A 27-year old female presented with clinical and biochemical thyrotoxicosis (TSH - 0.01 μIU/mL (ref. range: 0.27–4.2 μIU/mL); free thyroxine (FT4) - 1.58 ng/dL (ref. range 0.98–1.63 ng/dL); free triiodothyronine (FT3) - 4.56 pg/mL (ref. range 2.6–4.4 pg/mL). Clinical examination revealed tachycardia about 100 beats/min and no obvious goitre. Autoimmune profile was suggestive of Graves’ disease [anti-TSH-receptor antibodies (aTSHR) - 16.69 IU/L (ref. 0–1.75), anti-thyroid peroxidase antibodies (aTPO) - 1780 IU/mL (ref.: 0–34 IU/mL)]. The patient had a history of Hodgkin’s lymphoma, diagnosed and treated with chemo- and radiotherapy (including the neck) at the age of 18. At the age of 20 she developed severe hypothyroidism (TSH > 100 μIU/ml), though with high titres of both aTPO (150 IU/mL) and aTSHR (37.56 IU/mL) antibodies. Thyroid function tests normalised after treatment with L-thyroxine (100 μg o.d.). At the age of 26 she became “anxious” and experienced “heart palpitations”. She was found to have suppressed TSH, that remained suppressed even when the dose of L-thyroxine was reduced and then discontinued. After further four months she was found to have raised FT3 (see above). Thyroid scintigraphy revealed a normal and homogenous iodine uptake (41 %). The patient responded very well to treatment with low dose thiamazole (10 mg od, later 5 mg o.d.) that was discontinued after about 12 months. About a year later (while 16-week pregnant) she was off medication and had mild subclinical thyrotoxicosis (TSH - 0.035 μIU/mL, FT4 - 1.04 ng/dL, FT3 - 3.09 pg/mL) and raised aTSHR antibodies, albeit at lower titre than before (7.87 IU/L).\nAccording to the literature data thyroid dysfunction is one of the most common abnormalities seen after radiotherapy for Hodgkin's disease that includes the neck []. Primary hypothyroidism, the most common radiation-induced thyroid dysfunction, appears in 20–30 % patients who had therapeutic radiotherapy administered to the neck region, and this usually occurs within the first 5 years after therapy (peak 2–3 years after treatment) []. Irradiation of the thyroid may also increase the risk of Graves' disease (relative risk 7.2–20.4), or Graves' ophthalmopathy, thyroiditis, benign adenomas and thyroid cancer. The aetiology of radiation-induced thyroid dysfunction includes vascular damage, parenchymal cell damage and auto-immune reactions []. There are reports, that after neck irradiation Graves’ disease may develop in patients previously receiving thyroxine, and indeed 33 % of the patients with Graves’ hyperthyroidism had received thyroxine before its onset []. Therefore thyroid hormone-replacement therapy in patients with hypothyroidism after irradiation of the neck does not eliminate risk of other thyroid abnormalities at a later date. According to some authors, thyroiditis observed in Hodgkin’s disease may be the result of immune regulation disorders in Hodgkin’s disease []. Furthermore, a possibility of a change from hypo- to hyperthyroidism typical for Graves’ disease is has been known for some time [, ], and was also confirmed in more recent publications [, ].\nTakeda et al. [] demonstrated, by measuring changes in cyclic AMP, that thyroid stimulating and thyroid blocking antibodies may coexist within the same patient and their relative activities may change over the course of the disease. Our case illustrates that after neck irradiation, severe hypothyroidism can be followed by thyrotoxicosis. It should be noted that in our patient, both during hypo and hyperthyroidism, aTSHR were elevated. There are two types of aTSHR: thyroid stimulating antibodies (TSAb) and TSH-stimulation blocking antibodies (TBAb). TBAb block TSH-stimulation of the thyroid and cause hypothyroidism. On the other hand, TSAb stimulate the thyroid and result in Graves’ hyperthyroidism. In our opinion, in this case there was a gradual switch from TBAb into TSAb.\nIn some patients, TSAb and hyperthyroidism develop unexpectedly after hypothyroidism that is caused by TBAb []. Fan et al. [] described a case with documented cycles of hypothyroidism alternating with hyperthyroidism. Also, as mentioned above, some hypothyroid patients after irradiation of the neck, while treated for the Hodgkin's disease, developed hyperthyroidism []. A number of mechanisms may be involved in switching from TBAb to TSAb. Significantly, thyroxine treatment in some patients is associated with increase TSAb that - in extreme cases - might lead to development of hyperthyroidism in hypothyroid patients [], though whether this was a case in our patient is speculative as neck irradiation per se is considered to be capable of influencing changes in patients’ immune status.
A 44-year-old woman with 5-year history of Basedow’s disease had a total thyroidectomy. She had no past and family history and had no drug allergy. She was diagnosed as Basedow’s disease at 39 years old and after then she started taking 30 mg of thiamazole (MMI). In physical examination, she had no remarkable symptom such as palpitation, general fatigue and insomnia and did not have a goiter. Her height and body weight were 158.0 cm and 63.6 kg. Her vital signs were: heart rate 112 beats/min, blood pressure 132/86 mmHg. Laboratory data were as follows: white blood cell count, 4580 /μL (neutrophil 57.7%); red blood cell count, 476 × 104 /μL; hemoglobin, 12.7 g/dL; platelet, 26.5 × 104 /μL; Na, 142 mmol/L; K, 5.2 mmol/L. Renal and liver function was within normal range (creatinine (CRE), 0.38 mg/dL; blood urea nitrogen (BUN), asparate aminotransferase (AST), 25 U/L; alanine transaminase (ALT), 26 U/L; alkaline phosphatase (ALP), 231 U/L; γ-glutamyltranspeptidase (γ-GTP), 17 U/L; lactate dehydrogenase (LDH), 174 U/L). Thyroid-associated data were as follows: thyroid-stimulating hormone (TSH), < 0.010 μIU/mL; free triiodothyronine (FT3), 19.05 pg/mL; free thyroxine (FT4) 4.88 ng/dL; TRAb, 10.6 IU/L (electro chemiluminescence immunoassay (ECLIA), SRL Inc., Tokyo); TPOAb, 216.9 IU/mL (ECLIA, SRL Inc., Tokyo); TgAb antibody, 428.9 IU/mL (ECLIA, SRL Inc., Tokyo). Ultrasound examination revealed that the thyroid gland was hypervascular although it was not enlarged (Fig. ). Based on such findings, we finally diagnosed her as Basedow’s disease. Two weeks after starting MMI therapy, she had liver dysfunction (AST, 420 U/L; ALT, 368 U/L; ALP, 565 U/L; γ-GTP, 178 U/L; LDH, 337 U/L), and we changed the treatment of MMI to 300 mg of propylthiouracil (PTU) although her thyroid hormone levels were decreased (TSH, < 0.010 μIU/mL; FT3, 7.2 4 pg/mL; F T4 1.97 ng/dL). After then, her liver function was improved, and we tapered PTU. About 2 years later, her thyroid hormone levels were within normal range with 50 mg of PTU every other day, and her TRAb became negative. After then, we stopped PTU therapy.\nAbout 1.5 years later, she had low grade fever and palpitation and visited our office again. Her body weight was 70.9 kg. Her vital signs were: heart rate 116 beats/min, blood pressure 140/98 mmHg. Laboratory data were as follows: white blood cell count, 3710 /μL (neutrophil 58.3%); red blood cell count, 535 × 104 /μL; hemoglobin, 12.2 g/dL; platelet, 22.4 × 104 /μL; Na, 142 mmol/L; K, 4.2 mmol/L. Renal and liver function was within normal range (CRE, 0.52 mg/dL; BUN 9 mg/dL; AST, 25 U/L; ALT, 17 U/L; ALP, 218 U/L; γ-GTP, 19 U/L; LDH, 206 U/L). Thyroid-associated data were as follows: TSH, < 0.010 μIU/mL; FT3, 5.22 pg/mL; FT4, 1.85 ng/dL; TRAb, 4.6 IU/L; TPOAb, 147.4 IU/mL; TgAb, 591.2 IU/mL. Ultrasound examination revealed that the thyroid gland was not hypervascular compared to that at the onset of Basedow’s disease (Fig. ). Based on such findings, we finally diagnosed her as the relapse of Basedow’s disease. We started again 300 mg of PTU and tapered PTU dose. About 4 months later, her thyroid hormone levels became within normal range by taking 50 mg of PTU every other day. During the PTU therapy, her WBC levels were slightly lower and CRP levels were slightly higher, although she had no symptom in the whole body including in skin. We checked various autoimmune antibodies. Anti-double stranded DNA IgG antibody, anti-SS-A/Ro antibody and anti-SS-B/La antibody were all negative. However, anti-nuclear antibody (ANA), myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA) and proteinase3-anti-neutrophil cytoplasmic antibody (PR3-ANCA) were all positive (ANA, 37.8 (+); MPO-ANCA, 35.0 U/mL; PR3-ANCA, 36.9 U/mL).\nWe performed a total thyroidectomy. Table shows laboratory data before a total thyroidectomy in this subject taking 50 mg of PTU every other day. In general, the thyroid gland in subjects with Basedow’s disease shows diffuse goiter due to chronic stimulation. However, her thyroid was flat and atrophic although diffuse hyperplasia of the thyroid gland was observed in histopathological macroscopic findings (Fig. ). Furthermore, hyperplasia of the thyroid gland was shown in part and hyperplastic thyroid follicles with papillary infoldings was observed in histopathological microscopic examination. Tall follicular cells with papillae usually lacked fibrovascular cores and peripheral scalloping was present (Fig. ). On the other hand, a part of the thyroid area showed a dense lymphoplasmacytic infiltrate, accompanied by follicles containing germinal centers. In addition, a destroyed pattern of lymphoid follicle was observed (Fig. ).\nOne year later, thyroid-associated autoimmune antibodies were all decreased (TRAb, 2.2 IU/L; TSAb, 130% (enzyme immunoassay, SRL Inc., Tokyo); TPOAb, 98. 3 IU/mL; TgAb, 151.0 IU/mL), and 2 years later thyroid-associated autoimmune antibodies were further improved (TRAb, 1.1 IU/L; TSAb, 90%; TPOAb, 24.0 IU/mL; TgAb, 12.8 IU/mL). White blood cell count became within normal range (about 5000–7000 /μL (neutrophil 58–68%) and CRP level became almost normal (0.15–0.20 mg/dL).