Acute Hepatic Encephalopathy Research Articles

2495 Spontaneous Fungal Peritonitis Secondary to Candida glabrata in a Patient With Cardiac Cirrhosis

INTRODUCTION: Spontaneous fungal peritonitis (SFP) is an uncommon, but serious complication of liver cirrhosis. In one study, the one-month mortality rate was 73.3% as compared to 28% in SBP alone. The mortality remains high despite appropriate antifungal therapy partly due to delayed diagnosis. CASE DESCRIPTION/METHODS: We present a case of a 67 years-old male patient who presented with acute confusion and worsening abdominal distension for unknown duration. He has history of heart failure with reduced ejection fraction secondary to ischemic cardiomyopathy and liver cirrhosis presumed secondary to heart failure. He was found to have acute hepatic encephalopathy, anasarca, acute kidney injury, and septic shock. Abdominal exam showed tender, distended abdomen with positive fluid thrill. Spontaneous bacterial peritonitis (SBP) was suspected and ascitic fluid analysis was sent. It reported nucleated cells 3766/uL, 80% neutrophils, SAAG 1.7, glucose <20 mg/dl, and total protein 3.2 g/dl. Computed tomography of abdomen and pelvis without contrast showed massive ascites, but there was no evidence of bowel perforation (Figure 1). He was treated with Vancomycin and Zosyn for SBP and lactulose for hepatic encephalopathy. On day 3, gram stain of ascitic fluid reported budding yeast, and he was started on anidulafungin. The final culture reported Candida glabrata. Bacterial and fungal blood cultures were negative. Despite treatment, his encephalopathy persisted, and he had rapid accumulating ascitic fluid. Ascitic fluid culture was repeated which reported the same. A repeat CT abdomen showed perihepatic hematoma and free intraperitoneal air (Figure 2). He underwent exploratory laparotomy that revealed duodenal perforation. Despite surgical repair and antifungal, septic shock progressed, and patient died from multi-organ failure. Candida glabrata was sensitive to anidulafungin on retrospective review of sensitivity report. DISCUSSION: Although initial ascitic fluid analysis suggested secondary peritonitis, CT scan was negative for perforation or loculated infection. Our case highlights the high mortality rate of Candida peritonitis despite appropriate treatment. It is likely secondary to delayed antifungal and undiagnosed bowel perforations.

2494 Rare Case of Concomitant Acute Hepatic Failure and Renal Failure Induced by Intravenous Amiodarone

INTRODUCTION: Hepatotoxicity caused by chronic oral amiodarone is well documented with around 15–20%. However, acute liver failure due to intravenous Amiodarone is rare clinical presentation with 3% incidence rate. Incidence of concomitant renal failure is even more rare. There is no full explanation for the underlying mechanism. CASE DESCRIPTION/METHODS: 67-year-old male with PMH of CAD s/p coronary artery bypass graft, CKD, presented with chest pain for one week. In the ED, he was found to have atrial flutter. Due to unresponsiveness to IV beta blocker and Diltiazem, patient was loaded with IV Amiodarone and continued IV Amiodarone drip. 16 hours later patient developed acute hepatic failure with AST 4250 (10-42 IU/L), ALT 2422 (10-60 IU/L), INR 2.28 (2-3 conventional anticoagulation), acute renal failure with creatinine of 3.2 mg/dl (0.44-1.0 mg/dl), BUN of 44 mg/d (5-25 mg/dl). Patient was intubated due to acute hepatic encephalopathy. IV Amiodarone was stopped immediately. All workup for other causes of acute hepatic failure came back negative. He was started on intravenous N-Acetyl cysteine and required hemodialysis for acute renal failure. LFTs peaked 72 hours after discontinuation of Amiodarone. Kidney functions improved 5 days after discontinuation of amiodarone and hemodialysis stopped. DISCUSSION: Acute hepatic failure due to intravenous amiodarone is extremely rare with incidence of 3%. The underlying mechanism is still not fully understood. However, a case–control retrospective study argues that hepatotoxicity due to intravenous amiodarone cannot be differentiated from ischemic hepatitis from concomitant hypotension. Intravenous amiodarone is formulated with polysorbate 80 as a solubilizer, which has been shown to induce hypotension. In this case, patient had a stable blood pressure when amiodarone was started. Intravenous (IV) amiodarone toxicity can raise AST/ALT up to 100–200-fold (AST of 21000 and ALT of 9020 in our case) within a day of infusion which then reverses quickly after discontinuation of amiodarone. In this case, liver function tests increased after 26 hours of starting intravenous amiodarone and peaked after 72 hours of stopping the infusion. All cases of acute liver failure due amiodarone didn't survive except for one case. The most common cause of death is encephalopathy. Administration of N-Acetylcysteine was administered is associated with good outcome. Incidence of concomitant renal failure is extremely rare. It is caused by concomitant acute tubular necrosis.

A novel neural computational model of generalized periodic discharges in acute hepatic encephalopathy.

Acute hepatic encephalopathy (AHE) due to acute liver failure is a common form of delirium, a state of confusion, impaired attention, and decreased arousal. The electroencephalogram (EEG) in AHE often exhibits a striking abnormal pattern of brain activity, which epileptiform discharges repeat in a regular repeating pattern. This pattern is known as generalized periodic discharges, or triphasic-waves (TPWs). While much is known about the neurophysiological mechanisms underlying AHE, how these mechanisms relate to TPWs is poorly understood. In order to develop hypotheses how TPWs arise, our work builds a computational model of AHE (AHE-CM), based on three modifications of the well-studied Liley model which emulate mechanisms believed central to brain dysfunction in AHE: increased neuronal excitability, impaired synaptic transmission, and enhanced postsynaptic inhibition. To relate our AHE-CM to clinical EEG data from patients with AHE, we design a model parameter optimization method based on particle filtering (PF-POM). Based on results from 7 AHE patients, we find that the proposed AHE-CM not only performs well in reproducing important aspects of the EEG, namely the periodicity of triphasic waves (TPWs), but is also helpful in suggesting mechanisms underlying variation in EEG patterns seen in AHE. In particular, our model helps explain what conditions lead to increased frequency of TPWs. In this way, our model represents a starting point for exploring the underlying mechanisms of brain dynamics in delirium by relating microscopic mechanisms to EEG patterns.

P: 24 Comparative Morphological Analysis of Astroglia Reactivity in the Hippocampus of Rats With Acute and Chronic Hepatic Encephalopathy

BACKGROUND: Hepatic encephalopathy (HE) is a serious complication of advanced liver failure which represents the whole neuropsychiatric abnormalities resulting from liver disease ranging from abnormal behavior to coma. Impairment of cognitive function is well described in HE patients, while mechanisms of memory impairment in HE patients is still not fully understood, however, it may involve a possible gliopathy as well as neuropathy in various brain areas, including the hippocampus known as the main brain structure associated to the memorization process. The aim of the present investigation is to assess astroglia reaction of the hippocampus, in a comparative approach between acute and chronic HE in rat. METHODS: Sprague-Dawley rats were divided into 3 groups: controls; rats were treated with saline solution (NaCl 0.9 % i.p) during 3 days, chronic HE group: rats were subjected to Bile Duct Ligation and acute HE group; rats were subjected to 3 i.p injections of thioacetamide (TAA) 300 mg/kg BW. Astroglia was assessed through an immunohistochemical analysis using anti-GFAP antibody on frontal sections of the hippocampus following. RESULTS: Our data showed in the TAA rats (3 days following 3 TAA injections) compared to controls, a significant increase of GFAP immunoreactivity within the whole hippocampal areas, while astrocytic processes length and ramification were reduced, the GFAP-immunoreactive area was increased. In contrast to BDL rats, at the cirrhotic stage (4 weeks after surgery), showing the opposite tendency with a drop of the astrocytic GFAP-immunoreactive area as well as the astrocytic length and ramification levels. CONCLUSIONS: The present finding sustains a differential astroglial reactivity within the hippocampus of acute and chronic HE rats. Astrocytic morphology changes depends to the severity of liver failure and seems to HE type-dependent, while those astroglial changes lead to a severe gliopathy which may be behind the disturbed cognitive function, especially memory seen in patients with chronic as well as acute HE.

P: 77 The Contribution of the Blood-Brain Barrier and Choroid Plexus to the Pathology of Hepatic Encephalopathy

ABSTRACT: Cerebral edema and associated increase in intracranial pressure, along with brain herniation are the major complications found in patients with acute liver failure (Type A HE or acute hepatic encephalopathy, AHE) which represents the most frequent cause of death in these patients. The preponderance of experimental evidence favors a cytotoxic mechanism, and the only cell in brain that undergoes such swelling are astrocytes. While there is no evidence of blood-brain barrier break-down in patients or in experimental animals with AHE, it is unclear how a sustained astrocyte swelling (cytotoxic brain edema) occurring in AHE, ultimately results in increased intracranial pressure, brain herniation and subsequent coma and death in these patients. A major brain component that may be involved in the edema development is the choroid plexus, since epithelial cells of the choroid plexus produce cerebrospinal fluid. Under CNS pathological conditions, the barrier function of blood-CSF barrier is altered, along with changes in the ependyma, leading to a seepage of fluid out of the ventricular system, ultimately resulting in brain edema, along with the entry of inflammatory cells into the brain parenchyma. In preliminary studies, we found activated mast cells in the choroid plexus of the liver toxin thioacetamide (TAA)-treated rats, and such activation significantly increased cytokine production, histamine release and decreased levels of growth factors including platelet derived growth factor, insulin-like growth factor, fibroblast growth factor. We also found increased levels of the water channel proteins aquaporin 1 and 4 (AQP-1/AQP-4) in TAA-treated rat brain choroid plexus, and increased brain edema, while inhibition of mast cell activation diminished both AQP levels, as well as brain edema development. These findings strongly suggest that acute liver failure stimulates the activation of choroid plexus mast cells and the subsequent inflammation and AQP1/4 expression, which ultimately contributes to the sustained cytotoxic brain edema found in AHE. We anticipate that studies aimed at a better understanding of the role of choroid plexus inflammatory events in the development of brain edema associated with AHE, will greatly facilitate the identification of agents capable of ameliorating this debilitating condition.

P: 22 Deficit of Short Working Memory in Rat With Thioacetamide-Induced Progressive Acute Hepatic Encephalopathy Involving Serotonin Innervation and Astroglia Dysfunctions

BACKGROUND: Hepatic encephalopathy (HE) is defined as the whole neurological and neuropsychiatric disorders arising from both acute and chronic liver failures. Patients with chronic HE exhibited an impairment of learning and memory abilities as well as attention. The aim of the present study is to evaluate the progression of short working memory alteration in acute HE and to delineate the glial and the neuronal alterations which may underlie such cognitive impairment. METHODS: The study was performed in Sprague-Dawley rats with acute liver failure induced by thioacetamide (TAA) at a dose of 300 mg/kg i.p. Different stages of acute HE was defined as: 12 h, 24 h and 36 h following administration of TAA. Working memory was assessed by the T-Maze test via the percentage of alternation behavior, as well, an immunohistochemical analysis of GFAP in the hippocampus and serotonin (5-HT) within the dorsal Raphe nucleus (DRN). RESULTS: Our data showed a progressive loss of the alternation behavior, which was accompanied by a time dependent and region-specific changes of GFAP-immunoreactive astrocytes within the hippocampus together with a reduced 5-HT immunoreactivity within the DRN. CONCLUSIONS: Our data revealed for the first time, a progressive loss of short memory function in acute HE, resulting from acute liver dysfunction which may involve a possible gliopathy as well as a 5-HTergic dysfunctions.

A mathematical model for developing hepatitis E virus infection in human population

Hepatitis E is an acute viral infectious disease transmitted by fecal-oral route mainly through fecally contaminated drinking water, with cyclic outbreaks and frequent development of acute hepatic encephalopathy in pregnant women. Hepatitis E epidemic outbreaks occur in Central Asia, Africa and Latin America, whereasChina,India,Turkmenistan,Kazakhstan,Tajikistan,Uzbekistan,Kyrgyzstan,Bolivia,Mexico, andTaiwanrepresent endemic geographic regions. Hepatitis E in the structure of acute viral hepatitis morbidity during outbreaks ranges from 64.7% to 80%, whereas sporadic morbidity may be up to 10 to 18.8%. In contrast, percentage of hepatitis E in acute viral hepatitis varies from 0.5% to 12.6% in European countries and some territories of theRussian Federation. The latent active virus circulation was confirmed in various regions of theRussian Federation. All introduced cases were related to recent traveling to the regions with high incidence of hepatitis E, which course clinically did not differ from standard hepatitis E infection, but no cases of infection were recorded after exposure. Lack of contact transmission in this case was associated with low virus survival in environment. Patients with any clinical form including anicteric serve as a source of infection. An increased risk of hepatitis E infection is typical for livestock workers dealing with pigs, employe es of meat processing plants engaged in primary meat carcass processing and working at slaughterhouse. According to the World Health Organization, 20 million cases of hepatitis E virus infection are recorded annually, among which 3 million cases account for acute hepatitis E and related 70 000 lethal outcomes. Chronic liver disorders comprising up to 70% followed by death of pregnant women (40%) as well as acute liver and kidney failure reaching as low as 4% result in lethal outcome in hepatitis E patients. Creating a mathematical model for development of hepatitis E infection could allow to predict changes in its morbidity rate at controlled area. Here, for the first time we propose a mathematical model for developing hepatitis E in human population based on disease course, which may potentially predict an incidence rate for the most dangerous icteric hepatitis E as well as assess amount of individuals susceptible to it at morbidity rise in the geographic region.

Kinetic deterioration of short memory in rat with acute hepatic encephalopathy: Involvement of astroglial and neuronal dysfunctions

Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome resulting from acute or chronic hepatic impairments. The clinical features of HE include attention as well as a mild cognitive deficits associated with impaired attentional and executive networks in patients as well as in animal models of HE. The underlining pathomechanism of memory impairment in HE patients is still not fully understood; however, it may involve a possible gliopathy as well as neuropathy. The aim of the present investigation is to assess progression of short working memory deterioration in acute HE and to delineate the glial and the neuronal alteration which may underlie such cognitive impairment. The study was carried out in male Sprague-Dawley rats with acute liver failure induced by thioacetamide (TAA). The study was performed on different stages of acute HE; 12 h, 24 h and 36 h following administration of TAA. The liver functions were assessed via different biochemical markers (ALT, AST, bilirubin, urea and creatinine) and an histopathological examination of the liver tissue. While for the behavioral study, we used T-Maze test to assess short working memory using the percentage of alternation behavior, together with an immunohistochemical analysis of the Glial Fibrillary Acidic Protein (GFAP) as the key marker of astrocytes in the hippocampus, as well as serotonin (5-HT) for 5-HTergic neurons within the dorsal Raphe nucleus (DRN). Our data revealed a progressive loss of liver tissue integrity with inflammation and hepatocytes degeneration which was associated to obvious loss of the liver function. In parallel, we observed a gradual alteration of the alternation behavior, as a sign of altered short working memory in the acute HE rats. At the central level, the immunohistochemical study showed a time dependent region-specific changes of GFAP-immunoreactive astrocytes within the hippocampus. While within the DRN, serotonin levels declined progressively in a time-dependant manner. Our data revealed for the first time, a gradual loss of short memory function in acute HE, resulting from liver dysfunction. Such cognitive deterioration may involve a possible gliopathy as well as a 5-HTergic dysfunction which could be considered as a new key element for understanding the basis of memory and attention loss in HE patients.

Acute Toxic Leukoencephalopathy: Etiologies, Imaging Findings, and Outcomes in 101 Patients.

Prior studies regarding acute toxic leukoencephalopathy (ATL) are either small, or preliminary. Our aim was to evaluate etiologies of and differences in imaging severity and outcomes among various etiologies of ATL. MRIs of patients with suspected ATL over 15 years were retrospectively reviewed; inclusion criteria were: MRI <3 weeks of presentation with both DWI and FLAIR. These were jointly graded by two neuroradiologists via a previously described score of severity. Clinical outcome was evaluated via both modified Rankin (mRS) and ATL outcome (ATLOS) scores, each being correlated with the DWI and FLAIR scores. Etiologic subgroups of n > 6 patients were statistically compared. Of 101 included patients, the 4 subgroups of n > 6 were the following: chemotherapy (n = 35), opiates (n = 19), acute hepatic encephalopathy (n = 14), and immunosuppressants (n = 11). Other causes (n = 22 total) notably included carbon monoxide (n = 3) metronidazole (n = 2), and uremia (n = 1). The mean DWI/FLAIR severity scores were 2.6/2.3, 3.3/3.3, 2.1/2.1 and 2.0/2.5 for chemotherapeutics, opiates, AHE and immunosuppressants, respectively, with significant differences in both imaging severity and outcome (P = .003-.032) among subgroups, particularly immunosuppressant versus chemotherapy-related ATL and immunosuppressants versus opiates (P = .004-.032) related ATL. DWI and FLAIR severity weakly correlated with outcome (ρ = 0.289-.349, P < .005) but correlated stronger in the chemotherapy (ρ = 0.460-.586, P < .010) and opiate (ρ =.472-.608, P < .05) subgroups, which had the worst outcomes. ATL clinically resolved in 36%, with severe outcomes in 23% (coma or death, 9/16 deaths from fludarabine). Notable laboratory results were elevated CSF myelin basic protein levels in 8/9 patients and serum blood urea nitrogen levels in 24/91. Clinical outcomes of ATL vary on the basis of etiology, being worse in chemotherapeutic- and opiate-related ATL. Uremia may be a predisposing or exacerbating factor.

Glucuronidated bilirubin: Significantly increased in hepatic encephalopathy.

Bilirubin is produced by the breakdown of hemoglobin in senescent erythrocytes by macrophages and carried by albumin from blood circulation to the liver for removal in normal physiology. Glucuronic acid modification of bilirubin by UDP-glucuronyltransferase in the liver is the key event for its subsequent elimination from human body. Conditions that accelerate the breakdown of erythrocytes may cause an elevated blood level of unconjugated bilirubin whereas the factors affect the glucuronidated bilirubin formation and subsequent elimination may cause decreased or increased blood level of glucuronidated bilirubin, the water soluble "direct bilirubin" measured by clinical blood test. Studies showed that increased total serum bilirubin has a protective effect on cardiovascular and other related diseases, but it is unknown how direct bilirubin levels were related to different diseases. By taking advantage of the data collected in the clinical laboratory of our hospital, the direct bilirubin data from 192,535 patients with 72 clinically defined diseases were compared to that of healthy controls (10,497). Based on the mean, median, and p values, we found that patients with hepatic encephalopathy had the highest serum direct bilirubin level, which resembled acute hepatic encephalopathy caused by increased serum direct bilirubin level in neonates. In contrast, patients with uremia, nephrotic syndrome, and preeclampsia had significantly lower levels of serum direct bilirubin. Taken together, our data revealed that serum direct bilirubin levels were either increased or decreased in a disease-dependent manner. The possible molecular mechanisms of increased direct bilirubin levels in patients suffering hepatic encephalopathy are discussed.

Obesity Has Significant Impact on Mortality in Patients With Acute Alcoholic Hepatitis Fellows-in-Training Award (Obesity Category): Presidential Poster Award

Introduction: The prevalence of obesity is rapidly increasing in the United States (US). Obese alcoholic patients are at increased risk for developing cirrhosis and progressive liver failure. However, the impact of obesity on outcomes in patients hospitalized with acute alcoholic hepatitis (AAH) has not been examined. We aimed to evaluate the impact of obesity on mortality and other outcomes in patients hospitalized with AAH. Methods: Adult patients with a principal diagnosis of AAH were selected from the National Inpatient Sample (NIS) database. We studied the period between 2005 and 2014. Patients with an ICD 9 code for acute alcoholic hepatitis - 571.1 - were analyzed. The primary outcome was in-hospital mortality. Secondary outcomes were medical complications (e.g. acute renal failure, acute respiratory failure, hypovolemic shock) and healthcare resource utilization (e.g. length of stay, total hospitalization costs). Multivariable analysis was performed to identify independent predictors of in-hospital mortality after adjusting for confounders. Results: A total of 133,565 patients were hospitalized for AAH; 7,363 (5.5%) of the patients were obese. Demographic information is summarized in Table 1. In-hospital mortality was 5% among obese patients with AAH as compared to 4.1% in non-obese patients (Table 2). After adjusting for confounding variables obese patients with AAH had an increased odds of mortality as compared to non-obese patients [aOR: 1.16, P-value: 0.007]. Obese patients were also more likely to have acute renal failure (p<0.0001), acute respiratory failure (p<0.0001), hypovolemic shock (p<0.0001), coagulopathies (<0.0001), and hepatic encephalopathy (p<0.001). In addition, obese patients with AAH had significantly higher length of stay and hospitalization costs. Other predictors of in-hospital mortality included: younger age, male gender, race, weekend admission, smaller hospital bed-sizes, and urban non-teaching settings (Table:3) Conclusion: Obesity is an independent predictor of in-hospital mortality among patient admitted for AAH. The synergistic relationship between obesity and alcoholic hepatitis puts this patient population at significant risk for multi-organ failure and infection. It is also associated with a significant increase in the cost of hospitalization.1037_A Figure 1. Demographic characteristics1037_B Figure 2. Adverse outcome1037_C Figure 3. Multivariable Analysis

L-Carnitine as Treatment for Valproic Acid Induced Acute Liver Failure

Acute Liver Failure (ALF) is defined by the presence of acute liver injury, hepatic encephalopathy and elevated prothrombin time/international normalized ratio (INR) in a patient without cirrhosis or preexisting liver disease, with duration of illness less than 26 weeks. The disease often has a poor outcome. The causes of ALF include drug induced liver injury, viral, ischemic, and autoimmune hepatitis. Valproic acid, a commonly used anticonvulsant, has been associated with ALF in children and adults. A 54 year old African American male was transferred from inpatient psychiatry to the Coronary Care Unit because of acute chest pain and dyspnea secondary to non-ST elevation myocardial infarction complicated by new onset heart failure with reduced ejection fraction. The patient had been admitted to psychiatry for the management of schizophrenia with valproic acid and haldol three months prior to transfer to medicine. One day after the transfer he developed altered mental status. Laboratory tests were notable for elevated ProBNP 3401 pg/ml (normal range (NR) 0-1200), INR 2.59 (NR 0.8-1.2), ammonia 103 Mmol/L (NR 11-32), aspartate transaminase (AST) 8128 U/L (NR 15-37), alanine transaminase (ALT) 5296 U/L (NR 30-65). The patient was moved to the medical intensive care unit with the diagnosis of ALF secondary to valproic acid. An N-acetylcysteine infusion was started as this has been shown to have potential benefit in non-acetaminophen induced ALF. L-carnitine, which has been reported to interrupt the mechanism by which valproic acid causes liver toxicity, was started. The patient showed significant improvement in clinical and laboratory status after 48 hours of N-acetylcysteine drip and 120 hours of L-carnitine treatment. ALF is an uncommon but, known complication of valproic acid, regardless of serum drug levels. It has been reported that early treatment with L-carnitine can be beneficial especially, in cases of severe hepatotoxicity, coma, serum valproic acid levels > 450 mpg/ml or hyperammonemic encephalopathy. Valproic acid combines with carnitine leading to carnitine depletion. Supplementation of L-carnitine is postulated to increase the beta-oxidation of valproic acid, interrupting the mechanism by which valproic acid causes liver toxicity. Although ischemia might have contributed to ALF in this patient, there was a clear improvement within the time frame in which L-carnitine was administered. Therefore, monitoring liver function test is crucial.

TACE-Associated Hepatic Encephalopathy in the Absence of Decompensated Liver Disease

Hepatic encephalopathy is a common presentation of decompensated liver disease in patients with HCC, but occurs rarely outside the context of diffuse cirrhosis. We describe a case of severe encephalopathy in the setting of a routine TACE procedure for metastatic neuroendocrine tumor. This report seeks to raise awareness of the essential predilection for hepatic encephalopthy (HE) in patients with metastatic neuroendocrine tumor (NET), and may help to illuminate the mechanism of hepatic encephalopathy in the setting of NET. A 68 year old male with Grade II well-differentiated carcinoid tumor metastatic to the liver presented for chemoembolization of a hypervascular tumor in segment 4. He was known to have extremely high 5-HIAA and carcinoid syndrome. He had several ill-defined lesions in his liver without evidence of cirrhosis. Over the next 24 hours developed new confusion, dysarthria, and non-focal weakness. MRI was negative for any evidence of acute stroke or TIA. EEG revealed diffuse slowing and he was noted to have significant asterixis and clonus on exam. The patient did not have significantly elevated liver enzymes or fulminant hepatic failure. After several days he became increasingly obtunded with no localizing source. Lactulose was initiated for acute hepatic encephalopathy with gradual improvement in his asterixis, drowsiness, and confusion. Discussion We describe an unusual case of hepatic encephalopathy which occurred following localized chemoembolization of a NET in the absence of cirrhosis or widespread tumor burden. HE is known to occur in approximately 1% of patients with cirrhosis who undergo TACE, but occurs very rarely in the absence of cirrhosis. The exception to this is in patients with NET, who are known to have a poorly-understoond predilection for HE. In contrast to cirrhosis, patients with NET typically have well-preserved synthetic and detoxification function attributable to the remaining healthy hepatic tissue. This patient did not exhibit diffuse liver injury or elevated ammonia, but developed severe HE after TACE. This raises interesting questions about the mechanism of HE in NET -- arguing for a greater role of 5HIAA release in NET-associated HE, rather than transtumoral intrahepatic shunting of ammonia. Clinicians should be aware of the predilection towards hepatic encephalopathy in metastatic neuroendocrine tumors, and consider this etiology when neurologic symptoms arise in patients who have undergone recent embolization.2428 Figure 1 No Caption available.

Neuroinflammation in acute hepatic encephalopathy rats: imaging and therapeutic effectiveness evaluation using 11C-PK11195 and 18F-DPA-714 micro-positron emission tomography.

Neuroinflammation has an important influence in pathogenesis of acute hepatic encephalopathy (AHE). 11C-PK11195 and 18F-DPA-714 targeted to translocator protein (TSPO) have potential application in positron emission tomography (PET) as a molecular probe of neuroinflammation. The aim of this study was to compare these two radiotracers and their effectiveness in detecting neuroinflammation for the imaging of AHE rat models. Furthermore, using the new radiotracer 18F-DPA-714, we analyzed the effectiveness of therapeutic treatment for neuroinflammation in AHE. First, we performed a comparative study of 11C-PK1195 and 18F-DPA-714 PET to image neuroinflammation in AHE rats induced by thioacetamide. Twenty-four rats were divided into either control group (n = 12) or AHE group (n = 12). Next, each group was subdivided depending on the radiotracer used during PET imaging (n = 6). Radiotracer uptake values encompassing the whole brain were compared. Lastly, we used the optimized tracer to monitor anti-neuroinflammation effects in AHE-induced rats. Forty-six rats were divided into four groups: [normal saline (NS) group (n = 13), minocycline (MINO) group (n = 11), dexamethasone (DEXA) group (n = 11), MINO+DEXA group (n = 11)]. 18F-DPA-714 PET was performed and the uptake values were calculated. The rotarod test, biochemical indices, and histopathological examinations were quantitatively measured and compared. AHE rats showed reduced motor ability, elevated ammonia levels, and higher liver function indices (all P < 0.05) with unchanged inflammatory factors (all P > 0.05), compared to control group. Both 11C-PK11195 and 18F-DPA-714 PET can detect neuroinflammation of AHE rats. Behavioral studies showed that MINO and/or DEXA improved the motor ability in AHE rats (P < 0.05); however, no differences were found for liver function or inflammatory markers among the four groups (all P > 0.05). The average uptake values of whole brain and multiple brain areas in the MINO+DEXA group were lower compared to all other groups (all P < 0.05), which was demonstrated by CD11b stains of microglia. Our results show that both 11C-PK11195 and 18F-DPA-714 PET can detect neuroinflammation in AHE-induced rat models. Additionally, the combined use of minocycline and dexamethasone can effectively inhibit neuroinflammation in AHE-induced rats, which can be sensitively monitored by 18F-DPA-714 PET.

Fatal neurological complication after liver transplantation in acute hepatic failure patient with hepatic encephalopathy

Liver transplantation is a current definitive treatment for those with end-stage liver disease. Hepatic encephalopathy is a common complication of hepatic failure, which can be improved and aggravated by various causes. It is important to differentiate hepatic encephalopathy from other diseases causing brain dysfunction such as cerebral hemorrhage, which is also related to high mortality after liver transplant surgery. A 37-year-old patient was presented with acute liver failure and high ammonia levels and seizure-like symptoms. Computed tomography (CT) of his brain showed mild brain atrophy, regarded as a symptom of hepatic encephalopathy, and treated to decrease blood ammonia level. Deceased donor liver transplantation was performed and liver function and ammonia level normalized after surgery, but the patient showed symptoms of involuntary muscle contraction and showed loss of pupil reflex and fixation without recovery of consciousness. Brain CT showed brain edema and bilateral cerebral infarction, and the patient died after a few days. The purpose of this case report is to emphasize the importance of preoperative neurological evaluation, careful transplantation decision, and proper perioperative management of liver transplantation in patients with acute hepatic encephalopathy.

Dose-dependent impact of proton pump inhibitors on the clinical course of spontaneous bacterial peritonitis.

Spontaneous bacterial peritonitis is a severe complication in patients with cirrhosis leading to acute kidney injury, hepatic encephalopathy and a high mortality. In this study, we aimed to investigate the impact of proton pump inhibitors and the potential relevance of the taken dosage on the incidence and clinical course of spontaneous bacterial peritonitis. Overall, 613 consecutive patients with decompensated cirrhosis were included. All patients were carefully evaluated for proton pump inhibitors intake including the applied dosage and were further followed up for spontaneous bacterial peritonitis development as well as for the incidence of clinical complications like hepatic encephalopathy, acute kidney injury and mortality. Cumulative spontaneous bacterial peritonitis incidence did neither differ between the proton pump inhibitors and the no-proton pump inhibitors group nor between those taking the high (>40mg/d) and the low (10-40mg/d) proton pump inhibitors' dose. However, proton pump inhibitors' intake was associated with an impaired clinical course of spontaneous bacterial peritonitis reflected by a higher likelihood for acute kidney injury (71% vs 43%; P=.002), severe hepatic encephalopathy (15% vs 0%; P=.04) and an increased mortality (24% vs 0%; P=.008) within 28days after spontaneous bacterial peritonitis diagnosis. In particular, patients with proton pump inhibitors dosages >40mg/d had an increased short-term risk for acute kidney injury (adjusted hazard ratio: 1.86; P=.009) and mortality (adjusted hazard ratio: 2.05; P=.02). In contrast, there was no effect of proton pump inhibitors on acute kidney injury, hepatic encephalopathy and mortality in patients without spontaneous bacterial peritonitis irrespective of the applied proton pump inhibitors dosage. High dosages of proton pump inhibitors are associated with an adverse outcome in patients with spontaneous bacterial peritonitis. Thus, indication for high-dosage proton pump inhibitors therapy should be evaluated carefully in these patients.

S176. A Mean field model to study the triphasic waves in acute hepatic encephalopathy

Introduction Triphasic waves (TWs) are a distinctive electroencephalogram (EEG) pattern consisting of consisting ‘triphasic’ epileptiform discharges repeating at relatively regular intervals, most commonly in patients with acute, severe toxic/metabolic encephalopathy (TME). TWs share some similarities with EEG patterns seen in non-convulsive status epilepticus (NCSE), and show similar responses to benzodiazepine administration. Nevertheless the mechanisms underlying TWs are poorly understood, and their relationship to NCSE debated. Here we explore the conditions in a biologically plausible computational model of the EEG that lead to patterns resembling TWs, and attempt to relate these to mechanisms operative in one type of TME: acute hepatic encephalopathy (AHE). Methods Our work builds on an existing neural mean field model (NMFM) developed for how periodic discharges arise in severe cerebral anoxia (an adaptation of the bursting Liley model), through three types of processes: (a) metabolic failure leading to impaired synaptic transmission; and (b) increased neuronal excitability. In addition, the model accounts for effects of (c) GABA-ergic modulation by anesthetics. We identify pathophysiologic mechanisms involved in AHE which can lead to each of these effects, and relate these mechanisms to changes in the parameters of the NMFM. In this way our model relates “microscopic” (biochemical) mechanisms to “macroscopic” observations (EEG patterns). Then, we relate the simulated EEG patterns to clinical EEG data of patients with AHE through by constructing a comparison function, on the basis of different feature extraction methods, similarity measurements and optimization algorithms. Results The model is able to reproduce key qualitative features of EEG data from patients with AHE, including the approximate shape, irregular and slowed background, and semi-periodic pattern of TWs. In addition, we find that the dynamic evolution of EEG activity during AHE can be characterized through the change of four key parameters of proposed NMFM ((recovery time constants), (potentiation factor of EPSP), (decay rate of IPSP)), which reflect gradual changes in underlying physiological mechanisms. Conclusion Known alterations in cerebral physiology in acute hepatic encephalopathy are relatable to parameters of a biologically plausible mean-field model of the EEG. Our model represents a starting point for exploring the dynamical mechanisms underlying the EEG of severe encephalopathy.

Review of diffuse cortical injury on diffusion-weighted imaging in acutely encephalopathic patients with an acronym: “CRUMPLED”

PurposeAcute encephalopathic syndromes can present a diagnostic challenge due to the wide range of possible etiologies, which also can have vastly different outcomes. The presence of diffuse cortical injury (DCI) on diffusion-weighted imaging (DWI) can help narrow the differential diagnosis. The aim of this review is to categorize the range of possible etiologies of DCI into a useful acronym, "CRUMPLED". MethodsA review of the PACS system was completed to find a characteristic example of patients with DCI on DWI from different etiologies. The diagnosis was confirmed for each example via a subsequent review of the electronic medical record used to assess for data such as biopsy results, laboratory values, and clinical correlation. The electronic exhibit intends to demonstrate several sample cases of each letter within the acronym, and to demonstrate which types of DCI are potentially reversible or irreversible. Findings/DiscussionThe possible etiologies of DCI on DWI can be organized using the acronym "CRUMPLED": 'C' = Creutzfeldt-jakob disease, 'R' = reversible cerebral vasoconstriction syndrome; 'U' = urea cycle disorders (hyperammonemia) and Uremia; 'M' = mitochondrial (cytopathy/encephalopathy); 'P' = prolonged seizure and posterior reversible encephalopathy (PRES); 'L' = laminar necrosis (hypoxic-ischemic encephalopathy) and liver disease (acute hepatic encephalopathy); 'E' = encephalitis (infectious meningoencephalitis); 'D' = diabetes mellitus (hypoglycemia). Other secondary imaging findings (outside of DWI) can be used to help differentiate between the aforementioned etiologies, such as the use of ADC maps, FLAIR imaging, intravenous contrast. Conclusion"CRUMPLED" is proposed as a convenient acronym for the categorization of a diverse range of acute etiologies associated with DCI on DWI, arising from varying degrees of cytotoxic edema. These etiologies can range from being potentially reversible (e.g. hyperammonemia or prolonged seizures) to irreversible (e.g. hypoxic-ischemic injury).

Brain MRI findings in acute hepatic encephalopathy in liver transplant recipients.

Acute hepatic encephalopathy has significant morbidity and mortality in liver transplant recipients unless it is promptly treated. We evaluated the brain magnetic resonance (MR) imaging findings associated with acute hepatic encephalopathy in transplant recipients. We retrospectively reviewed the clinical and imaging data and outcomes of twenty-five liver transplant patients (16 male; mean age, 49.3years) with clinically diagnosed acute hepatic encephalopathy and forty liver transplant patients (20 males; mean age, 45.5years) without neurological symptoms suggestive of hepatic encephalopathy at our institution. Bilateral symmetric hyperintensities of the insular cortex and cingulate gyrus were observed in twenty-one patients (84.00%), bilateral symmetric extensive increased cortical signal intensity (involving two or more regions) was observed in 72.00% of the patients, leptomeningeal enhancement in 73.68%, and visualization of prominent venules in 52.00%. The most common symptom at diagnosis was rigidity (n=14), and the plasma ammonia levels ranged from 68.63 to 192.16μmol/L. After active treatment, 17 patients gradually recovered, four patients suffered from mild or moderate neurologic deficits, and four patients with widespread brain edema died. The specific brain MR imaging features were bilateral symmetric increased cortical signal intensity, especially in the insular cortex and cingulate gyrus, leptomeningeal enhancement, visualization of the prominent venules, and widespread brain edema. These features may indicate poor prognosis and should alert radiologists to the possibility of acute hepatic encephalopathy in liver transplant recipients and encourage clinicians to prepare appropriate treatment in advance.

Alpha-1 antichymotrypsin is involved in astrocyte injury in concert with arginine-vasopressin during the development of acute hepatic encephalopathy.

Background and aimsWe developed a bio-artificial liver (BAL) using a radial-flow bioreactor and rescued mini-pig models with lethal acute liver failure (ALF). The point of the rescue is the recovery from hepatic encephalopathy (HE). HE on ALF has sometimes resulted in brain death following brain edema with astrocyte swelling. Several factors, including ammonia and glutamine, have been reported to induce astrocyte swelling and injury. However, many clinicians believe that there are any other factors involved in the development of HE. Therefore, the aim of this study was to identify novel HE-inducible factors, particularly those inducing astrocyte dysfunction.MethodsMini-pig plasma samples were collected at three time points: before the administration of toxins (α-amanitin and LPS), when HE occurred after the administration of toxins, and after treatment with extracorporeal circulation (EC) by the BAL. To identify the causative factors of HE, each plasma sample was subjected to a comparative proteome analysis with two-dimensional gel electrophoresis and mass spectrometry. To assess the direct effects of candidate factors on the astrocyte function and injury, in vitro experiments with human astrocytes were performed.ResultsUsing a proteome analysis, we identified alpha-1 antichymotrypsin (ACT), which was increased in plasma samples from mini-pigs with HE and decreased in those after treatment with EC by BAL. In in vitro experiments with human astrocytes, ACT showed growth-inhibitory and cytotoxic effects on astrocytes. In addition, the expression of water channel protein aquaporin-4, which is induced in injured astrocytes, was increased following ACT treatment. Interestingly, these effects of ACT were additively enhanced by adding arginine-vasopressin (AVP) and were canceled by adding an AVP receptor antagonist.ConclusionsThese results suggest that ACT is involved in astrocyte injury and dysfunction in concert with AVP during the development of acute HE.