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INTRODUCTION
Living donor liver transplantation (LDLT) is an established treatment option for end-stage liver disease, addressing the shortage of deceased donors and reducing mortality rates on the waiting list [1-3]. However, due to limitations in LDLT, including a lack of donor voluntarism and stringent donor-selection criteria, a shortage of organs persists. Additionally, the prevalence of obesity has been consistently increasing globally, leading to a significant rise in non-alcoholic fatty liver disease (NAFLD) associated with a higher body mass index (BMI) [4]. This growing prevalence of obesity has created substantial challenges in selecting suitable living liver donors [5].
Recently, high-volume centers with extensive experience have been performing donor right liver resection (DRLR) only in highly selected donors with a high BMI [6-10]. However, there are not many studies on this topic, and conclusions regarding the impact of high BMI on donor outcomes are inconsistent. For instance, in 2015, Guler et al. [11] suggested that a BMI above 25 kg/m2 in living male donors, particularly when the remnant liver volume is less than 32.5%, is associated with an increased risk of major complications. In contrast, in 2017, Knaak et al. [6] reported no differences in complications between donors with BMI <30 kg/m2 and those with BMI ≥30 kg/m2, concluding that a higher BMI should not be a contraindication for living liver donation.
Over the past few decades, extensive research has been conducted on obesity, and it is now recognized as a disease [12,13]. Paradoxically, the number of living liver donors with a high BMI is increasing. Consequently, the need for evaluating the clinical outcomes of high BMI donors who underwent DRLR for LDLT is also rising. Therefore, we reviewed our experiences with DRLR in donors with a BMI ≥30 kg/m2. We aimed to verify its safety and feasibility by comparisons between two groups undergoing DRLR with BMI ≥30 kg/m2, or BMI ≤25 kg/m2. The findings from our study could significantly expand the pool of eligible living donors, thereby increasing opportunities for LDLT and potentially providing more recipients with life-saving transplants and improved survival outcomes.
MATERIALS AND METHODS
Study Design and Patient Population
This retrospective study included living donors who underwent DRLR with BMI ≥30 kg/m2, at a single institute between July 2015 and December 2020. Living donors who underwent DRLR with normal-weight (BMI ≤25 kg/m2) during the same period were included as a control group for comparison of clinical outcomes. Considering the different criteria for obesity— World Health Organization (WHO) defines obesity as a BMI of 30 kg/m2 or higher, while the Asian criteria set the cutoff value at 25 kg/m2 or higher [14]—donors with a BMI between 25 and 30 kg/m2 were excluded to minimize discrepancies arising from these different definitions. A total of 1,166 patients were included in this study. Of these, 1,125 patients had a BMI ≤25 kg/m2 and 41 patients had a BMI ≥30 kg/m2. We compared donor and recipient outcomes between these two groups using the greedy method. The flowchart of this study design is described in Fig. 1.
The primary endpoint was the comparison of living donor safety, including postoperative laboratory findings (peak aspartate transaminase, alanine transaminase, and total bilirubin), operative morbidity, and readmission rate. The secondary endpoints were the comparisons of incidence of surgical postoperative major complication.
Donor Evaluation and Selection Criteria
The details of the criteria for selecting suitable donors have been described in previously reported studies [3,15,16]. All living donor candidates were evaluated by laboratory test, volumetric computed tomography (CT), magnetic resonance (MR) cholangiography, and/or percutaneous core needle biopsy (PCNB). For donor candidates with a BMI ≥30 kg/m2, the indications for donation included the absence or well-controlled presence of comorbidities, minimal or no steatosis, and a sufficient future remnant liver volume. Additionally, our center routinely performs liver biopsies on potential donors with any comorbidities and/or BMI ≥30 kg/m2 to assess the degree of steatosis, and if hepatic steatosis was detected on ultrasound or CT scan, weight reduction is recommended, followed by reassessment.
Our protocol is to select donor candidates with less than 15% macrovesicular hepatic steatosis and a combined macrovesicular and microvesicular steatosis below 30% on PCNB for donations of right lobe (RL) [3]. There are exceptions allow moderate hepatic steatosis (30%–50%) for right liver donations without middle hepatic veins when fulfilled all of the following five criteria [15]. (1) Donor must be younger than 35 years old; (2) an estimated remnant left lobe (LL) to total liver volume (TLV) ratio of 35% or higher; (3) less steatosis in the LL compared to the RL on MR image; (4) sufficient graft-to-recipient weight ratio (GRWR) in the recipient; and (5) the recipient must have urgent medical needs for a liver transplant that preclude waiting for potential donor weight reduction.
Definitions
According to the WHO, obesity is defined as having a BMI of 30 kg/m2 or higher [17]. The distance from the anterior abdominal skin to the root of the celiac artery was termed the celiac artery distance (CAD) [18]. The distance measured along a horizontal plane perpendicular to the CAD was termed the celiac artery transverse distance (CATD). The CA-depth ratio is calculated as CAD/CATD. The readmission was defined the unplanned readmission within a 30-day after DRLR.
Statistical Analysis
Data were expressed as mean values±standard deviation or median values with ranges for continuous variables. Appropriate comparisons were made using the Student’s t-test, chi-square test, Fisher’s exact test, and Mann-Whitney test. Survival curves were estimated via the Kaplan-Meier method and compared using the log-rank test. For comparing outcomes of donors and recipients, donors in the obese group were individually matched 1:1 with those in the normal-weight group using the greedy method to reduce possible bias. Matching criteria included donor age, sex, estimated remnant liver volume, and type of operation, as well as recipient model for end-stage liver disease (MELD) score and GRWR. Statistical significance was defined as p<0.05. All statistical analyses were conducted using IBM SPSS Statistics version 21.0 (IBM Co., Armonk, NY, USA) and SAS version 9.3 (SAS Institute, Cary, NC, USA).
Ethical Approval
Conducted in full compliance with the ethical standards set forth by the Declaration of Helsinki and the Declaration of Istanbul. The living donor process for every case was assessed and approved by the National Institute of Organs, Tissue, and Blood Management, affiliated with the Ministry of Health and Welfare of the Republic of Korea. This study was approved by the Institutional Review Board of Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea (IRB no.: 2024-0744). The retrospective nature of this analysis negated the necessity for obtaining informed consent from participants.
RESULTS
Demographic and Clinical Characteristics of Donors
Table 1 demonstrates the donor demographics and clinical characteristics following BMI. Mean age of the donors were about 28 years and the male donors were significantly higher in the BMI ≤25 kg/m2 group (65.0%) compared to the BMI ≥30 kg/m2 group (48.8%, p=0.033). As expected, the BMI was significantly higher in the BMI ≥30 kg/m2 group, with a mean of 32.51±2.58 kg/m2 compared to 22.02±1.97 kg/m2 in the BMI ≤25 kg/m2 group (p<0.001). The alanine aminotransferase (ALT) levels were also significantly higher in the BMI ≥30 kg/m2 group (20.95 [11.17] IU/L) compared to the BMI ≤25 kg/m2 group (16.11 [8.41] IU/L, p<0.001). However, there was no significant difference in aspartate aminotransferase (AST) levels (p=0.153) and total bilirubin levels (p=0.088) between the two groups.
The CA-depth ratio was significantly higher in the BMI ≥30 kg/m2 group (0.36±0.04) compared to the BMI ≤25 kg/m2 group (0.31±0.04, p<0.001). The CT-measured graft volume was significantly higher in the BMI ≥30 kg/m2 group (940.22±197.10) compared to the BMI ≤25 kg/m2 group (704.89±126.03, p<0.001). Similarly, the graft weight measured after procurement was significantly higher in the BMI ≥30 kg/m2 group (904.54±167.65) compared to the BMI ≤25 kg/m2 group (681.24±114.76, p<0.001).
Macrovesicular steatosis was found during intraoperative liver biopsy to be 4.31% in the BMI ≥30 kg/m2 group, which, although less than 5%, was still significantly higher compared to the 1.87% observed in the BMI ≤25 kg/m2 group (p<0.001). There were no significant differences in incision type of donor hepatectomy between two groups and conventional J incision is mostly performed type of surgery.
In terms of anatomical factors of the donors, there were no significant differences in the portal vein type, hepatic artery, inferior hepatic vein and bile duct between two groups. The most common type of portal vein was type 1 (86.4% vs. 89.7%, p=0.932) and about half of the donors (544/1,166, 46.6%) had an inferior right hepatic vein.
Demographic and Clinical Characteristics of Recipients
The recipient demographic data and clinical outcomes categorized by BMI, are detailed in Table 2. Mean age of the recipients with donor BMI ≤25 kg/m2 group were 54.45±8.99 years and 53.54±10.32 years in the BMI ≥30 kg/m2 group (p=0.525). Male were account for above 70% of the recipients and there were no significantly differences. The most common cause of the original disease was viral hepatitis following alcoholic cirrhosis and there were no significantly differences between two groups. Combined hepatocellular carcinoma were founded about half of the recipients and ABO-incompatible LDLT were performed in 18.9% of the donor BMI ≤25 kg/m2 group and 17.1% of the donor BMI ≥30 kg/m2 group (p=0.765). The MELD scores were also similar between the groups, with a mean score of 14.86 ± 8.28 in the BMI ≤25 kg/m2 group and 14.46±8.24 in the BMI ≥30 kg/m2 group (p=0.763). The GRWR did not differ significantly, being 1.17±2.99 in the BMI ≤25 kg/m2 group and 1.24±0.35 in the BMI ≥30 kg/m2 group (p=0.872).
Perioperative Outcomes of Donors and Recipients
Perioperative outcomes of donors and recipients are described in Table 3. Operative time during donor hepatectomy was significantly longer in the BMI ≥30 kg/m2 group (388.85±72.53 minutes) compared to the BMI ≤25 kg/m2 group (366.73±62.33 minutes, p=0.027). However, there were no significant differences between the two groups in terms of warm ischemic time (p=0.522), peak AST (p=0.488), peak ALT (p=0.160), peak total bilirubin (p=0.129), lowest glomerular filtration rate (p=0.813), hospital stay (p=0.241), readmission rates (p=0.298), and postoperative major complications (p=0.623).
The hospital stay of the recipient was slightly longer in the BMI ≥30 kg/m2 group, with a mean of 30.16±29.00 days compared to 25.93±24.28 days in the BMI ≤25 kg/m2 group, but this difference was not statistically significant (p=0.338). Also, major complications in recipient including biliary stricture, leakage, portal vein stenosis and hepatic artery thrombosis were not statistically differences between two groups.
Comparison of Demographic and Clinical Characteristics and Perioperative Outcomes after Matching
Donor and recipient’s demographic data and clinical characteristics after matching are summarized in Table 4. The donor’s AST levels were significantly higher in the BMI ≥30 kg/m2 group (19.56 [3.39] IU/L) compared to the BMI ≤25 kg/m2 group (17.41 [4.08] IU/L, p=0.021). Similarly, ALT levels were also significantly higher in the BMI ≥30 kg/m2 group (21.00 [9.43] IU/L) compared to the BMI ≤25 kg/m2 group (14.82 [6.71] IU/L, p=0.003).
The CA-depth ratio was significantly greater in the BMI ≥30 kg/m2 group (0.36±0.04) compared to the BMI ≤25 kg/m2 group (0.30±0.03, p<0.001). The estimated graft volume was significantly higher in the BMI ≥30 kg/m2 group (939.71±211.06) compared to the BMI ≤25 kg/m2 group (681.41±128.87, p<0.001). Macrovesicular steatosis was significantly higher in the BMI ≥30 kg/m2 group (4.35±4.79) compared to the BMI ≤25 kg/m2 group (1.11±1.84, p< 0.001). The graft weight was also significantly higher in the BMI ≥30 kg/m2 group (921.18±167.91) compared to the BMI ≤25 kg/m2 group (672.59±103.37, p<0.001). The anatomical type of the graft (such as portal vein, artery and bile duct) were not significantly difference between two groups.
Following recipient demographics, after matching, the most of the variables except for GRWR, were not significantly different between the two groups. The GRWR was significantly higher in the donor BMI ≥30 kg/m2 group (1.27±0.36) compared to the donor BMI ≤25 kg/m2 group (1.06±0.23, p=0.004) after matching.
Perioperative outcomes of donors and recipients after matching are described in Table 5. Similar to the pre-matching results, the BMI ≥30 kg/m2 group had significantly longer operative times during donor hepatectomy. However, other postoperative outcomes, including blood test results, hospital stay, major complications, and readmission rates, did not show significant differences between the two groups.
Similar to the pre-matching analysis, there were no significant differences in the operative outcomes of the recipient including hospital stay, biliary complications, portal vein stenosis, and hepatic artery thrombosis.
DISCUSSION
In this study found that high BMI donors (≥30 kg/m2) exhibited significantly higher preoperative ALT levels, CA-depth ratios, estimated graft volumes, and macrovesicular steatosis compared to donors with BMI ≤25 kg/m2. Despite these differences, there were no significant differences in postoperative major complication rates, lengths of hospital stay, and readmission rates between the two groups. Furthermore, both groups had similar major surgical outcomes of recipients including biliary complications and lengths of hospital stay. This study emphasizes that with careful selection and thorough preoperative evaluation, LDLT from high BMI donors can be safely performed without compromising recipient outcomes.
Obesity is often associated with additional comorbidities such as cardiopulmonary dysfunction, diabetes, NAFLD, and stroke, which can lead to increased postoperative morbidity and mortality [13,19,20]. In addition to these medical issues, obesity and its associated body shape and composition create significant technical difficulties in general surgeries. The presence of extra adipose tissue surrounding abdominal organs and structures necessitates additional dissection, thereby requiring a longer operation time, and increasing the risk of unintentional injuries surrounding organs and tissues during surgery. Consequently, the technical challenges posed by obesity further complicate surgical procedures [21]. In terms of liver resection, the incidence of hepatic steatosis is approximately 25% higher in obese patients, leading to increased complication rates after hepatic surgery.
The outcomes in obese patients have been analyzed in several studies with inconsistent results [20,22-24]. Mathur et al. [20] conducted a retrospective cohort study to compare postoperative complications and a 30-day mortality in 3,960 patients undergoing liver resection, utilizing the American College of Surgeons National Surgical Quality Improvement Program database. They found that obesity is associated with higher perioperative complications compared to non-obese patients, without a significant increase in a 30-day mortality. On the contrary, Nomi et al. [25] studied 228 patients undergoing laparoscopic liver resection and demonstrated that a higher BMI does not adversely affect short-term outcomes of the procedure. Similarly, Utsunomiya et al. [26], in a study with a similar design, showed no significant difference between obese and non-obese patients regarding postoperative complications and long-term outcome after curative liver resection for hepatocellular carcinoma.
Given the varying opinions on the safety of liver resection in high BMI patients, and the increasing prevalence of obesity worldwide, DRLR is often performed in selective high BMI donors. However, the eligibility of obese donors for LDLT, where donor safety is paramount, remains a subject of debate. With the increasing number of liver donations from high BMI donors for LDLT, guidelines for high BMI donors are being established in several groups. However, guidelines for BMI cutoffs in living donor selection vary significantly across countries and centers, affecting the eligible donor pool in different regions [27]. For instance, the Indian contraindication (BMI >25 kg/m2) and the American contraindication (absolute: BMI >40 kg/m2; relative: BMI >35 kg/m2) greatly influence the potential donor pool before any further examining for comorbidities. These differing practices are partly due to variations in BMI distribution, with 19.7% of Indians versus 69.7% of Americans being at least overweight. Additionally, the WHO’s BMI stratification for the Asian population uses different cutoffs due to higher body fat percentages at lower weights compared to Western populations.
Multiple studies commonly emphasize that it is not the absolute BMI cutoff value in the guidelines that is crucial, but rather the careful selection through thorough preoperative evaluation, even within the specified BMI range. It is essential to ensure that there are no issues related to cardiopulmonary dysfunction, disturbances in metabolic function, or hemostasis that could increase postoperative complications. In particular, accurate assessment related to liver steatosis is necessary. Bhangui et al. [28] reported that the use of a right liver graft with approximately 20% macrovesicular steatosis does not compromise graft function or recipient outcomes and is safe for the selected donor in LDLT. Our retrospective study of 58 donors also found that outcomes of LDLT from donors with moderate hepatic steatosis of 30%–50% were comparable to those in donors without hepatic steatosis, with no significant differences in graft and remnant LL regeneration rates [15]. However, the use of steatotic liver grafts from live donors remains controversial in terms of donor safety and recipient outcomes. Therefore, in cases where donor candidates frequently have mild-to-moderate steatosis, weight loss before donation may be a good strategy to increase donor safety and ensure better recipient outcomes, except in urgent cases where the recipient’s condition does not allow for it [16,29,30].
This study has several limitations. First, the present study was limited due to its retrospective observational study design, with inherent risks of confounding factors and bias. Second, after matching, the study sample size was relatively small, which made detailed statistical analysis, such as multivariate analysis, impossible, potentially limiting the generalizability of the results. Lastly, although BMI is the simplest and most long-standing tool for measuring obesity, it has limitations in accuracy as it does not account for muscle mass or body fat percentage. However, there are several studies on the relationship between BMI and NAFLD [31,32], and among the studies concerning the safety of high BMI living donors who have donated their RL, this research has the largest sample size from a single center in Asia, as far as we know.
In conclusion, RL donation from high BMI living donors with ≥30 kg/m2 in LDLT can be performed safely in strictly selected cases sufficient remnant liver volume with almost no steatosis and comorbidities. Additionally, the outcomes of recipients were not impaired by the influence of high BMI donors per se through careful selection of cases. These findings could significantly expand the pool of eligible living donors, thereby increasing opportunities for LDLT and potentially providing more recipients with life-saving transplants and improved survival outcomes. However, given that obesity is now considered a disease and the inherent risks of surgery in obese individuals cannot be ignored, RL donation from high BMI living donors (≥30 kg/m2) should only be performed in the absence of other suitable living donors after thorough preoperative evaluation.
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