Klinische W°ches hdft

Klin. Wochenschr. 57, 529-531 (1979)

© Springer-Verlag 1979

Kurze wissenschaftliche Mitteilungen The Distribution of HLA-Antigens in German Patients with Idiopathic Hemochromatosis H. D y r s z k a , G . E b e r h a r d t a n d G . E c k e r t FachkIinik Rosenberg f~r Verdauungs- und Stoffwechselkrankheiten der Landesversicherungsanstalt Westfalen in Bad Driburg und Abteilung fiir Klinische Inmmnologie und Transfusionsmedizin der Medizinischen Hochschule Hannover

HLA-Antigene und idiopathische H~imochromatose in Deutschland Zusammenfassung. Bei 31 (30 nichtverwandten) Patienten mit idiopathischer H~imochromatose wurde tier HLA-Ph~inotyp bestimmt und mit dem Verteilungsmuster der HLA-Antigene in der deutschen Bev61kerung verglichen. Dabei fand sich ein signifikanter l~berschul3 von HLA-A3 (76,7% gegen 30,2%). Auch die Hfiufigkeit yon HLA-B7 war erh6ht (53,3% gegen 27,0%), erreichte jedoch bei Korrekturen ftir multiple Vergleiche nicht ganz die Signifikanzgrenze. Die Befunde stehen in ()bereinstimmung mit Beobachtungen f~r andere ethnische Gruppen und sprechen daffir, dab IH in erh6htem MaBe mit dem Haplotyp A3/B7 vergesellschaftet ist. Schliisselwiirter: HLA-Antigene tose

Idiopathische H/imochroma-

Summary. HLA-phenotypes were determined in 31 (30 unrelated) patients with hemochromatosis and compared to the distribution of HLA-antigens in the general German population. A significant excess of HLA-A3 was observed (76.7% vs. 30.2%). The fi'equency of HLA-B7 was also increased (53.3% vs. 27.0%). However, the difference did not quite reach the level of statistical significance, when correction for multiple comparisons was made. Our finding are in accord with previous observations for different ethnic groups, indicating an association of IH with the A3/B7 haplotype. Key words: HLA-antigens - Idiopathic hemochromatosis

The association of certain HLA-antigens with various diseases has been welt established. Recently, interest has been focused on HLAantigen patterns in idiopathic hemochromatosis (IH). All investigations carried out to date have shown an association of HLA-A3 with IH [5 9]. Furthermore, increased frequencies of HLA-B7 and HLA-B14 have been reported [5-9]. However, HLA-antigen frequencies show considerable ethnic variations [2]. We therefore examined the relationship of HLA-antigens with IH in patients in our area. The HLA phenotype was determined in 31 patients with IH and antigen frequencies were compared to those of the general population in Germany. Offprint requests to: Dr. H. Dyrszka (address see page 535)

Subjects and Methods Of the 31 patients 28 were male and 3 female. The age of the patients ranged from 38 to 67 years, the average age being 51.5 years. Except for two brothers all patients were unrelated. The diagnosis of IH was based on a negative history of chronic alcoholism, on clinical findings, determination of serum iron and total iron binding capacity, and on parenctlymal iron load of the liver. All but two patients underwent laparoscopy and liver biopsy. In two patients liver tissue was obtained by "blind" percutaneous liver biopsy. HLA-antigens were determined by the microlymphotoxicity method [12]. A total of 40 antigens was tested for. Statistical analysis was performed by the x2-test. Correction for multiple comparisons was made by multiplication of p with the total number of antigens tested for (=poorr) [3].

Results HLA phenotypes and clinical findings are listed in Table 1. The mean serum iron level was 223 gg/100 ml+ 8 (SEM). The mean saturation of the iron binding capacity was 81 + 4%. The frequencies of HLA A3 and HLA B7 are clearly in excess of the figures given for a large sample (n=5,046) of the German population [1]. 76.7% of our unrelated patient (n=30) were positiv for HLA A3 as opposed to a 30.2% frequency for the general population ()~z= 30.387, p < 0.0001, p . . . . . < 0.005). The percentage frequencies for HLA B7 were 53.3 vs. 27.0 (Xz - 10.463, p < 0.0025, p ..... < 0.1).

Discussion Our data confirm the association of IH and HLA-A3 for German patients. It seems unlikely that the predominance of HLA-A3 can be explained by geographical selection, as the German population shows little heterogeneity for the HLA-phenotype [1]. The frequency of HLA-A3 found in our patients is comparable to that reported previously by observers from different geographical areas [6--.9, 11]. Similarly, we tbund an excess of HLA-B7. The association of HLA-B7 with IH appears to show geographical differences [7-9, 13]. However, the increased frequency observed in our patients is in agreement with most reports [7, 8, 13]. In contrast, Simon et al. found an excess of HLA B14 in their patients with IH [9]. In any case, these findings are best explained by population and

530

K u r z e wissenschaftliche M i t t e i h i n g e n

Table 1. H L A - p h e n o t y p e a n d clinical m a n i f e s t a t i o n s in 31 p a t i e n t s w i t h i d i o p a t h i c h e m o c h r o m a t o s i s Patient

A s s o c i a t e d clinical findings

HLA A

H.A. H.B? W.B? A.B. M.D. B.E. K.E. R.E. W.G. K.G. G.G. H.G, E.G. G,G. R.H. J.H. H.H. A.K. H.K. A.K. K.L. J.L. H.O. K.R. F.V. H.V. W.S, E.S. E.S. H,W. G.W. n=31

3 2 2 1 3 3 3 3 2 3 3 3 2 3 3 3 t 2 2 2 3 3 2 3 3 2 3 3 3 3 2

B 29

2 w24 w24 w24 w24 28 3 w33

3 28 28

3

3

29

12 15 15 35 15 7 w51 7 7 12 I2 7 7 7 7 7 8 w51 w52 12 7 7 7 15 40 7 7 7 7 7 w44

MEL 1 18 40 40 37 w39 w39 w46 40 w22 w35 40 12 w44 37 27 w39 w35 w44 w39 40 15 17 w39

w44 40 8

+ + . + + . . + + + + + . + + + . + +

DIA 2 (+)b (+) + . . (+) . (+) (+)

.

.

.

.

.

n=14

.

. (+) + + . (+) (+) . + (+) + (+) + . . (+) (+) (+) n=20

CAR s

CIR 6

-t-

+ . . -

+ -

-

+ + + + + -

-

-

+ + + + + +

+ + -

+ -

+ + -

+ + + + + + + + +

-

+

+ +

+ +

.

.

. + . . + . -

+ .

ART 4

.

.

.

HYP 3

.

. .

-

.

.

.

. -

.

.

.

.

.

.

. . + . . + . -

.

.

.

.

.

. . .

n=5

.

.

.

.

-

-

+

+

-

+

n=9

n=7

n=19

.

.

.

1 m e t a n o d e r m a , 2 diabetes, 3 h y p o g o n a d i s m , 4 a r t h r o p a t h y , 5 c a r d i o p a t h y , 6 cirrhosis ~= b r o t h e r s b ( + ) = l a t e n t diabetes

family studies t h a t m a k e a h a p l o t y p i c a s s o c i a t i o n of I H a n d H L A genes m o s t likely, the m o s t c o m m o n H L A p h e n o t y p e being H L A A 3 / B 7 or H L A - A 3 / B 14 [10]. W e c o u l d only d e t e r m i n e the phenotypic H L A d i s t r i b u t i o n in our patients. A s s u m i n g the H L A - A 3 b l a n k p a t t e r n represents h o m o z y g o s i t y a t the A-locus, 4 3 % o f our p a t i e n t s w o u l d be c a r r y i n g the H L A - A 3 / B 7 h a p l o t y p e , all patients h o m o z y g o u s for H L A - A 3 also possessing H L A - B 7 . This is far in excess o f the e s t i m a t e d frequency of the H L A - A 3 / B 7 h a p l o t y p e (6.38%) in the G e r m a n p o p u l a t i o n [1]. T h e h i g h incidence o f h o m o z y g o s i t y a t B-loci r e p o r t e d for a s m a l l e r g r o u p o f G e r m a n patients w i t h I H [6] c o u l d n o t be d e m o n strated in o u r study, as only 4 o f o u r u n r e l a t e d p a t i e n t s c o u l d h a v e been h o m o z y g o u s at the B locus. O n the o t h e r h a n d , the excess frequencies of H L A - A 3 and H L A - B 7 were m u c h m o r e pron o u n c e d a m o n g our patients. O u r d a t a d o n o t ~illow conclusions as to the possible m o d e of t r a n s m i s s i o n o f IH. However, the two b r o t h e r s in o u r series possessed a n identical H L A p h e n o t y p e , w h i c h is in a c c o r d w i t h the p r o p o s e d recessive t r a n s m i s s i o n o f the I H gene o n c h r o m o s o m e 6 [10] a n d also with the c o n c o m i t a n t i n h e r i t a n c e of t w o s e p a r a t e genes responsible for the full expression of the disease as p r e v i o u s l y suggested [4].

References

1. Albert, E.D., Scholz, S , Bertrams, J., EwaId, R.W., W-estphal, E., R a t s c h k o , K.W., S p i e l m a n n , W., Seidl, S. : Represen'tative H L A - p h e n o t y p e a n d h a p l o t y p e frequencies of the G e r m a n popu l a t i o m Z. I m m u n . Forsch. 148, 367 371 (1975) 2. Bach, F.H., v a n R o o d , J J . : The m a j o r h i s t o c o m p a t i b i l i t y complex. N. Engl. J. Med. 295, 806-813 (1976) 3. Bodmer, W . F . : N a t . C a n c e r Inst. M o n o g r . 36, 127 (1973) 4. B o m f o r d , A., E d d l e s t o n , A . L . W . F . , K e n n e d y , L.A., Batchelor, J.R., Williams, R. : H i s t o c o m p a t i b i l i t y a n t i g e n s as m a r k e r s of a b n o r m a l iron m e t a b o l i s m in p a t i e n t s w i t h i d i o p a t h i c h a e m o c h r o m a t o s i s a n d their relatives. L a n c e t 1, 327-329 (1977) 5. H a h n , E.: D a s H L A - S y s t e m u n d innere E r k r a n k u n g e n . Internist 19, 491-500 (1978) 6. H e n k e , J., U n g a r , W. : H L A - a n t i g e n s in i d i o p a t h i c h a e m o c h r o m a t o s i s (i.h.). P r e l i m i n a r y report. Z. I m m u n . - F o r s c h . 154, 4 1 - 4 3 (1978) 7. L a u k e n s , P., Versieck, J., D e Potter, E., Barbier, F. : Association o f H L A - a n t i g e n s w i t h i d i o p a t h i c h e m o c h r o m a t o s i s . G a s t r o e n t e r o l o g y 74, 1351 (1978)

Kurze wissenschaftliche Mitteilungen 8. Shewan, W.G., Movat, S.A., Allan, T.M.: HLA-antigens in haemochromatosis. Br. Med. J. 1, 28I (1976) 9. Simon, M., Bourel, M., Fauchet, R., Genetet, B. : Association of HLA-A3 and HLA-B 14 antigens with idiopathic haemochromatosis. G.U.T. 17, 332-334 (1976) 10. Simon, M., Bourel, M., Genetet, B., Fauchet, R.: Hemochromatosis: Recessive inheritance and early detection by HLAtyping. N. Engl. J. Med. 297, I01%1021 (1977) 11. Simon, M., Bourel, M., Genetet, B., Fauchet, R., Edan, G., Brissot, P. : Idiopathic hemochromatosis and iron overload in alcoholic liver disease: differentiation by HLA phenotype. Gastroenterology 73, 655-658 (1977) 12. Terasaki, P.I., McCurdy, B., McClelland, J. : Microdroplet lymphocyte cytotoxicitytest. In: Manual of tissue typing techniques

531 (Eds. J.G. Ray, R.C. Scott et at.) pp. 50-55, NIH Bethesda, Maryland 20014, 1972 13. Walters, J.M., Watt, D.W., Stevens, F.M., McCarthy, C.F.: HLA antigens in haemochromatosis. Br. Med. J. 4, 520 (1975) Received November 16, 1978 Accepted January 26, 1979 Dr. Herbert Dyrszka Fachklinik Rosenberg ffir Verdauungs- und Stoffwechselkrankheiten derLandesversicherungsanstalt Westfalen D-3490 Bad Driburg Federal Republic of Germany