Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease

doi:10.1067/S0022-3476(03)00325-1

The Journal of Pediatrics

Volume 143, Issue 4, October 2003, Pages 500-505

https://doi.org/10.1067/S0022-3476(03)00325-1 Get rights and content

Abstract

Objective

To describe the clinical characteristics of nonalcoholic fatty liver disease (NAFLD) in children, including insulin resistance, and to test for correlation with liver pathology.

Study design

A retrospective review of children with biopsy-proven NAFLD at Children's Hospital San Diego from 1999 to 2002. Liver biopsy specimens were independently reviewed by two pathologists.

Results

Children with NAFLD (n = 43) were mostly male (70%), Hispanic American (53%) and obese (88%). The criteria for insulin resistance were met by 95% of subjects. Steatosis was predicted by the combination of quantitative insulin sensitivity check index, age, and ethnicity (P<.0001). Portal inflammation was predicted by the combination of ALT and fasting insulin (P = .0009). Perisinusoidal fibrosis was predicted by the combination of AST, fasting insulin, and BMI Z score (P<.0001). Portal fibrosis was predicted by the combination of right upper quadrant pain and homeostasis model assessment of insulin resistance (P = .0028).

Conclusions

We identified significant predictors of liver pathology in children with NAFLD. Children being evaluated for NAFLD should be screened for insulin resistance, which is nearly universal and correlates with liver histology.

Section snippets

Definition of NAFLD

The diagnosis of NAFLD is first suspected because of a persistent elevation of serum alanine aminotransferase (ALT) (>35 U/L) or in the setting of an echogenic liver detected by ultrasound. Diagnosis requires exclusion of other causes of chronic hepatitis including hepatitis B, hepatitis C, α-1 antitrypsin deficiency, autoimmune hepatitis, Wilson's disease, drug toxicity (valproate, tetracycline, methotrexate, amiodorone, or prednisone) and total parenteral nutrition. Alcohol intake is excluded

Study population

Clinical and laboratory details for the 43 subjects identified with NAFLD are shown in Table I. The median age was 12.5 years (range, 2-17). As demonstrated in other pediatric studies of NAFLD the subjects were predominantly male (70%). The racial and ethnic distribution of the study cohort was Hispanic 53%, white non-Hispanic 25%, black non-Hispanic 5%, and other 17% and did not differ by sex. For comparison, as of January 2000 the ethnic distribution of the population between 5 and 19 years

Discussion

A retrospective analysis of 43 children with biopsy-proven NAFLD identified significant predictors of liver steatosis, inflammation, and fibrosis. Steatosis is believed to be the “first hit” in the development of NASH.³³ The severity of steatosis was predicted by the combination of age, ethnicity, and insulin sensitivity (QUICKI). As age increased so did the amount of liver fat, possibly reflecting the duration of obesity. We diagnosed NAFLD more commonly in Mexican-American children than in

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A natural history study of paediatric non-alcoholic fatty liver disease over 10 years
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The long-term outcome of paediatric non-alcoholic fatty liver disease (NAFLD) has not been well established. Between 2008 and 2012, an unselected cohort of 133 children with severe obesity was screened for NAFLD. The aim of this study was to determine the 10-year natural history of NAFLD in this cohort.
All 133 participants of the original study were approached. Proton magnetic resonance spectroscopy (¹H-MRS) and the Enhanced Liver Fibrosis® (ELF) test were used to assess longitudinal changes in steatosis and fibrosis, respectively. Risk factors for disease progression were explored.
Fifty-one of the 133 participants (38%) from the original cohort were included. The mean follow-up time was 10.3 years (range 7–13 years), 65% were female and 92% had persistent obesity. The proportion of participants with steatosis remained unchanged (47%). Nine individuals developed steatosis and in nine individuals steatosis resolved. Predefined relevant individual changes in ¹H-MRS were seen in 38% of the participants. The mean ELF test did not change significantly (8.70 ± 0.58 vs. 8.51 ± 0.71, p = 0.22). However, 16% had a relevant increase in ELF test and 6% of those with NAFLD developed advanced fibrosis at follow-up. Changes in steatosis correlated with changes in established metabolic risk factors, alanine aminotransferase, and bariatric surgery. A change in the ELF test was associated with a change in triglycerides.
This 10-year follow-up study shows that one-third of the young adults who had childhood obesity develop steatosis and in one-third steatosis resolves. Six percent of those with NAFLD had developed advanced fibrosis at follow-up. These data underscore the importance of screening for NAFLD and monitoring for progression to advanced NAFLD in young people with obesity.
Childhood obesity accompanied by fat accumulation in the liver persists into young adulthood in the vast majority, and 6% develop serious liver injury. Worsening of metabolic disturbances increases the risk of liver injury.
Special Population: Pediatric Nonalcoholic Fatty Liver Disease
2023, Clinics in Liver Disease
Incidence of Type 2 Diabetes in Children With Nonalcoholic Fatty Liver Disease
2023, Clinical Gastroenterology and Hepatology
Type 2 diabetes (T2D) is a growing problem in children. Children with NAFLD are at potentially high risk for developing T2D; however, the incidence of T2D in this population is unknown. This study aimed to determine the incidence of T2D in children with NAFLD and identify associated risk factors.
Children with NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network were followed longitudinally. Incidence of T2D was determined by using clinical history and fasting laboratory values. Cumulative incidence curves were developed for time to T2D. A Cox regression multivariable model was constructed using best subsets Akaike’s Information Criteria selection.
This study included 892 children with NAFLD and with a mean age of 12.8 years (2.7) followed for 3.8 years (2.3) with a total 3234 person-years at risk. The incidence rate of T2D was 3000 new cases per 100,000 person-years at risk. At baseline, 63 children had T2D, and during follow-up, an additional 97 children developed incident T2D, resulting in a period prevalence of 16.8%. Incident T2D was significantly higher in females versus males (hazard ratio [HR], 1.8 [1.0–2.8]), associated with BMI z-score (HR, 1.8 [1.0–3.0]), and more severe liver histology including steatosis grade (HR, 1.3 [1.0–1.7]), and fibrosis stage (HR, 1.3 [1.0–1.5]).
Children with NAFLD are at high risk for existing and incident T2D. In addition to known risk factors for T2D (female and BMI z-score), severity of liver histology at the time of NAFLD diagnosis was independently associated with T2D development. Targeted strategies to prevent T2D in children with NAFLD are needed.
Fatty Liver Disease
2023, MacSween's Pathology of the Liver, Eighth Edition
Fatty liver disease (FLD) has a wide histopathology spectrum including simple steatosis, steatohepatitis with or without fibrosis, and cirrhosis that may be complicated by hepatocellular carcinoma (HCC). The two main entities that comprise FLD, alcohol-related liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) associated to metabolic dysfunction, have both similarities and differences. In this chapter, some of the features that are common to both are considered, followed by a review of the pathogenetic and pathological features of each and discussion on how the two can be distinguished clinically and histopathologically. NAFLD concurrent with other liver disease, NAFLD in other clinical settings and treatment options are also discussed.
Determinants of non-alcoholic fatty liver disease in young people: Maternal, neonatal, and adolescent factors
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Childhood Obesity: An Updated Review
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Supported in part by grant M01 RR00827 from the National Center for Research Resources of the National Institutes of Health for the General Clinical Research Center at University of California-San Diego.

Presented in abstract form at the 53rd Annual Meeting of the American Association for the Study of Liver Diseases, Boston, Massachusetts, November 5, 2002.

View full text

Original articleObesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease☆

Abstract

Objective

Study design

Results

Conclusions

Section snippets

Definition of NAFLD

Study population

Discussion

Clin Nutr

J Pediatr

Gastroenterology

Am J Med

Gastroenterology

Gastroenterology

J Hepatol

Gastroenterology

Hepatology

Gastroenterology

Am J Clin Nutr

J Pediatr

Am J Gastroenterol

J Hepatol

Liver Transpl

Gastroenterology

J Hepatol

J Pediatr

Prevalence and trends in overweight among US children and adolescents, 1999-2000

JAMA

Syndrome X in children: influence of ethnicity and visceral fat

Am J Human Biol

Non-alcoholic steatohepatitis: association with obesity and insulin resistance, and influence of weight loss

Diabetes Metab

Fatty liver and its fibrous changes found in simple obesity of children

J Pediatr Gastroenterol Nutr

Liver involvement in obese children. Ultrasonography and liver enzyme levels at diagnosis and during follow-up in an Italian population

Dig Dis Sci

Non-alcoholic steatohepatitis in children and adolescents

Med J Aust

Nonalcoholic steatohepatitis in children

J Pediatr Gastroenterol Nutr

Overweight children and adolescents: description, epidemiology, and demographics

Pediatrics

Obese children with steatohepatitis can develop cirrhosis in childhood

Am J Gastroenterol

The clinicopathologic spectrum and management of nonalcoholic fatty liver disease

Adv Anat Pathol

Nonalcoholic fatty liver disease

N Engl J Med

Original article
Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease☆