Exercise induces excessive normetanephrine responses in hypertensive diabetic patients.

BACKGROUND: Exaggerated sympathoadrenal function has been accused of contributing to hypertension in type-2 diabetes. Recently, plasma unconjugated (free) metanephrines were reported to be stable markers of catecholamine hypersecretion. Thus, we aimed to examine whether unconjugated metanephrines are reliable markers of stress response induced by standardized cycling exercise and to identify differences in such stress responses between hypertensive and/or diabetic patients. DESIGN: Type-2 diabetic patients with (DM/H; n= 8, 50 +/- 7 years, HbA1c: 7.7 +/- 0.6%) or without hypertension (DM/N; n = 6, 48 +/- 10 years, 7.5 +/- 1.8%) and nondiabetic hypertensive patients (H; n = 8, 56 +/- 4 years) were studied during incremental cycling exercise (15 min) to 75% of individual VO(2)max and during recovery (60 min). Plasma catecholamines and unconjugated metanephrines were measured by high-performance liquid chromatography with electrochemical detection. Hormone responses were quantified from the areas under the concentration-time curves and compared with those of age-, sex- and BMI-matched healthy volunteers (CON, n= 22). RESULTS: Blood pressure responses of DM/H and H, but not DM/N, were greater than those of CON (P < 0.01), whereas heart rates increased similarly in all groups. Unconjugated normetanephrine responses were only increased (P = 0.04) in DM/H (2156 vs. 1133 pg mL(-1) min(-1) but not in DM/N (1528 vs. 1300 pg mL(-1) min(-1) and H (1960 vs. 1425 pg mL(-1) min(-1) when compared with respective CON. Unconjugated metanephrines did not change from baseline, whereas catecholamine responses were comparable in all groups. CONCLUSIONS: The excessive response of plasma unconjugated normetanephrine to cycling may serve as a marker of exaggerated sympathoadrenal function in hypertensive type-2 diabetic patients.

Thyroxine treatment modified in infertile women according to thyroxine-releasing hormone testing: 5 year follow-up of 283 women referred after exclusion of absolute causes of infertility.

BACKGROUND: Mild hypothyroidism may contribute to disturbed reproductive function. We hypothesized that frequent thyroxine-releasing hormone (TRH) testing to fine-tune thyroxine (T4) therapy instituted upon every TRH-induced thyroid-stimulating hormone (TSH) rise above the mean of a healthy population (i.e. 15 mIU/l) would improve fecundity compared with historical data. METHODS: In a cohort of 283 infertile women followed over 5 years, we assessed (i) pregnancy, abortion and delivery rates, (ii) thyroid function over time in women who conceived compared with those who did not, and (iii) various thyroid parameters with respect to fertility. RESULTS: Overall conception rate of 37% was higher (P < 0.05) than previously reported and independent of thyroid function prior to T4 therapy, thyroxine dose or elevated thyroid autoantibodies. Never achieving basal TSH <2.5 IU/l or TRH-stimulated TSH <20 mIU/l with T4 therapy resulted in lower conception rates (P < 0.05). Median time to conception was 6 months, but 18 months in women who declined TRH testing (P < 0.02). Overall abortion rate was 9%. Only first trimester miscarriages occurred. CONCLUSIONS: Based on the presented protocol, high pregnancy and parturition rates were observed. Whether this is due to early T4 therapy remains to be determined. Abortions appeared to be associated with higher TSH but not with elevated thyroid antibodies.

Quantification of unconjugated metanephrines in human plasma without interference by acetaminophen.

BACKGROUND: Pheochromocytoma is a rare cause of hypertension resulting from increased catecholamine secretion. We aimed to develop a method to measure unconjugated plasma normetanephrine (NMN) and metanephrine (MN) without interference from acetaminophen, a widely prescribed drug for headaches. METHODS: Plasma samples were obtained from 48 subjects (23 males, 25 females; mean age, 49 +/- 14 years; hypertension, n = 37) under resting conditions. Following extraction on solid-phase cation-exchange columns, unconjugated metanephrines were analyzed by HPLC with electrochemical detection and with 4-hydroxy-3-methoxybenzylamine as an internal standard. Catecholamines were measured by HPLC. RESULTS: The assays were linear up to 2000 pg for NMN and for MN. Intraassay imprecisions (CVs) were 4.7% for NMN and 7.0% for MN, and the interassay CV was 12% for both NMN and MN. The limit of detection was 11 fmol for NMN and 17 fmol for MN. Ingestion of acetaminophen or its addition to plasma did not interfere with the MN peaks. Plasma NMN and MN were positively correlated (r = 0.52 and 0.49, respectively; P <0.01 for both) with the respective catecholamines. Plasma NMN (r = 0.27; P = 0.02) but not MN positively correlated with age, whereas only plasma catecholamines (and not metanephrines) were positively correlated (P <0.05) with diastolic blood pressure. CONCLUSIONS: This sensitive MN assay is not affected by simultaneous acetaminophen medication, and reveals a correlation of metanephrines with plasma and urinary catecholamines and age but not with blood pressure.

Serum calcium in thyroid disease.

Thyroid hormones are believed to influence calcium metabolism. In the present prospective study we investigated the influence of various thryroid diseases on serum calcium levels. In addition to screening for thyroid diseases we measured serum calcium concentrations (S-Ca) in individuals who came to our outpatient service for thyroid diseases from 1992 to 1998. 13,387 persons, among them 9017 patients with thyroid diseases and 4370 persons without thyroid dysfunction, were studied. S-Ca was found to be higher in patients with hyperthyroidism (2.36 +/- 0.11 mmol/L n = 1201, p < 0.05) than in those with subclinical hyperthyroidism (2.33 +/- 0.11 mmol/L, n = 494), with euthyroid goiter (2.32 +/- 0.10 mmol/l, n = 5599), with hypothyroidism (2.31 +/- 0.11 mmol/L, 344), with subclinical hypothyroidism (2.32 +/- 0.10 mmol/L, n = 1290) and in healthy persons (2.31 +/- 0.11 mmol/L, n = 4370). 173/13,387 persons had serum calcium levels < 2.1 mmol/L, among them 31 patients with hypoparathyroidism after strumectomy (31/592) and 2 patients with primary hypoparathyroidism. 106/13,387 persons showed a S-Ca of > 2.6 mmol/L, which in 30 cases was due to primary hyperparathyroidism. Of 55 persons with S-Ca of > 2.6 mmol/L and without any other reason for hypercalcaemia, 31 were found to be in a hyperthyroid state. In conclusion, a clinically not relevant influence on S-Ca was demonstrated in patients with hyperthyroidism as compared with other thyroid diseases and individuals with no thyroid diseases. Measurement of S-Ca in every patient being referred to a thyroid outpatient department is recommended because of the frequent occurrence of postoperative hypoparathyroidism and primary hyperparathyroidism in this setting.

Variant intra philadelphia translocation with rearrangement of BCR-ABL and ABL-BCR within the same chromosome in a patient with cALL.

A unique variant Philadelphia translocation accompanied by the loss of the short arm of chromosome 9 in a 32-year-old female with common acute lymphoblastic leukemia (cALL) is described. Furthermore, supernumerary chromosome 8 material was found as an insertion into the long arm of chromosome 2 and/or as ring chromosomes in addition to two normal chromosomes 8. The chromosomal abnormalities were identified by combined conventional chromosome banding analysis and fluorescence in situ hybridization (FISH). The BCR-ABL rearrangement was confirmed by FISH and reverse transcriptase-polymerase chain reaction (RT-PCR) studies. Possible mechanisms leading to this variant intra Philadelphia translocation are discussed. The aberrations found have prognostic implications, because 9p anomalies confer an adverse effect to the already poor prognosis of Philadelphia-positive ALL.

Low-density lipoprotein cholesterol in subclinical hypothyroidism.

The significance of subclinical hypothyroidism in regard to ensuing hyperlipidemia remains unclear. Because an unfavorable lipid profile would provide a possible explanation for the reported association of coronary-heart disease with this syndrome, we have evaluated the relationship of thyrotropin (TSH) with total cholesterol, low-density-lipoprotein (LDL) cholesterol, and triglycerides in patients with normal thyroid function (n = 4886) as well as subclinical (n = 1055) and manifest (n = 92) hypothyroidism. Serum concentrations of LDL cholesterol were similar in euthyroid persons (134+/-39 mg/dL) and in patients with subclinical hypothyroidism (137+/-40 mg/dL) but were higher (178+/-70 mg/dL, p < 0.01) in overt hypothyroidism. Within the group of subjects with subclinical hypothyroidism there was no apparent relationship between serum concentrations of TSH ranging from 4.0 to 49.0 microU/mL and concentrations of LDL cholesterol. Thus, there is no "threshold value" of TSH in these patients per se necessitating substitution therapy with thyroxine.

Risk factors for malignancy of thyroid nodules initially identified as follicular neoplasia by fine-needle aspiration: results of a prospective study of one hundred twenty patients.

Indeterminate or suspicious findings on fine-needle aspiration (FNA) of nodular thyroid disease (i.e., findings that neither give immediate indication for surgery nor lead to clear-cut conservative management) have been the key diagnostic problem in thyroid cytology for which the inability to differentiate cytologically benign from malignant follicular growth has been one reason. The aim of this cohort study of 120 consecutive (103 females, 17 males) patients with palpable nodular thyroid disease diagnosed as follicular neoplasia (FN) by FNA (defined by the triad of high numbers of follicular cells, microfollicular arrangement, and scanty or absent colloid) was to identify patients at high risk for malignancy based on the prospective evaluation of clinical features and to characterize the histologic entities of FN. Based on a 100% surgery rate we found an 18% malignancy rate (12 papillary carcinomas, 9 follicular carcinomas). Previously suggested factors with elevated risk for malignancy such as extremes of age, male gender, and large nodule size were not associated with increased risk as were cold nodules by 99mTc-scintigraphy (relative risk: 1.2, 95% confidence interval [CI] 0.4-3.3). However, hard lesions to palpation (relative risk 2.6, 95% CI: 1.2-5.6), solitary (relative risk: 2.6, 95% CI: 1.7-4.0), and hypoechoic FNs (relative risk: 3.4, 95% CI: 2.0-5.7) by ultrasound showed elevated risks of malignancy. In summary, suspicious palpation or ultrasound results may help to define a subgroup of patients with elevated risk of malignancy when FNA indicates the diagnosis of follicular neoplasm of the thyroid.

Diagnostic efficacy of unconjugated plasma metanephrines for the detection of pheochromocytoma.

BACKGROUND: Recently, measurement of plasma metanephrines was suggested to improve the detection of pheochromocytoma compared with the other common biochemical tests. OBJECTIVE: To examine the diagnostic precision of measurements of plasma metanephrines, plasma catecholamines, and urinary catecholamines and to assess their variability. METHODS: Plasma metanephrine as well as plasma and urinary catecholamine concentrations were measured by high-performance liquid chromatography with electrochemical detection. Before surgery, responses of plasma metanephrines and catecholamines to change of posture were determined. Intraoperatively, metanephrines and catecholamines were measured before skin incision, during maximal mechanical tumor manipulation, and repetitively after the tumor was separated from the circulation. Patients were reexamined 1 and 3 months after surgery. Patients with pheochromocytoma (n = 17) and with histologically proved other adrenal tumors (n = 14) were studied before, during, and after surgery. RESULTS: Measurement of plasma metanephrines and plasma and urinary catecholamines provided 100% and 82% sensitivity, respectively, for the detection of pheochromocytoma (P<.001). Levels of plasma catecholamines but not metanephrines increased in response to change of posture (norepinephrine, P =.03; epinephrine, P =.07) and intraoperative stress (norepinephrine, P =.002; epinephrine, P =.009). CONCLUSIONS: Plasma metanephrines offer improved efficacy for the diagnosis of pheochromocytoma. Less variability in response to external factors may favor plasma metanephrines in the screening for this disease. Arch Intern Med. 2000;160:2957-2963

Medical therapy of Graves' disease: effect on remission rates of methimazole alone and in combination with triiodothyronine.

In a prospective, randomized study of 135 newly diagnosed patients with hyperthyroidism due to Graves' disease we compared the effect on remission rates of additional triiodothyronine (T3) with conventional antithyroid drug therapy. To this end 114 patients were followed for at least 12 months (15.7+/-4.9, mean+/-s.d.) after the discontinuation of any therapy. After return of thyroid function to normal (8.5+/-7.4 weeks, mean+/-s.d.) patients were maintained on antithyroid medication for 9.0+/-2.5 months. They were then randomly assigned to one of three groups: group 1 (n=44) stopped methimazole, groups 2 (n=39) and 3 (n=31) continued with exogenous T3 (not exceeding 75 microgram/day in any patient) for a further 6 months either with (group 2) or without (group 3) a fixed dose of 10mg methimazole daily. The T3 dose was kept variable to keep TSH suppressed (<0. 1mU/l), which could be achieved in 82% of patients on 100% of their monthly visits. No serious side-effect requiring the discontinuation of the study occurred in any patient. Total T3, TSH-receptor antibodies and some previously suggested potential predictors of relapse including thyroid size by ultrasound, 24h urinary iodine excretion, history of cigarette smoking and ophthalmopathy were determined at the outset of the study and subsequently every 6 months (and total T3 every 4 weeks). No significant difference (P>0.05, Chi square) was seen in relapse of hyperthyroidism after a mean follow-up of 16 months (range: 12-31 months; groups 1:52%, 2:44% and 3:42%) in an area of low-to-moderate iodine intake (prevalence of 24h urinary iodine excretion <100 microgram/24h: 17 and 25% at two different measurements respectively). Concomitantly, no predictor of recurrence of disease could be identified, irrespective of treatment modality.

Spuriously high serum concentrations of TSH due to the use of an automatic pipetting device.

In a clinically hyperthyroid patient a TSH-value of 0.75 mU/L was measured. Upon retesting TSH was <0.1 mU/L. The patient's sample initially had been preceded, in the pipetting device, by a grossly hypothyroid patient's sample. Analogous problems were subsequently documented in 10 cases when samples of other hyperthyroid patients were preceded by samples with modestly to markedly elevated TSH. The spurious elevation of TSH (0.12 to 1.18 vs. <0.1 mU/L) appears to be due to a carryover effect from the respective previous sample within the used automatic pipetting system. This carryover was much larger than previously suggested, and occurred unpredictably.

Prevalence of primary hyperparathyroidism in 13387 patients with thyroid diseases, newly diagnosed by screening of serum calcium.

Primary Hyperparathyroidism (PHP) often goes unrecognised. Evidence of the influence of thyroid diseases on parathyroid activity exists. In order to determine the prevalence of primary hyperparathyroidism (PHP) in patients with thyroid diseases, a series of patients referred to an outpatient department for patients with thyroid diseases were examined for additional PHP. In addition to screening for thyroid diseases, serum calcium concentration (S-Ca) was measured in a series of persons who came to our outpatients' service for patients with thyroid diseases during the period 1992 to 1998. 13387 persons, median age 48 y, m = 2367, f = 11020, among them 9017 patients with thyroid diseases and 4370 persons without thyroid dysfunction, were studied. In patients with S-Ca outside the normal range, further diagnostic tests relating to PHP were performed. 106/13387 persons showed S-Ca > or = 2.6 mmol/L, in 31 cases due to PHP. In comparison to persons without thyroid diseases, the occurrence of PHP was significantly higher in patients with thyroid diseases (4/4370 = 0.09% vs. 26/9017 = 0.29%). Furthermore, 2 patients with normal S-Ca were diagnosed as having PHP in addition to another endocrine disease (acromegaly, multiple endocrine neoplasia type IIa, resp.). 31 of the 54 persons with S-Ca > 2.6mmol/L and who showed no other reasons for hypercalcaemia were found to be in a hyperthyroid state. The prevalence of PHP was significantly higher in patients with euthyroid goitre (p < 0.05) and in patients with thyroid carcinoma (p = 0.01) as compared to other persons with thyroid diseases. The groups of patients did not differ with regard to age. However, patients without thyroid diseases were significantly younger (median age 38y). Above the age of 50, the prevalence of PHP became higher in patients with euthyroid goitre or thyroid carcinoma than in those with a healthy thyroid gland. In contrast, in persons of under 50 y, there was no difference between these groups. The percentage of males with PHP was higher than in the total population studied (30% vs. 21.5%). In conclusion, a high occurence of PHP could be demonstrated in patients with thyroid diseases (0.29%) as compared to persons without thyroid dysfunction (0.09%), the highest prevalence being in patients with thyroid carcinoma. A clinically not relevant influence of thyroid function on S-Ca was seen in some patients with hyperthyroidism. Determination of S-Ca is recommended for each patient referred to a thyroid outpatients' department because of the high number of PHP cases in this context.

Serum uric acid concentration and thyroid-stimulating-hormone (TSH): results of screening for hyperuricaemia in 2359 consecutive patients with various degrees of thyroid dysfunction.

Serum uric acid concentration (sUA) and hyperthyroidism have been reported to positively correlate with each other. Furthermore, epidemiological data indicate that uric acid may be an independent risk factor for hypertension-associated morbidity and mortality. To evaluate whether screening for hyperuricaemia might be worthwhile in patients with hyperthyroidism we determined serum concentrations of uric acid in 2359 consecutive patients (1939 female, 420 male; age: 48 +/- 17 years, mean +/- SD) with various degrees of thyroid dysfunction (hyperthyroidism: n = 242; subclinical hyperthyroidism: n = 143, hypothyroidism: n = 71, subclinical hypothyroidism: n = 212) and in 1688 euthyroid subjects. No association (r = 0.03) between sUA and total T4/TSH was detected. The significant difference (p < 0.05) in serum uric acid between hyperthyroid (4.8 +/- 1.32 mg/dl) and euthyroid (4.5 +/- 1.32 mg/dl) patients was of no clinical significance. We conclude that routine determination of sUA in hyperthyroid patients is not warranted.

Consanguinity in question in two patients with congenital adrenal hyperplasia who bear an identical first and last name--second look.

Two patients with identical first and last name, both suffering from Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency, were investigated in our endocrine outpatient unit. The families of the two girls did not know of each other's existence. Although paternal ancestors were identified up to the 11th and 9th previous generations, respectively, and a common area of origin, roughly 50 km apart, in the northwestern part of the Czech Republic (formerly Austrian Silesia) was established, no common ancestor was found. The patients' respective paternal CYP 21B allele was identical. However, by means of analysis of class I-and class II-HLA regions in both patients and their respective parents no common paternal haplotype was established. In order to still postulate consanguinity by the same paternal haplotype it is necessary to assume that two recombinations in the HLA region must have occurred. The probability that these two events have taken place within the past 11 generations is 0.11%.

[Preventive iodine administration and iodine excretion in the Vienna area and in the forest quarter]. / Jodprophylaxe und Jodausscheidung in den Regionen Wien und Waldviertel.

In order to reduce the still substantial iodine deficiency in the Austrian population, compulsory iodisation of salt was increased in 1990 from 10 mg potassium iodide/kg salt to 20 mg potassium iodide/kg. In this investigation we evaluated the adequacy of iodine supply in Vienna and the Waldviertel, a rural region northwest of Vienna. Daily iodine excretion (which reflects daily iodine intake) was investigated in 92 persons from the Waldviertel (all without thyroid gland pathology) and 110 persons from Vienna (54 with unremarkable thyroid glands, 56 with endemic goiter). Daily iodine excretion was higher in persons from the Waldviertel (161 +/- 90.7 micrograms/24 h, p < 0.05) than in those from Vienna (with healthy thyroid glands 126.4 +/- 42.9 micrograms/24 h and with goiter 117.2 +/- 60.5 micrograms/24 h, resp.). In both populations iodine supply as defined by the WHO (excretion of > 150 ug iodine/day) was inadequate. The recommended level was not achieved in 50% of the persons from the Waldviertel region and in 75% of persons from Vienna (healthy thyroid glands 76%, goiter: 75%). Iodine deficiency (intake < 100 micrograms/24 h) was present in 42% persons from the Waldviertel and in 31% and 24% persons, respectively, from Vienna with unremarkable thyroid glands and goiter. We conclude that although the iodine content of salt was increased, an iodine deficiency was present in a considerable portion of the population of an industrialized country (approximately 40% of persons from a rural region and 30% from the city of Vienna).

How (not) to diagnose growth hormone deficiency in adults: stimulated serum concentrations of growth hormone in healthy subjects and in patients with pituitary macroadenomas.

The secretion of growth hormone (GH) stimulated by GH-releasing hormone ([GHRH] 100 micrograms intravenously [IV]) was determined in 33 patients with nonfunctioning pituitary macroadenomas before and after transsphenoidal adenomectomy and in 28 controls. Patients who needed substitution therapy for at least one additional pituitary hormone presented with lower GH secretion than the remaining patients with pituitary tumors. However, there was a marked overlap of stimulated GH secretion between these two groups (3.2 +/- 4.3 ng/mL and 7.2 +/- 6.6 ng/mL, respectively) and between either group with the control group (7.1 +/- 5.5 ng/mL). In an independent investigation, the effect of IV GHRH (100 micrograms) on the secretion of GH in seven healthy volunteers was shown to be comparable to that seen during an insulin tolerance test ([ITT] 0.1 U/kg IV). Thus, the GHRH stimulation test, a simple and comparatively unharmful procedure, is a useful alternative to the ITT in patients with potential pituitary defects. However, the pronounced overlap of stimulated serum GH concentrations in patients with pituitary macroadenomas and those estimated in healthy subjects and in patients with nonpituitary diseases underlines the difficulty in biochemically defining acquired GH deficiency in adults. We suggest that GH therapy in adults should primarily be instituted in patients with additional defects in anterior pituitary function.

Routine measurement of plasma calcitonin in nodular thyroid diseases.

In a prospective study, plasma concentrations of human calcitonin (hCT) were determined in 1062 consecutive patients with thyroid nodular disease. Basal plasma hCT was above the normal range (>6 pg/mL) in 55 patients and was elevated up to more than 100 pg/mL (range, 127-5459) in 3 of these 55 patients. A pentagastrin-induced rise in hCT up to more than 100 pg/mL was observed in only 1 of 38 patients with a basal concentration of hCT between 5-10 pg/mL, but was found in 10 of 31 patients with basal hCT ranging from 10-100 pg/mL. Histologically, 7 of the 14 patients with either basal or stimulated plasma concentrations of hCT above 100 pg/mL presented C cell hyperplasia, which in one case showed histological transition into a small (diameter, 3 mm) medullary thyroid carcinoma (MTC). Including this patient, MTC was found in 6 of the 12 patients. We conclude that the routine determination of hCT in all patients with thyroid nodular disease should be supplemented by pentagastrin-stimulation when the basal hCT concentration exceeds 10 pg/mL. Patients with basal and/or stimulated plasma CT concentrations of more than 100 pg/mL should be operated on because they run a substantial risk to suffer either MTC or C cell hyperplasia, a potentially precancerous condition. This will increase the chance of a timely diagnosis of MTC and provide the chance of curative surgery.

[The "cold" nodule of the thyroid gland: 20 years experience with 2,071 patients and diagnostic limits of fine needle biopsy]. / Der "kalte" Knoten der Schilddrüse: 20jährige Erfahrung mit 2071 Patienten und diagnostische Grenzen der Feinnadelbiopsie.

The files of 2071 patients with (Tc99m)-scintigraphically "cold" thyroid nodules (CTN) attending a teaching hospital were analysed retrospectively. Between 1975 and 1995 altogether 49 endocrinologists with varying degrees of experience carried out the clinical evaluation as well as fine needle aspiration biopsy (FNAB), and 33 pathologists undertook the cytological interpretation. By clinical criteria the CTN of 1272 patients were deemed benign, whilst malignancy was suspected in 301 patients (81% and 19% of evaluable cases, respectively). A cytological diagnosis was made in 47.3% of all FNAB performed ("benign" in 611 patients, "follicular neoplasia" in 86, and "malignant" in 39 patients; 39.3%, 5.5% and 2.5%, respectively). 36.5% of the clinically suspect CTN and all nodules with a cytological diagnosis of either "follicular neoplasia" or "malignant" in patients who could be followed up after the FNAB procedure were treated surgically, leading to a total of 420 histological diagnoses. 76% and 35% of the CTN classified as being suspicious of malignancy in the preoperative clinical and cytological evaluation, respectively, were found to be malignant on histology. A clinical assessment of "no abnormality" and "normal" cytology missed a malignant lesion in 16.3% and 15% of cases, respectively. Thus, under routine teaching hospital conditions, the selection of patients with CTN for surgery cannot be based on cytological criteria alone. The FNAB in this setting should be employed exclusively to supplement the clinical and scintigraphically findings.