A Hundred Years of Hashimoto's Thyroiditis

I t has been 100 years since Hakaru Hashimoto, a 31-year-old surgeon at Kyoto Imperial University, first described the unique pathological features of the disease that now bears his name in the thyroid resection specimens from four women presenting over a 7-year period (1). At the time, goiter was essentially a surgical disease, and this paper had its origins in the attempts then being made to identify alternative causes for goiter besides iodine deficiency. The essential features of this new disease were the absence of colloid accumulation, a massive predominance of lymphocytes, primarily lymphoid follicles, and interstitial changes. At least one woman had hypothyroidism and was treated with thyroid hormone replacement, another recent advance. Hashimoto was careful in his paper to distinguish his novel disease from Riedel's thyroiditis, and he recognized that although this was not Graves' disease clinically, there were histological similarities between the two conditions. Even more farsightedly he wondered whether the process he had observed was a thyroid form of the salivary and lacrimal gland lymphocytic infiltration found in Mickulicz's syndrome (now Sjögren's syndrome): Mickulicz was the teacher of Hayari Miyake, the head of Hashimoto's department.

Hashimoto's discovery was not exactly ignored for the next few decades, but recognition of its existence was certainly slow, possibly related in part to the publication of the paper in German (2). The condition was thought to be rare, and although the typical outcome was recognized to be hypothyroidism, the etiology of this curiosity was unknown. Graham and McCullagh (3) reported atrophy and fibrosis associated with “struma lymphomatosa (Hashimoto)” in 1931, but the exact relationship between goitrous and atrophic forms of thyroiditis was (and remains) unclear. As for Hashimoto, he went to Göttingen University in Germany to pursue his studies but was forced to return home after the outbreak of World War I. He took over his family's medical practice in rural Midai in 1916 and died in 1934 at the age of 52 years from typhoid contracted from a patient, without achieving the recognition he deserved (4).

Hashimoto's thyroiditis went on to become the archetype for human autoimmune diseases when Ivan Roitt, Deborah Doniach, and colleagues described the presence of thyroglobulin autoantibodies in the serum of such patients in 1956 (5). Their discovery followed the pioneering work of Noel Rose and Ernest Witebsky who had immunized rabbits with homologous thyroid extract and found that these animals developed thyroglobulin autoantibodies and a thyroid lymphocytic infiltrate resembling Hashimoto's thyroiditis (6). Rose and Witebsky had found it difficult to obtain human sera to test because this was still regarded as a rare disease (and the classic form is still uncommon), but they finally confirmed the presence of human thyroid autoantibodies in chronic thyroiditis in 1957 (7). Since then much work has been done to understand why the autoimmune process starts and what factors are responsible for creating the spectrum of thyroid autoimmunity of which Hashimoto's thyroiditis is a part.

In this issue of Thyroid, Caturegli and colleagues have marked the centenary of Hashimoto's seminal paper by reviewing the extensive surgical pathology archives of the Johns Hopkins Hospital for cases of Hashimoto thyroiditis, spanning an extremely long period from 1889 to 2012 and including 14,867 thyroidectomies (8). The results are fascinating and a fitting way to mark this important anniversary. First, the disease was not described in Baltimore until 1942, 30 years after Hashimoto's paper, and was regarded at the time as “very unusual.” The authors, however, have identified three earlier cases in the archive that in retrospect were indeed Hashimoto's thyroiditis, the first appearing in 1928. The study reveals a remarkable change in incidence, with very few cases for the first half of the period, and then a significant increase between 1943 and 1967, a constant incidence up to 1992 and then another significant increase over the last two decades.

Of course this retrospective pathological analysis can take little account of the clinical reasons for thyroid surgery, which will have a fundamental impact on the incidence, but the results are so striking that a rapid increase in the frequency of Hashimoto's thyroiditis in the second half of the 20th century seems an unavoidable conclusion. These results are buttressed by a review of 1050 Austrians patients who had surgery for benign goiter between 1979 and 2009; there was a significant increase in the incidence of both lymphocytic thyroiditis and Hashimoto's thyroiditis in resection specimens over this time (9). In addition, a striking rise in Hashimoto's thyroiditis has been reported recently in Italy. Between 1975 and 2005, there was a 10-fold rise in incidence: patients have become relatively younger, are more likely to be male, and have lower autoantibody responses (10).

While some of this change in incidence could be the result of increased thyroid function testing and earlier detection of disease, the overwhelming conclusion is that environmental factors must be responsible. Increased iodine intake is certainly one possible influence: a recent study showing increases in subclinical hypothyroidism and autoimmune thyroiditis in an area of more than adequate iodine intake is the latest among many such reports (11). But not all studies have shown an adverse effect of excess dietary iodine (possibly related to genetic factors and the rate of the increase in iodine intake in a population) and when it does occur, the effect of iodine may be transient. Nor is thyroid autoimmunity alone in this regard; celiac disease, type 1 diabetes, and multiple sclerosis have all increased in incidence over the last three decades. It is likely that aspects of urbanized living, such as higher standards of hygiene, increased prosperity, and increased exposure to environmental toxins, are responsible for this generalized trend, perhaps by altering the balance between T helper cell subtypes (12,13).

The second striking feature of the paper by Catureguli et al. (8) is the frequent association between Hashimoto's thyroiditis and papillary thyroid cancer, which was responsible for the increase in the number of surgical cases observed in the last two decades of the study. It is clear from the data in this paper and other recent literature that papillary thyroid cancer is increasing in incidence, and this is responsible for the associated Hashimoto's thyroiditis or, in other cases, a milder lymphocytic infiltrate, rather than the other way around. In the Johns Hopkins series there was also an increased frequency of lymphocytic infiltration and thyroiditis in Hürthle cell carcinoma and medullary thyroid cancer. Why neoplastic changes in the thyroid should produce such striking immunological changes is unknown, although, given the high population prevalence of thyroid autoimmunity, it is tempting to think that it must be easier to provoke autoimmune thyroiditis than other types of autoimmune disease: any perturbation in the thyroid milieu that releases antigens, including neoantigens, might thus account for this relationship. An alternative explanation is that they share a common predisposition through increases in dietary iodine, and certainly pathological studies have shown that both papillary carcinoma and lymphocytic thyroiditis increase in parallel following iodization (14).

Hashimoto would have been gratified to see the developments made in the last half century and especially by the recent studies, which have confirmed the relationship he suspected between his new entity and what we now call Sjögren's syndrome: the two conditions are associated clinically and immunologically (15). He would also have been intrigued by the recent description of a variant of Hashimoto's thyroiditis characterized by fibrosis as well as lymphocytic infiltration in the thyroid and accompanied by high numbers of IgG4 plasma cells and high serum IgG4 levels (16). Some of these cases may overlap with IgG4-related sclerosing disease (17) and thus present as Riedel's thyroiditis, the very condition that he had taken pains to exclude as the cause of the histological changes he observed. There is little doubt we have more surprises in store as we embark on a new century of discoveries in Hashimoto's thyroiditis.