Elsevier

Journal of Hepatology

Volume 57, Issue 6, December 2012, Pages 1312-1318
Journal of Hepatology

Research Article
Development and validation of a new histological score for pediatric non-alcoholic fatty liver disease

https://doi.org/10.1016/j.jhep.2012.07.027Get rights and content

Background & Aims

Pediatric non-alcoholic fatty liver disease (NAFLD) may present with a distinct histopathological pattern characterized by the presence of predominant portal-based injury and portal inflammation (PI). We aimed at developing a new grading score for pediatric NAFLD to be used in clinical trials that takes into account the presence of PI and the weight of histological features.

Methods

Our training set consisted of 203 children with biopsy-proven NAFLD. The diagnosis of non-alcoholic steatohepatitis (NASH) was based on Brunt’s criteria. Histological features were scored: steatosis (0–3), lobular inflammation (0–3), ballooning (0–2), and PI (0–2). Logistic regression analysis was performed to apply weight to each feature. The new score was called the Pediatric NAFLD Histological Score or PNHS. The validation set consisted of 100 children with NAFLD.

Results

The mean age of the initial cohort was 12.4 ± 3.4 years and significant fibrosis (fibrosis stage ⩾2) was present in 26 patients (12.8%). NASH was diagnosed in 135 patients with a mean NAS of 4.5 ± 1.4. The mean PNHS in the NASH group was 89 ± 20.5 compared to 21.9 ± 24.5 in the “not NASH” group, p <0.001. PNHS correlated with the presence of NASH according to the pathologist’s diagnosis, better than the NAFLD activity score (NAS), p = 0.011. The area under the ROC curve (AUC) for the diagnosis of NASH was 0.96 for PNHS. Similar findings were observed in the validation set with an AUC of 0.94.

Conclusions

PNHS may be used for histological grading of pediatric NAFLD with excellent correlation with the presence of NASH.

Introduction

Pediatric NAFLD encompasses a wide spectrum of disease ranging from hepatic steatosis characterized by hepatic lipid accumulation in the form of triglyceride (TG), to non-alcoholic steatohepatitis (NASH) characterized by the association of lipid accumulation with evidence of hepatocyte injury, inflammation, and various degrees of fibrosis to advanced fibrosis and cirrhosis [1], [2], [3]. Currently, a liver biopsy remains the gold standard to distinguish NASH from simple steatosis and establish the extent of liver damage and fibrosis [4].

Since the initial description by Ludwig et al., the histological criteria for diagnosing NASH have been evolving and several grading and staging systems have been proposed to assess the histologic severity of the disease [5], [6], [7]. The NAFLD activity score (NAS) was developed by the National Institute of Diabetes and Digestive and Kidney Diseases NASH Clinical Research Network (CRN) [8]. The score is based on the classification proposed earlier by Brunt et al. [5] and consists of the unweighted sum of scores for each of the following lesions: steatosis, hepatocyte ballooning, and lobular inflammation. This semiquantitative score was specifically developed for the assessment of response to therapeutic intervention. In children, it was based on a total of 18 cases that were each read once by nine pathologists for a total of 162 sets of observations [8]. Since the development of the original NAS, it has become evident that pediatric NASH may present with a distinct histopathological pattern characterized mainly by the presence of portal-based disease including portal inflammation (PI) [9], [10], [11]. Indeed, we and others have demonstrated that PI may represent an important feature of more severe disease in children with NASH [9], [11], [12]. In addition, some histological features are more indicative of the presence of NASH and should carry more weight when developing a histological score to identify patients for enrollment in therapeutic trials. For example, hepatocyte ballooning is a major distinguishing feature of NASH that confers an increased risk of disease progression [13]. The importance of ballooning has been emphasized by the results of the two largest randomized trials for NAFLD treatment in adults and children, namely the PIVENS and TONIC trials [14], [15].

As a result of these issues, when NAS is applied to the pediatric population, typically, only about half of patients can be categorized into a clear-cut pattern while the other half fall into the “borderline” category, supporting the need for a more reproducible scoring system to interpret liver histology in pediatric cases of NAFLD. This score should allow for a better separation of cases into clear-cut meaningful categories that would greatly facilitate inclusion and risk stratification of patients in therapeutic and diagnostic trials. Thus, the aim of this study was to develop and validate a new grading score for pediatric NAFLD that takes into account the presence of PI and the weight of each histological feature and to examine the level of agreement between this score and the pathologist diagnostic determination of NASH.

Section snippets

Study population

A total of 303 consecutive children with biopsy-proven NAFLD were included in this study. The study was approved by the Ethics Committee of the Bambino Gesù Children’s Hospital and Research Institute, Rome, Italy. Informed consent was obtained from each patient or responsible guardian. Inclusion criteria were persistently elevated serum aminotransferase levels, diffusely hyperechogenic liver on ultrasonography suggestive of fatty liver, and biopsy consistent with the diagnosis of NAFLD.

Patient characteristics

The main clinical and laboratory characteristics of the initial set of patients (n = 203) used to develop the new histological score are summarized in Table 1. The median age of the patients at the time of diagnosis was around 12 years and was not different between patients with or without NASH. Subjects with NASH were found to have significantly greater WC, higher WC percentile, WC/height ratio, total cholesterol, triglyceride levels and gamma glutamyl transferase (GGT), lower total bilirubin and

Discussion

The main finding of our study relates to the development and validation of a new histological score, the PNHS, to categorize NAFLD into NASH and “not NASH” for inclusion in pediatric clinical trials. Avoiding the “borderline NASH” category will allow for a better classification of children into groups with or without NASH. Our results demonstrated that: (1) there is a high level of agreement between categorization of NAFLD cases using PNHS and the pathologist’s diagnosis, (2) a PNHS of ⩾85 can

Financial support

Supported by grants from “Bambino Gesù” Children’s Hospital and Research Institute, Rome, Italy.

Conflict of interest

The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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