Ursodeoxycholic Acid in Bariatric Surgery

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Non-alcoholic Fatty Liver Disease; Morbid Obesity	Drug: Ursodeoxycholic Acid (UDCA)	Not Applicable

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	40 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Basic Science
Official Title:	Effects of Ursodeoxycholic Acid on Hepatobiliary Detoxification/Elimination Mechanisms and Hepatic Fatty Acid/Triglyceride Metabolism in Morbidly Obese Patients.
Study Start Date :	October 2008
Actual Primary Completion Date :	November 2009
Actual Study Completion Date :	May 2010

Arms and Interventions

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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

Outcome Measures

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Primary Outcome Measures :

1. Changes in regulators of lipid turnover [ Time Frame: Baseline and 3 weeks ]
   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

Secondary Outcome Measures :

1. Changes in serum bile acids and lipids [ Time Frame: Baseline and 3 weeks ]
   • 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)

Eligibility Criteria

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Ages Eligible for Study:	25 Years to 60 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

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Sponsors and Collaborators

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

More Information

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Responsible Party:	Hanns-Ulrich Marschall, Professor, senior consultant, Sahlgrenska University Hospital, Sweden
ClinicalTrials.gov Identifier:	NCT01548079 History of Changes
Other Study ID Numbers:	UDCAINBS
First Posted:	March 8, 2012
Last Update Posted:	December 3, 2013
Last Verified:	December 2013

Keywords provided by Hanns-Ulrich Marschall, Sahlgrenska University Hospital, Sweden:

ursodeoxycholic acid; fatty liver disease; morbid obesity; bariatric surgery; NAFLD

Additional relevant MeSH terms:

Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Obesity, Morbid; Digestive System Diseases; Obesity; Overnutrition	Nutrition Disorders; Overweight; Body Weight; Signs and Symptoms; Ursodeoxycholic Acid; Cholagogues and Choleretics; Gastrointestinal Agents