Lektin-reaktives Alpha-Fetoprotein bei Patienten mit Tyrosinämie Typ I

Zusammenfassung

Hintergrund: Trotz Einführung der medikamentösen Therapie mit NTBC besteht bei der Tyrosinämie Typ I weiterhin das Risiko der Entwicklung eines hepatozellulären Karzinoms (HCC). Wesentlich für die Risikoabschätzung eines Patienten ist bisher das Gesamt-α-Fetoprotein. Die mögliche klinische Bedeutung der L3-Subfraktion nach Lektin-Elektrophorese sollte untersucht werden. Patienten: Insgesamt 41 Patienten mit TTI wurden untersucht, davon 5 bei Erstmanifestation der Erkrankung. Die übrigen 36 Patienten befanden sich in Dauertherapie. Von diesen Patienten hatten 10 ein erhöhtes AFP, ohne dass bisher ein Tumor nachgewiesen worden war. Methoden: In einem Lektin-haltigen Agarosegel können Lektin-reaktive und nicht-Lektin-reaktive AFP-Fraktionen elektrophoretisch getrennt werden. Lektin-reaktives, L3-AFP wird vermehrt bei malignen Lebertumoren nachgewiesen. Ergebnisse: Von den 10 Patienten mit erhöhtem AFP, die als Risikopatienten für die Entwicklung eines Karzinoms einzuschätzen sind, fanden sich drei Patienten mit histologisch nachgewiesenem Karzinom, zwei von diesen Patienten wiesen ein erhöhtes L3-AFP auf. Schlussfolgerung: Möglicherweise könnte das Lektin-reaktive AFP als zusätzlicher Tumormarker verwandt werden. Die prospektive Evaluation des Lektin-reaktiven AFPs bei TTI an einem größeren Patientenkollektiv erscheint sinnvoll.

Abstract

Despite the introduction of NTBC into the treatment of tyrosinaemia type I (TT1) and a considerable improvement in the outcome of these patients, the principal risk of developing hepatocellular carcinoma (HCC) in this metabolic disorder remains mainly in those children with late introduction of NBTC after the second year of life. Serial total α-Fetoprotein (AFP) levels are used to evaluate the individual risk to develop malignant changes. A failure of AFP to decrease on adaequate treatment or a secondary increase after a period of falling levels have been an indication for liver transplantation. Lectin-reactive α-Fetoprotein is a recently described marker to distinguish hepatocellular carcinoma from benign liver disease in adult cirrhotic patients. Aims: To investigate if the analysis for Lectin-reactive α-Fetoprotein would lead to earlier detection of HCC compared to a judgement based on the evolution of standard total AFP alone. Patients: We report the analysis of 12 patients with TTI and histologically proven HCC. There of 5 were diagnosed under one year of age, but NTBC treatment was started between 2 years 3 month and 7 years of age except in one case in which NTBC was introduced when the diagnosis of TTI was made. The remainder of the patients cover up to the age of 15 years. All patients had been treated with NTBC. Methods: Lectin containing agarose gel for AFP electrophoresis leads to AFP separation according to different affinities of the varying carbohydrate chains of AFP to lectins. Results: AFP subfractions could be identified in all 12 patients. In 6 patients the L3-AFP rose before the total AFP. In 3 patients the rise in L3-AFP was consistent with the rise of the total AFP and in 3 patients the L3-AFP was raised after the total AFP or did not increase at all. Discussion: We were able to identify 6 out of 12 patients who had an early increase of L3-AFP before they developed a change in total AFP levels. The clinical significance of these early changes need to be determined. Lectin-affinity electrophoresis may have a potential role as an additional tool that may help to discriminate benign liver disease from HCC in TTI. Conclusions: We suggest the further evaluation of lectin-reactive AFP in TTI.

Tyrosinämie Typ I - α-Fetoprotein - Lektin-Elektrophorese - Hepatozelluläres Karzinom

tyrosinaemia type I - α-fetoprotein - lectin electrophoresis - hepatocellular carcinoma

Literatur

• 1 Baumann U, Crosby H A, Ramani P, Kelly D A, Strain A J. Expression of the stem cell factor receptor c-kit in normal and diseased pediatric liver: identification of a human hepatic progenitor cell?.  Hepatology. 1999;  30 112-117
• 2 Capurro M, Wanless I R, Sherman M, Deboer G, Shi W, Miyoshi E, Filmus J. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma.  Gastroenterology. 2003;  125 89-97
• 3 Dionisi-Vici C BC, Marcellini M. Tyrosinemia Type I with early metastatic hepatocellular carcinoma: combined treatment with NTBC, chemotherapy and surgical mass removal.  J Inherit Metab Dis. 1997;  20 (Suppl 1) 3
• 4 Dubois J, Garel L, Patriquin H, Paradis K, Forget S, Filiatrault D, Grignon A, Russo P, St-Vil D. Imaging features of type 1 hereditary tyrosinemia: a review of 30 patients.  Pediatr Radiol. 1996;  26 845-851
• 5 Grompe M. Pancreatic-hepatic switches in vivo.  Mech Dev. 2003;  120 99-106
• 6 Holme E, Lindstedt S. Nontransplant treatment of tyrosinemia.  Clin Liver Dis. 2000;  4 805-814
• 7 Holme E, Lindstedt S. Tyrosinaemia type I and NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione).  J Inherit Metab Dis. 1998;  21 507-517
• 8 Ishiguro T, Tsuchida Y. Clinical significance of serum alpha-fetoprotein subfractionation in pediatric diseases.  Acta Paediatr. 1994;  83 709-713
• 9 Knopfle G, Becker M, Rotthauwe H W. [Alpha1-fetoprotein: physiology, pathology and diagnosis especially in childhood (author's transl)].  Klin Padiatr. 1977;  189 207-226
• 10 Lee L A. Advances in hepatocyte transplantation: a myth becomes reality.  J Clin Invest. 2001;  108 367-369
• 11 Mitchell G R, P D ubois, J Alvarez F. Tyrosinemia. Mosby Year Book, St. Louis 2001
• 12 Mohan N, McKiernan P, Preece M A, Green A, Buckels J, Mayer A D, Kelly D A. Indications and outcome of liver transplantation in tyrosinaemia type 1.  Eur J Pediatr. 1999;  158 (Suppl 2) S 49-S 54
• 13 Paradis V, Degos F, Dargere D, Pham N, Degott J, Janeau C, Delforge D, Cubizole M, Bedossa P. Identification of a new marker of HCC by serum protein profiling of cirrhotic patients using SELDI-TOF protein chip.  Hepatology. 2003;  38 (Suppl 1) 1229
• 14 Russo P A, Mitchell G A, Tanguay R M. Tyrosinemia: a review.  Pediatr Dev Pathol. 2001;  4 212-221
• 15 Taketa K. Alpha-fetoprotein: reevaluation in hepatology.  Hepatology. 1990;  12 1420-1432
• 16 Taketa K, Endo Y, Sekiya C, Tanikawa K, Koji T, Taga H, Satomura S, Matsuura S, Kawai T, Hirai H. A collaborative study for the evaluation of lectin-reactive alpha-fetoproteins in early detection of hepatocellular carcinoma.  Cancer Res. 1993;  53 5419-5423
• 17 Taketa K, Sekiya C, Namiki M, Akamatsu K, Ohta Y, Endo Y, Kosaka K. Lectin-reactive profiles of alpha-fetoprotein characterizing hepatocellular carcinoma and related conditions.  Gastroenterology. 1990;  99 508-518
• 18 Tsuchida Y, Terada M, Honna T, Kitano Y, Obana K, Leibundgut K, Ishiguro T. The role of subfractionation of alpha-fetoprotein in the treatment of pediatric surgical patients.  J Pediatr Surg. 1997;  32 514-517
• 19 Waldmann T A, McIntire K R. Serum-alpha-fetoprotein levels in patients with ataxia-telangiectasia.  Lancet. 1972;  2 1112-1115
• 20 Yamamoto R, Azuma M, Hoshi N, Kishida T, Satomura S, Fujimoto S. Lens culinaris agglutinin-reactive alpha-fetoprotein, an alternative variant to alpha-fetoprotein in prenatal screening for Down's syndrome.  Hum Reprod. 2001;  16 2438-2444
• 21 Yamashita F, Tanaka M, Satomura S, Tanikawa K. Prognostic significance of Lens culinaris agglutinin A-reactive alpha-fetoprotein in small hepatocellular carcinomas.  Gastroenterology. 1996;  111 996-1001
• 22 Yamashita K, Taketa K, Nishi S, Fukushima K, Ohkura T. Sugar chains of human cord serum alpha-fetoprotein: characteristics of N-linked sugar chains of glycoproteins produced in human liver and hepatocellular carcinomas.  Cancer Res. 1993;  53 2970-2975

1 With kind permission of the following co-workers of the study group:J. E. Heubi, Cincinnati, C. Dionisi-Vici, Rom; J. A. Dias, Porto; O. Bernard, Paris; M. Stern, Tübingen; M. A. Vilaseca, Barcelona; B. Abu-Libdeh, Jerusalem; P. Jara, Madrid; D. Gould, New York; E. Pronicka, Warschau; R. de Kremer, Buenos Aires