Measurement of calcitonin by immunoassay analyzers.

BACKGROUND: Since Nichols Institute Diagnostics (NID) ended production of their automated calcitonin immunoassay, evaluation of an alternative calcitonin assay was necessary. METHODS: Calcitonin measured by the NID procedure was compared with a test from Diagnostic Products Corporation (DPC). Calcitonin was also measured by assays from DiaSorin (DS) and Scantibodies (SC). RESULTS: In 187 samples, detection failed either by NID (39%) or DPC (96%) assay; in 35% of samples, the tests agreed for non-measurable calcitonin. The regression line DPC=0.78 x NID-0.3 (r=0.998) fitted results from 236 samples with detectable calcitonin. A linear relationship, albeit with scattering at low concentrations, was observed. Importantly, stimulation by pentagastrin above basal calcitonin concentrations yielded similar results with both assays. Comparisons (DPC=0.80 x DS-3.4 and DPC=0.81 x SC-1.1) confirmed an aberrant calibration of the DPC test. To overcome the method bias, we propose a multiplication factor of 0.8 to convert NID to DPC results. CONCLUSIONS: Apparently due to non-specific effects, the DS and SC assays produced calcitonin results in samples from completely thyroidectomized patients, while the DPC assay correctly failed to detect calcitonin. Thus, the DPC assay on an Immulite 2000 analyzer may be used as a more accurate substitute for NID if the different calibration is noted.

Altered platelet plug formation in hyperthyroidism and hypothyroidism.

OBJECTIVE: Patients with thyroid diseases have abnormalities of blood coagulation including an alteration of von Willebrand factor (vWF) levels. Because vWF plays an important role in primary hemostasis, we hypothesized that heightened and decreased vWF levels in hyper- and hypothyroidism enhance and decrease platelet plug formation, respectively. METHODS: We followed a cohort of 120 patients with overt hyperthyroidism, patients with subclinical and overt hypothyroidism, and euthyroid controls. vWF and in vitro platelet plug formation as collagen-epinephrine-induced closure time (CEPI-CT) were measured at baseline and during therapy with thiamazole or T(4). RESULTS: Baseline vWF levels were higher in patients with hyperthyroidism and lower in patients with overt hypothyroidism than in controls (P < 0.01). High vWF antigen levels were associated with increased baseline platelet plug formation in patients with hyperthyroidism as compared with controls [114 sec (95% confidence interval, 105-122 sec) vs. 130 sec (120-140 sec), P = 0.01]. After 8 wk of therapy with thiamazole, serum concentrations of T(4) and vWF levels decreased to normal values (P < 0.01 vs. baseline), and CEPI-CT was prolonged as compared with baseline (P < 0.01). During therapy with T(4), vWF levels increased (P < 0.05 vs. baseline) and CEPI-CT was shortened as compared with baseline (P < 0.01). CONCLUSION: Hyperthyroidism-induced vWF elevation is associated with enhanced platelet function and therefore shortened CEPI-CT values. These changes may contribute to the higher risk for cardiovascular disease in patients with hyperthyroidism. Platelet plug formation decreases during therapy with thiamazole. Furthermore, CEPI-CT appears to be sensitive to detect acquired von Willebrand disease associated with overt hypothyroidism.

Sex-specific difference in the interconversion of cortisol and cortisone in men and women.

OBJECTIVE: Our objective was to demonstrate that the smaller oxoreductase activity of 11beta-HSD1 in women would shift the interconversion of cortisol and cortisone toward cortisone, resulting in a larger amount of generated labeled cortisone in healthy women than in healthy men. RESEARCH METHODS AND PROCEDURES: Using mass spectrometry, the amount of cortisone generated from a continuous infusion (8 am to 6 pm) of stable-labeled cortisol (1alpha,2alpha-d-cortisol) was determined in non-obese and in obese (BMI>35 kg/m2) men and women during steady-state conditions (from 2 pm to 6 pm). In this setting, the amount of generated labeled cortisone (expressed as % of the achieved steady-state concentrations of labeled cortisol) reflects the sum of the bi-directional conversion of cortisol into cortisone (and vice versa) by 11beta-hydroxysteroid dehydrogenase. RESULTS: The amount of generated labeled cortisone was higher in men than in women (p<0.0001). This sex difference was higher in obese than in non-obese patients (p=0.0062). CONCLUSIONS: The interconversion of cortisol and cortisone during steady-state conditions is shifted toward cortisol in men as compared with women. This suggests a higher overall oxoreductase activity of 11beta-hydroxysteroid dehydrogenase type 1 in men than in women. This sex-specific difference is maintained in obesity.

Vitamin D status and its relation to age and body mass index.

BACKGROUND/AIMS: While numerous studies have examined 25(OH)-vitamin D(3) (25-D) concentrations and their relation to parathyroid hormone (PTH) levels there is only limited information on the interrelation between 25-D, 1,25(OH)(2)-vitamin D(3) (1,25-D) and PTH. It was the aim of this study to assess the vitamin D endocrine system and its relation to age and body mass index (BMI). METHODS: This cross-sectional study comprised a convenience sample of 483 adults which attended the endocrinology outpatient service of a university hospital in the years 2002-2004. RESULTS: The mean concentrations of 25-D, 1,25-D, calcium and PTH were 21.0 +/- 10.6 ng/ml, 47.9 +/- 21.7 pg/ml, 9.48 +/- 0.48 mg/dl and 51.0 +/- 27.2 pg/ml, respectively. 25-D was related (p < 0.01) to BMI, age, PTH and 1,25-D. After correction for 25-D, we found no relation between BMI and 1,25-D. PTH was related (p < 0.01) to serum calcium, BMI, age and 1,25-D (p = 0015). There was a seasonal variation in both, 25-D and 1,25-D serum concentrations: 25-D levels were lowest in January and increased until July while the nadir and zenith of 1,25-D were found in April and October, respectively. CONCLUSION: Since BMI was negatively related to 25-D the prevalence of 25-D deficiency (<8.8 ng/ml) increased from 8.8% in subjects with BMI <30 kg/m(2) to 15.0% in subjects with BMI >30 kg/m(2). BMI, age and season should be taken into account when assessing a patients vitamin D status and more aggressive vitamin D supplementation should be considered for obese subjects.

A newly identified RET proto-oncogene polymorphism is found in a high number of endocrine tumor patients.

Multiple RET proto-oncogene transcripts, due to genomic variations and alternate splicing, have been described. To investigate endocrine tumor tissue characteristic RET proto-oncogene expression, we performed quantitative RT-PCR, Northern blot and Southern blot analyses of benign and malignant endocrine-derived tissues. We newly describe RET proto-oncogene expression in carcinoid-, gastrinoma- and insulinoma-derived tissue samples. In addition, the presence of a 3'-terminally truncated RET proto-oncogene mRNA variant in benign and malignant thyroid neoplasias, as well as in a pheochromocytoma, an ovarian carcinoma and a medullary thyroid carcinoma, is demonstrated. Southern blot analysis revealed no evidence of gross RET proto-oncogene rearrangements or deletions. As the underlying cause for a bi-allelic TaqI restriction fragment length polymorphism (RFLP), a C (allele 1)/T (allele 2) transition within intron 19, was characterized. This polymorphism is close to a recently described polyadenylation site and lies within a binding site for the nucleic acid binding protein Pbx-1. Screening of healthy subjects and of patients suffering from various endocrine malignancies revealed exclusively allele 1 homozygous and allele 1/allele 2 heterozygous genotypes. Heterozygous genotypes were found in a significantly higher percentage in samples derived from endocrine tumor patients when compared with those from healthy control subjects. Homozygosity for allele 2 was found exclusively in somatic DNA derived from endocrine tumors with high malignant potential. Analysis of DNA derived from varying regions within individual anaplastic thyroid carcinomas revealed an allele 1/allele 2 switch of the RFLP banding pattern, indicating loss of heterozygosity at the RET proto-oncogene locus. In conclusion, our data demonstrate presence of a 5'-terminal RET proto-oncogene transcript in endocrine tissues and reveal a bi-allelic RET proto-oncogene polymorphism. A heterozygous genotype for this polymorphism is found in a considerable number of endocrine tumor patients.

Production rates of cortisol in obesity.

OBJECTIVE: To determine the metabolic clearance rates (MCRs) and endogenous production rates (PRs) of cortisol (F) in grades 2 and 3 obese men (n = 9) and women (n = 6). RESEARCH METHODS AND PROCEDURES: The MCRs and the endogenous PRs of cortisol (F) were determined in grades 2 and 3 obese men (n = 9) and women (n = 6) using the stable isotope dilution technique and mass spectrometry. RESULTS: In obese women, endogenous PRs of F (0.6 +/- 0.4 mg/h) were similar to those of nonobese women, but MCRs of F were higher in obese women (9 +/- 4 L/h) compared with nonobese women (5 + 2 L/h; p < 0.05). The MCR of F was correlated with the ratio of excreted cortisone to F metabolites. Furthermore, obese women were characterized by an increased ratio of androsterone to etiocholanolone (p < 0.01). In obese men, the MCRs (11 +/- 6 L/h) and the endogenous PRs of F (0.6 +/- 0.3 mg/h) were both similar to those of nonobese men, but the MCR of F was directly correlated with the ratio of excreted cortisone to F metabolites (r = 0.7833, p = 0.012). DISCUSSION: These data demonstrate sex-specific differences in F metabolism in obesity. The rise in MCRs of F is more pronounced in obese women than in men. However, the increase in the MCR of F is moderate in both genders and exceeds the normal range only in a subgroup of obese individuals.

Relationship between serum lipoprotein ratios and insulin resistance in obesity.

BACKGROUND: The fasting serum lipid profile [triglycerides (TGs), total cholesterol (TC), and LDL- and HDL-cholesterol (LDL-C and HDL-C)] is used to calculate lipid ratios (TC/HDL-C, LDL-C/HDL-C, TG/HDL-C) that allow identification of individuals at increased risk for cardiovascular disease. Because these individuals are also frequently insulin resistant, this study analyzed the relationships between lipid ratios and insulin sensitivity. METHODS: In 132 obese [mean (SE) body mass index, 37.5 (0.6) kg/m(2)] outpatients without known diabetes mellitus, fasting serum lipid profiles and 75-g oral glucose tolerance tests were performed. Insulin sensitivity was assessed from surrogate estimates for fasting (QUICKI) and dynamic (OGIS) conditions. RESULTS: After exclusion of other endocrine diseases (n = 35), the remaining patients were classified as glucose tolerant (n = 56), glucose intolerant (n = 22), or as having type 2 diabetes (n = 19). QUICKI and OGIS indicated severe insulin resistance in all individuals with type 2 diabetes and impaired glucose tolerance compared with glucose-tolerant individuals: QUICKI, glucose tolerant, 0.302 (0.002); glucose intolerant, 0.290 (0.002); type 2 diabetes, 0.281 (0.005); P <0.001; OGIS (mL . m(-2) . min(-1)), glucose tolerant, 343 (7), glucose intolerant, 293 (9); type 2 diabetes, 256 (12); P <0.001. Serum TG (P <0.005) and TG/HDL-C ratios (P <0.05) were increased in individuals with impaired glucose tolerance. TG/HDL-C ratios negatively correlated with QUICKI (r = -0.370; P < 0.001) and OGIS (r = -0.333; P < 0.005) in nondiabetic individuals (glucose tolerant plus glucose intolerant), but not in patients with type 2 diabetes (not significant). CONCLUSIONS: This study demonstrates that the TG/HDL-C ratio positively correlates with insulin resistance in severely obese nondiabetic individuals.

Positron emission tomography imaging of adrenal masses: (18)F-fluorodeoxyglucose and the 11beta-hydroxylase tracer (11)C-metomidate.

PURPOSE: (11)C-metomidate (MTO), a marker of 11beta-hydroxylase, has been suggested as a novel positron emission tomography (PET) tracer for adrenocortical imaging. Up to now, experience with this very new tracer is limited. The aims of this study were (1) to evaluate this novel tracer, (2) to point out possible advantages in comparison with( 18)F-fluorodeoxyglucose (FDG) and (3) to investigate in vivo the expression of 11beta-hydroxylase in patients with primary aldosteronism. METHODS: Sixteen patients with adrenal masses were investigated using both MTO and FDG PET imaging. All patients except one were operated on. Five patients had non-functioning adrenal masses, while 11 had functioning tumours(Cushing's syndrome, n=4; Conn's syndrome, n=5; phaeochromocytoma, n=2). Thirteen patients had benign disease, whereas in three cases the adrenal mass was malignant (adrenocortical cancer, n=1; malignant phaeochromocytoma, n=1; adrenal metastasis of renal cancer, n=1). RESULTS: MTO imaging clearly distinguished cortical from non-cortical adrenal masses (median standardised uptake values of 18.6 and 1.9, respectively, p<0.01). MTO uptake was slightly lower in patients with Cushing's syndrome than in those with Conn's syndrome, but the difference did not reach statistical significance. The expression of 11beta-hydroxylase was not suppressed in the contralateral gland of patients with Conn's syndrome, whereas in Cushing's syndrome this was clearly the case. The single patient with adrenocortical carcinoma had MTO uptake in the lower range. CONCLUSION: MTO could not definitely distinguish between benign and malignant disease. FDG PET, however, identified clearly all three study patients with malignant adrenal lesions. We conclude: (1) MTO is an excellent imaging tool to distinguish adrenocortical and non-cortical lesions; (2) the in vivo expression of 11beta-hydroxylase is lower in Cushing's syndrome than in Conn's syndrome, and there is no suppression of the contralateral gland in primary aldosteronism; (3) for the purpose of discriminating between benign and malignant lesions, FDG is the tracer of choice.

Hyperprolactinaemia in hypothyroidism: clinical significance and impact of TSH normalization.

OBJECTIVES: Menstrual irregularities in hypothyroidism have been reported to occur less frequently than previously described. We therefore studied the influence of serum PRL in patients with newly diagnosed subclinical and overt hypothyroidism and in hyperprolactinaemic patients treated with T4 to distinguish the impact of hypothyroidism from that of confounding drugs on hyperprolactinaemia and menstrual irregularities. PATIENTS AND METHODS: PRL was determined in 1003 consecutive hypothyroid patients (TSH > 4.0 mU/l) at referral, and after TSH normalization in 84 (8%) initially hyperprolactinaemic (female, > 480 mU/l; male, > 432 mU/l) subjects. Medical history (psychotropic drugs and oestrogens) and menstrual patterns were assessed at referral and after 8 +/- 5 (mean +/- SD) months of T4 therapy. Pituitary magnetic resonance imaging (MRI) was offered to patients with persistently elevated PRL. RESULTS: Menstrual disturbancies (oligomenorrhoea/secondary amenorrhoea, O/A) were not more common (P = NS) in hyper- than in normoprolactinaemic women (26% and 16%, respectively). We observed no galactorrhoea and no correlation between PRL and TSH or O/A except in pregnant or lactating women (N = 11). Oestrogens or antidepressants (including selective serotonin reuptake inhibitors) did not cause hyperprolactinaemia but antipsychotic drugs did. PRL decreased with T4 therapy (P < 0.01) in patients not using confounding drugs (from 720 +/- 288 to 360 +/- 192 mU/l) but menstrual irregularities persisted. PRL remained unchanged in patients receiving antipsychotic treatment. PRL was also unchanged in patients with pituitary abnormalities (seven micro-, one macroadenoma). CONCLUSIONS: Hyperprolactinaemia was not an important feature in patients with newly diagnosed hypothyroidism. Neuroleptic drugs may cause persisting hyperprolactinaemia after TSH normalization. In addition, menstrual disturbancies do not relate to hyperprolactinaemia in hypothyroidism.

Long-term follow up of a "sporadic" unilateral pheochromocytoma revealing multiple endocrine neoplasia MEN2A-2 in an elderly woman.

A unilateral, apparently sporadic pheochromocytoma was removed from the right adrenal of a 73-yr-old Caucasian woman. At the time of surgery, germline DNA from the patient was not available. However, a continuous cell line (KNA) established from the tumor showed a heterozygous sequence variant TGC (cysteine) to TGG (tryptophan) in exon 10, codon 611 of the RET proto-oncogene. Subsequent genetic testing of the patient and her offspring revealed the same base-change in herself, one daughter, one son, and the only grandson, confirming hereditary disease classified as MEN2A-2. Clinical follow up of the patient revealed elevated serum calcitonin after 6 yr. Thyroidectomy was performed and revealed a small medullary thyroid carcinoma. The patient's children thus far show no evidence of MEN2, but C-cell hyperplasia has been diagnosed in the grandson. Our serendipitous finding of a MEN2A-2 mutation in a patient with initial diagnosis of late onset, unilateral, "sporadic" pheochromocytoma would argue for routine mutation screening of even elderly patients presenting with a pheochromocytoma.

Homocysteine: a risk factor for cardiovascular disease in subclinical hypothyroidism?

The role of homocysteine as a causal risk factor for cardiovascular disease remains controversial. Moderately elevated total plasma homocysteine levels have been reported in patients with overt hypothyroidism, a condition that is associated with an increased risk for cardiovascular disease. Recently, subclinical hypothyroidism has been identified as an independent risk factor for atherosclerosis and myocardial infarction in elderly women. Therefore, we measured prospectively total fasting plasma homocysteine levels in 37 consecutive subjects (6 males, 31 females, mean age 50 +/- 18 standard deviation [SD] years) with newly diagnosed subclinical hypothyroidism at baseline and after 3-4 months of levothyroxine supplementation. During levothyroxine treatment concentrations of thyrotropin (TSH) decreased from 10.1 +/- 5.8 (SD) to 1.5 +/- 1.8 mU/L. Fasting total plasma homocysteine levels were not elevated at baseline (9.9 +/- 2.9 micromol/L) and remained unchanged (9.6 +/- 3.5 micromol/L) after levothyroxine treatment. Serum folate or vitamin B(12) levels also remained unchanged. We conclude that subclinical hypothyroidism is not associated with hyperhomocysteinemia. Levothyroxine supplementation has no influence on total plasma homocysteine levels in subclinical hypothyroidism. Hence, total plasma homocysteine does not appear to contribute to the increased risk for atherosclerotic disease and myocardial infarction in patients with subclinical hypothyroidism.

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.

Multiple endocrine neoplasia type 1 (MEN1) in Austria.

Multiple endocrine neoplasia type 1 (MEN1) is a rare cancer predisposition syndrome. It results from the autosomal dominant inheritance of inactivating germ-line mutations of the MEN1 tumor suppressor gene. Mutation carriers are prone to develop tumors, preferentially, of the parathyroid and anterior pituitary glands as well as the enteropancreatic endocrine tissues. Because such tumors also occur without the MEN1 context, we have set up a molecular genetic screening program in Austria to discriminate between heritable and non-heritable tumor forms. Following the recognition of a MEN1-specific germ-line mutation in a tumor patient, we extend the screening to all first-degree relatives. To date, we have studied 42 individuals by sequencing the coding exons 2 to 10 of the MEN1 gene. A germ-line mutation was discovered in four of seven families suspected, clinically, to have MEN1, and in 3 of 22 (13.6%) patients with a presumed sporadic endocrine tumor. The respective mutations were also detected in three first-degree relatives of whom only one 6-year-old boy was asymptomatic at the time of investigation. The possibility to clearly discriminate between genetically predisposed and non-predisposed individuals has a significant impact on the diagnosis and clinical management of both patients and their relatives. Both symptomatic and asymptomatic mutation carriers can be closely monitored, thereby allowing early recognition and treatment of developing tumors. Non-affected relatives, on the other hand, do not require further controls. Finally, this approach also provides the information necessary for reliable genetic counseling.

Multiple endocrine neoplasia 1--current recommendations for diagnosis and treatment.

BACKGROUND: The principally affected glands in the MEN 1 syndrome (parathyroids, pancreas, pituitary and adrenal glands) are often diffusely or multi-centrically involved, making different therapeutic approaches necessary. METHODS: In a retrospective analysis of 10 patients with genetically proven (n = 7) or clinically suspected (n = 3) MEN 1 syndrome, recommendations for diagnosis, timing of interventions and surgical procedures are reviewed. RESULTS: All patients had primary hyperparathyroidism (PHPT). An extended bilateral exploration localized 4 or more enlarged glands in 6 patients and subtotal parathyroidectomy (SPTX) was performed. In 4 patients, only one (n = 2) or two (n = 2) enlarged glands were removed. Two patients were reoperated for persistent PHPT and one patient developed recurrent PHPT. In 3 out of 6 patients, neuroendocrine pancreatic tumors were the first manifestation. 2 patients had solitary, one patient multiple benign and one patient multiple malignant insulinomas. Tumors were removed by enucleation, distal pancreatic resection or a combination of both. Out of the 2 patients with gastrinomas, one underwent partial pancreatoduodenectomy and the other has refused operation up to now. During follow-up, no persistence or recurrence of hormone excess was diagnosed. Three patients had non-functioning bilateral lesions of the adrenal glands, and one of these additionally had a small, clinically insignificant pheochromocytoma. Adrenalectomy was performed during pancreatic surgery in 2 patients, and endoscopically in one patient. Pituitary tumors were treated in 3 patients. CONCLUSION: A high index of clinical suspicion, biochemical screening and menin gene testing, according to current guidelines, is mandatory for early diagnosis of MEN 1. In PHPT with multiglandular involvement and neuroendocrine pancreatic tumors, meticulous surgery can achieve a long-term cure in the majority of patients, with low morbidity.

Screening for medullary thyroid carcinoma: experience with different immunoassays for human calcitonin.

Calcitonin measurements in patients with nodular thyroid disease are helpful for early diagnosis and therapy of medullary thyroid carcinoma. We compared three commercial calcitonin assays routinely used: "CIS" (France), "Medgenix" (Belgium) and "Nichols-Advantage" (USA). In addition, we evaluated a two-step modification of the Medgenix-test and an enzyme immunoassay from Sangui (Japan). Method comparison studies revealed deviations from linear relationships between all routine assays. While histograms of CIS and Nichols results were similar at low concentrations with their highest frequency below 1 pg/ml, Medgenix showed a broad peak around 3 pg/ml. Correlation coefficients were 0.69 (CIS versus Medgenix) and 0.91 (CIS versus Nichols). In thyroidectomized patients, calcitonin was not detectable with CIS and Nichols, but the Medgenix test, which was more susceptible to interference, measured about 6 pg/ml. The immunoassay of Sangui showed insufficient analytical sensitivity. About 70-80% of calcitonin levels initially > 10 pg/ml were reproduced in the basal levels of the subsequent pentagastrin test. Average ratios (stimulated/basal level) were slightly higher for CIS and Nichols than for Medgenix. Prediction of a pathological stimulation from basal calcitonin was insufficient with CIS and Medgenix assays. If a calcitonin concentration of > 100 pg/ml (CIS) is considered as an indication for surgery, equivalent values are 71 pg/ml for Medgenix, and 96 pg/ml for Nichols. Using these criteria, about one third of patients who underwent pentagastrin stimulation showed pathological reactions. Reliable and sensitive calcitonin assays used for the screening of sporadic medullary thyroid carcinomas in patients pre-selected by nodular goiter are important for health and economic reasons, because they enable early therapy.

Recommendations for reporting C cell pathology of the thyroid.

BACKGROUND: Calcitonin screening programs have proved to be effective in early detection of medullary thyroid carcinoma, not only in patients with known risk factors for the development of hereditary tumors. Thus, more thyroidectomies, based on an abnormal pentagastrin test, can be expected. Here we give summarizing recommendations for reporting C cell pathology. METHODS: All patients underwent total thyroidectomy and were tested for germ-line mutations in the RET-Protooncogene. The entire surgical specimens were blocked and C-cell disorders were assessed using conventional histology and immunohistochemistry. RESULTS: Among 110 patients with an abnormal pentagastrin test, 60 (55%) had medullary thyroid carcinoma (T1 34% [n = 37], T2 14% [n = 16], T4 6% [n = 7]), and 50 (45%) had C cell hyperplasia only. C cell hyperplasia accompanying medullary thyroid carcinoma was found in 13 of 15 familial and in 28 of 45 sporadic patients. All C cell changes were found in the upper two thirds of the thyroid lobes and 83% of the medullary thyroid carcinomas could be identified with frozen sections. CONCLUSION: 1. Abnormal pentagastrin stimulation is always associated with either medullary thyroid carcinoma or C cell hyperplasia. 2. Blocking of the entire upper two thirds of the thyroid lobes is essential for reliable detection of C cell hyperplasia and small medullary thyroid carcinomas. 3. Most medullary thyroid carcinomas can be detected with intraoperative frozen sections. 4. The presence of C cell hyperplasia should always be reported; however its usefulness for indicating familial risk is limited and its role as a preneoplastic condition in patients without RET-protooncogene mutations remains to be elucidated.