Reappraisal of the Role of Alkaline Phosphatase in Hepatocellular Carcinoma

Abstract

Background: Alkaline phosphatase (ALP) is a marker of liver function and is associated with biliary tract disease. It was reported as a prognostic factor for hepatocellular carcinoma (HCC). The genetic expression in tumor-tissue microarrays and the perioperative serologic changes in ALP have never been studied for their correlation with HCC prognosis. Methods: The genetic expression of ALP isoforms (placental (ALPP), intestinal (ALPI) and bone/kidney/liver (ALPL)) was analyzed in tumor and non-cancerous areas in 38 patients with HCC after partial hepatectomy. The perioperative change in ALP was further analyzed in a cohort containing 525 patients with HCC to correlate it with oncologic outcomes. A total of 43 HCC patients were enrolled for a volumetry study after major and minor hepatectomy. Results: The genetic expression of the bone/kidney/liver isoform was specifically and significantly higher in non-cancerous areas than in tumors. Patients with HCC with a higher ALP (>81 U/dL) had significantly more major hepatectomies, vascular invasion, and recurrence. Cox regression analysis showed that gender, major hepatectomies, the presence of satellite lesions, higher grades (III or IV) and perioperative changes in liver function tests were independent prognostic factors for recurrence-free survival, and a postoperative increase in the ALP ratio at postoperative day (POD) 7 vs. POD 0 > 1.46 should be emphasized. A liver regeneration rate more than 1.8 and correlation analysis revealed that the ALP level at POD 7 and 30 was significantly higher and correlated with remnant liver growth. Conclusions: This study demonstrated that the perioperative ALP change was an independent prognostic factor for HCC after partial hepatectomies, and the elevation of ALP represented a functional biomarker for the liver but not an HCC biomarker. The higher regeneration capacity was possibly associated with the elevation of ALP after operation.

Keywords: alkaline phosphatase; hepatocellular carcinoma; liver regeneration.

Figure 1

The study design for the role of alkaline phosphatase in HCC. Of 628 HCC patients reviewed, 525 were eligible for analysis and 43 of them were further analyzed in volumetry analysis.

Figure 2

Higher expression of liver-specific alkaline phosphatase (ALP) in hepatocellular carcinoma (HCC) non-cancerous areas. (A) Analysis of genetic expression in HCC non-cancerous (N) and tumor (T) areas shows significant elevation of ALP. (B) Higher genetic expression of ALP is consistent among different patient etiologic factors. (C) Representative immunohistochemical staining of α-fetoprotein (AFP) and ALP in HCC. Stronger staining is noted at non-cancerous tumor area for ALP and tumor area for AFP (200 × X magnification). (* p < 0.05).

Figure 3

The analysis of recurrence-free survival. Kaplan–Meier survival curve for AFP and ALP in HCC in the perioperative period. (A), (B) and (C) Higher ALP in perioperative period at POD 0, 7 and 30 represented significant risk for HCC recurrence (p < 0.001). (D) AFP more than 200 ng/mL is a risk factor for recurrence, too. (E) and (F) ALP ratio > 1.46 (POD 7 vs. POD 0) and AFP ratio (POD 30 vs. POD 0) > 1.519 were independent factors for recurrence-free survival. Abbreviations: alkaline phosphatase (ALP) and α-fetoprotein (AFP).

Figure 4

Change in AFP and liver-function tests in the perioperative period between major and minor hepatectomies for HCC. (A) and (B) AFP was significantly decreased after operation, but ALP was significantly decreased at POD 2 and increased at POD 30 according to paired t-test. Patients with HCC had dynamic liver functional changes. (C) AFP showed significantly different between major and minor groups on POD 0. AST (G), ALT (H), ALP (D), albumin (F) and AFP showed significant differences in major and minor hepatectomies. The liver regeneration ratio (E) was calculated with postoperative liver volume/estimated preserved liver volume. The regeneration ratios were 1.91 ± 0.66 and 1.20 ± 0.15, respectively (p < 0.001). However, there was a dynamic change after partial hepatectomies, but ALP was significantly increased in both groups at POD 7 and POD 30. Abbreviations: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and albumin (Alb). * Statistical significance (* p < 0.05, ** p < 0.01, *** p < 0.001).

Figure 5

The perioperative ALP change and liver regeneration. (A) Total of 43 patients with volumetry analysis; AUROCs for liver regeneration rate >1.8 of ALP ratio (POD 30 vs. POD 0) and ALP at POD 30 were 0.808 (0.658–0.958) and 0.709 (0.540–0.878) (p = 0.002 and 0.031, respectively). (B) The increase in ALP after partial hepatectomies. The ALP ratio of POD 7 vs. 0 was significantly correlated with that of ALP POD 30 vs. 0 (Pearson correlation = 0.757, p < 0.001). (C) The ratio of ALP at POD 30 vs. 0 was significantly correlated with that of ALP at POD 30 (Pearson correlation = 0.919, p < 0.001).