Simon A.W.G. Dello

Are sarcopenia, obesity and sarcopenic obesity predictive of outcome in patients with colorectal liver metastases?

BACKGROUND The impact of body composition on outcomes after surgery for colorectal liver metastases (CRLM) remains unclear. The aim of the present study was to determine the influence of sarcopenia, obesity and sarcopenic obesity on morbidity, disease-free (DFS) and overall survival (OS). METHOD Between 2005 and 2012, all patients undergoing a partial liver resection for CRLM in the Maastricht University Medical Centre, and who underwent computed tomography (CT) imaging within 3 months before liver surgery, were included. Body composition was primarily based on pre-operative CT measurements. Sarcopenia was based on total muscle area at the level of the third lumbar vertebra and predefined body mass index (BMI)- and gender-specific cut-off values for sarcopenia were used. Body fat percentages were calculated and the top 40% for men and women were considered obese. RESULTS Of the 171 included patients undergoing liver surgery for CRLM, 80 (46.8%) patients were sarcopenic, 69 (40.4%) obese and 49 (28.7%) sarcopenic obese. The presence of sarcopenia, obesity or sarcopenic obesity did not affect the complication rates. However, readmission rates were significantly increased in patients with (sarcopenic) obesity (P < 0.05). Surprisingly, obesity seemed to prolong OS (P = 0.021) and was identified as an independent predictor [hazard ratio (HR):0.58 and P = 0.046] for better OS. Sarcopenia and sarcopenic obesity did not affect DFS or OS. CONCLUSION Sarcopenia, obesity and sarcopenic obesity did not worsen DFS, OS and complication rates after a partial liver resection for CRLM.

Sarcopenia negatively affects preoperative total functional liver volume in patients undergoing liver resection.

OBJECTIVES Sarcopenia may negatively affect short-term outcomes after liver resection. The present study aimed to explore whether total functional liver volume (TFLV) is related to sarcopenia in patients undergoing partial liver resection. METHODS Analysis of total liver volume and tumour volume and measurements of muscle surface were performed in patients undergoing liver resection using OsiriX(®) and preoperative computed tomography. The ratio of TFLV to bodyweight was calculated as: [TFLV (ml)/bodyweight (g)]*100%. The L3 muscle index (cm(2) /m(2) ) was then calculated by normalizing muscle areas (at the third lumbar vertebral level) for height. RESULTS Of 40 patients, 27 (67.5%) were classified as sarcopenic. There was a significant correlation between the L3 skeletal muscle index and TFLV (r= 0.64, P < 0.001). Median TFLV was significantly lower in the sarcopenia group than in the non-sarcopenia group [1396 ml (range: 1129-2625 ml) and 1840 ml (range: 867-2404 ml), respectively; P < 0.05]. Median TFLV : bodyweight ratio was significantly lower in the sarcopenia group than in the non-sarcopenia group [2.0% (range: 1.4-2.5%) and 2.3% (range: 1.5-2.5%), respectively; P < 0.05]. CONCLUSIONS Sarcopenic patients had a disproportionally small preoperative TFLV compared with non-sarcopenic patients undergoing liver resection. The preoperative hepatic physiologic reserve may therefore be smaller in sarcopenic patients.

Randomized controlled trial analyzing the effect of 15 or 30 min intermittent Pringle maneuver on hepatocellular damage during liver surgery

BACKGROUND & AIMS Aminotransferases are commonly used to determine the optimal duration of ischemic intervals during intermittent Pringle maneuver (IPM). However, they might not be responsive enough to detect small differences in hepatocellular damage. Liver fatty acid-binding protein (L-FABP) has been suggested as a more sensitive marker. This randomized trial aimed to compare hepatocellular injury reflected by L-FABP in patients undergoing liver resection with IPM using 15 or 30 min ischemic intervals. METHODS Twenty patients undergoing liver surgery were randomly assigned to IPM with 15 (15IPM) or 30 (30IPM) minutes ischemic intervals. Ten patients not requiring IPM (noIPM) served as controls. Primary endpoint was hepatocellular injury during liver surgery reflected by systemic L-FABP plasma levels. Between group comparisons were performed using area under the curve and repeated measures two-way ANOVA. RESULTS The IPM groups had similar characteristics. Aminotransferases did not differ significantly between 15IPM and 30IPM at any time point. L-FABP levels rose up to 1853±708 ng/ml in the 15IPM and 3662±1355 ng/ml in the 30IPM group after finishing liver transection and decreased rapidly thereafter. There were no significant differences between 15IPM and 30IPM in cumulative L-FABP level (p=0.378) or L-FABP level at any time point (p=0.149). Blood loss, remnant liver function and morbidity were comparable. CONCLUSIONS IPM with 15 or 30 min ischemic intervals induced similar hepatocellular injury measured by the sensitive marker L-FABP. The present study confirms the results of earlier trials, suggesting that IPM with 30 min ischemic intervals may be used.

Total intermittent Pringle maneuver during liver resection can induce intestinal epithelial cell damage and endotoxemia.

Objectives The intermittent Pringle maneuver (IPM) is frequently applied to minimize blood loss during liver transection. Clamping the hepatoduodenal ligament blocks the hepatic inflow, which leads to a non circulating (hepato)splanchnic outflow. Also, IPM blocks the mesenteric venous drainage (as well as the splenic drainage) with raising pressure in the microvascular network of the intestinal structures. It is unknown whether the IPM is harmful to the gut. The aim was to investigate intestinal epithelial cell damage reflected by circulating intestinal fatty acid binding protein levels (I-FABP) in patients undergoing liver resection with IPM. Methods Patients who underwent liver surgery received total IPM (total-IPM) or selective IPM (sel-IPM). A selective IPM was performed by selectively clamping the right portal pedicle. Patients without IPM served as controls (no-IPM). Arterial blood samples were taken immediately after incision, ischemia and reperfusion of the liver, transection, 8 hours after start of surgery and on the first post-operative day. Results 24 patients (13 males) were included. 7 patients received cycles of 15 minutes and 5 patients received cycles of 30 minutes of hepatic inflow occlusion. 6 patients received cycles of 15 minutes selective hepatic occlusion and 6 patients underwent surgery without inflow occlusion. Application of total-IPM resulted in a significant increase in I-FABP 8 hours after start of surgery compared to baseline (p<0.005). In the no-IPM group and sel-IPM group no significant increase in I-FABP at any time point compared to baseline was observed. Conclusion Total-IPM in patients undergoing liver resection is associated with a substantial increase in arterial I-FABP, pointing to intestinal epithelial injury during liver surgery. Trial Registration ClinicalTrials.gov NCT01099475

Gut and liver handling of interleukin-6 during liver resection in man

BACKGROUND Plasma interleukin-6 (IL-6) levels increase during liver resection. The source of this IL-6 is hitherto unclear. It has been demonstrated that the hepatosplanchnic area takes up IL-6 but the role of the gut and liver is unknown. The aim of the present study was to investigate the role of the gut and liver in IL-6 homeostasis during liver surgery. METHODS Before and after partial hepatectomy, IL-6 was measured in blood sampled from the radial artery, and the hepatic and portal vein. Blood flow was measured to assess IL-6 fluxes (flow times AV-differences) across the gut, liver and hepatosplanchnic area. RESULTS In 22 patients undergoing liver resection, IL-6 release from the gut after transection was 90.9 (30.1) ng/min (P < 0.001), whereas net IL-6 uptake by the liver equalled 83.4 (41.7) ng/min (P < 0.01). Overall hepatosplanchnic flux was 7.3 (43.5) ng/min after transection and did not differ significantly from zero. Overall hepatosplanchnic flux was 87.8 (41.5) ng/min in the major resection group and -59.8 (67.5) ng/min in the minor resection group (P < 0.05). DISCUSSION The gut releases IL-6 and the liver takes up IL-6 before and after liver resection. The loss of IL-6 uptake as a result of a small functional remnant liver could lead to higher IL-6 levels after surgery.

Ophthalmate detection in human plasma with LC-MS-MS.

Based on animal experimentations, ophthalmate (OPH) has recently been suggested as a potential plasma biomarker to probe hepatic GSH homeostasis. Up until now, the inability to accurately determine OPH concentrations in human plasma prohibited further studies of OPH metabolism in humans. This study therefore aimed to study the influence of delayed sample preparation on OPH concentrations using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Venous plasma samples from 5 healthy human volunteers were incubated for varying times (5, 30, 60 and 120 min) at temperatures of 4 °C and 37 °C to investigate potential enzymatic degradation. At 37 °C, the decrease in OPH reached significance after 120 min (74.6% (range: 56.2-100.0%; p<0.0001)). At 4 °C, the same trend was observed but did not reach significance. These findings indicate ongoing enzymatic activity, stressing the need for immediate sample deproteinization to obtain reliable plasma concentrations. To investigate the feasibility of the here developed method, baseline arterial plasma values of 21 patients scheduled for partial liver resection were determined to be 0.06±0.03 μmol/l (mean±s.d.). In addition, in pooled samples from 3 patients, an OPH calibration curve was spiked to arterial plasma, arterial whole blood and liver biopsy material, resulting in a linear calibration curve in all cases. Individual measurements of baseline samples revealed that both arterial whole blood and liver biopsy material contained significant levels of endogenous OPH, namely 16.1 (11.8-16.4) μmol/l and 80.0 (191.8-349.2) μmol/kg, respectively. In conclusion, the present LC-MS/MS assay enables the accurate measurement of OPH in human plasma, whole blood and liver biopsies. Freshly prepared samples and immediate deproteinization are mandatory to block enzymatic degradation.