Nonalcoholic Fatty Liver Disease Pediatric Database 2 (NAFLD Pediatric Database 2)

General Description

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver conditions associated with fat accumulation that range from benign, non-progressive liver fat accumulation to severe liver injury, cirrhosis, and liver failure. NAFLD is highly prevalent within the United States and is most common in adults who are overweight or have diabetes, insulin resistance, or hyperlipidemia. However, the disease also occurs in children and in persons who are not obese or diabetic. The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) was initiated by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in 2002 to conduct multicenter, collaborative studies on the etiology, contributing factors, natural history, complications and treatment of NASH.

The NAFLD Pediatric Database 2 was a multicenter, prospective follow-up study of patients with NAFLD or nonalcoholic steatohepatitis (NASH) which aimed to investigate the etiology, pathogenesis, natural history, diagnosis, treatment, and prevention of NAFLD and NASH. The study included longitudinal follow-up of participants enrolled in earlier NASH CRN studies and recruited new participants. The study population included pediatric patients 2- 17 years old at the time of enrollment with histologically confirmed NAFLD or NASH located in the United States. Comprehensive data, including demographics, medical history, symptoms, medication use, alcohol use and routine laboratory studies was collected on all participants at entry and at follow-up visits every 48 weeks from enrollment. A standard of care liver biopsy was collected at baseline if not previously collected, and specimens were collected every 48 weeks during follow-up.

Objectives

Primary objective(s): The NAFLD Pediatric Database 2 study aimed to elucidate, through the cooperative effort of a multidisciplinary and multicenter group of collaborators, the etiology, natural history, diagnosis, treatment, and prevention of NAFLD, and in particular its more severe form of NASH and its complications. Additional primary objectives included enrolling at least 650 pediatric patients with a diagnosis of NAFLD; increasing the population diversity of the NAFLD Database to provide greater representation of Hispanic, Native American, African American, and Asian patients; and expanding the specimen bank comprised of liver tissue, serum, plasma, and DNA obtained from patients undergoing a liver biopsy.

Secondary objective(s): The secondary objectives of the NAFLD Pediatric Database 2 were to continue the analysis of the data obtained in the previous NAFLD Database study; to add to current NASH CRN resources for developing clinical and pathological criteria for standardizing diagnostic and staging criteria for NAFLD or NASH-related cirrhosis; to develop Magnetic Resonance Imaging (MRI) or Magnetic Resonance Spectroscopy (MRS) protocols to evaluate the utility of these diagnostic modalities for the non-invasive staging and grading of NAFLD; and to add to NASH CRN resources for ancillary studies of the pathogenesis, diagnosis or diagnostic biomarker development, genomic, proteomic and lipidomic characterization, natural history and treatment of NAFLD or NASH-related cirrhosis.

Outcome Measure

The following measures were used to assess primary and secondary outcomes of interest: liver histology scores (derived from central reading of standard of care biopsy done during screening or follow-up), change in ALT and AST levels, change in glucose and insulin levels, change in lipid profiles, and change in body mass index (BMI) and anthropometric data.

Criteria

Inclusion criteria:

• At least 2 years of age and up to 17 years of age as of the initial screening interview and provision of consent
• Willingness to participate in the study for 1 or more years
• Having undergone liver biopsy within 120 days of enrollment
• Collection of serum and plasma up to 90 days before or 4- 90 days after standard of care liver biopsy
• Minimal or no alcohol use history consistent with NAFLD

Exclusion criteria:

• Total parenteral nutrition for more than 1 month within a 6 month period before baseline liver biopsy
• Short bowel syndrome
• History of gastric or jejunoileal bypass preceding the diagnosis of NAFLD. Bariatric surgery performed following enrollment is not exclusionary. Liver biopsies obtained during bariatric surgery cannot be used for enrollment because of the associated surgical or anesthetic acute changes and the weight loss efforts that precede bariatric surgery
• History of biliopancreatic diversion
• Evidence of advanced liver disease defined as a Child-Pugh-Turcotte score equal to or greater than 10
• Evidence of chronic hepatitis B as marked by the presence of HBsAg in serum (participants with isolated antibody to hepatitis B core antigen, anti-HBc total, are not excluded)
• Evidence of chronic hepatitis C as marked by the presence of anti-HCV or HCV RNA in serum
• Low alpha-1-antitrypsin level and ZZ phenotype (both determined at the discretion of the investigator)
• Wilson's disease
• Known glycogen storage disease
• Known dysbetalipoproteinemia
• Known phenotypic hemochromatosis (HII greater than 1.9 or removal of more than 4 g of iron by phlebotomy)
• Prominent bile duct injury (florid duct lesions or periductal sclerosis) or bile duct paucity
• Chronic cholestasis
• Vascular lesions (vasculitis, cardiac sclerosis, acute or chronic Budd-Chiari, hepatoportal sclerosis, peliosis)
• Iron overload greater than 3+
• Zones of confluent necrosis, infarction, massive or sub-massive, pan-acinar necrosis
• Multiple epithelioid granulomas
• Congenital hepatic fibrosis

Outcome

A total of 971 participants (101 of which were continuing participants from prior NASH CRN studies) were included in the NAFLD Pediatric Database 2. Data collection began on October 5, 2009 and concluded on May 31, 2020. The histologic scoring system for review and grading of liver biopsies was further refined and expanded, and participants are being followed into adulthood, to better understand the natural history of NAFLD during the adolescent to adult transition. Participants will continue to be followed in NAFLD Pediatric Database 3 study (DB3), the third phase of the longitudinal NAFLD database study.