Sunitinib (sutent)-induced thyrotoxicosis due to destructive thyroiditis: a case report.

Numerous drugs have been associated with destructive thyroiditis (subacute thyroiditis). Sunitinib, a tyrosine kinase inhibitor employed in renal cell carcinoma and gastrointestinal stromal tumors, has recently been linked to destructive thyroiditis with resultant hypothyroidism. We report a patient with transient overt thyrotoxicosis followed by hypothyroidism, apparently related to sunitinib therapy.     

Thyrotoxicosis induced by alpha-interferon therapy in chronic viral hepatitis

BACKGROUND AND OBJECTIVE: It has been well documented that treatment of chronic hepatitis B and C infection with interferon alpha (IFN-alpha) can lead to the induction of thyroid autoantibodies and hypothyroidism. Thyrotoxicosis, however, is less frequently observed and less well characterized. PATIENTS AND METHODS: We reviewed the medical records of patients who developed thyrotoxicosis while receiving IFN-alpha for either chronic hepatitis B or C infection at Westmead Hospital between 1996 and March 2001. RESULTS: Ten patients (four males and six females) were found to have biochemical thyrotoxicosis. The patients could be divided into two groups with different characteristics. The first group consisted of six patients who had clinical manifestations consistent with Graves' disease, with either diffuse uptake in thyroid scintigraphy and/or positive thyroid-stimulating antibodies. They all required prolonged treatment with antithyroid medications. The second group included three patients who had transient thyrotoxicosis, with progression to hypothyroidism after resolution of thyrotoxicosis. CONCLUSION: Our study suggests that IFN therapy may provoke two different forms of thyrotoxicosis: a Graves' disease picture or a biphasic thyroiditis pattern. The two entities should be differentiated, as they have different implications for treatment.     

Sunitinib and hypothyroidism

Sunitinib inhibits numerous tyrosine kinase receptors involved in tumor growth, angiogenesis, and metastatic invasion. It is indicated in case of metastatic renal carcinomas and gastrointestinal stromal tumors (GIST) resistant to imatinib. Prospective and retrospective studies have shown association between use of sunitinib and hypothyroidism affecting more than 50% of patients in some series. More amazing, was the non-visualisation of thyroid tissue evaluated with thyroid ultrasonography in two cases. Mechanisms of this side effect are not elucidated. Some studies have suggested destructive thyroiditis but no evidence of autoimmunity has been demonstrated. Anti angiogenic effect could be another hypothesis. Recently antithyroperoxidase activity of sunitinib has been demonstrated. Because hypothyroidism is easily accessible to treatment, screening of thyroid abnormalities is mandatory every three months to improve quality of life of these patients. This unique thyroid side effect of sunitinib with the non-visualisation of thyroid suggests a possible and promising antitumor activity in thyroid cancer.     

Transient thyroiditis after treatment with lenalidomide in a patient with metastatic renal cell carcinoma.

Lenalidomide, a recently developed immunomodulatory drug, shares the antiangiogenic and antitumor properties of thalidomide. While there is a known association between thalidomide and hypothyroidism, to our knowledge, there have been no prior reports of thyrotoxicosis associated with thalidomide or lenalidomide treatment. Herein, we report the case of a patient who developed transient thyrotoxicosis while receiving lenalidomide in a clinical trial for metastatic renal cell carcinoma. The time course and biochemical features of this patient's presentation are most consistent with immune-mediated subacute destructive thyroiditis. This case highlights the importance of monitoring thyroid function in the growing number of patients being treated with lenalidomide.     

Postpartum lymphocytic thyroiditis. Prevalence, clinical course, and long-term follow-up

A group of 238 women were surveyed for thyroid disease at six and 12 weeks post partum. Twenty-seven (11.3%) of 238 entered into the study were found to have thyroid disease. Fifteen (56%) of 27 had positive microsomal hemagglutinin antibody titers. A spectrum of thyroid disease was found: persistent hypothyroidism (two patients), transient thyrotoxicosis followed by persistent hypothyroidism (one) or transient hypothyroidism (three), euthyroid goiter (five), transient thyrotoxicosis (seven), transient hypothyroidism (three), high-normal thyroxine levels (five), and low-normal thyroxine levels (one). All nine patients who underwent biopsy had active lymphocytic thyroiditis. Three-year follow-up of 25 of the 27 affected individuals revealed that 12 (48%) still had thyroid disease. This study demonstrates that there is a high incidence of postpartum thyroid disease, usually of a transient nature, and that only about one fourth of the cases are detected or clinically obvious.     

Prevalence and characteristics of postpartum thyroid dysfunction in Tehran

OBJECTIVE: To determine the prevalence of postpartum thyroiditis (PPT), one of the autoimmune disorders of the thyroid which usually occurs in women in the first year after parturition. PPT presents with periods of transient thyrotoxicosis and hypothyroidism, in many cases resulting in permanent hypothyroidism. DESIGN: The study involved 1040 mothers who had contacted five health centers in Tehran for vaccination of their children. METHODS: Signs and symptoms of hypothyroidism and thyrotoxicosis, and the presence of goiter (using the World Health Organization classification), were sought. Serum T3, T4, TSH, anti-TPO and anti-Tg antibodies were measured at 3, 4.5, 6 and 9 months after parturition. In those with hypothyroidism or thyrotoxicosis and a matched group of normal women, thyroid sonography was performed. RESULTS: The prevalence of thyroiditis was 11.4%. Hypothyroidism and thyrotoxicosis occurred in 68 and 42 mothers respectively. Nine had thyrotoxicosis followed by hypothyroidism. There was one case of Graves' disease. Out of 68 hypothyroid patients, 33 women underwent treatment with levothyroxine (because of the severity of symptoms) for 12 months. Six women showed increased TSH at 6 weeks after discontinuation of thyroxine. Stage II goiter (World Health Organization classification) were observed in 21.8% of patients and in 6.7% of pospartum euthyroid women (P<0.001). Positive anti-TPO was found in 61.5% of patients and in 19% of the control group; positive anti-Tg was found in 58% of patients and in 6% of the control group (P<0.001). Sonographic changes were observed in 96% of the patients and in 7% of the control group (P<0.001). There was no significant correlation between the occurrence of thyroiditis and parity, the age of the mother, a previous history of thyroid disease in the patient or family, breast-feeding, or the gender of the child. CONCLUSION: The results of this study show a high prevalence of PPT in Tehranian women. This may be due to the length and frequency of follow-up and/or the transition from low to adequate iodine intake. The major difference with respect to other studies is the low frequency of the biphasic form of PPT.     

Hyperthyroidism following hypothyroidism

Two patients are presented who developed autonomous thyrotoxicosis following a diagnosis of primary hypothyroidism. In one of these patients, antibodies to the TSH receptor were typical of Graves' disease when measured as thyrotropin binding inhibitor immunoglobulins (TBII) and as human thyroid adenylate cyclase stimulating (HTACS) activity, while a needle biopsy of the thyroid gland was consistent with lymphocytic thyroiditis. Twenty-one other reported cases of this unusual sequence found in the literature are reviewed. This occurrence is more common than is generally appreciated.     

Postparathyroidectomy transient thyrotoxicosis.

Three patients are described who had spontaneously resolving transient thyrotoxicosis after resection of a parathyroid adenoma without thyroidectomy or an apparent thyroid abnormality before or during surgery. All had documented thyrotoxicosis that developed within 2 weeks after surgery, which was clinically symptomatic in two of three patients. The thyrotoxicosis was associated with subnormal radioactive iodine thyroid uptake when performed in the two symptomatic patients and was consistent with a postsurgical inflammatory etiology secondary to thyroid gland trauma during parathyroidectomy. In all patients, the clinical and biochemical evidence of thyrotoxicosis resolved within 2 months. Antithyroglobulin and antimicrosomal antibodies were not detected in the two patients who had a complete recovery 3 months after surgery. However, in the patient who had autoimmune thyroiditis, hyperthyroidism due to Graves' disease subsequently developed 19 months after parathyroidectomy and was associated with increasing titers of antithyroglobulin and antimicrosomal thyroidal autoantibodies. From these observations, we conclude that 1) spontaneously resolving transient thyrotoxicosis of varying severity may occur in some patients after parathyroidectomy, which could be secondary to intraoperative thyroid gland manipulation, and 2) while the occurrence of subsequent Graves' hyperthyroidism in a patient with underlying autoimmune thyroiditis may have been a coincidence, this observation also raises the possibility that thyroidal autoantigen released during parathyroidectomy may trigger the reactivation of autoimmune thyroid disease in a predisposed subject.     

Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase activity.

OBJECTIVE: Sunitinib is a novel tyrosine kinase inhibitor with antitumor and antiangiogenic effects. An observed higher than expected rate of hypothyroidism in sunitinib-treated patients prompted assessment of the incidence of hypothyroidism. DESIGN: Patients taking sunitinib had their thyroid function tests (TFTs) assessed via chart review. To explore potential effects on the thyroid, we examined the antiperoxidase activity of sunitinib by in vitro testing its effect on guaiacol oxidation and protein iodination by lactoperoxidase. MAIN OUTCOME: Of the 89 patients who took sunitinib, 49 patients were excluded from analysis for several reasons. Of the remaining 40 patients, 21 (53%, 24% of the original 89) developed elevated thyrotropin (TSH) after a median of 5 months (range 1-36 months). Median TSH was 21.4 mU/L (range 4.6-174 mU/L). In vitro, sunitinib had antiperoxidase activity that was about one-fourth the potency of propylthiouracil. CONCLUSIONS: Of the 40 patients who had TFTs assessed after starting sunitinib, 53% developed elevated TSH. We recommend that all patients treated with sunitinib be monitored for hypothyroidism. The mechanism of the antithyroid effect appears to be inhibition of peroxidase activity. Further research is needed to confirm the mechanism by which sunitinib induces hypothyroidism.     

Reversible primary hypothyroidism with blocking or stimulating type TSH binding inhibitor immunoglobulin following recombinant interferon-α therapy in patients with pre-existing thyroid disorders

OBJECTIVE  Treatment with recombinant interferon-α (rIFN-α) may induce autoimmunity. We have evaluated the effect of rIFN-α on pre-existing thyroid disease with special reference to changes in TSH receptor antibody.
DESIGN AND PATIENTS  Five patients, who had a history of autoimmune thyroid disease diagnosed between 2 and 16 years earlier (three patients had Graves' disease while two had Hashimoto's thyroiditis), were treated with rIFN-α for chronic hepatitis C. Before, during and after rIFN-α therapy, we determined thyroid function, antithyroid antibody, thyroid echogenicity and the surface phenotype of the peripheral and intrathyroidal lymphocytes.
RESULTS  Four of the patients developed overt hypothyroidism after 4–7 months of rIFN-α therapy, and two of them had a preceding history of low-uptake thyrotoxicosis. Recovery of thyroid function was observed in all four patients. Strongly positive blocking type TSH receptor antibody was detected and an increase in the percentage of CD19 positive cells in the intrathyroidal lymphocytes was also observed in three of the patients even though the goitre size increased in two of them. One of the patients became thyrotoxic later when stimulating type TSH receptor antibody became positive. Another patient suffered from reversible hypothyroidism although stimulating type TSH receptor antibody remained strongly positive throughout the clinical course.
CONCLUSIONS  Our data thus indicated a high incidence of an unusual type of reversible hypothyroidism with TSH receptor antibodies in patients with chronic hepatitis C and pre-existing autoimmune thyroid disease after recombinant interferon-α therapy through a mechanism involving both the humoral and cellular immune systems.     

The clinical picture, hormonal disorders and humoral immunity in patients with autoimmune thyroiditis

Altogether 93 patients with autoimmune thyroiditis were investigated. A great variability of the functional clinical symptomatology (from thyrotoxicosis up to manifest hypothyroidism) was revealed. Subclinical hypothyroidism was detected in a majority of patients. In some patients the clinical symptoms of thyrotoxicosis were combined with euthyroidism or subclinical hypothyroidism basing on the findings of the hormonal investigation which should be taken into account while choosing therapeutic tactics. Patients with autoimmune thyroiditis demonstrated a preserved circadian rhythm of cortisol secretion. Adrenocorticotropin-zinc-phosphate testing has shown good functional adrenocortical reserves; cortisol secretion did not depend on thyroid function nor did it differ from the indicator in the control group.     

The occurrence of thyrotropin binding-inhibiting immunoglobulins and thyroid-stimulating antibodies in patients with silent thyroiditis

Silent (painless) thyroiditis has been recognized as a clinical entity for over a decade and is characterized by spontaneously resolving thyrotoxicosis. Its etiology is uncertain; however, a few reports have indicated the occurrence of TSH binding-inhibiting immunoglobulins (TBII) and thyroid-stimulating antibodies (TSAb) in some of the patients. The present study was undertaken to evaluate thyroid function and the occurrence of TBII and TSAb and thyroid autoantibodies (antithyroglobulin and antimicrosomal) in 53 patients with silent thyroiditis during the course of their disease. The patients were divided into 2 major groups: I) those who developed transient hypothyroidism and II) those who did not. All patients initially had significantly increased concentrations of serum T4, free T4, and free T3, suppressed TSH levels, and decreased thyroid radioiodine uptake. TBII and TSAb were initially positive in 8 (15.1%) and 10 patients (18.9%), respectively. Forty patients were available for follow-up. TBII was positive in 6 of 24 (25.0%), and TSAb was positive in 8 of 24 (33.3%) of the patients who developed transient hypothyroidism during the course of their disease. Among the patients who did not become hypothyroid at any time, TBII was positive in only 2 of 16 (12.5%), and none of the patients became TSAb positive. The findings indicate that increased TSAb and TBII activity may be detected in patients with silent thyroiditis and, when present, are associated with transient hypothyroidism during the course of the disease.     

Iodine-induced subclinical hypothyroidism in euthyroid subjects with a previous episode of amiodarone-induced thyrotoxicosis.

Amiodarone-induced thyrotoxicosis (AIT) occurs most frequently in patients with underlying thyroid disease and is generally believed to be due to the iodine contamination of amiodarone and iodine released by the metabolism of the drug. We and others have suggested that the thyrotoxicosis may also be secondary to amiodarone-induced thyroiditis. To further determine the etiology of AIT, we administered large doses of iodides [10 drops saturated solution of potassium iodide (SSKI) daily] to 10 euthyroid patients long after an episode of AIT believed to be due at least in part to amiodarone-induced thyroiditis. Six of these 10 patients had an abnormal iodide-perchlorate discharge test before SSKI administration, indicating a subtle defect in the thyroidal organification of iodide. During SSKI administration, 6 patients developed marked iodine-induced basal and/or TRH-stimulated serum TSH elevations, 2 had suppressed basal and TRH-stimulated TSH values, and 2 had normal TSH responses compared to SSKI-treated euthyroid subjects with no history of amiodarone ingestion or thyroid disease. Serum T4 and T3 concentrations remained normal and unchanged during SSKI administration in both the AIT patients and control subjects. These results strongly suggest that excess iodine may not be the cause of the hyperthyroidism associated with amiodarone therapy, especially in those patients with probable amiodarone-induced thyroiditis. Furthermore, like patients with a previous history of subacute thyroiditis and postpartum thyroiditis, the present results suggest that some patients with a previous history of AIT may be at risk to develop hypothyroidism when given excess iodine.     

Phenotypes of Interferon-α-Induced Thyroid Dysfunction among Patients Treated for Hepatitis C Are Associated with Pretreatment Serum TSH and Female Sex

Context: Thyroid dysfunction is a common complication of interferon-α (IFNα) therapy, with many phenotypic patterns and the potential for significant morbidity. Objective: Our objective was to gain mechanistic insight and predict clinical presentations by determining the risk factors for distinct subtypes of IFNα-induced thyroid dysfunction. Design: ACHIEVE-1, a randomized trial conducted from 2005-2009, compared long-acting preparations of IFNα in 1323 patients with hepatitis C, genotype 1. Setting: A total of 149 outpatient clinics in North America, Europe, and Australia participated. Patients: We studied 1233 patients who were euthyroid at baseline. This population is 60% male and 82% Caucasian. Interventions: Patients were treated with pegylated IFNα2a weekly or albumin-IFNα2b every 2 wk for 48 wk. Serum TSH and free T(4) were measured before therapy and 12 or more times over 60 weeks. Main Outcome Measures: Thyroid dysfunction was defined as a TSH outside the normal range during the course of therapy. Low serum TSH indicated thyrotoxicosis, elevated TSH indicated hypothyroidism, and both abnormalities occurred in biphasic thyroiditis. Results: Of previously euthyroid patients, 16.7% developed abnormal TSH values during therapy, including 24 with TSH below 0.1 mU/liter, 69 with TSH over 5.5 mU/liter, and 76 with biphasic thyroiditis. Biphasic thyroiditis was over 8-fold more common among women than men using multivariate logistic regression analysis [odds ratio (OR) = 8.4; 95% confidence interval (CI) = 4.5-15.8]. Thyrotoxicosis was most strongly associated with a lower pretreatment TSH (OR = 4.1 per -1 mU/liter decline; 95% CI = 1.9-9), whereas hypothyroidism was strongly associated with higher pretreatment TSH (OR = 3.9 per 1 mU/liter increase; 95% CI = 3-5.2). Conclusions: Biphasic thyroiditis is common among women treated for hepatitis C with IFNα. Lower and higher pretreatment serum TSH are associated with greater likelihood of thyrotoxicosis and hypothyroidism, respectively. Antithyroid antibody levels were not available for the cohort, and thus we cannot clarify the role of pretreatment thyroid autoimmunity as a risk factor. Our results do show that readily identifiable patient characteristics are risk factors for specific patterns of IFN-induced thyroid dysfunction. These findings suggest that distinct mechanisms may underlie subtypes of thyroid dysfunction associated with immune-modulatory therapy for hepatitis C.     

Nilotinib-induced hypothyroidism in a patient with chronic myeloid leukemia

Peripheral edema often occurs in patients with chronic myeloid leukemia (CML) treated with kinase inhibitors (TKIs). However, there are few reports indicating that the edema is caused by TKIs-induced hypothyroidism. We present the case of a 76-year-old man with chronic-phase CML who suffered from severe systemic edema after introduction of nilotinib. Laboratory tests revealed hypothyroidism; the patient was euthyroid prior to introduction of nilotinib. After further examination, we attributed this hypothyroidism to nilotinib. His edema regressed dramatically after thyroid hormone replacement therapy, with continued treatment with nilotinib. Laboratory examination of thyroid function also improved markedly. Although sunitinib, a multi-targeted TKI, is associated with a high incidence of hypothyroidism, TKIs targeting Bcr-Abl have rarely been reported to cause hypothyroidism. We report nilotinib-induced hypothyroidism, and suggest that hypothyroidism should be considered as a possible etiology when patients receivingTKIs suffer from edema.     

Influence of endogenous T3-autoantibodies on thyroid hormone measurements in a woman with transient postpartum thyroiditis

Unreliable estimates of serum total T3 due to the presence of autoantibodies against T3 were observed in a woman who developed thyrotoxicosis followed by transient hypothyroidism after childbirth (postpartum thyroiditis). The T3 autoantibody levels changed during the postpartum period in a similar way to the thyroid microsomal antibodies. The total T3 values were constantly low, whereas the measurement of free T3 by the Amerlex analogue method deviated from the expected only at the time of maximal antibody levels. Thus, evaluation of thyroid function may be complicated by the simultaneous presence of thyroid hormone autoantibodies and transient postpartum thyroiditis.     

Triiodothyronine thyrotoxicosis complicating primary hypothyroidism in a patient with autoimmune thyroiditis

It is increasingly recognized that autoimmune thyroiditis can have a multifaceted presentation. Documented triiodothyronine thyrotoxicosis developed in a patient with a six-year history of primary hypothyroidism that was left untreated. Serologic and cytologic evidence confirmed the thyroid dysfunction as being on an autoimmune basis. Chronic lymphocytic thyroiditis may be seen with hyperthyroidism, hypothyroidism, or euthyroidism, and in an individual patient, spontaneous progression from one metabolic state to another may occur.     

Clinical characteristics of amiodarone-induced thyrotoxicosis and hypothyroidism in Japan.

Since amiodarone was introduced in Japan in 1992, the incidence of the drug-induced thyroid dysfunction has been increasing. We studied the thyroid function of 13 patients with amiodarone-induced thyrotoxicosis (AIT) and 11 patients with amiodarone-associated hypothyroidism (AAH) who had been referred to our Institute in the last 6 years. AIT and AAH developed after 39+/-21 and 20+/-16 months of amiodarone treatment, respectively. One patient developed AAH followed by AIT. The AIT ranged from subclinical to overt thyrotoxicosis. Four patients with moderate to marked AIT were treated with methimazole. Their thyrotoxicosis persisted for 3 to 9 months, despite administration of antithyroid agents. One patient with mild thyrotoxicosis was treated with prednisolone, resulting in a euthyroid state in a few months. Eight patients with asymptomatic to moderate thyrotoxicosis resolved spontaneously without any treatment. In four asymptomatic patients with AIT, serum levels of T3 and T4 were in the upper normal range or slightly high (< 12 microg/dl), accompanied by suppressed TSH (<0.1 microU/ml) and high thyroglobulin levels, suggesting destruction-induced thyrotoxicosis. Such a subclinical thyrotoxicosis developed repeatedly in one patient. Ultrasonographic studies revealed no nodular lesion in the thyroid, and color flow Doppler sonography demonstrated no hypervascularity in the thyroid gland in any AIT patient. Although it is postulated in Europe that there are two types of AIT, namely type I, which develops in patients with latent Graves' disease or toxic multinodular goiter, and type II, which develops in an apparently normal thyroid as destructive thyroiditis, all AIT patients we have seen so far had developed destructive type AIT. Sufficient intake of iodide and a very low incidence of toxic multinodular goiter may account for the rare incidence of type I AIT in our country. Mild to moderate AIT resolved spontaneously without discontinuing amiodarone, but it was discontinued in two of 13 AIT patients because of extrathyroidal adverse reactions.     

Transient thyrotoxicosis and persistent hypothyroidism due to acute autoimmune thyroiditis after interleukin-2 and interferon-alpha therapy for metastatic carcinoma: a case report.

A 59-year-old man with metastatic renal cell carcinoma developed symptomatic thyroid dysfunction following interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) therapy. Thyroid evaluation prior to this therapy revealed evidence of subclinical Hashimoto's thyroiditis. Symptomatic thyrotoxicosis, including atrial fibrillation, developed after the initial two courses of intermittent intravenous bolus therapy with human recombinant IL-2 and IFN-alpha. At 4 weeks after initiation of immunotherapy, the thyroid antimicrosomal antibody (AMA) titer rose from 1:6,400 to 1:25,600; thyroid-stimulating immunoglobulin was negative. A technetium 99m-pertechnetate thyroid scan obtained while the patient was thyrotoxic showed diminished uptake in a symmetrically enlarged gland. The patient was temporarily treated with propranolol, digoxin, and quinidine. The atrial fibrillation quickly resolved, and thyrotoxicosis abated over the following 5 weeks, while the AMA titer rose further to 1:102,400. By 11 weeks after initiation of immunotherapy, hypothyroidism developed and persisted through two subsequent courses of cytokine therapy at Weeks 16 and 18. The tumor metastases partially responded to the immunotherapy. The patient has remained hypothyroid up to 27 weeks of follow-up. This case history suggests that IL-2 and IFN-alpha therapy may precipitate a fulminant autoimmune thyroiditis syndrome in a vulnerable patient with preexisting autoimmune thyroid disease.     

Thyrotoxicosis associated with the use of amiodarone: the utility of ultrasound in patient management

Amiodarone is an anti‐arrhythmic drug that commonly affects the thyroid, causing hypothyroidism or thyrotoxicosis. Amiodarone‐induced thyrotoxicosis (AIT) is caused by excessive thyroid hormone biosynthesis in response to iodine load in autonomously functioning thyroid glands with pre‐existing nodular goitre or underlying Graves' disease (type 1 or AIT 1), or by a destructive thyroiditis typically occurring in normal glands (type 2 or AIT 2). Indeterminate or mixed forms are also recognized. The distinction is clinically useful as AIT 1 is treated predominantly with thionamides, whereas AIT 2 is managed with glucocorticoids. We review the tools used to differentiate type 1 from type 2 thyrotoxicosis, with specific reference to the imaging modalities used.