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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.

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Rennes University Hospital
Sponsor:
Information provided by (Responsible Party):
Rennes University Hospital
ClinicalTrials.gov Identifier:
NCT01949467
First received: September 20, 2013
Last updated: September 11, 2014
Last verified: September 2014
  Purpose

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.


Condition Intervention Phase
Hemochromatosis, Type 4
Ferroportin Disease
Dysmetabolic Hepatosiderosis
Diagnosis
Drug: iron fumarate
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Diagnostic
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.

Resource links provided by NLM:


Further study details as provided by Rennes University Hospital:

Primary Outcome Measures:
  • hepcidemia rate [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
    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 [ Time Frame: day 1 ] [ Designated as safety issue: No ]
    Modulation of serum level of other divalent cations.


Estimated Enrollment: 100
Study Start Date: February 2014
Estimated Study Completion Date: June 2017
Estimated Primary Completion Date: April 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
TDHS
20 Patients with Treated Dysmetabolic Hepatosiderosis (TDHS)
Drug: iron fumarate
All patients will receive a tablet of 66mg of iron, in the form of iron fumarate (Fumafer®) with 50 ml water.
UDHS
20 patients with untreated Dysmetabolic Hepatosiderosis (UDHS)
Drug: iron fumarate
All patients will receive a tablet of 66mg of iron, in the form of iron fumarate (Fumafer®) with 50 ml water.
TFPD
20 patients with treated Ferroportin Disease (TFPD)
Drug: iron fumarate
All patients will receive a tablet of 66mg of iron, in the form of iron fumarate (Fumafer®) with 50 ml water.
UFPD
20 patients with untreated Ferroportin Disease (UFPD)
Drug: iron fumarate
All patients will receive a tablet of 66mg of iron, in the form of iron fumarate (Fumafer®) with 50 ml water.
HV
20 Healthy volunteers (HV) patients
Drug: iron fumarate
All patients will receive a tablet of 66mg of iron, in the form of iron fumarate (Fumafer®) with 50 ml water.

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 :

  1. 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.
  2. To correlate amplitude of this response to the iron parameters modulation
  3. To correlate amplitude of this response to the concentration of divalent cations whose metabolism uses common genes to those involved in iron metabolism.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01949467

Contacts
Contact: Olivier LOREAL, MD (0)2.99.28.42.97 (post 86343) ext +33 olivier.loreal@univ-rennes1.fr

Locations
France
CHU Clermont-Ferrand Recruiting
Clermont-Ferrand, France
Contact: Marc Ruivard, MD         
Principal Investigator: Marc Ruivard, MD         
Principal Investigator: Christian Dualé, MD         
CHU Limoges Not yet recruiting
Limoges, France
Contact: véronique Loustaud-Ratti, MD         
Principal Investigator: Véronique Loustaud-Ratti, MD         
Principal Investigator: Déborah Postil, MD         
CHU Montpellier Not yet recruiting
Montpellier, France
Contact: Patricia Aguilar-Martinez, MD         
Principal Investigator: Florence GALTIER, MD         
Principal Investigator: Patricia Aguilar-Martinez, MD         
Chr Orleans Not yet recruiting
Orleans, France
Contact: Xavier Causse, MD         
Principal Investigator: Xavier Causse, MD         
CHU Paris Bicêtre Not yet recruiting
Paris, France
Contact: Catherine Buffet, MDPHD         
Principal Investigator: Catherine Buffet, MDPHD         
CHU Pontchaillou Not yet recruiting
Rennes, France, 35000
Contact: Olivier LOREAL, MD         
Principal Investigator: Olivier LOREAL, MD         
Principal Investigator: Fabrice Lainé, MD         
Sponsors and Collaborators
Rennes University Hospital
  More Information

No publications provided

Responsible Party: Rennes University Hospital
ClinicalTrials.gov Identifier: NCT01949467     History of Changes
Other Study ID Numbers: FERHEP
Study First Received: September 20, 2013
Last Updated: September 11, 2014
Health Authority: France: Agence Nationale de Sécurité du Médicament et des produits de santé
France: Committee for the Protection of Personnes

Keywords provided by Rennes University Hospital:
genetic hemochromatosis
HFE gene
ferroportin disease
dysmetabolic hepatosiderosis
hyperferritinemia
hepcidin
iron fumarate
physiopathological study
diagnosis
TRF2 gene
iron parameters
divalent cations

Additional relevant MeSH terms:
Hemochromatosis
Genetic Diseases, Inborn
Iron Metabolism Disorders
Iron Overload
Metabolic Diseases
Metabolism, Inborn Errors
Metal Metabolism, Inborn Errors
Hepcidins
Iron
Anti-Infective Agents
Growth Substances
Micronutrients
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses
Trace Elements

ClinicalTrials.gov processed this record on November 25, 2014