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ARTICLE
Evaluation of Underlying Liver Disease and Its Severity in Children Referred for Liver Transplant: a Single-Center Report From Nemazee Hospital of Shiraz

Objectives: Liver transplant has been used as a curative approach for children with end-stage liver diseases. Here, we describe the underlying causes for pediatric liver transplant performed at the Shiraz Organ Transplantation Center, Nemazee Hospital, Shiraz, Iran.

Materials and Methods: In this cross-sectional des-criptive study, children < 18 years old who were candidates for liver transplant from 2007 to 2010 at the Shiraz Organ Transplantation Center were included. Patients were evaluated for their underlying diseases leading to liver failure. Disease severity was assessed and compared with Pediatric End-Stage Liver Disease model and the Model for End-Stage Liver Disease scores.

Results: Of 107 patients, 60.8% were males and 39.2% were females. The mean age was 11.6 ± 4.9 years. Thirteen patients (12.5%) were < 2 years old, 26 (24%) were 2 to 6 years old, 33 (30.8%) were 6 to 12 years old, and 35 (32.7%) were 12 to 18 years old. Underlying liver diseases comprised biliary atresia (27.1%), cryptogenic cirrhosis (21.5%), autoimmune cirrhosis (13.1%), familial intrahepatic cholestasis (11.2%), Wilson disease (9.3%), tyrosinemia (7.4%), neonatal hepatitis (4.7%), congenital hepatic fibrosis (3.7%), and Caroli disease (1.9%). Jaundice (83.2%), ascites (57%), and esophageal varices (43%) were the most common clinical findings. Mean serum direct bilirubin, total bilirubin, international normalized ratio, and serum creatinine values were 3.6 ± 0.8 mg/dL, 9.3 ± 9.1 mg/dL, 2.1 ± 1.1, and 0.6 ± 0.2 mg/dL, respectively. The mean Pediatric End-Stage Liver Disease score in children < 12 years old was 11.4 ± 9.1. The mean Model for End-Stage Liver Disease score in children > 12 years old was 13.7 ± 5.9. There were no differences in scores among sex, age groups, or different etiologies.

Conclusions: Scores for disease severity were not significantly different with regard to different causes of underlying diseases for liver transplant in Iranian children.


Key words : Biliary atresia, Liver failure, Pediatric

Introduction

The first pediatric liver transplant (LT) procedure dates back to 1963.1 Children constitute 12.5% of candidates for LT.2 In pediatric patients, LT is challenging, especially in younger individuals, due to special requirements regarding technical, anatomic, and immunologic issues.3-7 New immunosuppression strategies, novel surgical approaches, and better pre- and posttransplant management procedures have affected the survival rate of liver allograft recipients.8,9

Liver transplant has dramatically improved survival rate and quality of life in patients with end-stage liver diseases.10 Although livers from deceased donors constitute the main source (90% to 92%) of donated liver allografts,4,11 a significant decrease in mortality of patients in the preoperative period is due to the introduction of living donors.12 Nevertheless, limited numbers of liver grafts still constitute the main obstacle for higher survival rates in pediatric patients.9

According to a report from the China Liver Transplant Registry, the number of LT surgeries in China was 20 877 from 1980 to 2011.11 In comparison, the United Network for Organ Sharing and Eurotransplant registries have reported 113 432 and 11 542 LT procedures, respectively, up until 2011.11 These numbers are expected to gradually increase with improving LT strategies in upcoming years.13,14

Since 1993, we have described multiple pediatric LT procedures in our center (the Shiraz Organ Transplantation Center, Shiraz, Iran).15-19 In another report, which described the first 50 pediatric LT procedures performed at the Shiraz Transplantation Center until 2006, we provided a full view on clinical conditions of these operations.20 Here, to explore the causes of liver failure in Iranian children, we provide a comprehensive report on the underlying causes for pediatric LT performed at our center.

Materials and Methods

Patients
In this cross-sectional descriptive study, patients under 18 years old who were candidates for LT at the Shiraz Organ Transplantation Center were included. Patients were evaluated for underlying diseases leading to liver failure. Disease severity was assessed by Pediatric End-Stage Liver Disease (PELD) and Model for End-Stage Liver Disease (MELD) scores. These candidates had been referred to the Shiraz University of Medical Sciences Liver Transplant Center in Nemazee Hospital between 2007 and 2010. Patients with metabolic diseases without liver involvement who may have had liver enzyme disturbances leading to secondary organ involvement were excluded from this study. In total, 107 patients met our inclusion criteria.

Gathering clinical and laboratory data
Patient age, sex, underlying disease, and growth status were obtained. Laboratory data gathered on admission included serum albumin, total bilirubin, international normalized ratio (INR), and serum creatinine results.

Calculating pediatric end-stage liver disease and model for end-stage liver disease scores
For children under 12 years old, patient priority for LT was determined according to PELD score. Based on this, age, growth failure, serum albumin, total bilirubin, and INR were used to calculate the score. For children above 12 years old, we used MELD score, which considers total bilirubin, INR, and serum creatinine.

Statistical analyses
Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 14, IBM Corporation, Armonk, NY, USA). Normality of data was checked by Shapiro-Wilks test. Frequencies were applied to present qualitative data. Means and medians were reported for PELD and MELD scores. Mann-Whitney U test was applied to assess differences in means of PELD and MELD scores between different pathologies, male versus female, and age groups.

Results

Of 107 patients, 60.8% were male and 39.2% were female. Mean patient age was 11.6 ± 4.9 years, and median age was 12 years. Patients were categorized into 4 age groups according to age at admission to wait list for LT. Thirteen patients (12.5%) were < 2 years old, 26 patients (24%) were 2 to 6 years old, 33 patients (30.8%) were 6 to 12 years old, and 35 patients (32.7%) were 12 to 18 years old.

Underlying liver diseases that led to requirement for LT are shown in Table 1. Biliary atresia (29/107; 27.1%) was the most common underlying disease. Other major causes included cryptogenic cirrhosis (23/107; 21.5%) and autoimmune cirrhosis (14/107; 13.1%). Regarding different age categories, biliary atresia was the most common underlying cause in children < 2 years old (76.9%) and 2 to 6 years old (30.8%), whereas cryptogenic cirrhosis was identified as the most common cause in children 6 to 12 years old (33.2%) and 12 to 18 years old (34.2%) (Table 2).

Jaundice was the most common clinical mani-festation in our patients (83.2%), and ascites (57%) and esophageal varices (43%) were the other prevalent clinical findings. Table 3 lists the clinical signs and symptoms of the study patients. Mean values for serum bilirubin, total bilirubin, INR, and serum creatinine were 3.6 ± 0.8 mg/dL, 9.3 ± mg/dL, 2.1 ± 1.1, and 0.6 ± 0.2 mg/dL, respectively.

For the PELD scoring system, each patient is assigned a number regarding 5 criteria: age, growth status, serum albumin level, serum bilirubin level, and INR. Patients with greater scores have priority to be transplanted. The mean PELD score in children < 12 years old was 11.4 ± 9.1. In children > 12 years old, the mean MELD score was 13.7 ± 5. 9. We observed no associations between PELD and MELD scores and age groups and males versus females. Mean MELD and PELD scores for individual pathologies are presented in Table 4 and Table 5, respectively. We observed no significant differences between PELD or MELD scores and the different causes of liver disease.

Discussion

Advancements in technical and management strategies have made LT an effective therapeutic option with a high cure rate in patients with end-stage liver diseases. Among 107 children (< 18 years old) on the wait list at our center from 2007 to 2010, underlying liver diseases included biliary atresia (27.1%), cryptogenic cirrhosis (21.5%), autoimmune cirrhosis (13.1%), familial intrahepatic cholestasis (11.2%), Wilson disease (9.3%), tyrosinemia (7.4%), neonatal hepatitis (4.7%), congenital hepatic fibrosis (3.7%), and Caroli disease (1.9%). Our previous report on 50 pediatric LT recipients in our center showed cryptogenic cirrhosis (30%), autoimmune cirrhosis (24%), biliary atresia (22%), Wilson disease (14%), progressive familial intrahepatic cholestasis (4%), fulminant hepatitis (4%), and tyrosinemia (2%) as the major diseases.20 Although the first 3 causes were the same in these 2 consecutive reports, the frequency of some showed elevating trends (ie, familial intrahepatic cholestasis and tyrosinemia). On the other hand, rates of children with cryptogenic cirrhosis, autoimmune cirrhosis, and Wilson disease decreased in our present report, whereas the ratio of biliary atresia remained similar. In another report on 138 infants and children who underwent LT (living, deceased donor, and split translations) until 2009 from our group, Wilson disease (20.3%), cryptogenic cirrhosis (16.7%), autoimmune cirrhosis (14.5%), biliary atresia (13.8%), tyrosinemia (9.4%), and progressive familial intrahepatic cholestasis (8.7%) constituted the main underlying causes of end-stage liver disease.21

In a recent 3-year study (2012-2015) from Pakistan on 14 pediatric LT recipients (≤ 17 years old; median age of 8.5 years old),10 28.6% children had Wilson disease and 28.6% had cryptogenic cirrhosis (ie, 4 patients each). Two children had Budd-Chiari syndrome (14.2%), and 1 child had biliary atresia (7.1%).10 In a report from the United States on 196 LT procedures on 155 children, biliary atresia comprised the dominant cause of liver failure in both infants (< 12 mo old) and children (1-18 years old).9 Other causes included metabolic disease, fulminate hepatitis, cystic fibrosis, cryptogenic cirrhosis, and tumors.9 In a study from Turkey, Aydogdu and colleagues described 67 LT procedures (32 deceased and 35 living grafts) in 61 pediatric patients.22 The most common causes included metabolic liver disease (27.8%), biliary atresia (22.9%), and cryptogenic cirrhosis (18%). Some other causes were also described, including autoimmune and viral hepatitis (9.8% and 6.5%, respectively) and fulminant liver disease (8.1%).22

In the China Liver Transplant Registry report, biliary atresia and Wilson disease were the most frequent causes for LT in pediatric patients.11 In general, biliary atresia is the most common cause for LT.23-25 This is followed by congenital disorders, with hereditary deficiency of α1-antitrypsin, as the most frequent cause for LT.26,27 Comparisons of these studies indicate a variable and wide picture on causes of liver failure in children; therefore, clinicians must consider the different etiologies for liver failure in children.

The PELD and MELD models for predicting requirements for LT based on severity and mortality risk of end-stage liver disorders28,29 have successfully decreased mortality rates in both pediatric and adult patients on wait lists for LT.30 In our study, mean PELD score was 11.4 ± 9.5 (range, 1-42) in children< 12 years old and mean MELD score was 13.7 ± 5.9 (range, 6-27) in patients > 12 years old (P > .05). The higher score in children older than 12 years indicated more severe conditions and higher preference for LT. A possible explanation for this observation may be due to different causes of liver failure among those < 12 or > 12 years old. In our study, the most common cause for children > 12 years old was cryptogenic cirrhosis, whereas biliary atresia was the most common cause in those < 12 years old.

Other reports have shown median PELD score of 23 (range, 1-54) in 61 pediatric LT recipients in Turkey.22 In a study of pediatric LT in the United States,9 19 children (> 1 year old) had PELD score > 28, whereas 11 and 7 children had scores of 7 to 16 and 17 to 27 at the time of LT, respectively.9 Among 74 infants (<1 year old), most had PELD score of 7 to 16, although 10 patients had scores of > 28 and 3 had PELD scores of -11 to 6.9

Both the PELD and MELD scoring systems have been used for prognostic analyses in previous studies.31-34 Patients within both age groups (< 1 year old and 1-18 years old) with higher PELD scores showed lower overall and 1-year survival rates than patients with lower PELD scores.9 The negative correlation of PELD score with 1-year survival has also been described by Barshes and associates.29 A MELD score of > 20 in children with biliary atresia was shown to be significantly associated with lower 2-year mortality rate.24 Although patient age is a factor incorporated into calculation of PELD score, we recognized no statistically significant difference in these scores with regard to age groups or males versus females. This observation indicates that prognosis of these patients could be dependent on some other pathologic factors (ie, underlying pathologies, genetic alternations, acquired and environmental factors, and therapeutic interventions).

In our study, we detected no significant dif-ferences in PELD/MELD scores among different underlying conditions. However, the highest PELD score was seen in children with biliary atresia and cryptogenic cirrhosis. Accordingly, the highest MELD score was also found in patients with cryptogenic cirrhosis, whereas children with autoimmune cirrhosis showed the second highest MELD score. Among those with the same pathology, there was no significant difference between MELD and PELD scores in children < 12 or > 12 years old. Nevertheless, it is recommended to explore the effects of other mentioned factors in determining clinical severity of end-stage liver diseases.

Conclusions

Our study showed a variety of underlying causes necessitating LT in Iranian children. The most common reasons for this were identified as biliary atresia, cryptogenic cirrhosis, and autoimmune cirrhosis. There was no significant difference between these pathologies, as well as other pathologies, regarding sex, age, or PELD/MELD scores. This highlights the possible role of other independent factors modulating progression of liver failure in these conditions. Accordingly, improved current prioritization criteria are needed for patients on wait lists for LT by identifying, validating, and incorporating more clinical and genetic parameters into our scoring systems.


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DOI : 10.6002/ect.2018.0047


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From the 1Shiraz Organ Transplantation Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran; the 2Pediatric Ward, Amir Al-Momenin Hospital, Zabol University of Medical Science, Zabol, Iran; and the 3Clinical Research Development Unit, Amir Al-Momenin Hospital, Zabol University of Medical Science, Zabol, Iran
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Iraj Shahramian, Pediatric Ward, Amir Al-Momenin Hospital, Zabol University of Medical Science, Zabol, Iran
Phone: +98 5432239031
E-mail: ir_buper@yahoo.com