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Susceptibility to Graves' disease is determined by a mixture of genetic, environmental and endogenousfactors [1]. The mechanisms involved have not yet been elucidated. Some previous studies have assumed that there is a close relation between Graves' disease and catecholamines[2~5]; however, there is no direct evidence to support this assumption.
Although Graves' disease is often accompanied by other autoimmune diseases[6~8], only a few cases of Graves' disease accompanied by pheochromocytoma have been described. Seven cases of pheochromocytoma and concurrent Graves' disease have been reported so far[9~15]. Only one of these cases was reported in Korean[15]. The association between pheochromocytoma and Graves' disease suggests that Graves' disease may be induced by excessive catecholamine secreted by a pheochromocytoma.
We report herein a case of a patient with Graves' disease who presented with a right adrenal tumor incidentally detected on chest computed tomography (CT) scans and was diagnosed with a pheochromocytoma. A brief review of the literature has been included.
Case Report
A 45-year-old woman was referred for the evaluation of a right adrenal incidentaloma. She experienced palpitation, nervousness and weight loss of 6 kg 1 month ago. She visited a local clinic and was diagnosed with Graves' disease. Propylthiouracil (100 mg, twice daily) and propranolol (20 mg, twice daily) were prescribed, but she took them irregularly.
Chest X-ray taken on the routine examination showed a solitary pulmonary nodule (SPN) in the right upper lobe. Thus, chest computed tomography was performed, which revealed an adrenal tumor incidentally on the right side. She was admitted for further evaluation. Her blood pressure was 130/80 mm Hg without orthostatic changes, and her pulse rate was 98 beats per minute. Her body temperature was 36.5℃. Physical examination revealed no abnormal findings except a prominent thyroid. Her thyroid gland was diffusely enlarged, and it was firm and nontender, a thyroid bruit was audible. There was no specific family history.
The results of laboratory tests including complete blood cell counts, liver function tests, serum electrolytes and urinalysis were normal. Thyroid function tests revealed free T4 3.91 ng/dL (normal range, 0.7~1.8), T3 370.2 ng/dL (normal range, 60~190 ng/dL) and thyroid stimulating hormone (TSH) 0.01 µIU/mL (normal range, 0.3~5 µIU/mL). TSH receptor antibody was 73.1% (reference range, 0~5%).
Two consecutive 24-hour urine samples were sent for the measurement of catecholamines, urinary metanephrine and vanillylmandelic acid (VMA) levels were normal. Urinary free cortisol, epinephrine and norepinephrine levels from 24 hour urine sample showed normal levels. Plasma renin activity and the aldosterone level were normal. Serum levels of intact parathyroid hormone (PTH) and calcitonin were within normal limits. Serum and urine hormone levels are shown in Table 1.
Abdominal CT revealed a 4.8 × 3.6 cm heterogenously enhanced mass in the right adrenal gland (Fig. 1). In addition, chest CT showed a 1.2 cm unenhanced SPN in the right upper lobe (Fig. 1). Chest X-ray was not taken previously, so changes in SPN size could not be compared with those from the previous chest X-ray. In addition, since fine needle aspiration cytology was unfeasible due to difficulty in approaching the nodule, positron emission tomography (PET) was performed. No pulmonary nodular uptake was noted on the PET scans, and the SPN was followed up at regular intervals thereafter. Ultrasonography of the thyroid gland showed enlargement of both lobes as well as an approximately 1.0 cm regular shaped nodule in the right lobe of the thyroid gland. And this nodule was diagnosed as benign by fine needle aspiration cytology.
After admission, propylthiouracil was administered at a dose of 100 mg twice daily, but it was discontinued due to the suspicion of agranulocytosis on hospital day 10. White blood cell counts were 2,850/mm3, and absolute neutrophil counts were 969/mm3. There was no evidence of infection, and white blood cell counts normalized after withdrawal of propylthiouracil. She improved after being treated with a dose of 15 mCi of radioiodine (131I).
However, since thyroid function tests performed at the 2 month follow-up showed free T4 2.91 ng/dL (normal range, 0.7~1.8), T3 290.2 ng/dL (normal range, 60~190 ng/dL) and TSH 0.01 µIU/mL (normal range, 0.3~5 µIU/mL), she was treated again with a dose of 15 mCi radioiodine (131I). Thereafter, the results of thyroid function tests were normalized. Because adrenal incidentaloma was 40 Hounsfield units (HU), and 4.8 × 3.6 cm heterogeneously enhanced, the patients underwent a right adrenalectomy using laparoscopic technique (Fig. 2). There were no specific problems during, before, or after the surgery. The final pathological diagnosis was adrenal pheochromocytoma (Fig. 3, 4).
Discussion
We reported a rare case of a patient with Graves' disease accompanied by pheochromocytoma whose urine catecholamines and their metabolites were normal. Graves' disease is considered to be an autoimmune disease. A combination of environmental and genetic factors, including polymorphisms in HLA-DR, CTLA-4, and PTPN22, contributes to susceptibility to Graves' disease[16]. Although Graves' disease is often accompanied by other autoimmune diseases, such as myasthenia gravis, Sjögren's syndrome and autoimmune hepatitis[6~8], only a few cases of Graves' disease accompanied by pheochromocytoma have been described.
Pheochromocytomas are catecholamine-producing tumors derived from chromaffin cells of the adrenal medulla and sympathetic ganglia. They are rare tumors, probably occurring in 0.1~0.2% of patients with hypertension[16]. These tumors may arise sporadically or may be inherited as features of multiple endocrine neoplasia type 2 or several other pheochromocytoma-associated syndromes[16]. There have been seven case reports describing a comorbidity of pheochromocytoma and Graves' disease[9~15]. Paschke et al[13] and Abe et al[14] reported relapse of Graves' disease in patients with pheochromocytoma. They suggested that increased catecholamines in pheochromocytoma act as an exacerbating factor for Graves' disease.
The thyroid gland is richly innervated by autonomic nerves. An increase in circulating catecholamines stimulates basal thyroid hormone secretion. However, the precise roles played by adrenergic components of the thyroid innervation in the regulation of glandular function remain unclear[17]. In some patients, adverse events precede the onset of Graves' disease, suggesting that stress plays an important role as an initiating factor for the disease through catecholamines[2]. Liggett et al observed that thyroid hormone excess is associated with increased sensitivity to catecholamines[3].
TSH is the main trophic factor that controls thyroid function and growth. TSH binds to its receptors and activates the α-subunit of the stimulatory G protein, leading to adenylate cyclase activation and subsequently cyclic AMP (cAMP) production[18]. Hyperthyroidism and goiter are primarily caused by the ability of thyroid-stimulating antibodies to increase the production of intracellular cyclic AMP. In human thyroid cells, catecholamines stimulate cAMP production[4].
Additionally, it is assumed that catecholamines may modulate the immune system. The production of thyroid-stimulating antibodies is dependent on T cells, and circulating T cells recognize multiple epitopes of thyrotropin receptors[5]. Abe et al[14] stated that the relapse of Graves' disease is related to an excess of catecholamines secreted by pheochromocytoma. Catecholamines inhibit Th1 cells and drive a Th2 shift. Graves' disease is thought to be a Th2-driven disease[19]. The definitive mechanism, however, is not well understood.
In our case, the clinical features were not suggestive of pheochromocytoma. There was no excess of catecholamines or their metabolites in plasma or urine.
In patients with pheochromocytoma, catecholamines release of the tumor, uptake and degradation of the released catecholamines may be intermittent, which may lead to normal concentrations of catecholamines in blood and urine, but increased catecholamines metabolites in urine[20]. Urine catecholamines have a sensitivity of 92%, whereas urine fractionated metanephrines have a sensitivity of 97% for the diagnosis of sporadic pheochromocytoma[21]. The conventional method for detecting pheochromocytoma is to identify an increase in urine catecholamines. However, many case reports have shown that urine catecholamines are normal[22,23]. Ozkaya et al[24] reported a case that was diagnosed as pheochromocytoma by pathological examination, although catecholamines and their metabolites in plasma and urine were normal. They called it sublaboratory pheochromocytoma.
In our case, it is uncertain whether beta blocker therapy affected false negative results of catecholamines. Beta-blockers are known to interfere most frequently with the interpretation of 24-hour urine catecholamines and their metabolites.
We reported herein a rare case of pheochromocytoma and concurrent Graves' disease. The relationship between these disease entities remains unclear. Further studies are needed to elucidate its mechanism. Our case provides important information on Graves' disease associated with pheochromocytoma.
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