Approach to Acute liver Failure

Approach to Acute liver FailureBader Alenezi, MDChairman of Internal MedicineJahra HospitalConsultant Gastroenterolgy & Hepatology

Outlines Definition Acute Liver failurecommon causes of ALF Acetaminophen toxicityDiagnosis and Initial Evaluation ALFManage complications of ALF Identify prognostic criteriaFuture therapy in ALF

Recognize ALF and some common causesID prognostic criteria when is xplant indiciatedList and manage common complications of ALFDescribe the mechanism of acetaminophen toxicity and apply timely and appropriate interventionsIdentify interventions that improve outcome in viral ALFIdentify common drugs that can lead to ALF and describe the management

3Acute liver Failure (ALF)Rare Represent the most sever form of liver injuryHard to treat Difficult to studyAcute liver FailureFulminant hepatitisFulminant hepatic failureSubfulminant liver failureSubacute hepatic necrosisSubacute liver failureHyperacute liver failure

ALF: DefinitionThe original term fulminant hepatic failurea severe liver injury, potentially reversible in nature and with onset of hepatic encephalopathy within 8 weeks of the first symptoms in the absence of pre-existing liver disease,

Trey C , Davidson CS. The management of fulminant hepatic failure. Prog Liver Dis 1970;3:282-98ALF: Definition The most widely accepted definition of ALF:

Coagulation abnormality, usually an INR >1.5, and any degree of mental alteration (encephalopathy) without preexisting cirrhosis and with an illness of 1.5Altered mental statusIllness of < 26 weeks duration

Hyperacute < 7 daysAcute 7-21 daysSubacute > 21 days and < 26 weeks

Fulminant (2 wks) vs subfulminant (2-12 wks)Acute liver failure used interchangeably w/ fulminant liver failure

This schema has fallen out of favor as it does not have prognostic significance distinct from other causes of illness. Hyperacute has better prognosis, but only because it is usually due to acetaminophen toxicity.Old definition included jaundice.9ALF: CausesAcetaminophen 39%Indeterminite 17%Idiosynchratic drug rxns 13%Viral hepatitis 12%HBV > HAV > HEV, HSVAutoimmune 4-5%Wilsons Disease 2-3%Mushroom PoisoningHerbal MedicationsVascularBud-ChiarriIschemicHepatic Vein Thrombosis

Reyes SyndromeFatty Liver of PregnancyHELLPOn the left: most common, in order of decreasing incidenceOn the right: other causes

Another categorization of drugs is into dose-dependent, idiosyncratic and hypersensitivity10U.S. ALF STUDY GROUP 2002 (308 Patients, 73% Women)

ALF: CausesALF in developed world 150 mg/kg) Doses as low as 3-4 gm/day rarely causes ALFVery high aminotransferase levels Serum levels exceeding 3,500 IU/L are highly correlated with acetaminophen poisoning low or absent levels do not rule out hepatotoxicity (remote ingestion or over several days) Rumack-Matthew Nomogram

Used to interpret plasma acetaminophen values to assess hepatotoxicity risk after a single, acute ingestionNomogram tracking begins 4 hours after ingestion (time when acetaminophen absorption is likely to be complete) and ends 24 hours after ingestion About 60% of patients with values above the "probable" line develop hepatotoxicity

Rumack-Matthew Nomogram

The standard acetaminophen toxicity nomogram may aid in determining the likelihood of serious liver damage can not be used if: 1- multiple doses over time2- when the time of ingestion is unknown3- When altered metabolism occurs such as in the alcoholic or fasting patient Larson AM. Acetaminophen hepatotoxicity. Clin Liver Dis. 2007;11: 525-48. Lee WM. Drug-Induced Hepatotoxicity. N Engl J Med 2003;349: 474-485.Treatment of Acetaminophen HepatotoxicityActivated charcoal for gastrointestinal decontamination best if given within 1hr of ingestion may be of benefit as long as 3 to 4 hours after ingestion. Administration of activated charcoal (standard dose 1 gm/kg orally) just prior to administration of N-acetylcysteine does not reduce the effect of N-acetylcysteine.

Sato RL,et al Efficacy of superactivated charcoal administration late (3 hours) after acetaminophen overdose. Am J Emerg Med 2003;21:189-191.Treatment: N-acetylcysteine (NAC)N-acetylcysteine (NAC), the antidote for acetaminophen poisoning effective and NAC should be given as early as possibleNAC is nearly 100% hepato protective when it is given within 8 hours but may still be of value 48 hours or more after ingestion

N-acetylcysteine (NAC)NAC orally (140 mg/kg by mouth or nasogastric tube diluted to 5% solution, followed by 70 mg/kg by mouth q 4 h x 17 doses) Oral administration has largely been replaced by intravenous administration (loading dose is 150 mg/kg in 5% dextrose over 15 minutes; maintenance dose is 50 mg/kg given over 4 hours followed by 100 mg/kg administered over 16 hours or 6 mg/kg/hr) N-acetylcysteine (NAC)Use of the IV formulation of NAC is preferred in the following situations:Altered mental statusGI bleeding and/or obstructionA history of caustic ingestionPotential fetal acetaminophen toxicity in a pregnant womanInability to tolerate oral NAC because of emesis refractory to proper use of antiemeticsWilson diseaseuncommon cause of ALF (2% to 3% of cases in the U.S.Early identification is critical because the fulminant presentation of Wilson disease is considered to be uniformly fatal without transplantationyoung patients with Coombs negative hemolytic anemia with serum bilirubin levels >20 mg/dLKayser-Fleischer rings are present in about 50% of patientsWilson diseaseSerum ceruloplasmin is typically low, but may be normal in up to 15% of cases and is reduced in ~50% of other forms of ALF.High plasma and urinary copper levels as well as hepatic copper measurement will confirm the diagnosis.Very low serum alkaline phosphatase or uric acid levels A high bilirubin to alkaline phosphatase ratio (>2.0) is a rapid, reliable indicator of Wilson disease

Wilson diseaseRx:penicillamine is not recommended in ALF due to risk of hypersensitivityrecovery is very rare absent transplantation.Patients must be promptly considered for liver transplantation (AASLD recommendation 2011)Autoimmune Hepatitis unrecognized preexisting chronic disease and yet still be considered as having ALF. AIH patients that develop ALF represent the most severe form of the disease.Autoantibodies absent (up to 30% of cases)Liver biopsy should be considered if autoimmune hepatitis is suspected and autoantibodies are negativeRecommended to receive corticosteroid therapyALF in PregnancyAcute Fatty Liver of Pregnancy/HELLP (Hemolysis, Elevated Liver Enzymes, Low Platelets) SyndromeNear the end of pregnancy will develop rapidly progressive hepatocyte failure.Increased fetal or maternal mortality.Triad of jaundice, coagulopathy, and low plateletsHypoglycemia and Features of pre-eclampsia are commonTransplantation may need to be considered if hepatic failure does not resolve quickly following delivery Budd-Chiari SyndromeAcute hepatic vein thrombosis Abdominal pain, ascites and striking hepatomegaly Diagnosis confirmed with hepatic imaging studies (computed tomography, Doppler ultrasonography, venography, magnetic resonance venography) Prognosis is poor Liver transplantation is indicated, provided underlying malignancy is excludedBudd-Chiari Syndrome

Ischemic Hepatitis and ALF Liver cell necrosis - massive Cardiac tamponade Acute heart failure Pulmonary embolus Hepatic artery thrombosis

Poisoning and ALFAmanita mushrooms (amanatoxins) - LD = 50 gms (3 mushrooms) - Toxins not destroyed by cooking - Rapid onset of HE in 4-8 days following severe emesis and diarrhea

Solvents - chlorinated hydrocarbons

Herbal remedies

Yellow phosphorus

Diagnosis and Initial Evaluation ALFIn all patients with clinical or laboratory of acute hepatitis PT and careful evaluation for subtle alterations in mentation should done If PT is prolonged by ~4-6 seconds or more (INR >1.5) and there is any evidence of altered sensorium, the diagnosis of ALF is established and hospital admission is mandatory.Transfer to intensive care unit (ICU) and contact with a transplant center if indicatedDiagnosis and Initial Evaluation ALFPhysical Exam:Determine presence or absence of pre-existing liver diseaseHepatic tendernessHepatic decompensation

Diagnosis and Initial Evaluation ALFHISTORY: Family members with liver disease? Recent cold sores Onset of jaundice Work environment- toxic agents Hobbies Herbal products/dietary supplements

Initial Laboratory Analysis

Prothrombin time/INR Chemistries Liver enzymes Arterial blood gas Acetaminophen level Toxicology screenViral hepatitis serologies (anti-HAV IgM, HBsAg, anti-HBc IgM, anti-HEV, anti-HCV, HCV RNA , HSV1 IgM, VZV)Initial Laboratory AnalysisCeruloplasmin level Pregnancy test (females) Ammonia (arterial if possible) Autoimmune Markers (ANA, ASMA, Immunoglobulin levels ) Liver Biopsy reserved for diagnostic dilemma (Transjugular approach)

Liver biopsy in ALF

Complications of Acute Liver Failure:CNS disturbancesHepatic encephalopathyCerebral edemaHemodynamic CollapseInfectionsCoagulopathy and bleedingRenal failureMetabolic derangements

Cerebral EdemaThere is increasing evidence that ammonia plays an important role in the pathogenesis of cerebral edema/ ICH arterial ammonia level >200 ug/dL cerebral herniation; rarely if 60mmHgICP < 20mmHgIntracranial Pressure

CPP = MAP ICPCPP< 60mmHgICP < 20mmHgCerebral Edema/Intracranial HypertensionGrade I/II Encephalopathy Consider transfer to liver transplant facility and listing for transplantation Brain CT: rule out other Avoid stimulation; avoid sedation if possible Antibiotics: surveillance and treatment of infection required; prophylaxis possibly helpful Lactulose, possibly helpfulGrade III/IV EncephalopathyIntubate trachea Elevate head of bed Consider placement of ICP monitoring device Immediate treatment of seizures required; prophylaxis of unclear value Mannitol: use for severe elevation of ICP or first clinical signs of herniation Hypertonic saline to raise serum sodium to 145-155 mmol/L Hyperventilation: effects short-lived; may use for impending herniation

Infection

Surveillance for and prompt antimicrobial treatment of infection required

Antibiotic prophylaxis possibly helpful but not provenProphylactic antibiotics and antifungals have not been shown to improve overall outcomes in ALFCoagulopathyVitamin K: give at least one dose FFP: give only for invasive procedures or active bleeding Platelets: give only for invasive procedures or active bleeding Recombinant activated factor VII: possibly effective for invasive procedures Prophylaxis for stress ulceration: give H2 blocker or PPIHemodynamics/Renal FailureVolume replacement Pressor support (dopamine, epinephrine, norepinephrine) as needed to maintain adequate mean arterial pressure Avoid nephrotoxic agents Continuous modes of hemodialysis if needed Vasopressin recommended in hypotension refractory to volume resuscitation and norepinephrineMetabolic ConcernsFollow closely: glucose, potassium, magnesium, phosphate Consider nutrition: enteral feedings if possible or total parenteral nutritionWhat are the potential outcomes?1. Recovery because of a successful interventionNAC for acetaminophen toxicityAntivirals for acute hepatitis B

2. Spontaneous recovery with supportive care3. Death

4. Rescue by liver transplantAssuming we dont have a proven intervention (#1), how do we differentiate between the others, thereby avoiding #3?Give everyone transplantsDifferentiate which patients will die if not transplanted and give a transplant to these patients52Predicting Outcomes in Acute Lifer FailureMost important predictive factors:Degree of encephalopathy

Suggested laboratory markers: Factor VAFPSerum Phosphate VII/V ratio > 30Gc globulin

Clinical algorithms:Kings College Criteria APACHE IIGrade II encephalopathy: 65-70%Grade IV: < 20%

Source 1I: trivial lack of awareness, slight tremorII: lethargy or apathy, disorientation, personality change, asterixisIII: somnolence to semi-stuporIV: coma, decerebration

Some markers: serum phosphate are only used in acetaminophen toxicity53Prognosis and Transplantationoverall mortality has improved to between 30-40%Transplant free-survival was >50% in acetaminophen, hepatitis A, shock liver, or pregnancy-related disease.other etiologies showed 3.5 mmol/L after early fluid resuscitation List for OLT if: pH3.0 mmol/L after adequate fluid resuscitationList for OLT if all 3 occur within a 24-hour period: 1- presence of grade 3 or 4 hepatic encephalopathy 2- INR >6.5 3- Creatinine >3.4 mg/dLKings College Criteria Non-acetaminophen:INR > 6.5 ORAny 3 of the following 5:Age < 10 or > 40Serum bilirubin > 18Jaundice to encephalopathy interval > 7 daysINR > 3.5Unfavorable EtiologyNon-A, non-B hepatitis, halothane, idiosyncratic drug reaction, WilsonsHistory: developed from a series of 588 patients w/ acute liver failure who were managed without transplant between 1973 and 1985. 2 parts.

Etiology: this includes other viral cuases: HSV or any other cuases: Wilsons, Pregnancy etc58AASLD RecommendationCurrently available prognostic scoring systems do not adequately predict outcome and determine candidacy for liver transplantation. Reliance entirely upon these guidelines is thus not recommended.(III)

AASLD Position Paper: The Management of Acute Liver Failure: Update 2011 William M. Lee, MD, Anne M. Larson, MD, and R. Todd Stravitz, MD

Liver Transplantation Urgent hepatic transplantation is indicated in acute liver failure where prognostic indicators sug- gest a high likelihood of death (II-3). Living donor or auxiliary liver transplantation may be considered in the setting of limited organ supply, but its use remains controversial

AASLD Position Paper: The Management of Acute Liver Failure: Update 2011 William M. Lee, MD, Anne M. Larson, MD, and R. Todd Stravitz, MD

Future therapy

Future therapy extracorporeal liver-assist devices:Nonbiologic dialysis-based systems for systemic detoxification Bioartificial devices that incorporate hepatic cells of porcine or human origin to replace both detoxification and synthetic functions.A multicenter RCT showed no survival benefit. Saliba F, et al. Ann Intern Med 2013;159:522-31Future therapy Liver Support Systems:Currently available liver support systems are not recommended outside of clinical trials; their future in the management of acute liver failure remains unclear

Future therapy Hepatocyte transplantationIntraportal & intraperitoneal infusion of isolated human hepatocytesSome success in neonates and children with inborn errors of metabolismLimited experience in pediatric acute liver failure Remains experimental.

Hughes RD,et al Current status of hepatocyte transplantation. Transplantation 2012;93:342-7.

Summary Management of ALF is real challenge for the treating teamALF should be treated in ICUTreatments for specific etiologiesConsideration of transplantation should be under-taken urgently