Symptomatic Hypothyroidism Research Articles

P8.09 - Case series of thyroid dysfunction induced by nivolumab (anti-PD-1; ONO-4538)

ABSTRACT Background: Nivolumab, a PD1-specific monoclonal antibody, was approved in Japan on July 2014 for patients with unresectable or metastatic melanoma. Patients: Nivolumab at 2 mg/kg every 3 weeks were initiated to 18 patients with unresectable or metastatic melanoma at University of Tsukuba Hospital. The median age was 71 (range, 39–80) and male:female ratio was 8:10. Of those, 15 patients had primary site at skin and the other 3 had at mucosa. Most of the patients was performance status (PS) score 0 or 1, except 1 patient with PS score 2. Results: Seventeen adverse events (AE) were recorded. Most common AE was thyroid dysfunction and observed in 5 (28%); hyperthyroidism in 2 and hypothyroidism in 3. Whereas no one with hyperthyroidism required treatment, 2 out of 3 with hypothyroidism were symptomatic, such as fatigue and gain weight. However, their symptoms were recovered by replacement of thyroid hormone. No patient required discontinuation of nivolumab due to AEs. Conclusion: According to our study population, using nivolumab was generally safe. Because most of AEs were mild and were manageable, nivolumab seems to be safer than Ipilimumab. However, we should keep in mind that nivolumab might induce thyroid dysfunction. Patients with symptomatic hypothyroidism required hormone replacement therapy.

Over-the-Counter-Drug-Induced Thyroid Disorders

Excessive iodine ingestion may cause thyroid dysfunction. In this case series, we report four patients who developed significant thyroid dysfunction after ingesting over-the-counter (OTC) drugs containing large concentrations of iodine. Four patients from a tertiary medical center are reported. Case 1 involved acute exacerbation of thyrotoxicosis induced by taking OTC Tri-iodine™ in a 35-year-old woman while still on methimazole therapy. Case 2 involved thyroid-extract-induced thyrotoxicosis following ingestion of Thyromine™, and was confirmed by laboratory studies and ¹³¹I thyroid uptake. Cases 3 and 4 involved severe, symptomatic hypothyroidism induced in 2 patients with underlying autoimmune thyroiditis (Hashimoto's disease) following ingestion of Iodoral™. In all cases, thyroid dysfunction resolved with appropriate management and discontinuation of the OTC drugs. These case reports demonstrate the significant risks associated with OTC preparations containing iodine in patients predisposed to thyroid dysfunction. There is no valid reason for taking high-dose OTC iodine supplements, which have been shown to cause harm and have no known benefit.

Subcutaneous application of levothyroxine as successful treatment option in a patient with malabsorption

SummaryBackground:Hypothyroidism can usually be treated effectively by oral levothyroxine supplementation. There are, however, some rare circumstances, when oral levothyroxine application is not sufficient, for example malabsorption, interactions with food or other medications, or various gastrointestinal diseases.Case Report:We present a 42 year old woman with refractory and severe symptomatic hypothyroidism after subtotal thyroidectomy in spite of high dose oral levothyroxine supplementation. By stepwise increasing oral levothyroxine dosage up to 2200 micrograms plus 80 micrograms of thyronine, no sufficient substitution could be achieved. After suspicion of enteral malabsorption due to a pathological D-Xylose-test, subcutaneous levothyroxine supplementation was started. Finally, a sustained euthyroid state could be achieved.Conclusions:For selected patients who do not respond to oral treatment subcutaneous application of levothyroxine can be a suitable and effective therapy.

THE EFFECT OF COMBINED ANTIHYPERTENSIVE THERAPY ON THE BASIC PARAMETERS OF THE LEFT VENTRICLE MYOCARDIUM STRUCTURE AND FUNCTION IN WOMEN WITH METABOLIC SYNDROME AND HYPOTHYROIDISM

Aim. To study the effect of combined antihypertensive therapy on the basic parameters of the left ventricle (LV) myocardium structure and function in women with arterial hypertension (HT), metabolic syndrome (MS) and hypothyroidism. Material and methods. Women (n=196) with HT grade 2–3 and MS were included into the study. Standard clinical examination including an assessment of thyroid status, ambulatory blood pressure (BP) monitoring and echocardiography was performed at baseline and after 6 months. The patients were split into 3 groups: control (without hypothyroidism) with subclinical and manifested (symptomatic) hypothyroidism (SH and MH). Depending on baseline heart rate (HR) patients of each group received a combination of amlodipine+losartan (A+L) in HR <85/min or a combination of amlodipine+moxonidine (A+M) in) in HR ≥85/min. Results. The significant antihypertensive effect was found in patients of the control group due to both A+L and A+M combination (target BP was reached in 85.7 and 88.2%, respectively). In patients with hypothyroidism significant antihypertensive effects was observed only during A+M therapy (target BP in SH and MH was achieved in 82.8 and 82.4%, respectively). In the control group A+L and A+M combinations increased a number of patients with normal LV geometry (85.7 and 86.7, respectively) and diastolic function (78.6 and 80%, respectively). In hypothyroidism A+M therapy resulted in more prominent increase in a number of patients with normal LV geometry (75% in both SH and MH) and diastolic function (in SH and MH 83.3 и 85.7%, respectively) than these in A+L therapy (р<0.05). Conclusion. The combination of A+M has advantages over A+L combination in antihypertensive efficacy as well as in the effect on the structural and functional state of the LV myocardium in women with HT and MS associated with hypothyroidism.

Role of Recombinant Human Thyrotropin (rhTSH) in the Treatment of Well-Differentiated Thyroid Cancer

Since the introduction of radioiodine (RAI) for treatment of well-differentiated thyroid cancer (DTC) more than 50years ago, prolonged periods of hypothyroidism were routinely used as part of the treatment regimen. Recombinant human TSH (rhTSH) was introduced in the 1990s as a tool to elevate the serum TSH without the need for thyroid hormone withdrawal and symptomatic hypothyroidism. After being initially approved as a diagnostic tool for use in RAI scanning and stimulated thyroglobulin testing, rhTSH was approved as an adjunct to RAI remnant ablation in patients without distant metastases in Europe in 2005 and in the US in 2007. Following successful use of rhTSH for diagnostic purposes, it has been extensively studied for use with therapeutic doses of RAI in the setting of RAI remnant ablation and is now an integral part of DCT therapy. The use of rhTSH in clinical practice in the last decade was coupled with the growing interest in an individualized, risk-stratified approach to the management of patients with DCT. While traditional treatment for DTC included surgery and RAI therapy for all patients, many more recent studies demonstrated the value of selective use of RAI only in patients who will probably benefit from treatment. This manuscript reviews the evolving role of rhTSH in the current risk adapted climate of thyroid cancer management with particular emphasis on the use of rhTSH as an aid to RAI therapy.

Hypercalcaemia in a dog with primary hypothyroidism : clinical communication

A 7-year-old female beagle was evaluated for symptomatic hypercalcaemia and primary hypothyroidism. Clinical findings were typical for hypothyroidism. Plasma parathyroid hormone was low and obvious causes for the hypercalcaemia were ruled out by means of abdominal ultrasonography, ultrasonography of the parathyroid glands, survey thoracic radiographs, and fine needle aspirate cytology of the spleen, liver, and peripheral lymph nodes. Treatment with thyroxine resulted in resolution of the hypercalcaemia after approximately 9 weeks of therapy. This is the 1st report of primary adult-onset hypothyroidism associated with symptomatic hypercalcaemia in a dog.

Diagnostic and Therapeutic Use of Human Recombinant Thyrotropin (rhTSH)(Thyrogen&#174;) in Well-Differentiated Thyroid Cancer - Current Indications and Future Perspectives - A Review

The management of well-differentiated thyroid cancer requires endogenous or exogenous thyrotropin (TSH) stimulation for diagnostic and therapeutic purposes. The rationale is to increase the sensitivity of follow-up tests and to optimize the radioiodine uptake, respectively. Withdrawal of L-thyroxine therapy in order to provoke endogenous stimulation and elevation of TSH is associated with symptomatic hypothyroidism that significantly affects quality of life. More importantly, because TSH stimulates growth of thyroid cells, prolonged TSH elevation may worsen the thyroid cancer, and the profound hypothyroidism may aggravate other underlying systemic diseases. As an alternative to thyroxine withdrawal, exogenous stimulation consists of two intramuscular injections of recombinant human thyrotropin α (rhTSH). This procedure is effective in terms of sufficient TSH stimulation and obviates development in the patient of the signs and symptoms of hypothyroidism. Taking into consideration the increased incidence of thyroid cancer, as well as the necessity for life-long follow-up, the optimal management of the disease must meet goals for efficacy, safety, quality of life and optimal cost/benefit ratio. This article reviews current standard procedures and potential novel clinical applications of rhTSH for the management of well-differentiated thyroid cancer. Keywords: rhTSH, Thyroid cancer, Remnant Ablation, Metastases, Follow-up

Fewer Dollars, More Sense

gliomas. 3 Notably, those patients with an early-onset and sustained elevation of thyroid-stimulating hormone (TSH)— defined as occurring within 3 months of entering the study— had a 6-month progression-free survival of 58% as compared with 0% of those who did not (P .002). In addition, the median survival for the former was 9.7 months as compared with 2.2 months for the latter (P .01). There were six magnetic resonance imaging responses in hypothyroid patients as compared with zero in the euthyroid individuals (P .02). The nadir of the free thyroxine decline also correlated positively with survival (P .003). Interestingly, only one patient developed symptomatic hypothyroidism. It has been demonstrated that the notoriously vascular GBM overexpresses—among a number of factors—vascular endothelial growth factor (VEGF), which is produced by tumor and stromal cells, including inflammatory cells. 2 VEGF then acts by paracrine mechanisms on local endothelial cells, resulting in their proliferation, survival, and migration. 4 In addition, the insulin-like growth factor-I receptor (IGF-1R) pathway is highly overexpressed in GBM. 5 The IGF-1R pathway can, in turn, induce VEGF mRNA expression via the mitogen-activated protein kinase pathway. 6 Relative to this, a GBM cell line has been shown to activate phosphophoinositol-3 kinase through IGF-1R, thereby bypassing the effects of epidermal growth factor receptor (EGFR) inhibition on phosphophoinositol-3 kinase. 7 The astrocyte (cell of origin of GBM) has been shown to be a focus of thyroid hormone (TH) action. 8 In that regard, TH has been shown to modulate expression of IGF-1R. Phosphorylation of IGF-1R by TH in 293T cell lines has been observed, whereas TH deprivation reduced proliferation in glioma cell lines. 8

Exemestane-Induced Subclinical Hypothyroidism

Several conditions and drugs induce subclinical hypothyroidism. We report the first case of subclinical hypothyroidism in a 65-year-old woman with breast cancer receiving therapy with the third-generation aromatase inhibitor exemestane 25 mg/day for 2 months. The patient presented with complaints of increasing fatigue and weakness since being commenced on exemestane and was taking no other drugs. There was no past history or family history of thyroid disease. Thyroid function tests prior to breast cancer surgery were normal. Detailed clinical examination and laboratory tests to determine the cause of the patient's increasing fatigue and weakness revealed only subclinical hypothyroidism, that is, an elevated level of thyroid-stimulating hormone (thyrotropin, TSH) only. Ultrasonography revealed a normal thyroid gland. Based on a diagnosis of symptomatic subclinical hypothyroidism, the patient was commenced on levothyroxine sodium 50 microg/day and exemestane was withdrawn. Thyroid dysfunction was restored 4 months after her admission with a significant improvement in symptoms. Levothyroxine sodium was withdrawn 6 months later and no recurrence of thyroid dysfunction occurred during a 1-year follow-up. We believe that the increasing fatigue and weakness in our patient might have been associated either with subclinical hypothyroidism or with administration of exemestane (a known adverse effect of the drug) or both. Further studies are required to investigate how exemestane influences thyroid function.

Reversible Paroxetine-Induced Symptomatic Hypothyroidism

Reversible Paroxetine-Induced Symptomatic Hypothyroidism

Hypothyroidism in Thyroid Carcinoma Follow-up: Orlistat May Inhibit the Absorption of Thyroxine

Orlistat is used in the management of obesity to reduce the absorption of fat. Thyroxine is used in the management of well-differentiated thyroid cancer to suppress thyroid-stimulating hormone (TSH) production. We report a case of symptomatic hypothyroidism occurring after the commencement of orlistat in a patient with papillary carcinoma of the thyroid.

Thyroid dysfunction in antiretroviral treated children.

A high rate of thyroid disorders has been described in HIV-infected adults treated with highly active antiretroviral therapy (HAART), but data on children are lacking. We aimed to assess thyroid function in pediatric patients. Fifty-two HIV-infected children receiving HAART were assessed for signs of thyroid dysfunction and serum concentrations of thyrotropin (TSH), free thyroxin (FT4), free triiodothyronine (FT3), thyroglobulin (TG), reverse triiodothyronine (rT3), anti-TG and antimicrosomal (anti-TSM) antibodies. Eighteen (35%) children showed thyroid abnormalities: isolated low FT4 value in 16; subclinical hypothyroidism in 1; and symptomatic hypothyroidism in 1. Children with low FT4 values as compared with the 34 children without thyroid dysfunction were similar for stage of disease, number of patients with undetectable HIV-RNA, FT3, TSH, TG, rT3, anti-TSM and anti-TG values, whereas they had shorter duration of HAART exposure (P = 0.019) and lower CD4 cell percentage (P = 0.035). The thyrotropin-releasing hormone (TRH) test was normal in all children with low FT4 values. Among children with low FT4, FT4 concentrations correlated positively with CD4 cell percentage (P < 0.05) and duration of HAART exposure (P < 0.05). The case with subclinical hypothyroidism had high basal TSH (7.3 microunits/ml), normal TSH response to TRH test and normal FT4, FT3, TG, rT3, anti-TG and anti-TSM antibodies. The case with symptomatic hypothyroidism had low FT4 (6.6 pg/ml) and high TSH (44 microunits/ml), TG (55 ng/ml), anti-TG (666 IU/ml) and anti-TSM (123 IU/ml). Thyroid abnormalities occur frequently in HAART-treated children even in the absence of clinical symptoms. These data suggest a need of regular thyroid function monitoring.

Management of papillary and follicular (differentiated) thyroid cancer: new paradigms using recombinant human thyrotropin.

The incidence of differentiated thyroid cancer (DTC) has increased in many places around the world over the past three decades, yet this has been associated with a significant decrease in DTC mortality rates in some countries. While the best 10-year DTC survival rates are about 90%, long-term relapse rates remain high, in the order of 20-40%, depending upon the patient's age and tumor stage at the time of initial treatment. About 80% of patients appear to be rendered disease-free by initial treatment, but the others have persistent tumor, sometimes found decades later. Optimal treatment for tumors that are likely to relapse or cause death is total thyroidectomy and ablation by iodine-131 ((131)I), followed by long-term levothyroxine suppression of thyrotropin (TSH). On the basis of regression modeling of 1510 patients without distant metastases at the time of initial treatment and including surgical and (131)I treatment, the likelihood of death from DTC is increased by several factors, including age >45 years, tumor size >1.0 cm, local tumor invasion or regional lymph-node metastases, follicular histology, and delay of treatment >12 months. Cancer mortality is favorably and independently affected by female sex, total or near-total thyroidectomy, (131)I treatment and levothyroxine suppression of TSH. Treatments with (131)I to ablate thyroid remnants and residual disease are independent prognostic variables favorably influencing distant tumor relapse and cancer death rates. Delay in treatment of persistent disease has a profound impact on outcome. Optimal long-term follow-up using serum thyroglobulin (Tg) measurements and diagnostic whole-body scans (DxWBS) require high concentrations of TSH, which until recently were possible to achieve only by withdrawing levothyroxine treatment, producing symptomatic hypothyroidism. New paradigms, however, provide alternative pathways to prepare patients for (131)I treatment and to optimize follow-up. Patients with undetectable or low Tg concentrations and persistent occult disease can now be identified within the first year after initial treatment by recombinant human (rh)TSH-stimulated serum Tg concentrations greater than 2 microg/l, without performing DxWBS. These new follow-up paradigms promptly identify patients with lung metastases that are not evident on routine imaging, but which respond to (131)I treatment. In addition, rhTSH can be given to prepare patients for (131)I remnant ablation or (131)I treatment for metastases, especially those who are unable to withstand hypothyroidism because of concurrent illness or advanced age, or whose hypothyroid TSH fails to increase.

Detection of Circulating Thyroid Cancer Cells by Reverse Transcription-PCR for Thyroid-stimulating Hormone Receptor and Thyroglobulin: The Importance of Primer Selection

Monitoring for thyroid cancer recurrence is routinely done through measurement of serum thyroglobulin (Tg) and 131I whole-body scanning (WBS) after total thyroidectomy and radioactive iodine ablation (1). Serum Tg has been a useful marker to detect residual or metastatic disease, but its limitations include interassay variability, insufficient sensitivity of some commercial assays, and the frequent presence of interfering anti-Tg antibodies in patient serum (2)(3). Although the ability of serum Tg to detect metastatic disease improves greatly after thyroid hormone withdrawal, hormone withdrawal produces symptomatic hypothyroidism and significant morbidity in many patients. Sensitive detection of circulating cancer cells by reverse transcription-PCR (RT-PCR) of tumor-specific mRNA appears to be a useful adjunct in monitoring of some other malignancies (4)(5). RT-PCR has been used to detect thyroid cells in circulation by amplifying transcripts of the thyroid tissue-specific Tg gene (6)(7)(8), but Tg mRNA can be found normally in circulation (7)(8). Recently, real-time quantitative RT-PCR has been reported to detect small amounts of Tg mRNA in the blood of healthy individuals and to identify thyroid cancer patients with recurrent and residual disease (9)(10)(11). Furthermore, Savagner et al. (11) reported that the amount of a Tg mRNA alternative splicing variant closely correlated with the thyroid volume and thyroid-stimulating hormone (TSH) concentration. Thyroid carcinomas contain functional TSH receptor (TSHR) (12)(13), and differentiated thyroid cancer micrometastases have been detected by RT-PCR of TSHR and Tg mRNAs (14). TSHR has not been exploited to detect circulating cancer cells, and smaller TSHR transcripts have been detected in human lymphocytes (15). We investigated the specificity of different PCR primer pairs in the amplification of TSHR and Tg mRNA signals in blood samples from healthy individuals and in thyroid cancer tissue. Selected primer …

Hypothyroidism in patients with multiple myeloma following treatment with thalidomide

Thalidomide is used for the management of several diseases, including the treatment of patients with multiple myeloma who have relapsed(1–3). As the number of patients receiving thalidomide for longer periods of time increases, several previously unrecognized adverse events have been observed (4–6). We observed symptomatic hypothyroidism, characterized by a high serum thyroid-stimulating hormone (TSH) level and low thyroxine level, in a patient with multiple myeloma during therapy with thalidomide. Indeed, known adverse effects of thalidomide, such as bradycardia, lethargy, and constipation, are potential manifestation of hypothyroidism. This led us to evaluate thyroid function tests, when available, in multiple myeloma patients who had received thalidomide in our clinical trials.

Hypothyroidism in primary hyperoxaluria type 1

We describe 4 patients, aged 3 months to 23 years, with end-stage renal disease and severe, symptomatic hypothyroidism. All 4 had primary hyperoxaluria type 1 (PH1) with diffuse tissue (kidneys, skeleton, eyes, heart) calcium-oxalate deposition, a condition known as oxalosis. The hypothyroidism responded to thyroid hormone replacement therapy. Clinical hypothyroidism within the framework of PH1/oxalosis was probably caused by thyroid tissue damage from an abundance of calcium oxalate. We recommend that thyroid function be monitored in patients with PH1 and oxalosis. (J Pediatr 2000;136:255-7)

Central hypothyroidism associated with retinoid X receptor-selective ligands.

The occurrence of symptomatic central hypothyroidism (characterized by low serum thyrotropin and thyroxine concentrations) in a patient with cutaneous T-cell lymphoma during therapy with the retinoid X receptor-selective ligand bexarotene led us to hypothesize that such ligands could reversibly suppress thyrotropin production by a thyroid hormone-independent mechanism and thus cause central hypothyroidism. We evaluated thyroid function in 27 patients with cutaneous T-cell lymphoma who were enrolled in trials of high-dose oral bexarotene at one institution. In addition, we evaluated the in vitro effect of triiodothyronine, 9-cis-retinoic acid, and the retinoid X receptor-selective ligand LGD346 on the activity of the thyrotropin beta-subunit gene promoter. The mean serum thyrotropin concentration declined from 2.2 mU per liter at base line to 0.05 mU per liter during treatment with bexarotene (P<0.001), and the mean serum free thyroxine concentration declined from 1.0 ng per deciliter (12.9 pmol per liter) at base line to 0.45 ng per deciliter (5.8 pmol per liter) (P<0.001) during treatment. The degree of suppression of thyrotropin secretion tended to be greater in patients treated with higher doses of bexarotene (>300 mg per square meter of body-surface area per day) and in those with a history of treatment with interferon alfa. Nineteen patients had symptoms or signs of hypothyroidism, particularly fatigue and cold intolerance. The symptoms improved after the initiation of thyroxine therapy, and all patients became euthyroid after treatment with bexarotene was stopped. In vitro, LGD346 suppressed the activity of the thyrotropin beta-subunit gene promoter in thyrotrophs by as much as 50 percent, an effect similar to that of triiodothyronine and 9-cis-retinoic acid. Hypothyroidism may develop in patients with cutaneous T-cell lymphoma who are treated with high-dose bexarotene, most likely because the retinoid X receptor-selective ligand suppresses thyrotropin secretion.

Minimally Symptomatic (Subclinical) Hypothyroidism

Minimally Symptomatic (Subclinical) Hypothyroidism

Selective IgA Deficiency, Hypothyroidism and Congenital Lymphoedema

The occurrence of selective IgA deficiency and hypothyroidism with congenital lymphoedema has never previously been documented, although the association of hypogammaglobulinaemia with congenital lymphoedema has previously been reported and can result in recurrent respiratory infections. We report a 34 year old woman with congenital lymphoedema who was found to have symptomatic autoimmune hypothyroidism and asymptomatic selective IgA deficiency.

Acquired von willebrand's disease: A rare manifestation of postpartum thyroiditis

This report describes the diagnosis of acquired type I von Willebrand disease in a 30-year-old woman (G5P5) who presented with complaints of excessive bleeding in the postpartum period. The patient's additional complaints of fatigue, depression, and inability to lose weight resulted in laboratory testing that indicated hypothyroidism due to thyroiditis. Clinical symptoms and laboratory tests for von Willebrand disease and hypothyroidism normalized with L-thyroxine replacement. Thyroiditis resulting in symptomatic hypothyroidism occurs in 2-4 per cent of postpartum women. The possibility of underlying hypothyroidism should be considered for those patients, especially if they are parous women, who appear to have an acquired bleeding disorder suggestive of von Willebrand disease.