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Hashimoto's thyroiditis is now considered the most prevalent autoimmune disease, as well as the most common endocrine disorder. It was initially described in 1912, but only rarely reported until the early 1950s. To celebrate this centennial, we reviewed the surgical pathology archives of the Johns Hopkins hospital for cases of Hashimoto's thyroiditis, spanning the period from May 1889 to October 2012. Approximately 15,000 thyroidectomies were performed at this hospital over 124 years. The first surgical case was reported in 1942, 30 years after the original description. Then, 867 cases of Hashimoto's thyroiditis were seen from 1942 to 2012, representing 6% of all thyroidectomies. Hashimoto's thyroiditis was the sole pathological finding in 462 cases; it accompanied other thyroid pathologies in the remaining 405 cases. The most commonly associated pathology was papillary thyroid cancer, an association that increased significantly during the last two decades. The most common indication for thyroidectomy was a thyroid nodule that was cytologically suspicious for malignancy. Hashimoto's thyroiditis remains a widespread, intriguing, and multifaceted disease of unknown etiology one century after its description. Advances in the understanding of its pathogenesis and preoperative diagnosis will improve recognition and treatment of this disorder, and may one day lead to its prevention.

Autonomously functioning, "hot", thyroid nodules are not common in children and adolescents. Such nodules are not considered alarming because they are assumed to be benign adenomas. Herein, we present a 15-year-old girl with a papillary thyroid carcinoma of 3.5 cm in diameter, which was functionally autonomous and scintigraphically hot.The patient, initially referred to our Endocrine Unit because of a thyroid nodule, returned 6 months later for symptoms of hyperthyroidism. Hyperthyroidism was confirmed biochemically. Radioactive iodine ((131)I) thyroid scintigraphy was consistent with an autonomous thyroid nodule. As per guidelines, the patient underwent surgery and a pathological examination revealed papillary carcinoma, follicular variant. The excised nodule was examined for activating mutations of the thyrotropin receptor (TSHR), Gsα (GNAS1), H-RAS, N-RAS, K-RAS, and BRAF genes by direct sequencing. No mutations were found. Nevertheless, two combined nonfunctioning mutations were detected: a single-nucleotide polymorphism (SNP) of the TSHR gene, in exon 7, at codon 187 (AAT→AAC, both encoding asparagine), and a SNP within exon 8 of the Gsα gene at codon 185 (ATC→ATT, both encoding isoleucine). Both SNPs were also identified in the germline DNA of the patient. The same SNPs were sought in the parents and brother of our patient. Her father was heterozygous for the TSHR SNP, her mother heterozygous for the Gsα SNP, and her brother was wild type.This case demonstrates that the presence of hyperfunctioning thyroid nodule(s) does not rule out cancer and warrants careful evaluation, especially in childhood and adolescence to overlook malignancy.

We previously reported that the spirochete Borrelia burgdorferi could trigger autoimmune thyroid diseases (AITD). Subsequently, we showed local amino acid sequence homology between all human thyroid autoantigens (human thyrotropin receptor [hTSH-R], human thyroglobulin [hTg], human thyroperoxidase [hTPO], human sodium iodide symporter [hNIS]) and Borrelia proteins (n = 6,606), and between hTSH-R and Yersinia enterocolitica (n = 1,153). We have now updated our search of homology with Borrelia (n = 11,198 proteins) and extended our search on Yersinia to the entire species (n = 40,964 proteins). We also searched the homologous human and microbial sequences for peptide-binding motifs of HLA-DR molecules, because a number of these class II major histocompatibility complex (MHC) molecules (DR3, DR4, DR5, DR8, and DR9) are associated with AITD. Significant homologies were found for only 16 Borrelia proteins (5 with hTSH-R, 2 with hTg, 3 with hTPO, and 6 with hNIS) and only 19 Yersinia proteins (4 with hTSH-R, 2 with hTg, 2 with hTPO, and 11 with hNIS). Noteworthy, segments of thyroid autoantigens homologous to these microbial proteins are known to be autoantigenic. Also, the hTSH-R homologous region of one Borrelia protein (OspA) contains an immunodominant epitope that others have found to be homologous to hLFA-1. This is of interest, as the hLFA-1/ICAM-1 ligand/receptor pair is aberrantly expressed in the follicular cells of thyroids affected by Hashimoto's thyroiditis. A computer-assisted search detected antigenic peptide binding motifs to the DR molecules implicated in AITD. In conclusion, our in silico data do not directly demonstrate that Borrelia and Yersinia proteins trigger AITD but suggest that a restricted number of them might have the potential to, at least in persons with certain HLA-DR alleles.

Subclinical exposure to microbic antigens that share amino acid sequence homology with self antigens might trigger autoimmune diseases in genetically predisposed individuals via molecular mimicry. Genetic predisposition to Graves' disease (GD) or Hashimoto's thyroiditis (HT) is conferred by HLA loci DR3 or DR5, respectively. Yersinia enterocolitica (YE) outer proteins (YOPs) are candidate triggers based on the high prevalence of serum antibodies (Ab) against YOPs in autoimmune thyroid diseases (AITD) and reactivity of these Ab with hTSH-R, suggesting homology between YOPs and hTSH-R. We have reported previously that the spirochete Borrelia burgdorferi (Bb) could be another trigger. We have explored further the homology of hTSH-R with YE and Bb. Using the Basic Local Alignment Search Tool (BLAST), we found four matches with YE and five matches with Bb . Residues 22-272, 186-330, 319-363 and 684-749 of hTSH-R matched YopM, Ysp, exopolygalacturonase and SpyA of YE (identity 23-31%, similarity 40-48%). Residues 112-205, 127-150, 141-260, 299-383 and 620-697 of hTSH-R matched outer surface protein A, flagellar motor rotation protein A, two hypothetical proteins (BBG02 and BBJ08) and DNA recombinase/ATP dependent helicase of Borrelia (identity 27-50%, similarity 40-75%). Interestingly, the above hTSH-R regions coincide with (or include) known human T-cell epitopes: aa 52-71, 140-176, 240-270, 340-380 and 441-661. Our data strengthen the hypothesis of Bb and YE as environmental triggers of AITD in genetically predisposed persons through molecular mimicry mechanisms.

Iodothyronine binding to plasma lipoproteins (Lp) and gel filtration elution patterns of cholesterol and triglycerides were evaluated in the total lipoprotein fractions (TLF) obtained from 10 healthy blood donors and 7 patients with hypothyroidism of brief duration. TLF (d < 1.210 kg/L) shown to be free of plasma T4 transport proteins (TBG, TTR, HSA) was equilibrated with 0.3 nM 125I-labeled T4, T3 or reverse T3 (rT3) and chromatographed on Sepharose CL-6B. Percent distribution of rT3 among the Lp subtypes was similar in the two groups (in normals: VLDL = 4.2 +/- 2.4, LDL = 15.6 +/- 4.2, HDL = 79.9 +/- 5.2) but HDL in hypothyroid subjects bound significantly more T4 (98.7 +/- 0.4 vs. 91.2 +/- 0.3%) and T3 (95.5 +/- 2.6 vs. 78.3 +/- 11.3%). Correspondingly less T4 and T3 was bound to VLDL and LDL. Whereas rT3 elution coincided with the major HDL cholesterol peak (202 +/- 17 kDa) and was the same in the two groups, both T4 and T3 eluted with smaller HDL particles and differed between hypothyroid and normal subjects. T4 eluted with somewhat larger HDL particles in hypothyroid subjects (176 +/- 24 kDa vs. 111 +/- 34 kDa) and T3 eluted with smaller HDL (94 +/- 30 kDa vs. 148 +/- 31 kDa). The major HDL-cholesterol peak in hypothyroid subjects had a slightly but significantly greater mass than in normals (241 +/- 28 kDa vs. 218 +/- 14 kDa). The HDL elution patterns also differed: in normals there were from 3 to 6 minor peaks on either side of the major peak, whereas in hypothyroid subjects there were only 0 to 2 minor peaks. In conclusion, iodothyronines bind to relatively small size HDL subfractions and these are different for T4, T3, and rT3; hypothyroidism of brief duration induces both quantitative and qualitative changes in iodothyronine distribution among lipoproteins and alters the microheterogeneity of HDL-cholesterol.