- Email: [email protected]
Sa1559 The Preventive Effect of Recombinant Human Soluble Thrombomodulin in the Sinusoidal Obstruction Syndrome in Mice
Sa1556
nuclear accumulation of Nrf2 and enhanced mRNA and protein expression of the Nrf2 target genes HO-1, NQO1 and GCLC. Meanwhile, Serum transaminases analysis and liver histological evaluation demonstrated pretreatment with CGA significantly decreased CCl4induced liver injury. CGA reduced CCl4-induced the increased MDA activity and increased the level of GSH, SOD and CAT in liver tissue. In addition, CGA reduced CCl4-induced the increased liver mRNA and serum levels expression of TNF- a, IL-1band IL-6. Conclusions Collectively, our results demonstrates that CGA facilitates Nrf2 nuclear accumulation, causing induction of antioxidant genes, which may be contribute to protection from CCl4-induced liver injury.This work was supported by National Natural Science Foundation of China ( NO.81200310 ).
AASLD Abstracts
Cytoprotective Effect of Soluble Thrombomodulin Attenuates Endothelial Cell Damage in Sinusoidal Obstruction Syndrome Satoshi Takada, Tomoharu Miyashita, Makoto Nakura, Shunsuke Kanou, Seiichi Munesue, Yasuhiko Yamamoto, Sachio Fushida, Tetsuo Ohta [Background] Hepatic sinusoidal obstruction syndrome (SOS) is a drug-induced liver injury, and its initial morphological change appears in liver sinusoidal endothelial cells (LSECs). Recently, recombinant human soluble thrombomodulin (rTM) was reported to have antiinflammatory and cytoprotective effects in an animal model. We investigated the cytoprotective and enhancement effects of the endothelial cell functions of rTM by using a monocrotaline (MCT)-induced SOS model. [Methods] In vitro model: Human umbilical endothelial cells were cultured for 24 hours and treated with MCT (2-4 mM) and/or rTM (10-100 ng/mL). Caspase activities and MTT assays were performed after 4-12 hours. Phospho-Akt (p-Akt) expression was assessed by using western blot, and cAMP and eNOS expressions were assessed by using enzyme-linked immunosorbent assay. In vivo model: Crl:female CD1 mice were divided into two groups according to the treatment administered, namely MCT only (270 mg/kg) and MCT + rTM (2 mg/kg). LSECs were identified as CD31+CD34+VEGFR3+ by using fluorescence-activated cell sorting (FACS). The function of the LSECs, including PAI-1, HGF, and eNOS, were assessed by performing quantitative reverse transcription polymerase chain reaction. [Results] In vitro model: Caspase 3 and 7 activities were significantly reduced (p < 0.05), and the cell viability assessed by using MTT assay was higher (p < 0.05) in the MCT + rTM group than in the MCT-only group (Fig. 1,2). The increases in the expression levels of p-Akt, cAMP, and eNOS were higher in the MCT + rTM group than in the MCT-only group. In vivo model: Liver damage in zone 3 was attenuated in the MCT + rTM group. FACS revealed that the number of LSECs were maintained in the MCT + rTM group. In the LSECs, the expression levels of eNOS and HGF were higher but that of PAI-1 was lower in the MCT + rTM group. [Conclusion] Soluble thrombomodulin can attenuate SOS by exerting a protective effect on the LSECs and enhancing their functions.
Sa1558 Risk of Non-Steroidal Anti-Inflammatory Drugs-Related Serious Drug-Induced Liver Injury: A Systematic Review and Meta-Analysis Sakkarin Chirapongsathorn, Chayakrit Krittanawong, Ann M. Farrell, Mohammad H. Murad, Patrick Kamath Backgrounds: Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most widely prescribed class of medications worldwide and many adverse events from these drugs are recognized, including gastrointestinal bleeding, cardiovascular events or nephrotoxicity. Several NSAIDs have been withdrawn from the market because of serious drug-induced liver injury (DILI) but epidemiologic data on NSAID-related DILI are very limited. We performed a systematic review and meta-analysis to evaluate the risk of serious DILI in patients taking NSAIDs. Methods: We conducted a comprehensive search of MEDLINE, Embase, Web of Science, Scopus databases and Cochrane Databased of Systemic Reviews through April 2015 and manually reviewed the literature. Attempts were made to contact the corresponding authors of the relevant studies for additional information when needed. Trial-specific risk ratios (RRs) were estimated and pooled using random-effect model metaanalysis. Between-study heterogeneity was assessed using the I2 statistic. The quality assessment of included studies and publication bias were assessed. Serious DILI defined by serum transaminases elevation > 2 times the upper limit of normal (ULN) and total bilirubin elevations > 2 ULN or hospitalization due to DILI or acute liver failure or death. Result: We included 6 observational studies (4 for case-control studies and two for cohort studies) at moderate risk of bias in which 5,045 events of serious DILI were reported. NSAIDs users had a significantly higher risk of serious DILI (RR, 2.13; 95% CI,1.76-2.58 ,I2 = 37%) compared to any other population that did not involve use of NSAIDs. Among included NSAIDs medications, flurbiprofen had the highest risk (RR, 5.54; 95% CI, 1.04-29.69) followed by sulindac (RR, 5.05; 95% CI, 2.14-11.94), ibuprofen (RR, 3.02; 95% CI, 2.63.53), and diclofenac (RR, 2.48; 95% CI, 2.25-2.74). There was no statistically significant increase risk for piroxicam (RR, 1.46; 95% CI, 0.78-2.73) and naproxen (RR, 1.19; 95% CI, 0.54-2.6). Conclusions: The use of NSAIDs may be associated with increased risk of serious DILI. Caution should be advised when using NSAIDs, especially flurbiprofen (discontinued in US), sulindac, ibuprofen and diclofenac.
Fig. 1
Figure 1 Summary risk ratios for serious drug-induced liver injury from non-steroidal antiinflammatory drugs (NSAIDs)
Sa1559 The Preventive Effect of Recombinant Human Soluble Thrombomodulin in the Sinusoidal Obstruction Syndrome in Mice Shunsuke Kanou, Satoshi Takada, Makoto Nakura, Tomoharu Miyashita, Seiichi Munesue, Yasuhiko Yamamoto, Sachio Fushida, Tetsuo Ohta
Fig. 2
Sa1557 Chlorogenic Acid Facilitates NRF2-Mediated Antioxidant Gene and Protects Against CCL4-Induced Liver Injury Haitao Shi, Ameng Shi, Lei Dong, Fei Dai, Xiaolan Lu, Yan Wang Backgroud/Aim Chlorogenic acid (CGA) is a type of polyphenol with anti-inflammatory and antioxidant activities. Our previous study showed CGA could inhibit CCl4-induced liver fibrosis in rats via anti-inflammatory activities. CGA has been reported to induce expression of the antioxidant enzymes in various cell lines. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays an important role in the cellular protection against oxidative stress through induction of several phase-2 detoxifying and antioxidant enzymes including heme oxygenase1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutamate-cysteine ligase catalytic subunit (GCLC). The aim of this study is to determine whether CGA protects against CCl4-induced liver injury through Nrf2 signaling. Methods 1) Sprague-Dawley (SD) rats were treated with CGA (15, 30, 60 mg/kg, intragastric administration once daily) for 7 days. The protein expression of Nrf2 in nuclear was detected by Western blot. The mRNA and protein expression of HO-1, NQO1 and GCLC were detected by Real-time PCR and Western blot, respectively. 2) SD rats were dosed with CGA (60 mg/kg, intragastric administration once daily) or vehicle once daily for 7 days. On the eighth day, rats were administered CCl4. Blood and livers were collected 24 h later. Histopathological analyses were carried out. Serum alanine aminotransferase (ALT) activity, Malonaldehyde (MDA), Superoxide dismutase (SOD) and glutathione (GSH) levels in liver were detected. The liver mRNA expression and serum levels of tumor necrosis factor alpha (TNF- a), interleukin (IL)-1b and IL-6 were detected with Real-time PCR and ELISA, respectively. Results CGA increased
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Background: Sinusoidal obstruction syndrome (SOS) is caused by treatments such as oxaliplatin-based chemotherapy in patients with colorectal liver metastasis. SOS is associated with decreased long-term survival. Damage to sinusoidal endothelial cells (SECs) initiates SOS. Recombinant human soluble thrombomodulin (rTM) is beneficial for treatment of disseminated intravascular coagulation. Recent reports indicate that rTM has cytoprotective effects. The aim of this study was to investigate the preventive effect of rTM against disruption of sinusoidal endothelium in monocrotaline (MCT)-induced SOS in mice. Methods: SOS was induced in mice by intraperitoneal administration of MCT (270 mg/kg). rTM (2 mg/ kg) was administered intraperitoneally 2 hours before MCT administration. Control mice received the same volume of phosphate buffered saline (PBS) instead of rTM. Forty eight hours after MCT administration, all mice were sacrificed and the liver tissue and blood were collected to evaluate SOS. Immunohistochemistry was used to evaluate disruption of SECs and infiltration of platelets in the space of Disse. Results: In the control group, liver histology showed endothelial damage of the central venule, necrosis of hepatocytes in zone 3, and dilation of the sinusoid in zone 1 and 2. In the rTM group, these changes were suppressed (Fig.1, 2). Immunohistochemistry showed that SECs were protected and platelet infiltration in the space of Disse significantly decreased in the rTM group compared to that observed for the control group. Depletion of platelet count was significantly suppressed in the rTM group compared to that in the control group (9.2 vs. 1.3 × 104/µl, P < 0.05). Conclusion: rTM inhibited the progression of MCT-induced SOS in mice.
Fig. 1 HE-stained liver tissue of the rTM group (×100).
Fig. 2 HE-stained liver tissue of the rTM group (×100).
Sa1560 An Analysis and Systematic Review of Deleterious Herbs Interaction With Current Pharmaceutical Agents for Hepatitis B and C Treatment Hongfeng Zhang BACKGROUND: End-stage liver disease (ESLD) accounts for 1 in 40 deaths in the world. In China, 90 % of hepatocellular carcinoma (HCC) is associated with the hepatitis B virus (HBV) infection, while in Japan, Europe and US, 50-70 % of HCC is hepatitis C virus (HCV) -related. The high efficacy and tolerability of new hepatitis therapies have unveiled other considerations as important for clinical decision-making, being drug interactions amongst the most relevant ones. It is particularly important as the hepatitis population is among the highest users of herbs and more vulnerable to harmful drug-herb interactions, which are often ignored by hepatologists. This is a systematic review and analysis of the scientific data on deleterious interactions between herbs and hepatitis drugs. METHODS: A comprehensive systematic literature search for deleterious interactions between herbs and hepatitis medications was conducted. PubMed, Medline, Scopus, Airiti Library were searched for relevant articles from 1990 to 2015. Literature lack of methods of assay or regulation and efficacy of botanical products was excluded. Data was abstracted for information related to preparation of herbs, evidence resources, patient population and study design. The mechanisms and the severity ratings were further identified using Lexicomp®, MicroMedex®, and Natural Medicines Comprehensive Database®. RESULTS: A total of 58 articles were selected from the initial 847 reference articles. Only clinical trials, prospective studies, retrospective cohort studies, case reports and animal studies were included. Original laboratory studies were excluded. We identified 247 unique sets of herb-hepatitis drug interactions, 158 specific herbs and 15 medications (i.e., interferon, peginterferon alfa-2b (PEG-IFN), ribavirin, boceprevir, telaprevir, sofosbuvir, ledipasvir, lamivudine, adefovir, tenofovir and prednisone) were involved. Documented deleterious interactions involved medications affecting the interferon (n =21, 8.5 %), peginterferon alfa-2b (PEG-IFN) (n =19, 7.6%), ribavirin (n = 16, 6.5%), boceprevir (n =30, 12.1%), telaprevir (n =24, 9.7%), sofosbuvir (n = 30, 12.6%), ledipasvir (n =28, 11.3%), lamivudine (n =15, 6.1%), adefovir (n =12, 4.9%), tenofovir (n =18, 7.3%), and prednisone(n =34, 13.8%). Among 165 interactions with the severity rating in any of the three databases, only 12 (6.5%) were found in all of the three databases, 41 (24.8 %) could be identified in two databases, while more than half (112, 67.9%) were documented in only one database. CONCLUSION: It is estimated that 500 million people are persistently infected with HBV and HCV and will develop chronic liver disease, cirrhosis and HCC eventually. Recognizing the importance of harmful interactions involving herbs and hepatitis drugs is valuable towards developing ultimate curative treatment for hepatitis across the world.
Figure (A) Liver biopsy of patient #5 shows scattered hepatocyte necrosis with focal sinusoidal dilatation and intra-canalicular and intra-hepatic cholestasis. (B) Liver biopsy of patient #8 shows marked intra-hepatic cholestasis and bile duct injury with mild peri-portal inflammation.
Sa1562 Risk Factors and a Predictive Score for Anti-Tuberculosis Drug-Induced Livery Injury (at-DILI) in Patients With Cirrhosis Passisd Laoveeravat, Nicha Wongjarupong, Chonlada Phathong, Rungsun Rerknimitr, Roongruedee Chaiteerakij Introduction Anti-tuberculosis drugs are one of the most common causes of drug-induced liver injury (DILI). Risk factors for anti-tuberculosis DILI (AT-DILI) in cirrhotics have not been well-studied. We aimed to 1) determine risk factors for developing AT-DILI in cirrhotics; and 2) develop a score for predicting risk of AT-DILI in cirrhotics. Methods All cirrhotics diagnosed with tuberculosis between 2006 and 2015 were identified (n=135). After careful chart review, 62 were excluded: 20 and 16 had incorrect diagnosis of cirrhosis and of tuberculosis, 9 had died before tuberculosis treatment, and 17 had inadequate information in the medical records. The final cohort comprised 73 patients. Baseline characteristics and laboratory results were retrospectively abstracted. AT-DILI was defined as described elsewhere with one of the followings: 1) elevated AST or ALT ‡5 times without symptoms; 2) elevated AST or ALT ‡3 times with symptoms (nausea, vomiting, abdominal pain or jaundice); or 3) total bilirubin (TB) >1.5 mg/dL or elevated TB >50% if baseline TB was >1 mg/dL. Factors associated with AT-DILI were identified using the logistic regression. A predictive score for AT-DILI was created based on odds ratios of derived significant factors. Results Of the 73 cirrhotics receiving treatment, 33 (45%) developed AT-DILI. The mean age and sex, and in-hospital mortality rate were not different between AT-DILI and no AT-DILI groups. The median duration for developing AT-DILI was 8.5 days, and 13 of 33 (41%) developed ATDILI within the first 7 days of drug initiation. By multivariate analysis, initial anti-tuberculosis regimen containing pyrazinamide, history of alcohol drinking, Child-Pugh class B and C cirrhosis were significantly associated with AT-DILI, with adjusted odds ratio (AOR) (95% CI) of 6.1 (1.6-27.8), 8.2 (2.2-31.3), 5.4 (1.2-24.7) and 10.1 (1.6-65.4), respectively. A predictive score comprising these factors was subsequently developed (Figure). Based on
Sa1561 Clinical and Histologic Features of Azathioprine-Induced Hepatotoxicity Sith Siramolpiwat, Dussadee Sakonlaya Background & aim: Hepatoxicity is an uncommon complication related with azathioprine. The incidence varies among studies, and most reports were performed in inflammatory bowel diseases patients. The aim of this study is to report the presenting features and outcomes of patients with clinically apparent hepatotoxicity due to azathioprine in general
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internal medicine clinic. Methods: All medical records of patients received azathioprine from 2010 to 2014 were retrospectively reviewed. Hepatotoxicity was defined as serum alanine aminotransferase (ALT) or aspatate aminotransferase (AST) or total bilirubin (TB) > 2 times the upper limit normal. Other causes of liver diseases were excluded. A Roussel Uclaf Causality Assessment Method (RUCAM) score was assigned to each case. All subjects were followed until the resolution of liver injury. Results A total of 293 patients receiving azathioprine were retrospectively reviewed. Common indications were connective tissue (35%), hematologic diseases (16%) and autoimmune ophthalmological disease (15%). According to the pre-defined criteria, 8 patients (2.7%) were diagnosed with azathioprineinduced hepatotoxicity. The median age was 45 years (range 23-73), and 6 (75%) were female. The causality score was considered to be highly probable (n=2) and probable (n= 6). The latency to onset of hepatotoxicity ranged from 7-236 days (median 70). Four patients (50%) were symptomatic at presentation, of which 3 had jaundice. There was a trend toward receiving concomitant oral corticosteroids in those with azathioprine-induced hepatotoxicity (88 vs. 52%, P=0.05). Median peak levels were ALT 295 U/L, AST 253 U/L, alkaline phosphatase 169 U/L, and TB 1 mg/dL. According to R-ratio, mixed pattern (50%) was more frequent than cholestatic (37.5%) and hepatocellular pattern (12.5%). Liver biopsies were performed in 2 patients at a median duration of 6 days after onset of hepatotoxicity (Case 5, 8), and showed hepatocellular and canalicular cholestasis with mild degree of portal and peri-portal inflammation with an increased in number of intrahepatic eosinophils. All patients recovered fully with a median time to normalization of liver biochemistries of 41 days (range 8-77). Two patients developed prolong cholestasis > 2 months. One patient developed hepatotoxicity again after re-administration of azathioprine. None had liver failure or required liver transplantation. Conclusion Hepatotoxicity is a relative uncommon among patients receiving azathioprine, and predominantly is mixed hepatocellular and cholestatic in nature. All patients recover fully after drug discontinuation; however, severe cholestasis can occur. Pattern of liver injury of 8 patients with azathioprine-induced hepatotoxicity
nuclear accumulation of Nrf2 and enhanced mRNA and protein expression of the Nrf2 target genes HO-1, NQO1 and GCLC. Meanwhile, Serum transaminases analysis and liver histological evaluation demonstrated pretreatment with CGA significantly decreased CCl4induced liver injury. CGA reduced CCl4-induced the increased MDA activity and increased the level of GSH, SOD and CAT in liver tissue. In addition, CGA reduced CCl4-induced the increased liver mRNA and serum levels expression of TNF- a, IL-1band IL-6. Conclusions Collectively, our results demonstrates that CGA facilitates Nrf2 nuclear accumulation, causing induction of antioxidant genes, which may be contribute to protection from CCl4-induced liver injury.This work was supported by National Natural Science Foundation of China ( NO.81200310 ).
AASLD Abstracts
Cytoprotective Effect of Soluble Thrombomodulin Attenuates Endothelial Cell Damage in Sinusoidal Obstruction Syndrome Satoshi Takada, Tomoharu Miyashita, Makoto Nakura, Shunsuke Kanou, Seiichi Munesue, Yasuhiko Yamamoto, Sachio Fushida, Tetsuo Ohta [Background] Hepatic sinusoidal obstruction syndrome (SOS) is a drug-induced liver injury, and its initial morphological change appears in liver sinusoidal endothelial cells (LSECs). Recently, recombinant human soluble thrombomodulin (rTM) was reported to have antiinflammatory and cytoprotective effects in an animal model. We investigated the cytoprotective and enhancement effects of the endothelial cell functions of rTM by using a monocrotaline (MCT)-induced SOS model. [Methods] In vitro model: Human umbilical endothelial cells were cultured for 24 hours and treated with MCT (2-4 mM) and/or rTM (10-100 ng/mL). Caspase activities and MTT assays were performed after 4-12 hours. Phospho-Akt (p-Akt) expression was assessed by using western blot, and cAMP and eNOS expressions were assessed by using enzyme-linked immunosorbent assay. In vivo model: Crl:female CD1 mice were divided into two groups according to the treatment administered, namely MCT only (270 mg/kg) and MCT + rTM (2 mg/kg). LSECs were identified as CD31+CD34+VEGFR3+ by using fluorescence-activated cell sorting (FACS). The function of the LSECs, including PAI-1, HGF, and eNOS, were assessed by performing quantitative reverse transcription polymerase chain reaction. [Results] In vitro model: Caspase 3 and 7 activities were significantly reduced (p < 0.05), and the cell viability assessed by using MTT assay was higher (p < 0.05) in the MCT + rTM group than in the MCT-only group (Fig. 1,2). The increases in the expression levels of p-Akt, cAMP, and eNOS were higher in the MCT + rTM group than in the MCT-only group. In vivo model: Liver damage in zone 3 was attenuated in the MCT + rTM group. FACS revealed that the number of LSECs were maintained in the MCT + rTM group. In the LSECs, the expression levels of eNOS and HGF were higher but that of PAI-1 was lower in the MCT + rTM group. [Conclusion] Soluble thrombomodulin can attenuate SOS by exerting a protective effect on the LSECs and enhancing their functions.
Sa1558 Risk of Non-Steroidal Anti-Inflammatory Drugs-Related Serious Drug-Induced Liver Injury: A Systematic Review and Meta-Analysis Sakkarin Chirapongsathorn, Chayakrit Krittanawong, Ann M. Farrell, Mohammad H. Murad, Patrick Kamath Backgrounds: Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most widely prescribed class of medications worldwide and many adverse events from these drugs are recognized, including gastrointestinal bleeding, cardiovascular events or nephrotoxicity. Several NSAIDs have been withdrawn from the market because of serious drug-induced liver injury (DILI) but epidemiologic data on NSAID-related DILI are very limited. We performed a systematic review and meta-analysis to evaluate the risk of serious DILI in patients taking NSAIDs. Methods: We conducted a comprehensive search of MEDLINE, Embase, Web of Science, Scopus databases and Cochrane Databased of Systemic Reviews through April 2015 and manually reviewed the literature. Attempts were made to contact the corresponding authors of the relevant studies for additional information when needed. Trial-specific risk ratios (RRs) were estimated and pooled using random-effect model metaanalysis. Between-study heterogeneity was assessed using the I2 statistic. The quality assessment of included studies and publication bias were assessed. Serious DILI defined by serum transaminases elevation > 2 times the upper limit of normal (ULN) and total bilirubin elevations > 2 ULN or hospitalization due to DILI or acute liver failure or death. Result: We included 6 observational studies (4 for case-control studies and two for cohort studies) at moderate risk of bias in which 5,045 events of serious DILI were reported. NSAIDs users had a significantly higher risk of serious DILI (RR, 2.13; 95% CI,1.76-2.58 ,I2 = 37%) compared to any other population that did not involve use of NSAIDs. Among included NSAIDs medications, flurbiprofen had the highest risk (RR, 5.54; 95% CI, 1.04-29.69) followed by sulindac (RR, 5.05; 95% CI, 2.14-11.94), ibuprofen (RR, 3.02; 95% CI, 2.63.53), and diclofenac (RR, 2.48; 95% CI, 2.25-2.74). There was no statistically significant increase risk for piroxicam (RR, 1.46; 95% CI, 0.78-2.73) and naproxen (RR, 1.19; 95% CI, 0.54-2.6). Conclusions: The use of NSAIDs may be associated with increased risk of serious DILI. Caution should be advised when using NSAIDs, especially flurbiprofen (discontinued in US), sulindac, ibuprofen and diclofenac.
Fig. 1
Figure 1 Summary risk ratios for serious drug-induced liver injury from non-steroidal antiinflammatory drugs (NSAIDs)
Sa1559 The Preventive Effect of Recombinant Human Soluble Thrombomodulin in the Sinusoidal Obstruction Syndrome in Mice Shunsuke Kanou, Satoshi Takada, Makoto Nakura, Tomoharu Miyashita, Seiichi Munesue, Yasuhiko Yamamoto, Sachio Fushida, Tetsuo Ohta
Fig. 2
Sa1557 Chlorogenic Acid Facilitates NRF2-Mediated Antioxidant Gene and Protects Against CCL4-Induced Liver Injury Haitao Shi, Ameng Shi, Lei Dong, Fei Dai, Xiaolan Lu, Yan Wang Backgroud/Aim Chlorogenic acid (CGA) is a type of polyphenol with anti-inflammatory and antioxidant activities. Our previous study showed CGA could inhibit CCl4-induced liver fibrosis in rats via anti-inflammatory activities. CGA has been reported to induce expression of the antioxidant enzymes in various cell lines. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays an important role in the cellular protection against oxidative stress through induction of several phase-2 detoxifying and antioxidant enzymes including heme oxygenase1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutamate-cysteine ligase catalytic subunit (GCLC). The aim of this study is to determine whether CGA protects against CCl4-induced liver injury through Nrf2 signaling. Methods 1) Sprague-Dawley (SD) rats were treated with CGA (15, 30, 60 mg/kg, intragastric administration once daily) for 7 days. The protein expression of Nrf2 in nuclear was detected by Western blot. The mRNA and protein expression of HO-1, NQO1 and GCLC were detected by Real-time PCR and Western blot, respectively. 2) SD rats were dosed with CGA (60 mg/kg, intragastric administration once daily) or vehicle once daily for 7 days. On the eighth day, rats were administered CCl4. Blood and livers were collected 24 h later. Histopathological analyses were carried out. Serum alanine aminotransferase (ALT) activity, Malonaldehyde (MDA), Superoxide dismutase (SOD) and glutathione (GSH) levels in liver were detected. The liver mRNA expression and serum levels of tumor necrosis factor alpha (TNF- a), interleukin (IL)-1b and IL-6 were detected with Real-time PCR and ELISA, respectively. Results CGA increased
AASLD Abstracts
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Background: Sinusoidal obstruction syndrome (SOS) is caused by treatments such as oxaliplatin-based chemotherapy in patients with colorectal liver metastasis. SOS is associated with decreased long-term survival. Damage to sinusoidal endothelial cells (SECs) initiates SOS. Recombinant human soluble thrombomodulin (rTM) is beneficial for treatment of disseminated intravascular coagulation. Recent reports indicate that rTM has cytoprotective effects. The aim of this study was to investigate the preventive effect of rTM against disruption of sinusoidal endothelium in monocrotaline (MCT)-induced SOS in mice. Methods: SOS was induced in mice by intraperitoneal administration of MCT (270 mg/kg). rTM (2 mg/ kg) was administered intraperitoneally 2 hours before MCT administration. Control mice received the same volume of phosphate buffered saline (PBS) instead of rTM. Forty eight hours after MCT administration, all mice were sacrificed and the liver tissue and blood were collected to evaluate SOS. Immunohistochemistry was used to evaluate disruption of SECs and infiltration of platelets in the space of Disse. Results: In the control group, liver histology showed endothelial damage of the central venule, necrosis of hepatocytes in zone 3, and dilation of the sinusoid in zone 1 and 2. In the rTM group, these changes were suppressed (Fig.1, 2). Immunohistochemistry showed that SECs were protected and platelet infiltration in the space of Disse significantly decreased in the rTM group compared to that observed for the control group. Depletion of platelet count was significantly suppressed in the rTM group compared to that in the control group (9.2 vs. 1.3 × 104/µl, P < 0.05). Conclusion: rTM inhibited the progression of MCT-induced SOS in mice.
Fig. 1 HE-stained liver tissue of the rTM group (×100).
Fig. 2 HE-stained liver tissue of the rTM group (×100).
Sa1560 An Analysis and Systematic Review of Deleterious Herbs Interaction With Current Pharmaceutical Agents for Hepatitis B and C Treatment Hongfeng Zhang BACKGROUND: End-stage liver disease (ESLD) accounts for 1 in 40 deaths in the world. In China, 90 % of hepatocellular carcinoma (HCC) is associated with the hepatitis B virus (HBV) infection, while in Japan, Europe and US, 50-70 % of HCC is hepatitis C virus (HCV) -related. The high efficacy and tolerability of new hepatitis therapies have unveiled other considerations as important for clinical decision-making, being drug interactions amongst the most relevant ones. It is particularly important as the hepatitis population is among the highest users of herbs and more vulnerable to harmful drug-herb interactions, which are often ignored by hepatologists. This is a systematic review and analysis of the scientific data on deleterious interactions between herbs and hepatitis drugs. METHODS: A comprehensive systematic literature search for deleterious interactions between herbs and hepatitis medications was conducted. PubMed, Medline, Scopus, Airiti Library were searched for relevant articles from 1990 to 2015. Literature lack of methods of assay or regulation and efficacy of botanical products was excluded. Data was abstracted for information related to preparation of herbs, evidence resources, patient population and study design. The mechanisms and the severity ratings were further identified using Lexicomp®, MicroMedex®, and Natural Medicines Comprehensive Database®. RESULTS: A total of 58 articles were selected from the initial 847 reference articles. Only clinical trials, prospective studies, retrospective cohort studies, case reports and animal studies were included. Original laboratory studies were excluded. We identified 247 unique sets of herb-hepatitis drug interactions, 158 specific herbs and 15 medications (i.e., interferon, peginterferon alfa-2b (PEG-IFN), ribavirin, boceprevir, telaprevir, sofosbuvir, ledipasvir, lamivudine, adefovir, tenofovir and prednisone) were involved. Documented deleterious interactions involved medications affecting the interferon (n =21, 8.5 %), peginterferon alfa-2b (PEG-IFN) (n =19, 7.6%), ribavirin (n = 16, 6.5%), boceprevir (n =30, 12.1%), telaprevir (n =24, 9.7%), sofosbuvir (n = 30, 12.6%), ledipasvir (n =28, 11.3%), lamivudine (n =15, 6.1%), adefovir (n =12, 4.9%), tenofovir (n =18, 7.3%), and prednisone(n =34, 13.8%). Among 165 interactions with the severity rating in any of the three databases, only 12 (6.5%) were found in all of the three databases, 41 (24.8 %) could be identified in two databases, while more than half (112, 67.9%) were documented in only one database. CONCLUSION: It is estimated that 500 million people are persistently infected with HBV and HCV and will develop chronic liver disease, cirrhosis and HCC eventually. Recognizing the importance of harmful interactions involving herbs and hepatitis drugs is valuable towards developing ultimate curative treatment for hepatitis across the world.
Figure (A) Liver biopsy of patient #5 shows scattered hepatocyte necrosis with focal sinusoidal dilatation and intra-canalicular and intra-hepatic cholestasis. (B) Liver biopsy of patient #8 shows marked intra-hepatic cholestasis and bile duct injury with mild peri-portal inflammation.
Sa1562 Risk Factors and a Predictive Score for Anti-Tuberculosis Drug-Induced Livery Injury (at-DILI) in Patients With Cirrhosis Passisd Laoveeravat, Nicha Wongjarupong, Chonlada Phathong, Rungsun Rerknimitr, Roongruedee Chaiteerakij Introduction Anti-tuberculosis drugs are one of the most common causes of drug-induced liver injury (DILI). Risk factors for anti-tuberculosis DILI (AT-DILI) in cirrhotics have not been well-studied. We aimed to 1) determine risk factors for developing AT-DILI in cirrhotics; and 2) develop a score for predicting risk of AT-DILI in cirrhotics. Methods All cirrhotics diagnosed with tuberculosis between 2006 and 2015 were identified (n=135). After careful chart review, 62 were excluded: 20 and 16 had incorrect diagnosis of cirrhosis and of tuberculosis, 9 had died before tuberculosis treatment, and 17 had inadequate information in the medical records. The final cohort comprised 73 patients. Baseline characteristics and laboratory results were retrospectively abstracted. AT-DILI was defined as described elsewhere with one of the followings: 1) elevated AST or ALT ‡5 times without symptoms; 2) elevated AST or ALT ‡3 times with symptoms (nausea, vomiting, abdominal pain or jaundice); or 3) total bilirubin (TB) >1.5 mg/dL or elevated TB >50% if baseline TB was >1 mg/dL. Factors associated with AT-DILI were identified using the logistic regression. A predictive score for AT-DILI was created based on odds ratios of derived significant factors. Results Of the 73 cirrhotics receiving treatment, 33 (45%) developed AT-DILI. The mean age and sex, and in-hospital mortality rate were not different between AT-DILI and no AT-DILI groups. The median duration for developing AT-DILI was 8.5 days, and 13 of 33 (41%) developed ATDILI within the first 7 days of drug initiation. By multivariate analysis, initial anti-tuberculosis regimen containing pyrazinamide, history of alcohol drinking, Child-Pugh class B and C cirrhosis were significantly associated with AT-DILI, with adjusted odds ratio (AOR) (95% CI) of 6.1 (1.6-27.8), 8.2 (2.2-31.3), 5.4 (1.2-24.7) and 10.1 (1.6-65.4), respectively. A predictive score comprising these factors was subsequently developed (Figure). Based on
Sa1561 Clinical and Histologic Features of Azathioprine-Induced Hepatotoxicity Sith Siramolpiwat, Dussadee Sakonlaya Background & aim: Hepatoxicity is an uncommon complication related with azathioprine. The incidence varies among studies, and most reports were performed in inflammatory bowel diseases patients. The aim of this study is to report the presenting features and outcomes of patients with clinically apparent hepatotoxicity due to azathioprine in general
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internal medicine clinic. Methods: All medical records of patients received azathioprine from 2010 to 2014 were retrospectively reviewed. Hepatotoxicity was defined as serum alanine aminotransferase (ALT) or aspatate aminotransferase (AST) or total bilirubin (TB) > 2 times the upper limit normal. Other causes of liver diseases were excluded. A Roussel Uclaf Causality Assessment Method (RUCAM) score was assigned to each case. All subjects were followed until the resolution of liver injury. Results A total of 293 patients receiving azathioprine were retrospectively reviewed. Common indications were connective tissue (35%), hematologic diseases (16%) and autoimmune ophthalmological disease (15%). According to the pre-defined criteria, 8 patients (2.7%) were diagnosed with azathioprineinduced hepatotoxicity. The median age was 45 years (range 23-73), and 6 (75%) were female. The causality score was considered to be highly probable (n=2) and probable (n= 6). The latency to onset of hepatotoxicity ranged from 7-236 days (median 70). Four patients (50%) were symptomatic at presentation, of which 3 had jaundice. There was a trend toward receiving concomitant oral corticosteroids in those with azathioprine-induced hepatotoxicity (88 vs. 52%, P=0.05). Median peak levels were ALT 295 U/L, AST 253 U/L, alkaline phosphatase 169 U/L, and TB 1 mg/dL. According to R-ratio, mixed pattern (50%) was more frequent than cholestatic (37.5%) and hepatocellular pattern (12.5%). Liver biopsies were performed in 2 patients at a median duration of 6 days after onset of hepatotoxicity (Case 5, 8), and showed hepatocellular and canalicular cholestasis with mild degree of portal and peri-portal inflammation with an increased in number of intrahepatic eosinophils. All patients recovered fully with a median time to normalization of liver biochemistries of 41 days (range 8-77). Two patients developed prolong cholestasis > 2 months. One patient developed hepatotoxicity again after re-administration of azathioprine. None had liver failure or required liver transplantation. Conclusion Hepatotoxicity is a relative uncommon among patients receiving azathioprine, and predominantly is mixed hepatocellular and cholestatic in nature. All patients recover fully after drug discontinuation; however, severe cholestasis can occur. Pattern of liver injury of 8 patients with azathioprine-induced hepatotoxicity