Att induced hepatitis.pptx new

Att induced hepatitis

1. A T T In d uced H e p a titis @ DRUG INDUCED LIVER INJUTY(DILI) BY LAKSHMI NARAYANAN GM-IV

2. D e finit ion I n the ab s ence o f s ym p t oms , el e v a t i o n of t r ansam i nase s u p t o 5 ti m es the uppe r li m it of norma l (UL N ) and in the p r esence of s ym p t om s u p t o th r ee t i mes the ULN o r tw i ce the ULN o f b i l iru b in Ri s k o f T B D ILI r an g es f r o m 5 t o as h igh as 33%. [ A T S 20 6]

3. In p a t i e n ts wi t h HI V , The AIDS C l i n i c al T ria l s G r ou p cri t eria is used , wh i ch is as f o ll o w s: G r ade 1 : T r ansami nase s 1. 2 5 - 2.5 × upper limi t o f n orma l (UL N ) G r ade 2 : 2.6 - 5 × ULN • G r ade 3 : 5 . 1 - 1 × ULN • G r ade 4 : >1 × UL N .17 DILI IN HIV

4. D e f i n i t i o n o f h ep a t o t o x ici t y in p a t i e n ts wi t h p r e vi ou s l i v er d i s eases is c o n t r o v e r s i al Schen k er et al r epor t ed th a t el e v a t i on s in the A L T and / o r A S T l e v els t o 5 - 10 I U / L mo r e than the b aseline l e v el s mig h t d e f i n e t o x ici t y ] DILI in LIVER DISEASE

5. Clini c al Spectrum A s ym p t om a t i c el e v a t i o n t o a cu t e li v er f ai l u r e A l l a g e g r ou p s i nc l u d i n g ch i l d r en

6. M E CHANISMS Id i o s ync r a t i c dama g e : Mo s t Com m on Dose - depende n t t o x ici t y ; Ind u cti o n o f he p a t i c en z ymes; Dru g -i nd u ced acu t e hep a t i t is; A l le r gic r eact ions Dru g i nduc e au t o immu n e l i k e h e p a t i t i s

7. Specific p a tt ern s of hep a tic dama g e D i s r u p ti o n o f i n t r acell u l ar c alci u m homeo s t asi s . Ce ll memb r ane b l e b f orma ti o n , r u ptu r e and cel l l y s is Cho l e s t a ti c da m a g e. D i sr u p ti o n o f the actin f i l ame n ts adjace n t t o the c anal i cul us I nt e r r up ti o n o f t r ansport pum p s and l os s o f vil l ous p r ocesses R eacti on s i n v o l vi n g c y t och r o m e P - 450 s yst em Ac t i v a ti o n o f apo p t ot ic p a t hw a y s and p r og r ammed cell de a th Inh ib ition o f m i t ochondr ial funct i on

8. Types of DIH A variety of clinical syndromes may be seen with DIH, even with a single drug. Hepatic adaptation. Drug-induced acute hepatitis or hepatocellular injury. Nonalcoholic fatty liver disease. Cholestasis. Granulomatous hepatitis.

9. Risk f ac t o r s f or T B DILI A g e: o l de r than 35 y ear s a r e a t 4 ti m es i nc r eased r i s k . TB men i ng it i s mo r e chances . 3 . Gende r : f ema l e g ender is a pos it i v e p r ed i c t or o f mo r e s e v e r e l i v er d i seas e i nc l ud i n g de a th

10. 3 . O r g an i n v o l v eme n t / e x t e n t o f T B d i s ease c a vi t o r y d i s ease, mu l t i bac i l lary T B and e x t r apu l monary o r g an esp men i ng it i s 4. Mal n ut r i t i on: P a t i e n ts with l o w al b u min (<3. 5 m g /d l) had th r ee f o ld h igher ri s k w eig h t l oss 5. A l c oho l :

11. 6. Hep a titis B:4 f o ld in HBsA g c arr i e r s c ompa r ed t o non - c arr i e r s ( K o r ean Study) H e p a titis C . C o i n f ecti o n with bo t h h e p a titis C and HI V e l e v a t ed the r i s k o f hep a t o t o x ic ity mo r e than 14 - f o l d . P r ese n ce o f HL A - DQB1 * 0201 a n d the a b sence o f H L A- DQA1 * 0102 with A T DILI

12. 10 . E thn i c v ari a t i ons : h igher ri s k o f D I H ha s been r epor t ed in Ind i an p a t i e n ts than in p a t i e n ts f r om the W e s t

13. P oor p r ogno s tic mar k e r s Jaun d ice Hypoa l b u mi n emia A s ci t es Encepha l op a t h y H igh p r oth r omb in t i me

14. Mil d t o xi c it y : If the A S T l e v el is less t ha n 5 t i mes the uppe r l i mit o f normal Mode r a t e t o xi c it y : A S T l e v el 5 - - 10 t i mes nor m al d e f i nes S e v e r e t o xi c it y : A S T l e v el g r e a t er than 10 t i mes normal WHO - STAGING

15. Causative Agents INH + rifampin > INH alone >> PZA alone > rifampin alone > ethionamide > PAS Potentially hepatotoxic drugs Isoniazid Rifampicin, Rifabutin Pyrazinamide Ethionamide , Prothionamide Para- aminosalicylic acid Drugs with much lower or little potential for hepatotoxicity Streptomycin, Kanamycin, Amikacin , Capreomycin Ethambutol Ofloxacin , Levofloxacin, Ciprofloxacin Cycloserine

16. ISONIAZID (INH) Metabolism:

17. Mechanism of injury Injury is mostly acute hepatocellular in type, mixed hepatocellular- cholestatic . Histopahology : N onzonal necrosis in up to 10% of severe cases as seen in viral hepatitis Subacute hepatic necrosis can be seen in 30% of cases.

18. Clinical presentation of hepatotoxicity May be asymptomatic, Constitutional symptoms may be seen early in severe hepatotoxicity, and may last from days to weeks. Nausea, Vomiting, Abdominal pain are seen in 50 to 75% Fever is noted in 10% Rash in 5% of patients. late signs of clinical worsening Overt jaundice , dark urine, clay-colored stools are. life-threatening hepatic dysfunction. Coagulopathy, Hypoalbuminemia , Hypoglycemia The regression of isoniazid hepatotoxicity usually takes weeks. Recovery is complete in most after discontinuation of isoniazid

19. 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.

20. PYRAZINAMIDE (PZA) Metabolism: Pyrazinamide is de- amidated to pyrazinoic acid in the liver 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 longer than that of either isoniazid or rifampin, approximately 10 hours. In patients with preexisting hepatic disease, t1/2 is increased to 15 hours. The kidneys clear metabolites of pyrazinamide, requiring intermittent dosing in patients with renal insufficiency

21. Mechanism of injury Pyrazinamide exhibit both dose dependent and idiosyncratic hepatotoxicity. Pyrazinamide alters nicotinamide acetyl dehydrogenase levels in liver  result in generation of free radical species. There may be 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. Pyrazinamide may induce hypersensitivity reactions with eosinophilia and liver injury or granulomatous hepatitis .

22. Prothionamide and ethionamide DIH is uncommon May produce elevated serum transaminases in about 10% of recipients, usually after 8–12 weeks. Usually resolves after drug discontinuation.

23. Para-aminosalicyclic acid (PAS) Hypersensitivity to PAS has been recorded in up to 5%. Onset usually between 2–6 weeks after commencing treatment. Rechallenge may result in recurrence of the abnormal response.

24. 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.

25. Routine Monitoring for Hepatotoxicity in Adults 1. Obtain baseline liver function tests (LFTs) 2 . Obtain follow-up LFTs: a. patients < 35 years old with normal baseline LFTs and without a history of hepatic disease: follow-up are not required unless the patient becomes symptomatic. b. patient > 35 years old, daily alcohol consumption, abnormal baseline LFTs, taking other potentially hepatotoxic medications, or who have viral hepatitis or history of liver disease, HIV infection, or prior TB DIH. obtain LFTs every 4-6 weeks.

26. Guideline f o r the Mana g eme n t o f A n ti- T ub e r culo s is T h e r a p y In du ced L i v er Injur y ,NHS,2013

27. S c o r e t o Diagnose R ous s el Uc l a f Cau s al i ty A s se s s m e n t M e thod (RUC A M ) T o t al r an g e o f t h e RUCAM is -9 t o +14

28. R R a tio F or Differentiate hepatocellular-mixed- cholestatic R = (A L T v al u e ÷ A L T ULN) ÷ ( AlP v al u e ÷ AlP ULN) R r a t i o s o f > 5 d e f i n e a hep a t oce l l u la r , < 2 a cho l e st a t i c , and b e t w een 2 and 5 a mi x ed p a t t ern o f en z ymes.

29. Me d i c a t i on s sho u ld b e r e st ar t ed a f t er the A S T / A L T c once n t r a t i o n r e tu r n s t o less than t w o t i mes the uppe r l i mit o f norma l .

30. R ei n t r oduction a n ti tube r culo s is r egimens 3 A r ms P a t i e n ts r ecei v ed m a x imum dose s o f I N H , RI F , P Z A s i mu l t aneous l y A T S gu i d el i n e RIF f o ll o w ed b y INH a f t er 7 d a y s , f o ll o w ed b y P Z A a f t er 7 d a y s , all with m a x imum doses B T S gu i d el i ne . I N H , RIF and P Z A w e r e g r adua l l y es c al a t ed s eque n t i ally a f t er t he m a x imum dos e o f the p r eced in g d rugs

31. R ecur r ence o f D ILI w as s i m i lar b e t w een the th r ee t r e a tme n t arms (p=0. 6 9)

32. R ando m i z ed s tu d y b y T ahaoglu and as s oc i a t es o n 4 5 p a t i e n ts c onc l ude d th a t r ei n t r oduct i on r egimens c o n t ai n i n g m a x imum dos e of a n t i tu b e r cu lo s is dr u gs i nc l ud i n g p y r az i nam i de ( g r ou p 1, n=2 5 ) c aused mo r e hep a t o t o x ici t y than g r adual r ei n t r oduct i o n w i t hout p y r az i nam i de

33. R ei n t r oduc t i o n R egimen A TS R a t m a x imum do s a g e f r om d a y 1, H a t m a x imum do s a g e f r om d a y 8 Z a t m a x imum do s a g e f r om d a y 15 B T S H a t do s a g e o f 1 m g /d a y f r o m d a y 1, m a x imum do s a g e f r o m d a y 4; R a t do s a g e o f 1 50 m g /d a y f r o m d a y 8, m a x i m um d o sa g e f r o m d a y 1 1; Z a t do s a g e o f 5 m g /d a y f r o m d a y 1 5 , m a x imum do s a g e f r o m d a y 18

34. T ask F o r ce o f t h e Eu r opea n R es p i r a t o r y Soc ie t y advi ses r e st arti n g al l the drug s s im u l t ane o usl y; A f t er a s e c on d ep i sod e o f he p at o t o x i c i ty the drugs nee d t o b e r ei n t r oduce d c onsecuti v ely

35. ATT In li v e r D i sease

36. F o r p a t i e n ts wi t h Ch i ld B : on ly one hep a t o t o x ic a g e n t, g ene r ally RIF p l u s EM B , c ou ld b e gi v en f o r 12 mo n th s , p r e f e r ably with anot h er a g e n t, s uc h as a f l uo r oqu i no l one , f or the f i r s t 2 mo n ths CDC

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