Drug induced liver injury: a review article

The incidence of drug induced liver injury [DILI] is about 1/1000 to 1/10000 among patients who receive therapeutic drug doses. Drug induced hepatotoxicity is a major cause of acute and chronic liver disease. The severity of liver damage ranges from nonspecific changes in liver structure to acute liver failure, cirrhosis and liver cancer. Some common agents that can cause liver injury are acetaminophen, antibiotics, statins, INH and herbal drugs. Drug-induced hepatotoxicity can be categorized based on the pattern of liver enzyme alteration [hepatocellular, cholestatic or mixed pattern], the mechanism of hepatotoxicity [direct, immune mediated or idiosyncratic] and hjstologic findings on liver biopsy [steatosis or sinusoidal obstruction syndrome]. Treatment options for DILI include discontinuing the drug, conservative measurements and liver transplantation in the case of non-acetaminophen induced hepatotoxicity

Effects of endotoxin on liver Smac apoptosis channel / 华中科技大学学报（医学）（英德文版）

To study the effect of endotoxin on liver apoptosis, L02 liver cells were cultured and passaged in vitro, and then stimulated by endotoxin at 10 mg/mL for 4, 8, 16 and 24 h respectively. Liver apoptosis was flow cytometrically and fluorescently detected. Immunohistochemistry was used to detect the delivery of smac and caspase9. The delivery of liver cell smac and the activity of caspase3 were measured by caspase3 assay kit. The hepatic failure models of rats were established by using D-galactosamine. The blood serum and liver tissues were collected for the detection of the liver function, the level of endotoxin and the activity of caspase3 by using chromogenic substrate limulus amebocyte lysate method (LAL) and caspase3 active assay kit. The expression of smac and caspase9 in liver cells was detected by Western blotting. With in vitro study, the L02 cells stimulated by LPS condensed into conglobation and formed apoptotic bodies. After those cells were stained by hoechst, the apoptotic cells displayed blue color under the fluorescent microscope. The apoptosis rate was increased over time and the apoptosis was mainly of advanced stage. Meanwhile, the rate of smac delivery and activity of caspase9 and caspase3 were increased on L02 cell membrane. In vivo, hepatic failure and obvious endotoxemia were induced by injection of more than 200 mg/kg D-GalN. Hepatic mitochondria smac was reduced with dosage of D-GalN and, on the contrary, the activity of caspase3 was increased. D-GalN at 200 mg/kg increased Caspase9 while D-GalN at 300 mg/kg decreased caspase9. Mitochondria signal channel plays an important role in the endotoxin-induced apoptosis of hepatic cells by promoting the release of smac from mitochondria to cytoplasm and activating caspase9 and caspase3 in its low-level channel.

Síndrome del ácido transretinoico: Reporte de un caso y revisión de la literatura / All-Trans retinoic acid Syndrome: Case Report and a Review of the Literature

Se describe el caso de una enferma con leucemia aguda promielocítica (LAP) que desarrolló síndrome del ácido transretinoico (SATRA) y se revisa la literatura. El SA TRA se presenta en enfermos con LAP tratados con ácido transretinoico (ATRA). Tiene incidencia de 5% a 27% con mortalidad de hasta 29%. Es secundario al efecto del ATRA sobre la diferenciación de los promielocitos, lo que desencadena respuesta inflamatoria sistémica, daño endotelial con síndrome de fuga capilar y obstrucción de la microcirculación e infiltración tisular. Clínicamente se manifiesta con fiebre, hipotensión, insuficiencia respiratoria, renal y hepática, infiltrados pulmonares, derrame pleural y pericárdico, y edema generalizado. El tratamiento es a base de suspensión del ATRA, medidas de apoyo y esferoides.

We described a patient with acute promyelocytic leukemia (APL) who developed all-trans retinoic acid syndrome (ATRAS) and reviewed the literature. ATRAS presents in patients with APL treated with all-trans retinoic acid (ATRA). It has an incidence from 5%-27% with mortality of 29%. It is secondary to ATRA effect on promyelocyte differentiation, which causes systemic inflammatory response syndrome, endothelium damage with increase in capillary permeability, microcirculation obstruction, and tissue infiltration. ATRAS clinical manifestations are fever, hypotension, respiratory, renal and hepatic insufficiency, lung infiltrates, pleural and pericardic efussion, and generalized edema. Treatment is based on ATRA suspension, support measures, and steroids.

Rodenticide-induced hepatotoxicity.

Hepatotoxicity following acute poisoning with rodenticides has been infrequently reported in literature. To emphasize the fact that this form of clinical presentation is not unusual we are reporting two cases of rodenticide poisoning masquerading as severe hepatic dysfunction.

Hepatic failure with flutamide.

A 41-year-old woman, who was on flutamide for hair loss for 3 months, presented with deep jaundice. She developed hepatic encephalopathy but gradually recovered after discontinuing flutamide. Flutamide can cause fatal toxic liver injury and hence should be used with close monitoring of liver profile.

Effect of experimental liver damage by CCl4 on the pharmacokinetics of zidovudine in rats

The effect of CCL4-induced hepatic damage on the pharmacokinetics of zidovudine [AZT] was investigated, in rats, in three phases. The animals were given AZT in phase I, and the results were considered as the control. In the second phase, the rats were administered an oral dose of ml/kg ccl4 to induce acute liver damage. Chronic liver damage was induced in phase III by SC injection of ccl4 [1 ml/kg] every other day for 4 weeks. Rats were administered AZT as an IP dose of 3mg/kg in the three phases. A sensitive HPLC assay was used to measure AZT serum concentrations. The mean AUC after no, acute, and chronic liver damage were 1.95,2.40, and 2.97 mg.hr/l, respectively [p<0.05]. the mean elimination half-life was significantly longer [p<0.05] in the induced chronic liver damage group [2.21 +/- 1.2 hr] compared with rats with rats with no treatment [0.7 +/- 0.23 hr] or with acute liver damage [1.31 +/- 0.28 hr]. the same trend was observed with MRT and AUMC among animals in different experiments. In addition, CI/F was significantly lower [p<0.01] for for rats in phase III compared with rats in the other phases. Rats with induced chronic liver damage eliminate AZT more slowly than rats with acute liver damage [p<0.05]. the present findings indicate that the rat model could be used tostudy the effect of liver impairment on the pharmacokinetics of AZT; the use of AZT in AIDS patients with hepatic impairmant should be closely monitored