1. Liver Failure Mackay Memorial Hospital Department of Internal Medicine Division of Gastroenterology R4 陳泓達 97/6/22

2. Liver failure: Liver failure: Clinical syndrome: sudden loss of liver parenchymal and metabolic function  Manifest as coagulopathy and encephalopathy encephalopathy

3. Acute liver failure : Acute liver failure : Defined as interval between onset of the illness and appearance of encephalopathy < 8 weeks

4. Etiology: Etiology: Western countries: heterogenous, drugs (acetaminophen, NSAID), viruses Developing countries: viruses, regional Difference (endemic area ?)

5. Journal of Gastroenterology and Hepatology(2002)17, S268 – S273

6.  Acetaminophen toxicity  Idiosyncratic drug toxicity  Hepatotropic viruses  Miscellaneous causes  Indeterminate acute liver failure (viruses can not be demonstrated ? )

8. Uncommon causes: Uncommon causes: Wilson ’ s disease, other infections (CMV, HSV, EBV), vascular abnormality, toxin, acute fatty liver of pregnancy, antoimmune hepatitis, ischemia, malignant infiltration

9. Symptoms and signs: Symptoms and signs: Jaundice, altered mental status, nausea/ vomiting, anorexia, fatigue, malaise, myalgia/arthralgia Most of them present hepatoencephalopathy and icteric appearance.

10. Non-specific Management HypoglycemiaEncephalopathyInfectionsHemorrhageCoagulopathy Hypotension(hypovolemia, vascular resistance ↓) Respiratory failure Renal failure Pancreatitis

11. Hypoglycemia: monitoring blood glucose, IV glucose supplement. Hypoglycemia: monitoring blood glucose, IV glucose supplement. Infection: aseptic care, high index of suspicion, preemptive antibiotic. Infection: aseptic care, high index of suspicion, preemptive antibiotic. Hemorrhage (i.e. GI): NG placement, H2 blocker or PPI. Hemorrhage (i.e. GI): NG placement, H2 blocker or PPI. Hypotension: hemodynamic monitoring or central pressures, volume repletion Hypotension: hemodynamic monitoring or central pressures, volume repletion

12. Respiratory failure (ARDS): mechanical ventilation. Respiratory failure (ARDS): mechanical ventilation. Renal failure (hypovolemia, hepatorenal syndrome, ATN): hemodynamic monitor, central pressure, volume repletion, avoid nephrotoxic agent Renal failure (hypovolemia, hepatorenal syndrome, ATN): hemodynamic monitor, central pressure, volume repletion, avoid nephrotoxic agent

13. Encephalopathy major complication major complication precise mechanism remains unclear precise mechanism remains unclear Hypothesis: Ammonia production Hypothesis: Ammonia production Treatment toward reducing ammonia production Treatment toward reducing ammonia production Watch out airway, prevent aspiration Watch out airway, prevent aspiration

14. Encephalopathy Stage 1: day-night reversal, mild confusion, somnolence Stage 1: day-night reversal, mild confusion, somnolence Stage 2: confusion, drowsiness Stage 2: confusion, drowsiness Stage 3: stupor Stage 3: stupor Stage 4: coma Stage 4: coma

15. Encephalopathy Predisposing factor of hepatic encephalopathy: GI bleeding, increased protein intake, hypokalemic alkalosis, hyponatremia, infection, constipation, hypoxia, infection, sedatives and tranquilizers

16. Encephalopathy TX upon ammonia hypothesis Correction of hypokalemia Correction of hypokalemia Reduction in ammoniagenic substrates: cleansing enemas and dietary protein restriction. Reduction in ammoniagenic substrates: cleansing enemas and dietary protein restriction. Lactulose: improved encephalopathy, but not improved outcome. Lactulose: improved encephalopathy, but not improved outcome. Dose  2-3 soft stools per day Dose  2-3 soft stools per day

17. Encephalopathy Oral antibiotics: neomycin  lack of evidence Oral antibiotics: neomycin  lack of evidence nephrotoxicity  limited use. nephrotoxicity  limited use.

18. Cerebral Edema Cerebral edema develops in 75 - 80 % of patients with grade IV encephalopathy. Cerebral edema develops in 75 - 80 % of patients with grade IV encephalopathy. precise mechanism : not completely understood precise mechanism : not completely understood Possible contributing factor: Possible contributing factor: osmotic derangement in astrocytes osmotic derangement in astrocytes changes in cellular metabolism changes in cellular metabolism alterations in cerebral blood flow alterations in cerebral blood flow

19. Cerebral Edema : Clinical manifestations: ↑intracranial pressure (ICP) and brainstem Herniation  the most common causes of death in fulminant hepatic failure ischemic and hypoxic injury to the brain hypertension, bradycardia, and irregular respirations, ↑ muscle tone, hyperreflexia

20. Cerebral Edema Monitoring of ICP: Monitoring of ICP: routinely used by more than one-half of liver transplantation programs in the United States Tx: to maintain ICP below 20 mmHg and the CPP above 50 mmHg. Tx: to maintain ICP below 20 mmHg and the CPP above 50 mmHg.

21. Coagulopathy diminished capacity of the failing liver to synthesize coagulation factors. diminished capacity of the failing liver to synthesize coagulation factors. The most common bleeding site: GI tract. The most common bleeding site: GI tract. Prophylactic administration of FFP: not recommended. Prophylactic administration of FFP: not recommended.  performed before transplant or invasive procedure  performed before transplant or invasive procedure

22. Specific Treatment ACT intoxication: charcol followed by NAC Drug induced hepatotoxicity: discontinue drugs supportive treatment Viral hepatitis: HBV: anti-HBV treatment, lamivudine : HSV/varicella zoster: acyclovir others: supportive care

23. Wilson ’ s disease: early diagnosis  liver transplant Wilson ’ s disease: early diagnosis  liver transplant autoimmune hepatitis: confirm diagnosis (liver biopsy), corticosteroid  liver transplant autoimmune hepatitis: confirm diagnosis (liver biopsy), corticosteroid  liver transplant acute fatty liver of pregnancy or the HELLP syndrome: obstetrical services, and expeditious delivery are recommended acute fatty liver of pregnancy or the HELLP syndrome: obstetrical services, and expeditious delivery are recommended

24. Acute ischemic injury (shock liver): cardiovascular support : Malignant infiltration: liver biopsy for diagnosis treat underlying disease. Indeterminate etiology: consider biopsy for diagnosis and further guide of treatment

25. Liver transplant Liver transplant: remain backbone of treatment of fulminant hepatic failure Liver transplant: remain backbone of treatment of fulminant hepatic failure reliable criteria to identify these patients who really need transplant. reliable criteria to identify these patients who really need transplant.  remain unresolved in fulminant hepatic failure.  remain unresolved in fulminant hepatic failure.

26. At King ’ s College hospital in London (not due to ACT) either PT>100 second or the presence of any three of the following variables: 1. age 40 years ; 2. an etiology of non-A, non-B hepatitis, halothane, drug induced liver failure; 3. duration of jaundice before onset of encephalopathy > 7 days, prothrombin time >50 s, and serum bilirubin > 300 mmol/L.

27.  Encephalopathy  Coagulopathy (PT)

28. Liver transplant Criteria: Criteria: In chronic liver disease most commonly used prognostic model MELD score (Model for End-stage Liver Disease ) 3.8[Ln serum bilirubin (mg/dL)] + 11.2[Ln INR] + 9.6[Ln serum creatinine (mg/dL)] + 6.4 Ln: natural logarithm. Ln: natural logarithm.

29. Liver transplant CONTRAINDICATIONS: CONTRAINDICATIONS: 1. Cardiopulmonary disease can not be corrected, or preclude surgery. 2. Malignancy outside of the liver within 5 years of evaluation, or can not be cured. 3. Active alcohol and drug use

30. Advanced age and HIV disease: relative contra- indication (site-specific management) Advanced age and HIV disease: relative contra- indication (site-specific management)

31. Liver support system Non-cell-based: plasmapheresis and charcoal- based hemoabsorption Non-cell-based: plasmapheresis and charcoal- based hemoabsorption Cell-based systems : known as bioartificial liver support systems Cell-based systems : known as bioartificial liver support systems

32. Liver support system Non-cell-based: not improved survival. Available systems: molecular adsorbents recirculation system (MARS) Cell-based systems: undergoing trial.