- Email: [email protected]
Influence of age, anthropometry, and hepatic and renal function on serum prostate-specific antigen levels in healthy middle-age men
ADULT UROLOGY
INFLUENCE OF AGE, ANTHROPOMETRY, AND HEPATIC AND RENAL FUNCTION ON SERUM PROSTATE-SPECIFIC ANTIGEN LEVELS IN HEALTHY MIDDLE-AGE MEN JA HYEON KU, MIN EUI KIM, NAM KYU LEE, YOUNG HO PARK,
AND
JAE OUK AHN
ABSTRACT Objectives. To test the hypothesis of a causal relationship between clinical parameters, including age, anthropometry, and hepatic or renal function tests and serum prostate-specific antigen (PSA) levels and to determine the predictors of high serum PSA concentrations in healthy middle-age men. Methods. Between January 1999 and December 2000, 6005 healthy men 40 to 59 years old who visited our hospital for a routine health checkup were entered into the study. The association between the clinical parameters and a high serum PSA level (greater than 2.5, 3.0, 3.5, or 4.0 ng/mL) was studied in three groups: the 10% with low clinical parameters, the 10% with high clinical parameters, and the remainder as a reference group. Results. The univariate logistic regression analysis indicated that high or low age, body weight, body mass index, creatinine, and creatinine clearance were significant factors in relation to serum PSA concentration compared with the reference group. In the multivariate model used, only older age was positively related to the serum PSA concentration. Conclusions. The results of anthropometry and hepatic and renal function tests do not influence the serum PSA level in this population. Our findings suggest that serum PSA may be a reliable marker in middle-age men without severe hepatic or renal disease. UROLOGY 61: 132–136, 2003. © 2003, Elsevier Science Inc.
A
lthough controversy exists regarding the use of prostate-specific antigen (PSA) testing because of the lack of randomized trials demonstrating a reduction in prostate cancer mortality, PSA testing is widely used to screen for prostate cancer. However, its sensitivity and specificity limit its use as a screening tool because serum PSA is not tissue specific,1,2 as well as cancer specific.3 In addition, the serum PSA concentration is directly correlated with age and prostate volume and is known to be
From the Department of Urology, Military Manpower Administration, Seoul; Department of Urology, Soonchunhyang University School of Medicine, Pucheon; Department of Urology, Soonchunhyang University School of Medicine, Chonan; Department of Urology, Soonchunhyang University School of Medicine, Seoul; and Department of Medical Informatics, Soonchunhyang University School of Medicine, Chonan, Korea. Reprint requests: Ja Hyeon Ku, M.D., Department of Urology, Military Manpower Administration, Joong-Ang Shin-geom so, San 159-1 Shin-gil 7 dong, Youngdeungpo-Ku, Seoul 150-057, Korea Submitted: June 5, 2002, accepted (with revisions): August 15, 2002
132
© 2003, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
different across ethnic groups.4 Moreover, underlying liver disease may be a possible cause for alteration of serum PSA levels.5 Therefore, to improve the accuracy of serum PSA testing for prostate cancer, a knowledge of PSA biochemistry and metabolism is required. The liver has a significant role in the elimination of serum PSA but the kidneys and lungs do not.6 Free PSA is eliminated by the kidneys but, because of their size, PSA bound to alpha1-antichymotrypsin is cleared through the liver. Because the complexed form constitutes the major molecule of PSA measured in the serum, one may expect the liver to play a role in the alteration of the serum PSA concentration. Because obesity is associated with endocrine changes and endocrine changes have been implicated in the etiology of prostate cancer, obesity has been suggested as a risk factor for prostate cancer.7–9 Although an association between obesity and the alteration in serum PSA levels would be expected, to our knowledge, no study has investigated the relationship between obesity and serum PSA concentration. 0090-4295/03/$30.00 PII S0090-4295(02)02001-0
TABLE I. Distribution of clinical parameters among men 40 to 59 years old Median Age (yr) Anthropometric measurements Height (cm) Weight (kg) BMI (kg/m2) Hepatic function tests AST (U/L) ALT (U/L) Alkaline phosphatase (U/L) Gamma-glutamyltransferase (U/L) Total bilirubin (moL/L) Renal function tests Urea nitrogen (mmoL/L) Creatinine (moL/L) Creatinine clearance (mL/s)
25th, 75th Percentiles
10th, 90th Percentiles
43, 51
41, 55
165.60, 173.10 62.50, 73.80 22.02, 25.49
162.40, 176.40 57.60, 79.30 20.47, 27.10
47 169.40 68.00 23.79 18.50 16.30 74.00 33.30 15.39
15.50, 12.00, 63.50, 23.10, 11.97,
23.40 23.50 86.80 53.05 20.52
13.40, 30.10 9.20, 35.70 55.20, 101.90 17.90, 87.34 10.26, 25.65
5.14 88.40 0.99
4.32, 6.07 79.56, 97.24 0.88, 1.12
3.68, 7.03 70.72, 106.08 0.79, 1.25
KEY: BMI ⫽ body mass index; AST ⫽ aspartate aminotransferase; ALT ⫽ alanine aminotransferase.
An improved understanding of PSA characteristics would help clarify which states might influence the serum PSA concentration. This study was designed to determine the predictors of high serum PSA concentrations in middle-age men. We regarded serum PSA levels greater than 2.5, 3.0, 3.5, and 4.0 ng/mL as PSA thresholds. MATERIAL AND METHODS Between January 1999 and December 2000, 6302 men 40 to 59 years old who visited the Health Promotion Center in our hospital for a routine health checkup were entered into this study. All men underwent detailed clinical examinations, including serum PSA determination (Tandem-R, Hybritech, San Diego, Calif). A digital rectal examination was performed in men 50 years old or older, independently, as part of their general health examinations according to the American Cancer Society guidelines.10 The digital rectal examination was performed by family medicine doctors who were unaware of the serum PSA findings. Subjects between 50 and 59 years old with abnormal digital rectal examination findings and/or a serum PSA level greater than 4.0 ng/mL underwent transrectal ultrasound-guided systematic sextant biopsy. Transaxial and sagittal scanning of the prostate was performed by a radiologist experienced in this procedure using a 6.5-MHz transducer (Ultramake 9, ATL, Washington, DC). Scanning was accomplished in the lateral decubitus position. Those who had a prior diagnosis of prostate cancer, prostate cancer detected by biopsy, a previous history of prostate surgery, or did not undergo serum PSA determination and testing of the clinical parameters were excluded. A total of 6005 men were included in the analysis. Anthropometric measurements of the subjects, including height, weight, and body mass index (BMI) were determined, and an analysis of this information will be separately reported. The BMI was calculated by dividing the weight in kilograms by the square of the height in meters. A blood sample was obtained for the determination of serum PSA, hepatic function tests, and renal function tests. Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, and total bilirubin were measured for the hepatic function testing. Urea nitrogen, creatinine, and creatUROLOGY 61 (1), 2003
inine clearance were used to determine the renal function. Creatinine clearance was calculated using the following formula: creatinine clearance ⫽ (140 ⫺ age) ⫻ weight ⫻ 60/72 ⫻ creatinine. The serum PSA levels were studied in three groups of men as determined by the anthropometric measurements and hepatic and renal function tests: the 10% who had low measurements, the 10% who had high measurements, and the remainder as a reference group. Odds ratios (OR) for high serum PSA levels (greater than 2.5, 3.0, 3.5, or 4.0 ng/mL) associated with these parameters and P values for trend were estimated by logistic regression analyses. In the univariate analyses, factors associated with high serum PSA levels were studied. Of these variables, only those that were statistically significant (P ⬍0.05) on the univariate analysis were included in the multivariate logistic model. Multivariate logistic regression analysis was used to determine the independent predictors of high serum PSA level. The association among these parameters and the risk of a high serum PSA level was described with maximal likelihood estimates of the relative risk and the 95% confidence intervals (CIs) as determined by a multiple logistic regression model. The 95% CIs were based on the standard error of the coefficients and normal approximation. A 5% level of significance was used for all statistical testing, and all statistical tests were two-sided. Statistical analyses were performed using a commercially available analysis program.
RESULTS The median serum PSA level (5th to 95th percentile range) was 0.90 ng/mL (0.31 to 2.54) for this population. Eighty percent of the subjects were 42 to 54 years old. The other clinical parameters were within the normal range for most subjects. Table I shows the distribution of the clinical parameters. To evaluate the influence of clinical parameters on high serum PSA levels, age, anthropometry, and liver and renal function tests were included in the univariate logistic model. On univariate logistic regression analysis, when 2.5 ng/mL was chosen as the PSA cutoff level, age, body weight, BMI, creat133
TABLE II. Multivariate predictors for increase in serum PSA level among men 40 to 59 years old Adjusted Odds Ratio (95% Confidence Interval) Predictor Age (yr) ⱕ41 42–54 ⱖ55 Body weight (kg) ⱕ57.60 57.70–79.20 ⱖ79.30 BMI (kg/m2) ⱕ20.47 20.48–27.09 ⱖ27.10 Creatinine (moL/L) ⱕ70.72 70.73–106.07 ⱖ106.08 Creatinine clearance (mL/s) ⱕ0.79 0.80–1.24 ⱖ1.25
PSA >2.5 ng/mL
PSA >3.0 ng/mL
PSA >3.5 ng/mL
PSA >4.0 ng/mL
0.76 (0.47–1.25) 1.00 1.66 (1.17–2.36)
0.65 (0.33–1.29) 1.00 1.67 (1.07–2.59)
0.86 (0.39–1.87) 1.00 2.15 (1.28–3.63)
0.70 (0.22–2.25) 1.00 2.61 (1.34–5.09)
0.60 (0.36–1.01) 1.00 0.76 (0.42–1.38)
0.67 (0.38–1.20) 1.00 0.47 (0.22–1.01)
— — —
— — —
1.55 (0.99–2.41) 1.00 0.79 (0.45–1.39)
— — —
— — —
— — —
1.12 (0.50–2.74) 1.00 1.27 (0.71–2.25)
1.29 (0.42–3.95) 1.00 1.91 (0.99–3.70)
1.42 (0.40–4.97) 1.00 2.15 (0.98–4.72)
— — —
1.43 (0.97–2.11) 1.00 0.71 (0.40–1.26)
1.30 (0.78–2.16) 1.00 0.74 (0.35–1.54)
1.21 (0.67–2.16) 1.00 0.83 (0.38–1.82)
— — —
KEY: BMI ⫽ body mass index.
inine, and creatinine clearance were associated with a high or low serum PSA level compared with the reference group. The other parameters were not appreciably related to the serum PSA level. The variables that were statistically significant on univariate analysis were selected for the multivariate logistic model to determine their association with the serum PSA level. On the multivariate model used, a positive association was observed between older age and a high serum PSA level (P ⫽ 0.010). The OR for the high serum PSA level increased with this parameter: 1.66 (95% CI, between high and low quartile 1.17 to 2.36), but body weight, BMI, creatinine, and creatinine clearance lost their statistical significance. When other PSA cutoff levels were chosen, only older age was positively related to a high serum PSA concentration (Table II). COMMENT We regarded a serum PSA level greater than 2.5, 3.0, 3.5, or 4.0 ng/mL as a PSA threshold for this population. This group may be considered a highrisk group for prostate cancer diagnosis in the future, because 48% of men whose initial PSA levels were between 2.6 and 4.0 ng/mL had an increase in their PSA level to greater than 4.0 ng/mL within 4 years, and 13% had cancer detected during this interval.11 In addition, Gann et al.12 reported that, compared with men whose PSA levels were less than 1.0 ng/mL, those with PSA levels of 2.01 to 4.0 134
ng/mL were 5.5 to 8.6 times more likely to develop aggressive prostate cancer within 10 years. As expected, on our multivariate model, men 55 years old or older had a risk of high serum PSA levels. Our findings are consistent with the general concept that the prostate is a dynamic organ undergoing changes in size and activity with age. However, in contrast to our expectation, we did not find that obese men had high serum PSA levels. Because the hormonal milieu has a strong influence on prostate carcinogenesis, anthropometry has been suggested as one of the causal components of prostate cancer. No single piece of evidence is sufficient to indicate obesity, but numerous investigators have used body weight or BMI as indicators of obesity. BMI is a fairly good indirect measurement of body fat, and this simple measurement correlates quite highly with other estimates of fatness.13 Conflicting results about a causal relationship between anthropometry and the risk of prostate cancer have led to much confusion. Some investigators have indicated that a greater BMI was an independent predictor of prostate cancer.7–9 In a northern Italian population, an OR of 3.89 (95% CI 1.70 to 8.99) was reported among men with a BMI greater than 28 kg/m2.7 In a Danish record-linkage study, an OR of 1.3 (95% CI 1.1 to 1.6) was found for obese men, with a decreasing trend with age.8 In a case-control study in Sweden with prospecUROLOGY 61 (1), 2003
tively collected exposure data, an increased trend was seen for BMI, with an OR of 1.44 (95% CI 0.98 to 2.11) for 26 to 29 kg/m2, and the BMI remained an independent risk factor in a multivariate analysis.9 However, others observed that body weight or BMI did not display any consistent relation with the risk of prostate cancer.14,15 Although this discrepancy may result from differences in age, race, or study method, additional research is needed to resolve this continuing controversy and to clarify the underlying mechanisms involved. The liver is the most likely site of PSA metabolism.6 A possible mechanism of hepatic clearance of PSA is by the hepatic serpin enzyme complex receptor. Because the hepatic serpin enzyme complex receptor may eliminate complexes between serine protease and their proteinase inhibitors,16 it is possible that this receptor is involved in the clearance of PSA bound to alpha1-antichymotrypsin from the circulation. An alternative mechanism is by way of the Kupffer cells. These cells contain carbohydrate-specific receptors and are responsible for clearing glycoproteins from the circulation.17 Because PSA is a glycoprotein, receptor-mediated endocytosis by Kupffer cells might be responsible for PSA metabolism. One might anticipate that chronic liver disease would prolong the half-life of serum PSA because of decreased clearance of PSA and would result in an increase in its serum concentration. However, no consensus has been reached regarding the influence of severe liver disease on serum PSA levels. Some investigators have noted that the serum PSA levels were not significantly different among healthy men and men with liver cirrhosis or chronic hepatitis.18,19 Williams et al.19 found that serum bilirubin and aminotransferases declined significantly after liver transplantation, but the mean serum PSA levels before and after liver transplantation were not different. Other investigators demonstrated that the mean serum PSA level was significantly lower in men with liver cirrhosis compared with healthy men.20,21 Jin et al.21 found that before liver transplantation, the serum PSA concentrations in men with severe liver disease were significant lower than those of healthy men and normalized after liver transplantation. Hepatic cirrhosis may influence estrogen and testosterone metabolism, with resultant increases in circulating estrogen levels and decreases in testosterone concentrations.22 These alterations might be anticipated to lower the serum PSA concentration in men with cirrhosis. Serum levels of aspartate aminotransferase and alanine aminotransferase may be useful for screening of disease activity in a given patient but enzyme release is an indirect indication of disease activity. In addition, in contrast to alanine aminotransferUROLOGY 61 (1), 2003
ase, which is found primarily in the liver, aspartate aminotransferase is present in many tissues, including heart, skeletal muscle, kidney, and brain, and is thus somewhat less specific as an indicator of liver function. Alkaline phosphatase is used for excretory function of the liver, and its clearance may be impaired in liver disease. On the contrary, the serum level of total bilirubin can be a sensitive indicator of synthetic function of the liver, because it is produced at a relatively constant rate. On univariate analysis in this study, we did not find any factors in the liver function tests to be associated with high PSA levels. Although liver function tests provide only indirect evidence of hepatic integrity, our findings suggest that significant alterations in serum PSA concentration are not obvious because of a relatively small PSA load in men without severe hepatic dysfunction. The measurement of the total glomerular filtration rate (GFR) of both kidneys provides a sensitive and commonly used index of overall renal excretory function. As the GFR falls, plasma level of creatinine, urea, and other substances normally excreted largely by filtration rise progressively. There is no ideal material of endogenous origin, but the most useful indicators of GFR are measurements of the plasma creatinine concentration and creatinine clearance. We undertook measurement of urea nitrogen, creatinine, and creatinine clearance as indicators of the GFR. Contrary to earlier observations, creatinine and creatinine clearance were possible factors for the alteration of serum PSA concentrations on univariate analysis when 2.5, 3.0, and 3.5 ng/mL were chosen as PSA cutoff levels. However, on our multivariate model, although low creatinine clearance had a trend for high serum PSA levels when 2.5 ng/mL was chosen as the PSA cutoff level, statistical significance was not observed (OR 1.43, 95% CI 0.97 to 2.11, P ⫽ 0.053). To date, consistent results that the kidneys do not play a significant role in the clearance of PSA from human serum have been reported. Kabalin and Hornberger23 assessed serum and urine PSA levels from men with indwelling percutaneous nephrostomy tubes for treatment of ureteral obstruction, and no PSA could be detected at the level of the renal pelvis. In addition, no appreciable accumulation of serum PSA was observed in those with chronic renal failure,24 and renal transplantation and dialytic therapy did not affect clinical serum PSA levels.25 In vitro studies have shown that PSA in the serum is complexed to alpha1-antichymotrypsin and alpha2-macroglobulin with molecular weights of 100 and 780 kDa, respectively.26 These complexed molecules, making up to 95% of the serum PSA, are far too large to be filtered through the glomerular membrane. Only a small fraction of PSA is found in the free form with a molecular 135
weight of 33 kDa, which approximates one half of the weight of albumin. In theory, this form of PSA is likely to be filtered in trace amounts from normal kidneys. Therefore, it is hypothesized that serum PSA levels are not influenced by renal function. REFERENCES 1. Diamandis EP, and Yu H: Nonprostatic sources of prostate-specific antigen. Urol Clin North Am 24: 275–282, 1997. 2. Black MH, and Diamandis EP: The diagnostic and prognostic utility of prostate-specific antigen for disease of the breast. Breast Cancer Res Treat 59: 1–14, 2000. 3. Catalona WJ, Partin AW, Slawin KM, et al: Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA 279: 1542–1547, 1998. 4. Masumori N, Tsukamoto T, Kumamoto Y, et al: Japanese men have smaller prostate volumes but comparable urinary flow rates relative to American men: results of community based studies in 2 countries. J Urol 155: 1324 –1327, 1996. 5. Bosch X, and Bernadich O: Increased serum prostatespecific antigen in a man and a woman with hepatitis A. N Engl J Med 337: 1849 –1950, 1997. 6. Kilic S, Yalcinkaya S, Guntekin E, et al: Determination of the site of metabolism of total, free, and complexed prostate-specific antigen. Urology 52: 470 –473, 1998. 7. Talamini R, La Vecchia C, Decarli A, et al: Nutrition, social factors and prostate cancer in a Northern Italian population. Br J Cancer 53: 817–821, 1986. 8. Moller H, Mellemgaard A, Lindvig K, et al: Obesity and cancer risk: a Danish record-linkage study. Eur J Cancer 30A: 344 –350, 1994. 9. Gronberg H, Damber L, and Damber JE: Total food consumption and body mass index in relation to prostate cancer risk: a case-control study in Sweden with prospectively collected exposure data. J Urol 155: 969 –974, 1996. 10. Mettlin C, Jones G, and Averette H: Defining and updating the American Cancer Society guidelines for the cancerrelated checkup: prostate and endometrial cancer. CA Cancer J Clin 43: 42–46, 1993. 11. Smith DS, Catalona WJ, and Herschman JD: Longitudinal screening for prostate cancer with prostate-specific antigen. JAMA 276: 1309 –1315, 1996. 12. Gann PH, Hennekens CH, and Stampfer MJ: A prospective evaluation of plasma prostate-specific antigen for detection of prostate cancer. JAMA 273: 289 –294, 1995.
136
13. Garn SM, Leonard WR, and Hawthorne VM: Three limitations of the body mass index. Am J Clin Nutr 44: 996 –997, 1986. 14. Nilsen TI, and Vatten LJ: Anthropometry and prostate cancer risk: a prospective study of 22,248 Norwegian men. Cancer Causes Control 10: 269 –275, 1999. 15. Nomura A, Heilbrun LK, and Stemmermann GN: Body mass index as a predictor of cancer in men. J Natl Cancer Inst 74: 319 –323, 1985. 16. Mast AE, Enghild JJ, Pizzo SV, et al: Analysis of the plasma elimination kinetics and conformational stabilities of native, proteinase-complexed, and reactive site cleaved serpins: comparison of alpha 1-proteinase inhibitor, alpha 1-antichymotrypsin, antithrombin III, alpha 2-antiplasmin, angiotensinogen, and ovalbumin. Biochemistry 30: 1723–1730, 1991. 17. Kolb-Bachofen V, Schlepper-Schafer J, Vogell W, et al: Electron microscopic evidence for an asialoglycoprotein receptor on Kupffer cells: localization of lectin-mediated endocytosis. Cell 29: 859 –866, 1982. 18. Kilic S, Guntekin E, Danisman A, et al: Serum free and total prostate-specific antigen levels in patients with liver disease. Urology 52: 825–828, 1998. 19. Williams PB, Eastham JA, Culkin DJ, et al: Influence of hepatic function on serum levels of prostate specific antigen. J Urol 158: 1867–1869, 1997. 20. Kubota Y, Sasagawa I, Sinzawa H, et al: Serum levels of free and total prostate-specific antigen in males with liver cirrhosis. Eur Urol 36: 409 –412, 1999. 21. Jin B, McCaughan GW, and Handelsman DJ: Effects of liver disease and transplantation on the human prostate. J Androl 20: 559 –565, 1999. 22. Chopra IJ, Tulchinsky D, and Greenway FL: Estrogenandrogen imbalance in hepatic cirrhosis: studies in 13 male patients. Ann Intern Med 79: 198 –203, 1973. 23. Kabalin JN, and Hornberger JC: Prostate-specific antigen is not excreted by human kidney or eliminated by routine hemodialysis. Urology 37: 308 –310, 1991. 24. Monath JR, Burkart JM, Freedman BI, et al: Effect of hemodialysis on prostate-specific antigen. Urology 42: 398 – 400, 1993. 25. Sasagawa I, Kubota Y, Hayami S, et al: Serum levels of total and free prostate specific antigen in men on hemodialysis. J Urol 160: 83–85, 1998. 26. Christensson A, Laurell 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.
UROLOGY 61 (1), 2003
INFLUENCE OF AGE, ANTHROPOMETRY, AND HEPATIC AND RENAL FUNCTION ON SERUM PROSTATE-SPECIFIC ANTIGEN LEVELS IN HEALTHY MIDDLE-AGE MEN JA HYEON KU, MIN EUI KIM, NAM KYU LEE, YOUNG HO PARK,
AND
JAE OUK AHN
ABSTRACT Objectives. To test the hypothesis of a causal relationship between clinical parameters, including age, anthropometry, and hepatic or renal function tests and serum prostate-specific antigen (PSA) levels and to determine the predictors of high serum PSA concentrations in healthy middle-age men. Methods. Between January 1999 and December 2000, 6005 healthy men 40 to 59 years old who visited our hospital for a routine health checkup were entered into the study. The association between the clinical parameters and a high serum PSA level (greater than 2.5, 3.0, 3.5, or 4.0 ng/mL) was studied in three groups: the 10% with low clinical parameters, the 10% with high clinical parameters, and the remainder as a reference group. Results. The univariate logistic regression analysis indicated that high or low age, body weight, body mass index, creatinine, and creatinine clearance were significant factors in relation to serum PSA concentration compared with the reference group. In the multivariate model used, only older age was positively related to the serum PSA concentration. Conclusions. The results of anthropometry and hepatic and renal function tests do not influence the serum PSA level in this population. Our findings suggest that serum PSA may be a reliable marker in middle-age men without severe hepatic or renal disease. UROLOGY 61: 132–136, 2003. © 2003, Elsevier Science Inc.
A
lthough controversy exists regarding the use of prostate-specific antigen (PSA) testing because of the lack of randomized trials demonstrating a reduction in prostate cancer mortality, PSA testing is widely used to screen for prostate cancer. However, its sensitivity and specificity limit its use as a screening tool because serum PSA is not tissue specific,1,2 as well as cancer specific.3 In addition, the serum PSA concentration is directly correlated with age and prostate volume and is known to be
From the Department of Urology, Military Manpower Administration, Seoul; Department of Urology, Soonchunhyang University School of Medicine, Pucheon; Department of Urology, Soonchunhyang University School of Medicine, Chonan; Department of Urology, Soonchunhyang University School of Medicine, Seoul; and Department of Medical Informatics, Soonchunhyang University School of Medicine, Chonan, Korea. Reprint requests: Ja Hyeon Ku, M.D., Department of Urology, Military Manpower Administration, Joong-Ang Shin-geom so, San 159-1 Shin-gil 7 dong, Youngdeungpo-Ku, Seoul 150-057, Korea Submitted: June 5, 2002, accepted (with revisions): August 15, 2002
132
© 2003, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
different across ethnic groups.4 Moreover, underlying liver disease may be a possible cause for alteration of serum PSA levels.5 Therefore, to improve the accuracy of serum PSA testing for prostate cancer, a knowledge of PSA biochemistry and metabolism is required. The liver has a significant role in the elimination of serum PSA but the kidneys and lungs do not.6 Free PSA is eliminated by the kidneys but, because of their size, PSA bound to alpha1-antichymotrypsin is cleared through the liver. Because the complexed form constitutes the major molecule of PSA measured in the serum, one may expect the liver to play a role in the alteration of the serum PSA concentration. Because obesity is associated with endocrine changes and endocrine changes have been implicated in the etiology of prostate cancer, obesity has been suggested as a risk factor for prostate cancer.7–9 Although an association between obesity and the alteration in serum PSA levels would be expected, to our knowledge, no study has investigated the relationship between obesity and serum PSA concentration. 0090-4295/03/$30.00 PII S0090-4295(02)02001-0
TABLE I. Distribution of clinical parameters among men 40 to 59 years old Median Age (yr) Anthropometric measurements Height (cm) Weight (kg) BMI (kg/m2) Hepatic function tests AST (U/L) ALT (U/L) Alkaline phosphatase (U/L) Gamma-glutamyltransferase (U/L) Total bilirubin (moL/L) Renal function tests Urea nitrogen (mmoL/L) Creatinine (moL/L) Creatinine clearance (mL/s)
25th, 75th Percentiles
10th, 90th Percentiles
43, 51
41, 55
165.60, 173.10 62.50, 73.80 22.02, 25.49
162.40, 176.40 57.60, 79.30 20.47, 27.10
47 169.40 68.00 23.79 18.50 16.30 74.00 33.30 15.39
15.50, 12.00, 63.50, 23.10, 11.97,
23.40 23.50 86.80 53.05 20.52
13.40, 30.10 9.20, 35.70 55.20, 101.90 17.90, 87.34 10.26, 25.65
5.14 88.40 0.99
4.32, 6.07 79.56, 97.24 0.88, 1.12
3.68, 7.03 70.72, 106.08 0.79, 1.25
KEY: BMI ⫽ body mass index; AST ⫽ aspartate aminotransferase; ALT ⫽ alanine aminotransferase.
An improved understanding of PSA characteristics would help clarify which states might influence the serum PSA concentration. This study was designed to determine the predictors of high serum PSA concentrations in middle-age men. We regarded serum PSA levels greater than 2.5, 3.0, 3.5, and 4.0 ng/mL as PSA thresholds. MATERIAL AND METHODS Between January 1999 and December 2000, 6302 men 40 to 59 years old who visited the Health Promotion Center in our hospital for a routine health checkup were entered into this study. All men underwent detailed clinical examinations, including serum PSA determination (Tandem-R, Hybritech, San Diego, Calif). A digital rectal examination was performed in men 50 years old or older, independently, as part of their general health examinations according to the American Cancer Society guidelines.10 The digital rectal examination was performed by family medicine doctors who were unaware of the serum PSA findings. Subjects between 50 and 59 years old with abnormal digital rectal examination findings and/or a serum PSA level greater than 4.0 ng/mL underwent transrectal ultrasound-guided systematic sextant biopsy. Transaxial and sagittal scanning of the prostate was performed by a radiologist experienced in this procedure using a 6.5-MHz transducer (Ultramake 9, ATL, Washington, DC). Scanning was accomplished in the lateral decubitus position. Those who had a prior diagnosis of prostate cancer, prostate cancer detected by biopsy, a previous history of prostate surgery, or did not undergo serum PSA determination and testing of the clinical parameters were excluded. A total of 6005 men were included in the analysis. Anthropometric measurements of the subjects, including height, weight, and body mass index (BMI) were determined, and an analysis of this information will be separately reported. The BMI was calculated by dividing the weight in kilograms by the square of the height in meters. A blood sample was obtained for the determination of serum PSA, hepatic function tests, and renal function tests. Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, and total bilirubin were measured for the hepatic function testing. Urea nitrogen, creatinine, and creatUROLOGY 61 (1), 2003
inine clearance were used to determine the renal function. Creatinine clearance was calculated using the following formula: creatinine clearance ⫽ (140 ⫺ age) ⫻ weight ⫻ 60/72 ⫻ creatinine. The serum PSA levels were studied in three groups of men as determined by the anthropometric measurements and hepatic and renal function tests: the 10% who had low measurements, the 10% who had high measurements, and the remainder as a reference group. Odds ratios (OR) for high serum PSA levels (greater than 2.5, 3.0, 3.5, or 4.0 ng/mL) associated with these parameters and P values for trend were estimated by logistic regression analyses. In the univariate analyses, factors associated with high serum PSA levels were studied. Of these variables, only those that were statistically significant (P ⬍0.05) on the univariate analysis were included in the multivariate logistic model. Multivariate logistic regression analysis was used to determine the independent predictors of high serum PSA level. The association among these parameters and the risk of a high serum PSA level was described with maximal likelihood estimates of the relative risk and the 95% confidence intervals (CIs) as determined by a multiple logistic regression model. The 95% CIs were based on the standard error of the coefficients and normal approximation. A 5% level of significance was used for all statistical testing, and all statistical tests were two-sided. Statistical analyses were performed using a commercially available analysis program.
RESULTS The median serum PSA level (5th to 95th percentile range) was 0.90 ng/mL (0.31 to 2.54) for this population. Eighty percent of the subjects were 42 to 54 years old. The other clinical parameters were within the normal range for most subjects. Table I shows the distribution of the clinical parameters. To evaluate the influence of clinical parameters on high serum PSA levels, age, anthropometry, and liver and renal function tests were included in the univariate logistic model. On univariate logistic regression analysis, when 2.5 ng/mL was chosen as the PSA cutoff level, age, body weight, BMI, creat133
TABLE II. Multivariate predictors for increase in serum PSA level among men 40 to 59 years old Adjusted Odds Ratio (95% Confidence Interval) Predictor Age (yr) ⱕ41 42–54 ⱖ55 Body weight (kg) ⱕ57.60 57.70–79.20 ⱖ79.30 BMI (kg/m2) ⱕ20.47 20.48–27.09 ⱖ27.10 Creatinine (moL/L) ⱕ70.72 70.73–106.07 ⱖ106.08 Creatinine clearance (mL/s) ⱕ0.79 0.80–1.24 ⱖ1.25
PSA >2.5 ng/mL
PSA >3.0 ng/mL
PSA >3.5 ng/mL
PSA >4.0 ng/mL
0.76 (0.47–1.25) 1.00 1.66 (1.17–2.36)
0.65 (0.33–1.29) 1.00 1.67 (1.07–2.59)
0.86 (0.39–1.87) 1.00 2.15 (1.28–3.63)
0.70 (0.22–2.25) 1.00 2.61 (1.34–5.09)
0.60 (0.36–1.01) 1.00 0.76 (0.42–1.38)
0.67 (0.38–1.20) 1.00 0.47 (0.22–1.01)
— — —
— — —
1.55 (0.99–2.41) 1.00 0.79 (0.45–1.39)
— — —
— — —
— — —
1.12 (0.50–2.74) 1.00 1.27 (0.71–2.25)
1.29 (0.42–3.95) 1.00 1.91 (0.99–3.70)
1.42 (0.40–4.97) 1.00 2.15 (0.98–4.72)
— — —
1.43 (0.97–2.11) 1.00 0.71 (0.40–1.26)
1.30 (0.78–2.16) 1.00 0.74 (0.35–1.54)
1.21 (0.67–2.16) 1.00 0.83 (0.38–1.82)
— — —
KEY: BMI ⫽ body mass index.
inine, and creatinine clearance were associated with a high or low serum PSA level compared with the reference group. The other parameters were not appreciably related to the serum PSA level. The variables that were statistically significant on univariate analysis were selected for the multivariate logistic model to determine their association with the serum PSA level. On the multivariate model used, a positive association was observed between older age and a high serum PSA level (P ⫽ 0.010). The OR for the high serum PSA level increased with this parameter: 1.66 (95% CI, between high and low quartile 1.17 to 2.36), but body weight, BMI, creatinine, and creatinine clearance lost their statistical significance. When other PSA cutoff levels were chosen, only older age was positively related to a high serum PSA concentration (Table II). COMMENT We regarded a serum PSA level greater than 2.5, 3.0, 3.5, or 4.0 ng/mL as a PSA threshold for this population. This group may be considered a highrisk group for prostate cancer diagnosis in the future, because 48% of men whose initial PSA levels were between 2.6 and 4.0 ng/mL had an increase in their PSA level to greater than 4.0 ng/mL within 4 years, and 13% had cancer detected during this interval.11 In addition, Gann et al.12 reported that, compared with men whose PSA levels were less than 1.0 ng/mL, those with PSA levels of 2.01 to 4.0 134
ng/mL were 5.5 to 8.6 times more likely to develop aggressive prostate cancer within 10 years. As expected, on our multivariate model, men 55 years old or older had a risk of high serum PSA levels. Our findings are consistent with the general concept that the prostate is a dynamic organ undergoing changes in size and activity with age. However, in contrast to our expectation, we did not find that obese men had high serum PSA levels. Because the hormonal milieu has a strong influence on prostate carcinogenesis, anthropometry has been suggested as one of the causal components of prostate cancer. No single piece of evidence is sufficient to indicate obesity, but numerous investigators have used body weight or BMI as indicators of obesity. BMI is a fairly good indirect measurement of body fat, and this simple measurement correlates quite highly with other estimates of fatness.13 Conflicting results about a causal relationship between anthropometry and the risk of prostate cancer have led to much confusion. Some investigators have indicated that a greater BMI was an independent predictor of prostate cancer.7–9 In a northern Italian population, an OR of 3.89 (95% CI 1.70 to 8.99) was reported among men with a BMI greater than 28 kg/m2.7 In a Danish record-linkage study, an OR of 1.3 (95% CI 1.1 to 1.6) was found for obese men, with a decreasing trend with age.8 In a case-control study in Sweden with prospecUROLOGY 61 (1), 2003
tively collected exposure data, an increased trend was seen for BMI, with an OR of 1.44 (95% CI 0.98 to 2.11) for 26 to 29 kg/m2, and the BMI remained an independent risk factor in a multivariate analysis.9 However, others observed that body weight or BMI did not display any consistent relation with the risk of prostate cancer.14,15 Although this discrepancy may result from differences in age, race, or study method, additional research is needed to resolve this continuing controversy and to clarify the underlying mechanisms involved. The liver is the most likely site of PSA metabolism.6 A possible mechanism of hepatic clearance of PSA is by the hepatic serpin enzyme complex receptor. Because the hepatic serpin enzyme complex receptor may eliminate complexes between serine protease and their proteinase inhibitors,16 it is possible that this receptor is involved in the clearance of PSA bound to alpha1-antichymotrypsin from the circulation. An alternative mechanism is by way of the Kupffer cells. These cells contain carbohydrate-specific receptors and are responsible for clearing glycoproteins from the circulation.17 Because PSA is a glycoprotein, receptor-mediated endocytosis by Kupffer cells might be responsible for PSA metabolism. One might anticipate that chronic liver disease would prolong the half-life of serum PSA because of decreased clearance of PSA and would result in an increase in its serum concentration. However, no consensus has been reached regarding the influence of severe liver disease on serum PSA levels. Some investigators have noted that the serum PSA levels were not significantly different among healthy men and men with liver cirrhosis or chronic hepatitis.18,19 Williams et al.19 found that serum bilirubin and aminotransferases declined significantly after liver transplantation, but the mean serum PSA levels before and after liver transplantation were not different. Other investigators demonstrated that the mean serum PSA level was significantly lower in men with liver cirrhosis compared with healthy men.20,21 Jin et al.21 found that before liver transplantation, the serum PSA concentrations in men with severe liver disease were significant lower than those of healthy men and normalized after liver transplantation. Hepatic cirrhosis may influence estrogen and testosterone metabolism, with resultant increases in circulating estrogen levels and decreases in testosterone concentrations.22 These alterations might be anticipated to lower the serum PSA concentration in men with cirrhosis. Serum levels of aspartate aminotransferase and alanine aminotransferase may be useful for screening of disease activity in a given patient but enzyme release is an indirect indication of disease activity. In addition, in contrast to alanine aminotransferUROLOGY 61 (1), 2003
ase, which is found primarily in the liver, aspartate aminotransferase is present in many tissues, including heart, skeletal muscle, kidney, and brain, and is thus somewhat less specific as an indicator of liver function. Alkaline phosphatase is used for excretory function of the liver, and its clearance may be impaired in liver disease. On the contrary, the serum level of total bilirubin can be a sensitive indicator of synthetic function of the liver, because it is produced at a relatively constant rate. On univariate analysis in this study, we did not find any factors in the liver function tests to be associated with high PSA levels. Although liver function tests provide only indirect evidence of hepatic integrity, our findings suggest that significant alterations in serum PSA concentration are not obvious because of a relatively small PSA load in men without severe hepatic dysfunction. The measurement of the total glomerular filtration rate (GFR) of both kidneys provides a sensitive and commonly used index of overall renal excretory function. As the GFR falls, plasma level of creatinine, urea, and other substances normally excreted largely by filtration rise progressively. There is no ideal material of endogenous origin, but the most useful indicators of GFR are measurements of the plasma creatinine concentration and creatinine clearance. We undertook measurement of urea nitrogen, creatinine, and creatinine clearance as indicators of the GFR. Contrary to earlier observations, creatinine and creatinine clearance were possible factors for the alteration of serum PSA concentrations on univariate analysis when 2.5, 3.0, and 3.5 ng/mL were chosen as PSA cutoff levels. However, on our multivariate model, although low creatinine clearance had a trend for high serum PSA levels when 2.5 ng/mL was chosen as the PSA cutoff level, statistical significance was not observed (OR 1.43, 95% CI 0.97 to 2.11, P ⫽ 0.053). To date, consistent results that the kidneys do not play a significant role in the clearance of PSA from human serum have been reported. Kabalin and Hornberger23 assessed serum and urine PSA levels from men with indwelling percutaneous nephrostomy tubes for treatment of ureteral obstruction, and no PSA could be detected at the level of the renal pelvis. In addition, no appreciable accumulation of serum PSA was observed in those with chronic renal failure,24 and renal transplantation and dialytic therapy did not affect clinical serum PSA levels.25 In vitro studies have shown that PSA in the serum is complexed to alpha1-antichymotrypsin and alpha2-macroglobulin with molecular weights of 100 and 780 kDa, respectively.26 These complexed molecules, making up to 95% of the serum PSA, are far too large to be filtered through the glomerular membrane. Only a small fraction of PSA is found in the free form with a molecular 135
weight of 33 kDa, which approximates one half of the weight of albumin. In theory, this form of PSA is likely to be filtered in trace amounts from normal kidneys. Therefore, it is hypothesized that serum PSA levels are not influenced by renal function. REFERENCES 1. Diamandis EP, and Yu H: Nonprostatic sources of prostate-specific antigen. Urol Clin North Am 24: 275–282, 1997. 2. Black MH, and Diamandis EP: The diagnostic and prognostic utility of prostate-specific antigen for disease of the breast. Breast Cancer Res Treat 59: 1–14, 2000. 3. Catalona WJ, Partin AW, Slawin KM, et al: Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA 279: 1542–1547, 1998. 4. Masumori N, Tsukamoto T, Kumamoto Y, et al: Japanese men have smaller prostate volumes but comparable urinary flow rates relative to American men: results of community based studies in 2 countries. J Urol 155: 1324 –1327, 1996. 5. Bosch X, and Bernadich O: Increased serum prostatespecific antigen in a man and a woman with hepatitis A. N Engl J Med 337: 1849 –1950, 1997. 6. Kilic S, Yalcinkaya S, Guntekin E, et al: Determination of the site of metabolism of total, free, and complexed prostate-specific antigen. Urology 52: 470 –473, 1998. 7. Talamini R, La Vecchia C, Decarli A, et al: Nutrition, social factors and prostate cancer in a Northern Italian population. Br J Cancer 53: 817–821, 1986. 8. Moller H, Mellemgaard A, Lindvig K, et al: Obesity and cancer risk: a Danish record-linkage study. Eur J Cancer 30A: 344 –350, 1994. 9. Gronberg H, Damber L, and Damber JE: Total food consumption and body mass index in relation to prostate cancer risk: a case-control study in Sweden with prospectively collected exposure data. J Urol 155: 969 –974, 1996. 10. Mettlin C, Jones G, and Averette H: Defining and updating the American Cancer Society guidelines for the cancerrelated checkup: prostate and endometrial cancer. CA Cancer J Clin 43: 42–46, 1993. 11. Smith DS, Catalona WJ, and Herschman JD: Longitudinal screening for prostate cancer with prostate-specific antigen. JAMA 276: 1309 –1315, 1996. 12. Gann PH, Hennekens CH, and Stampfer MJ: A prospective evaluation of plasma prostate-specific antigen for detection of prostate cancer. JAMA 273: 289 –294, 1995.
136
13. Garn SM, Leonard WR, and Hawthorne VM: Three limitations of the body mass index. Am J Clin Nutr 44: 996 –997, 1986. 14. Nilsen TI, and Vatten LJ: Anthropometry and prostate cancer risk: a prospective study of 22,248 Norwegian men. Cancer Causes Control 10: 269 –275, 1999. 15. Nomura A, Heilbrun LK, and Stemmermann GN: Body mass index as a predictor of cancer in men. J Natl Cancer Inst 74: 319 –323, 1985. 16. Mast AE, Enghild JJ, Pizzo SV, et al: Analysis of the plasma elimination kinetics and conformational stabilities of native, proteinase-complexed, and reactive site cleaved serpins: comparison of alpha 1-proteinase inhibitor, alpha 1-antichymotrypsin, antithrombin III, alpha 2-antiplasmin, angiotensinogen, and ovalbumin. Biochemistry 30: 1723–1730, 1991. 17. Kolb-Bachofen V, Schlepper-Schafer J, Vogell W, et al: Electron microscopic evidence for an asialoglycoprotein receptor on Kupffer cells: localization of lectin-mediated endocytosis. Cell 29: 859 –866, 1982. 18. Kilic S, Guntekin E, Danisman A, et al: Serum free and total prostate-specific antigen levels in patients with liver disease. Urology 52: 825–828, 1998. 19. Williams PB, Eastham JA, Culkin DJ, et al: Influence of hepatic function on serum levels of prostate specific antigen. J Urol 158: 1867–1869, 1997. 20. Kubota Y, Sasagawa I, Sinzawa H, et al: Serum levels of free and total prostate-specific antigen in males with liver cirrhosis. Eur Urol 36: 409 –412, 1999. 21. Jin B, McCaughan GW, and Handelsman DJ: Effects of liver disease and transplantation on the human prostate. J Androl 20: 559 –565, 1999. 22. Chopra IJ, Tulchinsky D, and Greenway FL: Estrogenandrogen imbalance in hepatic cirrhosis: studies in 13 male patients. Ann Intern Med 79: 198 –203, 1973. 23. Kabalin JN, and Hornberger JC: Prostate-specific antigen is not excreted by human kidney or eliminated by routine hemodialysis. Urology 37: 308 –310, 1991. 24. Monath JR, Burkart JM, Freedman BI, et al: Effect of hemodialysis on prostate-specific antigen. Urology 42: 398 – 400, 1993. 25. Sasagawa I, Kubota Y, Hayami S, et al: Serum levels of total and free prostate specific antigen in men on hemodialysis. J Urol 160: 83–85, 1998. 26. Christensson A, Laurell 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.
UROLOGY 61 (1), 2003