1. Obesity is increasingly common among liver transplantation (LT) recipients and donors. Outcomes following LT for selected patients with class I-III obesity are similar to those for nonobese recipients. In patients who are otherwise satisfactory candidates for LT, a high body mass index, as long as it does not present a technical barrier, should not be considered to be an absolute contraindication to LT.
2. The most common causes of death beyond the first year of LT are, in descending order of frequency, graft failure (especially secondary to hepatitis C virus recurrence), malignancy, cardiovascular disease, infections, and renal failure. Metabolic syndrome is an important risk factor for each of these etiologies of posttransplant death. Posttransplant diabetes, posttransplant hypertension, and an original diagnosis of cryptogenic cirrhosis, which is commonly associated with metabolic syndrome, are all associated with an increased risk of post-LT mortality. Features of metabolic syndrome should be screened for and treated in LT recipients.
3. Because of the physiological mechanism of post-LT hypertension, which includes renal arteriolar constriction secondary to calcineurin inhibition, calcium channel blocking agents are a good pharmacological treatment modality and have been shown to be effective in renal protection in randomized controlled trials of posttransplant hypertension.
4. It is rare for dietary changes and weight reduction to result in normalization of the lipid profile. Statins should thus be initiated early in the course of management of post-LT dyslipidemia. Forty milligrams of simvastatin per day, 40 mg of atorvastatin per day, and 20 mg of pravastatin per day are reasonable starting doses for post-LT hypercholesterolemia. It is important to remember that the effects of statin therapy are additive to those of a controlled diet (eg, a Mediterranean diet rich in omega-3 fatty acids, fruits, vegetables, and dietary fiber).
The World Health Organization estimates that, worldwide, 1.6 billion adults are overweight [body mass index (BMI) > 25] and 400 million are obese (BMI > 30). According to the most recent National Health and Nutrition Education Survey (NHANES), two-thirds of adults in the United States are overweight or obese. There are over 1 million Americans with a BMI greater than 60 kg/m2 (NHANES III data estimates).
The average adult gained approximately 10 lbs in the 1990s. Although the overall prevalence of obesity has recently begun to plateau, the prevalence of the most severe classes of obesity is rising sharply. The World Health Organization categorizes obesity according to BMI (overweight = BMI of 25-29.9 kg/m2, class I = BMI of 30-34.9 kg/m2, class II = BMI of 35-39.9 kg/m2, class III = BMI ≥ 40 kg/m2). The prevalence of class III obesity quadrupled and the prevalence of BMI ≥ 50 quintupled1 between 1986 and 2000. The epidemic of obesity has already had an impact on liver transplantation (LT).
Between 1990 and 2006, the proportion of LT recipients classified as obese increased from 15% in the early 1990s to just over 25% since 2002; this means an increase in the average recipient weight of approximately 1 kg per year (Fig. 1).
EFFECT OF OBESITY ON POST-LT OUTCOMES
Selecting potential recipients for LT requires projection of the relative risk of the procedure. For some biological variables, such as the mean pulmonary artery pressure, quite precise limits are known, above which LT is rarely performed. Data concerning the impact of BMI are, however, less abundant. In order for transplant centers to develop a rational approach to the management of obese patients, the effect of high BMI scores on patient and graft survival needs to be determined with reasonable accuracy. Obesity confers an increased risk for perioperative morbidity and mortality for a range of nontransplant surgical procedures.2 Studies of the impact of obesity on outcomes following LT have been less consistent. An analysis of the Scientific Registry of Transplant Recipients (SRTR) reported that post-LT mortality at 5 years was greater among recipients with class II (BMI ≥ 35 kg/m2) and class III (BMI ≥ 40 kg/m2) obesity than in nonobese recipients.3 The potential confounding effect of ascites on BMI-related outcomes is particularly important as the authors of an analysis of the SRTR concluded that “obesity should be considered a relative contraindication to LT.” A potentially important limitation of the SRTR analysis was, however, an inability to correct BMI for ascites. If recipients with greater amounts of ascites, which often occurs in the context of more severe liver disease and renal dysfunction, are at increased risk for postoperative morbidity and mortality, then the increased risk for postoperative morbidity and mortality that was been reported to be associated with higher BMI scores may in fact reflect the impact of ascites on postoperative outcomes. This important limitation of the SRTR analysis was addressed in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Liver Transplantation Database study.4 An analysis of the prospective, long-term follow-up NIDDK Liver Transplantation Database, in which BMI was corrected for ascites, found that preoperative BMI is not independently predictive of patient or graft survival. Indeed, a trend was seen for superiority in outcomes among recipients in the highest BMI category.
The impact of BMI on outcomes other than crude patient and graft survival, such as the frequency of treated infections, treated rejection, primary graft nonfunction, total days in the hospital, and total days in the intensive care unit, was also reported in the NIDDK analysis (Fig. 2). Lengths of stay for recipients with class III obesity were greater in comparison with all other classes (27 versus 16-17 days), but this difference narrowly failed to reach statistical significance. An association of class III obesity and greater length of hospital stay seems probable. Unfortunately, a definitive answer regarding the impact of BMI on secondary posttransplant outcomes remains elusive.
The results of the NIDDK study should not, however, be interpreted as indicating that patients with higher BMI scores can routinely be transplanted safely. The obese LT recipients described in this study almost certainly represent a highly selected group. Given the increased technical difficulties presented by patients with class I-III obesity, it is likely that the tolerance of comorbidities was low. All of the transplant centers participating in this analysis routinely screen for ischemic and other heart diseases in potential LT recipients. It is possible that acceptable parameters for cardiac ejection fraction and pulmonary hypertension were different in a patient with class III obesity and in a potential recipient with a normal BMI, for example. On the basis of the available data, it seems reasonable to conclude that outcomes following LT for selected patients with class I-III obesity are similar to those of nonobese recipients. In patients who are otherwise satisfactory candidates for LT, BMI scores within the ranges published to date should not be considered to be a contraindication to LT.
ACE, angiotensin-converting enzyme; BMI, body mass index; CNI, calcineurin inhibitor; CV, cardiovascular; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LT, liver transplantation; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NHANES, National Health and Nutrition Education Survey; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases; OLT, orthotopic liver transplantation; SRTR, Scientific Registry of Transplant Recipients.
POSTTRANSPLANT METABOLIC SYNDROME
Diagnosis of Metabolic Syndrome
With era-to-era improvements in patient and graft survival that are only recently beginning to plateau, there has been an increasing focus on causes of long-term morbidity and mortality. Metabolic syndrome is commonly defined by the presence of any 3 of the following 5 traits:
Abdominal obesity, which is defined as a waist circumference in men > 102 cm (40 in) and in women > 88 cm (35 in).
Serum triglycerides ≥ 150 mg/dL (1.7 mmol/L) or drug treatment for elevated triglycerides.
Serum high-density lipoprotein cholesterol < 40 mg/dL (1 mmol/L) in men and < 50 mg/dL (1.3 mmol/L) in women or drug treatment for low high-density lipoprotein cholesterol.
Blood pressure ≥ 130/85 mm Hg or drug treatment for elevated blood pressure.
Fasting plasma glucose ≥ 100 mg/dL (5.6 mmol/L) or drug treatment for elevated blood glucose.
The most common causes of death beyond the first year of LT are, in descending order of frequency, graft failure, malignancy, cardiovascular disease, infections, and renal failure5 (Fig. 3). Metabolic syndrome has emerged as an important risk factor for each of these etiologies of posttransplant death. Posttransplant diabetes (hazard ratio, 1.8; P < 0.0001), posttransplant hypertension (hazard ratio, 1.4; P = 0.03), and an original diagnosis of cryptogenic cirrhosis, which is commonly associated with metabolic syndrome (hazard ratio, 1.6; P = 0.01), are all associated with an increased risk of post-LT mortality.
Even recurrence of hepatitis C virus (HCV), the leading cause of death and graft loss among recipients with HCV infection, has been shown to be strongly associated with insulin resistance, a hallmark of metabolic syndrome.6 In multivariate analysis, insulin resistance (hazard ratio, 2.07; P = 0.024) is significantly associated with a higher probability of developing advanced fibrosis (stage 3-4) among recipients with HCV infection. Insulin resistance is also predictive of diminished responsiveness to interferon treatment.6 The prevalence and impact of posttransplant metabolic syndrome mandate consideration of the impact of immunosuppression and potential management strategies. Almost all LT recipients are maintained on tacrolimus or cyclosporine, which are both associated with the increased generation of reactive oxygen species and lipid peroxidation, important contributors to the pathobiology of complications of metabolic syndrome. In addition to increasing oxidative stress and lipid peroxidation, calcineurin inhibitors (CNIs) cause hypertension.
Posttransplant Insulin Resistance
Obesity and insulin resistance are the physiological engines of complications of metabolic syndrome. Ideally, treatment of metabolic syndrome should be centered around weight loss and exercise.7 Sustained weight loss is unusual, however, with just 2% of patients on low calorie or very low calorie diet programs able to maintain weight loss in the medium term. On the basis of our understanding of the pathogenesis of metabolic syndrome, insulin sensitization is an appealing additional approach to the treatment of post-LT metabolic syndrome. Thiazolidenediones are of uncertain benefit and carry attendant risks of weight gain and cardiac toxicities. Metformin may be a safer choice in the treatment of posttransplant insulin resistance. Screening for and treating insulin resistance should be considered in LT recipients. Fasting insulin and glucose levels are inexpensive parameters that can be used calculate the homeostasis model assessment of insulin resistance [fasting glucose (mmol/L) × fasting insulin (μU/mL)/22.5]. A homeostasis model assessment of insulin resistance score of >2.5 is a good index of insulin resistance.
Because of the physiological mechanism of post-LT hypertension, which includes renal arteriolar constriction secondary to calcineurin inhibition, calcium channel blocking agents are a good pharmacological treatment modality and have been shown to be effective in renal protection in randomized controlled trials of posttransplant hypertension.8 Thiazides are problematic in transplant recipients because of potentiation of CNI electrolyte abnormalities. Choices of calcium channel blockers include isradipine, amlodipine, and felodipine. Nifedipine is an inhibitor of intestinal cytochrome P450, resulting in increased CNI levels with potential for CNI toxicity, and may cause leg edema. Second-line therapies for post-LT hypertension include specific beta blockers (nonspecific beta blockers may reduce portal blood flow), angiotensin-converting enzyme (ACE) inhibitors, and loop diuretics. ACE inhibitors may exacerbate CNI-induced hyperkalemia.
Up to 45% of LT recipients develop hyperlipidemia, which generally persists regardless of dietary modification.9 In general, impaired lipid metabolism in LT recipients has been associated with corticosteroid administration, whereas hypertension has been associated with CNIs. However, although tacrolimus may be associated with less severity and lower frequencies than cyclosporine, both agents are associated with hyperlipidemia. The basis of the relatively prolipidemic effects of cyclosporine is not known, but cyclosporine may involve the inhibition of hepatic bile acid 26-hydroxylase, thereby decreasing bile acid synthesis from cholesterol and reducing the subsequent transport of cholesterol into bile and the intestine. Cyclosporine also binds to the low-density lipoprotein cholesterol receptor, thereby increasing circulating levels of low-density lipoprotein cholesterol. The observation that tacrolimus appears less likely to cause hypercholesterolemia than cyclosporine has led several groups to propose the conversion of LT recipients to tacrolimus-based immunosuppressive therapy from cyclosporine-based therapy in the setting of persistent hypercholesterolemia. Posttransplant hyperlipidemia is generally resistant to dietary interventions. Whether CNI dosing in general should be minimized in patients with posttransplant metabolic syndrome is not known, but there exists a theoretical possibility for such an approach. Corticosteroids are known to produce insulin resistance, truncal fat deposition, hypertension, and dyslipidemia. Only a small minority of patients require maintenance corticosteroids, which can and should be discontinued well before the end of the first postoperative year. Sirolimus is a potent hyperlipidemic agent.10 In addition to lowered CNI dosing, the type of CNI, and corticosteroid tapering, statins should be considered in patients with persistent hyperlipidemia. Because of the underlying precipitants of post-LT hyperlipidemia, it is rare for dietary changes and weight reduction to result in normalization of the lipid profile. Statins should thus be initiated early in the course of management of post-LT dyslipidemia. A concern with statin therapy is the development of myopathy, particularly when statins are given with cyclosporine A and tacrolimus, which inhibit cytochrome P450 3A4, the enzyme that metabolizes most statins. These risks can be minimized by the use of pravastatin, which is not extensively metabolized by cytochrome P450 3A4 and may have less intrinsic muscle toxicity. Forty milligrams of simvastatin per day, 40 mg of atorvastatin per day, and 20 mg of pravastatin per day are reasonable starting doses for post-LT hypercholesterolemia. It is important to remember that the effects of statin therapy are additive to those of a controlled diet (eg, a Mediterranean diet rich in omega-3 fatty acids, fruits, vegetables, and dietary fiber).
OBESITY AS A CAUSE OF POSTTRANSPLANT LIVER DISEASE: NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)/NONALCOHOLIC STEATOHEPATITIS (NASH)
NAFLD and NASH are common complications of overnutrition and obesity, affecting up to 30 million people in the United States, of which over 600,000 are likely to have cirrhosis.11 Although only a small minority of patients with NAFLD progress to end-stage liver disease or develop hepatocellular carcinoma, the number of patients at risk is large. A good index of longitudinal changes in the frequency of NAFLD as an indication for LT is the combined frequency of cryptogenic cirrhosis and NAFLD/NASH.
This combination of primary diagnoses has increased from 3.6% to 6.9% in the 5 years between 2001 and 2005, and this is the only indication to have increased in this time frame.12 This estimate does not include patients with hepatocellular carcinoma occurring on a background of cryptogenic cirrhosis or NASH as only the primary diagnosis (hepatocellular carcinoma in these cases) is recorded by the United Network for Organ Sharing at the time of listing for LT. A conservative estimate of the frequency of NAFLD as the underlying cause of liver disease among LT recipients would thus be 5% to 10% (equating to 325-650 recipients per year) on the basis of the current LT volume (http://www.ustransplant.org; Fig. 4). In contrast, the frequency of HCV as an indication for LT peaked in 2002 at 28% in the United States and has declined every year since (http://www.ustransplant.org; Fig. 4). It has been projected that NAFLD will be the most common indication for LT in the next 10 to 20 years.
Post-LT Physiology and NAFLD
The prevalence and severity of obesity increase after LT,13 and obesity is associated with a number of metabolic effects relevant to the development of hepatic steatosis. The prevalence and severity of metabolic syndrome also increase post-LT.14 Prosteatotic changes in adipokines have also been described after LT, including leptin (increased), adiponectin (decreased), and tumor necrosis factor (increased).15 Each of these changes may contribute to recurrent and de novo posttransplant NAFLD and associated insulin resistance.
Levels of oxidative stress, a feature of both animal models of steatohepatitis and humans with NAFLD, are increased post-LT, and this is probably related to CNIs. Recent studies have suggested that increased plasma malondialdehyde levels, markers of oxidative injury, vary with specific immunosuppressive therapies and are specifically worse with cyclosporine versus tacrolimus.16 Each of these effects may have important implications for the natural history of recurrence of NAFLD following LT. Whether CNI dosing should be minimized or tacrolimus should be used as a first-line therapy in patients with recurrence of NASH is not known, but there exists a theoretical basis for such an approach to the recurrence of NASH following LT.
Outcomes Following LT for NAFLD/NASH
Reported 1- and 3-year patient survival has been 93% and 81%, respectively, after LT for NASH, and these rates are generally comparable to those for other indications.17, 18 Recurrence of NAFLD is common, however.
Histological Recurrence of NAFLD and NASH
In the only prospective histological analysis reported to date, at 4 months, 60% of transplant recipients with NASH, 4% of transplant recipients with cholestatic disease, 12.5% of transplant recipients with alcoholic disease, and 8% of transplant recipients with HCV developed steatosis of grade 2 or higher (Fig. 3).19 At 1 year post-transplantation, 60% of transplant recipients with NASH had steatosis of grade 2 or higher, with half of these meeting the histological criteria for NASH. Of patients undergoing LT for NASH, 5% to 10% had recurrence that progressed to cirrhosis in long-term follow-up, with graft failure reported in about half of patients with cirrhotic stage recurrence (ie, a long-term absolute NASH recurrence–associated graft loss rate of 2.5%-5%). A more recent retrospective analysis had similar overall findings but observed no NASH recurrence graft loss.17 Pretransplant bariatric surgery and/or a history of panhypopituitarism and post-LT type 2 diabetes mellitus appear to be risk factors for more severe recurrence.
Patients undergoing LT for complications of cryptogenic cirrhosis also seem to be at risk for post-LT NAFLD, with steatosis occurring in about half and NASH occurring in 25% of patients in a retrospective study.20 This frequency was greater than that observed in control groups matched for age and weight with pre-LT diagnoses of primary biliary cirrhosis or alcoholic liver disease.
De Novo NAFLD
A single-center retrospective report of LT recipients without pre-LT NAFLD described de novo NAFLD in approximately 20% of patients and de novo NASH in approximately 10% of patients.21 In a multivariate analysis, the use of ACE inhibitors was associated with a reduced risk of developing NAFLD after orthotopic liver transplantation (OLT; odds ratio, 0.09; 95% confidence interval, 0.010-0.92; P = 0.042). An increase in BMI of greater than 10% after OLT was associated with a higher risk of developing NAFLD (odds ratio, 19.38; 95% confidence interval, 3.50-107.40; P = 0.001). Given the high prevalence of risk factors, it is not surprising that de novo NAFLD is common in the post-OLT setting, with a significant association with weight gain after transplantation.
Role of Protocol Liver Biopsy
The role of liver biopsy in the diagnosis and management of posttransplant NAFLD/NASH is still evolving. In addition to determining the severity of disease, liver biopsy can also be helpful in determining the effects of medical treatments and changes in immunosuppression. Because NASH recurs frequently, can be severe, and cannot be predicted by a biochemical profile, protocol liver biopsy, rather than aminotransferase-based liver biopsy, at postoperative years 1, 3, and 5 should be considered.
Treatment of NAFLD After LT
There are few randomized controlled studies of the treatment of NASH in general. There are none reported in the post-LT setting. All of the studies referenced in the following discussion were performed in a nontransplant setting, with the presumption that some of the same principles will apply. In lieu of a pharmacotherapy for NASH proven to be efficacious and safe, the treatment of NASH should focus on the associated conditions. In obese patients, who make up the majority of patients with NASH, treatment should be centered on weight loss and exercise programs, which have been proven to be efficacious in both adults and children.22 The attainment of an ideal body weight for height is not a prerequisite for improvement in aminotransferases and ultrasonographic evidence of steatosis. Rapid weight loss can exacerbate steatohepatitis and hepatic encephalopathy and should be avoided (eg, weight loss due to starvation diets or bariatric surgeries). A regimen of 140 minutes of exercise per week (eg, 4000 steps of brisk walking per day) and moderate calorie restriction (25 kcal/kg/day) are effective.
For many obese patients, sustained weight loss and exercise are unfortunately difficult to achieve, particularly in the setting of chronic liver disease. This has led to a proliferation of empirical and semi-empirical studies of pharmacotherapy of NASH. Most studies of pharmacotherapy of NASH have been small, with only a few being randomized with placebo controls. Histological follow-up is also lacking in many studies of potential treatments of NASH. Improved glycemic control will lower lipid levels in patients with NASH who have type II diabetes mellitus (approximately one-third of NASH patients). Glycemic control in the absence of weight loss will not, however, improve aminotransferases in this patient population.
Metronidazole has been reported to effective in improving steatosis in patients who develop NASH after jejunoileal bypass surgery. As jejunoileal bypass is relatively common among patients undergoing LT due to NASH, presumably because of bacterial overgrowth with translocation of lipopolysaccharides, consideration should be given to the following:
1Removal of the atrophic, redundant loop of the jejunum at the time of transplantation.
2Long-term use of suppressive antibiotics for the treatment of bacterial overgrowth post-transplantation.
On the basis of our understanding of the pathogenesis of NAFLD/NASH, insulin sensitization is an appealing approach to treatment. Histological and biochemical improvements in patients with NASH after therapy with a thiazolidenedione (pioglitazone) have been reported. Unfortunately, although pioglitazone produces histological and biochemical improvements in patients with NASH, it can be associated with a significant increase in BMI as well as possible idiosyncratic hepatotoxicity and is associated with a rebound in aminotransferase elevations on cessation.23 As peroxisome proliferator-activated receptor gamma agonists are adipogenic by nature, weight gain is likely to be a class effect of thiazolidenediones and to be enduring and may well negate any histological benefit in the long term.
Bariatric Surgery and LT
Post-LT survival among obese patients is comparable to that of leaner patients,4 although the hospital length of stay and complication frequencies are higher.24 As the prevalence of obesity among LT recipients is increasing, the severity and impact of post-LT obesity are likely to increase also, with an increasing number of patients meeting criteria for consideration of bariatric surgery. Several short-term studies have found a beneficial effect of gastric bypass surgery on NAFLD. However, there are scant data on the effects of bariatric surgery before, during, or after LT, including a report describing the beneficial outcome after bariatric surgery in 2 patients with recurrence of steatohepatitis post-LT.25 Bariatric surgery has also been employed prior to transplantation to improve candidacy and, theoretically, post-LT outcomes. It is important to consider some of the potential complications of bariatric surgery in LT recipients. Gastric bypass surgery can, for example, profoundly affect intestinal drug absorption. If weight-loss surgery is to performed pre-LT, thought should be given to sleeve gastrectomy, which preserves access to the gastric fundus (for management of variceal bleeding) and preserves the relative absorptive capacity. There is also a risk of hepatic decompensation due to exacerbation of steatohepatitis following bariatric surgery. The role of bariatric surgery in the context of LT continues to evolve.
Choice of Immunosuppression in Recurrent NASH
Corticosteroids are known to produce insulin resistance, truncal fat deposition, hypertension and dyslipidemia. Patients with metabolic syndrome post-transplantation have higher risks of developing a major vascular event, so immunosuppression in an indirect way can also affect posttransplantation outcomes negatively.14 Tacrolimus may be toxic to beta cells. In addition to increasing oxidative stress and lipid peroxidation, CNIs in general cause hypertension (as well as acute and chronic nephrotoxicity). Sirolimus, in addition to being associated with excess death rates, infections, and hepatic artery thrombosis, is a potent inducer of dyslipidemia. In lieu of randomized studies for determining optimal immunosuppression, steroid avoidance and minimization of calcineurin inhibition should be considered in recipients with NASH. There is increasing evidence that steroid avoidance and minimization of CNIs are safe and, moreover, reduce the frequency of metabolic complications post-LT.26