Impact of living donor liver with steatosis and idiopathic portal inflammation on clinical outcomes in pediatric liver transplantation: Beijing experience

Introduction

Nonalcoholic fatty liver disease (NAFLD) is a major health burden (1). This burden is expected to increase as incidence of obesity, diabetes mellitus and metabolic syndrome continues to grow. It is particularly relevant to Chinese population since lifestyle has changed dramatically as a result of industrialization and urbanization. The global projected growth of NAFLD is 0–30%, from 2016 to 2030, with the highest growth in China (2,3). This high prevalence of NAFLD definitely will affect liver transplantation (LT) donor pool.

Living donor LT (LDLT) is a standard of care for end stage liver diseases (4). Pediatric LDLT can be done with excellent results using left liver lobe or left lateral segment (5-7). Assessing the degree of donor hepatic steatosis is one important histological evaluation (8-11). Although mild macrovesicular steatosis (up to 30%) does not adversely affect recipients’ outcomes in adult whole-liver LTs (11-14) and is also believed to have no adverse effects on clinical outcome of LDLT recipients, there is a need to study this concept in detail in LDLT.

Mild idiopathic portal inflammation (IPI) is another frequently observed feature in ‘healthy’ living donor with a range from 6.0% to 16.0% (15-18). The impact of this finding has also not been reported in LDLT (18,19). One question of particular interest is the synergism of mild steatosis and mild or mild-moderate IPI’s impact on short- and long-term outcomes of pediatric LDLT. This pathologic constellation is crucial for the success of LT especially when dealing with high risk recipients presenting high pediatric end stage liver disease scores (pediatric end-stage liver disease, PELD ≥16) (20). The study aimed at (I) identifying the prevalence of macrovesicular steatosis (5–30%) and IPI (Ishak >1) in these ‘healthy’ living donors; (II) evaluating their impact on biochemical evolution, short-/long-term outcome and final outcomes post-LDLT; and (III) evaluating the impact of steatosis or IPI on clinical outcomes in high PELD score patients. We present the following article in accordance with the STROBE reporting checklist (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-20-685/rc).

Methods

Pediatric LDLT recipients (age <18-year-old) performed in Beijing Friendship Hospital, Capital Medical University from June 2013 to December 2018 were retrospectively reviewed. Living donor data including age, gender, body mass index (BMI), parameters of liver biochemical tests and imaging results were collected. Abdominal ultrasound and Computed Tomography scan were used routinely for donor assessment. Donors with obvious fatty liver on either imaging study were disqualified as the living donors until a weight loss 8–10% of baseline level and extent of fatty liver becomes mild degree or less. No donor consumed alcohol >20 g/day for female and >40 g/day for male in the study.

Recipients’ clinical data including baseline demographics, parameters of liver biochemical tests, indications for LDLT were collected from the hospital electronic data base. PELD score was calculated in pediatric patients.

Inclusion and exclusion criteria

Inclusion criteria were: (I) pediatric recipients defined as age <18-year-old. (II) LDLT.

Exclusion criteria were: (I) domino cross LT. (II) Sample size wedge liver specimen was <0.2 cm × 0.2 cm. (III) Re-transplantation.

Living donor liver biopsy processing and histopathological assessment

The living donor liver wedge biopsy tissues were routinely sampled during living donor liver graft procurement. The living donor liver biopsy were routinely taken at segment 3 (S3) by transplant surgeons in our center. The specimens were fixed in neutral formalin, embedded in paraffin, and routinely stained with hematoxylin and eosin (H/E) and other stains, including trichrome and reticulin. Corresponding slides were retrieved.

Histological features of the livers from the enrolled cases including steatosis and portal inflammation were systematically assessed by two liver pathologists. Hepatic macrovesicular steatosis was scaled as 0–5% and 5–30% steatosis according to the standard criterion (21). Portal inflammation was divided as no, mild and mild to moderate portal inflammation according to Ishak modified histological activity score system (22).

Recipients who received a living donor liver with hepatic macrovesicular steatosis 0–5% were defined as non-steatosis group, while 5-30% steatosis was defined as steatosis group. Similarly, recipients who received a living donor liver without portal inflammation were defined as non-IPI group and mild or mild to moderate portal inflammation was defined as IPI group.

Immunosuppressive management

Immunosuppressive induction started by methylprednisolone and maintenance therapy was mainly composed of tacrolimus/mycophenolate mofetil with/without low dose prednisolone. In case of tacrolimus intolerance or toxicity, cyclosporin was used.

Follow ups

Clinical follow up information including serum value of alanine aminotransferase (ALT) and total bilirubin (TBIL) at 1 week, 2 weeks and 4 weeks post LDLTs, short- (≤1-month post LDLT) and long-term complications (>1-month post LDLT), as well as graft/overall survival up to 5 years were retrieved from the clinical database.

Statistics

Variables were expressed as median (quantile 1–quantile 3) or percentage. The differences of continuous variables were identified by Wilcoxon test. The differences of categorical variables were identified by Chi-square test. In the statistical analysis of the changes in ALT and TBIL before and 1 week, 2 weeks and 4 weeks after LT, the mixed model was used in the repeated measurement of the blood parameters. The 1, 3, 5-year graft/overall survival were assessed by Kaplan-Meier analysis. Risk factors such as short- and long-term complications associated with the survival were identified using univariate and multivariate Cox proportional hazards regression model. All statistical analyses were performed using SAS software, version 9.4 (SAS Institute Inc., Cary, NC, US). P<0.05 was considered as statistically significant.

Ethical consideration

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by institutional ethics board of Beijing Friendship Hospital (No. 2018-P2-207-01) and informed consent was taken from all individual participants.

Results

From June 2013 to December 2018, a total of 531 pediatric LTs were performed in Beijing Friendship Hospital. 305 of 358 LDLT cases (85.2%) were enrolled in the study (Figure 1). Medium follow-up time post LDLT for recipients was 32.8 (24.8, 52.0) months.

Figure 1 Flowchart of the study. A total of 305 out of 358 living donor pediatric liver transplantation were enrolled in this study, 41 out of 305 cases received living donor livers with 5–30% steatosis, 85 out of 305 cases received living donor livers with mild or mild to moderate idiopathic portal inflammation (G ≥1). LT, liver transplantation.

The median age of donors was 31.2 (28.0, 35.8) years old (Figure 2A). Male accounted for 42.3%. The median BMI was 22.2 (20.1, 24.4) kg/m² (Figure 2B). 176/305 donors’ BMI (57.7%) was <23 kg/m², 69/305 (22.6%) between 23–25 kg/m² and 60/305 (19.7%) >25 kg/m². Median ALT and aspartate aminotransferase were 16.0 (12.0, 24.0; Figure 2C) and 19.6 (16.1, 23.7) IU/L respectively and gamma-glutamyl transpeptidase was 17.0 (12.0, 24.0) IU/L (Table 1).

Figure 2 Baseline and demographic data of donor and recipients. Age of living donors was 31.2 (28.0–35.8) years old without significant difference between male and female donors (A). Medium BMI was 22.2 (20.1–24.4) kg/m² (B) and average serum ALT (C) was within normal range. Age of recipients was 1.0 (0.6–3.6) years old (D) and male patient accounted for 51.8% (E). The main indication for liver transplantation was biliary atresia (F). BMI, body mass Index; ALT, alanine aminotransferase.

The median age of recipients was 1.0 (0.6, 1.5) years old (Figure 2D) and male accounted for 51.8% (Figure 2E). The indications for LDLT were biliary atresia (69.5%) followed by genetic/metabolic liver diseases (23) (23.3%) or other liver diseases (7.2%; Figure 2F). The medium PELD score was 16.0 (5.0, 26.0; Table 1).

Donor liver histological distribution of hepatic steatosis and IPI

Macrovesicular steatosis up to 30% was identified in 144/305 (47.2%) donors: 0 in 161/305 (52.8%), 0-5% in 103/305 (33.8%) and 5–30% in 41/305 (13.4%) (Figure 3A-3C). The median age of donors with steatosis was 31.6 (28.9,37.4) years old, male accounted for 58.5% and BMI 24.2 (20.9,25.4) kg/m². Median ALT, aspartate aminotransferase and gamma-glutamyl transpeptidase of these 41 donors with steatosis was 20.0 (16.0,27.0), 19.6 (17.1, 23.8) and 18.0 (15.0, 25.0) IU/L, respectively. 36/41 (87.8%) ALT was less than 40 IU/L. It is worthy to point out that age distribution of 41 donors with steatosis was: 18/41 (43.9%) in 20–30 years old, 20/41 (48.8%) in 30–40 years old, and 3/41 (7.3%) in 40–50 years old. Distribution of BMI of these steatotic donors was <23 kg/m²: 14 (34.1%), 23–25 kg/m²: 15 (36.6%) and >25 kg/m²: 12 (29.3%).

Figure 3 Histological analysis of 305 living donor wedged liver biopsy. One hundred and sixty-one out of 305 living donor liver had no steatosis, 103 cases had steatosis less than 5% (A) and 41 cases had steatosis from 5% to 30% (B,C). As for portal inflammation, 220 donor liver had no portal inflammation, 80 donor had mild portal inflammation (D) and 5 cases had mild to moderate portal inflammation (E,F). HE staining (100×).

IPI was present in 85/305 (27.9%): mild in 80/305 (26.2%) and mild to moderate in 5/305 (1.7%). 220/305 (72.1%) had no portal inflammation (Figure 3D-3F). Fourteen donors (4.6%) had both steatosis (≥5%) and IPI (≥ grade 1) in their livers. No obvious ballooning hepatocytes were perceived.

Impact of hepatic steatosis and/or IPI on the evolution of recipients’ ALT and TBIL at 1 week, 2 weeks and 4 weeks post LDLT

As compared to non-steatosis group, steatosis group had a comparable serum ALT level at 1 week, 2 weeks and 4 weeks post LDLT (all P value >0.05). Additionally, steatosis group had trend higher level of serum TBIL at 1 week, 2 weeks and 4 weeks post LDLT in comparison with non-steatosis group, however it was not statistically significant (P=0.247 for ALT and P=0.733 for TBIL; Table 2).

As compared to non-IPI group, the IPI group had a trend lower serum ALT and TBIL level at 1 week, 2 weeks and 4 weeks post LDLT without statistic difference (P=0.776 for ALT and P=0.724 for TBIL; Table 2).

As compared to recipients who received living donor livers without steatosis and IPI (non-steatosis and non-IPI group), those received living donor livers with both steatosis and IPI (steatosis and IPI group) had no significant difference of serum ALT and TBIL level at 1 week, 2 weeks and 4 weeks post LDLT (P=0.428 for ALT and P=0.640 for TBIL; Table 3).

Impact of hepatic steatosis and/or IPI on short- and long-term complications post LDLT

Steatosis group had trend reduced overall short-term complications (<1-month post-LDLT) as compared to non-steatosis group (25.0% vs. 37.3% P=0.131) without significant difference. When further dividing overall complications into surgical and acute rejection/infection associated subgroups, steatosis group had a trend lower proportion of acute rejection/infection related complications (22.0% vs. 32.2%, P=0.186) but trend higher surgical complications (14.6% vs. 11.7%, P=0.598) as compared to non-steatosis group without significant difference. Steatosis had trend higher overall long-term complications as compared to non-steatosis groups without significance (P=0.856; Table 2).

IPI group had marginal higher proportion of overall short-term complications (44.1% vs. 32.4%, P=0.059), including both infection/rejection (38.8% vs. 27.7%, P=0.060) and surgical complications (15.3% vs. 10.9%, P=0.293) in comparison to non-IPI group (no statistical difference). Similar trend was observed in long-term complications between IPI and non-IPI groups without significant difference statistically (Table 2).

Steatosis and IPI group didn’t have significantly higher incidence of overall short- and long-term complications than non-steatosis and non-IPI group (Table 3).

Impact of hepatic steatosis and/or IPI on graft/overall survival post LDLT

The graft survival of this cohort was 96.7%, 95.2% and 95.2% and the overall survival of this cohort was 97.1%, 96.3% and 96.3% respectively at 1-, 3-, 5-year post LDLT. Steatosis group (97.6%, 94.6% and 94.6%) and non-steatosis group (96.6%, 95.3% and 95.3%) had comparable graft survival (P=0.935) and overall survival 1-, 3-, 5-year post LDLT (steatosis group 97.6%, 97.6% and 97.6% vs. non steatosis group 97.0%, 96.1% and 96.1%, P=0.674 (Table 2, Figure 4A).

Figure 4 Comparative graft survival/overall survival between recipients receiving living donor liver with/without steatosis and/or idiopathic portal inflammation. Recipients received living donor liver with steatosis had no negative effects on graft survival and overall survival, without significant difference (A). Recipients had living donor liver with idiopathic portal inflammation had slightly lower graft or overall survival (B). Unexpectedly, recipients who had living donor liver with both steatosis and portal inflammation didn’t have syngenetic negative effects on recipients’ graft and overall survival (C).

Both IPI and non-IPI group had similar 1-, 3-, 5-year graft survival (94.1%, 94.1% and 94.1% vs. 97.7%, 95.6%, 95.6%, P=0.456) and 1, 3, 5-year overall survival (95.3%, 95.3% and 95.3% vs. 97.7%, 96.8% and 96.8%, P=0.506) post LDLT, despite the IPI group appeared to be slightly lower than the non-IPI group (Table 2, Figure 4B).

Recipients received living donor livers with both IPI and steatosis had no synergetic negative effects on 1-, 3-, 5-year graft survival (100.0%, 100.0% and 100.0% vs. 97.9%, 96.2%, 96.2%, P=0.447) and 1-, 3-, 5-year overall survival (100.0%, 100.0% and 100.0% vs. 97.9%, 96.8% and 96.8%, P=0.671) post LDLT compared with non-steatosis and non-IPI group (Table 3, Figure 4C).

Impact steatosis and/or IPI on donor-recipient matching stratified by PELD score

Using PELD score medium value 16 in the cohort as the cut off score, we divided recipients into higher PELD score group (PELD ≥16) and lower PELD score group (PELD <16). Our results showed higher PELD score recipients had trend lower graft survival (94.8%, 93.1% and 93.1% vs. 98.0%, 97.2% and 97.2%, P=0.115, Figure 5A) and overall survival rate (95.5%, 94.6% and 94.6% vs. 98.0%, 98.0% and 98.0%, P=0.146, Figure 5B) compared with low PELD score recipients (PELD <16) without statistic difference. When donor livers with steatosis (no IPI) were distributed to the higher PELD score recipients (≥16), these patients had similar graft survival (100.0%, 100.0% and 100.0% vs. 94.7%, 88.4% and 88.4%, P=0.102, Figure 5C) and overall survival (100.0%, 100.0% and 100.0% vs. 94.7%, 94.7% and 94.7%, P=0.255, Figure 5D) in comparison to lower PELD score recipients. When donor livers with IPI (no steatosis) were distributed to the higher PELD score recipients (≥16), these patients had trend lower graft survival (90.5%, 90.5% and 90.5% vs. 97.7%, 97.7% and 97.7%, P=0.174, Figure 5E) and overall survival (92.9%, 92.9% and 92,9% vs. 97.7%, 97.7% and 97.7%, P=0.311, Figure 5F) in comparison to lower PELD score recipients.

Figure 5 Comparative graft and overall survival between recipients having higher PELD score (≥16) and lower PELD score (<16). High PELD recipients score had a trendy lower graft survival (A) and overall survival (B) without significant difference. Furthermore, high PELD recipients had donor with non-steatosis (C,D) but idiopathic portal inflammation (E,F) had trendy negative effects on graft and overall survival. PELD, pediatric end-stage liver disease.

Identification of other clinical independent risk factor (s) for graft/overall survival in pediatric LDLT

Cox regression analysis revealed that only short-term complications (HR =3.343, 95% CI, 1.12–9.977, P=0.031) were independently associated with graft survival (Table 4). No additional independent risk factors associated with overall survival were identified. The subsequent logistic regression analysis showed that younger age (HR =0.990, 95% CI, 0.982–0.977, P=0.007), biliary atresia (HR =1.874, 95% CI, 1.091–3.218, P=0.023) and higher PELD score (HR =1.732, 95% CI, 1.076–2.789, P=0.024) were independently associated with short-term complications. Multi-variate regression analysis revealed that only high PELD score was independently associated with short-term complication (1.742, 95% CI, 1.064–2.900, P=0.033; Table 5).

Discussion

In our study, 41 out of 305 donors (13.4%) had NAFLD according to the histological criterion, i.e., steatosis ≥5%. A majority of subjects had low BMI (≤25 kg/m²) and did not have other risk factors, including alcohol overconsumption (24). Since there were no lobular inflammation, ballooning hepatocytes nor fibrosis histologically, these donors should be diagnosed of having ‘lean’ NAFLD, specifically nonalcoholic fatty liver (NAFL) (25).

NAFLD is a well-recognized liver disorder and the most common cause of chronic liver disease. It is composed of NAFL and nonalcoholic steatohepatitis. NAFL can be diagnosed either by imaging or histopathology, while the diagnosis of nonalcoholic steatohepatitis requires histopathology, the golden standard (26). The estimated prevalence of NAFLD varies from 25.2% globally to up to 20.0% in China in 2020 (24,27). NAFLD is often linked with metabolic syndromes, obesity and being overweight, but can also occur in normal weight population. ‘Lean’ NAFLD was initially labelled as a disorder predominantly involving Asian population. However, it can also occur in other ethnicities. The prevalence of ‘lean’ NAFLD in general population varies from 10.0% to 20.0%. Most of these large-scaled studies were image-based, i.e., 7.0% in the USA (24), 7.3% in China (28), 16.1% in Korea (29), 15.2% in Japan (30) and 19.3% in Hong Kong (31). Comparing to these image-based NAFLD studies, our study is the largest histopathology-approved NAFLD cohort among healthy Chinese selected for living liver donation. These subjects had nearly normal liver biochemistries and went through restrict selective criteria for living organ donation. The data here reasonably reflect current NAFLD, particularly NAFL status in healthy donor population in China.

For overweight or obesity donors, we recommend that a balanced nutrition, moderate-intensity physical activity and 5–10% weight loss before LT in order to reduce the extent of fatty liver disease (32). The donors for dietary changes recommend reducing the intake of saturated fat to <7% of total calories, reducing trans-fat intake, and maintaining dietary cholesterol intake at <200 mg/day and total fat at 25% to 35% of total calories. Moreover, engaging in regular moderate-intensity physical activity for at least 30 minutes for more than 5 days/week is recommended for these donors too (33).

Furthermore, our study showed that steatosis below 30% from living donors did not significantly impact on graft and overall survival. This result compares favorably with previous adult whole liver LT studies, where steatosis less than 30% were as generally accepted (18,19,34). Our results add strong evidence to the fact that mild steatosis does not significantly affect clinical outcomes in pediatric LDLT (13,35).

Idiopathic mild portal inflammation characterized by predominantly mononuclear inflammatory cells infiltration in portal tracts was frequently observed and its prevalence was up to 16% in ‘healthy living donors’ (15). Clinical significance of this mild IPI during donor liver assessment and its effects on recipients’ clinical outcomes have not been well studied yet. In the present study, our data for the first time showed that mild IPI alone didn’t have significant negative effects on post LDLT liver biochemical parameters normalization. However, the IPI group did have trend higher incidence of short- and long-term complications and lower graft and overall survival rates compared to non-IPI group, though without statistical significance. The surgical complications were divided into biliary complications and vascular complications. Biliary complications (bile leakage, cholangitis and biliary anastomotic stenosis, etc.) accounted for 7.2% (22/305), vascular complications (portal vein embolism, hepatic artery embolism, etc.) accounted for 5.2% (16/305). Additionally, in our study, about 4.6% donor livers had both steatosis (5–30%) and IPI (≥1). However, the combined histological features had no syngenetic disadvantage effect on recipients’ graft and overall survival rate.

Organ-recipient matching allocation is another ongoing topic in LT. When we further stratified recipients into two subgroups according to PELD score and found that higher PELD score group (PELD >16) received living donor livers with IPI but not steatosis had negative impact on graft/overall survival, though there was no different statistically. The results were in parallel to the previous study that high quality donor liver should be allocated to sicker recipients, which may benefit these patients in terms of reducing post LDLT complications and graft loss (36).

This is the largest cohort systemically investigating hepatic steatosis and IPI in healthy living donors, and their impact on clinical outcomes. However, there are limitations in our study. Firstly, since the majority of donors were 20 to 30 years old, and only donors with ≤30% hepatic steatosis were selected for donation, the findings on NAFLD prevalence can only reflect this particular population. Secondly, it was a single center retrospective study, the results need to be further validated by other centers or ethnic population.

Conclusions

This study validates that mild steatosis does not affect recipient’s graft and overall survival. However, mild IPI does have trend negative impact on graft and overall survival, especially when theses organs were allocated to higher PELD score recipients. Steatosis and IPI do not have syngenetic effects on graft and overall survival. This study aids in better care in pediatric living donor LT.

Acknowledgments

We are deeply grateful to Prof. em.Jan LERUT from Institute de Recherche Clinique (IREC), Université Catholique Louvain (UCL) Brussels, Belgium for his generous help in critical revision and language polishing.

Funding: This work was funded by the Digestive Medical Coordinated Development Center of Beijing Hospitals Authority (No. XXZ0301).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-20-685/rc

Data Sharing Statement: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-20-685/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-20-685/coif). ZZ serves as an unpaid editorial board member of Hepatobiliary Surgery and Nutrition. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by institutional ethics board of Beijing Friendship Hospital (No. 2018-P2-207-01) and informed consent was taken from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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