Common Causes & Management

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Oct 23, 2013 (3 years and 5 months ago)

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Common Causes & Management

José L. González, R3

John
A
. Donovan, MD


Why did I choose this topic and why is it
important for clinicians?


Identification of ALF


Regenerative
properties


Interventions


Liver
Transplant





Introduction


Acetaminophen Toxicity


Idiosyncratic Drug
Reactions


Viral Hepatitis


Complications and Management


Liver Transplant & Conclusion


N
-
Acetylcysteine

for non
-
acetaminophen causes of
acute liver failure by Dr.
Donovan.


Recognize Acute Liver failure


Understand Acetaminophen toxicity & apply appropriate
treatment


Understand common causes of Viral ALF and identify the
interventions that improve outcomes


Know which groups of drugs commonly cause liver injury


Identify prognostic criteria


Manage complications of ALF



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
)



Acetaminophen
39
%


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


GI decontamination


activated charcoal



N
-
Acetylcysteine



20 hour IV protocol


72 hour PO protocol



Liver Transplant




Arterial pH < 7.30 after adequate fluid resuscitation


OR


Grade III/IV
encephalopathy
AND


PT > 100 sec
AND


Cr > 3.3


Idiosyncratic: unpredictable and dose
-
independent


Pattern of injury varies


Cholestatic

(alkaline
phosphotase
)


Hepatocellular (ALT)


Mixed


Mechanism of Action


Covalent bonds

disruption of cell membrane


Inhibition of cellular pathways


Abnormal bile flow


Pump dysfunction


Apoptosis via TNF and
fas

pathways


Inhibition of mitochondrial synthesis

#1 antimicrobials

#2 CNS agents

#3 herbal supplements


-

weight loss

-

m
uscle building


What factors influence susceptibility?


<10 and >40
yoa
, obesity, female gender, DM,
etoh

use, genetic
variability



Importance of discontinuing medication after liver injury.


Likelihood of progression to liver failure is dependent on how long you
continue to take the drug after identification of liver injury.



What is the clinical course and natural history of disease?


Repair varies : days to weeks to months



Hepatitis B: 8%
+/
-

Hepatitis D


Hepatitis A: 4%


Hepatitis C: does not cause ALF


Hepatitis E: in developing countries


HSV, EBV


HBV: DNA virus


Antivirals: nucleoside or nucleotide analogs


Lamivudine,
adefovir
,
tenofovir
,
entecavir



Lamivudine Treatment Improves the Prognosis of Fulminant
Hepatitis B:


Serologies

for acute
Hep

B:
IgM

anti
-
hepatitis B virus core antibody


Retrospective cohort study, n = 33


10 patients received lamivudine


Endpoints: 1 week, overall survival


1wk: 90%
vs

65%

Overall: 70%
vs

26%



Factors associated with
increased mortality

Acute Liver Failure


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


Most important predictive factors:


Degree of encephalopathy



S
uggested laboratory markers:


Factor V


AFP


Serum
Phosphate


VII/V ratio > 30


Gc

globulin



Clinical algorithms:


King’s College Criteria


APACHE II


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


Which variable or clinical algorithm do we use?


Meta
-
analysis of Prognostic
Criteria


No prospective trials as of yet



Why is sensitivity important?


False negatives: death due to withholding liver transplants



Why is specificity important?


False positives: liver transplants in those that don’t need them




Reviewed raw data


Arterial pH, PT, Cr, Factor V,
Gc
-
globulin


King’s College Criteria, APACHE II score


Prospective study needed



sensitivity

specificity

King’s College Criteria

92%

69%

APACHE II

92%

81%

Common Complications of Acute Liver Failure


CNS disturbances


Hepatic encephalopathy


C
erebral edema


Hemodynamic
Collapse


Infections


Coagulopathy and bleeding


Renal failure


Metabolic derangements



(astrocytes) NH
3



glutamine + edema



Degree of encephalopathy correlates w/ cerebral edema


Grade I
-
II: 25
-
35%
risk


Grade III: 65% risk


Grade IV: 75% risk



Uncal

herniation


Compromises cerebral blood flow


hypoxic brain injury





CPP = MAP


ICP

CPP > 60mmHg

ICP < 20mmHg


CPP = MAP


ICP

CPP > 60mmHg

ICP < 20mmHg



HOB > 30º


Decreased patient stimulation


Hyperventilation


B
arbiturates


Mannitol


Corticosteroids


Hypertonic Saline


Hypothermia (32
-
33ºC)




Decreased SVR


Renal failure, pulmonary failure and cardiovascular
collapse


Restoration of hemodynamics:


Crystalloid initially


Once
euvolemic
, studies show albumin is better than crystalloid


Pressors


Alpha
adrenergics

(
epi
-

and
norepi
-
)


Not used: Dopamine,
Vassopressin



No benefit of NAC, prostaglandins and steroids


Etiology


Bacterial (90%): gram negative organisms, staphylococci


Fungal (30%)



SIRS has been shown to decrease survival rate



Should we use prophylactic antibiotics?


Decrease # of infections


But no improvement in outcomes


Routine surveillance blood, sputum, urine cultures and CXR


Coagulopathies:


Prolonged PT


Platelet dysfunction


Reduction in factors II, VII, IX and X


Defective production of
procoagulant

factors:


Proteins C and S


Antithrombin

III


Upregulation

of factor VIII


End Result:


Clinically significant spontaneous bleeding is relatively unusual in ALF,
even during liver transplant.


Overuse of blood products


Vitamin K



Platelets if clinically significant bleeding or < 10k



Limited role for prophylactic FFP, platelets, cryoprecipitate



Giving FFP takes away your best prognostic indicator



Recombinant VII



RF contributes to mortality and overall poor prognosis


Multi
-
factorial


Pre
-
renal


ATN (from prolonged pre
-
renal state
vs

nephrotoxic agents)


HRS


CVVD > HD





Lactic acidosis w/ compensatory respiratory alkalosis


Hypokalemia


Hypoglycemia (40%)


Hypophosphatemia


Hypomagnasemia



Early nutrition is important



Indicated when prognostic criteria suggest a high likelihood of
death


2004 UNOS data


5845 transplants


491 for acute liver failure = 8.4%



Of patients w/ ALF, 29% receive a transplant.


S
urvival rates in pre
-
transplant era ~ 15%
vs

40% now



Better prognosis: acetaminophen, HAV, ischemia, AFLP


Worse prognosis: HBV, AIH, Wilson’s, Bud
-
Chiari


Orthotopic

Liver Transplant


Auxiliary liver transplant


Xenotransplantation


Artificial /
Bioartificial

Hepatic Assist Devices


Detoxify, metabolize and synthesize


Hepatocyte Transplantation


ALF: INR > 1.5, AMS, < 26 weeks duration


Acetaminophen: charcoal, NAC


Idiosyncratic drugs


ALF: 1. antimicrobials, 2. CNS agents, 3.
herbal supplements.


Viral: HBV>HAV,
tx

w/ antivirals


ID
Prognostic criteria: APACHE II
vs

King’s College, Age, AMS,
etiology


Manage complications: increased ICP, hemodynamic instability,
RF, coagulopathies, metabolic
derrangements




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Amre
, D., and
Gaudreault
, P. Fulminant hepatic failure secondary to acetaminophen poisoning: A systemic review and meta
-
analysis of prognostic criteria determining the need for liver transplantation.
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Care Med 2003; 31:
299
-
305



Craig, D.G.N, Lee, A., Hayes, P.C. et al, Review article: the current management of acute liver failure. Alimentary Pharmacol
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and
Therapeutics 2010; 31:
345
-
348



Ganem
, D., and Prince, A.
Hepaitis

B Virus Infection


Natural History and Clinical Consequences. N
Engl

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1118
-
29



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, M.,
Chalasani
, N.,
Bjornsson
, E.
Drug
-
induced
liver injury: a clinical update. Current Opinion in Gastroenterology 2010;
26:222
-
226



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www.uptodate.com

2011



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, D.,
Riediger
, C. Weiss, K.H., et al. Fulminant hepatic failure: etiology and indications for liver transplantation. Nephrology
Dialysis Transplantation 2007; 22:
viii5
-
viii8



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Treatment
.
www.uptodate.com

2011



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Takaki
, A. Lamivudine Treatment Improves the Prognosis of Fulminant Hepatitis B. Inter Med 2008; 47:
1293
-
1299



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Engl

J Med. 2006; 345:
731
-
739



Ostapowicz
, G., Fontana, R.J.,
Shiodt
, F.V. Results of a prospective study of acute liver failure a 17 tertiary care centers in the United
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Polson, Julie and Lee, William M. AASLD Position Paper: The Management of Acute Liver Failure.
www.aasld.org

2005