Medikamentös-toxische Schädigung als wichtigste Ätiologie des akuten Leberversagens

Zusammenfassung

Hintergrund und Fragestellung: Die spezifische Therapie und Prognoseeinschätzung von Patienten mit akutem Leberversagen (ALV) ist abhängig von der Ätiologie. Traditionell gilt die fulminante Hepatitis B als wichtigste Ursache. In den letzten Jahren kamen aus dem angloamerikanischen und europäischen Raum Hinweise auf eine Zunahme der medikamentös-toxisch bedingten ALV („drug-induced liver injury“, DILI). Ziel dieser Arbeit ist die Identifikation aktueller Ätiologien des ALV in einem großen deutschen Transplantationszentrum.

Patienten und Methodik: Zwischen 1/2002 und 12/2012 wurden retrospektiv in die Daten von 161 Patienten analysiert, welche die Kriterien der „Acute-Liver-Failure Study Group Germany“ erfüllten (International normalized ratio [INR] ≥ 1,5; hepatische Enzephalopathie ≥ 1.  Grades). Erfasst wurden der klinische Verlauf und die Ätiologie.

Ergebnisse: DILI ist die häufigste Ursache des ALV in der untersuchten Kohorte. Bis zu 20 % der Patienten mit DILI sterben oder müssen eine Lebertransplantation erhalten. Patienten mit ALV unklarer Genese und ohne spezifische Therapieoption haben die schlechteste Prognose.

Folgerungen: In Europa besteht ein Nord-Süd-Gefälle bezüglich der Genese des ALV. Die idiosynkratische Medikamentenintoxikation (d.h. eine starke Überreaktion bzw. Unverträglichkeit, die nicht durch eine Immunreaktion ausgelöst wird) ist in Deutschland die häufigste Ursache, gefolgt von einer akuten Hepatitis B.

Abstract

Background and aim: Clinical course and mortality of acute liver failure (ALF) are determined by its causes. Traditionally, fulminant hepatitis B infection (HBV) was thought to be the predominant etiology of ALF in Germany. However, recent studies, conducted in American and European cohorts pointed to drug-induced liver injury (DILI) as the major cause. Aim of this study was to identify currently predominant etiologies of ALF in a monocenter study at a leading transplant center in Germany.

Patients and Methods: The data of 161 patients admitted with ALF from 1/2002 to 12/2012 were analyzed retrospectively. All patients fulfilled the criteria of the „Acute Liver Failure Study Group Germany“ (international normalized ratio (INR) ≥ 1.5, hepatic encephalopathy ≥ stage 1).

Results: DILI was the leading cause of ALF in this cohort. About 20 % of ALF patients with DILI died or received liver transplantats. Mortality rate was highest in ALF patients with unknown etiology and those without specific therapy available.

Conclusions: In Europe ALF etiologies exhibit a North-South divide. In Germany the most common cause for ALF is idiosyncratic pharmacological intoxication followed by acute hepatitis B.

Schlüsselwörter

akutes Leberversagen - Lebertransplantation - DILI

Keywords

acute liver failure - liver transplantation - DILI

• Literatur

• 1 Acharya SK, Panda SK, Saxena A et al. Acute hepatic failure in India: a perspective from the East. J Gastroenterol Hepatol 2000; 15: 473-479
• 2 Bechmann LP, Jochum C, Kocabayoglu P et al. Cytokeratin 18-based modification of the MELD score improves prediction of spontaneous survival after acute liver injury. J Hepatol 2010; 53: 639-647
• 3 Bernal W, Auzinger G, Dhawan A et al. Acute liver failure. Lancet 2010; 376: 190-201
• 4 Bernal W, Wendon J. Acute liver failure. N Engl J Med 2013; 369: 2525-2534
• 5 Bernuau J, Rueff B, Benhamou JP. Fulminant and subfulminant liver failure: definitions and causes. Semin Liver Dis 1986; 6: 97-106
• 6 Bower WA, Johns M, Margolis HS et al. Population-based surveillance for acute liver failure. Am J Gastroenterol 2007; 102: 2459-2463
• 7 Brandsaeter B, Höckerstedt K, Friman S. Fulminant hepatic failure: outcome after listing for highly urgent liver transplantation-12 years experience in the nordic countries. Liver Transpl 2002; 8: 1055-1062
• 8 Canbay A, Chen SY, Gieseler RK. Overweight patients are more susceptible for acute liver failure. Hepatogastroenterology 2005; 52: 1516-1520
• 9 Canbay A, Gerken G. [Specific therapy in acute liver failure]. Med Klin 2006; 101 (Suppl. 01) 111-114
• 10 Canbay A, Jochum C, Bechmann LP. Acute liver failure in a metropolitan area in Germany: a retrospective study (2002-2008). Z Gastroenterol 2009; 47: 807-813
• 11 Daniels D, Grytdal S, Wasley A. Surveillance for acute viral hepatitis – United States, 2007. MMWR Surveill Summ 2009; 58: 1-27
• 12 Dechêne A, Sowa JP, Gieseler RK. Acute liver failure is associated with elevated liver stiffness and hepatic stellate cell activation. Hepatology 2010; 52: 1008-1016
• 13 Escorsell A, Mas A, de la Mata M. Spanish Group for the Study of Acute Liver Failure Acute liver failure in Spain: analysis of 267 cases. Liver Transpl 2007; 13: 1389-1395
• 14 Hadem J, Stiefel P, Bahr MJ. Prognostic implications of lactate, bilirubin, and etiology in German patients with acute liver failure. Clin Gastroenterol Hepatol 2008; 6: 339-345
• 15 Hadem J, Tacke F, Bruns T. Etiologies and outcomes of acute liver failure in Germany. Clin Gastroenterol Hepatol 2012; 10: 664-669.e2
• 16 Hussaini SH, Farrington EA. Idiosyncratic drug-induced liver injury: an overview. Expert Opin Drug Saf 2007; 6: 673-684
• 17 Jochum C, Gieseler RK, Gawlista I. Hepatitis B-associated acute liver failure: immediate treatment with entecavir inhibits hepatitis B virus replication and potentially its sequelae. Digestion 2009; 80: 235-240
• 18 Khuroo MS, Kamili S. Aetiology and prognostic factors in acute liver failure in India. J Viral Hepat 2003; 10: 224-231
• 19 Koskinas J, Deutsch M, Kountouras D. Aetiology and outcome of acute hepatic failure in Greece: experience of two academic hospital centres. Liver Int 2008; 28: 821-827
• 20 Larson AM, Polson J, Fontana RJ. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005; 42: 1364-1372
• 21 Lee HC. Acute liver failure related to hepatitis B virus. Hepatol Res 2008; 38 (Suppl. 01) S9-S13
• 22 Lee WM. Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure. Hepatology 2004; 40: 6-9
• 23 Lee WM, Squires RH, Nyberg SL et al. Acute liver failure: summary of a workshop. Hepatology 2008; 47: 1401-1415
• 24 Manka P, Bechmann LP, Tacke F. Serum sodium based modification of the MELD does not improve prediction of outcome in acute liver failure. BMC Gastroenterol 2013; 13: 58
• 25 Rutherford A, King LY, Hynan LS. Development of an accurate index for predicting outcomes of patients with acute liver failure. Gastroenterology 2012; 143: 1237-1243
• 26 Schimanski CC, Burg J, Möhler M. Phenprocoumon-induced liver disease ranges from mild acute hepatitis to (sub-) acute liver failure. J Hepatol 2004; 41: 67-74
• 27 Schmidt LE, Larsen FS. MELD score as a predictor of liver failure and death in patients with acetaminophen-induced liver injury. Hepatology 2007; 45: 789-796
• 28 Wang YM, Tang YZ. Antiviral therapy for hepatitis B virus associated hepatic failure. HBPD INT 2009; 8: 17-24
• 29 Wei G, Bergquist A, Broomé U. Acute liver failure in Sweden: etiology and outcome. J Intern Med 2007; 262: 393-401
• 30 Yantorno SE, Kremers WK, Ruf AE et al. MELD is superior to King’s college and Clichy’s criteria to assess prognosis in fulminant hepatic failure. Liver Transpl 2007; 13: 822-828