Endocrine Journal 202, 49 (8), 399-397 ws Hashimoto’s Disease and Dr. Hakaru Hashimoto Nonuyuxt AMINO, Hisato TADA, You HIDAKA axp Kazuo HASHIMOTO* Department of Laboratory Medicine, Osaka University Graduate School of Medicine D2, Osaka 563-0871, Japan * Prof. Emeritus, Kanazawa University Introduction ‘There are many diseases or syndromes designated by a personal name. In the index of Harrison’s or Cecil's Textbook of Internal Medicine, there are around 200 names of doctors who discovered dis- ceases that are named for them. Of these, Japanese names are used in Hashimoto's thyroiditis, Kawa- saki’s disease and Takayasu’s arteritis. As a mark of respect for Dr. Hakaru Hashimoto, his picture is used in the logo of the Japan Thyroid Association (Fig. 1). Hashimoto’s disease is a very common ill- ness of the thyroid gland; however, surprisingly little is known about its discoverer, Hakaru Hashimoto. 1958 ‘The logo mark of the Japan Thyrotd Association. Fig. 1 ‘Correspondence to: Dr. Nobuyuki AMINO, Department of Laboratory Medicine, Osaka University Graduate School of Medicine D2, Osaka 565-0871, Japan Discovery of Hashimoto's Disease After joining the first Department of Surgery, Fukuoka Medical College of Kyoto Imperial Univer- sity, Hakaru Hashimoto examined thyroid tissue samples and discovered new pathological characteris- tics, He reported this as an independent new disease in Archiv fiir Klinishe Chirurgie, the German journal of clinical surgery in 1912 at the age of 31 (Fig. 2) [1]. This report marked the discovery of Hashimoto's disease. ‘The title of his paper is shown in Fig. 3. The paper itself was quite long (30 pages and 5 figures). It consisted of five sections, beginning with a brief introduction and followed by clinical descrip- tions of four middle-aged female patients. Then came the histological changes of thyroid tissues, which were the core of the paper. ‘The fourth section was a review of previous reports and a discussion, and the final section was five precisely drawn illustra- Fig. 2, Dr, Hakaru Hashimoto at aze 31394 AMINO eal x. Zur Kenntniss der lymphomatésen Voriinderung der Schilddriise (Struma lymphomatosa) Yon Dr. H, Hashimoto, (Hiersa Tatel VL) Fig. 3. Tide tions of pathological ‘The most impressive part of the paper was its very beginning. Obviously, Hakaru was confident that this was a newly dis- covered disease. Naming this *struma lymphomato- sa”, he emphasized infiltration of lymphoid cells and formation of lymphoid follicles with a germinal cen ter, neither of which had been reported previously. Regarding the changes of tissues, the paper summa- rized four histological characteristics that became the basis of acquiring the name, Hashimoto's disease. The first was the formation of lymphoid follicles, the second, marked changes in the thyroid epithelial cells, the third, extensive formation of new connec- tive tissue, and finally, diffuse round cell infiltration. Fig, 4 is a copy of Fig. 5 of the original paper. To emphasize that this was an independent new disease, Hakaru filled thirteen pages with almost perfect quotations from previously reported papers, and a comparative discussion of those observations and his. For example, Hakaru pointed out the similari- ties with the so-called! Mikulicz’ disease. Nowadays, this is thought (0 be an autoimmune disease, called Sjogren's syndrome. He also precisely cited similar infiltration of lymphoid cells in the thyroid glands of Basedow’s disease. It was a thorough, well-written article. However, this epoch-making discovery caught litte attention in the world of medicine at that time. It was not until the 1930s when struma lymphoma- tosa, reported by Hakaru Hashimoto, started to re~ ceive recognition in the medical world, In 1931, Drs, Graham and McCullagh reported the same dis. cease as struma lymphomatosa, which had been detailed by Hakaru Hashimoto, and endorsed the conclusion of original paper. Fig. 4. Cited Fig. 5. in the original paper. Histology of, struma Iymphomatosa a. Lymphoid follicle b. Degenerated thyroid follicle Giant cells, 4d. Hyperplastic interstitium with prominent round cell infiltration. that struma lymphomatosa was an independent ill ness [2]. Since then this disease has been referred 10 as Hashimoto’s thyroiditis in the United States and European countries. It was not until the 1950s, after World War Il, when the name Hashimoto’s disease, was reintro- duced back in Japan, This was performed by Dr. Hachinen Akita, who had been studying in the United States. He was a younger alumnus of Hakaru’s alma mater.HASHIMOTO'S DISEASE AND DR. HAKARU HASHIMOTO 398 The life of Dr. Hakaru Hashimoto Hakaru. Hashimoto was born May 5. third son in a family that had been prac cine for generations in the village of Mi tsuge about 9 kim east of Iga Ueno. Iga Ueno was originally a castle town in the mountainous part of the Kinki district, Historically, itis the home of the Iga school of Ninja. Iga Ueno is also known as the hometown of Basho Matsuo, the famous Haiku poet. Fig. 5 shows the monument of Dr. Hakaru Hashimoto in front of the house where he was born. Fig. 6 shows his original hospital. ‘The whole area of the hospital grounds must have been around 1,000 tsubo, a little less than one acte. The hospital has been maintained as a home for the aged and was re- cently rebuilt. After spending his childhood in his birthplace, Hakaru left and entered the First Mie Prefectural Junior High School at Tsu. Today, this the Mie Prefectural High School at Tsu and is under a new school system, It was about this time when Hakaru started thinking of pursuing medicin Given the fact that many of his classmates also be- ‘came active in the medical field, there may have been ‘some underlying factors that inspired the students to ae oe oe) aee: eo Fig. 5. ‘The monument of Dr. birthplace. Hakaru Hashimoto at his Fig. 6. The hospital of Dr. Hakaru Hashimoto. pursue studies in medical science. As for Hakaru, he was greatly influenced by his grandfather, Gen’i Hashimoto, a well-known doctor in that region who had studied Dutch medicine at the end of the Edo Era, He was trusted enough to be allowed to wear a sword as a doctor by the feudal lord. Aspiring to study medicine, Hakaru advanced to the third National High School at Kyoto under the old school system and on to the Department of Medi- cine at Kyusyu Imperial University. He entered the Department of Medicine at Kyusyu Imperial Univer sity in Fukuoka in 1903. Kyusyu Imperial University was founded originally as Fukuoka Medical College of Kyoto Imperial University that same year. In 1910, the college became Kyusyu Imperial Universi ty. Hakaru was the first graduate of this school. Upon graduation from the university in 1907, he entered the First Department of Surgery and studied under Prof. Hayari Miyake for four years. During this period, Hakaru Hashimoto examined the thyroid tissues removed from four patients of middle-aged ‘women and discovered new pathological characteris- ties never reported before. Soon after the publication of his paper, Hakaru Hashimoto went to Europe for further study. Hakaru must have aspired to test the results of his research in Western countries, where the level of medicine was advanced. For this purpose, he chose Germany. He studied pathology under Prof. Kauf- man at Goettingen University. However, within two years, World War I broke out and Hakaru was Forced to return Japan without accomplishing his purpose. Upon his return, Hakaru returned to his alma mater for a short time. However, he decided396 AMINO etal to take over the family practice in his hometown be- cause the family was financially strapped. Iwas April in 1916 that Hakaru started practicing medicine, He was 35 years old. It quickly became known throughout the countryside that a doctor, a graduate of the Imperial University who had studied abroad, had begun practicing medicine. Surgery was the main field in his hospital. Beside, he treated all patients equally regardless of their status. He ‘was a doctor who put into practice the saying “Medi- cine is a benevolent art”. Riding in the hospital's rickshaw, he traveled great distances across the ‘mountains and fields to visit patients. He did not get married until he was thirty-nine, four years after he ‘opened his practice. He had three sons and one daughter. Hakaru had too many patients (0 take care of. Fig. 7 shows a photo together with hospital employees at the hospital entrance. There was only ‘one occasion on which he invited his families to a ‘one-day picnic at Mt. Wakakusa in Nara (Fig. 8) Suddenly, at age 52, fate dealt him a crushing blow. He was infected with typhoid fever on one of his house calls. His life ended unexpectedly on January 9, 1934, without recognition for discovering Hashi- moto’s disease. Hakaru was a man who sincerely Fig. 7. Dr. Hakaru Hashimoto (the third person from the left) and hospital employees at the entrance of the hospital Fig. 8 A picture taken at a pienic with family members. Dr. Hakara Hashimoto is on the right. loved and cared for his patients. What's more, his pursuit of knowledge was marked by continuous effort and diligence. Hashimoto's Disease at Present As described above, Hashimoto's disease was ini- tially recognized by characteristic histopathological abnormalities in the thyroid gland, different from the abnormalities of thyroid cancer. In 1956, Drs. Roitt, Doniach ef al, [3] found autoantibodies in the sera of patients with Hashimoto's disease [3]. Coin- cidentally, in the same year, Drs, Rose and Witebsky reported that changes in the thyroid tissue of rabbits that were immunized with thyroid extracts as an anti- ‘gen were similar to the changes seen in Hashimoto's disease [4]. Following these discoveries, the concept of organ-specific autoimmune disease was cstab- lished, and Hashimoto's disease was recognized as cone such disease, In the nineteen-seventies, an anti- thyroid microsomal hemagglutination antibody test ‘was developed in Japan [5] and these antibodies were found in 10.0% of adult women in the general population. Moreover, one-third of these women were found to have slight enlargement of the thyroid gland [6]. Furthermore, postmortem histological ‘examination has revealed that positive anti-thyroid microsomal antibodies in subjects without overt thyroid disease are associated with the presence of lymphocytic infiltration in the thyroid gland [7] Thus the concept of Hashimoto’s discase has beenHASHIMOTO'S DISEASE AND DR. HAKARU HASHIMOTO 397 expanded on the basis of the concept of autoimmune thyroiditis, and mild cases of Hashimoto's disease are thought to exist in one of 30 adult women in the general population. It has also been clarified that postpartum thyroiditis frequently develops from these subclinical or mild cases of Hashimoto's thy- roiditis [8]. Following these discoveries, autoimmune abnor- malities have been found in many other diseases. Today, many diseases are known to be autoimmune diseases. The discovery of Hashimoto's disease was a significant step in the history of the discovery of abnormal autoimmunity and endocrine disorders. However, the root cause of the disease has yet to be clarified. Finding answers in this area is among the most important current goals in modern medicine. It just may be the wish of Hakaru Hashimoto, who received little recognition in his life, that this task is to be accomplished by a Japanese. The statue of Dr. Hakaru Hashimoto (Fig. 9) is looking to us, thy- roidologists, for break through in discovering the etiology of autoimmune diseases. Acknowledgements ‘The authors thank Mr. Kenichi Hashimoto, the Hakaru Hashimoto at the public Fig. 9. The statue of Dr hall of Ie. ‘eldest son of Dr. Hakaru Hashimoto, for giving us much important information about his father. We also thank Mr. Sunao Tsunetou for his help collect- ing valuable documents and materials. The skillful assistance of Ms. Yuko Sahara is also acknowledged. References 1, Hashimoto H (1912) Zur Kenntniss der lympho- matésen Verlinderung der Schilddrise (Struma lym phomatosa). Arch Klin Chir 97: 219-248. 2, Graham A, McCullagh EP (1931) Atrophy and fibro- sis associated with lymphoid tissue in the thyroid: Struma Iymphomatosa (Hashimoto), Arch Surg 22: 548-567. 3, Roitt IM, Doniach D, Campbell PN, Hudson RV (1986) Auto-antibodies in Hashimoto's disease (Lym- pphadenoid goiter). Lancet 2: 820-821 4, Rose NR, Witedsky E (1956) Studies on organ specificity: V. Changes inthe thyroid glands of rabbits following active immunization with rabbit thyroid ex- tracts. J Immunol 76: 417-427 5. Amino N, Hagan SR, Yamada N, Refetolf § (1976) ‘Measurement of circulating thyroid microsomal anti- bodies by the tanned red cell hemagglutination tech- nique: Its usefulness in the diagnosis of autoimmune thyroid disease. Clin Endocrinol 5: 115-125, 6. Amino N (1986) Antithyroid antibodies (Chapter 24). In: Ingber SH, Braverman LE (eds). The Thyroid, Sth ed, Philadelphia, JB Lippincott: 546-359. 7. Yoshida H, Amino N, Yagawa K, Uemura K, Satoh M, Miyai K, Kumahara Y (1978) Association of se- rum antithyroid antibodies with Iymphoeyti infiltra- tion of the thyroid gland: Study of 70 autopsied cases. J-Clin Endocrinol Metab 46: 859-862. 8, Amino N, Mori H, Iwatani Y, Tanizawa 0, Kawa- shima M, Tsuge I, Ibaragi K, Kumahara ¥, Miyai K (1982) High prevalence of transient postpartum thyrotoxicosis and hypothyroidism. N Engl J Med 306: 849-852.