at t induced hepatitis

7/28/2019 At t Induced Hepatitis

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ATT

INDUCED

HEPATOTOXICITY

Dr. K. K. Sharma


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INTRODUCTION

Drug-induced hepatotoxicity (DIH) is a problem of

increasing significance, and has been a long-standing

concern in the treatment of tuberculosis (TB) infection.

Identification of patients at increased risk for DIH is

important because hepatotoxicity causes significant

morbidity and mortality and modification of the drug

regimen may be required.

Drug-induced hepatotoxicity (DIH) is ultimately a

clinical diagnosis of exclusion. Other causes of liver

injury, should be methodically sought, and their absence

makes the diagnosis plausible.


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There are few clinical or laboratory manifestations thatspecifically suggest a liver injury is the result of atherapeutic drug, the most important clue is the temporal

relationship between initiation of a drug (or drugs) andthe appearance of the injury.

Rechallenge with the suspected offending agent withmore than twofold serum alanine aminotransferase (ALT)elevation, and discontinuation leading to a fall in ALT, isthe strongest confirmation of the diagnosis.

The liver has a central role in drug metabolism anddetoxification, and is consequently vulnerable to injury.

The pathogenesis and types of DIH varies, ranging from

hepatic adaptation to hepatocellular injury.

Contd.

(J Hepatology 1990;11:272276)


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THE LIVER: STRUCTURE

AND FUNCTION

The liver is situated between the alimentary tract and the

systemic circulation to maximize processing of absorbednutrients and to minimize exposure of the body to toxins

and foreign chemicals.

Consequently, the liver may be exposed to large

concentrations of exogenous substances and theirmetabolites.


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Hepatic Drug Metabolism

The splanchnic circulation carries ingested drugs directlyinto the liver, a phenomenon known as the first passthrough the liver.

Metabolic enzymes convert these chemicals throughphase 1 pathways of oxidation, reduction, or hydrolysis,which are carried out principally by the cytochrome P450class of enzymes.

Phase 2 pathways include glucuronidation, sulfation,acetylation, and glutathione conjugation to formcompounds that are readily excreted from the body.

Other subsequent steps include deacetylation anddeaminidation.

Many drugs may be metabolized through alternative

pathways, and their relative contributions may explainsome differences in toxicity between individuals.


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In phase 3 pathways, cellular transporter proteins

facilitate excretion of these compounds into bile or the

systemic circulation.

Transporters and enzyme activities are influenced by

endogenous factors such as circadian rhythms,

hormones, cytokines, disease states, genetic factors, sex,

ethnicity, age, and nutritional status, as well as by

exogenous drugs or chemicals.

Bile is the major excretory route for hepatic metabolites.

Compounds excreted in bile may undergo enterohepatic

circulation, being reabsorbed in the small intestine and

re-entering the portal circulation .

Contd.


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Mechanism of Hepatic Injury

A.Direct Hepatocellular Injury B.Cholestasis due to genetic

defect in transportes

C.Formation ofhaptens or neoantigens.

D.Antibody-dependent

cytotoxicT-cell responses

E.Apoptosis

F.Metabolic idiosyncratic reactionsLike mitochondirial damage


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Pathogenesis of DIH

DIH may result from

1. Direct toxicity of the primary compound,

2. a metabolite, or

3. from an immunologically mediated response,affecting hepatocytes, biliary epithelial cells, and/or livervasculature.

Mostly, the exact mechanism and factors contributing toliver toxicity remain poorly understood.

Most common types of DIH Unpredictable oridiosyncratic reactions

These hypersensitivity or metabolic reactions occurlargely independent of dose and relatively rarely for eachdrug, and may result in hepatocellular injury and/orcholestasis.


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Hepatocyte necrosis is often distributed throughout

hepatic lobules rather than being zonal.

Injurious free radicals cause hepatocyte necrosis in zones

farthest from the hepatic arterioles.

In hypersensitivity reactions, immunogenic drug or its

metabolites may be free or covalently bound to hepatic

proteins, forming haptens or neoantigens.

Antibody-dependent cytotoxic, T-cell, and occasionally

eosinophilic hypersensitivity responses may be evoked.

Contd.


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Released TNF-alpha, interleukin (IL)-12, and IFN-

gamma promote hepatocellular programmed cell death

(apoptosis), an effect opposed by IL-4, IL-10, IL-13, and

monocyte chemotactic protein-1 . (Semin Liver Dis 2002;22:137144).

Metabolic idiosyncratic reactions may result from

genetic or acquired variations in drug biotransformation

pathways, with synthesis or abnormally slow

detoxification of a hepatotoxic metabolite. Metabolicidiosyncratic reactions may have a widely variable latent

period, but recur within days to weeks after re-exposure

Contd.


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Types of DIH

A variety of clinical syndromes may be seen with DIH,

even with a single drug.

1. Hepatic adaptation.2. Drug-induced acute hepatitis or hepatocellular injury.

3. Nonalcoholic fatty liver disease.

4. Cholestasis.

5. Granulomatous hepatitis.


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Hepatic Enzyme Measurement

Increase in serum ALT(SGPT), is more specific forhepatocellular injury than an increase in AST(SGOT),

which can also signify abnormalities in muscle, heart, or

kidney. Increases in alkaline phosphatase and/or bilirubin with

little or no increase in ALT indicate cholestasis.

Alkaline phosphatase concentration may also increase

because of processes in bone, placenta, or intestine. Anincreased concentration of serum GGT is useful indistinguishing liver-related from other organ-relatedalkaline phosphatase increases.

Jaundice is usually detectable on the physical

examination when serum bilirubin exceeds 3.0 mg/dl.


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Clinical and Immunogenetic Risk

Factors for the Development of

DIH Older age

Poor nutritional status

High alcohol intake Female sex

Pre-existing liver disease

Patient with Viral hepatitis & HIV

Hypoalbuminaemia Moderately / far advanced tuberculosis

Dose & Duration of therapy and acetylator status.

Patient with DQB1*0201, DRB1*0301 and DRB1*0701

haplotypes

[SK Sharma,AIIMS ,American J of Res & Cri Care Med V166. pp. 916-919, (2002)]


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Causative Agents

INH + rifampin > INH alone >> PZA alone > rifampin

alone > ethionamide > PAS

(The use of antibiotics.5th edition.Oxford: Butterworth Heinemann, 1997.JAMA 1991;265:3323)

Potentially hepatotoxic drugs

Isoniazid

Rifampicin, Rifabutin

Pyrazinamide

Ethionamide, Prothionamide

Para-aminosalicylic acidDrugs with much lower or little potential for hepatotoxicity

Streptomycin, Kanamycin, Amikacin, Capreomycin

Ethambutol

Ofloxacin, Levofloxacin, Ciprofloxacin

Cycloserine


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ISONIAZID (INH)

Genetic polymorphisms of NAT-2 correlate with fast and slow acetylation phenotypes.

Microsomal enzymes further metabolize INH intermediates through phase 1 pathways.

Acetylator status:In fast acetylators, > 90% of the drug is excreted as acetyl-isoniazid,

whereas in slow acetylators, 67% of the drug is excreted as acetyl-isoniazidand rest is excreted as unchanged drug into the urine.

Metabolism:


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Mechanism of injury

Injury is mostly acute hepatocellular in type, though a

mixed hepatocellular-cholestatic picture has been

reported.

There are various metabolic products of isoniazid,including monoacetyl hydrazine, hydrazine and

isonicotinic acid, which have been suggested as being

hepatotoxic.

Reactive metabolites of MAH are probably toxic totissues through free radical generation.

Histopahology: Nonspecific changes resemble those of

viral hepatitis with nonzonal necrosis in up to 10% of

severe cases. Subacute hepatic necrosis can be seen in30% of cases.


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Clinical presentation of

hepatotoxicity

May be asymptomatic,

Symptomatic hepatotoxicity may occur at varying serumtransaminase concentrations.

Constitutional symptoms may be seen early in severehepatotoxicity, and may last from days to weeks.

Nausea, vomiting, and abdominal pain are seen in 50 to75% of patients with severe illness, whereas fever isnoted in 10% and rash in 5% of patients.

Overt jaundice, dark urine, and clay-colored stools arelate signs of clinical worsening.

Coagulopathy, hypoalbuminemia, and hypoglycemiasignify life-threatening hepatic dysfunction.

The regression of isoniazid hepatotoxicity usually takes

weeks. Recovery is complete in most afterdiscontinuation of isoniazid


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Rate of INH-induced liver injury

Minor elevations in alanine aminotransferase (ALT)

. Observed in 10% to 20% of patients

. Within 2 months of starting treatment

. Most resolve without stopping INH Severe liver injury with jaundice

. 1% of treated patients with INH

. 4% of patients receiving rifampin and isoniazid

. Rarely develops in children

. Risk of hepatitis inc. with concomitant alcohol use and age > 35 years

. Women at increased risk

Fulminant hepatic failure

. 10% of persons who develop jaundice

. Continued treatment during prodrome increases hepatic necrosis

. Resolution in nonfatal cases

Hepatitis Annual Update 2004athttp://clinicaloptions.com/hepatitis


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Onset of INH Induced

Hepatotoxicity

Hepatotoxicity occurs generally within weeks to months. Unlike

a classical hypersensitivity reaction, isoniazid rechallenge does

not always elicit rapid recurrence of hepatotoxicity.

Approximately 60% of the hepatotoxicity incidence occurred inthe first 3 months of treatment, and 80% of the incidence

occurred in the first 6months.

A retrospective case fatality review found that the median

interval from treatment initiation to symptom onset was 16

weeks. Reintroduction of isoniazid can be performed when liver

function tests have returned to normal but not if there has been

symptomatic evidence of liver impairment.

Liver function tests should be performed on a weekly basis for 4

weeks,and then according to the original protocol for monitoring.

Am J Respir Crit Care Med Vol 174. pp 935

952, 2006


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RIFAMPICIN (RMP)

Mechanisms of hepatotoxicity: Rifampicin probably inhibit the major bile salt exporter pump and

cause Conjugated hyperbilirubinemia.

Occasionally, subclinical, unconjugated hyperbilirubinemia or

jaundice without hepatocellular damage may also result from

dose-dependent competition with bilirubin for clearance at the

sinusoidal membrane or from impeded secretion at the canalicular

level.

This may be transient and occur early in treatment or in some

individuals with preexisting liver disease. Rifampicin occasionally can cause hepatocellular injury which

appears to be a hypersensitivity reaction, and it may be more

common with large, intermittent doses.

Rifampicin potentiate hepatotoxicities of other anti-TB

medications. This effect is thought to be due to enzyme induction.


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Clinical presentation, Rate &

Onset of hepatotoxicity.

Up to 1% of patients develop rifampin-induced hepatitis.

4% of patients receiving both rifampin and isoniaziddevelop hepatitis.

Asymptomatic increases in serum transaminases mayoccur in the first few weeks of therapy.

Idiosyncratic hypersensitivity reaction to rifampicin,manifested as anorexia, nausea, vomiting, malaise, fever,

mildly elevated ALT, and elevated bilirubin, usuallyoccurs in the first month of treatment initiation.

Hepatotoxicity is uncommon in children.


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The hyperbilirubinaemia is usually transient and due to

interference with bilirubin excretion by rifampicin; it

does not requires cessation of the drug.

But If the bilirubin has not decreased after 2 weeks, it

would be sensible to withdraw rifampicin.

There is evidence that the dose regimen appears

important; in one series of patients treated with

rifampicin and isoniazid, the rate of drug-inducedhepatitis was 21% when rifampicin was given daily and

5% when given twice weekly. [Eur Respir J, 1995, 8, 13841388].

Contd.


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PYRAZINAMIDE (PZA)

Metabolism:

Pyrazinamide is de-amidated to pyrazinoic acid in theliver and subsequently metabolized to 5-hydroxy-

pyrazinoic acid by xanthine oxidase, aldehyde oxidase,and xanthine dehydrogenase.

The half-life (t1/2) of pyrazinamide is notably longerthan that of either isoniazid or rifampin, approximately10 hours.

In patients with preexisting hepatic disease, t1/2 isincreased to 15 hours.

The kidneys clear metabolites of pyrazinamide, requiringintermittent dosing in patients with renal insufficiency


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Mechanism of injury

Pyrazinamide exhibit both dose dependent andidiosyncratic hepatotoxicity.

Pyrazinamide alters nicotinamide acetyl dehydrogenase

levels in liver result in generation of free radicalspecies.

There may be shared mechanisms of injury for isoniazidand pyrazinamide, because there is some similarity inmolecular structure.

Patients who previously had hepatotoxic reactions withisoniazid have had more severe reactions with rifampinand pyrazinamide.

Pyrazinamide may induce hypersensitivity reactions with

eosinophilia and liver injury or granulomatous hepatitis.


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Clinical presentation, Rate &

Onset of hepatotoxicity.

Asymptomatic increases in LFTs may occur early in

therapy

Studies in the 1950s suggested that elevatedtransaminases occurred in 20%, and overt hepatitis in

8%, of those treated with daily doses of pyrazinamide at

40 to 50 mg/kg., and a relationship to dose was noted.

Uncommon with doses of 20-30mg/kg/d or with highdose intermittent regimens

Rarely cases of fatal hepatic necrosis may occur.

Uncommon in children.


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Prothionamide and ethionamide

DIH is uncommon

May produce elevated serum transaminases in about 10%

of recipients, usually after 812 weeks.

Usually resolves after drug discontinuation.


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Para-aminosalicyclic acid (PAS)

Hypersensitivity to PAS has been recorded in up to 5%.

Onset usually between 26 weeks after commencing

treatment. (Eur Respir J, 1995, 8, 13841388)

Rechallenge may result in recurrence of the abnormal

response.


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Fluoroquinolones

DIH is very Rare.

The mechanism of fluoroquinolone hepatotoxicity is

believed to be a hypersensitivity reaction, often

manifested by eosinophilia.

Reversible transaminase elevation among the

fluoroquinolones may occur in up to 2 to 3% of cases.

Severe hepatocellular injury and cholestasis have been

reported to occur in less than 1% of all fluoroquinolone

recipients, excluding trovafloxacin, which was

withdrawn due to its hepatotoxicity.

For levofloxacin, the rate of severe hepatotoxicity was

reported to be less than 1 per 1,000,000. (Eur Respir J, 1995, 8, 13841388)


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Clinical monitoring

1. Face-to-face monthly assessments and patient education

for adverse drug events are essential.

2. Directly observed treatment (DOT) enhances treatment

adherence and monitoring.

3. The World Health Organization and the International

Union Against Tuberculosis and Lung Disease

(IUATLD) recommend only clinical monitoring in

patients with TB in low-income developing countries

like India.


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Routine Monitoring for

Hepatotoxicity in Adults

1. Obtain baseline liver function tests (LFTs)

a. serum transaminase enzymes:

1) aspartate aminotransferase (AST) [normal 0-40 u/l]

2) alanine aminotransferase (ALT) [normal 0-40 u/l]b. alkaline phosphatase [normal 25-115 u/l]

c. gamma glutamyl transpeptidase (GGTP) [normal 10-50 u/l]

d. total bilirubin [normal 0.2-1.5 mg/dl]

2. Obtain follow-up LFTs:

a. patients < 35 years old with normal baseline LFTs and without ahistory of hepatic disease: follow-up are not required unless the

patient becomes symptomatic.

b. patient > 35 years old, daily alcohol consumption, abnormal baselineLFTs, taking other potentially hepatotoxic medications, or who have

viral hepatitis or history of liver disease, HIV infection, or prior TBDIH. obtain LFTs ever 4-6 weeks.


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Interventions for hepatotoxicity

1. The first-line anti-TB drugs, especially rifampin, should not bediscontinued for mild gastrointestinal complaints, which may berelatively frequent in the initial weeks of anti-TB treatment.

2. If serum transaminase concentrations are more than five times theULN (with or without symptoms) or more than three times the ULNwith jaundice and/or hepatitis symptoms, then potentiallyhepatotoxic medications should be stopped immediately and the

patient evaluated promptly.

3. Serologic tests for hepatitis A, B, and C viruses should be obtained,

and the patient should be evaluated for biliary disease, use ofalcohol, and other hepatotoxic drugs.

4. Some experts recommend interrupting treatment for lesser increasesin patients with cirrhosis or encephalopathy.

5. If indicated, until the specific cause of abnormalities can bedetermined, clinicians should treat with at least three anti-TB agents

that are less likely to cause hepatotoxicity.


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Management in Adults

Asymptomatic patients with an increase in LFTs from baseline:

a. if the increase in LFTs is < 3-5x normal: continue the current

regimen and monitor for symptoms of liver dysfunction.

b. forasymptomatic patients, if the serum transaminases increases> 3-5x normal: hold INH until levels return to baseline.

1) if the patient is receiving a two drug regimen, substitute at least

one other drug (e.g.ethambutol) until the INH is restarted

2) if the transaminases increase with rechallenge of INH,

discontinue INH, substitute another drug (e.g. ethambutol) andadjust the treatment duration as required

c. if the serum total bilirubin increases: therapy usually does not

require modification (rifampin competes with bilirubin forelimination resulting in increased serum bilirubin initially;

bilirubin levels usually return to normal with continued therapy)


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Symptomatic patientsa. Hold all drugs and obtain LFTs

b. If LFTs are within the normal ranges, refer to the Management ofNausea/Vomiting.

c. If LFTs are elevated, hold drugs until symptoms resolve and the

transaminases decreases to < 2x normal.1) ethambutol and pyrazinamide should be started if drug therapy can not be

held secondary to the patients clinical condition

a) use streptomycin if pyrazinamide is suspected to be the cause ofhepatotoxicity

2) rechallenge the patient after resolution of signs and symptoms by addingdrugs to the regimen every 4 days.

a) rifampin for 3 days, if patients remains asymptomatic then add

b) INH for 3 days, if patients remains asymptomatic then add

c) pyrazinamide (15-20mg/kg/d) for 3 days

3) if signs and symptoms recur with rechallenge, discontinue the responsibledrug and modify the regimen and/or duration of therapy as required


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Rechallenge

1. After ALT returns to less than two times the ULN, rifampinmay be restarted with or without ethambutol.

2. After 3 to 7 days, isoniazid may be reintroduced, subsequently

rechecking ALT.3. If symptoms recur or ALT increases, the last drug added

should be stopped.

4. For those who have experienced prolonged or severehepatotoxicity, but tolerate reintroduction with rifampin and

isoniazid, rechallenge with pyrazinamide may be hazardous. In this circumstance, pyrazinamide may be permanently

discontinued.Although pyrazinamide can be reintroduced insome milder cases of hepatotoxicity, the benefit of a shortertreatment course likely does not outweigh the risk of severe

hepatotoxicity from pyrazinamide rechallenge.


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Commence anti-tuberculosis chemotherapy

Commence anti-tuberculosis chemotherapy


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THANKS

at t induced hepatitis

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