1. Approach to Acute liver Failure
Bader Alenezi, MD
Chairman of Internal Medicine
Jahra Hospital
Consultant Gastroenterolgy & Hepatology

3. Outlines Definition Acute Liver failure common causes of ALF
Acetaminophen toxicity
Diagnosis and Initial Evaluation ALF
Manage complications of ALF
Identify prognostic criteria
Future therapy in ALF
Recognize ALF and some common causes
ID prognostic criteria  when is xplant indiciated
List and manage common complications of ALF
Describe the mechanism of acetaminophen toxicity and apply timely and appropriate interventions
Identify interventions that improve outcome in viral ALF
Identify common drugs that can lead to ALF and describe the management

4. Acute liver Failure (ALF)
Rare
Represent the most sever form of liver injury
Hard to treat
Difficult to study

5. Acute liver Failure Fulminant hepatitis Fulminant hepatic failure
Subfulminant liver failure
Subacute hepatic necrosis
Subacute liver failure
Hyperacute liver failure

6. ALF: Definition The original term “fulminant hepatic failure”
“a 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;3:282-98

7. ALF: 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 <26 weeks duration.
AASLD Position Paper: The Management of Acute Liver Failure: Update 2011
William M. Lee, MD, Anne M. Larson, MD, and R. Todd Stravitz, MD

9. Defining Acute Liver Failure
INR > 1.5
Altered mental status
Illness of < 26 weeks duration
Hyperacute < 7 days
Acute 7-21 days
Subacute > 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.

10. ALF: Causes Autoimmune 4-5% Acetaminophen 39% Wilson’s Disease 2-3%
Indeterminite 17%
Idiosynchratic drug rxns 13%
Viral hepatitis 12%
HBV > HAV > HEV, HSV
Autoimmune 4-5%
Wilson’s Disease 2-3%
Mushroom Poisoning
Herbal Medications
Vascular
Bud-Chiarri
Ischemic
Hepatic Vein Thrombosis
Reye’s Syndrome
Fatty Liver of Pregnancy
HELLP
On the left: most common, in order of decreasing incidence
On the right: other causes
Another categorization of drugs is into dose-dependent, idiosyncratic and hypersensitivity

11. U.S. ALF STUDY GROUP 2002 (308 Patients, 73% Women)

12. ALF: Causes ALF in developed world << developing world
developing world viral infections (hepatitis A, B, and E) are the predominant causes.
Western world drug-induced liver injury is the most common cause of acute liver failure

14. ALF CAUSES: Viruses
Globally, hepatitis A and E infections are probably responsible for the majority of cases of ALF
ALF may occur after hepatitis B infection, Asian and Mediterranean countries.
Reactivation of HBV without established chronic liver disease treatment-induced immunosuppression during or after therapy for cancer
Antiviral prophylaxis before the initiation of chemotherapy, immunotherapy, or glucocorticoid therapy are effective in prevention

15. ALF CAUSES: Other Viruses
rare viral causes of acute liver failure :
Herpes simplex virus
CMV
Epstein–Barr virus
Parvoviruses
Ichai P, Samuel D. Etiology and prog- nosis of fulminant hepatitis in adults. Liver Transpl 2008;14:Suppl 2:S67-S79.

16. Drug-Induced Liver Injury (DILI)

17. Drug-Induced Liver Injury (DILI)
DILI is responsible for approximately 50% of cases of ALF in United States
Can be dose- dependent and predictable, as exemplified by acetaminophen-induced hepatotoxicity
Or may be idiosyncratic, unpredictable, and independent of dose
idiosyncratic drug hepatotoxicity usually within the first 6 months after drug initiation.
A potentially hepatotoxic medication used continually 1 to 2 years is unlikely to cause de novo liver damage.
Certain herbal preparations, weight loss agents and other nutritional supplements  need complete medication history.
Ostapowicz G,et al. Ann Intern Med

18. Acetaminophen Hepatotoxicity
Dose-related
Dose leading to ALF exceed 10 gm/day (>150 mg/kg)
Doses as low as 3-4 gm/day rarely causes ALF
Very 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)

19. Rumack-Matthew Nomogram
Used to interpret plasma acetaminophen values to assess hepatotoxicity risk after a single, acute ingestion
Nomogram 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

21. 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 time
2- when the time of ingestion is unknown
3- When altered metabolism occurs such as in the alcoholic or fasting patient
Larson AM. Acetaminophen hepatotoxicity. Clin Liver Dis. 2007;11:
Lee WM. Drug-Induced Hepatotoxicity. N Engl J Med 2003;349:

22. Treatment of Acetaminophen Hepatotoxicity
Activated 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:

23. Treatment: N-acetylcysteine (NAC)
N-acetylcysteine (NAC), the antidote for acetaminophen poisoning effective and
NAC should be given as early as possible
NAC is nearly 100% hepato protective when it is given within 8 hours
but may still be of value 48 hours or more after ingestion

25. 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)

26. N-acetylcysteine (NAC)
Use of the IV formulation of NAC is preferred in the following situations:
Altered mental status
GI bleeding and/or obstruction
A history of caustic ingestion
Potential fetal acetaminophen toxicity in a pregnant woman
Inability to tolerate oral NAC because of emesis refractory to proper use of antiemetics

27. Wilson disease uncommon 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 transplantation
young patients with Coombs negative hemolytic anemia with serum bilirubin levels >20 mg/dL
Kayser-Fleischer rings are present in about 50% of patients

28. Wilson disease
Serum 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

29. Wilson disease
Rx:
penicillamine is not recommended in ALF due to risk of hypersensitivity
recovery is very rare absent transplantation.
Patients must be promptly considered for liver transplantation
(AASLD recommendation 2011)

30. 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 negative
Recommended to receive corticosteroid therapy

31. ALF in Pregnancy
Acute Fatty Liver of Pregnancy/HELLP (Hemolysis, Elevated Liver Enzymes, Low Platelets) Syndrome
Near the end of pregnancy will develop rapidly progressive hepatocyte failure.
Increased fetal or maternal mortality.
Triad of jaundice, coagulopathy, and low platelets
Hypoglycemia and Features of pre-eclampsia are common
Transplantation may need to be considered if hepatic failure does not resolve quickly following delivery

32. Budd-Chiari Syndrome Acute 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 excluded

33. Budd-Chiari Syndrome

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

35. Poisoning and ALF Amanita 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

36. Diagnosis and Initial Evaluation ALF
In 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 indicated

37. Diagnosis and Initial Evaluation ALF
Physical Exam:
Determine presence or absence
of pre-existing liver disease
Hepatic tenderness
Hepatic decompensation

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

39. Initial Laboratory Analysis
Prothrombin time/INR
Chemistries
Liver enzymes
Arterial blood gas
Acetaminophen level Toxicology screen
Viral hepatitis serologies (anti-HAV IgM, HBsAg, anti-HBc IgM, anti-HEV, anti-HCV, HCV RNA , HSV1 IgM, VZV)

40. Initial Laboratory Analysis
Ceruloplasmin level
Pregnancy test (females) Ammonia (arterial if possible)
Autoimmune Markers (ANA, ASMA, Immunoglobulin levels )
Liver Biopsy reserved for diagnostic dilemma
(Transjugular approach)

41. Liver biopsy in ALF

42. Complications of Acute Liver Failure:
CNS disturbances
Hepatic encephalopathy
Cerebral edema
Hemodynamic Collapse
Infections
Coagulopathy and bleeding
Renal failure
Metabolic derangements

43. Cerebral Edema
There 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 <75 ug/dL
Degree of encephalopathy correlates w/ cerebral edema
Grade I-II: rare
Grade III: 25-35% risk risk
Grade IV: 65-75% risk
Uncal herniation
Compromises cerebral blood flow  hypoxic brain injury
NH3 is a byproduct of protein metabolism

44. Intracranial Pressure
CPP = MAP – ICP
CPP > 60mmHg
ICP < 20mmHg

45. Intracranial Pressure
CPP = MAP – ICP
CPP< 60mmHg
ICP < 20mmHg

46. Cerebral Edema/Intracranial Hypertension
Grade 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 helpful

47. Grade III/IV Encephalopathy
Intubate 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 mmol/L
Hyperventilation: effects short-lived; may use for impending herniation

48. Infection
Surveillance for and prompt antimicrobial treatment of infection required
Antibiotic prophylaxis possibly helpful but not proven
Prophylactic antibiotics and antifungals have not been shown to improve overall outcomes in ALF

49. Coagulopathy Vitamin 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 PPI

50. Hemodynamics/Renal Failure
Volume 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 norepinephrine

51. Metabolic Concerns
Follow closely: glucose, potassium, magnesium, phosphate
Consider nutrition: enteral feedings if possible or total parenteral nutrition

52. What are the potential outcomes?
1. Recovery because of a successful intervention
NAC for acetaminophen toxicity
Antivirals for acute hepatitis B
2. Spontaneous recovery with supportive care
3. Death
4. Rescue by liver transplant
Assuming we don’t have a proven intervention (#1), how do we differentiate between the others, thereby avoiding #3?
Give everyone transplants
Differentiate which patients will die if not transplanted and give a transplant to these patients

53. Predicting Outcomes in Acute Lifer Failure
Most important predictive factors:
Degree of encephalopathy
Suggested laboratory markers:
Factor V
AFP
Serum Phosphate
VII/V ratio > 30
Gc globulin
Clinical algorithms:
King’s College Criteria
APACHE II
Grade II encephalopathy: 65-70%
Grade IV: < 20%
Source 1
I: trivial lack of awareness, slight tremor
II: lethargy or apathy, disorientation, personality change, asterixis
III: somnolence to semi-stupor
IV: coma, decerebration
Some markers: serum phosphate are only used in acetaminophen toxicity

54. Prognosis and Transplantation
overall 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 <25% transplant-free survival.

56. Poor Prognosis in Patients With ALF (Etiology)
Idiosyncratic drug injury
Acute hepatitis B (and other non-hepatitis A viral infections)
Autoimmune hepatitis
Mushroompoisoning
Wilson disease
Budd-Chiari syndrome
Indeterminate cause

57. King’s College Criteria
Acetaminophen-Induced ALF:
Strongly consider OLT listing if:
arterial lactate >3.5 mmol/L after early fluid resuscitation
List for OLT if: pH<7.3 Or
arterial lactate >3.0 mmol/L after adequate fluid resuscitation
List 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/dL

58. King’s College Criteria
Non-acetaminophen:
INR > 6.5 OR
Any 3 of the following 5:
Age < 10 or > 40
Serum bilirubin > 18
Jaundice to encephalopathy interval > 7 days
INR > 3.5
Unfavorable Etiology
Non-A, non-B hepatitis, halothane, idiosyncratic drug reaction, Wilson’s
History: 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 etc…

59. AASLD Recommendation
Currently 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

60. 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

61. Future therapy

62. 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;159:522-31

63. Future 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

64. Future therapy Hepatocyte transplantation
Intraportal & intraperitoneal infusion of isolated human hepatocytes
Some success in neonates and children with inborn errors of metabolism
Limited experience in pediatric acute liver failure
Remains experimental.
Hughes RD,et al Current status of hepatocyte transplantation. Transplantation 2012;93:342-7.

65. Summary Management of ALF is real challenge for the treating team
ALF should be treated in ICU
Treatments for specific etiologies
Consideration of transplantation should be under-taken urgently