Lebertransplantation Wann muss man daran denken?...BM 10.01.2013 1SG ISP Symposium Lebertransplantation Wann muss man daran denken? B. Müllhaupt Gastroenterology and Hepatology Swiss

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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Outline

• Definition • Clinical presentation

– Encephalopathy – Infections – Renal Failure – Liver replacement therapy

• Outcome & Transplantation


Time up to >15 years

Liver

func

tion

Acute Hepatic Failure (5%) 100%

Liver failure

Acute on Chronic Hepatic Failure (95%)

INR>1.5


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


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



NAC Paracetamol

Keays et al BMJ 1991:303;1026-9


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.


NAC for Non-Paracetamol

Lee et al Gastroenterol 2009;137:856-64

173 pts with Non-Paracetamol ALF


Outline

• Definition/Etiology • Clinical presentation




• 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


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%


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


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


Management „noli me tangere“ NO SEDATIVES, NO OPOIDS Lactulose (HE Grad 1-2) Intubation (HE > Grade 3)


Bernal et al. Sem Liv Dis 2008;28:188-200


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



• Monitoring:

– Jugular Bulb O2

(Routine Kings Collg, if intubated) – Transcranial Doppler, etc

– ICP (epidural, subdural,intraparenchymal)


Use of ICP monitoring

332 pts with ALF and HE III-IV

28%

Vaquero et al. Liver Transpl 2005;11:1581-89


Use of ICP monitoring

Vaquero et al. Liver Transpl 2005;11:1581-89

No ICP

No ICP ICP ICP


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,


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


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


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


Renal Failure and Prognosis of ALF

O‘Grady et al. Gastroenterology 1989;97:439-445


Management of RF in ALF

• Identify and correct precipitating causes (sepsis, drugs, hypovolemia,)

•Aim: MAP >65 mm Hg

•(Early) continuos Hemofiltration (if OLT-candidate)


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)


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

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Sur

viva

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HR: 0.56 (0.36-0.86) p=0.0083


Outline

• Definition/Etiology • Clinical presentation




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)


Outcome

Ostapowicz et al Ann Intern Med 2002;137;947-54

http://www.annals.org/content/vol137/issue12/images/large/7FF1.jpeg


Dilemma of OLT in ALF Window for OLT

Natural History ? critical

limit for survival

Need for prognostic scores • Referral • Listing


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



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


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


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. + +


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


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


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


OLT Survival

Bernal et al Lancet 2010;376:190-201


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


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


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???


Survival USZ

1986-2007

HCC (n=40)

CI (n=101)

ALF (n=19)

2001-2007

HCC (n=55)

CI (n=191)

ALF (n=31)


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


Etiologies of ALF

Stravitz et al: Nat. Rev. Gastroenterol. Hepatol. 2009;6:542-553

Documents

Lebertransplantation Wann muss man daran denken?...BM 10.01.2013 1SG ISP Symposium Lebertransplantation Wann muss man daran denken? B. Müllhaupt Gastroenterology and Hepatology Swiss