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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01619215
Recruitment Status : Unknown
Verified March 2018 by Mazen Hassanain, King Saud University.
Recruitment status was:  Recruiting
First Posted : June 14, 2012
Last Update Posted : March 30, 2018
Information provided by (Responsible Party):
Mazen Hassanain, King Saud University

Brief Summary:

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 or disease
Obesity, Morbid Non-Alcoholic Fatty Liver Disease

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.

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Study Type : Observational
Estimated Enrollment : 35 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: The Effects of Bariatric Surgeries on Non-Alcoholic Fatty Liver Disease
Study Start Date : June 2012
Estimated Primary Completion Date : July 2018
Estimated Study Completion Date : July 2018

Bariatric Surgery
As the number of patients dropping out during follow-up, we had difficulty achieving our secondary outcomes, and so the team decided to continue the recruitment until all our outcomes are reached. Main part of the primary outcomes is finalised and published The effects of bariatric surgeries on nonalcoholic fatty liver disease. Aldoheyan T, Hassanain M, Al-Mulhim A, Al-Sabhan A, Al-Amro S, Bamehriz F, Al-Khalidi H. Surg Endosc. 2016 Jul 12

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

  2. 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. ]
    - 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).

  3. Assessment of NAFLD associated morbidities by detecting the local inflammatory changes after bariatric surgery. [ Time Frame: Baseline (tissues obtained intraoperatively). ]
    • 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.

  4. 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. ]
    • 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.

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

  6. 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. ]
    • 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.

  7. 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 ]
    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.

  8. Testing the efficacy of the non-invasive images in the diagnosis of NAFLD. [ Time Frame: Baseline (preoperatively), 1 year and 5 years postoperatively. ]
    • 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

Information from the National Library of Medicine

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, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
NAFLD patients

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01619215

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

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Saudi Arabia
King Khalid University Hospital Recruiting
Riyadh, Saudi Arabia, 7805
Contact: Tamader AlDoheyan, (MBBSc)    +966500083720   
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   
Contact: Maram AlKhamash    +966548327049    Malkhamash.c@KSU.EDU.SA   
Sponsors and Collaborators
King Saud University
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Principal Investigator: Dr.Mazen Hassanain, MBBS FRCSC PhD King Khalid University Hospital,King Saud University,Riyadh,KSA.
Additional Information:

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Responsible Party: Mazen Hassanain, Assistant Professor & consultant HPB and Transplant surgeon, King Saud University Identifier: NCT01619215    
Other Study ID Numbers: KSULDRCBSMH001
First Posted: June 14, 2012    Key Record Dates
Last Update Posted: March 30, 2018
Last Verified: March 2018
Additional relevant MeSH terms:
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Liver Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
Obesity, Morbid
Digestive System Diseases
Nutrition Disorders
Body Weight