Delayed-Onset Amiodarone Induced Thyrotoxicosis After Glucagon-Like Peptide-1 Agonist–Related Weight Loss

Abstract

Amiodarone is known to cause thyroid dysfunction, due to both direct cytotoxicity and high iodine content. Due to its lipophilic properties, amiodarone gets stored in the adipose tissue and may induce delayed amiodarone-induced thyrotoxicosis (AIT), months after discontinuation. We present the case of a 60-year-old man admitted with new-onset atrial fibrillation. He had a history of ventricular tachycardia, treated with amiodarone that was discontinued 14 months earlier. On admission, thyrotropin was undetectable, with markedly elevated free thyroxine and total triiodothyronine. He had no previous history of thyroid dysfunction or recent exposure to iodinated contrast. Additional history revealed that the patient had been taking tirzepatide 10 mg weekly resulting in a 54-kg weight loss over the previous 12 months. With this information, a spot urine iodine/creatinine (Cr) was measured and found to be significantly increased at 2323 µg/g Cr (SI: 2075 µmol/mol Cr) (normal reference range <584 µg/g Cr, [SI: <521 µmol/mol Cr]). He was treated with prednisone and methimazole with eventual resolution of hyperthyroidism. Delayed AIT should be considered in the differential diagnosis of new-onset thyrotoxicosis in patients previously treated with amiodarone who experience significant weight loss.

Introduction

Amiodarone is a potent antiarrhythmic drug used to treat both ventricular arrhythmias and atrial fibrillation. Its main metabolite is desethylamiodarone (DEA). Due to highly lipophilic properties, amiodarone and DEA are both stored in high concentrations in several tissues including the adipose tissue and muscle [1]. The amiodarone compound contains 2 iodine atoms representing about 37% by weight. Therefore, a 200-mg dose will contain about 75-mg organic iodine, which is metabolized to 6 mg of free iodine, about 20 times greater than the average daily iodine intake in the typical American diet of 0.3 mg [2]. Thyroid toxicity is one of the most common side effects of amiodarone treatment, due to its direct cytotoxic effect on thyrocytes, its release of iodine following catabolism, and its ability to inhibit 5′-deiodinase leading to alterations in thyroid hormone levels [1, 3]. Amiodarone-induced thyrotoxicosis (AIT) has been reported to occur long after drug discontinuation, likely due to the long half-life of amiodarone in tissues [4]. Specifically, the distribution half-life of amiodarone out of the central compartment to peripheral and deep tissue compartments may be as short as 4 hours; while the terminal half-life is long and variable (9-77 days) due to the slow mobilization of the lipophilic medication out of the deep compartment, primarily represented by adipocytes [5, 6]. Here, we report a case of delayed AIT, 14 months after the amiodarone was tapered off and after a weight loss of 54 kg following treatment with a glucagon-like peptide-1 agonist.

Case Presentation

A 60-year-old man was admitted to the hospital for further evaluation and management of paroxysmal atrial fibrillation with rapid ventricular response (Afib with RVR) in the setting of abnormal thyroid function tests. Cardiac history included atrial and ventricular arrhythmias, nonischemic cardiomyopathy status post implantable cardioverter-defibrillator placement, mechanical aortic valve placement, and chronic heart failure. Medical history also included class III obesity, type 2 diabetes mellitus, and obstructive sleep apnea. There was no history of thyroid dysfunction, and thyrotropin (TSH) 8 months prior was documented as normal at 2.7 mIU/L (reference range, 0.3-4.2 mIU/L [SI: 0.3-4.2 mIU/L]). Four months before this admission, the patient reported being told by his primary care physician that his TSH was “mildly elevated with normal free thyroxine (FT4).” For the ventricular tachycardia the patient had been treated with amiodarone for 2 years, with the medication being tapered off and replaced with sotalol 14 months prior to this hospital admission.

Diagnostic Assessment

Vital signs noted on admission included blood pressure of 133/85 mm Hg, irregular pulse 91/min, height of 177.8 cm, and weight of 106 kg. Pertinent physical examination included absence of goiter, irregularly-irregular heart rhythm, and fine tremor of the upper extremities. Laboratory tests on admission showed an undetectable TSH of less than 0.01 mIU/L, a markedly elevated FT4 greater than 7.7 ng/dL (SI: >99.0 pmol/L) (reference range, 0.9-1.7 ng/dL [SI: 11.6-21.9 pmol/L]), and an elevated total triiodothyronine (TT3) of 299 ng/dL (SI: 4.6 nmol/L) (reference range, 80-200 ng/dL [SI: 1.3-3.1 nmol/L]). Autoimmune hyperthyroidism, hyperthyroid phase of subacute thyroiditis, drug-related thyrotoxicosis, infectious, and iodinated contrast–induced causes were considered during the initial evaluation.

Treatment

Given the considerable alterations in thyroid function and history of previous therapy with amiodarone, empiric treatment was initiated with methimazole 20 mg every 8 hours, and prednisone, 40 mg daily, for a presumed diagnosis of autoimmune hyperthyroidism vs delayed AIT. Subsequently the thyroid receptor antibody (TRAb) and thyroid-stimulating immunoglobulin (TSI) levels were reported as negative. A radioactive iodine (RAI) uptake and scan was not obtained due to inpatient status as per institution policy and procedures, but a thyroid ultrasound demonstrated a normal-sized thyroid with heterogeneous parenchyma without increased vascularity, suggesting type 2 AIT. Due to the patient's altered cardiac status and persistent severe hyperthyroidism despite high-dose prednisone, the methimazole was not discontinued immediately.

Additional chart review revealed that for the past year the patient had been taking tirzepatide, 10 mg weekly, for diabetes control and weight management, with a resultant weight loss of 54 kg. With this information, a spot urine iodine to creatinine (Cr) ratio was measured and found to be significantly elevated at 2323 µg/g Cr (SI: 2075 µmol/mol Cr) (reference range, <584 µg/g Cr [SI: <521 µmol/mol Cr]). Detailed chart review and direct inquiries with all consulting services ruled out any exposure to iodinated contrast agent or other sources of excess iodine. There was no history of other weight-loss interventions, medical or surgical. The episode of Afib with RVR was managed with sotalol, 120 mg twice daily, and metoprolol succinate, 75 mg daily. The patient was discharged home on prednisone 40 mg daily and a slow taper of the methimazole, with periodic monitoring of the thyroid function (Table 1).

Table 1.

Timeline of thyroid function tests and medication dose adjustments

Laboratory test	Timeline											Normal range
	T − 10 wk	T0	T + 3 d	T + 11 d	T + 6 wk	T + 9 wk	T + 12 wk	T + 15 0wk	T + 18 wk	T + 24 wk	T + 28 wk
TSH	2.7 mIU/L	<0.01 mIU/L	<0.01 mIU/L	<0.01 mIU/L	<0.01 mIU/L	0.6 mIU/L	3.4 mIU/L	4.4 mIU/L	6.9 mIU/L	14.5 mIU/L	6.2 mIU/L	0.3-4.2 mIU/L
FT4	1.5 ng/dL (19.3 pmol/L)	>7.7 ng/dL (>99.1 pmol/L)	>7.7 ng/dL (>99.1 pmol/L)	3.8 ng/dL (48.9 pmol/L)	3.2 ng/dL (41.2 pmol/L)	0.9 ng/dL (11.6 pmol/L)	1.3 ng/dL (16.7 pmol/L)	1.3 ng/dL (16.7 pmol/L)	1.0 ng/dL (12.9 pmol/L)	1.0 ng/dL (12.9 pmol/L)	1.3 ng/dL (16.7 pmol/L)	0.9-1.7 ng/dL (11.6-21.9 pmol/L)
TT3	ND	299 ng/dL (4.6 nmol/L)	385 ng/dL (5.9 nmol/L)	140 ng/dL (2.2 nmol/L)	115 ng/dL (1.8 nmol/L)	48 ng/dL (0.7 nmol/L)	75 ng/dL (1.2 nmol/L)	ND	84 ng/dL (1.3 nmol/L)	85 ng/dL (1.3 nmol/L)	108 ng/dL (1.7 nmol/L)	80-200 ng/dL (1.3-3.1 nmol/L)
Prednisone	40 mg	40 mg	40 mg	40 mg	40 mg	40 mg	30 mg	20 mg	10 mg	5 mga	5 mg
Methimazole		20 mg 3×/d	20 mg 3×/d	20 mg 2×/db	10 mg 2×/d	10 mg daily	ND	ND	ND	ND	ND

T0, time of hospital admission.

Abbreviations: FT4, free thyroxine; ND, not determined; TSH, thyrotropin; TT3, total triiodothyronine.

^a Patient developed secondary adrenal insufficiency therefore remained on a low dose of prednisone pending reassessment of the pituitary-adrenal axis.

^b Methimazole taper was started. Abnormal values are shown in bold font. Values in parenthesis are International System of Units (SI).

Outcome and Follow-up

Three months from the AIT onset, the thyroid function normalized, prompting taper and eventual discontinuation of prednisone. Shortly after, the patient’s TSH was noted to be increased with a decline in the FT4 level, consistent with subclinical primary hypothyroidism, for which the patient is monitored, without thyroid hormone supplementation (see Table 1). This clinical course further supported the diagnosis of type 2 AIT. Furthermore, 5 months after the hospital discharge, tirzepatide was reinitiated at a dose of 2.5 mg weekly titrated up to 7.5 mg, for diabetes management and to prevent rebound weight gain, with no recurrence of hyperthyroidism after 6 months of therapy. The prolonged duration of corticosteroid therapy was complicated by a transient episode of adrenal insufficiency requiring a slower steroid taper.

Discussion

The etiology of new-onset thyrotoxicosis, especially in a hospitalized patient, can be difficult to establish. A careful review of medications and supplements may reveal drug-induced or iatrogenic hyperthyroidism. In a prior case report, new-onset biphasic subacute thyroiditis was diagnosed 2 months after initiation of tirzepatide, followed by resolution after drug discontinuation [7]. In contrast, our patient presented with a history of amiodarone therapy and high urinary iodine, which was more indicative of delayed AIT. In addition, he had been treated with tirzepatide for a year prior to the onset of hyperthyroidism.

The effects of amiodarone on the thyroid are complex. Its structural formula closely resembles that of T4. In peripheral tissues, amiodarone and its derivative, DEA, have been found to inhibit the 5′-deiodinase with a resultant increase in T4 levels and decrease in T3 levels, which may persist for months after drug withdrawal [8]. In addition to the effects related to the high iodine content, amiodarone has been demonstrated to have a direct cytotoxic effect on the thyrocytes, resulting in a destructive thyroiditis [9]. While most patients remain euthyroid during treatment, up to 32% were reported to experience hypothyroidism while up to 23% experience AIT [3]. AIT can be classified as type 1 and type 2. Type 1 AIT presents with increased synthesis of T4 and T3 due to increased substrate as a result of high iodine levels. These patients often have increased thyroid vascularity on ultrasound, and positive TRAb and TSI. Type 2 AIT is primarily a destructive thyroiditis due to direct cytotoxic effects. In type 2 AIT the hyperthyroidism is often followed by a hypothyroid phase, which can be transient or permanent. These patients have absent hypervascularity and negative TRAb and TSI. The utility of RAI uptake and scan is limited as the iodine content in amiodarone competes with the radiotracer, often yielding negative results. In clinical practice it is often difficult to differentiate between the 2 types, especially initially, which leads to empiric treatment with both methimazole and prednisone, such as in our case [10]. Our patient was admitted with a new episode of Afib with RVR and with undetectable TSH and high FT4 and TT3, consistent with thyrotoxicosis. Due to the history of previous therapy with amiodarone, empiric treatment with both methimazole and prednisone was initiated. The absence of a goiter and of hypervascularity on ultrasound, along with negative TRAb and TSI, were suggestive of type 2 AIT, although a mixed form could not be completely excluded. The diagnosis of AIT was further supported by significantly elevated urinary iodine levels, with no other identifiable sources of excess iodine. Moreover, the patient eventually transitioned to hypothyroidism, which is typically seen with type 2 AIT.

Although most AIT cases occur during treatment with amiodarone, delayed onset has been reported as late as 16 months after drug discontinuation [4]. While these studies did not report an exact cause, it has been hypothesized that the release of iodine from tissue as the drug is metabolized was a potential contributor [11]. This hypothesis is supported by the literature, which includes cases of thyroiditis related to excess iodine from sources other than amiodarone, such as during efforts to address iodine deficiency in several geographic areas worldwide [11]. Treatments for obesity, both surgical and medical, can result in significant weight loss over relatively short periods of time (months to a year), with potential changes in the volume of distribution of lipophilic drugs, including amiodarone and its metabolites.

We believe that, in this patient, the significant weight loss of 54 kg over 12 months led to a change in the volume of distribution of amiodarone and its metabolites, with release of high amounts of iodine in the central compartment as demonstrated by the increased urinary iodine. Two similar cases have been reported, one after gastric bypass [12] and another after sleeve gastrectomy [13]. Both these patients experienced significant weight loss (63 and 46 kg over 6 and 11 months, respectively) with the difference that they were treated with amiodarone at the time of the AIT diagnosis. A few reports of delayed AIT have been published. While no definitive explanations for these cases have been provided, a slow release of the amiodarone/iodine stored in the tissues was postulated as the cause [4, 14]. In addition to amiodarone, several other lipophilic substances including drugs and toxins have been reported to undergo changes in their volume of distribution with shifts toward the central compartment and inherent side effects [15].

With an increasing number of patients undergoing interventions resulting in rapid and significant weight loss, the medical community needs to be aware of potential unintended consequences, including delayed AIT in patients previously treated with amiodarone.

Learning Points

• Type 2 AIT can develop several months after discontinuation of amiodarone.

• Significant weight loss, especially over a short period of time can change the volume of distribution of amiodarone and its metabolites, increasing the risk of delayed AIT.

• While no specific guidelines exist, physicians should consider periodic monitoring of TSH after amiodarone discontinuation, especially in patients undergoing weight-loss interventions.

Contributors

All authors made individual contributions to authorship. All authors were involved in the diagnosis and management of the patient and manuscript submission. M.L.B. and C.G.C.: conceptualization and writing. A.M.C.: conceptualization, writing, and editing. V.J.B. and C.J.M.L.: conceptualization, review, and editing. All authors reviewed and approved the final draft.

Abbreviations

Afib with RVR

atrial fibrillation with rapid ventricular response

AIT

amiodarone-induced thyrotoxicosis

Cr

creatinine

DEA

desethylamiodarone

FT4

free thyroxine

TRAb

thyroid receptor antibody

TSH

thyrotropin

TSI

thyroid-stimulating immunoglobulin

TT3

total triiodothyronine

Funding

No public or commercial funding was received for this publication.

Disclosures

The authors have no disclosures to declare.

Informed Patient Consent for Publication

Signed informed consent obtained directly from the patient.

Data Availability Statement

Original data generated and analyzed for this case report are included in this published article.