- Email: [email protected]
The results of therapeutic plasma exchange in patients with severe hyperthyroidism: A retrospective multicenter study
Transfusion and Apheresis Science 48 (2013) 327–330
Contents lists available at SciVerse ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
The results of therapeutic plasma exchange in patients with severe hyperthyroidism: A retrospective multicenter study Muzaffer Keklik a,⇑, Leylagul Kaynar b, Mehmet Yilmaz b, Serdar Sivgin a, Musa Solmaz a, Cigdem Pala a, Sulbiye Aribas c, Gulsah Akyol a, Kursat Unluhizarci c, Mustafa Cetin a, Bulent Eser a, Ali Unal a a b c
Erciyes University, Department of Hematology and Apheresis Unit, 38039 Kayseri, Turkey Gaziantep University, Department of Hematology, Gaziantep, Turkey Erciyes University, Department of Endocrinology, Kayseri, Turkey
a r t i c l e
i n f o
Keywords: Hyperthyroidism Therapeutic plasma exchange
a b s t r a c t Hyperthyroidism characterized by elevated serum levels of circulating thyroid hormones. The aim of hyperthyroidism treatment is to achieve a euthyroid state as soon as possible and to maintain euthyroid status. However, drug withdrawal and utilization of alternative therapies are needed in cases in which leucopenia or impairment in liver functions is observed during medical therapy. In the present study, we aimed to present our cases which underwent therapeutic plasma exchange (TPE) due to severe hyperthyroidism. The results of 22 patients who underwent therapeutic plasma exchange due to hyperthyroidism in Apheresis Units of Erciyes University and Gaziantep University, between 2006 and 2012, were retrospectively reviewed. These cases had severe thyrotoxic values despite anti-thyroid drug use. After TPE, we observed a significant decrease in free thyroxin (FT4) (p < 0.001) and free triiodotyhronin (FT3) (p < 0.004) levels. There was statistically significant increase in the mean values of TSH levels after TPE (p < 0.001). Clinical improvement was achieved in hyperthyroidism by TPE in 20 cases (91%). Both FT3 and FT4 levels remained above the normal limits in two of 22 patients. TPE should be considered as an effective and safe therapeutic option to achieve euthyroid state before surgery or radioactive iodine treatment. TPE is a useful option in cases with severe hyperthyroidism unresponsive to anti-thyroid agents and in those with clinical manifestations of cardiac failure and in patients with severe adverse events during anti-thyroid therapy. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Endocrine and metabolic emergencies are relatively common conditions in acute care medicine [1]. Severe hyperthyroidism is a life-threatening condition. Graves’ disease, toxic adenoma and multi-nodular goiter are the most commonly encountered causes of hyperthyroidism. In most instances, the excessive production of thyroid hormones by the thyroid gland is the major cause of severe hyperthyroidism. The three most common treatments for ⇑ Corresponding author. E-mail address: [email protected] (M. Keklik). 1473-0502/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.transci.2013.04.010
hyperthyroidism are antithyroid drugs, radioactive iodine (RAI), and thyroidectomy [2,3]. The acute phase must be treated with standart treatments such as thiamazole, prednisolone, and nonselective beta-blockers. In patients with severe hyperthyroidism, further therapies are needed to restore euthyroid hormone status. Therapeutic plasma exchange (TPE) is an alternative treatment that has been proposed since the 1970s for hyperthyroidism [4–7]. TPE removes protein-bound substances including thyroid hormones. This retrospective study was performed as an analysis of our experience with TPE with regard to treatment outcomes and complications in adult patients with severe hyperthyroidism.
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M. Keklik et al. / Transfusion and Apheresis Science 48 (2013) 327–330
2. Patients and methods We retrospectively reviewed records of patients who were treated with TPE between 2006 and 2012 for severe hyperthyroidism at Apheresis Units of Erciyes and Gaziantep University. The list of patients was obtained from the TPE log-book of the apheresis units in our facility. These cases had severe thyrotoxic values despite anti-thyroid drug use. Data on demographics, etiologies of hyperthyroidism, thyroid hormone status (before and after TPE), TPE sessions were analyzed. Procedural complications and outcome are recorded. The reference ranges for the laboratory indices were 8.00–20.00 pg/mL for free thyroxin (FT4), 2.20–4.70 pg/ mL for free triiodothyronin (FT3), and 0.20–3.20 IU/mL for thyroid stimulating hormone (TSH). Fresh frozen plasma (FFP) was used in all cases as replacement fluid. TPE was performed via central venous access by using Fresenius ASTEC 204 device (Fresenius Com.Tec, Germany). TPE was carried out at the predicted plasma volume for 1.3 times every other day. Plasma volumes were calculated for each patient using the patient’s body surface area, sex, and hematocrit. Vital signs were monitored at the beginning and end of each procedure, and patients were monitored for adverse events during apheresis procedures. Serum FT3, FT4 and TSH levels were measured at 6 h after TPE sessions. In order to avoid severe hypocalcaemia during the TPE, all patients received an intravenous infusion of 10% calcium gluconate. Written informed consent was obtained from all patients after procedural risks were explained in detail before each procedure. Each session lasted for 2 h. Analysis were performed using SPSS 20.0 (IBM, Chicago) with considering a p < 0.05 statistically significant. Shapiro–Wilk’s test was used to check the data normality. To compare the differences of thyroid hormone levels before and after TPE, Wilcoxon t test was used.
3. Results Of the 22 patients, 16 (72.8%) were women and 6 (27.2%) were men. Median age was 47 (range: 22–74) years. Of these cases, there were nine cases with Graves’ disease and 13 cases with multi-nodular goiter. All cases had palpitation while there was tachycardia in 14 cases; sweating in 16 cases and tremor in 12 cases. Drugs were withdrawn by
the attending clinicians because of severe hepatotoxicity related to anti-thyroid drugs in 8 cases and leucopenia in 12 cases. Drugs were withdrawn by patients due to arthralgia in two cases. All patients received b-receptor antagonist and steroid drugs. Twenty-two patients received a total of 88 procedures. The median number of apheresis sessions was four (range: 2–9). The median processed plasma volume was 3000 mL (range: 1800–4000) for each cycle. Overall response to TPE was seen in 20/22 (91%) patients. No response to TPE was seen in two patients (9%). Table 1 lists laboratory data pre and post TPE. Table 2 lists pre and post procedural levels of thyroid hormones. The mean thyroid hormone concentrations (the mean ± SD) before TPE for FT3, FT4 and TSH were 17.25 ± 15 pg/mL, 34.31 ± 21 pg/mL and 0.03 ± 0.04 IU/mL, respectively. In neither case the process was terminated because of adverse events. Complications were mild and consisted of hypotension and hypocalcemia. Hypotension episodes occurred in five patients and hypocalcemia was observed in four patients. There was no catheter related complication such as hematoma, infection or thrombosis. Clinical improvement was achieved in 20 cases (91%); subsequently, RAI and surgery was performed to achieve permanent cure in 15 and five cases, respectively. After TPE, the mean FT3, FT4 and TSH levels were 5.34 ± 4 pg/ mL, 15.86 ± 14 pg/mL and 1.02 ± 1 IU/mL, respectively. There was statistically significant decrease in the mean values of FT3 (p < 0.001) and FT4 (p < 0.004) levels after TPE. We observed significant increase in the mean values of TSH levels after TPE (p < 0.001). Thyroid hormone levels remained high in two cases, one of these cases died as result of complicating the tachyarrhythmia following myocardial infarction. Her illness was toxic multi-nodular goiter and she was 60 years old (patient 5). For the other case (patient 6), a second TPE was performed, which again resulted only in minor and temporally improvement. Despite TPE, this patient had symptoms of thyrotoxicosis such as palpitation, tachycardia, tremor and sweating. She was diagnosed with Graves’ disease and antithyroid medication was withdrawn by the attending clinician because of arthralgia. Following antithyroid and nonsteroidal anti-inflammatory drugs she recovered. 4. Discussion Thyrotoxicosis is characterized by extremely elevated serum levels of circulating thyroid hormones leading to
Table 1 Laboratory data for therapeutic plasma exchange. Variables
Pretreatment, median (range)
Posttreatment, median (range)
p Value
Normal ranges
Hb (g/dl) WBC (103/lL) Plt (103/lL) BUN (mg/dl) Cre (mg/dl) AST (u/L) ALT (u/L) Ca (mg/dl) Alb (g/dl)
11.7 (8.2–15.3) 4.66 (1.30–34.12) 185 (64–392) 12.5 (7–48) 0.65 (0.40–1.44) 31.5 (18–1813) 39 (14–2339) 9.5 (8–10.7) 3.8 (2.8–4.6)
11.4 (7.9–13.6) 6.75 (0.6–28.3) 220 (77–412) 15 (9–39) 0.70 (0.40–1.09) 34 (17–66) 38 (16–80) 9.4 (7.9–10.6) 3.6 (3–4.1)
0.244 0.085 0.903 0.329 0.886 0.566 0.186 0.216 0.158
12–18 4.8–10.8 130–400 7.9–21 0.84–1.44 0–35 0–45 8.8–10.6 3.5–5.2
Abbreviations: Hb hemoglobin, WBC white blood cells, Plt platelet count, BUN blood urea nitrogen, Cre creatinine, AST aspartate transaminase, ALT alanine transaminase, Ca calcium, Alb albumin.
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M. Keklik et al. / Transfusion and Apheresis Science 48 (2013) 327–330 Table 2 Thyroid hormone levels before and after therapeutic plasma exchange. Patient
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Before TPE
After TPE
FT3 (pg/mL)
FT4 (pg/mL)
TSH (IU/mL)
FT3 (pg/mL)
FT4 (pg/mL)
TSH (IU/mL)
6.08 6.73 4.35 28.43 14.51 6.40 3.10 14.68 13.97 14.70 12.61 3.80 69.73 28.68 15.29 16.30 22.90 26.80 14.50 16.73 26.54 12.86
18.22 50.76 25.65 62.47 58.44 37.50 13.41 62.68 33.04 44.10 54.50 3.02 4.83 49.10 3.56 4.37 49.80 52.90 47.45 5.86 38.10 35.12
.16 .10 .01 .05 .01 .04 .04 .01 .06 .01 .02 .01 .01 .01 .01 .01 .01 .04 .01 .01 .01 .02
4.34 2.54 5.59 2.45 14.20 6.10 3.07 3.89 .91 4.20 5.27 9.17 13.45 2.12 12.38 2.41 3.10 4.80 3.30 3.65 8.24 2.47
15.37 11.06 25.90 14.76 47.20 51.20 12.91 15.20 3.68 23.10 38.50 3.78 6.47 9.80 3.14 1.46 13.40 16.70 17.20 2.34 6.45 9.35
.24 2.71 .27 .03 .01 .02 .10 5.72 4.85 .01 .12 .01 .03 .15 .10 .02 .04 .05 4.56 .15 .10 3.35
Abbreviations: TPE: therapeutic plasma exchange, FT4: free thyroxin, FT3: free triiodothyronin, TSH: thyroid stimulating hormone.
multisystem disease. Even with treatment, mortality stays high at approximately 30% [8]. It is difficult to estimate its exact incidence because no definitive and universally-accepted criteria exist for establishing the diagnosis, and in most cases, the results of laboratory tests are indistinguishable from those observed in patients with otherwise uncomplicated thyrotoxicosis [1]. But it is believed that thyrotoxicosis is less frequent nowadays than in the past, it may account for <1–2% of hospital admissions [9]. All patients with severe hyperthyroidism should be treated in an intensive care unit setting, given the profound disturbances in temperature, cardiovascular function, fluid and electrolyte balance. Therapeutic intervention has a fourfold aim: to reduce the production and secretion of thyroid hormones from the thyroid gland; to antagonize the peripheral action of thyroid hormones; to reverse systemic disturbances; and to address the precipitating event [1]. Antithyroid treatment options include medical therapy (propylthiouracil and methimazole), RAI and surgery. Medical treatments including antithyroid drugs usually achieve euthyroidism effectively. Thyroidectomy is performed in special circumstances such as poor response to antithyroid drugs, suspicious cytology, iodine-induced thyrotoxicosis, and upon patient’s request. But in patients who had elevated thyroid hormones should be rendered euthyroid before surgical procedures to prevent the side effects of hyperthyroidism [10,11]. TPE is an additional tool for removing circulating thyroxine in patients who do not respond quickly to conventional therapy [12]. TPE has been shown to have a clear benefit in the severe hyperthyroidism induced by Graves’ disease and multinodular goiter [6,13,14]. In our study, there were nine cases with Graves’ disease. Except one patient (case 6), all Graves’ disease patients recovered by TPE. We also treated 13 cases with multi-nodular goiter. Except one patient (case 5), clinical improvement was achieved in hyperthyroidism by TPE in
12 cases with multinodular goiter. The therapeutic benefit of TPE results from the removal of the pathological substances from the thyroid storm: hormones, cytokines, toxins, and so on. TPE also removes 50 -monodesiodase which converts T4 to T3 and this decreases T3 production [15]. However, this effect is usually transient and thyroid hormone levels increase within few days after TPE [16–18]. So, in our study, five patients underwent thyroid surgery and 15 patients received RAI treatment for permanent cure. Plasma or human albumin solutions provide new binding sites for circulating free hormones. In our study, fresh frozen plasma was used in all cases as replacement fluid. TPE is a recommendation of grade IIc and a category III in the last American Society for Apheresis (ASFA) guideline [8]. TPE should be conducted as early as possible in order to be efficient. TPE is a relatively safe method of treatment, providing it is performed by experienced staff and used for appropriate indications with all necessary precautions [19]. Side effects include transfusion reaction, citrate-related nausea and vomiting, vasovagal or hypotensive reactions, hypocalcemia, catheter dysfunction, bleeding, respiratory distress, and tetany or seizure. Death is rare and usually due to the underlying disease [20]. Our patient (case 5) died complicating the tachyarrhythmia in the course of myocardial infarction. Other complications consisted of hypotension (n: 5) and citrate related hypocalcemia (n: 4). These complications were mild. All of the hypotensive episodes and hypocalcemia were resolved briefly after intravenous infusion of saline or further calcium infusion. TPE for treatment of severe hyperthyroidism may be complicated by infections [21]. In the present study, there was no catheter related complication such as infection or bleeding. In conclusion, TPE is an effective treatment option for patients with severe hyperthyroidism. However, it has a transitory effect and thus several sessions should be performed, and it should be combined with other measures.
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References [1] Sarlis NJ, Gourgiotis L. Thyroid emergencies. Rev Endocr Metab Disord 2003;4(2):129–36. [2] Franklyn JA, Daykin J, Droic Z, Farmer M, et al. Long-term follow-up of treatment of thyrotoxicosis by three different methods. Clin Endocrinol 1991;34:71–6. [3] Cooper DS. Hyperthyroidism. Lancet 2003;362:459–68. [4] Ashkar PS, Katims RB, Smoak WM, Gilson AJ. Thyroid storm treatment with blood exchange and plasmapheresis. JAMA 1970;214:1275–9. [5] Ozbey N, Kalayoglu-Besisik S, Gul N, Bozbora A, et al. Therapeutic plasmapheresis in patients with severe hyperthyroidism in whom antithyroid drugs are contraindicated. Int J Clin Pract 2004;58:554–8. [6] Pasimeni G, Caroli F, Spriano G, Antonini M, et al. Refractory thyrotoxicosis induced by iodinated contrast agents treated with therapeutic plasma exchange. A case report. J Clin Apher 2008;23:92–5. [7] Braithwaite SS, Brooks MH, Collins S, Bermes EW. Plasmapheresis: an adjunt to medical management of severe hyperthyroidis. J Clin Apher 1986;3:119–23. [8] Szczepiorkowski ZM, Winters JL, Bandarenko N, Kim HC, Linenberger ML, Marques MB, et al. Apheresis applications committee of the American Society for Apheresis. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the apheresis applications committee of the American Society for Apheresis. J Clin Apher 2010;25:83–177. [9] Wartofsky L. Thyrotoxic storm. In: Braverman LE, Utiger RD, editors. Werner’s and Ingbar’s the thyroid: a fundamental and clinical text. Philadelphia, PA: Lippincott Williams & Wilkins; 2000. p. 679–84.
[10] Fisher JN. Management of thyrotoxicosis. South Med J 2002;95:493–505. [11] Houghton SG, Farley DR, Brennan MD, van Herden JA, et al. Surgical management of amiodarone-associated thyrotoxicosis: Mayo clinic experience. World J Surg 2004;28:1083–7. [12] Ezer A, Caliskan K, Parlakgumus A, Belli S, et al. Preoperative therapeutıc plasma exchange in patients with thyrotoxicosis. J Clin Apher 2009;24:111–4. [13] Muller C, Perrin P, Faller B, Richter S, et al. Role of plasma exchange in the thyroid storm. Ther Apher Dial 2011;15:522–31. [14] De Rosa G, Testa A, Menichella G, et al. Plasmapheresis in the therapy of hyperthyroidism associated with leukopenia. Haematologica 1991;76:72–4. [15] Pinsard D, Chadenas D, Pierre D, Walle T, et al. Plasma exchange and hyperthyroidism. Current indications. Ann Endocrinol 1985;46:89–98. [16] Aghini-Lombardi F, Mariotti S, Fosella PV, Grasso L, et al. Treatment of amiodarone iodine-induced thyrotoxicosis with plasmapheresis and methimazole. J Endocrinol Invest 1993;16:823–6. [17] Binimelis J, Bassas L, Marruecos L, Rodriguez J, et al. Masssive thyroxin intoxication: evaluation of plasma extraction. Intensive Care Med 1987;13:33–8. [18] Rajeswaran C, Shelton RJ, Gilbey SG. Management of amiodaroneinduced thyrotoxicosis. Swiss Med Wkly 2003;133:579–85. [19] Basic-Jukic N, Kes P, Glavasa-Boras S, Brunetta B, et al. Complications of therapeutic plasma exchange: experience with 4857 treatments. Ther Apher Dial 2005;9:391–5. [20] McLeod BC, Sniecinski I, Ciavarella D, et al. Frequency of immediate adverse effects associated with therapeutic apheresis. Transfusion 1999;39:282–8. [21] Binimelis J, Bassas L, Marruecos L, et al. Massive thyroxine intoxication: evaluation of plasma extraction. Intensive Care Med 1987;13:33–8.
Contents lists available at SciVerse ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
The results of therapeutic plasma exchange in patients with severe hyperthyroidism: A retrospective multicenter study Muzaffer Keklik a,⇑, Leylagul Kaynar b, Mehmet Yilmaz b, Serdar Sivgin a, Musa Solmaz a, Cigdem Pala a, Sulbiye Aribas c, Gulsah Akyol a, Kursat Unluhizarci c, Mustafa Cetin a, Bulent Eser a, Ali Unal a a b c
Erciyes University, Department of Hematology and Apheresis Unit, 38039 Kayseri, Turkey Gaziantep University, Department of Hematology, Gaziantep, Turkey Erciyes University, Department of Endocrinology, Kayseri, Turkey
a r t i c l e
i n f o
Keywords: Hyperthyroidism Therapeutic plasma exchange
a b s t r a c t Hyperthyroidism characterized by elevated serum levels of circulating thyroid hormones. The aim of hyperthyroidism treatment is to achieve a euthyroid state as soon as possible and to maintain euthyroid status. However, drug withdrawal and utilization of alternative therapies are needed in cases in which leucopenia or impairment in liver functions is observed during medical therapy. In the present study, we aimed to present our cases which underwent therapeutic plasma exchange (TPE) due to severe hyperthyroidism. The results of 22 patients who underwent therapeutic plasma exchange due to hyperthyroidism in Apheresis Units of Erciyes University and Gaziantep University, between 2006 and 2012, were retrospectively reviewed. These cases had severe thyrotoxic values despite anti-thyroid drug use. After TPE, we observed a significant decrease in free thyroxin (FT4) (p < 0.001) and free triiodotyhronin (FT3) (p < 0.004) levels. There was statistically significant increase in the mean values of TSH levels after TPE (p < 0.001). Clinical improvement was achieved in hyperthyroidism by TPE in 20 cases (91%). Both FT3 and FT4 levels remained above the normal limits in two of 22 patients. TPE should be considered as an effective and safe therapeutic option to achieve euthyroid state before surgery or radioactive iodine treatment. TPE is a useful option in cases with severe hyperthyroidism unresponsive to anti-thyroid agents and in those with clinical manifestations of cardiac failure and in patients with severe adverse events during anti-thyroid therapy. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Endocrine and metabolic emergencies are relatively common conditions in acute care medicine [1]. Severe hyperthyroidism is a life-threatening condition. Graves’ disease, toxic adenoma and multi-nodular goiter are the most commonly encountered causes of hyperthyroidism. In most instances, the excessive production of thyroid hormones by the thyroid gland is the major cause of severe hyperthyroidism. The three most common treatments for ⇑ Corresponding author. E-mail address: [email protected] (M. Keklik). 1473-0502/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.transci.2013.04.010
hyperthyroidism are antithyroid drugs, radioactive iodine (RAI), and thyroidectomy [2,3]. The acute phase must be treated with standart treatments such as thiamazole, prednisolone, and nonselective beta-blockers. In patients with severe hyperthyroidism, further therapies are needed to restore euthyroid hormone status. Therapeutic plasma exchange (TPE) is an alternative treatment that has been proposed since the 1970s for hyperthyroidism [4–7]. TPE removes protein-bound substances including thyroid hormones. This retrospective study was performed as an analysis of our experience with TPE with regard to treatment outcomes and complications in adult patients with severe hyperthyroidism.
328
M. Keklik et al. / Transfusion and Apheresis Science 48 (2013) 327–330
2. Patients and methods We retrospectively reviewed records of patients who were treated with TPE between 2006 and 2012 for severe hyperthyroidism at Apheresis Units of Erciyes and Gaziantep University. The list of patients was obtained from the TPE log-book of the apheresis units in our facility. These cases had severe thyrotoxic values despite anti-thyroid drug use. Data on demographics, etiologies of hyperthyroidism, thyroid hormone status (before and after TPE), TPE sessions were analyzed. Procedural complications and outcome are recorded. The reference ranges for the laboratory indices were 8.00–20.00 pg/mL for free thyroxin (FT4), 2.20–4.70 pg/ mL for free triiodothyronin (FT3), and 0.20–3.20 IU/mL for thyroid stimulating hormone (TSH). Fresh frozen plasma (FFP) was used in all cases as replacement fluid. TPE was performed via central venous access by using Fresenius ASTEC 204 device (Fresenius Com.Tec, Germany). TPE was carried out at the predicted plasma volume for 1.3 times every other day. Plasma volumes were calculated for each patient using the patient’s body surface area, sex, and hematocrit. Vital signs were monitored at the beginning and end of each procedure, and patients were monitored for adverse events during apheresis procedures. Serum FT3, FT4 and TSH levels were measured at 6 h after TPE sessions. In order to avoid severe hypocalcaemia during the TPE, all patients received an intravenous infusion of 10% calcium gluconate. Written informed consent was obtained from all patients after procedural risks were explained in detail before each procedure. Each session lasted for 2 h. Analysis were performed using SPSS 20.0 (IBM, Chicago) with considering a p < 0.05 statistically significant. Shapiro–Wilk’s test was used to check the data normality. To compare the differences of thyroid hormone levels before and after TPE, Wilcoxon t test was used.
3. Results Of the 22 patients, 16 (72.8%) were women and 6 (27.2%) were men. Median age was 47 (range: 22–74) years. Of these cases, there were nine cases with Graves’ disease and 13 cases with multi-nodular goiter. All cases had palpitation while there was tachycardia in 14 cases; sweating in 16 cases and tremor in 12 cases. Drugs were withdrawn by
the attending clinicians because of severe hepatotoxicity related to anti-thyroid drugs in 8 cases and leucopenia in 12 cases. Drugs were withdrawn by patients due to arthralgia in two cases. All patients received b-receptor antagonist and steroid drugs. Twenty-two patients received a total of 88 procedures. The median number of apheresis sessions was four (range: 2–9). The median processed plasma volume was 3000 mL (range: 1800–4000) for each cycle. Overall response to TPE was seen in 20/22 (91%) patients. No response to TPE was seen in two patients (9%). Table 1 lists laboratory data pre and post TPE. Table 2 lists pre and post procedural levels of thyroid hormones. The mean thyroid hormone concentrations (the mean ± SD) before TPE for FT3, FT4 and TSH were 17.25 ± 15 pg/mL, 34.31 ± 21 pg/mL and 0.03 ± 0.04 IU/mL, respectively. In neither case the process was terminated because of adverse events. Complications were mild and consisted of hypotension and hypocalcemia. Hypotension episodes occurred in five patients and hypocalcemia was observed in four patients. There was no catheter related complication such as hematoma, infection or thrombosis. Clinical improvement was achieved in 20 cases (91%); subsequently, RAI and surgery was performed to achieve permanent cure in 15 and five cases, respectively. After TPE, the mean FT3, FT4 and TSH levels were 5.34 ± 4 pg/ mL, 15.86 ± 14 pg/mL and 1.02 ± 1 IU/mL, respectively. There was statistically significant decrease in the mean values of FT3 (p < 0.001) and FT4 (p < 0.004) levels after TPE. We observed significant increase in the mean values of TSH levels after TPE (p < 0.001). Thyroid hormone levels remained high in two cases, one of these cases died as result of complicating the tachyarrhythmia following myocardial infarction. Her illness was toxic multi-nodular goiter and she was 60 years old (patient 5). For the other case (patient 6), a second TPE was performed, which again resulted only in minor and temporally improvement. Despite TPE, this patient had symptoms of thyrotoxicosis such as palpitation, tachycardia, tremor and sweating. She was diagnosed with Graves’ disease and antithyroid medication was withdrawn by the attending clinician because of arthralgia. Following antithyroid and nonsteroidal anti-inflammatory drugs she recovered. 4. Discussion Thyrotoxicosis is characterized by extremely elevated serum levels of circulating thyroid hormones leading to
Table 1 Laboratory data for therapeutic plasma exchange. Variables
Pretreatment, median (range)
Posttreatment, median (range)
p Value
Normal ranges
Hb (g/dl) WBC (103/lL) Plt (103/lL) BUN (mg/dl) Cre (mg/dl) AST (u/L) ALT (u/L) Ca (mg/dl) Alb (g/dl)
11.7 (8.2–15.3) 4.66 (1.30–34.12) 185 (64–392) 12.5 (7–48) 0.65 (0.40–1.44) 31.5 (18–1813) 39 (14–2339) 9.5 (8–10.7) 3.8 (2.8–4.6)
11.4 (7.9–13.6) 6.75 (0.6–28.3) 220 (77–412) 15 (9–39) 0.70 (0.40–1.09) 34 (17–66) 38 (16–80) 9.4 (7.9–10.6) 3.6 (3–4.1)
0.244 0.085 0.903 0.329 0.886 0.566 0.186 0.216 0.158
12–18 4.8–10.8 130–400 7.9–21 0.84–1.44 0–35 0–45 8.8–10.6 3.5–5.2
Abbreviations: Hb hemoglobin, WBC white blood cells, Plt platelet count, BUN blood urea nitrogen, Cre creatinine, AST aspartate transaminase, ALT alanine transaminase, Ca calcium, Alb albumin.
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M. Keklik et al. / Transfusion and Apheresis Science 48 (2013) 327–330 Table 2 Thyroid hormone levels before and after therapeutic plasma exchange. Patient
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Before TPE
After TPE
FT3 (pg/mL)
FT4 (pg/mL)
TSH (IU/mL)
FT3 (pg/mL)
FT4 (pg/mL)
TSH (IU/mL)
6.08 6.73 4.35 28.43 14.51 6.40 3.10 14.68 13.97 14.70 12.61 3.80 69.73 28.68 15.29 16.30 22.90 26.80 14.50 16.73 26.54 12.86
18.22 50.76 25.65 62.47 58.44 37.50 13.41 62.68 33.04 44.10 54.50 3.02 4.83 49.10 3.56 4.37 49.80 52.90 47.45 5.86 38.10 35.12
.16 .10 .01 .05 .01 .04 .04 .01 .06 .01 .02 .01 .01 .01 .01 .01 .01 .04 .01 .01 .01 .02
4.34 2.54 5.59 2.45 14.20 6.10 3.07 3.89 .91 4.20 5.27 9.17 13.45 2.12 12.38 2.41 3.10 4.80 3.30 3.65 8.24 2.47
15.37 11.06 25.90 14.76 47.20 51.20 12.91 15.20 3.68 23.10 38.50 3.78 6.47 9.80 3.14 1.46 13.40 16.70 17.20 2.34 6.45 9.35
.24 2.71 .27 .03 .01 .02 .10 5.72 4.85 .01 .12 .01 .03 .15 .10 .02 .04 .05 4.56 .15 .10 3.35
Abbreviations: TPE: therapeutic plasma exchange, FT4: free thyroxin, FT3: free triiodothyronin, TSH: thyroid stimulating hormone.
multisystem disease. Even with treatment, mortality stays high at approximately 30% [8]. It is difficult to estimate its exact incidence because no definitive and universally-accepted criteria exist for establishing the diagnosis, and in most cases, the results of laboratory tests are indistinguishable from those observed in patients with otherwise uncomplicated thyrotoxicosis [1]. But it is believed that thyrotoxicosis is less frequent nowadays than in the past, it may account for <1–2% of hospital admissions [9]. All patients with severe hyperthyroidism should be treated in an intensive care unit setting, given the profound disturbances in temperature, cardiovascular function, fluid and electrolyte balance. Therapeutic intervention has a fourfold aim: to reduce the production and secretion of thyroid hormones from the thyroid gland; to antagonize the peripheral action of thyroid hormones; to reverse systemic disturbances; and to address the precipitating event [1]. Antithyroid treatment options include medical therapy (propylthiouracil and methimazole), RAI and surgery. Medical treatments including antithyroid drugs usually achieve euthyroidism effectively. Thyroidectomy is performed in special circumstances such as poor response to antithyroid drugs, suspicious cytology, iodine-induced thyrotoxicosis, and upon patient’s request. But in patients who had elevated thyroid hormones should be rendered euthyroid before surgical procedures to prevent the side effects of hyperthyroidism [10,11]. TPE is an additional tool for removing circulating thyroxine in patients who do not respond quickly to conventional therapy [12]. TPE has been shown to have a clear benefit in the severe hyperthyroidism induced by Graves’ disease and multinodular goiter [6,13,14]. In our study, there were nine cases with Graves’ disease. Except one patient (case 6), all Graves’ disease patients recovered by TPE. We also treated 13 cases with multi-nodular goiter. Except one patient (case 5), clinical improvement was achieved in hyperthyroidism by TPE in
12 cases with multinodular goiter. The therapeutic benefit of TPE results from the removal of the pathological substances from the thyroid storm: hormones, cytokines, toxins, and so on. TPE also removes 50 -monodesiodase which converts T4 to T3 and this decreases T3 production [15]. However, this effect is usually transient and thyroid hormone levels increase within few days after TPE [16–18]. So, in our study, five patients underwent thyroid surgery and 15 patients received RAI treatment for permanent cure. Plasma or human albumin solutions provide new binding sites for circulating free hormones. In our study, fresh frozen plasma was used in all cases as replacement fluid. TPE is a recommendation of grade IIc and a category III in the last American Society for Apheresis (ASFA) guideline [8]. TPE should be conducted as early as possible in order to be efficient. TPE is a relatively safe method of treatment, providing it is performed by experienced staff and used for appropriate indications with all necessary precautions [19]. Side effects include transfusion reaction, citrate-related nausea and vomiting, vasovagal or hypotensive reactions, hypocalcemia, catheter dysfunction, bleeding, respiratory distress, and tetany or seizure. Death is rare and usually due to the underlying disease [20]. Our patient (case 5) died complicating the tachyarrhythmia in the course of myocardial infarction. Other complications consisted of hypotension (n: 5) and citrate related hypocalcemia (n: 4). These complications were mild. All of the hypotensive episodes and hypocalcemia were resolved briefly after intravenous infusion of saline or further calcium infusion. TPE for treatment of severe hyperthyroidism may be complicated by infections [21]. In the present study, there was no catheter related complication such as infection or bleeding. In conclusion, TPE is an effective treatment option for patients with severe hyperthyroidism. However, it has a transitory effect and thus several sessions should be performed, and it should be combined with other measures.
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