Liver transplantation and nonalcoholic fatty liver disease


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nonalcoholic fatty liver disease


nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) can manifest as a benign fatty infiltration of the liver or as nonalcoholic steatohepatitis (NASH), with inflammation and fibrosis progression leading to cirrhosis. As soon as patients with cirrhosis decompensate, liver transplantation is the optimal intervention. NASH-related cirrhosis is the third most common indication for transplantation in the current era and accounts for 10% to 13% of transplants performed.[1] NASH-related cirrhosis is the only underlying disease that is increasing in frequency in liver transplant recipients in comparison with other diseases, including hepatitis C and alcohol-related liver disease.[1] These data depict patients identified with NASH as the primary or secondary cause of cirrhosis in the Scientific Registry of Transplant Recipients and likely underestimate the number of patients with a secondary cause of NASH because most patients are identified by only 1 cause of disease. It is projected that NASH will usurp hepatitis C as the most common cause of liver disease in the transplant population in the coming years.

Patients with NASH tend to be older and more frequently female with a higher body mass index and metabolic complications (diabetes, hypertension, hyperlipidemia, and cardiovascular disease) before transplantation.[2] In comparison with other transplant recipients, patients with NASH who undergo transplantation have a higher likelihood of demonstrating metabolic syndrome and possibly renal failure after transplantation.[4] Animal studies[6] have demonstrated increased inflammatory responses to ischemia/reperfusion injury in mice with NASH versus control mice, but human studies have not been performed, and the clinical consequences remain to be determined. Despite all these issues, patients undergoing transplantation for NASH-related cirrhosis have similar graft and patient survival in most studies.[1] However, according to comparisons with patients with other specific underlying diseases, NASH patients may have lower 1- and 3-year survival rates than patients undergoing transplantation for cholestatic disease.[2] NASH patients who undergo transplantation have a higher frequency of infectious[2] or cardiovascular causes of death[3] and less frequently die of recurrent disease than other patients. Importantly, when patients are analyzed according to higher risk status (defined as age > 60 years and body mass index > 30 kg/m2 with pretransplant diabetes and hypertension), high-risk NASH patients have a 25% immediate mortality rate and a 50% 1-year mortality rate in comparison with Model for End-Stage Liver Disease score–matched controls. NASH patients not considered high-risk have survival rates similar to those of all other transplant recipients.[2]

Both steatosis and steatohepatitis can recur after liver transplantation. The exclusion of alcohol-related disease is still important to consider. In an earlier study of 25 patients undergoing transplantation for NASH or cryptogenic cirrhosis with biopsy after transplantation, 100% demonstrated steatosis within 5 years.[8] In a more recent large, single-center study of 257 patients undergoing transplantation for NASH or cryptogenic cirrhosis, steatosis was demonstrated in 18% of patients undergoing transplantation for NASH within 1 year and in 45% within 5 years.[7] Steatohepatitis, however, was less common and was found in only 7% of NASH recipients by 5 years and in 18% by 10 years in this study.[7] Fibrosis progression to cirrhosis occurred in 5% of NASH recipients over 5 years and in 10% of NASH recipients over 10 years. However, fibrosis progression over 10 years occurred in 30% of the patients in whom NASH developed in the allograft and in 8% to 9% of the patients with simple steatosis or no steatosis in the allograft.[7] In another study,[9] 54% of NASH patients with liver biopsies (or 39% of NASH patients who underwent transplantation) at a mean of 11 months after transplantation had recurrent NAFLD, with 73% of these patients diagnosed with recurrent NASH and 23% diagnosed with stage 2 to 4 fibrosis. Risk factors for recurrent NASH in this study included a high body mass index before and after transplantation, hypertriglyceridemia occurring after transplantation, and higher steroid dosing 6 months after transplantation.[9] Donor steatosis was not associated with recurrent NASH. Patients with recurrent NAFLD have survival rates after transplantation similar to those of NASH patients without recurrence.[9] The progression of recurrent disease has not been marked in most studies to date. One exception may be patients with panhypopituitarism; such patients are known to demonstrate severe NASH with relatively rapid progression of fibrosis in the nontransplant setting. The author has observed that patients with hypopituitarism who have undergone liver transplantation for NASH at her center have a relatively high frequency of severe and rapid recurrence of NASH with subsequent graft failure. Although the basis for the development of severe, progressive recurrent disease in these patients with hypopituitarism is not established, the successful treatment of NASH with growth hormone replacement has been reported. Optimizing the management of NASH associated with hypopituitarism will be an important area for future research.

Steatosis is linked to weight gain after transplantation. Weight gain after transplantation is common in all transplant recipients, regardless of the cause of the underlying disease, and is associated strongly with steatosis in the allograft.[10] Of course, the exclusion of alcohol-related steatosis is necessary in this setting. Patients who undergo transplantation for diseases other than NASH can demonstrate de novo NAFLD (Table 1).[11] Up to 3% of non-NASH, noncryptogenic transplant recipients demonstrate steatosis by 1 year, and 10% to 20% demonstrate steatosis by 5 years after transplantation.[7] NASH is less common in this population (5%–9%),[10] but long-term histological follow-up has suggested that up 30% of recipients with allograft NASH may demonstrate progressive disease over 3 to 5 years, even with the removal of hepatitis C patients from the data.[10]

Table 1. Frequency of NAFLD in the Allograft
Allograft HistologyNASH RecipientsNon-NASH Recipients (Noncryptogenic Disease)
  1. The data for this table were compiled from references 7 to 11.
NAFLD (steatosis) at 5 years39%–45%10%–20%
NASH (steatohepatitis) at 5 years7%–30%5%–9%
Fibrosis (>stage 2) at 5 years8%3%
5 years5% 
10 years10% 

The management of patients with recurrent steatohepatitis requires diligent control of diabetes, hypertension, and hyperlipidemia after transplantation. Weight loss, as in the case of nontransplant patients, is a fundamental component of management. Weight loss efforts are very challenging and frequently are unsuccessful. Bariatric surgery has been performed after liver transplantation according to several case reports.[12] All patients undergoing various bariatric procedures successfully lost weight, and metabolic syndrome comorbidities improved, but a histological benefit for NASH was not documented. Although the interventions in the cases described in the literature were successful, all operations were described by the authors as technically challenging, presumably because of adhesions from the previous transplantation surgery. Because of the possibility of publication bias, more data on the safety and efficacy of bariatric surgery in the liver transplant recipient are needed.

Presently, there is limited benefit from pharmacological interventions for NASH in the nontransplant setting, but vitamin E, peroxisome proliferator-activated receptor agonists, or both have some biochemical and histological benefits over 2 years, as reviewed elsewhere (See Ratziu in this issue of CLD).[16, 17] No data exist on the benefits or detriments of these agents specific to the liver transplant recipient, but because vitamin E is well tolerated with no drug-drug interaction, many practitioners have used this agent in the posttransplant setting. Peroxisome proliferator-activated receptor agonists have been used and are well tolerated in the patient with diabetes who has undergone liver transplantation and may be the preferred agents in the population with NASH, but more study is required on the risks and benefits of these agents in transplant patients.

In summary, the need for liver transplantation in patients with NAFLD is growing. Recurrent disease is described but seems to have minimal impact on short- and medium-term survival. Weight loss and diligent medical management of metabolic comorbidities are required to minimize the impact on long-term survival.