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 Previous Article | Table of Contents
Blood, Vol. 91 No. 9 (May 1), 1998:
p. 3524
CORRESPONDENCE
Congenital Anhaptoglobinemia Versus Acquired Hypohaptoglobinemia
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LETTER |
To the Editor:
Manoharan1 reported on family cases of low serum
haptoglobin (Hp) concentration (hypohaptoglobinemia). In this letter, it was postulated that they were cases of congenital Hp deficiency (anhaptoglobinemia), which the author described as an entity that has
received little recognition in literature. However, epidemiological studies have found numerous cases of anhaptoglobinemia all over the
world in the last four decades.2-5 In true
"anhaptoglobinemia" (Hp 0-0 phenotype), the expression of the Hp
gene is absent.2 This condition is present in approximately
1 of every 1,000 whites.2 In Melbourne
(Australia), 1.7% of the population carries the Hp 0-0 phenotype.3 In blacks, especially of West African origin (Nigeria, Cameroon), anhaptoglobinemia is more frequent (greater than
30%).4 The frequency of Hp 0-0 among blacks in the United States is 4%.5 An increase in the prevalence of
anhaptoglobinemia has also been reported among the white
elderly population.2
Manoharan1 further speculated about the inheritance of this
condition. Also, this subject has been studied in detail in literature.6,7 Primary anhaptoglobinemia has been reported to occur in families carrying a "silent allele" (Hp 0) with no gene product.6,7 These family studies do not support a
dominant type of inheritance.6,7 Next to the occurrence of
Hp 0-0, secondary familial hypohaptoglobinemia can occur as a
consequence of congenital diseases such as hemolytic disorders (eg,
hereditary red cell membrane and enzyme defects, thalassemia, sickle
cell anemia).7 After destruction of erythrocytes, Hp is
saturated when approximately 500 to 1,500 mg/L of free hemoglobin is
released into the plasma, which corresponds to only a moderate degree
of hemolysis.2 In view of the relatively low
hemoglobin-binding capacity of Hp, even common life style factors (eg,
repetitive physical exercise associated with limited mechanical trauma
to erythrocytes) may induce relative hypohaptoglobinemia.2
Difference between congenital and acquired hypohaptoglobinemia can
simply be made by an additional determination of hemopexin in
serum.2,8 Hemopexin binds free heme.8 After
saturation of the hemoglobin-binding capacity of Hp, serum hemopexin
levels start to decrease, whereas the Hp concentration remains at low level (less than 0.3 g/L). During intense hemolytic processes or in
chronic hemolytic diseases, determination of serum hemopexin should be
performed.2,8 In the case of an Hp 0-0 phenotype without
hemolysis, hemopexin levels will remain unchanged.
A critical point in the diagnosis of hypohaptoglobinemia is the age
dependency of the expression of the haptoglobin gene in infants. In
neonatal serum, no Hp can be detected.9 The protein is
detectable in less than 50% of children between the ages of 1 and 2 months.9 At the sixth month, failure to detect Hp becomes relatively rare in whites.
Another difficulty in interpreting low serum haptoglobin levels is the
fact that its reference values depend on the Hp phenotype.2 The reference values for Hp 2-2 in serum are considerably lower (0.38 to 1.50 g/L) than for Hp 2-1 (0.44 to 1.83 g/L) and Hp 1-1 (0.57 to
2.27 g/L).2 Therefore, Hp 2-2 subjects (30% to 50% of
whites) may be in a state of relative hypohaptoglobinemia compared with
the other phenotypes. To illustrate this, we performed a careful
reinvestigation of 10 serum samples with hypohaptoglobinemia (less than
0.3 g/L) and found no detectable trace of Hp on electrophoresis. Gel
permeation chromatography of these sera (based on differences in
molecular mass between the Hp phenotypes) demonstrated six cases of Hp
2-2, one case of Hp 2-1, and only three cases of "true" anhaptoglobinemia.
In conclusion, congenital anhaptoglobinemia cannot be regarded as a
rare phenomenon and should be distinguished from secondary hypohaptoglobinemia by additional determination of serum hemopexin concentration. Furthermore, hypohaptoglobinemia has important clinical
consequences: this condition is associated with heme iron accumulation
due to a less efficient clearance of free hemoglobin in body fluids,
resulting in iron-driven oxidative stress and vitamin C
depletion.10-11
Joris Delanghe
Michel Langlois
Marc De Buyzere
Central Laboratory
University
Hospital Gent
Gent, Belgium
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