Severe Hyperthyroidism Complicated by Agranulocytosis Treated with Therapeutic Plasma Exchange: Case Report and Review of the Literature.
1. IntroductionHyperthyroidism is an overproduction and persistent release of thyroid hormones, while thyrotoxicosis refers to the set of clinical manifestations secondary to excessive thyroid hormone action on the tissues [1]. Conventionally thyrotoxicosis is treated medically using agents which inhibit the synthesis and release of thyroid hormones [2]. TPE was first used as a modality in the treatment of hyperthyroidism in the 1970s; however, till this date the role of TPE in the treatment of hyperthyroidism is unclear [3, 4].
We present a case of Graves' disease complicated by agranulocytosis treated with TPE along with a pertinent review of the literature.
2. Case Description
A 21-year-old male patient presented to the emergency department with neck pain and dysphagia. He had been diagnosed with Graves' disease about 4 years ago; however, he was not taking any medication for the last 2 years. Upon further enquiry, the patient admitted to a history of weight loss, palpitations, tremors, and lack of sleep. Vital signs showed a heart rate of 130/minute, blood pressure of 132/67 mm Hg, respiratory rate of 18/minute, and temperature of 97.8. Examination revealed an anxious patient with bilateral lid lag, large smooth goiter with a thyroid bruit, and tremors of upper extremities. Laboratory assessment revealed a suppressed TSH, high free t4, free t3, positive antithyrotropin receptor antibodies (TRab), and thyroid stimulating immunoglobulin (TSI) confirming the diagnosis of Graves' disease (Table 1). Ultrasound of the neck showed an enlarged hypervascular thyroid gland consistent with Graves' disease. Methimazole and atenolol were started. Thyroidectomy was planned to be done once the thyroid function tests normalized. The patient was discharged from the hospital and was to follow up in the endocrine clinic in 1 month. Upon follow-up in the endocrine clinic, the patient admitted that he had been noncompliant with his medications for a week. He also complained of heat intolerance, weight loss, insomnia, palpitations, and a sore throat. Again noted on exam were tachycardia, a smooth goiter with bruit, tremors, and hyperactive reflexes in all extremities. TSH was suppressed, free t4 and total t3 were high, and complete blood count showed a low white blood cell count (WBC) and low absolute neutrophil count. A diagnosis of methimazole induced agranulocytosis was made and the patient was admitted to the hospital.
Hematology was consulted for TPE to control hyperthyroidism and also administration of filgrastim for neutropenia. Three treatments of plasma exchanges were done 2 days apart. The replacement fluid used was half albumin and half plasma. Filgrastim was administered daily. WBC and neutrophil counts improved significantly and normalized. Patient continued to improve clinically and his free t4, previously in the unmeasurable range, did come down. Thyroidectomy was done and pathology revealed an enlarged thyroid with diffuse hyperplasia. Postoperatively, he developed hypocalcemia and was treated with calcium carbonate. Levothyroxine was started for the treatment of postsurgical hypothyroidism. Upon follow-up, a month later in the endocrine clinic, the patient was doing well on levothyroxine.
3. Methods and Results
We searched PubMed using the following key words: hyperthyroidism and plasmapheresis. We restricted our search to publications in "English" and involving "human subjects." Abstract of meetings and unpublished results were not included in our study. The last search was done on 6/27/2017.
The initial search resulted in 91 articles; 64 articles were excluded based on the title and abstract. Eligibility criteria were those articles which used TPE to treat hyperthyroidism. 27 articles met the inclusion criteria and were included (Table 2) [4-30].
4. Discussion
Thyroxine (T4) has the highest concentration among iodothyronines in the plasma and is produced exclusively by the thyroid; triiodothyronine (T3) is primarily derived (about 80%) from the peripheral tissues by deiodination of T4. T4 is about 68% bound to thyroxine binding globulin (TBG), 11% to transthyretin, and 20% to albumin. T3 is 80% bound to TBG, 9% to transthyretin, and 11% to albumin [1]. This extensive protein binding aids in the clearance of thyroid hormones during therapeutic plasma exchange (TPE) [31].
TPE is an extracorporeal blood purification technique used to for eliminating large molecular substances from the plasma [30]. In contrast to dialysis which cannot clear protein bound substances, TPE can clear protein bound substances [13]. The process involves passing the patient's blood through a medical device and separating the plasma out; it is then replaced with a colloid (albumin or plasma) or a combination of crystalloid and colloid. TPE clears thyroid hormones which are protein bound; the colloid used to replace the plasma provides new binding sites for thyroid hormone which are cleared during the next TPE session [6]. Besides thyroid hormones, TPE may help in the clearance of cytokines, deiodinase enzyme, and Graves' antibodies which help not only in the resolution of thyrotoxicosis but also of Graves' ophthalmopathy and pretibial myxedema [31].
There are a number of replacement fluids available, plasma as a replacement fluid offers the advantage of not depleting coagulation factors and also replenishing thyroxine binding globulin [20]. Human albumin offers the advantage of having a larger pool of low affinity binding sites for thyroid hormone [9]. We recommend plasma as the replacement fluid in patients with coagulation disorders or those who are going for surgery.
TPE was first used for the treatment of hyperthyroidism in 1970 by Ashkar et al. on 3 cases of thyroid storm [4]. Our literature review showed that TPE was used in 16 cases not responding to standard treatment, 13 cases of agranulocytosis or other side effects of thionamides, 8 cases of amiodarone induced thyrotoxicosis, and 5 cases for preparation of thyroidectomy. Petry et al. used TPE for the treatment of thyroid storm in postsleeve pneumonectomy patient who did not respond to the conventional treatment and thyroidectomy was considered high risk [22]. Jha et al. reported a case of thyroid storm secondary to excessive consumption thyroid supplements successfully treated with TPE. TPE was particularly useful as the patient had been taking excessive supplements for six days making the use of gastric decontamination and cholestyramine less useful [30].
Lew et al. used double filtration plasmapheresis (DFPP) in a patient with Graves' disease who needed surgical debridement. DFPP is a process where the plasma is first separated from the blood and then large molecules like immunoglobulins and lipoproteins are removed. The advantage would be lesser removal of coagulation factors making it useful in a patient who has to undergo surgery; however, small molecules may not be removed effectively by this procedure[11]. Koball et al. used a single pass albumin dialysis (SPAD) in a patient who had no clinical improvement after two sessions of plasmapheresis. Albumin dialysis has been used to eliminate toxins which accumulate in liver failure. The authors hypothesized that since this was a continuous procedure it would be effective in removing a greater quantity of hormone from the blood. It was also noted that if the plasmapheresis was followed by SPAD it decreased the chance of rebound increase of thyroid hormones [13].
The American society of apheresis categorizes the use of TPE in the treatment of hyperthyroidism as category III which states that the role of TPE has not been established in the treatment of thyroid storm. The recommended frequency of treatment is daily to once in three days till clinical improvement is noted [3].
TPE in the treatment of hyperthyroidism can be used when conventional treatment is not working or contraindicated. As noted in our literature review, it can be used in a variety of scenarios with clinical and biochemical improvement. Limitations of TPE include lack of wide spread availability, potential for hemodynamic instability, and the risk of infections.
5. Conclusions
In summary, TPE is a useful adjunct in the treatment of hyperthyroidism; its use is suggested in cases with severe thyrotoxicosis with cardiac or neurological complications, or when standard antithyroid treatments are either unresponsive or contraindicated. It is also a useful adjunct in treating cases with levothyroxine overdose. TPE should be done daily till clinical improvement is noted. Thyroid hormone status is monitored by checking free t4 and free t3 before and after every TPE session; however, clinical and biochemical dissociation may exist. More research is needed into the usefulness of DFPP and SPAD in the treatment of hyperthyroidism.
https://doi.org/10.1155/2018/4135940
Conflicts of Interest
The authors declare that there are no conflicts of interest regarding the publication of this paper.
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Vishnu Garla, Karthik Kovvuru, Shradha Ahuja, Venkatataman Palabindala, Bharat Malhotra, and Sohail Abdul Salim
Department of Internal Medicine, University of Mississippi Medical Center, Jackson, MS, USA
Correspondence should be addressed to Vishnu Garla; vishnu.garla@gmail.com
Received 1 October 2017; Accepted 17 December 2017; Published 10 January 2018
Academic Editor: Osamu Isozaki
Table 1: Laboratory assessment on admission.
TSH (0.27-4.2 mcIu/ml) <0.01
Free t4 (0.9-1.7 ng/dl) >7.77
Free t3 (0.8-2.0 ng/ml) >6.51
WBC (4000-11,000 cells/cumm) 2.1
Absolute neutrophil count 0.4
TRab (0-1.75 IU/L) 26
TSI (0-1.3) 5.5
Table 2: Literature review.
Authors Cases Indication
Kaderli et al. 3 Amiodarone induced
thyrotoxicosis
Min et al. 1 Graves' disease
Aydemir et al. 1 Graves' disease
Bilir et al. 1 Graves' disease
Carhill et al. 2 Graves' disease
Vyas et al. 1 Exogenous
intoxication
Lew et al. 1 Graves' disease
Enghofer et 1 Graves' disease
al.
Koball et al. 1 Unknown
Ezer et al. 11 (7) Graves'
disease
(3) Toxic
multinodular
goiter
(1) Iodine induced
thyrotoxicosis
Adali et al. 1 Gestational
hyperthyroidism
sec to molar
pregnancy
Pasimeni et 1 Contrast induced
al. hyperthyroidism
Azezli et al. 1 Gestational
hyperthyroidism
sec to molar
pregnancy
Erbil et al. 1 Gestational
hyperthyroidism
sec to molar
pregnancy
Guvenc et al. 1 Toxic multinodular
goiter
Ozbey et al. 4 Graves' disease
Diamond et al. 3 Amiodarone
induced
thyrotoxicosis
Petry et al. 1 Graves' disease
Ozdemir et al. 1 Hyperthyroidism
Segers et al. 5 Thyrotoxicosis
Ligtenberg et Preparation for
al. surgery
Samaras et al. 1 Amiodarone
induced
thyrotoxicosis
Aghini- 2 Amiodarone
Lombardi et induced
al. thyrotoxicosis
De Rosa et al. 1 Hyperthyroidism
Binimelis et 6 Levothyroxine
al. intoxication
Jha et al. 1 Medicinal thyroid
overdose
Ashkar et al. 3 Hyperthyroidism
Authors Indication for Outcome
plasmapheresis
Kaderli et al. Amiodarone induced Underwent
thyrotoxicosis thyroidectomy
Min et al. Elevated liver Biochemical
function tests improvement with
about 40% decrease
in total T3
Aydemir et al. Jaundice Biochemical
improvement with
greater than 60%
decrease in FT4
and FT3
Bilir et al. Drug induced Underwent
angioneurotic thyroidectomy
edema
Carhill et al. (1) Increase in Clinical and
transaminases biochemical
(2) Unresponsive to improvement
standard treatment
Vyas et al. Exogenous etiology Clinical and
biochemical
improvement
Lew et al. Agranulocytosis Clinical and
and biochemical
hemophagocytosis improvement with
greater than 80%
decrease in FT4
and FT3
Enghofer et Fulminant Underwent
al. hepatitis thyroidectomy
Koball et al. Preparation for Clinical and
urgent biochemical
thyroidectomy improvement
Ezer et al. (7) Unresponsive to Clinical
standard treatment improvement noted
(3) Agranulocytosis
(1) Emergent
preparation
for thyroidectomy
Adali et al. Emergent Biochemical
preparation for improvement with
thyroidectomy >80% decrease in
FT3 and >75%
decrease in FT4
Pasimeni et Unresponsive to Clinical and
al. methimazole biochemical
improvement
Azezli et al. Preparation for Clinical and
emergent biochemical
thyroidectomy improvement with
75.1% decrease in
free t3 and 63.1%
decrease in free
t4
Erbil et al. Unresponsive to Biochemical
propylthiouracil improvement
Guvenc et al. Agranulocytosis Clinical and
biochemical
improvement
Ozbey et al. (1) Agranulocytosis Decrease in TT3 by
(1) PTU induced about 40-78% and
vasculitis FT4 by >69%
(1) Drug induced
urticarial
(1) Hepatotoxicity
Diamond et al. Unresponsive to Clinical improve-
standard treatment ment in 2 patients
Mild decrease in
the FT4
Petry et al. Status after Clinical and
sleeve biochemical
pneumonectomy improvement
Ozdemir et al. Unresponsive to Clinical and
standard treatment biochemical
improvement with
60% decrease in
FT4 and 75%
decrease in FT3
Segers et al. Thyrotoxicosis Clinical
improvement.
Decrease in FT3 of
63.5% and FT4 by
57.8%
Ligtenberg et Preparation for Decrease in FT3
al. surgery of 7% and 18%
Decrease in FT4
of 0% and 33%
Samaras et al. Unresponsive to Failure of
standard treatment treatment
resulting in death
of the patient
Decrease in TT3
and TT4 noted
after TPE with
rebound increase
in levels later
Aghini- Adjunct to Decrease in FT4
Lombardi et methimazole and FT3
al. Normalization of
TT4 and TT3
De Rosa et al. Agranulocytosis Biochemical
improvement with 51%
decrease in FT3, 47%
decrease in FT4, 60%
decrease in TT3, and
53% decrease in TT4
Binimelis et Cardiac and Clinical and
al. neurological biochemical
symptoms improvement in 15
days
Jha et al. Medicinal thyroid Clinical and
overdose biochemical
improvement with
43% decrease in
TT4 and 68%
decrease in TT3
Ashkar et al. Severe Clinical
hyperthyroidism improvement in 2-
3 days
Ft4: free thyroxine, Ft3: free triiodothyronine, TT4: total thyroxine,
TT3: total triiodothyronine, and TPE: therapeutic plasma exchange.
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| Title Annotation: | Case Report |
|---|---|
| Author: | Garla, Vishnu; Kovvuru, Karthik; Ahuja, Shradha; Palabindala, Venkatataman; Malhotra, Bharat; Salim, |
| Publication: | Case Reports in Endocrinology |
| Date: | Jan 1, 2018 |
| Words: | 3219 |
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