Hashimoto Thyroiditis

In a family with several cases of Hashimoto struma, DeGroot et al. (1962) demonstrated an abnormal, small, iodinated protein in the serum and suggested that a defect in thyroid basement membrane may account for the appearance of this protein in the blood. Three sibs, their father, and their paternal aunt were affected. The paternal grandparents were dead. Hall et al. (1962) presented data that they felt supported autosomal dominant inheritance of the tendency to thyroid autoimmunity. Hall et al. (1964) studied 6 families in which the father had thyroid autoantibody and the mother did not. In each case female children had thyroid autoantibodies. Transplacental transmission was thus ruled out and genetic transmission was suggested. Volpe et al. (1963) also found an impressive familial aggregation. Masi et al. (1964) found examples of mother-daughter, father-daughter, 3 sisters, and 2 sisters with Hashimoto struma. See review of Masi et al. (1965).

Matsuura et al. (1980) described familial neonatal transient hypothyroidism in the offspring of a mother with Hashimoto thyroiditis. They attributed the disorder in the infants to transplacental passage of maternal TSH-binding inhibitor immunoglobulins. Leung (1985) reported a family in which the mother and 3 offspring had 'hashitoxic' periodic paralysis, i.e., Hashimoto thyroiditis, thyrotoxicosis, and periodic paralysis (see 188580). Conaway et al. (1985) observed familial aggregation of lymphocytic thyroiditis in borzoi dogs. They suggested autosomal recessive inheritance. Shuper et al. (1987) found renal impairment in a 12-year-old boy and his 2 sisters, all of whom had Hashimoto thyroiditis. Three generations of the family had autoimmune thyroid disease. Proteinuria disappeared in all 3 children during the 3.5 years of follow-up.

Phillips et al. (1990) found that autoantibodies to thyroid peroxidase (TPO; 606765) were inherited as a dominant mendelian trait in females, with reduced penetrance in males. Similar results were obtained with thyroglobulin autoantibodies. Genetic linkage to HLA (see 142800) was excluded. Because of potential bias in the study carried out in families with autoimmune thyroid disease, Phillips et al. (1991) studied the inheritance of thyroid autoantibodies in 49 families unselected for autoimmune thyroid disease. Among 24 families with facioscapulohumeral muscular dystrophy, 10 with Friedreich ataxia, and 15 with schizophrenia, the prevalence rates of TPO and thyroglobulin antibodies were 27.8% and 26.7%, respectively, in women and 9.2% and 11.7%, respectively, in men. In 40 families in which one or more individuals had one or both of the autoantibodies, segregation analysis supported mendelian dominant inheritance in women but not in men.

The interaction of FAS (134637) with its ligand, FASL (134638), regulates a number of physiologic and pathologic processes of cell death. Giordano et al. (1997) noted that triggering of FAS contributes to the regulation of the immune response and tissue homeostasis, as well as to the immunologic clearance of virus or tumor cells. Hashimoto thyroiditis is an autoimmune disorder in which destructive processes overcome the potential capacity of thyroid replacement, estimated as about 5- to 10-fold in a life time. Apoptosis has been occasionally observed in histologic sections of normal thyroid; however, apoptotic cell death is abnormally accelerated during the pathologic phases, leading to clinical hypothyroidism in HT. Giordano et al. (1997) demonstrated that thyrocytes from HT glands, but not from nonautoimmune thyroids, express FAS. Interleukin-1-beta (147720), abundantly produced in HT glands, induced FAS expression in normal thyrocytes, and crosslinking of FAS resulted in massive thyrocyte apoptosis. The ligand for FAS was shown to be constitutively expressed both in normal and HT thyrocytes and was able to kill FAS-sensitive targets. Exposure to IL-1-beta induced thyrocyte apoptosis, which was prevented by antibodies that block FAS, suggesting to Giordano et al. (1997) that IL-1-beta-induced FAS expression serves as a limited factor for thyrocyte destruction. Thus, FAS-FASL interactions among HT thyrocytes may contribute to clinical hypothyroidism.

Interferon-gamma (IFNG; 147570) had been implicated with contradictory results in the pathogenesis of autoimmune (Hashimoto) thyroiditis, the third most prevalent autoimmune disease in the United States (Jacobson et al., 1997) and the most frequent cause of hypothyroidism in adults (Weetman, 1998). To test whether the local production of IFN-gamma can lead to thyroid dysfunction, Caturegli et al. (2000) generated transgenic mice that express constitutive Ifng in thyroid follicular cells. This expression resulted in severe hypothyroidism, with growth retardation and disruption of the thyroid architecture. The hypothyroidism derived from a profound inhibition of the expression of the sodium-iodide symporter gene.

Ochi et al. (2002) identified alpha-enolase (ENO1; 172430) as the autoantigen in Hashimoto encephalopathy, a rare autoimmune disease associated with Hashimoto thyroiditis.

The autoimmune thyroid diseases (AITDs) include Hashimoto thyroiditis and Graves disease (GRD; 275000). In both Graves disease and Hashimoto thyroiditis, thyroid-reactive T cells are formed and infiltrate the thyroid gland. Tomer et al. (1999) performed a whole-genome linkage study of a dataset of 56 multiplex, multigenerational AITD families (354 individuals) using 387 microsatellite markers. They identified 6 loci that showed evidence for linkage to AITD. Only one locus, on chromosome 6 (AITD1; 80 cM) was linked with both. This locus was close to, but distinct from, the HLA region. One locus on chromosome 13 (HT1; 96 cM) was linked to HT (maximum lod score, 2.1), and another locus on chromosome 12 (HT2; 97 cM) was linked to HT in a subgroup of the families (maximum lod score, 3.8). Three loci showed evidence for linkage with GRD: GD1 on chromosome 14 (99 cM; maximum lod score, 2.5), GD2 on chromosome 20 (56 cM; maximum lod score, 3.5), and GD3 on chromosome X (114 cM; maximum lod score, 2.5). Since GD2 showed the strongest evidence for linkage to GRD, they fine-mapped this locus to a 1-cM interval between markers at 55 and 56 cM on chromosome 20. The authors concluded that GRD and Hashimoto thyroiditis are genetically heterogeneous, with only one locus in common to both diseases on chromosome 6; that only one HT locus was identified in all families, probably due to heterogeneity of the HT phenotype; and 3 loci were shown to induce genetic susceptibility to GRD by interacting with each other. One of them, GD2, was fine-mapped to a 1-cM interval.

Sakai et al. (2001) undertook a genomewide analysis of 123 Japanese sib pairs affected with AITD. At 19 regions on 14 chromosomes, the multipoint maximum lod score was greater than 1. Chromosome 5q31-q33 yielded suggestive evidence for linkage to AITD as a whole, with a maximum lod score of 3.14 at marker D5S436, and chromosome 8q23-q24 yielded suggestive evidence for linkage to HT, with a maximum lod score of 3.77 at marker D8S272.

Akamizu et al. (2003) performed an association study using 6 microsatellite markers situated at or near the 5q31-q33 locus associated with AITD in a set of 440 unrelated Japanese AITD patients and 218 Japanese controls. They found significant allelic association between AITD and 3 markers located in 5q23-q33. Graves disease demonstrated significant associations with 2 of these markers, while Hashimoto thyroiditis did not show significant associations with any markers. When patients with Graves disease were stratified according to clinical manifestations, the association was significantly different from the other subgroup of each category.

Fetal microchimerism, the engraftment of fetal progenitor cells into maternal tissues, has been implicated in the etiology of autoimmune diseases. Klintschar et al. (2001) used PCR analysis to determine whether microchimerism occurred in thyroid gland specimens from female Hashimoto thyroiditis patients. Using primers unique to a Y-chromosomal sequence (SRY; 480000) and primers for a sequence that is Y/X-chromosomal homologous except for a 6-bp deletion in the X-chromosomal sequence (amelogenin; 300391), Klintschar et al. (2001) detected microchimerism in 8 of 17 Hashimoto patients, but in only 1 of 25 controls (nodular goiters). Both groups were of similar age and had comparable numbers of pregnancies and numbers of sons. The authors concluded that microchimerism is significantly more common in Hashimoto patients than in patients suffering from nodular goiter. They suggested that microchimerism might play a role in the development of Hashimoto disease, although they cannot completely exclude that microchimerism is just an 'innocent bystander' in a process triggered by other mechanisms.

Generalized vitiligo (see 606579) is a common autoimmune disorder in which patchy loss of skin and hair pigmentation results from loss of pigment-forming melanocytes from the involved regions. Alkhateeb et al. (2002) studied a 3-generation family in which vitiligo and Hashimoto thyroiditis occurred in numerous individuals. A genomewide scan of 24 family members, including 14 affected with autoimmune disease, revealed linkage of an oligogenic autoimmune susceptibility locus, termed AIS1 (607836), to a 14.4-cM interval at chromosome 1p32.2-p31.3 (multipoint lod score = 2.90). A 2-locus analysis of Hashimoto thyroiditis in family members segregating an AIS1 susceptibility allele showed suggestive linkage to markers in chromosome 6p22.3-q14.1 (affecteds-only multipoint lod score = 1.52), in a region spanning both the major histocompatibility complex and AITD1 (Tomer et al., 1999). The authors concluded that the 1p AIS1 locus is associated with susceptibility to autoimmunity, particularly vitiligo, in this family, and that a chromosome 6 locus, most likely AITD1, may mediate the occurrence of Hashimoto thyroiditis in AIS1-susceptible family members.

Ueda et al. (2003) identified polymorphisms of the CTLA4 gene (123890) as candidates for primary determinants of risk for the common autoimmune disorders Graves disease (275000), autoimmune hypothyroidism, and type I diabetes (see 222100 and 601388). In humans, disease susceptibility was mapped to a noncoding 6.1-kb 3-prime region of CTLA4, the common allelic variation of which (see 123890.0002) was correlated with lower mRNA levels of the soluble alternative splice form of CTLA4. In a mouse model of type I diabetes, susceptibility was also associated with variation in CTLA4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80 (112203)/CD86 (601020) ligand-binding domain.

Criswell et al. (2005) determined that the R620W functional SNP in PTPN22 (600716.0001) conferred risk of 4 separate autoimmune phenotypes (type 1 diabetes, 222100; rheumatoid arthritis, 180300, systemic lupus erythematosus, 152700; and Hashimoto thyroiditis) in a collection of 265 multiplex families assembled by the Multiple Autoimmune Disease Genetics Consortium (MADGC). In each of these families, at least 2 of the 9 'core' autoimmune diseases were present.

Allen et al. (2003) studied AITD in a homogeneous founder Caucasian population, the Old Order Amish of Lancaster County, Pennsylvania. They found AITD, defined by the presence of circulating antimicrosomal antibodies, to be relatively common in the Amish, with a prevalence of 22.7%. The prevalence of AITD-hypothyroidism was 9.2%. They performed a genomewide linkage analysis with 373 short tandem repeat markers in 445 subjects from 29 families. They observed suggestive evidence of linkage of AITD to a locus on chromosome 5q11.2-q14.3 (lod, 2.30; P = 0.0006 at 94 cM; closest marker, D5S428); Sakai et al. (2001) had also found linkage to the long arm of chromosome 5 in their study of Japanese sib pairs with AITD-hypothyroidism. AITD-hypothyroidism showed a more modest linkage peak to the same region (lod, 1.46; P = 0.005). The authors concluded that a gene on chromosome 5q11.2-q14.3 is likely to contribute to susceptibility to AITD in the Amish.

Vaidya et al. (2002) reviewed the genetics of AITD including hyperthyroid Graves disease, Hashimoto (goitrous) thyroiditis, atrophic autoimmune hypothyroidism, postpartum thyroiditis, and thyroid-associated orbitopathy (TAO). These different manifestations of AITD may occur synchronously, most frequently as the combination of Graves disease and TAO. Together, AITDs are the commonest autoimmune disorders in the population, affecting between 2 and 4% of women and up to 1% of men. Furthermore, AITD prevalence increases with advancing age, with more than 10% of subjects over 75 years of age having biochemical evidence of mild (subclinical) hypothyroidism, the majority of which is due to autoimmune disease. They reviewed the associations of AITD with other autoimmune disorders, monogenic and chromosomal disorders that have AITD as a component, and AITDs as complex genetic traits. Additionally they reviewed the relationship of HLA (see 142800) and MHC-linked genes with AITD, particularly with Graves disease, and the association of the CTLA4 gene and its polymorphisms with Graves disease and AITD.

Tomer et al. (2003) performed a whole-genome linkage study in an expanded dataset of 102 multiplex families with AITD (540 individuals), using 400 microsatellite markers. Seven loci showed evidence for linkage to AITD (either Graves disease or Hashimoto thyroiditis). Three loci, on chromosomes 6p (AITD1; 608173), 8q (AITD3; 608175), and 10q (AITD4; 608176), showed evidence for linkage with both Graves disease and Hashimoto thyroiditis (maximum multipoint heterogeneity lod scores (hlod) 2.0, 3.5, and 4.1, respectively). Three loci showed evidence for linkage with Graves disease: on 7q, 14q, and 20q. One locus on 12q showed evidence of linkage with Hashimoto thyroiditis, giving an hlod of 3.4. Comparison with the results obtained in an earlier dataset showed that the 20q locus (GRD2; 603388) and the 12q locus (Hashimoto thyroiditis 2; HT2) continued to show evidence for linkage in the expanded dataset. The results demonstrated that multiple genes may predispose to both Graves disease and Hashimoto thyroiditis and that some may be common to both diseases and some unique. The loci that continue to show evidence for linkage in the expanded dataset represent serious candidate regions for gene identification.

Kacem et al. (2003) analyzed polymorphic microsatellite markers around the SLC26A4 gene (605646), which encodes pendrin, an apical transporter of iodide to the thyroid, to investigate the role of SLC26A4 in the genetic control of AITDs. Using case-control and family-based designs in a sample from Tunisia, Kacem et al. (2003) found evidence that SLC26A4 may be a susceptibility gene for AITDs, with varying contributions in Graves disease and Hashimoto thyroiditis.

Barbero et al. (2004) described 3 patients with choanal atresia (608911) whose mothers received methimazole during pregnancy for the treatment of thyrotoxicosis (Graves disease and Hashimoto thyroiditis).

Shirasawa et al. (2004) used linkage and association analyses of over 500 autoimmune thyroiditis patients and controls to identify a novel zinc finger gene, designated ZFAT1 (610931), as a susceptibility gene at 8q23-q24. The T allele of the SNP Ex9b-SNP10 (610931.0001) was associated with increased risk for AITD (dominant model: odds ratio = 1.7, P = 0.00009). The authors suggested that Ex9b-SNP10 may play a critical role in B cell function by affecting the expression level of a truncated ZFAT1 splice variant through regulating expression of a small antisense transcript, and that this regulatory mechanism of SNPs might be involved in controlling susceptibility or resistance to human disease.

Using FISH, Invernizzi et al. (2005) assessed the presence of monosomy X in women with systemic sclerosis (SSC; 181750) or AITD and age-matched healthy women. The rate of monosomy X increased with age in all 3 groups, but it was significantly higher for women with SSC or AITD. Monosomy X was more frequent in peripheral T and B lymphocytes than in other blood cell populations, and there was no evidence of male fetal microchimerism. Invernizzi et al. (2005) proposed that chromosome instability is common to women with these autoimmune diseases and that haploinsufficiency for X-linked genes may be a critical factor for the female predominance in autoimmune disease.