The Subacute Thyroiditis, Since Its First Description by De Quervain (1904), Has Been Reported Under Many Synonyms

Endocrinol. Japon. 1964, 11 (2), 119～138

STUDIES ON SUBACUTE THYROIDITIS

SHOZO SAITO

Department of Radiology, School of Medicine, Gunma University, Maebashi

The subacute thyroiditis, since its first description by de Quervain (1904), has been reported under many synonyms. Terms given with reference to the histo- logic features of this disease include "pseudotuberculous thyroiditis", "granulo- matous thyroiditis", "gaint-cell thyroiditis", "de Quervain's thyroiditis", "struma granulomatosa" or "struma fibrosa, giant cell variant". The clinical findings have given rise to such names as" acute and subacute nonsuppurative thyroiditis", "acute noninfectious thyroiditis"and"subacute thyroiditis" . In recent writings, the disease is most commonly referred to as subacute thyroiditis. Later, de Quervain and Giordanengo (1936) collected reports of 54 cases of the disease, appearing in the literature since de Quervain's original description, and clearly distinguished it from other forms of thyroiditis. Several years ago, the disease had been considered relatively rare, but with recent advance in endocrinology, more attentions have been drawn by it, and more reports published on it. For the past six years, the author has treated 51 cases of subacute thyroiditis, and obtained findings of interest, which are outlined in this paper.

METHODS OF EXAMINATION

The disease was confirmed by Silverman's needle biopsy (Crile and Rumsey, 1950; Crile and

Hazard, 1951) of the thyroid in 36 of them, and the others were diagnosed by typical clinical symptoms, characteristic results of thyroidal function test and accelerated red cell sedimentation

rate and its clinical course.

Thyroid function test Basal metabolic rate (BMR) was examined by Knipping's method (normal range•}15%),

and serum protein-bound iodine (PBI) by modification of Barker's method (Barker and Humphrey,

1950). The latter in normal 50 subject ranged between 3.0 and 7.5r/dl. I131 thyroidal uptake (24-

hrs. value) in healthy 50 subjects ranged 10.0 to 45.5%. Thyroid-stimulating hormone (TSH) tests were performed in the following way: 250 units of TSH (MSE-Pretiron, Schering A. G., Berlin) was intramuscularly injected at one time, and after 24 hrs., PBI and I131 uptake were

determined, which were respectively compared with those before the injection. In the averages for 5 normal controls, PBI rose from 4.8•}1.9r/dl to 6.8•}2.8ƒÁ/dl, and I131 uptake from 21.0•}

9.6% to 37.8•}17.1%. Serum cholesterol level was measured by modification of Bloor's method

(Bloor, 1922).

Received for publication February 28, 1964. 120 SAITO Vol.11, No.2

Measurement of serum iron and unsaturated iron binding capacity (UIBC) The values were determined by method of Landers and Zak (1958). (normal range, serum iron 120•}32r/dl; UIBC 225•}56r/dl).

Electrophoretic analysis of serum proteins

Blood was drawn from the patients, in the fasting state, and the serum proteins were frac- tionated by modification of Tiselius electrophoretic method, the standard method of the Japanese

Society of Electrophoresis, using HT-B type apparatus.

Liver function test Tests were performed for serum protein level, Meulengracht's icterus index, Hijmans van den Bergh's bilirubin qualitative reaction, Takada Jezler reaction, cobalt reaction, Gros reaction, Kunkel zinc sulphate test, cadmium reaction, cephalin cholesterol flocculation test (CCF), thymol turbidity test (TTT), thymol flocculation test (TFT), and bromsulphalein test (BSP%/45min.).

Blood sugar tolerance test 1) Sakaguchi's sugar tolerance test: To the patients 270g of boiled rice and 2 eggs were given, and thereafter the test was performed every 20mins. for 3 hrs. The blood sugar in 10 normal subjects rose to a peak, averaging about 45% above the fasting level, within 40 to 60mins., and not exceeded 170mg/dl. And fall to the fasting level occurred about the end of 1 to 2 hrs. 2) Intravenous glucose tolerance test: Forty cc of 20%glucose was intravenously injected in 2 mins., and then every 10mins., blood sample was taken to determine glucose level. Time required to return to the initial level was always within 50mins., for 10 healthy controls. The possibility of abnormality in the glucose tolerance curve due to abnormalities of absorption from the intestine was obviated by intravenously injecting glucose (Cantarow and Trumper, 1955). 3) Insulin tolerance test: The purpose of the insulin tolerance test was to determine (1) the sensitivity of the organism to insulin, and (2) its responsiveness to insulininduced hypoglycemia. The blood sugar falls to about 45% of the fasting level 20 to 30mins. after intravenous injection of 2 units of insulin. And for convenience' sake, the so-called insulin sensitivity index (ISI) was computed from descending blood sugar curve (Kuzuya and Yagawa, 1952). The values for 20 healthy controls ranged 1.6 to 3.6. 4) Epinephrine tolerance test: The increase in blood sugar which follows administration of epinephrine has been utilized as an index of the quantity and availability of glycogen in the liver. After intramuscular injection of 0.01 cc per kg of a 1:1,000 solution of epinephrine hy- drochloride in 10 normal subjects, blood sugar concentration normally rose 30 to 45mg/dl in 40 to 60mins., returning to the resting level in 100 to 120mins. These blood sugar tests were executed at the time of empty stomach, and bleeding was made from the ear lobule, and the determination by Hagedorn-Jensen's method.

Thorn's test The test was performed principally by injecting ACTH, and the results of the same test with epinephrine were also referred to (Thorn, 1951).

Urinary excretion of 17-ketosteroid(17KS) The level was determined by Drekter's method (Drekter et al., 1952).

Purification of human thyroglobulin Thyroglobulin was extracted from cadavers without thyroid disease, and prepared by the ammonium sulfate salting-out technic of Derrien et al.(1948 and 1949).

Precipitation test By Oudin's serum agar technic (Oudin, 1952). June 1964 STUDIES ON SUBACUTE THYROIDITIS 121

Skin test Intracutaneously, 0.1 cc of 0.02% purified human thyroglobulin solution was injected, and 24 hrs. later the diameter of redness on the skin was measured. Data for 10 normal subjects are listed in Table 5. The diameters over 20mm and 20mm were defined positive.

Serum xerogel-figure The procedures reported by Shichijo (1942) were followed. The figure represents one of serum colloid reactions.

Electric skin resistance test One of thyroid function tests, which makes use of difference in electric resistance in different sites of the skin (Shichijo et al., 1958)

RESULTS

Age and sex Out of the 51 cases of subacute thyroiditis, 4 were males, and the other 47 were females. Thus women outnumbered men by 12 to 1. Forty six cases (90.2

%) were between 30 and 50 years of age. The youngest was 19 years, the oldest 62 years, and cases in the thirties numbered 21 (41.2%), the forties 19 (37.3 %), and the fifties 6 (11.8%) (Fig. 1). In 7 of the 51 cases, the disease developed in the season of epidemic influenza, and so gargling material and homogenized thyroid from 5 of these 7 were cultured in the chick embryo. And influenza virus was detected from gargling of 2, but could not from the thyroid.

Clinical symptoms in acute phase The complaints by the 51 cases are listed in Table 1. As local symptoms, thyroid swelling was observed in all cases (100%). The gland was somewhat ir- regular in shape, and firm in all cases. It was painful and tender to touch (96.1

%). Involvement was usually bilateral (80%), sometimes unilateral (20%). The pain radiated to the back of the neck, ears, jaws and shoulders (92.2%). In the majority, sore throat, cough and sputum were complained, and so before the treatment, they were misdiagnosed as having upper respiratory infection, and given large doses of sulfonamides and antibiotics without apparent effect on the course of the disease. Besides, hoarseness and dysphagia were observed. Local redness and fluctuation could not be demonstrated in any of the 51 cases. As to systemic symptoms, 46 of the 51 cases (90.2%) had fever, varying from low 37.0•Ž to spiking temperature course with peaks as high as 40.2•Ž. Much the same 44 cases (86.3%) had fatigability, 42 (82.4%) weakness, 41 (80.4%) headache, 37 (72.5%) palpitation, and 32 (62.7%) weight loss of over 2 kg, and 31 (60.8%) finger tremor. Moreover, excessive perspiration, anorexia, nervousness, salivation。 epiphora and arthralgia were also complained. Further, menstrual abnormality was observed in 27 of 38 female cases—oligo and hypomenorrhea in 27. And in the other cases, the menstruation was normal (Fig. 2). Laboratory data in acute phase (Table 2). 122 SAI TO Vol.11, No.2

Fig.1. Age

Table1. Clinical symptoms in acute phase(51 cases) June 1964 STU DIES ON SUBA CUTE THYRO IDITIS 123

Cases Acute phase Recovery phase

Hypo-and Normal Hyper-and Normal oligomenorrhea polymenorrhea

Fig. 2. Change in menstruation

Table 2. Main laboratory finding in acute phase 124 SAI TO Vol.11, No.2

Thyroid function test In all the 51 cases, BMR ranged -1.6 to +62.1%(Mean•}Standard Devi- ation+20.7•}13.2%),and the normal range of •} 15% was found in 17 cases

(33.3%). PBI ranged 3.8 to 16.8ƒÁ/dl (Mean, 6.9•}2.4ƒÁ/dl), the normal range 3.0 to 7.5ridr was observed in 41 cases(80.4%), and higher value of above 7.6ƒÁ/dl in 10(19.6%). I131 uptake ranged 0.2 to 10.8%(Mean 2.9•}2.8%), and low normal range was given by 2(3.9%), and extremely low values below 3% by 35

(68.6%). Results of examinations of 10 cases at 1 to 2 weeks after the onset, BMR + 15.4•`+32.8%(Mean+25.3%), PBI 6.1-16.8 ridl(Mean 10.2ƒÁ/dl), I131 uptake 0.2•`5.1%(Mean 1.2%).

TSH test The test was performed on 5 patients. I131 uptake, which ranged 0.2 to 4.7% before the administration of TSH(Mean 1.8+2.6%) changed to 0.8 to 12.1•“

(Mean 4.5•}7.1%), while PBI, which ranged 3.6 to 6.8r/dl(Mean 5.1•}1.9ƒÁ/dl) before the administration, rose to 4.0 to 6.4ƒÁ/dl(Mean 5.2•}1.5ƒÁr/dl). Thus the increase rate was significantly lower than that for healthy cases.

Serum cholesterol level The level of 11 cases ranged 140 to 225mg/dl(Mean 188.9•}26.5mg/dl). Lower values of below 150mg/dl were found in 2 cases(16.7%).

Erythrocyte sedimentation rate(Westergren's method) In all the 51 cases, the rate was uniformly elevated, ranging 20 to 142mm

per hr.(Mean 73.8+34.5mm/hr.). Results of 10 cases at 1 to 2 weeks after the onset was 73 to 132mm per hr.(Mean 105.2mm).

Hematological findings In 37 cases white cell count ranged 3,200 to 13,200/cmm(Mean 6,724 •} 2,244 cmm), above 10,000/cmm was observed in 4 cases(10.8%), range of 8,000 to 10,000/ cmm in 7(18.9%), 6,000 to 8,000/cmm in 10(27.0%), 4,000 to 6,000/cmm in 15

(40.5%), and below 4,000/cmm in 1(2.7%). Red cell count in 37 cases ranged 300•~104 to 523•~104/cmm (Mean(405.3•} 56.0)•~104/cmm), below 400•~104/cm occurred in 15(40.5%) and in 7 of these 15 cases below 350•~104/cmm(18.9%). Hemoglobin levels in all the cases ranged 57 to 105%(Mean 81.1•}7.3%), those of below 80% numbered 17(45.9%), and in 7 of these 17 below 70%(18.9%). Anemia was nearly normochromic. Serum iron level in 10, selected at random from the 51 cases, ranged 66 to 143r/dl(Mean 95.1•}28.8ƒÁ/dl), and in 5(50%) cases were moderately low levels. Unsaturated iron binding capacity in 6(60%) of these 10 cases was elevated

(range, 268 to 394r/dl; Mean 316.1•}40.3ƒÁ/dl)(Table 3). Serum copper for 3 cases 148•`154ƒÁ/dl(Mean 15.4ƒÁ/dl), all gave high values.

Fractions of serum proteins Tiselius fractionation of serum proteins was performed on 20 patients. In all of them(100%) r-globulin, in 17(85%) a-globulin, in 7(35%) B-globulin level JUIle 1964 STU DIES ON SUB ACU TE THY ROI DITIS 125 showed significant elevation. Further, in all the cases, serum albumin was decreased.

Liver function test In 16 cases examined, serum protein level ranged 6.5 to 7.5g/dl (Mean, 7.17 g/dl), Meulengracht's icterus index was normal, and Hijmans van den Bergh's bilirubin qualitative direct reaction was negative. Takada-Jezler reaction was positive in 7 (45%). Further, cobalt was slightly disturbed in 5 (31.3%), Kunkel in 2 (12.5%), CCF in 7 (45%), both TTT and TFT the same in 2 (12.5%), cadmium in 4 (25%) and BSP in 2 (12.5%) (Table 4).

Table 3. Serum iron and UIBC in acute phase

Table 4. Liver function tests in acute phase 126 SA ITO Vol.11, No.2

Serum levels of sodium and potassium (flame photometry) Serum sodium in 10 cases ranged 124 to 156 mEq/l (Mean, 138.4•} 10.7mEq/l), 4 (40%) showed lightly lower levels of below 135mEq/l, and the other 6 cases were normal. Serum potassium ranged 3.7 to 7.0mEq/l (Mean, 4.9 •} 1.2mEq/l), and 2 (20%) gave abnormally high levels of above 6mEq/l, and the other 8 were nearly normal.

Sugar tolerance test Fasting blood sugar level for 16 cases did not show any definite tendency. Test with Sakaguchi's diet in 11 of 12 cases revealed the rise to a peak ranging 112 to 175mg/dl, within 40 to 80mins., and in one of these 11 cases, the maximum exceeded 170mg/dl, and in 6 (50%), the return to the fasting level was delayed more than 2 hrs., indicating diminished glucose tolerance. Further, intravenous glucose tolerance test was performed on these 12 cases, and in 10 of them, blood sugar value returned to the initial level within 50mins., and in the other 2, it was slightly delayed (both in 60mins). In 10 of 16 cases, abnormal response to insulin-induced hypoglycemia, namely, delayed fall in blood sugar, was observed, and insulin sensitivity index was below 1.5. The other 6 were normal, but generally abnormal delay was not observed in the subsequent rise in blood sugar. (Fig. 3).

Fasting blood sugar level

―Subocute thyroiditis:Acutephase (15 coses) ―・―Subacutethyrolditis:Recovery phase (15 cases) ---Normal subiect:(10 cases)

Fig.3. insulin tolerance test

Epinephrine tolerance test was performed on 8 cases, and in 2, glycemic response to epinephrine diminished (less than 30mg/dl in 40 to 60 mins). The other 5 cases were approximately normal.

Thorn's test The test with 12 cases showed that decrease rate of blood eosinophils by epinephrine ranged-3.3 to-71.2% (Mean,-48.2•}14.0 %), and in 5 cases, June 1964 STUDIES ON SUBACUTE THYROIDITIS 127

the decrease rate was below the normal. When ACTH was administered, the decrease ranged-3.3 to-0.8% (Mean,-56.2•}15.0%), and in 2 cases it was below the normal.

Urinary 17 KS level The level for 11 cases ranged 4.2 to 8.6mg per day (Mean, 6.3mg/day), 6 cases showed the normal range, and the other 5 cases slight decrease.

Agar-gel precipitation test The test, performed on sera from 10 patients of this disease using purified human thyroglobulin, gave positive result for 6.

Skin test In 10 patients, purified human thyroglobulin solution was injected intracutaneously. Redness on the skin in 6 patients was more marked as compared with normal 10 subjects (Table 5), that is, 6 were positive and 4 negative. Besides, xerogel-figure test showed positive result in 8 of 12 cases (66.7%) in acute phase of this disease and electric skin resistance test revealed in 8 of 12 cases of the acute phase (66.7%) the type of hyperthyroidism, and in the other 4 cases

(33.3%) the normal type.

Table 5. Skin test: diameter of redness on the skin (24hrs. later)

Treatment and clinical course The 20 out of the 51 cases were not subject to any treatments, and their courses of the disease were observed. Three were given methylthiouracil, another 3 TSH, 1 cortisone, and 19 prednisolone, and laboratory examinations were performed in the course of the disease to compare the effects of these medicaments. In the untreated cases, the normal temperature was recovered in 1 to 4weeks after hospitalization (1 to 3months after the onset), and focal and referred pain and tenderness and other subjective symptoms disappeared in 3 to 6weeks after hospitalization (2 to 3 months after the onset), and swelling of the gland in 1 to 6 months after hospitalization (3 to 8 months after the onset). As to laboratory examinations, BMR and PBI returned to the normal in 2 to 4 weeks after hospitalization (1 to 3 months after the onset). In 3 cases, PBI was temporarily below the normal, and then returned to the normal, displaying the so-called rebound phenomenon. Erythrocyte sedimentation rate was restored to the normal nearly with the disappearance of goiter. 128 SAITO Vol.11, No.2

In the 3 cases, given methylthiouracil in a daily dose of 0.2g for 2 months, slight fever disappeared in 1 to 2 weeks after the beginning of the administration, local symptoms gradually subsided, and after about 2 months, erythrocyte sedimentation rate returned to the normal level, and goiter became invisible. BMR and PBI were restored to the normal in 2 to 3 weeks after the commencement of the administration. In the 3 cases, given TSH—Pretiron, a product of Schering, Germany—intramuscularly in a daily dose of 100 units for 2 to 4 weeks subjective symptoms improved in 2 to 3 weeks after the beginning of the administration in association with recovery of the normal PBI and BMR. Erythrocyte sedimentation rate returned to the normal in 3 to 5 weeks, and goiter disappeared in 1 to 2 months. In the 1 case, given cortisone in a daily dose of 200 mg for 15 days orally, local pain alleviated remarkably in 12 hrs. after the administration, and after 3 days, goiter showed tendency of remission. BMR and PBI were restored to the normal in a week, and after 3 weeks, erythrocyte sedimentation rate returned to the normal, and in 1 month, goiter disappeared. To the 19 cases, prednisolone was given in daily dose of 30 to 15mg for 1 to 3 weeks, and according to the improvement of the symptoms, the dose was gradually decreased to 10 or 5 mg, and in this way the administration was con- tinued for 3 to 6 weeks until the recovery of the normal erythrocyte sedimentation rate. In 12 to 24 hrs., focal and referred pain and tenderness remarkably subsided, and after several days they disappeared completely with the recovery of the temperature. Tachycardia, fatigability, weakness, and nervousness also disappeared, and appetite was restored. BMR and PBI returned to the normal level already in 1 to 2 weeks after the administration and PBI showed rebound phenomenon in 10 cases. Goiter disappeared in 1 to 2 months after the administration (1.5 to 4.5 months after the onset, Mean 3 months). The most remarkable change during the clinical courses of the above 51 cases was the one in I'31 uptake. Namely, it gradually returned to the normal level in cases in whom it first showed a slight fall, and in whom the disappearance of goiter and improvement of the symptoms were delayed (Fig. 4). When, however, the I131 uptake showed extraordinary low value in the beginning, and the disappearance of goiter and improvement of symptoms took place abruptly, this value transiently rose very high, and then with fluctuation gradually returned. toward the normal. Similar changes were also demonstrated by those given adrenocortical hormone (Fig. 5). It is a fact of great interest that in 3 cases given adrenocortical hormone and untreated 1 case, I131uptake remained high after the disappearance of goiter, returning to the normal after 1 to 2 years.

DISCUSSION

According to the statistics at New York Presbyterian Hospital (Harland and Franz, 1956), 7,448 cases underwent operation of the thyroid during 34 years from 1919 to 1953, and 261 of them, that is, 3.5%, had thyroiditis and 27 of the latter, that is, 0.36%, had subacute thyroiditis. From this and some other reports, sub- JUne1964 STUDIES ON SUBACUTE THYROIDITIS 129

Fig. 4. Change in I131 thyroidal uptake: Natural course (no specific therapy)

Fig. 5. Change in I131 thyroidal uptake: Treated cases (adrenocortical hormones) 130 SAITO Vol.11, No.2

acute thyroiditis can be assumed to represent between 0.5 and 2% of all the thyroid disorders, but recently the percentage seems to have been elevated. In Japan, subacute thyroiditis had been regarded as a rare disease as late as several years ago. However, as detailed reports of this disease were published its number also increased, indicating that those which were previously reported as chronic thyroiditis may have included considerable number of this disease. In this way, for the past several years, the reports of this disease have increased both at home and abroad. Some consider that the incidence rate of this disease has actually increased, while on the other hand it can also be presumed that advance in endocrinology has made the diagnosis of this disease easier by detailed studies of the characteristic symptoms or by bioptic investigation of the thyroid gland. The onset of this disease is said to be seen most frequently in the 3rd and 4 th decade. According to Werner (1955), two thirds of the total cases developed the disease in the thirties to the fifties. Of the 51 cases treated by the author, as many as 40 (78.4%) developed the disease in the thirties to the forties. As to the sex distribution of the disease, reports varied from 1:2 to 1:10, but all agreed in that females outnumbered the males. Out of the cases treated by the author, 4 were males, and 47 were females. The etiology of this disease still remains in obscurity. However, since several years ago, Crile (1948 and 1953) Lasser (1953), and Fraser and Harrison (1954) advanced the virus theory, and as its ground they mentioned the facts that no bacteria are demonstrated locally or in circulation in the patients, that the disease frequently follows the inflammation of the upper respiratory tract or the so-called common cold, which are assumedly viral, and that it is complicated with such viral diseases as influenza, water-pox, and sometimes with"cat scratch disease" (Shumway and Davis, 1954). Recently, Eylan et al. (1957) reported that 10 out of 11 cases with this disease gave positive complement fixation reaction, and furthermore they demonstrated mumps virus in 2 of them. Also Felix-Davies (1958) observed rise in mumps antibody titer in one case of this disease in acute phase, and fall of the titer with improvement of the disease. On the other hand, Danopoulos and Melissinos (1954) and Torikai and Kuma- oka (1959) took the rheumatism theory, and considered that remarkable efficacy for this disease of salicylic acid drugs, ACTH, cortisone, and prednisolone, accelerated erythrocyte sedimentation rate, and its frequent complication with articular rheumatism would support the view. Lately, autoimmunisation of the thyroid gland has been taken up as a factor bearing on this disease (Roitt et al. 1956; Witebsky and Rose, 1956). Also the author attempted precipitation test on sera from 10 cases of this disease, and found that 6 gave positive results. Recently a few reports have been published that the tanned cell hemagglutination test, which was performed with human group 0 erythrocytes treated with tannic acid by the method introduced by Boyden (1951), was more sensitive than precipitation test. Namely, Witebsky (1957) observed that such cases as were negative in precipitation showed positive result in the tanned cell hemagglutination test, and Blizzard et al. (1959) and the author (Shichijo et al., 1959) obtained positive results in one of 2 cases of sub- June 1964 STUDIES ON SUBACUTE THYROIDITIS 131

acute thyroiditis, and also in toxic goiter, myxedema, and nontoxic goiter. Further, the author observed that the test was positive also with spinal fluid from the positive patients (Saito, 1959; Shichijo et al., 1959). Cline et al.(1959) observed positivity in 2 of 3 cases of subacute thyroiditis, and also after the administration of radioactive iodine for hyperthyroidism. It may therefore be certain that the positivity will be shown after surgical treatment as well. Such production of the antibody is considered by Cline et al. (1959) to be due to some hyperplastic stimulus or nonspecific thyroid insult causing thyroglobulin release from the local confines of the thyroid follicle. According to Paine et al. (1957) the antibody in circulation will give positive hemagglutination at 4 weeks or more after the onset. The author attempted skin reaction on 10 cases of subacute thyroiditis using purified human thyroglobulin, and in 6 cases observed remarkable redness obvi- ously different from that in 10 healthy adults cases. This is a fact of interest. At any rate, the autoimmunization of the thyroid gland seems to play some role in the development of thyroiditis, but details still remain unclarified. On the other hand, the possibility of the hypersensitivity theory was suggest- ed by Lindsay and Dailay (1954). There are also the bacterial infection theory and the toxin theory. Further, on account of thyrotoxic symptoms seen in the acute phase of this disease, it is considered by some to be closely associated with the hyperfunction (Sheets, 1955; Perloff, 1956). Subacute thyroiditis develops either suddenly or gradually as observed in the author's cases. Some visit the hospital with the principal complaint of goiter alone. There seems to be such cases as are unconscious of the disease and do not visit the hospital. Frequently, before the patient becomes conscious of the goiter, he has sore throat, headache, cough and sputum, which develop in the inflammation of the upper respiratory tract. The patient in many cases becomes conscious of goiter at 1 to 2 weeks or 1 or 2 months after the development of the above symptoms. As the local symptoms, goiter, pain in the thyroid gland, and radiating pain are characteristic as are reported by many. Hoarseness and dysphagia are also observed in a few cases, but local redness and fluctuation such as seen in suppurative thyroiditis are absent. As systemic symptoms, fever, fatigability, and in a few cases, salivation (epiphora) and arthralgia. It is of interest that abnormal menstruation was seen in 27 of the 38 female cases (71.1 %) treated by the author, and in many cases, hypo-and oligomenorrhea (Saito 1959). Characteristic features in laboratory examinations are risen in erythrocyte sedimentation rate and low I131thyroidal uptake as against the normal or high BMR and PBI. Of course these results have wide range. For example, the I131uptake is nearly 0% when the thyroid is affected bilaterally and extensively. Also the results are significantly dependent on the course of the disease, BMR and PBI displaying high values in the acute phase, and PBI and I131 uptake sometimes showing rebound phenomenon, as reported by Volpe et al.(1958) and Saito (1959). Volpe et al.(1958) classified subacute thyroiditis into very severe, moderately severe and mild, and said that in the severe cases, BMR and PBI are high, and I131uptake abnormally low, while in the mild cases these tendencies are slight. As to the abnormal thyroid function in the acute phase of the disease, Werner 132 SAITO Vol.11, No.2

(1955) and Woolner et al. (1957) consider that thyroid hormone would temporarily be discharged into circulation owing to the destruction or degeneration of the follicular epithelium, exhibiting hyperthyroidism, whereas I131 uptake is low be- cause iodine-trapping ability would be lost. Besides, Robbins et al.(1951) attrib- ute the low 1131uptake rate to the depletion of TSH caused by massive release of thyroid hormone. Serum cholesterol seems to be normal or low as evidenced in the author's cases.

As to TSH test, Skillern et al. (1956), Skillern and Evans (1957) injected 4 units of thyrotropin to normal subjects and patients with subacute thyroiditis, and found that in the former, 1131 uptake after the injection showed significant increase over that before the injection, but that significant increase was not observed in

10 of the latter 12. Similar results were obtained also from the author's cases.

As to blood picture, Werner (1955) reported increase in leukocyte count rarely.

Out of the author's 37 cases, 4 showed counts of above 10,000, but many showed decrease. Eosinophile cell count was decreased in all of the author's cases in acute phase of the disease.

As to anemia, Skillern et al. (1956) observed normochromic anemia in 11 of

66 patients of subacute thyroiditis (16.7%). Out of the author's 37 cases, 7 (18.9

%) showed normochromic anemia. Further, serum iron was found decreased in

5 of 10 cases selected at random from our cases, and unsaturated iron binding capacity was increased in 6 of these 10 cases. This is a fact of great interest.

Scrum protein fractions were investigated by Werner (1955) on one case, and it was reported that albumin was decreased whilea-and 43-globulin were increased. Fromm et al. (1953) reported similar results from 2 cases. The results from the author's 20 cases were that albumin was decreased in all of them with increase in r-globulin, while a-globulin was increased in 17, and 43-globulin in 7. Further, spike in the descending ƒÀ-globulin was observed in the 10 cases in acute phase, and the reason is now under investigation.

Plasma protein fractions were investigated by Skillern et al.(1956) with 6 cases, and moderate decrease in albumin was observed in 5, slight increase in r-globulin in 2, increase in a1-and a2-globulin in 1, and slight increase in 43-globulin in 1.

Stemmermann (1956) observed, by paper electrophoresis, increase in a2-globulin in 4 cases of this disease, and considered that this is caused by the escape of thyroglobulin-containing colloid into circulation as a result of destruction of thyroid follicles. Skillern and Lewis (1958), however, attributed it to the catabolic effect of the inflammation on thyroidal and extrathyroidal tissue, especially on the latter. But as pointed out by Weissman and Perlmutter (1957) and Skillern and

Lewis (1958), these changes arc not specific to subacute thyroiditis, but can be observed in other pyretic or allergic diseases together inflammation and destruction of tissue.

Besides the above mentioned examinations, the author performed a few others to find abnormal results. Namely, 30 to 40% of the cases showed abnormality in liver function tests such as Ta kada-Jezler reaction, cobalt reaction, CCF test and cadmium reaction, and more than 10% showed abnormality in TTT, TFT and

BSP. Serum Na was low in 4 of 10 cases, and normal in 6. Serum K was high June1964 STUDIES ON SUBACUTE THYROIDITIS 133

in 2, and normal in 8. As to blood sugar test, 1 out of 12 cases showed the maximum 175mg/dl in Sakaguchi's test, 6 showed delayed recovery of the normal value, and insulin tolerance test showed abnormality in 10 of 16 cases. Moreover, in a few cases, abnormal Thorn's test and decrease in urinary 17 KS were observed, and many showed abnormal response in autonomic nervous function test with epinephrine. Eight of 12 cases in acute phase were positive in Shichijo's xerogel-figure test and electric skin resistance (Shichijo et al., 1958) indicated the type of hyperthyroidism in 5 of 7 cases. Considering nervousness, salivation (epiphora) and abnormal menstruation in addition to the above mentioned results, subacute thyroiditis is assumed to involve not only the thyroid gland but also the hypothalamus, hypophysis, adrenal, gonad and liver. The diagnosis of subacute thyroiditis can be made by the above mentioned characteristic clinical symptoms. As afore mentioned, the majority of the cases with subacute thyroiditis have enlargement of the thyroid gland with acute symptoms, focal and referred pain, but local redness and fluctuation can not be demonstrated in any cases. The gland is hard, and its surface is fine granular or smooth, and is swollen, retaining its original shape of a horseshoe, but no mark- edly enlarged. Some cases have history of goiter, and it is necessary to refer to it. In general it lacks ocular symptoms and signs unlike Basedow's disease. In laboratory examinations, it is characteristic of this disease that BMR and PBI are normal or high while I131 uptake is low. When infection with mumps virus or influenza is suspected, serological tests can be used with advantage. In questionable case diagnosis should be made by pathohistological examination, and usually Silverman's needle biopsy, as recommended by Crile (Crile and Rumsey, 1950: Crile and Hazard, 1951) is employed, though it has defet that only a small part can be removed so that diagnosis is sometimes difficult. In 36 out of 51 cases, the diagnosis was confirmed by needle biopsy (Saito, 1963). Subacute thyroiditis must be differentiated from pharyngitis, tonsilitis, and other inflammations of the upper respiratory tract. This disease is difficult to differentiate from hemorrhage into a nodule or cyst of nodular goiter, which is also a cause of sudden onset of fever, tenderness of the thyroid with swelling and pain, and an increase in sedimentation rate. Also is difficult the differentiation from suppurative thyroiditis. In this disease, however, different from subacute thyroiditis, the incident rate is lower, suppurative foci are demonstrated in the area adjacent to the affected site or some other parts of the body, and etiologic agent detected from the affected site or in circulation; and in general the onset is more abrupt and symptoms severer; further suppurative findings such as local redness and fluctuation are frequently found, antibiotics are effective, and leukocytes are increased. These points can be used in differentiation. Now difference from chronic thyroiditis will be outlined. Difference from Riedel's struma is much discussed by various workers. Hashimoto's struma is generally considered to be different from subacute thyroiditis, and differentiation can be made with reference to the above mentioned symptoms and results of laboratory examinations (Williams, 1962). 134 SAITO Vol.11, No.2

Differentiation from malignant goiter is sometimes difficult, and the above mentioned criteria are useless for this. It is therefore necessary to remove a piece of tissue surgically in order to establish the plan of the treatment. Furthermore, it is sometimes required to differentiate from cervical or media- stinal lymphadenitis, perithyroiditis, and infrequently also from acute exacerbation of chronic thyroiditis. As to the therapy for this disease, perfect rest was recommended by St. John and Nicholson (1951) as the first requirement, and for the pain, aspirin has been used. Danopoulos and Mclissinos (1954) and Torikai and Kumaoka (1959) reported on effective use of salicylic acid drug. Frequently, patients of this disease are given sulfonamide medicament and antibiotic with this diagnosis of inflammation of the upper respiratory tract, but these are generally said ineffective. Since de Quervain and Giordanengo(1936) observed efficacy of rentgen irradiation for this disease, many reports have been published on this therapy (Crile, 1948 and 1952; Osmond and Portmann, 1949; Allen and Reeves, 1951). The single dose ranged 100 to 200r, and total dose 600 to 2,000r, and in general focal irradiation seems to be employed. As a defect of this treatment, Allen and Reeves (1951) mentioned delayed effect and high recurrence rate, and Hendrick (1956) pointed out injury to thyroid tissue. Further, Frid and Wijnbladh (1956) warned of danger of pro- ducing myxedema. On the effect of methylthiouracil, reported King and Rosellini (1945), Harvill (1948), Cantwell (1948), and Fraser and Harrison (1954). In general, daily dose about 0.2g seems to be used for 1 to 2 months. In the author's cases, it appeared to be effective in mitigating acute symptoms, but ineffective in diminishing goiter and improving erythrocyte sedimentation rate. There are reports on the effect of propylthiouracil and others, derivatives of the above mentioned, but it is necessary to take caution for the side effect of agranulocytosis. Bassaleck (1951) considered subacute thyroiditis as contraindication for methylthiouracil, and Kracht (1955) reported that the administration of this medicament produced a pathohistological picture resembling that of thyroiditis. Also ultrashort wave and radioactive isotope have been used without so much effect. It is even reported that the latter conversely evokes thyroiditis (Hellwing and Wilkinson, 1956). Sometimes thyroidectomy has been reported to be used for the treatment of this disease. But since spontaneous healing frequently takes place in this disease, it can not be considered adequate therapy except in the case of heavy pressure by the swelling or when malignant goiter is suspected. Robbins et al. (1951) recommended the administration of TSH, and reported that 6 patients, treated with it in doses of 25 to 150 mg intramuscularly over a 1-day to 5-day period, showed remarkable response. In our cases, however, such effect could not be obtained. The medicaments which are most extensively used at present are ACTH and adrenocortical hormones such as cortisone and prednisolone. In all reports remarkable efficacy was observed not only for alleviation of symptoms, but also for diminution of goiter and improvement of erythrocyte sedimentation rate. The author obtained similar results with cortisone and prednisolone. Especially June 1964 STUDIES ON SUBACUTE THYROIDITIS 135

interesting was that besides the improvement of subjective symptoms, nervousness was removed, appetite increased, and pleasant feeling restored. In this way remarkable efficacy of these drugs were confirmed. Among the laboratory findings, the most remarkable change was observed in thyroid function. Namely, rebound phenomenon frequently took place in PBI, and it was observed relatively remarkably in cases on whom adrenocortical hormone produced marked effect. In such cases, I131 uptake transiently showed abrupt rise, and after fluctuations returned toward the normal level. On the other hand, when I131 uptake showed a slight fall in the beginning, the recovery was slow and gradual, and when the fall was extraordinary, the recovery was rapid, and the above mentioned fluctuation was remarkable. Such change could not be observed clearly in BMR. Other abnormalities in serum iron, unsaturated iron binding capacity, serum protein fractions, insulin tolerance test, Sakaguchi's blood sugar test, serum electrolyte, and seroxerogel figure were gradually restored to the normal with the disappearance of goiter and improvement of erythrocyte sedimentation. And oligo-and hypomenorrhea, which were visible in the beginning, turned into hyper- and polymenorrhea in the recovery phase, and returned to the normal after several months (Fig. 2). As to the prognosis of this disease, Werner (1955) followed up 17 cases for more than 10 years without finding any sequels. Recently, Sheets (1955) reported hyperthyroidism following subacute thyroiditis in one cases, Perloff (1956) observed the same in 5 cases, and Frid and Wijnbladh (1956) in 2 cases, Lindsay and Daily (1954) observed persisting hypothyroidism in 3 of 12 cases with this disease. Also myxedema has been reported to succeed this disease, though it is generally considered to be rare (Westwater, 1952). It was remarkable in our 4 cases, 3 given adrenocortical hormone and 1 untreated, 1131 uptake remained high, returning to the normal after 1 or 2 years (Saito 1959).

SUMMARY

In the past 6 years the author has treated 51 cases of subacute thyroiditis. Their data are summarized below: The disease was confirmed by Silverman's needle biopsy of the thyroid in 36 of them, and the others were diagnosed by typical clinical symptoms, characteristic results of thyroidal function test and accelerated red cell sedimentation rate and its clinical course. Of the total cases, 4 were males and 47 females, and the ages ranged 19 to 62 years, the thirties and forties together comprizing 40 cases (78.4%). As for clinical symptoms, goiters were observed in all of the total 51 cases, followed by local tenderness (96.1%), referred pain (92.2%), fever (90.2%), general lassitude (86.3%), headache (80.4%), palpitation (72.5%), body weight loss (62.7%), finger tremor and abnormal perspiration (60.8% each), and inflammation of the upper respiratorytract(41.2%). It was interesting that 27 out of 37 female cases (71.1%) had hypo- or oligomenorrhea, whereas in convalescence 29 of 38 (76.3%) had 136 SAITO Vol.11, No.2 hyper-or polyrnenorrhea.Goiters of all the cases were slight or moderate. Results of clinical and laboratory examination sinacute phasc: Ranges for 51 cases; body temperature 37.0～40.1℃(Mean±Standard Deviation 38.4± 0.7℃); pulse rate permin.72～162(95.4±21.5); BMR-1.6～+62.1%(+20.7 ±13.2%); serum PBI 3.8～16.8γ/dl(6.9±2.4γ/dl); thyroidal I 131 uptake 0.2～ 10.8%(2.9±2.8%); red cell sedimentation rate per hr.20～142mm(73.8± 34.5mm). Results of examinations of 10 casesat 1 to 2weeks after the onset: BMR+15.4～+32.8%(Mean+25.3%); serum PBI 6.1～16.8γ/dl(Mean 10.2

γ/dl); I131 uptake rate 0.2～5.1%(Mean 1.2%); red cell sed imentation rate per hour 73～132mm(Mean 105.2mm).Serum cholesterol for 11 cases 140～225 mg/dl(188.9±26-5mg/dl). Red cell count for 37 cases 300～523×104/cmm(405.3+56.0)×104),7giving below 350×104/cmm(18.9%); Sahli, svalue57～105%(81.1±7.3%),7giving below 70%(18.9%); white cell count 3,200～13,200/cmm(6,724±2,244/cmm),18 giving below 6,000/cmm(48.6%)andllabove 8,000/cmm(29.7%)and in 4 of these 11 cases above 10,000/cmm(10.8%).Blood eosinophile cell count was low in all the cases.Serum iron for 10 cases 66～143γ/dl(95.1±28.8γ/dl), 5givingmoderately low levels; UIBC 268～394γ/dl(316.1±40.3γ/dl),6 giving above 300γ/dl; serum copper for 3 cases 148～154γ/dl(Mean 154.0γ/dl), all giving high values.Serum protein tractions were determined by the Tiselius method with 20 cases, and the results were in agreement with past reports except that spike was observed in the descending fraction of p-globulin. As to liver function, there was abnormality in Takada-Jezler reaction, cobalt-reaction, cadmium reaction and CCF test, revealed delay in the recovery from hyperglycemia in 6 of 12 cases, and insulin tolerance test showed abnormality in 10 of 16 cases. Abnormality in Thorn's test, serum Na and serum K, and decrease in urinary 17 KS were observed in a few cases. Five cases in acute phase showed positivity in Shichijo's xerogel-figure, and skin electric resistance indicated the type of hyperthyroidism. Precipitation test was performed on 10 patients with subacute thyroiditis using human thyroglobulin as antigen, and the antibody was demonstrated in the serum from 6. Also skin test was performed with the above mentioned antigen, and redness could be demonstrated in 6 of 10 patients with this disease. Examinations of 20 adrenocortical hormone given cases and 20 non-given cases at 2 weeks intervals from the onset disclosed that in the treated cases body temperature, pulse rate, BMR and serum PBI rapidly returned to the normal level in one month in average, and I 131uptake rate in 2 to 4 weeks, and red cell sedimentation rate 1 to 3 months, whereas in the non-treated cases, body temperature, pulse rate, BMR and serum PBI were slowly restored to the normal in 1 to 2 months, and I131uptake rates in 2 to 3 months. Goiter disappeared in 1.5 to 4.5 months (Mean 3 months) in the treated cases, and 3 to 8 months (Mean 5 months) in the non-treated cases. It is a fact of great interest that in 3 cases given adrenocortical hormone and untreated 1 case, 1131 uptake remained high after the disappearance of goiter, returning to the normal after 1 to 2 years. June 1964 STUDIES ON SUBACUTE THYROIDITIS 137

ACKNOWLEDGEMENT

The author wishes to express his deep thanks to his teachers Profs. T. Tobe and K. Shichijo, who always have given him useful advices, and to Profs. N. Ui, S. Kawai and H. Takigawa, for their helps, and to his colleagues for their coop- eration.

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