Please select the eligibility criteria that correspond to the clinical trial below.
Title: NAFLD in T2DM: Prevalence in Hispanics and Role of Treatment
Brief Summary: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition frequently associated with type 2 diabetes (T2DM) and characterized by insulin resistance and hepatic fat accumulation. Liver fat may range from simple steatosis to severe steatohepatitis with necroinflammation and variable degrees of fibrosis (nonalcoholic steatohepatitis or NASH). Up to 40% of patients with NAFLD develop NASH in recent series. Risk factors for progression to NASH are unclear, but appears to be more common and progress more rapidly in older individuals, and in the presence of obesity and T2DM. Because the VA population in San Antonio, Texas, frequently combine these risk factors for NASH it was felt that a study targeting this very high-risk population was needed.

This study will establish the long-term efficacy (primary endpoint: liver histology) and safety of pioglitazone for the treatment of VA patients with T2DM and NASH. All patients diagnosed with NASH will be offered lifestyle modification/weight loss (current standard of care) while being randomized to pioglitazone, vitamin E or placebo for up to 3 years. We believe that in such a high-risk population for complications from NASH, a substantial benefit may be expected from early detection and treatment.

Specifically, the arms are: a) pioglitazone + vitamin E; b) vitamin E + placebo of pioglitazone; c) placebo of both. Patients are randomized to one of these 3 arms, and followed in a double-blind fashion for up to 18 months. Patients are then offered to continue into an open-label phase with pioglitazone + vitamin E or vitamin E alone for another 18 months.


Options:
A: * 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.
B: Inclusion Criteria:

* Patient diagnosed with type 2 diabetes based on American Diabetes Association (ADA) definition or who only take oral antidiabetic drug.
* CAPscore \>263

Exclusion Criteria:

* Criteria:

  * Taking any kind of antibiotics two weeks before recruitment;
  * History of alcohol consumption ;
  * pregnancy or lactation;
  * Professional athletes;
  * Other liver disease (viral/etc);
  * High dose synthetic estrogens, methotrexate , amiodarone, steroids, chloroquine, immunosuppressive drugs;
  * A history of Cardiovascular disease;
  * Renal disease, Celiac disease, Cirrhosis;
  * History of Upper Gastrointestinal surgery ;
  * A history of hypothyroidism or Cushing's syndrome;
  * History of drug dependence;
  * Body mass index (BMI) ≥35 kg/m2;
  * A restrictive diet or weight change ≥ 5 kg during the 3 months prior to study;
  * Any change in treatment with oral hypoglycemic; anti hypertensive and antilipid agents during the study;
  * Use of weight loss medications
C: Inclusion Criteria:

* age 6-19
* overweight or obesity
* ALT activity over 130% of upper limit norm
* hyperechogenicity of the liver on ultrasound

Exclusion Criteria:

* HCV, HBV infection
* cholestasis
* chronic/acute liver failure
* alpha-1-antitrypsin deficiency
* Wilson disease
* type 2 diabetes mellitus
* beta-oxidation defects
* alcohol consumption
* history of parenteral nutrition
* use of drugs
D: Inclusion Criteria:

* Be able to communicate meaningfully with the Investigator and be legally competent to provide written informed consent.
* Subjects of both genders from within the Veterans Administration Healthcare System with an age range between 18 to 70 years (inclusive).
* Have type 2 diabetes mellitus as defined by the American Diabetes Association guidelines.
* Female volunteers must be non-lactating and must either be at least one year post-menopausal, or be using adequate mechanical contraceptive precautions (i.e. intrauterine device, diaphragm with spermicide, condom with spermicide), or be surgically sterilized (i.e. bilateral tubal ligation, bilateral oophorectomy). Female patients who have undergone a hysterectomy are eligible for participation in the study. Female patients (except for those patients who have undergone a hysterectomy or a bilateral oophorectomy) are eligible only if they have a negative pregnancy test throughout the study period.
* The following laboratory values:

  * Hemoglobin at least 12 gm/dl in males or 11 gm/dl in females, WBC count 3,000/mm3 (neutrophil count 1,500/mm3) and platelets 100,000/mm3
  * Albumin equal or greater than 3.0 g/dl
  * Serum creatinine less than 1.8 mg/dl
  * AST and ALT up to 3.0 times upper limit of normal and alkaline phosphatase 2.5 times ULN

Exclusion Criteria:

* Any cause of chronic liver disease other than NASH (such as -but not restricted to- alcohol or drug abuse, medication, chronic hepatitis B or C, autoimmune, hemochromatosis, Wilson's disease, alpha1-antitrypsin deficiency).
* Any clinical evidence or history of ascitis, bleeding varices, or spontaneous encephalopathy.
* History of alcohol abuse (alcohol consumption greater than 20 grams of ethanol per day) or a positive AUDIT screening questionnaire.
* Prior surgical procedures to include gastroplasty, jejunoileal or jejunocolic bypass.
* Prior exposure to organic solvents such as carbon tetrachloride.
* Total parenteral nutrition (TPN) within the past 6 months.
* Subjects with type 1 diabetes mellitus.
* Patients on chronic medications with known adverse effects on glucose tolerance levels unless the patient has been on a stable dose of such agents for 4 weeks before entry into the study.
* Patients on drugs known to cause hepatic steatosis: estrogens or other hormonal replacement therapy, tamoxifen, raloxifene, oral glucocorticoids, chloroquine and others.
* Patients with a history of clinically significant heart disease (New York Heart Classification greater than grade II), peripheral vascular disease (history of claudication), or diagnosed pulmonary disease (dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation).
* Patients with severe osteoporosis (-3.0 at the level of spine and hip).
* Patients who have clinically significant acute or chronic medical conditions not specifically written in the protocol, but that based in the investigator's clinical judgment he/she considers unlikely that he will be able to complete study participation or that such participation may be potentially detrimental to his well-being.

Answer: D