ABSTRACT
Obesity now affects 15% of children and adolescents in the United States. Many of the complications of obesity are seen in children, including fatty liver disease, gallstones, hyperlipidemia, insulin resistance, and type 2 diabetes. Infants and children also have unique susceptibilities to and manifestations of liver disease caused by total parenteral nutrition. In addition to genetic and environmental influences on obesity, there is increasing evidence supporting the idea of “metabolic programming,” in which environmental influences at critical periods during development have permanent effects on an individual's predisposition to obesity and metabolic disease. Understanding the role the liver plays in the development and expression of the metabolic program will provide important insight into the pathogenesis and treatment of fatty liver disease, and of obesity itself.
KEYWORDS
Development - obesity - fatty liver steatohepatitis
REFERENCES
1
Ogden C L, Flegal K M, Carroll M D, Johnson C L.
Prevalence and trends in overweight among US children and adolescents, 1999-2000.
JAMA.
2002;
288
1728-1732
2
McLellan F.
Obesity rising to alarming levels around the world.
Lancet.
2002;
359
1412
3
Whitaker R C, Wright J A, Pepe M S et al..
Predicting obesity in young adulthood from childhood and parental obesity.
N Engl J Med.
1997;
337
869-873
4
Must A, Jacques P F, Dallal G E et al..
Long-term morbidity and mortality of overweight adolescents: a follow-up of the Harvard Growth Study of 1922 to 1935.
N Engl J Med.
1992;
327
1350-1355
5
Fagot-Campagna A, Pettitt D J, Engelgau M M et al..
Type 2 diabetes among North American children and adolescents: an epidemiologic review and a public health perspective.
J Pediatr.
2000;
136
664-672
6
Dean H J, Young T K, Flett B, Wood-Steiman P.
Screening for type 2 diabetes in aboriginal children in Northern Canada.
Lancet.
1998;
352
1523-1524
7
Dablea D, Hanson R L, Bennett P H et al..
Increasing prevalence of type 2 diabetes in American Indian children.
Diabetologia.
1998;
41
904-910
8
Sinha R, Fisch G, Teague B et al..
Prevalence of impaired glucose tolerance among children and adolescents with marked obesity.
N Engl J Med.
2002;
346
802-810
9
American Diabetes Association .
Type 2 diabetes in children and adolescents.
Diabetes Care.
2000;
23
381-389
10
Cook J S, Hoffman R P, Stene M A, Hansen J R.
Effects of maturational stage on insulin sensitivity during puberty.
J Clin Endocrinol Metab.
1993;
77
725-730
11
Moran A, Jacobs D, Steinberger D R et al..
Insulin resistance during puberty: results from clamp studies in 357 children.
Diabetes.
1999;
48
2039-2044
12
Murphy M J, Metcalf B S, Voss L D et al..
Girls at five are intrinsically more insulin-resistant than boys: The Programming Hypothesis Revisited-the EarlyBird study (EarlyBird 6).
Pediatrics.
2004;
113
82-86
13
Arsalnian S, Suprongsin C.
Insulin sensitivity, lipids, and body composition in childhood: is “syndrome X” present?.
J Clin Endocrinol Metab.
1996;
81
1058-1062
14
Travers J H, Jeffers B W, Bloch C A et al..
Gender and Tanner stage differences in body composition and insulin sensitivity in early pubertal children.
J Clin Endocrinol Metab.
1995;
80
172-178
15
Strauss R S, Barlow S E, Dietz W H.
Prevalence of abnormal serum aminotransferase values in overweight and obese adolescents.
J Pediatr.
2000;
136
727-733
16
Kinugasa A, Tsunamoto K, Furukawa N et al..
Fatty liver and its fibrous changes found in simple obesity of children.
J Pediatr Gastroenterol Nutr.
1984;
3
408-414
17
Fishbein M H, Miner M, Mogren C, Chalekson J.
The spectrum of fatty liver in obese children and the relationship of serum aminotransferases to severity of steatosis.
J Pediatr Gastroenterol Nutr.
2003;
36
54-61
18
Franzese A, Vajro P, Aregenziana 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
1428-1432
19
Molleston J P, White F, Teckman J, Fitzgerald J F.
Obese children with steatohepatitis can develop cirrhosis in childhood.
Am J Gastroenterol.
2002;
97
2460-2462
20
Kusonoki T, Sadawada T, Ohya N.
Fatty liver associated with simple obesity of childhood.
Jpn Med J.
1975;
2667
25-28
21
Rashid M, Roberts E A.
Nonalcoholic steatohepatitis in children.
J Pediatr Gastroenterol Nutr.
2000;
30
48-53
22
Schwimmer J B, Deutsch R, Rauch J et al..
Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease.
J Pediatr.
2003;
143
500-505
23
Kawasaki T, Hashimoto N, Kikuchi T et al..
The relationship between fatty liver and hyperinsulinemia in obese Japanese children.
J Pediatr Gastroenterol Nutr.
1997;
24
317-321
24
Angulo P.
Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis.
Hepatology.
1999;
30
1356-1362
25
Garcia-Monzon C, Martin-Perez E, Iacono E L et al..
Characterization of pathogenic and prognostic factors of nonalcoholic steatohepatitis associated with obesity.
J Hepatol.
2000;
33
716-724
26
Nakao K, Nakata K, Ohtsubo N et al..
Association between nonalcoholic fatty liver, markers of obesity, and serum leptin level in young adults.
Am J Gastroenterol.
2002;
97
1796-1801
27
Vajro P, Fontanella A, Perna C et al..
Persistent hyperaminotransferasemia resolving after weight reduction in obese children.
J Pediatr.
1994;
125
239-241
28
Bellentani S, Saccoccio G, Masutti F et al..
Prevalence of and risk factors for hepatic steatosis in Northern Italy.
Ann Intern Med.
2000;
132
112-117
29
Marchesini G, Brizi M, Bianchi G et al..
Metformin in non-alcoholic steatohepatitis.
Lancet.
2001;
358
893-894
30
Caldwell S H, Hespenheide E E, Redick J A et al..
A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis.
Am J Gastroenterol.
2001;
96
519-525
31
Promrat K, Lutchman G, Uwaifo G I et al..
A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis.
Hepatology.
2004;
39
188-196
32
Lavine J E.
Vitamin E treatment of non-alcoholic steatohepatitis in children: a pilot study.
J Pediatr.
2000;
136
734-738
33
Kigici M, Gultten M, Gurel S et al..
Ursodeoxycholic acid and atorvastatin in the treatment of nonalcoholic steatohepatitis.
Can J Gastroenterol.
2003;
17
713-718
34
Lavine J.
Pediatric initiatives within the nonalcoholic steatohepatitis-clinical research network (NASH-CRN).
J Pediatr Gastroenterol Nutr.
2003;
37
220-221
35
Kumar R, Nguyen K, Shun A.
Gallstones and common bile duct calculi in infancy and childhood.
Aust N Z J Surg.
2000;
70
188-191
36
Holcomb Jr G W, Holcomb GW I II.
Cholelithiasis in infants, children and adolescents.
Pediatr Rev.
1990;
11
268-274
37
Miltenburg D M, Schaffer 3rd R, Breslin T, Brandt M L.
Changing indications for pediatric cholecystectomy.
Pediatrics.
2000;
105
1250-1253
38
Wesdorp I, Bosman D, de Graaff A et al..
Clinical presentations and predisposing factors of cholelithiasis and sludge in children.
J Pediatr Gastroenterol Nutr.
2000;
31
411-417
39
Barker D JP.
Fetal origins of coronary heart disease.
BMJ.
1995;
311
171-174
40
Barker D JP, Hales C N, Fall C H et al..
Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome x): relation to reduced fetal growth.
Diabetologia.
1993;
36
62-67
41
Rich-Edwards J W, Stampfer M J, Manson J E et al..
Birthweight and risk of cardiovascular disease in a cohort of women followed up since 1976.
BMJ.
1997;
315
396-400
42
Ravelli A CJ, van der Meulen J HP, Michels R PJ et al..
Glucose tolerance in adults after prenatal exposure to famine.
Lancet.
1998;
351
173-177
43
Hales C N, Barker D JP.
The thrifty phenotype hypothesis.
Br Med Bull.
2001;
60
5-20
44
Van Assche F A, Holemans K, Aerts L.
Long-term consequences for offspring of diabetes during pregnancy.
Br Med Bull.
2001;
60
173-182
45
Ozanne S E, Hales C N.
Lifespan: catch-up growth and obesity in male mice.
Nature.
2004;
427
411-412
46
Hales C N, Desai M, Ozanne S E, Crowther N J.
Fishing in the stream of diabetes: from measuring insulin to the control of fetal organogenesis.
Biochem Soc Trans.
1996;
24
341-350
47
Burns S P, Desai M, Cohen R D et al..
Gluconeogenesis, glucose handling, and structural changes in livers of the adult offspring of rats partially deprived of protein during pregnancy and lactation.
J Clin Invest.
1997;
100
1768-1774
48
Angelico M, Della Guardia P.
Hepatobiliary complications associated with total parenteral nutrition.
Aliment Pharmacol Ther.
2000;
14
54-57
49
Capron J-P, Gineston J-L, Herve M-A, Braillon A.
Metronidazole in prevention of cholestasis associated with total parenteral nutrition.
Lancet.
1983;
1
446-447
50
Pappo I, Bercovier H, Berry E et al..
Antitumor necrosis factor antibodies reduce hepatic steatosis during total parenteral nutrition and bowel rest in the rat.
JPEN J Parenter Enteral Nutr.
1995;
19
80-82
51
Sugiura T, Tashiro T, Yamamori H et al..
Effects of total parenteral nutrition on endotoxin translocation and extent of the stress response in burned rats.
Nutrition.
1999;
15
570-575
52
Nakano K, Chijiiwa K, Noshiro H, Hirota I, Yamasaki T.
Human gallbladder bile becomes lithogenic during short-term intravenous hyperalimentation.
J Surg Res.
1992;
53
396-401
53
Lindor K D, Burnes J.
Ursodeoxycholic acid for the treatment of home parenteral nutrition-associated cholestasis. A case report.
Gastroenterology.
1991;
101
250-253
54
Duerksen D R, Van Aerde J E, Gramlich L et al..
Intravenous ursodeoxycholic acid reduces cholestasis in parenterally fed newborn piglets.
Gastroenterology.
1996;
111
1111-1117
55
Sitzmann J V, Pitt H A, Steinorn P A et al..
Cholecystokinin prevents parenteral nutrition-induced biliary sludge in humans.
Surg Gynecol Obstet.
1990;
170
25-31
Alison G HoppinM.D.
Massachusetts General Hospital Weight Center
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Email: ahoppin@partners.org.