Ursodeoxycholic Acid in Bariatric Surgery

Effects of Ursodeoxycholic Acid on Hepatobiliary Detoxification/Elimination Mechanisms and Hepatic Fatty Acid/Triglyceride Metabolism in Morbidly Obese Patients.

In an open-label trial, 20 otherwise healthy morbidly obese patients scheduled for bariatric surgery will be administered 20 mg/kg/day ursodeoxycholic acid for three weeks until the day before surgery. The maximum dose will be 3 g/day. Twenty other patients will serve as controls. Serum from days 1 and 21 will be analyzed for routine liver tests, bile acids, a complete lipid profile including FA and in addition for 7α-hydroxy-4-cholesten-3-one and fibroblast growth factor 19 (FGF-19), markers for bile acid synthesis its intestinal stimulation. For the evaluation of insulin resistance and possible pre-diabetes, plasma will be taken for the estimation of homeostasis model assessment (HOMA) index and oral glucose tolerance test (OGTT) will be performed at days 1 and 21. At surgery, a liver biopsy (0.5-1 g) and a white adipose tissue (WAT) specimen (1 cm2) will be taken and immediately frozen in liquid nitrogen for messenger ribonucleic acid (mRNA) and protein preparation for quantitative real-time polymerase chain reaction (RT-PCR) and Western analysis, respectively, histopathological Non-alcoholic fatty liver disease (NAFLD) grading, and measuring of hepatic and white adipose tissue (WAT) lipase activity. In all patients at randomization, abdominal ultrasound will be performed for the detection of NAFLD and gallstones and a blood sample will be taken for the analysis of polymorphisms of hepatic lipid synthesis, storage, fatty acid (FA) oxidation and export genes. Six month after operation, HOMA, OGTT and abdominal ultrasound will be repeated.

Study Overview

• Status: Completed
• Conditions: Non-alcoholic Fatty Liver Disease; Morbid Obesity
• Intervention / Treatment: Drug: Ursodeoxycholic Acid (UDCA)

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• BMI ≥ 35 kg/m2
• Patients eligible to bariatric surgery
• Patients should have given their written consent to participate in this study

Exclusion Criteria:

• Chronic liver disease other than NAFLD (viral hepatitis, autoimmune liver disease, hemochromatosis, homozygous alpha1-antitrypsin deficiency and Wilson disease)
• Partial ileal bypass
• Inflammatory bowel disease
• Uncontrolled diabetes mellitus (fasting blood glucose > 6.7 mmol/L), hypothyroidism or hyperthyroidism, or other significant endocrine disease.
• A subject who is euthyroid on a stable replacement dose of thyroid hormone is acceptable provided the TSH is within normal range.
• Other serious disease
• Known hypersensitivity to ursodeoxycholic acid
• Patients who will not comply with the protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control; Untreated controls
Active Comparator: Ursodeoxycholic acid; Oral ursodeoxycholic acid 20 mg/kg/day in three weeks	Drug: Ursodeoxycholic Acid (UDCA); 20mg/kg/day UDCA in three weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in regulators of lipid turnover	Trial objectives are to determine whether (i) Hepatic and/or visceral white adipose tissue (WAT) lipase activity determines fatty acid (FA) release/balance from lipid triglyceride (TG) droplets and FA-mediated lipotoxicity in NAFLD; differences in hepatic and/or WAT activity could explain individual susceptibility to pure NAFL versus NASH (ii) UDCA (20 mg/kg/day) improves insulin resistance in patients with NAFLD (iii) UDCA improves hepatobiliary transporter expression in NAFLD	Baseline and 3 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in serum bile acids and lipids	relative changes in hepatic basolateral transport proteins MRP3, MRP4, OATP, SLC21A1; relative changes in m RNA expression levels of BAAT; CYP3A4, CYP7A1, CYP27, CYP8B1, UGT1A1, UGT2B4, UGT2B7, SULT2A1, HNF-4α, PXR/NR1I2, RXR/NR1B1; PERK, XBP-1, SREBP-1c; TNF-α, IL-6, IL-10, MCP-1, CxCl-1; relative change in serum bile acids; relative change in plasma 7α-hydroxy-4-cholesten-3-one and FGF-19; relative changes in total cholesterol, LDL-C, HDL-C, Apo A1, Apo B, in Lp(A)	Baseline and 3 weeks

Collaborators and Investigators

• Sponsor: Sahlgrenska University Hospital, Sweden
• Investigators: Principal Investigator: Hanns-Ulrich Marschall, MD, PhD, Sahlgrenska Academy and University Hospital, Institute of Medicine, Dept. of Internal Medicine, University of Gothenburg, S-41345 Gothenburg

Publications and helpful links

General Publications

• Mueller M, Castro RE, Thorell A, Marschall HU, Auer N, Herac M, Rodrigues CMP, Trauner M. Ursodeoxycholic acid: Effects on hepatic unfolded protein response, apoptosis and oxidative stress in morbidly obese patients. Liver Int. 2018 Mar;38(3):523-531. doi: 10.1111/liv.13562. Epub 2017 Sep 18.

Study record dates

Study Major Dates

• Study Start: October 1, 2008
• Primary Completion (Actual): November 1, 2009
• Study Completion (Actual): May 1, 2010

Study Registration Dates

• First Submitted: February 22, 2012
• First Submitted That Met QC Criteria: March 5, 2012
• First Posted (Estimate): March 8, 2012

Study Record Updates

• Last Update Posted (Estimate): December 3, 2013
• Last Update Submitted That Met QC Criteria: December 2, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: bariatric surgery; NAFLD; ursodeoxycholic acid; fatty liver disease; morbid obesity
• Additional Relevant MeSH Terms: Digestive System Diseases; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Obesity, Morbid; Gastrointestinal Agents; Cholagogues and Choleretics; Ursodeoxycholic Acid
• Other Study ID Numbers: UDCAINBS

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No