Omega 3 Supplementation in Fatty Liver
Omega 3 Supplementation in Fatty Liver
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.
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.
Inclusion Criteria:

 -  18-70 years of age, both sexes

 -  With or without non-insulin-dependent diabetes or glucose intolerance

 -  Absence of alcoholism <20g (women) and <40g (men) of ethanol/day, drugs,
 schistosomiasis, hepatitis B or C and other chronic liver diseases cause determined

 -  Absence of autoantibodies and rates of copper and ceruloplasmin normal

 -  Biopsy-liver until 12 months previous, showing steatosis, lobular inflammatory
 infiltrate and ballooning of hepatocytes, which may be present or not Mallory's
 corpuscles and liver fibrosis stage I and II, NAS score> 5;

 -  Patients who agree to participate in the study and all signed informed consent.

 Exclusion Criteria:

 -  Poisoning by exogenous oxidants

 -  Pregnancy and lactation

 -  Prothrombin time <70% or platelet count <70 000/mm3, or any bleeding disorders,
 including alteration of the bleeding time

 -  Refusal to cooperate with research

 -  steatosis without signs of inflammation or ballooning or cirrhosis (stage IV)

 -  diabetes mellitus using insulin

 -  allergy to fish or flaxseed

 -  anti-inflammatory use of non-hormonal