acute liver failure: an orphan disease fulminant hepatic...
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Approach to Acute Liver Failure 2011Approach to Acute Liver Failure 2011
William M. Lee, MD
Professor of Internal Medicine
Meredith Mosle Chair in Liver Diseases
University of Texas Southwestern
Medical Center at Dallas
William M. Lee, MD
Professor of Internal Medicine
Meredith Mosle Chair in Liver Diseases
University of Texas Southwestern
Medical Center at Dallas
ACG Postgraduate Course 10/30/2011
www.acuteliverfailure.org
ACG Postgraduate Course 10/30/2011
www.acuteliverfailure.org
Acute Liver Failure: An Orphan Disease
Fulminant Hepatic Failure
Acute Liver Failure: An Orphan Disease
Fulminant Hepatic Failure
• Most severe form of liver injury but rare, 2000/yr• Most severe form of liver injury but rare, 2000/yr
• Devastating: survival <10% in earlier era
• Definition: INR ≥ 1.5, any grade enceph, acute illness
• UNOS Status 1a
• Fascinating
F t ti
• Devastating: survival <10% in earlier era
• Definition: INR ≥ 1.5, any grade enceph, acute illness
• UNOS Status 1a
• Fascinating
F t ti• Frustrating
• Hard to treat
• Difficult to study
• Frustrating
• Hard to treat
• Difficult to study
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Fulminant hepatic failure due to halothane
Hep B
Autoimmune HELLP
DILI
Acetaminophen
Hep A
CAUSE
Indeterminate
Budd-Chiari
Acute Liver FailureAcute Liver Failure
HSV Wilson Disease
CoagulopathyComa
InfectionRenal failureBleedingEFFECT Shock
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Apoptosis
Necrosis
Innate immunity Loss of oval cells
Local factors
CAUSE
Adaptive immunity
Acute Liver FailureAcute Liver Failure
DICCytokines
Poor toxin clearancePoor synthetic fxn
Increased infection risk
Cerebral edema Toxic cellular debris
No regeneration
EFFECT
Acute Liver Failure Study GroupRationale: Network to study a rare disease
Acute Liver Failure Study GroupRationale: Network to study a rare disease
• Began in 1998 13 adult 15 pediatric sites• Began in 1998 13 adult 15 pediatric sites• Began in 1998, 13 adult, 15 pediatric sites
• 1,850 cases in adult, ~1,100 in pediatric registry
• New added definition: ALI—INR > 2.0/no enceph
• Three directions:
Prospecti e clinical data sera plasma DNA tiss e
• Began in 1998, 13 adult, 15 pediatric sites
• 1,850 cases in adult, ~1,100 in pediatric registry
• New added definition: ALI—INR > 2.0/no enceph
• Three directions:
Prospecti e clinical data sera plasma DNA tiss e– Prospective clinical data, sera, plasma, DNA, tissue
– Numerous ancillary studies in progress
– Therapy trials: NAC trial done, others on the way
– Prospective clinical data, sera, plasma, DNA, tissue
– Numerous ancillary studies in progress
– Therapy trials: NAC trial done, others on the way
Funding: NIDDK U-01 through 2015
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Etiology of Acute Liver Failure in the USAAdult Registry (n = 1,696)
46%46%
12% 13%
n
APAP
n=787
Drug
n=202
Indeterminate
n=219
HepA/HepB
n=37/123
All Others
N=328
Age (median) 37 47 38 48/43 45
Comparison of Different ALF Etiology GroupsN = 1,696
Sex (% F) 76 66 60 46/45 73
Jaundice (Days)
(median)
0 8 8 3/5 4
Coma ≥3 (%) 53 37 50 51/55 43
ALT (median) 3846 685 849 2124/1702 677
Bili (median) 4.4 19.8 22.0 12.5/19.1 14.6
Tx (%) 9 40 45 32/41 30
Spontaneous Survival (%)
67 31 27 54/24 38
Overall Survival (%)
75 68 69 84/61 65
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Acetaminophen: our biggest problem
‘Suicidal’ vs. ‘Accidental’ APAP cases
N=606 Intentional Unintentional p-value(56=unk) (n=251) (n=296)
Female (%) 77 71 NS( )
Age 35 39 < 0.001
ACM dose(g) 38/38 47/7.5 NS
Coma (% >3) 39 55 < 0.026
ALT (IU/L) 6053 4207 < 0.0001
Alcohol use/abuse (%) 50/18 50/17 NS
Antidepress’t 39 34 NS
History of depression 45 24 < 0.001
Narcotic cpd (%) 18 63 < 0.001
Multiple preps 5 38 < 0.001
Spont surv (%) 70 65 NS
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Acetaminophen (APAP) adducts assayAcetaminophen (APAP) adducts assay
• HPLC-EC detects APAP-cysteine residues (smoking gun)
• Highly sensitive and specific
• Excellent correlation with AST
• Remains positive up to 9 days after ingestion
• HPLC-EC detects APAP-cysteine residues (smoking gun)
• Highly sensitive and specific
• Excellent correlation with AST
• Remains positive up to 9 days after ingestion
• Present in 20% of indeterminate cases, peds and adults• Present in 20% of indeterminate cases, peds and adults
Davern TJ, et al. Gastroenterology 2006;130:687-94James LP, et al. Pediatrics 2006;118:e676-681.
2.5
3.0
/L)/
mg
prot
ein
Known APAP
Indeterminate with adducts N=7
0.5
1.0
1.5
2.0
ceta
min
ophe
n-C
YS
(um
ol/
Other ALF APAP
No tox
IndeterminateN 29
A B C D E
nmolA
PA
P-C
YS
/m
0.0
0.5
Ac
Patient Group
N=29
Davern TJ, et al. Gastroenterology 2006;130:687-94
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• Cerebral edema: 10-30%• Cerebral edema: 10-30%
Multi-organ Failure in ALF
• Circulatory abnormality with shock
• Renal dysfunction: 55%
• Coagulopathy: 100% but is it real?
• Infection: 20%
• Circulatory abnormality with shock
• Renal dysfunction: 55%
• Coagulopathy: 100% but is it real?
• Infection: 20%Infection: 20%
• ARDS: <10%
• Cardiac abnormalities (rare)
Infection: 20%
• ARDS: <10%
• Cardiac abnormalities (rare)
Establish Diagnosis: Acute Liver Failure(Increased prothrombin time, altered mentation, recent onset hepatic illness)
Evaluate Etiology: History, lab
Acetaminophen? History, l l hi h AST NAC
Estimate Severity: Labs, Etiology, Coma grade
Admit to ICU
Yes, glevels, high AST
y pMushroom Toxicity: History,
muscarinic symptoms
Wilson Disease? High bilirubin, low AP
D i d d i l
NAC
Coma I-II
Silibinin
CVVH, OLT
Coma Iii-IV
List for OLTIntubate
In ICU, no sedation
Yes
Yes
Yes
no
no
no
Consider NAC for non-acetaminophen, nucleoside analogue for Hep B, good
coma care
Drug-induced, viral hepatitis, unknown.
(History, viral serologies) General measures: PPI, mannitol ready, observe for infection,
daily PT/INREvaluate for OLT
Yes
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Management of cerebral edemaManagement of cerebral edemaManagement of cerebral edemaManagement of cerebral edemaUS ALFSG: Management Strategies in Use
Most use: Most use: Many use:Many use:-- Head of bedHead of bed-- quiet roomquiet room-- brain imaging with CTbrain imaging with CT-- intubation for gr III/IV HEintubation for gr III/IV HE-- mannitol for ICHmannitol for ICH-- CVVHD if dialysis neededCVVHD if dialysis needed
f l h d if l h d i
yy- hyperventilation (ICH)hyperventilation (ICH)- antibiotic prophylaxisantibiotic prophylaxis
*Widely variable *Widely variable use of lactuloseuse of lactulose
-- careful hemodynamic careful hemodynamic monitoring monitoring (art line, CVP, PA cath)(art line, CVP, PA cath)
Approx 1/2 centers Approx 1/2 centers using ICP monitoringusing ICP monitoring
? Hypothermia?? Hypothermia?? Seizure prophylaxis?? Seizure prophylaxis?? Continuous EEG?? Continuous EEG?? Hypertonic saline? Hypertonic saline
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1,696 Patients enrolled660 (39%) listed
1,696 Patients enrolled660 (39%) listed
Spontaneoussurvivors
N=826(49%)
Died (NotTransplanted)
N=461(27%)
Transplanted N=409(24%)
AliveN=371(91%)
Died N=38(9%)
Overall survival: N=1,197 (71%)Overall survival: N=1,197 (71%)
Prognosis in ALF: Etiology is a Main DeterminantPrognosis in ALF: Etiology is a Main Determinant
Transplant free survival rates differ greatlyTransplant free survival rates differ greatly
Good prognosis:
• APAP 66%
• Ischemia 66%
• Pregnancy 55%
Good prognosis:
• APAP 66%
• Ischemia 66%
• Pregnancy 55%
Bad prognosis:
• Drugs 27%
• Indeterminate 25%
• Autoimmune 26%
Bad prognosis:
• Drugs 27%
• Indeterminate 25%
• Autoimmune 26%• Pregnancy 55%
• Hepatitis A 56%
• Pregnancy 55%
• Hepatitis A 56%• Hepatitis B 26%
• Wilson Disease 0%
• Hepatitis B 26%
• Wilson Disease 0%
(Age is NOT an important determinant)**Schiødt FV, et al. Liver Transplant 2009
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Transplant-free survival by etiology and coma grade
65%
56%
68%55%
56%
26%26% 27% 25%
Coma grade I-II patients had ~50% better survival than III-IV
Therapies for the overall condition ALF
Total body washout Detoxify No help; harmful
Therapy Rationale Result
Total body washout Detoxify No help; harmful
Heparin DIC No help; harmful
Steroids Inflammation No help
Prostaglandins Cytoprotection No help
Activated charcoal Clear toxins No help
Plasmapheresis Clear toxins Possible
Cell systems Replace liver May improve coma
Cell transplants Replace liver Not enough data
NAC GSH donor Positive trial
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Primary/secondary outcomes in the NAC trial
**p< 0.01
p< 0.09 *p< 0.035
p< 0.28
*p< 0.04p
p< 0.09
The most impressive difference was in transplant free survival in coma grades I-II. * = statistically significant
PLB NAC PLB NAC
Overall survival Transplant free survival
NAC Results by Etiology
DILI
N=45
17/26
65%
15/19
79%
7/26
27%
11/19
58%
AIH
N=26
10/15
67%
7/11
64%
4/15
27%
1/11
9%
HBV
N=37
6/12
50%
19/25
76%
2/12
17%
10/25
40%
Indeterm
N=41
18/26
69%
9/15
60%
6/26
23%
6/15
40%
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Ornithine Phenyl Acetate: STOP-ALF TrialLower ammonia to manage cerebral edema
Ornithine Phenyl Acetate: STOP-ALF TrialLower ammonia to manage cerebral edema
• Ammonia is the putative cause for cerebral edema• Ammonia is the putative cause for cerebral edemaAmmonia is the putative cause for cerebral edema
• OPA traps ammonia and allows renal excretion
• Could be used prophylactically or as treatment
• IV, few side effects, might work in cirrhosis also
• ALFSG will study in APAP patient group
Ammonia is the putative cause for cerebral edema
• OPA traps ammonia and allows renal excretion
• Could be used prophylactically or as treatment
• IV, few side effects, might work in cirrhosis also
• ALFSG will study in APAP patient group• ALFSG will study in APAP patient group
beginning in 12/11
• ALFSG will study in APAP patient group
beginning in 12/11
Acute Liver Failure 2011Determine quickly the diagnosis/etiology/severity
Acute Liver Failure 2011Determine quickly the diagnosis/etiology/severity
• Acetaminophen most common etiology, good • Acetaminophen most common etiology, good
prognosis, hyperacute features: 2/3 will survive
• DILI, Hep B, Autoimmune, Indeterminate poor
prognosis, slower evolution: 1 in 4 will survive
• NAC appears effective for non-acetaminophen
prognosis, hyperacute features: 2/3 will survive
• DILI, Hep B, Autoimmune, Indeterminate poor
prognosis, slower evolution: 1 in 4 will survive
• NAC appears effective for non-acetaminophen
with early coma grade
• Prognosis depends on coma grade and etiology
• When in doubt, assume the worst
with early coma grade
• Prognosis depends on coma grade and etiology
• When in doubt, assume the worst
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Acute Liver Failure 2011“Dos and Don’ts—if you don’t have to”
Acute Liver Failure 2011“Dos and Don’ts—if you don’t have to”
• Do: Quiet room head up 30o monitor closely for• Do: Quiet room head up 30o monitor closely forDo: Quiet room, head up 30 , monitor closely for
CNS change, replete volume, consider intubation
at coma grade 2-3
• Don’t:
– Sedate unless agitated
Do: Quiet room, head up 30 , monitor closely for
CNS change, replete volume, consider intubation
at coma grade 2-3
• Don’t:
– Sedate unless agitated
– Give FFP unless bleeding
– Give antibiotics without cause
– Give lactulose if planning OLT
– Give FFP unless bleeding
– Give antibiotics without cause
– Give lactulose if planning OLT
Acute Liver Failure 2011Summary/Conclusions
Acute Liver Failure 2011Summary/Conclusions
• Evaluate quickly take these cases seriously• Evaluate quickly take these cases seriouslyEvaluate quickly, take these cases seriously
• Refer to a transplant center if likelihood of OLT
– Subacute etiologies, advanced coma grades
• Good coma care
– Attention to volume, replace glucose, phosphate,
Evaluate quickly, take these cases seriously
• Refer to a transplant center if likelihood of OLT
– Subacute etiologies, advanced coma grades
• Good coma care
– Attention to volume, replace glucose, phosphate, tte t o to o u e, ep ace g ucose, p osp ate,
vigilance for infection, bleeding, consider CVVH
– Give specific antidotes: err on side of giving NAC
tte t o to o u e, ep ace g ucose, p osp ate,
vigilance for infection, bleeding, consider CVVH
– Give specific antidotes: err on side of giving NAC
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Study Sites (Adult) in the ALFSG 2009• UT Southwestern Lee/Larson/Sanders
• U Washington Liou
• UCSF Fix
• Mt. Sinai NYC Liu/Zuniga
• Univ Nebraska Omaha McCashland/Teten
• Baylor Dallas Murray/Coultrup• Baylor Dallas Murray/Coultrup
• Univ Pittsburgh Shakil/Gooch
• Northwestern Univ Ganger/Gottstein
• OHSU, Portland Zaman/Ingram/Wilson
• UCLA McClune/Peacock/Melgoza
• Michigan Fontana/Welch
• Univ Alabama Birmingham McGuire/Hogue
• Mass General Chung/Rutherford/Lundmark/Gustafson
• Columbia/Cornell NYC Brown/Odeh-Ramadan
VCU Stravitz/White/Topaz• VCU Stravitz/White/Topaz
• Mayo Clinic: Rochester, Jax Hay, Raj,Kramer: Groettum/Kontras
• UC Davis Rossaro/Dhaliwal
• Einstein Philadelphia Munoz/Riera/Carmody
• MUSC Charleston Reuben/Minshall
• Pennsylvania Reddy/Wirjosemito
• Yale University Schilsky/Emre/Engle/Snyder
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