Increases in end-stage liver disease brought on by childhood obesity

The prevalence of obesity has reached an all-time high. Data from two National Health and Nutrition Examination Surveys demonstrate that obesity has increased among children and teens over the last 20 years. For instance, in children age 2 to 5 years, the prevalence of obesity has increased from 5 percent to 13.9 percent; while for those age 6 to 11 years, the prevalence has increased from 6.5 percent to 18.8 percent; and for those age 12 to 19 years, prevalence increased from 5 percent to 17.4 percent. Paralleling this increase in obesity, there has been a corresponding increase in the rates of childhood hypertension, dyslipidemia and type 2 diabetes. Associated with these conditions there also has been an increasing incidence of nonalcoholic fatty liver disease (NAFLD) and especially its more severe histological form, nonalcoholic steatohepatitis (NASH). Based on current trends, these conditions are expected to become one of the most common causes of end-stage liver disease in both children and young adults.¹

Background and pathophysiology

NASH is a clinicopathological condition characterized by inflammation and fibrosis in the liver that are nearly identical to those induced by excessive alcohol intake, but in the absence of alcohol abuse.² Multivariate analysis suggests that although increased BMI is the sole independent variable predictive of NASH on liver biopsy in children, older age, obesity, diabetes and an increased AST/ALT ratio have been documented to be predictors of fibrosis on liver biopsy in adults. Furthermore, although chronic hyperinsulinemia coupled with insulin resistance may be important for the development of NASH, genetic differences related to carbohydrate and lipid metabolism may account for the heterogeneity of clinical findings as well as provide insight as to why some individuals with nonalcoholic fatty liver disease rapidly progress to steatohepatis or even cirrhosis.³ Although no genome-wide studies have been conducted in association with NASH to date, individual candidate gene investigations have identified several genes associated with increased susceptibility to NASH in adults and have led to the current "double hit" hypothesis of disease pathogenesis. The first "hit" is represented by fatty infiltration of the liver. Hepatic fat accumulation is common in alcoholic liver disease, insulin resistance, metabolic syndrome and in drug-induced liver disease. However, increase in fat deposition alone is insufficient in explaining the inflammation or fibrosis associated with NASH. Oxidative stress, due to excessive production of reactive oxygen species (ROS) within the cells, has been indicated as a possible factor responsible for the second "hit," leading to steatohepatitis in analogy with the proposed mechanisms of severe damage in alcoholic liver disease.

Diagnosis

The diagnosis of NAFLD or NASH should be considered in all obese patients (BMI greater than 95 percent for age and gender) with elevated liver transaminases. However, it remains controversial whether obese patients routinely should be screened for co-morbidities associated with obesity. We generally recommend screening for NAFLD or NASH in any obese patient with evidence of insulin resistance such as elevated fasting insulin or glucose levels, acanthosis nigrans or if the patient has any symptoms of liver involvement such as hepatomegaly or right upper quadrant pain. Once the elevated transaminases have been identified, further workup is based on the degree and the duration of the elevated transaminases. Accordingly, the differential diagnosis would include chronic viral processes such as hepatitis B or C as well as metabolic disorders such as Wilson disease, cystic fibrosis, alpha-1 antitrypsin deficiency or mitochondrial disorders. Additional diagnoses to consider include medication-related liver injury such as with tetracycline, valproic acid, methotrexate or total parenteral nutrition, as well as other genetic disorders such as Prader-Willi syndrome or Turner syndrome. Liver biopsy may be required in order to determine the etiology of the patient's elevated transaminases and confirm and stage the severity of liver disease. An algorithm regarding this workup is provided in Figure 1. Using this algorithm, all patients who underwent biopsy at Children's Hospital of Wisconsin demonstrated NASH, and more than 80 percent of individuals demonstrated fibrosis.

Treatment        

Currently, there are limited pharmacologic options that may be used for direct therapy of children with NAFLD/NASH. Insulin sensitizers, antioxidants, hepatoprotective agents and hypolipidemic drugs all have been studied for the treatment of NAFLD with some success, and therefore, require further evaluation in the pediatric population.⁴ Until then, a safe approach would be to ensure adequate intake of vitamins and minerals and limit the use of insulin-sensitizing agents to more severe cases where risk of disease complications outweighs risk of the medication. 

Bariatric surgery also has been considered as a viable treatment approach. In fact, a study from Brazil in 2006 followed 18 patients with biopsy-proven NAFLD who underwent Roux-en-Y gastric bypass surgery. Results of the study demonstrated that repeat biopsy two years after surgery showed resolution of steatosis in 84 percent of patients and resolution of fibrosis in 75 percent.⁵ The role of bariatric surgery in pediatrics remains controversial and has not been studied in NAFLD,⁶ but may be promising in severe cases.

Despite these promising therapies, lifestyle modification continues to be the mainstay of treatment for NAFLD. Simple changes in diet and exercise that lead to improvement in insulin sensitivity and lipid levels has been demonstrated to improve liver enzyme elevation associated with NAFLD.⁷ Even mild weight loss in obese children has been clinically proven to improve insulin sensitivity and liver enzyme elevation.⁷ As a result, weight reduction through a healthy diet and regular exercise remains the mainstay for the treatment of NALFD and its more severe histological form, NASH.^{6, 8}

References

1. Iacobellis A, Marcellini M, Andriulli A, et al. Non invasive evaluation of liver fibrosis in paediatric patients with nonalcoholic steatohepatitis. World J Gastroenterol. Dec 28 2006;12(48):7821-7825.

2. Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology. Dec 1999;30(6):1356-1362.

3. Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr. Jan 2000;30(1):48-53.

4. Ramesh S, Sanyal AJ. Evaluation and management of nonalcoholic steatohepatitis. J Hepatol. 2005;42 Suppl(1):S2-12.

5. Furuya CK, Jr., de Oliveira CP, de Mello ES, et al. Effects of bariatric surgery on nonalcoholic fatty liver disease: preliminary findings after two years. J Gastroenterol Hepatol. Apr 2007;22(4):510-514. 

6. Roberts EA, Yap J. Nonalcoholic Fatty Liver Disease (NAFLD): Approach in the Adolescent Patient. Curr Treat Options Gastroenterol. Sep 2006;9(5):423-431.

7. Nobili V, Marcellini M, Devito R, et al. NAFLD in children: a prospective clinical-pathological study and effect of lifestyle advice. Hepatology. Aug 2006;44(2):458-465.

8. Roberts EA. Nonalcoholic steatohepatitis in children. Curr Gastroenterol Rep. Jun 2003;5(3):253-259.

Vincent Biank, MD, is a pediatric gastroenterologist at Children's Hospital of Wisconsin. He also is an assistant professor of Pediatrics (Gastroenterology) at the Medical College of Wiconsin and a member of Children's Specialty Group.

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