EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: In this study, we aimed to determine whether the prostate-specific antigen level is a reliable marker of prostate cancer in patients with hepatic insufficiency, based on evaluation of alterations in serum prostate-specific antigen levels after liver transplant in patients with hepatic insufficiency.

Materials and Methods: Medical records of all patients who underwent liver transplant at our hospital between January 2003 and June 2017 were retrospectively reviewed. Male patients who were > 40 years old with available pre- and posttransplant serum total prostate-specific antigen levels were included in the study.

Results: Our study included 36 male patients with a mean age of 54.6 ± 5.3 years (range, 45-73 y) at the time of liver transplant. The mean pretransplant serum total prostate-specific antigen level was 0.75 ± 0.77 ng/mL, which was significantly lower than the mean posttransplant level of 1.29 ± 1.57 ng/mL (P < .05). The pretransplant serum total prostate-specific antigen level was measured a mean of 4.9 ± 5.4 months before liver transplant versus a mean 27.6 ± 16.3 months after transplant. Prostate-specific antigen velocity was 0.2 ng/mL/year. Biochemical tests of liver function, including the mean serum levels of bilirubin, international normalized ratio, and albumin, were normal after liver transplant at 1.37 ± 2.33 mg/dL, 1.22 ± 0.36, and 4.16 ± 0.69 g/dL, respectively.

Conclusions: Serum prostate-specific antigen levels may decrease in patients with hepatic insufficiency/cirrhosis; therefore, a low serum prostate-specific antigen level may not be a reliable marker for excluding prostate cancer in such patients. Transplant surgeons and clinicians must be aware of this so that all male transplant candidates > 40 years old are evaluated via digital rectal examination, regardless of the serum prostate-specific antigen level.

Key words : Cirrhosis, Hepatic insufficiency, Prostate cancer screening

Prostate cancer (PCa) is the most common solid neoplasm in Europe, with an incidence of 214 per 1000 men. Serum prostate-specific antigen (PSA) measurement and digital rectal examination (DRE) are widely used for PCa screening.¹ In addition, a transrectal ultrasonography-guided prostate biopsy is needed for a definitive diagnosis of PCa. In approximately 18% of patients, PCa is detected via a PCa-suggestive DRE, regardless of the serum PSA level.¹

Prostate-specific antigen is a single-chain 33-kDa glycoprotein serine protease released by prostate epithelial cells and is thought to be metabolized primarily by the liver.^2,3 Liver transplant is the standard treatment for acute and chronic hepatic failure and other metabolic disorders, including primary oxaluria. Patient evaluations before liver transplant are of vital importance, not only for identifying appropriate transplant recipients but also for maintaining graft survival. Screening for malignancies, such as breast, endocervical, colorectal, prostate, and skin cancer, is an essential part of patient evaluation before liver transplant.⁴

Data on the status of PSA in patients with hepatic sufficiency are inconsistent. Some studies have reported that the PSA level decreases in patients with hepatic insufficiency,^5,6whereas others report it increases.⁷ The present study aimed to determine whether PSA level is a reliable marker of PCa in patients with hepatic insufficiency, based on evaluation of alterations in the serum PSA level after liver transplant in patients with hepatic insufficiency.

Materials and Methods

The medical records of all patients who underwent liver transplant at Turkiye Yuksek Ihtisas Training and Research Hospital, Ankara, Turkey, between January 2003 and June 2017 were retrospectively reviewed. Male patients who were > 40 years old with available pre- and posttransplant serum total PSA (tPSA) data were included in the study. Active urinary tract infection was excluded via urine analysis, and none of the patients had urinary instrumentation within 3 weeks of blood sample collection for PSA analysis. Patients with a history of 5α-reductase inhibitor use were excluded from the study. Patient demographics, cause of hepatic insufficiency, serum tPSA levels before and after transplant, PSA velocity (PSAV), and posttransplant serum albumin, international normalized ratio, and bilirubin levels were evaluated. Prostate-specific antigen velocity was calculated as follows: (second-round PSA - first-round PSA)/years between PSA tests. The study protocol was approved by the institutional review board.

Statistical analyses were performed using IBM SPSS Statistics for Windows version 21.0 (IBM Corp., Armonk, NY, USA). Quantitative variables are shown as mean and SD. Quantitative measurements were compared using the paired sample t test. The level of statistical significance was set at P < .05.

In total, 137 male patients underwent liver transplant during the study period, of which 36 with a mean age of 54.6 ± 5.3 years (range, 45-73 y) at the time of transplant were included in the study. The causes of hepatic failure were as follows: viral hepatitis (n = 13), viral hepatitis plus hepatocellular carcinoma (n = 16), cryptogenic cirrhosis (n = 3), hepatocellular carcinoma (n = 1), toxic hepatitis (n = 1), and other (primary sclerosing cholangitis and hepatoportal sclerosis) (n = 2).

The mean pretransplant serum tPSA level was 0.75 ± 0.77 ng/mL, which was significantly lower than the mean posttransplant serum tPSA level of 1.29 ± 1.57 ng/mL (P < .05) (Table 1). The pretransplant serum tPSA level was measured a mean of 4.9 ± 5.4 months before liver transplant, whereas it was measured a mean of 27.6 ± 16.3 months after transplant. Prostate-specific antigen velocity was 0.2 ng/mL/year. Liver allografts of all 36 patients were functioning after liver transplant. The posttransplant mean serum bilirubin level (1.37 ± 2.33 mg/dL), international normalized ratio (1.22 ± 0.36), and albumin level (4.16 ± 0.69 g/dL) were normal.

Prostate-specific antigen is a widely used screening tool for PCa, which should be combined with DRE. An elevated serum PSA level and/or DRE suggestive of PCa might be an indication for a transrectal ultrasonography-guided biopsy, which is required for pathologic confirmation of PCa. Prostate-specific antigen is a 34-kDa glycoprotein produced primarily by human prostatic epithelial cells,8 and levels in serum can be affected by urinary instrumentation, DRE, and prostate biopsy.⁹ In addition, hepatic and renal diseases can also affect serum PSA levels.⁶ The liver is thought to be the most likely site of PSA metabolism, according to Agha and associates,² who also reported that the lungs and kidneys do not play a significant role in elimination of PSA. Likewise, Kilic and associates³ reported that the liver plays a significant role in elimination of tPSA and free PSA and that the kidneys play a significant role only in elimination of free PSA but that the lungs are not involved in elimination of tPSA or free PSA.

Serum PSA levels in patients with diseases of the liver, including chronic active hepatitis and cirrhosis, have been studied.^5-8,10,11 However, how PSA is affected by liver disease is not clearly known. Some researchers have reported that the serum PSA level decreases in patients with hepatic cirrhosis and/or insufficiency,^5,6,11 whereas others reported that it increases slightly.⁷ Williams and associates⁸ evaluated the mean serum PSA level in 10 male liver transplant recipients with a mean age of 46 years (range, 23-67 y) before and after liver transplant. The mean PSA level before transplant was 60 ± 0.24 ng/mL versus 0.81 ± 0.41 ng/mL after transplant, with the difference not significant. The group concluded that the serum PSA level is not affected by severe chronic liver disease. Jin and associates12 studied 15 male liver transplant recipients and reported that the mean serum PSA level was significantly lower before liver transplant (0.3 ± 0.2 ng/mL) and normal after liver transplant (1.4 ± 0.4 ng/mL) (P = .02); however, in that study, only 6 of the transplant recipients underwent both pre- and posttransplant examinations.

Kadayifci and associates7 examined the serum PSA levels in patients with chronic active hepatitis and hepatic cirrhosis and in healthy controls. The mean PSA level in patients with chronic active hepatitis, patients with hepatic cirrhosis, and control patients was 0.89 ± 0.15, 1.29 ± 0.53, and 0.93 ± 0.38 ng/mL, respectively. The serum PSA level was slightly higher in the cirrhosis patients than in the controls but not significantly. Similarly, Kilic and associates10 reported that the mean serum PSA level in patients with chronic active hepatitis and hepatic cirrhosis and in control patients was 0.69 ± 0.53, 0.63 ± 0.44, and 0.95 ± 0.65 ng/mL, respectively, with no significant difference shown between the groups (P > .05).

Prostate-specific antigen is an age- and race-dependent biomarker, and its level increases with age.13 A PSAV of ≥ 0.35 ng/mL/year is thought to be indicative of PCa. It is also recommended that PSAV should be based on ≥ 3 consecutive measurements over the course of 18 to 24 months.¹⁴ However, PSAV can also be calculated with 2 measurements. In one study, PSAV of patients diagnosed with PCa was found to be significantly higher than in patients with no PCa, at 0.29 versus 0.0 ng/mL/year (P < .001).15 Based on these findings, a significant increase in the PSA level is not expected during a short time interval, except in PCa patients. In the present study, 2 serum PSA measurements were obtained and the PSAV was 0.2 ng/mL/year.

In the present study, tPSA decreased in patients with hepatic insufficiency and returned to normal after liver transplant, which we believe may be indicative of the unreliability of PSA as a marker of PCa in patients with hepatic insufficiency. As such, DRE or other imaging modalities such as multiparametric magnetic resonance imaging may be more effective for PCa screening in this patient population. Moreover, transplant surgeons and clinicians must be aware of this entity, and all male liver transplant candidates who are > 40 years old should be evaluated via DRE, regardless of the serum PSA level.

The literature includes many studies on the serum PSA level in patients with liver diseases but most compared cirrhotic patients and healthy controls. In contrast, the literature includes only 2 small-scale studies (10 and 6 patients each) that compared the serum PSA levels before and after liver transplant. To date, the present study is the largest to compare the serum PSA levels in patients with hepatic insufficiency before and after liver transplant, with a significant difference shown. Additional larger-scale studies based on ≥ 3 consecutive PSA measurements and long-term follow-up are needed to confirm the present findings and to establish a lower PSA threshold considered suspicious for PCa in liver transplant candidates.

The serum PSA level may decrease in patients with hepatic insufficiency/cirrhosis; therefore, a low serum PSA level may not be a reliable marker for excluding PCa in such patients. Transplant surgeons and clinicians must be aware of this, and all male transplant candidates who are > 40 years old should be evaluated via DRE, regardless of the serum PSA level.

Volume: 17 Issue: 4 August 2019

FULL TEXT