Challenges and strategies for optimizing liver transplantation outcomes in morbidly obese cirrhotic patients: a narrative review

Abstract

The rising prevalence of morbid obesity (BMI > = 40) has introduced significant challenges in liver transplantation, particularly as metabolic dysfunction-associated steatohepatitis (MASH) becomes a leading cause of end-stage liver disease. Morbidly obese transplant candidates face higher perioperative complications, increased waitlist mortality, and worse post-transplant outcomes. This review explores these challenges and examines current strategies for managing morbid obesity in this population. Pre-operative weight loss and bariatric surgery prior to or in conjunction with transplantation have shown potential to improve eligibility and outcomes. Furthermore, emerging evidence suggests that BMI matching seems to influence graft function and survival. Finally, surgical techniques, such as robotic-assisted liver transplantation, while still novel and anecdotal, offer significant promise for reducing complications in this high-risk population.

Introduction

The rising prevalence of obesity, and specifically morbid obesity, defined as a body mass index (BMI) > = 40, is complicating the management of patients of chronic liver disease (CLD). In the most recent survey done by the CDC, in 2023, all US states and territories had an obesity prevalence higher than 20%, with three states (Arkansas, Mississippi, and West Virginia) having a prevalence of 40% or greater [1]. The prevalence of severe obesity was 9.4% overall, with there being higher severe obesity rates in adults aged 20–39 (9.5%) and 40–59 (12.0%) compared to those aged 60 and older (6.6%) [2]. With the worsening obesity epidemic, more patients with morbid obesity are developing liver-related pathology such as metabolic dysfunction-associated steatotic liver disease (MASLD) and its inflammatory counterpart, metabolic dysfunction-associated steatohepatitis (MASH). In a couple recent studies by Ferretti et al., Wong et al. and Cholankeril et al., MASH, formerly known as non-alcoholic steatohepatitis (NASH), is the fastest growing etiology of end stage liver disease (ESLD), and ever since 2008 has surpassed alcoholic liver disease to become second leading cause of liver transplant worldwide in males [3–5] after cirrhosis secondary to Hepatitic C (HCV), and in females, the leading cause [6]. Compared with other indications for liver transplant, recipients with MASH were on average 5 years older, more likely to be female, and unsurprisingly, more likely to be obese (63% vs. 32%) [7].

While liver transplantation remains the only curative treatment for patients with ESLD, morbidly obese patients present many challenges during the laborious transplant process, including higher rates of metabolic, cardiovascular, and renal complications, worse post-operative outcomes, and high waitlist mortality. This review paper will discuss these challenges in detail, as well as how current strategies for weight loss (lifestyle interventions, pharmacological, and surgical) in the perioperative period could affect short and long-term outcomes in this population.

Considerations in morbidly obese liver disease patients

Taking a closer look at the data surrounding liver disease in the morbidly obese, some studies show that up to 7–80% of bariatric surgery patients have MAFLD), while 25–55% of those patients progress to MASH [8]. Of the patients with MASH, about 20% will eventually progress to cirrhosis and end-stage liver disease (ESLD) [9]. Once progression to cirrhosis, management becomes more complex for those of higher body habitus, since patients become much more prone to co-morbidities such as coronary artery disease, diabetes, hypertension, dyslipidemia, metabolic syndrome and chronic kidney disease [10]. Additionally, as the cirrhosis decompensates, lifestyle measures become exponentially more difficult to implement, and bariatric surgery becomes riskier [11].

Despite the increasing need for liver transplant in morbidly obese patients, many are denied placement on the transplant waitlist due to concerns over perioperative risk, post-transplant outcomes, as well as difficulty in matching donors. Currently, the American Association for the Study of Liver Disease even considers BMI > = 40 as a soft contraindication for transplant for these exact reasons, and the European Association for the Study of the Liver guidelines state that a “multidisciplinary team should carefully evaluate patients with a BMI > = 35 before listing” [12]. When these patients do get listed, even after adjusting for common predictors of waitlist dropout, morbid obesity remained as one of the only predictors of waitlist removal or death (HR = 1.27), along with diabetes (HR = 1.14), likely from increased rates of acute-on-chronic liver failure or the many comorbid conditions discussed above [3]. These patients also had longer wait times for transplant and higher Model for End-Stage Liver Disease (MELD) scores on average [13, 14].

When these patients do meet the criteria for listing, they have worse outcomes. In a landmark systematic review done out of Italy including over a hundred thousand patients, researchers found that compared to obese patients with BMI < = 35, patients with BMI > = 40 had increased mortality risk at all time-periods up to 5 years (except at 3 years). Interestingly, however, patients whose BMI was between 35 and 40 did not show increased risk at any of these time frames. In addition, there was a significantly higher number of infections, reoperation, and vascular and cardiopulmonary complications in patients with BMI > = 30 compared to non-obese patients, with insufficient data to compare each obesity class. The length of hospital and/or ICU stay, however, was the same between obese and non-obese patients [13–15]. Conversely, a much smaller study done in the UK including two thousand patients, concluded that post-transplant survival up to 10 years is independent of recipient BMI; however biliary complication risk does correlate [5]. Yin et al. even found that a higher BMI was inversely associated with long-term mortality of patients with cirrhosis, supporting a “obesity paradox” phenomenon previously shown in various disease processes [16].

Looking more specifically at graft survival, a single-institution study showed that BMI > 35 and BMI < 35 groups had similar outcomes, while BMI < 18.5 patients had inferior graft and patient survival rates [5]. However, in another database-level study utilizing the Scientific Registry of Transplant Recipients (SRTR), morbidly obese recipients when compared with non-obese recipients showed significantly reduced 5-year graft survival (49% vs. 76%) [13].

Overall, morbidly obese patients are more likely to encounter obstacles during the transplant evaluation, tend to stay longer or have higher dropout on the waitlist, and are sicker at the time of transplant. Superobesity is associated with higher mortality, while obesity in general is associated with higher perioperative complications and reduced long term graft survival.

Impact of donor characteristics in transplantation of morbidly obese cirrhotics

Donor-recipient BMI matching plays an important role in liver transplant regardless of BMI. Common scores proposed for matching in the graft allocation process are divided into those focusing on donor liver quality like the Donor Risk Index (DRI) and Eurotransplant-Donor-Risk-Index (ET-DRI), those focusing more on recipient or graft outcomes like the Preallocation score to predict Survival Out-comes Following Liver Transplant Score (P-SOFT), Delta-MELD (D-MELD), or Italian Score for Organ allocation (ISO), and those consider both like the Balance of Risk (BAR) score. Out of these scoring systems, only the P-SOFT score considers BMI an important variable in post-transplant outcomes [17]. In a study done out of Ohio State University, Beal et al. found that while there is increased mortality at 30 days for obese donor– obese recipient pairs after controlling for confounding variables, this difference no longer persists long term, and that 1 year and overall survival favor the obese recipient - obese donor pair. The lowest mortality rates were between non-obese donor– obese recipient pairs at 1 year, 5 years, and overall. They speculate that the early disadvantage in patients receiving obese donor livers could be due to their increased fat content resulting in graft dysfunction [1]. Another study done by Marsman et al. reinforces this theory, also reporting lower liver graft survival with livers containing up to 30% fat compared to livers without fatty infiltration; however, this effect disappeared long-term [18]. Graft and patient survival between BMI > 50 and BMI < 50 were similar as well [19]. Beal et al. also discovered that there was a shorter length of stay in the obese recipient - obese donor pair and obese recipient– non-obese donor pair, compared to the non-obese recipient– non-obese donor pair, in line with the “obesity paradox” discussed above. Proposed mechanisms for this involve a shift in the anti-inflammatory status of obese patients and their excess nutritional reserves, helping them tolerate the metabolic stress of critical illness [20, 21]. Obese living donors compared to non-obese living donors were more likely to be female, and much more likely to have diabetes and hypertension. Lifestyle modifications such as diet and exercise could improve hepatic steatosis in this donor candidate population, but the postoperative complications were comparable whether or not weight-loss was achieved, and graft and recipient survival rates were the same [22]. No studies were found looking into characteristics of deceased donor candidates. Also of note, although donor obesity was perceived as lower quality by recipients, there was no significant effects of this perceived quality on re-listing or death [23]. Despite the non-conclusive evidence detailed above on the importance of obesity in the transplant process, especially in comparison to age, gender, and MELD score, donor-recipient BMI matching should remain an important topic of continued investigation. High-resolution magic-angle-spinning nuclear magnetic resonance (HR-MAS-NMR) is an emerging technology that has potential in evaluating metabolic profiling and could prove helpful in the matching process [24].

Obese donor orthotopic liver transplant (OLT) may lead to worse short-term outcomes but not in the long term, while obese OLT recipients have shorter hospital stays but similar outcomes overall. However, tangentially related to obesity, donor-recipient body surface area (BSA) mismatch has been shown to affect rates of portal vein thrombosis within the first three months, as well as overall graft survival [25]. Liver waitlist candidates with the smallest BSAs also had a lower chance of receiving a deceased donor liver transplant compared to peers with larger body habitus [26], once again emphasizing the importance of BMI matching.

Lastly, compared to deceased donor liver transplantation (DDLT) in obese candidates, there is not much literature on living donor liver transplantation (LDLT) outside of case reports [27]. But for morbidly obese transplant candidates, LDLT may offer certain advantages like shorter cold ischemia time (CIT), shorter waitlist time, and more precise donor-recipient matching. On the other hand, the benefit of DDLT is that whole-liver grafts are potentially more appropriate for larger and more metabolically demanding patients.

Preoperative weight loss measures

Due to the high risk of adverse outcomes linked to morbid obesity in liver transplantation, achieving weight loss during the preoperative period is an important goal. Options include lifestyle modifications, medical management, and bariatric surgery [11], but evidence on the effectiveness of lifestyle modifications or medical management for preoperative weight loss is currently limited. This may be in part due to the difficulties and risks in implementing these measures. Thorough nutritional assessment is imperative to minimize the risk of malnutrition, sarcopenia, inflammation, and fibrosis with dietary changes [11, 28, 29]. Exercise regimens are also limited by increased portal pressure and risk of variceal bleeding, which can be addressed with supervision and proper β-blockade therapy [11, 30]. With proper measures, nutritional intervention and supervised exercise programs have been shown to reduce body weight, hepatic venous pressure, incidence of sarcopenia [30], and metabolic dysfunction-associated steatotic liver disease (MASLD), damage, and fibrosis [31, 32].

Regarding medical management, diabetes medications play a crucial role due to the strong association between obesity, chronic liver disease, and diabetes. This connection is further intensified by the increased risk of persistent or new-onset diabetes, as well as MASLD, following immunosuppression after liver transplantation [33, 34]. Certain anti-obesity and diabetes drugs, particularly glucagon-like peptide-1 (GLP-1) receptor agonists and sodium glucose cotransporter 2 (SGLT2) inhibitors, have proven effective in managing diabetes in liver transplant recipients. A study by Zheng et al. compared outcomes among patients receiving GLP-1 receptor agonists, SGLT2 inhibitors, combination therapy, and dipeptidyl peptidase-4 (DPP-4) inhibitors. The results showed that GLP-1 receptor agonists, SGLT2 inhibitors, and combination therapy were associated with significant weight loss, with combination therapy also leading to lower HbA1c and alanine aminotransferase (ALT) levels [35]. Another study demonstrated that exenatide not only reduced fasting plasma glucose and promoted weight loss but also improved lipid profiles and MASLD-related markers in patients with type 2 diabetes, particularly those with a BMI ≥ 40 [36]. These drugs have shown to be well-tolerated [33, 37] and provide the additional benefit of reducing cardiovascular risk [30, 33]. While their use in pre-transplant weight loss has not yet been studied, they show great promise based on their positive effects in the post-transplant setting.

Role of bariatric surgery

With or without non-surgical management, bariatric surgery has demonstrated significant efficacy in the context of liver transplantation, outperforming medical therapy alone [38–40]. Bariatric procedures performed pre-, intra-, and post-transplant have been shown to improve outcomes in morbidly obese patients. However, the optimal timing and choice of bariatric surgery remain areas of ongoing research, with each approach offering specific advantages and indications [40].

As previously discussed, lifestyle modifications and medical management of morbidly obese patients awaiting liver transplantation are difficult to implement and must be closely monitored. Therefore, it is important to consider bariatric surgery as an option for patients awaiting transplant. Compared to medical weight loss, bariatric surgery is associated with higher sustained weight loss and significantly lower risk of diabetes, hypertension, and recurrent and de novo MASLD post-liver transplant [39]. In Sharpton et al., out of 32 morbidly obese liver transplant candidates who failed a medically supervised weight loss program and underwent sleeve gastrectomy, 28 (88%) patients were deemed eligible for transplant within 6 months. No intraoperative deaths or liver-associated morbidity were observed [41]. A separate study done by García-Sesma et al. involving 8 patients with liver cirrhosis showed similarly safe and favorable outcomes following sleeve gastrectomy [42]. In patients with decompensated cirrhosis where bariatric surgery is contraindicated due to increased risk of intra-operative bleeding from perigastric varices, intragastric balloon placement has also shown potential in short-term weight loss and optimizing morbidly obese patients for liver transplantation [43]. With these benefits in mind, difficulties in performing bariatric surgery on these patients must be considered and approached with caution. The presence of an expanded steatotic liver and anatomical differences, specifically increased intra-abdominal fat tissue, can lead to longer operative time, intra-operative bleeding, and anastomotic leakage [44]. Rogers et al. also suggest that transplant recipients with gastric bypass likely need higher doses of tacrolimus, sirolimus and mycophenolate mofetil compared to a non-bypass patient [45], likely because these immunosuppressive drugs are mainly absorbed in the upper gastrointestinal tract [46]. Lastly, the possibility of malnutrition and liver failure associated with bariatric surgery in general must also be considered [45].

Several studies have shown that bariatric surgery can slow the progression or even lead to the resolution of MASH and MASLD, potentially reducing the need for liver transplants [45–48]. Beyond significant weight loss, improvements have been observed in various biochemical markers, including insulin resistance, glucose metabolism, hypertension, plasma lipid levels, and transaminases [45, 48, 49]. Changes in gastrointestinal hormone activity have also been reported [47, 48]. These findings suggest that bariatric surgery may be beneficial even when liver transplantation is not required, though larger studies are needed to clearly define its role in treating MASLD [48].

To reduce risks associated with pre-transplant bariatric surgery, simultaneous transplantation and bariatric surgery has been explored and shown to be a viable alternative with normal allograft function and effective weight loss [49–51]. Zamora-Valdes et al. compared outcomes in patients that underwent liver transplantation alone versus simultaneous transplantation and sleeve gastrectomy. They found that despite appropriate weight loss in both groups, liver transplantation alone was associated with weight regain while transplant with sleeve gastrectomy resulted in higher persistence of weight loss, as well as lower prevalence of hypertension, insulin resistance, and hepatic steatosis [52]. Though there are many instances of successful simultaneous transplantation and bariatric surgery, its safety and efficacy are still not well-established [50, 51].

Evidence surrounding the prevalence of bariatric surgery complications following liver transplantation is not definitive. Several studies suggest that post-transplant sleeve gastrectomy is associated with low morbidity, satisfactory long-term results, and no increase in allograft rejection [53–55]. Like pre- and non-transplant patients, steatosis and obesity-related outcomes have improved following bariatric surgery in obese, posttransplant recipients with recurrent and de novo MASLD [56]. However, a study by Osseis et al. observed one instance of early gastric fistula followed by death due to multi-organ failure 19 months later, as well as chronic infection on a parietal mesh within a group of six patients who underwent post-transplant sleeve gastrectomy [57]. Lin et al. followed nine morbidly obese patients with prior liver transplant who underwent sleeve gastrectomy. Complications in three different patients included mesh dehiscence after synchronous incisional hernia repair, bile leak from the liver surface, and postoperative dysphagia requiring reoperation [58]. These early complications could be attributed to the development of surgical adhesions following initial liver transplantation [51, 58]. As with simultaneous transplantation and bariatric surgery, larger studies are necessary to reconcile differences in the outcomes observed in these studies.

Role of robotic surgery in morbidly obese patients with liver disease

Robotic liver surgery is gaining prominence in minimally invasive surgery due to its stable camera platform, elimination of tremors, enhanced dexterity, and improved ergonomics, making it particularly well-suited for complex liver procedures requiring precise tissue dissection and meticulous hemostasis [59]. Robotic surgery has been shown to be beneficial in morbidly obese kidney transplant recipients with fewer surgical site infections and similar graft and patient survival, and offers a safe alternative for morbidly obese patients who may otherwise be denied access to open kidney transplant [60]. However, robotic surgery in liver transplant has only been performed at a few centers worldwide and is currently selectively offered to patients with low MELD scores and low BMI. The existing literature primarily consists of anecdotal evidence, predominantly in the form of case studies that detail the successes of these procedures in one or a few patients. The following section will review the most recent literature and the role of laparoscopic and robotic-assisted liver transplantation in patients with liver disease.

The evolving role of laparoscopic techniques in liver transplantation is highlighted by recent innovations aimed at improving patient outcomes with minimal invasiveness. Dokmak et al. [61] introduces a hybrid approach combining pure laparoscopic total hepatectomy with graft implantation via a preexisting midline incision. This method demonstrates the feasibility and safety of laparoscopy in select cases, offering minimal invasiveness while retaining traditional techniques for safety. The surgery resulted in minimal blood loss and an uneventful recovery, indicating potential for further development.

Suh et al. [62] presents a pure laparoscopic LDLT where both hepatectomy and graft implantation were completed laparoscopically through a suprapubic incision. This fully laparoscopic technique provides advantages such as smaller incisions, reduced postoperative pain, and faster recovery, but requires specialized expertise due to its complexity and longer operation times. Lee et al. [63] shares a landmark case involving a 63-year-old patient with primary biliary cirrhosis who underwent total laparoscopic explant hepatectomy followed by robot-assisted engraftment. Despite a lengthy 12-hour surgery, successful completion and recovery from early allograft dysfunction illustrate the feasibility of combining robotic and laparoscopic techniques for select recipients.

In August 2023, the King Faisal Specialist Hospital in Riyadh performed the world’s first fully robotic recipient hepatectomy and liver graft implantation from a fully robotic living donor hepatectomy [64]. This approach enhances precision, safety, and visualization while requiring careful patient and graft selection, marking a significant step toward fully robotic liver transplantation (RLT).

Khan et al. [65] reported the first RLT in North America and globally using a whole graft from a deceased donor in a 62-year-old man with hepatitis C cirrhosis and hepatocellular carcinoma (HCC). The operation had a total console time of 8 h 30 min, with the patient experiencing an uneventful recovery without early allograft dysfunction or complications, further demonstrating the feasibility of RLT in carefully selected patients. A recent European series from Lisbon and Modena University Liver Transplant Centers reported six full robotic whole liver transplantations, showing favorable outcomes in patients with HCC and low MELD scores [66]. These cases highlight the potential benefits of robotic LDLT, including smaller incisions, precise tissue manipulation, and reduced postoperative pain, though further technical refinements are needed to enhance reproducibility. In the more unpredictable DDLT setting, the feasibility of robotic explant and implant is a more distant realization.

Conclusion

In conclusion, the increased prevalence of obesity, specifically morbid obesity, has significantly changed the landscape of liver transplantation, with MASH now quickly becoming one of the top etiologies of liver failure and subsequent transplant. These patients face unique challenges throughout the transplant process, including higher rates of comorbid conditions, longer wait times, and increased mortality, but their short and long-term outcomes post-transplant seem similar to those of their weight-controlled peers. Donor-recipient characteristics play an important role in both LDLT and DDLT, but ultimately, the presence of donor obesity does not seem to impact graft function and recipient morbidity and mortality.

In addition, preoperative weight loss interventions, ranging from lifestyle modifications and pharmacological measures to bariatric surgery, are crucial in morbidly obese patients. While non-surgical measures have some supporting evidence, bariatric surgery peri-operatively has shown significant benefits, including sustained weight loss as well as reduction of hypertension and even MASH progression. Simultaneous liver transplant and bariatric surgery is also being explored as a feasible option for better long-term weight management and reduced metabolic complications, but more extensive studies are needed to establish safety and efficacy.

The early data on robotic LDLT are promising and RLT may offer reduced postoperative pain and quicker recovery times, ultimately expanding the eligibility for liver transplantation. Continued research in this field is essential to optimize robotic techniques for this high-risk population.

Author contributions

J.Z. and S.M. contributed equally to the work as 1st authors. J.Z., S.M., C.B. performed the study design. J.Z., R.W., J.B. wrote the main manuscript text. J.Z., S. M., R.W., J.B., R.M., K.S., C.B. were involved in editing and finalizing the manuscript.

Funding statement

The authors declare no financial support for the research.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This study is a review of existing literature and does not involve human subjects, therefore consent to participation is not applicable.

Competing interests

The authors declare no competing interests.

Conflict of interest

The authors declare that they have no conflict of interest.