ACUTE LIVER FAILURE

Acute Liver Failure

Acute liver failure = fulminant hepatic failure Definition
Acute onset of liver disease with coagulopathy Development of hepatic encephalopathy No prior evidence of liver disease

Friedman and Keeffe EB. Handbook of Liver Disease 2004

Definitions of ALF in Current Use

France (Bernuau et al)
Trigger event Term Time to encephalopathy Term Time to encephalopathy Term Jaundice Fulminant hepatic failure 2 weeks Subfulminant hepatic failure 3-12 weeks

UK (OGrady et al)
Jaundice Hyperacute liver failure < 7 days Acute liver failure 8-28 days Subacute liver failure

Time to encephalopathy

29-84 days

Weinstein WM, Hawkey CJ and Bosch J. Clin Gastroenterol and Hepatol 2005

Bacon BR and et al. Comprehensive Clin Hepatol 2006

Etiology of ALF
Common Hepatitis A Hepatitis B Seronegative hepatitis Acetaminophen Idiosyncratic drug reactions Uncommon Wilson disease Infections : EBV, CMV, Herpes Vascular abnormalities Acute fatty liver of pregnancy AIH Malignant infiltration Ischemic hepatitis Toxins : Amanita phalloides

Weinstein WM, Hawkey CJ and Bosch J. Clin Gastroenterol and Hepatol 2005

Non-paracetamol-based Drugs Causing Acute Liver Failure

Bernal W et al. Lancet 2010;376:190-201

Initial Evaluation of ALF

History Medications Recreational drugs Prodome Travel Alcohol Past medical history Physical examination Vital signs Size of liver Mental status Rash

Weinstein WM, Hawkey CJ and Bosch J. Clin Gastroenterol and Hepatol 2005

Clinical Features of ALF

Whole body
Systemic inflammatory response High energy expenditure and catabolism Loss of metabolic function Decreased gluconeogenesis leading to hypoglycemia Decreased lactate clearance leading to lactic acidosis Decreased ammonia clearance leading to hyperammonaemia Decreased synthetic capacity leading to coagulopathy Acute lung injury ARDS Inadequate slucocorticoid production contributing to hypotension Frequent suppression, especially in viral and seronegative disease

Liver

Lungs

Adrenal gland

Bone marrow

Bernal W et al. Lancet 2010;376:190-201

Clinical Features of ALF

Circulating leucocytes
Impaired function and immunoparesis contributing to high risk of sepsis Hepatic encephalopathy Cerebral edema Intracranial hypertension High output state Frequent subclinical myocardial injury Particularly in paracetamol-related ALF Frequent dysfunction or failure Might be prominent in subacute disease and confused with chronic liver disease

Brain

Heart

Pancreatitis

Kidney Portal hypertension

Bernal W et al. Lancet 2010;376:190-201

Laboratory Studies
To identify cause of ALF Anti-HAV IgM HBsAg, Anti-HBc IgM Anti-HDV (if HBsAg positive) Drug screen ANA, SMA Serum ceruloplasmin, serum copper To assess severity PT, bilirubin, albumin ABG for arterial pH To assess complications Serum creatinine Chest X ray Electrolytes, blood sugar Arterial ammonia Laboratory for OLT listing Anti-HIV Anti-CMV, EBV EKG Blood type and crossmatch

Weinstein WM, Hawkey CJ and Bosch J. Clin Gastroenterol and Hepatol 2005

Clinical Stages of Hepatic Encephalopathy in ALF

Grade 0 1 2 3 4 Symptoms Normal Lack of awareness, short attention span, altered sleep pattern Agitation, lethargy, seizures Asleep, arousable by pain Unarousable Signs Normal Tremor, asterixis Asterixis, hyperreflexia Hyperreflexia Babinski, ankle clonus, decerebrate posture EEG Normal Symmetric slowing Symmetric slowing, triphasic waves Triphasic waves Delta (very slow) activity

Boyer TD, Wright TL and Manns MP. Zakim and Boyers Hepatology 2006

Management
Treatment Etiology Acetaminophen Hepatitis B Amanita phalloides Herpes simplex virus HELLP syndrome Autoimmune hepatitis Drug N-Acetylcysteine Lamivudine, Adefovir Penicillin G, N-Acetylcysteine Acyclovir Fetus delivery Steroids

Acute fatty liver of pregnancy Fetus delivery

Weinstein WM, Hawkey CJ and Bosch J. Clin Gastroenterol and Hepatol 2005

Paracetamol Poisoning
2 forms Single overdose exceed 7-10 g Repeated supratherapeutic ingestion (therapeutic misadventure)
Daily ingestion 10-20 g over three days Risk: malnourished, heavy alcoholic drinkers, drugs (phenobarbital, phenytoin, isoniazid, and zidovudine)

Paracetamol Poisoning
Categorized into 4 stages Preclinical toxic effects (normal serum ALT) Hepatic injury (elevated ALT) Hepatic failure (hepatic injury with hepatic encephalopathy) Recovery

Metabolism of Acetaminophen

The Rumack-Matthew Nomogram

Current FDA-approved Protocols

Oral Acetylcysteine Loading 140 mg/kg and repeat 70 mg/kg every 4 hours for a total 17 doses Intravenous Acetylcysteine Loading 150 mg/kg over a period of 15-60 minutes, followed by an infusion of 12.5 mg/kg over a 4-hour period, and finally an infusion of 6.25 mg/kg over 16-hour period

Hepatitis B

Features to Differentiate Acute Exacerbation of CHB from Acute HBV

Exacerbation of CHB Useful Features History Anti-HBc IgM titer Past or family history of CHB Negative or low (<1:1000) Recent sexual, blood, or percutaneous exposure to HBV High (1:1000) Acute Hepatitis B

HBV DNA level

Histology Follow-up HBsAg after 6 months

High (100,000 copies/mL)

Evidence of chronicity Positive

Low (<100,000 copies/mL)

No evidence of chronicity Negative (in more than 95% of patients)

Wong VWS, Chan HLY. J Gastroenterol Hepatol. 2009;24:1179-1186.

Serologic Profile of Acute HBV versus Exacerbation of CHB

Kumar M, et al. Dig Dis Sci. 2006;51:594-599.

Serum HBV DNA in Acute HBV versus Exacerbation of CHB

0.5 pg/mL 140,000 copies/mL or 25,000 IU/mL Kumar M, et al. Dig Dis Sci. 2006;51:594-599.

Features to Differentiate Acute Exacerbation of CHB from Acute HBV

Exacerbation of CHB Features of Uncertain Value Basal core promoter mutation Precore stop codon mutation Not Useful Features Symptoms and signs ALT levels Prodromal symptoms Jaundice and itching Abdominal discomfort Very high Prodromal symptoms Jaundice and itching Abdominal discomfort Very high Present Absent Acute Hepatitis B

Present

Absent

Wong VWS, Chan HLY. J Gastroenterol Hepatol. 2009;24:1179-1186.

LAM Therapy in Severe Acute HBV

Author, year
Patients (no.)
10 5 10 15

Study Design
Retrospective Prospective Prospective Prospective

HBsAg Loss
NA 100% 90% 73% (only 11 tested) 82% (NA for historic untreated) 92.5% vs 93.5% in untreated group at 1 yr

Anti-HBs Gain
NA 40% NA 60% (only 9 tested)

Survival
70% (vs 26%) 100% 90% 87% 82% vs 20% in historic controls 100% vs 100% in untreated group

Miyake et al, 2008 Lisotti et al, 2008 Delic et al, 2009 Schmilovitz-Weiss et al, 2004

Tillmann et al, 2006

17

Prospective, historic controls

NA

Kumar et al, 2007

31

Prospective, RCT

67.7% vs 85% in untreated group at 1 yr

Te HS. Curr Hepatitis Rep. 2010;9:119-123.

AASLD Guideline regarding Treatment of Acute Severe Hepatitis B

Recommendations for Treatment of Patients with Acute Symptomatic Hepatitis B: 1. Treatment is only indicated for patients with fulminant hepatitis B and those with protracted, severe acute hepatitis B. 2. Lamivudine or telbivudine may be used when the anticipated duration of treatment is short; otherwise, entecavir is preferred. 3. Treatment should be continued until HBsAg clearance is confirmed or indefinitely in those who undergo liver transplantation.

Lok A, McMahon BJ. Hepatology. 2009;50:661-662.

Wilson Disease

Wilson Disease
Autosomal recessive Impaired biliary excretion of copper Progressive accumulation of copper in various organs include liver, brain, cornea Prevalence 1:30,000 50,000 , equivalent among all ethnic groups

Gitlin JD. Gastroenterology 2003;125:1868-1877

Bacon BR et al. comprehensive Clin Hepatol 2006

Clinical Manifestation
Hepatic
Neurological Psychiatric Ocular Hematological Musculoskeletal Renal Cardiac Endocrine
Acute fulminant hepatitis, steatosis, chronic hepatitis
Extrapyrimidal, cerebellar manifestation

Depression, mania, delusions

KF ring, sunflower cataract Hemolysis, thrombocytopenia Osteoporosis, rickets, chondrocalcinosis Renal tubular acidosis, nephrolithiasis

Arrhythmias, cardiomyopathy
Hypoparathyroidism, delayed puberty

Clinical Features
Hepatic 20 40 Neurologic Psychiatric 10 Mixed form 30

Knawy BA et al. Hepatology : A practical approach 2004

Hepatic Form
Acute wilsonian hepatitis and fulminant wilson disease Indistinguishable from other forms Female : male = 2-3 : 1 AST, ALT not increase above 10 times Coomb s negative hemolysis
Alkaline phosphatase total bilirubin ratio below 2 suggestive fulminant hepatitis
Bacon BR et al. Comprehensive Clin Hepatol 2006

Hepatic Form
Chronic hepatitis Young patients (8-18 years) Nonspecific and mimics manifestations of chronic liver disease due to other causes Liver biopsy moderate steatosis, glycogen vacuolation of nuclei in periportal

Bacon BR et al. Comprehensive Clin Hepatol 2006

Neurologic Form
Develop in mid teens or in the 20 s Well documented in 45-55 years Initial mild tremor, speech and writing problem then progressive movement disorder Common symptoms dysarthria, dysphagia, apraxia and tremor-rigidity syndrome
Bacon BR et al. Comprehensive Clin Hepatol 2006

Psychiatric Form
Reduced school or work performance Depression, very labile mood Sexual exhibitionism Frank psychosis

Bacon BR et al. Comprehensive Clin Hepatol 2006

Kayser-Fleischer Rings
Superior

50% in hepatic form

90% in neurologic form

Lateral Inferior
Tanner MS. Comprehensive Clin Hepatol 2000; 21.1-21.12

Sunflower Cataract

Tanner MS. Comprehensive Clin Hepatol 2000; 21.1-21.12

Bacon BR et al. Comprehensive Clin Hepatol 2006

Roberts EA and Schilsky ML. Hepatology 2008

Tests for Diagnosis of Wilson Disease

Bacon BR et al. Comprehensive Clin Hepatol 2006

Management of Wilson Disease

1. 2. 3. 4. Initial therapy Maintenance therapy Non-pharmacologic management Family screening

Brewer GJ and Askari FK. J Hepatol 2005;42:S13-S21

Initial Therapy
Drug
Penicillamine (plus pyridoxine) Trientine Tetrathiomolybdate (TM)

Dose
1-2 gm/day

Side effect
Hypersensitivity reactions, BM suppression, SLE, Goodpastures syndrome Same side effect as penicillamine, but lessor, proteinuria BM suppression

1-2 g/day

60-120 mg/day

Zinc acetate

150-300 mg/day

Gastric irritation

Brewer GJ and Askari FK. J Hepatol 2005;42:S13-S21

Diagnosis Established Patient Classification For Initial Therapy

Presymptomatic
Treatment Recommendations 1. Zinc 2. Trientine

Neurologic/Psychiatric Treatment Rec. 1. TM + Zinc 2. Zinc or Trientine + Zinc Liver Failure Mild or Moderate (Nazer scope up to 7) Severe (Nazer scope over 7)

Hepatic

Transaminase Elevations Only Treatment Rec. 1. Zinc 2. Trientine

Treatment Rec. 1. Trientine + Zinc 2. Penicillamine + Zinc

Treatment Rec. 1. transplantation

Maintenance Therapy
For maintenance and therapy of presymptomatic and pregnant patient First choice : Zinc Second choice : Trientine

Brewer GJ and Askari FK. J Hepatol 2005;42:S13-S21

Non-pharmacologic Management
Diet Avoid chocolate, liver and shellfish Drinking water Use water with copper below 0.1 ppm (parts per million)

Brewer GJ and Askari FK. J Hepatol 2005;42:S13-S21

Management
General management Full hemodynamic monitoring ET tube for stage 3 encephalopathy
Airway protection Provision of respiratory support Management of intracranial hypertension

Parenteral glucose (D10 or 20) to prevent hypoglycemia

Boyer TD, Wright TL and Manns MP. Zakim and Boyers Hepatology 2006

Management
Correct electrolyte and acid-base disorders
Hyponatremia and hypernatremia Hypokalemic alkalosis Hyperkalemic acidosis

Nutrition enteral or parenteral route

Caloric goal : 35-40 Kcal/day Protein : 40 gm/day
Boyer TD, Wright TL and Manns MP. Zakim and Boyers Hepatology 2006

Management
Prevention of bleeding
Administration of vitamin K H2 blocker, PPI or sucralfate to prevent GI bleeding

Renal insufficiency: oliguria

Continuous arteriovenous or venovenous hemofiltration Minimize hypotension, decreased cerebral edema compare to standard hemodialysis
Boyer TD, Wright TL and Manns MP. Zakim and Boyers Hepatology 2006

Prevention and Management of Infection

16% 12% Chest Urinary tract 50% 22% IV catheter Blood only

Boyer TD, Wright TL and Manns MP. Zakim and Boyers Hepatology 2006

Prevention and Management of Infection

Prophylactic antibiotics reduce infections Cultures and microbiological screening Third-generation cephalosporin IV Fungal infections were suspected in patients
High fever unresponsive to antibiotics Profound leukocytosis

Boyer TD, Wright TL and Manns MP. Zakim and Boyers Hepatology 2006

Management
Hepatic encephalopathy Lactulose
No improvement and controversy Volume depletion, electrolyte disturbances and ileus Discontinue if no benefit after two enemas

Boyer TD, Wright TL and Manns MP. Zakim and Boyers Hepatology 2006

Management
Cerebral edema and Intracranial hypertension The most common cause of death Occur >75% of ALF patients with grade 4 encephalopathy Diagnosed by systemic HT, hyperventilation, abnormal pupillary reflexes, muscular rigidity and decerebrate posturing
Boyer TD, Wright TL and Manns MP. Zakim and Boyers Hepatology 2006

Management
Elevate head of bed 20-30o Hypothermia (32-33o C) Correct volume overload Maintain mean BP 50-60 mmHg Hyperventilate to keep PCO2 25-30 mmHg Treat agitation with intubation and sedation Intratracheal lidocaine before respiratory suctioning
Boyer TD, Wright TL and Manns MP. Zakim and Boyers Hepatology 2006

Management
Correct hypoxemia Monitor for and treat seizures
Phenytoin IV 15 mg/kg IV loading dose followed by 100 mg every 8 hrs.

Mannitol
IV bolus 1-2 mg/kg and can be repeated Ineffective in renal failure, serum osmolality > 320 mmol/l 20% of patients have increased intracranial pressure after administration of mannitol
Boyer TD, Wright TL and Manns MP. Zakim and Boyers Hepatology 2006

Management
Plasmapheresis Exchanging elements in plasma with normal components Exchange 10L of plasma: full replacement of the extracellular fluid compartment Removal toxins and repletion of factors synthesized by the liver Decrease plasma ammonia, improve HE within hours Mean arterial pressure improved, decreased cardiac index, increased vascular resistance

Lee WM et al. Hepatology 2007;47:1404-15

Management
Hepatic assist devices Non-cell-based detoxification systems
Open-loop approaches - single pass albumin dialysis system and plasma exchange Closed loop systems prometheus albumin dialysis system and MARS

Cell-based systems (bioartificial liver)

Management
NAC Intraveneous NAC improves transplant-free survival in early stage non-acetaminophen acute liver failure 173 patients, multicenter trial NAC 150 mg/kg/hr of NAC over 1 hour, followed by 12.5 mg/kg/hr for 4 hours, then continuous infusions of 6.25 mg/kg NAC for the remaining 67 hours

Intraveneous NAC Improves Transplant-free Survival in Early Stage Non-acetaminophen Acute Liver Failure

Lee WM et al. Gastroenterology 2009:137:856-64

Child-Turcotte-Pugh Score
Criteria Points 1 2 3

Total bilirubin (mg/dl)

Albumin (g/dl) INR Ascites Encephalopathy

<2
>3.5 <1.7 Absent Absent

2-3
3.5-2.8 1.7-2.2 Mild Grade I-II

>3
<2.8 >2.2 Severe Grade III-IV

King s College Criteria for OLT

Paracetamol-induced ALF
Arterial blood pH < 7.3 OR all of the following PT > 100 s (INR > 6.5) Serum creatinine > 300 mmol/L Grade III or IV HE

Non-paracetamol induced ALF PT > 100 s (INR > 6.5) OR any 3 of the following Age < 10 or > 40 yrs Etiology : non-A/non-B hepatitis, drug-induced Duration of jaundice to encephalopathy > 7 days PT > 50s (INR > 3.5) Serum bilirubin > 300 mmol/L

OGrady JG and et al. Gastroenterology 1989;97: 439-445

Criteria of Hospital Paul-Brousse, Villejuif

Hepatic encephalopathy, and factor V level

<20% in patient younger than 30 years <30% in patient 30 years or older

Model for End-Stage Liver Disease (MELD) 9.6 X ln(creatinine mg/dl) + 3.8Xln(bilirubin mg/dl) + 11.20Xln(INR) + 6.4

Score higher than 20 survival benefit with liver transplantation