The views expressed in the article are those of the authors and do not reflect the official policy or position of the Department of the Army, the Department of Defense, or the US Government.

Pericardial effusion is a well-documented complication of hypothyroidism. Evidence suggests a prevalence of pericardial effusion in the setting of hypothyroidism of about 3% to 6%, although it may be as high as 30% to 80% in patients with myxedema.¹ Hypothyroid-induced pericardial effusions typically accumulate gradually and rarely cause tamponade in the absence of prolonged hypothyroidism.² During interferon alfa therapy for chronic hepatitis C virus (HCV) infection, up to 40% of patients develop thyroid antibodies,³ and as many as 15% have pathologic thyroid values.⁴

Interferon alfa treatment for chronic HCV infection has been shown to induce thyroid antibodies de novo,⁵ as well as cause significant increases in thyroid antibody levels in patients with previously positive thyroid antibodies.⁶ We present a rare case of cardiac tamponade as the initial presentation of autoimmune hypothyroidism caused by interferon therapy for chronic HCV infection.

Case Presentation

A 34-year-old woman with a history of chronic HCV infection, treated with pegylated interferon alpha 2b and ribavirin for 5 months, presented with a 1-month history of profound fatigue, generalized edema, a 15-lb weight gain, dyspnea with exertion, and worsening hypoalbuminemia. She denied paroxysmal nocturnal dyspnea, chest pain, respiratory distress at rest, fevers, chills, or cough. Review of systems was remarkable for alopecia, irritability, cold intolerance, and decreased appetite. Notable findings on initial examination were: blood pressure, 118/86 mm Hg; pulse, 78 beats/min; pulsus paradoxus, 10 to 12 mm Hg; a jugular venous pressure, estimated at 8 cm H₂O; and 2+ pitting edema extending proximally to the lower abdomen. Cardiopulmonary examination was otherwise normal, and thyromegaly was not present.

Initial laboratory test results showed a thyroid-stimulating hormone (TSH) level of 28.1 mIU/mL (normal, 0.5-5.0 mIU/mL) and a free thyroxine level of 0.6 ng/dL (normal, 0.4-2.3 ng/dL). The TSH value before interferon therapy was 1.31 mIU/mL; thyroid antibodies were not measured before interferon therapy. Subsequent testing demonstrated autoimmune thyroid disease, with an elevated thyroid peroxidase antibody at 619 IU/mL.

The initial electrocardiogram showed diffuse low voltage (Figure 1), without electrical alternans. Chest x-ray demonstrated a normal cardiac silhouette, with a small left pleural effusion. Subsequent echocardiogram showed a moderate pericardial effusion, without evidence of chamber collapse; however, significant respiratory variation was seen on Doppler echocardiogram consistent with early tamponade physiology.

Figure 1—In patients with cardiac tamponade, the electrocardiogram often demonstrates diffuse low-voltage complexes.

Medical management was initially elected, given the gradual onset of symptoms, hemodynamic stability of the patient, and moderate pericardial effusion. The woman was diuresed cautiously for symptomatic volume overload and was given thyroid replacement therapy for clinical hypothyroidism; she was then followed closely as an outpatient.

During the next 6 weeks she developed progressive dyspnea on exertion, fatigue, and persistent edema despite adequate thyroid replacement therapy. Repeat clinical examination demonstrated a pulsus paradoxus of 18 mm Hg, jugular venous distension to 13 cm, and a positive hepatojugular reflux without associated tachycardia, hypotension, or muffled heart sounds. Repeat echocardiogram showed a 1.5-cm circumferential pericardial effusion, with a significant increase in respiratory variation in mitral valve blood flow (Figure 2), along with right atrial and right ventricular collapse (Figure 3) consistent with cardiac tamponade.

Figure 2—Doppler echocardiogram showing respiratory variation in mitral valve blood flow consistent with tamponade physiology.

Figure 3—A subcostal view of the echocardiogram demonstrates right ventricular collapse during diastole and a large pericardial effusion. RV = right ventricle; PE = pericardial effusion; RA = right atrium; LV = left ventricle.

The patient was referred for pericardiocentesis. A right heart catheterization demonstrated elevation and equalization of right-sided pressures, without evidence of constriction, and measurement of aortic pressure demonstrated a 35-mm Hg pulsus paradoxus (Figure 4). Pericardiocentesis was performed, and 300 cc of serous fluid was drained, which resulted in immediate symptomatic relief, resolution of pulsus paradoxus, and normalization of the right heart and pericardial pressures. The patient was followed clinically with serial echocardiograms and had no significant recurrence of the pericardial effusion. After completing 48 weeks of pegylated interferon alfa and ribavirin therapy, she achieved viral negativity.

Figure 4—Aortic tracing showing a pulsus paradoxus of 35 mm Hg, consistent with cardiac tamponade.

Discussion

Pericardial tamponade is a rare primary presentation of hypothyroidism. The accumulation of pericardial fluid in hypothyroidism is typically gradual and can lead to a large fluid accumulation of up to 6000 cc, without tamponade physiology.² Most cases of cardiac tamponade secondary to hypothyroidism have no clear precipitant; identified causes include infection, spontaneous pericardial hemorrhage, abdominal paracentesis, and hypothyroid therapy.⁷

This case represents a rare presentation, in which the rapid development of pericardial effusion with symptomatic cardiac tamponade was precipitated by autoimmune hypothyroidism from interferon therapy for chronic HCV infection.

The onset of autoimmune thyroid disease is a well-described complication associated with interferon therapy for chronic HCV infection. Hypothyroidism is the most common side effect, usually occurring about 6 months after initiating therapy.^8,9 Descriptions of severe hypothyroidism after interferon therapy, however, are limited to isolated case reports. Recently, a case of severe autoimmune thyroid disease presenting with Hashimoto's encephalopathy in the setting of interferon alfa and ribavirin therapy was reported.¹⁰

The majority of patients who develop hypothyroidism demonstrate thyroid antibodies, although a transient nonautoimmune hypothyroidism has also been described during interferon therapy.^8,11 Female gender, Asian ethnicity, and the presence of thyroid antibodies before therapy have been shown to be independent predictors for interferon-induced autoimmune thyroid dysfunction.^9,12 It is also possible that thyroid dysfunction is more common in patients with chronic HCV infection independent of treatment.¹¹

Some studies have found no increased risk for thyroid dysfunction with concomitant use of ribavirin and interferon,¹³ while others suggest that combination therapy may increase the risk for subsequent thyroid dysfunction without affecting thyroid autoantibody patterns.¹⁴ Reports also suggest that patients with high thyroid autoantibody titers are more likely to have persistent autoimmune thyroiditis, while in those with lower titers the thyroid disorder can be reversible.^15,16 The dose of and treatment response to interferon therapy do not appear to play a role in the development of thyroid disease,¹¹ and the absence of thyroid antibodies may be protective.¹⁶

Our patient had an unusual presentation of new, profound hypothyroidism during combined interferon alfa and ribavirin therapy. The patient was subsequently found to have a significantly elevated antithyroid peroxidase antibody titer, which increased her risk for persistent thyroid dysfunction. The concomitant use of ribavirin may have contributed to the rapid development of autoimmune thyroid disease, which led to the symptomatic pericardial effusion.

Conclusion

Many patients with chronic HCV infection who are receiving interferon alfa therapy will develop thyroid disease. Before the initiation of therapy with interferon alfa, patients should undergo testing for thyroid dysfunction, including measurement of thyroid antibodies. Such patients should be followed routinely for clinical and laboratory evidence of thyroid dysfunction, which may develop rapidly with overt clinical hypothyroidism as described here. With appropriate thyroid replacement, interferon therapy can usually be continued in the setting of thyroid dysfunction, without any significant complications, as long as patients are followed closely. Our patient's profound hypothyroidism should not adversely affect the potential to achieve a sustained virologic response against chronic HCV infection. She has been HCV-negative since week 4 of treatment and had undetectable viral levels 24 weeks after starting interferon therapy. Her hypothyroidism gradually resolved with thyroid replacement therapy, and she has not had reaccumulation of pericardial effusion since undergoing pericardiocentesis.

References

1. Kabadi U, Kumar S. Pericardial effusion in primary hypothyroidism. Am Heart J. 1990;120:1393-1395.
2. Karu AK, Khalife WI, Houser R, et al. Impending cardiac tamponade as a primary presentation of hypothyroidism: case report and review of literature. Endocr Pract. 2005;11:265-271.
3. Preziati D, La Rosa L, Covini G, et al. Autoimmunity and thyroid function in patients with chronic active hepatitis treated with recombinant interferon alpha-2a. Eur J Endocrinol. 1995;132:587-593.
4. Gehring S, Kullmer U, Koeppelmann S, et al. Prevalence of autoantibodies and the risk of autoimmune thyroid disease in children with chronic hepatitis C virus infection treated with interferon-alpha. World J Gastroenterol. 2006;12:5787-5792.
5. Marazuela M, Garcia-Buey L, Gonzalez-Fernandez B, et al. Thyroid autoimmune disorders in patients with chronic hepatitis C before and during interferon-alpha therapy. Clin Endocrinol (Oxf). 1996; 44:635-642.
6. Chen FQ, Okamura K, Sato K, et al. Reversible primary hypothyroidism with blocking or stimulating type TSH binding inhibitor immunoglobulin following recombinant interferon-alpha therapy in patients with pre-existing thyroid disorders. Clin Endocrinol (Oxf). 1996; 45:207-214.
7. Rachid A, Caum L, Trentini A, et al. Pericardial effusion with cardiac tamponade as a form of presentation of primary hypothyroidism. Arq Bras Cardiol. 2002;78:580-585.
8. Prummel M, Laurberg P. Interferon-alpha and autoimmune thyroid disease. Thyroid. 2003;13:547-551.
9. Dalgard O, Bjoro K, Hellum K, et al. Thyroid dysfunction during treatment of chronic hepatitis C with interferon alpha: no association. with either interferon dosage or efficacy of therapy. J Intern Med. 2002; 251:400-406.
10. Deutsch M, Koskinas J, Tzannos K, et al. Hashimoto encephalopathy with pegylated interferon alfa-2b and ribavirin. Ann Pharmacother. 2005;39:1745-1747.
11. Mandac JC, Chaudhry S, Sherman KE, et al. The clinical and physiologic spectrum of interferon-alpha induced thyroiditis: toward a new classification. Hepatology. 2006;43:661-672.
12. Pellicano R, Smedile A, Peyre S, et al. Autoimmune manifestations during interferon therapy in patients with chronic hepatitis C: the hepatologist’s view. Minerva Gastroenterol Dietol. 2005;51:55-61.
13. Moncoucy X, Leymarie F, Delemer B, et al. Risk factors and long-term course of thyroid dysfunction during antiviral treatments in 221 patients with chronic hepatitis C. Gastroenterol Clin Biol. 2005;29: 339-345.
14. Carella C, Mazziotti G, Morisco F, et al. The addition of ribavirin to interferon-alpha therapy in patients with hepatitis C virus-related chronic hepatitis does not modify the thyroid autoantibody pattern but increases the risk of developing hypothyroidism. Eur J Endocrinol. 2002;146:743-749.
15. Doi F, Kakizaki S, Takagi H, et al. Long-term outcome of interferon-alpha–induced autoimmune thyroid disorders in chronic hepatitis C. Liver Int. 2005;25:242-246.
16. Carella C, Mazziotti G, Morisco F, et al. Long-term outcome of interferon-alpha–induced thyroid autoimmunity and prognostic influence of thyroid autoantibody pattern at the end of treatment. J Clin Endocrinol Metab. 2001;86:1925-1929.