CASE REPORt CASE REPORt - APAMED Central

ONLINE FIRST | April 13, 2015 | http://dx.doi.org/10.15605/jafes.030.01.03

Case Report

Case Report

Thyrotoxic Pericardial Effusion Complicating Graves’ Disease in Pregnancy Marc Gregory Yu, Hannah Urbanozo, Marcelyn Fusilero Department of Medicine, University of the Philippines-Philippine General Hospital Manila

Abstract Pericardial effusion is a rare complication of Graves’ disease. A pregnant Filipino woman with diffuse goiter and hyperthyroid symptoms was initially treated as a case of Graves’ disease. She was readmitted for exertional dyspnea, orthopnea, and bipedal edema; an echocardiogram revealed a massive pericardial effusion. Workup for other causes of the effusion was unremarkable. The pericardial effusion resolved after pericardiostomy and anti-thyroid medications. This highlights the clinician’s role in determining the association between the two disease entities. Keywords: Graves’ disease, thyrotoxicosis, hyperthyroidism, pericardial effusion, pregnancy

BACKGROUND While sinus tachycardia, atrial fibrillation, and congestive heart failure are well-recognized cardiovascular manifestations of Graves’ disease,1 pericardial effusion due to thyrotoxicosis is rarely reported. This case highlights the clinician’s role in determining the association between the two disease entities.

improved with propylthiouracil, furosemide and was discharged.

propranolol

and

CASE A 32-year-old Filipino woman on the 19th week of her fourth pregnancy presented at the emergency room with a seven-year history of diffuse goiter associated with tremors, palpitations, heat intolerance, exophthalmos and exertional dyspnea. Prior to this consult, she was previously taking anti-thyroid medications which were discontinued five years ago upon improvement of symptoms, and was subsequently lost to follow up. On admission, the patient was febrile, tachycardic in atrial fibrillation, hyperreflexic, with fine finger tremors. Ophthalmologic examination revealed positive Dalrymple’s, Kocher’s, and Von Graefe’s signs, lagophthalmos, chemosis and periorbital edema. The thyroid gland was non-tender and diffusely enlarged, measuring 5x5 cm per lobe. Auscultation revealed bibasal fine crackles, and there was note of hyperpigmented, nonpitting in duration over the pretibial area of both legs, clubbing of the fingers and pedal edema. She was treated for Graves’ disease in thyroid storm, with congestive heart failure from thyrotoxic heart disease. Her chest radiograph showed left ventricular cardiomegaly (Figure 1). She ________________________________________ ISSN 0857-1074 e-ISSN 2308-118X Printed in the Philippines Copyright © 2015 by the JAFES Received January 31, 2015. Accepted March 19, 2015. http://dx.doi.org/10.15605/jafes.030.01.03 Published online first April 13, 2015. http://dx.doi.org/10.15605/jafes.030.01.03

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Figure 1. Chest radiograph taken on postero-anterior view during initial admission showing left ventricular cardiomegaly with pulmonary congestive changes. Corresponding Author: Marc Gregory Y. Yu, MD Department of Medicine University of the Philippines-Philippine General Hospital Taft Avenue, Ermita 1000 Manila, Philippines Tel. No.: +632-554-8400 Email: [email protected]

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ONLINE FIRST | April 13, 2015 | http://dx.doi.org/10.15605/jafes.030.01.03 Thyrotoxic Pregnancy Marc Gregory Y. Yu,inet al MarcPericardial Gregory Y.Effusion Yu, et alComplicating Graves’ Disease inThyrotoxic Pericardial Effusion Complicating Graves’ Disease Pregnancy 45 2

Nineteen days later, the patient noted recurrence of exertional dyspnea, bipedal edema and three-pillow orthopnea. No chest pain or fever was observed. Upon readmission, she was tachycardic with distended neck veins, muffled heart sounds and Grade 2 bipedal edema. Deep tendon reflexes were normal with no tremors. Chest radiograph now revealed multichambered cardiomegaly (Figure 2.)

determination of glucose and total protein levels. Table 1 summarizes the pericardial fluid analysis.

Figure 3. Initial 2D echocardiogram showing circumferential pericardial effusion with suspicious right ventricular collapse during late diastole, a sign of tamponade. Table 1. Pericardial Fluid Studies Qualitative Examinations

Dark red

Transparency

Slightly hazy

Red Blood Cells

6 283,000 x 10 /L

White Blood Cells

6 578 x 10 /L

Polymorphonuclear Cells

82%

Lymphocytes

17%

Distorted Cells

1%

Glucose

4.95 mmol/L

Total Protein

Bacterial Culture

59.01 mg/dL PMN 0-1/OIF Gram positive cocci in pairs 0-1/OIF No growth

AFB Smear

Negative

AFB Culture

No growth

TB PCR

Negative

Cell Block and Cytology

Negative

Gram Stain

Figure 2. Chest radiograph on readmission showing multichambered cardiomegaly and characteristic water-bottle sign indicative of massive pericardial effusion.

Results

Color

Laboratory Workup During the patient’s first admission, free thyroxine (FT4) levels were elevated (40.2 pmol/L), and thyroid stimulating hormone (TSH) was low (0.1 uIU/mL). On readmission, FT4 levels were normal (11.8 pmol/L) while TSH remained low (0.005 uIU/mL). Her 12-lead electrocardiogram showed atrial fibrillation in rapid ventricular response, with nonspecific ST-T wave changes. A 2D echocardiogram with color-flow Doppler during the second admission showed normal-sized chambers with left ventricular remodelling and mildly depressed left ventricular systolic function; adequate right ventricular systolic function; mild to moderate pulmonary hypertension; and massive pericardial effusion in impending tamponade (Figure 3). Pericardial fluid samples were sent for differential cell counts, cytology, acid-fast (AFB) and conventional gram stain and culture, tuberculous polymerase chain reaction (TB PCR) and www.asean-endocrinejournal.org Vol. 30 No. 1 May 2015

Fetal screening with congenital anomaly scan showed no gross fetal structural abnormalities, with an estimated sonographic weight that was appropriate for gestational age. Serum antinuclear antibody (ANA) to rule out the possibility of an autoimmune process was likewise negative. Treatment The patient underwent pericardiocentesis with low flow drainage while on dobutamine infusion, draining around 600 cc of serosanguinous fluid. Dobutamine was discontinued after the procedure, and the patient’s vital signs remained stable throughout admission except for intermittent episodes of tachycardia. Medical therapy included methimazole, digoxin, prednisone and furosemide. Propranolol was also initiated after initial diuresis to control the heart rate and decrease the adrenergic effects of the hyperthyroid state. The patient Vol. 30 No. 1 May 2015 www.asean-endocrinejournal.org

ONLINE FIRST | April 13, 2015 | http://dx.doi.org/10.15605/jafes.030.01.03 Gregory Y.Effusion Yu, et alComplicating Graves’ Disease inThyrotoxic Pericardial Effusion Complicating Graves’ Disease Pregnancy Thyrotoxic Pregnancy Marc Gregory Y. Yu,inet al 46 MarcPericardial 3

experienced gradual resolution of orthopnea, pedal edema and exertional dyspnea, with spontaneous conversion to normal sinus rhythm. On the 18th hospital day, she was subsequently discharged. Outcome and Follow up Two months after discharge, the patient underwent a repeat 2D echocardiogram (Figure 4) revealing the absence of the pericardial effusion but with pericardial thickening. There was also improvement of overall left ventricular systolic function after treatment with heart failure and anti-thyroid drugs. The patient went into preterm labor at 32 weeks of gestation. She delivered a live baby girl via spontaneous vaginal delivery, who was admitted to the neonatal intensive care unit and eventually discharged.

Figure 4. Repeat 2D echocardiogram after two months, showing absence of pericardial effusion but with thickened pericardium.

DISCUSSION Our patient initially presented with classic thyrotoxic symptoms associated with diffuse goiter, typical eye signs, pretibial dermopathy and acropachy. These findings, plus a high FT4 and low TSH, make the clinical diagnosis of Graves’ disease straightforward.2 In thyrotoxic patients, the most common cardiac complications are sinus tachycardia, atrial fibrillation and congestive heart failure,1,3,4 with reports of heart block5 and a cardiomyopathy that may or may not be reversible following return to a euthyroid state.6,7 These manifestations may be exaggerated in pregnancy owing to the physiologic increase in heart rate, stroke volume and cardiac output.8 In thyroid disorders, pericardial effusion is more commonly seen in 5-30% of hypothyroid patients.9 In contrast, its occurrence in Graves’ disease is somewhat rare;10-14 one study looking into the causes of pericardial effusion in 204 patients found no cases of thyrotoxicosis among them.15 This lack of published evidence linking Vol. 30 No. 1 May 2015 www.asean-endocrinejournal.org

pericardial effusion with thyrotoxicosis emphasizes the importance of a high index of suspicion to ascertain the association between the two disease entities.10 Our initial consideration for the patient’s effusion was an infectious etiology, specifically Mycobacterium tuberculosis, which is highly prevalent in the Philippines. Given that the patient is a female of reproductive age, the possibility of autoimmune pericarditis secondary to an underlying connective tissue disease such as systemic lupus erythematosus was also entertained.16 Malignancy was considered since it was found to be the most common etiology in a study among Filipino patients with pericardial effusion in tamponade.17 We also regarded the possibility that the effusion may have been due to the pregnancy itself, but it is usually mild and characteristically manifests as a transudate.18 Finally, the effusion may have been part of an unusual vasculitic sideeffect from PTU; however, this was also unlikely as the other typical vasculitic manifestations of rash, hemoptysis, cytopenia, hematuria and renal failure were absent in the patient.19 Since workup for all these causes eventually turned out unremarkable (the gram stain result was most likely a contaminant), with the effusion resolving after pericardiostomy and anti-thyroid drugs (making an idiopathic cause less likely), we concluded that thyrotoxicosis caused the patient’s effusion. It is interesting that the patient’s effusion was detected during readmission when she had already received antithyroid drugs and FT4 levels had normalized. This is consistent with reports showing that pericardial effusion resulting in tamponade can still develop in Graves’ thyrotoxicosis even during anti-thyroid treatment and with improving thyroid function tests.11 Moreover, although the patient was initially discharged improved, the fact that some of her hyperthyroid symptoms (tachycardia, dyspnea, edema) persisted on readmission with TSH being suppressed further from 0.1 to 0.005 uIU/mL showed that the thyrotoxicosis was still not adequately controlled. PTU, initially started due to its generally better safety profile for pregnancy, was subsequently shifted to methimazole, a more potent antithyroid drug. Since the apparent worsening of the patient’s heart failure symptoms on readmission was temporally associated with her recent thyrotoxic manifestations, thyrotoxicosis was considered as the underlying cause of the heart failure, despite the initiation of standard cardiac medications. This is consistent with reports showing that in some patients treated for hyperthyroidism, achievement of a euthyroid state is not by itself sufficient to fully reverse cardiomyopathy and left ventricular failure.6,7,20 Furthermore, the patient’s pregnant condition, persistent tachycardia, and atrial fibrillation could have also contributed independently to the exaggeration of the heart failure symptoms.8,21 Vol. 30 No. 1 May 2015 www.asean-endocrinejournal.org

ONLINE FIRST | April 13, 2015 | http://dx.doi.org/10.15605/jafes.030.01.03 Thyrotoxic Pregnancy Marc Gregory Y. Yu,inet al MarcPericardial Gregory Y.Effusion Yu, et alComplicating Graves’ Disease inThyrotoxic Pericardial Effusion Complicating Graves’ Disease Pregnancy 47 4

6. Umpierrez GE, Challapalli S, Patterson C. Congestive heart failure The pathophysiology of thyrotoxic pericardial effusion has due to reversible cardiomyopathy in patients with hyperthyroidism. been demonstrated to be similar to that of pretibial Am J of Med Sc. 1995; 310(3):99-102. myxedema, with a characteristic serous effusion attributed 7. Ebisawa K, Ikeda U, Murata M, Sekiguchi H, Nagai R, Yazaki Y et al. Irreversible cardiomyopathy due to thyrotoxicosis. Cardiology. to the transudation of albumin and decreased lymphatic 1994; 84:274–7. clearance of interstitial fluid proteins.22 On occasion, the 8. Jameson JL, Weetman AP. Disorders of the Thyroid Gland. In: effusion can also appear serosanguinous, as in our Braunwald E, Fauci AS, Kasper D, Hauser HL, Longo D, Jameson JL, et al Severe Hypertriglyceridemia Presenting as Superior Sagittal Sinusth Thrombosis 11,12 ThisSanyal, 192 Debmalya purported underlying pathophysiologic patient. editors. Harrison’s Principles of Internal Medicine, 15 edition. New York: McGraw-Hill; 2001. mechanism is the basis for several reports stating the 9. Spodick DH. Pericardial Diseases. In: Braunwald E, Zippes DP, Libby potential benefit of prednisone in these patients.10,13 Hence, P, editors. Heart Disease, 6th edition. Philadelphia: WB Saunders; 3. Allroggen H, Abbott RJ. Cerebral venous sinus thrombosis. or with hereditary thrombophilia areeven anticoagulated for we decided to continue prednisone after TB was 2001. Postgrad Med J. 2000; 76:12-15. 12 longerout duration due to high chances of recurrence. 10. Ovadia, S, Lysy y L, Zubkov T. Pericardial effusion as an expression ruled as an unlikely etiology of the effusion. http://dx.doi.org/10.1136/pmj.76.891.12.

Our case be considered among thefor 65–80% of CVST Even withmight treatment, the mortality rate thyrotoxicosis 10 An echocardiogram cases cardiac with one or morecan identifiable causes. Here, the main from sequelae reach 30%. cause beingrecommended elevated triglyceridemia which may have is therefore as part of the investigation to played a role in increasing our as patient’s thromboticfactor risk. rule out pericardial effusion a contributing This highlights a potential association potentially heralding the direct development of between cardiac CVST and hypertriglyceridemia in the absence of other tamponade. Conversely, in a patient presenting with an pre-disposingpericardial factors. Ifeffusion, such ait relationship between unexplained might be prudent to hypertriglyceridemia and CVST were to be found, new exclude Graves’ thyrotoxicosis despite the absence of diagnostic measures might beinwarranted this may classic signs and symptoms, addition toand routine testsalso for have an implication on the risk of recurrence and duration microbiology, inflammatory and oncologic markers and of anticoagulation in this group of patients. autoimmunity.

CONCLUSION This is the first documented case of its kind in the Philippines, and in the entire ASEAN region. Moreover, in Severe hypertriglyceridemia CVST. In this contrast to other reports may on trigger thyrotoxicosis-related rare case study, hypertriglyceridemia was thedealing only pericardial effusion, this is also so far the first case predisposing risk factor for developing CVST. Our case with a pregnant patient. The rarity of the association highlights the need for clinicians to consider CVST among emphasizes the need for vigilance. patients with uncontrolled hypertriglyceridemia. New diagnostic measures may become necessary which may References 1. S, Polonsky K, Larsen Kronenberg editors. Williams also Melmed have an implication on P,the risk of H, recurrence and Textbook of Endocrinology, 12th edition. Philadelphia: Elsevier duration of anticoagulant therapy in this group of Saunders; 2011. patients. 2. Baskin JH, Cobin RH, Duick DS, Gharib H, Guttler RB, Kaplan MM, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Evaluation and Treatment of Acknowledgement Hyperthyroidism and Hypothyroidism. Endocrine Practice. Dec; The authors thank Mr. Kingshuk Bhattacharjee for the 2002 medical 8(6): 457-469. writing assistance in the development of this manuscript. 3. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med. 2001; 344: 501–509. http://dx.doi.org/10.1056/ References NEJM200102153440707. 1. Stam J.G,Thrombosis cerebralHormone veins andAction sinuses. Engl J 4. Kahaly Dillmann of W.the Thyroid in New the Heart. Med.2005;Reviews. 352:1791-98. http://dx.doi.org/10.1056/NEJMra042354. Endocrine 2005; 26(5):704–728. http://dx.doi.org/10.1210/ 2. Bousser MG, Chiras J, Bories J, et al. Cerebral venous thrombosis – a er.2003-0033. review of A, 38 cases. 5. Sampana JasulStroke.1985; G. High 16:199-213. Grade AV Block Complicating http://dx.doi.org/10.1161/01.STR.16.2.199. Hyperthyroidism: A Case Report. Phil J Int Med. 2010 Jul-Sep;

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