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Severe Hyperthyroidism Complicated by Agranulocytosis Treated with Therapeutic Plasma Exchange: Case Report and Review of the Literature.

1. Introduction

Hyperthyroidism 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.

References

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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
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