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Tarun George

on 25 October 2012

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Transcript of TB AND THE LIVER

TB AND THE LIVER Direct liver involvement Pre-existent liver disease developing Tuberculosis DILI the diffuse hepatic involvement seen along with pulmonary or miliary tuberculosis
most common
symptoms of liver disease are often absent.
treated as pulmonary TB granulomatous hepatitis focal/local tuberculoma or abscess The portal of entry in the case of miliary tuberculosis is through the hepatic artery whereas in the case of focal liver tuberculosis it is via the portal vein
treat as extrapulmonary +- drainage diffuse hepatic infiltration without recognizable pulmonary involvement
Treated as extrapulmonary TB During 6 years, a total of 280 consecutive patients with TB were evaluated prospectively for the presence and etiology of liver involvement.
Thirty-eight cases were further classified as follows:
(A) hepatic TB (52.6%):
(1) granulomatous hepatitis - 26.3%,
(2) liver abscesses or pseudotumors - 26.3% and
(3) calcified hepatic granuloma - (0%);
(B) biliary TB (39.4%):
(1) biliary strictures - 5.2%,
(2) gall bladder involvement - 2.6% and
(3) biliary obstruction due to lymph node masses - 31.5%;
(C) mixed variety (7.8%):
(1) simultaneous granulomatous hepatitis and biliary stricture - 2.6%
(2) simultaneous lymph node involvement and calcified hepatic granuloma - 5.2%. Hepatobiliary tuberculosis in western India Deepak N Amarapurkar --India carries more than 20% of the world’s TB burden
-Infects approximately 12 other people in his lifetime
-70% of TB cases occur in the age group of 15-54 years,
-1000 deaths every day. TB and its burden --Twenty percent of patients develop asymptomatic elevation of liver enzymes which is self limiting
--ATT can be a cause of hepatotoxicity in 5% and is fatal in up to 0.2% of patients
--it is a leading cause of drug-induced liver injury in India TB – Drug Induced Liver Injury
--Antituberculosis drugs contributed to 58% cases of DILI(Bangalore)
--Acute liver failure ( New Delhi), anti-TB drugs contributed to 5.7% patients with ALF(70/ 1223), with 67% mortality. Most patients complain of fatigue, malaise, anorexia, or nausea, with or without vomiting.
Approximately one-third has generalized flu-like symptoms,
whereas some experience right upper quadrant pain.
Jaundice is the presenting feature in approximately 10 percent of cases Most cases occur within the first two to three months after initiation of therapy;
the remaining cases occur as late as 14 months .

Clinical features are indistinguishable from acute viral hepatitis Clinical Presentation: “Asymptomatic enzyme elevation” to “
Asymptomatic bilirubin elevation”
to “hepatitis” --symptomatic elevation in liver enzymes and or bilirubin . (malaise, poor appetite, vomiting weight loss, pruritus, dark coloured urine, scleral icterus, and pain in right upper quadrant)
  Typically, three patterns of liver test
 1. Hepatitis: ALT/ULN ÷ ALP/ULN ≥ 5
2. Cholestasis: ALT/ULN ÷ ALP/ULN ≤ 2
3. Mixed: 2-5                                                                            
  Isoniazid and pyrazinamide usually cause hepatitis while rifampicin usually causes cholestasis. The clinical entities of liver injury --ATT-ALF patients with a mortality rate of 67.1% (5.7% of ALF )
--median duration of ATT before ALF was 30 days
--median icterus to encephalopathy interval was 4.5 days In the absence of symptoms, elevation of transaminases 5 times the upper limit of normal (ULN)
in the presence of symptoms up to three times the ULN or
twice the ULN of bilirubin

**provided competing causes such as acute viral hepatitis, autoimmune hepatitis and others liver diseases are ruled out. Definition Pyrazinamide being the most hepatotoxic followed by isoniazid and rifampicin
Rifampicin combined with PZA is more hepatotoxic than with INH
Pyrazinamide contributes significantly to ALF

4-drug combination regimen, it is impossible to quantify DRUGS IMPLICATED Mechanisms Most cases of DILI are idiosyncratic
mediated through oxidative stress Pathogenesis and mechanisms --Idiosyncratic:
Not related to the pharmacological properties of the drug of the drug
Usually due to toxic metabolites ISONIAZID AHZ acetylated to the nontoxic derivative diacetylhydrazine excreted in the urine.

AHZ oxidized into ammonia
AHZ oxidized by the CytP450 pathway to form toxic reactive acetyl free radicals that can form covalent bonds with liver cell macromolecules, interfering with their function and hepatocellular necrosis and cell death Rifampicin is thought to enhance this effect by enzyme induction .
Rifampicin also inhibits the secretion of bilirubin–glucuronides into the bile.
It causes a build-up of conjugated bilirubin in hepatocytes and, consequently, a spillover into the plasma. It also impairs uptake mechanism resulting in elevation of unconjugated bilirubin Similar structure to INH, similar hepatotoxic profile
Hypersensitivity reaction with eosinophilia and liver injury or granulomatous hepatitis
Both idiosyncratic and dose dependent hepatotoxicity Not fully known
Alters nicotinamide acetyl dehydrogenase levels in liver resulting in generation of free radical species PYRAZINAMIDE Age: older than 35 years are at 4 times increased risk to develop TB DILI.
Gender :female gender is a positive predictor of more severe liver disease including death
Men outnumber women in the incidence of TB DILI
Organ involvement:
Cavitory disease, multibacillary TB and extrapulmonary organ involvement have been incriminated as positive predictors
--TB DILI was detected in 16-39% of children with tuberculous meningitis ( South India)
(attributed to the high dose of pyrazinamide
(20 mg/kg body weight) Risk Factors HIV alone – 4 fold
coinfection with hepatitis C increases the risk of TB - 14 fold Dosing schedules
-did not find a link between dosing schedule and hepatotoxicity
Genetic polymorphism:
The role of three enzymes important for metabolism of INH has been extensively investigated.
Slow acetylators lacking NAT2 activity with TB DILI
CYP 2E *1A/*1A was a risk factor for INH induced hepatitis
Glutathione S Transferase M1"null” mutation Malnutrition . low albumin (<3.5 mg/dl) had three fold higher risk of developing TB DILI
-weight loss as an important risk factor for DILI
Alcohol: equivocal-under-nutrition and depleted glutathione stores
Hepatitis B :increased 4 fold in HBsAg carriers
-high baseline HBV DNA in patient samples to be a risk factor for DILI.
-Consider acute flaire
Hepatitis C: 5 fold increased risk of DILI Adverse effects diminish treatment effectiveness
Lead to nonadherence
Contributes to treatment failure, relapse or the emergence of drug-resistance. Implication: Monitoring with liver tests is recommended in the following groups:
1 patients who consume alcohol
2 chronic hepatitis B or C
3 on concomitant hepatotoxic drugs,
4 have elevated baseline transaminase levels,
5 suffer from underlying liver disease and
6 with HIV Dosing:
Maximum dosage was determined according to body weight, as follows: H, 5 mg/kg; R, 10 mg/kg; and Z, 25 mg/kg. H, isoniazid; R, rifampicin; Z, pyrazinamide.
Education of the patient and their family members about the risk of TB drugs
Education of the patient and their family members about the risk of TB drugs Prevention of DILI INH, RIF and PYZ are to be withheld immediately.
second line drugs such as streptomycin or amikacin, ciprofloxacin or ofloxacillin, may be initiated till such time the liver tests return to normal, or jaundice abates or the transaminases drop to <2 × ULN.
N-acetylcysteine has been shown to be useful in drug induced liver injury.
Supportive care
Severe cases: Liver transplantation Management after diagnosis of DILI -Review the risks and benefits of continuing versus deferring treatment
-If treatment is continued, the regimen should be adjusted to minimize hepatotoxicity
-Very close clinical and laboratory monitoring of liver function tests and coagulation parameters
-Consider alternative antituberculous agents Although pyrazinamide can be reintroduced in some milder cases of hepatotoxicity,the benefit of a shorter treatment course likely does not outweigh the risk of severe hepatotoxicity from pyrazinamide rechallenge. Patients who have experienced prolonged or severe hepatotoxicity but tolerate reintroduction with rifampin and isoniazid, rechallenge with pyrazinamide may be hazardous.
In this circumstance, pyrazinamide may be permanently discontinued, with treatment extended to 9 months. Wait for ALT to return to less than two times the upper limit of normal
Restart Rifampicin with or without ethambutol
Isoniazid may be re introduced after 3 to 7 days
Recheck ALT, monitor symptoms
Reintroduce the next drug, Pyrazinamide
If symptoms recur or ALT increases, the last drug added should be stopped. BRITISH THORACIC SOCEITY
--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 AMERICAN THORACIC SOCEITY
R at maximum dosage from day 1,
H at maximum dosage from day 8,
Z at maximum dosage from day 15. AMERICAN THORACIC SOCEITY
THE TASK FORCE ATT RECHALLENGE The main principle is to reduce the number of hepatotoxic drugs from the treatment regimen and to increase the duration of treatment
pyrazinamide is considered to be the most hepatotoxic
Isoniazid and rifampicin are also hepatotoxic but their combination is more toxic
second line drugs PAS is hepatotoxic
**SAFE - aminoglycosides, ethambutol, quinolones and cycloserine. Management of tuberculosis in patients with underlying liver disease A--Monitoring
difficult in this group -fluctuations in the biochemical indicators
baseline levels
When Abnormal –
- repeated twice weekly for the first two weeks
- weekly monitoring till the end of two months
-and then monthly till the end of the treatment.
Screen symptoms -such as fatigue, myalgias, nausea, abdominal pain, fever and jaundice Management strategy Child’s grade A cirrhosis or MELD score <18 can be treated on regimes including two potentially hepatotoxic drugs. (b) modifying the drug therapy. Regimes without PZA -Most preferred regime
If not in initial phase of treatment –
INH, RIF, EMB given daily for 2 months; followed by
INH + RIF for 7 months Regimes without RIF The most effective drug against
INH+PZA+EMB+OFL for 2 months followed by INH+EMB+OFL for 10 months Regimes without INH
-two potentially hepatotoxic medications
- 6-month treatment duration RIF, EMB, and PZA for 6 months. (A) RIF + EMB + for the first 2 months.
RIF + EMB for 10 months

(B) INH + EMB and streptomycin can be given for 2 months
INH + EMB 10 months of Only one potentially hepatotoxic drug Used in a combination regimen are ethambutol, aminoglycosides, fluoroquinolones, ethionamide, cycloserine
. At least 3 antitubercular drugs
The duration of therapy should be around 18 to 24 months.
of streptomycin, ethambutol and a fluoroquinolone for 18-24 months.
NO TRIALS PROVING THIS… No potentially hepatotoxic drug MANAGEMENT Patients with advanced liver disease such as Child’s grade C cirrhosis or MELD score >25 should be treated with regimen containing only non-hepatotoxic drugs Child’s grade B cirrhosis or MELD score 18–25 should be treated with only one hepatotoxic drug Majority of patients (156 [89%] of 175) had successful reintroduction of anti‐TB drugs without recurrence of DIH.

Although the number of patients with recurrence of DIH appeared to be greater in arm I, this difference was insignificant.

This observation has important implications for a country, such as India, that has a high burden of sputum‐positive pulmonary TB, in which initiating isoniazid, rifampicin, and pyrazinamide simultaneously will help to achieve faster sputum conversion and reduce the risk of disease transmission. CONCLUSIONS Clinical Infectious Diseases 2010;50:833–839 © 2010 by the Infectious Diseases Society of America. All rights reserved.
DOI: 10.1086/650576

Safety of 3 Different Reintroduction Regimens of Antituberculosis Drugs after Development of Antituberculosis Treatment–Induced Hepatotoxicity

Surendra K. Sharma,1
DIH was diagnosed if criteria 1, 2, or 3 were present in combination with criteria 4 and 5.

(1) an increase 5 times the upper limit of the normal levels (50 IU/L) of serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) on 1 occasion or >3 times the upper limit of normal (>150 IU/L) on 3 consecutive occasions

(2) an increase in serum total bilirubin >1.5 mg/dL

(3) any increase in serum AST and or ALT level above pretreatment values
together with anorexia, nausea, vomiting, and jaundice

(4) absence of serological evidence of infection with hepatitis A, B, C, or E virus

(5) improvement in liver function test results (serum bilirubin level <1 mg/dL; AST and ALT level <100 IU/L) after withdrawal of anti‐TB drugs STUDY DESIGN:Inclusion criteria . Dr Hyman Zimmerman- drug-induced hepatocellular injury associated with jaundice is associated with a mortality rate of at least 10%

ALT elevation>3 times the upper limit of normal (ULN) and
with a bilirubin level>2 times the ULN
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