Serial Assessment of Growth Factors Associated with Liver Regeneration in Patients Operated with Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy

Abstract

Background: There is limited knowledge about the mechanisms behind the unparalleled growth of the future liver remnant (FLR) linked to associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). In this study, liver regenerative markers were examined in patients subjected to ALPPS. Methods: Ten patients with colorectal liver metastases treated with neoadjuvant chemotherapy and ALPPS were included. Plasma was sampled at 6 time points and biopsies from both liver lobes were collected at both stages of ALPPS. The levels of interleukin (IL)-6, hepatocyte growth factor (HGF), tumor necrosis factor-α, epidermal growth factor, and vascular endothelial growth factor in plasma were measured at each time point. Expression of mRNA for markers of proliferation and apoptosis was studied in the biopsies from both liver lobes taken at both stages. Results: ALPPS resulted in a peak of IL-6 after stage 1 (p = 0.004), which decreased rapidly and did not increase again after stage 2. HGF also increased after stage 1 (p = 0.048), and the HGF levels correlated significantly with the degree of growth of the FLR before stage 2 (p = 0.02, r² = 0.47). There was a correlation between peak levels of IL-6 and HGF (p = 0.03, r² = 0.84). Conclusions: IL-6 and HGF seem to be early mediators of hypertrophy after stage 1 in the ALPPS procedure. The peak HGF plasma level correlates with the degree of FLR growth in patients subjected to ALPPS.

Influence of cytokines, circulating markers and growth factors on liver regeneration and post-hepatectomy liver failure: a systematic review and meta-analysis

“…Thirteen single cohort observational studies, described serum IL-6 concentration in association with liver regeneration or PHLF 31 – 43 . Seven studies described peak concentration on first postoperative day after hepatectomy, with mean values ranging from 55.5 to 1027 pg/ml 34 , 38 – 43 .…”

“…Thirteen single cohort observational studies, described serum IL-6 concentration in association with liver regeneration or PHLF 31 – 43 . Seven studies described peak concentration on first postoperative day after hepatectomy, with mean values ranging from 55.5 to 1027 pg/ml 34 , 38 – 43 . One study described the IL-6 peak concentration between day of operation and first postoperative day 37 and two studies reported the peak on the day of the operation during the early post-hepatectomy phase 32 , 36 .…”

“…Four studies investigated the correlation between remnant liver growth and serum HGF 43 , 48 , 50 , 52 . However, all studies used different measures of liver growth: ratio of liver volume on POD14 to liver volume on POD0, growth of functioning liver remnant at POD1 after second stage of ALPPS (associating liver partition and portal vein ligation for staged hepatectomy) and the percentage of increase in the remnant liver volume after 28 days or 6 months after surgery.…”

Markers of liver regeneration—the role of growth factors and cytokines: a systematic review

“…ALPPS procedures resulted in a peak of IL-6 levels after stage 1, which decreased rapidly and did not increase after stage 2. Furthermore, a correlation between the peak IL-6 levels and HGF was detected [46]. In the setting of human living donor liver transplantation, higher levels of serum IL-6 were independently associated with increased graft volumes during the first postoperative week [147].…”

“…After a recovery period of 1-2 weeks, Stage 2 is performed in which the deportalized liver is removed to render the patient completely tumor-free [45]. Furthermore, HGF levels were found to be significantly elevated on PODs 1, 7, and 14 after living donor hepatectomy and were correlated with recipient liver volumes on POD 14 [11,[46][47][48][49][50][51][52][53][54][55]. Tomiya et al reported an association of serum HGF levels with hepatocellular dysfunction and systemic inflammation [56].…”