Relationship Between the Development of Impaired Glucose Tolerance, the Phenotype of CFLD, and the Risk of Liver Fibrosis

This study proposes to examine the relationship between the development of impaired glucose tolerance, the phenotype of CFLD, and risk of liver fibrosis.

Study Overview

• Status: Withdrawn
• Conditions: Cystic Fibrosis-related Diabetes; Cystic Fibrosis Liver Disease; CF - Cystic Fibrosis
• Intervention / Treatment: Device: Fibroscan

Detailed Description

Pancreas insufficiency is a well-established risk factor for development of CF related diabetes (CFRD), but increased insulin resistance has also been demonstrated in this population. Cystic fibrosis liver disease (CFLD) is a well-established risk factor for the development CFRD. In addition, patients with CFLD and CFRD at high risk of development of severe CFLD and cirrhosis. Recent work has shown that male CF patients with abnormal oral glucose tolerance tests were noted to have elevations in ALT but the significance of this finding has yet to be fully explored. Specifically, an unresolved question remains on whether the elevation in ALT reflects a steatohepatitis as would be observed in a non-CF population or if the increased insulin resistance contributes to fibrosis progression in the classic biliary type cirrhosis seen in cystic fibrosis (CF).

Metabolic dysfunction with increasing insulin resistance has been shown to be a key component to the development of non-alcoholic steatosis hepatitis in a non-CF population. The presence of hepatic steatosis has been demonstrated in the CF population, but thus far not been linked to the development of significant steatohepatitis or cirrhosis. One potential explanation for this discordance between effects of hepatic steatosis in the CF and non-CF population, is in the non-CF population it requires multiple decades for hepatic steatosis to result in steatohepatitis and progression to cirrhosis, therefore the progressive fibrosis may not be seen in the CF population due to limited life expectancy. However, as the life expectancy in of patients with CF is increasing with new therapy, the longer-term consequences of hepatic steatosis maybe apparent

Alternatively, the presence of increased insulin resistance has been correlated to increase fibrosis progression in other forms of liver disease such as hepatitis C. Therefore, another potential mechanism is the insulin resistance seen in patients with CFRD results in increased fibrosis and development of cirrhosis in patients with classic CFLD. Thus, further characterizing the underlying liver disease phenotype and fibrosis risk in this population is of interest. We propose to examine the relationship between the development of impaired glucose tolerance, the phenotype of CFLD, and risk of liver fibrosis.

• Study Type: Interventional
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mary C. Drinane, MD; Phone Number: (603) 650-5261; Email: Mary.C.Drinane@Hitchcock.org

Study Locations

• United States
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Men and women ≥ 18 with CF and one of the following:

  • Normal OGTT
  • Elevated OGTT
  • Known CFRD

Exclusion Criteria:

• Men and women without CF

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Fibroscan; One study visit for fibroscan measurement of the liver.	Device: Fibroscan; Subjects will fast for at least three hours, then have at least 10 fibroscan readings of their liver.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess Phenotype of CFLD	Assess phenotype of CFLD via a Fibroscan performed after a >3 hour fast	Visit 1, Day 1
Assess Value of Complete Blood Count of CFLD	Assess phenotype of CFLD via a complete blood count (CBC)	Visit 1, Day 1
Assess Hepatic Function of CFLD	Assess phenotype of CFLD via a hepatic function test	Visit 1, Day 1
Assess Oral Glucose of CFLD	Assess phenotype of CFLD via an oral glucose tolerance test	Visit 1, Day 1
Assess CFLD via abdominal imaging	Assess phenotype of CFLD via abdominal imaging (CT abdomen, Ultrasound, or MRI). If the subject has had a CT of the abdomen, Ultrasound or MRI of the abdomen as part of their standard care, the data will be collected. These procedures will not be performed as part of this study.	Visit 1, Day 1

Collaborators and Investigators

• Sponsor: Dartmouth-Hitchcock Medical Center
• Collaborators: Trustees of Dartmouth College
• Investigators: Principal Investigator: Mary C. Drinane, MD, Dartmouth-Hitchcock Medical Center

Publications and helpful links

General Publications

• Kayani K, Mohammed R, Mohiaddin H. Cystic Fibrosis-Related Diabetes. Front Endocrinol (Lausanne). 2018 Feb 20;9:20. doi: 10.3389/fendo.2018.00020. eCollection 2018.
• Toledano MB, Mukherjee SK, Howell J, Westaby D, Khan SA, Bilton D, Simmonds NJ. The emerging burden of liver disease in cystic fibrosis patients: A UK nationwide study. PLoS One. 2019 Apr 4;14(4):e0212779. doi: 10.1371/journal.pone.0212779. eCollection 2019.
• Colomba J, Netedu SR, Lehoux-Dubois C, Coriati A, Boudreau V, Tremblay F, Cusi K, Rabasa-Lhoret R, Leey JA. Hepatic enzyme ALT as a marker of glucose abnormality in men with cystic fibrosis. PLoS One. 2019 Jul 18;14(7):e0219855. doi: 10.1371/journal.pone.0219855. eCollection 2019.
• Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018 Jul;24(7):908-922. doi: 10.1038/s41591-018-0104-9. Epub 2018 Jul 2.
• Hui JM, Sud A, Farrell GC, Bandara P, Byth K, Kench JG, McCaughan GW, George J. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]. Gastroenterology. 2003 Dec;125(6):1695-704. doi: 10.1053/j.gastro.2003.08.032. Erratum In: Gastroenterology. 2004 Feb;126(2):634.

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2022
• Primary Completion (Estimated): June 1, 2023
• Study Completion (Estimated): December 1, 2023

Study Registration Dates

• First Submitted: December 21, 2021
• First Submitted That Met QC Criteria: February 4, 2022
• First Posted (Actual): February 8, 2022

Study Record Updates

• Last Update Posted (Actual): July 13, 2023
• Last Update Submitted That Met QC Criteria: July 12, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Hyperglycemia; Pancreatic Diseases; Liver Diseases; Fibrosis; Liver Cirrhosis; Glucose Intolerance; Cystic Fibrosis
• Other Study ID Numbers: STUDY02001342

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There is no plan to make IPD available to other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No