AKT Induced Hepatitis

Dr.Sunil Pawar

• 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.

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]

• 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

• 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]

• 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]

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

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

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

• 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

• 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.

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.

• 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

• 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.

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.

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.

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.

10. Ethnic variations: higher risk of DIH has been reported in Indian patients than in patients from the West

Poor prognosticmarkers

• Jaundice

• Hypoalbuminemia

• Ascites

• Encephalopathy

• High prothrombin time

• 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: info@WHO-UMC.org).

Management

Education

Education

Education

Patientsfamily members

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

• For patients with pre existing severe liver disease:

periodic measurement of LFT, prothrombin time and INR to assess hepatic synthetic function.

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

• 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

Guideline for the Management of Anti-Tuberculosis Therapy Induced Liver Injury,NHS,2013

• Medications should be restarted after the AST/ALT concentration returns to less than two times the upper limit of normal.

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

• 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

• 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.

Which drug to start first??

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

• 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

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

• 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

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.

• nR Ratio includes AST or ALT which ever is increased more in above calculation

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)

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

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

• 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

• 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

Isoniazid is associated with:

• Reactive metabolite

• Immunoallergic injury: HLA DQB1*0201

• Mitochondrial injury

• Impaired liver cell regeneration as hydralazine derivatives inhibit histone deacetylase

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

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

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

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)

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

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

• 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.

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”

• 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.

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

• 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.

• Allopurinol increases pyrazinamide hepatotoxicity.

• Allopurinol inhibits xanthine oxidase, which metabolizes pyrazinamide, decreasing its clearance

• 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

• 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

• 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

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

In liver Disease

• 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

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

• 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

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

Thank you !