Management of postoperative liver dysfunction, Drug induced and Halothane hepatitis

1. Management of postoperative liver dysfunction, Drug induced and Halothane hepatitis Dr. EmeniOphrii University College of Medical Science & GTB Hospital, Delhi

2. Postoperative Liver Dysfunction • Most cases due to preexisting unrecognised liver disease • Incidence of unrecognised deranged liver function 1:750 • Following abdominal procedure < 1% • Preexisting liver disease and upper abdominal surgery→high incidence of postoperative liver dysfunction • Most often, postoperative liver dysfunction manifests as jaundice.

3. Causes of Postoperative Jaundice Patient factors • Haemolytic disorders • Preexisting liver disease • Coagulopathy • Gilbert’s syndrome • Sepsis

4. Causes of Postoperative Jaundice …. Perioperative Factors Anaesthetic induced reduction in liver blood flow • Artificial ventilation • Hypoxia • Hypocapnia and hypercapnia • Anaesthetic agents – intravenous, inhalational • Regional anaesthesia

5. Perioperative factors……. Drugs • Halothane & other inhalational anaesthetics • Antibiotics • NSAIDS • Potential hemolytic drugs Effects of surgery • Laparotomy →mechanical interference with blood flow (retractors, gut handling, surgical packs) • Bleeding • Biliary tree trauma

6. Perioperative factors…. Other Factors • Hypotension • Blood transfusion: 1unit of blood adds 250mg of bilirubin • Viral hepatitis

7. Classification of postoperative jaundice • Based on time course – Immediate and delayed • Based on bilirubinemia with or without raised aminotransferases

8. Classification by time course Immediate postoperative Jaundice (<3 weeks) • Hemolysis • Hypotension/hypovolemia • Infection/sepsis • Bile duct ligation/strictures/surgical injury • Retained common duct stones • Acute viral hepatitis • Gilberts syndrome • Blood transfusions • Anaesthesia • Drugs • Postop pancreatitis • Heart failure

9. Classification by time course… Delayed postoperative jaundice (>3weeks) • Drugs • Blood transfusion • Post intestinal by pass status • Total parenteral nutrition

10. Classification based on bilirubinemia with or without raised aminotransferases • Bilirubinemia in the absence of plasma aminotransferase elevation • Bilirubinemia with mild – moderate aminotransferase elevation • Bilirubinemia with marked increase in plasma aminotransferases

11. Bilirubinemia in absence of plasma aminotransferase elevation Extravascularhemolysis Large hematoma (retroperitoneal) 1 litre=5000 mg bilirubin Intravascular hemolysis G6PD deficiency/sickle cell disease/blood transfusion (10% of 2 weeks old RBC in one unit undergo hemolysis) Congenital causes Gilberts disease(3-7% population) inborn defect in bilirubin liver transport and conjugation Precipitated by fasting/stress /illness

12. Bilirubinemia with mild –moderate aminotransferase elevation • Post op intrahepaticcholestasis • Biliary tract obstruction • Circulatory failure • Sepsis

13. Postoperative intrahepaticcholestasis • Middle age or elderly • Post orthopaedic/lengthy surgical procedures • Conjugated S.bil <3.5mg/dl, mildly ↑ aminotransferases, mod.↑ ALP level • Fever/liver tenderness/upper abdominal pain • Jaundice appears 2-3 days after surgery and recedes in 2-3 weeks

14. Extrahepaticbiliary tract obstruction • Retained stones following GB or biliary tract surgery • Unrecognised injury to hepatic duct post gastric/pancreatic/biliary/liver surgery • Acute cholecystitis • Acute pancreatitis • ↑ bil and ALP seen within 2-3 days of surgery

15. Circulatory failure • Open heart surgery/traumatic circulatory shock • Combination of mild hepatocellular dysfunction caused by low perfusion state to the liver and ↑pigment load due to blood transfusions Sepsis • Suggest primarily obstructive jaundice

16. Bilirubinemia with marked increase in plasma transferases Shock liver • Following prolonged circulatory shock • Centrilobularhepatocellular necrosis • Anoxia/hypoxia of hepatocytes during shock state • Vasopressers used to improve systemic BP accentuate hepatic hypoperfusion Viral hepatitis Drug induced hepatitis Halogenated anaesthetics-halothane

17. Q: How to investigate a Patient with Post Operative Liver Dysfunction?

18. History Contact history • Contact with jaundice patient in 6 months Drug history • Alcohol, barbiturates, amitryptiline, PCM, salicylates, antibiotics, chlorpromazine, phenytoin, methyldopa, OCP’s Past history • Blood transfusion • Biliary tract ds • Past history of jaundice • Administration of halogenated agents

19. History... Life style history • Occupation, Foreign travel, Social Risk Groups for viral hepatitis (iv drug users, homosexuals, tattoos ) Family history • Gilbert syndrome, haemochromatosis, Wilson’s ds Anaesthetic and surgical records

20. Investigations Serial liver function tests S. Amylase Blood cultures Other Investigations According to history and examination – if biliary obstruction, hepatic abscess or tumour→ USG, CT or MRI Serological test for viral hepatitis Antibody screening for volatile anaesthetics

22. Drug Induced Hepatitis

23. Drug Induced Hepatitis • More than 900 drugs/toxin/herbs cause liver injury • United states-approx 2000 cases of liver failure per year • Accounts for 25% of all cases of chronic active hepatitis • 25% of causes of fulminant hepatic failure

24. Pathophysiology and mechanism of drug induced liver injury Include both hepatocellular and extracellular mechanism • Disruption of hepatocytes • Disruption of transport proteins • Cytolytic T cell activation • Apoptosis of hepatocytes • Mitochondrial disruption • Bile duct injury

25. Drug toxicity mechanism • Direct / intrinsic hepatotoxins • Predictable, dose related effects • Biotransformation of the parent compound into reactive species or free radicals • Liver damage - centrilobular necrosis Ex. Carbon tetrachloride, acetaminophen

26. 2) Idiosyncratic events • Non predictable • Lack of dose response relations • Marked individual variability • More diffuse and marked degree of cholestasis • Inflammatory necrosis • Occasional appearance of auto antibodies • Ex. Phenytoin (hypersensitivity reactions), INH toxicity

27. Drugs and the resulting histological injury Drug Injury pattern Acute viral hepatitis Non specific hepatitis Granulomatoushep Chronic hepatitis Cholestasis Fatty liver change Hepatic vein thrombosis Massive necrosis • INH/halothane/diclofenac/phenytoin • Oxacillin/aspirin • Quinidine/allopurinol/phenylbutazone • Alphamethyldopa/methotrexate/amiodarone/dantrolene • Chlorpromazine/erythromycin/estrogen • Tetracycline/valproic acid/ethanol • OCPs • Acetaminophen/diclofenac/INH

28. Clinical manifestation Highly variable May range from asymptomatic ↑ in liver enzymes to fulminant hepatic failure

29. Asymptomatic elevation of aminotransferases -Pt receiving tacrine for alzheimer disease -Sulphonamides/salicylates/sulfonylureas/ quinidine/methyldopa/phenytoin/INH AST<ALT • Viral hepatitis • Acetaminophen/NSAIDS/ACE inhibitor/ erythromycin/griseofulvin/fluconazole AST:ALT if >2:1 • Alcoholic hepatitis

30. Diagnosis History: Type of drug, Dose, route of administration, Duration, Previous administration, Use of any concomitant drugs Previous Exposure : Latency period of idiosyncratic drug reactions is highly variable; hence, obtaining a history of every drug ingested in the past 3 months is essential Onset : The onset is usually within 5-90 days of starting the drug • Exclusion of other causes of liver injury/Cholestasis Dechallenge: A positive dechallenge is a 50% fall in serum Transaminase levels within 8 days of stopping the drug Significance: A positive dechallenge is very helpful in cases of use of multiple medications. Track record of the drug: Previously documented reactions to a drug aid in diagnosis.

31. Imaging studies To exclude causes of liver pathology • Ultrasonography Gall bladder, Bile ducts, Hepatic tumors • CT scanning CT scanning - detect focal hepatic lesions • MRI To detect cysts, hemangiomas, primary and secondary tumors

32. Management • No specific treatment Treatment is supportive and based on symptomatology • First step - Discontinue the suspected drug • Specific therapy against drug-induced liver injury is limited to the use (N-acetylcysteine in the early phases of acetaminophen toxicity) (L-carnitine is potentially valuable in cases of valproate toxicity) • Consult Hepatologist

33. Halothane Hepatitis

34. Halothane metabolism

36. Pathophysiology • Biotransformation to toxic metabolites or reactive intermediates • Oxidative biotransformation→trifluoroacetyl chloride →acylates protein → induce immune response • Serum antibodies recognise native liver microsomal proteins or liver microsomal proteins that are TFA modified by the TFA chloride metabolite of halothane

37. Pathophysiology….. • TFA protein induce humoral or T cell sensitization • Induce/inhibit hepatic biotransformation of enzymes and temporarily inhibit a number of biochemical processes

39. Type I Hepatotoxicity (mild) • Benign, self-limiting, and relatively common (25-30%) • Mild transient ↑ serum transaminase , glutathione S - transferase concentrations and altered postoperative drug metabolism • Jaundice/Clinically evident hepatocellular disease - Not Present • Results from reductive (anaerobic) biotransformation ofhalothane rather than the normal oxidative pathway

40. Type II Hepatotoxicity (fulminant) • Massive Centrilobular liver necrosis • Fulminant liver failure • No Histopathologic findings are specific • S/S- Fever, Jaundice, and Grossly ↑ serum transaminase • Immune mediated - Initiated by oxidative halothane metabolism to an intermediate compound This compound then binds to trifluoroacetylate proteins in the hepatic endoplasmic reticulum • Fatality rate - 50%-75% • Genetically predisposed individuals - probably

41. Comparison of type Ӏ and type II Mild Form (Type 1 ) • Incidence 1:5 • Repeat exposure not necessary • Mild elevation of ALT, AST • Focal necrosis • Self-limited Fulminant Form (Type II ) • Incidence 1:10,000-35,000 • Multiple exposures • Marked elevation of ALT, AST, bilirubin, alkaline phosphatase • Massive hepatic necrosis • Mortality rate: 50% Antibodies to halothane-altered protein antigens

42. Risk factors for halothane hepatitis • Multiple exposures (especially at intervals of < 6 wk) : Single greatest risk factor for halothane hepatitis • Prior history of post-anesthetic fever or jaundice • Obesity • Female sex • Middle age • Genetic predisposition

43. Investigations • CBC count - mild leukocytosis or eosinophilia (in 8-32% of patients with type II) • Bilirubin level • Serum transaminase levels elevated • ELISA - Halothane-related antibodies Serum autoantibodies present in 30-44% of patients with type II halothane hepatotoxicity

44. Investigations….. • Liver biopsy HistologicFindings • Acute yellow atrophy and widespread centrilobularhepatocellular necrosis

45. Management (Medical care) • No specific therapy • Supportive therapy • Maintain fluid and electrolyte balance • Support hemodynamics as necessary • Support ventilation as necessary • Correct any alterations in coagulation • Correct hypoglycemia • Treat any other complications of the comatose state • Restrict protein intake and administer oral lactulose or neomycin

46. Management (Surgical care) • Liver transplantation - If fulminant liver failure occurs and liver function does not recover Prognosis • If fulminant liver failure does not occur, patients usually fully recover • If fulminant liver failure occurs, the mortality rate can be 50%

47. Prevention • Avoid halothane when alternatives exist • Recent exposure- most important risk factor for type II fulminanthepatotoxicity • In patients with history of jaundice and fever following previous halothane exposure, all volatile anesthetics should be used with caution. • Patients with unexplained elevations of liver functions should not undergo anesthesia and elective surgery until a diagnosis has been confirmed

48. Halothane Hepatitis in pediatric group • 1st case reported in 1959 • Two retrospective studies have examined the incidence of halothane hepatotoxicity in children • 1 study shows incidence as 1:82,000. The other study shows incidence of 1:200,311 • Diagnosis confirmed by presence of S.antibodies that reacted with halothane altered hepatocyte antigens • Much rarer than in adults (reasons not clear)

49. Effects of other fluorinated inhalational agents • Incidence of liver injuries follows the order : H > E > I > D • Co relates with the extent of their oxidative metabolism. H≈20%, E≈2.5%, I ≈0.2%, D ≈0.01% • Cause liver injuries at a lower incidence than halothane • They form protein adducts that are identical in structure to those of halothane • Cross sensitization reaction occurs

50. Effects of other fluorinated inhalational agents… • Sevoflurane is not metabolized to antigenic TFA adducts • Few case reports in Japanese literature of sevoflurane being associated with postop hepatic dysfunction Any patient sensitized to any of the fluorinated inhaled anaesthetics should not be exposed to any of these agents