The prevalence of obesity is increasing in the United States and the rest of the world. The World Health Organization reported last year that over a billion people in the world are obese, surpassing 600 million malnourished people. In some ways, this is a reassuring sign that we are combating poverty in the world, but the impact of obesity on long-term morbidity, mortality, and utilization of health resources is similar or higher.1–5 The reports from the Centers for Disease Control and the National Health and Nutrition Examination Surveys suggest that >20% of the U.S. population is obese as defined by a body mass index (BMI) >30 kg/m2. Whereas infections are the most common causes of death in the malnourished, degenerative and vascular diseases are the common causes of death in obese people.1–5 The Centers for Disease Control estimates that approximately 100 billion dollars are spent every year in the United States on obesity-related type 2 diabetes mellitus and 22 billion on obesity-related osteoarthritis.
The United Network for Organ Sharing database from 1988 to 1996 showed that 16.8% of liver transplant recipients had BMI ≥30 kg/m2 and of these 5.3% were severely obese (BMI ≥35 kg/m2) and 2.1% were morbidly obese (BMI ≥40 kg/m2).6 The study reported in this issue of Liver Transplantation by Pelletier et al.7 shows that the prevalence of obesity has increased significantly in more recent years. Of those who underwent transplantation between 2001 and 2004, 32.5% were obese, and among them, 8.4% were severely obese and 3.2% were morbidly obese. Within a decade, it appears that the prevalence of obesity (BMI ≥30 kg/m2) has increased by 93% among liver transplant recipients, and moreover, there was 58% increase in severe obesity and 52% increase in morbid obesity. This increase is mostly a reflection of the changes in the general population. Fluid overload and inactivity, probably related to the advanced liver disease, may have contributed to the increased prevalence of obesity in this population, but it is difficult to assume that these factors have changed in the past decade.4 Nevertheless, these data indicate that we need to continue to monitor the outcomes of obese patients on a continuous basis as the epidemiology is rapidly shifting in the wrong direction.
The impact of obesity on renal transplantation has been studied more extensively than liver transplantation.8, 9 An analysis of 51,927 renal transplant recipients showed that extremes of BMI (<18 and >36) were associated with worse graft and patient survival.8 In addition, higher BMI was associated with delayed graft function and chronic graft failure. Registry data (from 1987 to 2002) on 6,658 children aged 2 to 17 yr who received renal transplantation showed that BMI >95 percentile (9.7% of the study population) for age was associated with a higher risk of death (relative risk 2.9 for cadaver and 3.7 for living donor) and graft loss (19% vs. 10% for nonobese) due to thrombosis.10 Obesity has also been described as a negative predictor of morbidity and mortality after combined kidney/pancreas, pancreas alone, lung and heart transplantation.11–14 Single center studies on liver transplantation have shown inconsistent results mainly because of the differences in the definition of obesity, sample size, reporting, and selection bias.15–19 These studies, however, showed a trend toward higher postoperative complications, length of hospital stay, and hospital costs for obese recipients.17, 19 In many of the above single center studies, patients with BMI >30 kg/m2 were grouped together and therefore, the impact of severe or morbid obesity on sold organ transplantation could not be assessed independently. Moreover, the sample size of these studies was inadequate to assess the independent effect of severe or morbid obesity on liver transplant outcomes. Nair et al.6 examined the United Network for Organ Sharing database from 1988 to 1996 and reported that liver transplant recipients with severe (BMI >35) or morbid (BMI >40) obesity are more likely to have a higher mortality. When adjusted for other comorbidities, however, only morbid obesity was an independent predictor of mortality. In both renal and liver transplant recipients, cardiovascular complications were the main cause of increased mortality.6, 9
Pelletier et al.7 examine survival benefits of liver transplantation according to recipient BMI. Using the Scientific Registry of Transplant Recipients database from September 2001 to December 2004, the authors report that transplant recipients, when compared to those who were listed and did not undergo transplantation, had survival benefits irrespective of their BMI. This is a valid conclusion based on the data presented, and one could even intuitively agree that any patient with advanced cirrhosis (Child-Turcotte-Pugh C or high Model for End-Stage Liver Disease scores) or liver cancer (even those who are outside the Milan or San Francisco criteria) would live longer than a comparable group that did not receive liver transplantation. These authors had previously reported similar findings on both kidney and liver transplant recipients using the Scientific Registry of Transplant Recipients database.20 In their previous study, these authors had reported that liver transplant recipients with BMI ≥35 kg/m2 had a higher mortality compared with other recipients with a lower BMI. In the current study, the authors do not compare mortality in a serious manner (they do not provide Kaplan-Meier survival values) based on BMI since the focus of their study was on survival benefit analysis. However, a cursory examination of Figure 1 in their article would suggest that the unadjusted deaths/1,000 patient yr increased with BMI <20 kg/m2 or >35 kg/m2. What could we conclude from this study? Before we attempt to answer this question, we need to define the question more clearly. If the question was whether morbidly obese patients with end-stage liver diseases are better off with liver transplantation (vs. no transplantation), the answer is a resounding “yes.” If one rephrases the question, and we ask whether we could use the donor organs more effectively by transplanting them into patients who are likely to have a better outcome, then we may have to say “may be we should.” This study has not attempted to answer this pertinent last question. As long as there is an organ shortage, and patients continue to die on the waiting list in this country without receiving liver transplantation in a timely manner, the transplant community has a responsibility to address this important question.
Morbid obesity is a surrogate marker of other serious comorbidities such as vascular diseases, diabetes, hyperlipidemia, cancer, and respiratory disorders, including sleep apnea. One of the important functions of the liver transplantation selection process is to determine whether the recipient can withstand a transplant operation and emerge with an acceptable quality of life and outcomes. If the morbidity and mortality associated with transplantation outweighs that of the chronic liver disease, then clearly transplantation is not in the best interest of the patient. It is clear from this study that morbidly obese patients benefited from liver transplantation. Shortage of organs, however, mandates that these precious resources be used in a more judicious manner. The immediate and late outcome of liver transplantation is dependent on many factors including age, race, BMI, presence of diabetes or coronary artery disease (CAD), pretransplantation serum creatinine, etiology, severity of liver disease (Model for End-Stage Liver Disease score or United Network for Organ Sharing status), donor age, donor steatosis, and cold ischemia time.21–29 Patients with diabetes or CAD are approximately 40% more likely to die within 5 yr from transplantation compared to nondiabetics or those without CAD.28 The presence of both diseases has a far more negative impact than either disease alone.28 Patients with morbid obesity often have more than 1 negative risk factor. A significant proportion of these patients is old and has occult cardiovascular disease, hyperlipidemia, diabetes mellitus, hypertension, renal impairment, or restrictive lung disease. These confounding risk factors add up and result in significant morbidity, mortality, and higher transplantation-related costs. Statistical tools could be used to compare the survival in morbidly obese patients after adjusting for many of these risk factors, but in real life, they come as a package and not “adjustable.” Moreover, population-based epidemiological studies have shown that obesity is an independent predictor of mortality.1–3, 5 Collective outcome data from liver and renal transplantation also indicate that morbidly obese patients have an increased morbidity and mortality compared to less obese patients.6–14, 16–20 These cumulative data mandate that morbidly obese patients be carefully evaluated for other serious comorbid illnesses before listing. Once listed, they should undergo careful surveillance and health maintenance programs to improve the outcomes.25 Occult CAD should be diagnosed (preferably by coronary arteriogram in patients >50 yr old) and treated promptly. Patients with significant CAD that is not amenable to stenting, or patients with renal failures who are not eligible for combined liver/kidney transplantation should not be listed. Hypertension, diabetes, and hyperlipidemia should be well controlled prior to transplantation. Patients with marked microalbuminuria may have occult small vessel disease and should be assessed thoroughly.30 Finally, morbidly obese patients with 1 or more other serious comorbidities such as uncontrolled hypertension, micro- and macrovascular complications, diffuse CAD, previous myocardial infarction or strokes (including transient ischemic attacks), or significant microalbuminuria should not be offered liver transplantation. This process will allow us to offer liver transplantation in a “selective” manner to some morbidly obese patients, thereby assuring a low morbidity and a better long-term survival. That should be our goal.