10 Review Article Bariatric surgery, obesity and liver transplantation Zunirah Ahmed1, Muhammad Ali Khan2, Luis Miguel Vazquez-Montesino3, Aijaz Ahmed3 1Houston Methodist, Houston, TX, USA; 2Division of Gastroenterology and Hepatology, University of Alabama Birmingham, AL, USA; 3Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA Contributions: (I) Conception and design: A Ahmed, Z Ahmed; (II) Administrative support: A Ahmed; (III) Provision of study materials or patients: A Ahmed; (IV) Collection and assembly of data: Z Ahmed, Khan MA; (V) Data analysis and interpretation: Z Ahmed, A Ahmed, LM Vazquez- Montesino; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Aijaz Ahmed, MD. Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 750 Welch Road, Suite # 210, Stanford, CA 94304, USA. Email: [email protected]. Abstract: The obesity epidemic has profoundly impacted the epidemiology and trends of liver disease. In the current era, non-alcoholic fatty liver disease (NAFLD) progressing to non-alcoholic steatohepatitis (NASH) has emerged as the second leading indication for liver transplant (LT) and has been associated with the rising rates of hepatocellular carcinoma (HCC) with and without underlying cirrhosis. Obesity has been associated with poor post-transplant outcomes including lower patient and graft survival; higher risk of post-operative metabolic complications; poor wound healing; and higher infection rates. Bariatric surgery is currently the most effective management of morbid obesity and has been offered to patients both in the pre and post LT setting. The techniques attempted in LT recipients most commonly include sleeve gastrectomy (SG), gastric bypass surgery with few cases of gastric banding and biliopancreatic diversion. However, there is lack of evidence-based data on the optimal management for patients with obesity and who are liver transplant candidates and/or recipients. In the following discussion, we present the highlights from a review of the literature. Keywords: Obesity; liver transplantation (LT) Received: 04 February 2020. Accepted: 06 July 2020. doi: 10.21037/tgh-2019-ltna-15 View this article at: http://dx.doi.org/10.21037/tgh-2019-ltna-15 Introduction cumulative annual incidence rate for developing HCC in patients with NASH-related cirrhosis is approximately Obesity is an escalating health issue with an estimated 0.34–4.26% (7). It is also the most rapidly growing prevalence in the United States of approximately 39% (1). etiology for acute on chronic liver failure related It is a growing problem which has impacted patients with hospitalizations and is associated with significant cost end-stage liver disease by affecting multiple metabolic burden (8). Furthermore, NASH is the most rapidly pathways of the liver (2) and being a crucial risk factor growing indication for liver transplantation (LT) in the for disease progression (3). Non-alcoholic fatty liver US since it was assigned as a UNOS diagnostic category disease (NAFLD) is the liver manifestation of obesity in 2001 and is on trajectory to become the most common with a clinicopathological disease spectrum ranging indication for LT over all (9,10). from isolated hepatic steatosis, to a more aggressive form of fatty liver disease known as non-alcoholic Impact of Obesity on LT steatohepatitis (NASH) and ultimately cirrhosis (4). Currently, NASH is emerging as an important causative Obesity plays a vital role in context of LT and effects can be factor for hepatocellular carcinoma (HCC) (5,6). The seen in both pre- and post-transplant setting. © Translational Gastroenterology and Hepatology. All rights reserved. Transl Gastroenterol Hepatol 2020 | http://dx.doi.org/10.21037/tgh-2019-ltna-15 Page 2 of 10 Translational Gastroenterology and Hepatology, 2020 Pre-LT Obesity that BMI is not a risk factors for poor patient and both liver and kidney graft survival (20). This study analyzed 7,205 Current American and European guidelines consider a pre- SLK transplants. Of these, 1,677 patients were overweight/ transplant body mass index (BMI) ≥40 kg/m2 as a relative obese (OW, BMI 30–39) and 183 were morbidly obese contraindication for LT based on poor post-transplant (MO, BMI ≥40). 29% of patients had NASH in the MO outcomes (11,12). Pre-transplant obesity has been found to group versus 16.4% and 4.7% in the OW and normal be an independent risk factor for long-term mortality, graft weight (NW) groups, respectively. The 1, 3 and 5 year dysfunction and increased postoperative events in patients overall patient survival, kidney and liver graft survivals undergoing LT (13,14) and data has shown that patients were comparable between the three groups. Multivariate having concomitant obesity and DM have a nearly doubled analysis identified diagnosis of hepatitis C, donor age, total risk of a complication event and at least tripled the diabetes mellitus, and delayed kidney transplant function risk of an infective, cardiovascular, or respiratory event (14). but not BMI as risk factors for poor patient and both liver Concomitant obesity and diabetes is also associated with and kidney graft survival (20). Additionally, a meta-analysis reduced post-liver transplant survival with greater impact evaluating long-term impact of pre transplant obesity on in older patients and those with HCC (15). A single center patient survival in liver transplant recipients showed that study in the UK showed that overweight and obese patients BMI does not specifically impact patient survival. However, have significantly higher morbidity in terms of infective obese patients have worse survival when analysis was complications after LT and, consequently, longer hospital performed in studies whose cohorts of obese and nonobese stay with increased resource utilization (16). In a large patients had similar causes of liver disease (21). single center study of 785 patients listed for OLT a BMI of >35 kg/m2 was associated with NASH cirrhosis (P<0.0001), higher Model for End-stage Liver Disease (MELD) score, Post-LT obesity and longer wait times for transplant (P=0.002) (17). This Obesity is common after solid organ transplantation and study categorized patients into six groups by pre-transplant it has been shown to be a frequent complication after 2 BMI, comprising those with BMIs of <18.0 kg/m , 18.0– LT (22,23). Studies from diverse geographical regions 2 2 2 24.9 kg/m , 25.0–29.9 kg/m , 30.0–35.0 kg/m , 35.1– describe mean weight gain of 2–9 kg within the first year 2 2 40.0 kg/m and >40 kg/m respectively. No differences after transplantation (24-26). Post-operative weight gain is were found in operative time, intensive care unit or multifactorial and the incidence of obesity has been found hospital length of stay, or perioperative complications. to be affected by BMI at transplantation, donor BMI, Graft and patient survival at intervals up to 3 years were marital status, occurrence of acute rejection, and prednisone similar between groups. However, when compared with dose (24). Genetic factor such as carriage of the D allele of 2 non-obese recipients, recipients with a BMI of >40 kg/m the ACE gene is also found to be strong, independent risk showed significantly reduced 5-year graft (49.0% versus factor for excess weight gain after LT (27). The potential 75.8%; P<0.02) and patient (51.3% versus 78.8%; P<0.01) impact of post-LT weight gain includes increased risk of survival (17). Among patients suffering from obesity, those new onset diabetes mellitus (NODM) (28,29), metabolic who are at the extremes of BMI have poor post-transplant syndrome (30,31) and its associated complications, such as outcome. An analysis of 73,538 adult liver transplants CVD (32), and de novo NASH in the allograft (33,34). showed that patients with extreme BMI (<18.5 and ≥40) In a UNOS database study NODM was reported when compared to the control had significant differences. in 26.4% of recipients (median follow-up, 685 days). Underweight patients were more likely to die from Independent predictors of NODM development included hemorrhagic complications (P<0.002) and cerebrovascular recipient age (≥50 vs. <50 years, HR =1.241), African accidents (P<0.04). The very severely obese patients had American race (HR =1.147), body mass index (≥25 vs. <25, a higher number of infectious complications and cancer HR =1.186), hepatitis C (HR =1.155), recipient cirrhosis events (P=0.02) leading to death (18). Obesity is also history (HR =1.107), donor age (≥60 vs. <60 year, HR associated with increased incidence of recurrence of HCC =1.152), diabetic donor (HR =1.151), tacrolimus (tacrolimus for patients with HCC undergoing LT (19). Contrary vs. cyclosporine, HR =1.236), and steroid at discharge (HR to most data identifying obesity as a risk factor for graft =1.594). Living donor transplant (HR =0.628) and induction survival, a retrospective study of UNOS database showed therapy (HR =0.816) were associated with a decreased © Translational Gastroenterology and Hepatology. All rights reserved. Transl Gastroenterol Hepatol 2020 | http://dx.doi.org/10.21037/tgh-2019-ltna-15 Translational Gastroenterology and Hepatology, 2020 Page 3 of 10 risk of NODM (35). Case-control study by Terto et al. bypass (LGB) or laparoscopic adjustable gastric banding illustrated that pre-existing systemic arterial hypertension (LAGB) (48). and immunosuppression (sodium mycophenolate and tacrolimus) increased the risk of new-onset diabetes after Roux-en-Y Gastric Bypass (RYGB) transplant (36). NODM results in increased susceptibility to infectious and CV complications, may lead to reduced long- RYGB has traditionally been the gold standard of BS in the term graft survival, and has a major impact on the quality of United States, however LSG is now emerging as preferred life and survival (37,38).