Myth: Liver Transplant Provides a Cure for Liver Disease

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Abbreviations

AIH

autoimmune hepatitis

HBV

hepatitis B virus

HCC

hepatocellular carcinoma

HCV

hepatitis C virus

LT

liver transplantation

MetS

metabolic syndrome

NAFLD

nonalcoholic fatty liver disease

NASH

nonalcoholic steatohepatitis

PBC

primary biliary cholangitis

PSC

primary sclerosing cholangitis

Liver transplantation (LT) is a lifesaving surgery indicated for patients with a wide variety of diseases. Although the potential for improved long‐term survival and quality of life exists, LT has considerable morbidity. It remains a misconception that LT is curative for all recipients; in fact, it is rare that LT offers a curative option. According to the OPTN/SRTR 2016 Annual Report, the most common indications for LT include hepatitis C (HCV), hepatitis B (HBV), alcoholic liver disease, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), hepatocellular carcinoma (HCC), and “other/unknown” thought to be comprised of nonalcoholic steatohepatitis (NASH). Although less common indications for LT may be curative, the majority have recurrence after LT (Fig. 1).1 We will discuss the most common causative factors of liver disease after LT (Table 1).

Figure 1.

Causative factors of disease in adult liver transplant recipients in 2016. Adapted with permission from the American Journal of Transplantation.1 Copyright 2018, American Society of Transplantation and the American Society of Transplant Surgeons.

Table 1.

Causes of Liver Disease After Liver Transplantation

Immune modulation may accelerate disease process

HCV

HBV

Immune‐modulation side effects may cause liver disease

Recurrent NASH

De novo MetS or NASH

De novo autoimmune disease

Immune modulation increases malignancy

Recurrent HCC

De novo malignancy

Transplant does not eliminate original risk for disease

Alcohol‐related liver disease

NASH

Autoimmune liver disease

PBC

PSC

Immune Modulation May Accelerate the Underlying Disease Process

Immune modulation is essential after LT to reduce cellular rejection; however, it provides an environment for rapid viral replication. In patients with active viremia (HCV or HBV) prior to transplantation, viremia invariably results in recurrence, and fibrosis progression is accelerated in the graft.2, 3, 4, 5 Fibrosing cholestatic variants led to poor early graft survival.6 With the advent of direct‐acting antivirals, the majority of patients with HCV recurrence can be cured after transplant, thus preventing graft loss.7, 8 Similarly, the advent of HBV prophylaxis allows recurrent HBV to be prevented in nearly all cases with the administration of HBV immunoglobulin and nucleos(t)ide analogues.9

Immune Modulation–Related Side Effects May Accelerate or Cause Liver Disease

NASH as an indication for liver transplant is rapidly increasing. With the prevalence rate of metabolic syndrome (MetS) in the general US population reaching 23%, NASH is projected to be the leading cause of LT in the near future.10, 11 The metabolic risk factors for NASH persist after LT and may be worsened by immunosuppression. Hepatic steatosis recurs in 40% to 70% of patients. One study demonstrated that at 18 months after LT, recurrent steatosis was seen in 70%, recurrent NASH seen in 24%, and stage II fibrosis or greater in 18%. Currently, 3‐year graft survival for NASH transplant recipients is 78%, but longer‐term studies are needed.1

Patients who receive LT for indications other than NASH remain at risk for de novo MetS and nonalcoholic fatty liver disease (NAFLD) because of the side‐effect profile of immunomodulation. Because MetS portends a high risk for death after LT this is of concern. The prevalence of MetS after LT is greater when compared with the general population (55% versus 23%).12 Both corticosteroids and calcineurin inhibitors promote de novo hypertension, diabetes, and hypercholesterolemia. Mtor inhibitors have been shown to increase rates of hyperlipidemia.13 With rates of MetS high, it is not surprising that the rate of de novo NAFLD was as high as 18% and de novo NASH 9% in short‐term follow‐up after liver transplant.14

Immunomodulation has been associated with de novo AIH after LT. The exact pathogenesis is not fully clarified but appears to be either donor or recipient cell‐triggered T cell activity. Historically, de novo AIH occurred after HCV therapy; however, it has been described with other causes of transplant and de novo in 1% to 2% of adult LT recipients overall. In patients who experienced development of plasma cell hepatitis, 30% progressed to cirrhosis and 33% died or had graft loss.15

Immune Modulation May Increase Malignancy

De novo malignancy is the second leading cause of late death after LT.16 LT recipients have a 2‐ to 3‐fold greater risk for malignancy than the general population.17 Immune modulation alters the protective effect of natural killer cells, macrophages, and T cells.18 Calcineurin inhibitors have been shown to have a dose‐dependent direct carcinogenic effect.19 For this reason, efforts are taken to minimize immunomodulation as much as possible after LT without causing rejection. De novo malignancy occurs in 2.6% to 8% of LT recipients, with lymphoma and skin cancer being most prevalent. Patients who have malignancy after LT have poor survival, and efforts for early detection must be initiated.

Patients with HCC are given priority with Model for End‐Stage Liver Disease exception points (Fig. 1). Four years after LT, recurrence rate was 8% in patients whose explanted liver fell within the Milan Criteria compared with nearly 50% in patients whose explant was substantially outside of the Milan Criteria.20 A 6‐month waiting time was initiated to reduce risk for cancer recurrence by selecting patients with better tumor biology. Even carefully selected patients are at risk for recurrent malignancy in part because of immune modulation. Use of MTOR inhibitors in low‐risk patients has been shown to improve recurrence‐free survival in the first few years after LT, but the effect is not long lasting.21

Transplant Does Not Eliminate Risk From the Original Disease

LT removes the fibrotic liver; however, if the graft is exposed to the same causative agent, fibrosis will recur and at a faster rate. For example, alcohol‐related liver disease does not recur after transplant if patients are able to maintain sobriety. Unfortunately, relapse rates range from 10% to 30% in patients with alcohol‐related liver disease. Among those with clinically significant relapse, recurrent cirrhosis developed in 33%, leading to decreased survival after 5 years post‐LT.22 Most transplant centers require 6 months of sobriety, completion of an alcohol treatment program, and frequent monitoring for alcohol use in efforts to reduce rates of recidivism. Younger age and shorter pretransplant abstinence were associated with higher rates of recurrence.23 Other risk factors include lack of social support, comorbid psychiatric disorders, family history of alcohol dependence, tobacco use, and noncompliance with clinic visits.24 Similarly, patients with NASH who do not achieve significant lifestyle modification are at risk for recurrence of NASH cirrhosis and potentially at a more rapid rate (see earlier Immune Modulation–Related Side Effects May Accelerate or Cause Liver Disease section).

Autoimmune liver diseases (AIH, PBC, and PSC) are particularly challenging to manage after LT, as evidenced by the highest rates of recurrence and graft loss. The risk for graft loss is so high that most transplant centers have separate immunosuppression protocols. Despite aggressive immunomodulation, recurrent disease progression is accelerated after LT. In a retrospective analysis of 400 patients, 17% of patients experienced recurrent PBC at a mean time of 36 months post‐LT.25 Even with optimal immunosuppression and preventative ursodeoxycholic, recurrent cirrhosis develops in 5.4% within 8 years of LT.26 Recurrence rates for PSC vary widely from 5.7% to 59.1%. One large cohort of 1399 patients transplanted for PSC found an 18.5% recurrence rate.27 Ten percent of patients transplanted for PSC had graft loss within 15 years.26 AIH has been shown to recur in 8% to 12% of transplanted patients at 1 year and 36% to 68% at 5 years.28 Hubscher et al.29 describe that 13 of 32 patients with recurrent AIH progressed to cirrhosis or graft failure.

Conclusion

LT improves the life expectancy in patients who otherwise would not survive. The long‐term survival after transplant continues to improve; however, it should be considered a lifesaving surgery, not a curative intervention. The majority of transplant recipients will have recurrent disease; some will progress to cirrhosis or graft failure. Patients and families should be educated about the risk for recurrence for their disease during the transplant evaluation process. This education should be ongoing after transplantation.