Treatment for Non-Alcoholic Fatty Liver With Different Doses of Vitamin E
Condition: Fatty Liver
MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease
Intervention: Vitamin E 200 IU/d; Vitamin E 400 IU/d; Vitamin E 800 IU/d; Diet and Exercise
Intervention description: Supplement-low dose; Supplement-intermediate dose; Supplement High Dose; Diet and Exercise for all Arms of the study at baseline
Intervention MeSH terms: Vitamins; Vitamin E; Tocopherols; Tocotrienols; alpha-Tocopherol
Phase: Phase 2
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 22.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Fatty Liver; Alpha-Tocopherol; Vitamin E; Non-Alcoholic Steatohepatitis

Summary:

      Background:

        -  Non-alcoholic fatty liver disease (NAFLD) is an excess accumulation of fat in the liver
           cells. It is associated with obesity, high blood pressure, high cholesterol, and
           diabetes. Some people with NAFLD only have excess fat in the liver. However, other
           people may develop a worse form of NAFLD with liver injury and scarring. This form,
           called non-alcoholic steatohepatitis (NASH), can lead to liver failure, liver cancer,
           and death. Not much is known about why some people develop NASH and others do not.

        -  Lifestyle changes such as diet, exercise, and weight loss can decrease the liver damage
           in NAFLD. Some studies show that vitamin E can also help treat NAFLD. The dose of
           vitamin E used in these studies is almost 40 times the recommended amount of vitamin E
           intake from food. It is unclear whether a lower dose could achieve the same effect.
           Researchers also want to study how vitamin E works at different doses to treat NAFLD.

      Objectives:

        -  To find out the most effective dose of vitamin E to treat NAFLD.

        -  To gain a better understanding of how NAFLD and NASH develop, and predict who will
           respond to treatment.

      Eligibility:

      - Individuals at least 18 years of age with suggestion of non-alcoholic fatty liver disease.

      Design:

        -  Participants will be screened with a physical exam and medical history. Blood and urine
           samples will be collected.

        -  For the first 12 weeks of the study, participants will meet with a nutritionist. They
           will have personalized diet and exercise plans. Treatment will be monitored with diaries
           and questionnaires to fill out at home. Participants will also wear a pedometer to
           measure physical activity.

        -  After the 12-week period, participants will have a full physical examination with the
           following tests:

        -  Blood tests

        -  Glucose tolerance tests

        -  Imaging studies (DEXA scan and magnetic resonance imaging)

        -  Liver and fatty tissue biopsy

        -  Two weeks after the tests, participants will start vitamin E treatment. They will take
           up to two pills a day, taken with fat-containing foods.

        -  4 weeks after starting treatment they will have a repeat full evaluation with imaging
           tests, blood work, and liver and fat biopsies.

        -  Participants who are taking vitamin E will take it for up to 120 weeks. They will have
           monitoring visits every 8 to 12 weeks. At the end of 120 weeks, they will have another
           full evaluation, with imaging tests, blood work, and liver and fat biopsies.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Clinical suspicion of NAFLD, defined by the presence of at least two of the following
        criteria:

          -  Suggestion of liver fat by an imaging study (ultrasound, CT scan, MRI or MR
             spectroscopy) performed in the 6 months prior to enrollment.

          -  Elevated aminotransferase levels (ALT > 31 U/L for men or > 19 U/L for women, or AST >
             30 U/L) on at least two occasions in the 6 months preceding enrollment.

          -  Presence of the metabolic syndrome, defined according to the modified AHA/NCEP
             criteria as the presence of at least three of:

               -  Abdominal obesity, defined as waist circumference > 102 cm for men or > 88 cm for
                  women

               -  Elevated triglycerides (> 150 mg/dL) or the use of medication to lower
                  triglycerides

               -  Reduced HDL cholesterol (< 40 mg/DL for men or < 50 mg/dL for women)

               -  Elevated blood pressure (> 135/80 mmHg) or use of medication for hypertension

               -  Elevated fasting glucose levels (> 100 mg/dL) or use of anti-diabetic medication

                    -  For the purpose of inclusion, the presence of overt diabetes mellitus type 2
                       will be considered equivalent to the presence of the metabolic syndrome,
                       even if the other criteria are absent.

          -  Estimated average alcohol consumption < 30 g/d for men or < 20 g/d for women in the 6
             months prior to enrollment and no binge-drinking behavior.

          -  Age > 18 years at enrollment

          -  Willingness to participate in the study

        EXCLUSION CRITERIA:

          -  Chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV). Patients
             who were treated successfully for HCV and achieved sustained virological response can
             be eligible for enrollment > 18 months after treatment cessation. Patients who are
             inactive carriers of HBV (HBV DNA < 1000 copies/mL, HBeAg negative, Anti HDV negative)
             for at least 12 months prior to enrollment are also eligible. Patients receiving
             antiviral therapy are ineligible.

          -  Concomitant liver disease such as autoimmune hepatitis, primary biliary cirrhosis,
             primary sclerosing cholangitis, Wilson s disease, alpha-1 antitrypsin deficiency.

          -  Presence of definite or probable drug-induced liver injury. In the case of
             lipid-lowering, anti-hypertensive or anti-diabetic medications that are suspected to
             cause elevation of aminotransferases, patients will be eligible if treatment is
             associated with stable enzyme levels for at least 6 months and inclusion criteria 1a.
             and 1c. are both present.

          -  Treatment with medications known to cause fatty liver disease such as atypical
             neuroleptics, tetracycline, methotrexate or tamoxifen

          -  Uncontrolled hypo- or hyperthyroidism.

          -  Decompensated advanced liver disease, defined as direct bilirubin > 0.5 g/dL, PT > 18,
             albumin < 3 g/dL, or history of ascites, encephalopathy, variceal bleeding,
             spontaneous bacterial peritonitis or liver transplant.

          -  Active coronary artery disease, defined as persistent angina pectoris, reversible
             ischemia on cardiac stress test or imaging, or the presence of significant coronary
             artery disease on imaging or catheterization. Patients with coronary artery disease
             that was treated by angioplasty or bypass surgery may be eligible if they have no
             evidence of active disease >= 1 year after intervention, can safely stop antiplatelet
             and anticoagulant medications before the performance of invasive procedures, and have
             adequate ventricular function as assessed by echocardiography or cardiology
             consultation. These patients will require cardiology consultation and clearance prior
             to enrollment.

          -  Congestive heart failure.

          -  Chronic kidney disease, with creatinine clearance < 60 ml/h.

          -  Uncontrolled diabetes mellitus. Patients may be enrolled if they have been on stable
             therapy with any anti-diabetic agent for at least 3 months prior to enrollment, are
             not foreseen by the physician treating their diabetes to require antidiabetic
             medication or dose changes during the trial and have an HbA1c <= 7.5% on enrollment.

          -  Treatment with vitamin E. Patients who are currently taking vitamin E as a supplement
             will be requested to stop for at least 3 months before becoming eligible for
             enrollment. Patients who are taking vitamin E for a medical indication other than
             NAFLD will not be eligible.

          -  Contraindication to or inability to undergo a liver biopsy.

          -  Patients who had a liver biopsy performed <= 2 years before enrollment, unless they
             are willing to undergo all of the trial biopsies, knowing that these biopsies are
             purely for research and are not clinically indicated. This will be clearly documented
             in the patients charts prior to enrollment.

          -  Patients with coagulopathy (PT/PTT values that are prolonged >= 3 seconds from the
             upper limit of the normal, including treatment with oral and parenteral
             anticoagulants), thrombocytopenia (<70,000), or platelet dysfunction will not be
             enrolled because of potential increase in risk of bleeding with vitamin E treatment.
             Antiplatelet agents taken for cardiovascular prevention will not exclude patients,
             unless they cannot be stopped safely for the performance of a liver biopsy.

          -  Maldigestion or malabsorption that can interfere with absorption of vitamin E
             including: steatorrhea of all causes, chronic pancreatitis, cystic fibrosis, short
             bowel syndrome, severe cholestasis, orlistat treatment and similar conditions

          -  Inability to swallow vitamin E capsules

          -  Allergy to vitamin E

          -  Alcohol or substance abuse within the past 12 months. Patients will be required to
             have an AUDIT score of 7 or less18, and drink no more than 14 drinks/week (for men) or
             7 drinks/week (for women).

          -  For women of childbearing age, pregnancy or inability (or unwillingness) to practice
             contraception for the duration of the study or breast feeding.

          -  Inability to understand and give informed consent for participation.