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Leverforeningen Ringsted 2014

Leversvigt og hjernepåvirkning. Leverforeningen Ringsted 2014. 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.

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Leverforeningen Ringsted 2014

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  1. Leversvigt og hjernepåvirkning Leverforeningen Ringsted 2014 Patienter med kronisk leversygdom (”acute-on-chronic liver failure”) Patienter med akut leversvigt ”acute liver failure” Fin Stolze Larsen Overlæge, dr.med., phd, Hepatologiskklinik, Rigshospitalet

  2. 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

  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, neuropsykiatriskforstyrrelse • Erassocieret med ophobningaftoxinerog inflammation • Er en komplikationsomsesvedakutellervedcirrose • Udviklingaf HE er et alvorligtpådecompensation – truendeleversvigt • HE erkarakteriseretved et bredtspectrum afneuropsykiatricmanifestationer: • Subtle, neurological abnormalities and changes in cognition (e.g. changes in reaction times in daily activities, such as driving) • Significantneurological impairment and clinical changes in intellect, behaviour, motor function and consciousness • In extreme cases patients may present with coma Sværhed-gradenafsymptomer 1Mullen et al, Sem Liv Dis, 2007. 2Morgan, In Sherlock's Disease of the Liver and Biliary System, 12th 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 0 5 4 3 1 2 Jepsen et al, Hepatology, 2010;51:1675–82.

  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 ? kronisk HE minimal HE Episodisk HE HE grade (West-Haven criteria) HE grade (West-Haven criteria) HE grade (West-Haven criteria) 4 4 4 • Not clinically detectable • West-Haven score 0 3 3 3 Clinical detectionlevel 2 2 2 Clinical detectionlevel 1 1 1 Clinical detectionlevel 0 0 0 Day to month Day to month 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 PharmacolTher, 2010;31:537–47. Ferenci et al, Hepatology, 2002;36:716–21. Recurrent episodes Clinically undetectable between episodes Episodic cognition changes West-Haven score 1-4

  8. Cordoba & Minguez. Sem Liv Dis 2008

  9. Common Precipitating Factors for HE • 50-80% of patients with episodic HE have identifiable precipitant • Hyponatriaemia common. • Hypokalemia and alkalosis facilitates ammonia production • Dehydration may precipitate worsening mental function in previously controlled HE Hypovolemia/diuretics Renal failure • Reduced clearance of urea, ammonia and other nitrogenous products • increased blood ammonia • Blood in GI tract leads to increased ammonia and nitrogen absorption • May lead to kidney hypoperfusion and impaired renal function Upper GI bleed • Tissue catabolism • Impaired renal function Infection Constipation • Increases intestinal production and absorption of ammonia Psychoactive medication • Worsen symptoms of HE • HE is the most common complication of TIPS • Related to liver hypoperfusion and increased availability of toxins TIPS Dietary protein • Infrequent cause Wolf. www.emedicine.medscape.com/article/186101. Nolte et al, Hepatology, 1998;1215–55.

  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 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.

  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: 996-1003.

  13. 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 2 4 6 8 10 12 14 16 18 20 0.0 Follow-up (months) 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 Sharma et al, Gastroenterology, 2009;137:885–91.

  14. 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.

  15. 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.

  16. Metronidazol og Vancomycin 1Morgan et al, Gut, 1982;23(1):1–7. 2Tarao et al, Gut, 1990;31(6):702–6.

  17. Rifaximin Fik HE igen Tid til næste HE episode • 58% risk reduction (NNT = 4 over 6 months) % % 100 80 60 Rifaximin550 mg bid Placebo (n=159) 40 (n=140) 20 Hazard ratio with rifaximin, 0.42 (95% CI, 0.28–0.64) p<0.001 0 Rifaximin 550 mg bid Placebo 0 28 56 84 112 140 168 (n=159) Dage (n=140) p<0.001, HR 0.42 (95% CI, 0.28–0.64) Bass et al, N Engl J Med, 2010;362:1071–81.

  18. Rifaximin Frekvensen og tiden til næste indlæggelse for HE • 50% risk reduction (NNT=9 over 6 months) Gen-indlæggelse (%) Patients (%) 100 80 60 Rifaximin Placebo 40 20 Hazard ratio with rifaximin, 0.50 (95% CI, 0.29–0.87) p=0.01 0 Rifaximin 550 mg bid Placebo 0 28 56 84 112 140 168 (n=140) Dage (n=159) Bass et al, N Engl J Med, 2010;362:1071–81.

  19. Rifaximin versus Lactulose • 15 days treatment PSE score 3 Rifaximin 1200 mg/d (n=30) * 2 Lactulose 30 g/d (n=28)* * * x 1 *p<0.01 vs control group xp<0.01 vs baseline x x 0 3 6 9 12 15 Tid (dage) *dose adjusted if diarrhoea Bucci et al, Curr Med Res Opin, 1993;13(2):109–18.

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

  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 • 2008-9, 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 encefalopatisygehistorie • 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. Large Gastric Varices Cava Left Renal Vein Portal blood flow into left Renal Vein

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

  27. 9 måneder senere • Ingen ny blødning i efterforløbet • Ingen varicer • Ingen ascites • Ammonium normal • Ingen genindlæggelser

  28. 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 %

  29. 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

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

  31. 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

  32. Behandlingsprincip Ranek & Tygstrup 1973

  33. Nedkøling Jalan et al. Lancet 1999, Transplantation 2003

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

  35. Antal patienter med hjerneødem

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

  37. 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

  38. Overlevelse efter plasmaferese

  39. 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,

  40. Nye lever-erstatningsbehandlinger på vej • Kunstige lever-erstatning

  41. Hvad betyder det at have HE før lever transplantation? RBANS Score (100 = “normal”) * * * * * ** ** *p<0.05 **p<0.001 Sotil et al, Liver Transpl, 2009; 15: 184–92.

  42. 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

  43. Hassanain et al. Hepatology 2007

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