Abstract
Alpha-2-macroglobulin (A2M) is a proteinase inhibitor. Cells synthesizing A2M are in first-order hepatocytes and in second-order activated Ito cells (in culture starting at day 4–5 after seeding). This study was undertaken in 525 alcoholic patients with different histological stages of alcoholic liver disease to assess if the A2M could improve the diagnostic value of PGA index for detection of cirrhosis or fibrosis among drinkers, particularly in patients without clinical symptoms of liver failure and portal hypertension, and to assess the specific correlation of serum A2M with the score of liver fibrosis adjusted for steatosis and alcoholic hepatitis and thereafter adjusted for GGT, PT, and ApoA1, the three components of the PGA index. In 525 alcoholic patients, we have demonstrated the independent diagnostic value of A2M. The predictive values of the weighted score, using linear discriminant function combining PT, GGT, ApoA1 and A2M of the PGAA score and of the PGA score were assessed in a training step and validated in a second step. Then, 316 alcoholic clinically asymptomatic patients were studied. In these patients, the discriminant function permitted correct classification of 72% of patients. The PGAA index had comparable diagnostic value with 70% of patients correctly classified. On the other hand, the PGA index including only PT, GGT, and ApoA1 had classified correctly less patients (65%) than the discriminant function and the PGAA index (P<0.01). For a value of 7, PGAA had 79% specificity and 89% sensitivity for the diagnosis of cirrhosis. A2M was positively correlated with the grade of fibrosis (r=0.39P<0.01). The correlation persisted whatever the degree of steatosis and the degree of alcoholic hepatitis and after adjustment for GGT, PT, and ApoA1. When liver biopsy is not possible, PGAA could be useful for the diagnosis of asymptomatic cirrhosis among drinkers.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Rhode H, Vargas L, Hahn E, Kalbfleisch H, Bruguera M, Timpl R: Radioimmunoassay for type III procollagen peptide and its application to human liver disease. Eur J Clin Invest 9:451–459, 1979
Nakayama H: Serum type IV collagen and laminin as a parameter of hepatic fibrosis. Tokyo Jikeikai Med J 104:807–820, 1989
Risteli J, Rhode H, Timpl R: Sensitive radioimmunoassay for 7 S collagen and laminin: Application to serum and tissue studies of basement membranes. Anal Biochem 113:372–378, 1981
Yamauchi M, Nakajima H, Ohata M, Hirakawa J, Mizuhara Y, Nakahara M, Kimora K, Fujisawa K, Kameda H: Detection of fibronectin receptor in sera: its clinical significance as a parameter of hepatic fibrosis. Hepatology 14:244–250, 1991
Poynard T, Abella A, Pignon JP, Naveau S, Leluc R, Chaput JC: Apolipoprotein A1 and alcoholic liver disease. Hepatology 6:1391–1395, 1986
Poynard T, Aubert A, Bedossa P, Abella A, Naveau S, Paraf F, Chaput JC: A simple biological index for detection of alcoholic liver disease in drinkers. Gastroenterology 100:1397–1402, 1991
Hall PK, Roberts RC: Physical and chemical properties of human plasma α2-macroglobulin. Biochem J 171:27–38, 1978
Clement B, Grimaud JA, Campion JP, Deugnier Y, Guillouzo A: Cell types involved in collagen and fibronectin production in normal and fibrotic human liver. Hepatology 6:225–234, 1986
Andus T, Ramadori G, Heinrich PC, Knittel T, Meyer Zum Buschenfelde KH: Cultured Ito cells of rat liver express the α2 macroglobulin gene. Eur J Biochem 168:641–646, 1987
Fruchart JC, Kora I, Cachera C, Clavey V, Duthilleul P, Moschetto Y: Simultaneous measurement of plasma apolipoprotein A1 and B by electroimmunoassay. Clin Chem 38:59–62, 1982
Szasz G: A kinetic photometric method for serum gamma glutamyl transpeptidase. Clin Chem 15:124–136, 1969
Fink PC, Romer M, Haeckel R, Fateh-Moghadam A, De Langhe J, Gressner AM, Dubs RW: Measurement of proteins with the Behring nephelometer. A multicenter evaluation. J Clin Chem Clin Biol Chem 27:261–276, 1989
Bedossa P, Poynard T, Naveau S, Martin E, Agostini H, Chaput JC: Observer variation in assessment of liver biopsies of alcoholic patients. Alcoholism Clin Exp Res 12:173–178, 1988
Review by an international group: Baptista A, Bianchi L, de Groote J, Desmet VJ, Gedigk P, Korb G, Mac Sween RNM, Popper H, Poulsen H, Schever PJ, Schmid M, Thaler H, Wepler W: Alcoholic liver disease: Morphological manifestation. Lancet 1:707–711, 1981
Bedossa P, Poynard T, Abella A, Aubert A, Pignon JP, Naveau S, Leluc R, Lemaigre G, Martin ED, Chaput JC: Apolipoprotein A1 is a serum and tissue marker of liver fibrosis in alcoholic patients. Alcohol Clin Exp Res 13:829–833, 1989
Murray-Lyon IM, Michin Clarke HG, McPherson K, Williams R: Quantitative immunoelectrophoresis of serum proteins in cryptogenic cirrhosis, alcoholic cirrhosis and active chronic hepatitis. Clin Chim Acta 39:215–220, 1972
Nalpas B, Boigne JM, Zafrani ES, Zimmermann R, Berthelot P: Perturbations de dix protéines plasmatiques au cours des hépatopathies alcooliques. Gastroenterol Clin Biol 4:646–654, 1980
Skrede S, Blomhoff JP, Elgjo K, Gjone E: Serum proteins in diseases of the liver. Scand J Clin Lab Invest 35:399–406, 1975
Munck Petersen C, Christiansen BS, Heickendorff L, Ingerslev J: Synthesis and secretion of α2-macroglobulin by human hepatocytes in culture. Eur J Clin Invest 18:543–548, 1988
Andus T, Bauer J, Gerok W: Effects of cytokines on the liver. Hepatology 12:364–375, 1991
Bachem MG, Burschel G, Krull N, Schlegel E, Boers W, Tiggelman MBC, Sell KM, Gressner AM: Interactions of α2-macroglobulin, TGFβ1 and lipocytes in fibrogenesis. Hepatology 16:100A, 1992 (abstract)
Weiner FR, Giambrone MA, Czaja MJ: Ito cell gene expression and collagen regulation. Hepatology 11:111–117, 1990
Edwards DR, Murphy G, Reynolds JJ, Whitham SE, Docherty AJP, Angel P, Heath J: Transforming growth factor beta modulated the expression of collagenase and metallo proteinase inhibitor. EMBO J 7:1899–1904, 1987
Bachem MG, Meyer D, Melchior R, Sell KM, Gressner AM: Positive and negative autocrine loops in the regulation of proteoglycan synthesis in myofibroblast-like cells include transforming growth factor type β1, decorin biglycan and α2-macroglobulin. Hepatology Pt 2; 14:113A, 1991 (abstract)
Thiele DL: Tumor necrosis factor: The acute phase response and the pathogenesis of alcoholic liver disease. Hepatology 9:497–498, 1989
Koj A: Definition and classification of acute phase proteins in the acute phase response to injury and infection.In: Gordon AH, Koj A, (eds). The acute phase response to injury and infection. Amsterdam, Elsevier, 1985, 139–144
Leebeek FWG, Kluft C, Knot EAR, De Maat MPM, Wilson JHP: A shift in balance between profibrinolytic and antifibrinolytic factors cases enhanced fibrinolysis in cirrhosis. Gastroenterology 101:1382–1390, 1991
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Naveau, S., Poynard, T., Benattar, C. et al. Alpha-2-macroglobulin and hepatic fibrosis. Digest Dis Sci 39, 2426–2432 (1994). https://doi.org/10.1007/BF02087661
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02087661