Μη αλκοολική λιπώδης διήθηση του ήπατος σε παιδιά Non-Alcoholic Fatty Liver Disease in Children

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1 ηµήτρης Παπανδρέου PhD, MS, RD. Ι ΑΚΤΩΡ ΙΑΤΡΙΚΗΣ Α.Π.Θ Μη αλκοολική λιπώδης διήθηση του ήπατος σε παιδιά Non-Alcoholic Fatty Liver Disease in Children Papandreou Dimitrios*, Rousso Israel and Mavromichalis Ioannis 2nd Department of Pediatrics, Aristotle University of Thessaloniki, School of Medicine, Greece Περίληψη: Σκοπός αυτής της ανασκόπησης είναι να παρουσιάσει συγκεντρωτικά όλα όσα είναι γνωστά σχετικά µε την παιδική ασθένεια «µη αλκοολική λιπώδης διήθηση του ήπατος» (NAFLD) σε ό,τι αφορά την παθογένεση, την διάγνωση, την ιστολογία και την θεραπεία. Η ασθένεια NAFLD όλο και περισσότερο αναγνωρίζεται ως σηµαντικός κίνδυνιε για την υγεία των παχύσαρκων παιδιών. Η NAFLD καλύπτει ένα φάσµα που ποικίλει από την λιπώδη διήθηση του ήπατος (στεάτωση), η οποία µπορεί να οδηγήσει σε λιπώδη διήθηση µε φλεγµονή γνωστή ως στεατοηπατίτιδα ή σε µη αλκοολική στεατοηπατίτιδα (NASH) που χαρακτηρίζεται από την πιθανή εξέλιξή της σε ίνωση, κύρωση και ασθένεια του ήπατος τελικής µορφής. Η NASH σχετίζεται µε την παχυσαρκία, τον διαβήτη, την ανθεκτικότητα στην ινσουλίνη και την υπερτρι-. γλυκεριδαιµία. Ενώ η πλειοψηφία των ατόµων µε παχυσαρκία και ανθεκτικότητα ινσουλίνης (IR) έχουν στεάτωση, µόνο µία µειοψηφία αναπτύσσουν στεατοηπατίτιδα. Παρότι η στεάτωση αποτελεί αναπόσπαστο στοιχείο του ορισµού της NAFLD σε ενήλικες και παιδιά, συχνά εµφανίζονται σηµαντικές διαφορές σε ό,τι αφορά το εύρος ή εναπόθεση του λίπους, την φλεγµονή και την ίνωση. Επιβεβαίωση της διάγνωσης της NAFLD µπορεί να γίνει συνήθως µε έρευνες εικόνας. Παρόλα αυτά για την επιβεβαίωση της ασθένειας χρειάζεται βιοψία ήπατος. Οι εφαρµοζόµενες θεραπείες βασίζονται στην απώλεια βάρους και την άσκηση ενώ διάφορες φαρµακευτικές αγωγές για ευαισθητοποίηση της ινσουλίνης δείχνουν να υπόσχονται πολλά. Keywords: Children, obesity, liver disease, non-alcoholic fatty liver, steatohepatitis. INTRODUCTION Hepatic steatosis is termed non-alcoholic fatty liver disease (NAFLD) not because of excessive alcohol consumption and is usually associated with insulin resistance and features of the metabolic

2 syndrome [1]. Less commonly,nafld may be as a result of secondary causes such as medications (e.g. cortico-steroids, methotrexate, amiodarone, tamoxifen), nutritional causes such as rapid weight loss or total parental nutrition or metabolic diseases such as lipodystrophy or dysbetalipoproteinaemia. Histologically, NAFLD may manifest as bland hepatic steatosis or may be accompanied by hepatocellular damage plus inflammation and/or fibrosis, which is termed nonalcoholic steatohepatitis (NASH) [2]. Correspondingly, NAFLD may present as a spectrum of diseases from asymptomatic steatosis with or without elevated liver aminotransaminases, or as cirrhosis with complications of liver failure and hepatocellular carcinoma. EPIDEMIOLOGY NAFLD is very common in the general population and may affect any age and ethnic group. One third (33%) of the adult general population has excessive fat accumulation in the liver [3]. This alarming prevalence of NAFLD is most likely as a result of the increasing prevalence of obesity. Obesity has emerged as a significant new health problem in the pediatric population. According to data from the National Health and Nutrition Examination Survey (NHANES) 14% to 16% of children between the ages of 6 and 19 years are obese. According to Ogden et al. [4], 30% of children aged 12 to 19 years old are overweight, defined as those greater than or equal to the age- and genderdetermined 85th percentile relative to historic norm. Extrapolation of changes over the past 40 years demonstrates that the prevalence is continuing to rise at a steady rate. Obesity is strongly associated with NAFLD [4]. More than 85% of children with NAFLD are obese. The overall prevalence of NAFLD in children is 2.6% but increases up to 53% in obese children [5,6]. Bergomi et al. [7] studied 175 obese children and found that 55% of the subject had elevated liver echogenicity. In this study, 15% of the patients had both liver echogenicity and elevated alanine aminotransferase (ALT). Studies have showed that 24-25% of children referred to obesity centers have elevated ALT [5,8]. Strauss et al. [9], studied the children/adolescents enrolled in the NHANES study and reported a low prevalence of 6% in overweight and 10% in obese adolescents with elevated ALT. Hsiao et al. [10] examined 210 obese children and found that 80% of them had fatty liver. Kinugasa et al. [8] found that of 299 obese Japanese children, 36 children (12%) exhibited elevated serum ALT. Of these 36 children, 11 underwent percutaneous liver biopsy, and all 11 demonstrated fatty liver. Three of the 11 had simple steatosis, one had cirrhosis, and the remaining had fatty liver with inflammation with and without fibrosis. Vajro et al. [11] evaluated 288 obese Italian children, of whom 10% had elevated aminotrans-ferase, and Tazawa et al. [12] found elevated ALT in 25% of 310 obese Japanese children. In another study in China [13], of 84 obese children, 65 children (77%) had hepatic steatosis. Apart from obesity, NASH is also connected to diabetes. A recent review concluded that up to a third of adults have diabetes or fasting hyperglycemia at the time of NASH diagnosis [14]. The coexistence of obesity and diabetes is likely to be additive in a study of severely obese diabetic adults, 98% had some degree of steatosis, 50% had steatohepatitis and 19 % had cirrhosis [15]. Review from reports from North America [16-18], Asia [8] and Australia [19] demonstrate a narrow mean age of presentation ranging from 11.6 to 13.5 years. In all reported studies, boys outnumbered girls, usually in a 2:1 ratio. NASH is reported in all races and ethnicities, but evidence supports that certain groups are at increased risk.

3 Hispanics are more likely than other ethnicities to have fatty liver on biopsy, even after correction for the degree of obesity [20]. PATHOGENESIS The pathogenesis of nonalcoholic fatty liver disease is partially understood. Steatosis reflects the net retention of lipids within hepatocytes. This results from an imbalance between the uptake and synthesis of fatty acids and their oxidation and export. Angulo [21] has described these mechanisms in detail. The most consistent pathogenic factor is insulin resistance, leading to enhanced lipolysis, which, in turn, increases circulating free fatty acids [22]. Hyperinsulinaemia and hyperglycaemia also promote de novo lipogenesis by up-regulating lipogenic transcription factors such as sterol regulatory binding protein-1c (SREBP-1c) and carbohydrate response element binding protein [23,24]. This increase in fatty acids overloads the mitochondrial β- oxidation system, and fatty acids accumulate in the liver. Fatty acids induce the cytochrome P450 4A and 2E1 isoenzymes-lypoxygenases that can generate free oxygen radicals [25]. These reactive oxygen species promote disease progression by both lipid peroxidation and cytokine induction [26]. Lipid peroxidation leads to the release of malondialdehyde and 4-hydroxyn-onenal which causes cell death and protein cross-linkage, resulting in the formation of Mallory s hyaline in the hepatocyte [27]. They also activate stellate cells, which leads to collagen synthesis and fibrosis [28]. Cytokine induction promotes inflammation [29]. Taken all together, these are the characteristic histologic features of nonal-coholic fatty liver disease. DIAGNOSIS Elevation of the hepatic enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are predictors of the presence of NAFLD and NASH, although significant liver disease can exist with levels of these transaminases in the normal range. Individual serum ALT, ranges from slightly over the upper limit of normal to 10 times more [16-19]. The degree of elevation of serum aminotransferase concentration, therefore, may have little pediatric value and may not distinguish between steatosis and steatohepatitis. Thus, apart from measuring the liver enzymes, serum triglyceride and markers of IR need to be assessed. As NASH is a diagnosis of exclusion, other causes of chronic liver disease, for example, metabolic diseases including Wilson disease, α-1 antitrypsin deficiency, viral hepatitis and drug/ alcohol ingestion must be excluded. Conditions mimicking NAFLD histologically may be excluded by careful history, physical and laboratory evaluations. In Table 1 are some alternative etiologies exhibiting steatosis or steatohepatitis. Imaging studies such as ultrasound, computed tomography and magnetic resonance imaging are accurate for detecting mode-rate to severe hepatic steatosis. The sensitivity and specificity of ultrasound for detecting > 33% steatosis is between 60-94% and 88-95% respectively, although falls with increasing BMI to 49 and 75% respectively, among morbidly obese individuals [30].

4 While hepatic ultrasound or MRI can detect a fatty liver and NAFLD, they provide little or no information on the presence or degree of fibrosis or cirrhosis. The identification of an accurate noninvasive or blood marker for NASH is the subject of intense research. Yet, at present liver biopsy is the only means to distinguish between steatosis and steatohepatitis, fibrosis or cirrhosis. A recent study showed that while severity of hepatic steatosis can be accurately detected radiologically when there is moderate of severe (>33%) fatty infiltration of the liver documented by a liver biopsy, radiological modalities (US, CT, and MRI) were unable to detect or characterize NASH or distinguish it from steatosis alone [31]. Liver biopsy is able to stage the disease. In addition, histological evaluation can be useful to exclude other liver disease [32-33]. HISTOLOGY Histological confirmation of NAFLD requires a minimum of 5 % steatosis. The histologic features of steatohepatitis, which include steatosis, inflammation, ballooning hepatocyte necrosis, Mallory s hyaline and fibrosis are indistinguishable from those of alcoholic liver disease. The histological distinction between NASH and simple steatosis is controversial; a recent consensus conference defined NASH as steatosis with hepatocellular ballooning plus lobular inflammation [2], although steatosis in conjunction with typical peri-cellular/peri-sinusoidal fibrosis is also considered as NASH despite of the absence of inflammatory features. Brunt et al. [34] suggested a system for grading and staging NASH. It is a system of grading from 1 to 3 depending on the degree of steatosis and/or inflammation and staging from 1 to 4 depending on the extend of fibrosis. Schwimmer et al. [35], has described two types of NASH, pediatric and adult, based on histologic features found in liver biopsies (Table 2).

5 TREATMENT Diet NASH is the tale of two hits. The first hit is fatty infiltration of the liver and the second is the oxidative stress [36]. Fatty infiltration of the liver is due to obesity and concomitant insulin resistance. In order to treat NASH, one of the things that should be treated is obesity. The key principle of obesity therapy is a well-balanced diet. Slow, consistent weight loss has been shown to be effective in childhood NAFLD, based on improvement of serum aminotransferases or liver sonogram [11,37]. Franzese et al. [5] treated Italian obese children with echogenic liver on ultrasound with caloric restriction for 2 to 6 months. Vajro et al. [11] have done the same thing to Italian obese children with elevated ALT. He found that all seven children normalized their ALT and demonstrated diminished bright liver on ultrasound after significant weight reduction. Franzese et al. [5] found that from 28 patients the liver echogenity resolved (N=24) or improved (N=4) with weight loss. The rate and degree of weight loss required for normalization of liver histology has not been established. A low glycemic index diet has been shown to be more effective than a low fat diet in lowering BMI [38]. On the other hand, very rapid weight loss associated with very low calorie diets (<500 kcal per day) can worsen hepatic inflammation and fibrosis [39]. Apart from diet, exercise improves liver biochemistry and hepatic steatosis. Drugs Another approach to decreasing hepatic injury through reduction in steatosis is treatment with insulin-sensitizing agents. Treatments strategies for NAFLD aim to prove insulin sensitivity and modify underlying metabolic risk factors. Metformin, reduces hyperinsulinemia and improves hepatic IR. It has been shown to reverse fatty liver in obese, leptin deficient mice [40], and has been used in the treatment of NASH in adults, who demonstrated significant reduction in serum ALT after 4 months of therapy [41]. Several others pharmacological agents have been used in order to treat NASH. Ursodeoxycholic acid (UDCA) at a dose of mg/kg/day has been shown to improve liver

6 biochemistry in NASH[42-44]. Another pharmacological agent used to treat NASH by reducing the oxidative stress is vitamin E. Vitamin E is a potent antioxidant, particularly effective against membrane lipid peroxidation. One open-label pediatric trial treated 11 obese children with elevated ALT and echogenic liver with oral vitamin E in doses ranging from 400 to 1200 units per day. After 2 to 4 months, all patients normalized the ALT, although continuation of vitamin E was necessary to retain the effect [45]. Finally, on the contrary, Vajro et al. [46] in a recent study examined the effects of vitamin E and weight loss in 28 children. Only weight loss reduced transaminases in all children while in the group treated with vitamin E, five of them had unchanged transaminases values and two had increased. N-acetylcysteine, a glutathione pro-drug, which is thought to protect the liver against oxidative stress, has shown improvement in transaminases when given to patients with NASH [47-48]. Finally, liver transplantation may be required for patients with decompensated cirrhosis or liver cancer. CONCLUSION NAFLD in children will continue to increase especially where the incidence of obesity is rising. Differential diagnosis may be required for the stage of the disease. Diet and exercise most likely will reduce NAFLD and obesity rates. Further studies are required to identify drug agents (Vit E, UDCA) that may help NAFLD subjects as well as to identify patients that will benefit the most of it. REFERENCES [1] Loria P, Lonardo A, Carruli L, et al. Review article: the metabolic syndrome and non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2005; 22(Supp2) : [2] Neuschawander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD single topic conference. Hepatology 2003; 37: [3] Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40: [4] Ogden CL, Flegal KM, Carroll MD, Johnson CL. Prevalence and trends in overweight among US children and adolescents. JAMA 2002; 288(14): [5] Franzese A, Vajro P, Argenziano A, et al. Liver involvement in obese children. Ultrasonography and liver enzyme levels at diagnosis and during follow up in an Italian population. Dig Dis Sci 1997; 42: [6] Tominaga K, Kurata JH, Chen YK, et al. Prevalence of fatty liver in Japanese children and relationship to obesity. An epidemiological ultrasonographic survey. Dig Dis Sci 1995; 40: [7] Bergomi A, Lughetti L, Corciulo N. Italian multicenter study on liver damage in pediatric obesity.

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10 disease: a randomized study. J Pediatr Gastroenterol. Nutr 2004; 38(1): [47] Angulo P, Lindor KD. Treatment of non-alcoholic steatohepatitis. Best Pract Res Clin Gastroenterol 2002; 16(5): [48] Pamuk GE, Sonsuz A. N-acetylcysteine in the treatment of nonalcoholic steatohepatitis. J Gastroenterol Hepatol 2003; 18(10): Τα κείµενα, τα στοιχεία και οι πληροφορίες του περιοδικού (newsletter) προσφέρονται µόνο για ενηµέρωση και προσωπική χρήση των αναγνωστών του και αποτελούν πνευµατική ιδιοκτησία της εταιρίας και των συγγραφέων τους. Απαγορεύεται η αναδηµοσίευση, αναδιανοµή, ανατύπωση και καθ' οποιονδήποτε τρόπο εκµετάλλευση των κειµένων, των πληροφοριών και των στοιχείων του περιοδικού (newsletter). Οι πληροφορίες και τα στοιχεία του περιοδικού εκφράζουν τις προσωπικές απόψεις των συγγραφέων, δεν αποτελούν υπόδειξη ιατρικής αγωγής ή θεραπείας και δεν υποκαθιστούν την επαγγελµατική ιατρική συµβουλή. Η επιλογή και χρήση των στοιχείων και των πληροφοριών του περιοδικού και τα εξ' αυτής αποτελέσµατα, γίνεται µε αποκλειστική ευθύνη του αναγνώστη. Η εταιρία SCIENCE TECHNOLOGIES, ο εκδότης και ο επιστηµονικός υπεύθυνος του Newsletter δεν φέρουν καµία οικονοµική ή ηθική ευθύνη για τα γραφόµενα ή για τις επιπτώσεις από τα γραφόµενα στο έντυπο αυτό. Οι συγγραφείς φέρουν την πλήρη ευθύνη των γραφόµενων στα κείµενά τους και η υποβολή κειµένων προς δηµοσίευση στο Newsletter σηµ αίνει ταυτόχρονη αποδοχή των παραπάνω όρων. Η ανάγνωση των κειµένων συνεπάγεται την αποδοχή των παραπάνω όρων. Copyright Science Technologies - All Rights Reserved