Key words : End-stage liver disease, Liver transplantation, Pediatric transplant, Rejection, Vitamin D synthesis

Introduction

Vitamin D plays a crucial role to maintain calcium and phosphorus balance in the body. Vitamin D deficiency can lead to numerous conditions such as hyperparathyroidism, bone loss and fractures, insulin resistance, diabetes, hypertension, malignancy, rheumatoid arthritis, and psoriasis.¹ The effects of vitamin D begin in the intrauterine period, where it is necessary for the proper immune tolerance of the embryo during implantation.² Moreover, vitamin D modulates the innate and adaptive immune systems, and its deficiency has been associated with an increased risk of autoimmune diseases and susceptibility to infections.³ Liver transplant (LT) has shown ongoing success in Turkey for more than 40 years as a life-saving intervention for patients with end-stage liver failure.^4-6 Although the role of vitamin D deficiency in autoimmune liver diseases remains controversial,⁷ it is known that vitamin D deficiency is prevalent among pediatric patients with end-stage liver failure and transplant recipients due to impaired hepatic function, posttransplant immunosuppressive therapies, and increased vitamin D catabolism.⁸ Children with chronic liver diseases are known to be prone to malnutrition due to various mechanisms including anorexia, nausea, metabolic disorders, and increased energy needs.⁹ This risk is particularly significant in cholestatic liver diseases, where coexistent pancreatic insufficiency may interfere with the absorption of fat-soluble vitamins including vitamin D. Vitamin D supplementation is not routinely recommended after LT to children. Following pediatric LT, vitamin D levels may or may not recover to normal levels. In a study with cessation of vitamin D supplementation after LT, the percentage of vitamin D-deficient cases (36% of patients) remained the same despite improvement of their liver functions.¹⁰ In another study reported by Kryskiewicz and colleagues, children with cholestatic liver diseases were supplemented only before the LT with 1 to 2 μg/kg vitamin D, and there was no difference found in vitamin D levels between pre-LT and post-LT time periods.¹¹ Contrary to this, another study found that vitamin D levels were very low in the first month after transplant, even though a high dose (300 000 IU) of vitamin D was administered before the transplant.¹² Vitamin D supplementation has been reported to be associated with lower risks of acute cellular rejection and susceptibility to infections after LT due to its immunomodulatory effects.¹³ For example, patients with heart transplants who received calcitriol after LT required lower doses of cyclosporin.¹⁴ In this study, we examined vitamin D levels in a group of pediatric LT recipients before and after LT and investigated the effects of vitamin D deficiency on transplant outcomes in our cohort.

Materials and Methods

This study was approved by the Ethics Committee of Baskent University Medical Faculty (KA15/383). A total of 138 pediatric LT patients were included. Seven patients underwent LT from deceased donors, whereas the liver grafts for 131 recipients were procured from living donors. Notably, all instances of living donor LT involved donors who are related with recipients up to the fourth degree. All of the patients in the cirrhosis and cholestatic liver diseases groups received oral vitamin D supplementation (800-1200 IU/d) before transplant, whereas all patients were given 400 to 800 IU/d vitamin D for 1 year after transplant routinely. Patients with metabolic diseases and acute liver failure were supported with vitamin D when necessary by their primary physicians, as reported in the clinical records. Age, sex, age at LT, posttransplant follow-up time, and patient survival were recorded. Patients were divided into 4 diagnostic groups according to their primary liver diseases. Group 1 comprised patients with cholestatic liver disease (n = 67; 48%), ie, biliary atresia, progressive familial intrahepatic cholestasis (stages 1, 2, and 3), Alagille syndrome, sclerosing cholangitis, and idiopathic neonatal cholestasis. Group 2 comprised patients with cirrhosis (n = 41; 30%), ie, Wilson disease, autoimmune hepatitis, cryptogenic cirrhosis, α1-antitrypsindeficiency, congenital hepatic fibrosis, and Caroli disease. Group 3 comprised patients with metabolic diseases (n = 19; 14%), ie, tyrosinemia patients with hepatocellular carcinoma, glycogen storage disease, Crigler-Najjar syndrome, mitoc-hondrial hepatopathies, familial hypercholes-terolemia, oxalosis, and urea cycle defects. Group 4 comprised patients with acute liver failure (n = 11; 8%). Creatinine, albumin, total bilirubin, direct bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, γ -glutamyl transferase, activated partial thromboplastin time, international normalized ratio, and vitamin D levels were measured simultaneously. Pediatric End-Stage Liver Disease (PELD) scores and Model for End-Stage Liver Disease (MELD) scores were recorded. Vitamin D levels (1 ng/mL = 1 μg/L = 2.5 nmol/L) were divided into 3 groups: sufficient (≧20 ng/mL), insufficient (15-20 ng/mL), and deficient (≦15 ng/mL).¹⁵ The season of the year when the vitamin D levels were measured was recorded. In this study, an immunoassay analyzer (Architect i2000SR, Abbott Diagnostics) and a chemiluminescent microparticle immunoassay kit (Architect 25-OH vitamin D reagent kit, Abbott Diagnostics) were used to measure the 25-hydroxyvitamin D form of vitamin D. Liver biopsies were performed when acute rejection was suspected or when unexplained liver function test abnormalities were observed. Acute cellular rejection was assessed according to the international Banff scheme and rejection activity index (RAI) scores.¹⁶

Statistical analyses

Mean values (with SD) and median values (with minimum and maximum) were used for numerical measurements. Numbers and percentages were used for descriptive statistics. In the diagnostic groups, the Shapiro-Wilk test was used to determine the distribution of numerical properties; also, because the distribution was not normal, nonparametric tests were used. Numerical feature comparisons in the 4 diagnostic groups were made with the Kruskal-Wallis test, and the subgroups that differed in the Kruskal Wallis test were determined by the Conover-Iman comparison test. The Mann-Whitney U test was used to compare numerical features in cholestasis and other groups. Cross-tabulation analysis and the Fisher-Freeman-Halton test were used to compare qualitative characteristics between diagnostic groups. The Wilcoxon and Friedman tests were used for comparisons of vitamin D levels over time. Comparisons over time in grouped data were made with McNemar and McNemar-Bowker tests. Relationships between numerical data were analyzed with the Spearman correlation coefficient. For statistical significance, P < .05 was accepted as significant, and the SPSS package (version 21.0, for Windows; IBM) was used in all statistical analyses.

Results

Pretransplant vitamin D levels
Demographic characteristics of 138 patients and patient groups are given in (Table 1). Vitamin D was measured in 90 (65%) of 138 patients at 1.68 ± 3.3 months (range, 0-12 months) before LT. Mean pretransplant vitamin D level was 25.2 ± 20.9 ng/mL (range, 2.8-100 ng/mL) (Table 2). Pretransplant vitamin D levels according to primary disease groups are given in (Table 2) and (Figure 1). Vitamin D levels were deficient in 33 (36.6%), insufficient in 21 (23.3%), and sufficient in 36 (40%) patients. There was no correlation between the vitamin D levels of the patients and the season in which the levels were measured (P > .05). A positive correlation (P = .05; r = 0.20) was observed between pre-LT vitamin D levels and albumin levels. No statistical difference in pre-LT vitamin D levels was found among the 4 diagnostic groups. However, patients with cholestatic liver disorders (group 1) had significantly lower pretransplant vitamin D levels compared with those in the noncholestatic groups (group 2, group 3, and group 4, combined; P = .04) (Table 3). When the data of 76 patients in the cholestatic liver diseases (n = 53) and cirrhosis (n = 23) groups were analyzed, a negative correlation with vitamin D and bilirubin levels was found (total bilirubin, P = .01 and r = -0.29; direct bilirubin, P = .007 and r = -0.30). There was no correlation between pre-LT vitamin D levels and albumin, international nor-malized ratio, PELD scores, or posttransplant RAI scores. There was also no significant relationship between pretransplant vitamin D levels and posttransplant mortality (P > .05).

Posttransplant vitamin D levels
Vitamin D levels were measured in 109 (79%) of 138 patients after LT (Figure 1). The first test was conducted at 34.9 ± 41.8 months (median, 14 months) after LT. Mean vitamin D level was 27.3 ± 18 ng/mL (range, 0.8-105). Posttransplant vitamin D levels were deficient in 30 (27.5%), insufficient in 15 (13.7%), and sufficient in 64 (58.7%) patients.

Consecutive pretransplant and posttransplant vitamin D levels
There were 61 patients for whom both pre-LT and post-LT vitamin D levels were tested. In this group, the number of patients with sufficient vitamin D levels increased from 22 (36%) before LT to 39 (64%) after LT (P = .01). There were 17 patients whose vitamin D levels were monitored before transplant, in the first year after transplant, and after the first year of LT. In these consecutive measurements, it was observed that the vitamin D levels increased over time (P = .008) (Table 4).

Vitamin D levels and rejection/survival
Liver biopsy was performed on 82 of 138 patients after LT when clinically indicated. At least 1 acute cellular rejection was found in 51 (62%) patients, chronic rejection in 1 (1%) patient, and no rejection in 30 (37%) patients. There were 31 (59.6%) acute rejections within the first 3 months after LT. Vitamin D levels before or after LT were not associated with rejection (P > .05) (Table 4). The mean RAI score of the patients with rejection was 5.4 ± 1.7, and there was no correlation with vitamin D levels (P > .05). Overall, 22 of 138 (16%) recipients died after LT. Overall survival rate at the time of the study was 84%. Posttransplant vitamin D levels were available in 10 of 22 cases of patients who died after transplant and 99 patients who survived. There was no significant relationship between posttransplant vitamin D levels and posttransplant patient deaths (Table 4).

Discussion

Our study aimed to assess the vitamin D status of pediatric patients who underwent LT by evaluating their vitamin D levels. Moreover, we sought to investigate the potential correlation between the primary disease groups and vitamin D levels and to explore the effect of vitamin D levels on disease severity and rejection. Although numerous beneficial effects of vitamin D have been explored in recent years, the general population often exhibits vitamin D deficiency due to factors such as limited sun exposure and clothing covering the skin.^17,18 Furthermore, hospitalized patients are more vulnerable to malnutrition and lack of exposure to sunlight, which limits their ability to obtain adequate vitamin D from sun or diet. Patients with liver diseases, particularly cholestatic diseases, are prone to vitamin D deficiency due to the impaired absorption of fat-soluble vitamins. Vitamin D levels should be regularly monitored in patients with chronic liver disease, because this essential nutrient plays a significant role in bone metabolism and the immune system. After LT, patients should undergo periodic vitamin D evaluations to determine whether additional doses are required or if adjustments to existing vitamin supplementation are necessary. It is worth considering that LT may address bone metabolism disorders and potentially prevent pathological fractures. A study reported that 7.2% of pediatric patients awaiting LT had bone fractures, whereas no fractures were reported after transplant.¹⁰ However, other reports suggest that pathological fractures may occur after transplant,^19,20 which supports the notion that vitamin D supplementation should be continued after LT. A study conducted in Turkey with 135 pediatric LT patients revealed that on the first day after transplant, vitamin D levels were 1.8 ng/mL.¹² However, after 1000 IU/d vitamin D supplementation starting on posttransplant day 7, more than 98% of the patients had vitamin D levels greater than 30 ng/mL by month 6. Notably, the study found that vitamin D levels did not significantly affect survival rates. Similarly, in our study, which included consecutive vitamin D level measurements prior to transplant, during the first year following transplant, and after the first year (n = 17), we observed a gradual increase in vitamin D levels after LT. This positive outcome may be attributed to daily vitamin D supplementation of 400 to 800 IU in our LT patients, as well as improvements in liver function. However, Yuksel and colleagues also stated that supplementation with 300 000 IU of vitamin D beforehand was not sufficient to maintain adequate vitamin levels immediately after pediatric LT.¹² Vitamin D deficiency can be inexpensively and easily treated, and its levels can be measured with a simple blood test. However, we were unable to include 64 patients (30%) who had undergone LT in our hospital in the study because their vitamin D levels had not been assessed at any time. Additionally, we observed that 90 patients (65%) had not been tested for vitamin D before transplant, and 36 patients (26%) had not been tested after transplant. The reasons for this discrepancy may be attributed to a lack of trust in routine vitamin D supplementation in the past and a disregard for vitamin D testing. Previous studies on vitamin D have demonst-rated that levels are generally higher during the summer months compared with the winter months.²¹ This can be attributed to increased sun exposure during the summer, which facilitates vitamin D synthesis in the skin through the influence of ultraviolet (UV) rays. However, our study did not observe a similar relationship. This could be because our patients were unable to benefit from sunlight not only during the winter season but also throughout the year due to their medical conditions and immobilization. In chronic liver diseases, especially cholestatic diseases, the absorption of fat-soluble vitamins is impaired, which affects absorption of vitamins A, D, E, and K. In addition to malabsorption, loss of fat tissue due to malnutrition decreases vitamin D storage area. Also, avoidance of outdoor activities also increases vitamin D deficiency. In a study by Jensen and colleagues, despite oral supplementation of 300 000 IU vitamin D for 2 to 3 days in 4 children with newly diagnosed cholestasis, vitamin D levels did not exceed 20 ng/dL in any of them after a month.²² In a study conducted on 92 children with biliary atresia, there was a negative correlation between bilirubin and vitamin levels, and defi-ciencies in vitamin A, vitamin D, and vitamin E were found in 16% to 37% of them.²³ Likewise, our study found that pretransplant vitamin D levels were lower in patients with cholestasis compared with patients without cholestasis, but this difference disappeared after transplant, likely due to the resolution of cholestasis after transplant. In studies on organ failures and transplant, low vitamin D levels are found in various organ failures and associated with poor prognosis and vice versa. Lowery and colleagues examined the vitamin D levels of 102 lung transplant patients before transplant and 100 days after transplant and found that 80% of the patients had vitamin deficiency. Infection was more common in this group, acute rejection was 2.4 times higher, and mortality after 1 year was 4.7 times higher.²⁴ Ebbert and colleagues stated 91% of their 29 pediatric renal transplant recipient were vitamin D deficient.²⁵ Filipov and colleagues found that 230 kidney transplant recipients with high vitamin D levels have lesser proteinuria, which is a risk factor for graft loss.²⁶ Various studies have been conducted to determine appropriate plans for vitamin D replacement. Krause and colleagues studied vitamin D levels in 109 patients with end-stage kidney disease; 95 patients were given a weekly regimen of 20 000 to 60 000 IU of oral vitamin D, and 14 patients were given whole-body irradiated with UV-B for more than 6 months. The oral supplementation group showed a 60% increase in vitamin levels, whereas the UV-treated group showed 400%.²⁷ Furthermore, UV rays enable the conversion of excess vitamin D to inactive products and do not allow vitamin D toxicity.²⁸ Our patient group also mostly used daily oral vitamin D supplements instead of going out in the sun. Considering the malabsorption in cholestatic patients, exposing those patients to the sunlight as much as possible to achieve better vitamin D levels seems to be a safe and effective method. Numerous studies have explored the link between vitamin D and the severity of liver disease. Vitamin D levels below 10 ng/mL were found to be associated with a high MELD score.²⁹ In adult patients with alcoholic cirrhosis and primary biliary cirrhosis, vitamin D levels were found to decrease, whereas Child-Pugh scores increased.³⁰ In a separate study of 107 adult patients awaiting LT, 66% were found to have vitamin D deficiency. This study revealed a negative correlation between vitamin D levels and Child-Pugh and MELD scores, as well as bilirubin, whereas a positive correlation was observed with albumin levels.³¹ Our research did not reveal a correlation between PELD scores and vitamin D levels. However, we did observe a negative correlation between vitamin D levels and total/direct bilirubin levels, along with a positive correlation between albumin levels. It is possible that this discrepancy may be due to the fact that the disease severity scores were calculated higher than the actual values, because fresh-frozen plasma and albumin supplements were administered to patients in order to achieve pretransplant stabilization. Nonetheless, because bilirubin levels are not affected by these interventions, we were able to establish a negative correlation between bilirubin levels and vitamin D, which may indicate an inverse proportionality between the severity of liver failure and vitamin D levels. The effects of vitamin D on immunity, infection, and posttransplant rejection are under investigated. Acute rejection, which is triggered by the pre-sentation of foreign antigens from the allograft to T lymphocytes by antigen-presenting cells, such as dendritic cells, can result in allograft damage and loss of function when T lymphocytes become activated and aggregate in the tissue.³² Vitamin D has an inhibitory role in cellular immunity, and vitamin D deficiency may lead to rejection via various mechanisms. For instance, vitamin D has been found to decelerate antigen-presenting cell maturation, thereby reducing T-cell activation.³³ Moreover, vitamin D promotes dendritic cell tolerance and the activation of regulatory T cells rather than effector T cells.³⁴ There is a synergistic effect between classical immunosuppressives and vitamin D.³⁴ For instance, lower doses of cyclosporine might be sufficient to prevent rejection in patients with heart transplant who are also receiving vitamin D for the treatment of osteoporosis.¹⁴ In patients who have undergone allogeneic stem cell transplant, vitamin D sup-plementation has been observed to modify the immune response by reduction of B cells and CD8 T cells. As a result, graft-versus-host disease was less common at the end of the first year after transplant.³⁵ In the past, acute cellular rejection was observed in liver recipients at a rate of 30% to 70% in the first year after transplant; however, this ratio has currently declined to 11.5%.^36,37 In a study conducted on adult LT recipients, vitamin D deficiency was found to be an independent risk factor for acute cellular rejection.¹³ Similarly, in a study by Rock and colleagues, low pretransplant vitamin D levels were associated with T-cell-mediated rejection in 82 pediatric LT recipients.³⁸ In our study, rejection occurred in 52 (37.6%) patients at some point after transplant, and we were unable to demonstrate a relationship between pretransplant or posttransplant levels of vitamin D and rejection or RAI scores. However, we attributed this to the retrospective nature of our study. Studies on vitamin D and its effects have gained momentum in recent years, and sought to contribute to the literature on the effects of vitamin D levels on transplant and complications in pediatric LT recipients. In conclusion, vitamin D level should be tested both before and after LT in children, and sup-plementation should be given individually.

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