J Gastrointest Surg (2015) 19:1713–1724 DOI 10.1007/s11605-015-2832-1

REVIEW ARTICLE

Donor Hepatic Steatosis and Outcome After Liver Transplantation: a Systematic Review Michael J. J. Chu 1 & Anna J. Dare 1 & Anthony R. J. Phillips 1,2,3 & Adam S. J. R. Bartlett 1,2,3

Received: 27 February 2015 / Accepted: 15 April 2015 / Published online: 28 April 2015 # 2015 The Society for Surgery of the Alimentary Tract

Abstract Background There is increasing need to expand availability of donor liver grafts, including steatotic livers. Steatotic liver is associated with poor outcome post-transplantation but with conflicting results in the literature. The aim of this systematic review was to evaluate the impact of steatotic livers on liver transplantation outcomes. Methods An electronic search of OVID Medline and Embase databases was performed to identify clinical studies that reported outcomes of steatotic livers in liver transplantation. Data were extracted, and basic descriptive statistics were used to summarise data pooled from individual clinical studies. Results Ninety-two articles were identified, of which 34 met the inclusion criteria, and stratified analysis were performed. There was a lack of standardised definition of primary non-function or impaired primary function amongst the studies and description of type of steatosis. Severely (>60 %) steatotic grafts are associated with increased risk of poor graft function, whilst moderate– severe (>30 %) steatotic grafts are associated with decreased graft survival. Conclusions Available evidence showed increased risk of poor graft outcome in moderate–severe steatotic livers. A large prospective multi-centred trial will be required to identify the true risks of steatotic livers. Consistent definition of primary non-function/impaired primary function and description of type of steatosis is also required. Keywords Fatty liver . Graft survival . Humans . Survival rate . Treatment outcome

Michael J. J. Chu and Anna J. Dare contributed equally to this work. Electronic supplementary material The online version of this article (doi:10.1007/s11605-015-2832-1) contains supplementary material, which is available to authorized users. * Michael J. J. Chu [email protected] 1

Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand

2

New Zealand Liver Transplant Unit (NZLTU), Auckland City Hospital, Auckland, New Zealand

3

Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand

Abbreviations ALT Alanine aminotransferase AST Aspartate aminotransferase CaCo Case–control study CaR Case report Co Cohort study DCD Donation after circulatory death DNF Delayed non-function EAD Early allograft dysfunction ECD Extended criteria donor EGD Early graft dysfunction INR International normalised ratio IPF Impaired primary function MELD Model for End-Stage Liver Disease ns Not stated OLT Orthotopic liver transplantation

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P PDF PNF PRISMA PT PTA PTT Re RR SGOT

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Prospective Primary dysfunction of graft Primary non-function Preferred Reporting Items for Systematic Reviews and Meta-analyses Prothrombin time Prothrombin time activity Partial thromboplastin time Retrospective Relative risk Serum glutamic oxaloacetic transaminases

Introduction The ongoing success of liver transplantation is dependent on overcoming the imbalance between demand for transplantation and availability of donor livers. This mismatch has driven many centres worldwide to utilise livers from ‘extended criteria donors’ (ECD).1 A consensus on definition of ECD is lacking; however, it implies higher risk relative to an ideal donor for graft function or graft failure.2 The term has been ascribed to liver grafts from older donors, donation after circulatory death (DCD) and hepatic steatosis. Despite concerns over the possibility of worse post-transplantation outcomes with ECD livers, centres have reported that judicious use in selected recipients can increase the number of available livers, whilst achieving acceptable short- and long-term outcomes, when compared to the prospects of remaining on the waiting list.3, 4 Wider utilisation of ECD organs may represent a mean for expanding liver transplantation in setting of organ shortages. Donor liver steatosis is considered a risk factor for poor post-transplantation outcome, with increased risk of primary non-function (PNF). Todo et al. published a case report describing PNF following implantation of two ‘greasy’-feeling livers in 1980s. These livers showed severe macrovesicular steatosis when the pre-transplant biopsy was examined retrospectively.5 Two other early studies investigating risk factors for early graft dysfunction corroborated Todo’s observation, noting that steatosis was an independent risk factor for PNF.6, 7 Subsequently, steatotic grafts—particularly those with macrosteatosis—were avoided. It is generally accepted that microvesicular steatosis is not associated with an increased risk of PNF, except in patients undergoing retransplant. 1 , 8 The outcome of recipients receiving macrosteatotic grafts has remained a subject of ongoing debate. In line with increasing utilisation of ECD organs, there has been acceptance of grafts with mild degrees (1500 U/L on any day during the first week post-transplant.14 Two investigators (AJD and MJJC) independently evaluated studies for inclusion in the review. Any differences in selection were referred to a third reviewer (ASRB) for arbitration. Study eligibility was determined using a standardised pro forma, with subsequent data extraction to an Excel spreadsheet. Information extracted from each publication included author, year of publication, study country/population, type of study (case control, prospective cohort study, retrospective cohort study etc.), single or multi-centre study, enrolment period, donor and recipient variables including mean age, recipient Model for End-Stage Liver Disease (MELD) score at time of transplant and mean follow-up time, type (macro- or mixed) and degree (% hepatocyte involvement) of steatosis, type of histological staining used, rates of PNF, IPF, graft survival rate at 1 year and patient survival rate at 1 and 3 years. Levels of Evidence Levels of evidence for each article included in the review as well as grades of recommendation were evaluated using the Oxford Centre for Evidence Based Medicine guidelines, outlined below. 1a. Systematic review of randomised controlled studies with homogeneity 1b. Individual randomised clinical trials 1c. All or none case studies 2a. Systematic review with homogeneity of cohort studies 2b. Individual cohort study 2c. Outcomes research 3a. Systematic review with homogeneity of case–control studies 3b. Individual case–control study 3c. Individual case–control study 4. Case series (and poor-quality cohort and case–control studies) 5. Expert opinion without explicit critical appraisal or based on physiology, bench research or first principles

Grades of Evidence A. Consistent level 1 studies B. Consistent level 2 studies or extrapolations from level 1 studies C. Level 4 studies or extrapolations from level 2 or 3 studies D. Level 5 evidence or troublingly inconsistent or inconclusive studies of any level

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Results There were 34 studies included in the final analysis (Fig. 1). Ten were prospective cohort studies, 20 were retrospective cohort studies, and 4 were case–control studies. The earliest was published in 1991 and drew from a transplant population between 1986 and 1990. Table 1 shows the characteristics of the included studies. Primary Non-function Twenty-five studies reported PNF rates (Table 2). There was significant heterogeneity amongst studies as to the definition of PNF (Supplemental Table 1) reflecting a lack of standardised criteria for this outcome. In addition, a number of studies did not report how they had defined PNF (Supplemental Table S1). The majority of studies, however, used a definition broadly consistent with that proposed by Todo et al.13 and later Stahl et al.12 as ‘death or re-transplant due to liver failure within 14 days of initial transplant which was not related to acute rejection’. Fifteen studies reported PNF rates in non-steatotic versus mildly steatotic grafts.7, 16–18, 20, 22, 23, 26, 28, 35, 38, 41, 43, 45, 47 There was no significant difference reported between PNF rates in these two groups in any of the studies. Nine studies reported PNF rates in non-steatotic versus moderately steatotic (30–60 %) grafts.7, 16, 18, 20, 23, 26, 35, 41, 43 There was no significant difference in PNF rates in the two groups in any of these studies, though there appeared to be a trend towards higher rates in the moderately steatotic groups in two of the studies;26, 43 however, these had very small number of patients. Seven studies combined their moderate (30–60 %) and severe (>60 %) steatosis groups into one group for the purpose of statistical analysis, owing to very small group numbers.17, 22, 28, 29, 31, 41, 47 Only one of these studies found a significantly increased rate of PNF in the moderate–severely steatotic livers compared to the non-steatotic livers.47 This study was one of the earliest conducted, drawing on data from 1986 to 1990. A slight trend towards higher rates of PNF was noted in two of the six studies, again with very small group numbers, which prevent meaningful conclusions.29, 31 Fourteen studies evaluated PNF rates in livers from severely (>60 %) steatotic livers compared to non-steatotic or mild (60 %) grafts compared to non-steatotic or mild steatotic grafts.7, 18–20, 23, 33, 35, 37, 42, 43 Six of the ten studies reported a significantly higher rate of IPF in severely steatotic grafts compared to non-steatotic7, 20, 33, 35, 43 or mildly steatotic grafts, or both.42 One study evaluated rates of IPF in steatotic (>6 %) grafts compared to non-steatotic (30 %) steatosis compared to grafts with 30 %) steatotic donor livers. Outcomes in the moderately steatotic groups were more variable across studies, with reported 1-year graft survival rates ranging from 33 to 100 %. In the largest series by Spitzer et al. 21, which utilised the United Network for Organ Sharing registry data from a 5-year period (2003– 2008), moderate–severe steatosis (defined as >30 % macrosteatosis on biopsy) of the donor liver significantly increased the risk of graft loss at 1 year by 71 % compared to the reference group (11 h, where it increased the risk of graft loss at 1 year by 54 %. Only five studies evaluated severe steatosis (>60 %), and all of these had ≤20 patients in the group. Three studies reported 1-year graft survival rates of ≥90 %,20, 24, 38 and one study reported 1-year graft survival of 82 %,15 whereas the fifth study reported a 1-year graft survival rate of only 25 %, albeit with very small patient numbers (n=4).18 Significant heterogeneity in the study populations existed, with only a minority of studies adjusting for confounding factors such as recipient age, sex, ethnicity, underlying diagnosis, comorbidity and MELD score in their reporting of graft survival rates, making comparison between studies in each group difficult. Patient Survival Fourteen studies evaluated patient survival at 1 year posttransplant, with eight of these studies also providing survival rates out to 3 years (Tables 5 and 6). Nine studies compared patient survival at 1 year in nonsteatotic grafts to that in mildly steatotic (30 % hepatic steatosis is associated with worse clinical outcome in patients post-transplantation. There is evidence of increased morbidity in recipients of steatotic livers.50 The degree of ‘acceptable’ hepatic steatosis is unclear and varies between transplant units. PNF is a devastating outcome with significant morbidity and mortality.7 The correlation in earlier studies between moderate and severe

J Gastrointest Surg (2015) 19:1713–1724 Table 5

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Patient survival at 1 year post-transplantation

Author

Year

No steatosis

Mild (60 %) steatosis

Chavin et al.15 Gabrielli et al.16 Teng et al.17 Deroose et al.20

2013 2012 2012 2011 2010 2009 2009 2009 2009 2007 2007 2006 2003 1993

77 % (n=60) 90 % (n=17)a 87.5 % (n=24) 87.5 % (n=39) 92 % (n=66) 56 % (n=12) 96.6 % (n=29)c 91.7 % (n=24) 82.6 % (n=46) 74 % (n=50) – 72 % 76 % (n=64)d 80 % (n=29)e

85 % (n=23)

95 % (n=28) 81 % (n=101) 87 % (n=92) 90.7 % (n=222) 85 % (n=34) – – 86.4 % (n=59) 73.1 % (n=90) 86.4 % (n=40) 86 % 90 % (n=796)d 82 % (n=329)

82 % (n=9) 78 % (n=7)f

Doyle et al.22 Noujaim et al.23 Li et al.24 Gao et al.25 Burra et al.28 Nikeghbalian et al.32 McCormack et al.33 Perez-Daga et al.34 Salizzoni et al.39 Markin et al.46 a

83.3 % (n=6)b 84.5 % (n=19) 81.5 % (n=22)b 63 % (n=11)b 93.1 % (n=23)c 83.3 % (n=24) 81.1 % (n=11)b 73 % (n=34) – 70 % – –

78 % (n=15)

89.7 % (n=18)c – – 95 % (n=20) 58 % –

Mild and moderate steatosis groups combined

b

Moderate and severe steatosis groups combined (>30 %)

c

Mild=40 % steatosis

d

No steatosis=15 % steatosis

e

Mild/Moderate=30 % steatosis compared Table 6

to 60 % steatotic livers are generally not acceptable, whilst 30–60 % steatotic livers may be utilised in certain circumstances (i.e. low MELD score, shorter cold ischaemic duration).50 Although some studies in this review have shown no difference in PNF/ IPF in grafts with >30 % steatosis, these studies did not disclose the type of steatosis,31, 51, 52 or the grafts were predominantly severe microvesicular steatosis.1, 15, 33 This confirms that grafts with >30 % macrovesicular steatosis is associated with increased rate of PNF and IPF.

Patient survival at 3 years post-transplantation

Author

Year

No steatosis (%)

Mild (60 %) steatosis (%)

Chavin et al.15

2013 2012 2012 2011 2010 2009 2007 2003

71 90a 58.3 74 86.4 73.9 – 61c

70

95 66.6 82 86.1 79.7 83.2 86c

82 78d

Gabrielli et al.16 Teng et al.17 Deroose et al.20 Doyle et al.22 Burra et al.28 McCormack et al.33 Salizzoni et al.39 a

Mild and moderate steatosis groups combined

b

Moderate and severe steatosis groups combined (>30 %)

c

No steatosis=15 % steatosis

d

Significant difference vs. non-steatotic grafts

41.7b 79 70.3b 81.1b – –

67

84.4 –

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This review showed that liver grafts with >30 % steatosis are associated with lower graft survival, but only a trend towards decreased recipient survival. Liver grafts with >30 % steatosis was first associated with poor outcome by Portmann et al.53 There is a general consensus that steatotic donor livers are associated with worse outcome.54, 55 This holds true for >60 % steatosis donor livers, but the controversy remains with donor livers of 30–60 % steatosis. This was reflected in a study of surgeons from USA and UK where there were differing opinions on acceptable upper limit of steatosis.10 Similarly, there is differing opinion on the impact of microvesicular steatosis,1, 8, 56 but current clinical data have shown that microvesicular grafts, irrespective of percentage, can be used without increasing the risk of PNF. This review has shown that 1-year graft survival is lower in liver grafts with >30 % steatosis, particularly macrovesicular steatosis, but there is a lack of clear histological description of macro- and microvesicular steatosis. Reasons for decreased graft survival in >30 % steatotic grafts includes increased difficulty of surgery, increased intra-operative blood loss and post-operative complications.33 Slower recovery of synthetic function and increased susceptibility to injury of these grafts may also play a role.57 Despite lower graft survival in >30 % steatotic livers, recipient survival was not shown to be adversely affected by severity of donor liver steatosis, although there was a trend towards decreased survival in some studies. This may be due to the dramatic decrease in steatosis in steatotic grafts post-liver transplantation,33 which may explain why moderate–severely steatotic livers do not significantly impact long-term recipient survival as the immediate risk to recipients is the early post-transplantation period from PNF. Once the recipients overcome the initial risk of PNF, longterm outcome may not be as clear-cut. The number of patients that received >30 % steatotic livers is small, and studies may not be sufficiently powered to detect a significant difference in patient survival. Despite the heterogeneity of these studies, >30 % steatotic liver grafts is associated with lower graft survival, and logically, this should impact on recipient survival, but further studies with larger patient numbers will be required to determine effect of steatosis on long-term recipient survival. The difference in assessment of hepatic steatosis amongst the studies makes data comparison difficult. There is lack of uniformity in the histological staining methods and a strong observer dependence in histological assessment of steatosis.58 There is also a lack of description of the type of steatosis in the studies included. It is imperative to differentiate between the two types of steatosis in reporting study results, as this would further clarify the true impact of macro- versus microvesicular steatosis on patient/graft outcome. It will also provide an opportunity to compare between future studies. This is particularly important, as there is ongoing debate about whether macro- or microvesicular steatosis is associated with poor outcome post-transplantation.9 Furthermore, the definitions of

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PNF/IPF have been variable, as there is a lack of consensus about the definition of PNF/IPF.59 This contributed to the heterogeneity and inconsistencies of the studies. As rates of PNF are low, there is likely significant type-II error in studies with small numbers of severely steatotic livers, as they would be insufficiently powered to detect differences. This is an unavoidable issue as the number of severe steatotic grafts being utilised is low, and a large multi-centred study would be required. The inconsistent findings across the studies can be attributed to the heterogeneity, including donor, preservation, operative and recipient factors, which precluded performing a meta-analysis. These factors are poorly reported in the literature and rarely accounted or adjusted for in studies, and may contribute to the variable results shown. Future studies will require a standardised definition of PNF/IPF, and this should be made by consensus in the transplantation world as it will improve future study quality. Similarly, additional large multi-centre registry would be required to overcome the heterogeneity and statistical issue, especially for severe steatotic liver grafts as these are rare occurrences. It may be useful to calculate the ‘number needed to harm’ of PNF in each group of steatotic livers, as it allows us to understand and convey the risks associated with hepatic steatosis. This would also allow comparison of the risk of hepatic steatosis against other ECD-related factors such as older donors or DCD. An improved understanding of the impact of additional risk factors such as cold ischaemic time, hepatitis C and age in the presence of steatosis would be essential to build a risk profile of each type of liver grafts, but this would require large registry-based studies. Ideally, a meta-analysis should be performed to better inform future decision about the utility of steatotic livers in liver transplantation, but it may be difficult due to the issues highlighted previously. Conclusion This review has shown that donor livers with severe steatosis are associated with an increased risk of PNF and IPF whilst donor livers with moderate-severe steatosis are more likely to be associated with decreased graft survival. Conflicting results between studies may be due to the heterogeneity of the study as well as inconsistent definitions of PNF/IPF. Future studies will need to be large prospective multi-centred trials to provide further information regarding the true risks. Until then, on the basis of the clinical evidence presented, liver transplant surgeons should proceed cautiously in using donor livers with greater than moderate hepatic steatosis.

Acknowledgements This work was directly supported by the University of Auckland Faculty Research Development Fund, Maurice Wilkins Centre for Biodiscovery and the Maurice & Phyllis Paykel Trust.

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