Massive Hepatocellular Necrosis Research Articles

Buckthorn Leaves and Fruits: A Comparative Study of Their Hepatoprotective Effects in Tetrachloride-Induced Liver Disorders in Rats

An overdose of carbon tetrachloride by injection leads to liver damage and massive hepatocellular necrosis, whereas sea buckthorn leaves and fruits have hepatoprotective properties. The aim of this study was to compare the hepatoprotective effects of sea buckthorn leaves and fruits in hepatotoxic rats induced by chlorocarbon. The experiment was carried out in an animal enclosure. Before the start of the experiment, all rats were given a basic diet for one week. The rats were then divided into six groups, each group comprising six rats. The 1st group received only a basic diet for twenty-eight days and served as the rats' normal negative control (C -ve). The other groups of rats (thirty in total) were administered carbon tetrachloride. The groups were divided into five groups, with four groups receiving BL (5% and 10%) and BF (5% and 10%) and one group acting as a control group that suffered from the disease but did not follow the experimental diet. In contrast to the control group (+), all liver values of the rats given different diets showed significant mean reductions. Group "4" (hepatotoxic rats fed ten percent BL) had the highest FI, BWG and ARR compared to the control group (+). For ALP, insignificant differences were found between groups "4" and "6". Mathematically, the best management considering the serum albumin has been documented for group"4" (rats fed on 10% BL) in comparison with control (+) group. Research results indicate its positive effect on the liver and improvement in the condition of liver tissue. It is important to recognise that research on sea buckthorn is still ongoing and further investigation is needed to validate its potential therapeutic applications and determine the appropriate dosages.

Cadmium implication in massive hepatocellular necrosis and hepatic amyloidosis and the protective role of ivermectin and Allium cepa in adult Wistar rats (Rattus Novergicus)

Cadmium implication in massive hepatocellular necrosis and hepatic amyloidosis and the protective role of ivermectin and Allium cepa in adult Wistar rats (Rattus Novergicus)

Histopathological spectrum of liver lesions at autopsy: A cross sectional study

Liver is the principal site of many metabolic activities and is vulnerable to many metabolic, toxic, microbial and circulatory insults. It is frequently involved in metastatic spread of malignancies from all parts of body. This study aimed to analyze histopathological spectrum of liver diseases in autopsy cases, and correlate with the clinical findings wherever available. It was an observational study conducted over a period of 2 years on 283 autopsy cases in department of Pathology of a tertiary care teaching institute in central India. Liver specimens were included in study irrespective of age, sex and cause of death. After fixation in 10% formalin the sections from representative area were submitted for processing, Hematoxylin and Eosin-stained sections were subjected for microscopic examination. Total 283 liver autopsy cases studied showed predominance of male (68.65%). Maximum cases were in the age group of 21 to 30 years (20.14%) followed by 31 to 40 years (18.28%). Fatty change was evident in a majority (32.08%) of the cases while a remarkable (26.49%) number of cases showed changes of congestion on histological examination. Massive hepatocellular necrosis and midzonal necrosis were seen in 2 cases each. Tubercular granulomas and metastasis of adenocarcinoma were seen in 3 cases each. Histological analysis of liver is important learning objective for pathologists to study silent diseases of liver which are incidentally seen in histopathology.

Research advances in the treatment of liver failure with mesenchymal stem cell-derived exosomes

Liver failure is a serious clinical syndrome in which multiple pathogenic factors exceed the liver's self-repair capability, resulting massive hepatocellular necrosis, rapid disease progression and high mortality. Liver transplantation is the most effective method for the treatment of liver failure, but it has disadvantages, such as insufficient liver donor and high cost. The clinical efficacy of mesenchymal stem cells in liver failure have been validated, but its application has been limited to certain extent. Cell-free-based therapies, especially mesenchymal stem cell-derived exosomes, has become a research hotspot in recent years. This paper reviews the research advances in the treatment of liver failure with the use of mesenchymal stem cell-derived exosomes.

Pathology of Lagovirus europaeus GI.2/RHDV2/b (Rabbit Hemorrhagic Disease Virus 2) in Native North American Lagomorphs.

Rabbit hemorrhagic disease, a notifiable foreign animal disease in the US, was reported for the first time in wild native North American lagomorphs in April 2020 in the southwestern US. Affected species included the desert cottontail (Sylvilagus audubonii), mountain cottontail (Sylvilagus nuttallii), black-tailed jackrabbit (Lepus californicus), and antelope jackrabbit (Lepus alleni). Desert cottontails (n=7) and black-tailed jackrabbits (n=7) collected in April and May 2020 were necropsied at the US Geological Survey National Wildlife Health Center and tested positive for Lagovirus europaeus GI.2, also known as rabbit hemorrhagic disease virus 2 (GI.2/RHDV2/b), by real-time PCR at the US Department of Agriculture's Foreign Animal Disease Diagnostic Laboratory. Gross and microscopic lesions were similar to those reported in European rabbits (Oryctolagus cuniculus) and other hare (Lepus) species with GI.2/RHDV2/b infection; they included epistaxis (12/13; 92%); massive hepatocellular dissociation (14/14; 100%) and necrosis or apoptosis (11/11; 100%); pulmonary congestion (12/12; 100%), edema (12/13; 92%), and hemorrhage (11/12; 92%); and acute renal tubular injury (3/8; 38%). As in previous reports, massive hepatocellular dissociation and necrosis or apoptosis was the most diagnostically distinct finding. As North American Sylvilagus and Lepus species appear to be susceptible to fatal GI.2/RHDV2/b infection, additional work is needed to understand the host range, pathogenicity, and potential population effects of GI.2/RHDV2/b in North America.

The cross-talk of NLRP3 inflammasome activation and necroptotic hepatocyte death in acetaminophen-induced mice acute liver injury.

Overdose acetaminophen (APAP) can result in severe liver injury, which is responsible for nearly half of drug-induced liver injury in western countries. Previous studies have found that there existed massive hepatocellular necrosis and severe inflammatory response in APAP-induced liver injury. However, the mechanistic linkage between necroptosis and NLRP3 inflammasome pathway in APAP-induced hepatotoxicity remains poorly understood. In order to investigate the relationship between inflammation and hepatocytes death in APAP hepatotoxicity, a time-course model for APAP hepatotoxicity in C57/BL6 mice was established by intraperitoneal (i.p) injection of 300 mg/kg APAP in this study. The activity of serum enzymes and pathological changes of APAP-treated mice were evaluated, and the critical molecules in necroptosis and NF-κB-NLRP3 inflammasome signaling pathway were determined by immunoblot and immunofluorescence analysis. The results demonstrated that APAP overdose resulted in a severe liver injury. Furthermore, the expression of critical molecules in NLRP3 inflammasome and necroptosis pathways peaked at 12-24 h, and then was decreased gradually, which is consistent with the pattern of pathological injury induced by APAP. Our further investigation found that the level of IL-1β in mouse liver was closely correlated with the level of phosphorylated MLKL following exposure to APAP. Furthermore, inhibition of necroptosis with necrostatin-1 significantly suppressed the activation of NLRP3 inflammasome signaling. Taken together, our results highlighted that the cross-talk between necroptosis and NLRP3 inflammasome played a critical role for promoting APAP-induced liver injury. Inhibition of the interaction of inflammation and necroptosis by pharmaceutical methods may represent a promising therapeutic strategy for APAP-induced liver injury.

S2424 Infliximab-Induced Acute Liver Failure in a Patient With Crohn’s Disease Requiring Orthotopic Liver Transplantation

INTRODUCTION: Among a plethora of adverse effects attributable to drugs of the TNF-α class, hepatotoxicity is rarely cited. We present the case of a patient with Crohn’s disease (CD) who was started on infliximab and subsequently developed acute liver failure (ALF) necessitating transplant. CASE DESCRIPTION/METHODS: A 25-year-old male with ileocolonic and perianal CD was started on infliximab and methotrexate. Two months later, he reported anorexia and weight loss after which methotrexate was discontinued. Three months after infliximab initiation, he developed acute onset pruritus, pale stools, and dark urine. Physical exam was remarkable for scleral icterus and jaundice without asterixis. At the time, total bilirubin was 10.7 mg/dL, International Normalized Ratio (INR) was 1.6, alkaline phosphatase (ALP) was 257 IU/L, aspartate aminotransferase (AST) was 2776 IU/L, and alanine transaminase (ALT) was 499 IU/L. The patient underwent evaluation for acute liver disease. Infectious serologies were negative. Ultrasound of the liver with Doppler studies was unremarkable for hepatic vasculature thrombosis. A liver biopsy demonstrated acute on chronic hepatitis with extensive hepatocellular necrosis (Figures 1 and 2). Given predominance of plasma cells along with mildly positive ANA and ASMA and exclusion of other potential etiologies, autoimmune hepatitis (AIH) induced by infliximab was likely. Empiric methylprednisolone was initiated. However, the patient’s clinical course deteriorated and he progressed into ALF. He then underwent successful transplantation. DISCUSSION: ALF secondary to infliximab has been reported in the literature at a greater frequency compared to other drugs of the TNF-α class. The mechanism of action likely involves development of AIH, characterized by typical clinical history, laboratory findings, and distortions in histological architecture. The prevalence and timeline for the development of hepatotoxicity has not been established. The mainstay of treatment involves steroid therapy, and if this fails, then liver transplantation must be considered. Although methotrexate has also been reported to cause hepatotoxicity, infliximab was considered to be etiology for AIH given the significantly longer half-life of infliximab and the more acute nature of hepatotoxicity. Patients must avoid anti-TNF-α therapy for life to prevent recurrence of ALF. Further studies are needed to risk stratify CD patients for development of ALF.Figure 1.: Massive hepatocellular necrosis with infiltration of portal lymphocytic and lymphoplasmacytic cells.Figure 2.: Acute hepatitis with massive hepatocellular necrosis.

Modulation of the extrinsic cell death signaling pathway by viral Flip induces acute-death mediated liver failure

During viral infections viruses express molecules that interfere with the host-cell death machinery and thus inhibit cell death responses. For example the viral FLIP (vFLIP) encoded by Kaposi’s sarcoma-associated herpesvirus interacts and inhibits the central cell death effector, Caspase-8. In order to analyze the impact of anti-apoptotic viral proteins, like vFlip, on liver physiology in vivo, mice expressing vFlip constitutively in hepatocytes (vFlipAlbCre+) were generated. Transgenic expression of vFlip caused severe liver tissue injury accompanied by massive hepatocellular necrosis and inflammation that finally culminated in early postnatal death of mice. On a molecular level, hepatocellular death was mediated by RIPK1-MLKL necroptosis driven by an autocrine TNF production. The loss of hepatocytes was accompanied by impaired bile acid production and disruption of the bile duct structure with impact on the liver-gut axis. Notably, embryonic development and tissue homeostasis were unaffected by vFlip expression. In summary our data uncovered that transgenic expression of vFlip can cause severe liver injury in mice, culminating in multiple organ insufficiency and death. These results demonstrate that viral cell death regulatory molecules exhibit different facets of activities beyond the inhibition of cell death that may merit more sophisticated in vitro and in vivo analysis.

Fulminant Liver Failure Secondary to Doxycycline Requiring Rescue Liver Transplantation

Introduction: Doxycycline is a broad-spectrum antibiotic of the tetracycline family that inhibits bacterial protein synthesis by binding the 30S ribosomal subunit. Due to its effectiveness in treating wide range of infections, doxycycline is one of the more commonly prescribed antibiotics in the United States. The hepatotoxicity of tetracyclines has been well characterized; however, only a few cases of fulminant liver failure attributed to doxycycline exist in English literature. We present a rare case of doxycycline induced liver failure requiring rescue liver transplantation. Case Report: A 36-year old female with past medical history only significant for a resected medulloblastoma presented with a two week history of fatigue, malaise, and jaundice. She had been prescribed doxycycline to treat a ureaplasma urealyticum genitourinary infection one week prior to her symptoms starting. On arrival, laboratory investigation revealed total bilirubin 12.8 mg/dL, AST 2620 IU/L, ALT 1990 IU/L, ALP 143 mg/dL. A complete inpatient workup for acute liver failure with laboratory and imaging studies was unrevealing and the patient's liver indices progressively worsened. Transjugular liver biopsy was performed which revealed massive hepatocellular necrosis with pigmented macrophage infiltrate and early fibrosis. The patient progressed to fulminant liver failure and received rescue orthotopic liver transplantation ten days after admission. The Roussel Uclaf Causality Assessment Method (RUCAM) score for this case was 8, indicating probable drug induced liver injury. Discussion: Drug induced liver injury is a commonly encountered clinical entity accounting for up to 10% of cases of acute hepatitis. The diagnosis pertaining to drug induced liver injury can be difficult and is a diagnosis of exclusion. Doxycycline is known to be hepatotoxic and generally produces mild transaminase elevation that is self-limiting. To our knowledge, less than five cases of doxycycline induced liver failure exist in reported literature. We present an unusual case of fulminant liver failure attributed to doxycycline, following extensive negative workup for alternative explanation. When suspecting drug induced liver injury, progressive worsening of liver function despite cessation of the offending drug should prompt evaluation for liver transplant.

Drug-Induced Liver Injury With Warzone: A War Against Drug Supplements?

Drug induced liver injury (DILI) is an important cause of hepatic injury and is a growing challenge given the increasing number of drugs. We describe a rare case of severe liver injury after the use of Warzone and Protex. A 29-year-old man with a history of depression and GERD presented with 2 weeks of progressive jaundice, pruritus and nausea after 3 weeks of initiating a body building supplement - Warzone (Trenavar, DMZ, Carbopol, Methystem, and Halodrol). Upon becoming jaundiced, Protex (milk thistle, n-acetyl cysteine, alpha lipoic acid and selenium) was self-initiated to support hepatic function. No family history of liver disease, recent travel or sick contacts. No alcohol use, illicit drug use, body piercing or tattoos. On exam, he was afebrile, hemodynamically stable, well appearing but icteric. No hepatosplenomegaly, encephalopathy or asterixis noted. Laboratory studies showed AST 183 U/L, ALT 524 U/L, total bilirubin 8.8 mg/dL (peaking at 52 mg/dL 4 weeks later), alkaline phosphatase 73 U/L and INR of 0.94. Hemogram, renal function, tests for autoimmune hepatitis, viral hepatitis, Wilson's disease, alpha 1 antitrypsin deficiency and hemochromatosis were unremarkable. Abdominal US and CT showed unremarkable liver and bile ducts, without stones or sludge. Liver biopsy showed marked cholestasis, moderate chronic inflammation with hepatocellular dropout consistent with DILI without any massive hepatocellular necrosis, interface hepatitis, macrovesicular steatosis, lymphoid aggregate, features of cholangitis or fibrosis. He was counseled to avoid supplements. Cholestyramine and ursodiol were initiated, with prednisolone 40 mg daily added 1 month later, as he continued to show cholestatic injury with rising bilirubin. With a 4 week taper of prednisolone, LFTs improved (AST 44 U/L, ALT 27 U/L, total bilirubin 38 mg/dL, and alkaline phosphatase 178 U/L). DILI is the leading cause of drug withdrawal from the United States market. The severity of liver injury due to androgenic or anabolic steroids ranges from minor transient serum enzyme elevations to profound prolonged cholestasis. Early recognition allows for prompt discontinuation of the inciting agent and treatment allowing for a successful recovery. Merely decreasing the dose of the offending agent or switching to another formulation is not appropriate and should be discouraged. Healthcare providers should be aware of the potential for liver injury due to supplements.

Seventh-Day Syndrome: A Catastrophic Event After Liver Transplantation: Case Report

Seventh-day syndrome (7DS) is an early serious complication of liver transplantation, characterized by sudden failure of a previously normally functioning liver graft ∼1 week after the surgery. Although it is an uncommon event, it has major associated mortality. As its etiology is yet to be recognized, the only currently available treatment is retransplantation. We present 3 cases of orthotopic liver transplantation recipients who had an initial uneventful recovery after surgery followed by a dramatic rise of serum liver enzyme levels ∼7 days later and hepatic failure with subsequent graft loss and death despite high-dose immunosuppressive therapy. Histologic findings showed massive centrolobular hemorrhage and hepatocellular necrosis with reduced inflammation. It is essential to review and accumulate more clinical and laboratory information to better understand this syndrome and to better prevent and treat it.

Use of serial assessment of disease severity and liver biopsy for indication for liver transplantation in pediatric Epstein-Barr virus-induced fulminant hepatic failure.

The decision to perform liver transplantation (LT) in patients with Epstein-Barr virus (EBV)-induced fulminant hepatic failure (FHF) relies on a precise assessment of laboratory and pathological findings. In this study, we analyzed clinical and laboratory data as well as the pathological features of the liver in order to evaluate the pathogenesis and the need for LT in 5 patients with EBV-induced FHF. According to the King's College criteria, the Acute Liver Failure Early Dynamic (ALFED) model, and the Japanese criteria (from the Acute Liver Failure Study Group of Japan), only 1 patient was considered to be a candidate for LT. However, explanted liver tissues in 3 cases exhibited massive hepatocellular necrosis together with diffuse CD8-positive T cell infiltration in both the portal area and the sinusoid. EBV was detected in the liver, plasma, and peripheral blood mononuclear cells (PBMNCs). In 2 cases indicated to be at moderate risk by the ALFED model, liver biopsy showed CD8-positive and EBV-encoded RNA signal-positive lymphocytic infiltration predominantly in the portal area, but massive hepatocellular necrosis was not observed. These patients were treated with immunosuppressants and etoposide under the diagnosis of EBV-induced hemophagocytic lymphohistiocytosis or systemic EBV-positive T cell lymphoproliferative disease of childhood. EBV DNA was detected at a high level in PBMNCs, although it was negative in plasma. On the basis of the pathological analysis of the explanted liver tissues, LT was proposed for the restoration of liver function and the removal of the EBV-infected lymphocytes concentrated in the liver. Detecting EBV DNA by a quantitative polymerase chain reaction in plasma and PBMNCs was informative. An accurate evaluation of the underlying pathogenesis is essential for developing a treatment strategy in patients with EBV-induced FHF.

A Case of Acute Liver Failure Associated With Synthetic Cannabis Use: Presidential Poster

Introduction: A previously healthy 27-year-old man was transferred to our institution with concerns for acute liver failure. He presented after 2-3 days of fatigue, anorexia, nausea, and vomiting. At the local hospital, he was found to have transaminases in the 10,000s, creatinine of 2.2, INR 6.5, and a lactic acid of >15, prompting transfer to our ICU. On arrival, the patient was alert but acutely ill-appearing. He denied use of any IV drugs, alcohol, or prescription medications. He admitted to current marijuana, synthetic cannabis, and tobacco use. He denied any OTC medications or supplements other than <2 gm of APAP used in the last 2 days since becoming ill. An infectious work-up was negative. An extensive liver evaluation showed no signs of autoimmune hepatitis, viral hepatitis, or toxin exposure. Tests for alpha-1-antitrypsin and Wilson’s disease were negative. Acetaminophen levels were low. Shortly after admission, the patient became obtunded, requiring intubation for airway protection. His acidosis worsened, and CVVH was initiated. Overnight, he developed significant hypoxia and hypotension. His clinical status continued to decline despite maximal intervention, and he was made DNR. He died a few hours later; less than 24 hours after admission. Autopsy revealed fulminant liver failure with massive (80-90%) acute hepatocellular necrosis. The patient was also found to have diffuse alveolar damage, consistent with ARDS, and ATN of the kidneys. Toxicology screen was positive for marijuana and 5F-PB-22, a synthetic cannabinoid. No other causes of the acute liver failure were identified. Although marketed as a harmless, legal alternative to marijuana, synthetic cannabinoids have been associated with cases of respiratory distress, acute kidney injury, psychosis, and death. Since this “synthetic marijuana” first appeared on the market in the early 2000s, the DEA has banned several chemical forms; however, the law has been unable to keep up with the influx of new formulations. 5F-PB-22 is a newer generation of synthetic cannabis and the first to contain an ester backbone in its chemical structure. This alteration appears to be associated with increased toxicity, with 5 deaths attributed to its use in less than a year. The constantly evolving structure of synthetic cannabinoids makes it difficult to predict associated complications. To our knowledge, this patient is the first to have acute liver failure associated with synthetic cannabis use. This case illustrates that new health problems continue to be identified and that all physicians should be familiar with these compounds. A complete history and high index of suspicion may help bring to light more conditions associated with synthetic cannabis use.

Laparoscopic liver biopsy in the diagnosis of hepatic epithelioid hemangioendothelioma: A case report.

Hepatic epithelioid hemangioendothelioma (HEH) is a rare vascular tumor of the liver, and its definitive diagnosis is completely dependent on histopathological verification. In the present study, we report the case of a patient whose percutaneous liver biopsy failed to reveal a diagnosis of HEH, twice, and who was ultimately diagnosed by laparoscopic liver biopsy. The patient was a 42-year-old female with mild right upper quadrant discomfort. Ultrasonography and magnetic resonance imaging showed multiple mass lesions scattered throughout the liver, but no evidence of extrahepatic diseases. The initial laboratory tests included liver function tests and tumor markers were within normal limits. Subsequently, two, ultrasound (US)-guided liver biopsies from the liver lesion were performed using an 18-gauge needle, and both of these showed massive hepatocellular necrosis. To obtain adequate tissue samples for histological examination, the patient underwent laparoscopic liver biopsy. The overall immunohistochemical findings supported the diagnosis of HEH. In the present case, two, US-guided percutaneous liver biopsies failed to diagnose HEH, and laparoscopic liver biopsy was safely performed to obtained adequate specimens for analysis. Although this method is not the preferred technique and has certain disadvantages, it is considered to be a useful and minimally invasive approach for liver lesions when other less-invasive diagnostic modalities fail or are difficult to be performed.

Acute Liver Failure Following a Year of Consumption of a Popular Sugar-free Energy Drink

Purpose: A 36-year-old Caucasian male without prior medical history initially presented to another facility with one week of right upper quadrant (RUQ) abdominal pain, jaundice and fatigue. After abnormal lab values (Table 1) were found, he left that facility and presented to this hospital. He admitted to weekend binge drinking and drank 10 beers three hours prior to symptom onset. He denied taking herbal remedies, homeopathic medications or other supplements. He drank up to three energy drinks (Figure 1) on a daily basis for the past year. Physical exam showed stable vital signs, jaundice, spider nevi and RUQ tenderness. Initial work-up was negative for viral, ischemic or autoimmune hepatitis. On HD #6, a liver biopsy showed severe active hepatitis with bridging necrosis consistent with an herbal/drug-toxicity pattern. On HD #9, the patient was discharged home, but was soon re-admitted for worsening LFTs. With an INR of 4.2, he was placed on the UNOS waiting list with a MELD score of 41. On HD #14 of this secondhospitalization, a suitable donor became available and the patient underwent successful liver transplantation. Gross liver pathology showed massive hepatocellular necrosis and parenchymal collapse consistent with drug-induced liver injury. He was discharged on post-operative day number seven.Table 1: Laboratory findingsFigure 1: Ingredients of sugar-free energy drink.Discussion: A similar case report by Vivekanandarajah et al. described a young woman who drank 10 cans of an energy drink for 2 weeks, resulting in acute hepatitis. The authors concluded that Vitamin B3 (niacin) was the culprit ingredient. Our case report details a patient who drank a sugar-free energy drink over a longer period and had a more serious clinical course. The patient's prior alcohol use may have provided a “first hit” on the liver, making it more susceptible to further insults. The energy drink in this case report contains many ingredients, some of which do not have a well-established safety profile. While drinking modest amounts of energy drinks appears to be relatively safe, frequent consumption over an extended period of time has recently been linked with hepatic injury.

Thioacetamide-induced Hepatocellular Necrosis Is Attenuated in Diet-induced Obese Mice

To assess modification of thioacetamide-induced hepatotoxicity in mice fed a high-fat diet, male C57BL/6J mice were fed a normal rodent diet or a high-fat diet for 8 weeks and then treated once intraperitoneally with thioacetamide at 50 mg/kg body weight. At 24 and 48 hours after administration, massive centrilobular hepatocellular necrosis was observed in mice fed the normal rodent diet, while the necrosis was less severe in mice fed the high-fat diet. In contrast, severe swelling of hepatocytes was observed in mice fed the high-fat diet. In addition, mice fed the high-fat diet displayed more than a 4-fold higher number of BrdU-positive hepatocytes compared with mice fed the normal rodent diet at 48 hours after thioacetamide treatment. To clarify the mechanisms by which the hepatic necrosis was attenuated, we investigated exposure to thioacetamide and one of its metabolites, the expression of CYP2E1, which converts thioacetamide to reactive metabolites, and the content of glutathione S-transferases in the liver. However, the reduced hepatocellular necrosis noted in mice fed the high-fat diet could not be explained by the differences in exposure to thioacetamide or thioacetamide sulfoxide or by differences in the expression of drug-metabolizing enzymes. On the other hand, at 8 hours after thioacetamide administration, hepatic total glutathione in mice fed the high-fat diet was significantly lower than that in mice fed the normal diet. Hence, decreased hepatic glutathione amount is a candidate for the mechanism of the attenuated necrosis. In conclusion, this study revealed that thioacetamide-induced hepatic necrosis was attenuated in mice fed the high-fat diet.

Intoxicação espontânea e experimental por Pterodon emarginatus (Fabaceae Faboideae) em bovinos e experimental em ovinos

Relatam-se mortalidades de bovinos nos Estados de Mato Grosso e Mato Grosso do Sul relacionadas ao consumo de folhas de Pterodon emarginatus. Três surtos ocorreram no período de seca na região Centro-Oeste, após a queda de árvores devido a ventos fortes ou após serem derrubadas para aproveitamento da madeira. Morreram 40 bovinos em três diferentes surtos. A intoxicação foi reproduzida com administração de folhas de P. emarginatus; a dose tóxica mínima foi 20g/kg para ovinos e 6g/kg para bovinos. Os sinais clínicos iniciaram-se entre 24 e 72 horas após o consumo da planta. A evolução clínica da doença letal foi de 12 a 36 horas. Os sinais clínicos se caracterizaram por apatia, depressão, andar a esmo, pressão da cabeça contra objetos. Em dois dos surtos, os bovinos que sobreviveram a fase aguda da doença, desenvolveram fotossensibilização. Os principais achados macroscópicos nos casos espontâneos e experimentais foram no fígado; estes se caracterizaram por hepatomegalia e evidenciação do padrão lobular na superfície capsular e de corte. Notaram-se também hemorragias nas serosas abdominais e torácicas. Microscopicamente observou-se necrose coagulativa hepatocelular, que variou de centrolobular a massiva, por vezes associada à congestão e hemorragia; ocorreu também marcada tumefação e vacuolização de hepatócitos na região periacinar. O diagnóstico foi baseado nos dados epidemiológicos, clínicos, patológicos e na reprodução experimental da intoxicação em bovinos e ovinos. Estes achados caracterizam P. emarginatus como planta hepatotóxica de interesse pecuário na região Centro-Oeste do Brasil.

Sawfly larval poisoning in cattle: Report on new outbreaks and brief review of the literature

Sawfly larval poisoning (SLP) is an acute hepatotoxicosis documented in livestock in Australia, Denmark and in countries of South America. It is caused by the ingestion of the larval stage of insects of the suborder Symphyta, order Hymenoptera, commonly known as "sawfly". Three species of sawfly are reportedly involved in the toxicosis. The insect involved in Australian SLP is Lophyrotoma interrupta (Pergidae), in Denmark the cause of SLP is the ingestion of the larvae Arge pullata (Argidae), and in South American countries documented outbreaks of SLP were caused by the ingestion of yet another sawfly, Perreyia flavipes (Pergidae). In all geographical areas where it occurred, SLP causes important livestock losses. In cattle, as well as in other affected species, the disease has a short clinical course and in many outbreaks affected cattle can be found dead. When observed, clinical signs include apathy, recumbence, tremors, paddling movements and death in 24-48 hours. Neurological signs such aggressiveness attributable to hepatic encephalopathy are also observed. In cases with a more protracted course icterus and photodermatitis may develop. Gross findings included ascites, petechiae and ecchymosis over serosal surfaces of thoracic and abdominal cavities, and an enlarged liver that displays accentuation of the lobular pattern and edema of the gall bladder wall. Sawfly larval body fragments and heads are consistently found in the fore stomachs and occasionally abomasum of affected cattle. Main microscopic lesions are restricted to the liver and consist of centrolobular (periacinar) to massive hepatocellular necrosis. In most lobules necrotic areas extended up to the portal triads where only a few viable hepatocytes remain. Mild to moderate lymphocyte necrosis is seen in lymphatic tissues. Cases occur in the winter months when the larval stages of the sawfly are developing. D-amino acid-containing peptides have been found to be the toxic principle in each sawfly involved in SLP. The octapeptide lophyrotomin is the major toxin in the in the larvae of Australian and Danish sawflies and is present in small amounts in the larvae of South American sawfly. The heptadecapeptide pergidin is the main toxin in the South American sawfly while small amounts of pergidin have been found in the other two species of toxic sawfly. During the winter of 2011 (July-August) four outbreaks of SLP were diagnosed in the State of Rio Grande do Sul, Brazil. The findings in those outbreaks are reported here and a brief review of the literature regarding SLP around the world is provided.

Intoxicação espontânea por Pterodon emarginatus (Fabaceae) em bovinos no estado de Goiás

Descreve-se um surto de intoxicação por Pterodon emarginatus em bovinos no Estado de Goiás. De um lote de 84 bovinos que comeram avidamente folhas e os frutos da planta após a queda acidental de uma árvore, todos os animais adoeceram e sete morreram. Os sinais clínicos observados foram eriçamento dos pelos, retração do flanco, apatia profunda, prostração, tremores musculares, ressecamento do focinho, tenesmo, incoordenação, relutância em movimentar-se e decúbito esternal prolongado. As atividades séricas de AST, ALT e GGT e os teores de bilirrubina estavam acentuadamente elevados. As principais alterações macroscópicas consistiam de hepatomegalia e áreas multifocais de necrose no fígado, além de hemorragias no coração, pleura parietal, mesentério, omento, serosa do rúmen, baço, pulmão, subcutâneo e musculatura esquelética intercostal e torácica. Microscopicamente, observou-se degeneração e necrose hepatocelular massiva moderada a acentuada, hiperplasia biliar multifocal moderada e bilestase multifocal leve. Adicionalmente, notou-se degeneração vacuolar multifocal moderada nos túbulos contorcidos dos rins.

Host genetic variation in susceptibility to Punta Toro virus

Infection of small laboratory animals by Punta Toro virus (PTV), family Bunyaviridae, genus Phlebovirus, is a model for the study of the human pathogen Rift Valley fever virus (RVFV). We have identified inbred mouse strains with significant differences in host response to the Adames strain of PTV. Nine inbred strains of mice representing major branches in the Mus musculus phylogeny were inoculated subcutaneously with a high dose of PTV in survival experiments. Two inbred strains of mice, NZW/LacJ and 129S1/SvImJ, died ∼4days after PTV infection, whereas 7 other strains survived the challenge and showed no clinical signs of disease. Histologically, 129S1/SvImJ mice showed massive hepatocellular necrosis and had additional lesions in lung, brain, and spleen, whereas NZW/LacJ mice had mild piecemeal hepatocellular necrosis. PTV viral loads in the livers of infected mice were determined by reverse transcriptase quantitative PCR. Inbred mice from strains that showed clinical signs and succumbed to PTV infection had higher liver viral loads than did mice of resistant strains. Hybrid F1 mice were generated by crossing susceptible 129S1 and resistant FVB/N mice and tested for susceptibility. The hybrid F1 mice showed significantly higher viral loads in the liver than the resistant parental FVB/N mice, suggesting that susceptibility is dominant. These findings will enable an unbiased genetic approach to identify host genes mediating susceptibility to PTV.