When a secondary form of pediatric non-alcoholic fatty liver disease should be suspected?

1. Introduction

Non-Alcoholic Fatty liver disease (NAFLD) is a multifactorial disorder – encompassing a wide spectrum of liver disorders, from simple steatosis to steatohepatitis (NASH), and ultimately fibrosis and cirrhosis – that has become not only the most common cause of abnormal liver function tests but also the major cause of chronic liver disease in pediatrics [1,2]. On the basis of its close association with the development of both cirrhosis and cardiometabolic impairments in adulthood, it represents a major health concern [2].

Currently, epidemiological data indicate that NAFLD affects approximately 3–11% of the general pediatric population and involves about 46% of overweight and obese children and adolescents [1–3]. The role of environmental and genetic factors has been well recognized in its complex pathophysiology. At the present time, the classical ‘two hits hypothesis’ needs to be updated. Indeed, recent studies suggest ‘multiple hits hypothesis’, which involve not only genetics (e.g. patatin like phospholipase containing domain 3 gene-PNPLA3-, G-protein – coupled – receptor-,GPR120-,transmembrane 6 superfamily member 2 gene-TM6SF2-, membrane-bound O-acyltransferase domain containing protein 7-MBOAT7-variants) [3–6] but also others factors such as lipotoxicity and gut microbiota [4–8].

Presence of liver steatosis is a cornerstone to the diagnosis of NAFLD and care should be taken to exclude conditions masquerading as fatty liver (e.g. autoimmune hepatitis, genetic, congenital conditions) [2]. Besides primary NAFLD–closely related to visceral obesity and insulin–resistance and highly associated with metabolic impairments-, there are various secondary forms of NAFLD (due to systemic, congenital or metabolic causes) requiring high attention by pediatricians because of in some case a correct diagnosis might be life-saving [3–11]. In fact, these forms might reveal several important liver diseases needing a major effort in early identification, management and – if possible – treatment.

Therefore, children with steatosis require careful evaluation to rule out potential secondary forms to other conditions (e.g. Wilsons’ disease) needing specific treatments.

To date, best practices in the management of pediatric NAFLD are not clearly elucidated.

1.1. Methods

A PubMed database search was conducted, using ‘NAFLD’, ‘secondary’, ‘children’, ‘'diagnosis' search terms from 2006 to 2018.

2. Clinical characteristics of primary NAFLD

Obesity is the most important risk factor for NAFLD [2,10,11]. This condition, in fact, is closely related to central obesity with insulin resistance and additional factors (e.g. oxidative stress, lipotoxicity), enhancing inflammatory activity, that lead to steatohepatitis [2]. As in adulthood, NAFLD in childhood is associated with an increased cardiometabolic risk. Given that, all NAFLD patients should be assessed for cardiovascular risk [2,10].

Primary NAFLD – that emerging as the hepatic component of the MetS in absence of other underlying diagnoses– typically occurs in overweight or obese children aged >10 years, although in these patients NAFLD may appear in preschool age (2–6 years) [2,12].

Natural history is generally asymptomatic, but patients occasionally present non-specific abdominal pain, malaise, and fatigue. However, the most common clinical findings are hepatomegaly and Acanthosis Nigricans, but physical examination usually only highlights central adiposity [3,9,13]. Particularly, recent data highlight the predictive role of W/H ratio -a useful clinical tool reflecting abdominal fat depots closely related to cardiometabolic consequences of obesity – not only for hepatic steatosis diagnosis but also for disease progression [13–15]. The presence of other cardiometabolic impairments – such as hypertension, hyperglycemia, hyperinsulinemia or dyslipidemia- increased transaminase levels, and ultrasound appearance of ‘bright liver’ also supported a primary NAFLD form. Improvement after weight loss confirms the diagnosis of liver disease obesity-related [11,13].

The most recent NASPGHAN NAFLD screening guidelines indicate alanine aminotransferase (ALT) levels as the best screening, while the routine liver ultrasound is not recommended because of its low sensitivity and specificity in detecting steatosis [13]. In fact, ALT screening represents an inexpensive, universally available, minimally invasive blood test with an acceptable sensitivity [13].

Children with persistently (>3 months) high ALT levels – more than twice the gender-specific upper limit of normality (22 U/L for girls and 26 U/L for boys) – should be evaluated for NAFLD or other causes of chronic liver disease [13–15]. NAFLD screening tests are also recommended in all obese children and in subjects aged 9–11 years, with overweight and additional risk factors such as clinical signs of insulin – resistance [13,15–17].

3. Clinical characteristics of secondary NAFLD

A NAFLD secondary form should be suspected in non-obese children (mostly aged<10 years) with elevated ALT (>2× upper normal limit) or persistently (>6 months) increased levels after a period of lifestyle intervention (at least 6 months), and clinical or ultrasonographic evidence of splenomegaly. In fact, ‘lean’ pediatric NAFLD is more likely to underlie secondary causes for hepatic steatosis or NAFLD-associated polymorphisms, whereas, in very lean children presenting severe insulin resistance, a diagnosis of lipodystrophy should be considered [2,9,13–15].

Several conditions characterized by the presence of fatty liver and/or hypertransaminasemia might mimic NAFLD, requiring more attention from caregivers because of its higher potential meaning of significant liver disease [10,17]. In fact, recent findings showed that liver diseases other than NAFLD were detected in 18% of children referred from primary care for suspected NAFLD [17]. In particular, autoimmune hepatitis was the most common alternative diagnosis, followed – in a minor percentage – by other forms of hepatitis included drug-induced (e.g. ariprazole, cetirizine, isotretinoin, minocycline and valproic acid), eosinophilic, granulomatous, idiopathic, viral (HBV-Hepatitis B Virus – and HCV-Hepatitis C Virus), secondary to alcohol abuse, associated with herbal supplement and associated with asymptomatic colitis [2,17].

Other alternative diagnoses of fatty liver disease are multiple secondary forms, due to genetic or congenital conditions (e.g. cystic fibrosis, hemochromatosis, Prader Willi syndrome, Bardet-Biedl syndrome, lipodystrophy and other rare insulin-resistance syndromes), nutritional causes (e.g. total parenteral nutrition, rapid weight loss) and other such as alcohol consumption, Obstructive Sleep Apnea Syndrome (OSAS), hypothyroidism or conditions likely associated to obesity-related NAFLD such as Polycystic Ovary syndrome (PCOS) [2,9–11,17].

Particularly, NAFLD is rare in children aged <10 years and extremely rare in those aged <3 years, although the presence of obesity and its main features (e.g. clinical and laboratory signs of insulin-resistance, sedentary lifestyle, family history of NAFLD or type 2 diabetes mellitus) may suggest NAFLD [11].

To exclude a secondary form of NAFLD, screening for common other causes of abnormal liver function is needed [9,13,15,17]. Basic tests include full blood count to assess for anaemia and evidence of splenic sequestration related to portal hypertension, hepatic panel (transaminase levels, albumin, bilirubin, gamma-glutamyl transferase, alkaline phosphatase, total proteins) to assess the chronicity and nature of aminotransferase elevation, urea and electrolytes and coagulation panel to reveal hepatic synthetic function [2,9,16]. Evaluation of hepatic (serum Ig and liver autoantibodies, viral serology – HBV, HCV, Cytomegalovirus (CMV), Epstein Barr Virus (EBV)-, alfa-1- antitrypsin level, serum ceruloplasmin, serum copper level, ferritin), endocrine (TSH, free T4), autoimmune (total IgG and tissue transglutaminase antibody, anti-nuclear antibody, anti-smooth muscle antibody, anti-liver cytosol 1 kidney microsomal antibody), and genetic (ceruloplasmin and/or 24-h urine copper, lysosomal acid lipase, alpha-1 antitrypsin phenotype, serum fasting insulin) etiologies are required. Ultrasound scan of liver, spleen and portal vein to rule out anatomical abnormalities or evaluate the degree of portal hypertension is also needed [2,9,11,17]. Further instrumental tests are magnetic resonance imaging (assessment of hepatic fat) and liver biopsy (evaluation of histology, copper, microvesicular fat, and fibrosis) [11,15]. Given its peculiarities (noninvasive, non-irradiating), magnetic resonance appears as a useful method in pediatrics, although at present is not applicable for a screening program [18]. Moreover, evidence showed the superiority of magnetic resonance (MRI) and MRI spectroscopy (MRS) in the quantitative evaluation of fat content [10,11]. In case of inconclusiveness of previous investigations, liver biopsy should be considered. In fact, it represents the gold standard for diagnosis in patients with fatty liver, given its ability to distinguish NAFLD from NASH and to identify other steatotic liver diseases [10,11]. To date, there is no consensus for indications for liver biopsy in pediatrics. It could be kept in mind that it is an expensive and invasive technique so that it should be considered with caution in children. Given that liver biopsy should be considered to assess NAFLD in children at increased risk of NASH and/or advanced fibrosis suggested by higher ALT (>80 U/L), splenomegaly, and AST/ALT ratio >1, or the presence of panhypopituitarism and type 2 diabetes [13].

However, alternative noninvasive markers, scoring systems, and ‘liquid biopsies’ are available to characterize NAFLD patients [19].

Thus, children with raised ALT levels should be screened for common condition of NAFLD and – if indicated by clinical and laboratory findings – tested for specialist diagnosis [9,15].

4. Conclusions

The potential clinical burden of NAFLD in childhood imposes an accurate evaluation by clinicians. Primary NAFLD has been recognized as part of the metabolic syndrome, in absence of other underlying diagnoses. Instead, secondary NAFLD represents a major concern, because of its need to rule out other multiple causes (e.g., metabolic, systemic or congenital) and, then, the lack of a standardized diagnostic workup. The lack of obesity, age < 10yr and persistently (>3 months) high ALT levels (more than twice the upper gender-specific limit of normality) or persistently (> 6 months) increased levels after 6 months of lifestyle intervention, and clinical or ultrasonographic evidence of splenomegaly should always raise the suspect of a secondary NAFLD.

In view of the potential identification of other clinically relevant liver diseases, an adequate screening for children with secondary NAFLD is thus required.

5. Expert opinion

Non-Alcoholic Fatty Liver Disease (NAFLD) represents the major cause of chronic liver disease in childhood. Given its close association with cardiometabolic impairments, it has become a major health concern. Despite primary NAFLD, considered as a part of the metabolic syndrome in absence of other underlying causes, diagnosis of secondary forms of NAFLD may represent a challenge for pediatricians. Children with steatosis need to be carefully evaluated to rule out potential liver diseases.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.