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Analysis of the Modulation of Serum Hepcidin Level in Response to Iron Oral Intake: Potential Interest for the Differential Diagnosis Between Ferroportin Disease and Dysmetabolic Hepatosiderosis.

Primary Purpose

Hemochromatosis, Type 4, Ferroportin Disease, Dysmetabolic Hepatosiderosis

Status
Completed
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
iron fumarate
Sponsored by
Rennes University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Hemochromatosis, Type 4 focused on measuring ferroportin disease, dysmetabolic hepatosiderosis, genetic hemochromatosis, hyperferritinemia, hepcidin, iron fumarate, physiopathological study, diagnosis, HFE gene, TRF2 gene, iron parameters, divalent cations

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria for patients:

  • Man or woman older than 18 years

  • Subject having a liver iron overload greater than or equal to 100 umol /g dry liver weight, confirmed by MRI (done performed with body antenna and complete deactivation of the surface antenna) and / or by biochemical assay on liver biopsy, and related to dysmetabolic hepatosiderosis or ferroportin disease.

    • The ferroportin disease will be retained when patients will present an hyperferritinemia without elevated transferrin saturation and a heterozygote mutation in the gene encoding ferroportin.
    • A dysmetabolic hepatosiderosis will be retained following the usual diagnostic investigation including sequencing of the gene for ferroportin (mutation proven negative), if patients do not show any other cause of iron overload and hyperferritinemia is not related to excessive alcohol intake, non-metabolic liver cytolysis (hepatitis C virus, wilson, autoimmune hepatitis, ...), hemolysis, or inflammatory syndrome.
  • Status towards the iron-depletive treatment : either no venesection performed (Dysmetabolic HepatoSiderosis and Ferroportin disease groups) or attack iron depletive treatment completed (Treated Dysmetabolic Hepatosiderosis and Treated Ferroportin Disease groups) with ferritin level less than 100 ng / ml, without anemia and with no venesection in the two last months.
  • Having given a free and informed consent in writing
  • Affiliate to the social security system.

Exclusion Criteria for patients:

  • Alcohol consumption greater than 30g/d
  • Chronic inflammatory disease.
  • HIV, HCV or HBV Infection.
  • Blood donation in the last three months.
  • Infection during the previous seven days before testing
  • Staying in altitude (>1500 m) dating less than 2 months
  • Night occupation or shift work.
  • Pregnancy
  • Exclusion period in the national register of persons suitable for biomedical research.
  • Protected adults (judicial protection, guardianship and trusteeship) and persons deprived of liberty

Inclusion criteria for healthy volunteers:

  • Man or woman older than 18 years.
  • Body Mass Index between 18 and 25 kg/m².
  • Non smoker or quit smoking for more than 6 months
  • Examen clinique normal. Normal clinical examination
  • Normal ECG.
  • Normal values for routine laboratory tests : serum iron, tranferrin saturation, CBC, ferritin, blood cell count C-reactive protein, AST, ALT, GGT, HDL and LDL cholesterol, triglycerides.
  • Having given a free and informed consent in writing
  • Affiliate or beneficiary to the social security system.

Exclusion criteria for healthy volunteers :

  • Progressive and/or chronic disease.
  • Infection during the previous seven days before testing
  • Drug use under 6 months.
  • Alcohol consumption greater than 30g/d
  • Medication ongoing or stopped from less than a week (except contraceptives).
  • History of blood transfusion or martial treatment.
  • Staying in altitude (>1500 m) dating less than 2 months
  • Night occupation or shift work.
  • Known infection by hepatitis B or C.
  • Positive serology for HIV.
  • Blood donation in the last three months.
  • Pregnancy.
  • Exclusion period in the national register of persons suitable for biomedical research.
  • Protected adults (judicial protection, guardianship and trusteeship) and persons deprived of liberty.

Sites / Locations

  • CHU Clermont-Ferrand
  • CHU Limoges
  • CHU Montpellier
  • CHU Pontchaillou

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Other

Other

Other

Other

Other

Arm Label

TDHS

UDHS

TFPD

UFPD

HV

Arm Description

20 Patients with Treated Dysmetabolic Hepatosiderosis (TDHS)

20 patients with untreated Dysmetabolic Hepatosiderosis (UDHS)

20 patients with treated Ferroportin Disease (TFPD)

20 patients with untreated Ferroportin Disease (UFPD)

20 Healthy volunteers (HV) patients

Outcomes

Primary Outcome Measures

hepcidemia rate
The primary endpoint is the maximum variation, of hepcidemia rate (Δmax) after iron oral intake. This variation will be compared between the different groups of included subjects

Secondary Outcome Measures

ratios between serum hepcidin level and iron parameters
Differential modulation, induced by the iron intake, of ratios between serum hepcidin level and iron parameters (serum iron, transferrin, ferritin) between the different groups.
serum level of other divalent cations
Modulation of serum level of other divalent cations.

Full Information

First Posted
September 20, 2013
Last Updated
March 25, 2019
Sponsor
Rennes University Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT01949467
Brief Title
Analysis of the Modulation of Serum Hepcidin Level in Response to Iron Oral Intake: Potential Interest for the Differential Diagnosis Between Ferroportin Disease and Dysmetabolic Hepatosiderosis.
Official Title
Prospective, Comparative (5 Groups), Non-randomized, Multicenter, Physiopathological Study, Evaluating Pharmacokinetic Characteristics of Serum Hepcidin Level in Response to Iron Oral Intake in Order to Evaluate Their Interest to Discriminate Patients With Dysmetabolic Hepatosiderosis or Ferroportin Disease.
Study Type
Interventional

2. Study Status

Record Verification Date
August 2018
Overall Recruitment Status
Completed
Study Start Date
February 10, 2014 (Actual)
Primary Completion Date
December 19, 2017 (Actual)
Study Completion Date
December 26, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Rennes University Hospital

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The diagnosis of iron overload is a common problem. It is important to optimize the diagnosis to ensure support for patients and their relatives especially regarding genetic disease. Iron overload revealed by a high level of serum ferritin and confirmed by the presence of an excessive amount of iron in the liver is a frequent situation. In a lot of case there is no increase in serum iron and transferrin saturation. This situation may arise in particular in patients with: a genetic iron overload related to mutation in the ferroportine gene, leading to a ferroportin disease. The diagnosis is based on the sequencing of the gene, a dysmetabolic hepatosiderosis, the most frequent situation , where iron overload is associated with abnormalities in the metabolism of carbohydrates and fats, whereas no genetic cause is identified. However, patients often have similar biological signs and despite the implementation of strict algorithm regarding the diagnostic procedure, it appears that a large number of patients are tested for the mutation in the ferroportin gene, and that mutation is not found in most cases. It is therefore essential to optimize the diagnosis process by introducing additional criteria. The investigators' hypothesis, based on the known elements, is that the response to a single dose of iron will modulate differently the iron parameters measured in serum, including hepcidin level which controls iron metabolism and metals associated with iron. This could be helpful for diagnosis procedure in patients with ferroportin disease or dysmetabolic hepatosiderosis.
Detailed Description
The quantification of serum hepcidin level is a potential method of investigation in iron metabolism disorders. However, apart from some extreme situations, the assay achieved solely is not helpful. This is due to the varying levels encountered from one subject to another for the same disease. This is related to the facts that values considered to be normal cover a wide range and that a value obtained for a given patient at a given time, can be influenced by many factors. It has been reported that a a single oral iron dose induced an increase of serum hepcidin level in healthy subjects which is abolished in subjects with genetic hemochromatosis linked to insufficient hepcidin expression related to mutations in the HFE or TFR2 genes. In patients with a dysmetabolic hepatosiderosis, it was suggested that the expected hepcidinemia increase found after an iron intake was altered, likely due to a slight inflammatory signal responsible for hepcidin induction. The investigators hypothesize that a dynamic response of iron parameters, including modulation of hepcidin level, to an iron intake will allow to discriminate patients with ferroportin disease or dysmetabolic hepatosiderosis, situations whose clinicobiological presentation is often confusing. Thus, the three objectives in this study will be : To define pharmacokinetic characteristics of serum hepcidin in response to iron oral intake and to determine the ability of this pharmacokinetic to discriminate dysmetabolic hepatosiderosis and ferroportin disease. To correlate amplitude of this response to the iron parameters modulation To correlate amplitude of this response to the concentration of divalent cations whose metabolism uses common genes to those involved in iron metabolism.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemochromatosis, Type 4, Ferroportin Disease, Dysmetabolic Hepatosiderosis, Diagnosis
Keywords
ferroportin disease, dysmetabolic hepatosiderosis, genetic hemochromatosis, hyperferritinemia, hepcidin, iron fumarate, physiopathological study, diagnosis, HFE gene, TRF2 gene, iron parameters, divalent cations

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
62 (Actual)

8. Arms, Groups, and Interventions

Arm Title
TDHS
Arm Type
Other
Arm Description
20 Patients with Treated Dysmetabolic Hepatosiderosis (TDHS)
Arm Title
UDHS
Arm Type
Other
Arm Description
20 patients with untreated Dysmetabolic Hepatosiderosis (UDHS)
Arm Title
TFPD
Arm Type
Other
Arm Description
20 patients with treated Ferroportin Disease (TFPD)
Arm Title
UFPD
Arm Type
Other
Arm Description
20 patients with untreated Ferroportin Disease (UFPD)
Arm Title
HV
Arm Type
Other
Arm Description
20 Healthy volunteers (HV) patients
Intervention Type
Drug
Intervention Name(s)
iron fumarate
Intervention Description
All patients will receive a tablet of 66mg of iron, in the form of iron fumarate (Fumafer®) with 50 ml water.
Primary Outcome Measure Information:
Title
hepcidemia rate
Description
The primary endpoint is the maximum variation, of hepcidemia rate (Δmax) after iron oral intake. This variation will be compared between the different groups of included subjects
Time Frame
Day 1
Secondary Outcome Measure Information:
Title
ratios between serum hepcidin level and iron parameters
Description
Differential modulation, induced by the iron intake, of ratios between serum hepcidin level and iron parameters (serum iron, transferrin, ferritin) between the different groups.
Time Frame
Day 1
Title
serum level of other divalent cations
Description
Modulation of serum level of other divalent cations.
Time Frame
day 1

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria for patients: Man or woman older than 18 years Subject having a liver iron overload greater than or equal to 100 umol /g dry liver weight, confirmed by MRI (done performed with body antenna and complete deactivation of the surface antenna) and / or by biochemical assay on liver biopsy, and related to dysmetabolic hepatosiderosis or ferroportin disease. The ferroportin disease will be retained when patients will present an hyperferritinemia without elevated transferrin saturation and a heterozygote mutation in the gene encoding ferroportin. A dysmetabolic hepatosiderosis will be retained following the usual diagnostic investigation including sequencing of the gene for ferroportin (mutation proven negative), if patients do not show any other cause of iron overload and hyperferritinemia is not related to excessive alcohol intake, non-metabolic liver cytolysis (hepatitis C virus, wilson, autoimmune hepatitis, ...), hemolysis, or inflammatory syndrome. Status towards the iron-depletive treatment : either no venesection performed (Dysmetabolic HepatoSiderosis and Ferroportin disease groups) or attack iron depletive treatment completed (Treated Dysmetabolic Hepatosiderosis and Treated Ferroportin Disease groups) with ferritin level less than 100 ng / ml, without anemia and with no venesection in the two last months. Having given a free and informed consent in writing Affiliate to the social security system. Exclusion Criteria for patients: Alcohol consumption greater than 30g/d Chronic inflammatory disease. HIV, HCV or HBV Infection. Blood donation in the last three months. Infection during the previous seven days before testing Staying in altitude (>1500 m) dating less than 2 months Night occupation or shift work. Pregnancy Exclusion period in the national register of persons suitable for biomedical research. Protected adults (judicial protection, guardianship and trusteeship) and persons deprived of liberty Inclusion criteria for healthy volunteers: Man or woman older than 18 years. Body Mass Index between 18 and 25 kg/m². Non smoker or quit smoking for more than 6 months Examen clinique normal. Normal clinical examination Normal ECG. Normal values for routine laboratory tests : serum iron, tranferrin saturation, CBC, ferritin, blood cell count C-reactive protein, AST, ALT, GGT, HDL and LDL cholesterol, triglycerides. Having given a free and informed consent in writing Affiliate or beneficiary to the social security system. Exclusion criteria for healthy volunteers : Progressive and/or chronic disease. Infection during the previous seven days before testing Drug use under 6 months. Alcohol consumption greater than 30g/d Medication ongoing or stopped from less than a week (except contraceptives). History of blood transfusion or martial treatment. Staying in altitude (>1500 m) dating less than 2 months Night occupation or shift work. Known infection by hepatitis B or C. Positive serology for HIV. Blood donation in the last three months. Pregnancy. Exclusion period in the national register of persons suitable for biomedical research. Protected adults (judicial protection, guardianship and trusteeship) and persons deprived of liberty.
Facility Information:
Facility Name
CHU Clermont-Ferrand
City
Clermont-Ferrand
Country
France
Facility Name
CHU Limoges
City
Limoges
Country
France
Facility Name
CHU Montpellier
City
Montpellier
Country
France
Facility Name
CHU Pontchaillou
City
Rennes
ZIP/Postal Code
35000
Country
France

12. IPD Sharing Statement

Learn more about this trial

Analysis of the Modulation of Serum Hepcidin Level in Response to Iron Oral Intake: Potential Interest for the Differential Diagnosis Between Ferroportin Disease and Dysmetabolic Hepatosiderosis.

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