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The ILTS Consensus Conference on NAFLD/NASH and Liver Transplantation: Setting the Stage

Burra, Patrizia MD, PhD1; Berenguer, Marina MD2; Pomfret, Elizabeth MD, PhD3

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doi: 10.1097/TP.0000000000002507
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Nonalcoholic fatty liver disease (NAFLD) is now recognized as the most common form of chronic liver disease in developed countries, affecting up to 25% of the population of many countries.1 In the United States, the estimated economic burden is in excess of US $100 billion per annum and is strongly correlated with rising obesity levels with a prevalence of up to 80% in the obese. Nonalcoholic steatohepatitis (NASH) is the most severe part of the spectrum of the disease and progresses to cirrhosis and development of hepatocellular carcinoma (HCC). First reported in the 1980s and relatively insignificant as an indication for liver transplantation (LT) until the mid 2000s, it is likely to surpass all other indications for LT within a few years. Although lifestyle changes in diet and exercise are the most important community wide treatment strategies, the hepatology community will be left managing the increasing number of patients with metabolic cirrhosis and HCC.2

A number of clinical guidelines on the management of NAFLD have been published by a variety of societies interested in the multifaceted problems of liver disease, diabetes, and obesity.3 Pais et al4 reported a list of NAFLD-related issues relevant to the setting of transplantation.

  • NAFLD as a frequent cause of cryptogenic cirrhosis, end-stage chronic liver disease and HCC;
  • the prevalence of NAFLD as an indication for LT both in Europe and the United States;
  • the impact of NAFLD on the donor pool;
  • access of NAFLD patients to LT and their management on the waiting list in regard to metabolic, renal and vascular comorbidities;
  • the prevalence and consequences of posttransplant metabolic syndrome, recurrent and de novo NAFLD;
  • alternative management and therapeutic options to improve the long-term outcomes.

Additional reviews have mainly focused on US perspectives of NAFLD/NASH and LT.5 The American Association for the Study of Liver Disease recently published the “Practice Guidance on NAFLD” with a paragraph on NASH, obesity, and LT.6 A comprehensive and detailed guideline on NAFLD and LT was supported by the British Transplantation Society, the British Society of Gastroenterology, the British Association for the Study of Liver, and NHS Blood and Transplant. These guidelines represented a consensus opinion from experts in the United Kingdom in the fields of hepatology, transplantation, and related disciplines, but as the authors stated, recommendations were made even when the evidence was weak, and the document thus represents a consensus statement rather than an evidence-based clinical guideline.7

No contemporary international guidelines exist for the assessment and management of patients with NAFLD/NASH undergoing liver transplantation. The International Liver Transplantation Society (ILTS) thus convened a Consensus Conference in San Servolo, Venice, Italy, on February 15, 2018, on NAFLD and NASH in the setting of liver transplantation. The meeting covered all aspects of the disease: epidemiology and prevention, medical treatment, lifestyle changes, and pharmacological therapy, the risk of developing HCC, patient surveillance and tumor management before and after transplantation, selection of patients with end-stage liver disease, indications for LT, management of recurrence of NAFLD or NASH, the development of de novo NAFLD/NASH after LT, and finally, NAFLD and NASH in the pediatric population.

ILTS convened experts in 6 working groups (WGs) with 2 chairs of each, to address the key management issues related to NAFLD/NASH. Each WG had key questions that were addressed via a critical review of the literature. Three months before the consensus conference, the WG members collected pertinent literature adhering to specific criteria agreed upon by the WG. The search strategy examined the published literature between 2011 and January 2018, using PubMed searching by using the specific words (ie, for HCC these were: nonalcoholic fatty liver disease [Medical Subject Headings (MeSH) Terms] and hepatocellular cancer [MeSH Terms] or hepatocellular carcinoma [MeSH Terms] or liver cancer, limits: Journal Article; Abstract; Humans and Adults).

Each WG functioned independently and reviewed an average of 200 selected articles. The chairs revised the list of articles according to standard criteria:

  • More than 50 nonalcoholic fatty liver disease patients included in the article;
  • Cohorts (prospective, retrospective), case-controls, meta-analyses reviews;
  • To exclude the basic studies focus on nonalcoholic fatty liver disease.

The 200 articles per WG were narrowed down to an average of 25 to 30 final selected articles which were reviewed to extract the important data and create a summary database including all variables considered adequate to answer the WG topic question. Finally, the chairs of each WG evaluated the whole database and derived recommendations following the GRADE SYSTEM8 and prepared and submitted a draft document 2 weeks before the consensus conference.

At the consensus conference, 1 of the 2 chairs of each WG presented the questions, answers, and proposed statements at the plenary session for discussion by the 80 consensus conference attendees. Each WG reconvened to address open questions where no agreement had been reached during the plenary discussion. Updated recommendations from each WG were then presented at the concluding plenary session for approval.

The quality of the evidence, benefits, and harms, as well as values and preferences, were carefully considered. The quality of evidence was rated as low, moderate, or high. The strength of the recommendation was rated as strong, moderate, or weak, reflecting confidence that adherence to guidance will result in more good than harm (Figure 1).

FIGURE 1
FIGURE 1:
Levels of Evidence and Strength of Recommendations matrix (from Kremer LC, Mulder RL, Oeffinger KC, et al. A worldwide collaboration to harmonize guidelines for the long-term follow-up of childhood and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Pediatr Blood Cancer. 2013;60:543-549).

The NAFLD/NASH consensus conference recommendations issued from the different WGs are presented in this special issue of Transplantation.9-14 This contemporary guidance is intended primarily for healthcare professionals caring for patients on the waiting list or post-LT, but should also assist policy makers in optimizing the care settings for LT candidates and recipients.

REFERENCES

1. Younossi ZM, Loomba R, Anstee QM, et al. Diagnostic modalities for nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and associated fibrosis. Hepatology. 2018;68:349–360.
2. Younes R, Bugianesi E. Should we undertake surveillance for HCC in patients with NAFLD? J Hepatol. 2018;68:326–334.
3. European Association for the Study of the Liver, European Association for the Study of Diabetes and European Association for the Study of Obesity. EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64:1388–1402.
4. Pais R, Barritt AST, Calmus Y, et al. NAFLD and liver transplantation: current burden and expected challenges. J Hepatol. 2016;65:1245–1257.
5. Malhi H, Allen AM, Watt KD. Nonalcoholic fatty liver: optimizing pretransplant selection and posttransplant care to maximize survival. Curr Opin Organ Transplant. 2016;21:99–106.
6. Chalasani N. Writing group for the AASLD NAFLD practice guidance. Reply. Hepatology. 2018;67:2478–2479.
7. Newsome PN, Allison ME, Andrews PA, et al. Guidelines for liver transplantation for patients with non-alcoholic steatohepatitis. Gut. 2012;61:484–500.
8. Atkins D, Best D, Briss PA, et al. Grading quality of evidence and strength of recommendations. BMJ. 2004;328:1490.
9. Rela M, Dhawan A, Cananzi M, et al. NAFLD and liver transplantation in children—working group report from the ILTS single topic conference on NAFLD. Transplantation. 2019;103:68–70.
10. Svegliati-Baroni G, Ratziu V, Ghabril M, et al. Recommendations for management and treatment of non alcoholic steatohepatitis. Transplantation. 2019;103:28–38.
11. Watt K, Germani G, Laryea M, et al. Management of recurrent and de novo NAFLD/NASH after liver transplantation. Transplantation. 2019;103:57–67.
12. Toso C, Reig M, Gambato M, et al. Should patients with NAFLD/NASH be surveyed for HCC? Transplantation. 2019;103:39–44.
13. Petta S, Younossi Z, Marchesini G, et al. Epidemiology of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis: implications for liver transplantation. Transplantation. 2019;103:22–27.
14. Berenguer M, Klinck J, Ghobrial M, et al. International liver transplantation consensus statement on end-stage liver disease due to nonalcoholic steatohepatitis and liver transplantation. Transplantation. 2019;103:45–56.
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