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

Cystic Fibrosis-related Diabetes Clinical Trial

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT05229640
• Other study ID #: STUDY02001342
• Status: Withdrawn
• Phase: N/A
• Start date: March 31, 2022
• Est. completion date: December 2023

Study information

• Verified date: July 2023
• Source: Dartmouth-Hitchcock Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: December 2023
• Est. primary completion date: June 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cystic Fibrosis
• Cystic Fibrosis Liver Disease
• Cystic Fibrosis-related Diabetes
• Fibrosis
• Glucose Intolerance
• Liver Cirrhosis
• Liver Diseases

Intervention

Device:
• Fibroscan
Subjects will fast for at least three hours, then have at least 10 fibroscan readings of their liver.

Locations

Country	Name	City	State
United States	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire

Sponsors (2)

Lead Sponsor	Collaborator
Dartmouth-Hitchcock Medical Center	Trustees of Dartmouth College

Country where clinical trial is conducted

United States, 

References & Publications (5)

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. — View Citation

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. — View Citation

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.gast — View Citation

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. — View Citation

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 20 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Assess Phenotype of CFLD	Assess phenotype of CFLD via a Fibroscan performed after a >3 hour fast	Visit 1, Day 1
Primary	Assess Value of Complete Blood Count of CFLD	Assess phenotype of CFLD via a complete blood count (CBC)	Visit 1, Day 1
Primary	Assess Hepatic Function of CFLD	Assess phenotype of CFLD via a hepatic function test	Visit 1, Day 1
Primary	Assess Oral Glucose of CFLD	Assess phenotype of CFLD via an oral glucose tolerance test	Visit 1, Day 1
Primary	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