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Serum -Glutamyltransferase Isoform Complexed to LDL in the Diagnosis of Small Hepatocellular Carcinoma

¹ Facoltà di Scienze Matematiche, Fisiche e Naturali, Università del Molise, I-86170 Isernia, Italy

² Centro di Ingegneria Genetica Scarl, and, Dipartimento di Biochimica, e Biotecnologie Mediche, Facoltà di Medicina e Chirurgia, Università di Napoli "Federico II", I-80131 Naples, Italy

³ Cattedra di Fisiopatologia Digestiva, Seconda Università di Napoli, I-80131 Naples, Italy
^a Address correspondence to this author at: Dipartimento di Biochimica e Biotecnologie Mediche, Via S. Pansini, 5, I-80131, Naples, Italy. E-mail salvator{at}unina.it

To the Editor:

Up to one-third of cirrhoses evolve into hepatocellular carcinoma (HCC), with ~90% of these cases developing on a preexisting cirrhosis (1). However, the detection of early-stage neoplastic transformation remains a challenge. In a recent series of studies, we reported that multivariate discriminant functions based on the serum concentrations of various biochemical indexes efficiently discriminate between chronic hepatobiliary diseases at different stages of their natural history (2)(3)(4). The multivariate analysis also allowed us to detect the neoplastic evolution in five of six cirrhotic patients ~6 months earlier than instrumental approaches (2). This result prompted us to evaluate the efficiency of serum biochemical indexes in detecting small HCC, i.e., <3 cm (5), developed on cirrhosis. We studied 21 new patients with small HCC diagnosed by ultrasound-guided fine-needle biopsy. The control population consisted of 51 cirrhotic patients diagnosed byhistology. The latter patients were monitored for signs of HCC for at least 2 years after biopsy. The following biochemical indexes were analyzed on freshly collected serum from patients: alpha-fetoprotein (AFP), carcinoembryonic antigen, lactate dehydrogenase (LD), LD isoenzymes, alkaline phosphatase and alkaline phosphatase isoenzymes, -glutamyltransferase (GGT) and the GGTL isoenzyme (i.e., GGT complexed to LDL and VLDL), 5'-nucleotidase, leucine aminopeptidase, cholinesterase, copper, iron, ferritin, and pseudouridine, using previously described procedures (2).

Serum LD5 (mean, 8.1 U/L in cirrhosis, 43.5 U/L in HCC; P <0.0001), GGTL (mean, 24.6 U/L in cirrhosis, 44 U/L in HCC; P <0.005), and AFP (mean, 55.9 µg/L in cirrhosis, 1440.9 µg/L in HCC; P <0.002) concentrations were significantly higher (Student t-test) in patients with small HCC than in controls. As shown in Fig. 1 A, at a cutoff of 20 U/L, GGTL had a diagnostic sensitivity of 80% and a diagnostic specificity of 92% for the diagnosis of small HCC, similar to those reported for ultrasound-guided biopsy (6). The same cutoff (i.e., 20 U/L) is the upper reference limit in healthy subjects (7). On the other hand, only 4 of 21 patients (19%) had serum AFP concentrations predictive for HCC (>400 µg/L; Fig. 1B ). Similarly, LD5 values overlapped in the two populations (Fig. 1C ). The receiver-operating characteristic plot analysis (8) confirmed that the area under the curve for GGTL (0.901) is significantly higher (P <0.001) than those for LD5 (0.708) and AFP (0.639). The multivariate discriminant analysis (2) failed to identify any function that increased the diagnostic efficiency of GGTL. This can be attributed to the fact that the other biochemical indicators included in the multivariate discriminant analysis (2) are less sensitive compared with GGTL for detecting small HCC (e.g., AFP and LD5 in Fig. 1 ).

View larger version (10K): [in this window] [in a new window]   Figure 1. Serum concentrations of GGTL (A), AFP (B), and LD5 (C) in cirrhotic patients and in patients with small (<3 cm) HCC.

GGT, overexpressed by liver neoplastic cells, forms complexes with LDL and VLDL. Complexes between GGT and LDL occur in serum as a consequence of the biliary impairment typical of the neoplastic liver (7) and produce the GGTL isoform. Serum GGTL analysis is rapid, noninvasive, and inexpensive. Our data suggest that this assay should be included (together to AFP and ultrasound scanning) in the protocol for the monitoring of cirrhotic patients.

Acknowledgments

This work was supported in part by grants from the Ministero dell' Univesitá e della Ricerca Scientica e Technologica, Consiglio Nazionale delle Ricerche (P.F. Biotecnologie), Regione Campania, and Associazione Italiana per la Ricerca sul Cancro. We thank Jean Gilder for assistance with the manuscript.

References

1. Kobayashi K, Sugimoto T, Makino H, Kumagai M, Unoura M, Tanaka N, et al. Screening methods for early detection of hepatocellular carcinoma. Hepatology 1985;5:1100-1105. [Web of Science][Medline] [Order article via Infotrieve]
2. Castaldo G, Oriani G, Lofrano MM, Cimino L, Topa M, Budillon G, et al. Differential diagnosis between hepatocellular carcinoma and cirrhosis through a discriminant function based on biochemical serum analytes. Clin Chem 1996;42:1263-1269. [Abstract/Free Full Text]
3. Castaldo G, Intrieri M, Calcagno G, Cimino L, Budillon G, Sacchetti L, et al. Ascitic pseudouridine discriminates between hepatocarcinoma-derived ascites and cirrhotic ascites. Clin Chem 1996;42:1843-1846. [Abstract/Free Full Text]
4. Castaldo G, Oriani G, Cimino L, Topa M, Budillon G, Salvatore F, et al. Discriminant function based on serum analytes differentiates hepatocarcinoma from secondary liver neoplasia. Clin Chem 1995;41:439-443. [Abstract/Free Full Text]
5. Shinagawa T, Ohto M, Kimura K, Tsunetomi S, Morita M, Saish H, et al. Diagnosis and clinical features of small hepatocellular carcinoma with emphasis on the utility of real time ultrasonography. A study in 51 patients. Gastroenterology 1984;86:495-502. [Web of Science][Medline] [Order article via Infotrieve]
6. De Sio I, Castellano L, Calandra M, Del Vecchio Blanco C. Ultrasound-guided biopsy for the diagnosis of hepatocellular carcinoma—a study based on 420 patients. J Hepatol 1997;26:1155.[Web of Science][Medline] [Order article via Infotrieve]
7. Sacchetti L, Castaldo G, Salvatore F. Electrophoretic behavior and partial characterization of disease associated serum forms of -glutamyltransferase. Clin Chim Acta 1988;177:167-172. [Web of Science][Medline] [Order article via Infotrieve]
8. Zweig MH, Campbell G. Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem 1993;39:561-577. [Abstract/Free Full Text]

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