Zusammenfassung
Die nichtalkoholische Fettlebererkrankung (NAFLD) ist heute die häufigste Lebererkrankung bei Kindern und Jugendlichen in den industrialisierten Ländern. In Deutschland sind nach aktuellen Untersuchungen bis zu 30% der adipösen Kinder und Jugendlichen von einer NAFLD betroffen. Das Spektrum der NAFLD bei Kindern und Jugendlichen reicht von der einfachen Leberverfettung (Steatosis hepatis), über die Fettleberentzündung (Steatohepatitis) bis hin zu Fibrose und Zirrhose, d. h. Funktionsverlust des Lebergewebes. Alter, Geschlecht, Ethnizität, Insulinresistenz und Sexualhormone sind wichtige Faktoren in der Pathogenese einer NAFLD bei Kindern und Jugendlichen. Die NAFLD ist zudem bereits im Kindes- und Jugendalter mit erheblicher, frühmanifester kardiovaskulärer Komorbidität assoziiert. Die vorliegende Literaturübersicht fasst aktuelle Daten zur Epidemiologie, Pathophysiologie, Komorbidität und Therapie der NAFLD im Kindes- und Jugendalter zusammen.
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in children and adolescents in industrialized countries. Recent studies have demonstrated a prevalence rate of NAFLD in overweight and obese children and adolescents in Germany of up to 30%. The spectrum of NAFLD ranges from pure fatty infiltration (simple steatosis) to inflammation (steatohepatitis, synonymous NASH) to fibrosis and cirrhosis. Age, gender, ethnicity, insulin resistance, and sex steroids are implicated in the pathogenesis of NAFLD in childhood and adolescence. Moreover, NAFLD in the pediatric age group is associated with marked cardiovascular comorbidities. This review focuses on current data regarding epidemiology, pathophysiology, comorbidities, and treatment of NAFLD in children and adolescents.
Literatur
Day CP (2011) Non-alcoholic fatty liver disease: a massive problem. Clin Med 11:176–178
Ebbeling CB, Pawlak DB, Ludwig DS (2002) Childhood obesity: public-health crisis, common sense cure. Lancet 360:473–482
Kurth BM, Schaffrath Rosario A (2007) Die Verbreitung von Übergewicht und Adipositas bei Kindern und Jugendlichen in Deutschland. Bundesgesundheitsbl Gesundheitsforsch Gesundheitsschutz 50:736–743
Wiegand S, Keller KM, Robl M et al (2010) Obese boys at increased risk for nonalcoholic liver disease: evaluation of 16,390 overweight or obese children and adolescents. Int J Obes (Lond) 34:1468–1474
Moran JR, Ghishan FK, Halter SA, Greene HL (1983) Steatohepatitis in obese children: a cause of chronic liver dysfunction. Am J Gastroenterol 78:374–377
Tominaga K, Kurata JH, Chen YK et al (1995) Prevalence of fatty liver in Japanese children and relationship to obesity. An epidemiological ultrasonographic survey. Dig Dis Sci 40:2002–2009
Park HS, Han JH, Choi KM, Kim SM (2005) Relation between elevated serum alanine aminotransferase and metabolic syndrome in Korean adolescents. Am J Clin Nutr 82:1046–1051
Schwimmer JB, Deutsch R, Kahen T et al (2006) Prevalence of fatty liver in children and adolescents. Pediatrics 118:1388–1393
Franzese A, Vajro P, Argenziano A et al (1997) Liver involvement in obese children. Ultrasonography and liver enzyme levels at diagnosis and during follow-up in an Italian population. Dig Dis Sci 42:1428–1432
Strauss RS, Barlow SE, Dietz WH (2000) Prevalence of abnormal serum aminotransferase values in overweight and obese adolescents. J Pediatr 136:727–733
Guzzaloni G, Grugni G, Minocci A et al (2000) Liver steatosis in juvenile obesity: correlations with lipid profile, hepatic biochemical parameters and glycemic and insulinemic responses to an oral glucose tolerance test. Int J Obes Relat Metab Disord 24:772–776
Chan DF, Li AM, Chu WC et al (2004) Hepatic steatosis in obese Chinese children. Int J Obes Relat Metab Disord 28:1257–1263
Burgert S, Taksali SE, Dziura J et al (2006) Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat. J Clin Endocrinol Metab 91:4287–4294
Sagi R, Reif S, Neuman G et al (2007) Nonalcoholic fatty liver disease in overweight children and adolescents. Acta Paediatr 96:1209–1213
Denzer C, Thiere D, Muche R et al (2009) Gender-specific prevalences of fatty liver in obese children and adolescents: roles of body fat distribution, sex steroids, and insulin resistance. J Clin Endocrinol Metab 94:3872–3881
Schwimmer JB, McGreal N, Deutsch R et al (2005) Influence of gender, race, and ethnicity on suspected fatty liver in obese adolescents. Pediatrics 115:e561–e565
Kleiner DE, Brunt EM, Van Natta M et al (2005) Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41:1313–1321
Schwimmer JB, Behling C, Newbury R et al (2005) Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology 42:641–649
Carter-Kent C, Brunt EM, Yerian LM et al (2011) Relations of steatosis type, grade, and zonality to histological features in pediatric nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr 52:190–197
Nobili V, Marcellini M, Devito R et al (2006) NAFLD in children: a prospective clinical-pathological study and effect of lifestyle advice. Hepatology 44:458–465
Carter-Kent C, Yerian LM, Brunt EM et al (2009) Nonalcoholic steatohepatitis in children: a multicenter clinicopathological study. Hepatology 50:1113–1120
Saverymuttu SH, Joseph AE, Maxwell JD (1986) Ultrasound scanning in the detection of hepatic fibrosis and steatosis. Br Med J (Clin Res Ed) 292:13–15
Joseph AE, Saverymuttu SH, al-Sam S et al (1991) Comparison of liver histology with ultrasonography in assessing diffuse parenchymal liver disease. Clin Radiol 43:26–31
Shannon A, Alkhouri N, Carter-Kent C et al (2011) Ultrasonographic quantitative estimation of hepatic steatosis in children With NAFLD. J Pediatr Gastroenterol Nutr 53:190–195
Fishbein M, Castro F, Cheruku S et al (2005) Hepatic MRI for fat quantitation: its relationship to fat morphology, diagnosis, and ultrasound. J Clin Gastroenterol 39:619–625
Vajro P, Lenta S, Socha P et al (2012) Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee. J Pediatr Gastroenterol Nutr 54:700–713
Rashid M, Roberts EA (2000) Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr 30:48–53
Schwimmer JB, Deutsch R, Rauch JB et al (2003) Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease. J Pediatr 143:500–505
Loomba R, Hwang SJ, O’Donnell CJ et al (2008) Parental obesity and offspring serum alanine and aspartate aminotransferase levels: the Framingham heart study. Gastroenterology 134:953–959
Schwimmer JB, Celedon MA, Lavine JE et al (2009) Heritability of nonalcoholic fatty liver disease. Gastroenterology 136:1585–1592
Romeo S, Sentinelli F, Cambuli VM et al (2010) The 148M allele of the PNPLA3 gene is associated with indices of liver damage early in life. J Hepatol 53:335–338
Santoro N, Kursawe R, D’Adamo E et al (2010) A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents. Hepatology 52:1281–1290
Santoro N, Zhang CK, Zhao H et al (2012) Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology 55:781–789
Day CP, James OF (1998) Steatohepatitis: a tale of two „hits“? Gastroenterology 114:842–845
Perseghin G (2011) Lipids in the wrong place: visceral fat and nonalcoholic steatohepatitis. Diabetes Care 34(Suppl 2):S367–S370
Cohen JC, Horton JD, Hobbs HH (2011) Human fatty liver disease: old questions and new insights. Science 332:1519–1523
Alisi A, Feldstein AE, Villani A et al (2012) Pediatric nonalcoholic fatty liver disease: a multidisciplinary approach. Nat Rev Gastroenterol Hepatol 9:152–161
Manco M, Marcellini M,Giannone G, Nobili V (2007) Correlation of serum TNF-alpha levels and histologic liver injury scores in pediatric nonalcoholic fatty liver disease. Am J Clin Pathol 127:954–960
Vos MB, Barve S, Joshi-Barve S et al (2008) Cytokeratin 18, a marker of cell death, is increased in children with suspected nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr 47:481–485
Wieckowska A, McCullough AJ, Feldstein AE (2007) Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: present and future. Hepatology 46:582–589
Nobili V, Parkes J, Bottazzo G et al (2009) Performance of ELF serum markers in predicting fibrosis stage in pediatric non-alcoholic fatty liver disease. Gastroenterology 136:160–167
Reinehr T, Roth CL (2008) Fetuin-A and its relation to metabolic syndrome and fatty liver disease in obese children before and after weight loss. J Clin Endocrinol Metab 93:4479–4485
Weyer C, Funahashi T, Tanaka S et al (2001) Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86:1930–1935
Yamauchi T, Kamon J, Minokoshi Y et al (2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 8:1288–1295
Krssak M, Petersen KF, Dresner A et al (1999) Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 42:113–116
Yamauchi T, Kamon J, Waki H et al (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946
Weiss R, Dufour S, Groszmann A et al (2003) Low adiponectin levels in adolescent obesity: a marker of increased intramyocellular lipid accumulation. J Clin Endocrinol Metab 88:2014–2018
Yokota T, Oritani K, Takahashi I et al (2000) Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 96:1723–1732
Kubota N, Terauchi Y, Yamauchi T et al (2002) Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 277:25863–25866
Bugianesi E, Pagotto U, Manini R et al (2005) Plasma adiponectin in nonalcoholic fatty liver is related to hepatic insulin resistance and hepatic fat content, not to liver disease severity. J Clin Endocrinol Metab 90:3498–3504
Vajro P, Fontanella A, Perna C et al (1994) Persistent hyperaminotransferasemia resolving after weight reduction in obese children. J Pediatr 125:239–241
Baldridge AD, Perez-Atayde AR, Graeme-Cook F et al (1995) Idiopathic steatohepatitis in childhood: a multicenter retrospective study. J Pediatr 127:700–704
Fishbein MH, Mogren C, Gleason T, Stevens WR (2006) Relationship of hepatic steatosis to adipose tissue distribution in pediatric nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr 42:83–88
Nielsen S, Guo Z, Johnson CM, Hensrud DD, Jensen MD (2004) Splanchnic lipolysis in human obesity. J Clin Invest 113:1582–1588
Despres JP, Lemieux I (2006) Abdominal obesity and metabolic syndrome. Nature 444:881–887
Stefan N, Kantartzis K, Haring HU (2008) Causes and metabolic consequences of fatty liver. Endocr Rev 29:939–960
Manco M, Marcellini M, Devito R et al (2008) Metabolic syndrome and liver histology in paediatric non-alcoholic steatohepatitis. Int J Obes (Lond) 32:381–387
Bremer AA, Mietus-Snyder M, Lustig RH (2012) Toward a unifying hypothesis of metabolic syndrome. Pediatrics 129:557–570
Schwimmer JB, Pardee PE, Lavine JE et al (2008) Cardiovascular risk factors and the metabolic syndrome in pediatric nonalcoholic fatty liver disease. Circulation 118:277–283
Weiss R, Dziura J, Burgert TS et al (2004) Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 350:2362–2374
Jones ME, Thorburn AW, Britt KL (2000) Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci U S A 97:12735–12740
Hewitt KN, Pratis K, Jones ME, Simpson ER (2004) Estrogen replacement reverses the hepatic steatosis phenotype in the male aromatase knockout mouse. Endocrinology 145:1842–1848
Clark JM, Brancati FL, Diehl AM (2002) Nonalcoholic fatty liver disease. Gastroenterology 122:1649–1657
Nishino M, Hayakawa K, Nakamura Y et al (2003) Effects of tamoxifen on hepatic fat content and the development of hepatic steatosis in patients with breast cancer: high frequency of involvement and rapid reversal after completion of tamoxifen therapy. AJR Am J Roentgenol 180:129–134
Schwimmer JB, Khorram O, Chiu V, Schwimmer WB (2005) Abnormal aminotransferase activity in women with polycystic ovary syndrome. Fertil Steril 83:494–497
Setji TL, Holland ND, Sanders LL et al (2006) Nonalcoholic steatohepatitis and nonalcoholic fatty liver disease in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 91:1741–1747
Veldhuis JD, Roemmich JN, Richmond EJ et al (2005) Endocrine control of body composition in infancy, childhood, and puberty. Endocr Rev 26:114–146
Lacort M, Leal AM, Liza M et al (1995) Protective effect of estrogens and catecholestrogens against peroxidative membrane damage in vitro. Lipids 30:141–146
Omoya T, Shimizu I, Zhou Y et al (2001) Effects of idoxifene and estradiol on NF-kappaB activation in cultured rat hepatocytes undergoing oxidative stress. Liver 21:183–191
Inoue H, Shimizu I, Lu G et al (2003) Idoxifene and estradiol enhance antiapoptotic activity through estrogen receptor-beta in cultured rat hepatocytes. Dig Dis Sci 48:570–580
Suzuki A, Abdelmalek MF, Schwimmer JB et al (2012) Association between puberty and features of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 10:786–794
Cook JS, Hoffman RP, Stene MA, Hansen JR (1993) Effects of maturational stage on insulin sensitivity during puberty. J Clin Endocrinol Metab 77:725–730
Bottner A, Kratzsch J, Muller G et al (2004) Gender differences of adiponectin levels develop during the progression of puberty and are related to serum androgen levels. J Clin Endocrinol Metab 89:4053–4061
Louthan MV, Theriot JA, Zimmerman E et al (2005) Decreased prevalence of nonalcoholic fatty liver disease in black obese children. J Pediatr Gastroenterol Nutr 41:426–429
Loomba R, Sirlin CB, Schwimmer JB, Lavine JE (2009) Advances in pediatric nonalcoholic fatty liver disease. Hepatology 50:1282–1293
Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S et al (2009) The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut 58:1538–1544
Nobili V, Marcellini M, Devito R et al (2006) NAFLD in children: a prospective clinical-pathological study and effect of lifestyle advice. Hepatology 44:458–465
Reinehr T, Schmidt C, Toschke AM, Andler W (2009) Lifestyle intervention in obese children with non-alcoholic fatty liver disease: 2-year follow-up study. Arch Dis Child 94:437–442
Wabitsch M, Moß A, Hauner H et al (2009) Therapie der Adipositas im Kindes- und Jugendalter. AWMF-Leitlinien-Register 050/002
Vos MB, Colvin R, Belt P et al (2012) Correlation of vitamin E, uric acid, and diet composition with histologic features of pediatric NAFLD. J Pediatr Gastroenterol Nutr 54:90–96
Lavine JE (2000) Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr 136:734–738
Nobili V, Manco M, Devito R et al (2008) Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: a randomized, controlled trial. Hepatology 48:119–128
Lavine JE, Schwimmer JB, Van Natta ML et al (2011) Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 305:1659–1668
Vajro P, Franzese A, Valerio G et al (2000) Lack of efficacy of ursodeoxycholic acid for the treatment of liver abnormalities in obese children. J Pediatr 136:739–743
Lopez-Huertas E (2012) The effect of EPA and DHA on metabolic syndrome patients: a systematic review of randomised controlled trials. Br J Nutr 107(Suppl 2):S185–S194
Nobili V, Bedogni G, Alisi A et al (2011) Docosahexaenoic acid supplementation decreases liver fat content in children with non-alcoholic fatty liver disease: double-blind randomised controlled clinical trial. Arch Dis Child 96:350–353
Schwimmer JB, Middleton MS, Deutsch R, Lavine JE (2005) A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis. Aliment Pharmacol Ther 21:871–879
Marion AW, Baker AJ, Dhawan A (2004) Fatty liver disease in children. Arch Dis Child 89:648–652
Arrese M (2009) Burning hepatic fat: therapeutic potential for liver-specific thyromimetics in the treatment of nonalcoholic fatty liver disease. Hepatology 49:348–351
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Denzer, C. Nichtalkoholische Fettlebererkrankung bei adipösen Kindern und Jugendlichen. Bundesgesundheitsbl. 56, 517–527 (2013). https://doi.org/10.1007/s00103-012-1639-4
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DOI: https://doi.org/10.1007/s00103-012-1639-4
Schlüsselwörter
- Nichtalkoholische Fettlebererkrankung
- Steatohepatitis
- Adipositas im Kindes- und Jugendalter
- Insulinresistenz
- Viszerales Fettgewebe