Liver Metabolic Functions in Patients With Citrin Deficiency and Healthy Subjects

NCT07055269 | Active Not Recruiting DMC

• 1 other identifier: 2025-00730
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Citrin is an aspartate-glutamate transporter in the liver that facilitates the urea cycle pathway for ammonia detoxification via ureagenesis. It is also thought to be involved in liver energy metabolism as a component of the malate-aspartate shuttle. The clinical presentation in patients supports the hypothesis that liver glycolytic, gluconeogenic and lipogenic functions are compromised in citrin deficiency, but none of the key hepatic pathway fluxes have been measured in patients to date. This is the first study that will examine the liver metabolic fluxes in patients with citrin deficiency. Liver metabolic functions will be examined by metabolic flux assays and biochemical measurements after application of stable isotopes 2H2O and \[U-13C6\]-fructose. Urea cycle metabolites and their enrichment after application of a stable isotope tracer 15NH4Cl will be measured to examine the liver's ability to detoxify ammonia into urea.

Conditions

Citrin Deficiency

Keywords

Citrin Deficiency; Adolescent and Adult Citrin Deficiency, AACD; SLC25A13; liver metabolic flux; ureagenesis; Citrin

Outcome Measures

Primary Outcomes (1)

• Liver metabolic flux

  Liver metabolic flux will be measured by assessing the distribution of the administered isotope tracers \[U-13C6\]-fructose and heavy water.

  5 days

Secondary Outcomes (5)

• Ureagenesis capacity

  1 day

• adverse events

  5 days

• liver fat content

  1 day

• Liver fibrosis

  1 day

• Clinical symptoms

  1 day

Study Arms (2)

AACD patient

EXPERIMENTAL

isotope tracer for ureagenesis and liver metabolic flux

Other: liver metabolic flux; Other: ureagenesis capacity

healthy volunteer

EXPERIMENTAL

isotope tracer for ureagenesis and liver metabolic flux

Other: liver metabolic flux

Interventions

liver metabolic flux OTHER

All participants will be given heavy water (2H2O, deuterium-labelled) and \[U-13C6\]-fructose orally, each followed by the collection of one blood plasma sample. Additional biochemical and clinical parameters including liver fat content by MRI, liver fibrosis and cirrhosis by ultrasound imaging and plasma biochemical profiles will be analyzed.

AACD patient; healthy volunteer

ureagenesis capacity OTHER

urea and urea cycle metabolites and their enrichment after oral administration of a stable isotope tracer 15NH4Cl will be measured to examine the liver's ability to detoxify ammonia.

AACD patient

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects with citrin deficiency, confirmed by genetic analysis to carry pathogenic variant(s) in the SLC25A13 gene
• Age from 18 years to 65 years inclusive
• Male or female
• Written informed consent has been given
• Understands and is willing, able and likely to comply with study procedures and restrictions
• Age from 18 years to 65 years inclusive, and not more than five years younger or older than the specified paired participant from the AACD group
• Same sex as the specified paired participant from the AACD group
• Same ethnicity the specified paired participant from the AACD group
• Written informed consent has been given
• Understands and is willing, able and likely to comply with study procedures and restrictions

You may not qualify if:

• acute and chronic disease requiring treatment of any kind, other than his/her AACD
• females who are pregnant or lactating or attempting to become pregnant
• use of any medication which, in the opinion of the investigator, is likely to interfere with liver function
• carry any pathogenic variant in the SLC25A13 gene
• current or recurrent disease that could affect the metabolic function of the liver
• acute and chronic disease requiring treatment of any kind
• females who are pregnant or lactating or attempting to become pregnant
• use of any medication which, in the opinion of the investigator, is likely to interfere with liver function
• weight loss ≥10% within 3 months before study screening
• daily alcohol consumption of more than 2 standard-sized beer for men and more than 1 standard-sized beer for women, or the equivalent
• BMI \> 30 kg/m2
• currently smoking \>1 cigarette daily
• liver transplant recipients
• type 1 and 2 diabetes
• currently on a ketogenic diet

Sponsors & Collaborators

• Johannes Haeberle: lead
• Citrin Foundation: collaborator
• Marc Hellerstein, University of Berkeley: collaborator

Study Sites (1)

University Children's Hospital Zurich

Zurich, 8008, Switzerland

Location

MeSH Terms

Conditions

Adult-onset citrullinemia type 2

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Head of Metabolic Laboratory

Model Details: Cross-sectional observational study, non-randomised

Study Record Dates

• First Submitted: June 25, 2025
• First Posted: July 8, 2025
• Study Start: October 20, 2025
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): September 1, 2026
• Last Updated: January 8, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

CH (1)