Prognostic value of post-thyroidectomy thyroglobulin levels in patients with differentiated thyroid cancer.

BACKGROUND: Thyroglobulin is an excellent biological marker of persistent or recurrent thyroid cancer during long-term follow-up. Most studies investigated its diagnostic value but not its prognostic value over time. We aim to study the prognostic value of thyroglobulin levels early after total thyroidectomy, before iodine ablation. METHODS: The study was based on the Rabin Medical Center registry of patients with non-medullary thyroid carcinoma. Data were collected on the clinical, laboratory, and outcome characteristics of 420 consecutive patients followed at our institution for whom early post-operative pre-ablation thyroglobulin values (baseline thyroglobulin) were available. RESULTS: Patients were classified into 4 groups by baseline thyroglobulin level: 0-2, 2-10, 10-100, and >100 ng/ml. Higher levels were associated with a shift toward male gender (p=0.01), larger tumor size (p=0.02), and a more extensive disease (p<0.0001). They were also related to disease persistence and evidence of disease at last follow-up (p<0.0001). The 10 ng/ml cut-off level identified patients with persistent disease with a sensitivity and specificity of 73%, positive predictive value of 43%, and negative predictive value of 89%. On multivariate analysis, the following variables were predictive of persistent disease: baseline thyroglobulin level, male gender, lymph-node involvement, distant metastases, higher tumor invasiveness, and larger tumor size. However, the predictive power of baseline thyroglobulin level was relatively weak (odds ratio 1.002, 95% confidence interval 1.00-1.04). CONCLUSIONS: In patients with well-differentiated thyroid cancer, a post-thyroidectomy thyroglobulin level <10 ng/ml is associated with a low probability of having persistent disease and can be used combined with other disease characteristics for decisions regarding treatment and follow-up.

Clinically silent chromaffin-cell tumors: Tumor characteristics and long-term prognosis in patients with incidentally discovered pheochromocytomas.

BACKGROUND: Chromaffin-cell tumors (CCT), a rare group of catecholamine producing endocrine neoplasms, are traditionally suspected and diagnosed in patients presenting with episodic hypertension, together with the classic triad of headache, sweating, and tachycardia. Asymptomatic CCT are increasingly diagnosed, frequently as "incidentalomas". We have conducted a multicenter retrospective study, to assess the characteristics of a group of patients with clinically silent CCT, compared with a group of patients with typical CCT. METHODS: Forty-three consecutive patients with CCT (24 with silent and 19 with typical tumors) have been retrospectively studied for a period of up to 20 yr (between 1989 and 2009); clinical picture, biochemical tests, as well as topographic and functional assessment were analyzed at diagnosis and periodically following treatment. Surgical samples were reviewed for neuroendocrine markers and for signs of invasiveness. RESULTS: Patients with clinically silent CCT were significantly older than the typical ones (56.3±3.4 vs 48.0±4.8 yr; p<0.05); 15 of them (63%) were completely asymptomatic, and 9 patients (37%) complained of non-specific abdominal symptoms. Hypertension was present in only 6 silent CCT patients (25%), it was well controlled [mean blood pressure (BP) 134/84 mmHg], and persisted after surgery in only 2 patients. Fourteen out of twenty-four silent CCT patients (58%) were managed pre-operatively with prophylactic combination of α and ß blockade, despite normal BP values. Clinically silent CCT were larger than typical CCT (mean diameter of 5.2±2.3 cm vs 4.6±1.5 cm, p<0.05) and secreted higher a mounts of normeta neph rines. All clinically silent CCT patients were defined as "cured" after surgery. CONCLUSION: Clinically silent CCT are more prevalent than previously reported. With an adequate pre-surgical diagnosis and patient preparation, the prognosis of silent tumors is usually excellent.

Subacute thyroiditis: clinical characteristics and treatment outcome in fifty-six consecutive patients diagnosed between 1999 and 2005.

OBJECTIVE: To identify predictive factors of clinical outcome of subacute thyroiditis. DESIGN: Retrospective case series of 56 consecutive patients treated in 3 outpatient clinics between 1999 and 2005. Medical records were reviewed for demographic data, seasonal disease distribution, laboratory and clinical course, treatment, and short-term outcome. MAIN OUTCOME: Mean age was 48.6+/-12 yr; 70% were females. Twenty-five percent had antithyroid antibodies and 9% had recurrent disease. Differences in occurrence by season were not significant (p=0.28). Ultrasound, performed in 35 patients, revealed thyroid nodules in 25 (median size, 17 mm). Ten patients received no treatment, and 43 received either non-steroidal anti-inflammatory drugs (NSAID) (no.=25) or glucocorticoids (no.=18); data for 3 patients were missing. Median disease duration was 77 days; mean peak free T4 (FT4) level was 43.7+/-25.3 pmol/l. A hypothyroid phase was documented in 31 patients, and remained permanent in 6. Peak FT4 level, but not erythrocyte sedimentation rate or clinical score, was positively correlated with the highest TSH level and with disease duration. Untreated patients had less severe clinical disease than treated patients, but a similar outcome. Patients given glucocorticoids had a shorter overall disease duration (p=0.03), with no differences in duration of hyperthyroidism, peak FT4 or highest TSH levels, compared with patients given NSAID. CONCLUSION: Subacute thyroiditis follows an unpredictable clinical course that is hardly affected by its clinical features or treatment.

Impact of a two-arm educational program for improving diabetes care in primary care centres.

Improvement of the quality of diabetes care is essential for reducing diabetes complications. Nevertheless, compliance with diabetes clinical practice recommendations is inadequate in primary care. The aim of this study was to assess the impact of diabetes education, when directed simultaneously to both diabetes care providers and patients, on the frequency of performance of relevant laboratory tests and improvement of metabolic control. A three-step educational program was applied at 45 community clinics of a health-managed organisation comprising 175 health care providers and 16,275 diabetic patients. At the end of a 2-year period, the proportion of diabetic patients with HbA1c tested at least once a year rose from 60 to 85%. The percentage of patients with HbA1c <7% rose from 38 to 50%, whereas the percentage with HbA1c >8.5% decreased from 27 to 19%. The number of patients visiting an eye clinic at least once yearly rose from 55 to 65% and of those undergoing microalbumin testing from 27 to 37%. There was a 20% increase in the number of patients with low-density lipoprotein cholesterol measurements. Our study demonstrates the efficacy of diabetes education when directed simultaneously to health care providers and diabetic patients. The improvement in quality of care induced by such intervention can translate into better metabolic control and, ultimately, the prevention of diabetes complications.

Pituitary and bilateral adrenal enlargement: an unusual presentation of hepatocellular carcinoma.

Pituitary metastases account for about 1% of operated pituitary lesions. Most derive from primaries in the breast or lung. Pituitary metastases from hepatocellular carcinoma (HCC) have rarely been reported. We describe a patient in whom headache and left external ophthalmoplegia were the only presenting signs of a clinically silent and radiographically undetectable HCC, that had metastasized to the pituitary and both adrenal glands. Pituitary histology and adrenal needle biopsy failed to establish the final diagnosis, which was reached only after surgical exploration of the abdomen. This case illustrates the difficulties encountered in the histopathological diagnosis of pituitary metastasis and the need for good clinical judgment when confronting pituitary tumors with atypical features.

Pulmonary function in patients with diabetes mellitus.

BACKGROUND: Pulmonary complications of diabetes mellitus have been poorly characterized. Although some authors have reported normal pulmonary function, others found abnormalities in lung volumes, pulmonary mechanics, and diffusing capacity. SUBJECTS AND METHODS: We studied pulmonary function in a group of patients with diabetes using a combined cardiopulmonary exercise test. Twenty-seven patients with diabetes aged 48 +/- 13 years participated in the study. RESULTS: Overall, forced vital capacity, forced expiratory volume in 1 second, and forced expiratory flow, midexpiratory phase, were within the predicted values, but the residual volume/total lung capacity ratio was slightly elevated. Comparison by diabetes type showed nonsignificant differences in forced expiratory volume in 1 second and forced expiratory flow, midexpiratory phase. Residual volume/total lung capacity ratio was significantly elevated in type 1 patients compared with type 2. Carbon monoxide diffusion capacity (DLCO) was normal in both groups. There was no correlation between the results on pulmonary function test and duration of disease, presence of microangiopathy, or glycemic control. The DLCO was significantly lower in patients with microangiopathic changes, but not when DLCO was corrected for alveolar volume. On the cardiopulmonary exercise test, maximal workload, maximum oxygen uptake, and maximal heart rate were less than predicted, whereas anaerobic threshold and ventilatory reserve were normal. No significant differences were noted in diabetes type, and there was no correlation between parameters of cardiopulmonary exercise test and the other variables. CONCLUSION: Spirometric values are preserved in patients with diabetes mellitus, and there are no defects in diffusing capacity. Cardiovascular factors may account for impaired physical performance. There is no need for routine screening of pulmonary function among diabetic patients.

Hospitalization for general medical conditions among diabetic patients in Israel.

BACKGROUND: Diabetes mellitus is a serious, costly and growing public health problem. Very few studies have been published on the economic impact of diabetes in Israel. OBJECTIVE: To estimate health fund expenditures and rates of hospitalization for general conditions among the diabetic population in Israel. METHODS: The total number of hospitalizations in Israel in 1998 of beneficiaries of the General Sick Fund (Kupat Holim Clalit) was obtained from its bureau of statistics. The diabetic and general populations were compared for age and gender distribution, days of hospitalization and cost of hospitalization. All hospitals in Israel were included. RESULTS: There were 618,317 general admissions for a total of 3,005,288 hospitalization days. The diabetic population accounted for 11.5% of all admissions and 13.7% of all hospitalization days. Analysis by age revealed that diabetic patients over age 45 represented 18.3% of all admissions and 17.5% of all hospitalization days. The average stay in hospital was 4.8 days per patient for the general population and 5.3 days for diabetic patients. The overall hospital expenditure of the GSF for general medical conditions among diabetic patients in 1998 was estimated at US $173,455,790, of which 57% accounted for the daily hospitalization cost. Of the total hospital expenditures for that year, 13.3% was allocated to patients with diabetes of whom 96.4% were over 45 years old. No significant difference was found between males and females. CONCLUSION: Hospital expenditures for diabetic people increase with patient age and represent one-fifth of the total health insurance expenditure for the middle-aged and elderly population.

Amiodarone-induced thyrotoxicosis type 2: a case report and review of the literature.

Amiodarone-induced thyrotoxicosis (AIT) is not an uncommon complication in countries with low iodine intake. Two types of AIT have been described. Type 1 is associated with an underlying disorder of the gland that becomes clinically evident because of the high intrathyroidal iodine content, which acts as a trigger for hyperthyroidism. Type 2 is characterized by an ongoing inflammatory process of the thyroid, with derangement of the parenchyma causing the release of thyroid hormones into the circulation. Yet, there are no definitive tools for the differential diagnosis of these two entities, and the therapeutic approach is still a subject of controversy. A case of AIT type 2 successfully treated with steroids is described followed by a review of the literature.

Changes in bone mineral density after discontinuation and early reinstitution of growth hormone (GH) in patients with childhood-onset GH deficiency.

We measured bone mass density (BMD) in 28 childhood-onset adult GHD patients (20 MPHD, 8 IGHD) treated with hGH until final height. Twelve were re-treated with hGH (0.06 U/kg/day three times per week) for 16-24 months and eight of them followed for up to 5 years. Age at start of the study was 23.6 +/- 5.7 years (mean +/- SD) and the interval since the first hGH treatment was 5.8 +/- 4.4 years Baseline BMD was 82% of young normal healthy subjects. Patients < 20 years had a lower BMD than those > 20 years (75 vs 87%;P = 0.004). In the 12 patients re-treated with GH, BMD was 5.3% above baseline at 6 months after treatment was stopped (P< 0.002), and remained so for 3.5 years in eight patients who completed follow-up. In conclusion, increases in BMD occur after cessation of growth, but continuation of hGH treatment after final height achievement may prevent the late osteopenia of patients with childhood-onset GHD.

Interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor alpha (TNF alpha) regulate insulin-like growth factor binding protein-1 (IGFBP-1) levels and mRNA abundance in vivo and in vitro.

TNF alpha and IL-1 alpha are thought to contribute to impaired anabolism in a variety of clinical states, including sepsis, cancer cachexia and the AIDS wasting syndrome. We asked whether cytokines exert direct effects on hepatic production of IGFBP-1, an important modulator of IGF bioavailability. C57BL/6 mice were treated with 100 micrograms/kg of recombinant IL-1 alpha or TNF alpha by intraperitoneal injection. Western ligand blotting and immunoprecipitation with specific antisera revealed that serum levels of IGFBP-1 (but not IGFBP-2, -3, -4, -5 or -6) are increased approximately 4 fold 2 h after treatment and then decline. Northern blotting confirms that hepatic IGFBP-1 mRNA abundance also is increased acutely in both IL-1 alpha- and TNF alpha-treated animals. Similar results obtained in adrenalectomized mice indicate that adrenal activation is not required for this effect. Cell culture studies show that cytokines exert direct effects on the production of IGFBP-1 by HepG2 hepatoma cells, increasing IGFBP-1 levels in conditioned medium and the abundance of IGFBP-1 mRNA approximately 3-fold. In contrast, transient transfection studies with IGFBP-1 promoter/luciferase reporter gene constructs show that IGFBP-1 promoter activity is reduced after 18 hr cytokine treatment. We conclude that IL-1 alpha and TNF alpha increase circulating levels of IGFBP-1, reflecting direct effects on hepatic IGFBP-1 mRNA abundance. Stimulation of hepatic IGFBP-1 production may contribute to alterations in IGF bioactivity and impaired anabolism in clinical conditions where cytokine production is high. Additional studies are required to identify specific mechanisms mediating effects of cytokines on hepatic production of IGFBP-1.

Circulating levels of insulin-like growth factor (IGF) binding protein-1 and -3 in aging men: relationships to insulin, glucose, IGF, and dehydroepiandrosterone sulfate levels and anthropometric measures.

Reduced secretion of GH and production of insulin-like growth factor I (IGF-I) contribute to altered body composition in human aging. IGF-binding proteins (IGFBPs) are important modulators of IGF action, yet little is known regarding their role and regulation in aging. Accordingly, we measured levels of IGFBP-1, an important short term modulator of IGF bioavailability that is suppressed by insulin, and levels of IGFBP-3, the major circulating IGF carrier protein, and examined their relationships to insulin, glucose, IGF, and dehydroepiandrosterone sulfate levels and anthropometric measures in old (63-89 yr) and young (23-39 yr) men. Serum levels of IGFBP-1 were increased 3-fold in old vs. young men despite high insulin levels in elders. Nevertheless, IGFBP-1 and insulin levels correlated in old and young men (r = - 0.49; P < 0.002 and r = -0.42; P < 0.025), suggesting that insulin continues to play an important role in the regulation of IGFBP-1 in aging. Glucose levels also were significantly inversely related to IGFBP-1 in old and young men (r = 0.37; P = 0.02 and r = -0.49; P < 0.01), and this relationship was not accounted for by the effect of insulin. IGF-I levels were reduced by 33% in elders (P < 0.001) and correlated with IGFBP-1 levels among old (r = -0.40; P < 0.01), but not young, men, indicating that low GH secretion and/or IGF-I production may contribute to the elevation of IGFBP-1 levels in aging. IGFBP-3 levels were reduced among elders, but not to the same extent as IGF-I, resulting in a relative excess of IGFBP-3 in elders (IGFBP-3/IGF-I ratio, 20.1 +/- 0.9 vs. 15.4 +/- 1.0; P < 0.001). The IGFBP-3/IGF-I ratio correlated with IGF-I levels in young and old men (r = -0.79; P < 0.001 and r = -0.82; P < 0.001), indicating that diminished GH secretion also may contribute to a relative excess of IGFBP-3 among elders. Dehydroepiandrosterone sulfate levels were low in elders, but did not correlate with IGF, IGFBP, insulin, or glucose levels in either age group. Serum levels of IGFBP-1 (but not IGF-I or -II or IGFBP-3) correlated with body mass index and upper arm fat and muscle areas in elders. These relationships were accounted for by the effects of insulin, suggesting that regulation of IGFBP-1 by insulin may play a role in determining body composition in aging. We conclude that insulin remains an important determinant of IGFBP-1 levels in elders, that the fasting glucose level is also a significant determinant of IGFBP-1 in both old and young subjects, and that reduced secretion of GH may contribute to impaired anabolism in aging through multiple mechanisms, including reduced production of IGF-I and alterations in circulating levels of both IGFBP-1 and -3. These findings are consistent with the concept that alterations in IGFBP levels may contribute to changes in IGF bioavailability and body composition in aging.