Debate: A Bridge Too Far Liver Transplantation for Nonalcoholic Steatohepatitis Will Overwhelm the Organ Supply

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1 LIVER TRANSPLANTATION 20:S32 S37, 2014 SUPPLEMENT Debate: A Bridge Too Far Liver Transplantation for Nonalcoholic Steatohepatitis Will Overwhelm the Organ Supply Julie Heimbach Liver Transplant Program, Mayo Clinic, Rochester, MN Received August 5, 2014; accepted August 22, Key Points: 1. Because of the dramatic imbalance between supply and demand and because transplantation relies on the incredible altruism of organ donors, the transplant community is compelled to consider efficacy when selecting transplant recipients. 2. The worldwide epidemic of obesity and subsequent nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH) is affecting both the demand for liver transplantation (LT) and the supply of available organs and will drive the continued drastic shortage of available liver allografts. 3. NASH is a risk factor for hepatocellular carcinoma, which is also a rapidly increasing indication for LT and another key driver of the organ shortage. 4. Perioperative complication rates and subsequent resource utilization rates are higher for obese patients, many of whom have NASH. 5. Outcomes for obese patients with NASH may be inferior to those for nonobese patients. 6. Long-term complications such as diabetes, heart disease, malignancies, and renal insufficiency may also be impacted by obesity/nash, which will affect long-term outcomes posttransplant. ORGAN SHORTAGE In the United States, approximately 16,000 patients are waiting for liver transplantation (LT), and each year we have an opportunity to provide transplantation to approximately 6000 of those patients, whereas approximately 1500 die while on the wait list and an additional 1500 are removed as they become too ill to undergo transplantation. 1 On average, there are 8 patients each day who either die waiting or are removed for being too sick. Over the past 10 years, despite a major initiative from the U.S. Health Resources and Services Administration to increase organ donation, we have not been able significantly to narrow the gap between the number of organs available and the number needed to give all patients who require it access to the lifesaving benefit of transplantation. 2 Until we can address this devastating imbalance, either by reducing the need for transplant or by increasing the organ supply, all decisions regarding LT must be considered both in the context of what is best for the individual patient and what is the best use of a liver allograft. EPIDEMIOLOGY OF OBESITY AND NONALCOHOLIC FATTY LIVER DISEASE Both in the United States and in many other areas around the world, obesity has reached epidemic proportions. In the United States, in the most recent National Health and Nutrition Examination Survey data, 34.9% of adults and 17% of children are obese Abbreviations: BMI, body mass index; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; ICU, intensive care unit; LOS, length of hospital stay; LT, liver transplantation; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases; OPTN, Organ Procurement and Transplant Network. Potential conflict of interest: Nothing to report. The arguments expressed herein are for the purpose of presenting the pro side of the debate and are not necessarily the opinions of the author. Address reprint requests to Julie Heimbach, M.D., Liver Transplant Program, Mayo Clinic, 200 First Street SW, Rochester, MN Telephone: ; FAX: ; heimbach.julie@mayo.edu DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases VC 2014 American Association for the Study of Liver Diseases.

2 LIVER TRANSPLANTATION, Vol. 20, No. S2, 2014 HEIMBACH S33 [body mass index (BMI) > 30 for adults, at or above 95% for U.S. Centers for Disease Control sexspecific BMI-for-age growth charts for children]. The prevalence of overweight or obese adults is 68.5% (BMI > 25), whereas in children it is 31.8% (at or above 85% BMI-for-age growth charts). 3 The worldwide prevalence of obesity has nearly doubled in the 20-year period from 1980 to 2008, and currently 10% of men and 14% of women are obese, which is approximately 502 million people. 4 Nonalcoholic fatty liver disease (NAFLD), defined as >5% fat in the liver in those with little to no alcohol intake, encompasses both those with NAFL (bland or simple steatosis), which rarely progresses to cirrhosis, and nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis, hepatocellular carcinoma (HCC), and liver-related mortality. 5 NAFLD is the most common liver disease in the Western world, and it is currently estimated that approximately one-third of the U.S. adult population has NAFLD. 6 The presence of NAFLD in Europe and the Middle East ranges from 20% to 30%, and in Asia, despite lower rates of obesity than in the rest of the world, there appears to be a similar prevalence of NAFLD (15%-30%). 5 Approximately one-third of patients with NAFL progress to NASH. 5-7 For patients with NASH, the risk of progression to cirrhosis is approximately 25%, (over 8 years of follow-up), and liver-related mortality in Western patients with NASH is 18% at 18 years of follow-up. 8,9 NASH-related cirrhosis is currently the most rapidly rising indication for LT in the United States. 10 This increased demand for LT from patients with NASH is coupled with the rising incidence of NAFLD in the population, which has obvious implications for availability of suitable allografts from living or deceased donors. HCC AND NASH HCC is a rapidly rising indication for LT. 11 In 2012, nearly 22% of the patients who underwent LT had a primary diagnosis of malignancy at listing, compared with 7% in 2002, 2 and an even greater percentage had HCC at the time of transplantation from the development of HCC in patients who were already on the wait list. Patients with NASH cirrhosis are at risk for the development of HCC, with an annual incidence of 2%-3%/year. 12 Although this is lower than the risk for patients with hepatitis C virus (HCV), the incidence of NAFLD far exceeds that of HCV in the United States. In a recent analysis of claims-based data, the overall burden of HCC resulting from NASHrelated cirrhosis was higher than that from HCVrelated cirrhosis. 13 It is anticipated that, as the incidence of NAFLD continues to increase around the world, in parallel with the obesity epidemic, there will be a shift from virus-related cirrhosis to NAFLD-related cirrhosis as the major risk for HCC. This increased disease burden of NASH-related HCC may further increase demand for LT. PERIOPERATIVE COMPLICATION RATES FOR OBESE PATIENTS UNDERGOING LT There have been multiple analyses of the impact of obesity on patients undergoing LT (Table 1). One of the earlier reports on this issue came in 2001 from Nair et al., 20 who noted increased rates of perioperative complications, increased length of hospital stay (LOS), and increased cost in patients with obesity compared with those of normal weight in a singlecenter retrospective analysis of 121 patients undergoing transplantation between 1994 and Another series from Vancouver on 167 patients undergoing transplantation from 1999 to 2003 noted increased wound infection rates, increased wound dehiscence, and increased ventral hernia rates. 16 Subsequently, a larger series from Gainesville, Florida, published in 2006 on 700 patients who were normal, overweight, or obese (BMI > 30), demonstrated no difference in length of stay, major surgical complications, or costs. 14 An additional report from the University of Wisconsin published in 2012 noted higher rates of biliary complications, longer intensive care unit (ICU) stay, greater infectious complications, higher rates of deep venous thrombosis, and higher blood product use. This series of 817 was notable for having a larger number of patients in the high-bmi categories of BMI > 35 (n 5 83) and BMI > 40 (n 5 47) compared with prior series in which most of the high- BMI patients had BMI of 30 to In 2009, Nair et al. 15 reported an updated analysis of outcomes of obese patients, and this time patients were divided into 5 groups with BMI < 30 being compared with successively higher BMI categories, and the endpoints reported in addition to death were LOS, reoperation, readmission, and blood product use. For all the endpoints, the rates were markedly higher in the BMI > 40 cohort, although because there were only 8 patients in this cohort the findings did not always reach statistical significance. The most recent series, published in 2013, comes from the United Kingdom and reports on 1325 patients, again noting increased length of ICU and hospital stay, and increased infectious complication rates. 19 Although different endpoints and different BMI cohorts make direct comparisons between series difficult, and some have reported no differences, the general trend is that of increased complication rates and greater resource utilization for obese patients compared with nonobese patients. POSTTRANSPLANT PATIENT AND GRAFT SURVIVAL The impact of obesity and NASH on patient and graft survival has also been reported by multiple groups using both national data sets as well as single center analyses (Table 2). Multiple reports of outcomes of obese recipients have been published using Organ Procurement and Transplant Network (OPTN) data.

3 S34 HEIMBACH LIVER TRANSPLANTATION, November 2014 TABLE 1. Summary of Studies Related to Effect of Obesity on Complications Following LT Author Year N BMI Cohort Findings Notes Fujikawa et al., , Nair et al., , Schaeffer et al , Canadian LaMattina et al., , Agopian et al., , Hakeem et al., , U.K. center 700 < >30 No difference in cost, LOS, reoperation, surgical complications, graft or patient 193 <30.0 No differences in resource >39.9 utilization, surgical complications, patient, or graft 167 < Increased wound complications, longer LOS <25.1 Increased operating time, LOS, infection, transfusion, infection, operative complication 1235 <18.5 Increased operative time, hospital stay, and blood loss <18.5 Longer hospital and ICU stay, increased infection ,0 >35,0 Only n 5 37 patients with BMI > 35 Scoring system combining diabetes, obesity and prior abdominal surgery Small numbers Patient and graft survival outcome similar Patient and graft outcome similar Patient and graft outcomes similar The first, by Nair et al., 21 looked at outcomes in obese patients using OPTN data from the 1988 to 1996 period and divided the cohorts into 5 separate groups based on BMI (25.0,,, , 40.1). They demonstrated worse outcomes for patients with severe obesity (BMI 40,1) at 30 days and 1, 2, and 5 years after transplant, and 5-year outcomes were also worse in the moderate-obesity (BMI ) group. These data were confirmed in a second study of OPTN data that looked at a larger patient cohort ( , n 5 73,538) and found worse outcomes for both those with a low BMI (<18.5) and those with a high BMI (>45). Not only was this a larger study population than in the previous report but the study also examined both low and high BMI, although there were only relatively small numbers of patients in these extreme cohorts (1827 and 1447, respectively, compared with 68,172 in the remaining group). 24 Another study looked at only more contemporary patients from 2001 to 2004 and analyzed survival for wait-listed candidates and posttransplant candidates. They used slightly different BMI cutoffs and found no difference in posttransplant outcomes based on BMI, and only the underweight patients had inferior survival while on the wait list. 22 The most recent analysis of OPTN data included only patients from the 2002 to 2011 period, and in this analysis the authors looked at males and females separately as well as the whole cohort. In addition, they looked at the change in BMI from listing to transplant to see whether weight gain or weight loss had any impact. Unlike the previous two studies, this study showed no adverse impact for obesity in males or females and no impact of the delta BMI except for females in the underweight category who had an improved outcome when they achieved a BMI > This study also demonstrated worse outcomes for recipients with a BMI < An interesting report from Leonard et al. 23 on long-term outcomes for obese patients using the NIDDK data set (prospective, multicenter data for patients transplanted from 1990 to 1994) as well as contemporary singlecenter data ( ) demonstrated that there was overall no difference in survival for obese recipients versus nonobese recipients when adjusted for ascites volume. They also noted that ascites was an independent predictor of outcome and that approximately 15% of obese patients changed to a lower BMI class when weight was adjusted for ascites volume noted at transplant. A lack of adjustment for ascites may be a confounding factor in other series in which this adjustment was not performed. Single-center analyses of outcomes have generally found few differences in outcome based on BMI (see Table 1), although UCLA recently reported their

4 LIVER TRANSPLANTATION, Vol. 20, No. S2, 2014 HEIMBACH S35 TABLE 2. Summary of Studies on Impact of Obesity on Patient and Graft Survival Outcomes Following LT Author Era N BMI Cohorts Findings Notes Nair et al., , UNOS data Pelletier et al., 9/ /2004, UNOS data Leonard et al., , NIDDK; , Mayo Clinic Dick et al., , UNOS data 25,647 wait-list candidates, 4488 transplanted 18,172 <25.1 Decreased patient survival for BMI > 40 at 30 days and years 1-5 and decreased for BMI > 35 at 5 years <20.0 Worse survival for wait-listed candidates with BMI < 20, no difference for obese candidates or recipients 1313 <18.5 No differences in survival except worse for BMI < ,538 <18.5 Decreased survival for BMI < 18.5 and for BMI > 40 Perez-Protto Single center 134 >38 versus No differences in patient et al., or graft survival Orci et al., , SRTR 38,194 <18.5 No differences in survival for obese and normal weight; BMI < 18.5 did worse; no difference for those with changes in BMI Earlier era of transplant Looked at both pretransplant and posttransplant survival Ascites was a predictor of post-lt death Small number of patients in extreme groups, relative to total Single center, compared specifically with cohort of normal weight Compared listing BMI with transplant BMI for high- and low-bmi patients

5 S36 HEIMBACH LIVER TRANSPLANTATION, November 2014 experience with LT for NASH patients and noted decreased survival in the NASH patients with BMI > Segal et al. 27 from Columbia University also noted decreased survival for patients with BMI > 30. Interestingly, in this series, the authors analyzed HCC outcomes and noted a higher recurrence rate and higher rates of aggressive tumor phenotype in obese patients with HCC and NASH, and they surmised that this migjht have contributed to the observed inferior outcomes for patients with BMI > 30. LONG-TERM COMPLICATIONS The results of studies on the impact of obesity on posttransplant survival are discordant, but the general trend for analyses that have included primarily more contemporary patients is that survival appears to be similar for obese and nonobese patients. This may be the result of improvements is patient selection and/or perioperative care. However, perhaps more important in light of the critical organ shortage is the impact of obesity on long-term outcomes. Watt et al. 28 analyzed the long-term causes of mortality using the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) data set and noted the most important causes of long-term mortality for individuals beyond 1 year posttransplant were graft failure, malignancies, cardiovascular complications, and renal failure, all of which can be influenced by obesity. Posttransplant diabetes, hypertension, and weight gain are common, and all are exacerbated by obesity. SUMMARY The obesity epidemic is one of the greatest health challenges currently facing the general population, and it will have a major impact on LT because of the associated rise in the incidence of NASH and NASH-related HCC. There is already a severe shortage of available liver allografts, which will be exacerbated by an increased demand for LT with the rising incidence of obesity-related liver disease. Because the obesity crisis also impacts the availability of suitable living and deceased organ donors, the impact will be far more significant. Research and public health initiatives aimed at further elucidating and counteracting obesity in both adults and especially children is paramount. REFERENCES 1. Based on OPTN data as of July 25, OPTN Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients. Rockville, MD: Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation. 3. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, JAMA 2014;311: World Health Organization. Global Health Observatory risk factors. obesity_text/en/. Accessed July Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 2013;10: Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012;142: Bhala N, Angulo P, van der Poorten D, Lee E, Hui JM, Saracco G, et al. The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study. Hepatology 2011;54: Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011;34: Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 2011;140: Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 2011;141: Singal AK, Guturu P, Hmoud B, Kuo YF, Salameh H, Wiesner RH. Evolving frequency and outcomes of liver transplantation based on etiology of liver disease. Transplantation 2013;95: Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zain NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010;51: Sanyal A, Poklepovic A, Moyneur E, Barghout V. Population-based risk factors and resource utilization for HCC: US perspective. Curr Med Res Opin 2010;26: Fujikawa T, Fujita S, Mizuno S, Shenkman E, Vogel B, Lipori P, et al. Clinical and financial impact of obesity on the outcome of liver transplantation. Transplant Proc 2006;38: Nair S, Vanatta JM, Arteh J, Eason JD. Effects of obesity, diabetes, and prior abdominal surgery on resource utilization in liver transplantation: a single-center study. Liver Transpl 2009;15: Schaeffer DF, Yoshida EM, Buczkowski AK, Chung SW, Steinbrecher UP, Erb SE. Scudamore CH. Surgical morbidity in severely obese liver transplant recipients a single Canadian centre experience. Ann Hepatol 2009;8: LaMattina JC, Foley DP, Fernandez LA, Pirsch JD, Musat AI, D Alessandro AM, Mezrich JD. Complications associated with liver transplantation in the obese recipient. Clin Transplant 2012;26: Agopian VG, Kaldas FM, Hong JC, Whittaker M, Holt C, Rana A, Zarrinpar A, et al. Liver transplantation for nonalcoholic steatohepatitis: the new epidemic. Ann Surg 2012;256: Hakeem AR, Cockbain AJ, Raza SS, Pollard SG, Toogood GJ, Attia MA, et al. Increased morbidity in overweight and obese liver transplant recipients: a single-center experience of 1325 patients from the United Kingdom. Liver Transpl 2013;19: Nair S, Verma S, Thuluvath PJ. Obesity and its effect on survival in patients undergoing orthotopic liver transplantation in the United States. Hepatology 2002;35: Nair S, Cohen DB, Cohen MP, Tan H, Maley W, Thuluvath PJ. Postoperative morbidity, mortality, costs,

6 LIVER TRANSPLANTATION, Vol. 20, No. S2, 2014 HEIMBACH S37 and long-term survival in severely obese patients undergoing orthotopic liver transplantation. Am J Gastroenterol 2001;96: Pelletier SJ, Schaubel DE, Wei G, Englesbe MJ, Punch JD, Wolfe RA, et al. Effect of body mass index on the survival benefit of liver transplantation. Liver Transpl 2007; 13: Leonard J, Heimbach JK, Malinchoc M, Watt K, Charlton M. The impact of obesity on long-term outcomes in liver transplant recipients results of the NIDDK liver transplant database. Am J Transplant 2008;8: Dick AA, Spitzer AL, Seifert CF, Deckert A, Carithers RL Jr, Reyes JD, Perkins JD. Liver transplantation at the extremes of the body mass index. Liver Transpl 2009;15: Perez-Protto SE, Quintini C, Reynolds LF, You J, Cywinski JB, Sessler DI, Miller C. Comparable graft and patient survival in lean and obese liver transplant recipients. Liver Transpl 2013;19: Orci LA, Majno PE, Berney T, Morel P, Mentha G, Toso C. The impact of wait list body mass index changes on the outcome after liver transplantation. Transpl Int 2013;26: Segal et al. 28. Watt KD, Pedersen RA, Kremers WK, Heimbach JK, Charlton MR. Evolution of causes and risk factors for mortality post-liver transplant: results of the NIDDK long-term follow-up study. Am J Transplant 2010;10:

Surgical Advances in Obese Candidates and Recipients

SUPPLEMENT Surgical Advances in Obese Candidates and Recipients Julie Heimbach Transplant Surgery, Mayo Clinic, Rochester, MN Received August 2, 2016; accepted August 25, 2016. The obesity epidemic is