The term NAFLD refers to a wide spectrum of histological hepatic lesions ranging from simple (usually macrovesicular) steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma as frequently seen in obese individuals (obesity-related liver disease). Its histologically proven prevalence in children in the United States (as revealed in autopsies after accidents) ranges from 9.6% in normal-weight individuals to 38% in obese ones. Due to its tendency to progress through this range in childhood or after the transition to adulthood, early diagnosis and treatment are important issues at all ages. Treatment should address not only the liver disease itself but also the entire spectrum of comorbidities to improve overall survival and quality of life [2
]. The European Society of Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) expert committee recommends that differential diagnoses of NAFLD should primarily be based on clinical features and ultrasonographic/blood tests. In ambiguous cases, liver biopsy should be considered [2
Due to the prevalence of obese and overweight individuals, there are some red flags to consider in order to correctly assess obesity-related steatosis. These are:
not being in the classical age range for NAFLD, and
being in the classical age range but with abnormalities in liver tests or hepatic ultrasounds not corresponding satisfactorily to a weight loss obtained by dietary/physical activity measures.
NAFLD usually does not occur in extremely young children (those younger than 3 years) and it is rare in children younger than 10 years. In these cases, however, the coexistence of central adiposity (waist circumference >90th percentile), elevated body mass index(BMI) (>85th percentile), clinical or laboratory signs of insulin resistance, family history of NAFLD or type 2 diabetes mellitus (DM), and a sedentary lifestyle may be indicative of NAFLD [2
early onset liver steatosis (for those <5 years of age) or clinical phenotypes of acute liver failure, neonatal conjugated jaundice, or large organomegaly are indicative of liver diseases other than NAFLD.
9. Discussion and Conclusions
In the diagnostic work up of NAFLD, anthropometric estimations and clinical features (BMI, waist circumference, and signs of insulin resistance (e.g. acanthosis nigricans) should be considered when predicting the risk of NAFLD. Signs such as belonging to a certain ethnic group (e.g. Hispanic) [57
] or a dietary history revealing large amounts of fructose intake may aid in strengthening a presumptive diagnosis of obesity- or diet-related NAFLD [58
]. First line approaches should include liver ultrasonography and simple laboratory tests [2
Ultrasonographic exams (compared to liver biopsies) have a sensitivity ranging from 60% to 96% and a specificity ranging from 84% to 100%, depending on the grade of steatosis severity [59
]. When considering other available imaging modalities which can obtain more accurate quantitative evaluations of fat content, a recent meta-analysis has confirmed the superiority of MRI and MRI spectroscopy (MRS) [61
]. MR elastography has also been used to accurately assess hepatic fibrosis [63
]. However, equipment for these techniques are not present in every hospital and are available mainly in specialized centers.
Standard liver function tests represent an option worth suggesting among laboratory exams [64
], although it should be noted that cases of normal transaminases-NAFLD are not infrequent and may therefore be misleading [2
When the patient is not responsive to physical-dietary interventions or when weight loss is not followed by transaminases/ultrasonographic improvement it is prudent to exclude the most common etiologies of fatty liver and hypertransaminasemia other than obesity-related NAFLD by measuring a number of indices with a stepwise approach as summarized in Table 2
More invasive investigations (the third step), including liver biopsies, could be justified, especially when these exams are inconclusive. Liver biopsies are in fact the gold standard for diagnosis in patients with fatty liver because in addition to its being able to distinguish NAFLD from NASH, it can also exclude or address the identification of other steatotic liver diseases (e.g., in general, IEM has a microvacuolar pattern). Yet, indications that liver biopsies are an essential test are still under discussion and there is no consensus to formulate precise guidelines [2
]. In fact, it is an expensive and invasive technique associated with possible complications, and, due to an unpredictable sampling variability, it is not exempt from false negative results [66
]. For these reasons, noninvasive biological markers, scoring systems, and imaging modalities (so called “liquid biopsies”) are being developed and investigated more and more to better assess NAFLD patients [68
As previously mentioned, a high prevalence of obesity may increase the risk of NAFLD overdiagnosis and possibly deprive the patient of a specific curative diet or drug therapy for another treatable condition. For example, a gluten free diet for patients with celiac disease as well as a fructose free diet for those with hereditary fructose intolerance will allow patients to be cured, have no symptoms, and have a normal life expectancy. Several other conditions also have effective therapies which can improve the liver health of young patients (e.g. copper chelation for Wilson’s disease and steroids for autoimmune hepatitis).
In conclusion, independently of patient BMI, pediatric fatty liver requires keen evaluation by considering several conditions for those of all ages before relying on a diagnosis of NAFLD.