Prediction by Ultrasound of the Risk of Hepatic Cirrhosis in Cystic Fibrosis (PUSH)

Prediction by Ultrasound of the Risk of Hepatic Cirrhosis in Cystic Fibrosis (PUSH)

The specific aims for this study are:

1. To determine if sonographic findings predict the risk of progression of liver disease to cirrhosis by comparing cystic fibrosis subjects with heterogeneous echogenicity pattern on ultrasound to those with normal echogenicity pattern on ultrasound
2. To develop a database and biorepository of serum, plasma, urine and DNA to aid the investigations in ascertaining the mechanisms, consequences, genetic risk factors and biomarkers for the development of cirrhosis
3. To determine if there are differences in health related quality of life, pulmonary or nutritional status in children with cystic fibrosis who have a heterogeneous echo pattern on ultrasound compared to those who have a normal echo pattern on ultrasound
4. To determine if Doppler velocity measurements of hepatic and splenic vessels predict an increased risk for the development of cirrhosis.
5. To determine if cirrhosis on ultrasound progresses to portal hypertension during the study period
6. To determine if homogeneous liver progresses to either cirrhosis or heterogeneous liver.
7. To determine the frequency of complications of portal hypertension during follow up in those identified with cirrhosis by year 6 of the study

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis; Pancreatic Insufficiency
• Intervention / Treatment: Procedure: Abdominal Ultrasound; Other: Sample collection procedures

Detailed Description

For subjects in longitudinal follow up, this study will:

1. Collect detailed clinical and demographic information about each subject at enrollment and during follow up,
2. Obtain and store imaging data from the subject at entry and during follow up,
3. Obtain and store serum, plasma and urine samples from the subject at entry (after matching) and during follow up,
4. Obtain and store DNA from the subject,
5. Obtain and store DNA from the biological parents,
6. Obtain and store quality of life data from the subject and parents at enrollment and during follow up

• Study Type: Observational
• Enrollment (Actual): 774

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital of Colorado
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School Of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital of
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins School of Medicine
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minneapolis Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 12 years (Child)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study population will consist of males and females 3 through 12 years of age with Cystic Fibrosis and pancreatic insufficiency who are enrolled in the CFF or Toronto CF registry studies. All racial and ethnic groups will be included.

Description

Inclusion Criteria:

• Children aged 3 through 12 years of age at time of enrollment diagnosed with Cystic Fibrosis and pancreatic insufficiency
• Enrolled in the CFF registry study or Toronto CF Registry
• CF defined as sweat chloride of >60 mEq/L on one occasion (using the value in the CF registry) or two disease-causing mutations of CFTR with evidence of end organ involvement.

• Pancreatic insufficient defined as one of the following:

  • CFTR Mutation associated with pancreatic insufficiency
  • Fecal elastase <100 mcg/gm (at any time)
  • 72 hour fecal fat with coefficient of fat absorption <85% (at any time)

Exclusion Criteria:

• Known cirrhosis
• Presence of Burkholderia cepacia
• Short bowel syndrome defined as not on full enteral feeds by 3 months of age
• Presence of other serious disease precluding participation in this study (This would include patients with known other causes of chronic liver disease)
• If in the opinion of the Investigator the study is not in the best interest of the patient
• Inability to comply with the longitudinal follow-up described below
• Failure of a family to sign the informed consent document or the HIPAA medical record release form

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Group A; Approximately 60 subjects with a heterogeneous echo pattern of the liver on abdominal ultrasound (HTG US).	Procedure: Abdominal Ultrasound; To establish eligibility and/or markers regarding echo pattern types.; Other Names: Doppler Ultrasound; Other: Sample collection procedures; Samples of urine, serum, plasma, and blood for DNA from children and blood for DNA from parents will be requested from participating subjects; Other Names: Doppler Ultrasound
Group B; Approximately 680 subjects with a normal echo pattern on abdominal ultrasound (NL US). Of these subjects, approximately 110 will be matched 1:1 with Group A participants and followed for the duration of the study. The remaining unmatched subjects will not be followed beyond their initial visit.	Procedure: Abdominal Ultrasound; To establish eligibility and/or markers regarding echo pattern types.; Other Names: Doppler Ultrasound; Other: Sample collection procedures; Samples of urine, serum, plasma, and blood for DNA from children and blood for DNA from parents will be requested from participating subjects; Other Names: Doppler Ultrasound
Group C; An estimated 30 subjects with cirrhosis pattern on abdominal ultrasound. These subjects will be followed in the study.	Procedure: Abdominal Ultrasound; To establish eligibility and/or markers regarding echo pattern types.; Other Names: Doppler Ultrasound; Other: Sample collection procedures; Samples of urine, serum, plasma, and blood for DNA from children and blood for DNA from parents will be requested from participating subjects; Other Names: Doppler Ultrasound
Group D; An estimated 30 subjects with diffusely homogeneous echogenic pattern at screening ultrasound will be followed in the study.	Procedure: Abdominal Ultrasound; To establish eligibility and/or markers regarding echo pattern types.; Other Names: Doppler Ultrasound; Other: Sample collection procedures; Samples of urine, serum, plasma, and blood for DNA from children and blood for DNA from parents will be requested from participating subjects; Other Names: Doppler Ultrasound

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Development of cirrhosis, as defined by imaging criteria	The primary objective of this prospective longitudinal study is to determine the utility of abdominal ultrasound (US) at enrollment to predict the development of cirrhosis in subjects with cystic fibrosis (CF) within a nine year period.	Nine years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effects on associated pulmonary and nutritional issues	Health related quality of life; Growth (length, weight and BMI Z-score, anthropometrics); AST,ALT,GGTP; FEV1, FVC; Sputum Culture (Pseudomonas, Burkholderia cepacia); Use of IV antibiotics; Hospitalization for treatment of pulmonary exacerbation; CBC (WBC, Hbg, ANC, platelet count); Fat soluble vitamin levels (Vitamin E, 25 hydroxy vitamin D, Vitamin A)	9years

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Collaborators: Cystic Fibrosis Foundation
• Investigators: Study Chair: Michael Narkewicz, MD, Children's Hospital Colorado; Study Director: Ed Doo, MD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Study Director: Averell Sherker, MD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications and helpful links

General Publications

• Leung DH, Ye W, Molleston JP, Weymann A, Ling S, Paranjape SM, Romero R, Schwarzenberg SJ, Palermo J, Alonso EM, Murray KF, Marshall BC, Sherker AH, Siegel MJ, Krishnamurthy R, Harned R, Karmazyn B, Magee JC, Narkewicz MR; Cystic Fibrosis Liver Disease Network (CFLD NET). Baseline Ultrasound and Clinical Correlates in Children with Cystic Fibrosis. J Pediatr. 2015 Oct;167(4):862-868.e2. doi: 10.1016/j.jpeds.2015.06.062. Epub 2015 Aug 5.

Helpful Links

• PUSH is a study in the ChiLDREN Network

Study record dates

Study Major Dates

• Study Start (Actual): January 12, 2010
• Primary Completion (Actual): February 26, 2021
• Study Completion (Actual): June 14, 2023

Study Registration Dates

• First Submitted: June 14, 2010
• First Submitted That Met QC Criteria: June 14, 2010
• First Posted (Estimated): June 15, 2010

Study Record Updates

• Last Update Posted (Estimated): November 3, 2023
• Last Update Submitted That Met QC Criteria: November 1, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Cystic Fibrosis; Pancreatic insufficiency
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Liver Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Liver Cirrhosis; Cystic Fibrosis; Exocrine Pancreatic Insufficiency
• Other Study ID Numbers: CFLD PUSH; U01DK062456 (U.S. NIH Grant/Contract)