Please select the eligibility criteria that correspond to the clinical trial below.
Title: Role of Pioglitazone and Berberine in Treatment of Non-alcoholic Fatty Liver Disease(NAFLD) Patients With Impaired Glucose Regulation or Type 2 Diabetes Mellitus
Brief Summary: The purpose of this study is to evaluate the effects and safety of pioglitazone and berberine on the basis of lifestyle intervention to non-alcoholic fatty liver disease patients with impaired glucose regulation or type 2 diabetes mellitus.


Options:
A: Inclusion Criteria:

1. Age: 18 -75, no limitation for ethnic and gender
2. Body Mass Index(BMI) \< 35 kg/m2
3. Patients with nonalcoholic steatohepatitis (NASH) based on liver biopsy obtained within 6 months before randomization. The histological evidence of NASH was defined as Non - alcoholic fatty liver disease activity score（NAS）≥ 4 (according to Nonalcoholic Steatohepatitis Clinical Research Network, NASH CRN) with a minimum 1 score for steatosis, lobular inflammation, and hepatocyte ballooning respectively.
4. Fibrosis stage 0-3 according to nonalcoholic steatohepatitis clinical research network（NASH CRN).
5. Without history of significant alcohol consumption for a period of more than 3 months within 5 years (\<10 g/day for female and \< 20 g/day for male).
6. The lab test results should meet the requirements:

   ① Alanine aminotransferase （ALT） \< 5 times of normal upper limit

   ② Creatinine (Cr)\< normal upper limit

   ③ Albumin （ALB）\> 3.5g/L

   ④ International normalized ratio（INR）= 0.8-1.3

   ⑤ Fasting plasma glucose(FPG) \< 126mg/dL（7mmol/L） and/or 2h postprandial plasma glucose (PPG) \< 200mg/dL（11.1mmol/L）and/ or HbA1C \< 6.5 %
7. If a participant with hypertension, he/she was required a stable antihypertensive drug(s) to keep blood pressure stable.(blood pressure \< 140/90 mmHg) 3 months prior to randomization.
8. If a participant using a statin or fibrate, he/she was required on a stable dose to keep lipid stable (triglyceride(TG) \< 1.7 mmol/L, total cholesterol (TC) \< 5.72 mmol/L, LDL-c \< 3.64 mmol/L) 3 months prior to randomization.
9. Women of childbearing potential: negative pregnancy test during screening or at randomization or willingness to use an effective form of birth control during the trial(at least include one barrier contraceptive method) and not breast feeding
10. Men must agree to use an effective form of birth control during the trial(at least include one barrier contraceptive method)
11. All participants are needed to sign the informed consent form.

Exclusion Criteria:

1. Evidence of other form of acute or chronic liver disease. (Virus hepatitis, Hereditary hemochromatosis, Hepatolenticular degeneration, Alcoholic liver disease, Drug-induced hepatopathy).
2. History of diabetic mellitus or use of antidiabetic drugs.
3. Known heart failure of New York Heart Association class 2, 3, or 4.
4. Wear of cardiac pacemaker.
5. Hypothyroidism (TSH \> 2 times of upper normal limit).
6. History of disease affecting drug absorption, distribution, metabolism (inflammatory bowel disease, gastrointestinal surgery, chronic pancreatitis, gluten allergy, vagotomy).
7. Use of anti-NASH drugs within 3 months before randomization (metformin, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitor, glucagon-like peptide-1(GLP-1), sodium glucose contransporter2(SGLT2), S-adenosylmethionine -e(SAM-e), polyene phosphatidyl choline, glycyrrhizin, bicyclol, reduced glutathione, betaine, fish oil, silymarin,oberbic acid/ursodeoxycholic acid (OCA/UDCA), phosphodiesterase (PDE)-inhibitor, gemfibrozil, vitamin E, long term antibiotic (\>1 week).
8. Positivity of antibody to Human Immunodeficiency Virus.
9. Inability to safely obtain liver biopsy.
10. Known intolerance to vitamin E
11. Inability to fill out diary card, to manage diet and exercise, poor compliance.
12. Dependence or abuse of alcohol and/or drugs.
13. Any other condition which in the opinion of investigator would impede compliance or hinder completion of the study.
B: Inclusion Criteria:

* Male or female 18 years of age or older.
* Diagnosed with NASH (refer to Section 5.2)
* AST and/or ALT greater than 40 IU/L.
* Must agree to adhere to alcohol consumption guideline.
* Weight gain//loss of no more than 10% between biopsy and screening or within 30 days of screening if the biopsy is performed during the screening period.
* No change in diabetic and/or lipid medications between biopsy and screening or within 30 days of screening if the biopsy is performed during the screening period

Exclusion Criteria:

* Use of silymarin or other milk thistle preparations for a period of 90 consecutive days or longer between biopsy and initial screening, or within 30 days prior to screening if the biopsy is performed during the screening period.

  * Use of other antioxidants or non-prescribed complementary alternative medications for a period of 90 consecutive days or longer between biopsy and initial screening, or within 30 days prior to screening if the biopsy is performed during the screening period.
  * Use of warfarin, metronidazole, or acetaminophen (greater than 2 grams per day) between screening and randomization.
  * Use of oral steroids for more than 14 days of screening or prior to randomization.
  * BMI ≥ 35 kg/m2 between screening and randomization.
  * Poorly-controlled diabetes (HbA1c \> 8 %) between screening and randomization
  * Diabetes mellitus treated with oral agents other than the secretagogues or metformin between screening and randomization. Sitagliptin is allowed.
  * For patients using anti-hyperlipidemic agents or accepted anti-diabetic agents, any change of agent or dose between screening and randomization.
  * Radiologic imaging consistent with cirrhosis or portal hypertension.
  * Evidence of decompensated liver disease
  * Platelet count \< 130 x 109 /L at screening.
  * History of bariatric surgery, or undergoing evaluation for bariatric surgery.
  * Known allergy/sensitivity to milk thistle or its preparations.
  * History of immunologically mediated disease
  * History of thyroid disease poorly controlled on prescribed medications.
  * History of solid organ or bone marrow transplantation.
  * Primary hepatic malignancy.
  * Secondary hepatic malignancy or extrahepatic malignancy.
  * Serum Creatinine of 176 μmol/L or greater or creatinine clearance (calculated according to Cockcroft-Gault) 60 mL/min or less, or on dialysis, at screening.
  * Severe illness or any other conditions that would make the patient, in the opinion of the investigator, unsuitable for the study.
  * Women with ongoing pregnancy or breast feeding, or contemplating pregnancy.
  * Women of childbearing potential who are not practicing an acceptable form of birth control.
  * Participation in a research drug trial within 30 days of screening.
  * Inability or unwillingness to give informed consent or abide by the study protocol.
C: Inclusion Criteria:

1. Patients must have an age range between 18 to 65 years (inclusive).
2. Patients with fatty liver confirmed by ultrasound.
3. Patients must meet the criteria for impaired glucose regulation or type 2 diabetes mellitus (FPG ≥ 5.6 mmol/L and/or a two hour glucose value ≥ 7.8 mmol/L).
4. Course of diabetic mellitus no more than 1 years
5. Diabetic patients have not received anti-diabetic drugs, including insulin, biguanides, sulfonylureas, thiazolidinediones, Alpha-glucosidase inhibitors, or glinides for 4 weeks before the time of enrollment
6. Patients have not received lipid-regulating drugs (statins, fibrates)for 4 weeks before the time of enrollment
7. Blood pressure \< 160/100 mmHg,after receiving lifestyle therapy and effective anti-hypertensive drugs.
8. Patients must stopped other drugs medications for four weeks prior to entering the treatment period, such as: silybin, ursodeoxycholic acid, Polyene Phosphatidylcholine, vitamin E, some herbs with effect of regulating lipid and protecting liver function, etc.
9. Liver fat content(LFC) assessed by 1H MRS ≥ 13%(LFC was calculated by dividing the integral of the methylene groups in fatty acid chains of the hepatic triglycerides by the sum of methylene groups and water).

Exclusion Criteria:

1. Any causes of chronic liver disease other than NAFLD (such as - but not restricted to - alcohol or drug abuse, medication, chronic hepatitis B or C, autoimmune, etc.);
2. Patients with significantly impaired liver function: ALT or AST ≥ 2 times upper limit of normal;
3. HBsAg (+) and/or HCV-Ab (+);
4. Patients with type 1 diabetes mellitus or gestational diabetes or special type diabetes, and patients with BMI \< 22 Kg/m2;
5. Course of diabetes more than 1 years;
6. Diabetics patients who have taken or are taking oral glucose-lowering drugs or insulin;
7. Diabetics patients with a HbA1c \> 7.5% on initial visit;
8. Patients with severe diabetes complications (diabetes ketoacidosis, diabetes coma or with symptomatic of diabetes coma; dysfunction of nerve, retinopathy, dysfunction of kidney）;
9. Patients with serum creatinine ≥ 1.5 mg/dL (133 umol/L);
10. Patients with a history of clinically significant heart disease (myocardial infarct, heart failure, and or severe cardiac rhythm);
11. Complicating severe infection, within 6 months after operation, severe trauma;
12. Patients with excess alcohol consumption≥140g/week(male); ≥ 70g/week(female);
13. Patients have participated other clinical trials within 24 weeks;
14. Patients with a history of drug allergy to TZDs and berberine;
15. Patients wth gestation or possible gestation or lactation, or males or females who expecting gestation during clinical trial;
16. Mental diseases patients;
17. Those who refuse to sign informed consent;
18. Any other conditions, which, in the opinion of the investigators would impede competence or compliance or possibility of hindering completion of the study;
19. Patients with serum triglyceride ≥ 5.0 mmol/L;
20. Patients with thyroid disease, including hyperthyroidism or hypothyroidism.
D: Inclusion Criteria:

* age 6-12
* parents or tutors able to give the written consent and follow the study procedures Value of BMI\>90°

Exclusion Criteria:

* - Any severe or concomitant clinical or psychiatric condition that, in the investigator's opinion, could affect the treatment, the evaluations and the inclusion in the protocol;
* Evidence of active liver disease due to other causes;
* Steroid treatment; immuno suppressive therapies, chemotherapy agents within 2 month from screening;
* Pregnancy or breastfeeding;
* Abuse of alcohol and drugs clinically relevant;
* Diabetes.

Answer: C