric ALF.

TNF‐α/HMGB1 inflammation signalling pathway regulates pyroptosis during liver failure and acute kidney injury

ObjectiveAcute kidney injury (AKI) is a common complication of acute liver failure (ALF). Pyroptosis is a necrosis type related to inflammation. This study aimed to investigate the role of TNF‐α/HMGB1 pathway in pyroptosis during ALF and AKI.MethodsAn ALF and AKI mouse model was generated using LPS/D‐Gal, and a TNF‐α inhibitor, CC‐5013, was used to treat the mice. THP‐1 cells were induced to differentiate into M1 macrophages, then challenged with either CC‐5013 or an HMGB1 inhibitor, glycyrrhizin. pLVX‐mCMVZsGreen‐PGK‐Puros plasmids containing TNF‐α wild‐type (WT), mutation A94T of TNF‐α and mutation P84L of TNF‐α were transfected into M1 macrophages.ResultsTreatment with CC‐5013 decreased the activation of TNF‐α/HMGB1 pathway and pyroptosis in the treated mice and cells compared with the control mice and cells. CC‐5013 also ameliorated liver and kidney pathological changes and improved liver and renal functions in treated mice, and the number of M1 macrophages in the liver and kidney tissues also decreased. The activation of TNF‐α/HMGB1 pathway and pyroptosis increased in the M1 macrophage group compared with the normal group. Similarly, the activation of TNF‐α/HMGB1 pathway and pyroptosis in the LPS + WT group also increased. By contrast, the activation of the TNF‐α/HMGB1 pathway and pyroptosis decreased in the LPS + A94T and LPS + P84L groups. Moreover, glycyrrhizin inhibited pyroptosis.ConclusionThe TNF‐α/HMGB1 inflammation signalling pathway plays an important role in pyroptosis during ALF and AKI.

Continuous renal replacement therapy and its impact on hyperammonaemia in acute liver failure

Objective: Hyperammonaemia contributes to complications in acute liver failure (ALF) and may be treated with continuous renal replacement therapy (CRRT), but current practice is poorly understood.Design: We retrospectively analysed data for baseline characteristics, ammonia concentration, CRRT use, and outcomes in a cohort of Australian and New Zealand patients with ALF.Setting: All liver transplant ICUs across Australia and New Zealand.Participants: Sixty-two patients with ALF.Main outcome measures: Impact of CRRT on hyperammonaemia and patient outcomes.Results: We studied 62 patients with ALF. The median initial (first 24 h) peak ammonia was 132 μmol/L (interquartile range [IQR], 91–172), median creatinine was 165 μmol/L (IQR, 92–263) and median urea was 6.9 mmol/L (IQR, 3.1–12.0). Most patients (43/62, 69%) received CRRT within a median of 6 hours (IQR, 2–12) of ICU admission. At CRRT commencement, three-quarters of such patients did not have Stage 3 acute kidney injury (AKI): ten patients (23%) had no KDIGO creatinine criteria for AKI, 12 (28%) only had Stage 1, and ten patients (23%) had Stage 2 AKI. Compared with non-CRRT patients, those treated with CRRT had higher ammonia concentrations (median, 141 μmol/L [IQR, 102–198] v 91 μmol/L [IQR, 54–115]; P = 0.02), but a nadir Day 1 pH of only 7.25 (standard deviation, 0.16). Prevention of extreme hyperammonaemia (> 140 μmol/L) after Day 1 was achieved in 36 of CRRT-treated patients (84%) and was associated with transplant-free survival (55% v 13%; P = 0.05).Conclusion: In Australian and New Zealand patients with ALF, CRRT is typically started early, before Stage 3 AKI or severe acidaemia, and in the presence hyperammonaemia. In these more severely ill patients, CRRT use was associated with prevention of extreme hyperammonaemia, which in turn, was associated with increased transplant-free survival.

3186 Fatal Case of Acetaminophen Toxicity in a Young Female Patient

INTRODUCTION: Acetaminophen is the most common cause of acute liver failure (ALF) in the United States. We report a fatal case of acetaminophen overdose after both delayed presentation for treatment and transplant evaluation in a non-liver transplant academic center. CASE DESCRIPTION/METHODS: An 18-year-old woman presented to the emergency department (ED) after attempting suicide by overdosing on acetaminophen. She ingested 48 of the 500 mg tablets (24-gram total dose) 18 hours prior to arrival to the ED. Her only symptom was back pain. Her medical history was significant for depression and three prior suicide attempts by acetaminophen overdose. Her mental status declined over the next few hours to the point of becoming non-verbal and mildly drowsy. On physical exam, patient was tachycardic and had self-inflicted scars to her forearms. Initial labs were significant for white blood cell count of 22,300 cells/mm3, bicarbonate of &lt;5 mmol/L (21-31), glucose 59 mg/dL (70-110), alkaline phosphatase 91 units/L (42-121), aspartate aminotransferase 479 units/L (5-34), alanine aminotransferase acetaminophen 228 mcg/mL (&lt;30), PT 27 seconds (9.4-12.5 sec), INR 2.5, and ammonia 147 mcmol/L (18-72). Venous blood gas revealed pH 6.819, pCO2 29 mmHg (39-51), pO2 51 mmHg (30-50), calculated bicarbonate of 4 mmol/L, and lactate of 14 mmol/L (0.5-2.20). Table 1 highlights changes in laboratory values during admission. The patient was admitted to the ICU, started on N-acetylcysteine (NAC) and bicarbonate infusions, and had urgent renal and general gastroenterology consultations. 48 hours after admission the patient was intubated due to deteriorating mental status and seizure activity. It was suspected that she was having cerebral edema and was emergently transferred to a liver transplant center. Ultimately, she did not undergo transplant and died from complications of ALF. DISCUSSION: Acetaminophen overdose carries a high risk of ALF and mortality. Survival depends on early treatment as high doses can overwhelm liver metabolism resulting in hepatotoxicity by N-acetyl-p-benzoquinoneimine (NAPQI). Treatment from time of ingestion was delayed in this case due to the patient's delay in seeking care. Transfer to transplant center was delayed due to lack of insurance, history of multiple attempts that affected her liver transplant candidacy, and under-appreciating risk of developing ALF. This case highlights the fatal complications of acetaminophen overdose, and underscores the importance of emergent transfer to transplant center.

P: 79 Central Inhibition of IGFBP3 Attenuates Symptoms of Hepatic Encephalopathy in a Mouse Model of Acute Liver Failure

BACKGROUND: Insulin-like growth factor binding protein 3 (IGFBP3) has a strong binding affinity for IGF proteins and can inhibit the function of IGF by preventing interaction with its receptor. In addition, IGFBP3 can exert IGF-independent effects via direct interaction with a putative IGFBP3 receptor. Little is known about the function of IGFBP3 in the brain, outside of a role in brain cancer development. We have recently demonstrated that IGF1 expression is suppressed in the frontal cortex in a number of rodent models of hepatic encephalopathy (HE) and central administration of recombinant IGF1 attenuates the neurological complications. However, the role of IGFBP3 in the pathogenesis of HE is unknown and is the aim of this study. METHODS: C57Bl/6 mice were injected with azoxymethane (AOM) to induce acute liver failure and HE. In parallel, mice were given an intracerebroventricular infusion of the IGFBP inhibitor, NBI31772 for 3 days prior to AOM injection. Cognitive impairment was monitored by reflex response assessment at various time points and neuromuscular deficits were assessed using a grip strength meter. Liver damage was determined by H&amp;E staining and serum chemistry. The expression of IGFBP3 and IGF1 was assessed in the cortex by qPCR, EIA and immunofluorescence using NeuN (neuronal), GFAP (astrocytic) or Iba1 (microglial) antibodies as a counterstain. Microglia activation was evaluated by assessment of field Iba1 staining and microglia cell morphology. Neuroinflammation was also measured by the expression of key proinflammatory cytokines. RESULTS: IGFBP3 was predominantly expressed in neurons of the cortex and increased once significant neurological deficits were observed after AOM injection. Pretreatment of mice with the IGFBP inhibitor had no effect on the underlying liver damage, but delayed the onset of neurological symptoms, attenuated the neuromuscular deficits, inhibited neuroinflammation and increased the bioavailability of the neuroprotective IGF1 after AOM injection, suggesting that IGFBP3 may be contributing to the pathogenesis of HE. CONCLUSIONS: Elevated cortical IGFBP3 expression contributes to the pathogenesis of HE in AOM-treated mice via a mechanism that may involve increasing IGF1 bioavailability, although IGF1-independent effects can not be ruled out. Targeting IGFBP3 in the cortex may prove promising for the development of adjunct therapies to manage the neurological complications of acute liver failure.

P: 5 Let7f Expression Is Upregulated in the Frontal Cortex During Acute Liver Failure and Contributes to Hepatic Encephalopathy via Downregulation of IGF1 Expression

BACKGROUND: Hepatic encephalopathy (HE) is a neurological complication that arises due to loss of liver function and is associated with increased blood-brain barrier (BBB) permeability, neuroinflammation and subsequent onset of cognitive decline. We have previously shown that increased circulating TGFβ levels induce BBB permeability and contribute to the development of HE. Associated with the aberrant TGFβ signaling during HE was an upregulation of the microRNA Let7f, a known modulator of IGF1 expression in the brain. However, whether Let7f contributes to the development of HE is unknown. The aims of this study were to assess the expression of Let7f in a mouse model of Type A HE and to determine its involvement in the neurological complications of acute liver failure (ALF). METHODS: C57Bl/6 mice were injected with azoxymethane (AOM) to induce ALF and HE. In parallel, mice were given an intracerebroventricular infusion of a Let7f antagomir or recombinant IGF1 (rIGF1) for 3 days prior to AOM injection. Cognitive impairment was monitored by reflex response assessment at various time points. Neuromuscular deficits were assessed using a grip strength meter, and a digigait analysis system was utilized to measure ataxia. Liver damage was assessed by hematoxylin and eosin staining and serum chemistry. IGF1, Let7f and proinflammatory cytokine expression were assessed by immunoblotting, immunohistochemistry and/or qPCR. Microglia were stained by IBA1 and cortex field staining and cell morphology were assessed. In vitro, mouse neurons were transfected with a Let7f mimic and treated with vehicle or rIGF1 for 4 to 24 hr. The expression and secretion of IGF1 and the proinflammatory chemokine, CCL2 was assessed by qPCR and EIA. RESULTS: Mice injected with AOM had increased Let7f and decreased IGF1 expression in the frontal cortex. Treatment with a Let7f antagomir attenuated the i) suppression of cortical IGF1, ii) neuroinflammation, and iii) neurological and neuromuscular deficits of AOM-treated mice. Specific targeting of IGF1 expression by Let7f was demonstrated in vitro, where treatment of neurons with a Let7f mimic suppressed IGF1 expression and secretion. Furthermore, treatment of neurons with Let7f mimic increased the expression of CCL2, which could be attenuated with the co-treatment with rIGF1. Lastly, infusion of rIGF1 to restore the dampened IGF1 signaling attenuated the neurological and neuromuscular deficits, as well as the neuroinflammation observed in AOM-treated mice. CONCLUSIONS: Elevated cortical Let7f expression contributes to the pathogenesis of HE in AOM-treated mice via mechanisms involving the suppression of IGF1 expression. These deleterious effects of Let7f during HE can be reversed by inhibiting Let7f expression or by increasing IGF1 concentration in the brain.

N-acetylcysteine treatment in viral-induced acute liver failure

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Acute liver failure (ALF) is characterized by acute derangement of liver function and carries high mortality. Viral hepatitis is still one of the main causes of ALF in the India as well in world. A prospective case control study was carried with the aim to determine the effect of N-acetylcysteine (NAC) on survival of viral-ALF patients.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; 37 patients with a diagnosis of viral-ALF were included in the study. 18 patients received NAC infusion for 72 hrs whereas 19 patients in control group received placebo. The variables evaluated were demographic, biochemical, outcome and length of hospital stay.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; Out of 37 viral-ALF patients, acute HEV-induced ALF (48.6%) was most common followed by HBV (24.3%) and HAV (21.6%). The two groups were comparable for the various baseline characteristics (age, INR, bilirubin, ALT, creatinine, albumin, grade of encephalopathy, mean grade of coma etc.). Use of NAC was associated with a shorter length of hospital stay of survived patients (p=0.024). A total of 20 of 37 (54.1%) patients died with ALF complications; 7 (38.9%) patients belonged to NAC group and 13 (68.4%) patients to control group (p=0.079). HEV induced ALF showed significant improved in survival than Non HEV induced ALF with NAC administration (p=0.022).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;HEV was the most frequently cause of viral-ALF. Overall survival was not improved by NAC. HEV induced ALF showed significant improved in survival than Non HEV induced ALF with NAC administration. NAC reduced duration of hospital stay.&lt;/p&gt;