Clinical trial NCT05229640: Relationship Between the Development of Impaired Glucose Tolerance, the Phenotype of CFLD, and the Risk of Liver Fibrosis
Official title: Relationship Between the Development of Impaired Glucose Tolerance, the Phenotype of CFLD, and the Risk of Liver Fibrosis
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: NA
Conditions: CF - Cystic Fibrosis
Cystic Fibrosis-related Diabetes
Cystic Fibrosis Liver Disease
Lead sponsor: Dartmouth-Hitchcock Medical Center
Sponsor class: OTHER
Collaborators: name: Trustees of Dartmouth College
First posted: 2022-02-08
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

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

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.

Eligibility criteria: 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

Primary outcomes:
measure: Assess Phenotype of CFLD
timeFrame: Visit 1, Day 1
measure: Assess Value of Complete Blood Count of CFLD
timeFrame: Visit 1, Day 1
measure: Assess Hepatic Function of CFLD
timeFrame: Visit 1, Day 1
measure: Assess Oral Glucose of CFLD
timeFrame: Visit 1, Day 1
measure: Assess CFLD via abdominal imaging
timeFrame: Visit 1, Day 1
Secondary outcomes:
Other outcomes:
Locations:
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
Study officials:
affiliation: Dartmouth-Hitchcock Medical Center
name: Mary C. Drinane, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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 2019.
citation: 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.
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.
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.gastro.2003.08.032.