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Nutrition in liver transplantation: too little or too much?

Plank, Lindsay D.a; Russell, Kylieb

Current Opinion in Clinical Nutrition and Metabolic Care: September 2015 - Volume 18 - Issue 5 - p 501–507
doi: 10.1097/MCO.0000000000000205
NUTRITION AND THE GASTROINTESTINAL TRACT: Edited by M. Isabel T.D. Correia and Alastair Forbes
Free

Purpose of review The purpose of this study was to review the most recent findings on approaches to managing the obesity and muscle wasting that are found in patients before and after liver transplantation.

Recent findings A number of articles have contributed to the accumulating evidence that morbid obesity is not an absolute contraindication to liver transplantation with survival outcomes similar across BMI groups. Obesity is, however, a risk factor for early post-transplant complications and obesity-related comorbidities markedly increase this risk. Very limited data are as yet available, dietary, or otherwise, related to amelioration of these comorbidities and evidence that weight loss leads to improved outcomes in obese patients is lacking. Abdominal computed tomography imaging is increasingly being used to identify muscle wasting, and poorer post-transplant survival is seen in patients with significant muscle wasting. This modality has confirmed the persistence of depleted muscle stores after transplant extending well beyond 1 year. Coupled with this is a high incidence of weight gain and metabolic syndrome and the associated risks. Although dietary intervention and exercise are considered possible approaches to address these issues, work in these areas so far is sparse.

Summary An urgent need exists for interventional studies on the basis of nutrition and/or exercise to address the challenges presented by both obesity and muscle wasting, which likely coexist in many patients in both the pretransplant and the post-transplant periods.

aDepartment of Surgery, University of Auckland

bNutrition Services, Auckland City Hospital, Auckland, New Zealand

Correspondence to Lindsay D. Plank, Department of Surgery, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Tel: +64 9 923 6949; fax: +64 9 377 9656; e-mail: l.plank@auckland.ac.nz

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INTRODUCTION

For patients with end-stage liver disease liver transplantation is the only effective therapy and patient survival rates of 80% at 3 years and 70% at 5 years can be expected currently in the USA [1,2]. Obesity is increasingly common in candidates for liver transplantation, irrespective of the underlying cause of their liver disease, reflecting the obesity epidemic in Western countries. Obesity is also a major risk factor for nonalcoholic fatty liver, now the leading cause of chronic liver disease in the USA [3]. Its progressive form, nonalcoholic steatohepatitis, leads to cirrhosis in an estimated 10–20% [4]. Nonalcoholic steatohepatitis is expected within 15 years to be the dominant indication for liver transplantation in the USA [5].

It is not therefore surprising that there is increasing attention directed at obesity in patients awaiting liver transplantation, in particular addressing how this may affect post-transplant outcomes, and what approaches may be implemented in such patients which might improve outcome. Excessive weight gain and its potential comorbidities have long been considered a significant risk for all patients following transplant, and the propensity for such weight gain among obese recipients heightens the importance of managing this risk.

Muscle wasting is a hallmark of end-stage liver disease and the apparently ‘over-nourished’ patient with cirrhosis is not immune to the cachexia of liver disease. Progressive muscle wasting in cirrhotic patients may be masked by obesity as well as by fluid retention. Here, we consider the most recent literature pertaining to obesity and muscle wasting in the pre and post-transplant periods and approaches to address these issues.

Box 1

Box 1

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PRETRANSPLANT OBESITY AND POST-TRANSPLANT OUTCOME

Historically, obese patients with end-stage liver disease have not been viewed favourably as candidates for liver transplantation and some centers have adopted a BMI limit beyond which transplantation is absolutely contraindicated. Earlier work [6] that indicated higher post-transplant mortality in obese recipients did not adjust for confounders that could also influence survival. Of note in this regard is the presence of ascites and more recent work [7] in which BMI was corrected for ascites showed that early and late (5 years) patient and graft survival were similar across all BMI categories.

The relationship between pretransplant BMI and outcome from liver transplantation continues to gain attention. A single-center study [8] evaluated post-transplant survival up to 7 years in 785 patients and, although short-term patient and graft survival were similar across BMI categories, morbid obesity (BMI > 40 kg/m2) was associated with worse survival at 5 and 7 years. Patient and graft survival in this BMI category at 5 years (51 and 49%, respectively) differed markedly from that found by Leonard et al.[7] (80 and 74%). Notably, Conzen et al.[8] did not adjust BMI for ascites on the basis that ascitic volumes were comparable across all BMI groups. Such adjustment may, however, as demonstrated by Leonard et al.[7], lead to differential movement of patients into lower BMI groups ultimately influencing the survival analysis, particularly after adjusting for the ascites volume.

Studies investigating obesity and post-transplant survival conducted between 1990 and July 2013 have been meta-analyzed by Saab et al.[9] and essentially confirm the lack of impact of BMI per se on patient survival. More recent studies support that conclusion [10▪,11,12]. Younassi et al.[10▪] and Singhal et al.[11] evaluated data from the US Scientific Registry of Transplant Recipients. After at least 5 years of follow-up and adjustment for potential confounders, obesity (BMI ≥30 kg/m2) was not predictive of survival [10▪]. Survival of morbidly obese patients (BMI ≥40 kg/m2) did not differ from that of patients with BMI < 40 over a median follow-up of 2 years [11]. After living donor transplantation, recipient BMI category (normal weight, overweight, obese) was not associated with survival on multivariate analysis [12]. Although not statistically significant, overweight and obese patients tended to show better 1, 3 and 5-year patient survival rates than their normal weight counterparts. Undoubtedly, selection bias may play a role in these comparisons of normal weight and overweight or obese categories; the perception that obesity confers worse survival may count against selection of such patients for transplant if other medical conditions are present.

Although survival data would suggest that obesity, as defined by BMI, is not associated with poorer survival, increased post-transplant morbidity in obese patients has been reported. Recent work supports that finding with increased 30-day complication rates for patients with BMI ≥30 kg/m2[13▪] and increased length of postoperative hospital stay in patients with BMI ≥40 kg/m2[11]. These are, however, not universal findings. No differences in lengths of stay or infections across BMI groups were reported by Conzen et al.[8] and Gunay et al.[12] also reported that complication rates were similar across BMI groups. Comparisons between studies are problematic, however, because of the selection biases that operate in evaluation of patients for transplant and the difficulty in quantifying these.

Studies investigating the influence of obesity on post-transplant outcomes have not generally considered the impact of comorbidities commonly associated with obesity which include the cluster of conditions (hyperglycemia, hypertension, dyslipidemia, and central obesity) that signify metabolic syndrome, and its complications, type 2 diabetes mellitus, and cardiovascular disease. Where follow-up post-transplant was at least 5 years, pretransplant diabetes was independently predictive of all-cause mortality whereas BMI and hypertension were not [10▪]. Pretransplant type-2 diabetes was also independently associated with cardiovascular mortality in this series. Diabetes pretransplant was associated with inferior post-transplant graft and patient survival (median follow-up 2 years), as well as longer hospital stay in another study based on the Scientific Registry of Transplant Recipients database [14]. In a single-center study [13▪], obesity in combination with type-2 diabetes was a stronger determinant of 30-day post-transplant complications than obesity alone. Diabetes concurrent with obesity more than tripled the risk of an infective, cardiovascular or respiratory complication. Although obesity is not an absolute contraindication to transplantation, it needs to be considered along with the comorbidities that often accompany that condition. In the interests of the most judicious use of donor organs, these comorbidities must be addressed by appropriate intervention.

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PRETRANSPLANT CACHEXIA AND POST-TRANSPLANT OUTCOME

Increased complication rates in the early post-transplant period in obese patients put these patients at risk of early mortality and suggest a need for targeted weight reduction pretransplant. The challenge is to achieve this without exacerbating the muscle wasting that is characteristic of end-stage cirrhotic patients. DiMartini et al.[15] found 62% of their obese patients who underwent transplantation were cachectic on the basis of skeletal muscle area of an abdominal transverse slice at L3-4 by computed tomography (CT). Cut-off values for identification of cachexia were based on those determined in cancer patients and which optimally stratify patients for mortality [16]. Muscle area (normalized by the square of height) was found to be predictive of longer length of ICU and hospital stay in men and women and poorer survival in men, independent of age, model for end-stage liver disease (MELD) score, comorbidity, and other covariates [15]. A number of other studies [17–19] have recently appeared also showing that muscle wasting as determined from abdominal imaging is independently prognostic of poor outcome from transplantation. Muscle wasting determined from cross-sectional imaging at L3 was independently associated with increased postoperative hospital stay and bacterial infections but not with survival in a study by Montano-Loza et al.[17]. Two studies from Japan [18,19] investigated mortality outcomes from living donor liver transplantation. Muscle wasting was identified from psoas muscle area and was independently predictive of poorer survival. Fat infiltration in muscle was assessed in multifidus muscle and was also an independent predictor of survival [18]. As a marker of muscle quality, intramuscular fat content may provide a surrogate for muscle strength and function. Low psoas muscle area was also shown on multivariate analysis to be a risk factor for sepsis occurring in the first 3 months after transplant [19]. The extent to which psoas area or an index based on that measure is related to lumbar muscle area or whole-body muscle mass is yet to be determined [20,21]. A common finding in all these studies is the higher incidence of muscle wasting in males compared with females which is in accord with assessments based on neutron activation analysis and anthropometry in cirrhotic patients. An advantage of imaging approaches for muscularity assessment over other methods, such as dual-energy X-ray absorptiometry, is that it is considered that they are not confounded by fluid retention [22]. These studies rely on the fact that many if not most patients assessed for liver transplant will undergo abdominal imaging as a routine procedure. In healthy volunteers who underwent magnetic resonance imaging, single abdominal slice muscle area at the L3 region was strongly and linearly related to total body muscle volume [23]. Validation against whole body imaging in a cirrhotic population has not, to our knowledge, been carried out.

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PRETRANSPLANT NUTRITIONAL INTERVENTION

It would be expected that nonvolitional weight loss might occur as disease worsens in both obese and nonobese patients, after accounting for fluid retention. Given the apparently greater impact of cachexia than obesity on survival, it could be argued that efforts should be directed at maintaining lean body mass irrespective of obesity. The presence of significant comorbid conditions, such as diabetes or cardiovascular disease, argues for approaches to address these to lessen their impact on post-transplant outcomes. Transplanting high BMI patients with comorbid conditions sooner, at lower MELD scores or assigning additional points for severe obesity, has been suggested [24]. The paucity of randomized trials of nutritional intervention in wait-listed patients continues to be a concern. We are aware of only two that investigated nutritionally related outcomes [25,26▪]. These studies focused primarily on pretransplant nutritional status. In the study by Le Cornu et al.[25] mid-arm muscle circumference as a marker of nutritional status appeared to improve in both the supplementation and the dietary advice groups. Plank et al.[26▪] compared an immunonutritional supplement enriched in n-3 fatty acids, arginine and nucleotides with a control product and in both arms of the trial muscle stores were preserved over a median duration of 61 days on supplementation. The specialized supplement conferred no advantage in the cohort as a whole nor in the subgroup of patients with significant protein depletion as assessed by neutron activation analysis.

Data on the mechanisms underlying the cachexia of cirrhosis have been very limited to date and without such data therapies directed at cachexia are also lacking. Branched chain amino acid (BCAA) concentrations are reduced in cirrhosis and improvements in nitrogen balance have been reported in cirrhotic patients treated with supplemental BCAAs [27]. BCAAs, particularly leucine, activate the mammalian target of rapamycin (mTOR), stimulating protein synthesis. In patients with alcoholic cirrhosis, a leucine-enriched BCAA supplement reduced whole-body proteolysis as assessed by tracer infusion methodology [28▪]. Serial muscle biopsies were obtained before and after ingestion of the supplement. At baseline, biopsied tissue showed elevated expression of the negative regulator of muscle protein synthesis, myostatin, impaired mTOR signaling and increased autophagy compared with controls. Following supplementation, myostatin expression was unchanged but mTOR signaling impairment was reversed and autophagy reduced. Interestingly, components of the ubiquitin–proteasome pathway were not altered. Longer term supplementation with similar leucine doses together with assessment of skeletal muscle mass is indicated.

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EXERCISE IN THE PRETRANSPLANT PATIENT

In noncirrhotics, exercise may play a valuable role in preserving or increasing skeletal muscle mass and reducing fat mass. Resistance exercise, however, increases portal hypertension in cirrhosis [29] with potentially serious consequences. Aerobic capacity as determined by cardiopulmonary exercise testing is impaired in liver transplant candidates and independently portends poor short-term survival before transplant [30] and poor survival after transplant [31]. As a potentially modifiable risk factor, aerobic capacity has received very little attention. A pilot study of a 12-week adapted physical activity program appeared well tolerated and acceptable in wait-listed patients [32]. Aerobic training on cycle ergometers and muscle strengthening sessions were held twice weekly for approximately 2 h. One patient stopped the program because of worsening hepatic disease. No complications caused by portal hypertension were seen. For the eight patients completing the program, significant improvements were seen in aerobic capacity, 6-min walk test distance and muscle strength. Larger studies are called for to investigate impact of these and similar exercise programs on post-transplant outcome.

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POST-TRANSPLANT NUTRITIONAL STATUS

Liver transplantation is associated with a significant loss of muscle mass [26▪]. This is compounded with the muscle wasting present in most patients undergoing this procedure. Although the clinical and metabolic abnormalities of cirrhosis no longer exist, a number of studies have shown muscle wasting persists post-transplant for at least 24 months [33]. Recent work with CT imaging pre and post-transplant with a median interval of 12.6 (range 0.5–25.2) months from transplant to post-transplant CT supports this long-term persistence [34▪]. Based on CT muscle area, muscle wasting was identified in 62% of the patients pretransplant and 87% posttransplant. Loss of muscle after transplant was associated with increased risk of diabetes. Skeletal muscle biopsies were taken at 24 months from three patients in that study, who had reduction in muscle area post-transplant, and analyzed for expression of genes regulating skeletal muscle mass. Myostatin expression was significantly elevated compared with controls, and these novel data suggest upregulation of this protein secondary to calcineurin inhibition by tacrolimus or cyclosporine. Other post-transplant immunosuppressive agents also impair protein synthesis and increase proteolysis: sirolimus and everolimus (via mTOR inhibition) and corticosteroids. Recurrent disease and complications occurring after transplant may also blunt the muscle anabolic response. In a selected cohort of patients who had an uncomplicated postoperative course, muscle wasting assessed by CT imaging before and 12–48 months after transplant showed no significant change over this period whereas 22 of 40 patients who had muscle wasting before transplant improved to 12 of 40 after transplant [35].

The return of appetite, improved psychological well-being, normalization of the hypermetabolic state and lack of dietary restrictions following transplant contribute to excessive weight gain [36], despite the limited muscle anabolism so that the weight gain is primarily body fat. Being overweight or obese pretransplant almost invariably means these patients will be overweight or obese after transplant and one-third of normal weight patients at transplant will become obese post-transplant [37]. In a retrospective review of 455 consecutive liver transplant recipients from 1999 to 2004 a progressive increase in BMI was seen from 1 month to 5 years post-transplant [38]. Obesity prevalence was 24% at 4 months and 40% at 5 years. Pretransplant BMI was independently predictive of obesity at 1 year. Ribeiro et al.[39] measured resting energy expenditure in patients an average of 6.5 years after transplant. Obesity prevalence was 26% and 60% were overweight. All were assessed as normo-metabolic on the basis of predicted energy expenditure by the Harris–Benedict equations. Hypometabolism, therefore, was discounted as a cause of excessive weight gain. The loss of afferent and efferent pathways between the liver and the hypothalamus in the liver transplant recipient should not be ignored as a factor influencing energy homeostasis and appetite [40]. We are not aware of studies confirming the impact of this factor on weight gain.

Weight gain and obesity post-transplant play significant roles in the development of metabolic syndrome. Metabolic syndrome and its clinical features are increasingly recognized as contributing significantly to post-transplant morbidity and major causes of long-term mortality, including cardiovascular disease, renal disease and cancer [1,37]. The immunosuppressive medications required following transplantation are implicated also in one or more of these metabolic derangements. Calcineurin inhibitors exacerbate hyperglycaemia, hypertension and dyslipidaemia along with corticosteroids which also cause hyperphagia [1,41]. Metabolic syndrome develops in over 50% of postliver transplant patients [42,43].

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POST-TRANSPLANT DIET AND EXERCISE

The chronic medical comorbidities patients experience post-transplant emphasize the increasing importance of effective long-term nutritional management. Historically, nutrition care has focused on providing postoperative support in the acute setting. The emphasis has been on a high-energy diet to meet increased nutrient needs and replenish muscle and fat stores [44]. This is appropriate in the immediate post-transplant phase given the hypermetabolism observed at 30-day post-transplant [45].

Beyond this period the influence of nutritional intake and physical activity on the energy balance in patients after liver transplant has not been well defined, but clearly may be important determinants of excessive weight gain. The longitudinal study by Ferreira et al.[45] has shown patients are in positive energy balance in the 12-month period following liver transplant, and there is evidence that this remains so over the longer term [39]. Physical activity at 1-year post-transplant was assessed as low or sedentary in 77% of patients [45] and at a mean follow-up interval of 6.5 years, 93% of patients were in these categories [39].

Given the positive energy balance, low physical activity and excessive weight gain reported, nutrition intervention and education regarding lifestyle modification and exercise should be mandatory. There are, however, few evidence-based guidelines for dietetic practice extending further than 1-year post-transplant [44]. The American Practice Guidelines recommend all post-transplant patients receive ongoing nutrition counselling to avoid obesity. This is based on grade C evidence as there are no randomized controlled trials [43].

There is also limited evidence around lifestyle interventions postliver transplant. We are not aware of any intervention trials combining exercise and nutrition counselling post-transplant, except that by Krasnoff et al.[46] published in 2006. In this trial, patients were randomized to usual care or individualized nutrition counseling and an exercise prescription over a period of 12 months after transplant. The intervention group showed more improvement in exercise capacity. Adherence to the intervention, however, was only 37% for both nutrition and exercise. The results were disappointing and may reflect the difficulty in overcoming post-transplant anabolic resistance and persisting physical fatigue. A recent small study [47] demonstrated improved performance in the 6-min walk test in patients 6–12 months after transplant who were randomized to 24 sessions of 30-min treadmill exercise. No improvement was seen in the control group.

The prevention of post-transplant morbidity relies on our understanding of the risk factors and the presence of modifiable causes. Systematic, evidence-informed nutritional and physical activity-based interventions are required to aid recovery from muscle deconditioning, prevent excessive weight gain and ameliorate the features of metabolic syndrome. The role of appropriate nutrition and exercise regimens after liver transplantation warrant further investigation.

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CONCLUSION

Although severe obesity is not an absolute contraindication to liver transplantation post-transplant morbidity is higher in this group, particularly if comorbid conditions are present. Weight loss might be indicated but poses a challenge given the coexisting muscle wasting in many of these patients which portends poor post-transplant survival. Weight gain and muscle wasting also coexist after transplantation and, just as in the pretransplant setting, effective approaches to managing patients with excess weight and poor muscle stores are lacking. Studies are required to evaluate the benefits of dietary counselling and appropriate nutritional intervention along with exercise.

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Acknowledgements

None.

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Financial support and sponsorship

None.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

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This retrospective study defined obesity by both BMI and percentage body fat cut-offs with similar results for the influence in multivariate analysis of obesity with and without comorbidities on 30-day post-transplant complications and length of stay.

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Keywords:

exercise; liver transplantation; morbidity; mortality; muscle wasting; nutrition intervention; obesity; weight gain

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