sevoflurane and desflurane hepatotoxicity · 2018-11-05 · at the completion of this lecture •...
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SEVOFLURANE AND DESFLURANE HEPATOTOXICITY
DOLORES B. NJOKU, MD
ASSOCIATE PROFESSOR
ANESTHESIOLOGY AND CRITICAL CARE MEDICINE, PEDIATRICS
AND PATHOLOGY
JOHNS HOPKINS UNIVERSITY
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DISCLOSURES
• MCGRAW – HILL EDUCATION
• ON-LINE PODCASTS/LECTURES
• INVENTION DISCLOSURE: RECOGNITION OF CRITICAL CYP2E1 EPITOPES, US PATENT NUMBER: 9,339,531, ISSUE DATE: 5/17/2016.
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AT THE COMPLETION OF THIS LECTURE• COMPREHEND THE PREVALENCE OF HEPATOTOXICITY ASSOCIATED WITH
SEVOFLURANE AND OTHER HALOGENATED ANESTHETICS.
• REVIEW ACCEPTED MECHANISMS OF HEPATOTOXICITY FROM SEVOFLURANE AND DESFLURANE AS WELL AS METHODS FOR CONFIRMATION OF THE DIAGNOSIS.
• RECOGNIZE GAPS IN KNOWLEDGE SURROUNDING THE PREVALENCE AND MECHANISMS OF SEVOFLURANE AND DESFLURANE HEPATOTOXICITY AND BEGIN TO DISCUSS HOW THESE GAPS MAY BE ADDRESSED.
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BACKGROUND
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LIVER DISEASE
• LIVER DISEASE AND CIRRHOSIS ARE THE SIXTH MOST COMMON CAUSE OF DEATH IN ADULTS BETWEEN THE AGES OF 25 AND 64 (NATIONAL CENTER FOR HEALTH STATISTICS, 2014).
• LIVER-RELATED MORTALITY IN THE UNITED STATES MAY BE UNDERESTIMATED (ASRANI ET AL., 2013).
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LIVER DISEASE
• DRUG-INDUCED HEPATITIS IS A LEADING CAUSE OF LIVER FAILURE AND IS THE MOST COMMON REASON AN APPROVED MEDICATION IS REMOVED FROM THE CONSUMER MARKET (BELL AND CHALASANI, 2009).
• MANY TYPES OF DRUG-INDUCED HEPATITIS ARE BELIEVED TO BE IMMUNE-MEDIATED.
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BOTH OF THE MODERN HALOGENATED ANESTHETICS HAVE BEEN ASSOCIATED WITH
HEPATOTOXICITY
Frost E.A.M. (2015) A Review of Mechanisms of Inhalational Anesthetic Agents. In: Kaye A., Kaye A., UrmanR. (eds) Essentials of Pharmacology for Anesthesia, Pain Medicine, and Critical Care. Springer, New York, NY
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BACKGROUND SUMMARY
• LIVER-RELATED MORTALITY IS AT AN ALL TIME HIGH IN THE US
• THE BURDEN OF DISEASE ASSOCIATED WITH THE LIVER MAY BE UNDERESTIMATED
• IMMUNE-MEDIATED HEPATITIS IS A FINAL COMMON MECHANISM THAT FOLLOWS MANY FORMS OF LIVER INJURY
• DESFLURANE AND SEVOFLURANE HAVE BEEN ASSOCIATED WITH HEPATOTOXICITY
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WHAT IS THE INCIDENCE OR PREVALENCE OF HEPATOTOXICITY ASSOCIATED WITH
DESFLURANE OR SEVOFLURANE?
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DESFLURANE
• INTRODUCED IN 1993
• PREVALENCE OF HEPATOTOXICITY: 1 IN 10 MILLION
• STACHNIK J. INHALED ANESTHETIC AGENTS. AM J HEALTH SYSTPHARM 2006; 63: 623–34.
• REPORTED CASES OF HEPATOTOXICITY: FIVE
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Year Age/ Sex
Procedure Prior exposure
PODOnset
Elevated LFTs
Infectious rule out
CYP2E1 or TFA testing
Outcome
1995 65y/o F Thyroidectomy
Yes 14 Yes Yes Yes survival
1999 37y/o F Tibial fx Yes 12 Yes Yes Yes survival
2005 81 y/o F
Hemi-colectomy
Yes 6 Yes Yes No survival
2007 15 mo M
Nissen Yes 2 Yes Yes No survival
2018 54y/o F Sleeve gastrec-
tomy
Yes 1 Yes Yes No survival
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SEVOFLURANE
• INTRODUCED IN 1999
• INCIDENCE OR PREVALENCE OF HEPATOTOXICITY: UNKNOWN
• STACHNIK J. INHALED ANESTHETIC AGENTS. AM J HEALTH SYSTPHARM 2006; 63: 623–34.
• REPORTED CASES: NINE
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Year Age/ Sex
Procedure Prior exposure
PODOnset
Elevated LFTs
Infectious rule out
CYP2E1 or TFA testing
Outcome
1991 infant Extra digit No 15 Yes Yes No Unk2007 75y/o F AVR Yes (4) 2 Yes Unk No Death2007 69y/o
Mvascular Yes (twice
in 2 days1 Yes Yes No Death
2010 66 y/o F
Lymph node 2 weeks after
mastectomy
Yes (twice in 2 days
15 Yes Yes No Death
2010 37y/o M
abdominal Unk 3 Yes EBV No survival
2010 47y/o F Renal transplant
Unk 2 Yes Unk No Death
2012 24 y/o F
colectomy Weeks apart
8wks Yes Yes Yes survival
2012 38 y/o M
Hand reconstruct
ion
No 8mos. Yes Yes Yes survival
2012 30 y/o F
crani No 8wks Yes Yes Yes survival
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SUMMARY:THE INCIDENCE OR PREVALENCE OF DESFLURANE
HEPATOTOXICITY IS 1 IN 10 MILLION
• DESFLURANE HEPATOTOXICITY HAS BEEN REPORTED AT LEAST 5 TIMES
• 80% OF CASES WERE IN FEMALE PATIENTS
• 20% OF CASES WERE IN MALE PATIENTS
• ALL REPORTED CASES HAVE SURVIVED
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SUMMARY:THE INCIDENCE OR PREVALENCE OF SEVOFLURANE
HEPATOTOXICITY IS UNCLEAR
• SEVOFLURANE HEPATOTOXICITY HAS BEEN REPORTED AT LEAST 9 TIMES
• 55% OF CASES WERE IN FEMALE PATIENTS
• 33% OF CASES WERE IN MALE PATIENTS
• IN 11% OF CASES THE SEX WAS UNKNOWN
• DEATH OCCURRED IN 44% OF PATIENTS AND OF THE PATIENTS THAT DIED, ALL WERE FEMALE.
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SUMMARY: IF METABOLISM IS THE KEY….
• WHY DID HEPATOTOXICITY OCCUR WITH DESFLURANE AND SEVOFLURANE?
• ARE THERE SUSCEPTIBLE PERSONS OR CONDITIONS THAT INCREASE SUSCEPTIBILITY DESFLURANE OR SEVOFLURANE HEPATOTOXICITY?
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WHAT ARE THE ACCEPTED MECHANISMS OF HEPATOTOXICITY FROM SEVOFLURANE AND
METHODS FOR CONFIRMATION OF THE DIAGNOSIS.
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CHARACTERISTICS OF IMMUNE-MEDIATED HEPATOTOXICITY FROM ANESTHETICS
• FEMALE
• URTICARIA OR SKIN RASH, SUGGESTING A DRUG ALLERGY
• EOSINOPHILIA
• SERUM AUTOANTIBODIES TO CYTOCHROME P450 2E1 (CYP2E1)
• SERUM ANTI-DRUG METABOLITE (TFA)
• LIVER INFLAMMATION ± FULMINANT LIVER FAILURE
• MILD OR MODERATE INCREASES IN LIVER ENZYMES
• FAMILY HISTORY OF AUTOIMMUNE DISEASE
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European Journal of ImmunologyVolume 39, Issue 6, pages 1652-1663, 4 JUN 2009 DOI: 10.1002/eji.200838135http://onlinelibrary.wiley.com/doi/10.1002/eji.200838135/full#fig7
WE NOW KNOW THIS……
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European Journal of ImmunologyVolume 39, Issue 6, pages 1652-1663, 4 JUN 2009 DOI: 10.1002/eji.200838135http://onlinelibrary.wiley.com/doi/10.1002/eji.200838135/full#fig7
CFA(viral
Mimic)
CFA+
TFA-S100
S100(liver
Proteins)
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McCarthy E, et al., mSphere, 2018
CYP2E1
WE ALSO KNOW THIS……
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PATIENTS WITH ANESTHETIC HEPATOTOXICITY DEVELOP ANTIBODIES TO ONE IMMUNOGENIC
PIECE OF CYP2E1
McCarthy E, et al., mSphere, 2018
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SUMMARY: IMMUNE-MEDIATED HEPATOTOXICITY
Activation of the Immune System
Cytokine, Chemokine or Other Tissue Factor Release
End Organ Inflammation/Immune dysregulation
Stress Chemical Antigens/Drug Metabolites
Viruses
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COULD REGULATORY CELLS BE UTILIZED TO REDUCE IMMUNE RESPONSES IN SEVOFLRANE OR
DESFLURANE HEPATOTOXICITY?
T regsB regs
Natural Killer CellsMacrophages
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Cottagiri M, et al., Cellular and Molecular Immunology, 2018
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IN ANESTHETIC HEPATOTOXICITY, IL-33 IS UPREGULATED WHILE IPEX IS DOWN-REGULATED
IL-3
3 (
pg
/mL
)
C o n t r o l An e s th e t ic H e p a t it is 0
2
4
6
8 * * *
0
5 0
1 0 0
1 5 0
2 0 0
2 5 0
IPE
X p
g/m
L
* *
C o n tro l A n e s th e tic H e p a titis
Cottagiri M, et al., Cellular and Molecular Immunology, 2018
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DYSREGULATED IL-33- IPEX EXPRESSION PROMOTES ANESTHETIC HEPATOTOXICITY
0 .0 1 0 .1 1 1 00
1 0 0
2 0 0
3 0 0
4 0 0
IL -3 3 (p g /m L )
IPE
X (
pg
/mL
)
A n e s th e tic H e p a titis
C o n tro l
R 2 = 0 .0 1
R 2 = 0 .5 *
Cottagiri M, et al., Cellular and Molecular Immunology, 2018
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SUMMARY: DEFICIENCY OF REGULATORY T CELLS INCREASES
HEPATOTOXICITY SEVERITY IN FEMALES
Females
MalesAnesthetic hepatotoxicity
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WHAT ARE THE GAPS IN KNOWLEDGE SURROUNDING THE PREVALENCE AND
MECHANISMS OF SEVOFLURANE HEPATOTOXICITY AND CAN WE BEGIN TO DISCUSS HOW THEY MAY
BE ADDRESSED
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WHAT IS THE INCIDENCE OR PREVALENCE OF PERIOPERATIVE LIVER INJURY?
WHAT IS THE INCIDENCE OR PREVALENCE OF SEVOFLURANE HEPATOTOXICITY?
IS SEVOFLURANE HEPATOTOXICITY MORE SEVERE IN FEMALES?
COULD T REGULATORY CELL MARKERS BE DEVELOPED AS CHECKPOINTS FOR SEVOFLURANE
OR DESFLURANE HEPATOTOXICITY ?
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Drug-induced hepatotoxicity: incidence of abnormal liver function tests consistent with volatile anaesthetic hepatitis in trauma patients
Jonathan Lin, David Moore, Brad Hockey, Rachel Di Lernia, Alexandra Gorelik, Danny Liew and Amanda Nicoll
Forty-seven (3%) of 1556 patients had abnormal post-operative liver biochemistry potentially attributable to volatile anaesthetic.
Liver Int. 2014 Apr;34(4):576-82
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ACKNOWLEDGMENTS AND QUESTIONS
MOUSE MODEL• JENELLE MELLERSON, MPH
• NICOLE WASHINGTON, RN, BSN
• MONICA TALOR, MS
• DELISA FAIRWEATHER, PHD
REGULATORY T CELLS
• ZHAOXIA LI, MD, PHD
• JOONHEE CHO, MD MS
• LINA KIM, MS
Regulatory B cells
• Merylin Cottagiri, MS• Maeva Nyandjo
CYP2E1 Epitope
• Elisa McCarthy• Zhaoxia Li, MD, PhD• Joonhee Cho, MD MS