Chemistry: analytical and immunological testing – Hemoglobin – myoglobin – or occult blood
Reexamination Certificate
1999-11-12
2001-07-31
Wallenhorst, Maureen M. (Department: 1743)
Chemistry: analytical and immunological testing
Hemoglobin, myoglobin, or occult blood
C436S063000, C436S070000, C436S010000
Reexamination Certificate
active
06268217
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to diagnosis of iron disorders.
Hemochromatosis is a common hereditary disorder that affects approximately 0.5% of persons of western European descent. In various populations, 60%-100% of cases are attributable to homozygosity for a missense mutation (cDNA nucleotide 845 G6A; C282Y) in HFE, a major histocompatibility class I gene on chromosome 6p. Some patients are compound heterozygotes for C282Y and another HFE allele (cDNA nucleotide 187 C6G; H63D), or are H63D homozygotes. However, C282Y and H63D are not known to occur on the same chromosome. Other persons with a hemochromatosis phenotype are homozygous for H63D, are heterozygous for C282Y or H63D, or are presumed to have an HFE or other mutation that is not presently detectable (wild-type; wt/wt). Regardless of HFE genotype, persons with a hemochromatosis phenotype usually have increased iron saturation of plasma transferrin, typically absorb increased quantities of iron, and often develop multisystem disease due to iron overload.
SUMMARY OF THE INVENTION
The invention is based on the discovery that peripheral blood erythrocyte parameters in hemochromatosis patients or those at risk of developing hemochromatosis is distinguished from the erythrocyte parameters of normal individuals. Hemoglobin (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MNCHC) values were significantly higher in hemochromatosis patients compared to normal control individuals. Accordingly, the invention provides a methods of diagnosing hemochromatosis or a predisposition thereto by detecting altered erythrocyte parameters.
A method of diagnosing hemochromatosis or a predisposition thereto in a mammal is carried out by determining the mean corpuscular volume (MCV) value of a blood sample from the mammal. An an increase of at least 5% compared to a normal control value indicates that said mammal has hemochromatosis or is predisposed to developing hemochromatosis. A normal control value or range is one obtained by testing an individual or pool of individuals who are wt/wt. Individuals used to determine a normal control value or range are neither homozygous nor heterozygous for a genetic mutation associated with hemochromatosis such as C282Y or H63D of the HFE gene. Preferably, the increase is at least 7%, more preferably at least 7.5%, more preferably at least 8%, more preferably at least 9%, and most preferably at least 10% higher than a normal control value or range. Preferably, the erythrocyte profile of the tested individual does not indicate an anemic condition. For example, a red blood cell count (RBC), hematocrit (Hct), or hemoglobin concentration (Hb) should be within a normal range but the MCV value is elevated compared to a normal value or range to indicate a diagnosis of hemochromatosis.
A method of diagnosing hemochromatosis or a predisposition thereto in a mammal is also carried out by determining that the MCV value of a blood sample from the mammal is at least 80 fL. Preferably, the value is at least 85 fL, and more preferably the value is in the range of 90-102 fL. An erythrocyte profile of hemochromatosis is distinguished from one previously thought to be associated with a hepatic disease in that the inventive profile diagnostic of hemochromatosis does not include an erythrocyte parameter, e.g., RBC, Hct, or Hb, which indicates anemia. Hemochromatosis is also diagnosed by determining the mean corpuscular hemoglobin (MCH) value, mean corpuscular hemoglobin concentration (MCHC), Hb, or Hct of a blood sample from the mammal. An increase of at least 5% (preferably at least 7%, more preferably at least 7.5%, more preferably at least 8%, more preferably at least 9%, and most preferably at least 10%) compared to a normal control value indicates that said mammal has hemochromatosis or is predisposed to developing hemochromatosis. As above, the erythrocyte profile indicative of a diagnosis of hemochromatosis does not include a parameter such as RBC, Hct, or Hb which indicates an anemic condition. Hemochromatosis is diagnosed by determining that the MCH value of a blood sample from the mammal is at least 26 pg. More preferably, the value is at least 28 pg, such as a value in the range of 30-35 pg.
The present method overcomes the insensitivity of the prior art because the standard value ranges of Hb, Hct, MCV, and MCH are not true “normal ranges” because at least 25% of the population contains at least one mutation associated with hemochromatosis. The data reported herein indicates that the inclusion of such individuals in the determination of the standard ranges of values results in ranges that are not reflective of a normal control, but are approximately 5-10% higher. The diagnostic methods of the invention are used to properly use information already obtained from standard hematological tests and extract the maximum information from the red blood cell indices.
The methods of measuring erythrocyte parameters are well known, but the interpretation of the results to diagnose hemochromatosis is new. Hemochromatosis was not diagnosed using the previous assays because the values of hemochromatosis patients would fall into the “normal ranges”. However, the normal ranges of the prior art were skewed because of the inadvertent inclusion of individuals which are homozygous or heterozygous for hemochromatosis-associated mutations (and which elevated Hb, Hct, MCV, or MCH values compared to individuals without a hemochromatosis-associated mutation
Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims.
REFERENCES:
patent: 5674681 (1997-10-01), Rothenberg
Khanh et al.Journal of Tropical Pediatrics,vol. 36, pp. 43-45, Feb. 1990.*
Barton et al.Blood ,vol. 92, No. 10, Suppl. 1 Part 1-2, pp. 12B, Nov. 15, 1998.
Barton James C.
Bertoli Luigi F.
Rothenberg Barry E.
Beattie Ingrid A.
Mintz, Levin, Cohn, Ferris, Glovsky and Popep, P.C.
Wallenhorst Maureen M.
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