A 2024 review article discusses the role of serotonin (5-HT) in liver diseases, highlighting its involvement in liver regeneration as well as its contribution to the progression of conditions like cirrhosis, fatty liver disease, viral hepatitis, and hepatocellular carcinoma (HCC). Regarding 5-HT's role in liver injury, two main mechanisms are proposed: liver toxicity from serotonin reuptake inhibitors (SSRIs) and acute liver injury resulting from dysregulation of the 5-HT degradation system (5DS). Several case reports have documented liver toxicity associated with SSRIs, including severe cholestasis and hepatic cell damage, cholestatic liver injury, and liver dysfunction, all of which improved after discontinuation of the drugs. Additionally, a 2021 retrospective study suggested perioperative use of SSRIs in patients undergoing hepatic resection may potentially be linked to liver function impairment and poor postoperative outcomes, highlighting the need for caution during the perioperative period (see Table 1). Dysregulation of 5DS is thought to contribute to liver injury by increasing serotonin breakdown and overproducing reactive oxygen species. This activates signaling pathways like JNK, p38 MAPK, and STAT3, promoting apoptosis and inflammation in liver cells. The imbalance leads to the release of pro-inflammatory cytokines which worsen liver damage. Inhibiting 5DS with 5-HTR2A antagonists has shown potential in preventing liver toxicity, suggesting therapeutic opportunities for liver diseases, though further research is needed to fully understand its clinical applications. [1]
Serotonin, particularly platelet-derived 5-HT, may play a role in liver regeneration, especially following partial hepatectomy or toxic injury. In animal models, serotonin has been shown to be essential for effective liver regeneration, but clinical evidence in humans remains limited. One 2014 study involving 60 patients undergoing liver resection provided insights into the role of intraplatelet 5-HT in liver regeneration and liver dysfunction. The study found that intraplatelet 5-HT levels significantly decreased immediately after liver resection (p<0.001) but gradually recovered within the first week. Moreover, reduced preoperative intraplatelet 5-HT levels were associated with delayed hepatic regeneration and poor clinical outcomes. Specifically, low preoperative intraplatelet 5-HT (<73 ng/mL) was linked to a higher incidence of postoperative liver dysfunction (p= 0.045) and increased morbidity (p=0.021). Patients with reduced intraplatelet 5-HT levels throughout the perioperative period also experienced delayed liver regeneration and adverse outcomes. Overall, the findings suggested that intraplatelet 5-HT may serve as a potential clinical marker for predicting postoperative liver dysfunction and delayed hepatic regeneration in patients undergoing liver resection. However, the impact of SSRIs on this process was not assessed in this study, leaving their potential influence unclear. [2], [3]
A 2016 observational study examined the incidence of drug-induced liver injury (DILI) in psychiatric inpatients treated with antidepressants. Data from 184,234 psychiatric inpatients were analyzed, revealing 149 cases of DILI (0.08%). The incidence of DILI was highest with mianserine (0.36%), agomelatine (0.33%), and clomipramine (0.23%). In contrast, SSRIs, including escitalopram, citalopram, and fluoxetine, had the lowest rates of DILI (0.03%), with escitalopram being the least likely to cause liver injury (0.01%). The most common symptoms of DILI included nausea, fatigue, loss of appetite, and abdominal pain. Additionally, the study found that the dosage at the time of DILI onset was higher in seven of the nine antidepressants examined compared to their median overall dosage. Overall, the findings suggested that SSRIs are less likely than the other antidepressants examined to precipitate DILI. However, the authors emphasized that patients with preexisting liver damage were at higher risk of DILI, and advised caution when prescribing antidepressants with potential liver-related adverse effects to these patients. [4]