Evidence Of Thyroiditis Research Articles

Juvenile primary acquired hypothyroidism in a dog with suspected renal dysplasia

AbstractA 1‐year 3‐month‐old, female, neutered crossbreed dog presented for investigation of polyuria, polydipsia and azotaemia. Subsequent biochemistry, endocrine testing and abdominal ultrasound identified hypercholesterolaemia, thyroglobulin autoantibody‐positive hypothyroidism, and IRIS stage II non‐hypertensive, non‐proteinuric suspected renal dysplasia, with a concurrent Escherichia coli urinary tract infection. The patient responded well clinically to levothyroxine treatment, with improvement in hypercholesterolaemia, azotaemia and demeanour at home. At follow‐up biochemistry assessment, hyperphosphataemia and hypercalcaemia (total and ionised) were documented, presumed to be driven by renal insufficiency and renal secondary hyperparathyroidism, although this aetiology was not definitively proven. Normalisation of these values was noted following renal diet implementation and addition of phosphate binders. This case highlights acquired primary hypothyroidism with evidence of thyroiditis in a juvenile dog with suspected congenital renal dysplasia.

RF23 | PSAT300 The Curious Case of Abnormal Thyroid Function Tests: Think Streptavidin Interference

Abstract Interpretation of abnormal thyroid function tests (TFTs) is routine in endocrine practice. However, when there is a discrepancy between biochemical parameters and the clinical picture, sleuthing is necessary to provide appropriate care.A 34-year-old woman was evaluated by an outside endocrine clinic for abnormal TFTs in the setting of worsening anxiety, night sweats, and menstrual irregularities. These showed elevated free thyroxine (FT4) levels (7.3; ref: 0.9-1.7 ng/dL), free triiodothyronine (FT3) levels (13.9; ref: 2.3-4.1 pg/mL) and total triiodothyronine (T3) (186; ref: 94-170 ng/dL) with normal TSH (0.65; ref: 0.27-4.20 mIU/L), negative microsomal and thyroid receptor antibodies. She denied use of contraceptives, biotin, lithium, glucocorticoids, prior radiation, or recent intravenous contrast. Mother and maternal aunt had unspecified thyroid disease. No physical signs of overt hyperthyroidism/hypothyroidism were noted. Our workup also showed elevated FT4 (1.8 ng/dL), FT3 (13.3 pg/mL), total thyroxine (T4) (24.8; ref: 5.5-10.2 µg/dL), T3 (>651; ref: 79-165 ng/dL), normal TSH (0.71; ref: 0.4-5.5 mIU/L), and normal gonadotropin alpha subunit; ultrasound showed no nodules nor evidence of thyroiditis. FT4 by equilibrium dialysis and liquid chromatography-mass spectrometry was normal (1.3; ref: 0.8-2.0 ng/dL). Human anti-mouse antibodies (HAMA) treated TSH was within normal limits (1.4; ref: 0.4-4.5 mIU/L; Siemens). Leading differential diagnosis was initially thyroid hormone resistance; however subsequent labs, done by PCP for non-specific symptoms, revealed a suppressed parathyroid hormone (PTH) (<6; ref 15-65 pg/mL) with normal serum calcium levels. Given no clinical correlate, lab interference was considered. All the testing, with the exception of the FT4 by mass spectrometry and HAMA TSH, were analyzed utilizing Roche Diagnostics (electrochemiluminescent immunoassays). To evaluate vendor-specific interferences, labs were analyzed utilizing Siemens (chemiluminescent immunoassay) which showed normal T4, T3, FT3, and PTH levels. Unlike the Siemens assays, Roche depends on the formation of a biotin-streptavidin complex during measurement and a ruthenium complex to produce a signal. HAMA and polyethylene glycol treatment also returned differing results from untreated samples possibly indicating the interference was a heterophilic antibody to an unknown target. An investigation by Roche Diagnostics showed evidence of streptavidin antibodies. Streptavidin is a common reagent in endocrine assays. The endogenous streptavidin antibody produces an unintended competition between streptavidin-biotin and streptavidin-antibody in the assay; resulting in falsely-low results for sandwich assays (e.g. PTH) and falsely-high results for competitive assays (e.g. FT3 and T4). The impact to the individual analyte is variable due to assay formulation (e.g. TSH).Interference from anti-streptavidin antibodies is a rare phenomenon and may cause unnecessary diagnostics or treatment. Analytical interference should be considered when clinically suspicious of results, and lab consultation is recommended. The patient was advised to obtain a Medic-Alert bracelet. She was also provided a letter detailing the findings so that providers may consult the laboratory prior to testing. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 12:54 p.m. - 12:59 p.m.

False-positive cytopathology results for papillary thyroid carcinoma: A trap for thyroid surgeons.

Current preoperative diagnosis of thyroid nodules remains imperfect despite recent advances in cytopathology and molecular diagnostics. False positivity in preoperative fine-needle aspiration cytology (FNAC) may lead to overtreatment of patients, including total thyroidectomy, and sometimes to lawsuits for misdiagnosis and malpractice. In this study, we analysed clinical characteristics and pathologic findings in patients with false positivity for papillary thyroid carcinoma (PTC) in FNAC. We retrospectively reviewed permanent pathology results from 3788 patients who underwent thyroid surgery. Among them, 48 patients had lesions that were deemed suspicious or positive (Bethesda class V or VI) for PTC in preoperative FNAC. We reviewed clinic-pathologic data, radiologic findings and surgical planning in these patients. The prevalence of pathologic thyroiditis was significantly higher among patients with false-positive FNAC results than in those with confirmed PTC (54.2% vs 9.2%, P<.001). The analysis of the permanent pathology reports showed that 26 patients had chronic lymphocytic thyroiditis and 22 patients had no evidence of thyroiditis. Among the patients without pathologic thyroiditis, 19 patients (86.4%) had nodular hyperplasia and three (13.6%) had follicular adenoma, while among the patients with pathologic thyroiditis, seven (26.9%) had no nodule, 14 (53.8%) had nodular hyperplasia, two (7.7%) had hyalinized nodules, two (7.7%) had follicular adenoma and one (3.8%) had a hyalinizing trabecular tumour. In 42 patients, the extent of surgery (total thyroidectomy or hemithyroidectomy) was to be determined according to the intra-operative frozen section biopsy results. Among them, four (10.5%) had inconclusive frozen section results, and 38 (90.5%) had benign results on frozen section. Patient counselling about the possibility of false positivity is still important. And the presence of thyroiditis might create confusion in the interpretation of cytopathologic results.

Histopathologic Findings of Autoimmunity in Thyroid, Pituitary, and Adrenal Diseases in Chronic Hepatitis C Postmortem Cases

To assess the histologic prevalence of immune-mediated thyroid, pituitary, and adrenal diseases in postmortem cases with hepatitis C. We reviewed 108 consecutive cases of chronic hepatitis C in patients in whom a complete postmortem examination was performed. All microscopic and histologic slides of the thyroid, pituitary, and adrenal reports were reviewed and assessed for evidence of autoimmune diseases. These were compared with a control group of 100 postmortem cases without hepatitis C. In chronic hepatitis C infection, there is a heightened immune response resulting in many autoimmune diseases. The commonest endocrinopathy in association with this chronic infection is thyroid disease, a finding confirmed in our current study. Among the 108 postmortem cases of hepatitis C, there were 14 cases (13%) with evidence of thyroiditis. No cases of pituitary or adrenal disease were found. The mean age of the patients was 52 years (range, 29 to 68). This frequency compared with 7 cases of thyroid disease (7%) in the control group (no significant difference between the 2 groups). On the basis of our postmortem data, thyroid disease was the only major endocrinopathy associated with hepatitis C infection, with a prevalence of 13%. This was comparable with other serologic and nonhistologic antemortem findings. There was no evidence of pituitary or adrenal involvement.

Thyroid peroxidase and the induction of autoimmune thyroid disease

Animal models of autoimmune thyroid disease are associated with thyroglobulin (Tg) as autoantigen whereas in man the autoimmune response to microsomal antigen/thyroid peroxidase (TPO) appears to play a major role in thyroiditis. Consequently, we have compared the ability of TPO and Tg to induce thyroid autoantibodies and thyroid damage in mice known to be susceptible (CBA/J) or resistant (BALB/c) to thyroiditis induced using murine Tg. Groups of three to five mice were immunized twice using Freund's complete adjuvant with 80-100 micrograms highly purified porcine (p) TPO, pTg, rat (r) Tg, human Tg, bovine serum albumin (BSA) or BSA + 0.2 micrograms pTg (the level of Tg contamination of TPO). Four weeks after immunization with TPO, plasma from CBA/J (but not BALB/c) mice contained IgG class antibodies which bound to TPO-coated tubes in the presence or absence of excess Tg (and could therefore be clearly distinguished from Tg antibodies) but there was no evidence of thyroiditis in either strain of mice. In contrast, in CBA/J mice immunized with rTg and, to a lesser extent in mice that had received pTg, thyroid tissue was infiltrated with lymphoid cells and/or neutrophils and antibodies to pTg (but not pTPO) were present. Our observations demonstrate that induction of TPO antibody alone is insufficient to lead to thyroiditis in CBA/J mice. Further, these studies emphasize the complex interactions between MHC and different thyroid antigens in the processes leading to thyroid destruction.

Cytokine gene expression in autoimmune thyroiditis in BioBreeding/Worcester rats.

The intrathyroidal cytokine gene expression in human autoimmune thyroid disease is difficult to interpret because surgical specimens mostly reflect the autoimmune disease at a late stage. Because it is not possible to investigate early stages of thyroiditis in humans, the Bio Breeding/Worcester (BB/W) rat was used as a model. To characterize the lymphocytic thyroiditis (LT) of BB/W rats further and to evaluate early increases of cytokine gene expression in LT, we investigated the interleukin (IL)-2, -4, -6, -10, -12p40, interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) gene expression in the thyroids, spleens, and livers of BB/W rats with and without histological evidence for thyroiditis. The gene expression of these cytokines was determined by Genescan (PE Applied Biosystems, Foster City, CA) fragment analysis using reverse polymerase chain reaction (RT-PCR). Serum thyroglobulin (Tg) antibody concentrations were measured and the extent of lymphocytic infiltration of one thyroid lobe was histologically graded. Cytokine gene expression in rats with and without LT was compared in three groups of rats: 55-day-old rats after 24 days of iodine administration, 75-day-old rats after 45 days of iodine administration, and 101-day-old rats. In the thyroids of the BB/W rats no expression of IL-4 or IL-10 was detectable. The number of rats with detectable TNF-alpha, IFN-gamma, IL-2, IL-12p40 gene expression was significantly higher in rats with LT. Rats with LT had significantly higher IL-12p40 mRNA levels. There were no significant differences in the IL-6 gene expression between rats with and without LT. A correlation between the level of lymphocytic infiltration and the TNF-alpha (r = 0.56, p < 0.0065) and TG antibody concentration (r = 0.62, p < 0.0065) was found. Therefore, the early cytokine gene expression in the BB/W rat is characterized by Th1-related cytokines like IL-2 and IFN-gamma. Whether the detected IL-12p40 (10 rats) and IFN-gamma (5 rats) gene expression in animals without LT is an early indicator for the development of LT remains to be determined.

Transfer of thyroiditis, with syngeneic spleen cells sensitized with the human thyrotropin receptor, to naive BALB/c and NOD mice.

In previous studies we have induced TSH binding-inhibiting Igs and thyroiditis in BALB/c mice and thyroiditis alone in NOD mice immunized with the extracellular domain of the human TSH receptor produced as a maltose-binding protein fusion in bacteria (MBP-ECD). In this study, our aim was to determine whether thyroiditis can be transferred to syngeneic naive recipients with in vivo and in vitro primed spleen cells. Groups of 6-week-old female BALB/c and NOD mice were immunized ip with MBP-ECD in an adjuvant of alum plus attenuated Bordetella pertussis toxin, on days 0 (100 micrograms), 14, 28, and 35 (50 micrograms). These mice (in vivo primed) and nontreated age- and sex-matched controls were killed on day 43, and their spleens and thyroids were removed, the latter to verify the induction of thyroiditis in the antigen-treated mice. Splenocytes were disrupted mechanically and cultured at 3 x 10(6)/ml in RPMI supplemented with 20 micrograms/ml MBP-ECD for 48-64 h. After this in vitro priming, some of the splenocytes received no further treatment, but a portion was fractionated into a CD4+-enriched population. Groups of 6-week-old female BALB/c and NOD mice were immunized into the tail vein with 100-200 microliters PBS containing approximately 10(5)-10(7) unfractionated T cells (both in vivo primed and not) and CD4+-enriched (in vivo primed) splenocyte populations. The animals were killed 16 days later, and their thyroids were examined histologically and by immunohistochemistry. In addition, levels of antibody to the MBP-ECD priming antigen were assessed by enzyme-linked immunosorbent assay in the antigen- and spleen-treated mice. In the donor animals, in vivo priming resulted in an extensive lymphocytic infiltration of the thyroids in both BALB/c and NOD mice and follicular destruction in the latter. There was no evidence of thyroiditis in all 9 BALB/c mice and all 4 NOD mice who received unfractionated T cells from mice that had not been primed in vivo. In contrast, transfer of MBP-ECD in vivo primed unfractionated T cells resulted in thyroiditis in 9 of 13 BALB/c mice and 5 of 6 NOD mice; similarly, the equivalent CD4+-enriched population produced extensive thyroiditis in 2 of 3 BALB/c mice and all three NOD mice. The most striking difference between the antigen- and spleen-treated mice was in the quantity of the infiltrate, which was much greater in the latter and extended throughout the thyroid glands of these animals. In common with mice treated directly with the MBP-ECD antigen, the infiltrates of both BALB/c and NOD recipient mice contained large numbers of activated T cells expressing the receptor for interleukin-2, and macrophages and dendritic cells were plentiful, particularly in the BALB/c mice, in which B cells and interleukin-10-positive T cells were also present. The most abundant infiltrates, containing numerous CD8+ T cells and follicular destruction, were observed in NOD mice receiving primed unfractionated T cells or CD4+-enriched T cells. In contrast to the donors, none of the recipient animals had circulating antibodies to the MBP-ECD antigen. In conclusion, we have shown that it is possible to transfer thyroiditis with spleen cells from mice primed in vivo with a human TSH receptor preparation. Furthermore, the thyroiditogenic activity appears to reside in the CD4+ population.

Thyroid function tests in patients with acquired immune deficiency syndrome and healthy HIV1‐positive out‐patients

The thyroid function tests as well as evidence of thyroiditis were studied in 18 male patients with acquired immune deficiency syndrome (AIDS) and 12 healthy HIV1-positive persons compared with an age-matched control group. Serum total thyroxine was not significantly different between the groups, but both serum total triiodothyronine, triiodothyronine uptake test, and free thyroid hormone indices showed significantly decreasing values from HIV1-positive healthy persons to AIDS patients compared with controls (P value from less than 0.05 to less 0.001). Serum TBG was elevated in HIV1-positive subjects and in patients with AIDS, with a significant inverse correlation with the T3-uptake test (Spearman's rho = 0.657, P less than 0.01). There was no correlation between thyroxine binding globulin and the other measured variables. The serum level of thyrotropine was not significantly different in the groups, whereas serum thyroglobulin was significantly lowered in the AIDS group. There was no correlation between thyroid function variables and survival time, hepatic function and ratio of T-helper to T-suppressor cells. No evidence of thyroiditis was observed. In conclusion thyroid tests showed an atypical outcome in HIV1-positive patients with or without AIDS compared with the pattern normally seen in non-thyroid illness, and should, therefore, caution the interpretation of the biochemical changes when diagnosing abnormal thyroid function in these patients.

2 The epidemiology of hypothyroidism

A committee of the Clinical Society of London appointed to investigate the subject of myxoedema, in its report of 1888, stated, 'The great majority of cases of myxoedema hitherto reported have reached, when first recognized, a well advanced stage', and a century later this is still all too true. The committee went on to express their hope 'that in the near future the disease may be detected in its beginnings, and to have the matter of variations carefully studied both as regards the frequency of this occurrence and the conditions accompanying the presence or subsidence of the general swelling'. Patients with overt thyroid disease are likely eventually to find their way to hospital, or at least seek medical attention, but such patients represent only the tip of the iceberg of hypothyroidism, which can be seen as part of the spectrum of autoimmune thyroid disease. If the disease is to be detected in its beginnings, then it is necessary to look for it in the community, where one might expect to find a pool of people with varying degrees of thyroid dysfunction, some of whom may have overt thyroid failure and others who possess a marker of autoimmune thyroiditis but may not manifest clinical features of hypothyroidism. Considerable progress has been made in understanding the underlying aetiologies of hypothyroidism and associated conditions but relatively little is yet known of its frequency in different communities. LIMITATIONS OF EPIDEMIOLOGICAL STUDIES Epidemiological studies are complicated by problems in the definition of hypothyroidism. Studies using clinical criteria alone are unlikely to estimate the true frequency of the condition because of the difficulties of distinguishing the patient with milder forms of hypothyroidism from the obese middle-aged depressed female without thyroid dysfunction. Thyroid antibodies have been shown to be associated with underlying histological evidence of thyroiditis (Goudie, Anderson and Gray, 1959; Bastenie et al, 1967) but not all patients with overt spontaneous myxoedema have demonstrable thyroid antibodies. Screening procedures based on single direct or indirect estimation of the thyroid hormone levels usually involve the selection (often somewhat arbitrary) of a value below which the patient is said to have hypothyroidism.

Endocrine Function in the Prader-Willi Syndrome

Five males and 2 females with the Prader-Willi Syndrome, aged 10-26 years, had low levels of circulating LH with a subnormal response to 100 and 500 mcg of gonadotrophin releasing hormone (Gn-RH) IV. Serum FSH response to Gn-RH was absent in 3, but normal in only one. Gonadotrophin response to Gn-RH increased in 4 patients during oral clomiphene (200 mg daily) given one to 6 weeks. This suggests that the pituitary gonadotrophes can function normally and that the deficiency is hypothalamic. Five males received 2000 u HCG twice weekly IM for up to 6 weeks. In 2 there was no response; in the remainder the rise in plasma testosterone was subnormal. Six of 7 patients had exaggerated TSH responses to 200 mcg thyrotrophin releasing hormone IV. All had normal thyroid function and serum prolactin and no evidence of thyroiditis. While gonadotrophin deficiency is present, primary gonadal failure may also be a feature of the hypogonadism.

Synergistic Action Between Iodine and Lithium

To the Editor.— I find of interest Dr. Wiener's comment (220:587, 1972) suggesting that a synergistic interaction between iodine and lithium carbonate may have been a major factor in precipitating a hypothyroid state in the patient whose case history was presented earlier in your column by E. D. Luby and colleagues (218:1298, 1971). It is our own experience that the production of a hypothyroid state in individuals receiving lithium is not uncommon, but in most instances antithyroid factors other than lithium, or a strong family history of thyroid disease are operative. This suggests that lithium is only a contributing rather than a sufficient cause in the production of the hypothyroid state. In 1971 1 we reported two cases of hypothyroidism occurring during lithium treatment. Since that time, another individual has come to our attention. Of these three individuals, one had evidence of thyroiditis, another an exceptionally strong history of three

A FOLLOW-UP OF THYROTOXIC PATIENTS TREATED BY PARTIAL THYROIDECTOMY

Eighty-four of eighty-eight thyrotoxic patients treated by thyroidectomy 2-9 years previously have been studied. In 11% of the patients the thyrotoxicosis recurred and 5% of patients became hypothyroid. Only half of these patients had been diagnosed before review. Thyrotoxicosis tended to recur in those patients with larger goitres and high pretreatment 131I-uptake values. Patients who became hypothyroid had more evidence of thyroiditis. Routine thyroid-function tests may be misleading after thyroidectomy. High radioiodine-uptake values and thyroid clearances may occur associated with a low plasma-inorganic-iodine and a normal absolute iodine uptake by the thyroid. Late thyroiduptake measurements are of little diagnostic help, and the protein-bound- 131I is frequently raised in the euthyroid patient. Estimation of the serum-protein-bound 127I completely separated the euthyroid, thyrotoxic, and hypothyroid patients, although some euthyroid patients had low normal values. Three patients had unilateral cord paralysis, but in only one was this permanent. No patient had clinical evidence of parathyroid insufficiency, but as a group the serum-calcium and phosphate-excretion index tended to be low.