The role of bariatric surgery in liver transplantation: timing and type

The prevalence of obesity is rapidly rising across the world, with more than one-third of Western populations now being classified as obese [1]. The complications from the obesity epidemic include increased rates of cardiac disease, diabetes mellitus, hypercholesterolemia-related problems and metabolic disorders [2]. Over 80% of obese patients suffer from non-alcoholic fatty liver disease (NAFLD). Of these, one-third will progress to non-alcoholic steatohepatitis (NASH), and one-quarter of NASH patients develop cirrhosis [3, 4]. NASH-related cirrhosis is predicted to become the leading indication of liver transplantation over the next decade [5].

Obesity can complicate liver transplantation (LT) by increasing morbidity due to higher infection rates and wound healing issues. But increasingly, concerns over NASH development in the transplanted organ due to immunosuppressive medications and/or elevated body mass index (BMI) have been raised [6, 7]. Historically, a BMI > 40 was considered a relative contraindication in many centres [8, 9], but with the rise in adiposity, this has been reconsidered. Lifestyle modification and/or medications still remain first-line in the management of obesity, but the role of bariatric surgery is important due to its longer-lasting effect and efficacy [10]. Recent studies have shown that bariatric surgery can stop the progression, or even reverse NAFLD [11]. Of the various techniques available, sleeve gastrectomy (SG) and Roux-en-Y bypass (RYBP) remain the most commonly performed. SG is solely a restrictive procedure, whereas RYBP is both a malabsorptive and a restrictive procedure [12]. Both have observed comparable weight loss and impact on comorbidities at mid- to long-term follow-up [13].

Recently, the role of bariatric surgery before or concomitant with LT has been explored. However, there remains no consensus on the timing of BS. Theoretically, performing BS prior to LT means that the patient may reduce weight (and improve associated comorbidities); however, it requires two separate operations and hospitalisations. Alternatively, concomitant BS and LT have the benefit of one anaesthetic, with shorter hospital stay, and prevent delays to LT [14]. This review aims to address the benefit of BS prior to LT, focusing on the benefits specific to the timing and type of BS.

A systematic review was performed according to the preferred reporting items for systematic reviews and meta-analyses checklist (PRISMA). No approval was required from the review board.

Obesity has shifted the indications for LT, with NASH now on the verge of becoming the leading indication [5]. The prevalence of cirrhosis related to NASH is likely to be underestimated, as more and more cryptogenic cirrhoses are now attributed to NASH [20, 21]. Obesity is also associated with higher morbidity and mortality in major abdominal surgery, including liver transplantation [22, 23].

Solid-organ transplantation is an inherently complex procedure, which is further complicated by obesity. Many factors increase the likelihood of weight gain after solid-organ transplantation, including the long-term use of immunosuppressive medications that are required for graft survival [24]. These factors however are inevitable in the LT setting, but efforts should be placed on effective weight loss in obese patients. Weight gain after LT was shown to be strongly influenced by pre-transplant obesity [25], which in turn may lead to de novo NASH or NASH recurrence [6]. In one study, patients having LT with an indication of NASH showed a NASH recurrence of 24.9% within 5 years [26]. Another study showed a higher recurrence rate of almost 100% within 5 years, in patients that showed evidence of NASH on their pre-transplantation biopsy [27]. This has led to increased efforts to facilitate weight loss to prevent these complications.

Medical and surgical options are both available to enhance weight loss. One trial noted a 5% body weight loss in 47% of patients treated with an anti-obesity medication as opposed to 25% in the placebo arm [28]. To date, there is a lack of studies to support weight loss surgery in patients awaiting LT. Bariatric surgery is known to give faster and longer-lasting outcomes compared to medical therapies [10], and has been shown to decrease the metabolic complications in obese patients, even reversing the NAFLD [29, 30].

Data collection and interpretation in these patients pose extra challenges. Ascites can obscure BMI measurements, with patients having larger volumes of ascites creating an overestimation of their BMI [7]. Another factor to consider is whether BMI accurately reflects their nutritional status. One of the studies analysed in this article used skeletal muscle index (SMI) as a surrogate for the nutritional status of patients [19]. They found the patients that underwent BS tended to have a lower SMI and have a higher mortality while waiting for transplantation. However, SMI measurements are not routinely performed, and doing repeated follow-ups on patients can be resource-demanding, while BMI measurements can be routinely performed.

Furthermore, after BS patients achieve the same BMI as their concurrent cohorts, they still may be suffering from metabolic comorbidities. There is evidence suggesting a high BMI in itself does not contribute to worse outcomes, but the comorbidities associated with obesity do [31]. Therefore it is important to consider these confounding factors when interpreting surgical outcomes, or when matching controls for the study.

The choice of the bariatric procedure has been debated. SG has been shown to improve liver function significantly more than RYBP surgery [32]. Generally, RYBP is associated with a higher rate of morbidity and mortality compared to SG, and in the LT setting, this is no exception. In two of the selected studies, most of the complications and mortality on the waiting list were in the RYBP subgroup [19, 33]. A meta-analysis comparing SG and RYBP showed, despite the higher excess weight loss in the RYBP cohort, the resolution of comorbidities was comparable in both groups, with SG being safer than RYBP [34]. A prospective study of 63 patients investigated the role of laparoscopic SG on NAFLD, with 100% of the patients showing reversal or reduction in the stage of NAFLD, with one patient showing complete regression of cirrhosis [35]. One theory that could explain the inferior outcomes of patients undergoing RYBP is the change in the way alcohol is absorbed after a RYBP surgery, with the difference in the pharmacokinetics of alcohol absorption deteriorating the liver function. Studies have shown that RYBP is associated with a higher alcohol use disorder compared to restrictive procedures [36‐38].

There is still no consensus on the timing of BS relative to LT. Mosko et al. [39] found an increase in mortality post-BS in compensated and non-compensated cirrhotic patients (OR 2.17 and 21.2 respectively). But it should be noted that in this study more malabsorptive BS were performed than restrictive BS, and as mentioned earlier, RYBP is associated with higher morbidity and/or mortality while awaiting LT [19, 33, 34]. A recent meta-analysis investigating the effect of BS in cirrhotic patients also found a higher post-operative bleeding, overall complication rate and an increased LOS in non-compensated cirrhotic patients, compared to their compensated counterparts. However, long-term mortality did not differ significantly between the two groups [40]. In a case series of 32 patients who underwent SG before LT, nine patients were either not enlisted for transplantation or delisted later as the MELD score improved so significantly that LT was deemed unnecessary [41]. This naturally has a high impact on the patients’ quality of life to avoid LT and its associated complications. Not only that, but it also reduces the number of patients waiting on the transplantation waiting list. Simultaneous BS and LT can be achieved to decrease the patient’s discomfort, and remove the need for two separate hospitalization and associated costs [14]. Still, many obstacles may impede a simultaneous procedure. Most LTs are done on an urgent basis, and many institutions may not have a bariatric surgeon available. Also, the complexity of the operation may not be suitable for all patients and strict criteria should be placed in patient selection. There are no described criteria to assess suitability for undergoing simultaneous BS and LT, and a BMI > 40 might be prohibitive depending on hospital guidelines. Many bariatric surgeons may prefer LT as a bridge to BS, to avoid complications such as bleeding and risk of decompensation and to ameliorate portal hypertension before BS. In our search strategy, none of the studies looked into patients with BS performed after LT. One of the main challenges in most centres is candidacy, as BMI > 40 is a contraindication for LT [8, 9]. BS after the LT is a challenging task; as it can be technically difficult due to adhesions, the patient will be under immunosuppression, and the operation itself may alter the absorption of immunosuppressive medication and place the graft at risk [14]. However, one study performing laparoscopic SG after LT showed that SG does not seem to affect the medication dosage after BS [42].

The lack of published reports comparing different strategies restricts the amount of data available for analysis. We acknowledge that the present review has some limitations including heterogeneity in study protocols along with lack of uniformity making analysis of the data difficult. Secondly, as highlighted earlier, patients in the BS + LT cohorts tended to be younger females, and MELD scores were not significantly high, which inevitably introduces selection bias that these outcomes may not be applicable to the general population. Analysis of data from a registry can help reduce the selection bias. In our study, the LT cohort had a lower average MELD score compared to the BS + LT cohort, which can partly be attributed to the higher number of hepatocellular carcinoma (HCC) in the LT cohort, which led to MELD exceptions for undergoing transplantation. Third, most studies included were retrospective studies, which would raise the possibility of bias or unknown cofounding variables and it is impossible to know how many operations were planned, but cancelled. Lastly, as the BMI > 40 in most centres is a prohibitive factor in performing LT, hence not enough data is available on simultaneous BS and LT to make a significant comparison possible.

In conclusion, patients undergoing BS have comparable outcomes in terms of overall patient survival, graft survival and post-operative morbidity, to patients undergoing LT alone. The comparable outcomes should however be seen in light of the fact that patients requiring BS start with a worse baseline, suffer from more comorbidities and in many centres do not qualify for LT, hence having comparable results to the general population undergoing LT is a success. When comparing BMI changes in patients with prior versus simultaneous BS + LT, no significant difference was found. Perhaps, more studies in the future can increase the data available and delineate any existing differences.