Effect of Fatty Liver on TCA Cycle Flux and the Pentose Phosphate Pathway

• Conditions: Fatty Liver
• Interventions: Drug: MRI Tracer

• Registration Number: NCT03480594
• Lead Sponsor: University of Texas Southwestern Medical Center

Brief Summary

The investigators plan to evaluate sensitivity and specificity of HP 13C-pyruvate as an imaging agent for detection of altered PDH flux in fatty liver.

Detailed Description

The investigators plan to determine whether nutritional state and fatty liver influence the production of \[13C\]bicarbonate from \[1-13C\]pyruvate via flux through the pyruvate dehydrogenase (PDH) reaction in healthy subjects compared to those with fatty liver. The long-term purpose of this work is to develop hyperpolarized 13C imaging as a method to directly assess metabolic pathways in the human liver. Many high-impact diseases such as insulin resistant states, fatty liver and inborn errors of metabolism are known to alter biochemical fluxes and for this reason it is important to detect altered activity in specific pathways.

Study Timeline

• Study First Submitted: 2018-03-21
• Study First Submitted QC: 2018-03-21
• Study First Posted: 2018-03-29
• Study Start: 2018-10-01
• Status Verified: 2024-01
• Last Update Submitted: 2024-01-08
• Last Update Posted: 2024-01-10
• Primary Completion: 2024-12-31
• Study Completion: 2024-12-31

Recruitment & Eligibility

• Status: ENROLLING_BY_INVITATION
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

• Ages 18 to 99 years.
• All races, ethnicities and gender identification may be included. Subjects must meet all of the inclusion and exclusion criteria to be included in the study.
• Either fatty liver diagnosis (defined as >5.6% fat content in the liver) or healthy control
• While all races and ethnicities will be included, subjects must be able to read and speak the English language. Once the protocol is established, Spanish-speaking participants will be included.
• Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

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Exclusion Criteria

Fatty Liver Subjects

• No subjects taking hypoglycemic agents or insulin will be enrolled. There is no exclusion based on fasting glucose.
• Subjects with major mental health conditions such as schizophrenia and bipolar disorder that would limit compliance with study requirements will not participate. In general, subjects with any form of medical instability such as seizure disorders, significant COPD, significant asthma, left ventricular dysfunction will not participate.
• Medications for control of hypercholesterolemia, hypertriglyceridemia or hyperglycemia.

Healthy Control Subjects

• Liver disease or other chronic illness
• Diagnosis of type I or type II diabetes
• No subjects taking hypoglycemic agents or insulin will be enrolled. There is no exclusion based on fasting glucose.
• A potential subject with any major medical, surgical or psychiatric condition will not participate. These conditions include but are not limited to thyroid disease, chronic metabolic illness, known vascular disease, current cancer diagnosis and/or treatment.
• Subjects with major mental health conditions such as schizophrenia and bipolar disorder that would limit compliance with study requirements will not participate. In general, subjects with any form of medical instability such as seizure disorders, significant COPD, significant asthma, left ventricular dysfunction will not participate.
• Medications for control of hypercholesterolemia, hypertriglyceridemia or hyperglycemia.

All Subjects

• No prior hepato-biliary surgery.
• Donated blood within the prior 4 weeks.
• Consume more than 10 grams of ethanol per day.
• Cirrhosis or any form of viral hepatitis.
• Prior documented hepatic reaction to drugs with a known hepatotoxicity profile such as isoniazid, methotrexate, phenytoin, propylthiouracil, valproate, etc.
• Pregnant/Lactating
• Receiving any other investigational agents.
• Any contraindication noted on the UTSWMC MRI Screening Form including implants contraindicated at 3T, pacemakers, Implantable Cardioverter Defibrillators (ICD), etc., and significant claustrophobia.

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Fatty Liver Patients	MRI Tracer	Hyperpolarized \[13C\] Pyruvate Injection in Fatty Liver patients
Healthy Control Subjects	MRI Tracer	Hyperpolarized \[13C\] Pyruvate Injection in Healthy Control Subjects

Primary Outcome Measures

Name	Time	Method
Bicarbonate:lactate ratio	One visit of 6 hours; two injections of HP pyruvate with MRI over 3 hours	1. The ratio of hyperpolarized \[13C\]bicarbonate relative to hyperpolarized \[1-13C\]lactate. This measurement will be monitored from the subject's liver over a \~4 minute period in the MRI system.

Secondary Outcome Measures

Name	Time	Method
Labeled glycerol fraction	One visit of 6 hours; ingestion of Oral Glycerol with blood draws over 3 hours	2. The fraction of \[U-13C\]glycerol that has passed through mitochondrial pathways prior to gluconeogenesis and the fraction of glucose, derived from \[U-13C\]glycerol, that has passed through the pentose phosphate pathway. This information will be acquired from 13C NMR spectroscopy of glucose and triglycerides from a venous blood sample, obtained after the hyperpolarization exam.

Trial Locations

Locations (1)

Advanced Imaging Research Center; 🇺🇸 Dallas, Texas, United States