Outcomes of liver transplantation for non-alcoholic steatohepatitis: A European Liver Transplant Registry study

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Graphical abstract

Highlights

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An increasing proportion of patients are being transplanted for non-alcoholic steatohepatitis (NASH) in Europe.
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Hepatocellular carcinoma was more common in patients transplanted with NASH.
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Survival in recipients with NASH is comparable to that of other disease indications.
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Age, BMI, and advanced liver disease predicted poorer outcomes in NASH recipients.

Abstract

Background & Aims

Little is known about outcomes of liver transplantation for patients with non-alcoholic steatohepatitis (NASH). We aimed to determine the frequency and outcomes of liver transplantation for patients with NASH in Europe and identify prognostic factors.

Methods

We analysed data from patients transplanted for end-stage liver disease between January 2002 and December 2016 using the European Liver Transplant Registry database. We compared data between patients with NASH versus other aetiologies. The principle endpoints were patient and overall allograft survival.

Results

Among 68,950 adults undergoing first liver transplantation, 4.0% were transplanted for NASH – an increase from 1.2% in 2002 to 8.4% in 2016. A greater proportion of patients transplanted for NASH (39.1%) had hepatocellular carcinoma (HCC) than non-NASH patients (28.9%, p <0.001). NASH was not significantly associated with survival of patients (hazard ratio [HR] 1.02, p = 0.713) or grafts (HR 0.99; p = 0.815) after accounting for available recipient and donor variables. Infection (24.0%) and cardio/cerebrovascular complications (5.3%) were the commonest causes of death in patients with NASH without HCC. Increasing recipient age (61–65 years: HR 2.07, p <0.001; >65: HR 1.72, p = 0.017), elevated model for end-stage liver disease score (>23: HR 1.48, p = 0.048) and low (<18.5 kg/m ²: HR 4.29, p = 0.048) or high (>40 kg/m ²: HR 1.96, p = 0.012) recipient body mass index independently predicted death in patients transplanted for NASH without HCC. Data must be interpreted in the context of absent recognised confounders, such as pre-morbid metabolic risk factors.

Conclusions

The number and proportion of liver transplants performed for NASH in Europe has increased from 2002 through 2016. HCC was more common in patients transplanted with NASH. Survival of patients and grafts in patients with NASH is comparable to that of other disease indications.

Lay summary

The prevalence of non-alcoholic fatty liver disease has increased dramatically in parallel with the worldwide increase in obesity and diabetes. Its progressive form, non-alcoholic steatohepatitis, is a growing indication for liver transplantation in Europe, with good overall outcomes reported. However, careful risk factor assessment is required to maintain favourable post-transplant outcomes in patients with non-alcoholic steatohepatitis.

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Most cited references 19

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Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants

Emily Sonestedt, Kim Overvad (2016)

Summary Background Underweight and severe and morbid obesity are associated with highly elevated risks of adverse health outcomes. We estimated trends in mean body-mass index (BMI), which characterises its population distribution, and in the prevalences of a complete set of BMI categories for adults in all countries. Methods We analysed, with use of a consistent protocol, population-based studies that had measured height and weight in adults aged 18 years and older. We applied a Bayesian hierarchical model to these data to estimate trends from 1975 to 2014 in mean BMI and in the prevalences of BMI categories (<18·5 kg/m2 [underweight], 18·5 kg/m2 to <20 kg/m2, 20 kg/m2 to <25 kg/m2, 25 kg/m2 to <30 kg/m2, 30 kg/m2 to <35 kg/m2, 35 kg/m2 to <40 kg/m2, ≥40 kg/m2 [morbid obesity]), by sex in 200 countries and territories, organised in 21 regions. We calculated the posterior probability of meeting the target of halting by 2025 the rise in obesity at its 2010 levels, if post-2000 trends continue. Findings We used 1698 population-based data sources, with more than 19·2 million adult participants (9·9 million men and 9·3 million women) in 186 of 200 countries for which estimates were made. Global age-standardised mean BMI increased from 21·7 kg/m2 (95% credible interval 21·3–22·1) in 1975 to 24·2 kg/m2 (24·0–24·4) in 2014 in men, and from 22·1 kg/m2 (21·7–22·5) in 1975 to 24·4 kg/m2 (24·2–24·6) in 2014 in women. Regional mean BMIs in 2014 for men ranged from 21·4 kg/m2 in central Africa and south Asia to 29·2 kg/m2 (28·6–29·8) in Polynesia and Micronesia; for women the range was from 21·8 kg/m2 (21·4–22·3) in south Asia to 32·2 kg/m2 (31·5–32·8) in Polynesia and Micronesia. Over these four decades, age-standardised global prevalence of underweight decreased from 13·8% (10·5–17·4) to 8·8% (7·4–10·3) in men and from 14·6% (11·6–17·9) to 9·7% (8·3–11·1) in women. South Asia had the highest prevalence of underweight in 2014, 23·4% (17·8–29·2) in men and 24·0% (18·9–29·3) in women. Age-standardised prevalence of obesity increased from 3·2% (2·4–4·1) in 1975 to 10·8% (9·7–12·0) in 2014 in men, and from 6·4% (5·1–7·8) to 14·9% (13·6–16·1) in women. 2·3% (2·0–2·7) of the world’s men and 5·0% (4·4–5·6) of women were severely obese (ie, have BMI ≥35 kg/m2). Globally, prevalence of morbid obesity was 0·64% (0·46–0·86) in men and 1·6% (1·3–1·9) in women. Interpretation If post-2000 trends continue, the probability of meeting the global obesity target is virtually zero. Rather, if these trends continue, by 2025, global obesity prevalence will reach 18% in men and surpass 21% in women; severe obesity will surpass 6% in men and 9% in women. Nonetheless, underweight remains prevalent in the world’s poorest regions, especially in south Asia. Funding Wellcome Trust, Grand Challenges Canada.

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Projections of primary liver cancer to 2030 in 30 countries worldwide

Patricia Valery, Mathieu Laversanne, Paul Clark … (2018)

Primary liver cancer (PLC) is the sixth most common cancer worldwide and the second most common cause of cancer death. Future predictions can inform health planners and raise awareness of the need for cancer control action. We predicted the future burden of PLC in 30 countries around 2030. Incident cases of PLC (ICD-10 C22) were obtained from 30 countries for 1993–2007. We projected new PLC cases through to 2030 using age-period-cohort models (NORDPRED). Age-standardized incidence rates per 100,000 person-years were calculated by country and sex. Increases in new cases and rates of PLC are projected in both sexes. Among men, the largest increases in rates are in Norway (2.9% per annum), US whites (2.6%), and Canada (2.4%), and among women in the US (blacks 4.0%), Switzerland (3.4%), and Germany (3.0%). The projected declines are in China, Japan, Singapore, and parts of Europe (e.g. in Estonia, Czech Republic, Slovakia). A 35% increase in the number of new cases annually is expected compared to 2005. This increasing burden reflects both increasing rates (and the underlying prevalence of risk factors) and demographic changes. Japan is the only country with a predicted decline in the net number of cases and annual rates by 2030. Conclusion Our reporting of a projected increase in PLC incidence to 2030 in 30 countries serves as a baseline for anticipated declines in the longer-term via the control of HBV and HCV infections through vaccination and treatment. However, the prospects that rising levels of obesity and its metabolic complications may lead to an increased increasing risk of PLC that potentially offset these gains, is a concern.

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Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis.

Zhiwen Liu, Ping Wang, D E Kang … (2012)

Studies of diabetes and hepatocellular carcinoma (HCC) yielded inconsistent findings. This meta-analysis was conducted to examine the association between diabetes and risk of HCC. Studies were identified by searching PUBMED and MEDLINE database up to February 2011. Pooled risk estimates were calculated using the random-effects model. Potential sources of heterogeneity were explored by subgroup analyses. A total of 17 case-control studies and 32 cohort studies were included in the meta-analysis. The combined risk estimate of all studies showed a statistically significant increased risk of HCC prevalence among diabetic individuals (RR = 2.31, 95% CI: 1.87-2.84). The pooled risk estimate of 17 case-control studies (OR = 2.40, 95% CI: 1.85-3.11) was slightly higher than that from 25 cohort studies (RR = 2.23, 95% CI: 1.68-2.96). Metformin treatment was potentially protective. On the contrary, long duration of diabetes and sulfonylureas or insulin treatment possibly increase HCC risk. Also meta-analysis of 7 cohort studies found a statistically significant increased risk of HCC mortality (RR = 2.43, 95% CI: 1.66-3.55) for individuals with (versus without) diabetes. This meta-analysis shows that diabetes is associated with moderately increased risk of HCC prevalence, as well as HCC mortality. Considering the rapidly increasing prevalence of diabetes mellitus, the study underlines the need for cancer prevention in diabetic individuals. Further investigation is needed to focus on the potential mechanism for the pathogenesis of HCC and the link between HCC and different types, severity, treatment and duration of diabetes. Copyright © 2011 John Wiley & Sons, Ltd.

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Author and article information

Contributors

Philip Noel Newsome

Journal

Journal ID (nlm-ta): J Hepatol

Journal ID (iso-abbrev): J. Hepatol

Title: Journal of Hepatology

Publisher: Elsevier

ISSN (Print): 0168-8278

ISSN (Electronic): 1600-0641

Publication date PMC-release: 1 August 2019

Publication date (Print): August 2019

Volume: 71

Issue: 2

Pages: 313-322

Affiliations

[1 ]National Institute for Health Research Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, UK

[2 ]Centre for Liver and Gastroenterology Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK

[3 ]Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

[4 ]Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria

[5 ]Department of Surgery, Campus Charité Mitte and Campus Virchow Klinikum, Charité – Universitätsmedizin Berlin, Berlin, Germany

[6 ]Berlin Institute of Health (BIH), Berlin, Germany

[7 ]Institute of Translational Medicine, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham, Mindelsohn Way, Birmingham, UK

[8 ]Hepato-Biliary Center, AP-HP Paul Brousse Hospital, University of Paris-Sud, Inserm U776, Villejuif, France

[9 ]Division of Transplantation, Department of Surgery, Medical University of Vienna, Währinger Gürtel, Vienna, Austria

[10 ]Department of Medical Statistics, Informatics and Health Economics, Innsbruck Medical University, Innsbruck, Austria

[11 ]King’s Liver Transplant Unit, King’s College Hospital NHS Foundation Trust, London, UK

[12 ]Cambridge Transplant Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge UK

[13 ]MRC Centre for Inflammation Research and Royal Infirmary, University of Edinburgh, Edinburgh, UK

[14 ]Laboratory of Abdominal Transplantation, Universitaire Zeikenhuizen Leuven, Leuven, Belgium

[15 ]Shiraz Organ Transplant, IJOTM Office, Namazi Hospital, Shiraz, Iran

[16 ]The Leeds Teaching Hospitals NHS Trust, Leeds, UK

[17 ]Liver Transplantation Center, Florence Nightingale Hospital, Istanbul, Turkey

[18 ]Department of Visceral and Transplant Surgery, University Hospital Essen, Essen, Germany

[19 ]Universitatsklinikum Leipzig, Chirurgische Klinik Und Poliklinik Ii Visceral, Transplantations, Thorax und Gefabchirurgie, Leipzig, Germany

[20 ]Institute of Clinical and Experimental Medicine, Transplant Center, Prague, Czech Republic

[21 ]Universitatsklinikum Jena, Allgemeine, Viszerale und Transplantationschirurgie, Jena, Germany

[22 ]Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK

[23 ]Service De Chirurgie Digestive, Hopital Henri Mondor, Creteil, France

Author notes

[* ]Corresponding author. Address: Centre for Liver and Gastroenterology Research and NIHR Biomedical Research Centre, 5th Floor Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, UK. Tel.: +44 121 415 8700; fax: +44 121 415 8701. P.N.Newsome@ 123456bham.ac.uk

[†]

Denotes joint first authorship.

[‡]

Denotes joint senior authorship.

Article

Publisher ID: S0168-8278(19)30272-7

DOI: 10.1016/j.jhep.2019.04.011

PMC ID: 6656693

PubMed ID: 31071367

SO-VID: 227a1b95-5144-4d6e-a68d-3ba1efaf5812

License:

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

History

Date received : 9 January 2019

Date revision received : 23 March 2019

Date accepted : 24 April 2019

Outcomes of liver transplantation for non-alcoholic steatohepatitis: A European Liver Transplant Registry study

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Graphical abstract

Highlights

Abstract

Background & Aims

Methods

Results

Conclusions

Lay summary

Related collections

Karger: Gastroenterology

Most cited references 19

Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants

Projections of primary liver cancer to 2030 in 30 countries worldwide

Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis.

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