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

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

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

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

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!!!

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)

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

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

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

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

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

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

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

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

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

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

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?

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

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

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 mEq/L

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

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

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

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!!!

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

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

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

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

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)

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

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

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)

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

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

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

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

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

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