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PRKAR2B in adrenocortical adenomas

Mon, 09 Jun 2008 12:00:00 GMT

The cAMP/protein kinase A (PKA) pathway has important implications in adrenocortical tumourigenesis. PKA is a heterotetramer with two regulatory subunits (encoded by 4 genes: PRKAR1A, PRKAR1B, PRKAR2A and PRKAR2B) and two catalytic subunits. Inactivating mutations in PRKAR1A have been observed in Carney complex and a subset of adrenocortical tumours (ACT). Most adrenocortical adenomas are non-secreting, but some cause symptoms caused by excess steroid secretion. Malignant adrenocortical cancers (ACC) can have consequences that are due to both steroid oversecretion and tumor growth or metastasis. This study by Vincent-Dejean et al aimed to search for alterations in PKA subunits in ACT which have no PRKAR1A mutation, and the consequences on PKA activity. The study used 35 ACT of which 10 were non-secreting adrenocortical adenomas (ACA-NS), 13 cortisol-secreting adenomas (ACA-S) and 12 were malignant (ACC). The PKA subunits were analysed using western blot and RT-qPCR and sequencing analysis of the PRKAR2B gene. Of the ACA-S adenomas, a subgroup (ACA-S2) with a 96% PRKAR2B protein decrease compared to normal adrenal levels was identified. Basal PKA activity was high in ACA-S2. These sACA with loss of PRKAR2B protein were small, benign, cortisol-secreting tumours with a homogenous phenotype. Loss of the PRKAR2B protein was due to a post-transcriptional mechanism, which represents a new mechanism of cAMP pathway alteration in adrenocortical tumourigenesis.

The results demonstrate that deficiency of PRKAR2B protein is a common event in cortisol-secreting ACA, which could involve up to 50% of these adenomas. The authors conclude that the state of various subunits of PKA varies between ACC and ACA, and is likely to reflect different pathological mechanisms. Vincent-Dejean, C., Cazabat, L., Groussin, L., Perlemoine, K., Fumey, G., Tissier, F., Bertagna, X., Bertherat, J. European Journal of Endocrinology 158: 829-839. DOI: 10.1530/EJE-07-0819

Significance of low levels of thyroglobin in fine needle aspirates in differentiated thyroid cancer patients

Fri, 09 May 2008 12:00:00 GMT

Differentiated thyroid cancer (DTC) patients treated by surgery may develop recurrence in the form of metastatic lymph nodes, meaning that long-term follow-up is important. Cytological analysis of the washout from a fine needle aspiration (FNA) biopsy to determine thyroglobin (Tg) levels has been reported previously to have 100% sensitivity and 96% specificity and is recommended for follow-up of DTC patients. However, there is no standardized method in performing the needle washout, and the possibility of interferences between Tg and Tg antibodies has been suggested. A study by Borel et al., used 34 DTC patients with 53 cervical lymph nodes, 26 non-thyroidectomized patients with thyroid-unrelated cervical mass as negative controls and 13 patients with 21 thyroid nodules as positive controls, from which the levels of FNATg were measured. All 26 negative controls showed FNATg levels less than 1ng /FNA while all 21 positive controls showed FNATg levels 127 – 210 000 ng/FNA. Among the DTC patients 25 lymph nodes in 16 patients were benign and showed 1 with low FNATg levels (6ng/FNA) while the remainder were undetectable; 19 lymph nodes with a malignant cytology showed high FNATg levels, except in 2 oncocytic DTC metastasis (6.6 and 7ng/FNA), finally FNATg was also high in a lymph node with a non-informative FNA cytology which proved to be a DTC metastasis. FNA was performed using spinal needles, cells were spread onto a glass slide and 1 ml saline solution was aspirated through the needle using a triple pumping action. The washout was analysed using an IRMA to determine FNATg levels. The results show the correct detection of thyroid cells in the FNATg of the positive group and no evidence of interference of serum Tg in the negative group. The authors conclude that the method of FNATg of lymph nodes reported in this study provides a useful method of detecting lymph node metastasis in the follow-up of DTC patients and that low levels of FNATg can be an indication of DTC metastasis. Borel, A-L., Boize, R., Faure, P., Barbe, G., Boutonnat, J., Sturm, N., Seigneurin, D., Bricault, I., Caravel, J-P., Chaffanjon, P., Chabre, O. European Journal of Endocrinology, 158, 691-698. DOI: 10.1530/EJE-07-0749

Effects of GH treatment in GH-deficient adults on adiponectin, leptin and pregnancy-associated plasma protein-A

Mon, 21 Apr 2008 12:00:00 GMT

Untreated GH deficient (GHD) adults have shown increased cardiovascular morbidity and mortality, increased atherosclerotic plaques, and increased intima-media thickness of carotid arteries. Along with the altered body composition of GHD adults, changes in lipid profile, insulin resistance and lowered exercise capacity, this leads to a high cardiovascular risk for such patients. Pregnancy-associated plasma protein-A (PAPP-A) has been proposed as a marker of an increased risk of atherothrombotic events in general, with levels correlating with carotid intima-media thickness, an early indicator of cardiovascular events. Joaquim et al conducted a clinical study on 14 GHD adults in whom levels of PAPP-A, leptin, fibrinogen and high-sensitive C-reactive protein (hsCRP) were measured at baseline and after 1 year of GH replacement therapy. The study found that at baseline GHD adults had higher PAPP-A, leptin, fibrinogen and hsCRP levels than controls. GH therapy was shown to decrease levels of PAPP-A and fibrinogen, while leptin and adiponectin levels showed no change. The fourteen adult onset GHD patients were assessed and matched with 28 healthy control subjects, for age, sex, body mass index and menopausal status. Blood samples were taken after an overnight fast, centrifuged, and analysed for a number of constituents including, PAPP-A leptin, fibrinogen and hsCRP using appropriate assays for each. The study concluded that PAPP-A serum concentrations were higher in GHD patients than in matched controls and that GH therapy lowered PAPP-A levels. Although the study used a small number of patients, it is the first to study PAPP-A levels in GHD adults and represents a novel finding. The authors speculate that GH therapy may reverse early onset atherosclerosis and decrease the cardiovascular risk in these patients. It is recommended that further and larger studies are required to determine whether the decrease in PAPP-A levels as observed in this study does lead to a reduction in cardiovascular events in GHD patients. Joaquin, C., Aguilera, E., Granada, M.L., Pastor, M.C., Salinas, I., Alonso, N., Sanmartí, A. European Journal of Endocrinology, 158, 483-490. DOI: 10.1530/EJE-07-0554