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

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

Hyppighed af kronisk leversygdom –

Skrumpelever = cirrose per år

Primær biliær cirrose

Primær scleroserende kolangitis

Autoimmun hepatitis

Alkoholisk leversygdom

Kronisk hepatitis C

Kronisk hepatitis B

Sekændær biliær cirrose

Medicin

Ukendte årsager

Hjertesvigt

Årsager til cirrose

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)

Significant neurological impairment and clinical changes in intellect, behaviour,

motor function and consciousness

In extreme cases patients may present with coma

1Mullen et al, Sem Liv Dis, 2007. 2Morgan, In Sherlock's Disease of the Liver and Biliary System, 12th ed: Blackwell Publishing Ltd; 2011.

Sværhed-

graden af

symptomer

Prognosen og overlevelsen hos patienter med

cirrose og HE

HE at baseline: 5-year mortality is 85%

Jepsen et al, Hepatology, 2010;51:1675–82.

100

0 1 2 3 4 5

Døde (%)

Hepatic encephalopathy

Ascites + variceal bleeding

Ascites alone

Variceal bleeding alone

No complications

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 ?

Not clinically detectable

West-Haven score 0

Recurrent episodes

Clinically undetectable between

episodes

Episodic cognition changes

West-Haven score 1-4

Bajaj, Aliment Pharmacol Ther, 2010;31:537–47. Ferenci et al, Hepatology, 2002;36:716–21.

Above clinical detection

level but changes may be

subtle

May have acute episodes of

greater severity

West-Haven score 0-4

1

2

3

4

0 Day to month

Clinical

detection

level

Episodisk HE

HE grade (West-Haven criteria)

1

2

3

4

0 Day to month

minimal HE

HE grade (West-Haven criteria)

Clinical detection

level

1

2

3

4

0 Day to month

kronisk HE

HE grade (West-Haven criteria)

Clinical detection

level

Cordoba & Minguez. Sem Liv Dis

2008

Common Precipitating Factors for HE

Wolf. www.emedicine.medscape.com/article/186101.

Nolte et al, Hepatology, 1998;1215–55.

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

Constipation • Increases intestinal production and absorption of ammonia

Psychoactive medication

• Worsen symptoms of HE

Hypovolemia/ diuretics

• Hyponatriaemia common. • Hypokalemia and alkalosis facilitates ammonia production • Dehydration may precipitate worsening mental function in previously

controlled HE

Dietary protein

• Infrequent cause

Infection • Tissue catabolism • Impaired renal function

increased blood ammonia

TIPS • HE is the most common complication of TIPS • Related to liver hypoperfusion and increased availability of toxins

50-80% of patients with episodic HE have identifiable precipitant

Behandling af HE: overblik Vigtige behandlingsmål

Sikre ABC

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

1Blei & Cordoba, Am J Gastroenterology, 2001; 96(7):1968–76. 2Morgan, In Sherlock's Disease of the Liver and Biliary System. 12th ed: Blackwell Publishing Ltd; 2011.

Patienten

Toxiner

(e.g. NH3)

Udløsende

faktor ABC

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

Sharma et al, J Gastroenterol Hepatol, 2011; 26: 996-1003.

Patients with HE (%)

*

*p=0.03

Lactulose for at forhindre gentagelse af udvikling af HE

Sharma et al, Gastroenterology, 2009;137:885–91.

Follow-up (months)

1.0

0.8

0.6

0.4

0.2

0.0 2 4 6 8 10 12 14 16 18 20

p=0.001

Probability of breakthrough hepatic encephalopathy

Patients at risk

Lactulose

Placebo

61

64

60

62

59

59

58

50

51

37

45

33

38

28

28

19

10

13

7

8

1

4

Placebo (n=64)

Lactulose (n=61)

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

1Strauss et al, Hepatogastroenterology, 1992;39(6):542–5.

2Blanc et al, Gastroenterol Clin Bpol, 1994;18(12):1063–8.

3Miglio et al, Curr Med Res Opin, 1997;13(10):593–601.

Study Population Design Results Side-effects

Strauss et al,

Hepatogastro-

enterology

1992

39 hospitalised

cirrhotic pts (mostly

Child-Pugh C) with

grades I-III HE

Control of precipitating factors +

protein restriction + neomycin

(1 g every 4 h) or placebo

Mortality, or average time to

regression of HE, similar with

both regimens

Ototoxicity

Nephrotoxicity

Staphylococcal

enterocolitis

Blanc et al,

Gastroenterol Clin

Biol

1994

80 cirrhotic pts with

grades II-IV HE

5 days treatment with placebo

(n=40) or lactulose-neomycin

(n=40)

Mortality and recovery

similar with both regimens;

Lactulose/-neomycin

generally not-well tolerated

Miglio et al, Curr

Med Res & Opin

1997

49 cirrhotic patients

with grade I-II HE

6 months (14 days/mth) treatment

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

Metronidazol og Vancomycin

1Morgan et al, Gut, 1982;23(1):1–7.

2Tarao et al, Gut, 1990;31(6):702–6.

Study Population Design Results Side-effects

Morgan et al, Gut

1982

18 cirrhotic patients

(mostly hospitalised)

with mild to severe HE

Cross-over trial of neomycin

4g/d or metronidazole

800 mg/d for 7 days

14/18 improved; no

difference between

neomycin and

metronidazole

Peripheral

neuro-

toxicity

Tarao et al,

Gut 1990

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;

Grade of HE

improved in all pts

after vancomycin,

but lack of placebo

group clouds

interpretation of

results

Enteric

bacteria

resistance

Rifaximin

58% risk reduction (NNT = 4 over 6 months) Bass et al, N Engl J Med, 2010;362:1071–81.

22

46

0

50%

p<0.001, HR 0.42 (95% CI, 0.28–0.64)

%

Dage

Hazard ratio with rifaximin, 0.42

(95% CI, 0.28–0.64)

p<0.001

100

80

60

40

20

0 0 28 56 84 112 140 168

Rifaximin

550 mg bid

Placebo

(n=140)

(n=159) Rifaximin

550 mg bid

Placebo

(n=140)

(n=159)

Tid til næste HE episode Fik HE igen

Rifaximin

50% risk reduction (NNT=9 over 6 months)

Bass et al, N Engl J Med, 2010;362:1071–81.

14

23

0

25Gen-indlæggelse (%) Patients (%)

Dage

Frekvensen og tiden til næste indlæggelse for HE

Hazard ratio with rifaximin, 0.50

(95% CI, 0.29–0.87)

p=0.01

Rifaximin Placebo

100

80

60

40

20

0 0 28 56 84 112 140 168

(n=159)

(n=140)

Rifaximin

550 mg bid Placebo

Rifaximin versus Lactulose

15 days treatment

Bucci et al, Curr Med Res Opin, 1993;13(2):109–18.

*

* *

x x

x

*p<0.01 vs control group xp<0.01 vs baseline

0

1

2

3

3 6 9 12 15

Tid (dage)

PSE score

Rifaximin 1200 mg/d (n=30)

Lactulose 30 g/d (n=28)*

*dose adjusted if diarrhoea

Rifaximin versus Lactulose

Bivirkninger

Bucci et al, Curr Med Res Opin, 1993;13(2):109–18.

Bivirkning Rifaximin

(n=30)

Lactulose

(n=28)

Diare – 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%)

Vægt-tab 2 (6.7%) 8 (28.6%)

Ytrebø & Jalan,

Hepatology 2009

Nye behandlinger:

I stedet for L-ornithine-L-aspartate ”LOLA”

(HepaMerz) kommer måske L-ornithine phenylacetate

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 venous system

Portal blood flow into V. Coronaria

3-Phase CT

Large Gastric Varices

Left Renal Vein Portal blood flow into left Renal Vein

Cava

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

Bernal W et al. J Hepatol, Feb. 2013,

Årsager hos 3300 patienter behandlet på Kings College Hospital

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

Time since insult

Qu

an

tita

tive

liv

er

fun

ctio

n

Coma limit

Regeneration limit

Survival limit

I

III

II

Intensive care

Liver transplant or death

Liver support

Ranek & Tygstrup 1973

Behandlingsprincip

Nedkøling

Jalan et al. Lancet 1999, Transplantation 2003

Indomethacin

Tofteng et al. J CBF & Metabol. 2004

Antal patienter med hjerneødem

Bernal W et al. J Hepatol, Feb. 2013,

Overlevelse ved akut leversvigt

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

0 7 14 21 28 35 42 49 56 63 70 77 84

Time (days)

LTx censored survival

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Cu

mu

lative

Pro

po

rtio

n S

urv

ivin

g (

%)

SMT

HVP

HVP (n=92)

SMT (n=90)

LogRank: p=0.0058

Overlevelse efter plasmaferese

Survival for each group

0 7 14 21 28 35 42 49 56 63 70 77 84

Time (days)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Cu

mu

lative

Pro

po

rtio

n S

urv

ivin

g (

%)

+HVP/+LTx (n=24)

+HVP/-LTx (n=68)

-HVP/-LTx (n=58)

-HVP/+LTx (n=32)

Cox proportional hazard:

LTx: p=0.000002

HVP: p=0.0076

Admission characteristics and outcome of 387 patients

who underwent ELT for ALF

Bernal W et al. J Hepatol,

Feb. 2013,

Overlevelsen efter levertransplantation ved akut

leversvigt

•Kunstige lever-erstatning

Nye lever-erstatningsbehandlinger på vej

Hvad betyder det at have HE før lever

transplantation?

86.4

93.1 92.793.9 94.3

88.7

95.4

90.6

93

98.9

95.9

92.5

75

100

Immediate

memory

Visuospacial Language Attention Delayed

memory

TOTAL

HE prior to OLT (n=25) No HE (n=14)

Sotil et al, Liver Transpl, 2009; 15: 184–92.

*

*

* *

** **

*p<0.05

**p<0.001

RBANS Score (100 = “normal”)

*

Albumin-dialysis

Advantages: • Removes albumin-bound

substances

• Has good biocompatibility

• Provides renal replacement

Disadvantages: • Adverse effects similar to

HD (?)

• Requires albumin

• expensive

Transport: diffusion

Membrane: high-flux

Dialysate: albumin solution

Toxins: albumin-bound + water-

soluble

Hassanain et al. Hepatology 2007