Omega 3 Supplementation in Fatty Liver
Condition: Fatty Liver
MeSH terms: Fatty Liver
Study type: Interventional
Phase: Phase 3

Summary: 
      Nonalcoholic fatty liver disease (NAFLD) is a clinical and pathological condition, whose
      spectrum can range from steatosis to steatohepatitis and cirrhosis, in patients without a
      history of alcohol abuse. Nonalcoholic steatohepatitis (NASH), the severe form of (NAFLD),
      has emerged as a clinically important type of chronic liver disease in industrialized
      countries and is characterized pathologically by hepatocellular ballooning, Mallory's
      hyaline, scattered inflammation and perisinusoidal fibrosis. NASH associated with cirrhosis
      can decompensate into subacute liver failure, progress to hepatocellular cancer and reoccur
      post transplantation.In the absence of established treatment, therapy is generally directed
      to treatment of risk factors for metabolic syndrome. Recently, some studies have been
      demonstrated that Polyunsaturated fatty acids (PUFAs), omega3 type, could reduced TNFalfa,
      IL6, aminotransferases, insulin resistance and steatosis verified by ultrasound. Neverthless,
      this is the first study that evaluate liver histology after six months of PUFA (omega3) in
      the treatment of patients with NASH.
    

Detailed description: 
      Nonalcoholic fatty liver disease (NAFLD) is a clinical and pathological condition, whose
      spectrum can range from steatosis to steatohepatitis and cirrhosis, in patients without a
      history of alcohol abuse. Nonalcoholic steatohepatitis (NASH), the severe form of (NAFLD),
      has emerged as a clinically important type of chronic liver disease in industrialized
      countries and is characterized pathologically by hepatocellular ballooning, Mallory's
      hyaline, scattered inflammation and perisinusoidal fibrosis. NASH associated with cirrhosis
      can decompensate into subacute liver failure, progress to hepatocellular cancer and reoccur
      post transplantation.

      The 'two-hit' hypothesis has been proposed to explain the pathogenesis of NASH, with an
      initial metabolic disturbance (insulin resistance) causing steatosis and a second pathogenic
      stimulus promoting oxidative stress, increased generation of reactive oxygen species (ROS),
      lipid peroxidation, and resultant NASH . Insulin resistance plays a major role in hepatic fat
      accumulation through increased influx of free fatty acids (FFA) from peripheral fat stores
      due to enhanced lipolysis, increased de novo hepatocyte triglyceride synthesis from glucose
      and reduced apo B production, which diminishes fat export from the liver.

      In the absence of established treatment, therapy is generally directed to treatment of risk
      factors for metabolic syndrome. Recently, some studies have been demonstrated that
      Polyunsaturated fatty acids (PUFAs), omega3 type, could reduced TNFalfa, IL6,
      aminotransferases, insulin resistance and steatosis verified by ultrasound. Nevertheless,
      this is the first study that evaluate liver histology after six months of PUFA (omega3) in
      the treatment of patients with NASH.

      Based on these aspects, the aim of this prospective investigation, is evaluate the
      effectiveness of PUFA (omega3) in the treatment of patients with NASH.

      METHODS Population This study will be developed in the center of study of DHGNA/NASH in the
      Central Institute of the Hospital of the Clinics in São Paulo, Brazil. This study comprised
      60 patients diagnosed with NASH based on liver biopsy findings. In addition, all of the
      patients will have elevated alanine aminotransferase (ALT) and/or aspartate aminotransferase
      (AST) levels on at least two occasions over 6 months prior to enrollment. Other causes of
      liver disease included a hepatobiliary system ultrasound, viral serology, autoantibody
      titers, serum iron, ferritin and transferrin saturation, ceruloplasmin and copper levels and
      alpha1-antitrypsin will be exclude. Patients who have a > 100 g/week alcohol intake
      determined by a detailed personal history, questioning of family members, and investigation
      of previous medical records, will be excluded. Patients with steatohepatitis accompanying
      other liver diseases, or systemic diseases other than obesity, hyperlipidemia, and diabetes
      or with intake of hepatotoxic drugs or lipid-lowering agents were excluded. Specific informed
      consent was obtained for the study and the protocol was approved by the Internal Review Board
      of University of São Paulo. Diagnosis of diabetes type II, hypertension, dyslipidemia were
      based on the criteria of the American Diabetes Association (fasting glucose above 100mg/dl;
      Triglyceride > 150mg/dl; HDL < 40mg/dl in man or < 50mg/dl in woman; > 130mmHg systolic or >
      85mmHg diastolic)28. Overweight corresponded to body mass index (BMI) ≥ 25 kg/m2 and obesity
      to BMI ≥ 30 kg/m2.

      Study Design Randomized, double blind, placebo controlled. Patients will be randomized into
      two groups: Group I / control: 30 NASH patients will be receive placebo orally for 6 months
      Group II /(PUFA-(omega3) : 30 NASH patients will be receive PUFA-(omega3) orally for 6 months

      Laboratorial Assays ( every 2 months)

        -  AST, ALT, FA, GGT, BT/D/I, albumine, INR, plaquettes, Fe, fasting glucose insulin, ,
           peptide C, leptin, Total cholesterol, HDL. LDL, Triglycerides,

        -  TNFalfa, IL6, adiponectin, lipidic leuckocyte profile, EPA (eicosapentaenoic acid), DHA
           (docosahexaenoic)

      Histological diagnosis Liver tissue will be fixed in 4% formaldehyde and processed for
      hematoxylin-eosin (HE) and Masson Trichrome stains for histological analysis. All specimens
      will be scored by a single liver pathologist with expertise in NAFLD: macro- and
      microvascular fatty change, zonal distribution, foci of necrosis, portal and perivenular
      fibrosis, and inflammatory and fibrotic infiltrate with zonal distribution. The specimens
      will be blindly scored according to the NASH Activity Score (NAS) devised by the Pathology
      Committee of the NASH Clinical Research Network 29. According to the NAS, scored parameters
      included macro- and microvascular fatty change, zonal distribution, foci of necrosis, portal
      and perivenular fibrosis, and inflammatory and fibrotic infiltrate with zonal distribution.
    

Intervention name(s): Omega 3
Intervention type(s): Dietary Supplement
Intervention description(s): Omega-3 group (n=30) received capsules containing 945 mg of Omega-3 PUFA [α linolenic acid/ 64%, eicosapentaenoic acid (EPA)/16% and docosahexaenoic acid (DHA)/21%], in 3 capsules/ day
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double (Care Provider, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Nonalcoholic fatty liver; omega 3