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. 2026 Aug 10;54(8):03000605261464004. doi: 10.1177/03000605261464004

Threshold-based association between controlled attenuation parameter–defined hepatic steatosis and hepatectomy-associated ischemia–reperfusion injury: A retrospective cohort study

Yiyun Gao 1,#, Ye Zhang 1,#, Jian Xu 1,#, Jinguo Xia 1,✉, Wenyu Shao 1,✉, Haoming Zhou 1,✉
PMCID: PMC13474231  PMID: 42573100

Abstract

Objective

Fatty liver is known to aggravate hepatic ischemia–reperfusion injury; however, the relationship between the preoperative controlled attenuation parameter measured by transient elastography and ischemia–reperfusion injury after hepatectomy has not been fully clarified. This study aimedt to explore the association between controlled attenuation parameter–defined hepatic steatosis and hepatic ischemia–reperfusion injury after hepatectomy.

Methods

In this single-center retrospective study, 1461 patients who underwent hepatectomy between 2022 and 2024 were included and stratified into four groups according to controlled attenuation parameter–based steatosis grades. The primary endpoints were peak alanine aminotransferase and aspartate aminotransferase levels within 3 days after surgery. Secondary endpoints comprised additional postoperative laboratory indices and short-term clinical outcomes, including complications and mortality. Data were analyzed using multivariable linear regression, restricted cubic spline modeling to explore nonlinear associations, and propensity score matching to compare patients with grade 3 and grade 0 steatosis.

Results

Compared with the nonsteatotic group, only patients with severe fatty liver (controlled attenuation parameter > 292 dB/m) exhibited significantly higher postoperative alanine aminotransferase and aspartate aminotransferase levels. However, restricted cubic spline analysis did not demonstrate a significant positive dose–response relationship between controlled attenuation parameter and liver enzyme levels. In multivariable models, severe fatty liver was independently associated with elevated peak alanine aminotransferase, whereas no consistent association was observed for aspartate aminotransferase. After propensity score matching, severe steatosis remained associated with higher alanine aminotransferase, without significant differences in aspartate aminotransferase or major short-term clinical outcomes.

Conclusions

Preoperative controlled attenuation parameter assessment is most valuable for identifying patients with severe hepatic steatosis, who appear more susceptible to aggravated ischemia–reperfusion injury after hepatectomy, rather than for predicting ischemia–reperfusion injury severity across the full controlled attenuation parameter spectrum.

Keywords: Controlled attenuation parameter, portal triad clamping, partial hepatectomy, hepatic ischemia–reperfusion injury, hepatic steatosis

Introduction

Liver resection is the preferred treatment for various liver diseases,1–3 including hepatocellular carcinoma, cholangiocarcinoma, hepatic hemangioma, and focal nodular hyperplasia. Intermittent Pringle's maneuver (IPM), a method for hepatic inflow occlusion, has been widely used to reduce and control intraoperative bleeding during liver resection.4–6 However, IPM inevitably causes ischemia–reperfusion injury (IRI) of the remnant liver,7,8 leading to a series of metabolic and oxidative stress responses, inflammatory reactions, and ultimately liver tissue damage.9,10 Hepatic IRI has been implicated as one of the primary causes of liver failure and other complications after liver resection.11,12

With the increasing prevalence of obesity and metabolic syndrome, metabolic-associated fatty liver disease (MAFLD) has become a common chronic liver disease worldwide.13–15 Numerous studies have shown that steatotic livers are more vulnerable to IRI. The pathological process of hepatic IRI involves multiple mechanisms, including mitochondrial damage and ATP depletion during ischemia, along with massive production of reactive oxygen species (ROS), calcium overload, and cytokine release during reperfusion, which collectively lead to cell apoptosis and necrosis.16–18 Lipid peroxidation (LP), particularly mitochondrial membrane lipid peroxidation, is regarded as a core molecular event in IRI. When lipid droplets accumulate in hepatocytes, the hepatic sinusoidal microcirculation is compressed, resulting in insufficient oxygen supply, which promotes ROS generation and inflammatory responses,19,20 further exacerbating IRI. Both experimental and clinical studies have suggested that steatotic livers may be more susceptible to ischemia–reperfusion-related injury and postoperative dysfunction,21–23 leading to delayed postoperative liver regeneration, posthepatectomy liver failure (PHLF), and an increased risk of complications.

For the preoperative assessment of hepatic fat content, the controlled attenuation parameter (CAP), a quantitative index derived from FibroScan transient elastography, has attracted widespread attention because of its noninvasiveness, rapidity, and sensitivity to fat content. Studies have shown that CAP values are significantly correlated with the degree of hepatic fat infiltration.24,25 Although CAP has demonstrated good performance in hepatic fat quantification and MAFLD management, no studies have systematically explored the association between CAP-defined hepatic steatosis and early postoperative hepatocellular injury after liver resection. Therefore, this study aimed to investigate the relationship between preoperative CAP parameters and postoperative IRI, providing evidence to support preoperative risk assessment in clinical practice.

Patients and methods

Study population

We retrospectively analyzed patients who underwent hepatectomy at a tertiary hospital in China between 2022 and 2024. The inclusion criteria were as follows: (a) adult patients aged 18 years or older; and (b) patients who underwent elective hepatectomy during hospitalization. The exclusion criteria were as follows: (a) previous liver surgery or related interventions; (b) preoperative use of anticancer drugs; (c) intraoperative microwave ablation; (d) liver blood flow occlusion performed using methods other than the Pringle maneuver; (e) missing medical records or unrecorded occlusion time; (f) diagnosis of liver cysts or metastatic tumors; (g) concurrent resection of other organs (except the gallbladder); and (h) American Society of Anesthesiologists (ASA) grade 4.

Among the initial 2315 patients (Figure 1), the following exclusions were made: 261 had previously undergone liver surgery, 77 had metastatic tumors, 15 had liver cysts, 30 underwent concurrent organ resection, 33 used anticancer drugs, 6 had ASA grade 4, 72 received microwave ablation, 187 underwent non-Pringle occlusion, and 173 had incomplete records.

Figure 1.

Figure 1.

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Flowchart of the eligibility of participants included in the present study.

Data collection and definitions

Patient demographics, surgical details, laboratory test results, and postoperative pathology data were collected from medical records. At our medical center, routine blood tests are performed preoperatively and on the first postoperative day. Severe complications were defined as Clavien–Dindo grade 3 or higher. Benign and malignant tumors were classified based on pathological examination. Hepatic steatosis and liver stiffness were assessed preoperatively using transient elastography. CAP was used to estimate hepatic fat content, whereas liver stiffness measurement (LSM) was used to estimate fibrosis-related liver stiffness. CAP and LSM were obtained before surgery using transient elastography. Measurements were performed after fasting by the same experienced operator, and the median values of valid measurements were recorded. CAP was expressed in dB/m and LSM in kPa. Tumor size ≥5 cm was defined as large tumor size. According to the manufacturer's recommendations, patients were classified as having grade 0 fatty liver (<238 dB/m, steatosis <11%), grade 1 fatty liver (238–259 dB/m, steatosis >11%), grade 2 fatty liver (259–292 dB/m, steatosis >34%), or grade 3 fatty liver (>292 dB/m, steatosis >67%) based on CAP values. Preoperative hepatoprotective medication use was defined as documented use of liver-protective agents before surgery during the index hospitalization.

Study endpoints

The primary endpoints were the peak serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within 3 days after hepatectomy. These markers have previously served as surrogate indicators of hepatocellular injury and are widely used as reference indices for evaluating hepatic ischemia–reperfusion injury.26,27 Secondary endpoints included various other laboratory parameters and short-term clinical outcomes. The laboratory parameters assessed were total bilirubin, albumin, creatinine, white blood cell count, and hemoglobin, all measured on the first postoperative day. Short-term clinical outcomes included length of postoperative hospital stay, incidence of severe complications (defined as Clavien–Dindo grade 3 or higher 28 ), need for intensive care unit (ICU) care, and postoperative mortality. Liver failure was defined according to the “50–50 criteria” on POD 5. 29

Statistical analysis

For variables that did not conform to a normal distribution, continuous data were expressed as median (interquartile range), and differences were analyzed using the Kruskal–Wallis test or Mann–Whitney U test, as appropriate. Dunn multiple comparison test was further used to compare postoperative ALT and AST levels between patients with different grades of fatty liver and those with grade 0 fatty liver. Categorical variables were presented as number (percentage) and were compared using the chi-square (χ2) test or Fisher's exact test. Restricted cubic spline (RCS) analysis was used to evaluate the nonlinear relationship between liver enzyme levels (dependent variables) and CAP values (independent variable), with four knots selected for the spline. In addition, multivariable linear regression analysis was performed with postoperative ALT and AST levels as dependent variables. Data processing and analysis were conducted using R version 4.3.3 software and the Zstats v1.0 package (www.zstats.net). All p values were two-sided, and p < 0.05 was considered statistically significant. The study was conducted in accordance with the Declaration of Helsinki of 1975, as revised in 2024, and relevant ethical guidelines. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. 30

Results

Demographic data

A total of 1461 patients who underwent hepatectomy were included in the study (Table 1). Patients were stratified according to CAP-based steatosis grades: 840 patients were classified as grade 0, 239 as grade 1, 220 as grade 2, and 162 as grade 3. To further assess the pathological relevance of CAP-based stratification, postoperative hematoxylin and eosin (H&E)-stained liver specimens were reviewed for the degree of macrovesicular steatosis. Patients in higher CAP categories generally showed greater histologic steatosis, supporting the consistency between CAP classification and pathologic steatosis grading in this cohort (Figure 2). No significant differences were observed across CAP-based steatosis grades in age, sex, ASA classification, or LSM. However, body mass index (BMI) differed significantly across CAP-based steatosis grades and was higher in patients with more severe steatosis. The proportions of patients with hypertension and diabetes mellitus increased significantly with increasing CAP grade (p < 0.001). These findings suggest that higher CAP-defined steatosis grades were associated with a more pronounced metabolic phenotype. The proportion of patients receiving preoperative hepatoprotective medication did not differ significantly among groups (p = 0.468). No differences were observed in the number of intraoperative Pringle clamping cycles (p = 0.094), total Pringle clamping time (p = 0.110), operative time (p = 0.126), or pathologic diagnosis (p = 0.898) across groups. Additionally, there were no significant differences in the maximum diameter of the resected specimen (p = 0.599), number of lesions (p = 0.684), or surgical approach (p = 0.652).

Table 1.

Comparison of characteristics of patients undergoing hepatectomy with different CAP.

Variables Steatosis <11% (n = 840) 11% ≤ steatosis <34% (n = 239) 34% ≤ steatosis <67% (n = 220) Steatosis ≥67% (n = 162) p
Outcomes
Peak ALT, (U/L) 219.05 (119.68, 393.55) 219.50 (106.95, 377.85) 236.05 (129.33, 435.07) 284.20 (176.68, 494.65) <0.001
Peak AST, (U/L) 235.95 (132.07, 424.98) 205.70 (122.00, 379.25) 249.45 (132.77, 452.00) 263.30 (174.72, 495.80) 0.013
TBIL, (μmol/L) 18.10 (13.30, 25.20) 17.80 (13.40, 26.40) 19.00 (14.10, 25.25) 18.35 (13.83, 24.62) 0.893
ALB, (g/L) 34.50 (31.80, 36.80) 35.70 (33.00, 38.10) 35.10 (33.08, 37.60) 36.35 (32.92, 38.68) <0.001
Cr, (μmol/L) 61.85 (51.62, 72.27) 64.20 (53.00, 73.65) 65.05 (53.42, 77.02) 66.30 (57.02, 76.97) 0.003
HB, (g/L) 124.00 (113.00, 136.00) 129.00 (118.00, 140.00) 129.00 (121.00, 139.00) 131.00 (122.25, 142.00) <0.001
WBC, (109/L) 11.02 (8.62, 13.84) 11.96 (9.80, 14.30) 11.68 (9.19, 14.56) 12.07 (9.91, 14.59) <0.001
Postoperative hospital stays 7.00 (6.00, 10.00) 7.00 (6.00, 9.00) 7.00 (6.00, 9.00) 7.00 (6.00, 10.00) 0.752
ICU 21 (2.50) 11 (4.60) 3 (1.36) 6 (3.70) 0.153
PHLF 13 (1.55) 7 (2.93) 1 (0.45) 0 (0.00) 0.056
Complication 64 (7.62) 14 (5.86) 13 (5.91) 12 (7.41) 0.705
Death 7 (0.83) 3 (1.26) 1 (0.45) 1 (0.62) 0.856
Baseline characteristics
Pringle clamping cycles 2.00 (1.00, 3.00) 2.00 (1.00, 2.00) 2.00 (1.00, 3.00) 2.00 (1.00, 3.00) 0.094
Pringle clamping time, (min) 30.00 (18.00, 45.00) 30.00 (18.50, 45.00) 30.00 (20.00, 48.50) 32.00 (20.00, 49.50) 0.110
Operation time, (min) 150.00 (105.00, 200.00) 150.00 (110.00, 210.00) 152.00 (108.25, 210.00) 164.50 (120.00, 213.75) 0.126
Maximum diameter of the resected specimen, (cm) 8.50 (5.50, 12.00) 9.00 (5.60, 12.00) 9.00 (6.00, 12.00) 9.00 (6.50, 11.00) 0.599
CAP, (dB/m) 202.00 (182.00, 221.00) 247.00 (243.00, 253.00) 275.00 (267.00, 282.00) 313.00 (301.00, 330.00) <0.001
E, (kPa) 6.61 (4.90, 11.10) 6.20 (5.00, 10.05) 6.73 (5.00, 10.00) 7.10 (5.73, 10.15) 0.171
Age 58.00 (49.00, 67.00) 59.00 (53.00, 67.00) 60.00 (52.00, 69.00) 59.00 (51.00, 67.00) 0.071
Sex, n (%) 0.973
Male 519 (61.79) 150 (62.76) 137 (62.27) 103 (63.58)
Female 321 (38.21) 89 (37.24) 83 (37.73) 59 (36.42)
BMI 22.47 (20.71, 24.22) 24.77 (23.28, 26.53) 25.93 (24.03, 27.65) 26.57 (24.81, 29.09) <0.001
ALT, (U/L) 20.70 (14.10, 33.55) 21.90 (15.10, 31.80) 24.55 (15.62, 36.70) 26.80 (18.60, 36.95) <0.001
AST, (U/L) 24.75 (18.90, 35.60) 23.00 (18.60, 31.80) 24.80 (19.03, 31.83) 23.70 (19.52, 33.12) 0.331
TBIL, (μmol/L) 12.80 (9.70, 16.90) 12.30 (9.90, 16.20) 12.80 (9.70, 16.12) 11.90 (8.90, 15.38) 0.154
ALB, (g/L) 38.60 (36.50, 40.90) 39.20 (37.30, 41.50) 39.75 (38.10, 41.70) 40.35 (38.02, 41.88) <0.001
Cr, (μmol/L) 64.00 (55.40, 73.43) 64.40 (56.45, 75.05) 65.85 (55.20, 76.58) 66.50 (56.92, 75.02) 0.171
WBC, (109/L) 4.88 (3.85, 6.14) 5.27 (4.22, 6.36) 5.22 (4.33, 6.15) 5.61 (4.76, 6.76) <0.001
RBC, (109/L) 4.28 (3.92, 4.60) 4.45 (4.04, 4.77) 4.49 (4.12, 4.77) 4.50 (4.22, 4.84) <0.001
HB, (g/L) 131.00 (120.00, 141.25) 135.00 (123.00, 146.00) 136.00 (126.75, 147.00) 138.00 (127.25, 147.75) <0.001
PLT, (109/L) 162.00 (117.00, 208.25) 167.00 (130.00, 215.00) 173.00 (137.00, 217.50) 179.50 (145.00, 214.25) 0.002
INR 1.06 (1.01, 1.11) 1.04 (1.00, 1.08) 1.03 (0.99, 1.08) 1.02 (0.98, 1.06) <0.001
Hepatitis, n (%) 359 (42.74) 82 (34.31) 73 (33.18) 55 (33.95) 0.007
Diabetes, n (%) 115 (13.69) 37 (15.48) 50 (22.73) 39 (24.07) <0.001
Hypertension, n (%) 191 (22.74) 81 (33.89) 94 (42.73) 71 (43.83) <0.001
Preoperative hepatoprotective medications, n (%) 388 (46.19) 108 (45.19) 90 (40.91) 68 (41.98) 0.468
Transfusion, n (%) 172 (20.48) 35 (14.64) 31 (14.09) 27 (16.67) 0.052
Operation, n (%) 0.652
Laparoscopy 460 (54.76) 139 (58.16) 121 (55.00) 84 (51.85)
Open 380 (45.24) 100 (41.84) 99 (45.00) 78 (48.15)
Pathology, n (%) 0.898
Benign 255 (30.36) 78 (32.64) 69 (31.36) 48 (29.63)
Malignant 585 (69.64) 161 (67.36) 151 (68.64) 114 (70.37)
Number, n (%) 0.684a
1 772 (91.90) 219 (91.63) 199 (90.45) 145 (89.51)
2 58 (6.90) 15 (6.28) 16 (7.27) 15 (9.26)
>=3 10 (1.19) 5 (2.09) 5 (2.27) 2 (1.23)
Resected mass diameter ≥5 cm, n (%) 0.008
0 148 (17.62) 36 (15.06) 34 (15.45) 10 (6.17)
1 675 (80.36) 198 (82.85) 177 (80.45) 149 (91.98)
2 17 (2.02) 5 (2.09) 9 (4.09) 3 (1.85)
ASA, n (%) 0.159
1 62 (7.38) 16 (6.69) 8 (3.64) 6 (3.70)
2 635 (75.60) 190 (79.50) 180 (81.82) 125 (77.16)
3 143 (17.02) 33 (13.81) 32 (14.55) 31 (19.14)
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ALB: albumin; ALT: alanine aminotransferase; ASA: American Society of Anesthesiologists; AST: aspartate aminotransferase; BMI: body mass index; CAP: controlled attenuation parameter; Cr: creatinine; E: elasticity; HB: hemoglobin; INR: international normalized ratio; PHLF: posthepatectomy liver failure; PLT: platelet (count); RBC: red blood cell (count); TBIL: total bilirubin; WBC: white blood cell (count).

a

Simulated p-value.

Complication: Clavien–Dindo classification grade ≥ 3.

Figure 2.

Figure 2.

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H&E staining of liver tissue specimens from patients with fatty liver stratified according to CAP grades. Grade 0: steatosis <11%; Grade 1: 11% ≤ steatosis <34%; Grade 2: 34% ≤ steatosis <67%; Grade 3: steatosis ≥67%.

H&E: hematoxylin and eosin.

Primary and secondary outcomes

Patients with different CAP grades showed significant differences in postoperative peak ALT (p < 0.001) and AST (p = 0.013). Pairwise comparisons showed that patients with grade 3 CAP-defined steatosis had higher postoperative peak ALT and AST levels than patients with grade 0 steatosis, whereas no significant differences were observed between grade 0 and grades 1 or 2 (Figure 3).

Figure 3.

Figure 3.

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Comparison of postoperative peak ALT and AST levels among patients with different degrees of fatty liver classified according to CAP (dB/m) values. (a, b) All patients. (c–r) Patients in different subgroups.

ALT: alanine aminotransferase; AST: aspartate aminotransferase; CAP: controlled attenuation parameter.

Among the other postoperative laboratory tests, total bilirubin did not differ significantly among the four groups (p = 0.893). However, albumin (p < 0.001), creatinine (p = 0.003), hemoglobin (p < 0.001), and white blood cells (p < 0.001) showed significant differences, with values increasing as CAP grade increased.

For short-term outcomes, there were no differences in postoperative hospital stay (p = 0.752), incidence of severe complications (p = 0.705), ICU admission rate (p = 0.153), incidence of PHLF (p = 0.056), or perioperative mortality (p = 0.856) across CAP grades.

Subgroup analysis

Further analyses explored postoperative peak ALT and AST levels in patients with different CAP grades stratified by sex, age, pathology, and surgical approach (Figure 3). The results showed that grade 3 fatty liver was associated with higher postoperative ALT or AST levels than grade 0 fatty liver in most subgroups, whereas no significant differences were observed for grades 1 or 2.

Relationship between CAP values and postoperative ALT/AST

RCS trend analysis was used to assess the relationship between CAP values and postoperative ALT/AST (Figure 4). In the unadjusted RCS model, CAP values were not significantly associated with postoperative peak ALT (p = 0.063) or AST (p = 0.272). Similar results were observed after adjustment for total Pringle clamping time (ALT: p = 0.309; AST: p = 0.398). These findings indicate that CAP did not provide continuous predictive information for postoperative ALT or AST elevation.

Figure 4.

Figure 4.

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Restricted cubic spline (RCS) trend analysis of the relationship between CAP (dB/m) values and postoperative peak ALT and AST levels. (a) Relationship between CAP (dB/m) values and peak ALT. (b) Relationship between CAP (dB/m) values and peak ALT after adjustment for ischemia time as a covariate. (c) Relationship between CAP (dB/m) values and peak AST. (d) Relationship between CAP (dB/m) values and peak AST after adjustment for ischemia time as a covariate.

ALT: alanine aminotransferase; AST: aspartate aminotransferase; CAP: controlled attenuation parameter.

When CAP was treated as a continuous variable (Table 2), both univariable and multivariable analyses showed no significant association with postoperative ALT or AST levels.

Table 2.

Linear regression analysis examining the relationship between different grades of CAP (dB/m) values and the peak levels of postoperative ALT and AST.

Variables Model 1 Model 2 Model 3 Model 4
β (95% CI) p β (95% CI) p β (95% CI) p β (95% CI) p
CAP grade (ALT)
0 0.00 (reference) 0.00 (reference) 0.00 (reference) 0.00 (reference)
1 13.73 (−43.38 to 70.84) 0.638 12.82 (−43.51 to 69.15) 0.656 9.36 (−43.70 to 62.42) 0.730 13.73 (−43.38 to 70.84) 0.638
2 18.03 (−40.97 to 77.03) 0.549 15.48 (−42.83 to 73.78) 0.603 7.76 (−47.17 to 62.70) 0.782 18.03 (−40.97 to 77.03) 0.549
3 91.17 (24.32 to 158.01) 0.008 85.98 (20.11 to 151.86) 0.011 63.52 (1.39 to 125.66) 0.045 91.17 (24.32 to 158.01) 0.008
CAP grade (AST)
0 0.00 (reference) 0.00 (reference) 0.00 (reference) 0.00 (reference)
1 −17.07 (−90.31 to 56.16) 0.648 −20.80 (−93.43 to 51.82) 0.575 −25.08 (−94.46 to 44.30) 0.479 −17.07 (−90.31 to 56.16) 0.648
2 −12.73 (−88.39 to 62.92) 0.742 −20.47 (−95.64 to 54.71) 0.594 −28.57 (−100.40 to 43.27) 0.436 −12.73 (−88.39 to 62.92) 0.742
3 55.23 (−30.49 to 140.95) 0.207 46.67 (−38.26 to 131.60) 0.282 22.00 (−59.25 to 103.25) 0.596 55.23 (−30.49 to 140.95) 0.207
CAP (ALT) 0.37 (−0.06 to 0.80) 0.089 0.36 (−0.07 to 0.78) 0.099 0.20 (−0.19 to 0.60) 0.317 0.37 (−0.06 to 0.80) 0.089
CAP (AST) −0.02 (−0.57 to 0.53) 0.949 −0.06 (−0.61 to 0.48) 0.820 −0.23 (−0.75 to 0.29) 0.388 −0.02 (−0.57 to 0.53) 0.949
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ALT: alanine aminotransferase; AST: aspartate aminotransferase; CAP: controlled attenuation parameter; CI: confidence interval.

Model 1: Crude.

Model 2: Adjusted for sex, ASA, and age.

Model 3: Adjusted for sex, ASA, Pringle clamping time, operation time, and age.

Model 4: Adjusted for pathology, number, sex, ASA, Pringle clamping time, operation time, E(kPa), age, operation, diabetes, hypertension, and preoperative hepatoprotective medications.

When CAP was treated as a categorical variable, univariable and multivariable linear regression analyses (Table 2) revealed that only grade 3 CAP-defined steatosis (vs. grade 0) was associated with higher peak ALT levels. Multivariable Model 2 was adjusted for sex, ASA classification, and age. Model 3 further included operative time and ischemia time. Model 4 additionally included pathologic type, number of lesions, liver stiffness, hypertension, diabetes mellitus, preoperative hepatoprotective medication use, and surgical approach.

Analysis after propensity score matching

To further compare patients with grade 3 CAP-defined steatosis and those with grade 0 steatosis, 1:2 propensity score matching was performed to balance baseline and intraoperative characteristics (SMD < 0.1; Supplementary Table 1).

Matched analysis (Table 3) showed that patients with grade 3 CAP-defined steatosis had higher postoperative peak ALT levels than those with grade 0 steatosis (283.25 [175.50, 474.70] vs. 232.00 [126.65, 431.15], p = 0.018), but no differences in AST (261.70 [170.42, 479.52] vs. 270.00 [142.25, 487.00], p = 0.366) or total bilirubin (p = 0.874). To minimize the potential influence of preoperative baseline transaminase differences on postoperative peak values, we further analyzed postoperative transaminase increments (ΔALT and ΔAST), calculated as the postoperative peak value minus the corresponding preoperative baseline level. In the matched cohort, patients with grade 3 CAP-defined steatosis exhibited a significantly higher ΔALT than patients with grade 0 steatosis (245.90 [146.68, 445.70] vs. 209.80 [100.45, 394.10] U/L, p = 0.029). In contrast, no significant difference in ΔAST was observed between the two groups (240.25 [144.62, 459.85] vs. 236.70 [113.90, 452.90] U/L, p = 0.304). Among the secondary postoperative laboratory indices, albumin, hemoglobin, creatinine, and white blood cell count differed between the matched groups. No differences were observed in postoperative hospital stay (p = 0.296), severe complications (p = 0.603), ICU admission rate (p = 0.801), incidence of PHLF (p = 0.352), or perioperative mortality (p = 1.000).

Table 3.

Comparison of outcomes after propensity score matching.

Variables 0 (n = 303) 3 (n = 160) p
ΔALT, (U/L) 209.80 (100.45, 394.10) 245.90 (146.68, 445.70) 0.029
ΔAST, (U/L) 236.70 (113.90, 452.90) 240.25 (144.62, 459.85) 0.304
Peak ALT, (U/L) 232.00 (126.65, 431.15) 283.25 (175.50, 474.70) 0.018
Peak AST, (U/L) 270.00 (142.25, 487.00) 261.70 (170.42, 479.52) 0.366
TBIL, (μmol/L) 18.00 (13.45, 23.70) 18.25 (13.78, 24.25) 0.874
ALB, (g/L) 34.50 (31.50, 37.00) 36.35 (32.98, 38.75) <0.001
Cr, (μmol/L) 62.60 (53.65, 74.00) 66.40 (57.08, 77.15) 0.049
HB, (g/L) 124.00 (112.00, 135.00) 131.00 (122.75, 142.00) <0.001
WBC, (109/L) 11.01 (8.63, 13.66) 12.09 (9.93, 14.61) 0.003
Postoperative hospital stays 7.00 (6.00, 10.00) 7.00 (6.00, 10.00) 0.296
ICU, n (%) 10 (3.30) 6 (3.75) 0.801
PHLF, n (%) 4 (1.32) 0 (0.00) 0.352
Complication, n (%) 27 (8.91) 12 (7.50) 0.603
Death, n (%) 2 (0.66) 1 (0.62) 1.000
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ALB: albumin; ALT: alanine aminotransferase; AST: aspartate aminotransferase; Cr: creatinine; HB: hemoglobin; ICU: intensive care unit; PHLF: posthepatectomy liver failure; PLT: platelet (count); RBC: red blood cell (count); TBIL: total bilirubin; WBC: white blood cell (count).

Complication: Clavien–Dindo grade ≥ 3.

To explore whether liver stiffness modified the association between severe CAP-defined steatosis and postoperative transaminase elevation, we conducted a stratified analysis within the matched cohort using a LSM cutoff of 12 kPa, in accordance with the EASL Clinical Practice Guidelines on noninvasive tests for liver disease severity. 31

In the LSM ≥ 12 kPa subgroup, postoperative peak ALT was numerically higher in patients with grade 3 steatosis than in those with grade 0 steatosis, although the difference did not reach statistical significance (343.15 [229.60, 505.43] vs. 269.30 [141.10, 581.10] U/L, p = 0.381). No significant difference in peak AST was observed between the two groups (358.75 [251.45, 537.83] vs. 405.90 [177.50, 661.90] U/L, p = 0.807).

In the LSM < 12 kPa subgroup, postoperative peak ALT was significantly higher in patients with grade 3 steatosis than in those with grade 0 steatosis (263.20 [168.10, 467.53] vs. 229.65 [126.32, 397.92] U/L, p = 0.046), whereas peak AST remained comparable between the two groups (246.05 [147.60, 470.73] vs. 244.20 [139.22, 450.67] U/L, p = 0.488).

Discussion

Based on a retrospective cohort of 1461 patients who underwent hepatectomy at a single center, this study investigated the association between preoperative CAP-quantified hepatic steatosis and hepatic ischemia–reperfusion injury after hepatectomy. The results showed that when CAP was treated as a continuous variable, it was not significantly associated with peak ALT or AST levels within 3 days after surgery. After categorization of CAP, only severe fatty liver (CAP > 292 dB/m) was independently associated with a higher peak ALT level, whereas no consistent association was observed with AST. After propensity score matching, patients with severe fatty liver had higher ALT levels than patients without fatty liver, but there were no statistically significant differences in AST or short-term clinical outcomes, including severe complications, ICU admission, length of hospital stay, and perioperative mortality. Overall, these findings suggest that the clinical value of CAP lies primarily in identifying a high-risk subgroup of patients with severe fatty liver, rather than serving as a continuous predictor of postoperative liver injury severity across the full CAP spectrum.

Mechanistically,32–35 severe hepatic steatosis may increase vulnerability to ischemia–reperfusion-related stress through several interconnected pathways. Excess lipid accumulation impairs mitochondrial β-oxidation and respiratory chain function, thereby reducing ATP reserves and increasing susceptibility to mitochondrial permeability transition during reperfusion. Because mitochondria are a major source of ROS during hepatic ischemia–reperfusion injury, pre-existing mitochondrial dysfunction in steatotic hepatocytes may amplify oxidative stress and promote hepatocellular membrane injury. In parallel, lipid overload provides abundant substrates for LP, and recent experimental evidence indicates that fatty liver ischemia–reperfusion injury can be aggravated by LP stress and ferroptosis-related hepatocyte injury. Steatosis may also disrupt sinusoidal microcirculation and enhance sterile inflammatory activation, further reducing hepatic tolerance to transient inflow occlusion. However, because our study did not directly measure mitochondrial injury, oxidative stress, LP, ferroptosis, or inflammatory biomarkers, these pathways should be regarded as biologically plausible explanations rather than mechanisms demonstrated by the present data.

The EASL 2021 MAFLD Guidelines 31 advocate a stepwise approach of “serum scoring → elastography” and propose a benchmark strategy of “using MRI-PDFF for fat measurement and CAP for accessible screening.” The latest AASLD 2023 Guidelines 36 recommend CAP for bedside screening and MRI-PDFF for accurate quantification. Compared with MRI-PDFF, the advantage of preoperative assessment of fatty liver using the CAP via transient elastography (VCTE) lies in its accessibility and suitability for perioperative decision-making. CAP and LSM can be obtained immediately during the same bedside examination, enabling rapid identification of steatosis while stratifying the risks of fibrosis and potential portal hypertension. Moreover, numerous studies and reviews have shown that LSM can predict complications and PHLF after hepatectomy, thereby directly contributing to preoperative risk assessment and surgical planning.37,38 Although MRI-PDFF is more accurate for fat quantification, it is less convenient than CAP for rapid preoperative decision-making because of limitations related to cost, patient acceptance, and the inability to perform the examination at the bedside. 36 To our knowledge, this study is among the first to evaluate the association between preoperative CAP-defined steatosis and early postoperative hepatocellular injury after hepatectomy.

A retrospective cohort study 39 reported that patients with a BMI >30 kg/m2 who also had hypertension and diabetes were at increased risk of perioperative complications. The median BMI in that study population was 35, which was substantially higher than the median BMI of 26.5 observed among patients with grade 3 fatty liver in the present study. A systematic review suggested that livers with >30% macrovesicular steatosis have lower tolerance to IRI; 40 however, this review was based primarily on animal models. Another study that assessed hepatic steatosis using MRI found that MRI liver fat fraction (LFF) ≥ 5% was associated with severe postoperative complications (Clavien–Dindo grade ≥3) and higher postoperative transaminase levels. 41 Despite differences in measurement methods, these studies support the broader concept that hepatic steatosis may increase vulnerability to postoperative liver injury. However, our findings further suggest that this association may not be linear across the full CAP spectrum and may be concentrated primarily among patients with severe CAP-defined steatosis.

In our cohort, severe CAP-defined steatosis was associated with a broader metabolic phenotype, including higher BMI, a higher prevalence of hypertension and diabetes mellitus, and differences in several baseline laboratory indices. This finding suggests that severe steatosis may represent MAFLD-related cardiometabolic dysregulation rather than isolated hepatic fat accumulation. Although multivariable adjustment and propensity score matching were used to reduce measured confounding, residual confounding related to metabolic status, systemic inflammation, and unmeasured steatohepatitis cannot be excluded. Therefore, the postoperative ALT elevation observed in patients with severe steatosis should be interpreted as reflecting a combined phenotype of metabolic and hepatic vulnerability under perioperative stress rather than definitive evidence of isolated ischemic susceptibility. This interpretation supports the use of CAP for threshold-based risk stratification rather than as a continuous predictor of postoperative IRI severity.

This study has several limitations. First, its single-center retrospective design may have introduced selection bias, information bias, and residual confounding; therefore, prospective multicenter validation is warranted. Second, CAP measurements may be influenced by operator-related factors, patient body habitus, and technical conditions. Third, the relatively small number of patients with severe CAP-defined steatosis may have limited the statistical power to detect differences in perioperative clinical outcomes. Fourth, ALT and AST were used as surrogate markers of early postoperative hepatocellular injury rather than definitive indicators of hepatic ischemia–reperfusion injury, and they cannot fully reflect liver functional impairment, microscopic pathologic injury, or prognosis. Finally, mechanistic biomarkers of hepatic ischemia–reperfusion injury were not assessed; therefore, the mechanisms linking severe CAP-defined steatosis to postoperative ALT elevation remain hypothesis-generating.

Conclusion

Although continuous CAP values were not significantly associated with the severity of hepatic ischemia–reperfusion injury (IRI) after hepatectomy, severe fatty liver (specifically defined as CAP >292 dB/m) was associated with an increased risk of IRI. Therefore, the clinical significance of preoperative CAP measurement lies primarily in identifying patients with severe hepatic steatosis, who may be at higher risk of developing more severe IRI after liver surgery.

Supplemental Material

sj-docx-1-imr-10.1177_03000605261464004 - Supplemental material for Threshold-based association between controlled attenuation parameter–defined hepatic steatosis and hepatectomy-associated ischemia–reperfusion injury: A retrospective cohort study
sj-docx-1-imr-10.1177_03000605261464004.docx (33.5KB, docx)

Supplemental material, sj-docx-1-imr-10.1177_03000605261464004 for Threshold-based association between controlled attenuation parameter–defined hepatic steatosis and hepatectomy-associated ischemia–reperfusion injury: A retrospective cohort study by Yiyun Gao, Ye Zhang, Jian Xu, Jinguo Xia, Wenyu Shao and Haoming Zhou in Journal of International Medical Research

Acknowledgments

None.

Footnotes

Ethical statement: This retrospective study was approved by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (Ethics Approval Number: 2024-SR-734). Because this study involved no direct contact with patients and used only de-identified historical medical records, the requirement for written informed consent was waived by the Ethics Committee. All patient information was de-identified before data analysis to ensure that individual patients could not be identified.

Author contributions: Conceptualization: Haoming Zhou, Wenyu Shao, Jinguo Xia. Data curation: Yiyun Gao, Ye Zhang. Formal analysis: Yiyun Gao. Methodology: Yiyun Gao; Software: Jian Xu. Writing - original draft: Yiyun Gao. Writing - review & editing: Jinguo Xia, Wenyu Shao, Haoming Zhou.

Funding: This study was supported by the National Natural Science Foundation of China (no. 82370668), Natural Science Foundation of Jiangsu Province (Outstanding Youth Fund project) (BK20240053), and Study on the Application of Three-Dimensional Clinical Capacity Enhancement Project of Jiangsu Province Hospital (JSPH-MB-2023-20).

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Supplemental material: Supplemental material for this article is available online.

References

  • 1.Ma KW, Cheung TT, She WH, et al. Major postoperative complications compromise oncological outcomes of patients with intrahepatic cholangiocarcinoma after curative resection—a 13-year cohort in a tertiary center. Asian J Surg 2019; 42: 164–171. [DOI] [PubMed] [Google Scholar]
  • 2.Chen YW, Huang MT, Chang TC. Long term outcomes of simultaneous laparoscopic versus open resection for colorectal cancer with synchronous liver metastases. Asian J Surg 2019; 42: 217–223. [DOI] [PubMed] [Google Scholar]
  • 3.Marom G, Khoury T, Gazla SA, et al. Operative treatment of hepatic hydatid cysts: a single center experience. Asian J Surg 2019; 42: 702–707. [DOI] [PubMed] [Google Scholar]
  • 4.Huang Y, Xu L, Wang N, et al. Preoperative dexamethasone administration in hepatectomy of 25-min intermittent Pringle’s maneuver for hepatocellular carcinoma: a randomized controlled trial. Int J Surg 2023; 109: 3354–3364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Nakayama H, Okamura Y, Higaki T, et al. Effect of blood product transfusion on the prognosis of patients undergoing hepatectomy for hepatocellular carcinoma: a propensity score matching analysis. J Gastroenterol 2023; 58: 171–181. [DOI] [PubMed] [Google Scholar]
  • 6.Huang Y, Liao A, Pu X, et al. A randomized controlled trial of effect of 15- or 25-minute intermittent Pringle maneuver on hepatectomy for hepatocellular carcinoma. Surgery 2022; 171: 1596–1604. [DOI] [PubMed] [Google Scholar]
  • 7.Doi S, Yasuda S, Hokuto D, et al. Impact of the prolonged intermittent Pringle maneuver on post-hepatectomy liver failure: comparison of open and laparoscopic approaches. World J Surg 2023; 47: 3328–3337. [DOI] [PubMed] [Google Scholar]
  • 8.Reiniers MJ, Olthof PB, van Golen RF, et al. Hypothermic perfusion with retrograde outflow during right hepatectomy is safe and feasible. Surgery 2017; 162: 48–58. [DOI] [PubMed] [Google Scholar]
  • 9.Peralta C, Jiménez-Castro MB, Gracia-Sancho J. Hepatic ischemia and reperfusion injury: effects on the liver sinusoidal milieu. J Hepatol 2013; 59: 1094–1106. [DOI] [PubMed] [Google Scholar]
  • 10.Cannistrà M, Ruggiero M, Zullo A, et al. Hepatic ischemia reperfusion injury: a systematic review of literature and the role of current drugs and biomarkers. Int J Surg 2016; 33: S57–S70. [DOI] [PubMed] [Google Scholar]
  • 11.van Mierlo KM, Schaap FG, Dejong CH, et al. Liver resection for cancer: new developments in prediction, prevention and management of postresectional liver failure. J Hepatol 2016; 65: 1217–1231. [DOI] [PubMed] [Google Scholar]
  • 12.Tian C, Tian H, Li W, et al. Effects of remote ischemic conditioning on postoperative recovery after hepatectomy: a randomised controlled trial. Liver Int 2025; 45: e70041. [DOI] [PubMed] [Google Scholar]
  • 13.Eslam M, Sanyal AJ, George J. MAFLD: a consensus-driven proposed Nomenclature for metabolic associated fatty liver disease. Gastroenterology 2020; 158: 1999–2014.e1991. [DOI] [PubMed] [Google Scholar]
  • 14.Ng CH, Huang DQ, Nguyen MH. Nonalcoholic fatty liver disease versus metabolic-associated fatty liver disease: prevalence, outcomes and implications of a change in name. Clin Mol Hepatol 2022; 28: 790–801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Chan KE, Koh TJL, Tang ASP, et al. Global prevalence and clinical characteristics of metabolic-associated fatty liver disease: a meta-analysis and systematic review of 10 739 607 individuals. J Clin Endocrinol Metab 2022; 107: 2691–2700. [DOI] [PubMed] [Google Scholar]
  • 16.Tang SP, Mao XL, Chen YH, et al. Reactive oxygen Species induce fatty liver and ischemia-reperfusion injury by promoting inflammation and cell death. Front Immunol 2022; 13: 870239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Li F, Guan Z, Gao Y, et al. ER Stress promotes mitochondrial calcium overload and activates the ROS/NLRP3 axis to mediate fatty liver ischemic injury. Hepatol Commun 2024; 8: e0399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Prieto I, Monsalve M. ROS Homeostasis, a key determinant in liver ischemic-preconditioning. Redox Biol 2017; 12: 1020–1025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Imarisio C, Alchera E, Bangalore Revanna C, et al. Oxidative and ER stress-dependent ASK1 activation in steatotic hepatocytes and Kupffer cells sensitizes mice fatty liver to ischemia/reperfusion injury. Free Radic Biol Med 2017; 112: 141–148. [DOI] [PubMed] [Google Scholar]
  • 20.Chen H, McKeen T, Chao X, et al. The role of MLKL in hepatic ischemia-reperfusion injury of alcoholic steatotic livers. Int J Biol Sci 2022; 18: 1096–1106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Reddy SK, Marsh JW, Varley PR, et al. Underlying steatohepatitis, but not simple hepatic steatosis, increases morbidity after liver resection: a case-control study. Hepatology 2012; 56: 2221–2230. [DOI] [PubMed] [Google Scholar]
  • 22.Selzner M, Clavien PA. Failure of regeneration of the steatotic rat liver: disruption at two different levels in the regeneration pathway. Hepatology 2000; 31: 35–42. [DOI] [PubMed] [Google Scholar]
  • 23.Liu R, Cao H, Zhang S, et al. ZBP1-mediated Apoptosis and inflammation exacerbate steatotic liver ischemia/reperfusion injury. J Clin Invest 2024; 134: e180451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Eddowes PJ, Sasso M, Allison M, et al. Accuracy of FibroScan controlled attenuation parameter and liver stiffness measurement in assessing steatosis and fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology 2019; 156: 1717–1730. [DOI] [PubMed] [Google Scholar]
  • 25.Oeda S, Takahashi H, Imajo K, et al. Accuracy of liver stiffness measurement and controlled attenuation parameter using FibroScan® M/XL probes to diagnose liver fibrosis and steatosis in patients with nonalcoholic fatty liver disease: a multicenter prospective study. J Gastroenterol 2020; 55: 428–440. [DOI] [PubMed] [Google Scholar]
  • 26.Meurisse N, Mertens M, Fieuws S, et al. Effect of a combined drug approach on the severity of ischemia-reperfusion injury during liver transplant: a randomized clinical trial. JAMA Netw Open 2023; 6: e230819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Nasralla D, Coussios CC, Mergental H, et al. A randomized trial of normothermic preservation in liver transplantation. Nature 2018; 557: 50–56. [DOI] [PubMed] [Google Scholar]
  • 28.Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004; 240: 205–213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Paugam-Burtz C, Janny S, Delefosse D, et al. Prospective validation of the “fifty-fifty” criteria as an early and accurate predictor of death after liver resection in intensive care unit patients. Ann Surg 2009; 249: 124–128. [DOI] [PubMed] [Google Scholar]
  • 30.von Elm E, Altman DG, Egger M, et al. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med 2007; 147: 573–577. [DOI] [PubMed] [Google Scholar]
  • 31.. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis - 2021 update. J Hepatol 2021; 75: 659–689. [DOI] [PubMed] [Google Scholar]
  • 32.George J, Lu Y, Tsuchishima M, et al. Cellular and molecular mechanisms of hepatic ischemia-reperfusion injury: the role of oxidative stress and therapeutic approaches. Redox Biol 2024; 75: 103258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Rokop ZP, Zhang W, Ghosh N, et al. Exacerbated ischemia-reperfusion injury in fatty livers is mediated by lipid peroxidation stress and ferroptosis. Surgery 2024; 175: 1539–1546. [DOI] [PubMed] [Google Scholar]
  • 34.Wang H, Mehal W, Nagy LE, et al. Immunological mechanisms and therapeutic targets of fatty liver diseases. Cell Mol Immunol 2021; 18: 73–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Hu H, Wu D, Xu J, et al. 366.7: NAFLD aggravates hepatic IR injury by inhibiting hepatocyte Nrf2 and activating macrophage STING signaling. Transplantation 2024; 108. [Google Scholar]
  • 36.Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, et al. AASLD Practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology 2023; 77: 1797–1835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Patel K, Sebastiani G. Limitations of non-invasive tests for assessment of liver fibrosis. JHEP Rep 2020; 2: 100067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD): executive summary. Diabetologia 2024; 67: 2375–2392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Bhayani NH, Hyder O, Frederick W, et al. Effect of metabolic syndrome on perioperative outcomes after liver surgery: a national surgical quality improvement program (NSQIP) analysis. Surgery 2012; 152: 218–226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Chu MJ, Hickey AJ, Phillips AR, et al. The impact of hepatic steatosis on hepatic ischemia-reperfusion injury in experimental studies: a systematic review. Biomed Res Int 2013; 2013: 192029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.d'Assignies G, Fayard C, Leitao H, et al. Liver steatosis assessed by preoperative MRI: an independent risk factor for severe complications after major hepatic resection. Surgery 2016; 159: 1050–1057. [DOI] [PubMed] [Google Scholar]

Associated Data

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Supplementary Materials

sj-docx-1-imr-10.1177_03000605261464004 - Supplemental material for Threshold-based association between controlled attenuation parameter–defined hepatic steatosis and hepatectomy-associated ischemia–reperfusion injury: A retrospective cohort study
sj-docx-1-imr-10.1177_03000605261464004.docx (33.5KB, docx)

Supplemental material, sj-docx-1-imr-10.1177_03000605261464004 for Threshold-based association between controlled attenuation parameter–defined hepatic steatosis and hepatectomy-associated ischemia–reperfusion injury: A retrospective cohort study by Yiyun Gao, Ye Zhang, Jian Xu, Jinguo Xia, Wenyu Shao and Haoming Zhou in Journal of International Medical Research

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