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Liver Transplantation for Nonalcoholic Steatohepatitis

New Evidence of a Profound Increase Across Age Cohorts

Paul, Sonali, MD1; Charlton, Michael, MD, FRCP1

doi: 10.1097/TP.0000000000002513
In View: Commentary

1 The University of Chicago Medicine, Chicago, IL.

Received 24 October 2018.

Accepted 26 October 2018.

The authors declare no funding or conflicts of interest.

Both authors contributed to the writing of the article.

Correspondence: Michael Charlton, MD, FRCP, The University of Chicago Medicine 5841 S. Maryland Ave, Chicago, IL 60637. (

The rising prevalence and incidence of nonalcoholic fatty liver disease (NAFLD) has been well documented, with 25% of the global population estimated to have NAFLD.1 Of these, 30% will develop nonalcoholic steatohepatitis (NASH), with 15% to 25% of patients with NASH progressing to cirrhosis and a quarter of patients with cirrhosis developing hepatocellular carcinoma (HCC), dying a liver-related death or undergoing liver transplant (LT).2 From a healthcare resource utilization perspective, a recent analysis estimated the burden of disease for a patient with private insurance to cost approximately US $7804 for a new NAFLD diagnosis (mainly from liver biopsies, imaging, and hospitalizations) and US $3789 for long-term management, significantly higher than a similar patient with similar metabolic comorbidities but without NAFLD (estimated to be US $2298).3 Nonalcoholic fatty liver disease, along with its comorbidities, including obesity, type 2 diabetes mellitus (T2DM), and the metabolic syndrome (METs), is thus an unmitigated and evolving public health crisis, with increased healthcare-associated costs and resource utilization that have only begun to be realized.

Although indisputably a global phenomenon, there has been emerging evidence that the burden of NAFLD falls unevenly across age cohorts. A community-based study in Minnesota, for example, reported that the incidence of NAFLD increased by a factor of 5 overall between 1997 and 2014, versus sevenfold in young adults aged 18 to 39 years.4 The increasing number of young patients being listed for liver transplantation is consistent with the well-documented younger age of onset of obesity in the United States. In this issue of Transplantation, Shingina and colleagues4 present evidence that end-stage liver disease secondary to NASH is affecting a broader range of birth cohorts than has hitherto been reported. In an analysis of 20 years of United Network for Organ Sharing (UNOS) data spanning 1995 to 2015, the authors report several important new findings. First, over 180 000 people were placed on the LT waiting list in a 20-year span, 18 000 for NASH, with an increase in the number of patients with NASH registered for LT, with and without HCC, relative to all other indications for LT.5 This trend was most marked in younger patients ages 35 to 55 years and was not observed for other (non-NASH) indications for liver transplantation. The authors term this the “Adipose Wave Effect” and postulate that parallel increases in the frequency rates for NASH, with and without HCC, suggest that end-stage liver disease secondary to NASH is occurring at steadily younger ages in concert with younger ages of onset of obesity and NASH. Although patients older than 50 years account for well over 70% of patients listed for NASH, the rate of increase in listing was just as great among patients born after 1971 (47 years old). For patients with NASH complicated by HCC, the rate of listing for liver transplantation was, by far, the greatest among the youngest cohort (born after 1971).

This article brings to light the issue of whether we should reconsider screening for NASH. For screening to have value, the course of disease needs to be reversible through effective treatment before the onset of advanced fibrosis and its complications. Current screening guidelines by the American Association for the Study of Liver Diseases do not recommend screening for NAFLD in any populations, citing the uncertainties related to diagnostic testing and treatment options in addition to the unknown long-term benefits of screening.6 Although NAFLD screening in the general population is not recommended, screening in high-risk populations may be warranted, particularly when effective pharmacotherapies become available in 2019 to 2020 as anticipated at the conclusion of the phase 3 studies currently underway. Paradoxically, guidelines from Europe, where NASH has substantially lower prevalence than those in the United States, recommend screening in high risk populations (Table 1). Further research is urgently needed to determine the optimal screening test(s) and algorithms to limit the impact of fibrosing NASH.



While we await pharmacotherapies for fibrosing NASH, diet, exercise, and risk factor modification are effective treatment when successfully implemented.7 Presuming effective screening strategies and therapies become available and are implemented, a sharp increase in hepatology referrals is likely. The number of hepatologists and transplant hepatologists is less than 1000, and multidisciplinary clinics needed to effectively address the protean manifestations of METs and NASH are only beginning to emerge. An action plan is needed. The article by Shingina and colleagues demonstrates that the epidemic of NASH-related liver failure and cancer is not going to be as bad as projected. It is going to be much worse.

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