Liver Transplant for Hepatocellular Carcinoma in the United States

Evolving Trends Over the Last Three Decades

Marc Puigvehí; Dana Hashim; Philipp K. Haber; Amreen Dinani; Thomas D. Schiano; Amon Asgharpour; Tatyana Kushner; Gaurav Kakked; Parissa Tabrizian; Myron Schwartz; Ahmet Gurakar; Douglas Dieterich; Paolo Boffetta; Scott L. Friedman; Josep M. Llovet; Behnam Saberi


American Journal of Transplantation. 2020;20(1):220-230. 

In This Article


Study Population

Between October 1987 and September 2017 there were a total of 132 731 adult DDLT recipients in the United States. Of these 27 855 (21%) underwent an initial DDLT for an HCC-related indication. Overall, 22 280 (80%) of the HCC-related LT recipients had been granted HCC MELD exception points. Baseline characteristics of the study population are summarized in Table 1. The median age of LT recipients was 59 years, and 77% of the patients were males. Overall, 69.5% of patients had T2 TNM stage tumor. Median lab MELD of the cohort at the time of transplantation was 12.[9–17]

The most common underlying etiology was HCV (48.9%) followed by HCV/ALD (10.6%), ALD alone (8.1%), NAFLD (6.1%), HBV (5.8%), and cryptogenic (3%). HCV patients, compared to NAFLD, were younger (58.4 vs 63.9 years), mostly male (76.9% vs 65.2%), with lower body mass index (BMI) (27.9 vs 32.3 kg/m2), and lower MELD at transplant (12 vs 14) (all P < .001, Table S2). Proportion of diabetes (70.4% vs 23.9%) and hypertension (47.9% vs 28.2%) were significantly higher among NAFLD patients compared to HCV (both P < .001) (Table S2).

The characteristics of the donors for the different etiologies of HCC-related LT are presented in Table S3.

Etiology Trends of HCC-related LT

There was a remarkable increase in HCC-related LT from 222 (5.3%) in 2001 to 977 (21.8%) in 2002, following the implementation of the MELD system and MELD exceptions for HCC recipients (P < .001) (Figure 1). After 2002, the number and proportion of HCC-related LT continued to increase steadily until 2015 (30.5% in 2008, 36.1% in 2015). Following the MELD policy change in 2015 that would deprioritize HCC patients, the rate of HCC as an indication for DDLT declined from 36.1% in 2015 to 30% in 2016 (P < .001) (Figure 1). Although the first patient undergoing LT for HCV-related HCC was reported in 1991, the first LT for NAFLD-related HCC was not until 2003. In the entire pre MELD era (1987–2001) the most frequent underlying liver disease for patients with HCC undergoing LT was HCV (31%) followed by an unknown etiology (23.8%). In the MELD era, patients with unknown liver disease only accounted for 3.8% of all patients with HCC-related LT (P < .001). The proportion of HCV-related HCC peaked at 55.5% in 2010 and slightly decreased in 2016 and 2017 (46.3% and 45.7%, respectively). On the other hand, there has been a steady increase in the number and proportion of NAFLD patients from 2003 (n = 4, 0.4%) to 2016 (n = 276, 13.2%). In parallel, the NAFLD/HCV ratio has decreased from 1/145 in 2003 (one NAFLD-related transplant for every 145 HCV-related transplants) to 1/12 in 2010 and 1/4 in 2017.

Figure 1.

The trend of HCC-related liver transplants in the United States based on SRTR data. A, total number (n); B, percentage

Considering the different HCV treatment eras, the proportion of HCV-related LT kept an increasing trend in the IFN-only era (48.2%) and the early IFN-DAA era (53%) but started to decrease in 2015 coinciding with the IFN-free DAA era (50.3%) (Figure S1). Conversely, NAFLD-related LT rose constantly from the IFN-only era (3.1%) to the early IFN-DAA era (7%) and the DAA era (11.3%), with the highest proportion in 2016–2017 (13.3%) (Figures 2 and S1). Consequently, NAFLD is now the second leading cause of HCC-related LT in the IFN-free DAA era, after HCV. However, it is important to note that 9% of patients have concomitant HCV and ALD diagnosis. Hypothetically, if the recipients with HCV/ALD (9%) are counted towards the ALD-only group (9%), then ALD will be the second leading cause of HCC-related LT (18%) (Figure S1E).

Figure 2.

Annual trend of etiologies of liver disease in LT recipients with HCC in the United States. A, total number (n); B, percentage [Color figure can be viewed at]

Outcomes and Survival in HCC Patients

The causes of death were different according to etiology. HCV patients had a higher rate of graft-related death compared to NAFLD patients (12.4% vs 4.8%, P < .001). On the contrary, NAFLD individuals showed a higher rate of cardiovascular-related death (13.3% vs 7.8%, P < .001) (Table 2).

The main determinants of death (HR, 95% CI, P value) in the IFN era (2002–2013) as determined through Cox regression multivariate analysis were HCV etiology (1.155, 1.0179–1.237, P < .001), alpha-fetoprotein (1.288, 1.200–1.382, P < .001), and diabetes (1.188, 1.102–1.280, P < .001) (Figure 3A and Table S4A). Remarkably, in the DAA era, etiology was not related to survival neither in the univariate (0.963, 0.836–1.110, P = .603) nor in the multivariate analysis (1.115, 0.892–1.394, P = .338) (Figure 3B and Table S4B). Only tumor size (1.189, 1.079–1.311, P = .001) was related to an impaired survival in the DAA era.

Figure 3.

Determinants of death in HCC-related LT. A, IFN-era (2002–2013); B, DAA-era (2014–2017) [Color figure can be viewed at]

Overall, HBV patients had the best survival among the different etiologies (log-rank < 0.001) (Figure S2). This difference in outcome was maintained when only patients transplanted in the MELD era were taken into consideration (Figure 4A). In the same period, HCV patients had lower survival compared to NAFLD patients (log-rank = 0.030) (Figure 4B). This impaired survival was conveyed through a markedly worse outcomes during the IFN-only era, and the early IFN-DAA era (log-rank = 0.031) as no significant difference was observed in the IFN-free DAA era (log-rank = 0.321) (Figure 4C). When evaluating the survival changes according to the HCV treatment era, HCV-related LT showed a significant improvement, comparing the IFN-only to the early IFN-DAA era (log-rank < 0.001) and the early IFN-DAA era to the DAA era (log-rank = 0.002) (Figure 4D). In contrast, NAFLD patients showed improved survival only when comparing the IFN-only era to the early IFN-DAA era (log-rank = 0.001), but no difference compared to the DAA era (log-rank = ns).

Figure 4.

Kaplan–Meier estimates of survival based on etiology of liver disease in HCC liver transplant recipients. A, MELD era (2002–2017); B, IFN era (2002–2013); C, DAA era (2014–2017); D, survival according to HCV treatment era in HCV and NAFLD patients (2002–2017) [Color figure can be viewed at]