Heinrich Vierhapper

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.

CYP11B1 mutations causing congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency.

Accurate knowledge of the molecular basis of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency is a prerequisite for genetic counseling, prenatal diagnosis, and treatment. Analysis of nine patients suffering from severe manifestations of this disorder led to the identification of seven novel mutations in their CYP11B1 genes. A Caucasian patient was homozygous for the missense mutation R448H, previously found only in Jews of Moroccan origin. An Iranian patient was found to be homozygous for a different mutation in the same codon, R448C. Of four unrelated patients, two were homozygous for a nonsense mutation (W247X), whereas two others were compound heterozygotes for W247X in combination with either R448H or E371G. Two other patients were homozygous for either the missense mutation A331V or an in-frame CTG insertion adjacent to codon 464 (InsCTG464). One patient was a compound heterozygote for two mutations in exon 2, a 28-bp deletion (delta 28bpEx2) and the missense mutation V129M. All of the missense mutations and the CTG insertion caused a complete loss of steroid 11 beta-hydroxylating activity when expressed in cultured cells. These data support previous suggestions of mutational hot spots in CYP11B1 and confirm that severe clinical manifestations are associated with complete loss of enzymatic activity.

Sporadic versus familial medullary thyroid microcarcinoma: A histopathologic study of 50 consecutive patients

By means of calcitonin screening programs, sporadic and hereditary medullary thyroid carcinoma (MTC) can be detected at an early stage. We investigated the histopathologic findings of 16 familial (mean age 32 ± 21 years, female/male ratio 1.6:1) and 34 sporadic (mean age 58 ± 15 years; female/male ratio 2.4:1) MTCs with stage T1 comparatively. Patients with hereditary tumors were younger. Hereditary tumors were more often found multifocal (13 of 16 vs 3 of 34; p <0.001), bilateral (11 of 16 vs 3 of 34; p <0.001), displaying desmoplastic stroma (14 of 16 vs 19 of 34; p = 0.02), and accompanied by C cell hyperplasia (16 of 16 vs 24 of 34; p = 0.01), but all of these factors were present in some sporadic patients. Only tumors with desmoplastic stroma showed lymph node metastasis, which was observed in eight of the 50 patients. After surgery all patients showed permanent normalization of calcitonin levels. We conclude that 1) morphologic parameters considered to indicate familial MTC risk are of no value in the individual patient, 2) many sporadic MTCs develop on the background of CCH, 3) tumors with desmoplastic stroma are more likely to develop lymph node metastasis, and 4) early detection of MTC permits curative surgery in the majority of patients.

Thyroid ultrasound versus antithyroid peroxidase antibody determination: a cohort study of four hundred fifty-one subjects.

Autoimmune thyroiditis is mirrored by a hypoechoic ultrasound pattern. We determined diagnostic precision of thyroid sonography compared to that of anti-thyroid peroxidase antibody (TPOAb) concentration. Ambulatory patients with unknown thyroid status (n = 451; 407 female, ages 44 +/- 16 years; 45 male, ages 50 +/- 14 years) excluding those with suspected hyperthyroidism or on drugs known to cause hypothyroidism were recruited consecutively. Subjects were recruited from a specialized thyroid outpatient unit with higher frequencies of thyroid disorders than in the general population. Before determination of thyroid function and TPOAb concentration thyroid volume (normal values: women < 12 mL, men < 14 mL) and echogenicity (grade 1 = normal: similar to submandibular gland, hyperechoic to neck muscles; grade 2: hypoechoic to submandibular gland, hyperechoic to neck muscles, grade 3: iso-/hypoechoic to neck muscles) were determined. Positive predictive value of grade 3 pattern for detection of autoimmune thyroiditis was 94% (with overt hypothyroidism) and 96% (with any degree of hypothyroidism), that of grade 2 or 3 85% and 87%, respectively. Negative predictive value of grade 1 pattern for detection of euthyroid TPOAb negative subjects was 91%. Goiter was present in 31% and 21% of TPOAb postive and negative subjects, respectively, while 11% and 15% had an atrophic thyroid gland (p = not significant [n.s.]). Given a high intraobserver and interobserver agreement abnormal thyroid ultrasound patterns were highly indicative of autoimmune thyroiditis and allowed the detection of thyroid dysfunction with 96% probability.

Metabolic Effects of Fish-Oil Supplementation in Patients With Impaired Glucose Tolerance

To determine the impact of fish-oil supplementation on glucose and lipid metabolism in patients with impaired glucose tolerance (IGT), 30 ml fish oil containing 3.8 g eicosapentaenoic acid (EPA; 20:5 ω 3) and 2.5 g docosahexaenoic acid (DHA; 22:5 ω 3) were given to eight obese subjects with IGT (mean ± SD age 50.3 ± 8.0 yr) in addition to their regular diet for 2 wk. Studies were performed in randomized order versus an isocaloric control period with a washout phase of 3 wk. Hyperinsulinemic clamp examinations (1 and 10 mU · kg−1 · min−1) were performed. Glucose disposal rate (M value) rose from basal 14.3 ± 5.1 to 17.9 ± 4.4 μmol · kg−1 · min−1 after fish oil (P < 0.001) during the 1-mU clamp, whereas no change was seen during the 10-mU clamp (without fish oil, 42.2 ± 8.9 μmol · kg−1 · min−1; with fish oil, 45.1 ± 9.8 μmol · kg−1 · min−1;NS). Basal hepatic glucose output remained unaffected by fish oil, whereas fractional glucose clearance after intravenous glucose loading (2.4 mmol/kg body wt, t = 30 min) tended to increase (K value: without fish oil, 2.15 ± 1.02%/min; with fish oil, 2.74 ± 1.26%/min; NS). Neither the fasting concentrations of glucose and insulin nor induced glycemia and insulin response during intravenous glucose loading calculated as incremental area under the curve changed after fish-oil supplementation. Supplementation of ω-3 fatty acids led to a mean decrease in total cholesterol of 15.2% (5.78 ± 1.19 to 4.90 ± 0.83 mM, P <0.02), low-density lipoprotein cholesterol of 20% (4.14 ± 1.00 to 3.36 ± 0.90 mM, P <0.02), apolipoprotein B concentration of 16% (1.25 ± 0.43 to 1.06 ± 0.30 g/L, P < 0.05), and total serum triglycerides of 41% (1.71 ± 0.79 to 1.02 ± 0.39 mM, P < 0.05). High-density lipoprotein cholesterol remained unchanged. Because whole-blood viscosity consistently fell, probably due to an increased erythrocyte deformability, the observed changes in lipid metabolism and blood rheology may also help reduce cardiovascular risk factors in subjects with IGT.

FDG-PET in adrenocortical carcinoma.

Adrenal cortical carcinoma (ACC) is a rare malignant neoplasm with a poor prognosis. Radical surgery of the primary tumor and of local as well as of distant recurrence is the only effective treatment, and requires accurate and early localization of recurrent tumors. In this regard, we prospectively scanned 10 patients with ACC, 8 during follow-up and 2 at primary work-up. In all patients PET scans from the neck to the upper thighs were obtained 45 minutes after injection of 370 MBq [18F]FDG. Reading was done visually, with the investigator blinded to the results of other diagnostic modalities. All known sites of ACC lesions showed markedly increased FDG uptake. In 3 patients, previously unknown lesions were identified by PET in the lung (one lesion), the abdomen (3 lesions), and the skeleton (multiple), respectively. One false positive liver focus was shown by PET aside from the true positive lung metastases in the same patient. The sensitivity/specificity of PET based on different organs was 100/97%, that based on the number of PET-detected lesions (N = 23) was 100/95%. PET altered or influenced the tumor stage in 3/10 patients, modifying the subsequent therapeutic management in 2/10 patients. We conclude that FDG-PET is highly useful in ACC and should be included in the work-up for initial staging as well as for follow-up.

Value of Peptide Receptor Scintigraphy Using 123I-Vasoactive Intestinal Peptide and 111In-DTPA-D-Phe1-Octreotide in 194 Carcinoid Patients: Vienna University Experience, 1993 to 1998

PURPOSEnTo report our experience with both (123)I-vasoactive intestinal peptide (VIP) and (111)In-DTPA-D-Phe(1)-octreotide for imaging to identify primary and metastatic tumor sites in carcinoid patients.nnnPATIENTS AND METHODSnOne hundred ninety-four patients with a verified or clinically suspected diagnosis of a carcinoid tumor were injected with (111)In-DTPA-D-Phe(1)-OCT for imaging purposes, while 133 patients underwent scanning with both (123)I-VIP and (111)In-DTPA-D-Phe(1)-OCT in random order. Imaging results were compared with computed tomography scans, results of conventional ultrasound, endosonography, and endoscopy, and results of surgical exploration in case of inconclusive conventional imaging.nnnRESULTSnPrimary or recurrent carcinoid tumors could be visualized with (111)In-DTPA-D-Phe(1)-OCT in 95 (91%) of 104 patients; metastatic sites were identified in 110 (95%) of 116 patients. In 11 (51%) of 21 patients with suggestive symptoms but without identified lesions by conventional imaging, focal tracer uptake located the carcinoid tumor. In addition, metastatic disease was demonstrated in three patients after resection. In a direct comparison in the 133 patients who underwent both imaging modalities, (111)In-DTPA-D-Phe(1)-OCT was found to be superior to (123)I-VIP, with 35 (93%) of 38 versus 32 (82%) of 38 scans being positive in primary or recurrent tumors, 58 (90%) of 65 versus 53 (82%) of 65 being positive in patients with metastatic sites, and seven (44%) of 16 versus four (25%) of 16 being positive in patients with symptoms but otherwise negative work-ups. Overall, additional lesions not seen on conventional imaging were imaged in 43 (41%) of 158 versus 25 (25%) of 103 scans with (111)In-DTPA-D-Phe(1)-OCT and (123)I-VIP, respectively.nnnCONCLUSIONnBoth peptide tracers have a high sensitivity for localizing tumor sites in patients with ascertained or suspected carcinoid tumors, with (111)In-DTPA-D-Phe(1)-OCT scintigraphy being more sensitive than (123)I-VIP receptor scanning. Both, however, had a higher diagnostic yield than conventional imaging, as verified by surgical intervention or long-term follow-up. The combination of both peptide receptor scans does not seem to further enhance diagnostic information.

Endothelin-1-stimulated glucose production in vitro in the isolated perfused rat liver

The effect of endothelin-1 (ET-1) on production rates of glucose, lactate and cyclic adenosine monophosphate (cAMP) was studied in isolated rat livers perfused in a non-recirculating system. Continuous infusion of ET-1 (0.5 to 10 nmol/L) resulted in a dose-dependent increase in hepatic glucose production, reaching a maximum of 7.56 +/- 1.04 mumols.min-1.100 g bodyweight (BW)-1 at 10(-9) mol/L ET-1 versus 1.32 +/- 0.13 mumols.min-1.100 g BW-1 (P less than .01) after 60 minutes in control experiments. The integral ET-1-induced glucose release (37 +/- 20 mumols.g liver-1) was accompanied by a 15% decrease in hepatic glycogen content (basal, 116 +/- 12, after ET-1, 99 +/- 8 mumols glucose.g liver-1, P less than .05), while 10(-9) mol/L ET-1 affected neither hepatic lactate nor cAMP release versus control experiments. ET-1-induced glucose output was abolished during nominally Ca(2+)-free perfusions (-41.3 +/- 65.2 mumols.100 g BW-1, P less than .01), but was unaffected by 10(-6) mol/L verapamil and only slightly attenuated by 10(-6) mol/L nicardipine (376.3 +/- 101.4, NS, and 244.4 +/- 70.0 mumols.100 g BW-1, P less than .05, respectively). Dantrolene (10(-5) mol/L), an inhibitor of Ca2+ release from the endoplasmic reticulum, reduced glucose release elicited by 10(-9) mol/L ET-1 to 241.1 +/- 57.3 mumols.100 g BW-1 (P less than .05). Pharmacological concentrations of insulin (1 U/L) were required to inhibit ET-1-dependent glucose release by 59% (P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Sporadic hypercalcitoninemia: clinical and therapeutic consequences

Calcitonin screening is not accepted as the standard of care in daily practice. The clinical and surgical consequences of calcitonin screening in a series of patients with mildly elevated basal calcitonin and pentagastrin stimulated calcitonin levels are presented. 260 patients with elevated basal (>10 pg/ml) and stimulated calcitonin levels (>100 pg/ml) were enrolled in this prospective study. None of the patients was member of a known medullary thyroid carcinoma family. Thyroidectomy and bilateral central and lateral neck dissections were performed. Testing for the presence of germ-line mutations was performed in all patients. Histological and immunohistochemical findings were compared with basal and stimulated calcitonin levels. All patients were subsequently followed biochemically. C-cell hyperplasia (CCH) was found in 126 (49%) and medullary thyroid cancer was found in 134 (51%) patients. RET proto-oncogen mutations were documented in 22 (8%) patients (medullary thyroid cancer:18, CCH:4). In 56 (46%) of 122 patients, sporadic CCH was classified neoplastic (carcinoma in situ). Of 97 (72%; 10 with hereditary medullary thyroid cancer) had pT1 (International Union against Cancer recommendations 2002) and 33 (25%) had pT2 or pT3 and 4 (3%) pT4 tumors. Of 39 (29.1%) had lymph node metastases. 106 (79.1%; 15 (38.5%) with lymph node metastases) patients were cured. Evaluation of basal and stimulated calcitonin levels enables the prediction of medullary thyroid cancer. All patients with basal calcitonin >64 pg/ml and stimulated calcitonin >560 pg/ml have medullary thyroid cancer. Medullary thyroid cancer was documented in 20% of patients with basal calcitonin >10 pg/ml but <64 pg/ml and stimulated calcitonin >100 pg/ml but <560 pg/ml.

Effect of Insulin Antibodies on Insulin Pharmacokinetics and Glucose Utilization in Insulin-dependent Diabetic Patients

To determine the impact of insulin-binding antibodies on total (TIRI) and free insulin (FIRI) as well as on insulin sensitivity, 10 insulin-dependent diabetic patients (IDDM) with poststimulatory C-peptide <100 pmol/L and an insulin binding capacity (IBC) between <1 and 294 μg/L serum were studied during and after a 1-h nonprimed, constant-rate insulin infusion (study 1: 0.057 U/kg body wt, study 2: 0.286 U/kg body wt). Euglycemia was maintained by variable glucose infusion. Control studies were performed in 5 healthy subjects. Basal TIRI (mU/L) was lowest in healthy subjects (16 ± 1 [SE]) and elevated in diabetic patients (IBC <25 μg/L: 72 ± 11, IBC >25 μg/L: 1772 ± 842), whereas serum concentrations of FIRI were considerably smaller but still two- to threefold greater (P < 0.01) in the patients than in healthy subjects (13 ± 1). After intravenous (i.v.) insulin administration, almost identical increments in serum TIRI were seen in healthy subjects and in diabetic patients with low IBC (<25 μg/L), whereas those with high IBC (<25 μg/L) had a heterogeneous response. The increments of free serum insulin induced by the infusion of 0.057 and 0.286 U of insulin/kg body wt were almost identical for healthy subjects and diabetic patients, whereas overall glucose utilization, as estimated by the glucose infusion rate necessary to maintain euglycemia, was mostly lower in the diabetic patients (low IBC: study 1: 3.2 ± 0.4 mg/kg min, study 2: 4.0 ± 0.3; high IBC: study 1: 1.2 ± 0.1, study 2: 3.8 ± 0.3) than in healthy subjects (study 1: 3.9 ± 0.6, study 2: 6.1 ± 0.5). Insulin clearance remained constantly within the normal range, but tended to be elevated in diabetic patients with high IBC, who also displayed a 50–100% rise in apparent insulin half-life. We conclude that elevated insulin-binding capacity: (1) increases serum total insulin, but affects serum free insulin only to a minor extent, and (2) is associated with a rise in apparent free insulin half-life in diabetic patients with high IBC only. (3) Insulin sensitivity is significantly impaired in IDDM and is not improved by short-term normal glycemia; and (4) the relative contribution of insulin antibodies and nonimmunologic factors to impaired insulin action in IDDM cannot be separated by the euglycemic clamp technique.