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WO1998038515A1 - Test de depistage de l'hematochromatose - Google Patents

Test de depistage de l'hematochromatose Download PDF

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Publication number
WO1998038515A1
WO1998038515A1 PCT/CA1998/000174 CA9800174W WO9838515A1 WO 1998038515 A1 WO1998038515 A1 WO 1998038515A1 CA 9800174 W CA9800174 W CA 9800174W WO 9838515 A1 WO9838515 A1 WO 9838515A1
Authority
WO
WIPO (PCT)
Prior art keywords
uibc
mixture
sample
value
subject
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CA1998/000174
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English (en)
Inventor
Paul C. Adams
John NINNESS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
London Health Services Centre
Original Assignee
London Health Services Centre
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by London Health Services Centre filed Critical London Health Services Centre
Priority to AU62865/98A priority Critical patent/AU6286598A/en
Publication of WO1998038515A1 publication Critical patent/WO1998038515A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/90—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving iron binding capacity of blood

Definitions

  • the invention relates to methods for screening human subjects for hemochromatosis .
  • Hereditary hemochromatosis is a common autosomal recessive disease in Caucasians, with a prevalence of approximately 1 in 300(1 to 4). Excessive intestinal absorption of dietary iron in homozygotes leads to the progressive accumulation of iron in tissues. Life- threatening clinical manifestations, such as liver failure, diabetes, and heart failure, usually occur after a latent period of 40-60 years. The diagnosis of hemochromatosis is often missed, and the disease is commonly discovered during the management of incidental illnesses or periodic health examinations (5) .
  • Factors contributing to underdiagnosis include (1) asymptomatic status of most patients until irreversible tissue injury has occurred, (2) lack of specificity of symptoms when present, (3) confusion with alcoholic liver disease, and (4) lack of awareness of hemochromatosis, including appropriate investigations . Early detection and treatment of the disease can prevent the development of impotence, heart failure, cirrhosis, and hepatocellular carcinoma and result in long-term survival similar to the general population (5-7) .
  • hemochromatosis a prime target for population screening (4) .
  • the conventional preliminary screening test currently in use to diagnose hemochromatosis is the transferrin saturation test, which is a two stage test involving determination of both serum iron and total serum iron-binding capacity.
  • a method for conducting an initial screening of a human subject to determine whether the subject is a candidate for further diagnostic testing for hemochromatosis, the method comprising (a) obtaining a sample of a biological fluid from the subject, and
  • Figure 2 shows UIBC in a random sample of blood donors that have been classified as homozygotes, heterozygotes and normals by genetic testing for the hemochromatosis gene (C282Y mutation of the HFE gene) .
  • Figure 3 shows the percentage of homozygotes for hemochromatosis in random blood donors with a serum UIBC greater than and less than 23 ⁇ mol/L. (hh - homozygote, Hh - heterozygote, N - normal) . Prescreening with UIBC greatly reduces the number of patients that require genetic testing.
  • the present invention provides, in accordance with one embodiment, a less expensive and more convenient, one-step test for screening for hemochromatosis in a subject by determining the unsaturated iron-binding capacity (UIBC) of the serum of the subject.
  • the method is an indirect colorimetric method for measuring the iron binding capacity in serum.
  • an assay method is employed wherein a known amount of iron is added to the serum sample in excess of that required to saturate any available iron-binding transferrin sites and the excess unbound iron is measured by interacting it with a chelator with which it forms a detectable chelate- iron complex.
  • the complex is a coloured complex which can be determined spectrophotometrically .
  • Ferrozine * is a preferred chelator.
  • a method for establishing a reproducible cut-off value for serum UIBC in a population, wherein a UIBC value lower than the cut-off value indicates that the tested subject is a candidate for further investigation.
  • the method comprises determining UIBC values of serum samples from a population to be examined, by the method described herein, and analysing these values in relation to the hemochromatosis genotype of the subjects tested. Parameters including TS% and ferritin levels of the samples may be included in further analyses .
  • the cut-off UIBC value for screening for hemochromatosis is in the range of about 18 to about 31 ⁇ mol/L.
  • UIBC and percentage transferrin saturation (TS%) were measured in serum samples from 114 hospital patients .
  • Total iron was measured using the Unimate 5 reagent system for total iron (Hoffman-LaRoche, Mississauga, Ontario) .
  • the method was a modification of the Unimate 7 system for UIBC (Hoffman, La Roche, Mississauga, Ontario), as follows. Materials
  • Reagent Rl Buffer containing 250 mM Tris, pH 8.4, 50 mM NaHC0 3 and 41 ⁇ M sodium azide.
  • Reagent R2 Chromogen solution containing 160 mM hydroxylamine and 20 mM Ferrozine (disodium salt of 3- (2- pyridyl)-5, 6-bis (4-sulphophenyl) -S-triazine) .
  • Hemolysis-free blood samples were collected in iron- free tubes and serum was obtained from the samples .
  • the absorbance (A of the solution was read at 550 nm using a Titertek Plus microplate reader. 40 ⁇ l R 2 was then added to test mixture and mixing was continued for 20 minutes at setting 5 on microtitre plate reader. Absorbance at 550 nm was read again (A 2 ) .
  • TS% values of 45% to 62% have been suggested as the threshold above which hemochromatosis should be suspected.
  • Figure 1 shows that this threshold corresponds to UIBC values lower than 18 to 31 ⁇ mol/L.
  • a TS% higher than 55% corresponds to a UIBC value lower than 23 ⁇ mol/L.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Cell Biology (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

Procédé permettant d'effectuer un dépistage initial chez un individu pour déterminer si ce dernier doit être soumis à une autre épreuve diagnostique de l'hématochromatose. Le procédé se déroule de la manière suivante: (a) on prélève un échantillon d'un fluide biologique chez l'individu; et (b) on détermine la valeur de capacité de liaison du fer non saturé (CLFNS) de l'échantillon; une valeur CLFNS inférieure à une valeur de seuil sélectionnée indiquant que l'individu doit être soumis à une autre épreuve diagnostique.
PCT/CA1998/000174 1997-02-28 1998-03-02 Test de depistage de l'hematochromatose Ceased WO1998038515A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU62865/98A AU6286598A (en) 1997-02-28 1998-03-02 Test for hemochromatosis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CA 2198790 CA2198790A1 (fr) 1997-02-28 1997-02-28 Test pour diagnostiquer l'hemochromatose
CA2,198,790 1997-02-28

Publications (1)

Publication Number Publication Date
WO1998038515A1 true WO1998038515A1 (fr) 1998-09-03

Family

ID=4160069

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA1998/000174 Ceased WO1998038515A1 (fr) 1997-02-28 1998-03-02 Test de depistage de l'hematochromatose

Country Status (3)

Country Link
AU (1) AU6286598A (fr)
CA (1) CA2198790A1 (fr)
WO (1) WO1998038515A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001035095A3 (fr) * 1999-11-12 2002-02-07 Barry E Rothenberg Test de diagnostic d'hemochromatose

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3887332A (en) * 1972-04-12 1975-06-03 Eiken Chemical Method of determining unsaturated iron binding capacity in serum
US4308027A (en) * 1978-11-08 1981-12-29 R.C.C. Societa' Ricerche Di Chimica Clinica S.R.L. Method and composition for direct determination of iron in blood serum
US4588695A (en) * 1983-09-26 1986-05-13 Wako Pure Chemical Industries, Ltd. Determination of unsaturated iron-binding capacity
US4961970A (en) * 1987-09-03 1990-10-09 Boehringer Mannheim Gmbh Method for determining iron in a body fluid sample
US5420008A (en) * 1991-12-02 1995-05-30 Oriental Yeast Co., Ltd. Assay method and assay reagent for serum iron or unsaturated iron binding capacity

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3887332A (en) * 1972-04-12 1975-06-03 Eiken Chemical Method of determining unsaturated iron binding capacity in serum
US4308027A (en) * 1978-11-08 1981-12-29 R.C.C. Societa' Ricerche Di Chimica Clinica S.R.L. Method and composition for direct determination of iron in blood serum
US4588695A (en) * 1983-09-26 1986-05-13 Wako Pure Chemical Industries, Ltd. Determination of unsaturated iron-binding capacity
US4961970A (en) * 1987-09-03 1990-10-09 Boehringer Mannheim Gmbh Method for determining iron in a body fluid sample
US5420008A (en) * 1991-12-02 1995-05-30 Oriental Yeast Co., Ltd. Assay method and assay reagent for serum iron or unsaturated iron binding capacity

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BAYNES R D ET AL: "A SCREENING TEST FOR DETECTING IRON OVERLOAD IN POPULATION STUDIES.", S AFR MED J 74 (4). 1988. 167-169. CODEN: SAMJAF ISSN: 0038-2469, XP002067528 *
FISHER V L ET AL: "Performance characteristics of Sigma Diagnostics iron- UIBC assay.", 46TH NATIONAL MEETING OF THE AMERICAN ASSOCIATION FOR CLINICAL CHEMISTRY, INC., NEW ORLEANS, LOUISIANA, USA, JULY 17-21, 1994. CLINICAL CHEMISTRY 40 (6). 1994. 1059-1060. ISSN: 0009-9147, XP002067531 *
FU F: "UIBC ASSAY FOR THE TECHNICON CHEM 1 SYSTEM.", JOINT MEETING OF THE AMERICAN ASSOCIATION FOR CLINICAL CHEMISTRY AND THE CANADIAN SOCIETY OF CLINICAL CHEMISTS, CHICAGO, ILL., USA, JULY 13-18, 1986. CLIN CHEM 32 (6). 1986. 1104. CODEN: CLCHAU ISSN: 0009-9147, XP002067532 *
LEYLAND M J ET AL: "IMMUNO RADIOMETRIC ASSAY FOR FERRITIN IN HUMAN SERUM.", SCAND J HAEMATOL 14 (5). 1975 385-392. CODEN: SJHAAQ ISSN: 0036-553X, XP002067530 *
MEYER T ET AL: "PHENOTYPIC EXPRESSION OF THE HLA LINKED IRON-LOADING GENE IN MALES OVER THE AGE OF 40 YEARS A POPULATION STUDY USING SERIAL SERUM FERRITIN ESTIMATIONS.", J INTERN MED 227 (6). 1990. 397-406. CODEN: JINMEO, XP002067529 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001035095A3 (fr) * 1999-11-12 2002-02-07 Barry E Rothenberg Test de diagnostic d'hemochromatose

Also Published As

Publication number Publication date
AU6286598A (en) 1998-09-18
CA2198790A1 (fr) 1998-08-28

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