Increased Serum Liver Enzymes Research Articles

Acute and Sub-chronic Toxicity of Aqueous Extract of Roots of Khaya senegalensis (Desr.) A. Juss. in Mice and Rats Respectively

Aim: Khaya senegalensis is one of the key medicinal plants used discretionarily in traditional medicine as remedies to several health conditions. This study aimed to establish the safety of Khaya senegalensis root aqueous extract in experimental animals with the purpose of optimizing its therapeutic value. 
 Methodology: A total of 74 animals (20 rats and 54 mice) were randomly assigned into two main groups based on toxicity plan; acute and sub-chronic toxicity. Mice were divided into 9 groups (6 per group) for the acute toxicity study while rats were divided into 4 groups (5 per group) for sub-chronic toxicity assessment. 
 Results: The acute concentrations of the extract in mice induced dose-dependent clinical signs severities such as: twitching, increase rate of respiration, sedation, abdominal muscle contractions and increased motor activity. The lethal dose 50 value of the extract was estimated as 320mg/ kg body. The sub-chronic concentrated grades in the rats especially the higher doses elicited significantly increased serum liver enzymes values when compared to the control, while at low dose the values were comparable to that of the control. Also observed were the evidences of renal cellular pathology ranging from mild to severe tubular cell degeneration, tubular cell depletion and congestion of the renal cortex. The liver pathologies such as hepatic portal congestion, cytoplasmic vacuolations and nuclear degeneration were strikingly visible mostly at the higher doses. The lymphocyte and platelet counts were the only haematological parameters that increased significantly more particularly at low dose when compared with the control.
 Conclusion: This study has shown that Khaya senegalensis seems to be safe only at low doses. However, caution should be taking in its administration for therapeutic purposes especially when long-term usage is desired.

Multimodal Blockade of the Renin-Angiotensin System Is Safe and Is a Potential Cancer Treatment for Cats.

Simple SummaryAs activation of the renin-angiotensin system (RAS) promotes cancer cell growth, medications that inhibit RAS activation could reduce cancer progression. However, studies in people in which RAS has been inhibited by a single treatment have not been consistently beneficial, possibly as RAS can be activated by many different cellular pathways. Multiple treatments have been used to more consistently block RAS in people, but such multimodal treatments have never previously been evaluated in veterinary species. In the present study, the safety of multimodal RAS inhibition using a combination of five treatments was assessed in six cats with cancer. Cats were treated for 8 weeks and none of the cats developed low blood pressure, evidence of kidney or liver disease, or significant adverse effects. Of the six cats enrolled in the study, one cat was withdrawn from the study due to difficulties administering the medications and another cat died of an unrelated cause. Two cats were euthanatized due to cancer progression during the study period while two cats completed the 8-week treatment period. The study showed that a multimodal blockade of RAS has the potential to be a safe and cost-effective treatment for cancer in cats.The role of the renin-angiotensin system (RAS) in cancer growth and progression is well recognized in humans. However, studies on RAS inhibition with a single agent have not shown consistent anticancer effects, potentially due to the neoplastic cells utilizing alternative pathways for RAS activation. To achieve more complete RAS inhibition, multimodal therapy with several medications that simultaneously block multiple steps in the RAS has been developed for use in humans. In the present study, the safety of multimodal RAS inhibition using atenolol, benazepril, metformin, curcumin, and meloxicam was assessed in six cats with squamous cell carcinomas. Cats were treated for 8 weeks, with blood pressure measured and blood sampled five times during the treatment period. None of the cats developed hypotension, azotemia, or increased serum liver enzyme concentrations. The packed cell volume of one cat decreased to just below the reference range during treatment. One cat was reported to have increased vomiting, although this occurred infrequently. One cat was withdrawn from the study due to difficulties administering the medications, and another cat died of an unrelated cause. Two cats were euthanatized during the study period due to cancer progression. Two cats completed the 8-week study period. One was subsequently euthanized due to cancer progression while the other cat is still alive 32 weeks after entering the study and is still receiving the multimodal blockade of the RAS. This is the first evaluation of multimodal blockade of the RAS in veterinary species. The study showed that the treatment is safe, with only mild adverse effects observed in two treated cats. Due to the small number of cats, the efficacy of treatment could not be evaluated. However, evidence from human studies suggests that a multimodal blockade of RAS could be a safe and cost-effective treatment option for cancer in cats.

Long-term exposure to ambient air pollution and serum liver enzymes in older adults: A population-based longitudinal study

To investigate the association of long-term exposure to ambient air pollution with serum liver enzymes in older adults. In this longitudinal study, we investigated 318,911 adults aged 65 years or older and assessed their long-term residential exposure to particulate matter with an aerodynamic diameter ≤2.5 µm (PM_2.5), particulate matter with an aerodynamic diameter ≤10 µm (PM₁₀), sulfur dioxide (SO₂), nitrogen dioxide (NO₂), carbon monoxide (CO), and ozone (O₃). Linear mixed models and generalized linear mixed models were implemented for exposure-response analyses. Each interquartile range (IQR) increase of PM_2.5, PM₁₀, SO₂, NO₂, CO, and O₃ exposures was significantly associated with a 4.6%, 4.6%, 5.6%, 4.6%, 6.2%, and 3.6% increase in alanine aminotransferase (ALT), and a 4.6%, 5.2%, 3.6%, 3.3%, 6.1%, and 4.0% increase in aspartate aminotransferase (AST), respectively. Each IQR increase of PM_2.5, PM₁₀, SO₂, NO₂, CO, and O₃ exposures was significantly associated with a 23%, 24%, 28%, 17%, 31%, and 19% increase in odds of elevated ALT (>40 U/L), and a 32%, 39%, 40%, 32%, 57%, and 25% increase in odds of elevated AST (>40 U/L), respectively. Long-term exposure to ambient air pollution was significantly associated with increased serum liver enzyme levels in older adults, suggesting that air pollution exposures may induce hepatocellular injury.

LBA01-07 OVERALL SAFETY AND INCIDENCES OF ADVERSE EVENTS BY TIME INTERVAL WITH DAROLUTAMIDE PLUS ANDROGEN-DEPRIVATION THERAPY AND DOCETAXEL IN THE PHASE 3 ARASENS TRIAL

You have accessJournal of UrologyCME1 May 2022LBA01-07 OVERALL SAFETY AND INCIDENCES OF ADVERSE EVENTS BY TIME INTERVAL WITH DAROLUTAMIDE PLUS ANDROGEN-DEPRIVATION THERAPY AND DOCETAXEL IN THE PHASE 3 ARASENS TRIAL E. David Crawford, Matthew R. Smith, Bertrand Tombal, Karim Fizazi, Maha Hussain, Cora N. Sternberg, Arash Rezazadeh Kalebasty, Ronald Tutrone, Neal D. Shore, Laurence Belkoff, Silke Thiele, Rui Li, Iris Kuss, Heikki Joensuu, and Fred Saad E. David CrawfordE. David Crawford More articles by this author , Matthew R. SmithMatthew R. Smith More articles by this author , Bertrand TombalBertrand Tombal More articles by this author , Karim FizaziKarim Fizazi More articles by this author , Maha HussainMaha Hussain More articles by this author , Cora N. SternbergCora N. Sternberg More articles by this author , Arash Rezazadeh KalebastyArash Rezazadeh Kalebasty More articles by this author , Ronald TutroneRonald Tutrone More articles by this author , Neal D. ShoreNeal D. Shore More articles by this author , Laurence BelkoffLaurence Belkoff More articles by this author , Silke ThieleSilke Thiele More articles by this author , Rui LiRui Li More articles by this author , Iris KussIris Kuss More articles by this author , Heikki JoensuuHeikki Joensuu More articles by this author , and Fred SaadFred Saad More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002669.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In ARASENS, darolutamide (DARO)+androgen-deprivation therapy (ADT)+docetaxel significantly reduced risk of death by 32.5% (hazard ratio [HR] 0.675; 95% confidence interval [CI] 0.568–0.801; P <0.0001) vs ADT+docetaxel in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC). We report adverse events (AEs) and their incidences by time interval from ARASENS (NCT02799602). METHODS: Pts with mHSPC were randomized 1:1 to DARO 600 mg twice daily or matching placebo (PBO)+ADT+docetaxel. AE incidences by time interval were defined as number of pts with new-onset AE or worsening AE in an interval (every 3 months for year 1; 6 months for year 2) divided by number of pts in that interval. For AEs associated with AR pathway inhibitors, exposure-adjusted incidence rates (EAIR) are presented per 100 pt years to adjust for differences in treatment duration between groups. RESULTS: Of 1306 pts randomized, safety was evaluated in 1302 pts who received DARO (652) or PBO (650). Incidences of any-grade AEs (99.5%; 98.9%), grade 3–5 AEs (70.2%; 67.5%), serious AEs (44.8%; 42.3%), and discontinuations of DARO/PBO due to AEs (13.5%; 10.6%) were comparable for both groups. The most frequently reported AEs were alopecia (40.5%; 40.6%), neutropenia (39.3%; 38.8%), and fatigue (33.1%; 32.9%); incidences in both groups were highest in the first 6 months of treatment during the docetaxel treatment period and progressively decreased thereafter (Table). Similar trends were observed for other AEs reported in >10% of pts in either treatment group, including peripheral edema, diarrhea, nausea, increased serum liver enzyme concentrations, and peripheral neuropathy. Most AEs associated with AR pathway inhibitors showed ≤2% difference between DARO and PBO. Rash (16.6%; 13.5%) and hypertension (13.7%; 9.2%) (both grouped preferred terms) occurred in more pts receiving DARO vs PBO, but EAIRs were similar between groups (rash: 6.2; 7.3; hypertension: 5.1; 5.0). CONCLUSIONS: DARO+ADT+docetaxel significantly increased overall survival without added toxicity. In general, AE incidence was similar in both groups, with the highest incidence during the first 6 months of overlapping docetaxel treatment. Source of Funding: Bayer AG and Orion Pharma © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e1038 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information E. David Crawford More articles by this author Matthew R. Smith More articles by this author Bertrand Tombal More articles by this author Karim Fizazi More articles by this author Maha Hussain More articles by this author Cora N. Sternberg More articles by this author Arash Rezazadeh Kalebasty More articles by this author Ronald Tutrone More articles by this author Neal D. Shore More articles by this author Laurence Belkoff More articles by this author Silke Thiele More articles by this author Rui Li More articles by this author Iris Kuss More articles by this author Heikki Joensuu More articles by this author Fred Saad More articles by this author Expand All Advertisement PDF DownloadLoading ...

Hepatoprotective Effect of Pancha Lavana Dravagam Against Paracetamol induced Hepatotoxicity in Wistar Albino Rats - An in-Vivo Study

Objective: To evaluate the liver protective effect of Pancha Lavana Dravagam (PLD) against Paracetamol induced hepatotoxicity in wistar albino rat models.&#x0D; Methods: The hepatoprotective activity of PLD was evaluated using paracetamol induced liver damage in rats. Wistar albino rats were divided into five groups of six animals each. Paracetamol 1gm/kg bw, p.o. was given to produce liver toxicity. The normal control was given the vehicle (water 1ml/kg bw, p.o). Two test groups with PLD 1ml/kg, 2ml/kg bw, p.o. were tested for hepatoprotective potential. Silymarin 50mg/kg bw, p.o. was given as standard drug. All these drugs were administered for 7 days. On 8th day, the animals were sacrificed and blood was collected from retro-orbital plexus and analyzed for serum enzymes like Serum Glutamate Pyruvate Transaminase (SGPT), Serum Glutamate Oxaloacetate Transaminase (SGOT), Serum Alanine Phosphate (ALP), Total Bilirubin, Total Proteins and liver was excised for histopathological analysis.&#x0D; Results: In toxicant control group, paracetamol produced liver toxicity due to decrease in glutathione (GSH) by oxidative stress and mitochondrial dysfunction of hepatic cells. It resulted in an increase of serum liver enzymes like SGPT, SGOT, ALP and Total Bilirubin. This increased serum liver enzymes were reduced significantly in the test drug PLD treated groups and Standard group. The histology of liver tissues was also improved in PLD treated groups when compared to the toxicant group.&#x0D; Conclusion: Since, no scientific evidence is available to claim the hepatoprotective effect of PLD, in vivo studies were conducted. It demonstrated that it has a potent hepatoprotective effect against the paracetamol induced hepatotoxicity by suppression of the reactive oxygen species and increasing the anti-oxidant glutathione in liver cells.

Curcumin activation of nuclear factor E2-related factor 2 gene (Nrf2): Prophylactic and therapeutic effect in nonalcoholic steatohepatitis (NASH)

BackgroundsModern dietary habits have been associated with Nonalcoholic Steatohepatitis (NASH). Curcumin is a natural herbal found to suppress cellular oxidative states and could be beneficial in NASH. This study investigates the effect of curcumin in an animal model of NASH. Materials and methodsFifty rats were allocated into five groups. Control, High Fat Diet (HFD), curcumin prophylactic (CP) and therapeutic (CT) groups. HFD regimen was given for 16 weeks. Curcumin was given along with HFD (prophylactic) or after establishment of the model for two weeks (therapeutic). Livers and blood samples were harvested for histological, biochemical, and molecular studies. Key findingsLivers from HFD groups showed vascular, inflammatory, cellular degenerative and fibrotic changes. The hepatic damage was reflected by the increased serum liver enzymes. HFD groups showed excessive fibrotic change. Interestingly, curcumin administration as prophylactic or therapeutic significantly preserved and/or restored liver structure. This was evidenced by the normalization of the liver enzymes, preservation and/or reversibility of cellular changes and the decrease of the stage of fibrosis. Nuclear factor E2-related factor 2 gene (Nrf2) expression showed no changes in the HFD groups, however it showed upregulation in curcumin treated groups. Thus, the protective and therapeutic effect of curcumin could be induced through upregulation of the Nrf2 gene. Curcumin has a beneficial prophylactic and therapeutic effect that could hinder the development and/or treat NASH in susceptible livers. SignificanceCurcumin has a beneficial prophylactic and therapeutic effect that could hinder the development and/or treat NASH in susceptible livers.

Boldo-Induced Hepatotoxicity: A Case of Unexplained Jaundice.

Herbal medicines are commonly used by the public.Peumus boldus leaves consumed as an infusion can be hepatotoxic and may cause otherwise unexplained jaundice or abnormal liver enzyme values, particularly in elderly patients.A detailed clinical history is crucial to establish the consumption of alternative medicines in order to identify possible adverse effects and toxicity.

Feline comorbidities: What do we really know about feline triaditis?

Feline triaditis describes concurrent pancreatitis, cholangitis and inflammatory bowel disease (IBD). The reported prevalence is 17-39% in ill referral patients. While the aetiology is poorly understood, it is known to include infectious, autoimmune and physical components. What is not known is whether different organs are affected by different diseases, or the same process; indeed, triaditis may be part of a multiorgan inflammatory disease. Feline gastrointestinal tract anatomy plays its role too. Specifically, the short small intestine, high bacterial load and anatomic feature whereby the pancreatic duct joins the common bile duct before entering the duodenal papilla all increase the risk of bacterial reflux and parenchymal inflammation. Inflammation may also be a sequela of bowel bacterial translocation and systemic bacteraemia. Cholangitis, pancreatitis and IBD manifest with overlapping, vague and non-specific clinical signs. Cholangitis may be accompanied by increased serum liver enzymes, total bilirubin and bile acid concentrations, and variable ultrasonographic changes. A presumptive diagnosis of pancreatitis is based on increased serum pancreatic lipase immunoreactivity or feline pancreas-specific lipase, and/or abnormal pancreatic changes on ultrasonography, though these tests have low sensitivity. Diagnosis of IBD is challenging without histopathology; ultrasound findings vary from normal to mucosal thickening or loss of layering. Triaditis may cause decreased serum folate or cobalamin (B12) concentrations due to intestinal disease and/or pancreatitis. Triaditis can only be confirmed with histopathology; hence, it remains a presumptive diagnosis in most cases. The literature on feline triaditis, pancreatitis, cholangitis and IBD is reviewed, focusing on histopathology, clinical significance and diagnostic challenges. Current management recommendations are provided. Further studies are needed to understand the complex pathophysiology, and in turn improve diagnosis and treatment.

Morphophysiological Changes in the Liver of Wistar Rats Exposed to Acute and Chronic Concentrations of Vitellaria paradoxa

Background: Vitellaria paradoxa is a tropical plant with diverse folkloric health benefits that could be optimised in health product development. This study was therefore designed to investigate morphophysiological changes in the liver of rats exposed to acute and chronic concentrations of Vitellaria paradoxa Methods: A total of seventy-four (74) animals (Wistar rats and mice) were randomly assigned into two main groups based on toxicity plan; acute group consist of 9 sub-groups [0 (control), 10, 20, 40, 80,160, 320, 640 and 1280 mg/kg; n=6] while the chronic group consists of 4 sub-groups [0 (control), 32, 64 and 128 mg/kg; n=20] were orally exposed to Vitellaria paradoxa. The 96 hour LC50 value of Vitellaria paradoxa was calculated as 640mg/kg body Results: The acute concentrations of Vitellaria paradoxa induced dose-dependent severity in clinical signs such as: twitching, increase rate of respiration, sedation, abdominal muscle contractions and increased motor activity. The chronic concentrated grades of Vitellaria paradoxa more particularly the higher doses (64 and 128mg/kg) elicited significantly increased serum liver enzymes (ALT, ALP and AST) values compared to the control. Similarly, several hepatic histoarchitectural lesions such as: mild to severe, central venous and sinusoidal congestion, hepatic degeneration, and necrosis with loss of cord arrangement were strikingly visible at the higher doses. There was no significant difference in the haematological parameters across the different concentrations Conclusion: This study has shown that Vitellaria paradoxa seems to be unsafe following a prolonged administration. Therefore, caution should be taken in its both short and long term usage

Ameliorative effects of dietary Chlorella vulgaris and β-glucan against diazinon-induced toxicity in Nile tilapia (Oreochromis niloticus)

The present study was carried out to investigate the toxic effects of diazinon on growth performance, hepato-renal function, antioxidant system, innate immune response and comparing the protective role of dietary Chlorella vulgaris (CV) algae and β-glucan in intoxicated Nile tilapia (Oreochromis niloticus). One hundred and eighty healthy Nile tilapia (20 ± 6.1 g) were distributed equally into four groups; control group, DZN group (0.28 mg/L), DZN-CV group (5% CV) and DZN-β-glucan group (0.1% β-glucan) and treatments conducted for about 60 days. The results revealed that administration of DZN significantly increased serum liver enzymes, uric acid, creatinine, and malondialdehyde (MDA) in different tissues. Meanwhile, glutathione (GSH) and superoxide dismutase (SOD) in different tissues, as well as IgM, C-reactive protein (CRP), respiratory burst, lysozyme and bactericidal activities were significantly decreased in DZN group. In addition, expression of TNF-α gene was up-regulated and IL-10 was down-regulated in spleen of DZN intoxicated fish. The treatment of DZN exposed fish with CV and β-glucan supplemented diets ameliorated hepatic damage and enhanced antioxidant activity and innate immune responses. Furthermore, dietary Chlorella vulgaris and β-glucan have a potent anti-inflammatory effect as they remarkably increased the expression of IL-10 and decreased TNF-α gene expression. The results also revealed that fish in DZN-CV group had the highest survival rate, final body weight (FBW) and body weight gain (BWG). On the other hand, feed conversion ratio (FCR), specific growth rate (SGR), and protein efficiency ratio (PER) of control, DZN-CV, and DZN- β-glucan were higher than DZN group. However, the hepatosomatic index (HSI) and spleen-somatic index (SSI) were higher in DZN group than other experimental groups. Overall, CV and β-glucan can be recommended as a feed supplement to improve immunosuppression, oxidative damage, growth performance and hemato-biochemical alterations induced by DZN toxicity in Nile tilapia.

Antioxidant and Anti-Inflammatory Effects of Nano-Selenium against Cypermethrin-Induced Liver Toxicity

Cypermethrin (Cym) is a synthetic class II pyrethroid that is widely used and has a big risk to health. Cypermethrin produces oxidative stress and enhances inflammatory damage of liver. The present study was designed to investigate the ameliorating effects of NSe against Cym-induced hepatotoxicity in rats. For this purpose, twenty four male rats were divided into three groups. Group (I) was gavaged with Cym (control group), group (II) gavaged daily with Cym (1 mg/kg body weight), and group (III) gavaged with Cym + NSe (2.5 mg kg body weight/day, three times a week) for 21 days. Cypermethrin increased serum liver enzymes, oxidative stress and inflammatory markers. Administration of NSe significantly reduced the increased serum liver enzymes and inflammatory parameters and restored the antioxidant capacity in liver. Our results suggest that Nse exhibits promising hepato-protective effects against Cym-induced oxidative damage and inflammation.

P3-067 - A case of liver metastases with hyperbilirubinemia that was safely treated with chemotherapy (FOLFOX plus Cetuximab)

The liver and lungs are the most common sites of metastasis from colorectal cancer. Multiple liver metastases from colorectal cancer may result in severe liver dysfunction. The systemic chemotherapy for cases with severe liver dysfunction with hyperbilirubinemia and ascites is challenging. A 48-year-old man presented to our hospital with a complaint of anorexia and defecation difficulty for approximately two months' duration. Physical examination revealed jaundice and apparently enlarged liver within the right upper quadrant that extended 6 cm below the right costal margin. Laboratory data showed increased serum liver enzymes (AST 160 IU/L, ALT 38 IU/L, ALP 3674 IU/L, LDH 1347 IU/L), a total bilirubin level of 6.2 mg/dL and increased tumor markers (CEA 4536 ng/mL, CA 19-9 4363 U/mL). A CT scan revealed multiple liver metastases and moderate ascites. Endoscopic examination revealed sigmoid colon adenocarcinoma harboring with wild-type RAS. FOLFOX (folinic acid/5-FU/oxaliplatin) was started at full standard doses. We started Cetuximab after 1 week and then FOLFOX plus Cetuximab therapy was given every two weeks (Cetuximab was given weekly). Five weeks after the start of treatment, a CT scan showed that liver metastases were reduced in size and ascites disappeared. Laboratory date showed a decrease in serum liver enzymes (AST 30 IU/L, ALT 12 IU/L, ALP 785 IU/L, LDH 247 IU/L) and a total bilirubin level of 1.1 mg/dL. Serious adverse events didńt occur except for grade 3 skin reaction. The Systemic chemotherapy has been administered on an outpatient basis for seven months since the treatment initiation. FOLFOX plus Cetuximab therapy was effective and safe even in the patient with severe liver dysfunction.

PROTECTIVE EFFECT OF MORINGA PEREGRINA LEAVES EXTRACT ON ACETAMINOPHEN -INDUCED LIVER TOXICITY IN ALBINO RATS.

Background:Acetaminophen is a common antipyretic drug but at overdose can cause severe hepatotoxicity that may further develop into liver failure and hepatic centrilobular necrosis in experimental animals and humans. This study was undertaken to assess the ameliorative role of Moringa peregrina leaves extract against acetaminophen toxicity in rats.Materials and methods:Induction of hepatotoxicity was done by chronic oral administration of acetaminophen (750 mg/kg bwt) for 4 weeks. To study the possible hepatoprotective effect, Moringa peregrina leaves extract (200 mg/kg bwt) or Silymarin (50 mg/kg bwt) was administered orally, for 4 weeks, along with acetaminophen.Results:acetaminophen significantly increased serum liver enzymes and caused oxidative stress, evidenced by significantly increased tissue malondialdehyde, glutathione peroxidase, hepatic DNA fragmentation, and significant decrease of glutathione and antioxidant enzymes in liver, blood and brain. On the other hand, administration of Moringa peregrina leaves extract reversed acetaminophen-related toxic effects through: powerful malondialdehyde suppression, glutathione peroxidase normalization and stimulation of the cellular antioxidants synthesis represented by significant increase of glutathione, catalase and superoxide dismutase in liver, blood and brain, besides, DNA fragmentation was significantly decreased in the liver tissue.Conclusion:acetaminophen induced oxidative damage can be improved by Moringa peregrina leaves extract-treatment, due to its antioxidant potential.

Retrospective evaluation of acute liver failure in dogs (1995-2012): 49 cases.

To characterize the clinical presentation and outcome of dogs with acute liver failure (ALF). Retrospective case series from January 1995 to December 2012. University teaching hospital. Forty-nine dogs were diagnosed with ALF defined as the acute onset of clinical signs accompanied by serum hyperbilirubinemia and coagulopathy (prothrombin time >1.5 times the upper limit of the reference interval) with or without signs of hepatic encephalopathy. Medical records were retrospectively analyzed for clinical presentation, history, physical examination findings, clinicopathologic data, diagnostic imaging findings, hepatic histopathology, treatment, and outcome. Presenting signs included anorexia (28/49, 57%), vomiting (25/49, 51%), neurologic abnormalities (17/49, 35%), and polydipsia/polyuria (10/49, 20%). Neurologic impairment compatible with hepatic encephalopathy occurred at some point during hospitalization in 28/49 (57%) of dogs. Common clinicopathologic abnormalities on presentation other than hyperbilirubinemia and increased serum liver enzyme activity included thrombocytopenia (25/49, 51%), hypoalbuminemia (23/49, 46%), leukocytosis (17/49, 34%), anemia (14/49, 29%), hypokalemia (13/49, 27%), and hypoglycemia (10/49, 20%). The causes of ALF included neoplasia (13/49, 27%), presumptive leptosporosis (4/49, 8%), and ischemia (1/49, 2%). The remaining cases were idiopathic although 15 of these dogs had exposure to possible hepatotoxins. Common lesions in the 35/49 (71%) dogs that had hepatic histopathology were necrosis (19/39, 48%), lipidosis (16/39, 41%), vacuolar change (7/49, 14%), and inflammation (4/49, 8%). Complications included ascites (20/49, 41%), bleeding tendencies (14/49, 29%), pancreatitis (12/49, 24%), and acute tubular necrosis (11/49, 22%). Seven (14%) dogs survived to discharge. Survivors had higher alanine aminotransferase activity, and were more likely to maintain normal albumin concentrations and not develop clinical bleeding or ascites during hospitalization. Canine ALF is associated with multiple etiologies and a high mortality rate. Strategies to increase survival are urgently required.

Panax ginseng Meyer prevents radiation-induced liver injury via modulation of oxidative stress and apoptosis

BackgroundRadiotherapy is one of the most important modalities in cancer treatment; however, normal tissue damage is a serious concern. Drug development for the protection or reduction of normal tissue damage is therefore a clinical issue. Herein, we evaluated the protective properties of Panax ginseng Meyer and its corresponding mechanisms. MethodsC56BL/6 mice were orally pretreated with P. ginseng water extract (PGE; 25 mg/kg, 50 mg/kg, or 100 mg/kg) or intraperitoneally injected melatonin (20 mg/kg) for 4 d consecutively, then exposed to 15-Gy X-ray radiation 1 h after the last administration. After 10 d of irradiation, the biological properties of hematoxicity, fat accumulation, histopathology, oxidative stress, antioxidant activity, pro-inflammatory cytokines, and apoptosis signals were examined in the hepatic tissue. ResultsThe irradiation markedly induced myelosuppression as determined by hematological analysis of the peripheral blood. Steatohepatitis was induced by X-ray irradiations, whereas pretreatment with PGE significantly attenuated it. Oxidative stress was drastically increased, whereas antioxidant components were depleted by irradiation. Irradiation also notably increased serum liver enzymes and hepatic protein levels of pro-inflammatory cytokines. Those alterations were markedly normalized by pretreatment with PGE. The degree of irradiation-induced hepatic tissue apoptosis was also attenuated by pretreatment with PGE, which was evidenced by a terminal deoxynucleotidyl transferase 2′-deoxyuridine 5′-triphosphate nick-end labeling assay, western blotting, and gene expressions analysis, particularly of apoptotic molecules. ConclusionWe suggest that PGE could be applicable for use against radiation-induced liver injury, and its corresponding mechanisms involve the modulation of oxidative stress, inflammatory reactions, and apoptosis.

Reduced Lysosomal Acid Lipase Activity in Adult Patients With Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is characterized by intra-hepatic fat accumulation and mechanisms involved in its pathogenesis are not fully explained. Lysosomal Acid Lipase (LAL) is a key enzyme in lipid metabolism. We investigated its activity in patients with fatty liver.LAL activity (nmol/spot/h) was measured in 100 adult healthy subjects (HS) and in 240 NAFLD patients. A sub-analysis on 35 patients with biopsy-proven non-alcoholic steatohepatitis (NASH) was performed.Median LAL activity was 1.15 (0.95–1.72) in HS. It was significantly reduced in NAFLD [0.78 (0.61–1.01), p<0.001 vs. HS]. A further reduction was observed in the subgroup of NASH [0.67 (0.51–0.77), p<0.001 vs. HS]. Patients with LAL activity below median had higher values of serum total cholesterol (p<0.05) and LDL-c (p<0.05), and increased serum liver enzymes (ALT, p<0.001; AST, p<0.01; GGT, p<0.01). At multivariable logistic regression analysis, factors associated with LAL activity below median were ALT (OR: 1.018, 95% CI 1.004–1.032, p=0.011) and metabolic syndrome (OR: 2.551, 95% CI 1.241–5.245, p=0.011), whilst statin use predicted a better LAL function (OR: 0.464, 95% CI 0.248–0.866, p=0.016).Our findings suggest a strong association between impaired LAL activity and NAFLD. A better knowledge of the role of LAL may provide new insights in NAFLD pathogenesis.

P450-mediated O-demethylated metabolite is responsible for rat hepatobiliary toxicity of pyridyltriazine-containing PI3K inhibitors.

The dysregulation of phosphatidylinositol 3-kinase (PI3K)-dependent pathways is implicated in several human cancers making it an attractive target for small molecule PI3K inhibitors. A series of potent pyridyltriazine-containing inhibitors of class Ia PI3Ks were synthesized and a subset of compounds was evaluated in exploratory repeat-dose rat toxicology studies. Daily oral dosing of compound 1: in Sprague Dawley rats for four consecutive days was associated with hepatobiliary toxicity that included biliary epithelial hyperplasia and hypertrophy, periductular edema, biliary stasis, and acute peribiliary inflammatory infiltrates. These histological changes were associated with clinical pathology changes that included increased serum liver enzymes, total bile acids, and bilirubin. The predominant clearance pathway of 1: was shown in vitro and in a bile-duct cannulated rat (14)C-ADME study to be P450-mediated oxidative metabolism. An O-demethylated pyridine metabolite, M3: , was identified as a candidate proximal metabolite that caused the hepatotoxicity. Co-administration of the pan-P450 inhibitor 1-aminobenzotriazole with 1: to rats significantly reduced the formation of M3: and prevented liver toxicity, whereas direct administration of M3: reproduced the toxicity. Structural changes were introduced to 1: to make the methoxypyridine ring less susceptible to P450 oxidation (compound 2: ), and addition of a methyl group to the benzylic carbon (compound 3: ) improved the pharmacokinetic profile. These changes culminated in the successful design of a clinical candidate 3: (AMG 511) that was devoid of liver toxicity in a 14-day rat toxicity study. Herein, we describe how a metabolism-based structure-activity relationship analysis allowed for the successful identification of a PI3K inhibitor devoid of off-target toxicity.

Intraductal papillary neoplasm of the bile duct developing in a patient with primary sclerosing cholangitis: A case report

We report a case of intraductal papillary neoplasm of the bile duct (IPNB) that developed in a patient with primary sclerosing cholangitis. A 46-year-old woman was admitted to our hospital with obstructive jaundice. The liver function tests demonstrated increased serum liver enzyme levels. Computed tomography showed dilatation of the intrahepatic bile ducts. Abdominal ultrasonography revealed a highly echoic protruding lesion in the posterior bile duct near the right lobe of the liver. The lesion was suspected to be IPNB, but we were unable to confirm whether it was a carcinoma. A right hepatectomy was performed, and this showed that the dilated bile duct was filled with mucin and contained several yellowish papillary tumors. Histologically, the neoplastic biliary epithelium showed papillary growth in the dilated lumen. The tumor was diagnosed as IPNB, high-grade intraepithelial neoplasia secreting abundant mucin. No recurrence has been detected 3 years after surgery.

Bone Marrow and Nonbone Marrow Toll Like Receptor 4 Regulate Acute Hepatic Injury Induced by Endotoxemia

BackgroundToll-like receptors (TLRs) are expressed in immune cells and hepatocytes. We examined whether hepatic Toll-like receptor 4 (TLR4) is involved in the acute hepatic injury caused by the administration of lipopolysaccharide (LPS) (septic shock model).MethodsWild type (WT), TLR4-deficient and chimera mice underwent myeloablative bone marrow transplantation to dissociate between TLR4 expression in the liver or in the immune-hematopoietic system. Mice were injected with LPS and sacrificed 4 hours later.ResultsCompared to TLR4 deficient mice, WT mice challenged with LPS displayed increased serum liver enzymes and hepatic cellular inflammatory infiltrate together with increased serum and hepatic levels of interleukin 1β (IL-1β), tumor necrosis factor α (TNFα) ,Up-regulation of hepatic mRNA encoding TLR4, IκB and c-jun expressions. TLR4 mutant mice transplanted with WT bone marrow were more protected than WT chimeric mice bearing TLR4 mutant hemopoietic cells from LPS, as seen by IL-1β and TNFα levels. We then used hepatocytes (Huh7) and macrophages from monocytic cell lines to detect TLR mRNA expression. Macrophages expressed a significantly higher level of TLR4 mRNA and TLR2 (more than 3000- and 8000-fold respectively) compared with the hepatocyte cell line. LPS administration induced TLR4 activation in a hepatocyte cell line in a dose dependent manner while TLR2 mRNA hardly changed.ConclusionsThese results suggest that TLR4 activation of hepatocytes participate in the immediate response to LPS induced hepatic injury. However, in this response, the contribution of TLR4 on bone marrow derived cells is more significant than those of the hepatocytes. The absence of the TLR4 gene plays a pivotal role in reducing hepatic LPS induced injury.

SP0102 Toward new diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis

Macrophage activation syndrome (MAS) is a severe, potentially fatal complication of systemic juvenile idiopathic arthritis (sJIA) with features of hemophagocytosis, leading to coagulopathy, pancytopenia, and liver and central nervous system...