Onset Of Hepatotoxicity Research Articles

FRI523 A Case Of Acute Liver Failure Within 48 Hours Of Initiation Of High Dose Thionamides For Thyroid Storm

Abstract Disclosure: L. Noor: None. J. Mullally: None. Thionamides, including methimazole and propylthiouracil, are medications used to treat hyperthyroidism and have rarely been associated with liver failure. Based on prior large retrospective studies, the onset of hepatotoxicity from thionamides occurs most commonly 4-12 weeks after ​​initiation, with the earliest cases occurring 7 days after initiation. We describe a case of very early onset acute liver failure within two days of initiation of high dose methimazole and PTU. A 43 year old female with past medical history of long-standing Graves’ disease and atrial fibrillation, presented to an outside hospital with upper respiratory symptoms and weight loss. On presentation, her vitals and physical examination were within normal limits. Initial labs showed normal LFTs, undetectable TSH, high FT3 6.75 pg/ml (n 2.0-4.4 pg/ml), high TT4 18 μg/dL (n 5.0-12.0 μg/dL) and PCR positive for COVID-19. She was started on methimazole 40 mg every 12 hours, beta-blocker, dexamethasone and remdesvir. The next day, she was found to be tachycardic, tachypneic with EKG showing atrial fibrillation with RVR and chest Xray showing flash pulmonary edema. She was intubated, methimazole was changed to PTU 200 mg every 4 hours and dexamethasone was changed to hydrocortisone 100 mg every 8 hours. An esmolol drip, potassium iodide and cholestyramine were started. She also received a single dose of intravenous amiodarone 300 mg for atrial fibrillation with RVR. The next day, labs showed new LFT abnormalities with AST 6647(n<35 U/L), ALT 1694 (n<55 U/L), ALP 132 (n<150 U/L), total bilirubin 8.4 (n<1.3 mg/dl). PTU was stopped and she was transferred to our hospital for liver transplant evaluation. On admission to our hospital, labs showed ALT 2728, AST 4930, ALP 180, T bilirubin 15.7, TSH 0.002, FT4 1.5 and TT3 29.6. She was started on hydrocortisone and propranolol. Viral and autoimmune hepatitis panel, acetaminophen and alcohol levels were negative. Abdominal ultrasound was unremarkable. Liver biopsy showed severe cholestatic hepatitis, perivenular necrosis and marked bile duct damage with neutrophilic inflammation, consistent with DILI. LFTs gradually improved over the following weeks. On hospital day 23, an uneventful total thyroidectomy was performed for definitive management of Graves’. We present a unique and rare case of acute liver failure within 48 hours of high dose methimazole and PTU administration for presumed thyroid storm. The patient recovered with gradual improvement in her LFTs and was successfully managed with total thyroidectomy. To our knowledge, this case represents the earliest onset of acute liver failure from thionamide use. Risk factors appear to include very high dose methimazole and PTU exposure as well as potentially the patient’s intermittent use of methimazole in the past. Further study is needed to clarify potential risk factors of thionamide-induced hepatotoxicity as data is limited. Presentation: Friday, June 16, 2023

ANTI TUBERCULAR DRUGS INDUCED HEPATOTOXICITY IN A NEW TERTIARY CARE HOSPITAL OF A TRIBAL DISTRICT OF ODISHA

Objective: India accounts for about one-fourth of the global TB burden. WHO TB statistics for India for 2018 gives an estimated incidence fig. of 2.69 million cases (199 per one lakh population). Drug-induced Hepatotoxicity is responsible for significant morbidity and mortality of the TB patient if these drugs continued after symptoms of hepatotoxicity develop. Whether the hepatotoxicity is due to individual drugs or due to additive effects is still unclear. The management therapy for TB patients with anti-TB DIH is imperative to ensure successful TB treatment and not recurrence DIH. Aim of the current study is to find out the pattern of Liver enzyme raised after antitubercular therapy in the tribal population of Koraput district where different phylogenetic populations reside where clinically it was observed by the physician little early onset of hepatotoxicity than national and international data.
 Methods: A prospective study was done after clearance from the Institutional Ethical Committee, Saheed Laxman Nayak Medical College, Koraput, from January 2019 to December 2019. Patients with>15 y of age with pulmonary and extrapulmonary tuberculosis with normal liver enzymes were included. Patients having abnormal liver enzymes before treatment, seropositive TB patients with human immunodeficiency virus infection, pregnant ladies and children<15 y of age were excluded.
 Results: Out of 922 patients in total; 4.78% (44) tuberculosis patients developed anti TB DIH. 68.18% (30) patients are below 50 y of age and 31.82% (14) are above 50 y of age group among TB patients with DIH. Age has no statistically significant influence on the occurrence of anti-TB DIH, but there is a statistically significant influence of sex on the occurrence of anti TB DIH. The mean occurrence of anti TB DIH is 18±18.16 d. One case of anti TB DIH patients shows signs and symptoms as early as on day 6th. The commonest symptoms are nausea and vomiting in 64% of patients who developed DIH. Interruption of ATT after DIH occurred in 79.54% of patients with recurrence in only 9.9% of patients after the reintroduction of ATT.
 Conclusion: Anti TB DIH mostly occurred between 7-28 d of starting the ATT in this geographical region. The duration of the anti TB ATT regimen is prolonged due to DIH. We recommend that all patients should have LTs 2 w after starting ATT, even if asymptomatic.

Prevalence Of Hepatotoxicity In HIV-Positive, Tuberculosis And HIV+TB Co Infected Patients In Tertiary Care Hospitals , Sindh

Hepatotoxicity is historically the 3rd most common reason for drug withdrawal and toxicity-related discontinuation of treatment. This study was aimed at determining the incidence and the onset of hepatotoxicity and at evaluating the relationship of some risk factors for hepatotoxicity among Human Immunodeficiency Virus- (HIV-) positive, tuberculosis (TB), and HIV/TB patients on treatment. This was a prospective follow-up study involving 125 participants from the HIV/AIDS and TB treatment centres in Tertiary Care hospital of Larkana and Sukkur, Sindh. These TB and HIV patients were initiated on RHEZ (R = Rifampicin, H = Isoniazid, E = Ethambutol, and P = Pyrazinamide) and TELE (efavirenz/tenofovir/lamivudine), respectively, and followed up for 12 weeks between September 2018 and November 2019. The levels of liver enzymes (transaminases, gamma- glutamyltransferase, alkaline phosphatase, and unconjugated/total bilirubin) were measured spectrophotometrically using serum. The Chi-squared (χ2) test was used to assess the association between risk factors and hepatotoxicity, while the Kaplan-Meier survival analysis with the log-rank test was used to determine the occurrence of hepatotoxicity in the different groups. We followed the general study population for a total person time of 6580 person-days, with an incidence rate and cumulative incidence of 8 cases per 1000 person-days (53/6580 person-days) and 42.4% (53/125), respectively (95% confidence interval), recorded after 12 weeks of follow-up of all the participants. The onset of hepatotoxicity in the total study population was statistically significant (χ2 = 9:5334; p = 0:022979; CI = 95%), with the majority observed at week eight of follow-up. Also, the incidence rate and cumulative incidence of hepatotoxicity with respect to HIV/AIDS, TB, and HIV/TB patients, respectively, at 95% confidence interval were: 8 cases per 1000 person-days (32/3843 person-days) and 32/76 (42.1%), 6 cases per 1000 person- days (12/1932 person-days) and 12/32 (37.5%), and 11 cases per 1000 person-days (9/805 person-days) and 9/17 (52.9%). This study shows that the incidence rate and cumulative incidence of hepatotoxicity in HIV/AIDS, TB, and HIV/TB patients on treatment were high . Also, it is very important to check these patients’ liver function especially within the first 12 weeks of treatment.

Awareness of immune-related adverse events among medical residents in a community hospital.

e15154 Background: Immunotherapy has paved the way for new frontiers in the management of certain advanced cancers. Immune checkpoint inhibitors (ICI) have substantially improved prognosis in patients with advanced malignancy. Primary targets for ICIs include programmed cell death receptor 1 (PD-1), programmed cell death ligand 1 (PD-L1) and Cytotoxic T-lymphocyte-associated antigen 4(CTLA-4). These treatments have a wide range of adverse effects distinct from traditional chemotherapy regimens. We conducted a survey to assess the awareness of immune-related adverse events (IRAE) among medical residents in a community hospital. Methods: Internal medicine residents in a community hospital were given a survey of 10 questions related to IRAEs. A total of 40 responses were collected and analyzed. Results: 22.50% respondents were aware that nephrotoxicity is not a common side effect of immunotherapy. 35% were aware that cutaneous toxicities are the most common IRAEs. 42.50% were aware that hair loss is not a common side effect of ICIs. 42.50% were aware that patients do not need pretreatment with anti-emetics before immunotherapy. 45% were aware that the onset of hepatotoxicity is usually not seen within the first week of starting immunotherapy. 50% were aware that immunotherapy is associated with the development of pneumonitis. 62.5% were aware that steroids formed mainstay of treatment in IRAEs. 65% were aware that immunotherapy is associated with thyroid-related side effects. 67.5% were aware that patients with pre-existing autoimmune conditions are at greater risk for immune-related adverse effects. 70% were aware that immune related colitis was not treated with antibiotics. Conclusions: With the rapid advancement and use of immunotherapy the incidence of IRAEs is increasing. Involvement of single or multiple organ systems as well as flare of previously well controlled autoimmune disease can add to the challenge. As we gain more experience, long term data will emerge to help predict at-risk patients. This is a dynamic area of research and new treatments are under development. 6/10 questions were answered correctly by less than 50% respondents and 4/10 were answered correctly by 50-70% respondents. At present no data is available to gauge awareness regarding IRAEs among internists. Our survey suggests a lack of awareness among medical residents on many fronts. Lack of awareness leads to inappropriate treatment and prolonged hospital stay. Active efforts need to be taken to educate residents regarding immunotherapy and IRAEs to achieve better patient outcomes.

Abnormal Levels of Liver Enzymes and Hepatotoxicity in HIV-Positive, TB, and HIV/TB-Coinfected Patients on Treatment in Fako Division, Southwest Region of Cameroon.

Hepatotoxicity is historically the 3rd most common reason for drug withdrawal and toxicity-related discontinuation of treatment. This study was aimed at determining the incidence and the onset of hepatotoxicity and at evaluating the relationship of some risk factors for hepatotoxicity among Human Immunodeficiency Virus- (HIV-) positive, tuberculosis (TB), and HIV/TB patients on treatment. This was a prospective follow-up study involving 125 participants from the HIV/AIDS and TB treatment centres in three hospitals in Fako Division of Cameroon. These TB and HIV patients were initiated on RHEZ (R = Rifampicin, H = Isoniazid, E = Ethambutol, and P = Pyrazinamide) and TELE (efavirenz/tenofovir/lamivudine), respectively, and followed up for 12 weeks between September 2018 and November 2019. The levels of liver enzymes (transaminases, gamma-glutamyltransferase, alkaline phosphatase, and unconjugated/total bilirubin) were measured spectrophotometrically using serum. The Chi-squared (χ2) test was used to assess the association between risk factors and hepatotoxicity, while the Kaplan-Meier survival analysis with the log-rank test was used to determine the occurrence of hepatotoxicity in the different groups. We followed the general study population for a total person time of 6580 person-days, with an incidence rate and cumulative incidence of 8 cases per 1000 person-days (53/6580 person-days) and 42.4% (53/125), respectively (95% confidence interval), recorded after 12 weeks of follow-up of all the participants. The onset of hepatotoxicity in the total study population was statistically significant (χ2 = 9.5334; p = 0.022979; CI = 95%), with the majority observed at week eight of follow-up. Also, the incidence rate and cumulative incidence of hepatotoxicity with respect to HIV/AIDS, TB, and HIV/TB patients, respectively, at 95% confidence interval were: 8 cases per 1000 person-days (32/3843 person-days) and 32/76 (42.1%), 6 cases per 1000 person-days (12/1932 person-days) and 12/32 (37.5%), and 11 cases per 1000 person-days (9/805 person-days) and 9/17 (52.9%). This study shows that the incidence rate and cumulative incidence of hepatotoxicity in HIV/AIDS, TB, and HIV/TB patients on treatment were high in Fako Division, Cameroon. Also, it is very important to check these patients' liver function especially within the first 12 weeks of treatment.

Regorafenib induced severe toxic hepatitis: characterization and discussion.

Regorafenib is the first small-molecule multikinase inhibitor which showed survival benefits in pretreated metastatic colorectal cancer (mCRC) patients. Besides classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect. Patients with refractory mCRC treated with regorafenib in our institution were reviewed. Severe treatment-related liver toxicity was investigated. Clinical history, liver histology and genetic assessment (sequence analysis) of cytochrome P3A4 (CYP3A4) and uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) involved in regorafenib metabolization were here reported for patients with severe hepatotoxicity. Among the 93 reviewed patients, 3 presented severe and icteric toxic hepatitis which was fatal for 1 patient. Histopathological liver lesions were different depending on the onset of hepatotoxicity (acute or subacute): acinar zone 3 necrosis in case of acute symptoms, and portal tract inflammation with porto-central bridging and fibrosis in the delayed presentation. None of the patients had CYP3A4 gene mutations. Similar polymorphisms in UGT1A9 gene promoter region (UGT1A9 variant -118T9>10 [rs3832043]) were found in both patients who presented acute hepatitis. Moreover, it appears retrospectively that both of them already experienced significant toxicity under irinotecan-based chemotherapy. This is the first report of severe hepatotoxicity with available liver histology and genetic assessment of enzymes involved in regorafenib metabolization. This report also reminds the importance of close liver tests monitoring during regorafenib treatment.

Polymorphisms of CYP2D6 Gene and Gefitinib-Induced Hepatotoxicity

IntroductionGefitinib induces severe hepatotoxicity in approximately a quarter of Japanese patients with epidermal growth factor receptor (EGFR) mutation–positive non–small-cell lung cancer (NSCLC). Gefitinib is metabolized by cytochrome P450 (CYP) enzymes—including CYP3A4/5, CYP1A1, and CYP2D6—in the liver. We hypothesized that polymorphisms of the CYP2D6 gene may account for gefitinib-induced hepatotoxicity. Patients and MethodsPolymorphisms of the CYP2D6 gene were analyzed in 55 patients with NSCLC who experienced grade ≥ 2 transaminase elevation from gefitinib. The distribution of the CYP2D6 genotype was compared with that of the healthy Japanese population. The correlations between the nonfunctional allele *5 or the reduced-function allele *10 and hepatotoxicity-related clinical factors were also examined. ResultsThe distribution of the CYP2D6 genotype in the study participants was not different from that of the general Japanese population, reported previously. Existence of allele *5 or *10 did not correlate with clinical factors such as onset of hepatotoxicity within 2 months, grade ≥ 3 serum transaminase elevation, and tolerability to dose reduction or rechallenge of gefitinib. However, in 7 patients taking CYP3A4-inhibitory drugs, rechallenge of gefitinib again caused hepatotoxicity in 4 patients with allele *5 or *10 but not in 3 patients with normal alleles (P = .029). Moreover, switching to erlotinib did not cause hepatotoxicity in any of 17 patients with allele *5 or *10 but did in 3 of 8 patients without these alleles (P = .024). ConclusionReduced function of CYP2D6 may partly account for gefitinib-induced hepatotoxicity when CYP3A4 is inhibited. Erlotinib could be safely used in patients with decreased CYP2D6 activity even after they experienced gefitinib-induced hepatotoxicity.

Successful Antibiotic Treatment of Mycobacterium abscessus Pulmonary Disease in an Immunocompetent Individual

The number of subjects with Mycobacterium abscessus lung disease is increasing. The optimal treatment to prevent clinical relapse in these patients has not been well established. At times, antibiotic regimens have also been shown to produce long-term sputum conversion. We describe a case of M. abscessus lung disease in an immunocompetent individual with successful outcome at 24 months, following antibiotic therapy. Initially, an empirical treatment was started intravenously with amikacin (700 mg once-daily), cefoxitin (4 g every 8 h), and oral clarithromycin (500 mg twice daily). Although, the symptoms resolved rapidly, the anti-mycobacterial drugs were discontinued three weeks later, following the onset of hepatotoxicity. Two weeks after discontinuation of therapy, the liver enzymes were returned to normal levels, and amikacin and clarithromycin were reintroduced and continued for another 8 months, when the individual developed hearing loss, which led to further discontinuation of antibiotic therapy. During the subsequent 24 months, broncoscopy, sputum AFB examination and mycobacterial culture were negative. Our management suggests that prompt, individualized and protracted treatment can be curative, in case of mild disease.

A Multi-Scale Modeling Framework for Individualized, Spatiotemporal Prediction of Drug Effects and Toxicological Risk

In this study, we focus on a novel multi-scale modeling approach for spatiotemporal prediction of the distribution of substances and resulting hepatotoxicity by combining cellular models, a 2D liver model, and whole body model. As a case study, we focused on predicting human hepatotoxicity upon treatment with acetaminophen based on in vitro toxicity data and potential inter-individual variability in gene expression and enzyme activities. By aggregating mechanistic, genome-based in silico cells to a novel 2D liver model and eventually to a whole body model, we predicted pharmacokinetic properties, metabolism, and the onset of hepatotoxicity in an in silico patient. Depending on the concentration of acetaminophen in the liver and the accumulation of toxic metabolites, cell integrity in the liver as a function of space and time as well as changes in the elimination rate of substances were estimated. We show that the variations in elimination rates also influence the distribution of acetaminophen and its metabolites in the whole body. Our results are in agreement with experimental results. What is more, the integrated model also predicted variations in drug toxicity depending on alterations of metabolic enzyme activities. Variations in enzyme activity, in turn, reflect genetic characteristics or diseases of individuals. In conclusion, this framework presents an important basis for efficiently integrating inter-individual variability data into models, paving the way for personalized or stratified predictions of drug toxicity and efficacy.

Clinical presentation of hepatotoxicity-associated crizotinib in ALK-positive (ALK+) advanced non-small cell lung cancer (NSCLC).

7598 Background: Severe hepatotoxicity has been observed with most receptor tyrosine kinase inhibitors. Crizotinib, a first-in-class oral inhibitor of ALK, was recently FDA approved for the treatment (tx) of advanced (ALK+) NSCLC. We provide a review of hepatotoxicity in the crizotinib clinical development program. Methods: Relevant tx-emergent adverse event (AE) reports from 2 pooled single-arm trials in patients (pts) with ALK+ NSCLC who received crizotinib 250 mg BID (n=588) up to Jun 2011 were reviewed. Five reports of severe hepatotoxicity received through Dec 13, 2011 were also evaluated. Results: Incidence of elevation in ALT and AST lab values by CTCAE grade are shown in the table. Additionally, 16 all-grade (7 grade 3 or 4) cases of pertinent hepatic events have been reported. Transaminase elevations generally occurred in the first 2 months of tx and were usually reversible. Pts usually resumed tx at a lower dose without recurrence; however, 4 (<1%) required permanent discontinuation from tx. Five (<1%) cases of severe, potentially drug-related hepatotoxicity (2 fatal) were reported through Dec 13, 2011, with an estimated exposure of 1400 pts. Pts presented with fatigue, nausea, anorexia, weakness, and abdominal pain. Time from starting crizotinib to onset of hepatotoxicity was <6 weeks in 4 cases, while significant transaminase elevation was observed after 6 months in the fifth case. Significant hepatic metastases and abnormal enzymes at baseline were present in 1 (fatal) case, while baseline transaminases were normal in 3 cases, or just above the upper limit of normal in 1 case. Conclusions: Crizotinib is uncommonly associated with severe hepatotoxicity and was reported in <1% of pts. Nausea, malaise, decreased appetite, vomiting, and abdominal pain may indicate hepatic toxicity. ALT and total bilirubin should be monitored monthly and as clinically indicated. Discontinuation of crizotinib is recommended when severe drug-induced hepatic toxicity is suspected or diagnosed. [Table: see text]

Understanding lactic acidosis in paracetamol (acetaminophen) poisoning.

Paracetamol (acetaminophen) is one of the most commonly taken drugs in overdose in many areas of the world, and the most common cause of acute liver failure in both the UK and USA. Paracetamol poisoning can result in lactic acidosis in two different scenarios. First, early in the course of poisoning and before the onset of hepatotoxicity in patients with massive ingestion; a lactic acidosis is usually associated with coma. Experimental evidence from studies in whole animals, perfused liver slices and cell cultures has shown that the toxic metabolite of paracetamol, N-acetyl-p-benzo-quinone imine, inhibits electron transfer in the mitochondrial respiratory chain and thus inhibits aerobic respiration. This occurs only at very high concentrations of paracetamol, and precedes cellular injury by several hours. The second scenario in which lactic acidosis can occur is later in the course of paracetamol poisoning as a consequence of established liver failure. In these patients lactate is elevated primarily because of reduced hepatic clearance, but in shocked patients there may also be a contribution of peripheral anaerobic respiration because of tissue hypoperfusion. In patients admitted to a liver unit with paracetamol hepatotoxicity, the post-resuscitation arterial lactate concentration has been shown to be a strong predictor of mortality, and is included in the modified King's College criteria for consideration of liver transplantation. We would therefore recommend that post-resuscitation lactate is measured in all patients with a severe paracetamol overdose resulting in either reduced conscious level or hepatic failure.

Protective effect of N-acetylcysteine on antituberculosis drug-induced hepatotoxicity

Isoniazid, rifampicin, and pyrazinamide, the first-line antituberculosis (anti-TB) drugs, are associated with hepatotoxicity. To study the hepatoprotective effect of N-acetylcysteine (NAC) on liver injury induced by anti-TB drugs. A randomized clinical trial was conducted on 60 new TB patients who were aged 60 years or more. Patients were randomized into two groups. In group I (n=32), drug regimen included daily doses of isoniazid, rifampicin, pyrazinamide, and ethambutol. Patients in group II (n=28) were treated with the same regimen and NAC. The patients were followed up for 2 weeks. Liver enzymes and bilirubins were measured at baseline, after 1 and 2 weeks of treatment, and whenever the patients presented with clinical symptoms of hepatotoxicity. The mean+/-SD values of aspartate aminotransferase and alanine aminotransferase were significantly higher in group I than in group II after 1 and 2 weeks of treatment. Hepatotoxicity occurred in 12 patients with (37.5%) group I and none in group II. The mean duration of treatment before the onset of hepatotoxicity was 4.67+/-4.58 days. NAC protects against anti-TB drug-induced hepatotoxicity.

Can we prevent fatalities due to antituberculous drugs?

Objective: To assess the incidence and risk factors for liver toxicity in patients on anti-tuberculosis treatment. Method: All patients with a diagnosis of tuberculosis, who were to receive ATT during the study period, were included in the present study for prospective periodic laboratory monitoring for the development of hepatotoxicity. Results: Of the 352 patients studied, 61 patients (17%) had elevated hepatic transaminases value after starting antituberculous therapy (ATT), 36 grade 1 (10%), 7 grade 2 (2%), 12 grade 3 (3.4%), and 6 patients grade 4 (1.7%). The incidence of severe hepatotoxicity (grades 3, 4) among treated patients was 5.1% (18 patients). The mean duration of treatment before onset of hepatotoxicity was 36 days. Although the majority of patients developed hepatic dysfunction within the first 2 months of treatment, significant hepatotoxicity (grades 3, 4) did occur at a later date in some patients (28%). Univariate analysis did not show any significant relationship between age, sex, and ethnic origin with hepatotoxicity in this study. The only significant risk factor was coexisting hepatitis B or C. None of our patients died from complications of liver-related illness attributed to anti-TB drugs.

Hepatotoxic Interaction of Sulindac with Lipopolysaccharide: Role of the Hemostatic System

Sulindac (SLD) is a nonsteroidal anti-inflammatory drug (NSAID) that has been associated with a greater incidence of idiosyncratic hepatotoxicity in human patients than other NSAIDs. One hypothesis regarding idiosyncratic adverse drug reactions is that interaction of a drug with a modest inflammatory episode precipitates liver injury. In this study, we tested the hypothesis that lipopolysaccharide (LPS) interacts with SLD to cause liver injury in rats. SLD (50 mg/kg) or its vehicle was administered to rats by gavage 15.5 h before LPS (8.3 x 10(5) endotoxin unit/kg) or its saline vehicle (i.v.). Thirty minutes after LPS treatment, SLD or vehicle administration was repeated. Rats were killed at various times after treatment, and serum, plasma, and liver samples were taken. Neither SLD nor LPS alone caused liver injury. Cotreatment with SLD/LPS led to increases in serum biomarkers of both hepatocellular injury and cholestasis. Histological evidence of liver damage was found only after SLD/LPS cotreatment. As a result of activation of hemostasis induced by SLD/LPS cotreatment, fibrin and hypoxia were present in liver tissue before the onset of hepatotoxicity. Heparin treatment reduced hepatic fibrin deposition and hypoxia and protected against liver injury induced by SLD/LPS cotreatment. These results indicate that cotreatment with nontoxic doses of LPS and SLD causes liver injury in rats, and this could serve as a model of human idiosyncratic liver injury. The hemostatic system is activated by SLD/LPS cotreatment and plays an important role in the development of SLD/LPS-induced liver injury.

Evaluation of patient-related factors associated with causality, preventability, predictability and severity of hepatotoxicity during antituberclosis treatment

For evaluation the extent of antituberculosis drug-induced hepatotoxicity and also to determine the patient-related factors associated with causality, preventability, predictability and severity of hepatotoxicity induced by antituberculosis medications, a prospective study was conducted on 112 patients in a tertiary care university teaching hospital for three years. Causality, preventability, predictability and severity of hepatotoxicity were determined based on the available standard algorithms. Of 112 patients, 31 (27.7%) demonstrated hepatotoxicity. Two patients died from complications of liver-related illness. The mean duration of treatment before the onset of hepatotoxicity was 16.7 ± 3.2 days. Malnutrition was present in 17 of 112 patients. Most of hepatotoxicity (25/31 or 80.6%) occurred within the first month of treatment. Reintroduction of antituberculosis drugs was possible in 29 of 31 patients. Univariate and multivariate analysis did not show significant relationships between the rate of hepatotoxicity with age, sex, nutrition and nationality. Our results showed that hepatotoxicity induced by antituberculosis drugs is a nonpreventable and unpredictable reaction. The causality of this reaction is classified as category A based on European grading of causality. This study noted that the frequency of hepatotoxicity induced by antituberculosis drugs in Iranian patients is higher than other studied populations.

Mitochondrial dysfunction is an early manifestation of 1,1-dichloroethylene-induced hepatotoxicity in mice.

Hepatotoxicity induced by 1,1-dichloroethylene (DCE) is mediated by cytochrome P450-dependent metabolism to reactive intermediates, including the epoxide. We have tested the hypothesis that mitochondria are a primary target of toxicity by investigating dose- and time-dependent effects of DCE on mitochondrial respiration. Hepatotoxicity, as assessed by serum alanine aminotransferase (ALT) activity, was evaluated. We have also determined the effectiveness of N-acetyl-L-cysteine (NAC) in protecting against respiratory perturbations and hepatotoxicity. Liver mitochondria were isolated 2 h after DCE (50, 75, 100, 125, and 150 mg/kg) treatment. Glutamate (complex I)- and succinate (complex II)-supported mitochondrial respiration was assessed by measurement of state 3 (ADP-stimulated) and state 4 (resting) rates of oxygen consumption. The corresponding respiratory control ratios (RCRs, state 3/state 4) and ADP:O ratios were then calculated. A DCE dose of 125 mg/kg significantly inhibited glutamate- and succinate-supported state 3 respiration, leading to a significant reduction in corresponding RCRs and ADP:O ratios. In time-dependent studies, state 3 respiration rates and RCRs for glutamate-supported respiration were significantly decreased as early as 20 min after DCE (125 mg/kg) treatment, whereas those for succinate-supported respiration were significantly decreased at 90 min. Additionally, ADP:O ratios for glutamate-supported respiration were significantly decreased starting at 60 min, and those for succinate-supported respiration at 90 min. Alterations in mitochondrial function preceded significant increases in ALT activity, which was first manifested at 2 h. Pretreatment with NAC (1200 mg/kg) abrogated DCE-induced GSH depletion and inhibited disturbances in mitochondrial respiration. Moreover, NAC protected against increased ALT activity, suggesting that the protective effect of NAC is due to increased GSH for conjugation reactions and/or its antioxidant property. These results showed that DCE-mediated mitochondrial dysfunction is an early event that preceded the onset of hepatotoxicity.

Liver function: Postprandial urea nitrogen elevation and indocyanine green clearance in the dog

A method for evaluation of liver function, based on the postprandial elevation of urea nitrogen in the serum of beagles is described. Biopsy specimens were obtained and alkaline phosphatase, serum glutamic-oxalacetic transaminase, and indocyanine green clearance also were determined after the induction of liver injury by carbon tetrachloride or ethionine. The postprandial elevation of urea nitrogen was significantly reduced by both agents. In ethionine-treated animals the depression of postprandial urea nitrogen elevation was the most effective of the clinical diagnostic tests indicating the onset of hepatotoxicity. Indocyanine green clearance, however, was the most satisfactory test for determining residual hepatic damage during the recovery studies after carbon tetrachloride administration.