Effect of Iron Depletion by Phlebotomy Plus Lifestyle Changes vs. Lifestyle Changes Alone on Liver Damage in Patients With Nonalcoholic Fatty Liver Disease With Increased Iron Stores

Patients will be randomized to lifestyle changes alone or lifestyle changes associated with iron depletion.

Iron depletion will be achieved by removing 350 cc of blood every 10-15 days according to baseline hemoglobin values and venesection tolerance, until ferritin < 30 ng/ml and transferrin saturation < 25%. Weekly phlebotomies will be allowed for carriers of the C282Y HFE mutation. Smaller phlebotomies (250 cc) will be allowed for carriers of beta-thalassaemia trait. Maintenance phlebotomies (as much as required) will then be instituted to keep iron stores depleted (ferritin < 50 ng/ml and transferrin saturation < 25%, MCV <85 fl). Before starting treatment, patients will undergo ECG, and in the presence of hyperglycemia or hypertension also echocardiography (see exclusion criteria).

Change in diabetes medication dosage or start of new therapy will be allowed for HbA1C values <6% or ≥ 7%. According to accepted criteria, previously untreated patients should be treated with metformin. If possible, newly diagnosed hypertension should be treated with Ace-inhibitors.

Study Overview

• Status: Unknown
• Conditions: Nonalcoholic Fatty Liver Disease
• Intervention / Treatment: Other: Iron depletion treatment

• Study Type: Interventional
• Enrollment (Anticipated): 150
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20122
    • Recruiting
    • U.O. Medicina Interna 1/B
    • Contact: Silvia Fargion, Prof.; Phone Number: 39-02-5503-3301; Email: silvia.fargion@unimi.it
    • Principal Investigator: Silvia Fargion, Prof.
    • Sub-Investigator: Luca Valenti, Md

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 18 < 75 years
• Ferritin > 250 ng/ml and/or stainable iron at biopsy
• NAS ≥ 2 and/or NAS 1 and stage≥1 at liver histology
• Willingness to maintain diet and exercise during the full course of the study
• Written informed consent to participate to the study and to have the specific genetic tests performed
• Ability to comply with all study requirements

Exclusion Criteria:

• Pregnant or lactating female
• Diagnosis of or a history of:
• Type 1 diabetes, diabetes that is a result of pancreatic injury, or secondary forms of diabetes, e.g. Cushing's syndrome or acromegaly
• Acute metabolic complication such as ketoacidosis or hyperosmolar state within the past 6 months
• Alcohol consumption > 20 g/day for females and > 30 g/day for males
• BMI ≥ 35 Kg/ m2
• Other liver disease such as viral hepatitis, autoimmune hepatitis, Wilson disease, as defined by ceruloplasmin below normal limits and liver histology consistent with Wilson disease. Alpha-1-antitrypsin deficiency as defined by alpha-1-antitrypsin level less than 80 mg/dl or PiZ/PiZ or PiZ/PiS genotype. *Hemochromatosis, as defined by homozygosity for the C282Y HFE mutation or compound heterozygosity for C282Y/H63D mutations or Hepatic Iron Index ≥ 1.9.
• Advanced liver disease (Child B/C cirrhosis), portal hypertension, hepatocellular carcinoma.
• Congestive heart failure (NYHA I-IV) and unstable ischemic heart disease, systolic dysfunction (ejection fraction < 45%)
• Any of the following ECG abnormalities: II or III degree Atrial Ventricular *Block, QT>500msec, repolarization defect suggestive of ischemia
• Malignancy within the last 5 years
• Serum creatinine levels > 1.5 mg/dl males, > 1.4 mg/dl females
• TSH outside of normal range
• Use of drugs known to induce NAFLD: corticosteroids, methotrexate, zidovudine, amiodarone, GH, estrogens, tamoxifene, tetracycline
• Lipodystrophy, dysbetalipoproteinemia, inflammatory bowel disease, HIV infection
• Basal hemoglobin levels < 11 g/dl

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1	Other: Iron depletion treatment; Effect of iron depletion by phlebotomy plus lifestyle changes vs. lifestyle changes alone on liver damage in patients with nonalcoholic fatty liver disease with increased iron stores

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To determine in a 24 month controlled study whether iron depletion by phlebotomy improves insulin sensitivity, and thereby reduces hepatic steatosis and inflammation in subjects with nonalcoholic steatohepatitis	24 months

Secondary Outcome Measures

Outcome Measure	Time Frame
To assess the effect of iron depletion on glucose tolerance status. Glucose tolerance will be determined by OGTT in subjects without type 2 diabetes (T2D), and by HbA1c levels and the change in dosage of pharmacological therapy in those with T2D.	24 months

Collaborators and Investigators

• Sponsor: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Study record dates

Study Major Dates

• Study Start: October 1, 2007
• Primary Completion (Anticipated): March 1, 2009

Study Registration Dates

• First Submitted: April 9, 2008
• First Submitted That Met QC Criteria: April 11, 2008
• First Posted (Estimate): April 14, 2008

Study Record Updates

• Last Update Posted (Estimate): April 14, 2008
• Last Update Submitted That Met QC Criteria: April 11, 2008
• Last Verified: July 1, 2007

More Information

Terms related to this study

• Keywords: Nonalcoholic fatty liver disease associated with increased iron stores
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: 111.2007