TO THE EDITOR
Hepatectomy remains a cornerstone treatment for selected patients with primary liver cancers, secondary hepatic malignancies such as colorectal liver metastases, and certain biliary tract diseases requiring liver resection[1,2]. However, hepatectomy is associated with substantial surgical trauma and a considerable risk of severe postoperative complications, particularly post-hepatectomy liver failure (PHLF), which can markedly increase perioperative morbidity and mortality[2-5]. Therefore, strategies to mitigate perioperative liver injury and accelerate postoperative recovery of liver function are of significant clinical importance.
A recent study by Xie et al[6], entitled “Effectiveness of magnesium isoglycyrrhizinate on perioperative hepatic function protection in patients undergoing hepatectomy”, evaluated the efficacy of magnesium isoglycyrrhizinate (MgIG) for perioperative liver protection in hepatectomy patients. After propensity score matching (PSM), the study demonstrated that perioperative MgIG administration, including preoperative prophylaxis and postoperative treatment, was associated with a significantly reduced incidence of postoperative liver injury, lower transaminase elevations, and faster liver function recovery compared with postoperative MgIG therapy alone. Even in the absence of preoperative prophylaxis, postoperative MgIG combined with conventional hepatoprotective agents improved the rate of transaminase reduction compared with conventional hepatoprotective therapy alone. These findings are clinically relevant and suggest that MgIG may have substantial potential in preventing postoperative liver injury. Nevertheless, from a clinical pharmacy perspective, several issues warrant further consideration before MgIG prophylaxis can be broadly recommended in routine perioperative practice. These include methodological interpretation of the original study, patient selection, medication safety, drug interaction monitoring, pharmacokinetic/pharmacodynamic rationale, and pharmacoeconomic value.
Critical evaluation of the original research
The study by Xie et al[6] provides valuable real-world evidence because it included a large cohort of hepatectomy patients and compared different patterns of perioperative hepatoprotective therapy. However, its retrospective design inevitably limits causal inference, as treatment allocation in observational studies is susceptible to confounding by indication and selection bias[7,8]. Although PSM can reduce baseline imbalance between groups, it can only adjust for measured confounders[9,10]. Important unmeasured variables may still influence the observed association between MgIG prophylaxis and postoperative liver outcomes[7].
Medical care and nursing
The study enrolled adult patients with normal alanine aminotransferase and aspartate aminotransferase levels within three days before surgery and included the extent of hepatectomy as one of the key matching variables[6]. However, several important clinical factors were not incorporated, including cirrhosis, Child-Pugh classification, indocyanine green retention rate at 15 minutes (ICG-R15), portal hypertension, intraoperative blood loss, transfusion status, and operative duration. These variables are closely associated with postoperative liver dysfunction and PHLF[2]. First, patients with cirrhosis or higher Child-Pugh scores exhibit reduced regenerative capacity and heightened oxidative and inflammatory stress after hepatectomy[10]. The European Association for the Study of the Liver (EASL) Clinical Practice Guidelines on the management of hepatocellular carcinoma recommend restricting resection to Child-Pugh A patients without clinically significant portal hypertension[11], suggesting that the anti-inflammatory and membrane-stabilizing effects of MgIG may be particularly valuable in this subgroup. Second, ICG-R15 and future liver remnant (FLR) are well-established determinants of hepatic reserve. The Makuuchi criteria[12] and the Asian Pacific Association for the Study of the Liver (APASL) consensus[13] identify ICG-R15 > 10% and inadequate FLR (< 30% in normal liver, < 40% in chronic liver disease) as major predictors of PHLF. In such patients with borderline reserve, the hepatoprotective effect of MgIG is likely to be more clinically meaningful. Third, portal hypertension alters hepatic perfusion and drug distribution, potentially affecting MgIG pharmacokinetics and its protective threshold[11]. Finally, intraoperative blood loss and transfusion requirements reflect the severity of ischemia-reperfusion injury (IRI), which is the principal pathophysiological target of MgIG through glycyrrhizin-mediated inhibition of HMGB1 and NF-κB signaling[14,15]. Therefore, the magnitude of MgIG’s benefit is likely proportional to the ischemic burden. Although Xie et al[6] demonstrated the potential efficacy of MgIG in preventing postoperative liver injury, patient selection criteria remain to be refined. From a pharmaceutical care perspective, risk-based stratification is particularly important. Based on recommendations from International Study Group of Liver Surgery, EASL, and APASL, together with the Brisbane 2000 terminology for hepatectomy extent[11-17], we propose the following framework for future investigation of prophylactic MgIG use: High-risk patients-major or extended hepatectomy (≥ 3 Couinaud segments)[17], cirrhosis or Child-Pugh B[12], ICG-R15 > 10%[12], borderline FLR (< 30%-40%)[13], routine prophylactic MgIG is recommended. Intermediate-risk patients- minor hepatectomy with chronic hepatitis, Child-Pugh A with mild fibrosis, MgIG should be considered on an individualized basis according to the intraoperative course. Low-risk patients-minor resection (< 2 segments), normal parenchyma, and normal ICG-R15 and baseline liver function tests. Prophylactic MgIG is not routinely recommended. Failure to apply such stratification may lead to unnecessary drug exposure, increased healthcare costs, and preventable adverse events, such as hypokalemia, sodium retention, and hypertension[18]. Future prospective studies should therefore incorporate baseline hepatic reserve indices (e.g., Child-Pugh classification, and ICG-R15) and intraoperative risk parameters to define the optimal indications, dosing regimens, and treatment duration of MgIG in the perioperative setting[1,7,8].
Safety and drug interactions
Although the study provided detailed evidence regarding the hepatoprotective effects of MgIG, its assessment of adverse drug reactions was relatively limited. A key distinction should be made between adverse effects associated with glycyrrhizin-containing compounds as a class and those specifically documented for intravenous MgIG. Glycyrrhizin is the primary active component of the traditional Chinese medicinal herb Glycyrrhiza (Glycyrrhizae Radix et Rhizoma) and has multiple biological activities, including immunomodulatory, antioxidant, anti-inflammatory, and hepatoprotective effects[19,20]. MgIG, a fourth-generation glycyrrhizin preparation, is a magnesium salt composed mainly of 18α-glycyrrhizin stereoisomers. It is widely used for liver protection in China and is generally considered well tolerated[21,22]. Available clinical data and registered prescribing information suggest that MgIG is generally well tolerated, with most reported adverse reactions being mild; mineralocorticoid-like events such as hypokalemia, edema, and blood pressure elevation appear to be uncommon in clinical use[6,23].
However, these data should not be interpreted as indicating that MgIG is free of glycyrrhizin-related risks. Excessive glycyrrhizin exposure may induce pseudohyperaldosteronism, characterized by sodium and water retention, potassium loss, edema, hypertension, and suppression of the renin-angiotensin-aldosterone system. After intestinal hydrolysis, glycyrrhizin yields pharmacologically active glycyrrhetinic acid, which inhibits 11β-hydroxysteroid dehydrogenase and other enzymes involved in corticosteroid metabolism, thereby increasing cortisol-mediated activation of mineralocorticoid receptors and producing aldosterone-like effects[24]. Nevertheless, much of the available safety evidence derives from oral licorice ingestion or older glycyrrhizin preparations rather than perioperative intravenous MgIG. Therefore, the frequency and clinical relevance of these events during short-course intravenous MgIG therapy should be regarded as lower-certainty and MgIG-specific, rather than directly extrapolated from oral licorice toxicology. This adverse reaction requires particular attention during the postoperative phase, when patients are prone to electrolyte imbalances and abnormal fluid distribution[2,25]. In the study by Xie et al[6], patients with preoperative electrolyte disturbances, renal dysfunction, severe cardiovascular disease, or significant central nervous system abnormalities were excluded. This approach improves internal validity and reduces confounding, but it also limits the generalizability of the safety findings to more complex surgical populations encountered in real-world practice.
In addition, potential interactions with common perioperative medications were not fully explored. These may include diuretics, corticosteroids, antihypertensive agents, nephrotoxic drugs, and other glycyrrhizin-containing hepatoprotective preparations, which may increase the risk of electrolyte disturbances, blood pressure instability, renal function impairment, or cumulative glycyrrhizin exposure[2,26,27]. Moreover, potential drug interactions were not fully explored. Interactions with loop or thiazide diuretics and systemic corticosteroids are supported by the known pharmacology of glycyrrhizin/glycyrrhetinic acid and by clinical reports of licorice-associated hypokalemia and mineralocorticoid excess[26,28-30]. In contrast, interactions between MgIG and antihypertensive agents, nephrotoxic drugs, or other glycyrrhizin-containing hepatoprotective preparations remain largely theoretical or extrapolated; they may plausibly increase the risk of blood pressure instability, renal function fluctuation, or cumulative glycyrrhizin exposure, but have not been well quantified specifically for intravenous MgIG in the perioperative setting. Accordingly, these potential interactions should be presented as pharmacologically plausible concerns requiring targeted pharmacovigilance rather than as definitively established MgIG-specific interactions. Therefore, when MgIG is used perioperatively, clinical pharmacists and perioperative physicians should jointly monitor serum potassium, serum sodium, renal function, blood pressure, fluid balance, and concomitant medications. Such multidisciplinary pharmaceutical care may be particularly important for elderly patients, those with cardiovascular or renal comorbidities, and patients requiring intensive postoperative fluid management.
Pharmacokinetic mechanism and administration timing
The superior outcomes observed with perioperative MgIG compared with postoperative monotherapy suggest a possible prophylactic pharmacological effect. Xie et al[6] reported that perioperative MgIG reduced the risk of liver injury on postoperative days 3 and 7 compared with postoperative therapy alone, and multivariate analysis identified prophylactic MgIG as an independent protective factor. MgIG has been shown to exert hepatoprotective effects through multiple mechanisms, including attenuation of oxidative stress, inhibition of autophagy, suppression of inflammatory responses, and mitigation of ischemic injury[31,32]. The original study also described the involvement of several inflammatory pathways, including the phospholipase A2/arachidonic acid cascade, NF-κB pathway, MAPK/activator protein-1 pathway, and STAT3 signaling axis[6].
From a pharmacological perspective, the potential advantage of preoperative MgIG administration is biologically plausible, because liver injury associated with hepatectomy usually begins during parenchymal transection, vascular inflow occlusion, or immediately after hepatic reperfusion. These events rapidly trigger oxidative stress, sterile inflammation, mitochondrial dysfunction, and cytokine-mediated injury cascades[33-35]. Therefore, achieving effective intrahepatic drug exposure before the onset of IRI may theoretically provide greater protection than rescue treatment initiated only after hepatocellular damage has already occurred. However, this interpretation should be regarded as hypothesis-generating rather than definitive, because direct pharmacokinetic/pharmacodynamic evidence defining the optimal intrahepatic MgIG concentration, administration window, and minimum effective duration in hepatectomy patients is still lacking. Available pharmacokinetic information on MgIG and related glycyrrhizin-derived compounds provides some indirect support for this hypothesis. As an intravenous formulation, MgIG bypasses gastrointestinal absorption and can rapidly achieve systemic exposure. Glycyrrhizin-related compounds are known to undergo extensive plasma protein binding and preferential hepatobiliary disposition, with hepatic uptake, biliary excretion, and possible enterohepatic circulation contributing to their liver-oriented distribution profile[36-38]. Experimental and clinical pharmacokinetic studies of glycyrrhizin derivatives have also suggested that these compounds or their metabolites are eliminated mainly through biliary and fecal routes, while hepatic transport processes may influence liver exposure and systemic clearance[37-39]. These ADME characteristics are consistent with the rationale that preoperative administration may allow MgIG to reach the liver before surgical ischemic and inflammatory insults occur. Nevertheless, extrapolation from glycyrrhizin-class pharmacokinetics to perioperative MgIG use should be made cautiously, because MgIG-specific tissue concentration data in patients undergoing hepatectomy remain insufficient.
Mechanistically, MgIG may protect against hepatectomy-related liver injury by interrupting several early pathways involved in IRI. First, hepatic ischemia and reperfusion promote excessive reactive oxygen species production, lipid peroxidation, mitochondrial permeability transition, and depletion of endogenous antioxidant defenses[36]. Glycyrrhizin derivatives have been shown to enhance antioxidant enzyme activity, including superoxide dismutase and glutathione peroxidase, thereby limiting oxidative hepatocellular injury[37]. By reducing oxidative stress, MgIG may also indirectly attenuate redox-sensitive inflammatory pathways such as NF-κB and MAPK signaling. Second, the HMGB1/TLR4/NF-κB axis is a central mediator of sterile inflammation during hepatic IRI. HMGB1 released from stressed or necrotic hepatocytes can activate Kupffer cells and recruited macrophages through TLR4-dependent signaling, leading to NF-κB nuclear translocation and subsequent transcription of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, inducible nitric oxide synthase, cyclooxygenase-2, and adhesion molecules. Glycyrrhizin has been reported to directly bind HMGB1 and inhibit its cytokine activity, providing a mechanistic basis for suppression of sterile inflammation[40-42]. Therefore, MgIG may reduce post-hepatectomy inflammatory injury by limiting HMGB1-mediated activation of the TLR4/NF-κB pathway and decreasing downstream cytokine production and neutrophil infiltration.
In the study by Xie et al[6], patients received prophylactic MgIG for three days before surgery at a dose of 150 mg once daily, with an average total treatment duration of approximately eight days. Whether shorter preoperative administration provides equivalent protection, whether high-risk patients require longer preoperative treatment, and whether dosing should be individualized according to body weight, baseline liver function, hepatic reserve, and surgical extent remain unclear. Future prospective studies should clarify the relationships among dose, systemic exposure, intrahepatic exposure, and hepatoprotective efficacy to determine the optimal timing and duration of MgIG administration.
Pharmaceutical economics evaluation
Before broad perioperative prophylaxis with MgIG is recommended, formal pharmacoeconomic evaluation is essential. Xie et al[6] concluded that adding preoperative MgIG to postoperative therapy may promote liver function recovery and benefit more surgical patients. However, the economic value of this strategy depends on whether the cost of additional prophylactic MgIG is offset by reductions in postoperative complications and healthcare resource utilization. Future studies should assess specific economic endpoints, including: Total hospitalization cost; length of postoperative hospital stay; intensive care unit admission and duration; incidence and treatment cost of PHLF; rates of major complications; readmission rates; need for albumin, plasma, blood products, or artificial liver support; additional laboratory monitoring costs; drug acquisition and administration costs; quality-adjusted life years where long-term follow-up is available. A cost-effectiveness analysis comparing standard perioperative care with MgIG prophylaxis should ideally be conducted separately in low-, intermediate-, and high-risk surgical populations. It is possible that MgIG prophylaxis may be economically attractive in patients at high risk of postoperative liver dysfunction but less cost-effective in low-risk patients undergoing minor hepatectomy. Therefore, pharmacoeconomic evidence should be integrated with clinical risk stratification rather than assessed only at the overall cohort level.
The limitations of this comment
As a narrative interpretation grounded in a single real-world study, this commentary is inherently constrained by the quality and scope of the underlying evidence. Our appraisal cannot resolve the residual confounding intrinsic to the retrospective PSM design of Xie et al[6]. Some safety and interaction concerns are extrapolated from the broader pharmacology of glycyrrhizin-containing compounds rather than from direct MgIG-specific perioperative evidence. For these reasons, the views presented in this letter should be regarded as exploratory and as a framework to guide future prospective, mechanism-informed, and safety-focused studies in hepatectomy patients, rather than as definitive clinical recommendations.
