NAFLD in Children: Causes and Diagnosis

NAFLD in Children

• Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common cause of chronic liver disease in children.
• Two major factors contributing to NAFLD are obesity and insulin resistance.
• The prevalence of these factors is rapidly increasing in children worldwide, causing NAFLD to become an important problem.

Thesis Statement

• The histological features of NAFLD in adults have been well-described, but the standard criteria for the diagnosis of NAFLD or NASH in children are underdeveloped.
• Pediatric studies of NAFLD have described patterns of inflammation and fibrosis that differ from those reported in adults.
• There are important differences between children and adults in the histological features associated with NASH.

Objectives

• To define the liver biopsy findings in a large series of children with clinical features consistent with NAFLD.
• To define distinct patterns of nonalcoholic steatohepatitis (NASH) in children.
• To determine the prevalence of NASH in children and test its potential association.

Definition of Terms

• NAFLD: an excess accumulation of fat in the liver that is not caused by alcohol consumption.
• NASH: a serious liver condition that arises from NAFLD, characterized by inflammation and damage to liver cells.
• Cirrhosis: a severe condition where healthy liver tissue is permanently replaced by scar tissue.
• Macrovesicular steatosis: characterized by an abnormal build-up of fat within liver cells, the earliest stage of NAFLD.

Hepatocytes and Portal Hypertension

• Hepatocytes: the powerhouses of the liver, performing vital functions such as metabolism, detoxification, protein synthesis, and bile production.
• Portal hypertension: a condition where the liver gets damaged or blocked, causing blood to back up and pressure to rise.

Pathophysiology

• The study of the abnormal functional changes that occur at the cellular and organ level during a disease or injury.

Materials and Methods

• Study conducted at Children’s Hospital in San Diego, California, focusing on pediatric patients diagnosed with NAFLD between 1997 and 2003.
• Subjects were identified retrospectively and prospectively, with written assent from subjects and consent from parents.
• Institutional review board approvals were obtained from the University of California–San Diego and Children’s Hospital, San Diego.

Diagnostic Criteria

• NAFLD diagnosis was made after excluding other causes of chronic hepatitis.
• Clinical data collected included demographic details, anthropometric measures, liver chemistry results, fasting insulin, and glucose levels.

Insulin Sensitivity Assessment

• Insulin sensitivity was assessed using two models: QUICKI and HOMA-IR.
• QUICKI is calculated as the reciprocal of the log of fasting insulin multiplied by fasting glucose.
• HOMA-IR is calculated as fasting insulin multiplied by fasting glucose divided by 22.5.
• Insulin resistance was defined as QUICKI ≤ 0.339 and HOMA-IR ≥ 2.0.

Histopathology

• Liver biopsies were performed percutaneously on the right lobe using a 15-gauge needle.
• Biopsies were ensured to be 1.5 cm or longer in length.
• Sections of the biopsies were stained with various techniques, including hematoxylin-eosin, periodic acid Schiff, and Masson trichrome.

Histological Features Evaluated

• Steatosis: quantified by the percentage of hepatocytes containing macrovesicular or microvesicular fat.
• Steatohepatitis features: such as balloon degeneration of hepatocytes, Mallory hyaline, glycogen nuclei, megamitochondria, lipogranulomas, and iron deposition.
• Fibrosis: evaluated perisinusoidal fibrosis and portal fibrosis using METAVIR criteria.

Type 1 and Type 2 NASH

• Type 1 NASH: characterized by steatosis with ballooning degeneration and/or perisinusoidal fibrosis, without significant portal inflammation.
• Type 2 NASH: characterized by steatosis with portal inflammation and/or fibrosis, but without ballooning degeneration or perisinusoidal fibrosis.

Key Findings

• 106 children participated in the study, with 92% being obese.
• 65% of the subjects were boys, and 35% were girls.
• 8% of the subjects had type 2 diabetes mellitus.
• 19% had mild steatosis, 28% had moderate steatosis, and 53% had severe steatosis.
• 83% had lipogranuloma, and 55% had glycogenated nuclei.
• 70% had portal inflammation, and 60% had portal fibrosis.

Discussion

• This study represents the largest biopsy series of pediatric NAFLD in 2005 and demonstrates a histological spectrum ranging from simple steatosis to NASH and cirrhosis.

• The histological profile most commonly observed in the subjects was a combination of severe steatosis with mild portal inflammation and fibrosis.

• Using cluster analysis, distinct histological patterns were identified, including two forms of steatohepatitis.

• This study further determined that age, sex, race, ethnicity, and severity of obesity are all associated with steatohepatitis.### The Role of Intestinal Microflora in Obesity

• An imbalance between Firmicutes and Bacteroids bacteria in obese individuals could be a potential therapeutic target for obesity treatment.

NAFLD in Boys vs Girls

• NAFLD is more common in boys than in girls, with boys being more likely to have NASH Type 2.
• Hormonal differences, specifically lower estrogen levels in boys, could contribute to this increased risk.
• Females with PCOS are also at higher risk of NAFLD due to shared risk factors such as insulin resistance, obesity, and hyperandrogenism.

Estrogen in Fatty Liver

• Estrogen has protective effects against NAFLD, promoting fatty acid breakdown.
• When estrogen levels decline, women are at higher risk of NAFLD, progressing from simple steatosis to NASH.

Girls with Type 1 vs Type 2 NASH

• Girls with Type 2 NASH are several years younger than those with Type 1 NASH and are more likely to be prepubertal with hormone profiles similar to boys with Type 2 NASH.
• In contrast, girls with Type 1 NASH are postmenarchal, with higher estrogen levels, supporting the role of estrogen in protecting against Type 2 NASH.

Type 1 vs Type 2 NASH

• Type 2 NASH is more common in children of Asian and Native American races, while Type 1 NASH is more common in the "White" race or those with European ancestry.

Conclusion

• The study highlights the importance of distinguishing between Type 1 and Type 2 NASH as distinct subtypes of pediatric NAFLD.
• Key differences between these categories include obesity levels, age, gender, and race/ethnicity.
• The findings have important implications for the investigation of the development, genetic factors, progression, and response to treatment of nonalcoholic fatty liver disease in children.