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

General Description

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver conditions that can progress to significant fibrosis and cirrhosis. There are an estimated 40-90 million individuals within the United States with NAFLD, 10- 30% of whom have NASH and may develop NASH-related cirrhosis. Identifying through non- invasive means those individuals who are at risk for progressive liver disease remains challenging.

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 Adult Database 2 continued the longitudinal follow-up of participants enrolled in earlier NASH CRN studies and recruited new participants with recent liver biopsies. Comprehensive data, including demographics, medical history, symptoms, medication use, alcohol use and routine laboratory studies were collected on all participants at entry and at annual visits for up to 10 years after enrollment. A liver biopsy was collected at baseline if not collected in a prior NASH CRN study. Study questionnaires administered at enrollment included Skinner Lifetime Drinking history, Alcohol Use Disorders Identification Test (AUDIT) and Beverage Questionnaire (BEVQ-15).

Specimens were collected every 48 weeks during follow-up. If liver biopsies were obtained as part of routine patient care, they were scored using the NASH CRN NAFLD Activity Score (NAS) and fibrosis score. The Interim drinking history (AUDIT-C) and BEVQ-15 were collected at follow-up visits.

Objectives

Primary objective(s): To further investigate the etiology, pathogenesis, natural history, diagnosis, treatment, and prevention of nonalcoholic fatty liver disease (NAFLD) and in particular its more severe form of NASH and understand disease variations occurring in an ethnically diverse group of patients.

Secondary objective(s): To provide a resource for developing clinical and pathological criteria for standardizing diagnostic and staging criteria for NAFLD or NASH-related cirrhosis through development of novel biomarkers and technologies such as genomics and innovative imaging technologies.

Outcome Measure

The primary and secondary objectives of the NAFLD Adult Database 2 were intentionally broad to answer expected unaswered questions related to the etiology, natural history, diagnosis, treatment, and prevention of NAFLD. The following measures were used to answer outcomes of interest: liver histology scores (from central reading of liver biopsy at entry, standard of care biopsy done during screening or follow-up, or liver biopsy obtained from previous NASH CRN study participation), glucose, insulin, ALT and AST levels, lipid profile, body mass index and anthropometric data, alcohol consumption data and medication use.

Criteria

Inclusion criteria:

• Age at least 18 years during the consent process
• Willingness to be in the study for 1 or more years
• Ability and willingness to give written, informed consent to be screened for and, if eligible, to be enrolled into the Database 2 study
• Minimal or no alcohol use history consistent with NAFLD (see exclusion criteria)
• Collection of a liver biopsy that is obtained within 120 days of enrollment as part of standard of care or for evaluation in FLINT trial
• Collection of biosamples (serum, plasma, DNA, and, if available, liver tissue) within 90 days prior to enrollment and 0-90 days before or 4-90 days after the standard of care liver biopsy

Exclusion criteria:

• Clinical or histological evidence of alcoholic liver disease or alcohol consumption during the two years before entry (> 20g/day for men, >10g/day women)
• History of total parenteral nutrition
• History of gastric or jejunoileal bypass preceding the diagnosis of NAFLD
• Biliopancreatic diversion or bariatric surgery
• Evidence of advanced liver disease with Child-Pugh-Turcotte score equal to or greater than 10
• Short bowel syndrome
• Suspected or confirmed hepatocellular carcinoma
• Positive for HIV
• Evidence of HBV or HCV infection
• Low alpha-1-antitrypsin level and ZZ phenotype
• Wilson's disease
• Known glycogen storage disease, dysbetalipoproteinemia, phenotypic hemochromatosis
• Vascular lesions
• Iron overload greater than 3+
• Zones of confluent necrosis, infarction, massive or sub-massive, pan-acinar necrosis
• Multiple epithelioid granulomas
• Congenital hepatic fibrosis
• Polycystic liver disease
• Other metabolic or congenital liver disease
• Disseminated or advanced malignancy
• Concomitant severe underlying systemic illness or active drug use or dependence that in the opinion of the investigator would interfere with completion of follow-up

Outcome

A total of 2501 participants (657 of which were continuing participants from prior NASH CRN studies) were included in the NAFLD Adult Database. 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 FibroScan examinations implemented. A landmark manuscript was published on the clinical outcomes in adult patients with NAFLD.

Participants will continue to be followed in NAFLD Database 3 study (DB3), the third phase of the longitudinal NAFLD database study.