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An inadequate volume of future liver remnant (FLR) remains an absolute contraindication to liver resection. FLR measurement correlates with surgical outcome and is fundamental to identify those patients that may benefit from portal vein embolization (PVE) and to assess the liver volume change post-embolization. Therefore, preoperative volumetric analysis of the FLR has become a fundamental component of surgical planning to ensure adequate residual liver volume and, consequently to reduce the risk of postoperative liver failure. This review describe the rationale for FLR measurement, methods of measuring FLR volume, and indications for portal vein embolization based on liver volumetry are also summarized.
Indications for liver surgery in patients with primary and metastatic malignancies have been significantly revised over the course of the last decade (1-2). Criteria for resectability have been expanded over the last few years to include any patient in whom all disease can be resected with a negative margin and who has adequate residual liver volume (2-3). Instead of defining the resectability by what is removed, assessment of resectability now depend on what will remain after resection. As a consequence the assessment of the functional remnant liver is essential to avoid postoperative liver insufficiency which remains the most potentially serious and limiting complication of liver resection (4). Various tools have been proposed to predict the functional remnant liver function (5). These include biochemical tests based on hepatic clearance of compounds and volumetric studies based on radiological imaging. Biochemical tests, used commonly in Eastern countries, have been developed to assess liver function in patients with chronic liver disease, and as such they reflect the function of the entire liver, rather than the function of the anticipated liver remnant (6-7). Measurement of future liver remnant (FLR) mainly based on computed tomography (CT) analysis has become popular to estimate the risk of postoperative hepatic insufficiency in patients undergoing major or extended liver resections (8-16). FLR measurement correlates with surgical outcome, as shown by studies in which patients with smaller FLR volumes had more complications (8,9,11,14-16). Furthermore, liver volumetry is fundamental to identify those patients that may benefit from portal vein embolization (PVE) and to assess the liver volume change post-embolization (17). The aims of this review are to describe the rationale for FLR measurement, methods of measuring FLR volume, and indications for portal vein embolization based on liver volumetry.
An online search of the Medline database was undertaken using the keywords 'liver volumetry', future liver remnant', 'residual liver volume', and 'portal vein embolization' in various combinations. No date or language restriction was used. Manual cross-referencing was performed.
Rationale for preoperative liver volume assessment
Based on improved perioperative mortality and survival results, the frontiers of liver surgery are extending towards more extended liver resections leaving smaller fractions of residual liver (1-2). Despite recent improvements in surgical and anaesthetic techniques, liver surgery is still accompanied by a certain risk of postoperative liver failure, which remains the most important cause of mortality and prolonged hospital stay after major liver resection (4).
Although many variables influence the risk of postoperative hepatic insufficiency, the preoperative evaluation of the FLR volume represents the most important predictor of postoperative liver failure. Inadequate reserve in the remaining liver leads to a decrease in liver function, inability to regenerate, and progression to liver failure (5). Several studies have demonstrated that FLR volume serves as a predictor of the remnant liver function (8-16). FLR volume is related to the risk of liver dysfunction after hepatectomy (10-15) and postoperative peak bilirubin concentration and prothrombin time (12,14). Hence, FLR volume is used as a surrogate for altered risk of postoperative liver failure. This rationale is also based on data indicating that the increase in FLR volume following PVE is associated with improvement in liver function (18-19).
Moreover, FLR measurement correlates with morbidity, as reported by studies in which patients with smaller FLR volumes had more complications (11,15, 20-21). Loss of hepatic phagocytes and reduced synthesis of proteins involved in antigen recognition are considered to be responsible for the increase susceptibility to infections following extended liver resection (22-23). Schindl et al. found a significant relation between the extent of liver resection, FLR volume, and the incidence of postoperative infection. However, a precise FLR volume to predict the risk of infective complications could not be defined (15). Owing to the high individual variability in the ratio of respective liver segments, volumetric evaluation of the FLR is essential to avoid postoperative hepatic insufficiency following liver resection. In Western patients without underlying disease, the right liver accounts for about two thirds (65%) of the total liver volume, and the left liver accounts for about one third (35%). The left lateral section (II+III liver segments) contributes about one sixth (16%) of the total liver volume (TLV) or about one half of the left liver volume. Segment IV contributes about 17% of the TLV, while the caudate lobe contributes for about 2% of the TLV (24). In a study from M. D. Anderson Cancer Centre, liver segment volumes were measured in 102 patients without underlying liver disease who underwent helical CT for pathologies unrelated to the liver or biliary tree (24). The authors reported a large degree of interpatient variability in liver volumes, with the right and left liver contributions to the TLV ranging from 49 to 82% and 17 to 49%, respectively. Remarkably, the left lateral section (II+III segments) comprised 5 to 27% of the TLV, representing â°¤ 20% of the TLV in > 75% of patients. These findings support the need for routine measurement of the future liver remnant in patients without underlying liver disease requiring an extended right hepatectomy, or in all patients with chronic liver disease scheduled to undergo resection of 2 or more segments. The FLR estimated preoperatively is the major determinant factor for PVE in addition to the clinical consideration of presence or absence of underlying liver disease (17). In patients with insufficient FLR, PVE increases the safety of resection and expands the indications for resection. In addition to absolute liver volume, hypertrophy of the FLR in response to embolization predicts outcome from hepatectomy (25). CT volumetry is also essential for assessment of liver volume change and planning of liver resection following PVE (17).
Methods for Future Liver Remnant Evaluation
Several methods for liver volume determination have been proposed, such as scintigraphy (26), ultrasound (27), computed tomography (8-13), and magnetic resonance imaging (28). However, following the initial report of Heymsfield et al. (29), CT volumetric evaluation became the most used method in the fields of liver resection (8-13) and transplantation (30-31).
Historically, CT measurements of liver volumes were inaccurate due to partial volume effect, variability with respiratory phases, and inter-observer variation (32). However, modern advances, including the development of helical and multiphasic CT (33) and the availability of software for 3D reconstruction (34), have reduced error rates for measuring liver volumes to < 5% (35). Three-dimensional CT volumetric evaluation is performed by first manually outlining the hepatic segmental contours of each slice, measuring the enclosed area, and multiplying the surface area by slice thickness to calculate the volume. Contrast-enhanced multiphasic CT is performed to help demarcate vessels that constitute the landmarks of the hepatic segments. Volumes of interest are the FRL, the liver to be resected, and that of the tumour. The radiologist responsible for the volumetric analysis manually outlines the area of interest on the computer screen (Figure 1.). Recently automatic and semi-automatic methods have been proposed for liver segmentation (36).
The most important information obtained through volumetry is the ratio of the TLV and the volume of the liver to be resected. To calculate this ratio, volumes of each tumour were measured and subtracted from the calculation to yield a ratio of the estimated total non-tumorous remnant liver as follows: (resected volume - tumour volume)/ (TLV - tumour volume) (37-38). This method has been demonstrated to be accurate to within 5% of the actual liver volumes (35). However, FLR calculated using this ratio can be misestimated in the case of large or multiple metastases, the volume of which must be subtracted from the TLV, or in the presence of areas of non-functional liver resulting from biliary or vascular obstruction (12). In addition, in patients undergoing portal vein embolization (PVE), the atrophy of the embolized liver may significantly influence the CT measured changes in TLV that follow the procedure (17). To reduce these difficulties, a standardized measurement of the TLV has been proposed, where total liver volume is estimated by a formula that closely correlates the volume measured by CT with the body surface area (BSA) or body weight in adult patients (30, 39). In 1995 Urata et al, introduced the concept of total estimated liver volume (TELV), based on the observation that in adults without chronic liver disease, liver volume correlates linearly with body size and weight (30). They compared CT volumetry in 96 Japanese children and young adults to generate a formula to calculate TELV based on body surface area (BSA). They also found that in subject > 16 years, the TELV correlated directly with body weight. A similar relationship was determined, using magnetic resonance imaging, in a study of 16 North American children (40). This formula has been applied to calculate the graft to TLV ratio for living related donor liver transplantation (41-42), and the FLR to TLV ratio before liver resection (12). However, this formula has not gained general acceptance in Western centres, and its accuracy has been questioned. In addition, body weight, rather than BSA, has been used to estimate graft volume before liver transplantation, particularly donor recipient weight ratio (43-44).
On applying the Urata equation to data from a large German population (n =1,365; 4-80 yr old) in whom TLV was measured at autopsy, Heinemann et al. found that the model underestimated the observed TLV by 323 cm3 greater than expected based on the Japanese formula (45). Also, a multicenter study of 292 North Americans/North Europeans by Vauthey et al. (14-90 yr old) reported underestimation of TLV using the Urata equation (39). The authors of this study developed a new linear model, based on BSA that included the additional effect of age. Pooled-sample regression analysis demonstrated that after adjusting for BSA, age and body mass index were not associated with TELV. A formula to estimate TELV based on BSA was determined, with TELV= 794+1267 x BSA. The authors found a consistently high degree of correlation between TELV and BSA at all participating centres, where different CT scanners and 3D reconstruction techniques were used. The validity of this formula was corroborated by its close correlation with two independent equations derived from Western autopsy studies (45-46) and by a meta-analysis that showed this formula to be the least biased of 12 different formulas and a precise method for TLV calculation (47).
The ratio of the CT- measured FLR volume to TELV based on BSA yields the standardized FLR (sFLR) volume. The sFLR provides a determination of the percentage of the TELV that will remain after hepatic resection. Standardized liver volumetry represents a simple, accurate, and reproducible approach that overcomes the drawbacks of the traditional methods for liver volumetry. In addition, in countries where obesity affects a high proportion of the population, such a method ensures that the patient's size is properly taken into consideration. However, it is still debated to which index the FLR volume should be standardized. In a recent study on 68 consecutive non-cirrhotic patients who underwent major hepatectomy after PVE, FLR volumes standardized to BSA or BW were compared to assess their ability to predict postoperative hepatic dysfunction after hepatic resection (48). The authors found excellent correlation between FLR standardized to BW versus BSA, with both methods similarly predictive of postoperative hepatic dysfunction.
Implications for PVE
In patients who are otherwise candidates for hepatic resection, an inadequate FLR may be the only obstacle to curative resection. In these cases, PVE has been proposed to induce hypertrophy of the remnant liver and to expand the indications for resection (25). However, there is no consensus on what constitutes a safe residual liver volume. Part of the disagreement is secondary to the variability of methods used for calculating the FLR and the lack of universally accepted definitions for liver failure. Besides the FLR volume, the underlying liver diseases such as, cholestasis, acute or chronic inflammation, steatosis, fibrosis, or cirrhosis must be considered, because these factors will contribute to how much future liver remnant is needed to decrease postoperative complications and liver failure. Shoup et al evaluated patients with non-cirrhotic livers undergoing hepatectomy for colorectal metastases (11). Using semi-automated contouring and volumetric analysis of preoperative scans, the FLR volume was calculated. For patients undergoing extended liver resection and with 25% or less of FLR volume, 90% developed liver failure as defined by increased bilirubin and prothrombin time compared with patients with >25% of liver remaining after extended liver resection. Schindl et al. identified a critical FLR of 26.6% for safe hepatectomies in patients with normal liver (15), a similar critical FLR (26.5%) was recently calculated by Ferrero et al (14). However different definitions of liver dysfunction were used in all these studies.
When standardized FLR was considered, a FLR/BW ratio of =0.4 and FLR/TLV of =20% provided equivalent thresholds for performing safe hepatic resection (48). In a study from Vauthey et al, in which selection for hepatic resection was based on a sFLR value of >20%, 127 patients with colorectal liver metastases were able to undergo extended hepatectomy with a morbidity rate of 31% and a near zero mortality (0.7%) (49).
The same group has recently analyzed a large series of consecutive patients after extended right hepatectomy. Among 290 patients who underwent liver volumetry, sFLR was <20% in 38 patients, 20.1% to 30% in 144, and >30% in 108. Rates of postoperative liver insufficiency and death from liver failure were similar between patients with sFLR 20.1% to 30% and sFLR >30% but higher in patients with sFLR <20% (50). In general, PVE only needs to be considered in patients with normal liver when an extended right hepatic resection is anticipated; PVE is rarely necessary prior to extended left hepatectomy because the right posterior sector typically constitutes about 30% of the total liver volume (24,51). The safe FLR in patients with chronic liver disease is less clear. Unlike patients affected by metastatic cancer or benign liver diseases, patients with hepatocellular carcinoma or obstructing tumors may have underlying chronic liver disease or cholestasis with impaired liver function (2,5,7, 52). Yamanaka and colleagues demonstrated that the residual liver volume measured by CT was a significant predictor for postoperative liver failure in patients with underlying liver disease (16). Kubota et al proposed that in patients with an ICG-R15 between 10% and 20% the resections <50% of non-tumorous liver volume was acceptable. They recommended that when the volume of non-tumorous parenchyma to be resected is >60% with a concomitant ICGR-15 of 10% to 20%, PVE should be considered to increase the volume of residual liver (37). Shirabe et al. identified a critical residual liver volume of 250 mL/m2 for safe liver resection in patients with underlying hepatitis. In patients with residual liver volume of less than 250 mL/ m2 the presence of diabetes mellitus was an important risk factor of liver failure.
However, CT may be inaccurate in cirrhotic patients because of enlarged or shrunken livers and does not provide a reliable assessment of the severity of cirrhosis (2,5,52). Tu et al. have recently proposed a quantitative assessment of hepatic functional reserve in cirrhotic patients by combining CT volumetry with 4 grades of liver cirrhosis severity based-on CT imaging (53). The authors found that the combination of these two parameters provide a better evaluation of hepatic functional reserve.
The presence of cholestasis is also associated with higher risk of postoperative liver dysfunction. Suda et al. analyzed a series of 111 patients the majority of whom suffered from obstructive jaundice who underwent extended hepatic resection for biliary tract malignancies (54). The authors reported that the extent of liver that can be safely resected is limited in the case of cholestatic liver, even after this condition is relieved. A FLR <40% was associated to significantly increased postoperative liver dysfunction and PVE should be considered. In cases of chronic liver disease, Farges et al. recommend PVE in all patients before right hepatectomy, the argument being a reduction in postoperative complications and liver failure, and decreasing the postoperative hospital stay (55). The authors performed a prospective study of PVE in patients undergoing right hepatectomy for either metastatic liver disease or primary liver cancer. They reported significantly fewer complications in patients with chronic liver disease and FLR < 40% when PVE was used to increase the FLR volume. In contrast, there was no benefit from PVE in patients with normal liver function who underwent a right hepatectomy. The minimum FLR that must remain after resection in patients with various types of chemotherapy-related liver injury remains poorly defined. An early study proposed a ratio of at least 40% of FLR to minimise postoperative complications in patients who have received high-dose chemotherapy (56). Ferrero et al have indicated a minimal FLR of 35.3% in patients with neoadjuvant chemotherapy (14). While a more recently study found that preoperative chemotherapy was not a risk factor for hepatic insufficiency, and outcomes were not different between patients with and without PVE as long as preoperative sFLR was >20% (50). Patients with high BMI, diabetes, and/or metabolic syndrome are at risk for steatohepatitis and impaired liver regeneration and thus may have a similar or even higher FLR requirement, but more precise criteria should be defined for these populations. Liver function is decreased in patients with underlying liver disease. Therefore, one can argue that determining the synthetic functionality of the residual liver is more important than determining the volume, especially in patients with parenchymal disease. Dinant et al. have recently reported that for assessing the risk of liver failure after liver resection, the preoperative measurement of 99mTc-mebrofenin uptake in the remnant liver on hepatobiliary scintigraphy proved more valuable than measurement of the FRL on CT (57). However, physiological studies can be also used to complement volumetric study to estimate liver function. Kubota et al. proposed indocyanine green retention at 15 minutes, in conjunction with the extent of planned resection (37). More recently, Stockmann et al. have proposed determination of liver function based on combination of C-methacetin kinetics and CT volumetry (58). Many biochemical tests have been evaluated, but their role seem limited as an adjunct to the necessary CT volumetry especialy when the underlying liver is compromised. Guidelines have been proposed regarding the minimal residual liver volume, based on multiple studies demonstrating a correlation between FLR and postoperative outcome. PVE is indicated when the FLR volume is 20 per cent or less of the total liver volume (TLV) in patients with normal liver, 30 per cent or less of the TLV in patients who have had extensive chemotherapy, and 40 per cent or less of the TLV in patients with well compensated cirrhosis (1) (Fig. 2).
Assessment of the liver volume change following PVE
CT volumetry it is also essential to assess the hyperthrophic response following PVE. After right PVE in patients without cirrhosis, an 30-80% absolute increase in volume of the non-embolized liver and 6-10% increase in the FLR/TLV ratio occur during the first 3 weeks followed by a plateau during which the FLR volume increased only slightly (10,59). In patients with chronic liver disease the rate of liver regeneration is slower (55). Patients who show slow liver growth and those with small FLRs after 3 weeks are unlikely to experience rapid growth beyond this time point (59). More important than FLR seems to be the degree of hypertrophy (DH) defined as the difference between the sFLR before and after PVE, this measurement provides a dynamic, time-dependent variable, and it should be taken into account when planning treatment. Ribero et al. in a study of 112 patients who underwent PVE, reported that patients with a DH of not more than 5 per cent had a significantly higher risk of overall, major and liver-related complications, hepatic dysfunction and mortality (59). This study demonstrated the importance of the hypertrophic response of the liver to PVE, and the value of DH as predictors of postoperative liver failure. However, the cut-off values in this study were determined in patients with normal or moderate hepatic injury and further studies are necessary in patients with cirrhosis or hepatic injury from extensive chemotherapy.
An inadequate residual liver volume remains an absolute contraindication to liver resection.
Therefore, preoperative volumetric analysis of the FLR has become a fundamental component of surgical planning to ensure adequate residual liver volume and, consequently to reduce the risk of postoperative liver failure. Owing to the high individual variability in the ratio of respective liver segments, volumetric evaluation of the FLR is essential in patients without underlying liver disease requiring an extended right hepatectomy, or in all patients with chronic liver disease scheduled to undergo right hepatectomy. Standardized liver volumetry represents a simple straightforward method to estimate the FLR volume and postoperative function that overcomes the pitfalls associated with the traditional methods of measuring liver volumes.
Figure 1: CT measurement of the future liver volume remnant (NOT definitive)
Figure 2: Surgical decision of appropriateness of PVE based on CT volumetric analysis.
DH: degree of hypertrophy of the FLR before and after PVE.
Table 1: Studies Analyzing the Impact of Remnant Liver Volume on Postoperative Course