Despite substantial scientific interest in dietary influences on NAFLD, little information is available about diet in children with NAFLD compared with the histologic features of the disease. In this registry-based study, we were able to examine self-reported diet and compare this to rigorously measured histology. We found that diet (after the diagnosis of NAFLD) did not differentiate simple steatosis and NASH. We also found several interesting associations that suggest areas for further investigation, including low consumption of vitamin E, weak associations between vitamins E and C and increased histologic severity, and finally, strong associations between uric acid (a surrogate marker for fructose consumption) and histologic severity.
We did not find any significant differences in diet when we compared children with “NASH” to “not NASH.” Each group reported similar consumption of fat, sugar-sweetened beverages, antioxidants, and other micronutrients. Diet comparisons by NAS score, representing a composite of these findings, also did not differ significantly. These findings suggest that diet is not the primary cause of whether a child with NAFLD has NASH or not.
In our cohort of children with NAFLD, the median reported consumption of vitamin E in all groups was less than half of the US RDA of vitamin E (for adolescents 22.5 IU/day) (11). Because of the registry design, our study did not include obese children without NAFLD, so we do not have a disease-free control group for comparisons. In general, obese children have not been identified as having lower reported intake of vitamins E and C. Data from the National Health and Nutrition Examination Survey (1988–1994) demonstrated that children who were obese had similar reported intake of these vitamins as well as fruits and vegetables compared with nonobese children (12).
In our study, we found weak associations with vitamins E and C consumption compared with steatosis and ballooning, respectively. Both vitamin C and vitamin E function as scavengers of hydoxyl, peroxyl, and superoxide radicals and protect against plasma lipid and low-density lipoprotein peroxidation (13) and other oxidative stress, and thus could be important in preventing the progression of NAFLD. Vitamin E has been tested as a treatment for NAFLD (14–17) in part because antioxidant deficiency may lead to increased lipid peroxidation and cell death due to mitochondrial compromise (evident as ballooning on liver biopsy). In the recently published Pioglitazone or Vitamin E for Nonalcoholic Steatohepatitis randomized controlled trial comparing pioglitazone, vitamin E, and placebo in adults with NASH, vitamin E therapy was associated with improved ALT, aspartate aminotransferase, steatosis, lobular inflammation, and ballooning (18), suggesting a protective role in hepatocytes. In the Treatment of Nonalcoholic Fatty Liver Disease in Children treatment trial of adolescents with NAFLD, 58% of those treated with vitamin E had resolution of NASH or borderline NASH, which was significantly better than those taking placebo (28%), and those taking vitamin E demonstrated significant improvement in NAFLD Activity scores (19).
There are several previous nonpathology-based published studies that also examine the diet of children with and without presumptive NAFLD based on surrogate markers. Quiros-Tejeira et al found a small increase in consumption of dietary cholesterol in the suspected NAFLD children compared with normal ALT subjects (20). De Piano et al (6) studied 43 adolescents, including 13 with NAFLD (based on ultrasound evaluation), and found no significant differences in total energy, percentage of protein, percentage of carbohydrates, percentage of fat, or cholesterol consumption compared with obese adolescents without echogenic livers. Papandreou et al (21) compared adolescents with and without NAFLD (using ultrasound for fat assessment) and found that total energy, percentage of protein, and percentage of fat were similar; however, they found an increase in carbohydrates and sugar intake in children with NAFLD.
We were also interested in examining sugar consumption in our subjects because added sugars are known to be associated with dyslipidemia (22) and fructose can be used to induce fatty liver in animal models (23). Adolescents are the highest consumers of both added sugars and fructose, making them a high-risk group for potential effects (24). Because the Block Brief Questionnaire lacks a detailed breakdown of sugar, we used sugar-sweetened beverages [the largest source (24)] as a surrogate marker of fructose intake. Interestingly, we did not find any difference in reported sugar-sweetened beverage consumption between groups. Previous studies of adult NAFLD patients, including a registry study using a design similar to ours (25), have found increased reported intake of sugar-sweetened beverages, elevated uric acid levels (26–29), and associations between uric acid and fibrosis severity (25). Uric acid levels increase with fructose intake (30), and intake of fructose correlates with uric acid levels in the general population (31). Because of this it has been used as a surrogate marker of fructose intake. Despite the lack of difference in reported sugar-sweetened beverage consumption, our groups differed significantly in uric acid level, with the highest levels found in the definite NASH group (P = 0.008). When definite NASH was compared with steatosis alone (not NASH), there was a trend toward a higher uric acid level in those with definite NASH (P = 0.07). Because sugar-sweetened beverages only account for an average of ∼40% fructose in the diet (24), our subjects may have substantial fructose intake from other sources (eg, processed foods) that we were unable to measure given the limitations of our dietary instrument. In addition, it is possible that uric acid has an independent effect in NAFLD, unrelated to fructose intake. Further studies with both histology and more detailed diet information will be needed to understand the relation of fructose to NAFLD and more specifically to NASH in children.
A possible limitation of our study may be a reporting or recall bias because most participants reported a relatively healthy diet. For example, median sugar-sweetened beverage intake was reported as 1 glass or can or less per week. In the United States, average intake of sugar-sweetened beverages for children age 12 to 19 years represented 356 cal/day (32), which would translate to 2.5 cans of a typical 12-oz can of soda or more than three 8-oz glasses of fruit-like drink per day. Thus, our subjects report a much lower than average consumption of sugar-sweetened beverages. In addition, less than one-fourth of our subjects reported >40% fat intake, the definition of a high-fat diet. There are several factors that may account for this finding. All of our participants had already undergone a substantial medical procedure (liver biopsy) and had been given a diagnosis of NAFLD. This event may have been an effective trigger for lifestyle improvements, including alterations in diet. At the time of diagnosis, many patients are instructed to decrease intake of sugar-sweetened beverages, increase intake of fruits and vegetables, and reduce fat intake as part of standard therapy. Most of our subjects were evaluated at 1 to 2 months after the liver biopsy, possibly a peak time for implementing an improved diet. The Block Brief Questionnaire asks participants to reflect on their diet during the last year; however, the recall may be more influenced by their present diets or they may wish to appear in conformance with recently provided nutritional advice for a healthy diet. Overall, these effects may be less important because it would likely affect all participants, regardless of histologic variation.
In summary, macronutrients did not differentiate between simple steatosis and NASH in the children in our study. We found that children with NAFLD consumed less than the recommended amounts of vitamin E, and that there was a weak association between lower consumption of both vitamins E and C and pathologic severity of NAFLD. Uric acid, a surrogate marker of dietary fructose, was significantly increased in those children with definite NASH compared with milder forms of NAFLD. Prospective studies are needed to evaluate diet in potential subjects before diagnosis and nutritional counseling (and ideally before NAFLD onset) to better confirm dietary contributors to this disease.
Appendix: Members of the Nonalcoholic Steatohepatitis Clinical Research Network
Baylor College of Medicine, Houston, TX: Stephanie Abrams, MD; Diana Arceo, MD, MS; Denise Espinosa; Leanel Angeli Fairly, RN
Case Western Reserve University Clinical Centers: MetroHealth Medical Center, Cleveland, OH: Carol Hawkins, RN; Yao-Chang Liu, MD; Margaret Stager, MD. Cleveland Clinic Foundation, Cleveland, OH: Arthur McCullough, MD; Srinivasan Dasarathy, MD; Ruth Sargent, LPN
Seattle Children's Hospital & Research Institute, Seattle, WA: Melissa Coffey; Karen Murray, MD; Melissa Young
Children's National Medical Center, Washington DC: Parvathi Mohan, MD; Kavita Nair
Duke University Medical Center, Durham, NC: Manal Abdelmalek, MD; Anna Mae Diehl, MD; Marcia Gottfried, MD (2004–2008); Cynthia Guy, MD; Paul Killenberg, MD (2004–2008); Samantha Kwan; Yi-Ping Pan; Dawn Piercy, FNP; Melissa Smith
Indiana University School of Medicine, Indianapolis, IN: Prajakta Bhimalli; Naga Chalasani, MD; Oscar W. Cummings, MD; Lydia Lee, Linda Ragozzino, Raj Vuppalanchi, MD
Riley Hospital for Children, Indianapolis, IN: Elizabeth Byam; Ann Klipsch, RN; Jean Molleston, MD; Girish Subbarao, MD
Johns Hopkins Hospital, Baltimore, MD: Kimberly Pfeifer; Ann Scheimann, MD; Michael Torbenson, MD
St Louis University, St Louis, MO: Sarah Barlow, MD (2002–2007); Jose Derdoy, MD (2007-); Joyce Hoffmann; Debra King, RN; Andrea Morris; Joan Siegner, RN; Susan Stewart, RN; Brent A. Tetri, MD; Judy Thompson, RN
University of California, San Diego: Cynthia Behling, MD, PhD; Janis Durelle; Joel E. Lavine, MD, PhD; Susana Mendoza; Jeffrey B. Schwimmer, MD; Claude Sirlin, MD; Tanya Stein, MD; Zobeida Palomares
University of California, San Francisco: Bradley Aouizerat, PhD; Kiran Bambha, MD; Nathan M. Bass, MD, PhD; Linda D. Ferrell, MD; Danuta Filipowski, MD; Raphael Merriman, MD (2002–2007); Mark Pabst; Monique Rosenthal; Philip Rosenthal, MD; Tessa Steel (2006–2008).
University of Washington Medical Center, Seattle: Matthew Yeh, MD, PhD
Virginia Commonwealth University, Richmond, VA: Sherry Boyett, RN; Melissa J. Contos, MD; Michael Fuchs, MD; Amy Jones; Velimir AC Luketic, MD; Bimalijit Sandhu, MD; Arun J. Sanyal, MD; Carol Sargeant, RN, MPH; Kimberly Selph; Melanie White, RN
Virginia Mason Medical Center, Seattle, WA: Kris V. Kowdley, MD; Jody Mooney, MS; James Nelson, PhD; Sarah Ackermann; Cheryl Saunders, MPH; Vy Trinh; Chia Wang, MD
Washington University, St Louis, MO: Elizabeth M. Brunt, MD
National Cancer Institute, Bethesda, MD: David Kleiner, MD, PhD
National Institute of Child Health and Human Development, Bethesda, MD: Gilman D. Grave, MD; Terry TK Huang, PhD, MPH
National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, MD: Edward Doo, MD; James Everhart, MD, MPH; Jay Hoofnagle, MD; Patricia R. Robuck, PhD, MPH (Project Scientist); Leonard Seeff, MD
Johns Hopkins University, Bloomberg School of Public Health (Data Coordinating Center), Baltimore, MD: Patricia Belt, BS; Frederick L. Brancati, MD, MHS; Jeanne M. Clark, MD, MPH; Ryan Colvin, MPH; Michele Donithan, MHS; Mika Green, MA; Rosemary Hollick (2003–2005); Milana Isaacson; Wana Kim; Alison Lydecker, MPH (2006–2008), Pamela Mann, MPH; Laura Miriel; Alice Sternberg, ScM; James Tonascia, PhD; Aynur Ünalp-Arida, MD, PhD; Mark Van Natta, MHS; Laura Wilson, ScM; Katherine Yates, ScM.
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