Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Blood Cells, Molecules, and Diseases (1996) 22(17) Sept 15: 195204
INTRODUCTION
195
Blood Cells, Molecules, and Diseases (1996) 22(17) Sept 15: 195204
routine medical care delivery in the greater Birmingham area were included; no screening of any
group to diagnose hemochromatosis probands was
performed. Normal subjects were randomly recruited from the same geographic area. All probands and normal control subjects were Caucasians.
METHODS
Patient Population and Definition of
Hemochromatosis
196
Blood Cells, Molecules, and Diseases (1996) 22(17) Sept 15: 195204
Table 1. Frequencies of HLA-A3, -B7, and -B14 Phenotypes in Alabama Caucasian Subjects
HLA Phenotype
Hemochromatosis Probands, %
(n)
p*
Odds Ratio
A3
62.5 (80/128)
27.4 (361/1,318)
0.00001
3.0
B7
42.2 (54/128)
25.6 (338/1,321)
0.00075
2.0
B14
18.0 (22/128)
6.4 (84/1,314)
0.00002
3.1
A3, B7
37.5 (48/128)
3.6 (48/1,318)
0.00001
15.9
A3, B14
10.2 (13/128)
1.1 (14/1,318)
0.00001
10.5
Statistical Methods
The data set for HLA phenotype frequency
analyses consisted of observations from 128 homozygous hemochromatosis probands and 1,318 normal control subjects. The D6S105 phenotype was
determined in forty-five probands and in 95 normal control subjects, each randomly chosen. Descriptive results are expressed as the mean 6 1
197
Blood Cells, Molecules, and Diseases (1996) 22(17) Sept 15: 195204
HLA-A3 Heterozygotes
(n 5 16)
Age, years
49 6 14
48 6 11
47 6 10
41 6 34
23 6 19
16 6 10
0.87 6 0.80
0.49 6 0.37
0.39 6 0.35
362
261
2 6 1
219 6 51
199 6 36
194 6 59
85 6 18
73 6 21
68 6 24
HLA-A3 Negative
(n 5 18)
1,160 6 1,012
931 6 1,182
66.7
56.3
61.1
56 (5)
19 (3)
33 (6)
Arthropathy, % (n)
44 (4)
31 (5)
22 (4)
11 (1)
6 (1)
Hypogonadism, % (n)
33 (3)
Cardiomyopathy, % (n)
11 (1)
773 6 659
* Results are expressed as mean 6 SD (range). All parameters except therapeutic phlebotomy data represent the findings at the time of
diagnosis of hemochromatosis.
value of p ,0.05 in comparison with presumed HLA-A3 homozygotes.
value of p ,0.05 in comparison with presumed HLA-A3 heterozygotes.
198
Blood Cells, Molecules, and Diseases (1996) 22(17) Sept 15: 195204
Allele 8 Heterozygotes (n 5 20 )
Age, years
47 6 11
47 6 11
51 6 10
37 6 35
23 6 13
12 6 6
0.81 6 0.77
0.52 6 0.34
362
261
261
191 6 47
213 6 36
194 6 67
75 6 24
78 6 19
65 6 23
1,264 6 1,495
746 6 523
829 6 734
58.3
60.0
72.7
42 (5)
15 (3)
55 (6)
Arthropathy, % (n)
33 (4)
25 (5)
36 (4)
8 (1)
9 (1)
Hypogonadism, % (n)
25 (3)
Cardiomyopathy, % (n)
8 (1)
0.25 6 0.13
* Results are expressed as mean 6 SD (range). All parameters except therapeutic phlebotomy data represent the findings at the time of
diagnosis of hemochromatosis.
value of p , 0.05 in comparison with D6S105 allele 8 homozygotes.
value of p , 0.05 in comparison with D6S105 allele 8 heterozygotes.
HLA-A3 Heterozygotes
HLA-A3 Negative
11
12
53 6 39
29 6 21
19 6 10
1.13 6 1.01
0.59 6 0.40
0.48 6 0.38
463
361
2 6 1
Males (n)
Induction phlebotomy, units
Females (n)
25 6 23
11 6 4
11 6 10
0.54 6 0.31
0.28 6 0.17
0.23 6 0.22
261
1 6 1
1 6 1
* There were no significant differences in mean age of probands among these groups.
value of p , 0.05 in comparison with presumed HLA-A3 homozygotes.
value of p , 0.05 in comparison with corresponding data from males.
199
Blood Cells, Molecules, and Diseases (1996) 22(17) Sept 15: 195204
Table 5. Phlebotomy Requirements, Sex, and D6S105 Allele 8 in Homozygous Hemochromatosis Probands*
Allele 8 Homozygotes
Allele 8 Heterozygotes
Allele 8 Negative
13
48 6 40
28 6 12
1.04 6 0.93
0.64 6 0.34
0.30 6 0.13
462
3 6 1
2 6 0
22 6 22
15 6 10
0.47 6 0.33
0.44 6 0.42
0.25 6 0.13
2 6 1
1 6 1
1 6 0
Males (n)
Induction phlebotomy, units
Females (n)
Induction phlebotomy, units
14 6 6
3
12 6 6
* There were no significant differences in mean age of probands among these groups.
value of p , 0.05 in comparison with D6S105 allele 8 homozygotes.
value of p , 0.05 in comparison with D6S105 allele 8 heterozygotes.
value of p , 0.05 in comparison with corresponding data from males.
200
Blood Cells, Molecules, and Diseases (1996) 22(17) Sept 15: 195204
histocompatibility complex (MHC), which corresponds to the HLA region of the human genome
(37). Among our male probands, the severity of
iron overload was greater, on the average, than in
females, in accordance with hormonal and other
sex-associated differences in iron intake, absorption, and loss (36). However, significant differences in iron overload among subjects stratified by
genetic markers could still be discerned. Further,
the predominant factor in determining the concordance of iron overload severity in HLA-identical
sibling hemo-chromatosis homozygotes is also
genetic (38). Taken together, these observations
suggest there is allelic and/or locus heterogeneity
of the hemochromatosis gene(s), and that the iron
absorption and phenotypic variability among hemochromatosis probands is more attributable to
genetic influence than to other factors.
The serum ferritin concentration, hepatocyte
iron grade, and hepatic iron index measure the
relative severity of iron overload in hemochromatosis homozygotes. Among our groups of probands stratified by genetic markers, the mean
ferritin concentrations and hepatocyte iron grades
were not significantly different. However, these
parameters indicated trends which corresponded
with the significant differences in mean units of
phlebotomy and mean phlebotomy iron indices.
Among Australian hemochromatosis patients who
expressed two copies of a common, ancestral
haplotype, there was a significantly greater mean
hepatic iron index in comparison with those
heterozygous for or those without this haplotype.
Further, there were differences between the hepatic iron indices of Australian males and females
(26) which correspond to the differences in units
of blood removed by phlebotomy in our male and
female Alabama probands stratified by genetic
markers. Therefore, the hepatic iron index may
distinguish among groups of hemochromatosis
patients stratified by genetic markers, but the other
commonly measured parameters of iron stores
appear to be less sensitive and less specific than
quantification of excess body iron by phlebotomy.
We evaluated target organ injury characteristic
of iron overload, and found that cirrhosis and
201
Blood Cells, Molecules, and Diseases (1996) 22(17) Sept 15: 195204
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
ACKNOWLEDGMENTS
13.
14.
202
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
Blood Cells, Molecules, and Diseases (1996) 22(17) Sept 15: 195204
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
203
Blood Cells, Molecules, and Diseases (1996) 22(17) Sept 15: 195204
43.
204