HLA antigens in Graves' disease.

HLA typing of 86 patients with Graves' disease was performed for the A, B, C and D series antigens. An increased frequency of HLA-B8 (47 per cent) and Dw3 (51 per cent) compared with controls (23.7 and 21 per cent, respectively) was observed. The increase of B8 and Dw3 was almost exclusively found in a group of 48 patients with relapse of disease, whereas the frequency of B8 and Dw3 in patients without relapse did not differ significantly from that of the control group. No association with the presence of exophthalmos, thyroid antibodies, or antibodies to Yersinia enterocolitica serotype 3 could be found.     

HLA immunogenetic heterogeneity in black American patients with Graves' disease

Seventy-three American black patients with Graves' disease were typed for HLA-A, HLA-B, and HLA-DR antigens. There was a slight increase in HLA-DRw6 antigen frequency compared with 238 normal American black controls, but this was not significant after correction for the number of antigens tested. A significant increase in HLA-DR4 and HLA-DRw6 frequency was found in a subgroup of patients with exophthalmos (22.9% and 29.2% compared with 7.6% and 10.1% of normal black controls). There was a significant increase in HLA-DRw6 in a subgroup of patients who were thyroid antibody-positive (26.0%). The increment in HLA-DRw6 was higher in 32 patients who had both exophthalmos and who were antibody positive (37.5%). A significant increase in HLA-DR5 was found in a subgroup of patients who did not have exophthalmos and who were antibody-negative (83.3%). Our findings support previous evidence for immunogenetic heterogeneity in patients with toxic Graves' disease. In American blacks HLA-DRw6 is in some way associated with the disease in contrast to the well-recognized HLA-DR3 association in whites.     

The genetics of Graves' disease: HLA and disease susceptibility

To relate genetic variation in Graves' disease (GD) susceptibility to polymorphism at MHC loci, clinical and family studies were undertaken in eastern Hungary. Among 1980 relatives of 534 index patients, 2.9% of siblings, 2.7% of offspring, and 3.0% of parents had GD. HLA haplotype combinations in affected sibling pairs were determined in the present data and combined with data in the literature (12 sibling pairs from Farid 1981, 12 from Chan et al. 1980, and 15 from Sasazuki et al. 1983); 43, 23, and 1 affected sibling pairs shared, respectively, 2, 1, and 0 HLA haplotypes. This distribution is inconsistent with simple dominant inheritance, but is consistent with simple recessive inheritance of HLA-related susceptibility over a range of gene frequencies (0.2-0.4). A frequency of 0.3 gives the best fit and is consistent with penetrance of 7.1% for the recessive susceptibility genotype; the data, however, can accommodate penetrance values up to 16%. The distribution of HLA haplotypes in 33 families related disease susceptibility more strongly to DR than to other loci. The distribution of HLA-B8 genotypes in 256 patients was in close agreement with Hardy-Weinberg equilibrium proportions, also favoring recessive inheritance of MHC-related susceptibility. The probability that an individual will be affected with GD can be predicted, based on sex, HLA genotype, and family history. For example, 14.9% of DR3-positive women with an affected first degree relative are likely to be affected. These predictions can be tested as family data accumulate.     

HLA B8 and Graves' disease (author's transl)]

HLA typing has been carried out in 100 caucasions with Graves' disease and compared with 270 healthy controls. 25 HL-A antigens were characterized using a lymphocytotoxicity micro-technique. Analysis of the results reveals an increased incidence of HLA-B8 antigen (35% in patients as compared to 16.3% in controls) with a high degree of statistical significance: p = 0.0002 and corrected p (X 25) = 0.005. We did not observe a clear-cut correlation between the presence of HLA-B8 and different characteristics of the disease: sex, age of onset, familial history, exophtalmia, goiter, severity. The knowledge of the relationships between the HLA B8 gene and several auto-immune diseases is a strong argument in favor of the auto-immune nature of Graves' disease. The association between HLA B8 and Graves' disease could be explained by a close linkage between the second HLA locus and one or several Ir-IrG loci, occupied in predisposed individuals by "predisposing" alleles. In these subjects, an antigenic contact with an exogenous etiological agent would induce a pathological immune response, with production of thyroid stimulating IgG.     

The HLA association with Graves' disease is sex-specific in Hong Kong Chinese subjects

OBJECTIVE Graves' disease is associated with different HLA genes in Caucasians and the Chinese, in whom the HLA associations may be stronger in males than females. Common HLA-associated susceptibility in both races may occur at the HLA-DQ loci. The aims of this study were to examine the HLA-A, B, DR and DQ associations with Graves' disease in a Hong Kong Chinese population and to determine whether the HLA associations differ between the sexes and between subjects with and without thyrotoxic periodic paralysis. DESIGN HLA-A, B and DR types were determined by serological typing and DQA1 and DQB1 alleles by oligonucleotide probing of the respective enzymatically amplified gene. PATIENTS Ninety-seven Chinese patients with Graves' disease (31 males with, 35 males without and 31 females without thyrotoxic periodic paralysis) and 105 racially matched healthy controls. MEASUREMENTS Frequencies of HLA types/alleles at each locus were compared between patients and controls and between the Graves' subgroups using the χ² test. RESULTS HLA-B46, DR9 and DQB1*0303 were associated with Graves' disease in males only; these associations were weaker in males with thyrotoxic periodic paralysis. DR12, DQA1*0401 and DQB1*0301 were protective, regardless of sex or the presence of thyrotoxic periodic paralysis. The positive HLA associations in the Hong Kong Chinese were distinct from those in Caucasians whereas the protective haplotype was similar to that described in Caucasians. CONCLUSIONS These findings call in question the role of HLA genes in disease susceptibility but suggest a role for HLA in protection from Graves' disease.     

Familial hereditary thrombocytopenia and HLA

Three generations of a Jewish family with hereditary thrombocytopenia (HT) are described. The disease was manifested clinically by mild bleeding tendency since infancy. Circumcision, however, did not result in excessive bleeding. HLA study in this family indicated that the HT locus is not linked to HLA.     

Familial hypercholesterolemia and HLA antigens

Hereditary factors play an important role in the etiology and progression of coronary heart disease (CHD), most probably by causing the appearance and the levels of its risk factors. To investigate if there is a correlation between familial hypercholesterolemia and HLA system antigens, 25 subjects of 7 families with familial hypercholesterolemia were compared with 14 normocholesterolemic related subjects. Compared to normocholesterolemic kindreds, the familial hypercholesterolemic subjects have a significant increased HLA-Bw35 antigen and a lack of HLA-A1. Therefore, the correlation found with some HLA system phenotypes improves our knowledge about familial hypercholesterolemia and aids in the identification of subjects affected with this disorder of lipid metabolism, which is one of the most important CHD risk factors.     

Graves病合并妊娠

妊娠期甲状腺激素代谢的生理性改变使Graves病的诊治更加复杂。妊娠期Graves病必须使用抗甲状腺药物（ATD）治疗,尽可能使用最低剂量的ATD维持母体游离甲状腺素（n）于非孕期的正常高值附近是最理想的选择。胎儿甲状腺功能取决于通过胎盘屏障的促甲状腺激素（TSH）受体抗体（TRAb）与ATD之间的平衡。晚孕早期母体TRAb滴度升高是胎儿发生甲状腺功能亢进的一个危险因素,此时亦应行胎儿甲状腺超声检查。临床可以通过调整孕妇ATD用量治疗胎儿甲状腺功能亢进。若妊娠期Graves病未得到控制,或孕妇曾因Graves病行放射性碘治疗或甲状腺切除术,怀孕时TRAb仍阳性者,须于分娩时检测脐带血TSH及FT4（总甲状腺素）。     

Autoimmune hepatitis associated with Graves' disease

A 31-year-old woman with Graves' disease with a 12-month-history of propylthiouracil intake and autoantibodies in the sera was admitted to our hospital. The differential diagnosis between autoimmune hepatitis and propylthiouracil-induced hepatitis was intractable. Steroid therapy was started and she showed a complete response to the treatment. Liver biopsy demonstrated acute hepatitis and plasma cell infiltration. A second liver biopsy, which was performed 10 months after starting steroid therapy, showed some inflammatory cells in the portal tracts. These findings suggest that she had been suffering from autoimmune hepatitis.     

Graves' disease presenting with severe cholestasis

BACKGROUND: Hyperthyroidism has been associated with liver function abnormalities; however, cholestasis as the presenting feature of adolescent Graves' disease has not been previously reported. PATIENT SUMMARY: The patient was a 17-year-old girl who presented with severe cholestasis and was found to have Graves' disease. She also had a positive hepatitis A immunoglobulin M antibody but her clinical course, the liver histopathology, and her mildly elevated transaminases indicated that the acute hepatitis A infection was not dominant at the time of presentation with severe cholestasis. Other causes of cholestasis, including congestive heart failure, autoimmune hepatitis, and viral infection, were excluded. Treatment with methimazole resolved the hyperthyroidism, and the cholestasis improved, as well. CONCLUSION: Severe cholestasis is a rare presenting feature of Graves' disease. With careful monitoring, methimazole can be used to treat the hyperthyroidism in the setting of cholestasis.     

Graves' disease with unusual histological findings

We reported three cases of Graves' disease which showed unusual histological findings featuring solid follicles, multinucleated giant cells and diffuse infiltration of histiocytes as well as lymphocytes in the whole section of the resected thyroid. Characteristics of these three cases were as follows: (1) Clinically, longer duration of the disease and exophthalmos were their prevailing findings. (2) On laboratory data, antimicrosomal antibody showed extremely high titers with 100,000 to 400,000. (3) Their operative findings were different from ordinary Graves' goiters in that colors of the goiter were yellow-red or gray-red, surface was rough and coarse, consistency was firm, and adhesions with the adjacent connective tissue were noted. (4) Postoperative clinical outcome was quite similar to that of ordinary Graves' patients. From these findings, these three cases were considered to be different from either so-called Hashitoxicosis or silent thyroiditis or Graves' disease with granulomatous foci, and it was suggested that these three cases might be a subgroup of Graves' disease or another hyperthyroidism than ordinary Graves' disease. Further accumulation and analysis of such cases will be necessary in order to answer this question.