Leversvigt og hjernepåvirkning

Transkript

1 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

2 Hyppighed af kronisk leversygdom Skrumpelever = cirrose per år Der er er patienter med cirrose i Danmark Der er 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

3 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

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

5 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 Jepsen et al, Hepatology, 2010;51:

6 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

7 Hvordan viser HE sig? minimal HE HE grade (West-Haven criteria) 4 Episodisk HE HE grade (West-Haven criteria) 4 kronisk HE HE grade (West-Haven criteria) Clinical detection level 3 2 Clinical detection level Day to month 0 Day to month 0 Clinical detection level Day to month Not clinically detectable West-Haven score 0 Recurrent episodes Clinically undetectable between episodes Episodic cognition changes West-Haven score 1-4 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: Ferenci et al, Hepatology, 2002;36:

8 Cordoba & Minguez. Sem Liv Dis 2008

9 Common Precipitating Factors for HE 50-80% of patients with episodic HE have identifiable precipitant Hypovolemia/ diuretics Renal failure Upper GI bleed Hyponatriaemia common. Hypokalemia and alkalosis facilitates ammonia production Dehydration may precipitate worsening mental function in previously controlled HE Reduced clearance of urea, ammonia and other nitrogenous products 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 Psychoactive medication TIPS Dietary protein Increases intestinal production and absorption of ammonia Worsen symptoms of HE HE is the most common complication of TIPS Related to liver hypoperfusion and increased availability of toxins Infrequent cause Wolf. Nolte et al, Hepatology, 1998;

10 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 ABC Toxiner (e.g. NH 3 ) Patienten Udløsende faktor 1 Blei & Cordoba, Am J Gastroenterology, 2001; 96(7): Morgan, In Sherlock's Disease of the Liver and Biliary System. 12th ed: Blackwell Publishing Ltd; 2011.

11 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.

12 Laktulose til at forhindre HE Patients with HE (%) * *p=0.03 Sharma et al, J Gastroenterol Hepatol, 2011; 26:

13 Lactulose for at forhindre gentagelse af udvikling af HE Probability of breakthrough hepatic encephalopathy Placebo (n=64) Lactulose (n=61) p= Patients at risk Lactulose Placebo Follow-up (months) Sharma et al, Gastroenterology, 2009;137:

14 Antibiotika til behandling af HE Bacteria equipped with urease can produce ammonia 1 Urea + H 2 O CO 2 + NH 3 Therefore antibiotics targeting these bacteria can reduce the ammonia load 2 Adverse effects and risk of opportunistic infections (i.e. Clostridium difficile). Commonly used traditional antibiotics for HE 1,2,3 : Neomycin Metronidazole Vancomycin 1 Morgan, In Sherlock's Disease of the Liver and Biliary System. 12th ed: Blackwell Publishing Ltd; Phongsamran et al, Drugs, 2010; 70(9): Mullen et al, Sem Liv Dis, 2007.

15 Antibiotika: Neomycin Study Population Design Results Side-effects Strauss et al, Hepatogastroenterology 1992 Blanc et al, Gastroenterol Clin Biol 1994 Miglio et al, Curr Med Res & Opin hospitalised cirrhotic pts (mostly Child-Pugh C) with grades I-III HE 80 cirrhotic pts with grades II-IV HE 49 cirrhotic patients with grade I-II HE Control of precipitating factors + protein restriction + neomycin (1 g every 4 h) or placebo 5 days treatment with placebo (n=40) or lactulose-neomycin (n=40) 6 months (14 days/mth) treatment with neomycin (1 g tid, n=24) or rifaximin (400 mg tid, n=25) Mortality, or average time to regression of HE, similar with both regimens Mortality and recovery similar with both regimens; Lactulose/-neomycin generally not-well tolerated Both treatments reduce NH 3 levels, p<0.001, and neuropsychotic symptoms Ototoxicity Nephrotoxicity Staphylococcal enterocolitis 1 Strauss et al, Hepatogastroenterology, 1992;39(6): Blanc et al, Gastroenterol Clin Bpol, 1994;18(12): Miglio et al, Curr Med Res Opin, 1997;13(10):

16 Metronidazol og Vancomycin Study Population Design Results Side-effects Morgan et al, Gut 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 neurotoxicity Tarao et al, Gut 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 1 Morgan et al, Gut, 1982;23(1): Tarao et al, Gut, 1990;31(6):702 6.

17 Rifaximin 50 % Fik HE igen 46 % 100 Tid til næste HE episode Rifaximin 550 mg bid (n=140) Placebo (n=159) 0 Rifaximin 550 mg bid (n=140) Placebo (n=159) 20 Hazard ratio with rifaximin, 0.42 (95% CI, ) p< Dage p<0.001, HR 0.42 (95% CI, ) 58% risk reduction (NNT = 4 over 6 months) Bass et al, N Engl J Med, 2010;362:

18 Rifaximin Frekvensen og tiden til næste indlæggelse for HE Gen-indlæggelse (%) Patients (%) Rifaximin Placebo 40 0 Rifaximin 550 mg bid (n=159) Placebo (n=140) 20 Hazard ratio with rifaximin, 0.50 (95% CI, ) p= Dage 50% risk reduction (NNT=9 over 6 months) Bass et al, N Engl J Med, 2010;362:

19 Rifaximin versus Lactulose 15 days treatment PSE score 3 Rifaximin 1200 mg/d (n=30) 2 * Lactulose 30 g/d (n=28)* 1 x * * *p<0.01 vs control group x p<0.01 vs baseline x x 0 *dose adjusted if diarrhoea Tid (dage) Bucci et al, Curr Med Res Opin, 1993;13(2):

20 Rifaximin versus Lactulose Bivirkninger 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%) Bucci et al, Curr Med Res Opin, 1993;13(2):

21 Nye behandlinger: I stedet for L-ornithine-L-aspartate LOLA (HepaMerz) kommer måske L-ornithine phenylacetate Ytrebø & Jalan, Hepatology 2009

22 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 , Hospital en gang om ugen med HE Altid træt, Flyttet til plejehjem UL: cirrosis, ingen ascites. Gastroskopi: store varicer i mavesækken

23 Andre årsager til encefalopati sygehistorie PP (=koag. Faktor II, VII, X) normal INR 1,0 = Normal Bilirubin 10 = Normal Albumin 33 = let nedsat

24 Portal blood flow into V. Coronaria Portal venous system 3-Phase CT

25 Cava Left Renal Vein Large Gastric Varices Portal blood flow into left Renal Vein

26

27 Balloon-occluded Retrograde Transvenous Obliteration (BRTO) of spleno-renal shunt with Aetoxysclerol Ballon

28 9 måneder senere Ingen ny blødning i efterforløbet Ingen varicer Ingen ascites Ammonium normal Ingen genindlæggelser

29

30 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 %

31 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

32 Årsager hos 3300 patienter behandlet på Kings College Hospital Bernal W et al. J Hepatol, Feb. 2013,

33 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 Schmidt & Larsen 2006

34 Quantitative liver function Behandlingsprincip Intensive care Liver support Liver transplant or death III I II Coma limit Survival limit Regeneration limit Time since insult Ranek & Tygstrup 1973

35

36 Nedkøling Jalan et al. Lancet 1999, Transplantation 2003

37 Indomethacin Tofteng et al. J CBF & Metabol. 2004

38 Antal patienter med hjerneødem

39 Overlevelse ved akut leversvigt Bernal W et al. J Hepatol, Feb. 2013,

40 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

41 Overlevelse efter plasmaferese Cumulative Proportion Surviving (%) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% LTx censored survival LogRank: p= HVP (n=92) SMT (n=90) SMT HVP 0% Time (days)

42 Cumulative Proportion Surviving (%) 100% 90% 80% 70% 60% 50% 40% 30% Survival for each group 20% Cox proportional hazard: -HVP/-LTx (n=58) 10% LTx: p= HVP: p= % Time (days) -HVP/+LTx (n=32) +HVP/+LTx (n=24) +HVP/-LTx (n=68)

43 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,

44 Nye lever-erstatningsbehandlinger på vej Kunstige lever-erstatning

45 Hvad betyder det at have HE før lever transplantation? RBANS Score (100 = normal ) ** * * * 93 * ** 88.7 * Immediate memory Visuospacial Language Attention Delayed memory TOTAL *p<0.05 **p<0.001 HE prior to OLT (n=25) No HE (n=14) Sotil et al, Liver Transpl, 2009; 15:

46 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 + watersoluble

47 Hassanain et al. Hepatology 2007