4
Tissue Anfigens (1987) 30, 34-37 HLA-DR factors associated with postpartum hypothyroidism : an early manifestation of Hashimoto’s thyroiditis? 0. PRYDS’, H.-H. LERVANG’, H. P. (dSTERGAARD KRISTENSEN~, B. K. JAKOBSEN3 and A. SVEJGAARD3 ‘Department of Paediatrics, Central Hospital of Naestved, *Department of Medicine, Central Hospital of Slagelse, and ‘Tissue Typing Laboratory of the Department of Clinical Immunology, State University Hospital of Copenhagen (Rigshospitalet), Denmark Thirty-three Danish women selected from a prospective study of postpartum thy- roiditis were HLA-DR typed. All women had positive titers of antimicrosomal anti- bodies, and 20 women developed thyroid dysfunction after delivery. DR5 and the phenotype 4,5 were significantly increased in the whole group (p <O.N1) and strongly associated to hypothyroidism (p <0.01), whereas DR3 was insignificantly increased in thyrotoxic women. It is concluded that postpartum hypothyroidism is an autoimmune disorder and may be an early manifestation of Hashimoto’s thy- roiditis. Received for publication 25 February, accepted 21 April I987 In human autoimmune disease, the role of ge- netic factors in determining the nature of the autoimmune process is clearly evident. Thus, varying associations have been found between HLA-DR and autoimmune disorders. In au- toimmune thyroid disease, DR3 and Graves’ disease are strongly associated, while Hashi- moto’s thyroiditis is weakly associated with DR5 (Svejgaard et al. 1984). During the last decade, increasing attention has been drawn to the syndrome called Postpartum Thyroid- itis (PPT), which is frequent with prevalences of 3.9-6.5% (Amino et al. 1982, Jansson et al. 1984, Lervang et al., in press). PPT is charac- terized by transient hyper- andor hypothyroi- dism within the first months after delivery, and has several autoimmune features. Most of the women have antimicrosomal antibodies (TMAb) in high titers as well as lymphocytic infiltration of the thyroid gland. Previously, we and others reported an association be- tween PPT and DR4 (Lervang et al. 1984. Jansson et al. 1985). On the other hand, DR3 and 5 have been found increased among North American women with PPT (Farid et al. 1983). In order to investigate the discrepancy, we have studied the HLA-DR antigens in a fur- ther 20 women with PPT and 13 euthyroid wo- men with TMAb in the postpartum period.

HLA-DR factors associated with postpartum hypothyroidism : an early manifestation of Hashimoto's thyroiditis?

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Tissue Anfigens (1987) 30, 34-37

HLA-DR factors associated with postpartum hypothyroidism : an early manifestation of Hashimoto’s thyroiditis? 0. PRYDS’, H.-H. LERVANG’, H. P. (dSTERGAARD KRISTENSEN~, B. K. JAKOBSEN3 and A. SVEJGAARD3

‘Department of Paediatrics, Central Hospital of Naestved, *Department of Medicine, Central Hospital of Slagelse, and ‘Tissue Typing Laboratory of the Department of Clinical Immunology, State University Hospital of Copenhagen (Rigshospitalet), Denmark

Thirty-three Danish women selected from a prospective study of postpartum thy- roiditis were HLA-DR typed. All women had positive titers of antimicrosomal anti- bodies, and 20 women developed thyroid dysfunction after delivery. DR5 and the phenotype 4,5 were significantly increased in the whole group (p < O . N 1 ) and strongly associated to hypothyroidism (p <0.01), whereas DR3 was insignificantly increased in thyrotoxic women. It is concluded that postpartum hypothyroidism is an autoimmune disorder and may be an early manifestation of Hashimoto’s thy- roiditis.

Received for publication 25 February, accepted 21 April I987

In human autoimmune disease, the role of ge- netic factors in determining the nature of the autoimmune process is clearly evident. Thus, varying associations have been found between HLA-DR and autoimmune disorders. In au- toimmune thyroid disease, DR3 and Graves’ disease are strongly associated, while Hashi- moto’s thyroiditis is weakly associated with DR5 (Svejgaard et al. 1984). During the last decade, increasing attention has been drawn to the syndrome called Postpartum Thyroid- itis (PPT), which is frequent with prevalences of 3.9-6.5% (Amino et al. 1982, Jansson et al. 1984, Lervang et al., in press). PPT is charac- terized by transient hyper- andor hypothyroi-

dism within the first months after delivery, and has several autoimmune features. Most of the women have antimicrosomal antibodies (TMAb) in high titers as well as lymphocytic infiltration of the thyroid gland. Previously, we and others reported an association be- tween PPT and DR4 (Lervang et al. 1984. Jansson et al. 1985). On the other hand, DR3 and 5 have been found increased among North American women with PPT (Farid et al. 1983).

In order to investigate the discrepancy, we have studied the HLA-DR antigens in a fur- ther 20 women with PPT and 13 euthyroid wo- men with TMAb in the postpartum period.

HASHIMOTOS THYROIDITIS? 35

Table 1 . HLA-A, B. C and DR phenotypes of 33 women with TMAb in the postpartum period. The results are divided according to thyroid dysfunction and euthyroidism.

Patient Thyroid A B C DR No. status

1 T 28.29 40,SO W6 4,7 2 T 1 8,17 w6 3.1 3 T 3.31 5.40 w2,w3 4 . ~ 8 4 T 2.3 8,15 w3 3 . ~ 6 5 T 1,11 8,351~53 w4 35 6 T 1 2 15.39 w3 w8.9 7 T 3.30 7.35 w4 2,4 8 T+H 2,24 7,w53 w4 2.w6 Y T+H 1 14.15 w3,w8 3,4

10 T+H 2 40 w2,w3 2 . ~ 6 11 T+ H 23.24 7.8 2.5 12 T+H 2,28 15,44 w3 4.5 13 T+H 2 40 w3 2 . ~ 6 14 T+H 29 18,WSO w6 W8,WlO 15 H 2.3 13,18 w6 2.7 16 H ?,I1 15,44 w3 45 17 H 1.2 5 3 5 18 H 1.25 8.18 3.5 19 H 1 2 5.8 w6 4.1 20 H 2,24 18.40 W 3 4.5 21 E 2 18,44 4 . ~ 6 22 E 1 1.29 35,45 w4 1.2 23 E 2.11 18,44 4 24 E 2.28 15,44 w3 4.5

26 E 32 40,44 w2 4.5 21 E 2.29 15,18 w3 5 . ~ 6 28 E 1.31 8.35 w4 3,w6 29 E 1.2 40 ~ 2 . ~ 3 1 ,w6 30 E 1 8 3.5

32 E 2 5,40 w3 4,9 33 E 2,24 39.40 w3 ~ 6 . ~ 8

3

25 E 2 5.15 wl ,w3 2,4

31 E 3,32 17,44 W6 2,7

T = Thyrotoxicosis alone; T+H = Thyrotoxicosis and Hypothyroidism; H = Hypothyroidism alone; E = Euthyroidism.

Material and methods toxicosis was defined as free T4 > 27 pmol/l (normal 9-27 pmol/l with elevated T4- or T3

Five hundred and ninety-one Danish women were investigated biochemically 3 months af- ter delivery. Twenty-three developed PPT, while 15 TMAb-positive women remained eu- thyroid during follow-up. Details are reported elsewhere (Lervang et al. in press). Thyro-

indices (product of total T4E3 and T3 resin- uptake test, respectively) and hypothyroidism as TSH > 5 mU/L (normal 5 5mUll).

It was possible to HLA-DR type 33 TMAb- positive women : seven with thyrotoxicosis al- one, seven with thyrotoxicosis followed by hy-

36 PRYDS ET AL

Table 2 . Selected HLA-DR antigen andphenotype frequencies (YO) in women grouped according to rhe thyroid stare in rhe postpartum period and in Controls.

N DR3 (Yo) DR4 (Yo) DRS (Yo) DR4.S (Yo)

Thyrotoxicosis alone 7 43 43 14 0

Hypothyroidism 7 14 29 29 14 Thyrotoxicosis and

Hypothyroidism alone 6 17 50 67** (16.5) 33** (45.8)

PPT total 20 25 40 35** ( 4.4) 15** (16.2) Euthyroidisrn 13 15 46 31* ( 3.7) 15* (16.6) All TMAb-positive 33 21 42 33***( 4.1) lS"'(16.4)

Controls 1177 24.7 34.2 10.8 5 1.1 9:

Figures in brackets are Relative Risks. * , * * , .** indicate ' significance at the 0.05, 0.01 and 0.001 levels, respectively. 9: : DRS was only studied in 1018 Controls.

pothyroidism, six with hypothyroidism alone and 13 with euthyroidism. HLA-DR typing was performed as described by Jakobsen et al. (1981), and the DR antigen and phenotype frequencies were compared to those of 101811177 healthy Danish controls. Free T4 was estimated by equilbrium dialysis, and TMAb was measured by haemagglutination technique (Thymune M - Wellcome).

For statistical analysis, Fisher's exact test (one-tailed) was used without correcting the probabilities for the number of DR antigens investigated because of the a priori suspicion of associations with both DR4 and 5 (Lervang et al. 1984, Jansson et al. 1985, Farid et al. 1983). Relative risk (RR) was calculated ac- cording to Svejgaard et al. (1984).

Results

The results for the total HLA A,B,C and DR typings are given in Table 1.

Table 2 shows the frequencies of DR3, 4 and 5 in the TMAb-positive women and con- trols. Only the DR5 antigen frequency differs

significantly (33.0 vs 10.8%); (p = 0.0006). The DR4 antigen frequency is insignificantly increased (42.0 vs 34.2%), while that of DR3 is slightly decreased (21.0 vs 24.7%).

Furthermore, the frequencies of DR3. 4 and 5 and of the DR4.5 phenotype have been analysed according to the functional state of the thyroid gland (Table 2). The DR5 antigen is increased in all major groups, but the differ- ence is not significant for subgroups of pa- tients with thyrotoxicosis alone or thyrotox- icosis followed by hypothyroidism. The strength of the significant DR5 associations varies from a relative risk of 3.7 for euthyroid women to 16.5 for isolated hypothyroidism. DR4 is insignificantly increased in all groups except patients with thyrotoxicosis followed by hypothyroidism. DR3 is insignificantly in- creased in the small group of patients with thyrotoxicosis alone.

The DR4,5 phenotype is significantly in- creased in all major groups showing signifi- cant DR5 associations, and in every case the relative risk is higher (between 16.4 and 45.8) than the corresponding ones for DR5. How-

HASHIMOTOS THYROIDITIS? 37

ever, because the DR antigens can be com- bined in many different phenotypes, the p- values may not reflect the true significance level.

Discussion

This study disclosed an association between the presence of TMAb and the HLA-DR5 antigen, especially when present together with DR4 in phenotype. Furthermore, an even stronger association was observed in wo- men with postpartum hypothyroidism.

From a Swedish study of 50 women with TMAb in early pregnancy, Jansson et al. (1984) found increased frequencies of DR4 and the DR phenotypes 3,4 and 4,5, respec- tively. Above all, hypothyroidism after deliv- ery was associated with DR4 (Jansson et al. 1985).

While DR3 was only slightly increased in our group and the Swedish group of patients with postpartum thyrotoxicosis, Farid et al. (1983) found both DR3 and 5 significantly in- creased in 25 women with symptomatic thyro- toxicosis after delivery. Unfortunately, data on DR5 in women with hypothyroidism andor TMAb in the latter study were not given, but it seems likely that the DR3 in- crease resulted from the patient selection.

Based on available evidence, there is little doubt that both DR4 and 5 predispose to tran- sient hypothyroidism, which apparently re- quires an unknown cofactor, as several DR4 andlor 5 positive women with. TMAb re- mained euthyroid. The DR5 association sug- gests that postpartum hypothyroidism may be an early, often transient, manifestation of Hashimoto’s thyroiditis.

References

Amino, N. , Mori, H., Iwatani, Y., Tanizawa, 0.. Kawashima. M., Tsuge, I., Ibaragy, K. Kumah- ara, Y . & Miyai, K. (1982) High prevalence of transient post-partum thyrotoxicosis and hypo- thyroidism. N Engl J Med 306, 849-852.

Farid, N. R., Hawe, B. S. & Walfish. PG. (1983) Increased frequency of HLA-DR 3 and 5 in the syndromes of painless thyroiditis with transient thyrotoxicosis: evidence for an autoimmune ae- tiology. Clin Endocrinol 19, 699-704.

Jakobsen, B. K . , Morling, N., Platz, P., Ryder, L. P., Thomsen, M. & Svejgaard, A. (1981) HLA-DR phenotype and HLA-D,DR haplotype frequencies in 704 unrelated Danes. Tissue Anti- gens 18, 270-275.

Jansson, R., Bernander, S., Karlsson, A,, Levin, K. & Nilsson, G. (1984) Autoimmune thyroid dysfunction in the postpartum period. J Clin En- docrinol Metab 58, 681-687.

Jansson. R., Sitwenberg, J. & Dahlberg, P. A. (1985). Influence of the HLA-DR4 antigen and the iodine status on the development of autoim- mune postpartum thyroiditis. J Clin Endocrinol Metab 60, 168-173.

Lervang, H . H., Pryds, O., 0stergaard Kristensen. H. P., Jakobsen, B. K. & Svejgaard. A. (1984) Postpartum autoimmune thyroid disorder asso- ciated with HLA-DR 4?. Tissue Antigens 23,25& 252.

Lervang, H. H., Pryds, 0. & 0stergaard Kristen- sen, H. P. Thyroid dysfunction after delivery: in- cidence and clinical course. Acla Med Scand (in press).

Svejgaard, A., Platz, P. & Ryder, L. P. (1984) HLA and disease susceptibility : clinical implications. Clin Immunol Rev A 4, 567-580.

Adress: Ole Prydr, Department of Neonatology (GN 5024), Rigshospitalet , Blegdamsvej , 2100 Copenhagen 0. Denmark