אי ספיקת כבד חריפה Acute Liver Failure

אי ספיקת כבד חריפהAcute Liver Failure פרופ' ריפעת ספדי מנהל היחידה למחלות כבד מרכז רפואי הדסה ע"כ, י"ם 17/2/2013 safadi@hadassah.org.il

אי ספיקת כבד חריפהAcute Liver Failure (ALF) FULMINANT HEPATIC FAILURE: (FHF) FULMINANT HEPATITIS: (FH)

FULMINANT HEPATIC FAILURE: (FHF) • Definition: • Acute hepatic failure within: • 0-1 week (Hyperacute) • 1-4 weeks (Acute) • 4-12 weeks (Subacute) • Manifestations: • Hepatic encephalopathy, INR↑

Hepatic Encephalopathy (HE) • HE is a serious & potentially fatal complication in: • Acute liver failure • Cirrhosis • Portal-systemic Shunt w/o hepatocellular disease • Metabolic Defects

Encephalopathy- Grades • 1. Minor disturbances of consciousness or motor function • 2. Drowsy but responsive to commands • 3. Stuporous but responsive to pain • 4. Unresponsive to pain • Seizures may appear at any grade

HE spectrum: Minimal HE (MHE) to overt HE with risk of cerebral edema & death West-Haven criteria

Coagulopathy • Low levels of coagulation factors: • Factor 2 • Factor 7 • Factor 9 • Factor 10 • Disturbed vit. K absorption (cholestasis) • Thrombocytopenia/pathia

FULMINANT HEPATIC FAILURE: MAJOR COMPLICATIONS: • Cerebral edema • Bleeding • Sepsis • Renal failure • Respiratory failure • Metabolic acidosis • Hypoglycemia • Pancreatitis

ETIOLOGY (With Therapeutic Implications) • Acetaminophen • Drugs – prescription, recreational • Viral - HAV, HBV, HDV, HEV; CMV, EBV, VZV, HSV, Parvovirus, • Enteroviridae • Poisoning – Amanita phalloides • Wilson’s disease • Autoimmune hepatitis • Acute fatty liver of pregnancy / HELLP • Budd Chiari Syndrome • Miscellaneous – Acute ischemic injury, malignant • infiltration, sepsis. • Indeterminate AASLD Position Paper: The Management of Acute Liver Failure Polson & Lee, Hepatology 2005; 41: 1179-97

FULMINANT HEPATIC FAILURE: (FHF) Prescribed medicines “ACAMOL”

ETIOLOGY Acetaminophen: 45% suicidal 55% accidental

ETIOLOGY – “OTHER”

FHF- Course: Recovery Transplantation Fulminant Hepatitis Death

Which patients are LT candidates? ALF Etiology Clinical course Progression rate King’s College Criteria Deterioration? LTx

Rating Scheme for the Strength of the Evidence Grade I: Randomized controlled trials Grade II-1: Controlled trials w/o randomization Grade II-2: Cohort/ case-control analytic studies Grade II-3: Multiple time series, dramatic uncontrolled experiments Grade III: Opinions of respected authorities, descriptive epidemiology Decision-Making

Diagnosis & Initial Evaluation • ALF Patients should be admitted & monitored frequently, preferably in an ICU(Grade III). • Contact with a transplant center & plans to transfer appropriate patients with ALF should be initiated early (Grade III). • The precise etiology of ALF should be sought to guide further management decisions (Grade III).

בדיקות דם • ביוכימיה: • אלקטרו', סוכר, ת' כליה • TP Albumin • אנזימי כבד הפטוצליולרים: ALT AST הפרעה הפטוצליולרית • אנזימי כבד כולסטטים: gGT ALK-PhosBilirubin הפרעה כוליסטטית • סד'/ ת' קרישה • מיטבולי: TSH FerritinCeruloplasmina1AT ACE • סירולגיה נגיפית: נגיפים היפטו/לימפוטרופים • סירולוגיה אמונית ANA AMA LKM ASMA ANCA ASCA IG PEP IEP CELIAC

כלים זמינים לאבחון הדמייה: • לא חודרנית: US /CT /MRI /MRCP • חודרנית: ERCP/ אנגיוגרפיה ± חודרנית ביופסיה אנדוסקופיות:להערכת דליות... לפרוסקופיה: ביופסיות מכוונות/ עמוקות...

Role of transjugular liver biopsy in ALF Hepatology 1993;18:1370 • 61 ALF pts., 2 to 82 yr, retrospectively analyzed. • Transjugular biopsy was successful in 60/61. • 8 minor complications managed conservatively. • In 34/54 (63%), the presumed clinical diagnosis was confirmed by biopsy. • In 11 (20%), biopsy clarifies clinical uncertainty • In 9/54 (17%) the diagnosis was altered by biopsy

טיפולTherapy אי ספיקת כבד חריפהAcute Liver Failure (ALF) FULMINANT HEPATIC FAILURE: (FHF)

Hepatic Encephalopathy Pathogenesis NH3 Toxins NH3 Shunting GABA-BD receptors Failure to metabolize NH3 The Gut Microbiota (Bacterial action) & Protein load

HE Treatment Flumazenil nMDR inhibition • ↑ NH3 fixation in liver: • L-ornithine L-asprtate (LoLa) • BCAA • Benzoate Shunt occlusion or reduction • ↓ Gut NH3 production: • Adjust diet protein • Lactulose & Lactilol • Antibiotics • Probiotics

Encephalopathy- Aggravating Factors • Gastrointestinal hemorrhage • Hypovolemia • Potassium depletion • Hypoglycemia • Uremia • Infection • Constipation • Sedatives and anaesthetics • High protein intake

Conservative management • Grade I/II Encephalopathy • Consider transfer/listing to liver transplant facility • Brain CT: rule out other causes • Avoid stimulation, avoid sedation • Lactulose: possibly helpful

Hemodynamics/Renal Failure • Pulmonary artery catheterization • Volume replacement • Pressor support • Avoid nephrotoxic agents • Continuous modes of hemodialysis if needed • Vasopressin: not helpful; potentially harmful • Metabolic Concerns • Follow closely: glucose, K+, Mg++, Phosphate • Consider nutrition: enteral feedings or TPN

Infection • Periodic surveillance cultures to detect bacterial & fungal infections (Grades II-2, III). • Antibiotic prophylaxis possibly helpful but not proven (Grades II-2, III). • Coagulopathy • Replacement therapy (PLT/FFP): • only in the setting of hemorrhage • or prior to invasive procedures • (Grade III). • Gastrointestinal (GI) Bleeding • Prophylaxis for bleeding associated with stress • (Grades I, III).

CNS & Intracranial Pressure Monitoring • Grade III/IV Encephalopathy • Intubate trachea • Consider placement of ICP monitoring • Immediate treatment of seizuresrequired; prophylaxis of unclear value • Mannitol: use for severe elevation of intracranial pressure or first clinical signs of herniation • Hyperventilation: effects short-lived; may use for impending herniation

Acetaminophen Hepatotoxicity • With known/suspected overdose within 4h, give activated charcoal just prior to NAC (Grade I). • Begin NAC promptly in all patients where the quantity of acetaminophen ingested, serum drug level, or rising aminotransferases indicate impending or evolving liver injury (Grade II-1). • NAC may be used in cases of ALF in which acetaminophen ingestion is possible or when knowledge of circumstances surrounding admission is inadequate (Grade III).

NAC for non-acetaminophen-induced ALF • MEDLINE search (1966-March 2003) • International Pharmaceutical Abstracts (1970-2003) • Cochrane Library (2003, issue 3) databases. • All studies were small & do not provide conclusive evidence that NAC benefits this subgroup of patients. • IV NAC should not be used routinely for treatment of non-acetaminophen-induced ALF. Ann Pharmacother. 2004 Mar;38(3):498

Viral Hepatitis HAV, HBV, HEV related ALF must be treated with supportive care (Grade III). Lamivudine is safe in patients with severe acute or fulminant hepatitis B, leading to fast recovery with the potential to prevent liver failure and liver transplantation when administered early enough. • Schmilovitz-Weiss H, et al. Lamivudine treatment for acute severe hepatitis B: a pilot study-15.Liver Int. 2004. • Tillmann HL, et al.Safety & efficacy of lamivudine in 17 patients with severe acute or fulminant HBV, a multicenter experience.J Viral Hepat. 2006.

Wilson's disease or AIH? • Patients with AIH may be salvaged by steroid treatment. • On the contrary, liver transplantation is currently the only life saving therapeutic option available for patients with WD who present with fulminant liver failure

Budd-Chiari Syndrome • BCS with hepatic failure is an indication for liver transplantation, provided underlying malignancy is excluded (Grade II-3).

Mushroom Poisoning • Consider penicillin G & silymarin(Grade III). • Should be listed for transplantation(Grade III). • Drug Induced Hepatotoxicity • Obtain details concerning all drugs, herbs & dietary supplements taken (Grade III). • Determine ingredients of non-prescription medications whenever possible (Grade III). • Discontinue all but essential medications (Grade III) • Steroids?

Kings College selection criteria for transplantation according to etiology of FLF

Kings College selection criteria for transplantation according to etiology of FLF • Aetaminophen: • Arterial pH< 7.3 • Or • PT>100 sec & Serum Creatinine > µ300 mol/l when Encephalopathy grade III or IV.

Kings College selection criteria for transplantation according to etiology of FLF • Not Aetaminophen: • PT>100 sec (irrespective of Encephalopathy grade). • Or • Any 3 of the following (irrespective of Enceph. grade): • Age < 10 or > 50 years • Cryptogenic, halothane or other drug toxicity • Jaundice to Encephalopathy interval > 7 days. • Serum Bilirubin > 300 µmol/l

Waiting list: • Air Transportation • Liver support technology • Living related transplantation • Auxiliary liver transplantation

Long-distance transportation of 43 patients with liver diseases is safe & feasible Liver Transpl 2005;11:650(Grade II-III).

ALF- Referral Centers 1987-1998: Total 46 cases USA, Germany (n=2) 4%

ALF- Referral Centers 1999-2006: Total 21 USA, China (n=2) 10%

Waiting list: • Air Transportation • Liver support technology • Living related transplantation • Auxiliary liver transplantation

Liver Support Systems: • A variety of systems have been tested to date, with no certain evidence of efficacy. • Sorbent systems: • Detoxification, no hepatocyte replacement. • Such systems, may show loss of platelets & worsening of coagulation across the device. • Transient improvement of encephalopathy may be observed but no long-term benefit

Hepatocytes (w or w/o sorbents): • Few controlled trials • Some reports suggest no benefit to outcome, ±transplantation (HEPATOL 1996;24:1446). • A multi-center trial did report improved short-term survival with a porcine hepatocyte-based bioartificial liver (Ann Surg 2004;239:660). • A recent meta-analysis, considering all forms of devices together: no efficacy for bio-artificial liver devices for the treatment of ALF (Kjaergard LL, et al. JAMA 2003;289:217).

MARS

אי ספיקת כבד חריפה Acute Liver Failure