Is the perfect screening of paediatric non‐alcoholic fatty liver disease still an unmet target?

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children and its frequency reflects the global obesity epidemic. Its histological spectrum ranges from simple steatosis, defined as >5% microvesicular or macrovesicular fat accumulation, to steatosis with lobular inflammation and hepatocellular injury. The latter includes non-alcoholic steatohepatitis, with or without fibrosis and/or cirrhosis.1 A meta-analysis2 confirmed that the overall global prevalence of the NAFLD among children with obesity exceeded 50%. It averaged 7.4% in the general paediatric population, with the highest values in the North American and Asian continents. If this trend continues, the prevalence is predicted to reach 30.7% by 2040.2 But why are obesity and its related comorbidities showing endless increases? Genetic and epigenetic components, increasingly harmful lifestyle habits and environmental changes that start as early as conception and pregnancy3 play an obvious role in its onset and development. Ineffective recognition and inadequate prompt care and cures may also contribute (Figure 1). Primary care physicians still have insufficient knowledge to identify adult and paediatric patients requiring specialist and subspecialist referrals at an early stage, despite the fact that NAFLD has been discussed for more than 20 years.4 A Canadian survey showed that most primary care physicians did not screen for paediatric NAFLD, were not familiar with its clinical spectrum and cited a lack of knowledge as the greatest barrier.5 A study of Dutch paediatricians indicated that screening for paediatric NAFLD was widely, but not universally, performed, and showed wide variations. These findings have highlighted the need for the dissemination and implementation of robust clinical guidelines among primary care professionals and physicians working in various subspecialist clinics that treat children with obesity and/or its comorbidities.6 The new study by the same Dutch group in this issue of Acta Paediatrica is particularly welcome.7 The research by Draijer and Voorhoeve is important because it particularly focuses on the ongoing feasibility of screening for paediatric NAFLD in real life. In 2017, the authors introduced a NAFLD screening protocol to primary care providers working in several Dutch outpatient obesity clinics. The protocol is based on alanine aminotransferase measurements, according to the North American Society of Paediatric, Gastroenterology, Hepatology and Nutrition.8 The medical files of patients who visited from 2017–2020 were evaluated and this showed that although 84% of the children were screened for NAFLD, 39% of them did not maintain contact or were not re-examined. This was particularly due to physicians failing to order follow-up measurements or loss to follow-up. Focus group discussions with the healthcare workers who had been using the screening protocol indicated that there were certain barriers to completing the screening. These barriers, which were related to guidelines and lack of knowledge, ultimately led to diminished adherence to the guidelines after an abnormal initial screening result. Patient-related factors that inhibited initial screening were loss to follow-up before blood sampling and/or refusal to undergo the laboratory tests. One particular physician-related factor was that they did not think it was relevant to test in children with mild obesity and mild hypertransaminasemia. Draijer and Voorhoeve's findings7 appear to echo the results from a study conducted in a North American tertiary hospital that also had quite comparably established guidelines.9 Overall, these results suggest that guidelines may perform better in the real world when they have been previously implemented in healthcare settings, as described by another North American study.10 Despite this, a number of problems persist regarding the intrinsic difficulties encountered by healthcare workers, due to (a) the lack of a specific marker of NAFLD, and (b) a tendency to rely on own laboratory's alanine aminotransferase level cut-offs for disease screening. Another problem may arise once NAFLD has been suspected in a child or adolescents with chronically elevated liver enzymes and known risk factors. That is understanding whether NAFLD is the real and only cause of hypertransaminasemia. Other causes of chronic hepatitis that mimic NAFLD must also be evaluated, especially if the patient is unable to achieve a weight-related reduction in hypertransaminasemia and fatty liver, because they may require specific treatment. A differential diagnosis of chronic liver diseases should include those with metabolic and genetic liver diseases11 and, in principle, also those without hepatic steatosis.12 None of the patients in the Draijer and Voorhoeve study had another liver disease that could have mimicked NAFLD. However, this task is not generally an easy one, because the ongoing global obesity pandemic means we can no longer assume that we are dealing with a non-NAFLD liver condition typically seen in lean patients. Moreover, it requires some specific subspecialist experience to spot, for example, the possibly misleading presence of autoimmune antibodies in the serum samples. With the exception of kidney microsomal antibodies, these are frequently encountered in NAFLD cohorts with paediatric obesity in the absence of autoimmune hepatitis. Their fluctuation and resolution are common during serial monitoring.13 Draijer and Voorhoeve's Dutch experience adds to what we know about paediatric NAFLD screening in Europe,7 but their well-designed study has a number of inevitable and evitable limitations, which they acknowledge. The inevitable ones regard the per protocol use of alanine aminotransferase as the only screening tool. Despite its low cost, this is not the most optimal non-invasive test and determining an exact cut-off for NAFLD is still being debated.14 Its modest accuracy has been documented by the possible occurrence of NAFLD in patients with normal transaminases.15 The poor generalisability of the authors' findings,7 particularly to North African and East Asian people living in the Netherlands, must also be taken into account. The evitable limitations include the scarcity of certain useful information that might have added value to their results. For example, the availability of the liver ultrasound results would have made it possible to compare the procedure with other guidelines and reports. Information on possible consanguinity should also have been highlighted. In fact, due to the ethnic background of their patients, and the findings of other studies,16, 17 we would have expected some consanguinity and, therefore, cases of genetic fatty liver. In addition, the authors did not state alternative diagnoses ruled out during gastrointestinal consultations. Despite the aforementioned limitations, we believe that Draijer and Voorhoeve's study7 is commendable for two reasons. Firstly, it clearly shows that the physicians' adherence and screening rates may have benefitted from the previous implementation of the programme among health workers. Having said that, further efforts are necessary to stress the importance of the cost-effectiveness of screening and increase the awareness of low and normal alanine aminotransferase levels when testing for NAFLD. The study also raises the question about whether or not we need more updated guidelines that simplify the tasks performed by primary care professionals and paediatric specialists. It would be good if these could be agreed upon by the different societies. Ezaia et al.15 compared how well the two leading international scientific society guidelines detected suspected NAFLD in at-risk children with obesity or overweight. The authors found quite different results, in terms of accuracy. The first was the North American Society of Paediatric, Gastroenterology, Hepatology and Nutrition strategy, which defines NAFLD as aminotransferase that is more than two times the gender-specific cut-off.8 The second was the European Society for Paediatric Gastroenterology Hepatology and Nutrition strategy, which is based on hypertransaminasemia and/or fatty liver on ultrasound.18 Ezaizi et al. found that the European guidelines performed more NAFLD diagnoses than the North American guidelines and that a significant percentage of children with fatty infiltration on their ultrasounds had alanine aminotransferase below the prescribed cut-off values.15 Therefore, novel non-invasive reliable biomarkers that can eventually replace liver biopsies for diagnosis, disease stratification and monitoring response to therapy are eagerly awaited.19 It is evident that this special population requires huge efforts to improve their quality of life and future prospects. As paediatricians, we have a unique opportunity to identify patients who are at risk in a timely manner. At present, being able to measure widely available serum transaminases, and use bedside ultrasound equipment, allow us to screen and monitor NAFLD quite easily. We know how difficult it is to ask children and adolescents with overweight and obesity and related comorbidities to make lifestyle changes and we have a limited therapeutic arsenal to help them. Therefore, we cannot underestimate the added impact of demonstrating objective evidence of liver injuries when asking them to modify their food and physical activity choices. Identifying NAFLD also means that new and future validated treatments can be offered without further delay.4 Last, but not least, paediatric patients with obesity should be screened for other components of metabolic syndrome as well as NAFLD. It has been proposed that NAFLD should be renamed metabolic-associated fatty liver disease, due to the limitations of the current term and its definition. The reference to alcohol in NAFLD has been problematic for children, as alcohol consumption is not usually a concern (Figure 1).20 Whatever the condition is called, the main issue is the strict relationship between fatty liver and obesity and the fact that it can be reversed with weight loss. The current, and extremely worrying, global obesity crisis requires strong campaigns that prevent obesity and the cascade of related conditions. The authors have no conflicts of interest to declare.

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