Recognise and Refer NAFLD in Children

Dr Jez Thompson Reviews the Current Evidence and Guidance on Nonalcoholic Fatty Liver Disease in Children, and Considers the Role of General Practice in Diagnosing and Supporting Patients

Nonalcoholic fatty liver disease (NAFLD) in children and adolescents has been described in the medical literature for more than 20 years.^1,2 Just as in adults, it is characterised by the abnormal accumulation of liver fat without a primary cause of liver dysfunction, such as chronic viral hepatitis, an autoimmune condition, hepatotoxic drug use, or excess alcohol consumption.^2,3 In all age groups, NAFLD represents a spectrum of liver conditions ranging from isolated fatty liver (steatosis) to nonalcoholic steatohepatitis (NASH; in which there is hepatocellular inflammation and injury), fibrosis and, finally, cirrhosis, with the potential for hepatocellular carcinoma.^3–5 However, simple fatty liver often follows a benign, nonprogressive clinical course,⁴ and NAFLD remains a rare indication for liver transplantation in children.⁶

This article covers the aspects of NAFLD in children that are relevant to primary care practitioners, discussing prevalence, presentation, and risk factors before turning to the less well-defined areas of screening and management. 

Terminology

It is worth noting that, although the term ‘NAFLD’ is most commonly used to describe fatty liver in children, some authors have argued that the term is inappropriate for children, in whom alcohol consumption is usually not a concern.^7,8 These authors have suggested renaming and redefining the condition as ‘metabolic (dysfunction)-associated fatty liver disease’ (MAFLD).^7,8 Further proposed changes in nomenclature are outlined in Table 1.^9,10

Table 1: Proposed Nomenclature Changes^9,10

Prevalence

In recent years, the prevalence of NAFLD in young people has been increasing;^4,5,11,12 it is now the most common cause of liver disease in children and teenagers,^3,13 with an estimated worldwide prevalence of 5–10%.³ In one retrospective review of American children who underwent an autopsy for any cause of death between 1993 and 2003, the overall prevalence of fatty liver was 13%.¹⁴ This study also found that the prevalence of fatty liver varied by ethnic background (with the highest rates in Asian and Hispanic children and the lowest in Black children) and increased with age, rising from 0.7% for ages 2–4 years to 17.3% in 15–19 year olds.¹⁴ The highest rates of fatty liver were seen in children who were obese (38%).¹⁴

Other studies have confirmed a significantly higher prevalence of NAFLD in obese children,^3,15 and boys have been shown to have higher rates of NAFLD than girls.³ The prevalences of NASH and advanced fibrosis in children at the time of NAFLD diagnosis are thought to be around 20–50% and 10–20%, respectively.³

Symptoms and Presentation

In the paediatric population, NAFLD tends to be diagnosed most often in the peripubertal period, with an average age at presentation of 12–13 years.³ Although several studies have suggested that diagnoses of NAFLD are increasing in very young children, it is not clear whether this trend reflects greater screening activity or a true increase in prevalence.³

Children diagnosed with NAFLD are nearly always asymptomatic at diagnosis,⁵ and fatty liver is often an incidental finding on imaging—for example, upper abdominal ultrasound^16,17—or after further investigation of a child with an abnormal alanine transaminase (ALT) result on panel blood testing.^5,16 When symptoms are present, right-upper-quadrant pain may be a feature—it has been suggested that this is caused by the hepatic capsule stretching as a result of liver fat deposition.⁵ Other, nonspecific symptoms can include fatigue and malaise.¹⁸

This lack of symptoms is a critical issue that impedes the identification and diagnosis of children with NAFLD. In future, more prompt and effective screening is likely to enable earlier diagnosis and intervention for children with NAFLD.¹⁹

Risk Factors

The greatest single risk factor for paediatric NAFLD is obesity:³ in one study of 408 children with obesity, the prevalence of NAFLD was 26.0% overall (29.4% in males and 22.6% in females).²⁰ However, obesity and NAFLD do not inevitably go hand in hand, and clinicians should be aware that most children with obesity do not have NAFLD.^3,20 

The key risk factors for NAFLD in children are outlined in Box 1.^1,3,20–22 Overall, the available evidence suggests that the aetiology of NAFLD is multifactorial, and that it is related to a complex interplay of hormonal, nutritional, genetic, and environmental factors.^3,8

Case Finding

Because most children with NAFLD are asymptomatic, screening of children at risk of NAFLD plays an important role in case finding.^23,24 Indeed, more effective screening and case finding is likely to have a significant impact on the long-term health of children with NAFLD; untreated, the condition can progress to significant morbidity but, for many, may be effectively reversed with simple lifestyle modifications.^23,24 

However, there is a lack of evidence and consensus on what screening practices should be implemented, and how.^18,23–27 Indeed, in one survey of Dutch paediatricians involved with obesity care, the large majority of respondents reported that they lacked guidance on screening and follow up of NAFLD in children.²⁸ This combination of inconsistent guidance and clinicians’ lack of knowledge about screening strategies may be a significant barrier to the effectiveness of screening implementation.^23,28

Current NICE guidance on NAFLD recommends offering regular screening with liver ultrasound scans specifically to children (aged 1–16 years) and young people (aged 16–18 years) who do not misuse alcohol and have type 2 diabetes and/or metabolic syndrome (see Box 2 for further details).²⁵ In this context, ‘metabolic syndrome’ is defined as a group of chronic conditions, including central obesity, insulin resistance, type 2 diabetes, hypertension, and dyslipidaemia, that confer increased cardiovascular risk.²⁵ 

Uncertainty About Screening Best Practice

There is, however, no international consensus on screening. In its 2017 guideline, the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition broadly recommends screening for NAFLD with ALT testing (using gender-specific upper limits of normal) in all obese children, and in overweight children with additional risk factors, from 9–11 years.^23,24 This guidance advises against using routine ultrasound, because of its low sensitivity and specificity.²⁴ As a further contrast, the European Society for Paediatric Gastroenterology, Hepatology and Nutrition recommends screening for NAFLD in all overweight and obese children and adolescents, specifying that clinicians should use a combination of ultrasound scanning and liver function tests for this purpose.¹⁸ 

This lack of consensus is related to the scarcity of good-quality data to support a particular screening method.^23,25 The effectiveness of ALT testing, for example, is called into question by evidence that many children with signs of NAFLD on ultrasound have normal ALT levels, with other studies showing that advanced fibrosis has been well documented in children with normal liver enzyme tests.²³ It is because of this lack of evidence that both the American Association for the Study of Liver Diseases and the British Society of Gastroenterology do not recommend any one specific method of NAFLD case finding in children.^26,27 For the same reason, NICE recommends that researchers prioritise research into noninvasive tests for diagnosing NAFLD and advanced liver fibrosis in children and young people.²⁵ 

Referral of Suspected NAFLD

Once NAFLD is suspected in a child, they should be referred to a paediatric specialist in hepatology in tertiary care for further assessment and investigation.²⁵ This is the case regardless of whether the suspicion follows the investigation of symptoms or an incidental finding of abnormal ultrasound or ALT.²⁵

Diagnosis, Clinical Assessment, and Investigation

Following referral, the receiving clinician will exclude other primary causes of fatty deposition in the liver.^23–25 Once a definitive diagnosis of NAFLD has been made, ongoing investigations will focus on establishing the severity of the condition, in particular the presence or absence of liver fibrosis.^23,25

Options for noninvasive testing include the Enhanced Liver Fibrosis (ELF) test²⁵ and magnetic resonance spectroscopy,²³ with further investigations including transient elastography and, if indicated, liver biopsy, which remains the gold-standard diagnostic test in children.^16,23,24 In June 2023, NICE recommended Fibroscan^®, a transient elastography device, for assessing liver fibrosis and cirrhosis in primary and community care settings where it would be used effectively, with the intention of increasing early detection of liver disease and reducing health inequalities.²⁹ Although this guidance does not mention children, and current roll-out initiatives in the UK are focused on adults,³⁰ some secondary and tertiary providers in the UK are introducing Fibroscanning for children as an alternative to more invasive testing.^31,32

Alternative adult-based scoring systems for the identification of fibrosis in NAFLD, such as the Fibrosis-4 index and the NAFLD Fibrosis Score, have not been found to have acceptable parameters when applied to children, and the ELF test has only been assessed in a limited capacity.^5,16,25

Management

The intention of NAFLD management in children is to reduce the burden of disease and improve patients’ long-term outcomes.²³ Treatment is generally considered effective if a patient experiences a reduction in liver fat content and hepatocyte inflammation, and a regression of fibrosis.^23,24 Management takes two main forms: lifestyle modification and pharmacotherapy.

Lifestyle Modification

First and foremost, NICE recommends offering advice on physical activity and diet to all people with NAFLD who are overweight or obese, also suggesting that clinicians consider lifestyle interventions for all people with NAFLD regardless of their body mass index (BMI).^25,33 Indeed, healthier eating and increased physical activity—with a view to losing weight—are the most commonly recommended treatments for fatty liver disease in children, and are considered the mainstay of management.^5,23,25 Evidence indicates that weight loss of 10% or greater is effective in the management of NAFLD in adults,⁵ with weight loss of 7–10% even reversing NAFLD in many children.⁸

However, the degree of weight loss to recommend in children with NAFLD necessary to achieve biochemical and histological improvement has not yet been properly established, nor has a specific dietary intervention.¹⁶ Some children may only need to maintain their weight as they grow taller instead of losing weight, thus decreasing their BMI over time.¹⁶

Research has indicated that a low-added-sugar diet may be effective as a primary treatment recommendation for children with NAFLD.³⁴ Other studies have suggested that a Mediterranean-type diet may be particularly effective for young people with fatty liver.³⁵

Pharmacological Approaches

The development of pharmacological approaches for the treatment of NAFLD, and especially NASH, is an active area of research in both adults and children.^24,25,36 However, as yet, no treatments have been licensed.²⁵

One potential pharmacological approach has been to prevent liver cell death using antioxidants, such as vitamin E.^5,23 This therapy is supported by the results of the Treatment of NAFLD in Children (TONIC) trial: although the trial found that neither metformin nor vitamin E was superior to placebo for improving ALT level or liver histology in children aged 8–17 years with biopsy-proven NAFLD, daily vitamin E (800 IU) was determined to be associated with greater resolution of NASH when compared with placebo.³⁷ 

In line with this evidence, current NICE guidance on NAFLD recommends considering vitamin E treatment for children (aged 1–16 years) with advanced liver fibrosis in tertiary care settings only; for young people (aged 16–18 years) with advanced liver fibrosis, vitamin E can be considered in secondary or tertiary care settings.²⁵ These recommendations are off label, and are made regardless of the presence of diabetes.^25,38

Although pioglitazone is being considered as a potential therapy for NAFLD in adults and is recommended in NICE guidance in certain circumstances, it is not indicated in children because of its side effects, including weight gain and worsening of cardiac failure.^23,25,39 Other pharmacological approaches currently under investigation include targeting:^5,23

• metabolic factors with glucagon-like peptide-1 receptor agonists, such as liraglutide
• profibrotic pathways with lysyl oxidase homolog 2 inhibitors, such as simtuzumab
• the gut–liver axis with fibroblast growth factor-19 agonists, such as NGM282
• inflammatory processes with CC chemokine receptors type-2 and -5 inhibitors, such as cenicriviroc.

Metformin has also been studied for the management of NAFLD in children, including as part of the TONIC trial, but further research is required before it can be recommended.^23,24,37,40 Other researchers are investigating the role of the gut biome and probiotics in managing the condition.^5,23,41

Bariatric Surgery

Although bariatric surgery is not recommended as a treatment for paediatric NAFLD, it may be considered in exceptional circumstances for severely obese children and young people with advanced NAFLD who are near physiological maturity and have other serious comorbidities, such as type 2 diabetes, idiopathic intracranial hypertension, or debilitating sleep apnoea.^23,33 NICE’s guidance on bariatric surgery in obesity identifies NAFLD as a condition that can be improved after bariatric surgery.³³

Summary

Paediatric NAFLD is a growing concern for healthcare practitioners, but a dearth of conclusive evidence has led to guidance that is often frustratingly vague. It is to be hoped that ongoing research will help to clarify this confusion. In the meantime, practitioners can still help to lower patients’ risk of progression to liver inflammation and fibrosis by engaging in effective case finding and referral, and management through the promotion of lifestyle change.