Advanced Molecular Imaging of Cholestatic Disorders in Humans: Pathophysiological Characterization
试验速览
- 阶段
- 不适用
- 状态
- Enrolling By Invitation
- 入组人数
- 22
- 试验地点
- 1
- 主要终点
- The aim of this study is to apply the 11C-CSAR PET/CT method to quantify hepatobiliary secretion kinetics of 11C-Csar in both healthy human participants and patients with various cholestatic disorders, including those of genetic origin.
研究概览
简要总结
Purpose The primary goal is to study liver diseases with defects in bile excretion. Investigators aim to do this using a radioactive tracer that mimics human bile and can be visualized with a PET/CT scanner. This will help us understand where these defects occur and how they might be treated in the future.
Background Patients with liver diseases affecting bile excretion are at risk of developing cirrhosis. When bile cannot be excreted normally, it accumulates in the liver, damaging its function. It can also build up in the skin, causing yellowing and itching. Currently, patients are monitored using blood tests that do not always reflect the severity of liver disease. There are a few medications available, but they have limited efficacy.
Advanced PET/CT scanning with the radioactive tracer 11C-Csar offers a way to investigate this. 11C-Csar has been developed, tested, and approved for human use at Aarhus University Hospital and has been used in previous patient studies.
The study aims to use this method to show how 11C-Csar moves through the liver and bile ducts in both healthy individuals and patients with a genetic liver disease. Investigators aim to:
- Observe how defects affect the liver handling of bile acids.
- Determine the excretion kinetics of 11C-Csar, including specific rate constants.
- Compare standard blood tests with 11C-Csar PET/CT findings to assess how well blood tests reflect actual liver damage.
- Visualize potential targets for future interventions.
Study Plan The scientific study involves a single examination day at the Department of Nuclear Medicine and PET. Participants will arrive fasting in the morning. An intravenous line will be placed in both arm veins, a catheter in a wrist vessel, and a hepatic vein catheter. The hepatic vein catheter will be inserted by a trained liver specialist using local anesthesia and ultrasound guidance, confirmed by X-ray. The tracer 11C-Csar and the dye indocyanine green (ICG) will be administered through the IV lines. ICG will be infused 90 minutes before scanning, and 11C-Csar will be administered at the start of the scan. Blood samples will be taken from the liver and wrist during the scan, which lasts about 45 minutes. After the scan, the catheters will be removed, and the participant can go home shortly after. Approximately 250-300 ml of blood will be drawn, which poses no risk to the participants. The total participation time is expected to be around 4 hours. Some patients may be offered a second scan if they develop new symptoms, repeating the scan when liver blood tests normalize.
Participants Patients with bile accumulation liver diseases will be informed of the study during visits to the Department of Hepatology and Gastroenterology, AUH. Healthy controls will be recruited through advertisements on webpages dedicated for the purpuse. Interested individuals will receive written information.
Side Effects, Risks, and Discomfort The risk of phlebitis and bleeding from IV insertion is minimal, as these procedures are performed daily.
The total radiation exposure from the PET/CT scan with 11C-Csar is 2.5 mSv.
Funding The study is researcher-initiated, with no financial interests for the involved researchers.
Publication of Results Both negative, positive, and inconclusive results will be published. The study results will be submitted to peer-reviewed international journals in liver disease and/or radiology and presented at national and international scientific conferences.
Ethics The study will be conducted following the principles of the Helsinki Declaration II with amendments and after approval by the Regional Ethics Committee for Midtjylland. While there is no immediate benefit for patients, the results will enhance our understanding of liver disease with bile acid accumulation. Investigators believe the risks and potential side effects are outweighed by the expected benefits.
详细描述
Background
Cholestasis is defined as a decreased flow of bile from the liver to the duodenum, either due to reduced excretion from the liver, defects in the enterohepatic circulation or blockage of the biliary tree. Bile acids are essential for the absorption of lipophilic compounds from the intestine. [1] When bile acids accumulate in the liver, it causes damage to the tissue.
Patients with cholestasis typically present with jaundice and pruritus caused by the bile acids accumulating in the skin. Elevated blood levels of alkaline phosphatases (AP), gamma-glutamyl transferase, and sometimes bilirubin are observed [2]. The clinical workup includes ultrasound sonography (US) to exclude tumours/stones and specific blood tests, including autoantibodies, immunoglobulins, etc. A thorough history of familial diseases and medicine intake is also important for workup [1]. A liver biopsy can be necessary to evaluate hepatic histopathological changes in the liver. Treatment depends on the specific cause. The present project deals with medical causes of cholestasis as described below, i.e., not mechanical obstruction such as cancer or gallstones.
Monitoring medical cholestatic disorders relies on continuous blood measurements of AP, bilirubin, etc. Still, these tests do not necessarily convey information about the degree of cholestasis from a functional point of view.
The enterohepatic circulation Intact enterohepatic circulation is important since de novo synthesis of bile acids does not play a significant role in enterohepatic circulation.[3] Bile acids are absorbed in the terminal ilium by the ileal bile acid transporter (ASBT/SLC10A2) and secreted into the portal vein, which delivers the bile acids back to the liver. Here, the Na+-taurocholate co-transporting peptide (NTCP) and organic anion- transporting proteins (OATPs) mediate bile uptake from the sinusoids to hepatocytes.[4] The bile salt export pump (BSEP) facilitates the transport from hepatocytes into bile canaliculi. The multidrug resistance proteins 3 and 4 (MRP3/ABCC3, MRP4/ABCC4) and the heteromeric organic solute transporter (OSTa/b/SLC51A/SLC51B) mediate backflux from hepatocytes to blood. [3] All these transporters can be defective in different genetic diseases and lead to cholestasis, which is the case in patients with progressive familial intrahepatic cholestasis (PFIC), including protein-truncating mutations in tight-junction protein 2 gene (TJP2) and mutations in bile salt export pump (BSEP). Some of these patients will debut with drug-induced liver disease (DILI) or have recurrent cholestasis.
研究设计
- 研究类型
- Observational
- 观察模型
- Other
- 时间视角
- Other
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Criteria for inclusion of healthy individuals
- •No prior or current history of liver diseases
- •No medication that interferes with the hepatobiliary system
- •Age above 18
- •A signed consent must be present on the day of the 11-CSAR PET/CT scan.
- •A negative pregnancy test performed on the day of the scan.
排除标准
- •Prior cholecystectomy
- •Pregnancy
- •Assessed ineligibility by a medical doctor based on blood parameters measured at inclusion if these are abnormal.
- •Claustrophobia or the inability to remain still during a 45-minute scan.
- •Criteria for inclusion of patients with cholestasis
- •Cholestasis at the time of inclusion, measured by elevated AP, bilirubin, or both.
- •Ultrasound sonography which ruled out mechanical obstruction.
- •Age above 18
- •A signed consent must be present on the day of the 11C-CSAR PET/CT scan.
- •A negative pregnancy test performed on the day of the scan. Criteria for exclusion of patients with cholestasis
- •Pregnancy
- •Claustrophobia or the inability to remain still during a 45-minute scan.
- •Coagulation deficiency that does not allow hepatic vein catheter (relative).
结局指标
主要结局
The aim of this study is to apply the 11C-CSAR PET/CT method to quantify hepatobiliary secretion kinetics of 11C-Csar in both healthy human participants and patients with various cholestatic disorders, including those of genetic origin.
时间窗: through study completion, an average of 2 years
Changes in the hepatobiliary excretion kinetics of 11C-CSar between patients and healthy
次要结局
未报告次要终点