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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The evidence for defining a safe minimal remnant volume after living donor hepatectomy is insufficient. The aim of this study was to evaluate the outcomes of living donors with a remnant/total volume ratio (RTVR) < 30% after right hepatectomy according to the following selection criteria: the preservation of the middle hepatic vein (MHV), an age < 50 years, and no or mild fatty changes in healthy adults. All living donors who underwent right hepatectomy preserving the MHV at our institution between January 2005 and September 2011 were divided into 2 groups: group A with an RTVR < 30% and group B with an RTVR ≥ 30%. Perioperative data, complications by the Clavien classification, and outcomes with at least 15.1 months' follow-up were compared. Twenty-eight donors were enrolled in group A, and 260 were enrolled in group B. The estimated liver volume was strongly correlated with the actual graft weight (R2 = 0.608, P < 0.001). The calculated donation liver volume and the RTVR were significantly different between the 2 groups (P = 0.03 and P < 0.001, respectively). The peak postoperative aspartate aminotransferase levels, alanine aminotransferase levels, and international normalized ratios did not differ between the 2 groups. The peak total bilirubin level was higher for group A versus group B (P = 0.04). The hospital stay was longer for group A versus group B (P < 0.001). All donors recovered completely, and there were no significant differences in overall complications between the 2 groups. In conclusion, right hepatectomy preserving the MHV with an RTVR < 30% can be safely indicated for carefully selected living donors less than 50 years old with no or mild fatty changes. Liver Transpl 19:872-878, 2013. © 2013 AASLD.

Abbreviations
ALT

alanine aminotransferase

AST

aspartate aminotransferase

CT

computed tomography

INR

international normalized ratio

LDLT

living donor liver transplantation

MHV

middle hepatic vein

RTVR

remnant/total volume ratio

TB

total bilirubin

US

ultrasonography

The evidence for defining a safe future remnant volume on the basis of preoperative evaluations in living donors undergoing right hepatectomy for living donor liver transplantation (LDLT) is insufficient.

Living donor hepatectomy is still under rigid scrutiny because of its high level of ethical challenge and its technical complexity. Recently, advances in radiological techniques have resulted in an improved preoperative evaluation of the functional liver mass. However, no consensus has been established for safe remnant/total volume ratio (RTVR) limits. The current practice of arbitrarily requiring an RTVR of at least 30% is based on the experience of early studies.[1, 2] On the contrary, it has been reported that an extended resection of 80% of the functional parenchyma can be performed in the absence of chronic liver disease for hepatobiliary malignancies.[3]

In the current era of robustly accumulated experience in LDLT and recent improvements in surgical techniques and perioperative management, it could be hypothesized that an RTVR > 20% may be the lowest limit for living donor right hepatectomy.

There should be no compromise on donor safety, but in the current era of living donor surgery performed worldwide, lowering the remnant liver volume safely could be compatible with the continuing efforts to expand the donor pool for right liver LDLT.

The aim of this study was to evaluate the outcomes of living donors with an RTVR < 30% after right hepatectomy according to the following selection criteria: the preservation of the middle hepatic vein (MHV), an age < 50 years, and no or mild fatty changes in healthy adults.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Study Design

All living donors who underwent right hepatectomy preserving the MHV at the National Cancer Center of Korea between January 2005 and September 2011 were considered for this retrospective study, and the institutional review board approved the study. Donor characteristics, operative outcomes, and postoperative complications were reviewed from a prospectively maintained database. To assess the outcomes of living donors with a remnant volume < 30%, the donors were divided into 2 groups: group A with an RTVR < 30% and group B with an RTVR ≥ 30%. The 2 groups were then compared.

The primary endpoint was donor complications stratified by grade according to the Clavien classification.[4] The secondary endpoints included operative outcomes (operative time, blood loss, transfusion requirement, macrovesicular steatosis on pathology, actual graft weight, mean daily drain amount, and postoperative hospital stay) and postoperative peak serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TB) as well as the international normalized ratio (INR). Postoperative liver failure was defined as a prothrombin time < 50% and a TB level > 50 μmol/L on postoperative day 5 (the 50-50 criteria).[5]

Donor Selection and Evaluation

The donor selection criteria and evaluation have been described elsewhere.[6] Briefly, all living donors volunteered and signed an informed consent form concerning the items deliberated by the ethics group of the Vancouver Forum,[7] and all LDLT cases were homologated by the Korean Network for Organ Sharing after full medical and psychiatric assessments by health care professionals.

The imaging evaluation included Doppler ultrasonography (US), computed tomography (CT) with volumetry, and intraoperative cholangiography or magnetic resonance cholangiography. Triphasic CT was performed to delineate the vascular anatomy, to assess the removal of the MHV, and to calculate the volumes of the whole liver, right liver, and remaining left liver; the volume determination was performed via the tracing of the right liver graft and whole liver on 3-mm CT slices, and the enclosed area was calculated and integrated. The estimated RTVR was defined as follows:

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In addition, the standardized liver volume was calculated from the donor's body surface area (m2) with a mathematical formula[8]:

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The estimated remnant/standardized volume ratio was defined as follows:

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Steatosis in each donor was graded as none (a liver structure normal on US), mild (a slight increase in echogenicity and normal visualization), moderate (a diffuse increase in echogenicity and slightly impaired visualization), or severe (a marked increase in echogenicity and poor or no visualization) on the basis of increasing echogenicity of the liver parenchyma versus the right kidney and decreased visualization of the diaphragm and intrahepatic vessel borders.[9]

Liver biopsy was performed selectively for donors in whom a moderate degree of steatosis was suspected from imaging studies. Steatosis was assessed as the percentage of hepatocytes in a microscopic field containing a lipid vacuole larger than the diameter of the nucleus and displacing the nucleus. Steatosis was graded as none (<5%), mild (5%-33%), moderate (>33%-66%), or severe (>66%).[10] Donors with <33% hepatic steatosis were considered acceptable candidates for living donation.

Upper and lower endoscopy examinations were routinely performed for donor candidates who were older than 40 and 50 years, respectively, or who had any gastrointestinal symptom. No potential donor with any concomitant abnormal medical or psychological condition was allowed to undergo the donor operation. Furthermore, smoking and oral contraceptives were prohibited for all donor candidates within the 6 weeks before surgery in order to reduce the risk of venous thromboembolic disease.

In principle, an RTVR ≥ 30% by CT volumetry was chosen as the preferred minimum cutoff. However, when donors were less than 50 years old, were in good physical and psychological health, and did not have more than a mild fatty liver or any medical disorders (including laboratory abnormalities), an RTVR < 30% was selected carefully; in such cases, the MHV was absolutely preserved in the donors.

Surgical Procedure

The technical specifications of refinements made over the study period in living donor right hepatectomy have been reported previously.[11-13] The current surgical technique is as follows.

An upper midline incision above the umbilicus is used, and a wound protector is installed. After mobilization of the right liver with the sizable inferior right hepatic veins saved (if present), the right Glisson's pedicle is dissected after cholecystectomy and transection of the inferior parenchyma of the caudate lobe up to the hepatic hilum. A tape is located along the inferior vena cava, with its upper end between the right hepatic vein and the MHV and with its lower end between the right and left Glisson's pedicles on the left side of the saved inferior right hepatic vein, if it exists. Parenchymal transection is performed along the right side of the main trunk of the MHV, with the hanging maneuver employed consistently from the start of the liver parenchyma transection until the tape is exposed. Any MHV branch more than 5 mm in diameter is saved for reconstruction. After complete parenchymal transection, heparin (5 IU/kg) is given intravenously, and then the right Glisson's pedicle is dissected into the right hepatic artery, portal vein, and hepatic duct. The right hepatic duct is cut just 2 mm to the right side of the confluence under a clear view, and the stump is closed. The right hepatic artery, portal vein, and hepatic vein are divided at each bifurcation without narrowing of the remnant stumps in time for the recipient's operation. The graft is removed to a basin containing histidine tryptophan ketoglutarate solution. Then, the falciform ligament is reconstructed to maintain the remnant left liver in its original anatomic position to ensure that the remnant liver is well perfused, and a drain is placed in the right liver fossa.

Postoperative Care and Follow-Up

All the donors were extubated before they left the operating room. Prophylaxis for thromboembolism with early mobilization and compressive stockings was started on the day before the operation and was continued until discharge, but low-molecular-weight heparin was used in donors more than 60 years old for 1 week after the operation. Patient-controlled intravenous analgesia was applied for 3 days after surgery. Early feeding and early ambulation (no later than 2 days after the operation) were encouraged. Routine laboratory tests were checked daily for 3 consecutive postoperative days and then every other day during the hospital stay. Follow-up CT was routinely checked 1 week, 1 month, and 1 year after operation. After discharge, all donors were followed with routine laboratory tests 1 month after surgery, 3 months later, and every 6 months thereafter.

Statistical Analysis

Categorical and continuous variables were compared with Fisher's exact test and the Mann-Whitney U test, respectively. Linear regression analyses of the actual right liver graft weight and its volumetric assessment by CT were performed to determine the regression line described by a linear equation, and the results were depicted as lines and scatter plots. Correlations between results of US imaging and histopathological results (the percentage of macrovesicular steatosis) were assessed with the Spearman correlation coefficient.

A P value less than 0.05 was considered statistically significant. All analyses were performed with SAS 9.1.3 for Windows (SAS Institute, Cary, NC).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

A comparison of the intraoperatively measured weights of right liver grafts and their volumetric assessment by CT showed a good correlation for all donors (P < 0.001, R2 = 0.608; Fig. 1A) and for the 28 donors with an RTVR < 30% (P < 0.001, R2 = 0.628; Fig. 1B), and this validated the volumetric measurements by CT. Preoperative measurements of hepatic fat by US had a moderate correlation with the histopathological steatosis assessment (P < 0.001, r = 0.508; Fig. 2).

image

Figure 1. Scatter plots showing good linear correlations between the actual graft weight and the volumetric assessment of the right liver by CT in (A) all donors and (B) the 28 donors with an RTVR < 30%.

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image

Figure 2. Scatter plot representing the correlation between the histopathological results (the percentage of macrovesicular steatosis) and the degree of steatosis by US [(0) normal, (1) mild, and (2) moderate].

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Donor Characteristics

During the study period, 300 living donors underwent right hepatectomy, but 12 donors were excluded from the analyses because their right liver grafts included the MHV. Therefore, 288 donors were enrolled, with 28 in group A and 260 in group B.

Donor characteristics are listed in Table 1. There were no significant differences in sex, age, body mass index, or fatty changes between the 2 groups. The calculated donation liver volume (P = 0.03), the RTVR (P < 0.001), and the remnant/standardized volume ratio (P < 0.001) were significantly different between the 2 groups.

Table 1. Donor Characteristics According to the RTVR
CharacteristicGroup A: RTVR < 30% (n = 28)Group B: RTVR ≥ 30% (n = 260)P Value
  1. a

    The data are presented as medians and ranges.

Age (years)231 (21-49)31 (16-60)0.19
Sex: male17 (60.7)160 (61.5)0.93
Body mass index (kg/m2)222.9 (18.5-27.8)23.0 (15.2-36.0)0.93
Estimated donation volume (cm3)2942 (604-1451)813 (450-1418)0.03
RTVR (%)228.5 (23.1-29.9)37.5 (30.0-50.1)<0.001
Remnant/standardized volume ratio (%)226.8 (19.5-34.5)36.5 (25.0-53.3)<0.001
Fatty change on US [n (%)]  0.85
No23 (82.1)218 (83.8) 
Mild5 (17.9)29 (11.2) 
Moderate0 (0)13 (5.0) 

Operative Outcomes

There were no significant differences between the 2 groups in terms of operative parameters except for the hospital stay and the actual graft weight, which were longer and greater, respectively, in group A (Table 2).

Table 2. Operative Outcomes According to the RTVR
ParameterGroup A: RTVR < 30% (n = 28)Group B: RTVR ≥ 30% (n = 260)P Value
  1. a

    The data are presented as medians and ranges.

Operative time (minutes)a268 (160-382)252 (156-414)0.08
Blood loss (mL)a300 (100-1400)400 (50-1000)0.51
Blood transfusion [n (%)]1 (3.6)2 (0.8)0.17
Macrovesicular steatosis on pathology [n (%)]  0.87
<5%24 (85.7)228 (87.7) 
5%-33%4 (14.3)32 (12.3) 
>33%0 (0)0 (0) 
Actual graft weight (g)a787 (400-1222)631 (400-1078)0.04
Mean drain amount for 6 days (mL/day)a185 (55-655)188 (48-623)0.71
Postoperative hospital stay (days)a10 (7-21)8 (6-34)<0.001

Morbidity and Mortality

The postoperative peak serum AST levels, ALT levels, and INRs did not differ between the 2 groups (Table 3). The median peak serum TB level was higher for group A versus group B (3.9 versus 3.4 mg/dL, P = 0.04). The liver enzyme elevation and hyperbilirubinemia in the immediate postoperative period declined smoothly over a week in all donors (data not shown). No donors developed postoperative liver failure (as previously defined).

Table 3. Postoperative Laboratory Data According to the RTVR
 Group A: RTVR < 30% (n = 28)Group B: RTVR ≥ 30% (n = 260)P Value
  1. a

    The data are presented as medians and ranges.

Peak AST (IU/L)a159 (81-342)156 (75-707)0.93
Peak ALT (IU/L)a167 (67-343)159 (56-533)0.87
Peak prothrombin time (INR)a1.62 (1.29-2.81)1.60 (1.20-2.93)0.49
Peak TB (mg/dL)a3.9 (2.1-9.3)3.4 (1.0-12.0)0.04
Postoperative liver failure [n (%)]0 (0)0 (0) 

The median duration of the postoperative follow-up was 39.4 months (range = 17.5-89.2 months) for group A and 41.3 months (range = 15.1-94.0 months) for group B. All donors recovered completely and returned to their previous activities, and there were no significant differences in overall complications between the 2 groups (Table 4).

Table 4. Complications Graded by the Clavien System According to the RTVR
GradeGroup A: RTVR < 30% (n = 28)Group B: RTVR ≥ 30% (n = 260)Total (n = 288)P Value
  1. NOTE: The data are presented as numbers or as numbers and percentages.

I2 (7.1)16 (6.1)18 (6.2)0.69
1 wound infection10 wound infections11 wound infections 
1 biloma2 bilomas3 bilomas 
 2 MHV partial thromboses2 MHV partial thromboses 
 1 left portal vein partial thrombosis1 left portal vein partial thrombosis 
 1 hematoma1 hematoma 
II1 (3.6)7 (2.7)8 (2.8)0.56
1 transfusion2 transfusions3 transfusions 
 3 cases of mechanical ileus3 cases of mechanical ileus 
 1 case of hypophosphatemia1 case of hypophosphatemia 
 1 main portal vein stenosis1 main portal vein stenosis 
IIIa1 (3.6)4 (1.5)5 (1.7)0.43
1 biloma2 bilomas3 bilomas 
 1 pneumothorax1 pneumothorax 
 1 biliary stricture1 biliary stricture 
IIIb2 (7.1)10 (3.8)12 (4.2)0.41
1 case of bleeding8 cases of bleeding9 cases of bleeding 
1 biliary stricture1 pleural effusion1 pleural effusion 
 1 diaphragmatic hernia1 diaphragmatic hernia 
  1 biliary stricture 
IVa01 (0.4)1 (0.3)>0.99
01 case of rhabdomyolysis1 case of rhabdomyolysis 
IVb000
V000
Total6 (21.4)38 (14.6)44 (15.3)0.34

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

A major concern for right liver LDLT is the remnant liver volume, which has been reported to be closely related to complications in living donors.[14, 15] Therefore, exploring the lowest limit of the RTVR in living liver donors may be an ethical challenge because it can entail potential risk. However, the outcome after living donor hepatectomy is due not only to the remnant liver volume size but also to other donor factors at the time of surgery such as age, fatty changes, and undetected underlying illness. Moreover, in the setting of delayed recovery of liver function in donors with a small RTVR, a second complication (eg, a bile leak, an infection, or an accident of anticoagulation) can potentially contribute to a cycle of fatal complications.

It was reported that the outcomes of 9 donors with an RTVR < 30% were similar to those of donors with an RTVR ≥ 30%.[16] Living donors, a highly select healthy cohort, are expected to tolerate smaller remnant liver volumes than patients with diseased livers, but specific indications for safe remnant liver volumes under certain accompanying conditions have yet to be addressed.

A small remnant liver volume can lead to small-for-size syndrome, which is characterized by prolonged postoperative hyperbilirubinemia, coagulopathy, and ascites. In addition to the small remnant liver volume itself, other factors such as venous outflow congestion, donor age, and steatosis determine the development of small-for-size syndrome.[17] Therefore, in this study, an RTVR < 30% was strictly restricted to those donors who met the following criteria: the preservation of the MHV, an age < 50 years, and no or mild fatty changes in healthy adults.

In this study, 28 donors (9.7%) had an RTVR < 30%, with the lowest being 23.1%. Actually, the only significant difference in outcomes concerned the peak serum TB level, which was higher in group A versus group B. The significantly longer hospital stay for group A versus group B was due to the donor care policy of our institution: donors with an RTVR < 30% require more careful observation than otherwise provided because of concerns about potential morbidity related to a small remnant liver volume. Otherwise, no statistical differences were observed in the overall outcomes of the 2 groups. In all donors, serum AST, ALT, and TB levels and INRs were normalized within 1 month.

The degree of steatosis acceptable for living donors remains undetermined, with an upper limit of steatosis as high as 50% reported.[18] At our institution, the upper limit for hepatic steatosis is 33% even in living donors with an RTVR < 30% predicted by preoperative CT volumetry. US was used to detect hepatic steatosis in this study. Although US is a widely available and low-cost technique, it is neither quantitative nor useful in the detection of low levels of steatosis.[19] However, as shown in Fig. 2, no donor who preoperatively had no or mild steatosis on US had histological steatosis > 30% despite the moderate correlation between the results of US imaging and the histopathological results. Therefore, US can be used effectively to exclude at least moderate to severe degrees of steatosis. This is the reason that liver biopsy is performed selectively in donors in whom a moderate degree of steatosis is suspected on US. Of course, severe steatosis on US is an absolute contraindication for living donation.

In this study, removal of the MHV with the graft was not performed in any donor for whom the predicted RTVR was <30%. Although previous reports have suggested that the inclusion of the MHV with living donor right lobe grafts can be performed safely in most donors,[20, 21] in donors with a small remnant liver volume, procuring the MHV as part of the right liver graft may potentially increase donor morbidity because the apparent functional mass can be compromised by venous congestion of Couinaud segment IV of the remnant left liver. Liver fixation via the suturing of the falciform ligament to the abdominal wall will also ensure that a venous outflow obstruction or impairment does not occur and compromise function.

Surgical experience is another variable that must be considered when one is deciding whether to accept the selection criteria for an RTVR < 30% after right hepatectomy. Any complication, including near-miss events such as bleeding, infections, biliary leakage, and strictures, may tip the balance against donor safety in this situation. For liver resection, programs with large patient volumes generally have better short-term surgical outcomes and long-term survival outcomes.[22] At our center, the single surgeon in the liver transplant program performs more than 150 liver resections per year (including living donor procedures). Whether the same safety outcomes for donor procedures can be achieved by centers performing fewer liver resections merits further study.

This study suggests that living donors with an RTVR < 30% deserve consideration under the aforementioned 3 conditions when no other donor is available within a suitable waiting time in the present era of accumulated experience and improved surgical techniques and postoperative care. Further studies are warranted to investigate the factors affecting the function of small remnant livers and thereby define the safe lower limits for living donation.

In conclusion, right hepatectomy preserving the MHV with an RTVR < 30% can be safely indicated for carefully selected living donors less than 50 years old with no or mild fatty changes.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES