- Email: [email protected]
Molecular risk assessment of methyl isocyanate-induced liver carcinogenesis
Abstracts
JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY
21st Annual Conference of Indian National Association for the Study of Liver (INASL), March 22–24, 2013 Hyderabad International Convention Centre, Hyderabad, India
DRUG INDUCED LIVER INJURY (DILI)
Anoop Shivaram Alva, Amit Bhasin, Shanthi Vijayaraghavan Department of Gastroenterology, Sri Ramachandra Medical College, Chennai, India
Introduction: Drugs are known to be an important etiological factor of acute hepatitis. Corticosteroids have been considered relatively safe in this regard. However, cases of acute hepatotoxicity induced by methylprednisolone have been reported.We present a case of a 38 year old lady who developed acute hepatitis following treatment with oral Methylprednisolone for interstitial lung disease. Case Report:A 38 year old lady presented with insidious, gradually progressive jaundice associated with an urticarial rash and pruritis following treatment of ILD with Methylprednisolone 16mg BD for 30 days.Upon admission, her labs revealed total bilirubin: 3.32 mg/dl with direct: 1.33 mg/dl, AST: 1428 U/L, ALT: 2618 U/L, alkaline phosphatase: 134 U/L, albumin: 3.2 gm/dl and INR: 1.36. Blood counts including Absolute Eosinophil count were normal. Viral serology, autoimmune markers and Wilson's workup were negative. Ultrasound abdomen and Doppler study were normal. Liver biopsy showed features of cholestatic hepatitis with early fibrosis. Her liver function improved with supportive management. There was no relapse on discontinuation of steroids. LFT was normal at 6 months of follow-up. Discussion: We report a case of hepatotoxicity related to oral Methylprednisolone treatment with CIOMS/RUCAM causality score of 8. We identified 13 case reports of methylprednisolone induced hepatotoxicity on literature review. In this patient, AIH-DILI was considered, however the acute onset, temporal relationship, absence of relapse after steroid withdrawal, negative autoimmune markers and liver biopsy findings were in favor of drug induced hepatitis. Conclusion: We report a case of Methylprednisolone induced liver injury. We believe that the awareness of this adverse drug reaction has to be created. Corresponding author. Anoop Shivaram Alva. E-mail: [email protected]
© 2013, INASL
HEPATO-PROTECTIVE ACTIVITY OF AMANAKKU KARKAM (SIDDHA FORMULATION) IN RATS G. Pramod Reddy,1 R. Kiruthiga,2 Gowthaman,2 P. Satya Rajeswaran,1 R. Ganesan,1 JegaJothiPandian1 1 Siddha Central Research Institute (CCRS), Min. of Health & Family Welfare, Govt of India, Chennai, India, 2School of Chemical & Biotechnology, Sastra University, Tanjavur, India
Background and Aims: The present study was conducted to evaluate the hepatoprotective activity of aqueous extract of Amanakkukarkam (Siddha Formulation) against paracetamol induced liver damage in rats. Methods: The Amanakkukarkam was administered orally to the animals with hepatotoxicity induced by paracetamol. Silymarin was given as reference standard. Results: The formulation was effective in protecting the liver against the injury induced by paracetamol in rats. This was evident from significant reduction in serum enzymes alkaline aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), acid phosphatase (ACP), protein and bilirubin. Conclusion: It was concluded from the result that the AmanakkuKarkam possesses hepatoprotective activity against paracetamol induced hepatotoxicity in rats. Corresponding author. G. Pramod Reddy. E-mail: [email protected]
MOLECULAR RISK ASSESSMENT OF METHYL ISOCYANATE-INDUCED LIVER CARCINOGENESIS Kewal Krishan Maudar, Parduman Kumar Mishra, Puneet Gandhi, Nabila Akhtar Bhopal Memorial Hospital and Research Centre, Bhopal, India
Introduction: The increased incidence of hepatocellular carcinoma (HCC) over the last 50-60 years has been largely attributed to three factors: lifestyle, age and diffusion of environmental carcinogens. Molecular implications of isocyanates, ubiquitous chemicals with wide range of
Journal of Clinical and Experimental Hepatology | March 2013 | Vol. 3 | No. 1S | S37–S40
DILI
A RARE CASE OF METHYLPREDNISOLONE INDUCED HEPATITIS
21ST ANNUAL CONFERENCE—2013
ABSTRACTS
DILI
industrial applications, on liver carcinogenesis still remain elusive. Aims: To study the role of isocyanate in liver carcinogenesis. Methods: Experiments were performed on the cultured human liver epithelial cell line to ascertain the possible molecular risks associated with isocyanate exposure using Nsuccinimidyl N-methylcarbamate, a chemical entity that mimics the effects of methyl isocyanatein vitro. Qualitative and quantitative assessment of phosphorylation states of ATM, H2AX, ATR and p53, put forth the kinetics of DNA damage. Analyses of apoptosis in treated cells and inflammatory cytokines secreted in culture supernatant were done through annexin-V FITC/PI assay and cytometric bead array respectively. Cytogenetic studies along with inter simple sequence repeat PCR were done in control and treated cells to check for the possible precariousness at the chromosomal and microsatellite levels of the genome. Results: An increasing trend of all the DNA damage responsive parameters along with the apoptotic index were displayed in treated cells. Isocyanate exposed cells secreted an elevated levels of inflammatory cytokines in the culture supernatant. Cytogenetic analysis and inter simple sequence repeat PCR revealed varied chromosomal anomalies with greater instability at the microsatellite level. Conclusion: To conclude, these findings demonstrate that human liver epithelial milieu could confront with molecular risks due to isocyanate exposure attributing to defective DNA repair pathway along with de-regulated cell cycle and genomic instability which may accelerate the development of HCC.
been suspected. Despite drug discontinuation, weakness, skin itching, weight loss intensified. She was hospitalized to our clinic six weeks after disease onset. There were significant jaundice and visible traces after scratching; tachycardia. Liver and spleen were not palpable. Laboratory analyses showed elevation of ALT> AST (5-6 times higher ULN), total bilirubin (36 times higher ULN) due to both fractions, hypoalbuminemia (2.6 g/dl). Tests for autoantibodies were negative. Serum thyroid-stimulating hormone level was less than 0.01 uIU/ml (N: 0.4–4), free thyroxine two times higher ULN. Liver biopsy revealed parenchymatous and canalicularbilirubinostasis, necrosis of some hepatocytes. We diagnosed: Thiamazole-induced hepatitis. Hepatic failure: jaundice, hypoalbuminemia, thyrotoxicosis. In spite of drug withdrawal and administration of Ademethionine, UDCA, plazmapheresis, we observed a very slow regression of jaundice. Prednisolone prescription led to a rapid full patient's recovery with normalization of all biochemical markers during a month. The patient passed later radioactive iodine ablation of the thyroid gland. Discussion: Here we observed a mixed (dose-dependent and idiosyncratic) liver injury. There was an untypical form of hepatotoxicity - hepatocellular damage with jaundice, without increase in laboratory markers of cholestasis, what makes the uniqueness of this clinical case. Conclusion: Severe jaundice is a rare adverse effect of antithyroid drugs’ therapy. The liver injury is usually reversible after drug withdrawal but in some cases can require Prednizolone administration. Physicians should keep in mind such a rare adverse reaction of antithyroid drugs.
Corresponding author. Kewal Krishan Maudar. E-mail: [email protected]
Corresponding Author. Maria Sergeevna Zharkova. E-mail: [email protected]
A CASE OF SEVERE JAUNDICE CAUSED BY THIAMAZOLE THERAPY
HCV INFECTION IN THE HIV PATIENT IN ORAN ALGERIA
Maria Sergeevna Zharkova, Marina Trofimovich Maevskaya, Elena Nikolaevna Shirokova, Tatjana Petrovna Nekrasova, Marina Victorovna Ivashkin
Nadjet Allab Mouffok, Fatima Bensadoun, Ahmed Kouiad Belkadi
Hepatology Department, University Clinical Hospital N 2, First Moscow State Medical University, Moscow, Russia
Introduction: Co-infections of HIV and HCV are frequent and became a concern considering the longevity of the HIV patient thanks to the HAART. Objectives: to determine the frequency of Co-infection VIH/VHC, the various implied genotypes, the clinical and biological characteristics, the assumption of responsibility in Oran hospital and the difficulties encountered. Methods: retrospective study on file during the period of 2003 to 2012, the patients included are those which were infected by the HIV and had positive HCV antibodies. The epidemiologic, clinical, biological characteristics (ALAT, prothrombin, albumin, bilirubin, fibrotest-Acti
Objective: Hepatotoxicity is a rare serious adverse reaction to antithyroid agents. It occurs with a frequency of 0.1– 0.2% of treated patients. Here we describe a case of severe jaundice with expected poor prognosis in a Thiamazoletreated patient with thyrotoxicosis. Case report: A 48-year-old woman with thyrotoxicosis developed jaundice after two weeks of Thiamazole therapy (40 mg/day). Viral hepatitis and mechanical biliary obstruction were excluded. Drug-induced liver injury had
S38
CHUOran
© 2013, INASL
JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY
21st Annual Conference of Indian National Association for the Study of Liver (INASL), March 22–24, 2013 Hyderabad International Convention Centre, Hyderabad, India
DRUG INDUCED LIVER INJURY (DILI)
Anoop Shivaram Alva, Amit Bhasin, Shanthi Vijayaraghavan Department of Gastroenterology, Sri Ramachandra Medical College, Chennai, India
Introduction: Drugs are known to be an important etiological factor of acute hepatitis. Corticosteroids have been considered relatively safe in this regard. However, cases of acute hepatotoxicity induced by methylprednisolone have been reported.We present a case of a 38 year old lady who developed acute hepatitis following treatment with oral Methylprednisolone for interstitial lung disease. Case Report:A 38 year old lady presented with insidious, gradually progressive jaundice associated with an urticarial rash and pruritis following treatment of ILD with Methylprednisolone 16mg BD for 30 days.Upon admission, her labs revealed total bilirubin: 3.32 mg/dl with direct: 1.33 mg/dl, AST: 1428 U/L, ALT: 2618 U/L, alkaline phosphatase: 134 U/L, albumin: 3.2 gm/dl and INR: 1.36. Blood counts including Absolute Eosinophil count were normal. Viral serology, autoimmune markers and Wilson's workup were negative. Ultrasound abdomen and Doppler study were normal. Liver biopsy showed features of cholestatic hepatitis with early fibrosis. Her liver function improved with supportive management. There was no relapse on discontinuation of steroids. LFT was normal at 6 months of follow-up. Discussion: We report a case of hepatotoxicity related to oral Methylprednisolone treatment with CIOMS/RUCAM causality score of 8. We identified 13 case reports of methylprednisolone induced hepatotoxicity on literature review. In this patient, AIH-DILI was considered, however the acute onset, temporal relationship, absence of relapse after steroid withdrawal, negative autoimmune markers and liver biopsy findings were in favor of drug induced hepatitis. Conclusion: We report a case of Methylprednisolone induced liver injury. We believe that the awareness of this adverse drug reaction has to be created. Corresponding author. Anoop Shivaram Alva. E-mail: [email protected]
© 2013, INASL
HEPATO-PROTECTIVE ACTIVITY OF AMANAKKU KARKAM (SIDDHA FORMULATION) IN RATS G. Pramod Reddy,1 R. Kiruthiga,2 Gowthaman,2 P. Satya Rajeswaran,1 R. Ganesan,1 JegaJothiPandian1 1 Siddha Central Research Institute (CCRS), Min. of Health & Family Welfare, Govt of India, Chennai, India, 2School of Chemical & Biotechnology, Sastra University, Tanjavur, India
Background and Aims: The present study was conducted to evaluate the hepatoprotective activity of aqueous extract of Amanakkukarkam (Siddha Formulation) against paracetamol induced liver damage in rats. Methods: The Amanakkukarkam was administered orally to the animals with hepatotoxicity induced by paracetamol. Silymarin was given as reference standard. Results: The formulation was effective in protecting the liver against the injury induced by paracetamol in rats. This was evident from significant reduction in serum enzymes alkaline aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), acid phosphatase (ACP), protein and bilirubin. Conclusion: It was concluded from the result that the AmanakkuKarkam possesses hepatoprotective activity against paracetamol induced hepatotoxicity in rats. Corresponding author. G. Pramod Reddy. E-mail: [email protected]
MOLECULAR RISK ASSESSMENT OF METHYL ISOCYANATE-INDUCED LIVER CARCINOGENESIS Kewal Krishan Maudar, Parduman Kumar Mishra, Puneet Gandhi, Nabila Akhtar Bhopal Memorial Hospital and Research Centre, Bhopal, India
Introduction: The increased incidence of hepatocellular carcinoma (HCC) over the last 50-60 years has been largely attributed to three factors: lifestyle, age and diffusion of environmental carcinogens. Molecular implications of isocyanates, ubiquitous chemicals with wide range of
Journal of Clinical and Experimental Hepatology | March 2013 | Vol. 3 | No. 1S | S37–S40
DILI
A RARE CASE OF METHYLPREDNISOLONE INDUCED HEPATITIS
21ST ANNUAL CONFERENCE—2013
ABSTRACTS
DILI
industrial applications, on liver carcinogenesis still remain elusive. Aims: To study the role of isocyanate in liver carcinogenesis. Methods: Experiments were performed on the cultured human liver epithelial cell line to ascertain the possible molecular risks associated with isocyanate exposure using Nsuccinimidyl N-methylcarbamate, a chemical entity that mimics the effects of methyl isocyanatein vitro. Qualitative and quantitative assessment of phosphorylation states of ATM, H2AX, ATR and p53, put forth the kinetics of DNA damage. Analyses of apoptosis in treated cells and inflammatory cytokines secreted in culture supernatant were done through annexin-V FITC/PI assay and cytometric bead array respectively. Cytogenetic studies along with inter simple sequence repeat PCR were done in control and treated cells to check for the possible precariousness at the chromosomal and microsatellite levels of the genome. Results: An increasing trend of all the DNA damage responsive parameters along with the apoptotic index were displayed in treated cells. Isocyanate exposed cells secreted an elevated levels of inflammatory cytokines in the culture supernatant. Cytogenetic analysis and inter simple sequence repeat PCR revealed varied chromosomal anomalies with greater instability at the microsatellite level. Conclusion: To conclude, these findings demonstrate that human liver epithelial milieu could confront with molecular risks due to isocyanate exposure attributing to defective DNA repair pathway along with de-regulated cell cycle and genomic instability which may accelerate the development of HCC.
been suspected. Despite drug discontinuation, weakness, skin itching, weight loss intensified. She was hospitalized to our clinic six weeks after disease onset. There were significant jaundice and visible traces after scratching; tachycardia. Liver and spleen were not palpable. Laboratory analyses showed elevation of ALT> AST (5-6 times higher ULN), total bilirubin (36 times higher ULN) due to both fractions, hypoalbuminemia (2.6 g/dl). Tests for autoantibodies were negative. Serum thyroid-stimulating hormone level was less than 0.01 uIU/ml (N: 0.4–4), free thyroxine two times higher ULN. Liver biopsy revealed parenchymatous and canalicularbilirubinostasis, necrosis of some hepatocytes. We diagnosed: Thiamazole-induced hepatitis. Hepatic failure: jaundice, hypoalbuminemia, thyrotoxicosis. In spite of drug withdrawal and administration of Ademethionine, UDCA, plazmapheresis, we observed a very slow regression of jaundice. Prednisolone prescription led to a rapid full patient's recovery with normalization of all biochemical markers during a month. The patient passed later radioactive iodine ablation of the thyroid gland. Discussion: Here we observed a mixed (dose-dependent and idiosyncratic) liver injury. There was an untypical form of hepatotoxicity - hepatocellular damage with jaundice, without increase in laboratory markers of cholestasis, what makes the uniqueness of this clinical case. Conclusion: Severe jaundice is a rare adverse effect of antithyroid drugs’ therapy. The liver injury is usually reversible after drug withdrawal but in some cases can require Prednizolone administration. Physicians should keep in mind such a rare adverse reaction of antithyroid drugs.
Corresponding author. Kewal Krishan Maudar. E-mail: [email protected]
Corresponding Author. Maria Sergeevna Zharkova. E-mail: [email protected]
A CASE OF SEVERE JAUNDICE CAUSED BY THIAMAZOLE THERAPY
HCV INFECTION IN THE HIV PATIENT IN ORAN ALGERIA
Maria Sergeevna Zharkova, Marina Trofimovich Maevskaya, Elena Nikolaevna Shirokova, Tatjana Petrovna Nekrasova, Marina Victorovna Ivashkin
Nadjet Allab Mouffok, Fatima Bensadoun, Ahmed Kouiad Belkadi
Hepatology Department, University Clinical Hospital N 2, First Moscow State Medical University, Moscow, Russia
Introduction: Co-infections of HIV and HCV are frequent and became a concern considering the longevity of the HIV patient thanks to the HAART. Objectives: to determine the frequency of Co-infection VIH/VHC, the various implied genotypes, the clinical and biological characteristics, the assumption of responsibility in Oran hospital and the difficulties encountered. Methods: retrospective study on file during the period of 2003 to 2012, the patients included are those which were infected by the HIV and had positive HCV antibodies. The epidemiologic, clinical, biological characteristics (ALAT, prothrombin, albumin, bilirubin, fibrotest-Acti
Objective: Hepatotoxicity is a rare serious adverse reaction to antithyroid agents. It occurs with a frequency of 0.1– 0.2% of treated patients. Here we describe a case of severe jaundice with expected poor prognosis in a Thiamazoletreated patient with thyrotoxicosis. Case report: A 48-year-old woman with thyrotoxicosis developed jaundice after two weeks of Thiamazole therapy (40 mg/day). Viral hepatitis and mechanical biliary obstruction were excluded. Drug-induced liver injury had
S38
CHUOran
© 2013, INASL