Post on 18-Feb-2020
BM 10.01.2013 SG ISP Symposium 1
Lebertransplantation Wann muss man daran denken?
B. Müllhaupt Gastroenterology and Hepatology
Swiss HPB-Center University Hospital Zurich
17. St. Galler IPS-Symposium 2013 LEBER – akutes Leberversagen
15.01.2013
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44j Frau
HE: - - +
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Outline
• Definition • Clinical presentation
– Encephalopathy – Infections – Renal Failure – Liver replacement therapy
• Outcome & Transplantation
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Time up to >15 years
Liver
func
tion
Acute Hepatic Failure (5%) 100%
Liver failure
Acute on Chronic Hepatic Failure (95%)
INR>1.5
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Acute liver failure INR > 1.5 + encephalopathy
• w/o preexisting liver disease
• Duration of less than 26 weeks
Exceptions in spite on the possibility of cirrhosis:
• Wilson‘s disease
• Vertically acquired hepatitis B
• Autoimmune hepatitis
if disease known <26 weeks
Lee et al Hepatology 2011
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Principles of Care
1. Identification and removal of cause of hepatic injury
2. Optimization of conditions for hepatic regeneration
3. Anticipation and prevention of complications
4. Early identification and transplantation of non-survivors
Lee et al Hepatology 2011
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NAC Paracetamol
Keays et al BMJ 1991:303;1026-9
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NAC Protocol
IV Protocol • Loading dose of 150 mg/kg over 15 min • 50 mg/kg over four hours. • 100mg/kg over 16 hour • Continue the final infusion until death, transplantation or recovery from
encephalopathy
Oral Protocol • Loading dose of 140 mg/kg.
• Dose of 70 mg/kg every four hours for a total of 17 doses.
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NAC for Non-Paracetamol
Lee et al Gastroenterol 2009;137:856-64
173 pts with Non-Paracetamol ALF
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Outline
• Definition/Etiology • Clinical presentation
– Encephalopathy – Infections – Renal Failure – Liver replacement therapy
• Outcome & Transplantation
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• Liver Excretion: Jaundice Synthesis: Coagulopathy (Konakion iv, but no FFP!) Metabolism: Hypoglycemia (Monitoring!) Detoxification: Encephalopathy and Brain Edema (no
sedatives,no opiates) Perfusion: Portal Hypertension (Late!)
• Immune-Defence Infections • Cardiovascular (SVRS low, CI high, VO2 low)
• Renal Dysfunction • Pulmonary Problems
Systems Involved in FHF
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Encephalopathy & Brain Edema
Encephalopathy Brain edema
Stage 1: Lack of awareness rarely
Euphoria or anxiety
Asterixis can be detected
Stage 2: Lethargy or apathy rarely
obvious asterixis
Stage 3: Somnolence to semistupor 25-35%
Stage 4: Coma 65-75%
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Ammonia & HE
Clemmesen et al. Hepatology 1999:29:648-653
44 pts with HE III-IV Mostly ACT
80 pts with ALF Mostly HEV
Bhatia et al Gut 2006;55:98-104
Bernal et al Hepatology 2007;46:1844-52
358 pts with ALF Mostly ACT
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Astrocyte
Presynaptic Nerve
Terminal
Postsynaptic Neuron
Capillary
Encephalopathy & Brain Edema Glutamine Hypothesis
modified from Blei et al. J Hepatol 31: 771-776, 1999
Neurochemistry Inter 2005;47:71-77
GLN
GLU
GS
GLN
GLU
GLU GLT-1
NH3
ARG CIT nNOS NO? CBF
CO? Ox Stress HO-1
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Management „noli me tangere“ NO SEDATIVES, NO OPOIDS Lactulose (HE Grad 1-2) Intubation (HE > Grade 3)
Encephalopathy & Brain Edema
Bernal et al. Sem Liv Dis 2008;28:188-200
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Astrocyte
Presynaptic Nerve
Terminal
Postsynaptic Neuron
Capillary
Glutamine Hypothesis
ARG CIT nNOS NO CBF
GLN
GLU
GS
GLN
GLU
GLU GLT-1
NH3
Phenytoin?
Hypothermia Indomethacin Hyperventilation
Hypertone NaCl
Mannitol
CO? Ox Stress HO-1
Stravitz et al Crit Care Med 2007;35:2498-2508
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Encephalopathy & Brain Edema
• Monitoring:
– Jugular Bulb O2
(Routine Kings Collg, if intubated) – Transcranial Doppler, etc
– ICP (epidural, subdural,intraparenchymal)
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Use of ICP monitoring
332 pts with ALF and HE III-IV
28%
Vaquero et al. Liver Transpl 2005;11:1581-89
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Use of ICP monitoring
Vaquero et al. Liver Transpl 2005;11:1581-89
No ICP
No ICP ICP ICP
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Infections in ALF
• Bacterial: ~90% of cases - proven in 80% - suspected in 10% - cause of death in 11%
• Fungal: 1/3 of cases - cause of death in 13% - >90% Candida albicans - mostly with bact infection - mortality 2/3
Rolando et al. Hepatology 1990:11: 49-53, Gazzard et al. Q J Med 1975;176: 615-626, Larcher et al. Gut 1982; 23:1037-1043, Rolando et al. J Hepatol 1991:12: 1-9,
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Chest 51% (5d)
UTI 21.6% (2d)
IV Lines 11.8%
Blood only 15.7% (3d)
Sites/Timing
Bacterial Infections in ALF
! 30% w/o Fever and
elevated WBC count !
Rolando et al. Hepatology 1990;11:49-53
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Pragmatic Approach
• Low threshold
• Routine antibacterial and antifungal to all with: – HE III/IV
– Fullfilling/likely fullfilling transplant criteria
– Signs of systemic inflammation but no HE
Stravitz et al Crit Care Med 2007;35:2498-2508
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Frequency of Renal Failure in ALF
• 22/40 (55%) consecutive pts with FHF – 70% of paracetamol-induced FHF – 50% of FHF due to other causes
• Form of Renal Failure – 60% „functional“ (prerenal/HRS) – 20% ATN – 20% indeterminate
Ring-Larsen et al. Gut 1981:22;585-591
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Renal Failure and Prognosis of ALF
O‘Grady et al. Gastroenterology 1989;97:439-445
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Management of RF in ALF
• Identify and correct precipitating causes (sepsis, drugs, hypovolemia,)
•Aim: MAP >65 mm Hg
•(Early) continuos Hemofiltration (if OLT-candidate)
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Potential for Liver Support • Ex vivo Pig Liver Perfusion • Hepatocyte Transplantation
• Stem Cell Transplantation
• Artificial Livers
•No trials showing evidence for improvement
• Bioartificial Livers
(BAL=neg trial Demetriou et al Ann Surg 2004;239: 660–670)
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Potential for Liver Support • High volume plasma exchange (PE)
• RCT 192 pat SMT vs SMT + high volume PE (10l daily) for 3d
• 1998-2009
Larsen et al. AASLD 2010
No effect in pts undergoing liver transplantation
48
59
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SMT SMT+PE
Sur
viva
l
HR: 0.56 (0.36-0.86) p=0.0083
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Outline
• Definition/Etiology • Clinical presentation
– Encephalopathy – Infections – Renal Failure – Liver replacement therapy
• Outcome & Transplantation
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Outcome
Williams R. Sem Liv Dis 1996;16:343-348
Bernal AASLD 2010
76
55
434038
2322200
20
40
60
80
100
73-77 77-79 80-82 83-85 86-88 89-91 92-94 2008
Mannitol
OLT Liver Failure Unit
n = 3305 patients
Decrease in ICH from 57% (73-8) to 19% (04-08)
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Outcome
Ostapowicz et al Ann Intern Med 2002;137;947-54
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Dilemma of OLT in ALF Window for OLT
Natural History ? critical
limit for survival
Need for prognostic scores • Referral • Listing
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Referral to transplant center
1. Patients with ALF should be admitted and
monitored frequently, preferably in an ICU (III).
2. Contact with a transplant center and plans to
transfer appropriate patients with ALF should be
initiated early (HE I-II) in the evaluation process
(III). LEE, LARSON, AND STRAVITZ
Lee et al Hepatology 2011
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Kings College Criteria for SU Listing
Paracetamol pH <7,3 or All three of the
following – PTT (INR) >6.5 – Crea >300 umol/l – Encephalopathy 3/4
Non-Paracetamol PTT (INR) > 6.5 or >3 of following
– Age <10 or >40 yrs. – Drug-induced/NANB – Jaundice >7d prior E – INR > 3.5 – Bilirubin >300 umol/l
O‘Grady et al Gastroenterology 1989;97: 439-445
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PPV % NPV % Acc %
(range) (range) (range)
Paracetamol 73-84 71-94 72-92
Non-Para 68-98 25-82 61-94
Kings College Criteria for SU Listing
Riordan et al Sem Liver Dis 2003;23:203-215
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Clichy Criteria for SU Listing
Bernuau et al. J Hepatol 1996:25 (suppl 1);63
Survival w/o OLT Criteria pos. 11%
Age <30 yrs. >30 yrs.
Faktor V <20 % <30%
Encephalop. + +
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Clichy Criteria for SU Listing
88/110 Paracetamol Izumi et al. Hepatology 1996;23:1507-11
Paracetamol PPV Acc
<20% + HE I-IV 49 56
<20% +HE III-IV 73 80
KCH 92 83
Acute liver failure study group index
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Coma grade II-IV
Bilirubin
INR
Phosphat
Log M-30
Threshold value: 0.4285
Sens: 85.6, Spec 64.7, ACC 75.7 Rutherford et al. Gastroenterol 2012;143:1237-43
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Outcome of FHF (3 weeks)
Ostapowicz et al Ann Intern Med 2002;137;947-54
308 patients
Spont Survivers 132 (43%)
Transplanted 89 (29%)
Dead bef OLT 77 (28%)
Died 14 (16%)
Alive 75 (84%)
INR > 1.5 and any hepatic encephalopathy
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OLT Survival
Bernal et al Lancet 2010;376:190-201
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Predictors of survival
• Recipient age
• BMI > 29kg/m2
• History of liver support
• Krea > 2mg/dl (180umol/l)
5 yr Survival
4 factors present: 47%
4 factors absent: 83%
Barshes et al Hepatology 2004;40(Suppl 1):A260
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Complications (%) of OLT
FHF ESLD (n=51) (n=233)
Reoperation 37 18
Reintubation 45 19
Tracheostomy 16 3
Bacteremia 45 19
Chest Infection 29 11
Fungal Infection 60 12 all p<0.05
Wade et al. Hepatology 1995: 21: 1328-1336
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SUMMARY - Key Messages
• ALF=syndrom: involves many organ systems
• Dysbalance between damage and repair
• High mortality (brain edema, infections)
• Refer early (Q <40%) to TPL center
• OLT=best available therapy
• (Bio)artificial liver still looks promising???
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Survival USZ
1986-2007
HCC (n=40)
CI (n=101)
ALF (n=19)
2001-2007
HCC (n=55)
CI (n=191)
ALF (n=31)
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Etiology • Paracetamol
• Amanita phalloides
• Virushepatitis (A, B, D, E, HSV)
• M. Wilson
• Autoimmunhepatitis
• Acute fatty liver of pregnancy/HELPP
• Ischemic liver failure
• Budd-Chiari Syndrome
• Malignant infiltration
• Unknown
• Medi-toxic
Charcoal (<4h)
Charcoal, Silymarin
NA, Acyclovir
Pencillamin
Steroids
Delivery
Bernal et al Lancet 2010;376:190-201
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Etiologies of ALF
Stravitz et al: Nat. Rev. Gastroenterol. Hepatol. 2009;6:542-553