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University College of Medical Science & GTB Hospital, Delhi

ACUTE PARENCHYMAL LIVER DISEASES : PATHOPHYSIOLOGY, PRE-OPERATIVE CONSIDERATIONS AND PATIENT PREPARATION. Dr. Manisha Desai. University College of Medical Science & GTB Hospital, Delhi. INTRODUCTION. Acute hepatitis is a common condition

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University College of Medical Science & GTB Hospital, Delhi

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  1. ACUTE PARENCHYMAL LIVER DISEASES : PATHOPHYSIOLOGY, PRE-OPERATIVE CONSIDERATIONS AND PATIENT PREPARATION Dr. Manisha Desai University College of Medical Science & GTB Hospital, Delhi

  2. INTRODUCTION • Acute hepatitis is a common condition • India is endemic for certain types of viral hepatitis • Frequency of unsuspected liver disease – 1 in 700 of otherwise healthy surgical candidates

  3. ACUTE HEPATITIS • Recent infection or inflammation of liver - < 6 months • Viral hepatitis • Hepatitis A, B, C, D and E • Herpes Simplex virus • Cytomegalovirus • Epstein Barr virus • Adenovirus

  4. Non viral infection • Bacterial infections – pyogenic abscesses • Alcohol • Toxins – Amanita toxin in mushrooms,Carbon tetra chloride • Drugs – Acetaminophen , Halothane, antitubercular drugs • Ischemic hepatitis • Pregnancy • Metabolic disease – Wilson’s disease

  5. Clinical features in viral hepatitis Clinically all types present in same manner: • Prodromal symptoms - anorexia, nausea and vomitting, fatigue, malaise, myalgia, photophobia,low grade fever. Serum sickness like syndrome (fever,arthralgia,rash) in HBV Dark urine, clay coloured stools 1-5 days before onset of jaundice LAB : AST, ALT are elevated. • Jaundice- prodromal symptoms diminish. Liver enlargement and tenderness LAB : AST, ALT attain their peak; Se. bilirubin – 5-20 mg/dl 3. Recovery phase – symptomatic improvement. Hepatomegaly and abnormal LFT’s may persist.

  6. HEPATITIS A • Acute phase : • anti-HAV (IgM) positive from onset of symp and persists for 4 months • Se. aminotransferase ↑ • Fecal HAV shedding • anti-HAV (IgG) – • Present indefinitely Immune to re-infection. • 90-100% population in India acquire antibody and become immune by adolescence. Complete clinical and biochemical recovery in 60% pts by 2 months; almost all by 6 months.

  7. HEPATITIS B • Intermediate endemicity in India.Major cause of CLD and HCC. • Hepadnavirus . DNA virus • Compact structure with overlapping genes permits HBV to code for multiple proteins Antigens – 1) HBsAg- envelope protein. coded by S gene. 2) HBeAg- nucleocapsid protein. coded by precore region. secreted in bld 3) HBcAg- nucleocapsid protein, not secreted.

  8. …… Hepatitis B Population at high risk : • Hemophiliacs • Drug addicts • Health care workers • Infants born to HBsAg + mothers or mothers with acute Hep B in 3rd trimester/early post partum.

  9. …..Hepatitis B • HBsAgpreceeds increase in enzyme levels by 2-6 wks. Persists for entire symptomatic phase. Usually disappears 1 month after onset of jaundice. Rarely persists for 6 months. Anti-HBs persists for life. Window period may exist. • HBcAg is not seen. Anti-HBc seen 1-2 wks after appearance of HBsAg. Maybe the only marker seen in window period. • HBeAg appears concurrently with HBsAg. Indicates active replicative infection • Among healthy adults, acute HBV is self-limited in 95-99%. Complete clinical and biochemical recovery 3-4 months after onset of jaundice in 75% of uncomplicated cases. • Persistence of HBsAg beyond 6 months- Carrier state

  10. HEPATITIS C Population at high risk: • patients requiring hemodialysis • organ transplantation • drug addicts • More severe disease in alcoholics, co-infection with HBV and HIV

  11. ……Hepatitis C HCV RNA – within few days of exposure Episodic pattern of aminotransferase elevation Anti-HCV demonstrated in early phase

  12. HEPATITIS D • Defective virus; requires HBV for transmission. • Co-infection with HBV or superinfection of HBsAg carrier • Superinfection can transform inactive or mild chronic Hep B into severe, progressive disease and cirrhosis or even fulminant hepatitis. • In Co-infection: HDV RNA PCR is the most sensitive ;Anti-HDV IgM followed by IgG . anti-HBc will be of IgM class. • In super infection: both IgM and IgG anti-HDV rise and persist . anti-HBc will be of IgG class • Loss of HBsAg is a reliable marker for resolution of Hep D

  13. HEPATITIS E Population at risk : • Those exposed to contaminated water supplies • Pregnancy- HEV is the MC cause of viral hepatitis and FHF in pregnancy in India. pregnant pts in 2nd/ 3rd trimester have a worse outcome. Incidence of FHF - 22%. Mortality rates of 15-25%. Abortions, stillbirths,neonatal death increased

  14. serology in hepatitis E • Serum HEV RNA - in pre icteric phase , disappears after peak in aminotransferases • ALT rises 10 days before onset of symptoms, peaks when jaundice occurs, then declines • IgMab seen just before peak ALT. Disappears 5-6 months later. • IgGab detectable 1 year after acute infection

  15. Other hepatitis causing pathogens • Cytomegalovirus- perinatal/blood transfusions/organ transplantation/ immunocompromised. CMV IgMab • Epstein-Barr virus- transmission via oral secretions. Monospot test, EBV IgMab • Herpes Simplex virus- immunocompromised. Rapid and lethal course. • Bacteria- E.coli, Klebsiella,Streptococcusviridans, anaerobic bacteria --- pyogenic liver abscess

  16. LAB TESTS • Hemogram – transient neutropenia and lymphopenia followed by relative lymphocytosis. (atypical lymphocytes) • RBS- vomitting, poor intake, poor glycogen contribute to hypoglycemia. • Se.aminotransferases • Se.ALP - usually normal • PT- if prolonged, worse prognosis • Gama globulin- mild elevation • Se. Albumin- usually normal • Hep A – IgM anti-HAV • Hep B- HBsAg- titre has little relation to severity HBeAg- indicator of relative infectivity. HBV DNA is a better indicator Anti-HBc- in window period Anti-HBsAg- rarely detectable in acute hepatitis • Hep C – HCV RNA- gold standard anti-HCV • Hep D- HDV antigen-detectable only briefly Anti-HDV

  17. Morphologic lesions (common to all viral hepatitis) • Panlobular infiltration with mononuclear cells. • Hepatic cell necrosis, ballooning of cells, acidophilic degeneration of hepatocytes( Councilman or apoptotic bodies) • Hyperplasia of kupffer cells • Variable degree of cholestasis (marked in Hep E) • Hepatic regeneration- mitotic figures, rosette or pseudoacinar formation • Bridging/subacute/confluent necrosis or interface hepatitis - bridging between lobules as a result of large areas of cell dropout. bridge formed by condensed reticulum, cell debris. → prognostic significance in chronic hepatitis, NOT in acute hepatitis.

  18. TREATMENT OF VIRAL HEPATITIS • Specific treatment is not necessary • High calorie diet • Severe acute hepatitis B- Lamivudine • Acute hepatitis C- long acting pegylated interferon + ribavirin…. Mainly to decrease progression to chronicity • Glucocorticoid therapy- no value; maybe deleterious increasing risk of chronicity

  19. ALCOHOLIC HEPATITIS • Alcohol → Acetyldehyde → Acetate • Asymptomatic → life threatening decompensation • Decompensation precipitated by vomitting, diarrhea, increased alcohol intake, infection • Tender smooth hepatomegaly • ↑ bilirubin, AST, GGT, ALP , PT • Histology- Neutrophilic infiltrate around necrotic hepatocytes- Mallory bodies ; pericellular fibrosis – chicken wire appearance

  20. DRUG INDUCED HEPATITIS • Drug induced liver injury (DILI) • Liver principal site for metabolism of compounds extrinsic or intrinsic • Phase 1- hydroxylation Phase 2- conjugation Phase 3- transport into bile /blood • Pattern of injury : hepatocellular, cholestatic,mixed,steatosis (micro and macro) • The hepatocellular pattern resembles acute hepatitis

  21. Pathogenesis of DILI

  22. TYPES OF DILI

  23. On liver biopsy, Acute Zone 3 necrosis Indistinguishable from acute viral hepatitis • C/f: similar to viral hepatitis • Lab tests : normal hemogram; eosinophelia with allergic type reactions ALT and AST markedly ↑ ALP normal or mildly elevated Se.bilirubin variable. High levels negative prognosis • Course : rapid improvement clinically and biochemically • Rx: stop offending drug. N acetylcysteine for acetaminophen; prednisolone , azathioprine

  24. ACETAMINOPHEN HEPATITIS • Hyperacute LF. • Dose- variable. usually 15 g. • Renal failure in 70% • ↑ AST > ALT within 12-24 hrs, peak at 3 days and resolve rapidly • Centrilobular (zone 3) necrosis without inflammation • Rx – N-acetylcysteine

  25. Mechanism of Acetaminophen toxicity Acetaminophen 80% (N) <5% (N) ; Glucuronidation Oxidation by CYP2E1 excreted in urineNAPQI → non toxic by GSH In toxicity, GSH ↓, NAPQI ↑ (P/W saturated in toxicity) Rx – N- Acetyl Cysteine(↑ GSH)

  26. HALOTHANE HEPATITIS • Immune mediated • Risk factors : - Females -Middle aged -Obese -Enzyme induction -Prior anesthetic exposure -Genetics

  27. After 7-10 days of anaesthesia • fever, rash, arthralgia, jaundice,Mild hepatomegaly with liver tenderness • leucocytosis, eosinophilia • Cross sensitivity to other inhalational anesthetics has been noted • Committee on safety of medicines (CSM) recommends that halothane must not be used within 3 months of previous exposure unless there s a definite reason to do so and it should not be used if there was history of unexplained pyrexia or jaundice within 1 week of previous exposure .

  28. ISCHEMIC HEPATITIS • Misnomer. Centrilobular necrosis in absence of inflammation • Increases O2 uptake by increasing extraction- 95% O2 extracted in single pass → resistance to ischemia • Compensation diminished in severe ischemia – MI, tamponade, hypovolemic shock, septic shock • Budd Chiari syndrome, intrahepaticsickling in SCA • Clinical picture dominated by the cause • Serum AST, ALT ↑↑ (> 200 times normal) • Serum LDH ↑ (30 times normal) • Mortality – 75%

  29. PREGNANCY RELATED CONDITIONS Acute Fatty liver of pregnancy • Rare ; usually 3rd trimester • encephalopathy, coagulation disorder, DIC,liver failure • Following delivery, liver function improves PIH • HELLP syndrome – 10% • Rapidly resolves after delivery

  30. WILSON’S DISEASE • AR disorder , mutations in ATP7B gene-membrane bound copper transporting ATPase • ↑ hepatic Cu, ↓ serum Cu, ↓ ceruloplasmin • Widespread hepatic necrosis → Cu being released into circulation → hemolysis • Presentation- children. May mimic acute hepatitis • ↑ serum bilirubin (mainly indirect), ↑ serum aminotransferases

  31. ACUTE LIVER CELL FAILURE • All causes of acute hepatitis can cause Acute liver cell failure (ALF) • ALF – jaundice, coagulopathy, encephalopathy • Mortality – 40-95% • Worldwide, viral hepatitis - most common UK, acetaminophen toxicity – most common • depending on time interval between onset of jaundice and encephalopathy: Hyperacute (0-7 days) ALF Acute (8-28 days) Subacute (> 28 days) • Fulminant hepatitis – encephalopathy within 8 weeks of onset of symptoms

  32. Effects on all organ systems • Metabolism – hypoglycemia, protein breakdown, lipolysis • CVS- hyperdynamic state, ↑ C.O., ↓SVR ↓ CVP , MAP maintained profound vasodilation – collapse • RS – Hyperventilation – resp.alkalosis V-Q mismatch, pulm edema , ARDS • Kidneys – ARF in 40-80%.due to ↓ effective bld volume, sepsis , hepatorenal syndrome • Bleeding diathesis • ↑ susceptibility to infection

  33. CNS : Hepatic encephalopathy Accumulation of endogenous toxins – altered brain metabolism and neurotransmission. Most imp- Ammonia. Cerebral autoregulation fails – cerebral edema and ↑ ICP Precipitants- Excessive dietary protein, Constipation, Diarrhoea n vomiting, GI bleeding, Infection, Azotemia, Diuretic therapy, Paracentesis, Hypoxia, hypotension, Anemia, Hypoglycemia, Sedatives, Hypnotics, Surgical stress

  34. Etilology specific therapy • Correction of fluid and electrolyte imbalance • Nutrition- 35-40Kcal/day enteral or parenteral • Frequent blood glucose monitoring • Prevention of bleeding and infection • Mannitol infusion • Hemodialysis • Orthoptic liver transplantation

  35. CONCERNS FOR SURGERY IN A PATIENT WITH LIVER DISEASE • Multiple functions of the liver : - synthesis of serum proteins, - metabolism of drugs, - excretion - detoxification -filtering of portal venous blood • Any or all of this may be disturbed • Alteration in the pharmacokinetics of anaesthetics, muscle relaxants, sedatives and analgesics →post –operative hepatic dysfunction and delayed recovery.

  36. Greater risk of bleeding, infection • Mild elevations of aminotransferase, ALP, bilirubin levels are frequent after surgeries whether under GA/Regional anaesthesia → transient and of no significance if there’s no pre-existing liver disease • However, clinically important hepatic dysfunction is more likely to occur in patients with pre-existing liver disease – precipitation of ACUTE LIVER CELL FAILURE . • Concern of occupational exposure of medical personnel

  37. Assessment of perioperative risk remains inexact because of paucity of prospective studies • Harville and Summerskill in 1963 reported mortality rates of 9.5% to 13% in acute viral hepatitis patients who underwent laparotomy and major post-op complications in 11% • alcoholic hepatitis, mortality rates as high as 55% • alcoholic or nonalcoholic fatty liver does not contraindicate elective surgery

  38. Ref : Friedman L.S. Hepatology June 1999 ; 1617-1623

  39. PRE-OP EVALUATION • history-taking to identify risk factors -H/O jaundice- remote history of Hep A – no significance - previous blood transfusions - tattoos - illicit drug use - sexual promiscuity - a family history of jaundice or liver disease - a history of jaundice or fever after anesthesia - alcohol use - complete review of current medications.

  40. Symptoms like fatigue, malaise, pruritus, fever, passage of dark urine or clay coloured stools, jaundice • Physical examination : - vital signs - ICTERUS - ascites,hepatictenderness,hepatomegaly - any evidence of encephalopathy, coagulopathy • Nature of surgery – abdominal surgeries esplaparotomy are high risk surgeries.

  41. PRE-OP WORKUP • Complete hemogram with platelet count • Blood sugar • KFT – Blood urea, Se.creatinine, Se.electrolytes • LFT • Prothrombin time • Serology – viral markers • ECG • CXR – pleural effusion • Se.ammonia- in encephalopathy

  42. ALGORITHM FOR PRE-OP EVALUATION OF PATIENT WITH KNOWN OR SUSPECTED LIVER DISEASE

  43. Abstinence from alcohol is advised to avoid - alcohol withdrawal in the postoperative period - enhancement of halothane hepatotoxicity by alcohol - toxicity with therapeutic doses of acetaminophen in alcoholics • No good evidence for duration of abstinence that should occur

  44. Patient Preparation Goal Preserve existing liver function and avoid factors that may be detrimental to liver Optimization • correct anemia • Correct metabolic, fluid & electrolytes imbalance • Correct coagulation abnormality – Vit K (1-5mg oral/subcutaneous for 1-3 days), FFP, platelets (PLT count > 50,000/mm3 and INR < 1.5) • Syp. Lactulose 30 ml every 6 hrs orally – first line therapy in encephalopathy

  45. - Thiamine , folate and Vit B supplementation in alcoholics if nutrition or glucose has to be given • - Frequent blood glucose monitoring – to avoid hypoglycemia • -Antibiotics be started for infection • - Informed high risk consent • - Arrange blood • - Preoperative medication • Sedation – should be avoided, it can precipitate or exacerbate encephalopathy

  46. SUMMARY • Acute hepatitis especially of viral etiology is a common disease entity. • Patients of acute hepatitis of any cause undergoing surgery are at an increased risk of developing hepatic dysfunction and acute liver cell failure, remarkably increasing mortality rates. Diagnosis, pre-operative evaluation and optimization of the patient is therefore of great importance.

  47. REFERENCES • Miller RD. Anesthesia. Philadelphia, Elsevier, 2010: pp 1026-1028 • Zakim, Boyer. Hepatology – A textbook of liver disease. Philadelphia, Elsevier, 2006 : ch 21, 31-35 • Harrison. Principles of Internal Medicine. McGraw Hill, 2008 : ch : 295,298,299 • Freidman LS. The Risk of Surgery in Patients With Liver Disease. Hepatology 1999; 29:1617-23. • Martin P. Perioperative considerations for patients with liver disease. Cleveland clinic journal of medicine 2009; 76:S93-97 • Keegan MT. Preoperative Assessment of the Patient with Liver Disease. American Journal of Gastroenterology 2005; 100:2116–27

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