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Recovery from Liver Failure after Hepatectomy for Hepatocellular Carcinoma in Cirrhosis: Meaning of the Model for End-Stage Liver Disease
Recovery from Liver Failure after Hepatectomy for Hepatocellular Carcinoma in Cirrhosis: Meaning of the Model for End-Stage Liver Disease Alessandro Cucchetti, MD, Giorgio Ercolani, MD, Matteo Cescon, MD, Matteo Ravaioli, MD, Matteo Zanello, MD, Massimo Del Gaudio, MD, Augusto Lauro, MD, Marco Vivarelli, MD, Gian Luca Grazi, MD, Antonio Daniele Pinna, MD Hepatectomy for hepatocellular carcinoma in cirrhosis is followed by an impairment of liver function that can lead to patient death. The model for end-stage liver disease (MELD) is considered an index of hepatic functional reserve, and its assessment on postoperative course may properly identify individuals at risk of liver failure. STUDY DESIGN: Two hundred hepatectomies for hepatocellular carcinoma in cirrhosis were reviewed. Irreversible postoperative liver failure was defined as an impairment of liver function after hepatectomy that led to patient death or required transplantation. The MELD scores at postoperative days (POD) 1, 3, 5, and 7 were calculated and kinetics of changes investigated with t-test; logistic regression was applied to identify predictive variables of postoperative liver failure. RESULTS: Kinetics of postoperative MELD score showed an impairment of liver function between PODs 1 and 3; 185 patients in whom postoperative liver failure did not develop showed a considerable decrease in MELD score between PODs 3 and 5 (11.9 ⫾ 2.8 and 10.6 ⫾ 2.4, respectively, p ⬍ 0.001). On the contrary, 15 patients, who experienced the event, showed an increase in MELD score between PODs 3 and 5 (18.2 ⫾ 3.9 and 18.3 ⫾ 3.6, respectively; p ⫽ 0.845). Multivariate analysis showed preoperative MELD score (p ⬍ 0.001), major hepatectomy (p ⫽ 0.028), and MELD score increase between PODs 3 and 5 (p ⫽ 0.011) as independent predictors of irreversible postoperative liver failure. Scores are reported as mean ⫾ SD. CONCLUSIONS: Recovery from liver impairment after hepatectomy for hepatocellular carcinoma in cirrhosis starts from POD 3; MELD scores increasing between PODs 3 and 5 may identify patients at risk of liver failure and represents the trigger for beginning intensive treatment or evaluating salvage transplantation. (J Am Coll Surg 2006;203:670–676. © 2006 by the American College of Surgeons) BACKGROUND:
Hepatocellular carcinoma (HCC) represents one of the most common tumors worldwide and, in most instances, arises in patients with chronic underlying liver disease secondary to hepatitis B or C virus infection.1 Therapeutic strategies for early HCC include liver resection and liver transplantation, but in light of donor shortage, liver resection remains the most applied therapeutic approach in well-compensated cirrhotic patients, offering the chance for cure and providing longterm survival.2-6
In addition to the evaluation of tumor status, careful assessment of liver function reserve is critical in patient selection to avoid postoperative liver failure and mortality. Several approaches have been proposed to assess hepatic function reserve,7-10 but of all the tools, the ChildTurcotte-Pugh (CTP) classification11,12 remains the main indicator of the extent of resection that a cirrhotic liver can tolerate.13 The model for end-stage liver disease (MELD) was recently developed to predict the mortality of cirrhotic patients undergoing transjugular intrahepatic portosystemic shunts (TIPSS)14 and subsequently applied as a disease severity index for priority on the waiting list for liver transplantation.15,16 The MELD score can be considered an index of hepatic function, and recent reports demonstrated that the preoperative
Competing Interests Declared: None. Received April 26, 2006; Revised June 6, 2006; Accepted June 20, 2006. From the Department of Surgery and Transplantation, University of Bologna, Policlinico S Orsola-Malpighi, Bologna, Italy. Correspondence address: Alessandro Cucchetti, MD, Policlinico Sant’OrsolaMalpighi, University of Bologna, Via Massarenti, 9, 40138 Bologna, Italy.
© 2006 by the American College of Surgeons Published by Elsevier Inc.
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Abbreviations and Acronyms
CTP FFP HCC INR MELD OR POD
⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽
Child-Turcotte-Pugh fresh frozen plasma hepatocellular carcinoma international normalized ratio model for end-stage liver disease odds ratio postoperative day
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tients without histologic evidence of cirrhosis were excluded from the analysis, and only the 200 cirrhotic patients formed the final study group. Hepatic functional reserve was preoperatively rated using both the CTP score, according to the classification proposed by Pugh and Colleagues,12 and the MELD score, calculated according to the formula16: MELD ⫽ 共0.957 ⫻ Loge共creatinine in mg ⁄ dL兲 ⫹ 0.378
MELD score accurately predicts development of postoperative liver failure after hepatectomy for HCC in cirrhosis,17,18 but variations in the MELD score after liver resection have never been investigated. Several clinical and biochemical variables, namely ascites, jaundice, prolonged prothrombin time, increase of serum creatinine and bilirubin levels, and decrease of albumin serum level are typical markers of impaired liver function; in particular, serum bilirubin and prothrombin time are frequently altered in the early postoperative days after hepatectomy19; this condition allows postoperative assessment of the MELD score. The aim of this study was to evaluate the reliability and usefulness of the postoperative MELD score in the early prediction of liver failure after hepatectomy for HCC in cirrhotic patients; its relationship with other clinical and biochemical variables, known to affect surgical outcomes was also investigated. METHODS Between January 1997 and December 2005, 286 patients underwent curative hepatic resection for HCC in chronic liver disease at the Department of Surgery and Transplantation of the University of Bologna; the policy of our center about indications for hepatic resection has already been published.2 Of these patients, 34 were not included in the analysis for the following reasons: incomplete clinical data (27 patients), presence of chronic renal insufficiency that did not allow a reliable measurement of the MELD score (4 patients), and early postoperative death from acute myocardial infarction (2 patients) and pulmonary embolism (1 patient). In the 252 patients in the initial study group, fibrosis stage was scored on the resected specimen, according to the classification of Ishak and associates20 as cirrhosis versus noncirrhosis. Underlying histologically proved cirrhosis was present in 200 patients (79.4%) and chronic hepatitis without cirrhosis in 52 (20.6%). Pa-
⫻ Loge共bilirubin in mg ⁄ dL兲 ⫹ 1.12 ⫻ Loge共INR兲 ⫹ 0.643兲 ⫻ 10.
In particular, for calculation of both CTP and MELD scores, only biochemical values from the laboratory at our center were used. The extent of the hepatectomy referred to the International Hepato-Pancreato-Biliary Association (IHPBA) classification.21 All resections were performed to achieve a tumor-free margin of at least 1 cm based on intraoperative morphologic examination and ultrasonography. Major hepatic resection was defined as the removal of more than two segments. None of the patients forming this study group underwent preoperative portal vein embolization. Postoperative admission to the ICU was reserved for patients with cardiovascular or pulmonary comorbidities, those who underwent major hepatectomies, or those with severe intraoperative bleeding. Our policy about the use of postoperative fresh frozen plasma (FFP) was to avoid transfusions until the international normalized ratio (INR) value was higher than 1.50; occasionally, the sole presence of other clinical and biochemical signs of hepatic decompensation such as renal impairment or massive ascites, requiring drainage, led to the use of FFP. Transfusion occurred in a total of 41 patients (20.5%). The aim of this study was to investigate how the early kinetics of liver function tests correlated with the development of postoperative irreversible liver failure, defined as a growing impairment of liver function after hepatectomy that led to patient death or required transplantation. For this purpose, serum creatinine, bilirubin, and INR were sampled routinely on postoperative days (POD) 1, 3, 5, and 7, and the MELD score was calculated for each time point as previously described. The study protocol was in accordance with the Declaration of Helsinki and subsequent amendments.
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Statistical analysis
Continuous variables were expressed as mean and standard deviation. The postoperative course of the MELD score was investigated and reported in clustered multiple variable graphs; MELD scores at each time point considered were compared using the paired sample t-test and in subgroups using the independent t-test. Logistic regression was first applied to each single variable to identify their odds ratios in determining postoperative liver failure; variables that proved statistically significant in univariate analysis were entered in a forward conditional regression model to identify independent predictive variables of the event. A p value ⬍ 0.05 was considered significant in all analyses. Statistical analysis was done using the SPSS Version 10.0 software for PC computers (SPSS) and clustered multiple variable graphs were constructed using MedCalc Version 7.2.1.0 (MedCalc Software). RESULTS Baseline characteristics of the study population are shown in Table 1. Surgery consisted of minor hepatic resections in 191 patients (95.5%) and of major hepatic resections in the remaining 9 (4.5%). In particular, 108 wedge resections (54.0%), 56 segmentectomies (28.0%), 13 left lateral sectionectomies (6.5%), 7 right posterior sectionectomies (3.5%), 4 right anterior sectionectomies (2.0%), 3 left medial sectionectomies plus segmentectomy 8 (1.5%), 6 left hepatectomies (3.0%), and 3 right hepatectomies (1.5%) were performed. Developed in 15 patients (7.5%). Irreversible postoperative liver failure. Of these, four patients were successfully treated with liver transplantation, resulting in an overall mortality for postoperative liver failure of 5.5%. Mean time from operation to patient death or liver transplantation was 59.4 ⫾ 48.6 days (range ⫽ 14 to 166 days). Ten of 15 patients were classified as CTP class A and 7 underwent a minor hepatectomy (3 wedge resections, 1 segmentectomy, and 3 right posterior sectionectomies); in the remaining 3 patients, who underwent major hepatectomy, 2 left hepatectomies and 1 right hepatectomy were performed. The other five patients, classified as CTP class B, underwent a minor hepatectomy in all cases: three wedge resections and two segmentectomies were performed. All patients were treated early with FFP transfusion starting from POD 1 or POD 3; the mean number of units of FFP adminis-
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Table 1. Baseline Characteristics of the Study Population Variables
Age, y Range ⬎ 65, n (%) Male gender, n (%) Hepatitis serology, n (%) Hepatitis C Hepatitis B Hepatitis B ⫹ C Negative Presence of esophageal varices, n (%) Presence of mild ascites, n (%) Serum albumin, g/dL Platelet count, ⫻103/mm3 Serum creatinine, mg/dL Serum bilirubin, mg/dL International normalized ratio Aspartate aminotransferase, IU/L Aspartate aminotransferase ⬎ 2N, n (%) CTP score Range CTP Class A, n (%) CTP Class B, n (%) MELD score MELD score ⱖ 11, n (%) Size of the largest tumor, cm Solitary tumor, n (%) Extent of hepatectomy, n (%) Subsegmentectomy (wedge) Segmentectomy Bisegmentectomy Major resection Intraoperative RBC transfusion, U
Patients in study (n ⴝ 200)
63.9 ⫾ 8.9 101 (50.5) 153 (76.5) 133 (66.5) 34 (17.0) 11 (5.5) 22 (11.0) 54 (27.0) 10 (5.0) 3.8 ⫾ 0.4 138 ⫾ 69 0.96 ⫾ 0.24 0.97 ⫾ 0.50 1.16 ⫾ 0.10 84.4 ⫾ 69.9 92 (46.0) 5.4 ⫾ 0.6 188 (94.0) 12 (6.0) 8.8 ⫾ 1.6 30 (15.0) 4.2 ⫾ 2.3 171 (85.5) 108 (54.0) 56 (28.0) 27 (13.5) 9 (4.5) 0.56 ⫾ 1.1
Continuous variables are reported in mean and standard deviation. CTP, Child-Turcotte-Pugh; INR, international normalized ratio; MELD, model for end-stage liver disease.
tered until death or transplantation was 0.86 ⫾ 0.24 per day. Kinetics of postoperative MELD score
We first analyzed kinetics of the MELD scores of 185 patients in whom irreversible postoperative liver failure did not develop after hepatectomy (Fig. 1). Postoperative MELD score reached a maximum on POD 3 (11.9 ⫾ 2.8), slightly higher than that on POD 1 (11.8 ⫾ 2.3; p ⫽ 0.594) and considerably higher than the preoperative score (8.6 ⫾ 1.3; p ⬍ 0.001 in both cases). On POD 5, we observed a considerable reduction
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Predictive factors of liver failure
Figure 1. Postoperative course of model for end-stage liver disease score (mean ⫾ standard deviation) at different time points of patients who did not experience postoperative liver failure (continuous line) and of patients who experienced irreversible postoperative liver failure (dotted line). POD, postoperative day.
in MELD score compared with that on POD 3 (10.6 ⫾ 2.4; p ⬍ 0.001), and on POD 7 the MELD score reached a minimum (10.1 ⫾ 2.3; p ⬍ 0.001 in comparison with POD 5), but was still higher than the preoperative value (p ⬍ 0.001). In 26 of 185 patients (14%), FFP was administered during the postoperative course; all of these patients received transfusion starting after POD 5. In the 15 patients who experienced irreversible postoperative liver failure, a progressive increase in MELD score was observed at all the time points considered. An initial increase in MELD score from POD 1 (16.9 ⫾ 2.6) to POD 3 (18.2 ⫾ 3.9; p ⫽ 0.087) was observed; then, in contrast to what was observed in patients in whom liver failure did not develop, a slight increase was observed on POD 5 (18.3 ⫾ 3.6; p ⫽ 0.845 in comparison with POD 3), rising to a maximum on POD 7 (19.1 ⫾ 4.5; p ⫽ 0.279 in comparison with POD 5). Considering the entire study population, a decrease in MELD score between POD 3 and POD 5 was observed in 169 patients (84.5%). Of the 31 patients (15.5%) who experienced an increase in MELD score between PODs 3 and 5, 9 (29%) subsequently experienced irreversible postoperative liver failure, considerably more than the number of patients who experienced a decrease in MELD score (6 patients; 3.6%; p ⫽ 0.001).
Table 2 reports univariate and multivariate analyses of potential risk factors associated with development of irreversible postoperative liver failure after hepatectomy in cirrhotic patients. Variables notably associated with the event at the univariate analysis were CTP class B (p ⬍ 0.001), preoperative MELD score ⱖ 11 (p ⬍ 0.001), major hepatectomy (p ⬍ 0.001), and the increase in postoperative MELD score between PODs 3 and 5 (p ⬍ 0.001). Multivariate analysis showed that only preoperative MELD score (odds ratio [OR] ⫽ 38.42; 95% CI ⫽ 7.57 to 194.91; p ⬍ 0.001), major hepatectomy (OR ⫽ 15.83; 95% CI ⫽ 1.35 to 185.47; p ⫽ 0.028) and the increase in MELD score between PODs 3 and 5 (OR ⫽ 6.21; 95% CI ⫽ 1.52 to 25.36; p ⫽ 0.011) were independent predictors of liver failure; CTP class B lost its statistical significance (OR ⫽ 2.28; 95% CI ⫽ 0.41 to 12.88; p ⫽ 0.349). Kinetics of postoperative MELD score by covariates
Figure 2 reports the postoperative course of the MELD score at different time points of patients who did not experience postoperative liver failure, with a preoperative MELD score ⬍ 11, and of patients with a preoperative MELD score ⱖ 11. Even if the postoperative MELD score remained higher at each time point considered in patients with a preoperative MELD score ⱖ 11, a reduction between PODs 3 and 5 was observed in both groups. In particular, in patients with a preoperative MELD score ⱖ 11, the postoperative MELD score decreased from 14.5 ⫾ 3.3 on POD 3 to 13.1 ⫾ 2.6 on POD 5 (p ⫽ 0.002). Similarly, in patients with a preoperative MELD score ⬍ 11, the MELD score decreased from 11.6 ⫾ 2.6 on POD 3 to 10.3 ⫾ 2.2 on POD 5 (p ⬍ 0.001). In both groups, a minimum MELD score was reached on POD 7. Figure 3 reports the postoperative course of MELD scores at different time points of patients undergoing minor hepatectomy who did not experience postoperative liver failure, compared with those who underwent major hepatectomy. The two groups had a similar postoperative MELD score kinetic and a reduction between PODs 3 and 5 was observed in both: in patients who underwent major hepatectomy, the postoperative MELD score decreased from 11.7 ⫾ 1.9 on POD 3 to 10.6 ⫾ 1.6 on POD 5 (p ⫽ 0.005), and in patients who underwent minor
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Table 2. Predictive Factors of Postoperative Liver Failure after Hepatectomy Variables
Age ⬎ 65 y Male gender Viral cirrhosis Presence of esophageal varices CTP Class B Preoperative MELD score ⱖ 11 Major hepatectomy Aspartate amino transferase ⬎ 2N Intraoperative blood transfusion Increase of MELD score between PODs 3 and 5
Odds ratio
Univariate analysis 95% CI
p Value
Odds ratio
Multivariate analysis 95% CI
p Value
0.46 0.83 1.79 1.39 12.7 37.16 7.46 2.51 2.93
0.15–1.41 0.25–2.75 0.22–14.29 0.45–4.26 3.42–47.24 9.57–143.92 1.66–33.5 0.83–7.64 0.96–8.93
0.175 0.764 0.583 0.567 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 0.104 0.058
— — — — 2.28 38.42 15.83 — —
— — — — 0.41–12.88 7.57–194.91 1.35–185.47 — —
— — — — 0.349 ⬍ 0.001 0.028 — —
11.11
3.61–34.22
⬍ 0.001
6.21
1.52–25.36
0.011
CTP, Child-Turcotte-Pugh; MELD, model for end-stage liver disease; POD, postoperative day.
DISCUSSION Postoperative liver failure is one of the most feared complications of liver resection, and it is even more dreaded in patients with liver cirrhosis because resection removes functional liver tissue from an organ whose function is already marginal. Preoperative assessment of liver function, prediction of postoperative functional reserve, and accurate monitoring of postoperative course are of paramount importance to minimize surgical risk.
This study demonstrated that three variables, namely, preoperative MELD score, extent of hepatectomy, and increase in postoperative MELD score on POD 5 are independent predictors of irreversible postoperative liver failure that leads to death or requires salvage liver transplantation. Analysis of postoperative MELD kinetics confirmed that an impairment of liver function occurs between POD 1 and POD 3; there is then a notable trend to return to normal values on POD 5 and on POD 7. So assessment of the MELD score on POD 5 seems to be crucial for the early detection of patients who will experience irreversible liver failure; the prevalence of the event was 3.6% when a decrease in MELD score was
Figure 2. Postoperative course of model for end-stage liver disease (MELD) score (mean ⫾ standard deviation) at different time points of patients who did not experience postoperative liver failure with preoperative MELD score ⬍ 11 (continuous line) and of patients with preoperative MELD score ⱖ 11 (dotted line). POD, postoperative day.
Figure 3. Postoperative course of model for end-stage liver disease score (mean ⫾ standard deviation) at different time points of patients who did not experience postoperative liver failure who underwent minor hepatectomy (continuous line) and of patients who underwent major hepatectomy (dotted line). POD, postoperative day.
hepatectomy, the MELD score decreased from 11.8 ⫾ 2.7 on POD 3 to 10.6 ⫾ 2.4 on POD 5 (p ⬍ 0.001). In both groups, a minimum MELD score was reached on POD 7.
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observed between PODs 3 and 5, but rose to 29% when the MELD score increased. The impact of this variable in determining prognosis was confirmed by multivariate analysis, in which the increase of MELD score on POD 5 proved to be an independent prognostic factor of postoperative liver failure. At present, this is the first report that evaluates recovery from postoperative liver failure by MELD score assessment and its impact on prognosis after hepatectomy for HCC in cirrhosis. The possibility of having an early postoperative index of liver failure may help in beginning intensive treatment to avoid comorbidities, such as infections or renal impairment, that will almost certainly lead to patient death. Alternatively, patients eligible for liver transplantation may enter a transplantation program. Patients with a preoperative MELD score ⱖ 11 are at a high risk of experiencing irreversible postoperative liver failure17; a preoperative MELD score ⱖ than 11 proved to be an independent predictor of the event, leading to removal of the CTP score from the multivariate analysis and confirming the better accuracy of the preoperative MELD score in detecting patients at a high risk of liver failure after hepatectomy. Strict postoperative care must be taken in these patients to properly identify the increase in MELD score on POD 5; intensive care must be guaranteed to promptly avoid comorbidities or to support the patient until a salvage liver transplantation can be performed. Assessment of the extent of the hepatectomy is of paramount importance in evaluating the resectability of a lesion occurring in a cirrhotic liver. Normal livers can tolerate removal of up to 70% of their volume,22 and livers with chronic hepatitis without cirrhosis can tolerate removal of up to 60% of their volume.23 On the contrary, the presence of cirrhosis limits the benefit of performing major hepatectomies, and an incidence of postoperative death of approximately 30% can be expected.19 This study confirms that patients undergoing major hepatic resection, defined as the removal of three or more segments, are at a high risk of postoperative liver failure. But not all patients undergoing major hepatectomy will experience irreversible liver failure; analysis of the kinetics of the postoperative MELD score showed that the decrease in its value between PODs 3 and 5 represents an optimal postoperative predictor of the resolution of the transient liver impairment despite the extent of hepatectomy.
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In this study, 20.5% of the population received FFP transfusion, so one could argue that our policy in FFP transfusion may have led to an alteration of the result because administration of coagulation factors inevitably leads to a modification of INR. But all 15 patients who experienced irreversible liver failure underwent repeated FFP transfusions starting from PODs 1 or 3, and despite this treatment, no notable improvement in INR values or decrease in MELD score were observed between PODs 3 and 5. On the contrary, all remaining patients, who did not experience irreversible postoperative liver failure and received FFP, started FFP administration after POD 5, so the decrease in MELD kinetics observed between PODs 3 and 5 is not biased. A report by Balzan and colleagues24 recently suggested postoperative criteria to detect patients at a high risk of liver failure and postoperative death after hepatectomy; the so called “50 to 50” criteria were based on postoperative liver biochemistry at POD 5 and defined as the concomitant presence of bilirubin serum levels ⬎ 50 mol/L (corresponding to 3 mg/dL) and prothrombin time values ⬍ 50% (corresponding to INR value of 1.70). In our series, the concomitant presence of these factors was very unusual; even if bilirubin levels ⬎ 3 mg/dL were observed in 19 patients (9.5%), the concomitant presence of an INR value ⬎ 1.70 was observed in only 2 patients (1.0%) who subsequently died. This condition may be explained by the fact that 60% of the hepatectomies reported by Balzan and associates24 were major hepatectomies performed in a population of 88% noncirrhotic patients, and removal of three or more segments led inevitably to a worsened impairment of postoperative liver function. On the contrary, in our study, performed on a cirrhotic population, the great majority of patients underwent minor hepatectomy (95.5%) so that a lower impairment of liver function was expected. The small sample in this study fulfilling the “50 to 50 criteria” did not allow any statistical comparison with postoperative MELD score. In conclusion, a physiologic increase in MELD score after hepatectomy in cirrhotic livers has to be expected, and recovery from liver impairment starts from POD 5; the increase in MELD score between PODs 3 and 5 may help in identifying patients at a high risk of liver failure and may represent the trigger for beginning intensive treatment to avoid comorbidities or to evaluate a transplantation program.
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Author Contributions Study conception and design: Cucchetti, Ercolani, Cescon Acquisition of data: Cucchetti, Del Gaudio, Ravaioli, Zanello Analysis and interpretation of data: Cucchetti, Ercolani, Cescon Drafting of manuscript: Cucchetti, Ercolani, Lauro, Vivarelli Critical revision: Grazi, Pinna
12.
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1. Bosch FX, Ribes J, Borras J. Epidemiology of primary liver cancer. Semin Liver Dis 1999;19:271–285. 2. Grazi GL, Ercolani G, Pierangeli F, et al. Improved results of liver resection for hepatocellular carcinoma on cirrhosis give the procedure added value. Ann Surg 2001;234:71–78. 3. Fan ST, Lo CM, Liu CL, et al. Hepatectomy for hepatocellular carcinoma: toward zero hospital deaths. Ann Surg 1999;229: 322–330. 4. Takayama T, Makuuchi M, Hirohashi S, et al. Early hepatocellular carcinoma as an entity with a high rate of surgical care. Hepatology 1998;28:1241–1246. 5. Poon RT, Fan ST, Lo CM, et al. Extended hepatic resection for hepatocellular carcinoma in patients with cirrhosis: is it justified? Ann Surg 2002;236:602–611. 6. Belghiti J, Regimbeau JM, Durand F, et al. Resection of hepatocellular carcinoma: a European experience on 328 cases. Hepatogastroenterology 2002;49:41–46. 7. Miyagawa S, Makuuchi M, Kawasaki S, Kakazu T. Criteria for safe hepatic resection. Am J Surg 1995;169:589–594. 8. Lau H, Man K, Fan ST, et al. Evaluation of preoperative hepatic function in patients with hepatocellular carcinoma undergoing hepatectomy. Br J Surg 1997;84:1255–1259. 9. Ercolani G, Grazi GL, Callivà R, et al. The lidocaine (MEGX) test as an index of hepatic function: its clinical usefulness in liver surgery. Surgery 2000;127:464–471. 10. Radaelli CA, Dufour JF, Wagner M, et al. Preoperative galactose elimination capacity predicts complications and survival after hepatic resection. Ann Surg 2002;235:77–85. 11. Child CG II, Turcotte JG. Surgery and portal hypertension.
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In: Child CG III, ed. The liver and portal hypertension. Philadelphia: Saunders; 1964:50–58. Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60:646–649. Wayne JD, Lauwers GY, Ikai I, et al. Preoperative predictors of survival after resection of small hepatocellular carcinomas. Ann Surg 2002;235:722–731. Malinchoc M, Kamath PS, Gordon FD, et al. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 2000;31:864–871. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001;33:464–470. Freeman RB, Wiesner RH, Harper A, et al. The new liver allocation system: moving toward evidence-based transplantation policy. Liver Transpl 2002;8:851–858. Cucchetti A, Ercolani G, Vivarelli M, et al. Impact of model for end-stage liver disease (MELD) score on prognosis after hepatectomy for hepatocellular carcinoma on cirrhosis. Liver Transpl 2006;12:966–971. Teh SH, Christein J, Donohue J, et al. Hepatic resection of hepatocellular carcinoma in patients with cirrhosis: Model of End-stage Liver Disease (MELD) score predicts perioperative mortality. J Gastrointestinal Surg 2005;9:1207–1215. Farges O, Malassagne B, Flejou JF, et al. Risk of major liver resection in patients with underlying chronic liver disease: a reappraisal. Ann Surg 1999;229:210–215. Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22:696–699. Committee of the International Hepato-Pancreato-Biliary Association. IHPBA Brisbane 2000 Terminology of Liver anatomy and resections. Abingdon, United Kingdom: Taylor & Francis; 2:333–339. Stone HH, Long WD, Smith RB 3rd, Haynes CD. Physiologic consideration in major hepatic resections. Am J Surg 1969;117: 78–84. Kubota K, Makuuchi M, Kusaka K, et al. Measurement of liver volume and hepatic functional reserve as a guide to decisionmaking in resectional surgery for hepatic tumors. Hepatology 1997;26:1176–1181. Balzan S, Belghiti J, Farges O, et al. The “50-50 criteria” on postoperative day 5: an accurate predictor of liver failure and death after hepatectomy. Ann Surg 2005;242:824–828.
Hepatocellular carcinoma (HCC) represents one of the most common tumors worldwide and, in most instances, arises in patients with chronic underlying liver disease secondary to hepatitis B or C virus infection.1 Therapeutic strategies for early HCC include liver resection and liver transplantation, but in light of donor shortage, liver resection remains the most applied therapeutic approach in well-compensated cirrhotic patients, offering the chance for cure and providing longterm survival.2-6
In addition to the evaluation of tumor status, careful assessment of liver function reserve is critical in patient selection to avoid postoperative liver failure and mortality. Several approaches have been proposed to assess hepatic function reserve,7-10 but of all the tools, the ChildTurcotte-Pugh (CTP) classification11,12 remains the main indicator of the extent of resection that a cirrhotic liver can tolerate.13 The model for end-stage liver disease (MELD) was recently developed to predict the mortality of cirrhotic patients undergoing transjugular intrahepatic portosystemic shunts (TIPSS)14 and subsequently applied as a disease severity index for priority on the waiting list for liver transplantation.15,16 The MELD score can be considered an index of hepatic function, and recent reports demonstrated that the preoperative
Competing Interests Declared: None. Received April 26, 2006; Revised June 6, 2006; Accepted June 20, 2006. From the Department of Surgery and Transplantation, University of Bologna, Policlinico S Orsola-Malpighi, Bologna, Italy. Correspondence address: Alessandro Cucchetti, MD, Policlinico Sant’OrsolaMalpighi, University of Bologna, Via Massarenti, 9, 40138 Bologna, Italy.
© 2006 by the American College of Surgeons Published by Elsevier Inc.
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Abbreviations and Acronyms
CTP FFP HCC INR MELD OR POD
⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽
Child-Turcotte-Pugh fresh frozen plasma hepatocellular carcinoma international normalized ratio model for end-stage liver disease odds ratio postoperative day
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tients without histologic evidence of cirrhosis were excluded from the analysis, and only the 200 cirrhotic patients formed the final study group. Hepatic functional reserve was preoperatively rated using both the CTP score, according to the classification proposed by Pugh and Colleagues,12 and the MELD score, calculated according to the formula16: MELD ⫽ 共0.957 ⫻ Loge共creatinine in mg ⁄ dL兲 ⫹ 0.378
MELD score accurately predicts development of postoperative liver failure after hepatectomy for HCC in cirrhosis,17,18 but variations in the MELD score after liver resection have never been investigated. Several clinical and biochemical variables, namely ascites, jaundice, prolonged prothrombin time, increase of serum creatinine and bilirubin levels, and decrease of albumin serum level are typical markers of impaired liver function; in particular, serum bilirubin and prothrombin time are frequently altered in the early postoperative days after hepatectomy19; this condition allows postoperative assessment of the MELD score. The aim of this study was to evaluate the reliability and usefulness of the postoperative MELD score in the early prediction of liver failure after hepatectomy for HCC in cirrhotic patients; its relationship with other clinical and biochemical variables, known to affect surgical outcomes was also investigated. METHODS Between January 1997 and December 2005, 286 patients underwent curative hepatic resection for HCC in chronic liver disease at the Department of Surgery and Transplantation of the University of Bologna; the policy of our center about indications for hepatic resection has already been published.2 Of these patients, 34 were not included in the analysis for the following reasons: incomplete clinical data (27 patients), presence of chronic renal insufficiency that did not allow a reliable measurement of the MELD score (4 patients), and early postoperative death from acute myocardial infarction (2 patients) and pulmonary embolism (1 patient). In the 252 patients in the initial study group, fibrosis stage was scored on the resected specimen, according to the classification of Ishak and associates20 as cirrhosis versus noncirrhosis. Underlying histologically proved cirrhosis was present in 200 patients (79.4%) and chronic hepatitis without cirrhosis in 52 (20.6%). Pa-
⫻ Loge共bilirubin in mg ⁄ dL兲 ⫹ 1.12 ⫻ Loge共INR兲 ⫹ 0.643兲 ⫻ 10.
In particular, for calculation of both CTP and MELD scores, only biochemical values from the laboratory at our center were used. The extent of the hepatectomy referred to the International Hepato-Pancreato-Biliary Association (IHPBA) classification.21 All resections were performed to achieve a tumor-free margin of at least 1 cm based on intraoperative morphologic examination and ultrasonography. Major hepatic resection was defined as the removal of more than two segments. None of the patients forming this study group underwent preoperative portal vein embolization. Postoperative admission to the ICU was reserved for patients with cardiovascular or pulmonary comorbidities, those who underwent major hepatectomies, or those with severe intraoperative bleeding. Our policy about the use of postoperative fresh frozen plasma (FFP) was to avoid transfusions until the international normalized ratio (INR) value was higher than 1.50; occasionally, the sole presence of other clinical and biochemical signs of hepatic decompensation such as renal impairment or massive ascites, requiring drainage, led to the use of FFP. Transfusion occurred in a total of 41 patients (20.5%). The aim of this study was to investigate how the early kinetics of liver function tests correlated with the development of postoperative irreversible liver failure, defined as a growing impairment of liver function after hepatectomy that led to patient death or required transplantation. For this purpose, serum creatinine, bilirubin, and INR were sampled routinely on postoperative days (POD) 1, 3, 5, and 7, and the MELD score was calculated for each time point as previously described. The study protocol was in accordance with the Declaration of Helsinki and subsequent amendments.
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Statistical analysis
Continuous variables were expressed as mean and standard deviation. The postoperative course of the MELD score was investigated and reported in clustered multiple variable graphs; MELD scores at each time point considered were compared using the paired sample t-test and in subgroups using the independent t-test. Logistic regression was first applied to each single variable to identify their odds ratios in determining postoperative liver failure; variables that proved statistically significant in univariate analysis were entered in a forward conditional regression model to identify independent predictive variables of the event. A p value ⬍ 0.05 was considered significant in all analyses. Statistical analysis was done using the SPSS Version 10.0 software for PC computers (SPSS) and clustered multiple variable graphs were constructed using MedCalc Version 7.2.1.0 (MedCalc Software). RESULTS Baseline characteristics of the study population are shown in Table 1. Surgery consisted of minor hepatic resections in 191 patients (95.5%) and of major hepatic resections in the remaining 9 (4.5%). In particular, 108 wedge resections (54.0%), 56 segmentectomies (28.0%), 13 left lateral sectionectomies (6.5%), 7 right posterior sectionectomies (3.5%), 4 right anterior sectionectomies (2.0%), 3 left medial sectionectomies plus segmentectomy 8 (1.5%), 6 left hepatectomies (3.0%), and 3 right hepatectomies (1.5%) were performed. Developed in 15 patients (7.5%). Irreversible postoperative liver failure. Of these, four patients were successfully treated with liver transplantation, resulting in an overall mortality for postoperative liver failure of 5.5%. Mean time from operation to patient death or liver transplantation was 59.4 ⫾ 48.6 days (range ⫽ 14 to 166 days). Ten of 15 patients were classified as CTP class A and 7 underwent a minor hepatectomy (3 wedge resections, 1 segmentectomy, and 3 right posterior sectionectomies); in the remaining 3 patients, who underwent major hepatectomy, 2 left hepatectomies and 1 right hepatectomy were performed. The other five patients, classified as CTP class B, underwent a minor hepatectomy in all cases: three wedge resections and two segmentectomies were performed. All patients were treated early with FFP transfusion starting from POD 1 or POD 3; the mean number of units of FFP adminis-
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Table 1. Baseline Characteristics of the Study Population Variables
Age, y Range ⬎ 65, n (%) Male gender, n (%) Hepatitis serology, n (%) Hepatitis C Hepatitis B Hepatitis B ⫹ C Negative Presence of esophageal varices, n (%) Presence of mild ascites, n (%) Serum albumin, g/dL Platelet count, ⫻103/mm3 Serum creatinine, mg/dL Serum bilirubin, mg/dL International normalized ratio Aspartate aminotransferase, IU/L Aspartate aminotransferase ⬎ 2N, n (%) CTP score Range CTP Class A, n (%) CTP Class B, n (%) MELD score MELD score ⱖ 11, n (%) Size of the largest tumor, cm Solitary tumor, n (%) Extent of hepatectomy, n (%) Subsegmentectomy (wedge) Segmentectomy Bisegmentectomy Major resection Intraoperative RBC transfusion, U
Patients in study (n ⴝ 200)
63.9 ⫾ 8.9 101 (50.5) 153 (76.5) 133 (66.5) 34 (17.0) 11 (5.5) 22 (11.0) 54 (27.0) 10 (5.0) 3.8 ⫾ 0.4 138 ⫾ 69 0.96 ⫾ 0.24 0.97 ⫾ 0.50 1.16 ⫾ 0.10 84.4 ⫾ 69.9 92 (46.0) 5.4 ⫾ 0.6 188 (94.0) 12 (6.0) 8.8 ⫾ 1.6 30 (15.0) 4.2 ⫾ 2.3 171 (85.5) 108 (54.0) 56 (28.0) 27 (13.5) 9 (4.5) 0.56 ⫾ 1.1
Continuous variables are reported in mean and standard deviation. CTP, Child-Turcotte-Pugh; INR, international normalized ratio; MELD, model for end-stage liver disease.
tered until death or transplantation was 0.86 ⫾ 0.24 per day. Kinetics of postoperative MELD score
We first analyzed kinetics of the MELD scores of 185 patients in whom irreversible postoperative liver failure did not develop after hepatectomy (Fig. 1). Postoperative MELD score reached a maximum on POD 3 (11.9 ⫾ 2.8), slightly higher than that on POD 1 (11.8 ⫾ 2.3; p ⫽ 0.594) and considerably higher than the preoperative score (8.6 ⫾ 1.3; p ⬍ 0.001 in both cases). On POD 5, we observed a considerable reduction
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Predictive factors of liver failure
Figure 1. Postoperative course of model for end-stage liver disease score (mean ⫾ standard deviation) at different time points of patients who did not experience postoperative liver failure (continuous line) and of patients who experienced irreversible postoperative liver failure (dotted line). POD, postoperative day.
in MELD score compared with that on POD 3 (10.6 ⫾ 2.4; p ⬍ 0.001), and on POD 7 the MELD score reached a minimum (10.1 ⫾ 2.3; p ⬍ 0.001 in comparison with POD 5), but was still higher than the preoperative value (p ⬍ 0.001). In 26 of 185 patients (14%), FFP was administered during the postoperative course; all of these patients received transfusion starting after POD 5. In the 15 patients who experienced irreversible postoperative liver failure, a progressive increase in MELD score was observed at all the time points considered. An initial increase in MELD score from POD 1 (16.9 ⫾ 2.6) to POD 3 (18.2 ⫾ 3.9; p ⫽ 0.087) was observed; then, in contrast to what was observed in patients in whom liver failure did not develop, a slight increase was observed on POD 5 (18.3 ⫾ 3.6; p ⫽ 0.845 in comparison with POD 3), rising to a maximum on POD 7 (19.1 ⫾ 4.5; p ⫽ 0.279 in comparison with POD 5). Considering the entire study population, a decrease in MELD score between POD 3 and POD 5 was observed in 169 patients (84.5%). Of the 31 patients (15.5%) who experienced an increase in MELD score between PODs 3 and 5, 9 (29%) subsequently experienced irreversible postoperative liver failure, considerably more than the number of patients who experienced a decrease in MELD score (6 patients; 3.6%; p ⫽ 0.001).
Table 2 reports univariate and multivariate analyses of potential risk factors associated with development of irreversible postoperative liver failure after hepatectomy in cirrhotic patients. Variables notably associated with the event at the univariate analysis were CTP class B (p ⬍ 0.001), preoperative MELD score ⱖ 11 (p ⬍ 0.001), major hepatectomy (p ⬍ 0.001), and the increase in postoperative MELD score between PODs 3 and 5 (p ⬍ 0.001). Multivariate analysis showed that only preoperative MELD score (odds ratio [OR] ⫽ 38.42; 95% CI ⫽ 7.57 to 194.91; p ⬍ 0.001), major hepatectomy (OR ⫽ 15.83; 95% CI ⫽ 1.35 to 185.47; p ⫽ 0.028) and the increase in MELD score between PODs 3 and 5 (OR ⫽ 6.21; 95% CI ⫽ 1.52 to 25.36; p ⫽ 0.011) were independent predictors of liver failure; CTP class B lost its statistical significance (OR ⫽ 2.28; 95% CI ⫽ 0.41 to 12.88; p ⫽ 0.349). Kinetics of postoperative MELD score by covariates
Figure 2 reports the postoperative course of the MELD score at different time points of patients who did not experience postoperative liver failure, with a preoperative MELD score ⬍ 11, and of patients with a preoperative MELD score ⱖ 11. Even if the postoperative MELD score remained higher at each time point considered in patients with a preoperative MELD score ⱖ 11, a reduction between PODs 3 and 5 was observed in both groups. In particular, in patients with a preoperative MELD score ⱖ 11, the postoperative MELD score decreased from 14.5 ⫾ 3.3 on POD 3 to 13.1 ⫾ 2.6 on POD 5 (p ⫽ 0.002). Similarly, in patients with a preoperative MELD score ⬍ 11, the MELD score decreased from 11.6 ⫾ 2.6 on POD 3 to 10.3 ⫾ 2.2 on POD 5 (p ⬍ 0.001). In both groups, a minimum MELD score was reached on POD 7. Figure 3 reports the postoperative course of MELD scores at different time points of patients undergoing minor hepatectomy who did not experience postoperative liver failure, compared with those who underwent major hepatectomy. The two groups had a similar postoperative MELD score kinetic and a reduction between PODs 3 and 5 was observed in both: in patients who underwent major hepatectomy, the postoperative MELD score decreased from 11.7 ⫾ 1.9 on POD 3 to 10.6 ⫾ 1.6 on POD 5 (p ⫽ 0.005), and in patients who underwent minor
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Table 2. Predictive Factors of Postoperative Liver Failure after Hepatectomy Variables
Age ⬎ 65 y Male gender Viral cirrhosis Presence of esophageal varices CTP Class B Preoperative MELD score ⱖ 11 Major hepatectomy Aspartate amino transferase ⬎ 2N Intraoperative blood transfusion Increase of MELD score between PODs 3 and 5
Odds ratio
Univariate analysis 95% CI
p Value
Odds ratio
Multivariate analysis 95% CI
p Value
0.46 0.83 1.79 1.39 12.7 37.16 7.46 2.51 2.93
0.15–1.41 0.25–2.75 0.22–14.29 0.45–4.26 3.42–47.24 9.57–143.92 1.66–33.5 0.83–7.64 0.96–8.93
0.175 0.764 0.583 0.567 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 0.104 0.058
— — — — 2.28 38.42 15.83 — —
— — — — 0.41–12.88 7.57–194.91 1.35–185.47 — —
— — — — 0.349 ⬍ 0.001 0.028 — —
11.11
3.61–34.22
⬍ 0.001
6.21
1.52–25.36
0.011
CTP, Child-Turcotte-Pugh; MELD, model for end-stage liver disease; POD, postoperative day.
DISCUSSION Postoperative liver failure is one of the most feared complications of liver resection, and it is even more dreaded in patients with liver cirrhosis because resection removes functional liver tissue from an organ whose function is already marginal. Preoperative assessment of liver function, prediction of postoperative functional reserve, and accurate monitoring of postoperative course are of paramount importance to minimize surgical risk.
This study demonstrated that three variables, namely, preoperative MELD score, extent of hepatectomy, and increase in postoperative MELD score on POD 5 are independent predictors of irreversible postoperative liver failure that leads to death or requires salvage liver transplantation. Analysis of postoperative MELD kinetics confirmed that an impairment of liver function occurs between POD 1 and POD 3; there is then a notable trend to return to normal values on POD 5 and on POD 7. So assessment of the MELD score on POD 5 seems to be crucial for the early detection of patients who will experience irreversible liver failure; the prevalence of the event was 3.6% when a decrease in MELD score was
Figure 2. Postoperative course of model for end-stage liver disease (MELD) score (mean ⫾ standard deviation) at different time points of patients who did not experience postoperative liver failure with preoperative MELD score ⬍ 11 (continuous line) and of patients with preoperative MELD score ⱖ 11 (dotted line). POD, postoperative day.
Figure 3. Postoperative course of model for end-stage liver disease score (mean ⫾ standard deviation) at different time points of patients who did not experience postoperative liver failure who underwent minor hepatectomy (continuous line) and of patients who underwent major hepatectomy (dotted line). POD, postoperative day.
hepatectomy, the MELD score decreased from 11.8 ⫾ 2.7 on POD 3 to 10.6 ⫾ 2.4 on POD 5 (p ⬍ 0.001). In both groups, a minimum MELD score was reached on POD 7.
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observed between PODs 3 and 5, but rose to 29% when the MELD score increased. The impact of this variable in determining prognosis was confirmed by multivariate analysis, in which the increase of MELD score on POD 5 proved to be an independent prognostic factor of postoperative liver failure. At present, this is the first report that evaluates recovery from postoperative liver failure by MELD score assessment and its impact on prognosis after hepatectomy for HCC in cirrhosis. The possibility of having an early postoperative index of liver failure may help in beginning intensive treatment to avoid comorbidities, such as infections or renal impairment, that will almost certainly lead to patient death. Alternatively, patients eligible for liver transplantation may enter a transplantation program. Patients with a preoperative MELD score ⱖ 11 are at a high risk of experiencing irreversible postoperative liver failure17; a preoperative MELD score ⱖ than 11 proved to be an independent predictor of the event, leading to removal of the CTP score from the multivariate analysis and confirming the better accuracy of the preoperative MELD score in detecting patients at a high risk of liver failure after hepatectomy. Strict postoperative care must be taken in these patients to properly identify the increase in MELD score on POD 5; intensive care must be guaranteed to promptly avoid comorbidities or to support the patient until a salvage liver transplantation can be performed. Assessment of the extent of the hepatectomy is of paramount importance in evaluating the resectability of a lesion occurring in a cirrhotic liver. Normal livers can tolerate removal of up to 70% of their volume,22 and livers with chronic hepatitis without cirrhosis can tolerate removal of up to 60% of their volume.23 On the contrary, the presence of cirrhosis limits the benefit of performing major hepatectomies, and an incidence of postoperative death of approximately 30% can be expected.19 This study confirms that patients undergoing major hepatic resection, defined as the removal of three or more segments, are at a high risk of postoperative liver failure. But not all patients undergoing major hepatectomy will experience irreversible liver failure; analysis of the kinetics of the postoperative MELD score showed that the decrease in its value between PODs 3 and 5 represents an optimal postoperative predictor of the resolution of the transient liver impairment despite the extent of hepatectomy.
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In this study, 20.5% of the population received FFP transfusion, so one could argue that our policy in FFP transfusion may have led to an alteration of the result because administration of coagulation factors inevitably leads to a modification of INR. But all 15 patients who experienced irreversible liver failure underwent repeated FFP transfusions starting from PODs 1 or 3, and despite this treatment, no notable improvement in INR values or decrease in MELD score were observed between PODs 3 and 5. On the contrary, all remaining patients, who did not experience irreversible postoperative liver failure and received FFP, started FFP administration after POD 5, so the decrease in MELD kinetics observed between PODs 3 and 5 is not biased. A report by Balzan and colleagues24 recently suggested postoperative criteria to detect patients at a high risk of liver failure and postoperative death after hepatectomy; the so called “50 to 50” criteria were based on postoperative liver biochemistry at POD 5 and defined as the concomitant presence of bilirubin serum levels ⬎ 50 mol/L (corresponding to 3 mg/dL) and prothrombin time values ⬍ 50% (corresponding to INR value of 1.70). In our series, the concomitant presence of these factors was very unusual; even if bilirubin levels ⬎ 3 mg/dL were observed in 19 patients (9.5%), the concomitant presence of an INR value ⬎ 1.70 was observed in only 2 patients (1.0%) who subsequently died. This condition may be explained by the fact that 60% of the hepatectomies reported by Balzan and associates24 were major hepatectomies performed in a population of 88% noncirrhotic patients, and removal of three or more segments led inevitably to a worsened impairment of postoperative liver function. On the contrary, in our study, performed on a cirrhotic population, the great majority of patients underwent minor hepatectomy (95.5%) so that a lower impairment of liver function was expected. The small sample in this study fulfilling the “50 to 50 criteria” did not allow any statistical comparison with postoperative MELD score. In conclusion, a physiologic increase in MELD score after hepatectomy in cirrhotic livers has to be expected, and recovery from liver impairment starts from POD 5; the increase in MELD score between PODs 3 and 5 may help in identifying patients at a high risk of liver failure and may represent the trigger for beginning intensive treatment to avoid comorbidities or to evaluate a transplantation program.
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Author Contributions Study conception and design: Cucchetti, Ercolani, Cescon Acquisition of data: Cucchetti, Del Gaudio, Ravaioli, Zanello Analysis and interpretation of data: Cucchetti, Ercolani, Cescon Drafting of manuscript: Cucchetti, Ercolani, Lauro, Vivarelli Critical revision: Grazi, Pinna
12.
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