Z Gastroenterol 2010; 48(1): 46-55
DOI: 10.1055/s-0028-1109980
Übersicht

© Georg Thieme Verlag KG Stuttgart · New York

ALT als Screeningparameter für Lebererkrankungen: eine kritische Evaluation der Evidenz

ALT Screening for Chronic Liver Diseases: Scrutinizing the EvidenceH. Wedemeyer1 , W. P. Hofmann2 , S. Lueth3 , P. Malinski1 , R. Thimme4 , F. Tacke5 , J. Wiegand6
  • 1Klinik für Gastroenterologie, Hepatologie and Endokrinologie, Medizinische Hochschule Hannover
  • 2Medizinische Klinik 1, Klinikum der J.-W.-Goethe-Universität
  • 3Medizinische Klinik, UKE
  • 4Abteilung Innere Medizin II, Medizinische Universitätsklinik Freiburg
  • 5Medizinische Klinik III, Universitätsklinikum Aachen
  • 6Department für Innere Medizin, Dermatologie und Neurologie, Klinik für Gastroenterologie und Rheumatologie, Universität Leipzig
Further Information

Publication History

Manuskript eingetroffen: 9.11.2009

Manuskript akzeptiert: 7.12.2009

Publication Date:
13 January 2010 (online)

Zusammenfassung

Erhöhte Serum-Aminotransferasen können eine Leberschädigung anzeigen. Dementsprechend wird im Rahmen von Screeninguntersuchungen bei Verdacht auf Lebererkrankungen eine Bestimmung der Aspartat-Aminotransferase (AST) und Alanin-Aminotransferase (ALT) durchgeführt. Ziel der vorliegenden Arbeit ist es, die Evidenz für ALT-Bestimmungen als Screeningtest für Leberkrankungen kritisch zu hinterfragen. Zusammenfassend stellen wir fest, dass 1. erhöhte Serum-ALT-Werte mit hoher Spezifität und guter Sensitivität Lebererkrankungen anzeigen, 2. 10 – 25 % der erwachsenen deutschen Bevölkerung erhöhte ALT-Werte aufweisen, 3. ALT-Werte bei vielen, aber nicht bei allen Patienten mit Lebererkrankungen erhöht sind, 4. erhöhte ALT-Werte mit einer erhöhten leberspezifischen Mortalität assoziiert sind, 5. erhöhte ALT Werte auch als Risikofaktor für primär nicht hepatische Erkrankungen wie Diabetes Mellitus Typ 2, metabolisches Syndrom, kardiovaskuläre Erkrankungen und Tumorerkrankungen angesehen werden müssen, 6. für viele Lebererkrankungen, die mit einem ALT-Screening identifiziert werden, effiziente Therapien vorliegen, die klinische Endpunkte verhindern können, 7. ALT-Testungen wahrscheinlich kosteneffektiv sind, wobei hier allerdings weitere Studien für Deutschland notwendig sind.

Abstract

Elevated serum amino-transferase levels may be associated with liver injury. Testing for aspartate aminotransferase (AST) or alanine aminotransferase (ALT) is part of many routine screening approaches. The aim of this manuscript was to scrutinize the evidence for using ALT testing as a primary screening parameter for liver diseases. We conclude that (i) elevated serum ALT levels indicate a high specificity and a reasonable sensitivity liver injury, (ii) 10 – 25 % of German adults have elevated ALT levels, (iii) ALT values are increased in the majority but not all patients with acute and chronic liver disease (iv) elevated ALT-values are associated with an increased risk of liver-specific mortality, (v) elevated ALT values are also a risk factor for non-hepatic diseases including diabetes mellitus type 2, metabolic syndrome, cardiovascular diseases and malignancies, (vi) many liver diseases identified by an ALT screening can be treated successfully including prevention of development of clinical endpoints, (vii) an ALT-screening is very likely to be cost-effective although studies are needed for Germany to support this conclusion.

Literatur

  • 1 Craxi A, Almasio P. Diagnostic approach to liver enzyme elevation.  J Hepatol. 1996;  25 (Suppl 1) 47-51
  • 2 Kew M C. Serum aminotransferase concentration as evidence of hepatocellular damage.  Lancet. 2000;  355 (9204) 591-592
  • 3 Stasia M J. et al . Aspartate aminotransferase macroenzyme complex in serum identified and characterized.  Clin Chem. 1994;  40 (7 Pt 1) 1340-1343
  • 4 Sonntag O. Hemolysis as interference factor in clinical chemistry.  J Clin Chem Clin Biochem. 1986;  24 127-139
  • 5 Heins M, Heil W, Withold W. Storage of Serum or whole blood samples? Effects of time and temperature on 22 serum analytes.  Eur J Clin Chem Clin Biochem. 1995;  33 231-238
  • 6 Park G J. et al . Aspartate aminotransferase: alanine aminotransferase ratio in chronic hepatitis C infection: is it a useful predictor of cirrhosis?.  J Gastroenterol Hepatol. 2000;  15 (4) 386-390
  • 7 Kuntz H D, May B. Quantitative liver function diagnosis.  MMW Munch Med Wochenschr. 1983;  125 (29 – 30) 678-680
  • 8 Schmidt E SF. Diagnostik des Ikterus.  Dtsch Med Wochenschr. 1984;  109 139-144
  • 9 Elinav E. et al . Correlation between serum alanine aminotransferase activity and age: an inverted U curve pattern.  Am J Gastroenterol. 2005;  100 (10) 2201-2204
  • 10 Zeuzem S. et al . Peginterferon alfa-2a (40 kilodaltons) and ribavirin in patients with chronic hepatitis C and normal aminotransferase levels.  Gastroenterology. 2004;  127 (6) 1724-1732
  • 11 Baumeister S EVH, Marschall P. et al . Impact of fatty liver disease on health care utilization and costs in a general population: a 5-year observation.  Gastroenterology. 2008;  134 85-94
  • 12 Arndt V BH, Rothenbacher D, Zschenderlein B. et al . Elevated liver enzyme activity in construction workers: prevalence and impact on early retirement and all-cause mortality.  Int Arch Occup Environ Health. 1998;  71 (6) 405-412
  • 13 Wiegand J KT, Lobstein S, Brand F. et al . Low prevalence of chronic hepatitis C, but high prevalence of elevated aminotransferases in a cohort of 2026 patients referred for orthopaedic surgery in the eastern part of Germany.  Z Gastroenterol. 2006;  44 (1) 11-14
  • 14 Lobstein S KT, Liebert U, Wojan M. et al . Prevalence, aetiology and associated co-morbidities of elevated aminotransferases in a german cohort of orthopaedic surgery patients.  Z Gastroenterol. 2008;  46 (5) 415-420
  • 15 Papatheodoridis G VGJ, Christodoulou D, Manolakopoulos S. et al . High prevalence of elevated liver enzymes in blood donors: associations with male gender and central adiposity.  Eur J Gastroenterol Hepatol. 2007;  19 (4) 281-287
  • 16 Kim H CNC, Jee S H, Han K H. et al . Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study.  BMJ. 2004;  328 (7446) 983
  • 17 Ruhl C EEJ. Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States.  Gastroenterology. 2003;  124 (1) 71-79
  • 18 Ruhl C EEJ. Elevated serum alanine aminotransferase and gamma-glutamyltransferase and mortality in the United States population.  Gastroenterology. 2009;  136 477-485
  • 19 Fraser A LM, Lawlor D A. Prevalence of elevated alanine aminotransferase among US adolescents and associated factors: NHANES 1999 – 2004.  Gastroenterology. 2007;  133 (6) 1814-1820
  • 20 Vliet van M, Rosenstiel I A, Schindhelm R K. et al . The association of elevated alanine aminotransferase and the metabolic syndrome in an overweight and obese pediatric population of multi-ethnic origin.  Eur J Pediatr. 2009;  168 (5) 585-591
  • 21 McMahon von B. The natural history of chronic hepatitis B virus infection.  Hepatology. 2009;  49 45-55
  • 22 Cornberg M PU, Dollinger M M. et al . Prophylaxis, diagnosis and therapy of hepatitis B virus (HBV) infection: the German guidelines for the management of HBV infection.  Z Gastroenterol. 2007;  45 1281-1328
  • 23 Fattovich G ON, Pasino M. et al . Long-term outcome of chronic hepatitis B in Caucasian patients: mortality after 25 years.  Gut. 2008;  57 84-90
  • 24 Assy N BZ, Djibre A. et al . Lower baseline ALT cut-off values and HBV DNA levels better differentiate HBeAg- chronic hepatitis B patients from inactive chronic carriers.  World J Gastroenterol. 2009;  15 3025-3031
  • 25 Chiang J CLC, Wang J H. et al . Identifying hepatitis C virus: endemic areas and estimating the viral antibody prevalence based on the prevalence of ALT elevation.  Trans R Soc Trop Med Hyg. 2009;  103 917-923
  • 26 Schlosser B DD, Möckel M. et al . Ist ein generelles Hepatitis C Screening sinnvoll? Anti-HCV Prävalenz bei 13.832 konsekutiven Patienten einer internistischen und chirurgisch-traumatologischen Notaufnahme.  Z Gastroenterol. 2009;  47 961
  • 27 Wiese M BF, Lafrenz M, Porst H. et al . Low frequency of cirrhosis in a hepatitis C (genotype 1b) single-source outbreak in germany: a 20-year multicenter study.  Hepatology. 2000;  32 91-96
  • 28 Kenny-Walsh E. Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin.  N Engl J Med. 1999;  340 1228-1233
  • 29 Clark J. The epidemiology of nonalcoholic fatty liver disease in adults.  J Clin Gastroenterol. 2006;  40 (Suppl 1) S5-S10
  • 30 Bacon B RFM, Janney C G, Neuschwander-Tetri B A. Nonalcoholic steatohepatitis: an expanded clinical entity.  Gastroenterology. 1994;  107 1103-1109
  • 31 Argo C KNP, Al-Osaimi A M, Caldwell S H. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis.  J Hepatol. 2009;  51 371-379
  • 32 Luth S HJ, Kanzler S. et al . Serologic markers compared with liver biopsy for monitoring disease activity in autoimmune hepatitis.  J Clin Gastroenterol. 2008;  42 926-930
  • 33 Feld J JDH, Arenovich T. et al . Autoimmune hepatitis: effect of symptoms and cirrhosis on natural history and outcome.  Hepatology. 2005;  42 53-62
  • 34 Alempijevic T KM, Jesic R. et al . Biochemical markers for non-invasive assessment of disease stage in patients with primary biliary cirrhosis.  World J Gastroenterol. 2009;  15 591-594
  • 35 Twaddell W SLJ, Berk P D. Evolution from primary biliary cirrhosis to primary biliary cirrhosis/autoimmune hepatitis overlap syndrome.  Semin Liver Dis. 2008;  28 128-134
  • 36 Tischendorf J JHH, Kruger M, Manns M P. et al . Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: A single center study.  Am J Gastroenterol. 2007;  102 107-114
  • 37 Stremmel W NC, Strohmeyer G. Diagnose der primären Hämochromatose.  Dtsch Med Wochenschr. 1993;  118 227-229
  • 38 Beaton M AP. Assessment of silent liver fibrosis in hemochromatosis C 282Y homozygotes with normal transaminase levels.  Clin Gastroenterol Hepatol. 2008;  6 713-714
  • 39 Korman J DVI, Balko J. et al . Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests.  Hepatology. 2008;  48 1167-1174
  • 40 Betro M GOR, Edwards J B. Gamma-glutamyl transpeptidase and other liver function tests in myocardial infarction and heart failure.  Am J Clin Pathol. 1973;  60 679-683
  • 41 Ruhl C EEJ. Epidemiology of nonalcoholic fatty liver.  Clin Liver Dis. 2004;  8 501-519
  • 42 Perry I JWS, Shaper A G. Prospective study of serum gamma-glutamyltransferase and risk of NIDDM.  Diabetes Care. 1998;  21 732-737
  • 43 Vozarova B SN, Lindsay R S, Saremi A. et al . High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes.  Diabetes. 2002;  51 1889-1895
  • 44 Goessling W MJ, Vasan R S. et al . Aminotransferase levels and 20-year risk of metabolic syndrome, diabetes, and cardiovascular disease.  Gastroenterology. 2008;  135 1935-1944
  • 45 Sato K KHT, Nakamura Y, Harita N. et al . Liver enzymes compared with alcohol consumption in predicting the risk of type 2 diabetes: the Kansai Healthcare Study.  Diabetes Care. 2008;  31 1230-1236
  • 46 Wannamethee S GSA, Lennon L, Whincup P H. Hepatic enzymes, the metabolic syndrome, and the risk of type 2 diabetes in older men.  Diabetes Care. 2005;  28 2913-2918
  • 47 Ford E SSM, Bergmann M M, Thamer C. et al . Liver enzymes and incident diabetes: findings from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study.  Diabetes Care. 2008;  31 1138-1143
  • 48 Fraser A HR, Sattar N, Ebrahim S. et al . Alanine aminotransferase, gamma-glutamyltransferase, and incident diabetes: the British Women’s Heart and Health Study and meta-analysis.  Diabetes Care. 2009;  32 741-750
  • 49 Andre P BB, Vol S, Charles M A. et al . Gamma-glutamyltransferase activity and development of the metabolic syndrome (International Diabetes Federation Definition) in middle-aged men and women: Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort.  Diabetes Care. 2007;  30 2355-2361
  • 50 Schindhelm R KDJ, Nijpels G, Bouter L M. et al . Alanine aminotransferase predicts coronary heart disease events: a 10-year follow-up of the Hoorn Study.  Atherosclerosis. 2007;  191 391-396
  • 51 Monami M BD, Lamanna C, Melani C. et al . Prognostic value of serum liver enzymes levels in type 2 diabetic patients.  Diabetes Metab Res Rev. 2007;  23 625-630
  • 52 Lee T HKW, Benson J T, Therneau T M. et al . Serum aminotransferase activity and mortality risk in a United States community.  Hepatology. 2008;  47 880-887
  • 53 Stojakovic T SH, Trauner M, Pieske B. et al . Serum gamma-glutamyl transferase and mortality in persons undergoing coronary angiography – The Ludwigshafen Risk and Cardiovascular Health Study.  Atherosclerosis. 2009;  [epub ahead of print]
  • 54 Haring R WH, Nauck M, Dorr M. et al . Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyl transpeptidase levels.  Hepatology. 2009;  50 1403-1411
  • 55 Yun K ESC, Yoon Y S, Park H S. Elevated alanine aminotransferase levels predict mortality from cardiovascular disease and diabetes in Koreans.  Atherosclerosis. 2009;  205 533-537
  • 56 Ruttmann E BL, Concin H, Diem G. et al . Gamma-glutamyltransferase as a risk factor for cardiovascular disease mortality: an epidemiological investigation in a cohort of 163,944 Austrian adults.  Circulation. 2005;  112 2130-2137
  • 57 Strasak A MPR, Klenk J, Hilbe W. et al . Prospective study of the association of gamma-glutamyltransferase with cancer incidence in women.  Int J Cancer. 2008;  123 1902-1906
  • 58 Kazemi-Shirazi L EG, Winkler S, Schickbauer T. et al . Gamma glutamyltransferase and long-term survival: is it just the liver?.  Clin Chem. 2007;  53 940-946
  • 59 Mallat A, Hezode C, Lotersztajn S. Environmental factors as disease accelerators during chronic hepatitis C.  J Hepatol. 2008;  48 (4) 657-665
  • 60 El-Zayadi A R. Heavy smoking and liver.  World J Gastroenterol. 2006;  12 (38) 6098-6101
  • 61 Ishak K. et al . Histological grading and staging of chronic hepatitis.  J Hepatol. 1995;  22 (6) 696-699
  • 62 Desmet V J. et al . Classification of chronic hepatitis: diagnosis, grading and staging.  Hepatology. 1994;  19 (6) 1513-1520
  • 63 Liaw Y F. et al . Lamivudine for patients with chronic hepatitis B and advanced liver disease.  N Engl J Med. 2004;  351 (15) 1521-1531
  • 64 Schiff E. et al . Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results.  Liver Transpl. 2007;  13 (3) 349-360
  • 65 Veldt B J. et al . Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis.  Ann Intern Med. 2007;  147 (10) 677-684
  • 66 Mallet V. et al . Brief communication: the relationship of regression of cirrhosis to outcome in chronic hepatitis C.  Ann Intern Med. 2008;  149 (6) 399-403
  • 67 Niederau C. et al . Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B.  N Engl J Med. 1996;  334 (22) 1422-1427
  • 68 Kashi M R, Torres D M, Harrison S A. Current and emerging therapies in nonalcoholic fatty liver disease.  Semin Liver Dis. 2008;  28 (4) 396-406
  • 69 Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: Selected practical issues in their evaluation and management.  Hepatology. 2009;  49 (1) 306-317
  • 70 Belfort R. et al . A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis.  N Engl J Med. 2006;  355 (22) 2297-2307
  • 71 Ratziu V. et al . Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial.  Gastroenterology. 2008;  135 (1) 100-110
  • 72 Manns M P, Strassburg C P. Autoimmune hepatitis: clinical challenges.  Gastroenterology. 2001;  120 (6) 1502-1517
  • 73 Manns M P, Woynarowski M BM. et al . Budesonide 3 mg TID is superior to Prednisolon in Combination with Azathioprine in the Treatment of Autoimmune Hepatitis.  J Hepatol. 2008;  48 (Suppl 2) 369
  • 74 Kirk A P. et al . Late results of the Royal Free Hospital prospective controlled trial of prednisolone therapy in hepatitis B surface antigen negative chronic active hepatitis.  Gut. 1980;  21 (1) 78-83
  • 75 Niederau C. et al . Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis.  N Engl J Med. 1985;  313 (20) 1256-1262
  • 76 Smolarek C, Stremmel W. Therapy of Wilson disease.  Z Gastroenterol. 1999;  37 (4) 293-300
  • 77 Sroczynski G. et al . Long-term effectiveness and cost-effectiveness of antiviral treatment in hepatitis C.  J Viral Hepat. 2009;  [epub ahead of print]
  • 78 Brady B SU, Sroczynski G. et al . Pegylated interferon combined with ribavirin for chronic hepatitis C virus infection: an economic evaluation (Technology Report No. 82).  Ottawa: Canadian Agency for Drugs and Technologies in Health. 2007; 
  • 79 Wright M. et al . Health benefits of antiviral therapy for mild chronic hepatitis C: randomised controlled trial and economic evaluation.  Health Technol Assess. 2006;  10 (21) 1-113, iii
  • 80 Singer M E, Younossi Z M. Cost effectiveness of screening for hepatitis C virus in asymptomatic, average-risk adults.  Am J Med. 2001;  111 (8) 614-621
  • 81 Toy M. et al . Potential impact of long-term nucleoside therapy on the mortality and morbidity of active chronic hepatitis B.  Hepatology. 2009;  50 (3) 743-751
  • 82 Buti M. et al . Modeling the cost-effectiveness of different oral antiviral therapies in patients with chronic hepatitis B.  J Hepatol. 2009;  51 (4) 640-646
  • 83 European Association For The Study Of The Liver EASL Clinical Practice Guidelines: management of chronic hepatitis B.  J Hepatol. 2009;  50 (2) 227-242
  • 84 EASL Clinical Practice Guidelines: management of cholestatic liver diseases.  J Hepatol. 2009;  51 (2) 237-267
  • 85 Ghany M G. et al . Diagnosis, management, and treatment of hepatitis C: an update.  Hepatology. 2009;  49 (4) 1335-1374
  • 86 Marcellin P. et al . Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.  N Engl J Med. 2004;  351 (12) 1206-1217
  • 87 Bourliere M, Kahloun A, Gascou-Tessonnier G. Analogs and fibrosis regression in hepatitis B.  Gastroenterol Clin Biol. 2009;  33 (10 – 11) 923-929
  • 88 Schiff E. et al . Efficacy and safety of entecavir in patients with chronic hepatitis B and advanced hepatic fibrosis or cirrhosis.  Am J Gastroenterol. 2008;  103 (11) 2776-2783
  • 89 Poynard T. et al . Longitudinal assessment of histology surrogate markers (FibroTest-ActiTest) during lamivudine therapy in patients with chronic hepatitis B infection.  Am J Gastroenterol. 2005;  100 (9) 1970-1980
  • 90 Lau G K. et al . Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.  N Engl J Med. 2005;  352 (26) 2682-2695
  • 91 Manns M P. et al . Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.  Lancet. 2001;  358 (9286) 958-965
  • 92 McHutchison J G. et al . Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group.  N Engl J Med. 1998;  339 (21) 1485-1492
  • 93 Fried M W. et al . Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.  N Engl J Med. 2002;  347 (13) 975-982
  • 94 Di Bisceglie A M. et al . Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon.  N Engl J Med. 2008;  359 (23) 2429-2441
  • 95 Suzuki A. et al . Effect of changes on body weight and lifestyle in nonalcoholic fatty liver disease.  J Hepatol. 2005;  43 (6) 1060-1066
  • 96 Hickman I J. et al . Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life.  Gut. 2004;  53 (3) 413-419
  • 97 Tock L. et al . Nonalcoholic fatty liver disease decrease in obese adolescents after multidisciplinary therapy.  Eur J Gastroenterol Hepatol. 2006;  18 (12) 1241-1245
  • 98 Milman N. et al . Clinically overt hereditary hemochromatosis in Denmark 1948 – 1985: epidemiology, factors of significance for long-term survival, and causes of death in 179 patients.  Ann Hematol. 2001;  80 (12) 737-744
  • 99 Falize L. et al . Reversibility of hepatic fibrosis in treated genetic hemochromatosis: a study of 36 cases.  Hepatology. 2006;  44 (2) 472-477

Prof. Dr. Heiner Wedemeyer

Klinik für Gastroenterologie, Hepatologie and Endokrinologie, Medizinische Hochschule Hannover

Carl-Neuberg-Str. 1

30625 Hannover

Email: Wedemeyer.Heiner@mh-hannover.de

    >