Is liver transaminases assessment an appropriate tool for the screening of non-alcoholic fatty liver disease in at risk obese children and adolescents?

¿Es útil la valoración de las transaminasas hepáticas para el screening del hígado graso no alcohólico en niños y adolescentes obesos?

G. Rodríguez^1,2, S. Gallego³, C. Breidenassel⁴, L. A. Moreno⁵ y F. Gottrand⁶

¹"Growth, Exercise, Nutrition and Development" (GENUD) Research Group. Dpto de Pediatría, Radiología y Medicina Física, University of Zaragoza; and Hospital Clínico Universitario 'Lozano Blesa'. Zaragoza (Spain).
²Instituto Aragonés de Ciencias de la Salud (Spain).
³Servicio de Pediatría Hospital Ernest Lluch de Calatayud. Zaragoza (Spain). ]]> ⁴Institut für Ernährungs- und Lebensmittelwissenschaften - Ernährungphysiologie. Rheinische Friedrich Wilhelms Universität (Germany).
⁵"Growth, Exercise, Nutrition and Development" (GENUD) Research Group. EU. Ciencias de la Salud, University of Zaragoza (Spain).
⁶Unité de Gastroentérologie, Hépatologie et Nutrition, Clinique de Pédiatrie, Hôpital Jeanne de Flandre. EA3925, IFR114, Faculté de médecine, université Lille², Lille (France)

Correspondence

RESUMEN

La prevalencia de obesidad en niños ha aumentado considerablemente en todo el mundo y el hígado graso no alcohólico (HGNA) es una de las complicaciones más frecuentemente asociadas al exceso de adiposidad. El HGNA provoca elevación de las transaminasas hepáticas y una alteración hepática que pueden desencadenar fibrosis, cirrosis e incluso malignización. El HGNA aparece asociado a las complicaciones metabólicas de la obesidad, sobre todo a la resistencia a la insulina. El objetivo del presente artículo es revisar el rol que tienen las enzimas hepáticas como predictor no invasivo del HGNA en niños. Aunque la elevación de las enzimas hepáticas no valora con exactitud el daño hepático, pueden suponer un test no invasivo para el screening del HGNA en niños y adolescentes y un marcador de su evolución. Las transaminasas hepáticas deben ser determinadas de rutina en el diagnóstico del HGNA en niños y adolescentes. En este sentido, parece necesario encontrar unos estándares de referencia para los niveles de transaminasas en niños y adolescentes.

Palabras clave: Transaminasas. Síndrome metabólico. Obesidad. Hígado graso no alcohólico.

ABSTRACT

Key words: Transaminases. Metabolic syndrome. Obesity. Nonalcoholic fatty liver disease.

Introduction

The prevalence of childhood obesity has increased dramatically all over the world during the last decades. The rising incidence of obesity in today's environment is associated with many obesity-related health complications, including cardiovascular diseases, diabetes, hyperlipidemia, hypertension, and nonalcoholic fatty liver disease (NAFLD)^1-3. In Europe the combined prevalence of childhood overweight and obesity is higher than 30% in countries such as Spain, Italy or Portugal; and about 20% in many other countries^4,5. These trends are continuously increasing and, as it is well known, 'obesity epidemic' extends beyond Europe. However, a levelling-off of the obesity prevalence with reverse trends towards increasing childhood overweight have recently reported in the US, France or Sweden^6-8. Despite these findings, overweight and obesity among children need to be considered as a global problem.

The increase in the prevalence of obesity is often related to a rise in obesity comorbidities, both during childhood and in adult age, because of its early onset and longer duration. Despite the fact that overweight has become a serious problem among children and teenagers, the data suggest low rates of diagnosis of overweight, obesity and related comorbidities. A high prevalence of obesity during childhood could trigger off NAFLD, that might end up in serious increases in liver related morbidity and mortality⁹.

One focus of interest in obesity research and clinical practice is the relation between obesity and the metabolic syndrome (MS), with the development of NAFLD as other consequence of this association. Obesity, especially central body fatness, is associated with dyslipidemia, hypertension, insulin resistance/hyperinsulinemia and impaired glucose tolerance/type 2 diabetes^10,11. This cluster of metabolic abnormalities that already appears in obese children and adolescents increases the risk of cardiovascular diseases¹². As well as obesity is associated with MS, fatness is also the major risk factor for NAFLD in children. There is a direct association between abdominal fat and liver fat content which is probably accounted for a general increase in visceral fat due to adiposity at this body region¹³. Studies from obese children populations report that about 35% of these children have NAFLD^3,14-16. Parallel to the increasing prevalence of obesity, NAFLD could cause end stage liver disease already during childhood and adolescence while for other complications (dyslipidemia, hypertension, type 2 diabetes) the consequences are observed mostly during adulthood.

Serum liver enzymes are routinely utilised for the assessment of cytolysis in various conditions. They are also used as markers of NAFLD in children and adolescents but many unanswered questions remain: a) Are liver transaminases able to predict and/or to diagnose NAFLD appropriately? b) Are there adequate liver enzyme cut-offs and population reference values for the screening of NAFLD? c) Are transaminases good markers of NAFLD evolution (to fibrosis/cirrhosis) d) Are transaminases a reliable tool for assessing NAFLD evolution under treatment (weight loss, drug therapy). The aim of this review is to address these questions and to try to provide the current evidence based status on these issues.

NAFLD definitions

The spectrum of NAFLD includes steatosis alone (type 1), steatosis plus inflammation (type 2), steatosis plus hepatocyte injury or ballooning degeneration (type 3), and steatosis plus sinusoidal fibrosis, Mallory bodies, or both (type 4). NASH is considered to be the most severe form of NAFLD (types 3 and 4) and is associated with an array of adverse clinical outcomes, including cirrhosis, hepatocellular carcinoma, and advanced liver disease, which can lead to liver-related death¹⁸.

NAFLD physiopathology and prevalence

Given the close relations between obesity, the MS, and the development of NAFLD, it is not surprising that many NAFLD patients have multiple components of the MS, even whether they are no overweight or obese. This fact has been recently shown also in obese children with NAFLD which are more likely (50% versus 15%) to have MS than obese children without NAFLD (Odds ratio 5.0 after multiple adjustment; 95% CI 2.6 to 9.7) (19). Insulin resistance is present as an important factor in these associations and, by itself, is a significant predictor of NAFLD and NASH in most adult patients^18,20,21, even in 10-15% of them who are not overweight²². Many studies have shown an association of insulin resistance with NAFLD and NASH on the basis of impaired glucose tolerance or impaired fasting glucose^18-22. Despite elevated insulin concentrations, adipose tissue fatty acid flux is not suppressed in NAFLD patients, which indicates the presence of peripheral insulin resistance²³. However, the association between NAFLD and obesity in children seems to be independent of hyperinsulinemia in this age group¹⁹. Further studies are needed to clarify this controversial aspect in children and whether differences exits about NAFLD physiopathology between adults and children .

In most NAFLD patients, it is thought that overnutrition or inappropriate diet lead to chronic elevated plasma concentrations of glucose, insulin and free fatty acids (FFA)²⁴. Glucose uptake in the liver is not insulin dependent, and increased glucose concentrations in the blood directly lead to increased glucose uptake by the liver. Insulin-mediated stimulation of de novo lipogenesis leads to an increased conversion of glucose to fatty acids²⁵. Together, the increased concentrations of both glucose and FFA in the blood contribute to excessive accumulation of neutral lipids in the liver and subsequent elevation of serum transaminases. It has been recently shown that fast-food-based hyperalimentation can induce a rapid and severe elevation of serum alanine transaminase in healthy subjects²⁶. In summary, NAFLD can be considered as a multifactorial disease that may involve a complex interaction of genetic, diet and lifestyle factors, all of them combined to form the NAFLD phenotype, as discussed in several recent reviews^1-3,23.

The original "two-hit hypothesis" of NASH suggests that the accumulation of lipids in the liver (hit one) is followed by a cascade of prooxidative, hepatotoxic events (hit two), which are caused by a mechanism still unknown²⁷. Elevated concentrations of circulating tumour necrosis factor (TNF) have been documented in NAFLD patients with implications in fatty liver disease physiopathology^28,29. Small intestinal bacterial overgrowth and deficiencies in various nutrients, including essential fatty acids, choline, 25-hydroxyvitamin D₃ and amino acids, may also be involved in the development and progression of this disorder; however, limited evidence exists to support these mechanisms^20,21.

In order to determine the real prevalence of NAFLD it is necessary to tackle various questions. The most important issue is that liver biopsy is required to make an appropriate diagnosis of NAFLD, although it is not well accepted in children as a diagnostic tool for NAFLD population prevalence studies. In consequence, increased serum transaminase concentrations are used for fatty liver disease screening in the majority of studies, although their sensitivity and specificity in the diagnosis of NAFLD has not yet been verified in children. Ultrasonographic techniques can also be employed for this aim, although this method is unlikely to determine the NAFLD intensity or the differences between simple steatosis and steatohepatitis. Finally, other challenge to estimate NAFLD prevalence is the choice of an adequate and representative study population³².

Nonalcoholic fatty liver is commonly associated with long-term elevations in liver enzymes such as alanine transaminase (ALT) and γ-glutamyl transferase (GGT) as useful and non invasive surrogate markers of NAFLD or liver dysfunction³³. The overall prevalence of suspected fatty liver disease as determined by elevated transaminase population data is estimated about 3-9% among children and adolescents, depending on the population background^32,34. When the sample is composed of overweigh / obese children and adolescents, the prevalence of suspected fatty liver from elevated transaminases in these groups range from 10 to 25% depending on age, gender and ethnicity^15,16,32,35. From a retrospective study conducted from autopsies performed in 742 children and adolescents age 2 to 19 years, fatty liver (defined as >5% of hepatocytes containing macrovesicular fat) was present in 13% of subjects with the highest rate in obese children (38%)³⁶. Therefore, results from NAFLD prevalence considerably varies depending on the screening method and population characteristics. NASH must be suspected if there is two- to threefold increase in transaminases levels and ultrasound liver brightness^32,33. However, formal diagnosis requires liver biopsy².

MS is very common in children affected by fatty liver disease, being observed in more than 50% of them^9,19,37. Patients with MS show levels of transaminases significantly higher than children without MS³⁸, and fibrosis and severe steatosis are frequently reported. Among comorbidities, dyslipidemia and hypertension are largely described in fatty liver disease, while insulin resistance and excessive body weight (either obesity or overweight) are almost universal findings²⁹. Manco et al⁴⁰, have shown significant histological findings in children with MS associated with clinical and biochemical variables. In this study, necroinflammation correlated positively with BMI zscore, insulin resistance, fasting glucose, total cholesterol, transaminase concentrations and white blood cell count. Fibrosis was associated with higher body weight and BMI z-score, cholesterol and triglyceride concentrations, insulin resistance, fasting insulin and insulin during the oral glucose tolerance test^40,41. Abdominal rather than generalized obesity contributes to liver fibrosis in children with NAFLD and waist circumference is the main anthropometric predictor of this association⁴². In the presence of MS, NAFLD/NASH should be investigated by repeated measurement of liver enzymes and liver ultrasounds, and it is suggested that the role and timing of liver biopsy must be evaluated in future studies⁴⁰.

Screnning and diagnosis of nafld in obese children and adolescents

Serum transaminases (alanine transaminase: ALT and aspartate transaminase: AST) play a key role in animal amino acid metabolism. Elevated levels of these enzymes are quite sensitive for liver injury indicating a high hepatocyte cell membrane permeability that let enzymes leak out into the blood stream. However, transaminases may also be elevated in other conditions. ALT is not commonly found outside the liver but AST elevation, which frequently indicates liver damage, may also be present in heart and skeletal muscle injuries. For these reasons, serum ALT has been used as a surrogate marker for fatty liver disease in population studies. High serum ALT concentrations are associated with increased hepatic fat fraction and increased intra-abdominal visceral adipose tissue, even in statistical models excluding age as a contributing factor in serum ALT variability³². Therefore, subjects with elevated serum ALT and fatty liver have more severe steatosis and higher visceral adiposity than their counterparts and, also in children, these changes are likely the result of metabolic alterations derived from insulin resistance. At the beginning of insulin resistance setting up, affected individuals have mild steatosis and normal serum ALT. As insulin resistance progresses, individuals develop severe steatosis, elevated serum ALT, and visceral adiposity^32,40. Persistent elevations of ALT and GGT over time even within the reference range have been related to MS and adverse cardiovascular risk profile in adolescents and young adults⁴³.

There are no many publications about AST or ALT population reference values and normal individual aminotransferase level variations in children and adolescents^32,44. Although there is no single standard cutoff point for abnormal high serum aminotransferase levels, the most commonly used criterion is a value of 40 U/L for both ALT and AST^32,35,44. However, many other cut-off points ranging from 30 U/L to 45 U/L have been also used to define elevated serum ALT levels in children and adolescents^32,45-47. Very recently, according to 95^th percentile levels for ALT in healthy liver disease-free children, Schwimmer et al.⁴⁸ have proposed that 25.8 U/L in boys and 22.1 U/L in girls provided better sensitivity without less specificity to reliable detect chronic liver disease. Therefore, to assess appropriately the risk of NAFLD from aminotranferase measurement, it could be of interest to update and to standardize specific serum ALT/AST values depending on age, gender or race.

Even though most patients with NAFLD have elevated transaminases, it is known that many obese children show normal transaminases together with incipient evidence of fatty liver⁴⁹. The levels of serum transaminases have been brought into question because population standards have been determined from samples that could include people with undiagnosed liver diseases such as NAFLD related to obesity³². In addition, liver biopsy, which is not well accepted for population studies in children, is required to evaluate the utility of serum transaminases level in NAFLD management⁴⁹. Therefore, the reliability and cost analysis of serum transaminases in relation with NAFLD screening have not been appropriately determined to date and data from several risk populations are not available yet. Other non-invasive markers with high sensitivity and specificity for the screening of NAFLD/NASH were not available and serum transaminases assessment represented the best choice until current new useful tools have been reported^50,51. The Enhanced Liver Fibrosis (ELF) panel of serum markers (tissue inhibitor of matrix metalloproteinase 1, hyaluronic acid and aminoterminal peptide of pro-collagen III) is a test validated recently for staging liver fibrosis also in pediatric patients with NAFLD selecting those children that require biopsy⁵⁰. Other noninvasive possibility to predict accurately liver fibrosis in children with NAFLD is FibroScan (transient elastography)⁵¹.

In order to make a precise diagnosis of NAFLD, it is necessary to exclude other chronic liver diseases, including B and C hepatitis, autoimmune hepatitis, and drug-induced liver damage. On the other hand, the coexistence of various signs in an obese subject such us elevated aminotranferases, hepatomegaly or echogenic liver, together with insulin resistance or other MS feature, may suggest NAFLD development. Nevertheless, histological evaluation continues to be the only way of estimating precisely the degree of liver steatosis, necroinflammatory lesions and fibrosis found in NASH, distinguishing NASH from simple steatosis³².

Treatment of NAFLD

To lose weight, a decrease in visceral fat, to improve insulin sensitivity and antioxidant therapy have been the approaches explored in NAFLD therapy. Several case series and uncontrolled trials have assessed the efficacy of weight loss programs in improving transaminases levels and the appearance of the liver by ultrasonography; however, there are very few published data in children showing the effect of diet and exercise on liver histology after weight loss^32,52,53. Nobili et al⁵² showed that a simple 12-month lifestyle educational program was able to improve both insulin resistance and liver disease in children with NAFLD monitored by serum levels of transaminases. Other study from the same group⁵³, which is an extension of the aforementioned study and constitutes the first biopsy-proven trial after 24 months of NAFLD lifestyle intervention, has shown that diet and physical activity modification induce weight loss and a significant improvement in liver histology (grade of steatosis, lobular inflammation and hepatocyte ballooning).

With regard to drug therapy effects, recent studies in children with biopsy-proven fatty liver disease have shown different results^41,42,53. Metformin is able to significantly improve NAFLD and ALT levels and no adverse effects have been found due to its use; in consequence, the NASH Clinical Research Network (CRN) is currently testing metformin NAFLD monotherapy in a randomised trial with children⁴⁶. Therapy with antioxidants has also been tested in children with NASH. After biopsy verification in children and adolescents, alpha-tocopherol plus ascorbic acid association during 24 months does not seem to improve the efficacy of lifestyle intervention alone⁵³. Ursodeoxycholic acid (UDCA) has also been studied as a potential therapy in adults and children with NAFLD. In obese children with increased serum transaminases level and ultrasonographic images of bright liver, after lifestyle modification and/or UDCA treatment during 6 months, diet alone determined weight loss and resolved aminotranferase abnormalities and the appearance of steatosis but the addition of UDCA did not improve these results; therefore, UDCA administration seems not to be effective for the treatment of obesity-related NAFLD⁵⁴.

Final comment.

The increase in obesity prevalence observed during the last decades has come along with a consequent rise of all obesity associated comorbidities. Nowadays, NAFLD is the most common form of liver disease in children and adolescents. Right now, liver biopsy is the most appropriate tool for NAFLD diagnosis and classification but, although biopsy is recommended when obesity-related liver disease is suspected, it is not well accepted as a population screening criterion in all obese children. Natural history of NAFLD in obese children, liver histopathology, later evolution during adulthood and response to different treatments have to be all clarified in the future. The role of liver enzyme measurements in the screening and management of NAFLD remains to be established. Reference transaminase cut-offs in children and adolescent populations should also be determined. Currently, there are still many important questions without clear solutions about the ability of liver transaminases to predict and/or to diagnose NAFLD appropriately and when liver biopsy has to be used for this aim.

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Correspondence:
Gerardo Rodríguez.
Departamento de Pediatría, Radiología y Medicina Física.
Facultad de Medicina, Universidad de Zaragoza.
Domingo Miral, s/n.
50009 Zaragoza
E-mail: gereva@comz.org