The Prevalence of Elevated Serum C-Reactive Protein Levels in Inflammatory and Noninflammatory Thyroid Disease

Elizabeth N. Pearce, Fausto Bogazzi, Enio Martino, Sandra Brogioni, Enia Pardini, Giovanni Pellegrini, Arthur B. Parkes, John H. Lazarus, Aldo Pinchera, Lewis E. Braverman

Disclosures
In This Article

Abstract and Introduction

C-reactive protein (CRP) levels have not been routinely used to diagnose thyroid disease, although many thyroid conditions involve inflammation. This study was intended to determine whether CRP levels could differentiate between inflammatory and noninflammatory thyroid conditions, especially between type II inflammatory amiodarone-induced thyrotoxicosis (AIT) and type I iodine-induced AIT. Serum high-sensitivity CRP levels were measured in 100 euthyroid controls (7 taking amiodarone) and 353 patients with one of the following thyroid conditions: AIT, subacute thyroiditis, toxic diffuse goiter, nodular goiter, Hashimoto's thyroiditis, short-term hypothyroidism, or postpartum thyroiditis. No patients with nontoxic multinodular goiter (n = 34), toxic nodular goiter (n = 23), or toxic diffuse goiter, either untreated (n = 49) or euthyroid while taking methimazole (n = 33), had positive CRP levels (>10 mg/L). The occurrence of positive CRP levels among patients with Hashimoto's thyroiditis (n = 35), short-term hypothyroidism (n = 38), and postpartum thyroiditis (n = 70) did not differ significantly from controls. The occurrence of positive CRP values did not differ significantly between patients with type I and type II AIT and controls. Six of 7 patients (86%) with untreated subacute thyroiditis had positive CRP levels (p < 0.00001). These results indicate that there is only a limited role for measurement of CRP levels in the diagnosis of thyroid diseases other than subacute thyroiditis.

C-reactive protein (CRP) was first discovered in the 1930s in the plasma of patients with pneumococcal pneumonia.[1] It is one of the constituents of the acute-phase reaction and tends to be elevated in acute and chronic inflammatory conditions. Its secretion is increased in response to a complex network of cytokines, especially interleukin-6 (IL-6) and either IL-1 or tumor necrosis factor- .[2] The function of CRP is not fully understood, but may involve proinflammatory and anti-inflammatory effects.[3]

Because serum CRP levels are elevated in inflammatory conditions, its presence can aid in the diagnosis of multiple disease states. CRP is markedly increased early in bacterial infections; therefore, it has been shown to be a useful marker for sepsis in neonates.[4] CRP levels have prognostic value in systemic inflammatory diseases such as rheumatoid arthritis[5] or active systemic vasculitis.[6] They can also help in the clinical management of more local inflammatory disorders such as Crohn's disease.[7] Elevated serum CRP levels have been used as a marker for renal transplant rejection.[8,9] In addition, elevated serum CRP has been shown to be an important risk factor for diseases not traditionally thought of as inflammatory conditions. A growing body of evidence suggests that elevated CRP levels may be a predictor of atherosclerotic cardiovascular disease,[10,11,12,13] and increased CRP levels may even be linked to the development of insulin resistance and type 2 diabetes.[14,15,16]

To date, CRP levels have not been routinely used as a diagnostic tool for thyroid disease, although a number of thyroid conditions involve inflammatory processes. One goal of this study was to determine whether CRP levels could be used to help distinguish between entities such as postpartum thyroiditis, subacute thyroiditis, and type II amiodarone-induced thyrotoxicosis (AIT), which are inflammatory disorders, and toxic multinodular goiter, Graves' disease, type I AIT, and Hashimoto's thyroiditis, which are not primarily inflammatory. It has previously been determined that CRP levels do not help to distinguish nonthyroidal illness from true thyroid dysfunction.[17]

AIT is a condition that can be difficult to diagnose definitively. Amiodarone is an iodinated benzofuranic drug. Approximately 37% of amiodarone by weight consists of iodine and the iodine is released at a rate of 7-21 mg of iodide per day.[18] Amiodarone is widely used for the management of recurrent ventricular arrhythmias and paroxysmal atrial fibrillation and flutter.[19,20] However, amiodarone is associated with multiple toxicities, including various effects on the thyroid and the peripheral metabolism of the thyroid hormones, recently reviewed elsewhere.[21] Amiodaroneinduced hypothyroidism occurs in up to 20% of patients in areas with sufficient dietary iodine, and is therefore relatively common in the United States. AIT occurs in 1%-23% of patients taking amiodarone, and is more prevalent in iodine-deficient regions.[22] Type I AIT is defined as iodine-induced excessive thyroid hormone synthesis and release, and is more likely to occur in patients with preexisting subclinical thyroid disorders, especially nodular goiter. Type II AIT is a destructive thyroiditis that causes release of preformed thyroid hormone from the damaged thyroid gland. It is likely that both types of AIT may coexist in some patients.

It is important to distinguish between the two forms of AIT, because the therapies for the two differ. Type I AIT is best treated by high doses of antithyroid drugs, with the possible addition of potassium perchlorate to prevent further uptake of iodine by the thyroid, while type II disease generally responds to high-dose corticosteroids and less so to iopanoic acid.[23] Color-flow Doppler sonography may show hypervascularity in type I disease but reduced blood flow in type II disease.[24,25] Radioactive iodine uptake values are typically low in type II AIT, and usually so in type I disease in the United States, but may be normal or elevated in Europe, where ambient iodine intake is lower. Serum IL-6 has been found to be markedly elevated in most patients with type II disease, but only slightly elevated in some patients with type I AIT,[26] although this observation has not been confirmed in other studies.[24] However, a single non-invasive, inexpensive, readily available, and reliable method for distinguishing between these two entities is not currently available.

The aim of this study was to determine whether CRP levels could help to differentiate between various inflammatory and noninflammatory thyroid conditions, and especially to explore the possibility of using elevated CRP levels as a marker for type II AIT.

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