Serum free and total prostate-specific antigen levels in patients with liver disease

ADULT UROLOGY

SERUM FREE AND TOTAL PROSTATE-SPECIFIC ANTIGEN LEVELS IN PATIENTS WITH LIVER DISEASE SAHI˙R KILIC¸, EROL GU¨NTEKI˙N, AHMET DANIS¸MAN, ERDAL KUKUL, I˙NCI˙ SU¨LEYMANLAR, ¨K AND METI˙N SEVU

ABSTRACT Objectives. To determine the effect of liver diseases on serum free prostate-specific antigen (fPSA) levels, total prostate-specific antigen (tPSA) levels, and fPSA/tPSA ratios. Methods. Serum concentrations of tPSA and fPSA were measured in 18 men with histologically confirmed liver cirrhosis, 20 men with histologically proved chronic hepatitis, and 20 healthy men. All patients underwent a standard urologic evaluation, including history, physical examination, urine analysis, serum fPSA and tPSA determinations, and liver function tests (serum bilirubin, serum glutamic oxaloacetic transaminase, and serum glutamic pyruvic transaminase). Results. Patients with liver cirrhosis had slightly lower fPSA levels than did control subjects or patients with chronic hepatitis, but these differences did not reach statistical significance. tPSA levels also were not significantly different among the three groups. Conclusions. In the presence of liver disease, despite the limited liver reserve, tPSA and fPSA are specific and reliable markers in the clinical management of prostatic diseases in this population. This result should be taken into account when serum concentrations of fPSA, tPSA, and the fPSA/tPSA ratio are evaluated in patients with liver disease. UROLOGY 52: 825–828, 1998. © 1998, Elsevier Science Inc. All rights reserved.

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rostate-pspecific antigen (PSA), a single-chain 33-kDa glycoprotein serine protease, is the most useful clinical marker for the diagnosis and management of prostate cancer.1 Attention has recently been brought to the two different molecular forms of PSA, namely, free and complexed PSA.2– 4 PSA is predominantly bound to alpha1-antichymotrypsin, which constitutes approximately 70% to 90% of total PSA (tPSA). Furthermore, serum PSA also binds in trace amounts to alpha1-antitrypsin and alpha2-macroglobulin. Approximately 10% to 30% of tPSA is not bound to proteins and is called free PSA (fPSA).2– 4 The potential for increasing the sensitivity and specificity of diagnosing prostate cancer using free or complexed PSA or proportions of fPSA to tPSA has been reported in a number of studies.4 –7 However, these observations have been made in From the Departments of Urology and Gastroenterology, University of Akdenı˙z, School of Medicine, Antalya, Turkey Reprint requests: Sahir Kilic¸, M.D., Akdenı˙z U¨niversitesi Tip Faku¨ltesi, U¨roloji Anabilim Dali, 07070 Antalya, Turkey Submitted: March 9, 1998, accepted (with revisions): May 26, 1998 © 1998, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED

patients with normal liver function. This issue is important, because recently Agha et al.8 reported that the liver appears to be the most likely site of PSA metabolism. In another study, we also showed that fPSA was metabolized by the kidney and tPSA and fPSA were metabolized by the liver (unpublished data). Therefore, liver disease might cause an artifactual increase in serum levels of tPSA and fPSA, leading to a high incidence of false results in patients with liver disease. In this study, our aim was to determine the effect of liver disease on serum fPSA, tPSA, and the fPSA/ tPSA ratio. MATERIAL AND METHODS Serum concentrations of tPSA and fPSA were measured in 18 men with histologically confirmed liver cirrhosis, 20 men with histologically proved chronic hepatitis, and 20 healthy men. None of the 58 men had renal functional impairment or clinical evidence of prostatic disease. Their ages ranged from 50 to 70 years (mean 55) in the liver cirrhosis group, from 46 to 62 years (mean 50) in the chronic hepatitis group, and from 50 to 68 years (mean 53) in the control group. The age distribution was similar among the three groups. After written informed consent was obtained, all the men 0090-4295/98/$19.00 PII S0090-4295(98)00393-8 825

TABLE I. Age distribution and the mean 6 standard deviation for serum total and free prostate-specific antigen and liver function tests for the three groups Control (n 5 20) Mean age (yr) SGOT (U/L) SGPT (U/L) Bilirubin (mg/dL) fPSA (ng/mL) tPSA (ng/mL)

24 20 0.3 0.27 0.95

53 66 65 6 0.1 6 0.20 6 0.65

Liver Cirrhosis (n 5 18) 115 90 2.4 0.21 0.63

55 6 30 6 25 6 0.4 6 0.04 6 0.44

Chronic Hepatitis (n 5 20) 88 104 1.7 0.28 0.69

50 6 24 6 28 6 0.3 6 0.16 6 0.53

KEY: SGOT 5 serum glutamic-oxaloacetic transaminase; SGPT 5 serum glutamic pyruvic transaminase; fPSA 5 free prostate-specific antigen; tPSA 5 total prostate-specific antigen.

TABLE II. Statistical significance of total and free prostate-specific antigen values between control subjects and patients with liver disease Comparison Control group vs liver cirrhosis group Control group vs chronic hepatitis group

fPSA

tPSA

P . 0.05

P . 0.05

P . 0.05

P . 0.05

KEY: Abbreviations as in Table I.

underwent a standard urologic evaluation, including history, physical examination, urine analysis, serum fPSA and tPSA determination, and liver function tests (serum bilirubin, serum glutamic oxaloacetic transaminase, and serum glutamic pyruvic transaminase). Serum levels of fPSA and tPSA were determined using a chemiluminescent enzyme assay (Immulite PSA, EURO/DPC, United Kingdom), before or at least 1 month after any rectal or urethral manipulation to avoid false elevation of PSA. In normal men and in men with benign prostatic hyperplasia or carcinoma of the prostate, Immulite PSA assay results were found to be equivalent to those by the Hybritech assay (r 5 0.97, r 5 0.99, and r 5 0.99, respectively).9 Men were excluded from the study if they had had any recent urinary tract infection. The statistical analyses were made by using the Mann-Whitney U test. Mean tPSA and fPSA concentrations for each group were calculated with standard deviations. P , 0.05 was considered to be statistically significant.

RESULTS The age distribution and the mean 6 standard deviations for liver function test results and fPSA and tPSA levels for the three groups are given in Table I. As is shown, fPSA and tPSA were normal in men with liver disease and in control subjects. In addition, no differences with regard to age distribution were found. The P values for fPSA and tPSA among these groups are given in Table II. As shown in Table I, patients with liver cirrhosis had slightly lower fPSA 826

levels (0.21 6 0.04 ng/mL) than did control subjects (0.27 6 0.20 ng/mL) and patients with chronic hepatitis (0.28 6 0.16 ng/mL), but these differences did not reach statistical significance. tPSA levels among these groups also were not significantly different. COMMENT Because the sensitivity and specificity of PSA are not sufficient to make it an ideal marker for screening and early detection of prostate cancer, the concepts of PSA density,10,11 PSA velocity,12 age-specific PSA ranges,13,14 and recently, fPSA levels and fPSA/tPSA ratios have been investigated.4 –7 The purpose of each parameter is to enhance the accuracy of PSA in diagnosing prostate cancer. To date, however, little effort has been directed toward assessing the mechanisms and effects of degradation and clearance of this enzyme from human serum. Data obtained from studies of other proteases and protease-protease inhibitor complexes showed that PSA alpha1-antichymotrypsin binds to the liver serpin receptor and PSA alpha2-macroglobulin to the alpha-macroglobulin receptor on reticuloendothelial cells, removing the complexes from the bloodstream.15,16 Agha et al.8 reported that the liver appears to be the most likely site of PSA metabolism. Recently, we evaluated fPSA and tPSA metabolism in three different sites, using selective blood samples that were obtained from infrarenal, infrahepatic, and suprahepatic inferior vena cava, superior vena cava, renal vein, hepatic vein, pulmonary artery, and femoral artery. We found that the liver had a significant role in the elimination of tPSA and fPSA (unpublished data). Additionally, Kadayifci et al.17 found no significant differences between serum PSA levels in patients with liver diseases and healthy subjects. Recently Williams et al.18 evaluated 10 men with chronic hepatic insufficiency undergoing liver transplantation and conUROLOGY 52 (5), 1998

cluded that severe hepatic dysfunction does not significantly alter serum tPSA levels. Although in 4 patients they found no difference in the fPSA levels before and after liver transplantation, the number of patients was not sufficient to reach a statistical conclusion. In the present study, despite the evidence of hepatic metabolism and clearance of fPSA and tPSA from the serum, no significant difference was found between the peripheral venous serum tPSA and fPSA levels in patients with liver disease and in control subjects. All the patients with liver disease had tPSA and fPSA levels within the normal range. Ideally, the fPSA/tPSA ratio is useful when the tPSA level is between 4 and 10 ng/mL. In the present study, tPSA levels in all patients were less than 4 ng/mL. Thus, fPSA/tPSA ratios do not alter in patients with hepatic dysfunction. Contrary to our hypothesis that impairment of liver function might produce significant PSA elevations, we found that the limited liver reserve is sufficient to maintain serum tPSA and fPSA levels within the normal range. To our knowledge, these are the first data about the effects of liver disease on fPSA serum levels and fPSA/tPSA ratios reported in a large number of patients. In conclusion, we believe that even in the presence of liver disease, despite the limited liver reserve, tPSA and fPSA may be reliable markers in the clinical management of prostatic diseases in this population. This result should be taken into account when serum concentrations of fPSA, tPSA, and the fPSA/tPSA ratio are evaluated in patients with liver disease. Our results require additional studies to clearly demonstrate the reliability of these markers in patients with both liver and prostate disease. ACKNOWLEDGMENT. To professor Edward Messing from the Department of Urology, University of Rochester for his valuable comments in reviewing the manuscript. REFERENCES 1. Wang MC, Valenzuela LA, Murphy GP, et al: Purification of human prostate-specific antigen. Invest Urol 17: 159 – 163, 1979. 2. Christensson A, Laurel CB, and Lilja H: Enzymatic activity of prostate-specific antigen and its reactions with extracellular serine proteinase inhibitors. Eur J Biochem 194: 755– 763, 1990. 3. Lilja H, Christensson A, Dahlen U, et al: Prostate-specific antigen in serum occurs predominantly in complex with a1-antichymotrypsin. Clin Chem 37: 1618 –1625, 1991. 4. Stenman UH, Leinonen J, Alfthan H, et al: A complex between prostate-specific antigen and a1-antichymotrypsin is the major form of prostate-specific antigen in serum of patients with prostate cancer: assay of the complex improves clinical sensitivity for cancer. Cancer Res 51: 222–226, 1991. 5. Christensson A, Bjork T, Nilsson O, et al: Serum prostate-specific antigen complexed to a1-antichymotrypsin as an indicator of prostate cancer. J Urol 150: 100 –105, 1993. UROLOGY 52 (5), 1998

6. Leinonen J, Lovgren T, Vornanen T, et al: Double-label time resolved immunofluorometric assay of prostate-specific antigen and of its complex with a1-antichymotrypsin. Clin Chem 39: 2098 –2103, 1993. 7. Catalona WJ, Smith DS, Wolfert RL, et al: Evaluation of percentage of free serum prostate-specific antigen to improve specificity of prostate cancer screening. JAMA 274: 1214 – 1220, 1995. 8. Agha AH, Schechter E, Roy JB, et al: Prostate-specific antigen is metabolized in the liver. J Urol 155: 1332–1335, 1996. 9. Witherspoon L, Shuler S, and Lapeyroleria T: Immulite prostate specific antigen (PSA) assay. Clin Chem 41: S224, 1995. 10. Benson MC, Whang IS, Pantluck A, et al: Prostate-specific antigen density: a means of distinguishing benign prostatic hyperplasia and prostate cancer. J Urol 147: 815– 816, 1992. 11. Seeman E, Whang MS, Ollsson CA, et al: PSA density (PSAD): role in patient evaluation and management. Urol Clin North Am 20: 653– 663, 1993. 12. Oesterling JE, Chute CG, Jacobsen SJ, et al: Longitudinal changes in serum PSA (PSA velocity) in a communitybased cohort of men. J Urol 149: 412A, 1993. 13. Oesterling JE, Jacobsen SJ, Chute CG, et al: Prostatespecific antigen in a community-based population of healthy men: establishment of age-specific ranges. JAMA 270: 860 – 864, 1993. 14. Collins GN, Lee RJ, McKelvic GB, et al: Relationship between prostate-specific antigen, prostate volume and age in the benign prostate. Br J Urol 71: 445– 450, 1993. 15. Pizzo SV, Mast AE, Feldman SR, et al: In vivo catabolism of a1-antichymotrypsin is mediated by the serpin receptor which binds a1-proteinase inhibitor, antithrombin II and heparin cofactor II. Biochim Biophys Acta 967: 158 –162, 1988. 16. Travis J, and Salvesen GS: Human plasma proteinase inhibitors. Annu Rev Biochem 52: 655–709, 1983. 17. Kadayifci A, Benekli M, Simsek H, et al: Prostatic acid phosphatase and prostate specific antigen in liver disease. Int Urol Nephrol 28: 67–71, 1996. 18. Williams PB, Eastman JA, Culkin DJ, et al: Influence of hepatic function on serum levels of prostate specific antigen. J Urol 158: 1867–1869, 1997.

EDITORIAL COMMENT As cited in the current report, venous sampling studies have demonstrated that the most likely site of PSA metabolism is the liver, and multiple hepatic metabolic pathways have been suggested (eg, enzyme complex receptor inactivation and Ku¨pffer cell-mediated endocytosis). Previous investigations of possible effects of liver disease on serum PSA values have been reported. Kadayifci et al.1 noted normal PSA values in individuals with liver disease. Our group2 has compared PSA values in 10 patients with liver failure before and after liver transplantation and noted no significant difference in the pre- and posttransplantation values. In 4 of the 10 patients in our previous study,2 both unbound or fPSA and tPSA fractions were measured. Neither free nor bound forms of PSA were statistically significantly altered by liver failure or subsequent transplantation (P 5 0.60) in this small subset of patients. In the present study, serum values of fPSA and tPSA were compared among three age-matched groups: 18 men with liver cirrhosis, 20 men with chronic hepatitis, and 20 healthy men serving as control subjects. No statistically significant 827