1. Acute Liver Failure - ALF Yaakov Maor M.D. Department of Gastroenterology and Hepatology Sheba Medical Center, Tel-Hashomer

2. פרשת מקרה בן 51, יליד ישראל מנכ"ל חברה נימצא 6 חודשים בהודו 3 שבועות הרגשה רעה, חוסר תיאבון, בחילות לפני שבועיים שתן כהה ובהמשך צהבת מיומיים "שינוי בהתנהגות" וישנוניות הוטס לארץ ישירות לחדר מיון

3. פרשת מקרה בבדיקה: ישנוני אך ניתן להערה דופק 100 לדקה, ל"ד 100/60, חום  c37.3 צהבת בולטת בלחמיות ובעור רעד מסוג Flapping Tremor ללא סימני מחלת כבד כרונית בטן רכה, הכבד נמוש בקצהו, הטחול אינו מוגדל

4. פרשת מקרה בבדיקות מעבדה: Bilirubin-15 mg/dL ALT-1800 IU/L; AST-1200 IU/L; ALP-220 IU/L Glucose-80 mg/dL; Creatinine-1.2 mg/dl INR-2.9 Hb-12.8 g/dL; WBC-4,300; PLT-133,000 pH-7.43; Lactate-21 mg/dL Ammonia-90 µg/dL

5. Acute Liver Failure Definition – Accurate diagnosis of the syndrome Etiology – Determine prognosis and specific treatment Initial resuscitation and treatment of complications Timely transfer to a Transplant Center!!!

6. Definition Rapid development of hepatocellular dysfunction – Coagulopathy (INR  1.5), Jaundice Encephalopathy!!! Absence of a prior history of liver disease (Wilson’s disease, autoimmune hepatitis)

7. Definition Interval between the onset of illness and ALF <26 weeks (US ALF Study Group) Jaundice-to-encephalopathy interval (Prognosis): - Hyperacute liver failure – Within 7 days - Acute liver failure – 7 – 21 days - Subacute liver failure – 21 days – 26 weeks

8. Etiology Viral infection – HAV, HBV (HDV), HCV?, HEV Acetaminophen – Predictable, Direct (ETOH) Idiosyncratic Hepatotoxicity – Halothane, Anti-TB Idiopathic (15-44%) – Occult viral infection? Rare: Autoimmune hepatitis, Wilson’s disease, Budd-Chiari syndrome, Pregnancy related, Toxins - Amanita Phalloides, Cancer

9. 68% 50% 13% 0% 25% 11% 50% 12% 63% 17% Transplant-Free Survival Rate Unfavorable Idiopathic Drugs (not ACPA) HBV (acute on chronic) Wilson Transplant-free survival – 11% (0-25%) Etiology

10. Etiology-Specific Therapies Acetaminophen - N-Acetylcysteine Hepatitis B – Lamivudine Pregnancy-associated – Urgent delivery Budd-Chiari syndrome - Angioplasty Amanita Phalloides - Penicillin, Silibinin

11. פרשת מקרה לחולה נימצאו נוגדנים: Anti HAV IgM אובחנה הפטיטיס A חריפה!

12. Natural History of ALF: Nausea Jaundice LFT ’ s  Coagulopathy DEATH Acute Hepatitis SIRS Acute Liver Dysfunction Acute Liver Failure Encephalopathy Hypoglycemia M. acidosis Infection M O F Cerebral Edema

13. החייאה וניהול ראשוני – ביחידה לטיפול נמרץ ניטור מצב הכרה וסימנים חיוניים החייאת נוזלים ומעקב תפוקת שתן מעקב ומתן גלוקוז - היפוגליקמיה מעקב בדיקות דם כולל: אנזימי כבד בילירובין גלוקוז קראטינין ואלקטרוליטים INR, פקטורV לקטט גאזים אמוניה עורקית ס.ד

14. Encephalopathy – Precipitating Factors Non-neurological: Sepsis and SIRS! Hypoglycemia Hypoxemia Renal failure Neurological: Occult seizures - 33% stage 3 – 4 encephalopathy Cerebral edema

15. Stages of Encephalopathy Stage 1 – Affect, insomnia, concentration Stage 2 - Drowsiness, disorientation, confusion, Agitation! Asterixis appears Stage 3 - Marked somnolence and incoherence Stage 4 - Coma

16. Encephalopathy - Management Quient enviroment! Maintain the patient's head at a 30° to improve jugular venous outflow Sedative-hypnotic drugs should be avoided – Clinical monitoring – Use Propofol!!! Treat reversible conditions e.g., hypoglycemia Patients encephalopathy stage 3 – 4 – intubation: - airway protection -  Intra Cranial Pressure – ICP

17. Encephalopathy - Management Brain CT - Mass, intracranial hemorrhage, and evidence of brainstem herniation Correlation between CT evidence of cerebral edema ande ICP is imperfect Monitor and treat deeply sedated patients with phenytoin for sub-clinical seizure?

18. ICP Monitoring Most accurate way to detect intracranial hypertension Should be limited to specialized units and to patients awaiting LTS with stage 3 – 4 encephalopathy Has not been shown to increase survival Aims: - ICP <20-25 mm Hg - Cerebral perfusion pressure (CPP) = Mean Arterial Pressure (MAP) – Intra Cranial Pressure (ICP) >50-60 mm Hg

19. ICP Monitoring Requires correction of underlying coagulopathy – Prognostic factor Portal of entry for infectious organisms Can precipitate intracranial hemorrhage Trans-cranial Doppler has not been validated for ICP monitoring

20. Treatment of  ICP Osmotherapy Mannitol – IV bolus of 0.5 to 1 g/kg 20% solution – May be repeated until plasma osmolarity reaches 320m Osm/L Therapy with mannitol requires preserved renal function (or hemofiltration) Hypertonic NaCl 30% – Maintain serum Na + levels of 145-155 mEq/L

21. Treatment of  ICP Hyperventilation - Cerebral vasoconstriction -  CBF New therapies: - N-Acetylcysteine (In non-acetaminophen ALF) Recently: Patients with early encephalopathy showed higher spontaneous survival rate - Mild hypothermia (32  C - 34  c)  ICP via  CBF Not in use !!! - Lactulose – No proven benefit - Barbiturate

22. Coagulopathy Avoid plasma/PLT administration: - Index of hepatic function - Volume overload Indications: - Bleeding - Invasive procedures - Prophylactic: PLT count 7 aFVII may be advantageous

23. Coagulopathy Monitor INR q 6-12 h (Obtain Factor V when INR> 2.5) INRDay 3# 2 4# 3 5# 4 Transfer to transplant Center

24. Infections Develop in 80% of patients Accounts for 25% of patients who are excluded from liver transplantation Clinical recognition of infection is difficult: SIRS may occur without infection Infection may be without fever/leukocytosis in 30% High level of suspicion for infection should be maintained with a low threshold for administration of antibiotics!!!

25. Management - General ICU admission and supportive treatment Timely transfer to a Transplantation Center Liver transplantation – The Only Established & Definitive Treatment

26. Predictors of Prognosis Patients with ALF fall into two categories: Intensive medical care enables recovery of hepatic function – Allow time for regeneration!!! Require liver transplantation to survive

27. Predictors of Prognosis Determinant of prognosis: Regeneration Liver dysfunction Encephalopathy and Brain edema Multi-Organ Failure – MOF

28. Predictors of Prognosis Avoid the following two scenarios: Death of the patient despite intensive medical care without consideration of transplantation Unnecessary liver transplantation when recovery would have occurred spontaneously – Surgical mortality, lifelong immunosuppression

29. Liver Transplantation Clinical decision making aided by prognostic markers Before the era of liver transplantation – <50% survival Liver transplantation for ALF – 63% - >70% (Lower than other etiologies)

30. King’s College Hospital Criteria ALF secondary to acetaminophen overdose: pH <7.30 (irrespective of encephalopathy grade) or Hepatic encephalopathy grade III-IV INR >6.5 Creatinine >3.4 mg/dL Arterial Lactate >27 mg/dL

31. King’s College Hospital Criteria ALF with other causes: INR >6.5 (irrespective of encephalopathy grade) or any three of the following (irrespective of encephalopathy grade) Age 40 years Non-A, non-B hepatitis or drug-induced origin Duration of jaundice before encephalopathy >7 days Bilirubin >17.6 mg/dL INR >3.5

32. Clichy Criteria Stage III-IV encephalopathy associated with: Factor V level <20% in patients <30 years Factor V level 30 years (Based on cohort of patients with acute hepatitis B)

33. Predictors of Prognosis Model for End-Stage Liver Disease (MELD) Score – (Bilirubin; INR; Creatinine) Elevated Alpha-Fetoprotein (Indicator of regeneration) APACHE II

34. Liver Transplantation Contraindications to transplantation: - Irreversible brain damage (CPP <40 mm Hg) - Active extra-hepatic infection - Multiple-organ failure syndrome – MOF Consider living-related liver transplantation

35. פרשת מקרה הוחל טיפול ב- N-Acetylcysteine 6 מ"ג לק"ג לשעה אבל... מצב הכרה – ישנוני יותר – שלב אנצפלופתי II-III הונשם ומקבל Propofol INR עלה ל- 6; פקטור V- 15% קראטינין עלה ל- 1.9 mg/dl

36. העברה למרכז השתלות קשר טלפוני ראשוני העברה כאשר: אנצפלופתיה דרגה II חמצת, לקטטמיה, היפוגליקמיה קואגולופתיה מטפסת Intensive care Etiology – specific Rx. Consultation with LTS center Contraindication for LTS No Yes Continue intensive support Transfer to LTS center – National status one Re-assess for recovery or contraindication for LTS Ongoing intensive care Liver Transplantation No Yes

37. פרשת מקרה נוצר קשר עם מרכז השתלות בבלגיה הועבר בהטסה להמתנה להשתלת כבד

38. Experimental Therapy Provide a bridge to liver transplantation/ Spontaneous regeneration and recovery Auxiliary liver transplantation Extracorporeal liver support devices: - Hemodiadsorption systems - Bioartificial liver devices Nonhuman liver transplantation Hepatocyte transplantation