pISSN: 2234-8646 eISSN: 2234-8840 http://dx.doi.org/10.5223/pghn.2014.17.4.248 Pediatr Gastroenterol Hepatol Nutr 2014 December 17(4):248-256
PGHN
Original Article
The Clinical Significance of Serum Ferritin in Pediatric Non-Alcoholic Fatty Liver Disease Ji Hoon Na, So Won Park, Yunkoo Kang, Hong Koh and Seung Kim Department of Pediatrics, Severance Children’s Hospital, Yonsei University College of Medicine, Seoul, Korea
Purpose: Non-alcoholic fatty liver disease (NAFLD) in children has become an important public health issue because of its high prevalence and severity. Several noninvasive methods for estimating NAFLD are under investigation. We aimed to evaluate the usefulness of serum ferritin as a biomarker of severity of pediatric NAFLD patients. Methods: A total of 64 NAFLD patient were enrolled from Severance Children’s Hospital from March 2010 to February 2013. Serum ferritin levels, liver related laboratory tests, liver magnetic resonance imaging (MRI) (2-dimensional [2D] proton density-fat fraction) and NAFLD severity markers were compared between obese group and overweight group. Correlation analyses were performed between serum ferritin and laboratory values including NAFLD severity markers. Results: In obese group, serum ferritin, alanine aminotransferase (ALT), total bilirubin, international normalized ratio (INR), MRI 2D proton density-fat fraction, aspartate aminotransferase (AST) to platelet ratio index (APRI) and fibrosis-4 (FIB-4) (an index score calculated from platelet count, ALT, AST and age) were significantly higher than those of overweight group. NAFLD severity markers, APRI and FIB-4, and liver specific important laboratory values, AST, ALT, INR, cholesterol, triglyceride and low density lipoprotein show significant correlation with serum ferritin in NAFLD patients. Conclusion: Serum ferritin concentrations could be a candidate of useful severity marker in the pediatric NAFLD patients. Key Words: Non-alcoholic fatty liver disease, Child, Ferritins, Biological markers, Obesity
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of liver diseases ranging from hepatocellular steatosis to irreversible liver cirrhosis and
is closely related to obesity and metabolic syndrome [1]. Metabolic syndrome is characterized by obesity, hyperlipidemia, diabetes mellitus (DM), and insulin resistance. In adults, as well as hypertension, obesity, and DM, the frequency of metabolic syndrome
Received：August 28, 2014, Revised：September 23, 2014, Accepted：October 3, 2014 Corresponding author: Seung Kim, Department of Pediatrics, Severance Children’s Hospital, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 120-749, Korea. Tel: +82-2-2227-2743, Fax: +82-2-393-3080, E-mail:
[email protected] Copyright ⓒ 2014 by The Korean Society of Pediatric Gastroenterology, Hepatology and Nutrition This is an openaccess article distributed under the terms of the Creative Commons Attribution NonCommercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
PEDIATRIC GASTROENTEROLOGY, HEPATOLOGY & NUTRITION
Ji Hoon Na, et al：The Clinical Significance of Serum Ferritin in Pediatric NAFLD
is increasing gradually. Metabolic syndrome can be manifested as NAFLD in the liver [2-4]. The prevalence of NAFLD is also increasing due to the increase in the rate of metabolic syndrome. NAFLD is raising the morbidity and mortality rates associated with the liver [5]. In western countries, the morbidity of NAFLD is 20-30% of total adults and 90% of obese adults. Moreover, non-alcoholic steatohepatitis (NASH) is affecting an estimated 2-3% of the general population and up to 37% of obese individuals [1]. Approximately 10% of patients with NAFLD progress to NASH, and 8-26% of NASH patients progress to cirrhosis [2]. The prevalence of NAFLD in children and young adults is also increasing rapidly. Studies have reported about 3% prevalence of NAFLD in the general pediatric population and 53% in obese children [1]. Due to the Westernized lifestyle and diet, pediatric NAFLD is expected to increase significantly in the future globally. Furthermore, NAFLD can have more severe influence to children due to longer duration of the disease. Therefore, as with adults, the importance of the early diagnosis and proper treatment of NAFLD and NASH in children is increasing in order to prevent liver cirrhosis and hepatocellular carcinoma. NAFLD can be diagnosed after the exclusion of other liver diseases and identifying image studies of the fatty liver [6]. To diagnose NASH, various methods―including magnetic resonance imaging (MRI) proton density-fat fraction (PDFF), which has been actively studied recently―are being used. MRI PDFF is a non-invasive and quantitative means of quantifying hepatic steatosis in patients with NAFLD [7]. However, the exact cut-off value has yet not been established, and the MRI equipment itself is not easily obtained due to its high price. Confirmation of the disease can be made only by pathology, which is characterized as steatosis, lobular inflammation, and hepatocellular ballooning [2,8]. However, liver biopsy is invasive in children. Furthermore, there is the possibility of sampling error of liver biopsy specimens [9]. Therefore, to follow up on the progression of NAFLD, repeated liver biopsies are nearly impos-
sible, especially for children. Thus, researchers are seeking non-invasive and cost-effective tools for the diagnosis of NAFLD and NASH. They are making efforts to develop biological markers to predict the progression from simple fatty liver to NASH, liver fibrosis, cirrhosis, and hepatocellular carcinoma [10]. In recent adult studies, serum ferritin levels were reported to be an independent predictor of advanced hepatic fibrosis in patients with NAFLD based on its correlation with hepatic inflammation and hepatic iron storage [10]. Serum ferritin levels are known to be elevated in patients with NAFLD and seem to be related to insulin resistance and hepatocyte damage [11]. So researchers are interested in serum ferritin as a biomarker that can reflect the inflammatory change of the liver for children as well. In fact, pediatric gastroenterologists are more earnestly seeking simple and noninvasive biologic markers for NAFLD. If simple and non-invasive biologic markers for NAFLD are found, it will be very helpful in disease management due to improved compliance of follow-up. Also early detection or screening could be possible for the pediatric NAFLD patients who may progress to liver cirrhosis. Proper medical treatment to the patients could be provided at an appropriate time accordingly. We also can expect an additional effect that might reduce patient's medical expenses from other expensive and invasive diagnostic methods and its possible complications. For these reasons, we were to investigate the clinical significance of serum ferritin in pediatric NAFLD patients as a candidate of effective and less-invasive biological marker.
MATERIALS AND METHODS Study design A total of 64 patients diagnosed as NAFLD at Severance Children’s Hospital, Seoul, Korea, from March 2010 to February 2013 were included in this study. We selected patients whose repetitive alanine aminotransferase (ALT) was abnormal (30 U/L or more for men and 19 U/L or more for women) [12] for unknown reasons in the regular check-up. Patients with ALT elevation for certain reasons (e.g., hepatitis B,
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hepatitis C, hepatitis A, Wilson’s disease, hemochromatosis, etc.) were excluded. No patients in the population reported active substance abuse or significant systemic illnesses or were taking drugs known to cause hepatic steatosis. All patients had a diagnosis of NAFLD based on cryptogenic etiology and MRI-PDFF imaging with steatosis ＞5% [7]. Laboratory tests (e.g., iron profiles, liver function tests, and lipid profiles), MRI PDFF values were obtained from patients’ medical records and analyzed. NAFLD severity markers―such as the aspartate aminotransferase (AST) to platelet (PLT) ratio index (APRI), AST/ALT ratio (AAR), and fibrosis-4 (FIB-4)―that are known as predictors of liver fibrosis were also calculated and analyzed [11,13]. 1. Differences between obese and overweight group
We aimed to evaluate whether the body mass index (BMI) influences the variables associated liver and serum ferritin. Therefore, we examined the differences in the laboratory values, MRI PDFF values and NAFLD severity makers between overweight and obese groups, which were divided by BMI percentile.
Obesity was defined as a BMI in the 95th percentile or higher, while overweight was defined as a BMI in the 85th-95th percentile considering age and sex. 2. Correlation of laboratory values and NAFLD severity markers with serum ferritin level
To evaluate the significance of serum ferritin level, correlation between several liver specific laboratory values, MRI 2-dimensional (2D) PDFF and NAFLD severity markers with serum ferritin were analyzed.
Statistical analysis Baseline characteristics were presented as the median and range in parentheses. The obese group and overweight group were compared using MannWhitney U test. Correlations between laboratory and serum ferritin were assessed by Spearman analysis. For better understanding, the scatter plot of NAFLD severity markers was displayed with Spearman correlation coefficient. All tests were two-sided and a p-value of 0.05 was considered to be statistically significant. Also, statistical analyses were conducted with IBM SPSS Statistics version 20.0 (IBM Co.,
Table 1. Characteristics of Patients of Non-Alcoholic Fatty Liver Disease (NAFLD) Children Variable Age AST (IU/L) ALT (IU/L) Albumin (g/dL) Total bilirubin (mg/dL) 3 Platelet count (10 /μL) INR Transferein saturation (%) Serum iron (μg/dL) Cholesterol (mg/dL) Triglyceride (mg/dL) HDL (mg/dL) LDL (mg/dL) MRI 2D PDFF NAFLD severity markers APRI AAR FIB-4
Total (n=64) 13.35 52.00 108.50 4.70 0.50 312.00 0.98 27.00 96.00 189.50 135.50 47.00 118.00 36.00
(9.80-20.00) (12.00-451.00) (16.00-591.00) (4.10-5.20) (0.20-1.80) (189.00-587.00) (0.86-1.11) (2.00-335.10) (11.00-185.00) (109.00-374.00) (53.00-516.00) (25.00-68.00) (42.00-178.00) (6.00-47.20)
0.40 (0.14-1.92) 0.54 (0.30-1.84) 0.24 (0.11-0.95)
Overweight (n=16) 11.70 49.50 94.00 4.70 0.45 339.50 0.98 29.00 97.00 178.00 175.50 48.00 103.20 32.80
(10.10-15.10) (30.00-101.00) (55.00-155.00) (4.30-4.90) (0.20-0.70) (266.00-403.00) (0.94-1.11) (17.00-316.00) (58.00-127.00) (155.00-374.00) (70.00-289.00) (25.00-61.00) (81.60-146.00) (6.00-47.20)
0.33 (0.24-0.95) 0.52 (0.30-1.84) 0.16 (0.12-0.61)
Obese (n=48) 14.15 54.00 120.50 4.60 0.50 303.00 0.98 26.50 95.50 191.50 131.50 47.00 122.00 41.20
(9.80-20.00) (12.00-451.00) (16.00-591.00) (4.10-5.20) (0.20-1.80) (189.00-587.00) (0.86-1.10) (2.00-335.10) (11.00-185.00) (109.00-269.00) (53.00-516.00) (27.00-68.00) (42.00-178.00) (22.00-46.60)
0.42 (0.14-1.92) 0.54 (0.30-1.76) 0.26 (0.11-0.95)
p-value
