Akt induced hepatitis dr.sunil
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AKT Induced Hepatitis
Dr.Sunil Pawar
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• Why is Drug-induced Liver Injury Important?
– Accounts for 0.1 to 3% of hospital admissions
– 600 liver transplants / year in US
– Most common cause of acute liver failure in US, with acetaminophen the top contributor
1 Dig Dis Sci 2007;52:2463-71. 2 Ostapowicz GM. et al. Ann Intern Med 2002;137:947–954.
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Definition
• In the absence of symptoms, elevation of transaminases up to 5 times the upper limit of normal (ULN) and in the presence of symptoms up to three times the ULN or twice the ULN of bilirubin
• Risk of TB DILI in these diverse studies ranges from 5 to as high as 33%. [ATS 2006]
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• In patients with HIV, the AIDS Clinical Trials Group criteria is used, which is as follows:
• Grade 1: Transaminases 1.25 - 2.5 × upper limit of normal (ULN)
• Grade 2: 2.6 - 5 × ULN
• Grade 3: 5.1 - 10 × ULN
• Grade 4: >10 × ULN.17
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• Definition of hepatotoxicity in patients with previous liver diseases is controversial
• Schenker et al reported that elevations in the ALT and/or AST levels to 50-100 IU/L more than the baseline levels might define toxicity
Schenker S, Martin RR, Hoyumpa AM. Antecedent liver disease and drug toxicity. J Hepatol 1999; 31: 1098-1105 [PMID: 10604586 DOI: 10.1016/S0168-8278(99)80325-0]
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• Saigal et al hepatotoxicity was diagnosed if ALT/AST levels increased to more than fivefold of the baseline level, or to more than 400 IU/L, or if the bilirubin increased by 2.5 mg/dLafter exclusion of superimposed acute hepatitis.
Saigal S, Agarwal SR, Nandeesh HP, Sarin SK. Safety of an ofloxacin-based antitubercular regimen for the treatment of tuberculosis in patients with underlying chronic liver disease: a preliminary report. J Gastroenterol Hepatol 2001; 16: 1028-1032 [PMID: 11595068 DOI: 10.1046/j.1440-1746.2001.02570.x]
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Clinical Spectrum
• Asymptomatic elevation to acute liver failure
• All age groups including children
• TB DILI develops more commonly in males
• ALF and Severity is more common in females
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MECHANISMS
(i) Idiosyncratic damage : Most Common
(ii) Dose-dependent toxicity;
(iii) Induction of hepatic enzymes;
(iv) Drug-induced acute hepatitis;
(v) Allergic reactions
(vi) Drug induce autoimmune like hepatitis
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Specific patterns of hepatic damage
• Disruption of intracellular calcium homeostasis. Cell membrane bleb formation, rupture and cell lysis
• Cholestatic damage. Disruption of the actin filaments adjacent to the canaliculus
• Interruption of transport pumps and loss of villous processes
• Reactions involving cytochrome P-450 system
• Activation of apoptotic pathways and programmed cell death
• Inhibition of mitochondrial function
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• Histopathological evidence resembling that of viral hepatitis showing hepatocyte necrosis, ballooning degeneration and inflammatory infiltrates : dose-related toxicity
• Presence of eosinophilic infiltrates on liver biopsy and recurrence of hepatotoxicity on re-challenge with the drug suggest: hypersensitivity
• Mediated through oxidative stress
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• DIH caused by rifampicin occurs earlier and produces a patchy cellular abnormality with marked periportal inflammation.
• systemic allergic reaction
• Unconjugated hyperbilirubinaemia as a result of competition with bilirubin for uptake at hepatocyte plasma membrane.
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Synergy? Additive?
• Acetyl-isoniazid, the principal metabolite of isoniazid, is converted to monoacetylhydrazine.
• The microsomal p-450 enzymes convert monoacetyl hydrazine to other compounds resulting in hepatotoxicity.
• Rifampicin is thought to enhance this effect by enzyme induction.
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• Acetyl-isoniazid formation occurs in larger amounts in rapid rather than slow acetylators, it was suggested that rapid acetylators are more prone to hepatotoxicity.??
• Products of hydrolysis rather than acetylation are the critical toxic metabolites of isoniazid: greater in slow acetylators
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• 20% of patients develop asymptomatic elevation of liver enzymes which is self limiting (as a result of adaptation or discontinuance) in a majority of patients
Forget EJ, Menzies D. Adverse reactions to first-line antituberculosis drugs. Expert Opin Drug Saf. 2006;5:231–49.
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Risk factors for TB DILI
1. Age: older than 35 years are at 4 times increased risk. Other studies conclude all age group have same risk.
2. Children may be more sensitive. TB meningitis more chances .
2. Gender: female gender is a positive predictor of more severe liver disease including death
Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin. A meta-analysis. Chest. 1991;99:465–71.
Singla R, Sharma SK, Mohan A, Makharia G, Sreenivas V, Jha B, et al. Evaluation of risk factors for antituberculosis treatment induced hepatotoxicity. Indian J Med Res. 2010;132:81–6.
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3. Organ involvement / extent of TB disease cavitory disease, multibacillary TB and extrapulmonary organ esp meningitis
4. Malnutrition:
• Patients with low albumin (<3.5 mg/dl) had three fold higher risk
• weight loss
5. Alcohol:
Parthasarathy R, Sarma GR, Janardhanam B, Ramachandran P,Santha T, Sivasubramanian S, et al. Hepatic toxicity in South Indian patients during
treatment of tuberculosis with short-course regimens containing isoniazid, rifampicin and pyrazinamide. Tubercle. 1986;67:99–108.
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6. Hepatitis B:4 fold in HBsAg carriers compared to non-carriers (Korean Study)7. Hepatitis C. Coinfection with both hepatitis Cand HIV elevated the risk of hepatotoxicity more than 14-fold.8. Genetic polymorphism: N-acetyltransferase 2 (NAT2), CYP 2E1 and glutathione S-transferase are INH metabolising enzymes9. Presence of HLA-DQB1*0201 and the absenceof HLA-DQA1*0102 with AT DILI
Sharma SK, Balamurugan A, Saha PK, Pandey RM, Mehra NK. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment.Am J Respir Crit Care Med. 2002;166:916–9.
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10. Ethnic variations: higher risk of DIH has been reported in Indian patients than in patients from the West
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Poor prognosticmarkers
• Jaundice
• Hypoalbuminemia
• Ascites
• Encephalopathy
• High prothrombin time
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• Mild toxicity: If the AST level is less than 5 times the upper limit of normal
• Moderate toxicity: AST level 5--10 times normal defines
• Severe toxicity: AST level greater than 10 times normal
World Health Organization Collaborating Center for International Drug Monitoring. Adverse drug reaction terminology (ART), 1979. http://www.WHO-UMC.org (or e-mail: [email protected]).
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Management
Education
Education
Education
Patientsfamily members
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Management
• Rule out other causes First
• Baseline : serum transaminases, bilirubin, alkaline phosphatase, and Creatinine, and a blood platelet count are recommended for all adults beginning treatment for TB disease.
ATS
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• For patients with pre existing severe liver disease:
periodic measurement of LFT, prothrombin time and INR to assess hepatic synthetic function.
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Monitoring with liver tests is recommended
• Patients who consume alcohol• Individuals with chronic hepatitis B or C• Concomitant hepatotoxic drugs• Elevated baseline transaminase levels• Underlying other liver disease• HIV• Have experienced prior isoniazid hepatitis• Pregnant or are within 3 months postpartum• Older than 35 years
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• Healthy individuals older than 35 years:
Baseline and scheduled monitoring of ALT
Monitoring schedules in such cases may be
1. Monthly;
2. Every other month;
3. At 1, 3, and 6 months in those taking a 9-month regimen
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Guideline for the Management of Anti-Tuberculosis Therapy Induced Liver Injury,NHS,2013
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• Medications should be restarted after the AST/ALT concentration returns to less than two times the upper limit of normal.
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Reintroduction anti tuberculosis regimens
• 3 Arms
1. Patients received maximum doses of INH, RIF, PZA simultaneously
2. ATS guideline RIF followed by INH after 7 days, followed by PZA after 7 days, all with maximum doses
3. BTS guideline. INH, RIF and PZA were gradually escalated sequentially after the maximum dose of the preceding drugs
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• Recurrence of DILI was similar between the three treatment arms (p=0.69)
Sharma SK, Singla R, Sarda P, Mohan A, Makharia G, Jayaswal A, et al. Safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosistreatment-induced hepatotoxicity. Clin Infect Dis.2010;50:833–9
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• Randomized study by Tahaoglu and associates on 45 patients concluded that reintroduction regimens containing maximum dose of antituberculosis drugs including pyrazinamide (group 1, n=25) caused more hepatotoxicity than gradual reintroduction without pyrazinamide
Tahaoðlu K, Ataç G, Sevim T, Tärün T, Yazicioðlu O, Horzum G, et al. The management of anti-tuberculosis drug-induced hepatotoxicity. Int J Tuberc Lung Dis. 2001;5:65–9.
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Which drug to start first??
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Reintroduction Regimen
ATS
• R at maximum dosage from day 1,
• H at maximum dosage from day 8
• Z at maximum dosage from day 15
BTS / NHS 2013
• H at dosage of 100 mg/day from day 1, maximum dosage from day 4;
• R at dosage of 150 mg/day from day 8, maximum dosage from day 11;
• Z at dosage of 500 mg/day from day 15, maximum dosage from day 18
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• Task Force of the European Respiratory Society advises
restarting all the drugs simultaneously;
After a second episode of hepatotoxicity the drugs need to be reintroduced consecutively
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Score to Diagnose
Roussel Uclaf Causality Assessment Method (RUCAM)
• Clinical, biochemical, serologic and radiologic features of liver injury
• Validated, standardized causality assessment tool to assess the probability of drug-relatedness for drug-induced liver injury
• Total range of the RUCAM is -9 to +14
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• Assigns weighted scores to following clinical & laboratory data:
1. time to onset (from start and cessation of the implicated drug)
2. time to >50% improvement in enzymes after drug cessation
3. risk factors
4. concomitant drug use
5. alternative non-drug related causes of liver injury
6. previous information on hepatotoxicity of the drug
7. response to re-administration or rechallenge (intentional or accidental)
Lucena MI et al. Hepatology 2001;33:123-130. Danan G J Clin Epidemiol 1993; 46: 1323–1330 Toxicologic Pathology 2005; 33: 155-164
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R Ratio
• For differentiating “hepatocellular”, “mixed”, or “cholestatic.
R = (ALT value ÷ ALT ULN) ÷ (Alk P value ÷ Alk P ULN)
• R ratios of >5 define a hepatocellular, <2 a cholestatic, and between 2 and 5 a mixed pattern of enzymes.
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• nR Ratio includes AST or ALT which ever is increased more in above calculation
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Drug-induced Liver Injury Relationship to Autoimmune Hepatitis
• AIH with DILI: who develop DILI (acute on chronic injury)
• Drug-induced AIH : Patients in whom AIH is unmasked or possibly induced by DILI; good response to steroids but relapse after withdrawal of immunosuppression.
• Immune-mediated DILI or drug-induced autoimmune-like hepatitis: Clinical, biochemical and histological signs similar to AIH; good response to steroids but expect long term remission after withdrawal of steroids
Modified from ( Weiler-Normann C, Schramm C. J Hepatol 2011:55:747-749; Czaja AJ. Dig Dis Sci 2011;56:958-976)
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Risk Factors for Drug-induced Autoimmune-like Hepatitis
• Advanced age • Female gender • Dose effects • Drug interactions • Alcohol • Cross-sensitization • Genetic predisposition • Hepatic drug metabolism
Czaja AJ. Dig Dis Sci 2011;56:958-976
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ISONIAZID
• Hepatotoxicity occurs generally within weeks to months
• Approximately 60% of the hepatotoxicity incidence occurred in the first 3 months of treatment
• Median interval from treatment initiation to symptom onset was 16 weeks
• Isoniazid rechallenge does not always elicit rapid recurrence of hepatotoxicity
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• Severity increases with age, with higher mortality in those older than 50 years
• Asian males : risk double than white males and nearly 14 times that of black males.
• No difference for women of any race.
• There do not appear to be consistent racially based risks for high-grade hepatotoxicity
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• Pregnant women in the third trimester and in the first 3 months of the postpartum period may be at higher risk for the development of hepatitis
• women may be at higher risk for death from isoniazid-related hepatitis
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Isoniazid is associated with:
• Reactive metabolite
• Immunoallergic injury: HLA DQB1*0201
• Mitochondrial injury
• Impaired liver cell regeneration as hydralazine derivatives inhibit histone deacetylase
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Hy’s Law
• Hy's law is a rule of thumb that a drug is at high risk of causing a fatal DILI when given to a large population, if it caused cases of liver injury that satisfied certain criteria when given to a smaller population
• states that hepatocellular DILI with jaundice indicates a serious reaction leads to death or liver transplantation in >10% of cases
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Hepatocellular injury • requires exclusion of other causes of liver injury: viral
hepatitis, fatty liver, alcohol damage, ischemia, etc• causality assessment • ☯AT alone may not indicate serious damage, but higher
frequency and degree of AT☯ are also predictive of serious hepatotoxicity (“Rezulin Rule”, AT>3x ULN in >2% subjects)
Jaundice • must exclude other causes of cholestasis: extra-and
intrahepatic (screen with elevated alkaline phosphatase) • severity of jaundice is an important predictor of mortality
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Parameters were predictive with respect to ALF/OLT development
• TBL level and the AST/ALT ratio at the 3 time points,
• Hepatocellular injury at DILI recognition and TBL peak, and ALT peak
• female sex at DILI recognition and were significant
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New Algorithm
• Episodes with AST levels greater than 17.3 ULN and TBL levels greater than 6.6 ULN were found to have a higher risk of ALT/OLT progression
• AST level of 17.3 or less ULN could also be enhanced further based on their AST/ALT ratio (P < .001), whereby having an AST/ALT ratio of greater than 1.5 further increased the risk of ALF/OLT in this group
• 82% specificity and 80% sensitivity (AUROC, 0.8)
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Drug Induced Acute liver failure
• Defined by:1. Encephalopathy: any degree of mental
alteration, e.g. day/night confusion, disorientation, sleepiness
2. Coagulopathy (INR>1.5)3. Absence of preexisting cirrhosis4. Injury of < 26 weeks duration• Poor prognosis of non-APAP drug-induced acute
liver failure• 75% mortality without liver transplant
Polson J. Hepatol 2005; 41: 1179-1197; Ostapowicz G. Ann Intern Med. 2002;137:947-954;Escorell A. Liver Transpl 2007; 13:1389-1395
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Continuing drug in acute drug-induced liver injury is associated with an increased risk of:
1. Acute liver failure
2. Chronic drug-induced liver injury
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• Acute liver failure related to idiosyncratic drug reactions is typically delayed
• Encephalopathy ensuing up to 26 weeks after jaundice.
Robles-Diaz M, Lucena MI, Kaplowitz N, Stephens C, Medina-Cáliz I, González-Jimenez A, Ulzurrun E, Gonzalez AF, Fernandez MC, Romero-Gómez M, Jimenez-Perez M, Bruguera M, Prieto M, Bessone F, Hernandez N, Arrese M, Andrade RJ; Spanish DILI Registry; SLatinDILI Network; Safer and Faster Evidence-based Translation Consortium. Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury. Gastroenterology. 2014 Jul;147(1):109-118.e5. doi: 10.1053/j.gastro.2014.03.050. Epub 2014 Apr 1.PubMed PMID: 24704526.
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Rifampicin
• Conjugated hyperbilirubinemia probably is caused by rifampin inhibiting the major bile salt exporter pump
• More common with large, intermittent doses
• Hypersensitivity reactions have been reported in combination with renal dysfunction, hemolytic anemia, or “flulike syndrome”
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• Cholestasis may be insidious.
• Idiosyncratic hypersensitivity reaction to rifampin, manifested as anorexia, nausea, vomiting, malaise, fever, mildly elevated ALT, and elevated bilirubin, usually occurs in the first month of treatment initiation
• In addition to AST elevation, if increases in bilirubin and alkaline phosphatase occur.
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Pyrazinamide
• The half-life (t1/2) of pyrazinamide is approximately 10 hour
• Dose dependent and idiosyncratic hepatotoxicity
• Hypersensitivity reactions with eosinophilia and liver injury or granulomatous hepatitis
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• Shared mechanisms of injury for isoniazid and pyrazinamide, because there is some similarity in molecular structure.
• Patients who previously had hepatotoxic reactions with isoniazid have had more severe reactions with rifampin and pyrazinamide.
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• Allopurinol increases pyrazinamide hepatotoxicity.
• Allopurinol inhibits xanthine oxidase, which metabolizes pyrazinamide, decreasing its clearance
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• Ethambutol: one report of ethambutol-related liver cholestatic jaundice, with unclear circumstances
• Moxifloxacin-related transaminase elevation has been reported in 0.9% of cases
• For levofloxacin, the rate of severe hepatotoxicity was reported to be less than 1 per 1,000,000.
• hepatotoxicity is believed to be a hypersensitivity reaction, often manifested by eosinophilia
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• Hepatotoxicity has been recognized to occur in about 2% of patients treated with ethionomide or prothionamide and in 0.3% of patients treated with para-aminosalicylic acid
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• Several regimens are recommended if baseline serum ALT is more than three times the ULN, and TB is not believed to be the cause:
1. Isoniazid and rifampin for 9 months with ethambutol
2. In patients with cirrhosis, rifampin and ethambutol, with levofloxacin, moxifloxacin, gatifloxacin, or cycloserine, for 12 to 18 months
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3. For patients with encephalopathic liver disease, ethambutol combined with a fluoroquinolone, cycloserine, and capreomycinor aminoglycoside for 18 to 24 months.
4. Some avoid aminoglycosides in severe, unstable liver disease due to concerns about renal insufficiency, or bleeding from injected medication
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In liver Disease
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• For patients with Child B : only one hepatotoxic agent, generally RIF plus EMB, could be given for 12 months, preferably with another agent, such as a fluoroquinolone, for the first 2 months
CDC
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N-Acetyl cysteine (NAC) 60 new TB patients aged ≥ 60 years were randomized into two groups.
• In Group Ⅰ (n = 32), the drug regimen included daily doses of isoniazid, rifampicin, pyrazinamide, and ethambutol.
• Group Ⅱ (n = 28) were treated with the same regimen and NAC.
Baniasadi S, Eftekhari P, Tabarsi P, Fahimi F, Raoufy MR, Masjedi MR, Velayati AA. Protective effect of N-acetylcysteine on antituberculosis drug-
induced hepatotoxicity. Eur J Gastroenterol Hepatol 2010; 22: 1235-1238 [PMID: 20461008 DOI: 10.1097/MEG.0b013e32833aa11b]
The mean values of aspartate aminotransferase and alanine aminotransferase were significantly higher in group Ⅰ than in group Ⅱ(with NAC) after 1 and 2 wkof treatment
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• hepatoprotective effect of silymarin on DILI has been shown in rats.
• The herbal formulation of Curcuma longa and Tinospora cordifolia prevented hepatotoxicity significantly
Tasduq SA, Peerzada K, Koul S, Bhat R, Johri RK. Biochemical manifestations of anti-tuberculosis drugs induced hepatotoxicityand the effect of silymarin. Hepatol Res 2005; 31: 132-135
Adhvaryu MR, Reddy N, Vakharia BC. Prevention of hepatotoxicitydue to anti tuberculosis treatment: a novel integrative approach. World J Gastroenterol 2008; 14: 4753-4762
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Liver Transplant
• In patients with acute decompensation and/or intolerance of antitubercular drugs, liver transplantation has been performed on an urgent basis
• Post-transplantation setting, rifampicin should be used carefully because drug interactions may change the drug levels significantly
• Switching to rifabutin may be beneficial
Lefeuvre S, Rebaudet S, Billaud EM, Wyplosz B. Management of rifamycins-everolimus drug-drug interactions in aliver-transplant patient with pulmonary tuberculosis. Transpl Int 2012; 25: e120-e123
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Thank you !