NASH: The Ethical Dilemma

Fig. 1

Increasing frequency of NASH as an indication for orthotopic liver transplantation. NASH is on course to become the most common indication for liver transplantation in the coming decades and in recent years has been the third most common indication for liver transplantation in the United States (Adapted from Charlton et al. 2011)

O’leary (2014), however, looked at Scientific Registry of Transplant Recipient data from 2012 and suggested that when extrapolated out to 2020, nonalcoholic steatohepatitis will not surpass hepatitis C virus as the most common indicator. Indeed, O’leary notes that using this methodology, hepatocellular carcinoma will become the most common indication for transplant in 2020 barring changes in allocation policy. While the indication of nonalcoholic steatohepatitis has increased many times from 2002 to 2012, cryptogenic cirrhosis has fallen quite significantly by a similar percentage over the same period suggesting, perhaps, that some patients whose indication for liver transplant was previously listed as cryptogenic cirrhosis are now being categorized at time of listing for transplant as having nonalcoholic steatohepatitis. It is possible that better appreciation of the scope of the disease has altered listing practices rather than the disease truly accounting for higher percentages of patients being listed. However, Yalamanchili et al. (2010) showed that nonalcoholic fatty liver disease is twice as common in patients transplanted from nonalcoholic steatohepatitis than in those transplanted for cryptogenic cirrhosis suggesting that only a minority of patients with cryptogenic cirrhosis have cirrhosis tied to nonalcoholic steatohepatitis.

The cohort that is being listed for transplant for nonalcoholic steatohepatitis is dramatically different than the overall cohort of patients who are listed. Charlton’s analysis of the Scientific Registry of Transplant Recipients (2004) showed that patients who were transplanted for nonalcoholic steatohepatitis-associated cirrhosis were older, had larger body mass indices, and greater prevalences of diabetes and hypertension than other patients listed for liver transplantation.

These risk factors suggest that patients transplanted for nonalcoholic steatohepatitis may present with greater risk factors for poor graft and patient survival after transplant. However, large-scale examinations of patients transplanted for NASH and cryptogenic cirrhosis were similar to overall survival rates. In an examination of data from the Scientific Registry of Transplant Recipients of patients transplanted from 2001 to 2009, survival rates at 1 and 3 years following transplant for NASH were 84 % and 78 %, respectively, compared with 86 % and 79 % for CC and 87 % and 78 % (Charlton et al. 2011) (Fig. 2).

Fig. 2

SRTR outcomes data for liver transplant recipients transplanted for NASH (Data from the Scientific Registry of Transplant Recipients has shown that survival rates at 1 and 3 years following liver transplant are similar among patients transplanted with NASH and those overall) (Adapted from Charlton et al. 2011)

Compounding the problem is the fact that the rise in obesity and the metabolic syndrome that has led to increasing numbers of patients with end-stage liver disease due to nonalcoholic steatohepatitis is also reflected in the general population. The increasing prevalence of obesity has led to further increases in hepatic steatosis in potential liver donors thus potentially reducing the numbers of organs available for transplant (Khullar et al. 2014). This concern will likely grow in the coming years if projections of increasing rates of obesity and the metabolic syndrome come to fruition raising concerns for a dual problem- increasing numbers of patients requiring transplant for end-stage liver disease due partly to the metabolic syndrome and obesity facing a diminishing pool of organs caused by a decrease due to the same proportional rise in obesity.

As significant differences in morbidity and mortality following orthotopic liver transplantation for nonalcoholic fatty liver disease are not seen, some have advocated for more rigorous screening of liver transplant candidates with nonalcoholic fatty liver disease-induced end-stage liver disease. Indeed, O’leary in 2014 proposed that the focus should be in identifying patients at risk for posttransplant complications and treating them. Data have shown that morbidity and mortality in these patients are mostly tied to cardiovascular morbidity and mortality following liver transplant and not to direct transplant-related complications such as delayed graft function, rejection, biliary complications, and other factors. If controlling for the risk factors in this at-risk population results in equal outcomes, then intense scrutiny should be taken to identify those patients who are most at risk for cardiovascular disease and engage in preventative measures.

Another argument made to explain the lack of a significant rise in patients being transplanted for nonalcoholic fatty liver disease as an indication is that as time on the waiting list has gone up significantly over the past decade, so have the chances that those patients with multiple comorbid conditions due to nonalcoholic fatty liver disease-related conditions such as diabetes mellitus and cardiovascular disease will be removed from the waiting list due to these comorbid conditions while waiting for transplant (O’Leary 2014). As a result, while more patients with nonalcoholic fatty liver disease-related end-stage liver disease are being listed, fewer patients make it to transplant. Longer waiting list times have in essence “selected” the fittest patients for transplants thus resulting in equivalent outcomes.

Adding to this is data showing that patients with nonalcoholic liver disease are less likely to be transplanted than their counterparts with other forms of liver disease. One such study showed that patients with nonalcoholic steatohepatitis-induced cirrhosis were more commonly denied listing due to comorbid conditions than patients with hepatitis C virus-induced cirrhosis (72 % vs. 27 %) (O’Leary et al. 2011).

If one examines patients with elements of the metabolic syndrome with regard to posttransplant outcomes, there are indications that some patients have poorer outcomes than patients overall. In one study of 37 patients with body mass indices greater than 35 who were referred for liver transplant, for example, patients with a body mass index greater than 35 were more likely to experience weight gain, steatosis on biopsy, graft loss, and death. Consequently, there have been series examining pretransplant sleeve gastrectomy prior to liver transplantation (Heimbach et al. 2013).

Obesity continues to be an active area of interest with regard to posttransplant outcomes out of concerns that obese patients will suffer from increased morbidity and mortality following transplant as a result of the metabolic consequences of obesity. Indeed, in their landmark guideline on selection for liver transplantation, the AASLD in 2005 unequivocally said that it considered morbid obesity a contraindication to liver transplant. It also recommended weight loss in all patients awaiting liver transplantation with a body mass index greater than 35 (Murray and Carithers 2005).

Nair et al. showed that morbidly obese patients with a body mass index greater than 40 kg/m² had significantly higher rates of primary graft nonfunction and significantly increased 1 and 2 year mortality rates. Five year mortality and morbidity rates were also significantly higher in severely obese (body mass index between 35.1 and 40 kg/m²) and morbidly obese patients due to increased cardiovascular mortality. Their data also showed that 7 % of all patients undergoing orthotopic liver transplantation are morbidly obese (Nair et al. 2002).

Another perspective on outcomes following liver transplant for nonalcoholic fatty liver disease is that nonalcoholic fatty liver disease is a systemic disease and that orthotopic liver transplant only treats the hepatic complications (O’Leary 2014). Nonalcoholic fatty liver disease is felt to be a marker for worsening complications of the metabolic syndrome meaning that the systemic complications of the core disease, the metabolic syndrome, may be coexistent. One study of patients receiving renal transplants revealed that patients with nonalcoholic fatty liver disease had more carotid atherosclerosis and higher proportions of plaque than other patients (Mikolasevic et al. 2014).

A major tenet of liver transplant evaluation in all patients is that risk factors for poor outcomes following transplant should be identified and, when possible, be treated. As a consequence, patients with the metabolic syndrome should be medically optimized prior to liver transplantation in addition to encouragement that they undergo supervised weight loss (Khullar et al. 2014). Blood pressure should be brought under control and better glycemic control achieved in patients with diabetes mellitus.

Nonalcoholic fatty liver disease does recur after transplant in addition to appearing as a de novo complication in patients transplanted for other indications (Contos 2001; Patil and Yerian 2012). Unlike in pretransplant populations where elevated aminotransferases in the presence of hepatic steatosis on imaging absence of evidence of other etiologies is enough to make a diagnosis, in posttransplant patients biopsy is necessary. This is because the posttransplant patient has many other reasons to have abnormal aminotransferases.

Transplant Outcomes

They may have acute cellular rejection, recurrent viral hepatitis, biliary complications, and other common posttransplant complications that need to be eliminated prior to diagnosing a posttransplant patient with elevated aminotransferases with nonalcoholic steatohepatitis. A thorough search for other causes should be executed prior to making a diagnosis.

Studies on recurrence demonstrate great variability in recurrence rates. This is thought due to differences in populations, biopsy timeline protocols, and differences in histological criteria making it difficult to establish recurrence rates. Histology is important both in differentiating nonalcoholic steatohepatitis from other posttransplant complications and in assessing severity. While posttransplant steatosis is relatively common, steatohepatitis is less common and steatohepatitis-induced cirrhosis even less. Histology is thus the most reliable assessment for recurrent disease in the transplant recipient (Patil and Yerian 2012).

The risk factors that lead to the pretransplant diagnosis of nonalcoholic fatty liver disease oftentimes remain present in the posttransplant syndrome. The metabolic syndrome of obesity, hyperlipidemia, and impaired glucose tolerance are also accelerated in the posttransplant setting. One major reason for this is the immunosuppression regimen itself. The most commonly used calcineurin inhibitors, tacrolimus and cyclosporine, both promote elements of the metabolic syndrome. While generally not used chronically, the prednisone dose used in liver transplantation promotes weight gain and hyperglycemia. Tacrolimus is associated with the development of diabetes mellitus and cyclosporine with hypertension and hyperlipidemia (Haddad et al. 2006; Tueck 2003).

For many reasons extending beyond prevention of the development of the metabolic syndrome and nonalcoholic steatohepatitis, steroid avoidance regimens in transplant patients have been extensively studied. Steroid-avoidant protocols post transplant have shown no differences in death, graft loss, and infection in patients who have been on steroid-free protocols and have the potential to reduce the diabetes mellitus and obesity associated with steroids thus reducing risk factors for nonalcoholic fatty liver disease (Khullar et al. 2014; Segev et al. 2013).

Rates of de novo steatosis have been shown to be 18–40 % and rates of de novo nonalcoholic steatohepatitis 9–13 % (Lim et al. 2007; Seo et al. 2007). If the patient has a body mass index increase post transplant of 10 % more than their pretransplant body mass index, then they have a higher risk of developing nonalcoholic fatty liver disease.

These data make it clear that while nonalcoholic fatty liver disease itself may not be a risk factor for poor outcomes following orthotopic liver transplant, the conditions that are associated with the disease may put patients at risk for poor outcomes following liver transplantation. Most prominently, obesity, cardiovascular disease, and diabetes mellitus may present challenges for outcomes following liver transplant. It may not be that nonalcoholic fatty liver disease alone leads to increases in morbidity and mortality, but this disease may increase the likelihood that patients will have concurrent conditions which may bring out cardiovascular disease which in turn may lead to poor outcomes.

It has been mentioned earlier in this chapter that some have suggested that the reason for relatively good outcomes following liver transplantation among patients transplanted for an indication of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis is the fact that those patients who make it to transplant are those patients who have been screened for cardiovascular risk and obesity beforehand and transplanted precisely because they have been rigorously identified as being low risk for these conditions. This reasoning would suggest that current methodologies’ being used nationally to screen patients for transplant has been adequate at controlling for any increased risk for poor cardiovascular outcomes that these patients may bring.

These survival data do not, however, take into account worsening rates of obesity in this country and the possibility that in the future, patients with nonalcoholic fatty liver disease may be worse off metabolically than patients today due to longer-term obesity and diabetes mellitus. Furthermore, these data do not look at very long-term outcomes. Though survival rates may be similar at 5 and 10 years, we do not yet know what they will look like at 20 and 25 years.

We are currently using indirect markers of the metabolic syndrome such as obesity and insulin resistance as surrogates for the true nature of the disease. Perhaps soon we will be able to use molecular markers in clinical practice to better predict outcomes of the metabolic syndrome. In turn, precision will improve in the ability to predict long-term morbidity and mortality among patients with nonalcoholic fatty liver disease.

Transplant Evaluation

For now, the transplant physician must continue to rely on current assessments of risk for poor outcomes. Focus must be placed both on assessing global cardiovascular risk in patients with nonalcoholic steatohepatitis as cardiovascular disease is the predominant cause of poor outcomes following liver transplantation. As well, it should be appreciated that any metabolic issues prior to transplant such as obesity, hyperlipidemia, and diabetes mellitus will likely only be compounded following liver transplant mostly due to the effects of immunosuppression.

With regards to obesity, the American Association for the Study of Liver Disease recommend that patients with morbid obesity and a body mass index greater than 40 should not be offered transplant. Patients who have a body mass index between 35 and 40 should be asked to lose significant amounts of weight prior to listing. Any overweight patient with a body mass index less than 35 should also be encouraged to lose weight (Murray and Carithers 2005).

The patient with nonalcoholic fatty liver disease being evaluated for transplant who has diabetes mellitus or hyperlipidemia should show that they have brought their lipid levels and hemoglobin A1C under good control. All patients with nonalcoholic fatty liver disease regardless of age or risk factors should also have rigorous cardiovascular stress testing with liberal use of cardiac catheterization to assess directly for coronary atherosclerosis.

With a population that is rapidly growing more overweight, such tactics in selection criteria may appear to be overly utilitarian in their approach to obese patients. However, the ethics of liver transplantation are by nature extraordinarily utilitarian given the mismatch in numbers between organ donors and recipients. When seen in this regard, rigorous selection criteria simply maximize benefit while minimizing risk.

One analogy that is frequently cited in ethical discussions about selection of patients for transplant for nonalcoholic steatohepatitis is that of the patient with alcoholism. While alcoholism is now seen to be a multifactorial illness based on a complex interplay of genetics, physiology, and behavior, patients are still not offered liver transplant unless they have had significant periods of abstinence from alcohol and have passed muster with a rigorous psychosocial evaluation that examines risk factors for recidivism.

In much the same way, it can be argued that patients with obesity and the metabolic syndrome should be asked to make behavioral changes as alcoholic patients are asked to abstain from alcohol. While the arguments for obesity being a purely behavioral problem are weak, the behavior is under some control of the patient, and this component needs to be used in order to ensure the best outcomes following transplant. Significant weight loss will reduce risk factors prior to liver transplant as well as reducing the chances of recidivism post transplant thus minimizing the inevitable worsening of metabolic risk factors that occurs following liver transplant.

Conclusion

Nonalcoholic fatty liver disease which includes the subset of patients with nonalcoholic steatohepatitis is a common condition associated with the metabolic syndrome of obesity, insulin resistance, and hyperlipidemia that can lead to cirrhosis and end-stage liver disease. The prevalence and morbidity from this condition is only expected to grow as the metabolic risk factors for nonalcoholic fatty liver disease such as obesity and diabetes mellitus continue to grow in the US population. With this come predictions that the future will see growing numbers of patients undergoing liver transplant with an indication of nonalcoholic steatohepatitis.

As nonalcoholic steatohepatitis is also seen as a risk factor for other diseases, in particular cardiovascular disease, concern has arisen regarding risk factors for poor outcomes following liver transplantation. While overall morbidity and mortality do not seem to be significantly different among patients transplanted for nonalcoholic steatohepatitis when compared with other indications, this may be a result of rigorous screening of candidates for risk factors for cardiovascular disease and nonlisting of morbidly obese candidates in most cases. Such rigorous selection criteria should continue unless transplant programs are better able to directly identify those candidates at risk for morbidity and mortality from the metabolic syndrome.

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