The Effects of Bariatric Surgeries on Non-Alcoholic Fatty Liver Disease

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by King Saud University
Sponsor:
Information provided by (Responsible Party):
Mazen Hassanain, King Saud University
ClinicalTrials.gov Identifier:
NCT01619215
First received: May 27, 2012
Last updated: July 7, 2014
Last verified: July 2014
  Purpose

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease. In the absence of chronic alcohol abuse or other liver diseases, NAFLD incorporates a wide spectrum of liver pathologies and is defined by fatty infiltration of the liver (simple hepatosteatosis). It can progress to non-alcoholic steatohepatitis (NASH) and later fibrosis, cirrhosis, and eventually some patients may develop hepatocellular carcinoma with or without cirrhosis. The exact cause of NAFLD is yet to be cleared and it is, therefore, an active area for research. The diagnosis of NAFLD is achieved through histological examination of liver biopsies (invasive), non-invasive markers using serum biomarkers and imaging techniques are still under development. Pathological diagnosis can be then subcategorized based on several scoring systems. More widely used are the Brunt Score or NAS (NAFLD activity score) and the Kleiner's modified NAS.

Obesity is highly associated with NAFLD, as the epidemic of obesity has made NAFLD more prevalent. In addition insulin resistance has been linked to NAFLD and this is explained by the increased influx of free fatty acids (FFAs) into the liver. FFA undergoes either β-oxidation or esterification with glycerol to form triglycerides (TGs), resulting in an additional source of fat in the liver. Due to the strong association of NAFLD with obesity, weight reduction procedures are used for the management of NAFLD. In fact, this has been shown to be effective by several studies. However, other studies have reported liver deterioration after bariatric intervention. This conflict is what makes the effects of bariatric procedures a challenging field for further studies. Consequently in this study we are aimed to examine histologic, metabolic and liver function changes induced by the different therapeutic bariatric procedures.


Condition
Obesity.
Non-Alcoholic Fatty Liver Disease.

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: The Effects of Bariatric Surgeries on Non-Alcoholic Fatty Liver Disease

Resource links provided by NLM:


Further study details as provided by King Saud University:

Primary Outcome Measures:
  • Assessment of NAFLD histological changes after bariatric surgery (adjustable gastric banding, sleeve gastrectomy, gastric bypass, and duodenal switch). [ Time Frame: Intra-operatively, 3 months and 1 year postoperatively. ] [ Designated as safety issue: Yes ]
    Histological evaluation is done by applying the NAFLD activity score (NAS). The stage of fibrosis will be determined by the five-point (stage 0 to 4) scale.


Secondary Outcome Measures:
  • Assessment of liver function after bariatric surgery. [ Time Frame: Preoperatively, 3 months, 6 months, 1 year and annually for 5 year postoperatively. ] [ Designated as safety issue: Yes ]
    • Measure serum albumin, bilirubin, INR, anti-thrombin-III, ALT, GGT, AST, protein C and S levels.
    • Measure albumin synthesis using radiolabeled amino acids.

  • Assessment of NAFLD associated morbidities by detecting the systemic inflammatory changes after bariatric surgery. [ Time Frame: preoperatively, 3 months, 6 months, 1 year and annually for 5 year postoperatively. ] [ Designated as safety issue: Yes ]
    - Study systemic inflammatory changes by measuring the serum levels of several inflammatory mediators: ESR, C-reactive protein, interleukins (IL-1, IL-4, IL-6, IL-8, IL-10, IL-16), adipokines (adiponectin, leptin, adipsin and Chemerin), MCP1, osteopontin, and growth factors (TNF-α, and VEGF).

  • Assessment of NAFLD associated morbidities by detecting the local inflammatory changes after bariatric surgery. [ Time Frame: Baseline (tissues obtained intraoperatively). ] [ Designated as safety issue: Yes ]
    • Hepatic expression of α-SMA, collagen α1, TGF-β1, MCP-1, IL-6, IL-8, leptin and adiponectin receptors. PAI1, ACRP30, ADIPOQ.
    • Visceral adipose tissue to assess the expression of NOD-like receptor pyrin domain-containing-3 inflammasome (Nlrp3); are inflammatory markers that recognize certain signals that leads to caspase-1 activation and subsequent IL-1 and IL-18.
    • Subcutaneous adipose tissue to assess the expression of adiponectin, IL-6 and TNF-α.

  • Assessment of NAFLD associated morbidities by detecting the metabolic changes after bariatric surgery. [ Time Frame: Preoperative, 3 months, 6 months, 1 year and annually for 5 years postoperatively. ] [ Designated as safety issue: Yes ]
    • Hormonal changes: serum levels of ghrelin, peptide YY, amylin, cholecystokinin, insulin, glucagon, epinephrine, and cortisol.
    • Non-hormonal changes: HbA1c, FFA, HDL, cholesterol, triglycerides, fasting glucose.

  • Assessment of NAFLD associated morbidities by detecting the endothelial changes after bariatric surgery. [ Time Frame: Preoperative, 6 months, 1, 2 and 5 years postoperatively. ] [ Designated as safety issue: Yes ]
    • Doppler Ultrasound (Duplex) for the carotid arteries.
    • Measuring the levels of progenitor cells.

  • Studying the genetic factors expressing for the inflammatory changes differences in responders. [ Time Frame: Baseline (for liver, visceral and subcutaneous fat). Postoperatively (for liver only): 3 months, 1 year and 5 years after the surgery. ] [ Designated as safety issue: Yes ]
    • TMA construction using the formalin stored liver, visceral fat and abdominal wall muscle.
    • Detecting mRNA expression from frozen tissue (liver, visceral fat and abdominal wall muscle) with respect of inflammation, insulin action, lipid metabolism, liver regression and apoptosis.
    • Deep gene sequencing for subgroup of patients with variables clinical responses or with genetic differences determined form the above testing.

  • Long-term follow-up to examine the correlation between the type of surgery and clinical outcomes associated with NAFLD (liver cirrhosis, incidence of cancer, and mortality). [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
    Histological evaluation is done by applying the NAFLD activity score (NAS). The stage of fibrosis will be determined by the five-point (stage 0 to 4) scale.

  • Testing the efficacy of the non-invasive images in the diagnosis of NAFLD. [ Time Frame: Baseline (preoperatively), 1 year and 5 years postoperatively. ] [ Designated as safety issue: Yes ]
    • Magnetic Resonance Studies.
    • Fibroscan.
    • Ultrasound.


Biospecimen Retention:   Samples With DNA

Blood (serum, plasma, and RNA isolate) Liver core biopsy Subcutaneous fat Visceral fat Abdominal wall muscle


Estimated Enrollment: 35
Study Start Date: June 2012
Estimated Study Completion Date: January 2016
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Groups/Cohorts
Bariatric Surgery

Detailed Description:

35 consecutive patients referred for bariatric surgery will be recruited either at the obesity clinic, or from inpatient (scheduled for bariatric surgery). A detailed history and a complete physical examination will be done at the first visit along with anthropometric measures; routine blood tests, liver function, hormonal assessment, and certain metabolic and inflammatory markers will be evaluated. They will also have an abdominal ultrasound for initial NAFLD assessment, fibroscan to detect liver fibrosis, and an MRI to measure hepatic fat content and body fat composition including intra-abdominal and extra-abdominal fat. These patients will be asked to lose a certain amount of kilos (depending on their BMI and the surgeon preference) out of their original weight, in order to become candidates for bariatric surgery at King Saud University Hospital (KKUH).

At the second visit, (if they lose the recommended amount weight) we will assess their weight loss; obtain blood for the same hormonal and inflammatory markers assessment. Nonetheless, if they did not lose weight and the treating surgeon gave them a third appointment, we will consider their third visit as a second visit; preforming all the investigations mentioned above. In this case we will interpret their results with respect to the total duration of "before surgery" weight loss.

During the operation, tissue biopsy will be taken with a core needle biopsy for the liver and a sharp non-thermal instrument for subcutaneous fat, visceral fat, and abdominal muscle immediately after skin incision. A CAP certified tissue manager would process all tissues. Liver biopsy will be sliced it to two parts; the first half is for histological evaluation, but the other half will be stored for tissue studies. The histologic slides will be stained with hematoxylin and eosin (H&E), and Masson Trichrome stains for microscopic evaluation. This evaluation will be provided by a single histopathologist who will be blinded to the patients' clinical condition, and the order of the biopsy.

Follow Up:

After the surgery follow up appointments will be scheduled 3 months, 6 months, 1 year, and annually till 5 years. The followings will be done in each visit:

  1. Thorough physical exam as per the CRF.
  2. Take a blood sample to evaluate liver function, metabolic, and inflammatory changes using the same parameters as those in the baseline.
  3. Request for: fibroscan and abdominal ultrasound. Second, third and fourth liver biopsies will be taken percutaneously 3 months, 1 year, and 5 years following the initial biopsy respectively. These biopsies will be obtained using core tissue biopsy with ultrasound guidance for the same histological assessment and tissue studies. Another MRI will be schedule 1 year after the surgery.

Specimens collected under this trial will be part of the King Saud University Liver Disease Research Centre Biobanking and will follow all policy and procedures within the biobanking protocol as approved by the IRB committee.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

NAFLD patients

Criteria

Inclusion Criteria:

  • Age between 18 to 60 years.
  • Eligible for obesity surgery according to the following criteria:

    • BMI > 30 kg/m2.
    • Ability to demonstrate eating habit control by reducing 10% of the original weight prior to surgery
    • Pass the nutritional and the psychological assessment
    • Pass the preoperative testing to determine the operative risk
  • Ultrasound diagnosis of NAFLD prior to surgery.
  • Written informed consent.

Exclusion Criteria:

  • Unwilling to take part in the study, or asked to be removed from the study at any time.
  • History of alcohol intake > 20 g/day for 5 or more years
  • Evidence autoimmune hepatitis, chronic hepatitis B or C virus, HIV, genetic hemochromatosis, alpha-1 antitrypsin deficiency, Wilson disease, or cirrhosis.
  • Pregnancy.
  • Currently taking known hepatotoxic medications.
  • Failure to attend follow-up for a minimum of 1 year.
  • Non-Saudi patients
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01619215

Contacts
Contact: Manal Hassan, BPharm +966566905250 ManHassan.c@KSU.EDU.SA
Contact: Atheer Al-Sabhan, MBBS +966505299995 Atheer.Sabhan@gmail.com

Locations
Saudi Arabia
King Khalid University Hospital Recruiting
Riyadh, Saudi Arabia, 7805
Contact: Tamader AlDoheyan, (MBBSc)    +966500083720    AlDoheyan.Tamader@gmail.com   
Contact: Maram AlKhamash    +966548327049    Malkhamash.c@KSU.EDU.SA   
Sub-Investigator: Fahad Bamehriz, MBBS         
Sub-Investigator: Hisham Al-Khalidi, MBBS         
Sub-Investigator: Talal Al-Tuwaijri, MBBS         
Sub-Investigator: Amna Al-Mulhim, MBBS         
Sub-Investigator: Atheer Al-Sabhan, MBBS         
Sub-Investigator: Shaden Al-Amro, MBBS         
Sub-Investigator: Tamader AlDoheyan, (MBBSc)         
King Khalid University Hospital Recruiting
Riyadh, Saudi Arabia, 7805
Contact: Tamader Al-Doheyan, (MBBSc)    +966500083720    AlDoheyan.Tamader@gmail.com   
Contact: Maram AlKhamash    +966548327049    Malkhamash.c@KSU.EDU.SA   
Sponsors and Collaborators
King Saud University
Investigators
Principal Investigator: Dr.Mazen Hassanain, MBBS FRCSC PhD King Khalid University Hospital,King Saud University,Riyadh,KSA.
  More Information

Additional Information:
Publications:

Responsible Party: Mazen Hassanain, Assistant Professor & consultant HPB and Transplant surgeon, King Saud University
ClinicalTrials.gov Identifier: NCT01619215     History of Changes
Other Study ID Numbers: KSULDRCBSMH001
Study First Received: May 27, 2012
Last Updated: July 7, 2014
Health Authority: Saudi Arabia: Ethics Committee

Additional relevant MeSH terms:
Fatty Liver
Liver Diseases
Obesity
Digestive System Diseases
Overnutrition
Nutrition Disorders
Overweight
Body Weight
Signs and Symptoms

ClinicalTrials.gov processed this record on July 31, 2014