Early diagnosis of and surgical strategy for adrenal medullary disease in MEN II gene carriers

Sixteen multiple endocrine neoplasia type II (MEN II) gene carriers--12 who had undergone thyroidectomy because of medullary carcinoma of the thyroid and 4 whose thyroid glands had been removed because of C cell hyperplasia--were examined for the presence of pheochromocytomas. No patient had sought medical advice for pheochromocytoma symptoms. Fourteen patients had MEN IIa syndromes, one patient had a MEN IIb and another patient had a mixed syndrome of von Recklinghausen's neurofibromatosis and MEN II. Eight patients had undergone unilateral adrenalectomy for pheochromocytoma 11 +/- 4 years before. The patients underwent clinical examination, determination of the urinary excretion of catecholamines and metabolites, and 131I-metaiodobenzylguanidine (131I-MIBG) and CAT scans. 131I-MIBG scanning was performed with images 1, 4, and 7 days after the radionuclide injection. In seven of eight patients who had undergone unilateral adrenalectomies, the 131I-MIBG scans showed accumulation of the radionuclide in the remaining adrenal gland. Bilateral adrenal accumulation of the radionuclide was demonstrated in seven of eight MEN IIa gene carriers who had not undergone adrenalectomy. Five patients, two of whom had undergone adrenalectomy, were found to have unilateral pheochromocytomas less than 2 cm in diameter. Only one of these five patients had an elevated excretion of urinary catecholamines. Between day 4 and day 7 after 131I-MIBG injection, adrenal glands with pheochromocytomas increased their relative accumulation of the radionuclide significantly more (p less than 0.02) than did adrenal glands without any demonstrable pheochromocytomas. All the pheochromocytomas were viewed by means of CAT scans. Only one MEN IIa patient had bilateral pheochromocytomas, but our findings indicate that there is a tendency to bilateral adrenal medullary hyperfunction in most MEN II gene carriers. As 131I-MIBG and CAT scans can facilitate the early diagnosis of pheochromocytomas, unilateral adrenalectomy can safely be performed in most MEN IIa patients. Bilateral pheochromocytomas develop in a majority of patients with MEN IIb syndromes. Bilateral adrenalectomy should therefore be performed in these patients.     

A case of Sipple syndrome whose bilateral pheochromocytomas were resected separately after a 3-year interval

A 23-year-old woman who had undergone total thyroidectomy and parabronchial lymphadenectomy at the Department of Otolaryngology in our hospital was suspected to have a thyroid carcinoma. Histological examination revealed a medullary carcinoma of the thyroid and normal parathyroid glands. Because a computed tomographic scan after surgery revealed a tumor of the left adrenal gland, the patient was examined at our department two months after the thyroidectomy, 1994. Endocrinic examinations and 123I-MIBG scintigraphy revealed a left adrenal pheochromocytoma of Sipple syndrome. She then underwent left adrenalectomy. Histological diagnosis was pheochromocytoma of the left adrenal gland. Three years after the surgery, a right adrenal tumor was detected by computed tomography. Although results of endocrine examinations were normal, 131I-MIBG scintigraphy showed a hot spot in the right adrenal gland. Right adrenal pheochromocytoma was diagnosed 3 years after surgery for a contralateral adrenal pheochromocytoma. Although surgery was recommended, the patient consented to right adrenalectomy, 1 year later after marriage and before becoming pregnant. Histological examination of the resected specimen revealed pheochromocytoma of the right adrenal gland.     

MRI of pheochromocytoma--comparison with CT, 131I-MIBG, urinary catecholamine level and operative findings]

16 patients (7 male, 9 female) ranging in age from 13 to 71 (44.1 +/- 18.4) years old with clinically diagnosed pheochromocytoma were prospectively evaluated with CT (N = 16), MRI (N = 16), 131I-MIBG (N = 10) and operative findings in order to evaluate their diagnostic efficacy. 1. Normal adrenal glands appeared less intense than the liver on T1-weighted image (T1WI), less intense than or isointense with the liver on both proton density image (PDI) and T2-weighted image (T2WI). 2. Pheochromocytomas with high urinary noradrenaline level appeared less intense than the liver on T1WI, more intense on T2W1 and showed accumulation of radioisotope on 131I-MIBG scintigraphy. In cases with normal urinary noradrenaline level, they appeared less intense than or isointense with the liver on all pulse sequences (T1WI, PDI and T2WI). 3. Although diagnostic accuracy of localization was 81.3% (13/16) by CT, 93.8% (15/16) by MRI and 90% (9/10) by 131I-MIBG scintigraphy, MIBG scintigraphy showed higher diagnostic ability in cases with multiple lesions or recurrent tumors.     

Limitations of 131I-MIBG scintigraphy in locating pheochromocytomas

131I-metaiodobenzylguanidine (131I-MIBG) scintigraphy for the location of pheochromocytomas has proved to be a major advance in patient management. In combination with computerized tomographic scanning, nearly all pheochromocytomas can be located before surgery and invasive investigations are now indicated only in exceptional cases. However, there are still lessons to be learned concerning the optimal administration and interpretation of 131I-MIBG scintigraphy. With careful attention to detail and an awareness of isotope distribution, false positive studies should be extremely rare. While the incidence of false negative studies is uncommon, these certainly occur. A patient with sporadic bilateral adrenal medullary hyperplasia, bilateral pheochromocytomas, and additional benign pheochromocytomas arising in paraganglia tissue anterior to the abdominal aorta is presented. The right adrenal pheochromocytoma was not identified on 131I-MIBG imaging. We conclude that even with current locating techniques, the traditional surgical approach to pheochromocytoma should not be abandoned. This involves transabdominal exploration of both adrenal glands and careful examination of all possible sites of extra-adrenal pheochromocytomas.     

ACTH-independent bilateral macronodular adrenocortical hyperplasia (AIMAH): a case report]

We report a case of adrenocorticotropic hormone (ACTH)-independent macronodular adrenocortical hyperplasia (AIMAH). A 54-year-old Japanese man was admitted to our hospital for further examination of obesity and hypertension. Endocrinological studies showed that plasma cortisol was high (22.5 micrograms/dl) without diurnal rhythm, and plasma ACTH was low. Two or 8 mg of dexamethasone did not suppress the plasma cortisol levels. Abdominal computed tomography revealed nodular hyperplasia of bilateral adrenal glands. Adrenal scintigraphy showed the positive uptake of 131I-adosterol to bilateral adrenal glands. Brain magnetic resonance imaging revealed no abnormalities. He was diagnosed as having Cushing's syndrome with bilateral adrenal hyperplasia, and bilateral adrenalectomy was performed. Left and right adrenal glands were 52 g and 35 g, respectively, and were occupied by yellow nodular lesions. Histologically, hyperplastic lesions were composed of clear cells. Finally he was diagnosed with AIMAH.     

带蒂肾上腺背部皮下移位术治疗肾上腺皮髓质增生

目的 探讨带蒂肾上腺背部皮下移位术治疗肾上腺皮髓质增生的临床疗效. 方法 肾上腺增生患者20例.男6例,女14例.平均年龄36岁.高血压病史6个月～5年.临床表现为向心性肥胖、多血质、紫纹等15例,阵发性肌无力、痉挛、多尿等2例,持续性高血压、阵发性加剧3例.20例均行内分泌检查,其中15例24 h尿17-羟皮质醇(17-OH)41～96μmol/24 h(正常值8～28μmol/24 h)、17-酮类固醇(17-KS)98～164μmol/24 h(正常值28～76μmol/24 h),4例香草基扁桃酸(VMA)90～210μmol/24 h(正常值5～45μmol/24 h),3例肾上腺素(E)349～463 nmol/24 h(正常值0～82 nmol/24 h)、去甲肾上腺(NE)705～1069 nmol/24 h(正常值0～591 nmol/24 h)和多巴胺(DA)2742～4478 nmol/24 h(正常值424～2612 nmol/24 h);3例血醛固酮(Ald)卧位543～720pmol/L(正常值28～139 pmol/L)、立位978～1224 pmol/L(正常值138～415 pmol/L),4例血钾2.6～3.2 mmol/L(正常值4.1～5.6 mmol/L).螺旋CT扫描示双侧肾上腺均匀性增大15例,单侧结节3例;MRI检查4例,显示双侧肾上腺弥漫性增大3例;131间位碘代苄胍(MIBG)肾上腺髓质显像检查5例,显示肾上腺增大3例.术前诊断库欣综合征11例、原发性醛固酮增多症2例、嗜铬细胞瘤1例、肾上腺髓质增生2例、库欣综合征-儿茶酚胺症4例.20例均采用带蒂肾上腺背部皮下移位术治疗,游离、结扎肾上腺中、下极血管,保留上极血管与膈肌相连形成蒂状结构,牵拉至11肋间皮下固定. 结果 20例手术均顺利完成,其中行双侧移位3例,单侧移位及对侧肾上腺切除1例.平均手术时间120 min,平均出血量40 ml,未发生明显外科并发症.术后平均10 d出院.病理诊断20例均为肾上腺皮髓质增生.17例术后随访6个月～8年,平均3年.彩色多普勒超声检查示移位的肾上腺1.5～2.0 cm×2.0～2.5 cm,呈中、低回声,流速0.04～0.07 m/s;其中13例患者临床症状消失,24 h尿17-OH、17-KS、E、NE、DA和VMA、血钾和Ald均恢复正常;4例血压、17-OH和17-KS仍偏高,再行对侧肾上腺移位或切除后,恢复正常. 结论 带蒂肾上腺背部皮下移位术是治疗肾上腺皮髓质增生的有效方法.     

Diagnosis and surgical treatment of adrenal tumors

Adrenal surgery is necessary for the management of functioning adrenal tumors, such as aldosterone-producing adenoma, cortisol-producing adenoma, and pheochromocytoma. The role of adrenal imaging in primary hyperaldosteronism is to separate the surgically resectable unilateral aldosteronoma from bilateral hyperplasia. Once the clinical diagnosis of primary hyperaldosteronism is confirmed, adrenal computed tomography (CT) with 3-mm sections should be the first imaging study. If the results of CT and NP-59 scintigraphy are equivocal, adrenal venous sampling is necessary. Cortisol-producing adrenocortical adenomas are seen as adrenal masses 2.5 cm or larger in diameter in CT scanning. When an adrenal mass measures more than 5 cm in diameter, a functioning adrenal carcinoma should be considered. Symptomatic pheochromocytomas are almost always 2 cm or larger. On MR scanning, pheochromocytomas are extremely bright on T2-weighted images. In patients with ectopic pheochromocytomas, 131I-MIBG scintigraphy should be mandatory. In the past decade, laparoscopic adrenalectomy has replaced open adrenalectomy as a standard operative procedure for benign adrenal tumors. Adrenal-sparing laparoscopic surgery has recently become a feasible option in patients with hereditary bilateral pheochromocytomas.     

Sixty Adrenal Masses of Large Dimensions: Hormonal and Morphologic Evaluation

Objectives. To evaluate the nature and function of adrenal masses of large dimensions (macrotumors).Methods. Sixty consecutive patients (31 women, 29 men, age range 15 to 84 years) with adrenal masses 4.0 cm in diameter or larger (range 4.0 to 15.0 cm) underwent morphologic study by computed tomography (CT); the majority also underwent 131-I-6beta-norcholesterol (131I-NC) or 131I-MIBG scintigraphy. Basal evaluation of glucocorticoids, mineralcorticoids, and catecholamines was performed in all patients, and in 38 cases determination of androgens was also made. In addition, on the basis of various clinical suspicions, a dynamic hormonal study was performed.Results. Macrotumors were benign in 78.3% of cases and included pheochromocytomas (n = 17), nonfunctioning cortical adenomas (n = 12), and cortisol-secreting tumors (n = 7, Cushing’s syndrome). Malignant forms were 21.7% of the total, including pheochromocytomas (n = 3), cortical carcinomas (n = 6), and metastases (n = 4). On CT, malignant masses were larger (8.4 ± 0.9 cm) than benign ones (5.7 ± 0.3 cm) (P < 0.0001) and the mass size was strictly related to malignancy (P < 0.03). CT did not offer other diagnostic criteria for malignancy, except irregular margins and regional lymph node enlargement, which were more frequently (P < 0.0001) found in malignant forms. 131I-MIBG scintigraphy showed tracer uptake in all pheochromocytomas, both benign and malignant. By contrast, on 131I-NC scintigraphy, cortical malignancies never accumulated the radiotracer, whereas uptake was observed in all cases of solid cortical benign adenomas. Patients with cortical carcinomas showed plasma sex steroids above the normal range, pheochromocytomas were asymptomatic in 15% of cases, and almost half of the patients with Cushing’s syndrome did not show clinical features of the disease (pre-Cushing’s syndrome).Conclusions. Adrenal macrotumors frequently show endocrine activity and the medulla seems to be involved more than the cortex. Pheochromocytomas and cortisol-secreting adenomas are sometimes asymptomatic. Malignancy is often found in macromasses and, at least for the cortical forms, size of the tumor on CT, 131I-NC uptake on scintigraphy, and determination of levels of sex steroids seem to be useful criteria for predicting the nature of the mass.     

~(131)I-MIBG肾上腺髓质显像诊断儿茶酚胺症

目的　评价13 1I MIBG肾上腺髓质显像对儿茶酚胺症的诊断价值。　方法　总结 96例儿茶酚胺症及 197例其他疾病患者行13 1I MIBG肾上腺髓质显像的临床资料。　结果　 6 0例嗜铬细胞瘤显像 5 6例 (93.3% ) ,36例肾上腺髓质增生显像 33例 (91.7% ) ;138例原发性高血压、49例肾上腺及其他部位非嗜铬细胞瘤性占位、4例嗜铬细胞瘤术前、10例手术治愈的嗜铬细胞瘤患者、3例肾上腺髓质增生患者呈阴性显像。本组总阳性率 92 .7% (89/ 96 ) ,明显高于生化、B超、CT、MRI等检查的阳性率。　结论　13 1I MIBG肾上腺髓质显像对儿茶酚胺症具有良好的定位、定性价值。对静止期、异位及多发的嗜铬细胞瘤、恶性嗜铬细胞瘤转移灶、肾上腺髓质增生的诊断价值优于其它检查。同时可用于原发性高血压及其他占位性病变与儿茶酚胺症的鉴别诊断。     

Clinical experience of adrenal incidentaloma with particular reference to adrenal cortical function

The adrenal function mainly cortical one, was evaluated in 16 patients with incidentally discovered adrenal masses. Pathological examination was possible in 15 cases. The finding consisted of adrenocortical adenoma in 9, adrenocortical nodular hyperplasia in 1, adrenal medullary hyperplasia in 1, metastatic tumor in 2 and adrenal cyst in 2. Another case of adrenal cyst was diagnosed by percutaneous puncture. In all cases peripheral levels of plasma cortisol, plasma aldosterone concentration and plasma renin activity were normal. Plasma catecholamine levels were also normal except in a case of adrenal medullary hyperplasia. On the other hand, the cases of adrenocortical adenoma displayed elevation of urinary 17-hydroxycorticosteroids in 6/9 (67%), a loss of plasma cortisol circadian rhythm in 3/7 (43%) and insufficient suppression on dexamethasone (DXM) suppression test in 6/9 (67%). Their adrenal scintigraphy (with 131I-6 beta-iodomethyl-9-nor-cholest-5 (10)-en-3 beta-ol) revealed an increased ipsilateral up-take and insufficient suppression after DXM in all, while a diminished contralateral up-take in 4/9 (44%). These data suggested that a considerable number of adrenal incidentalomas may not be truly "non-functioning". Two patients with cortical adenoma experienced post operative adrenal insufficiency (25%). It was suggested that a pre-operative loss of plasma cortisol circadian rhythm was the most prognosticating of the post operative adrenal insufficiency, rather than insufficient DXM suppression or scintigraphic absence of contralateral up-take. Among the patients with malignancy, differentiation of incidental adrenal adenoma from metastasis by size alone may not be reliable.     

Clinical and endocrinological features of adrenocorticotropic hormone- independent bilateral macronodular adrenocortical hyperplasia

PURPOSE: We report clinical findings in 5 patients with adrenocorticotropic hormone independent bilateral macronodular adrenocortical hyperplasia. MATERIALS AND METHODS: In 4 males and 1 female 32 to 61 years old (median age 50) we evaluated clinical symptoms, endocrinological and radiological characteristics, treatment modality and postoperative clinical course. RESULTS: All cases presented with some features of Cushing's syndrome. Endocrinological examination revealed autonomous adrenal cortisol production with suppressed adrenocorticotropic hormone and a loss in the diurnal circadian rhythm of plasma cortisol. Abdominal computerized tomography showed bilateral enlargement of the adrenal glands with multiple nodules. 131Iodine labeled adosterol scintigraphy demonstrated remarkable bilateral uptake by the adrenal glands. The pituitary gland appeared normal on magnetic resonance imaging. Open unilateral complete adrenalectomy and contralateral partial adrenalectomy were performed in patient 1, open bilateral complete adrenalectomy was done in patients 2 and 3, and 2 and 1-stage laparoscopic bilateral complete adrenalectomy was performed in patients 4 and 5. Single removed adrenal glands weighed 32 to 108 gm. (median 60). The histological diagnosis was macronodular adrenocortical hyperplasia in all cases. Postoperative followup was 3 to 90 months. Clinical symptoms of Cushing's syndrome disappeared or improved after surgery in all cases. CONCLUSIONS: Although adrenocorticotropic hormone independent bilateral macronodular adrenocortical hyperplasia is a rare form of Cushing's syndrome, physicians are advised to consider it when diagnosing and treating cases of Cushing's syndrome with enlarged bilateral adrenal glands. Bilateral complete adrenalectomy is currently recommended as the treatment of choice.     

Pheochromocytoma in multiple endocrine neoplasia type II: an example of the two-hit theory of neoplasia

Six kindreds in which pheochromocytomas were present as manifestations of the autosomal dominantly inherited multiple endocrine neoplasia (MEN) type II were studied. The patients underwent bilateral total adrenalectomy with the finding that the pheochromocytomas were bilateral, multifocal, and associated with distinct medullary hyperplasia and reduction in the normal corticomedullary ratio-- features not usually seen in patients with sporadic pheochromocytoma. These findings were exemplified in recent cases of a 34-year-old woman and a 40-year-old man who both had undergone total thyroidectomy for medullary carcinoma of the thyroid. Diagnoses of pheochromocytoma were made by catecholamine studies, computerized tomography, and 131I meta-iodobenzylguanidine (MIBG) scan. Bilateral adrenalectomy was performed with the finding of multiple bilateral pheochromocytomas and adrenal medullary hyperplasia. As in hereditary medullary carcinoma of the thyroid, the histologic findings in pheochromocytomas of the MEN II syndrome are consistent with Knudson's two-mutational-event theory for the initiation of neoplasia, with adrenal medullary hyperplasia representing the manifestation of the first or genetic mutational event and being present invariably in the hereditary cases.     

Parathyroid imaging: comparison of 201Tl-99mTc subtraction scintigraphy, computed tomography and ultrasonography

From 1982 to 1985, twenty-nine patients with suspected hyperparathyroidism were examined using 201Tl-99mTc subtraction scintigraphy (Tl-Tc), computed tomography (CT) and ultrasonography (US). For diagnosing neoplasm (adenoma or cancer), the sensitivities of the three procedures were 80 per cent or more, with no statistically significant differences. For diagnosing hyperplasia of the parathyroid glands, CT scan had the highest sensitivity (47 per cent). The most frequent source of error was minimally enlarged glands, weighing less than 500 mg. The second highest source of error was thyroid nodules, such as adenomatous goiter or cancer. Serum calcium and c-PTH levels were significantly higher in those with a parathyroid neoplasm than in those with hyperplasia (p less than 0.01, p less than 0.05, respectively). We concluded that hyperplasia is less easy to detect than neoplasm, and CT scan is superior to Tl-Tc or US scan for localizing hyperplasia.     

Diagnosis of pheochromocytoma by 131I-MIBG scintigraphy

Between February, 1984, and June, 1988, 131I-metaiodobenzylguanidine (131I-MIBG) scintigraphy was performed on 48 patients with suspected pheochromocytoma at our hospital. Whole body image and/or spot images were obtained 24, 48 and 72 hours after injection of 0.5 mCi of 131I-MIBG. In 10 of 12 patients with surgically proven pheochromocytoma, 131I-MIBG was accumulated in the primary and metastatic tumor. 131I-MIBG scintigraphy was negative in 2 patients. One case of renal cyst had the accumulation of 131I-MIBG but the disease could be confirmed. By 131I-MIBG scintigraphy sensitivity was 83% (10/12), and specificity was 97% (35/36). Heart intensity was much higher in patients with nonpheochromocytoma than those with pheochromocytoma. Thus 131I-MIBG scintigraphy proved to be safe, non-invasive and specific in the diagnosis of pheochromocytoma.     

Dilemmas in the early diagnosis and treatment of multiple endocrine adenomatosis, type II.

Fifteen patients with the diagnosis of multiple endocrine adenomatosis, type II, syndrome (MEA II) were reported from a single center to discuss the dilemmas of early detection and treatment of the adrenal medullary, thyroid, and parathyroid gland diseases. Ten patients came from three families. Three of the patients died, none in hypertensive crisis. Bilateral adrenal medullary disease was present in six patients. Five patients with proved pheochromocytoma had hypertension. All had diagnostic urinary catecholamine values. Nine normotensive patients without proved pheochromocytoma but in a high-risk category for adrenal medullary disease, have multiple suspicious urinary cathecholamines suggestive of adrenal medullary hyperplasia. Bilateral adrenalectomy is recommended for proved adrenal medullary disease in the MEA II syndrome. Medullary carcinoma of the thyroid gland was found in 13 patients and is believed to be present in two others. Five of the proved cases were occult, being discovered by elevation of pentagastrin-stimulated serum calcitonin levels, justifying total thyroidectomy. Parathyroid hyperplasia was found in three patients with preoperative hypercalcemia and in four others with preoperative normocalcemia. Conservative treatment of parathyroid gland hyperplasia in the MEA II syndrome is substantiated. Metachronous phenotypic expression of the syndrome components was significant.     

Multiple endocrine neoplasia type 2. Biological and clinical aspects

CLASSIFICATION: Medullary thyroid carcinoma (MCT), a rare thyroid malignancy originating from the parafollicular C cell, may occur either as a hereditary or a non-hereditary entity. Hereditary MCT can occur either alone, familial MCT (FMCT), or in multiple endocrine neoplasia type 2 (MEN 2), associated with other endocrinopathies such as pheochromocytoma and/or hyperparathyroidism (MEN 2A and 2B). These hereditary disorders are due to germline mutation in the RET proto-oncogene. Early diagnosis and treatment significantly improve the outcome of patients with MCT. DIAGNOSIS: In hereditary MTC, the MTC is usually multifocal and bilateral. Serum calcitonin measurement, a marker of disease, is superior to fine needle aspiration cytology in suggesting the diagnosis of MCT. Other investigations including ultrasonography, chest X-ray, computerized tomography and MRI may provide valuable topographic details in the assessment of the location and size of the primary tumor and metastases. The adrenomedullary disease is usually multicentric and bilateral, often detected after the onset of MCT; this disease is sought by measurement of urinary metanephrines and fractionated catecholamines. The tumor should be localised by computed tomography or MRI scans; 131I-MIBG scintigraphy is used to confirm diagnosis. Primary hyperpathyroidism generally have no symptoms, although hypercalciuria and renal calculi may occur; we screen for this disease by measurement of serum calcium, once hypercalcemia is documented, serum intact PTH should be measured to confirm the diagnosis. High-resolution small part sonography is sometimes used to differentiate parathyroid hyperplasia from solitary adenoma.     

Parathyroid imaging: Comparison of201Tl-99mTc subtraction scintigraphy,computed tomography and ultrasonography

From 1982 to 1985, twenty-nine patients with suspected hyperparathyroidism were examined using²⁰¹Tl-^99mTc subtraction scintigraphy (Tl-Tc), computed tomography (CT) and ultrasonography (US). For diagnosing neoplasm (adenoma or cancer), the sensitivities of the three procedures were 80 per cent or more, with no statistically significant differences. For diagnosing hyperplasia of the parathyroid glands, CT scan had the highest sensitivity (47 per cent). The most frequent source of error was minimally enlarged glands, weighing less than 500 mg. The second highest source of error was thyroid nodules, such as adenomatous goiter or cancer. Serum calcium and c-PTH levels were significantly higher in those with a parathyroid neoplasm than in those with hyperplasia (p<0.01, p<0.05, respectively). We concluded that hyperplasia is less easy to detect than neoplasm, and CT scan is superior to Tl-Tc or US scan for localizing hyperplasia.     

Bilateral pheochromocytomas with von Hippel-Lindau disease: a case report

A case of bilateral pheochromocytomas with von Hippel Lindau disease (VHL) is reported. A 32-year-old man visited Kumamoto Red Cross Hospital for further examination of hypertension. Computed tomography revealed bilateral adrenal tumors and noradrenalin levels in serum and urine were elevated. Suspecting bilateral pheochromocytoma, he was reffered to our hospital for further examination and treatment. 131I-MIBG scintigraphy showed accumulation in bilateral adrenal glands. Moreover, he had cerebellar and spinal hemangioblastomas. Bilateral adrenalectomies and left nephrectomy were performed because tumor thrombus extended into the left renal vein, and pathological diagnosis was pheochromocytoma. His sister had been diagnosed as VHL disease. We diagnosed the patient as VHL disease because of the existence of cerebellar and spinal hemangioblastomas, bilateral pheochromocytomas, missense mutation and his family history. This is the eleventh case of bilateral pheochromocytomas with VHL disease reported in Japanese literatures.     

Tubulointerstitial nephritis and uveitis syndrome associated with hyperthyroidism

We report a 17-year-old male patient with tubulointerstitial nephritis and uveitis (TINU) associated with hyperthyroidism. He presented with a 2-month history of fatigue, loss of appetite, low-grade fever, and a 12-kg weight loss when he was admitted to our hospital. He had iritis, which was complicated by fibrin in the anterior chamber, diagnosed by slit-lamp examination. On laboratory examinations, deteriorated renal function (blood urea nitrogen level was 25.9 mg/dl and creatinine level was 2.82 mg/dl) and elevated urinary levels of N-acetyl-β-D-glucosaminidase (33.1 U/l) and β2-microglobulin (78 600 μg/l) were observed. Serum thyroid-stimulating hormone (TSH) was undetectable, at less than 0.01 μIU/ml, and free triiodothyronine and free thyroxine were elevated, up to 5.23 pg/ml and 2.85 ng/dl, respectively. The titers of antithyroglobulin and antithyroid microsomal and TSH-receptor antibodies were not elevated. Abdominal and thyroidal ultrasonography showed evident bilateral enlargement of the kidneys and diffuse enlargement of the thyroid gland. Iodine-123 scintigraphy showed low uptake in the thyroid gland. The biopsied renal specimen showed mild edema and severe diffuse infiltration of mononuclear cells and few eosinophils in the interstitium, without any glomerular or vascular abnormalities. Based on the clinical features and pathological findings, a diagnosis of TINU syndrome with associated hyperthyroidism was made. Treatment was started with 30 mg/day of prednisolone. The iritis disappeared, and the patient's clinical status improved remarkably. This case suggests the possibility of thyroid dysfunction in some patients with TINU syndrome, and we believe thyroid function should be measured in all TINU patients. Moreover, histopathological diagnosis of the thyroid glands before treatment is necessary for TINU patients with thyroid dysfunction.     

Calcitonin concentrations in patients with chronic kidney disease and medullary thyroid carcinoma or c-cell hyperplasia

It is currently not known which level of pentagastrin-stimulated calcitonin serum concentration indicates medullary thyroid carcinoma in patients with chronic kidney disease (CKD). We examined CKD stage 3-5 patients who had total thyroidectomy because of a pentagastrin-stimulated calcitonin concentration greater than 100 pg/ml, and tested the diagnostic performance of basal and pentagastrin-stimulated calcitonin levels for differentiating medullary thyroid carcinoma and C-cell hyperplasia in this patient population. A total of 180 CKD patients presented with an elevated calcitonin level and had a pentagastrin stimulation test. Forty patients showed a maximum pentagastrin-stimulated calcitonin concentration greater than 100 pg/ml, and 22 patients had a total thyroidectomy. Seven of these 22 patients presented with a medullary thyroid carcinoma, all other patients showed C-cell hyperplasia. Patients with medullary thyroid carcinoma showed higher unstimulated (212 pg/ml (36-577) vs 42 pg/ml (17-150); P < 0.001) and higher maximum pentagastrin-stimulated calcitonin concentrations (862 pg/ml (431-2423) vs 141 pg/ml (102-471); P < 0.001) as compared to patients with C-cell hyperplasia. The sensitivity (100%) and specificity (93%) estimates suggested that a maximum pentagastrin-stimulated calcitonin concentration greater than 400 pg/ml indicates the presence of medullary thyroid carcinoma in patients with CKD. Receiver-operating characteristic (ROC) analysis revealed an area under the ROC plot of 0.99 for maximum pentagastrin-stimulated calcitonin concentrations. A maximum pentagastrin-stimulated calcitonin concentration greater than 400 pg/ml appears to be a clinically meaningful threshold for thyroidectomy.