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Hepatische Enzephalopathie und Sarkopenie: pathogenetische Bedeutung und therapeutische Implikationen von Ammoniak

Hepatic encephalopathy and sarcopenia: pathogenic role and therapeutic implications of ammonia

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Zusammenfassung

Hepatische Enzephalopathie und Sarkopenie sind häufige Komplikationen einer Leberzirrhose, die die Prognose dramatisch verschlechtern. Ammoniak spielt eine zentrale Rolle in der Pathogenese der hepatischen Enzephalopathie und dessen Senkung ist das Ziel therapeutischer Ansätze. Neuere Erkenntnisse legen außerdem nahe, dass Ammoniak auch bei der Entstehung der Sarkopenie im Rahmen einer Leberzirrhose entscheidend ist und dieser Pathomechanismus eine potenzielle Zielstruktur für künftige medikamentöse Therapien darstellt. Aufgrund des hohen Risikos, im Rahmen einer Leberzirrhose eine Sarkopenie zu entwickeln, sollten Patienten regelmäßig bezüglich des Ernährungsstatus evaluiert und gegebenenfalls eine weiterführende Sarkopeniediagnostik eingeleitet werden. Während zur Behandlung und Prophylaxe der hepatischen Enzephalopathie neben der adäquaten Ernährungstherapie auch medikamentöse Therapieoptionen bestehen, wird zur Behandlung der Sarkopenie ein multimodaler Ansatz aus Ernährungstherapie und körperlichem Training verfolgt.

Abstract

Hepatic encephalopathy and sarcopenia are common complications of liver cirrhosis with profound implications on prognosis. The importance of ammonia for the pathogenesis of hepatic encephalopathy (HE) is well known and lowering ammonia levels is an accepted therapeutic principal in managing HE. However, there is emerging evidence that ammonia also plays a key role in development of sarcopenia and might provide a target for future pharmacological therapy against sarcopenia. Due to the high risk of malnutrition and sarcopenia, patients suffering from cirrhosis should be evaluated routinely for their nutritional status and, if at risk, diagnostic measures for sarcopenia should be initiated. While there are well-established pharmacological approaches for the treatment of hepatic encephalopathy, sarcopenia requires a multimodal approach with optimal nutritional counselling and therapy as well as physical exercise.

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Literatur

  1. Labenz C, Baron JS (2018) Prospective evaluation of the impact of covert hepatic encephalopathy on quality of life and sleep in cirrhotic patients. Aliment Pharmacol Ther 48:313–321

    CAS  PubMed  Google Scholar 

  2. Montagenese S, Jasmohan SB (2019) Impact of hepatic encephalopathy in cirrhosis on quality-of-life issues. Drugs 79:11–16

    Google Scholar 

  3. Stewart CA, Malinchoc M et al (2007) Hepatic encephalopathy as a predictor of survival in patients with end-stage liver disease. Liver Transpl 13:1366–1371

    PubMed  Google Scholar 

  4. Wong RJ, Gish RG et al (2014) Hepatic encephalopathy is associated with significantly increased mortality among patients awaiting liver transplantation. Liver Transpl 20:1454–1461

    PubMed  Google Scholar 

  5. Kim M, Liotta EM et al (2019) Impaired cognition predicts the risk of hospitalization and death in cirrhosis. Ann Clin Transl Neurol 6:2282–2290

    PubMed  PubMed Central  Google Scholar 

  6. Bajaj JS, Schubert CM et al (2010) Persistence of cognitive impairment after resolution of overt hepatic encephalopathy. Gastroenterology 138:2332–2340

    PubMed  Google Scholar 

  7. Riggio O, Ridola L et al (2011) Evidence of persistent cognitive impairment after resolution of overt hepatic encephalopathy. Clin Gastroenterol Hepatol 9:181–183

    PubMed  Google Scholar 

  8. Wijdicks EFM (2016) Hepatic encephalopathy. N Eng J Med 375:1660–1670

    CAS  Google Scholar 

  9. Hassouneh R, Bajaj JS (2021) Gut microbiota modulation and fecal transplantation: an overview on innovative strategies for hepatic encephalopathy treatment. J Clin Med 10:330

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Bajaj JS, Salzman NH et al (2019) Fecal microbial transplant capsules are safe in hepatic encephalopathy: a phase 1, randomized, placebo-controlled trial. Hepatology 70:1690–1703

    CAS  PubMed  Google Scholar 

  11. Butterworth RF (2014) Hepatic encephalopathy in alcoholic cirrhosis. Handb Clin Neurol 125:589–602

    PubMed  Google Scholar 

  12. Praktiknjo M, Simón-Talero M (2020) Total area of spontaneous portosystemic shunts independently predicts hepatic encephalopathy and mortality in liver cirrhosis. J Hepatol 72:1140–1150

    PubMed  Google Scholar 

  13. Laleman W, Simón-Talero M (2013) Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: a multicenter survey on safety and efficacy. Hepatology 57:2448–2457

    PubMed  Google Scholar 

  14. Felipo V, Butterworth RF (2002) Neurobiology of ammonia. Prog Neurobiol 67:259–279

    CAS  PubMed  Google Scholar 

  15. Desjardins P, Bandeira P et al (1997) Increased expression of the peripheral-type benzodiazepine receptor-isoquinoline carboxamide binding protein mRNA in brain following portocaval anastomosis. Brain Res 785:255–258

    Google Scholar 

  16. Itzhak Y, Roig-Cantisano A et al (1995) Acute liver failure and hyperammonemia increase peripheral-type benzodiazepine receptor binding and pregnenolone synthesis in mouse brain. Brain Res 705:345–348

    CAS  PubMed  Google Scholar 

  17. Lavoie J, Layrargues GP et al (1990) Increased densities of peripheral-type benzodiazepine receptors in brain autopsy samples from cirrhotic patients with hepatic encephalopathy. Hepatology 11:874–878

    CAS  PubMed  Google Scholar 

  18. Butterworth RF (2016) Neurosteroids in hepatic encephalopathy: novel insights and new therapeutic opportunities. J Steroid Biochem Mol Biol 160:94–97

    CAS  PubMed  Google Scholar 

  19. Schafer DF, Jones EA (1982) Hepatic encephalopathy and the gamma-aminobutyric-acid neurotransmitter system. Lancet 1:18–20

    CAS  PubMed  Google Scholar 

  20. Roy S, Layrargues GP et al (1988) Hepatic encephalopathy in cirrhotic and portacaval shunted dogs: Lack of changes in brain GABA uptake, brain GABA levels, brain glutamic acid decarboxylase activity and brain postsynaptic GABA receptors. Hepatology 8:845–849

    CAS  PubMed  Google Scholar 

  21. Butterworth RF, Lavoie J et al (1988) Affinities and densities of high-affinity [3H]muscimol (GABA-A) binding sites and of central benzodiazepine receptors are unchanged in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Hepatology 8:1084–1088

    CAS  PubMed  Google Scholar 

  22. Butterworth RF (2011) Hepatic encephalopathy: a central neuroinflammatory disorder. Hepatology 53:1372–1376

    PubMed  Google Scholar 

  23. American Association for the Study of Liver Diseases, European Association for the Study of the Liver (2014) Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. J Hepatol 61:642–659

    Google Scholar 

  24. Gerbes AL et al (2019) Aktualisierte S2k-Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) „Komplikationen der Leberzirrhose“. Z Gastroenterol 57:611–680

    PubMed  Google Scholar 

  25. Morgan MY (2016) Current state of knowledge of hepatic encephalopathy (part III): non-absorbable disaccharides. Metab Brain Dis 31:1361–1364

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Weber FL, Banwell JG et al (1987) Nitrogen in fecal bacterial fibre, and soluble fractions of patients with cirrhosis: effects of lactulose and lactulose plus neomycin. J Lab Clin Med 110:259–263

    PubMed  Google Scholar 

  27. Gluud LL, Vilstrup H et al (2016) Nonabsorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD003044.pub3

    Article  PubMed  PubMed Central  Google Scholar 

  28. Bass NM, Mullen KD et al (2010) Rifaximin treatment in hepatic encephalopathy. N Engl J Med 362:1071–1081

    CAS  PubMed  Google Scholar 

  29. Kimer N, Krag A et al (2014) Systematic review with meta-analysis: the effects of rifaximin in hepatic encephalopathy. Aliment Pharmacol Ther 40:123–132

    CAS  PubMed  Google Scholar 

  30. Sharma BC, Sharma P et al (2013) A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol 108:1458–1463

    CAS  PubMed  Google Scholar 

  31. Goh ET, Stokes CS et al (2018) L‑ornithine L‑aspartate for prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD012410.pub2

    Article  PubMed  PubMed Central  Google Scholar 

  32. Hsu CS, Kao JH (2018) Sarcopenia in chronic liver disease. Expert Rev Gastroenterol Hepatol 12:1229–1244

    CAS  PubMed  Google Scholar 

  33. Nam NH, Kaido T et al (2019) Assessment and significance of sarcopenia in liver transplantation. Clin Transplant 33:1–7

    Google Scholar 

  34. Kalafateli M, Mantzoukis K et al (2017) Malnutrition and sarcopenia predict post-liver transplantation outcomes independently of the Model for End-stage Liver Disease score. J Cachexia Sarcopenia Muscle 8:113–121

    PubMed  Google Scholar 

  35. Romiti A, Merli M et al (1990) Malabsorption and nutritional abnormalities in patients with liver cirrhosis. Ital J Gastroenterol 22:118–123

    CAS  PubMed  Google Scholar 

  36. Morrison WL, Bouchier IA et al (1990) Skeletal muscle and whole-body protein turnover in cirrhosis. Clin Sci 78:613–619

    CAS  Google Scholar 

  37. Dasarathy S, Merli M (2016) Sarcopenia from mechanism to diagnosis and treatment in liver disease. J Hepatol 65:1232–1244

    PubMed  PubMed Central  Google Scholar 

  38. Meyer F, Bannert K et al (2020) Molecular mechanism contributing to malnutrition and Sarcopenia in patients with liver cirrhosis. Int J Mol Sci 21:5357

    CAS  PubMed Central  Google Scholar 

  39. Orr R, Fiatarone Singh M (2004) The anabolic androgenic steroid oxandrolone in the treatment of wasting and catabolic disorders: review of efficacy and safety. Drugs 64:725–750

    CAS  PubMed  Google Scholar 

  40. Guillot A, Tacke F (2019) Liver macrophages: old dogmas and new insights. Hepatol Commun 3:730–743

    PubMed  PubMed Central  Google Scholar 

  41. Beyer I, Mets T et al (2012) Chronic low-grade inflammation and age-related sarcopenia. Curr Opin Clin Nutr Metab Care 15:12–22

    CAS  PubMed  Google Scholar 

  42. Butterworth RF (2019) Can J Gastroenterol Hepatol. https://doi.org/10.1155/2019/8182195

    Article  PubMed  PubMed Central  Google Scholar 

  43. Kumar A, Davuluri G et al (2017) Ammonia lowering reverses sarcopenia of cirrhosis by restoring skeletal muscleproteostasis. Hepatology 65:2045–2058

    CAS  PubMed  Google Scholar 

  44. Damink OSW, Jalan R et al (2009) Interorgan ammonia trafficking in liver disease. Metab Brain Dis 24:169–181

    Google Scholar 

  45. Qiu J, Tsien C et al (2012) Hyperammonemia-mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis. Am J Physiol Endocrinol Metab 303:E983–E993

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Jindal A, Jagdish RK (2019) Sarcopenia: ammonia metabolism and hepatic encephalopathy. Clin Mol Hepatol 25:270–279

    PubMed  PubMed Central  Google Scholar 

  47. Cruz-Jentoff AJ et al (2010) Sarcopenia: European consensus on definition and diagnosis: report of the European Working Group on Sarcopenia in Older People. Age Ageing 39:412–423

    Google Scholar 

  48. European Association for the Study of the Liver (2019) EASL clinical practice guidelines on nutrition in chronic liver disease. J Hepatol 70:172–193

    Google Scholar 

  49. Bischoff SC (2020) ESPEN practical guideline: clinical nutrition in liver disease. Clin Nutr 39:3533–3562

    PubMed  Google Scholar 

  50. Gluud LL, Dam G et al (2015) Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD001939.pub2

    Article  PubMed  PubMed Central  Google Scholar 

  51. Sinclair M et al (2016) Testosterone therapy increases muscle mass in men with cirrhosis and low testosterone: a randomised controlled trial. J Hepatol 65:906–913

    CAS  PubMed  Google Scholar 

  52. Reynolds N, Downie S et al (1999) Treatment with L‑ornithine-L-aspartate infusion restores muscle protein synthesis responsiveness to feeding in patients with cirrhosis. J Hepatol 30:65

    Google Scholar 

  53. Tsien C, Shah SN et al (2013) Reversal of sarcopenia predicts survival after a transjugular intrahepatic portosystemic stent. Eur J Gastroenterol Hepatol 25:85–93

    PubMed  Google Scholar 

  54. Praktiknjo M, Book M et al (2018) Fat-free muscle mass in magnetic resonance imaging predicts acute-on-chronic liver failure and survival in decompensated cirrhosis. Hepatology 67(3):1014–1026

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Campus Virchow Klinikum und Campus Charité Mitte, Charité – Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Deutschland

    M. Kluge, M. Demir &  Frank Tacke

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  1. M. Kluge
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  2. M. Demir
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  3. Frank Tacke
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Correspondence to Frank Tacke.

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F. Tacke hat Forschungsgelder von Gilead, Allergan, Bristol-Myers Squibb und Inventiva erhalten. Frank Tacke hat Vortrags- oder Beraterhonorare von Allergan, Gilead, AbbVie, BMS, Falk, Boehringer, Merz, MYR, CSL Behring, Intercept, Inventiva, Novartis, Pfizer und Ionis erhalten. M. Kluge und M. Demir geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

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C. Trautwein, Aachen

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Kluge, M., Demir, M. & Tacke, F. Hepatische Enzephalopathie und Sarkopenie: pathogenetische Bedeutung und therapeutische Implikationen von Ammoniak . Gastroenterologe 16, 160–171 (2021). https://doi.org/10.1007/s11377-021-00518-2

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