1. Brian Kim USC Transplant Hepatology October 16, 2018
Acute Liver Failure
Brian Kim
USC Transplant Hepatology
October 16, 2018

2. Definition
Acute liver failure (ALF) or fulminant liver failure is most commonly defined as the onset of encephalopathy within 26 weeks (or whatever threshold used) of development of jaundice
Liver injury with encephalopathy and impaired synthetic dysfunction (INR ≥ 1.5) in a patient without known cirrhosis or pre-exisiting liver disease
Exceptions can include patient with HBV, AIH, Wilson Disease, but not alcoholic liver disease

3. Acute Liver Failure Onset of jaundice to encephalopathy Hyper-acute
< 7 days
Acute
7-28 days
Sub-acute
5-26 weeks

4. Acute Liver Failure is not…
Acute on chronic liver failure or decompensated cirrhosis
Preexisting liver disease (cirrhosis)
Bleeding
Infection
Cancer
Acute alcoholic hepatitis
Acute liver injury
Jaundice +/- coagulopathy
Normal mental status
May deteriorate into ALF

5. Acute Liver Failure vs. Decompensated Cirrhosis
ALF patients generally present with severe hepatic dysfunction
Hepatic encephalopathy as a result of hepatic necrosis/cytokine release
High INR as a result of hepatic necrosis
Decompensated cirrhotic patients generally present with portal hypertension complications
Variceal hemorrhage
Ascites
Hepatic encepahlopathy as a result of portosystemic shunting (macro vs. micro)
Can have considerable overlap
ALF can potentially have considerably higher mortality than patients with decompensated cirrhosis (more on this later)

6. Acute liver failure Approximately 2000 cases annually in the US
3/4 white
3/4 female
Median age 38 years
ALFSG

7. Causes Acetaminophen Other drugs (>400 associated with ALF)
Augmentin
INH
Valproic acid
Toxins – mushrooom (Amanita phalloides)
Viral hepatitis
HAV
HBV +/- HDV
HEV
HSV
Autoimmune hepatitis
Wilson disease
Budd-Chiari
Shock liver
Hyperthermia
Acute fatty liver of pregnancy
Malignant infiltration
Hemophagocytic lymphohistiocytosis (HLH)
Reye’s syndrome
Indeterminate (15-20%)
Not causes of ALF
Alcohol
Hemochromatosis
NASH
HCV?

8. Etiologies of ALF in the US (N=324)
ALFSG

9. Clinical Presentation
Symptoms can be nonspecific
Fatigue
Nausea/vomiting
Abdominal pain
Confusion
Physical Exam
Alteration in mental status
Asterixis, clonus
Evidence of liver injury on labs
Elevated AST/ALT, TB, INR
Renal failure
Pancytopenia

10. Diagnostic Work-Up
Thorough history to obtain potential etiologies (pmh, family history, medication hx, ingestions, etc)
Physical exam
Find subtle mental status changes
Signs of underlying chronic liver disease

11. Diagnostic Work-up Labs Imaging Transjugular liver biopsy LFTs, INR
Viral serologies
Acetaminophen level
Arterial ammonia
AFP, phos pH
Imaging
Ultrasound with dopplers
Transjugular liver biopsy

12. Some Etiology Specific Therapies
Acetaminophen
Wilson disease
activated charcoal if recent ingestion
plasmaphresis - temporizing
Autoimmune hepatitis
N-acetyl-cysteine
steroids?
HBV
Pregnancy related
lamivudine, entecavir or tenofovir
delivery
HSV
acyclovir
Mushroom poisoning
silibinin (milk thistle), penicillin G

13. How do people die from ALF?
Cerebral edema
Infection/sepsis

14. Hepatic encephalopathy
Part of the diagnosis of acute liver failure
Decreased ammonia and false neurotransmitter metabolism
Increased cytokine release from hepatic necrosis

15. Grades of Encephalopathy
Changes in behavior with minimal change in level of consciousness
Gross disorientation, drowsiness, possibly asterixis, inappropriate behavior
Marked confusion; incoherent speech, sleeping most of the time but arousable to vocal stimuli
Comatose, unresponsive to pain, decorticate or decerebrate posturing

17. Cerebral Edema Most serious complication of acute liver failure
Combination of cytotoxic and vasogenic edema
Osmotic disturbances from cytokine/toxin release
Increased blood flow from impaired cerebrovascular autoregulation
Lead to intracranial hypertension (ICH) with uncal herniation
Cerebral edema and ICH seen in 35% of patient with grade III and 75% in grade IV encephalopathy
CT imaging is rarely helpful early

18. Cerebral Edema Grade I/II Grade III/IV Close monitoring
Avoid all sedation
Questionable role of lactulose – may make liver transplant difficult
Grade III/IV
Intubation with sedation
Efforts to reduce intracranial pressure (ICP)
Elevated head of bed
Hyperventilation
Mannitol infusion
Hypertonic saline
CRRT
Hypothermia
ICP monitoring
Cerebral perfusion pressure = MAP – ICP; goal ICP<20mmHg and keep CPP >60mHg
controversial

19. Infection Patients at risk for bacterial and fungal infection
Empiric antibiotics do appear to reduce incidence of infection
Start empiric, broad spectrum antibiotics in all patients with hypotension and SIRS
Consider empiric antifungal coverage in patients renal failure

20. Bleeding Risk for DIC/hyperfibrinolysis
Elevated INR may not reflect bleeding risk
Spontaneous bleeding risk is rare
Routine FFP transfusion not recommended
INR followed for prognosis
Vitamin K is fine

21. Management of Other Complications
Continuous renal replacement therapy (CRRT) for volume overload and renal failure – especially in patients with advanced encephalopathy and hypotension
Vasopressor support
Glucose drip for hypoglycemia

22. Prognosis Overall mortality 30-40%
Multiple factors influence mortality
Cause of liver failure
acetaminophen has best outcome, >50% survival
idiopathic drug reaction has poorest outcome, <25% survival
Degree of encephalopathy
Important to determine prognosis to determine who needs a liver transplant

23. Encephalopathy and Prognosis
Grade of Encephalopathy
Short-term transplant-free Survival
Short-term survival after liver transplant
I-II
52%
77%
III-IV
33%
56%

24. King’s College Criteria
Prognostic system developed from King’s College Hospital in London
Predict transplant-free mortality
Meta-analysis shows 68-69% sensitivity, 82%-92% specificity
Two separate criteria
Acetaminophen
Non-acetaminophen

25. King’s College Criteria - Acetaminophen
pH <7.3 or arterial lactate >3.0mmol/L after early fluid resuscitation Or
All three:
Grade III/IV encephalopathy
INR > 6.5
Cr >3.4 mg/dL

26. King’s College Criteria – Non-acetaminophen
INR > 6.5 Or
Three of five
Age < 10 or > 40 years
INR ≥ 3.5
TB ≥ 17mg/dL
Unfavorable etiology – Wilson, idiopathic drug reaction, non A, B hepatitis
Development of encephalopathy > 7 days after jaundice

27. Management Supportive care
Follow mental status, transaminases, and INR closely
Early involvement and transfer to transplant center
Liver transplantation
Rapid work-up with thorough psycho-social evaluation
Listed as ”Status 1”
1 year survival is lower than for other Tx
After 1 year, survival improved

28. Future Directions Better prognostic score Better monitoring of ICP
Liver dialysis

29. Key Points
ALF is marked by rapid deterioration in liver function resulting in encephalopathy and coagulopathy
Early recognition and involvement of transplant hepatology is essential
Determining etiology may help to target early therapy to prevent deterioration – especially in acetaminophen
Supportive care is hallmark of ALF treatment
Determining prognosis can help determine who will best benefit from liver transplantation