- Email: [email protected]
Surgical management of amiodarone-induced thyrotoxicosis
Surgical management of amiodarone-induced thyrotoxicosis CHRISTINE B. FRANZESE,
MD,
CHRIS Y. FAN,
MD,
and BRENDAN C. STACK JR,
MD,
Jackson, Mississippi, and Hershey,
Pennsylvania OBJECTIVE: Amiodarone can cause thyroid dysfunction in patients with or without previous thyroid disease. With increased use from its placement in advanced cardiac life support guidelines and cardiac transplant programs, the incidence of amiodarone-induced thyrotoxicosis (AIT) will likely increase. Medical management is complex and nonuniform and frequently fails. This study investigates the role of surgery in AIT and proposes indications for surgical management. STUDY DESIGN AND SETTING: Two AIT case reports at a tertiary care institution and 31 surgical AIT cases in the world literature are reviewed. METHODS: The 2 AIT cases involved patients with cardiomyopathy and resistant arrhythmias. Despite medical therapy, both patients’ conditions failed to improve. Thirty-one surgical cases of AIT in the literature are evaluated with respect to symptoms and onset, medical therapy, AIT classification, pathology, perioperative management, and complications. RESULTS: Both patients underwent total thyroidectomy without difficulty or complication, one as an overnight stay and one as an inpatient with an intraaortic balloon pump. One patient received a successful cardiac transplant and the other remains a viable candidate. In the literature, the majority (80%) of surgical cases are AIT type II (less common type) with no underlying thyroid disease.
From the Department of Otolaryngology–Head and Neck Surgery (Dr Franzese), University of Mississippi Medical Center, and the Division of Endocrinology and Metabolism (Dr Fan) and Division of Otolaryngology–Head and Neck Surgery (Dr Stack), Penn State Milton S. Hershey Medical Center. Presented as a poster at the Annual Meeting of the American Academy of Otolaryngology–Head and Neck Surgery, San Diego, CA, September 22-25, 2002. Reprint requests: Brendan C. Stack, Jr, MD, Division of Otolaryngology–Head and Neck Surgery, H091, Penn State University College of Medicine, 500 University Dr, Hershey, PA 17033; e-mail, [email protected]. Copyright © 2003 by the American Academy of Otolaryngology–Head and Neck Surgery Foundation, Inc. 0194-5998/2003/$30.00 ⫹ 0 doi:10.1016/S0194-5998(03)01590-0
Range and duration of symptoms varied, in addition to type and duration of medical management. Almost all patients underwent total thyroidectomy, and all were successful with no mortality and minimal morbidity. CONCLUSION: AIT can develop in any patient during or after amiodarone therapy. Medical management is extremely difficult due to the absence of a proven therapeutic armamentarium, and surgery offers a safe, viable option. Surgical management should play a larger role in treatment algorithms and should be strongly considered for patients whose conditions necessitate continuation of amiodarone, or with severe symptoms resistant to medical therapy. (Otolaryngol Head Neck Surg 2003; 129:565-70.)
A miodarone, a benzofuranic acid derivative, is used in the treatment of numerous malignant atrial and ventricular tachyarrhythmias.1,2 Although it may reduce cardiac-related mortality and improve survival rates, amiodarone can cause serious thyroid dysfunction in patients with or without previous thyroid disorders.1,3 The molecular structure of amiodarone is similar to that of thyroxine and triiodiothyronine, and its administration greatly expands both systemic and thyroidal iodine pools.1,4 Conventional doses of 300 mg/d provide 10.5 mg of free iodine daily, vastly more than the normal dietary requirement of 0.2 to 0.8 mg/d.5 Amiodarone-induced thyrotoxicosis (AIT) is estimated to develop in 2% to 3% of patients in iodine-sufficient areas and in 10% to 15% or more in iodine-deficient populations.5,6 Although many cases are mild, a significant number become life threatening. Because amiodarone is lipid soluble with a long half-life (ranging from 22 to 60 or more days), simply discontinuing the drug often provides no relief. Due to a release from the inhibitory effect of amiodarone on the 5⬘-monodeiodinase enzyme, withdrawal of the drug can cause a paradoxical worsening of the patient’s condition.1,5 565
Otolaryngology– Head and Neck Surgery November 2003
566 FRANZESE et al
Table 1. Thyroid function tests and imaging results of initial workup Test
Case 1
Case 2
TSH T4 T3 Thyroid ultrasound
⬍0.01 IU/mL ⬎23.0 g/dL 171.0 ng/dL Normal echo texture. No lesions identified. No abnormality of blood flow identified on Doppler evaluation. Left lobe measures 4.7 cm ⫻ 2.2 cm ⫻ 1.8 cm. Right lobe measures 5.2 cm ⫻ 2.3 cm ⫻ 1.9 cm. The thyroid lobes are slightly elongated but normal in size. Less than 0.8% uptake in a 24-hour period
⬍0.01 IU/mL 19.0 g/dL 131.0 ng/dL Thyroid diffusely enlarged. No nodules or lesions identified. Right lobe measures 6.0 cm ⫻ 2.5 cm ⫻ 2.0 cm Left lobe measures 7.0 cm ⫻ 2.0 cm ⫻ 2.0 cm
Radioiodine uptake
Medical management of AIT is a challenge. Available treatment regimens are far from uniform and do not consistently provide success.1,3 There is no accepted standard therapy or uniform pharmaceutical dosage regimen, and the length of therapy remains undefined. Many patients fail medical therapy or cannot discontinue amiodarone because it is the only drug effective against resistant arrhythmias. Total thyroidectomy regimen was reserved as an option of last resort for management, yet a number of AIT cases successfully managed with surgery have been reported. As amiodarone use increases and the incidence of AIT rises, the role of surgery in treatment algorithms should be reconsidered. MATERIALS AND METHODS Case 1 A 55-year-old male heart transplant candidate with dilated cardiomyopathy was admitted after a near-syncopal episode. The patient had a similar previous episode secondary to the new onset of atrial fibrillation. The patient’s rate was controlled and converted to normal sinus rhythm on amiodarone, which he continued. Before his second admission, he began to experience shortness of breath at rest, fatigue, nervousness, tremor, lightheadedness, and occasional chest pain. He had no prior personal or family history of thyroid disease. No abnormalities were demonstrated on thyroid palpation. Electrocardiogram revealed a return to atrial fibrillation. Multiple attempts at cardioversion failed to convert the patient’s rhythm. Thyroid function tests, ultrasound, and radioiodine uptake were
Not performed
consistent with AIT (Table 1). An attempt to withdraw amiodarone resulted in severe bouts of rapid ventricular tachyarrhythmias resistant to other antiarrhythmics, and amiodarone was restarted. Propylthiouracil and high-dose steroids (40 mg/d) for 8 weeks were unsuccessful. The patient’s thyroid function tests remained elevated, and his symptoms continued to worsen. Case 2 A 36-year-old female heart transplant candidate with a history of dilated cardiomyopathy was referred for evaluation as an outpatient for refractory hyperthyroidism. She was currently taking amiodarone due to a history of atrial fibrillation and malignant tachyarrhythmias responsive only to this drug. However, she also had a history of thyroiditis, and amiodarone therapy had caused the return and exacerbation of her symptoms of fatigue, anxiety, tremor, sweating, lightheadedness, and diarrhea. Thyroid function tests and ultrasound were consistent with AIT (Table 1). She elected surgical treatment of her thyrotoxicosis. Literature Review Thirty-one cases of AIT in a total of 8 studies reported in the literature managed surgically are evaluated with respect to type and duration of symptoms, duration of amiodarone therapy, type and duration of medical therapy, pathology and AIT classification, perioperative management, and complications.1,3-5,7,8
Otolaryngology– Head and Neck Surgery Volume 129 Number 5
FRANZESE et al
567
Fig 1. Time course of T3 levels for both cases.
RESULTS Case 1 Despite medical management, the patient’s condition continued to deteriorate with increasingly difficult to control arrhythmias. Because amiodarone was the only drug effective against the arrhythmias, surgical treatment was elected. Preoperatively, an intraaortic balloon pump was placed to assist cardiac output during surgery. The patient underwent a total thyroidectomy. Complete intravenous general anesthesia was administered, with the patient intubated and no inhalational anesthetic agents. There were no operative difficulties or postoperative complications. On pathologic examination, the gland weighed 27 g and demonstrated no gross abnormalities. Histopathology demon-
strated lymphocytic infiltration with evidence of follicular disruption. Within a few days postoperatively, the patient’s condition improved and he was able to be cardioverted successfully to normal sinus rhythm (Fig 1). He remained on amiodarone postoperatively and a few months later underwent a successful cardiac transplant (Table 2). Case 2 Preoperatively, the patient was placed on Lugol’s iodine solution. She underwent total thyroidectomy. Complete intravenous general anesthesia was used similar to case 1, with the patient intubated and no inhalational agents given. The decision was made to perform her surgery as an
Otolaryngology– Head and Neck Surgery November 2003
568 FRANZESE et al
Table 2. Postoperative thyroid function tests Test
Case 1
Case 2
TSH T4
1.2 IU/mL 6.5 g/dL
5.5 IU/mL 3.9 g/dL
outpatient, because her condition was not yet medically unstable and her cardiologist had cleared her for outpatient surgery. However, the cardiology staff and surgical intensive care unit team were on standby during the surgery and postoperatively. There were no operative difficulties or postoperative complications. On pathologic examination, the gland weighed 23 g and also had no gross abnormalities. Histopathology demonstrated fibrosis and follicular destruction associated with numerous macrophages and small foci of lymphocytes. Postoperatively, the patient was observed overnight in the outpatient surgery unit and discharged the next morning. Within a few days, the patient’s symptoms had resolved (Table 2). The patient remains on the cardiac transplant list (Fig 1). Literature Review A male predispostion was demonstrated, with a male-female ratio of approximately 3:1, which is consistent with previous reports.1,3,6 Also, the majority of cases, nearly 80%, can be classified as AIT type II (Table 3). Duration of amiodarone therapy prior to symptoms ranged from 2 to 55 months. type and duration of symptoms varied, with symptoms lasting a few days to 35 months. The most common symptom reported was shortness of breath. The most common finding was new onset or return to an arrhythmia, and the most common arrhythmia was atrial fibrillation. Surprisingly, only 55% (17 patients) received and failed medical therapy, with the other half treated initially by surgery. Of the medical failures, 9 patients (53%) were treated with PTU alone, with dosage ranging from 300 to 1200 mg/d and treatment duration ranging from 2 weeks to 3 months. Seven patients were treated with PTU in combination with another drug (high-dose steriods, -blockers, radioactive iodine) with therapy ranging from 1 to 5 months. Only 1 patient was treated without PTU, using a combination of methimazole and potassium perchlorate for 6 weeks and steroids and iopanioc acid for 4 weeks. Two
patients in the medical failure group were considered “terminal” before surgery. Various reasons were given in regard to decision-making in the 14 patients managed initially with surgery; these included patients with severe, acute onset of symptoms, critically ill patients, patients who declined medical management, and where the surgeon thought that this option was the treatment of choice. An attempt to withdraw amiodarone was made in 15 patients. Three patients had failure and were restarted on the drug due to arrhythmias. Despite successful withdrawal in the other patients, all remained thyrotoxic with symptoms. Twelve patients received preoperative -blockers, with 2 of these patients having severe bradycardia. All except 8 patients underwent total thyroidectomy. These 8 patients had subtotal thyroidectomy. All cases used general intravenous anesthesia, and all patients experienced dramatic symptom improvement after surgery. Postoperatively, 3 patients experienced transient hypocalcemia, 2 patients had short-lived arrhythmias, 1 patient had a delayed extubation, and 1 patient had pneumonia. There were no perioperative deaths. However, there was 1 death 4 months postoperatively from ventricular arrhythmia despite continued amiodarone therapy. DISCUSSION AIT can develop any time during or after amiodarone therapy, although it is more commonly seen in patients in iodine-deficient locales and patients with underlying thyroid pathology. AIT can generally be classified into 1 of 2 major forms, although mixed types are thought to exist. AIT type I occurs in patients with previously known or documented abnormal thyroid glands (nodular goiter, Graves’ disease, etc) and is secondary to excessive hormone production.3 AIT type II affects an apparently normal gland and is the result of uncontrolled release of preformed hormone3 (Table 4). This classification scheme is based on the patient’s past medical history, past physical examinations, and past laboratory/ultrasound examinations, if any. It does not take into account postoperative pathology, as the great majority of patients with AIT do not, at present, undergo surgery.9 The pathogenesis of the 2 forms is thought to take place through different mechanisms of action.
Otolaryngology– Head and Neck Surgery Volume 129 Number 5
FRANZESE et al 569
Table 3. Summary of reviewed case results Study
Hamior et al1 Brennan7 Mulligan et al4 Farwell et al8 Total
Gender
AIT
Medical therapy
11 Males 4 Females 7 Males 1 Female 5 Males 2 Females 1 Male 24 Males 7 Females
1 Type I 14 Type II 8 Type II
9 Patients (60%)
2 Transient hypocalcemia
1 Patient (12.5%)
1 Delay to extubate
4 Type I 3 Type II 1 Type I 6 Type I 25 Type II
6 Patients (86%)
1 Pneumonia and arrhythmia 1 Arrhythmia 1 Transient hypocalcemia
1 Patient (100%) 17 Patients (54%)
Complication
Table 4. Classification of AIT
Previous thyroid abnormality Mechanism Radioactive iodine uptake Serum interleukin-6
AIT type I
AIT type II
Yes Accelerated hormone synthesis Normal or raised Normal or slightly raised
None Uncontrolled release of preformed hormone Low or absent Profoundly raised
In type I AIT, increased iodine exposure triggers increased hormone synthesis within autonomously functioning areas of the gland, via the Jod-Basedow phenomenon.3,10 In type II AIT, an amiodarone-induced destructive process allows unregulated release of thyroid hormone from damaged follicles.1,3,10 Although this classification may be helpful in deriving a treatment strategy, it does not guarantee the success of a particular treatment regimen (Table 4). Medical management is challenging and not well understood and lacks a proven, consistent therapeutic armamentarium. Ideally, hormoneblocking agents such as PTU, methimazole, and potassium perchlorate are used to treat type I AIT. Antiinflammatory agents (high-dose corticosteroids) are given to patients with type II AIT.3 Many drug regimens do not follow this strategy. No studied regimens have demonstrated reliable success or dosage requirements, and no study has defined the length of therapy needed for successful treatment.1,4,7,10 Most involve long-term therapy with a substantial delay before efficacy and significant side effects. Methimazole requires highdose maintenance and potassium perchlorate, which causes nephrotoxicity and bone marrow suppression, requires a minimum of 8 weeks of therapy. Neither drug (either alone or in combination) is uniformly successful.4 Corticosteroids in-
hibit 5⬘-monodeiodinase activity and can worsen T4 thyrotoxicosis.7 Those interventions, such as plasmapheresis and hemodialysis, which can provide acute relief, produce only transient effects, and are extremely expensive and impractical in the long term.1 In AIT type II, as iodine uptake is usually suppressed, thyroid ablation with radioactive iodine is usually futile. For type I, the full effects of I131 are delayed, and it can induce release of thyroid more hormone, endangering the patient with acute thyrotoxic decompensation.1,6,7 Simply withdrawing amiodarone is not always feasible. Discontinuing the drug can lead to paradoxical worsening of hyperthyroidism and cardiac status. Amiodarone inhibits conversion of T4 to T3 in peripheral tissues and within the pituitary gland.10 Release of the deiodination mechanism through drug withdrawal can result in elevated free T3 production.5 This effect may take up to 8 months to resolve after withdrawal.1,8 Amiodarone is also the only drug effective against resistant, malignant arrhythmias, and discontinuation may not even be an option for the patient. Interestingly, in the reviewed cases, only little more than half had failed prior therapy, with the rest undergoing surgery as the primary therapy. In some cases, this was reported to be due to the sudden severe onset of the disease, but in others, primary surgical management was reported as the
Otolaryngology– Head and Neck Surgery November 2003
570 FRANZESE et al
treatment of choice. In addition, despite the fact that AIT type I is more common, most of the surgical patients reported can be classified as having AIT type II. Whether this is due to the possibility that AIT type II may present in a more sudden or severe fashion or that it is more resistant to medical treatment is unclear. Although the classification system has not changed medical therapy, perhaps it may have some impact on the position of surgery on a practitioner’s treatment algorithm. All cases had total or near-total thyroidectomy. This is recommended, as any remnant tissue poses a risk for future reoccurrences of AIT.5 Although used in 39% of these cases, perioperative -blockers should be avoided because, combined with amiodarone, they may produce profound bradycardia and sinus arrest.10 It is also advisable to avoid volatile, inhalational anesthetics during surgery as these can precipitate arrhythmias in hyperthyroid patients.1 Among reviewed cases, there was minimal morbidity and no perioperative mortality, despite many of these patients being described as critically ill and 2 described as “terminal.” These cases help to demonstrate that surgical management provides a safe and effective treatment option and allows the possibility of continuation of amiodarone. It should be seriously considered as an option for those patients whose conditions necessitate the continuation of amiodarone or those with severe symptoms resistant to medical therapy.3,10 Other surgical candidates might include those patients who are not candidates for medical therapy (brittle diabetics, renal failure) and those controlled with medical therapy but with significant drug side effects. CONCLUSION Amiodarone has recently been placed on the advanced cardiac life support resuscitation guidelines. It is now one of the first-line medications to
be used in unstable ventricular tachycardia and fibrillation. It has also been shown to improve survival rates in patients with heart failure and has gained acceptance as standard therapy in many heart transplant programs. As its use becomes increasingly commonplace, the incidence of AIT will likely increase. Surgical management should play a larger role in AIT treatment algorithms and should be strongly considered for those patients whose conditions necessitate the continuation of amiodarone or those with severe symptoms despite amiodarone withdrawal and resistant to medical therapy. REFERENCES
1. Hamoir E, Meurisse M, Defechereux T, et al. Surgical management of amiodarone-associated thyrotoxicosis: too risky or too effective? World J Surg 1998;22:53742. 2. Weetman AP. Amiodarone-induced thyrotoxicosis: invited commentary. World J Surg 1993;17:627. 3. Bartalena L, Brodioni S, Grasso L, et al. Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: results of a prospective study. J Clin Endocrinol Metab 1996;81:2930-3. 4. Mulligan DC, McHenry CR, Kinney W, et al. Amiodarone-induced thyrotoxicosis: clinical presentation and expanded indications for thyroidectomy. Surgery 1993;114: 1114-9. 5. Meurisse M, Hamoir E, D’Silva M, et al. Amiodaroneinduced thyrotoxicosis: is there a place for surgery? World J Surg 1993;17:622-26. 6. Trip MD, Wiersinga W. Incidence, predictability, and pathogenesis of amiodarone-induced thyrotoxicosis and hypothyroidism. Am J Med 1991;91:507-11. 7. Farwell A, Abend S, Huang SK, et al. Thyroidectomy for amiodarone-induced thyrotoxicosis. JAMA 1990;263: 1526-8. 8. Brennan MD, van Heerden JA, Carney JA. Amiodaroneassociated thyrotoxicosis: experience with surgical management. Surgery 1987;102:1062-7. 9. Newman CM, Price A, Davies DW, et al. Amiodarone and the thyroid: a practical guide to the management of thyroid dysfunction induced by amiodarone therapy. Heart 1998;79:121-7. 10. Brennan MD. Surgical management of amiodarone-associated thyrotoxicosis: invited commentary. World J Surg 1998;22:542-3.
MD,
CHRIS Y. FAN,
MD,
and BRENDAN C. STACK JR,
MD,
Jackson, Mississippi, and Hershey,
Pennsylvania OBJECTIVE: Amiodarone can cause thyroid dysfunction in patients with or without previous thyroid disease. With increased use from its placement in advanced cardiac life support guidelines and cardiac transplant programs, the incidence of amiodarone-induced thyrotoxicosis (AIT) will likely increase. Medical management is complex and nonuniform and frequently fails. This study investigates the role of surgery in AIT and proposes indications for surgical management. STUDY DESIGN AND SETTING: Two AIT case reports at a tertiary care institution and 31 surgical AIT cases in the world literature are reviewed. METHODS: The 2 AIT cases involved patients with cardiomyopathy and resistant arrhythmias. Despite medical therapy, both patients’ conditions failed to improve. Thirty-one surgical cases of AIT in the literature are evaluated with respect to symptoms and onset, medical therapy, AIT classification, pathology, perioperative management, and complications. RESULTS: Both patients underwent total thyroidectomy without difficulty or complication, one as an overnight stay and one as an inpatient with an intraaortic balloon pump. One patient received a successful cardiac transplant and the other remains a viable candidate. In the literature, the majority (80%) of surgical cases are AIT type II (less common type) with no underlying thyroid disease.
From the Department of Otolaryngology–Head and Neck Surgery (Dr Franzese), University of Mississippi Medical Center, and the Division of Endocrinology and Metabolism (Dr Fan) and Division of Otolaryngology–Head and Neck Surgery (Dr Stack), Penn State Milton S. Hershey Medical Center. Presented as a poster at the Annual Meeting of the American Academy of Otolaryngology–Head and Neck Surgery, San Diego, CA, September 22-25, 2002. Reprint requests: Brendan C. Stack, Jr, MD, Division of Otolaryngology–Head and Neck Surgery, H091, Penn State University College of Medicine, 500 University Dr, Hershey, PA 17033; e-mail, [email protected]. Copyright © 2003 by the American Academy of Otolaryngology–Head and Neck Surgery Foundation, Inc. 0194-5998/2003/$30.00 ⫹ 0 doi:10.1016/S0194-5998(03)01590-0
Range and duration of symptoms varied, in addition to type and duration of medical management. Almost all patients underwent total thyroidectomy, and all were successful with no mortality and minimal morbidity. CONCLUSION: AIT can develop in any patient during or after amiodarone therapy. Medical management is extremely difficult due to the absence of a proven therapeutic armamentarium, and surgery offers a safe, viable option. Surgical management should play a larger role in treatment algorithms and should be strongly considered for patients whose conditions necessitate continuation of amiodarone, or with severe symptoms resistant to medical therapy. (Otolaryngol Head Neck Surg 2003; 129:565-70.)
A miodarone, a benzofuranic acid derivative, is used in the treatment of numerous malignant atrial and ventricular tachyarrhythmias.1,2 Although it may reduce cardiac-related mortality and improve survival rates, amiodarone can cause serious thyroid dysfunction in patients with or without previous thyroid disorders.1,3 The molecular structure of amiodarone is similar to that of thyroxine and triiodiothyronine, and its administration greatly expands both systemic and thyroidal iodine pools.1,4 Conventional doses of 300 mg/d provide 10.5 mg of free iodine daily, vastly more than the normal dietary requirement of 0.2 to 0.8 mg/d.5 Amiodarone-induced thyrotoxicosis (AIT) is estimated to develop in 2% to 3% of patients in iodine-sufficient areas and in 10% to 15% or more in iodine-deficient populations.5,6 Although many cases are mild, a significant number become life threatening. Because amiodarone is lipid soluble with a long half-life (ranging from 22 to 60 or more days), simply discontinuing the drug often provides no relief. Due to a release from the inhibitory effect of amiodarone on the 5⬘-monodeiodinase enzyme, withdrawal of the drug can cause a paradoxical worsening of the patient’s condition.1,5 565
Otolaryngology– Head and Neck Surgery November 2003
566 FRANZESE et al
Table 1. Thyroid function tests and imaging results of initial workup Test
Case 1
Case 2
TSH T4 T3 Thyroid ultrasound
⬍0.01 IU/mL ⬎23.0 g/dL 171.0 ng/dL Normal echo texture. No lesions identified. No abnormality of blood flow identified on Doppler evaluation. Left lobe measures 4.7 cm ⫻ 2.2 cm ⫻ 1.8 cm. Right lobe measures 5.2 cm ⫻ 2.3 cm ⫻ 1.9 cm. The thyroid lobes are slightly elongated but normal in size. Less than 0.8% uptake in a 24-hour period
⬍0.01 IU/mL 19.0 g/dL 131.0 ng/dL Thyroid diffusely enlarged. No nodules or lesions identified. Right lobe measures 6.0 cm ⫻ 2.5 cm ⫻ 2.0 cm Left lobe measures 7.0 cm ⫻ 2.0 cm ⫻ 2.0 cm
Radioiodine uptake
Medical management of AIT is a challenge. Available treatment regimens are far from uniform and do not consistently provide success.1,3 There is no accepted standard therapy or uniform pharmaceutical dosage regimen, and the length of therapy remains undefined. Many patients fail medical therapy or cannot discontinue amiodarone because it is the only drug effective against resistant arrhythmias. Total thyroidectomy regimen was reserved as an option of last resort for management, yet a number of AIT cases successfully managed with surgery have been reported. As amiodarone use increases and the incidence of AIT rises, the role of surgery in treatment algorithms should be reconsidered. MATERIALS AND METHODS Case 1 A 55-year-old male heart transplant candidate with dilated cardiomyopathy was admitted after a near-syncopal episode. The patient had a similar previous episode secondary to the new onset of atrial fibrillation. The patient’s rate was controlled and converted to normal sinus rhythm on amiodarone, which he continued. Before his second admission, he began to experience shortness of breath at rest, fatigue, nervousness, tremor, lightheadedness, and occasional chest pain. He had no prior personal or family history of thyroid disease. No abnormalities were demonstrated on thyroid palpation. Electrocardiogram revealed a return to atrial fibrillation. Multiple attempts at cardioversion failed to convert the patient’s rhythm. Thyroid function tests, ultrasound, and radioiodine uptake were
Not performed
consistent with AIT (Table 1). An attempt to withdraw amiodarone resulted in severe bouts of rapid ventricular tachyarrhythmias resistant to other antiarrhythmics, and amiodarone was restarted. Propylthiouracil and high-dose steroids (40 mg/d) for 8 weeks were unsuccessful. The patient’s thyroid function tests remained elevated, and his symptoms continued to worsen. Case 2 A 36-year-old female heart transplant candidate with a history of dilated cardiomyopathy was referred for evaluation as an outpatient for refractory hyperthyroidism. She was currently taking amiodarone due to a history of atrial fibrillation and malignant tachyarrhythmias responsive only to this drug. However, she also had a history of thyroiditis, and amiodarone therapy had caused the return and exacerbation of her symptoms of fatigue, anxiety, tremor, sweating, lightheadedness, and diarrhea. Thyroid function tests and ultrasound were consistent with AIT (Table 1). She elected surgical treatment of her thyrotoxicosis. Literature Review Thirty-one cases of AIT in a total of 8 studies reported in the literature managed surgically are evaluated with respect to type and duration of symptoms, duration of amiodarone therapy, type and duration of medical therapy, pathology and AIT classification, perioperative management, and complications.1,3-5,7,8
Otolaryngology– Head and Neck Surgery Volume 129 Number 5
FRANZESE et al
567
Fig 1. Time course of T3 levels for both cases.
RESULTS Case 1 Despite medical management, the patient’s condition continued to deteriorate with increasingly difficult to control arrhythmias. Because amiodarone was the only drug effective against the arrhythmias, surgical treatment was elected. Preoperatively, an intraaortic balloon pump was placed to assist cardiac output during surgery. The patient underwent a total thyroidectomy. Complete intravenous general anesthesia was administered, with the patient intubated and no inhalational anesthetic agents. There were no operative difficulties or postoperative complications. On pathologic examination, the gland weighed 27 g and demonstrated no gross abnormalities. Histopathology demon-
strated lymphocytic infiltration with evidence of follicular disruption. Within a few days postoperatively, the patient’s condition improved and he was able to be cardioverted successfully to normal sinus rhythm (Fig 1). He remained on amiodarone postoperatively and a few months later underwent a successful cardiac transplant (Table 2). Case 2 Preoperatively, the patient was placed on Lugol’s iodine solution. She underwent total thyroidectomy. Complete intravenous general anesthesia was used similar to case 1, with the patient intubated and no inhalational agents given. The decision was made to perform her surgery as an
Otolaryngology– Head and Neck Surgery November 2003
568 FRANZESE et al
Table 2. Postoperative thyroid function tests Test
Case 1
Case 2
TSH T4
1.2 IU/mL 6.5 g/dL
5.5 IU/mL 3.9 g/dL
outpatient, because her condition was not yet medically unstable and her cardiologist had cleared her for outpatient surgery. However, the cardiology staff and surgical intensive care unit team were on standby during the surgery and postoperatively. There were no operative difficulties or postoperative complications. On pathologic examination, the gland weighed 23 g and also had no gross abnormalities. Histopathology demonstrated fibrosis and follicular destruction associated with numerous macrophages and small foci of lymphocytes. Postoperatively, the patient was observed overnight in the outpatient surgery unit and discharged the next morning. Within a few days, the patient’s symptoms had resolved (Table 2). The patient remains on the cardiac transplant list (Fig 1). Literature Review A male predispostion was demonstrated, with a male-female ratio of approximately 3:1, which is consistent with previous reports.1,3,6 Also, the majority of cases, nearly 80%, can be classified as AIT type II (Table 3). Duration of amiodarone therapy prior to symptoms ranged from 2 to 55 months. type and duration of symptoms varied, with symptoms lasting a few days to 35 months. The most common symptom reported was shortness of breath. The most common finding was new onset or return to an arrhythmia, and the most common arrhythmia was atrial fibrillation. Surprisingly, only 55% (17 patients) received and failed medical therapy, with the other half treated initially by surgery. Of the medical failures, 9 patients (53%) were treated with PTU alone, with dosage ranging from 300 to 1200 mg/d and treatment duration ranging from 2 weeks to 3 months. Seven patients were treated with PTU in combination with another drug (high-dose steriods, -blockers, radioactive iodine) with therapy ranging from 1 to 5 months. Only 1 patient was treated without PTU, using a combination of methimazole and potassium perchlorate for 6 weeks and steroids and iopanioc acid for 4 weeks. Two
patients in the medical failure group were considered “terminal” before surgery. Various reasons were given in regard to decision-making in the 14 patients managed initially with surgery; these included patients with severe, acute onset of symptoms, critically ill patients, patients who declined medical management, and where the surgeon thought that this option was the treatment of choice. An attempt to withdraw amiodarone was made in 15 patients. Three patients had failure and were restarted on the drug due to arrhythmias. Despite successful withdrawal in the other patients, all remained thyrotoxic with symptoms. Twelve patients received preoperative -blockers, with 2 of these patients having severe bradycardia. All except 8 patients underwent total thyroidectomy. These 8 patients had subtotal thyroidectomy. All cases used general intravenous anesthesia, and all patients experienced dramatic symptom improvement after surgery. Postoperatively, 3 patients experienced transient hypocalcemia, 2 patients had short-lived arrhythmias, 1 patient had a delayed extubation, and 1 patient had pneumonia. There were no perioperative deaths. However, there was 1 death 4 months postoperatively from ventricular arrhythmia despite continued amiodarone therapy. DISCUSSION AIT can develop any time during or after amiodarone therapy, although it is more commonly seen in patients in iodine-deficient locales and patients with underlying thyroid pathology. AIT can generally be classified into 1 of 2 major forms, although mixed types are thought to exist. AIT type I occurs in patients with previously known or documented abnormal thyroid glands (nodular goiter, Graves’ disease, etc) and is secondary to excessive hormone production.3 AIT type II affects an apparently normal gland and is the result of uncontrolled release of preformed hormone3 (Table 4). This classification scheme is based on the patient’s past medical history, past physical examinations, and past laboratory/ultrasound examinations, if any. It does not take into account postoperative pathology, as the great majority of patients with AIT do not, at present, undergo surgery.9 The pathogenesis of the 2 forms is thought to take place through different mechanisms of action.
Otolaryngology– Head and Neck Surgery Volume 129 Number 5
FRANZESE et al 569
Table 3. Summary of reviewed case results Study
Hamior et al1 Brennan7 Mulligan et al4 Farwell et al8 Total
Gender
AIT
Medical therapy
11 Males 4 Females 7 Males 1 Female 5 Males 2 Females 1 Male 24 Males 7 Females
1 Type I 14 Type II 8 Type II
9 Patients (60%)
2 Transient hypocalcemia
1 Patient (12.5%)
1 Delay to extubate
4 Type I 3 Type II 1 Type I 6 Type I 25 Type II
6 Patients (86%)
1 Pneumonia and arrhythmia 1 Arrhythmia 1 Transient hypocalcemia
1 Patient (100%) 17 Patients (54%)
Complication
Table 4. Classification of AIT
Previous thyroid abnormality Mechanism Radioactive iodine uptake Serum interleukin-6
AIT type I
AIT type II
Yes Accelerated hormone synthesis Normal or raised Normal or slightly raised
None Uncontrolled release of preformed hormone Low or absent Profoundly raised
In type I AIT, increased iodine exposure triggers increased hormone synthesis within autonomously functioning areas of the gland, via the Jod-Basedow phenomenon.3,10 In type II AIT, an amiodarone-induced destructive process allows unregulated release of thyroid hormone from damaged follicles.1,3,10 Although this classification may be helpful in deriving a treatment strategy, it does not guarantee the success of a particular treatment regimen (Table 4). Medical management is challenging and not well understood and lacks a proven, consistent therapeutic armamentarium. Ideally, hormoneblocking agents such as PTU, methimazole, and potassium perchlorate are used to treat type I AIT. Antiinflammatory agents (high-dose corticosteroids) are given to patients with type II AIT.3 Many drug regimens do not follow this strategy. No studied regimens have demonstrated reliable success or dosage requirements, and no study has defined the length of therapy needed for successful treatment.1,4,7,10 Most involve long-term therapy with a substantial delay before efficacy and significant side effects. Methimazole requires highdose maintenance and potassium perchlorate, which causes nephrotoxicity and bone marrow suppression, requires a minimum of 8 weeks of therapy. Neither drug (either alone or in combination) is uniformly successful.4 Corticosteroids in-
hibit 5⬘-monodeiodinase activity and can worsen T4 thyrotoxicosis.7 Those interventions, such as plasmapheresis and hemodialysis, which can provide acute relief, produce only transient effects, and are extremely expensive and impractical in the long term.1 In AIT type II, as iodine uptake is usually suppressed, thyroid ablation with radioactive iodine is usually futile. For type I, the full effects of I131 are delayed, and it can induce release of thyroid more hormone, endangering the patient with acute thyrotoxic decompensation.1,6,7 Simply withdrawing amiodarone is not always feasible. Discontinuing the drug can lead to paradoxical worsening of hyperthyroidism and cardiac status. Amiodarone inhibits conversion of T4 to T3 in peripheral tissues and within the pituitary gland.10 Release of the deiodination mechanism through drug withdrawal can result in elevated free T3 production.5 This effect may take up to 8 months to resolve after withdrawal.1,8 Amiodarone is also the only drug effective against resistant, malignant arrhythmias, and discontinuation may not even be an option for the patient. Interestingly, in the reviewed cases, only little more than half had failed prior therapy, with the rest undergoing surgery as the primary therapy. In some cases, this was reported to be due to the sudden severe onset of the disease, but in others, primary surgical management was reported as the
Otolaryngology– Head and Neck Surgery November 2003
570 FRANZESE et al
treatment of choice. In addition, despite the fact that AIT type I is more common, most of the surgical patients reported can be classified as having AIT type II. Whether this is due to the possibility that AIT type II may present in a more sudden or severe fashion or that it is more resistant to medical treatment is unclear. Although the classification system has not changed medical therapy, perhaps it may have some impact on the position of surgery on a practitioner’s treatment algorithm. All cases had total or near-total thyroidectomy. This is recommended, as any remnant tissue poses a risk for future reoccurrences of AIT.5 Although used in 39% of these cases, perioperative -blockers should be avoided because, combined with amiodarone, they may produce profound bradycardia and sinus arrest.10 It is also advisable to avoid volatile, inhalational anesthetics during surgery as these can precipitate arrhythmias in hyperthyroid patients.1 Among reviewed cases, there was minimal morbidity and no perioperative mortality, despite many of these patients being described as critically ill and 2 described as “terminal.” These cases help to demonstrate that surgical management provides a safe and effective treatment option and allows the possibility of continuation of amiodarone. It should be seriously considered as an option for those patients whose conditions necessitate the continuation of amiodarone or those with severe symptoms resistant to medical therapy.3,10 Other surgical candidates might include those patients who are not candidates for medical therapy (brittle diabetics, renal failure) and those controlled with medical therapy but with significant drug side effects. CONCLUSION Amiodarone has recently been placed on the advanced cardiac life support resuscitation guidelines. It is now one of the first-line medications to
be used in unstable ventricular tachycardia and fibrillation. It has also been shown to improve survival rates in patients with heart failure and has gained acceptance as standard therapy in many heart transplant programs. As its use becomes increasingly commonplace, the incidence of AIT will likely increase. Surgical management should play a larger role in AIT treatment algorithms and should be strongly considered for those patients whose conditions necessitate the continuation of amiodarone or those with severe symptoms despite amiodarone withdrawal and resistant to medical therapy. REFERENCES
1. Hamoir E, Meurisse M, Defechereux T, et al. Surgical management of amiodarone-associated thyrotoxicosis: too risky or too effective? World J Surg 1998;22:53742. 2. Weetman AP. Amiodarone-induced thyrotoxicosis: invited commentary. World J Surg 1993;17:627. 3. Bartalena L, Brodioni S, Grasso L, et al. Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: results of a prospective study. J Clin Endocrinol Metab 1996;81:2930-3. 4. Mulligan DC, McHenry CR, Kinney W, et al. Amiodarone-induced thyrotoxicosis: clinical presentation and expanded indications for thyroidectomy. Surgery 1993;114: 1114-9. 5. Meurisse M, Hamoir E, D’Silva M, et al. Amiodaroneinduced thyrotoxicosis: is there a place for surgery? World J Surg 1993;17:622-26. 6. Trip MD, Wiersinga W. Incidence, predictability, and pathogenesis of amiodarone-induced thyrotoxicosis and hypothyroidism. Am J Med 1991;91:507-11. 7. Farwell A, Abend S, Huang SK, et al. Thyroidectomy for amiodarone-induced thyrotoxicosis. JAMA 1990;263: 1526-8. 8. Brennan MD, van Heerden JA, Carney JA. Amiodaroneassociated thyrotoxicosis: experience with surgical management. Surgery 1987;102:1062-7. 9. Newman CM, Price A, Davies DW, et al. Amiodarone and the thyroid: a practical guide to the management of thyroid dysfunction induced by amiodarone therapy. Heart 1998;79:121-7. 10. Brennan MD. Surgical management of amiodarone-associated thyrotoxicosis: invited commentary. World J Surg 1998;22:542-3.