Liver resection for HCC in patients with metabolic syndrome: questions answered, questions raised

NAFLD has become more common as a result of the socioeconomic growth of recent decades.1 This condition serves as a precursor to additional parenchymal alterations that may manifest as fibrosis, cirrhosis, and HCC. In this setting, patients with metabolic syndrome (MS) represent a rapidly growing proportion of the population with HCC evaluated for curative treatments such as resection or even transplantation. On this ground, information on expected outcomes of surgical candidates is welcomed and in this issue of Hepatology Berardi and colleagues provided some interest findings2. As first, 1087 cases were collected from 2001 to 2021 deriving from Italy, United States, Canada, and Spain and 75% of patients were gathered in the most recent decade. For the period and countries in study, data from the World Bank Organization allows to estimate an average annual percentage change of +0.8% per year for prevalence of overweight in the population (Spain +0.7%, Italy: +0.8%, United States and Canada +0.9%, all with P<0.001 at join point regression analysis) thus, confirming that HCC on MS is becoming a contingent problem.3 However, it should be noted that the majority of patients were enrolled after the implementation of more accurate diagnostic standards,4,5 and as a result, the present findings may not accurately portray the current trajectory of HCC on NAFLD. These aspects underline the necessity for a global agreement on NAFLD nomenclature.6 The characteristics and the surgical results of the patients under study lead to some important issues. In the present cohort, patients with MS and HCC have multiple comorbidities. Obesity was present in 45.2% of patients, hypertension was up to 78.1%, diabetes was 56.4%, ischemic heart disease was present in 20.1% of patients, so that the median American Society of Anesthesiologist class was 3 and the median Charlson Comorbidity Index was 6. Such features are well recognized risk factors for several postoperative outcome measures, including increased rate of severe complications, prolonged in-hospital stay, increased mortality, and readmission rate, according to the American College of Surgeons NSQIP surgical risk calculator.7 Consequently, it may be expected worrisome outcomes in this patient population. Instead, despite these features, the 90-day mortality was acceptable (2.9%) with a low major morbidity (13.8%), resulting in a median hospital stay of 6 days and a readmission rate of 8.5%. This means that despite comorbidities, patients were carefully selected and, of utmost importance, properly managed both during and after surgery. That is, a high American Society of Anesthesiologist score and a Charlson Comorbidity Index did not represent absolute contraindications to liver resection, if adequately treated. Some important aspects appear when evaluating factors associated with the 90-day major morbidity. Major hepatectomy related to an OR of 4.56 (P<0.001), presence of clinical signs of portal hypertension to an OR of 2.56 (P=0.004) and minimally invasive approach related to a OR of 0.56 (P=0.026). The first 2 findings were expected, since strictly dependent of the degree of liver dysfunction, as highlighted by the increased odds due to NASH (OR: 1.79; P=0.048) and cirrhosis (OR: 2.64; P=0.004) in respect to fatty liver only. Instead, the interpretation of the beneficial effect of minimally invasive approach opens 2 questions. First, since the study period encompasses most of the learning curve in minimally invasive liver surgery (MILS), there is the possibility that most patients treated with this approach were selected due to lower difficulty score 8 spuriously ameliorating their clinical outcomes. On the counterpart, MILS can represent a possible technique to extend surgical indications, due to the lower rate of morbidity, blood loss and major complications in respect to the open approach.9 Probably the true lies in between these 2 aspects and future studies may provide an answer, by encompassing most recent periods, to dilute the learning curve effect and unveil MILS benefits. On the basis of their analysis, authors subsequently provided a personalized calculator available at https://childb.shinyapps.io/NomogramMajorMorbidity90days/. This calculator allows to predict the 90-day major morbidity after surgery. This calculator requires some comments. First, it did not fulfill Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) guidelines, since it was not externally validated. Authors opted for an explorative analysis only, thus predictions lacks of both discrimination and calibration evaluations. Consequently, the present calculator requires confirmation, using eventually different cohorts, to assess its reliability. Second, this calculator can provide information to communicate with the patient about risks of hepatic resection, but questions about benefits remain unanswered. That is, HCC patients can be submitted to potentially curative therapies alternative to resection, including radiofrequency ablation and eventually transplantation. Patients can also be considered as resectable but embolization can be adopted due to the perceived low benefits expected from surgery.10 Therefore, future efforts should be aimed at comparing present estimates to those of alternative therapies, and considering survival rather than an early-outcome measure, to provide a comprehensive evaluation in this fragile patient population.4 In conclusion, the analysis proposed by Berardi and colleagues provided an important step toward the personalization of therapy of HCC patients and MS. The minimally invasive approach represents the most immediate protective measure to apply in these patients to optimize outcomes, especially considering that most of them suffer from several concomitant comorbidities. Starting from this step, future research should be aimed at provide credibility to present estimates, long-term results and comparation with alternative strategies.

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