Electronic letters to:

Review:
Leon A. Adams, Paul Angulo, and Keith D. Lindor
Nonalcoholic fatty liver disease
CMAJ 2005; 172: 899-905 [Abstract] [Full text] [PDF]
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Electronic letters published:

[Read eLetter] NAFLD in children
Diana Mager   (9 May 2005)
[Read eLetter] Nonalcoholic fatty liver disease and its pathogenesis
Pankaj Madan   (30 March 2005)

NAFLD in children 9 May 2005
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Diana Mager
Division of Gastroenterology, Hepatology & Nutrition, The Hospital for Sick Children

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Re: NAFLD in children

diana.mager{at}sickkids.ca Diana Mager

Lindor et al. provide an excellent and up-to-date review of nonalcoholic fatty liver disease (NAFLD) in adults but they do not discuss NAFLD in children (1). Childhood NAFLD has been reported globally since our first large clinical series from the Hospital for Sick Children in Toronto was published (2). In part this reflects the increasing prevalence of obesity in childhood (3,4). NAFLD is typically diagnosed in children 12 -14 years-old, but serious liver disease associated with NAFLD has been reported in children as young as five years of age (5,6). In adults NAFLD must be differentiated from alcoholic liver disease, but in children NAFLD must be distinguished from various rare metabolic disorders which cause fatty liver (such as Wilson disease). The typical child suffers from over- nutrition, is asymptomatic or has vague abdominal pain and may have abnormal liver biochemistries. As in adults, an important feature of childhood NAFLD is hyperinsulinemia associated with relative insulin resistance, as shown by clinical studies using the homeostasis model of insulin resistance (HOMA-IR) (5). Whether oxidative damage to the liver is prominent in childhood NAFLD is a question currently being investigated. NAFLD in adults can progress to cirrhosis with chronic liver failure requiring liver transplantation or to hepatocellular carcinoma, but the long-term outcome for children with NAFLD is unknown. Cirrhosis has been reported in a few children (6). Although simple steatosis (hepatic fat accumulation without inflammation and fibrosis) carries a benign prognosis in adults, the long-term outcome for children with simple steatosis is uncertain. Current treatment strategies in NAFLD are aimed at eliminating or reducing risk factors associated with NAFLD: they involve weight loss and increased physical activity. In children few data are available regarding pharmacological interventions such as vitamin E, ursodiol and metformin (7-9). Well-designed prospective studies in children are urgently needed to determine the best overall medical management. Childhood NAFLD may be the hepatic manifestation of the metabolic dysregulation leading to type 2 diabetes, hypertension and cardiovascular disease. Given that childhood NAFLD is highly prevalent—estimated at 3-10% of obese children—we need to intervene now so as to avoid cirrhosis, as well as these diseases, in the current generation of children.

Diana Mager, PhD RD Eve Roberts, MD FRCPC Division of Gastroenterology, Hepatology and Nutrition, and Metabolism Research Program, The Hospital for Sick Children, Departments of Paediatrics, Medicine and Pharmacology, University of Toronto.

References. 1. Adams LA, Angulo P, Lindor KD. Nonalcoholic fatty liver disease. CMAJ 2005; 172: 899-905. 2. Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr 2000; 30: 48-53. 3. Canning PM, courage ML, Frizzell LM. Prevalence of overweight and obesity in a provincial population of Canadian preschool children. CMAJ 2004: 171: 240-242. 4. Janssen I, Katzmarzyk PT, Boyce WF, Vereecken C, Mulvihill C, Roberts C, Currie C, Pickett W and the Health Behavior in School-aged Children Obesity Working Group. Comparison of overweight and obesity prevalence in school-aged youth from 34 countries and their relationships with physical activity and dietary patterns. Obesity Reviews 2005; 6: 123-132. 5. Schwimmer JB, Deutsch R, Rauch JB, Behling C, Newbury R, Lavine JE. Obesity, insulin resistance and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease. J Pediatr 2003; 143: 500-505. 6. Roberts EA. Non-alcoholic fatty liver disease (NAFLD) in children. Front Biosci 2005; 10: 2306-2318 (in press). 7. Lavine JE. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr 2000; 136: 734-738. 8. Vajro P, Franzese A, Valerio G, Iannucci MP & Aragione N. Lack of efficacy of ursodeoxycholic acid for the treatment of liver abnormalities in obese children. J Pediatr 2000; 136: 739-743. 9. Schwimmer JB, Middleton MS, Deutsch R, Lavine JE. A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non- alcoholic steatohepatitis. Aliment Pharmacol Ther 2005; 31: 871-879.

Conflict of Interest:

None declared
Nonalcoholic fatty liver disease and its pathogenesis 30 March 2005
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Pankaj Madan
University College of medical Sciences and GTB Hospital

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Re: Nonalcoholic fatty liver disease and its pathogenesis

pankajmadaan{at}rediffmail.com Pankaj Madan

I read with interest the review on “Non alcoholic fatty liver disease” (NAFLD) by Adams et al. The authors have rightly stated that obesity is associated with this disease. I wish to point out that visceral adiposity in particular is highly correlated with NAFLD and the correlation with subcutaneous obesity is relatively weaker (1).

This intra-abdominal fat directly delivers the fatty acids into the portal vein and promotes insulin resistance (1). It has been seen that individuals with truncal obesity have very low levels of adiponectin and high levels of TNF-á. (2). TNF-á secretion from adipose tissue is strongly associated with obesity-related insulin resistance, suggesting that TNF-á may function in a paracrine fashion in adipose tissue while adiponectin expression from adipose tissue is associated with higher degrees of insulin sensitivity and lower TNF-á expression (3). In addition, TNF-á has been shown to decrease levels of adiponectin (4). Thus a combination of increased TNF-á and decreased adiponectin leads to severe insulin resistance leading to NAFLD. Various modalities for treatment of NAFLD e.g. weight loss or use of drugs like thiazolidinediones increase adiponectin levels (4,5).

Adams et al, while writing about the inflammatory and and fibrotic mediators in NAFLD, want us to believe that adiponectin promotes liver fibrosis in NAFLD while the evidence points towards to exactly the opposite. I think this issue needs clarification from the authors.

References:

1. Kelley DE, McKolanis TM, Hegazi RA, et al. Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metab 2003;285:E906–16.

2. Misra A, Garg A. Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature. Medicine 2003;82:129–46.

3. Kern PA, Di Gregorio GB, Lu T, et al. Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Diabetes 2003;52:1779–85.

4. Bruun JM, Lihn AS, Verdich C, et al. Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans. Am J Physiol Endocrinol Metab 2003;285:E527–33.

5. Yu JG, Javorschi S, Hevener AL, et al. The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes 2002;51:2968–74.

Conflict of Interest:

None declared