Evidence for serotonin as a relevant inducer of liver regeneration after liver resection in humans

Abstract

Liver regeneration (LR) involves a complex interplay of growth factors and antagonists. In this context, platelet-derived serotonin (5-HT) has been identified as a critical inducer of LR in mice. Clinical evidence for a role of 5-HT in LR in humans is lacking. Accordingly, serum and plasma 5-HT was monitored perioperatively in 60 patients undergoing liver resection, of which 35 served as exploration and 25 as validation sets. Intraplatelet (IP) levels of 5-HT were calculated by subtraction of plasma 5-HT from serum values. Serum markers of liver function were used to evaluate LR and liver dysfunction (LD). In the exploration setting, IP 5-HT levels significantly decreased after liver resection (P < 0.001) and gradually recovered during the first week. IP 5-HT measured before surgery specifically predicted LD in the subsequent 7 days (area under the curve: 0.721; P 5 0.029). Patients suffering from postoperative LD and morbidity were found to have reduced IP 5-HT levels during the entire perioperative period. Furthermore, we validated that reduced preoperative IP 5-HT (<73 ng/mL) was associated with an increased incidence of postoperative LD and morbidity (P 50.045 and P 5 0.021) and were able to demonstrate that IP 5-HT levels were an independent predictor of poor clinical outcome. Conclusions: These findings provide evidence that IP 5-HT correlates with LR in humans: Patients with low IP 5-HT before liver resection suffered from delayed hepatic regeneration. Therefore, IP 5-HT levels may prove a helpful clinical marker to predict postoperative LD and clinical outcome before hepatic resection and initiate suitable interventions. (HEPATOLOGY 2014;60:257-266)

Importance of platelet-derived growth factors in liver regeneration

“…Ultimately, it should be mentioned that we found an increased incidence of postoperative liver dysfunction in patients receiving selective serotonin reuptake inhibitors, known to substantially reduce intra-platelet 5-HT levels, in patients undergoing liver resection [25]. However, all these potential therapeutic options have to be explored and validated in sufficiently powered prospective clinical trials.…”

“…Apart from α-granule-derived proteins, platelet dense granules represent a storage pool for small molecules, such as serotonin (5-HT), which is also of central importance for liver regeneration [7,25]. Furthermore, it was reported recently that platelet RNAs are also involved in hepatocyte proliferation processes [26].…”

Serum alkaline phosphatase levels accurately reflect cholestasis in mice

“…1,2 However, there is an ongoing discussion regarding the suitability of serum tests to monitor cholestasis in such models. Therefore, we compared serum samples of four different well established mouse models for sclerosing cholangitis, including lithocholic acid (LCA)-fed, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice as a model for toxic/chemically induced cholangitis, multidrug resistance protein-2 (Mdr2; Abcb4) knockout mice (Mdr2…”

Postoperative Decrease in Platelet Counts Is Associated with Delayed Liver Function Recovery and Complications after Partial Hepatectomy

“…However, the implications of this phenomenon have been documented only recently (Alkozai et al 2010;Lesurtel et al 2014;Starlinger et al 2014). Starlinger et al (2014) demonstrated that reduced intra-platelet serotonin levels together with decreased platelet counts are associated with an increased morbidity and liver dysfunction after hepatectomy. Alkozai et al (2010) reported that immediate postoperative platelet counts below 100 × 10 3 /μL were associated with delayed liver function recovery after hepatectomy.…”