Lisette T. Hoekstra

Physiological and biochemical basis of clinical liver function tests: a review

Objective:To review the literature on the most clinically relevant and novel liver function tests used for the assessment of hepatic function before liver surgery. Background:Postoperative liver failure is the major cause of mortality and morbidity after partial liver resection and develops as a result of insufficient remnant liver function. Therefore, accurate preoperative assessment of the future remnant liver function is mandatory in the selection of candidates for safe partial liver resection. Methods:A MEDLINE search was performed using the key words “liver function tests,” “functional studies in the liver,” “compromised liver,” “physiological basis,” and “mechanistic background,” with and without Boolean operators. Results:Passive liver function tests, including biochemical parameters and clinical grading systems, are not accurate enough in predicting outcome after liver surgery. Dynamic quantitative liver function tests, such as the indocyanine green test and galactose elimination capacity, are more accurate as they measure the elimination process of a substance that is cleared and/or metabolized almost exclusively by the liver. However, these tests only measure global liver function. Nuclear imaging techniques (99mTc-galactosyl serum albumin scintigraphy and 99mTc-mebrofenin hepatobiliary scintigraphy) can measure both total and future remnant liver function and potentially identify patients at risk for postresectional liver failure. Conclusions:Because of the complexity of liver function, one single test does not represent overall liver function. In addition to computed tomography volumetry, quantitative liver function tests should be used to determine whether a safe resection can be performed. Presently, 99mTc-mebrofenin hepatobiliary scintigraphy seems to be the most valuable quantitative liver function test, as it can measure multiple aspects of liver function in, specifically, the future remnant liver.

Tumor progression after preoperative portal vein embolization.

Objective:To evaluate tumor growth in a series of patients undergoing liver resection after portal vein embolization (PVE). Background:The regenerative response after PVE leading to compensatory hypertrophy of the nonembolized liver segments potentially enhances tumor growth. Methods:Portal vein embolization was performed in 28 patients diagnosed with colorectal metastases between 2004 and 2011. Tumor volume was measured by computed tomography (CT) volumetry before and after PVE. Tumor growth rate (TGR) was measured by CT volumetry and compared with that of a non-PVE control group with colorectal metastases of whom 30 had 2 CT scans preoperatively. Also, newly diagnosed tumors in the future remnant liver (FRL) after PVE and after resection were analyzed. Results:The median TGR of PVE patients was 0.53 mL/d (interquartile range [IQR], 0.02–1.88) versus 0.09 mL/d (IQR, −0.04 to 0.40; P = 0.03) in non-PVE patients. The TGR was 0.15 (IQR, −0.52 to 0.66) mL/d before PVE and 0.85 (IQR, −0.10 to 1.62) mL/d after PVE in the same patients (P = 0.03). Seven patients (25%) showed new tumor lesions in the FRL after PVE, of whom 3 patients (11%) were not resectable. Patients (8 of 19; 42%) after PVE also showed a higher rate of recurrent metastases in the remnant liver at follow-up than non-PVE patients (1 of 28; 4%). Survival was significantly better for non-PVE patients, with a 3-year survival rate of 77% versus 26% in patients undergoing PVE. Conclusions:Portal vein embolization is associated with increased TGR and new tumor in the FRL and recurrent tumor after resection. Short intervals and interval chemotherapy between PVE and resection are, therefore, advised.

Management of giant liver hemangiomas: an update

Liver hemangiomas are the most common benign liver tumors and are usually incidental findings. Liver hemangiomas are readily demonstrated by abdominal ultrasonography, computed tomography or magnetic resonance imaging. Giant liver hemangiomas are defined by a diameter larger than 5 cm. In patients with a giant liver hemangioma, observation is justified in the absence of symptoms. Surgical resection is indicated in patients with abdominal (mechanical) complaints or complications, or when diagnosis remains inconclusive. Enucleation is the preferred surgical method, according to existing literature and our own experience. Spontaneous or traumatic rupture of a giant hepatic hemangioma is rare, however, the mortality rate is high (36–39%). An uncommon complication of a giant hemangioma is disseminated intravascular coagulation (Kasabach–Merritt syndrome); intervention is then required. Herein, the authors provide a literature update of the current evidence concerning the management of giant hepatic hemangiomas. In addition, the authors assessed treatment strategies and outcomes in a series of patients with giant liver hemangiomas managed in our department.

Posthepatectomy Bile Leakage: How to Manage

Background: Biliary leakage after liver resection continues to be reported. Management of bile leakage has changed in recent years, with nowadays non-surgical procedures as the preferred treatment. Methods: Biliary leakage and management were assessed in 381 patients who underwent liver resection between January 2005 and April 2011. Results: The overall rate of biliary leakage after liver resection was 5.0%, with a higher incidence in patients who had undergone concomitant hepaticojejunostomy (HJ; 13.6 vs. 3.2%). Hospital stay (p = 0.047), major resections (p = 0.018), operation time (p = 0.011), and relaparotomy (p = 0.002) were risk factors for postoperative bile leakage. Multivariate analysis identified relaparotomy as an independent factor (OR 4.216, p = 0.034). Bile leakage in patients without HJ (n = 10) was managed in 6 patients by percutaneous transhepatic biliary drainage (PTD), and in 3 patients by endoscopic drainage. One patient was treated surgically. All patients with an HJ and postoperative bile leakage (n = 9) underwent PTD. Conclusion: The incidence of posthepatectomy biliary leakage has decreased over time, while PTD and endoscopic stenting are effective treatment modalities. PTD is the treatment of choice in bile leakage after resection combined with HJ.

Vascular Occlusion or Not during Liver Resection: The Continuing Story

Background: Vascular occlusion can be applied during liver resection to reduce blood loss. Herein, we provide an update of the current evidence concerning vascular occlusion. Methods: A systematic literature search was conducted to review the effects of liver in- and outflow occlusion techniques during liver resection, focusing on blood loss and hepatic ischemia-reperfusion injury. Results: The Pringle maneuver (PM) is effective in controlling blood loss; however, there is no indication for routine vascular clamping during hepatic resection in uncomplicated patients. During complex resections and in patients with abnormal liver parenchyma, the intermittent PM is preferred over continuous clamping. Total hepatic vascular exclusion (THVE) is indicated only in resection of tumors involving the inferior caval vein or the caval hepatic junction. THVE can be applied with the preservation of caval vein flow. This mode of selective hepatic vascular exclusion results in less blood loss in combination with the PM. Conclusion: If clamping is necessary during complex resections or in abnormal liver parenchyma, intermittent PM is advised. THVE or selective hepatic vascular exclusion may be considered in tumors involving the inferior caval vein or the caval hepatic junction. There is no evidence supporting the use of ischemic preconditioning, maintenance of a low central venous pressure or of pharmacological interventions during liver resection.

Accurate Quantitation of Ki67-positive Proliferating Hepatocytes in Rabbit Liver by a Multicolor Immunohistochemical (IHC) Approach Analyzed with Automated Tissue- and Cell-Segmentation Software

Determination of hepatocyte proliferation activity is hampered by the presence of Ki67-positive non-parenchymal cells. We validated a multicolor immunohistochemical (IHC) approach using multispectral tissue and cell segmentation software. Portal vein branches to the cranial liver lobes of 10 rabbits were embolized, leading to atrophy of the cranial lobes and hyperplasia of the caudal lobes. Slides from cranial and caudal lobes (n=20) were double-stained (CK8+18 and Ki67) and triple-stained (CK8+18, Ki67, and CD31). The Ki67 proliferation index was calculated using automated tissue and cell segmentation software and compared with manual counting by two independent observers. A substantial variation was seen in the number of Ki67-positive hepatocytes in the different specimens in both double and triple staining (range, 0–50). Correlation coefficients between manual counting and the digital analysis were 0.76 for observer 1 (p<0.001) and 0.78 for observer 2 (p<0.001) with double staining and R2 = 0.91 for observer 1 and R2 = 0.89 for observer 2, p<0.001 with triple staining. In conclusion, in rabbit, the hepatocellular proliferation index can be reliably determined using automated tissue and cell segmentation software in combination with IHC multiple staining. Our findings may be useful in clinical practice when Ki67 proliferation index yields prognostic significance.

Effects of Prolonged Pneumoperitoneum on Hepatic Perfusion During Laparoscopy

Objective: To assess the influence of prolonged pneumoperitoneum (PP) on liver function and perfusion in a clinically relevant porcine model of laparoscopic abdominal insufflation. Background: PP during laparoscopic surgery produces increased intra-abdominal pressure, which potentially influences hepatic function and microcirculatory perfusion. Methods: Six pigs (49.6 ± 5.8 kg) underwent laparoscopic intra-abdominal insufflation with 14 mm Hg CO2 gas for 6 hours, followed by a recovery period of 6 hours. Two animals were subjected to 25 mm Hg CO2 gas. Hemodynamic parameters were monitored, and damage parameters in the blood were measured to assess liver injury. Liver total blood flow and function were determined by the indocyanine green (ICG) clearance test. Intraoperative hepatic hemodynamics were measured by simultaneous reflectance spectrophotometry (venous oxygen saturation StO2 and relative tissue hemoglobin concentration rHb) and laser Doppler flowmetry (blood flow and flow velocity). Postmortem liver samples were collected for histological evaluation. Results: A decrease in microvascular perfusion was observed during PP. After 6 hours of PP, ICG clearance increased (P < 0.001), indicating a compensatory improvement of overall liver blood flow resulting in concomitantly improved microcirculatory perfusion (P = 0.024). Minimal parenchymal damage (aspartate aminotransferase) of the liver was seen after 6 hours of PP (P = 0.006), which seemed related to PP pressure. Minor histological damage was observed. Conclusions: The liver sustains no additional damage due to prolonged PP during laparoscopic surgery. Our findings suggest that prolonged PP does not hamper liver function or cause liver damage after extended laparoscopic procedures.

Initial Experiences of Simultaneous Laparoscopic Resection of Colorectal Cancer and Liver Metastases

Introduction. Simultaneous resection of primary colorectal carcinoma (CRC) and synchronous liver metastases (SLMs) is subject of debate with respect to morbidity in comparison to staged resection. The aim of this study was to evaluate our initial experience with this approach. Methods. Five patients with primary CRC and a clinical diagnosis of SLM underwent combined laparoscopic colorectal and liver surgery. Patient and tumor characteristics, operative variables, and postoperative outcomes were evaluated retrospectively. Results. The primary tumor was located in the colon in two patients and in the rectum in three patients. The SLM was solitary in four patients and multiple in the remaining patient. Surgical approach was total laparoscopic (2 patients) or hand-assisted laparoscopic (3 patients). The midline umbilical or transverse suprapubic incision created for the hand port and/or extraction of the specimen varied between 5 and 10 cm. Median operation time was 303 (range 151–384) minutes with a total blood loss of 700 (range 200–850) mL. Postoperative hospital stay was 5, 5, 9, 14, and 30 days. An R0 resection was achieved in all patients. Conclusions. From this initial single-center experience, simultaneous laparoscopic colorectal and liver resection appears to be feasible in selected patients with CRC and SLM, with satisfying short-term results.

Bile salts predict liver regeneration in rabbit model of portal vein embolization

BACKGROUND Portal vein embolization (PVE) is employed to increase future remnant liver (FRL) volume through induction of hepatocellular regeneration in the nonembolized liver lobe. The regenerative response is commonly determined by CT volumetry after PVE. The aim of the study was to examine plasma bile salts and triglycerides in the prediction of the regenerative response following PVE. METHODS PVE of the cranial liver lobe was performed in 15 rabbits, divided into three groups: NaCl (control), gelatin sponge (short-term occlusion), and polyvinyl alcohol particles with coils (PVAc, long-term occlusion). In all rabbits CT volumetry and blood sampling were performed prior to PVE and on days 3 and 7. Plasma bile salts and triglycerides were correlated with volume increase of the nonembolized liver lobe. RESULTS After 3 and 7 d, respectively, FRL volume was increased in both embolized groups, with the largest hypertrophy response observed in the PVAc group. Plasma bile salt levels were increased after PVE, especially in the PVAc group at day 3 (P < 0.01 compared to gelatin sponge). Plasma bile salts at day 3 predicted FRL volume increase at day 7 showing a positive correlation of 0.811 (P < 0.001). Levels of triglycerides were not significantly altered in either of the PVE procedures. CONCLUSIONS Plasma bile salt levels early after PVE strongly correlated with the regenerative response in a rabbit model of PVE, showing more pronounced elevation with larger volume increase of the nonembolized lobe. Therefore, plasma bile salts, but not triglycerides, can be used in the prediction of the regenerative response after PVE.

Predictors of posthepatectomy ascites with or without previous portal vein embolization.

Aim: To identify predictors of postoperative ascites after liver resection for patients with or without preoperative portal vein embolization (PVE). Methods: Patients undergoing PVE prior to hepatectomy (PVE group; n = 37) were compared with patients who underwent liver resection without PVE (n = 503). Ascites was defined as postoperative daily drainage of clear ascitic fluid exceeding 200 ml/day. Pre-, intra-, and postoperative variables were retrospectively analyzed using uni- and multivariate analyses. Results: Postoperative ascites was present in 13.5% (5/37) of patients who underwent PVE before hepatectomy, compared to 5.8% (29/503) in the group undergoing liver resection without PVE (p = 0.061). In all patients, cirrhosis (OR 54.505, p < 0.001), operation time (OR 1.004, p = 0.014), and the use of the Pringle maneuver (OR 2.336, p = 0.041) were independent risk predictors for ascites in multivariate analysis. In PVE patients, cirrhosis (OR 0.156, p < 0.001) was the only independent significant predictor of ascites after resection. In patients undergoing liver resection without PVE, independent risk factors with multivariate analysis were operation time (OR 1.005, = 0.001) and cirrhosis (OR 26.609, p < 0.001). Conclusion: Operation time and the use of the Pringle maneuver were significant predictors of ascites after hepatectomy. Cirrhosis was a significant risk factor associated with postoperative ascites.