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Impact of prior SARS-CoV-2 infection on postoperative recovery in patients with hepatocellular carcinoma resection

BMC Gastroenterology volume 24, Article number: 317 (2024) Cite this article

Abstract

Background

The impact of prior SARS-CoV-2 infection on postoperative recovery of patients who underwent liver resection for hepatocellular carcinoma (HCC) remains uncertain given the lack of sufficient evidence.

Aim

To investigate the impact of prior SARS-CoV-2 infection on postoperative recovery of patients who underwent liver resection for hepatocellular carcinoma (HCC).

Methods

Patients who were pathologically diagnosed with HCC and underwent elective partial hepatectomy in Guangdong Provincial People’s Hospital between January 2022 and April 2023 were enrolled in this retrospective cohort study. The patients were divided into two groups based on their history of SARS-CoV-2 infection. Rehabilitation parameters, including postoperative liver function, incidence of complications, and hospitalization expenses, were compared between the two groups. Propensity score matching (PSM) was performed to reduce confounding bias.

Results

We included 172 patients (58 with and 114 without prior SARS-CoV-2 infection) who underwent liver resection for HCC. No significant differences in the rehabilitation parameters were observed between the two groups. After PSM, 58 patients were selected from each group to form the new comparative groups. Similar results were obtained within the population after PSM.

Conclusion

Prior SARS-CoV-2 infection does not appear to affect postoperative rehabilitation, including liver function, postoperative complications, or hospitalization expenses among patients with HCC after elective partial hepatectomy.

Peer Review reports

Introduction

Liver cancer is a common type of cancer and cause of cancer-related deaths globally [1]. Partial hepatectomy remains the mainstay treatment, particularly for the early stages of cancer. Partial hepatectomy involves removing diseased liver tissue while preserving healthy portions and is widely performed for the treatment of various liver conditions [2], such as primary liver cancer and liver metastases [3]. Patients with existing liver conditions such as nonalcoholic fatty liver disease and viral hepatitis are more vulnerable to adverse outcomes, as COVID-19 combines viral- and immune-mediated damage in an inflamed environment, significantly increasing the severity and mortality [4,5,6,7,8]. Initially, SARS-CoV-2 was seen as primarily affecting the lower respiratory tract, with a range of manifestations from asymptomatic to severe, affecting various organs including the liver [9]. SARS-CoV-2 infects host cells by binding to the cell receptor angiotensin-converting enzyme II, which is widely expressed in bile duct cells, thereby causing direct harm [10]. This intense inflammation triggers immune-related damage in multiple organs, including the liver, resulting in increased blood levels of inflammatory markers such as ferritin and cytokines [e.g., interleukin (IL)-2 andIL-6] [11]. Severe cases may lead to sepsis, worsening inflammation, and liver injuries such as hypoxic–ischemic damage, cholestasis, and hepatocyte injury [12]. This damage is further aggravated by drug-induced liver injury caused by antiviral drugs such as oseltamivir, umifenovir and chloroquine [13]. Patients with existing liver disease are more vulnerable, as SARS-CoV-2 infection combines viral and immune-mediated damage in an inflamed environment [14, 15]. As severe cases are associated with asymptomatic or mild degrees of liver abnormalities, regular monitoring is important, especially for patients with severe COVID-19 [16, 17].

It is increasingly recognized that SARS-CoV-2 infection could pose a risk for patients with liver cancer, potentially worsening the hepatic conditions [6]. A US multicenter study found higher mortality rates among patients with liver cancer who were infected with SARS-CoV-2, which increased substantially in the presence of comorbidities such as obesity, diabetes, hypertension, hyperlipidemia, or advanced age (≥ 65 years). A retrospective analysis of 119 patients with liver cancer who were infected with SARS-CoV-2 revealed that approximately one-third required hospitalization. Two-thirds of the patients had elevated transaminase and alkaline phosphatase levels, which were associated with higher mortality rates. High C-reactive protein level and severe respiratory failure upon admission were observed in these patients [6, 18,19,20].

However, the impact of prior SARS-CoV-2 infection on short-term liver function and postoperative outcomes for patients with HCC undergoing partial hepatectomy remains uncertain. Therefore, there is an urgent need to determine whether prior SARS-CoV-2 infection affects the recovery of patients with liver cancer following partial hepatectomy.

Materials and methods

Data sources

We enrolled 172 patients who had undergone partial hepatectomy and had their clinicopathological data assessed at the Department of Hepatobiliary Surgery, Guangdong People’s Hospital between January 2022 and April 2023. Inclusion criteria were: age 18–80 years; pathologically diagnosed with HCC(All postoperative pathological diagnoses of patients follow the WHO Classification of Tumours of the Digestive System [21], and all pathological tissue specimens are processed by skilled technicians and identified and diagnosed by pathologists with years of experience); preoperative liver function categorized as Child–Pugh class A or B; patients can undergo elective surgery based on the ECOG physical condition score, and the Barcelona liver cancer staging system stages them as A or B (Eastern Cooperative Oncology Group (ECOG) performance status was recorded by the referring clinician, with Child-Pugh Score calculated and alpha-fetoprotein (AFP) recorded from contemporaneous blood tests available at referral. Barcelona Clinic Liver Cancer (BCLC) staging was retrospectively calculated from data collected at the time of the MDT discussion by the investigators.); SLD and participated voluntarily with signed informed consent from patients and their families. The exclusion criteria were: need for emergency surgery; and acute illness or acute worsening of a chronic condition. The patient selection process is described in Fig. 1.

Fig. 1
figure 1

The patient selection process

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Data collection

A comprehensive collection of clinical data was conducted on patients who underwent partial hepatectomy in the Hepatobiliary Department of Guangdong Provincial People’s Hospital. The standard definition of previous infection with COVID-19 was: (1) symptoms of upper respiratory tract infection, such as dry throat, sore throat, cough, fever, etc.; (2) one or more of the following etiological examination results: positive SARS-CoV-2 nucleic acid test; and detection of SARS-CoV-2 antigen; (3) symptom relief after outpatient or inpatient treatment; (4) did not enter the intensive care unit for treatment due to organ failure; (5) after treatment, etiological examination turned negative; and (6) etiological examination before the operation was negative. The patients were divided into two groups according to their SARS-CoV-2 infection history.

Following this, relevant clinical parameters were extracted from the medical records: age; gender; medical history; anesthesia level; variations in preoperative and postoperative test results [including alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), total bilirubin (Tbil)]; amount of intraoperative blood transfusion and bleeding; occurrence of postoperative complications (All complications are defined according to the Clavien Dindo classification [22] ,such as liver function decompensation, and insufficiency or failure); and reoperation (especially invasive procedures). The total hospitalization expenses and length of postoperative hospital stay were also recorded.

Definition of indicators

Postoperative liver failure was defined according to the International Liver Surgery Research Group classification criteria in 2011 [23]. These refer to deterioration in the ability of the liver to maintain its synthetic, secretory and detoxification functions. Postoperative liver failure was characterized by abnormal Tbil levels and International Normalized Ratio (INR) values; that is, if the Tbil and INR values exceeded the preoperative baseline levels on or after postoperative day 5. Cases involving biliary obstruction were not included in this definition. Liver injury was graded as follows: mild: ALT < 2 times the upper limit of normal (ULN); moderate: 2 times ULN < ALT < 5 times ULN; and severe: ALT > 5 times ULN.

The severity of SARS-CoV-2 infection was based on the criteria outlined in the SARS-CoV-2 Infection Diagnosis and Treatment Plan (Trial Version 10). This assessment categorized the severity of SARS-CoV-2 infection as light, moderate or severe.

Follow-up

All patients who underwent partial hepatectomy received liver function tests on postoperative days 3 and 5, and their SARS-CoV-2 infection history was investigated and registered during hospitalization, All patients had resolution of symptoms more than 7 weeks from the date of surgery, and no lung infection was confirmed by chest CT or x-ray before surgery. In addition, we extended the follow-up of enrolled patients, and all patients underwent outpatient follow-up and personalized evaluation on the 30th day after surgery. Based on the obtained data, no patients showed any clear surgical complications. Because our aim is to study the short-term liver function of patients and the incidence of complications, we will no longer include data from the 30th day after surgery in the table for analysis.

Statistical methods

To analyze the baseline characteristics of patients, continuous data were presented as median (interquartile range; IQR), and group differences were analyzed using an independent group t-test when the data were normally distributed, and a nonparametric (Mann–Whitney) test when the data were not normally distributed. Categorical data were expressed as frequency (percentage) and analyzed using the χ2 test and Fisher’s exact test. PSM was performed to reduce confounding bias for the patients from the two groups in a 1:1 ratio, and the caliper value was set to 0.5. All statistical analyses were performed using SPSS version 26.0. The incidence of postoperative complications was calculated and compared between the two groups. P < 0.05 was considered statistically significant.

Results

Baseline characteristics of enrolled cases

This study involved a comprehensive analysis of 172 adult patients who underwent partial hepatectomy. Fifty-eight patients had previously contracted mild SARS-CoV-2 infection and all of them belonged to Child–Pugh class A (score: 5 or 6). Preoperative blood coagulation profiles were within normal ranges (INR 1.0–1.5); thus, liver function score grading and INR were excluded from further analysis. No cases of liver failure were observed in the selected patients.

Table 1 provides a comprehensive summary of the baseline characteristics of enrolled cases, which covered patient information, clinical attributes, preoperative liver function indices, and postoperative liver function indices at postoperative days 1 and 5. The median age of the participants was 56.5 (IQR 46.3–65.0) years. In the preoperative infection group, the median time between SARS-CoV-2 infection and surgery was 83.5 (IQR 62.0–96.8) d. The majority of patients were male (137; 79.7%). One hundred and four (60.5%) patients had hepatic inflow occlusion, 47 (27.3%) liver cirrhosis, 79 (45.9%) hepatitis, and none had preoperative hyperbilirubinemia. Preoperative hypoproteinemia was found in three (1.7%) patients. The median preoperative values for the liver injury markers were: α-fetoprotein (AFP) 7.71 (IQR 2.83–246.02) µmol/L, ALT 25.0 (IQR 17.0–37.0) U/L, AST 27.0 (IQR 22.0–35.0) U/L, Tbil 12.75 (IQR 9.90–15.20) µmol/L, and ALB 38.44 (IQR 36.01–40.88) g/L. Patients were divided into two groups based on prior SARS-CoV-2 infection: 58 in the infection group (33.7%) and 114 in the noninfection group (66.3%). The infection group had a significantly higher proportion of males and higher median preoperative AFP and Tbil values compared with the noninfection group (P < 0.05).

Table 1 Baseline characteristics of enrolled cases
Full size table

Surgical procedure, postoperative complications, and laboratory examination of enrolled cases

Table 2 provides a comprehensive summary of the surgical procedure, postoperative complications, and laboratory findings for the selected patients who underwent partial hepatectomy. Twenty-four (14%) patients required intraoperative blood transfusion, and seven (4.1%) required postoperative ALB transfusion. Postoperative complications were observed in 20 patients (11.6%), including seven (4.1%) cases of pulmonary infection, two (1.2%) of pulmonary embolism, 13 (7.6%) of atelectasis, three (1.7%) of bile leakage, one (0.6%) of compromised wound healing, two (1.2%) of postoperative bleeding, and 16 (9.3%) of postoperative serous effusion. Four (2.3%) patients had other postoperative complications, 25 (14.5%) had hyperbilirubinemia and 47 (27.3%) had hypoproteinemia on postoperative day 1, and 17 (9.9%) patients presented with hyperbilirubinemia and four (2.3%) with hypoproteinemia on postoperative day 5.

Table 2 Surgical procedure, postoperative complications, and laboratory examination of enrolled cases
Full size table

The median hospitalization cost was 16 108.10 (IQR 12 318.94–18 932.64) AUD and the median postoperative hospital stay was 8 (IQR 7.0–11.0) d. The median duration of the indwelling catheter was 6 (IQR 4.75–7.0) d and median intraoperative blood loss was 200 (IQR 80.0–400.0) mL. The laboratory findings on postoperative day 1 were: ALT 226.50 (IQR 115.25–383.50) U/L; AST 258.50 (IQR 144.25–434.0) U/L; Tbil 22.35 (IQR 16.45–28.35) µmol/L; and ALB 32.96 (IQR 29.63–35.75) g/L. Five days after surgery, these parameters were: ALT 81.50 (IQR 43.0–135.75) U/L; AST 36.0 (IQR 28.0–50.75) U/L; Tbil 18.80 (IQR 13.73–26.28) µmol/L; and ALB 36.19 (IQR 32.98–38.68) g/L. Patients were categorized into two groups based on their SARS-CoV-2 infection status before surgery. Statistical analysis of the surgical procedure, postoperative complications, and laboratory findings using the Mann–Whitney U test or χ2 test revealed P > 0.05, suggesting that there were no significant differences between the two groups.

Baseline characteristics of the cases after PSM

Table 3 provides a comprehensive overview of the demographic and clinical characteristics of the matched cases along with the laboratory test results. Among the matched cases, the median age of the patients was 55.5 (IQR 43.25–65.0) years, and the majority of the patients were male (88; 75.9%). All patients had HCC (100%) and 63 (54.3%) underwent hepatic inflow occlusion, and 35 (30.2%) had liver cirrhosis. No patients had preoperative hyperbilirubinemia, and only one (0.9%) had preoperative hypoproteinemia. Preoperative laboratory values were carefully examined, revealing a median AFP level of 6.01 (IQR 2.76–212.69) ng/mL; median ALT 23.50 (IQR 16.25–38.75) U/L; median AST 27.50 (IQR 21.0–35.0) U/L; median Tbil 12.35 (IQR 9.40–15.38) µmol/L; and median ALB 38.30 (IQR 36.19–40.78 g/L). The patients were categorized into two groups based on their SARS-CoV-2 infection status. The comparative analysis between the two groups revealed P > 0.05, indicating no significant differences between the groups.

Table 3 Baseline characteristics after propensity score matching
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Surgical procedure, postoperative complications, and laboratory examination of the cases after PSM

Table 4 provides a detailed overview of the surgical procedures, postoperative complications, and results of laboratory examinations for the matched cases. Among these, 13 (11.2%) patients received intraoperative blood transfusion, and six (5.2%) received ALB transfusion. Ten (8.6%) patients experienced overall postoperative complications, which included six (5.2%) cases of pulmonary infection, six (5.2%) of atelectasis, and two (1.7%) of postoperative bile leakage.

Table 4 Surgical procedure, postoperative complications, and laboratory examination of the cases after propensity score matching
Full size table

However, instances of postoperative pulmonary embolism and poor wound healing were not observed. In addition, postoperative wound bleeding occurred in a single case (0.9%), and postoperative serous effusion was identified in seven (6.9%). Other postoperative complications were documented in two patients (1.7%), hyperbilirubinemia in 14 (12.1%), and hypoproteinemia in 29 (25.0%). The median cost of hospitalization was 15 482.80 (IQR 12 350.16–18 446.62) AUD, and the median duration of the indwelling catheter was 6 (IQR 4–7) d.

The median length of postoperative hospital stay was 8 (IQR 7–10) d, and the median intraoperative blood loss was 200 (IQR 50.0–387.50) mL. Postoperative laboratory assessments further revealed that at day 1 the median ALT level was 222.50 (IQR 112.50–383.50) U/L, whereas the median AST level was 239.0 (IQR 114.0–434.0) U/L. In addition, the median Tbil level was 23.05 (IQR 16.03–28.18) µmol/L and median ALB level was 33.15 (IQR 29.95–35.90) g/L. The laboratory tests conducted on postoperative day 5 revealed median ALT level of 70.0 (IQR 41.25–123.0) U/L; median AST 34.0 (IQR 25.0–48.0) U/L; median Tbil 17.95 (IQR 13.45–25.15) µmol/L; and median ALB 36.50 (IQR 33.23–38.74) g/L. The patients were divided into two groups based on prior SARS-CoV-2 infection. The comparative analysis of postoperative complications and laboratory test outcomes between these groups revealed P > 0.05, indicating no significant differences between the groups.

Discussion

COVID-19 has been associated with liver injury, even in patients without pre-existing liver conditions [24]. The extent of liver injury in COVID-19 cases is generally mild [25] and is more pronounced in males, older adults, and people with high body mass index. The levels of liver enzymes such as ALT, AST and Tbil may increase in COVID-19 patients, but these changes are usually temporary and tend to resolve during recovery [26]. Studies have shown an association between acute liver injury, elevated liver enzymes, and severity of COVID-19. Abnormal liver function and hypoproteinemia might serve as indicators of disease severity. Patients with chronic liver diseases are more susceptible to liver injury and complications from COVID-19 [27,28,29,30]. However, severe progression of COVID-19 is not consistently seen in patients with viral hepatitis [31,32,33,34,35,36]. COVID-19 patients with liver cirrhosis are at a greater risk of adverse outcomes and the mortality was high among patients with more advanced cirrhosis and increased age [37,38,39,40].

Studies have demonstrated that chronic liver disease does not inherently lead to a higher risk of severe COVID-19 [41]. A history of liver disease or liver cancer does not independently predict severe complications from COVID-19 or increased mortality [42]. In addition, studies have shown that COVID-19 patients with liver function damage are common, but severe liver function damage is rare. Male patients, critically ill patients, liver computed tomography low-density values and potential drugs for liver damage are all risk factors. However, with recovery from the disease, the liver function of most patients also gradually recovered [43]. However, our current study has certain limitations. Firstly, the cohort is limited by its small sample size, retrospective nature, single center, and only including patients with liver cancer undergoing elective surgery after SARS-CoV-2 infection. This may restrict our ability to analyze meaningful statistical differences, and the results may not be applicable to patients requiring emergency surgery. Further research with larger populations in multicenter settings is needed in the future. Secondly, due to China’s previous “Zero COVID-19” policy implemented for nearly 3 years, some patients who had previously been infected with SARS-CoV-2 may not have received a formal diagnosis or may have concealed their medical history, resulting in their classification as COVID-19 negative. Although all surgical patients were required to provide this medical history, this study may not have captured all preoperative SARS-CoV-2 infected individuals. Thirdly, the timing of the occurrence of COVID-19-related complications was not collected, so it remains unknown whether the increase in complications in some COVID-19 negative patients after surgery was due to postoperative SARS-CoV-2 infection or vice versa. However, we have followed the strict inclusion criteria and adopted scientific statistical methods. From our conclusions, we can still believe that it is safe for HCC patients who have previously suffered from COVID-19 to undergo hepatectomy after recovery, and the possibility of serious complications in the short term is very low. Therefore, previous research and this study show that, in patients undergoing partial hepatectomy, prior SARS-CoV-2 infection had no effect on short-term liver function and did not increase the risk of postoperative complications. As for the impact of COVID-19 on elderly patients with hepatocellular carcinoma, and the study of hepatectomy for patients in the state of COVID-19, we will expand the population and conduct further analyses in multicenter settings to explore whether there are differences in such groups and their impact on postoperative complications and prognosis.

Conclusion

This study found that prior SARS-CoV-2 infection, including asymptomatic or mild cases, did not lead to notable differences in liver function among patients with HCC. After partial hepatectomy, there were no significant differences in the short-term liver function, postoperative complications, or healthcare expenditure between the patients with and without a history of SARS-CoV-2 infection. Prior SARS-CoV-2 infection had no impact on postoperative recovery in patients with HCC who underwent partial hepatectomy.

Data availability

The data and images of the patient are contained in the medical record system of Guangdong Provincial People’s Hospital. In addition, the data supporting the conclusions of this article are included within the manuscript, figures, and tables.

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Authors and Affiliations

  1. Department of Hepatobiliary Surgery, Guangdong Provincial People’s Hospital, Guangzhou, China

    Dan Fang, Bi-Ling Gan, Shun-an Zhou, Lian- QunXu, Zhen-Rong Chen & Ning Shi

  2. Peking Union Medical College, Beijing, China

    Zhi-Hong Chen & Fan Wu

  3. Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China

    Lei Wu & Hao-Sheng Jin

  4. Huankui Academy, Nanchang University, Nanchang, China

    Chu-Lin Guo

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Contributions

Dan Fang, Lei Wu and Bi-Ling Gan contributed equally to this work. Dan Fang, Lei Wu and Bi-Ling Gan conception and design, drafting of the article, Hao-Sheng Jin， Ning Shi: conception and design, drafting of the article, Chu-Lin Guo, Zhi-Hong Chen, Shun-an Zhou: conception and design, drafting of the article, Fan Wu: conception and design, drafting of the article, Lian-Qun Xu: critical revision of the article for important intellectual content, Zhen-Rong Chen: conception and design, analysis and interpretation of the data. All authors read and approved the final manuscript.

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Correspondence to Ning Shi or Hao-Sheng Jin.

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This research involving de-identifed retrospective medical data was per formed in accordance with the Declaration of Helsinki and approved by our institutional review board at Guangdong Provincial People’s Hospital. All patients enrolled in the study had no cognitive impairment and signed the informed consent.

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Fang, D., Wu, L., Gan, BL. et al. Impact of prior SARS-CoV-2 infection on postoperative recovery in patients with hepatocellular carcinoma resection. BMC Gastroenterol 24, 317 (2024). https://doi.org/10.1186/s12876-024-03412-7

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BMC Gastroenterology

ISSN: 1471-230X

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