Plancher fra Fin Stolze Larsen´s oplæg

Leverforeningen
Ringsted 2014
Leversvigt og hjernepåvirkning
Patienter med kronisk leversygdom
(”acute-on-chronic liver failure”)
Patienter med akut leversvigt
”acute liver failure”
Fin Stolze Larsen
Overlæge, dr.med., phd, Hepatologisk klinik, Rigshospitalet
Hyppighed af kronisk leversygdom –
Skrumpelever = cirrose per år
Der er er 12.000 patienter med cirrose i Danmark
Der er 1.700 nye patienter der får diagnosticeret cirrose i
Danmark
Forløbet er forskelligt fra sygdom til sygdom
De fleste har en velkompenseret sygdom uden
komplikationer
Der udføres ca.50 levertransplantationer per år i Danmark
Årsager til cirrose
Primær biliær cirrose
Primær scleroserende kolangitis
Autoimmun hepatitis
Alkoholisk leversygdom
Kronisk hepatitis C
Kronisk hepatitis B
Sekændær biliær cirrose
Medicin
Ukendte årsager
Hjertesvigt
Hepatisk encefalopati (HE) - levercoma
 En alvorlig, reversibel, neuropsykiatrisk forstyrrelse
 Er associeret med ophobning af toxiner og inflammation
 Er en komplikation som ses ved akut eller ved cirrose
 Udvikling af HE er et alvorligt på decompensation – truende leversvigt
 HE er karakteriseret ved et bredt spectrum af neuropsykiatric manifestationer:
 Subtle, neurological abnormalities and changes in cognition (e.g. changes in
reaction times in daily activities, such as driving)
Sværhed-  Significant neurological impairment and clinical changes in intellect, behaviour,
motor function and consciousness
graden af
symptomer  In extreme cases patients may present with coma
1Mullen
2Morgan,
In Sherlock's Disease of the Liver and Biliary System,
12th
et al, Sem Liv Dis, 2007.
ed: Blackwell Publishing Ltd; 2011.
Prognosen og overlevelsen hos patienter med
cirrose og HE
 HE at baseline: 5-year mortality is 85%
Døde (%)
100
Hepatic encephalopathy
Ascites + variceal bleeding
Ascites alone
Variceal bleeding alone
No complications
0
1
2
3
4
5
Jepsen et al, Hepatology, 2010;51:1675–82.
Klassifikation af HE
 Type A:
ved akut leversvigt
 Type B:
ved shunt (“portal systemic bypass” uden leversydom
 Type C:
ved cirrose med portal hypertension med eller uden
shunts
Hvordan viser HE sig ?
minimal HE
HE grade (West-Haven criteria)
HE grade (West-Haven criteria)
HE grade (West-Haven criteria)
4
4
4
3
3
3
2
2
Clinical detection
level
1
0


kronisk HE
Episodisk HE
Clinical
detection
level
1
1
0
Day to month
Not clinically detectable
West-Haven score 0




2
0
Day to month
Recurrent episodes
Clinically undetectable between
episodes
Episodic cognition changes
West-Haven score 1-4



Clinical detection
level
Day to month
Above clinical detection
level but changes may be
subtle
May have acute episodes of
greater severity
West-Haven score 0-4
Bajaj, Aliment Pharmacol Ther, 2010;31:537–47.
Ferenci et al, Hepatology, 2002;36:716–21.
Cordoba & Minguez. Sem Liv Dis
2008
Common Precipitating Factors for HE
 50-80% of patients with episodic HE have identifiable precipitant
Hypovolemia/
diuretics
• Hyponatriaemia common.
• Hypokalemia and alkalosis facilitates ammonia production
• Dehydration may precipitate worsening mental function in previously
controlled HE
Renal failure
• Reduced clearance of urea, ammonia and other nitrogenous products
Upper
GI bleed
• Blood in GI tract leads to increased ammonia and nitrogen absorption
• May lead to kidney hypoperfusion and impaired renal function
Infection
• Tissue catabolism
• Impaired renal function
increased blood ammonia
Constipation
• Increases intestinal production and absorption of ammonia
Psychoactive
medication
• Worsen symptoms of HE
TIPS
Dietary
protein
• HE is the most common complication of TIPS
• Related to liver hypoperfusion and increased availability of toxins
• Infrequent cause
Wolf. www.emedicine.medscape.com/article/186101.
Nolte et al, Hepatology, 1998;1215–55.
Behandling af HE: overblik
 Vigtige behandlingsmål
 Sikre ABC
Toxiner
(e.g. NH3)
 Identifikation og
eliminering af udløsende
faktorer
 Nedsætte nitrogen “load”
(ammonia) i tarmen
 Episodisk HE: forhindre
“trigger faktors”
 Kronisk HE: Focus på at
forbedre patient’ens
kliniske tilstand og QoL
Patienten
ABC
1Blei
2Morgan,
Udløsende
faktor
& Cordoba, Am J Gastroenterology, 2001; 96(7):1968–76.
In Sherlock's Disease of the Liver and Biliary System. 12th ed: Blackwell Publishing Ltd; 2011.
Behandlinger for HE
 Ammonium-reducerende behandlinger
 Ikke-optagelige disaccharides
 Antibiotika (e.g. Neomycin,vancomycin, rifaximin-α)
 L-Ornithine-L-Aspartate (Hepa-Merz)
 Diæt med lavt protein indhold; Ikke anfalet
 Behandling for “False neurotransmitter hypothesis”
 Forgrenede aminosyre
 Behandling for “GABA-hypothesis”
 Anti-benzodiazepin receptor antagonist (i.e. Flumazenil)
 Andre
 Zinc
Ferenci, Sem Liv Dis, 2007.
Laktulose til at forhindre HE
Patients with HE (%)
*
*p=0.03
Sharma et al, J Gastroenterol Hepatol, 2011; 26: 996-1003.
Lactulose for at forhindre gentagelse af udvikling af HE
Probability of breakthrough hepatic encephalopathy
1.0
Placebo (n=64)
Lactulose (n=61)
0.8
0.6
0.4
p=0.001
0.2
0.0
2
4
8
10
12
14
16
18
20
38
28
28
19
10
13
7
8
1
4
Follow-up (months)
Patients at risk
Lactulose
Placebo
6
61
64
60
62
59
59
58
50
51
37
45
33
Sharma et al, Gastroenterology, 2009;137:885–91.
Antibiotika til behandling af HE
 Bacteria equipped with urease can produce ammonia1
Urea + H2O  CO2 + NH3
 Therefore antibiotics targeting these bacteria can reduce the ammonia
load2
 Adverse effects and risk of opportunistic infections
(i.e. Clostridium difficile).
 Commonly used traditional antibiotics for HE1,2,3:
 Neomycin
 Metronidazole
 Vancomycin
1Morgan,
In Sherlock's Disease of the Liver and Biliary System. 12th ed: Blackwell Publishing Ltd; 2011.
2Phongsamran et al, Drugs, 2010; 70(9):1131–48.
3Mullen et al, Sem Liv Dis, 2007.
Antibiotika: Neomycin
Study
Population
Design
Results
Strauss et al,
Hepatogastroenterology
1992
39 hospitalised
Control of precipitating factors + Mortality, or average time to
cirrhotic pts (mostly
protein restriction + neomycin regression of HE, similar with
Child-Pugh C) with
(1 g every 4 h) or placebo
both regimens
grades I-III HE
Blanc et al,
Gastroenterol Clin
Biol
1994
80 cirrhotic pts with
grades II-IV HE
 Mortality and recovery
similar with both regimens;
 Lactulose/-neomycin
generally not-well tolerated
5 days treatment with placebo
(n=40) or lactulose-neomycin
(n=40)
Side-effects
Ototoxicity
Nephrotoxicity
Staphylococcal
enterocolitis
Miglio et al, Curr
Med Res & Opin
1997
49 cirrhotic patients 6 months (14 days/mth) treatment
with grade I-II HE
with neomycin
(1 g tid, n=24) or rifaximin (400
mg tid, n=25)
Both treatments reduce NH3
levels, p<0.001, and
neuropsychotic symptoms
1Strauss
et al, Hepatogastroenterology, 1992;39(6):542–5.
et al, Gastroenterol Clin Bpol, 1994;18(12):1063–8.
3Miglio et al, Curr Med Res Opin, 1997;13(10):593–601.
2Blanc
Metronidazol og Vancomycin
Study
Morgan et al, Gut
1982
Tarao et al,
Gut 1990
Population
Design
18 cirrhotic patients Cross-over trial of neomycin
(mostly hospitalised)
4g/d or metronidazole
with mild to severe HE
800 mg/d for 7 days
12 cirrhotic pts with
HE (mostly
grade II).
Unresponsive to
lactulose
Double-blind, cross-over
trial with all pts given oral
vancomycin 2g/d for 8
weeks and then lactulose
(titrated to 2-4 stools/day) or
continuing vancomycin
2d/d;
Results
Side-effects
14/18 improved; no
difference between
neomycin and
metronidazole
Peripheral
neurotoxicity
Grade of HE
improved in all pts
after vancomycin,
but lack of placebo
group clouds
interpretation of
results
Enteric
bacteria
resistance
1Morgan
et al, Gut, 1982;23(1):1–7.
2Tarao et al, Gut, 1990;31(6):702–6.
Rifaximin
Fik HE igen
%
50
Tid til næste HE episode
46
%
100
80
60
22
Rifaximin
550 mg bid
(n=140)
40
Hazard ratio with rifaximin, 0.42
(95% CI, 0.28–0.64)
p<0.001
20
0
Rifaximin
550 mg bid
(n=140)
Placebo
(n=159)
0
Placebo
(n=159)
0
28
56
84
112
140
168
Dage
p<0.001, HR 0.42 (95% CI, 0.28–0.64)
 58% risk reduction (NNT = 4 over 6 months)
Bass et al, N Engl J Med, 2010;362:1071–81.
Rifaximin
Frekvensen og tiden til næste indlæggelse for HE
Gen-indlæggelse (%)
23
25
Patients (%)
100
80
14
60
Rifaximin
Placebo
40
Hazard ratio with rifaximin, 0.50
(95% CI, 0.29–0.87)
p=0.01
20
0
Rifaximin
550 mg bid
(n=159)
Placebo
(n=140)
0
0
28
56
84
112
140
168
Dage
50% risk reduction (NNT=9 over 6 months)
Bass et al, N Engl J Med, 2010;362:1071–81.
Rifaximin versus Lactulose
 15 days treatment
PSE score
3
Rifaximin 1200 mg/d (n=30)
2
*
1
x
*p<0.01 vs control group
xp<0.01 vs baseline
Lactulose 30 g/d (n=28)*
*
*
x
x
12
15
0
3
6
9
Tid (dage)
*dose adjusted if diarrhoea
Bucci et al, Curr Med Res Opin, 1993;13(2):109–18.
Rifaximin versus Lactulose
Bivirkninger
Rifaximin
(n=30)
Lactulose
(n=28)
–
15 (53.6%)
Mavesmerter
2 (6.7%)
1 (3.6%)
Flatulence /udspilet mave
5 (16.7%)
17 (60.7%)
Mavekatar
“ondt i maven”
–
13 (46.4%)
Nedsat appetit
–
1 (39.3%)
2 (6.7%)
8 (28.6%)
Bivirkning
Diare
Vægt-tab
Bucci et al, Curr Med Res Opin, 1993;13(2):109–18.
Nye behandlinger:
I stedet for L-ornithine-L-aspartate ”LOLA”
(HepaMerz) kommer måske L-ornithine phenylacetate
Ytrebø & Jalan,
Hepatology 2009
Sygehistorie om atypisk HE
•
•
•
•
•
•
•
•
•
Mand, 59 år
kronisk Hep C and Alk Cirrose
1994-blødning fra esophagus varicer
DM-”End stage kidney disease” (2008).
Mid 2008 Hemodialysis x 3 per uge
2008-9, Hospital – en gang om ugen med HE
Altid træt, Flyttet til plejehjem
UL: cirrosis, ingen ascites.
Gastroskopi: store varicer i mavesækken
Andre årsager til encefalopati
sygehistorie
•
•
•
•
PP (=koag. Faktor II, VII, X) normal
INR 1,0 = Normal
Bilirubin 10 = Normal
Albumin 33 = let nedsat
Portal blood flow into V. Coronaria
Portal venous system
3-Phase CT
Large Gastric Varices
Cava
Left Renal Vein
Portal blood flow into left Renal Vein
Balloon-occluded Retrograde Transvenous Obliteration
(BRTO) of spleno-renal shunt with Aetoxysclerol
Ballon
9 måneder senere
•
•
•
•
•
Ingen ny blødning i efterforløbet
Ingen varicer
Ingen ascites
Ammonium normal
Ingen genindlæggelser
Akut leversvigt
• Udvikling af HE inden for 26 uger efter påvist
leverskade hos en patient uden tidligere kendt
leversygdom
• HE grad (III-IV): Hyppigheden er 10/million
• Tidligere var dødeligheden (uden lever-Tx) 80 %
Akut leversvigt
Udløsende årsager
•
•
•
•
•
•
•
Paracetamol
Hepatitis A, B (C, E)
Ukendt årsag
Medicin og andre stoffer (disulfiram, halothan, ect.)
Amantatoxin (svampeforgiftning)
Budd-Chiari (blodprop i levervenerne)
Autoimmun hepatitis (akut lever-gigt)
• Mefødte metaboliske sygdomme (urea cycle
defects, Wilsons sygdom)
• Hjertesvigt
Årsager hos 3300 patienter behandlet på Kings College Hospital
Bernal W et al. J Hepatol, Feb. 2013,
Komplikationer som påvirker hjernen hos
patienter med leversygdom
• Høj ammonium
• Svær infektion / sepsis – “septic encephalopathy”
• Ændringer I det systemiske kredsløb med lavt blodtryk
• Lavt blodsukker
• Lungeskade (ARDS, hepatopulmonalt syndrom og
portopulmonal hypertension) med hypoxia
•
•
•
•
Elektrolyt ændringer – lav Na+ og phosphate
Nyresvigt
Koagulopati - blødning
Lave trombocyter - blødning
Rolando et al 1997, 2000
Rahman & Hodgson. 2001
Schmidt & Larsen 2006
Quantitative liver function
Behandlingsprincip
I
Intensive care
II
Coma limit
Liver support
Survival limit
Liver transplant or death
III
Regeneration limit
Time since insult
Ranek & Tygstrup 1973
Nedkøling
Jalan et al. Lancet 1999, Transplantation 2003
Indomethacin
Tofteng et al. J CBF & Metabol. 2004
Antal patienter med hjerneødem
Overlevelse ved akut leversvigt
Bernal W et al. J Hepatol, Feb. 2013,
Lever- erstatnings behandling …. fremtiden?
Advantages:
• Removes all molecules
• Substitutes plasma products
– coagulation factors
• Is well tolerated
– Improves HE, CMRgl and O2
– increases CPP and CBF
– No effect upon ICP,
– Increases MAP & SVRI
– Decreases CI/DO2 but not
VO2
– Increases splanchnic removal
NH4+
Disadvantages:
• Limited transport of water-soluble
substances
• Unselective removal substances
• Requires donor plasma
Transport: filtration/convection
Membrane: plasma-filter
Replacement: donor plasma
Toxins: all; entire plasma phase
Overlevelse efter plasmaferese
LTx censored survival
Cumulative Proportion Surviving (%)
100%
90%
LogRank: p=0.0058
SMT
HVP
80%
70%
HVP (n=92)
60%
50%
40%
30%
SMT (n=90)
20%
10%
0%
0
7
14
21
28
35
42
49
Time (days)
56
63
70
77
84
Survival for each group
Cumulative Proportion Surviving (%)
100%
-HVP/+LTx (n=32)
90%
80%
+HVP/+LTx (n=24)
70%
60%
+HVP/-LTx (n=68)
50%
40%
30%
20%
-HVP/-LTx (n=58)
Cox proportional hazard:
LTx: p=0.000002
HVP: p=0.0076
10%
0%
0
7
14
21
28
35
42
49
Time (days)
56
63
70
77
84
Overlevelsen efter levertransplantation ved akut
leversvigt
Admission characteristics and outcome of 387 patients
who underwent ELT for ALF
Bernal W et al. J Hepatol,
Feb. 2013,
Nye lever-erstatningsbehandlinger på vej
•Kunstige lever-erstatning
Hvad betyder det at have HE før lever
transplantation?
RBANS Score (100 = “normal”)
100
98.9
95.4
93.1
*
*
* 93
92.7
95.9
*
94.3
93.9
*
92.5
90.6
**
88.7
**
86.4
75
Immediate
memory
Visuospacial
Language
HE prior to OLT (n=25)
Attention
Delayed
memory
TOTAL
No HE (n=14)
*p<0.05
**p<0.001
Sotil et al, Liver Transpl, 2009; 15: 184–92.
Albumin-dialysis
Advantages:
• Removes albumin-bound
substances
• Has good biocompatibility
• Provides renal replacement
Disadvantages:
Transport: diffusion
• Adverse effects similar to
HD (?)
• Requires albumin
• expensive
Membrane: high-flux
Dialysate: albumin solution
Toxins: albumin-bound + watersoluble
Hassanain et al. Hepatology 2007