Acute Liver Failure: An Orphan Disease Fulminant Hepatic ...universe-syllabi.gi.org/acg2011_39_slides.pdf · Acute Liver Failure DIC Cytokines Poor toxin clearance Poor synthetic

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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