Brian D. Saunders

Trends in Utilization of Adrenalectomy in the United States: Have Indications Changed?

Minimally invasive approaches have dramatically reduced morbidity associated with adrenalectomy. There has been concern that an increased frequency of adrenal imaging along with the advantages of less morbidity could influence the indications for adrenalectomy. We tested the hypothesis that adrenalectomy has become more common over time and that benign diseases have been increasingly represented among procedural indications. The Nationwide Inpatient Sample (NIS) database was utilized to determine the incidence of adrenalectomy and the associated surgical indications in the United States between 1988 and 2000. All discharged patients were identified whose primary ICD-9-CM procedure code was for adrenalectomy, regardless of the specific surgical approach (laparoscopic adrenalectomy was not reliably coded). This subset was then queried for associated ICD-9-CM diagnostic codes. Linear regression and t-tests were utilized to determine the significance of trends. The total number of adrenalectomies increased significantly, from 12.9 per 100,000 discharges in 1988 to 18.5 per 100,000 discharges in 2000 (p = 0.000003). The total number of adrenalectomies with a primary ICD-9-CM code for malignant adrenal neoplasm did not increase significantly: from 1.2 per 100,000 discharges in 1988 to 1.6 per 100,000 discharges in 2000 (p = 0.47). The total number of adrenalectomies with a primary ICD-9-CM diagnostic code for benign adrenal neoplasm increased significantly, from 2.8 per 100,000 discharges in 1988 to 4.8 per 100,000 discharges in 2000 (p = 0.00002). The average percentage of adrenalectomies performed for malignant neoplasm was significantly higher during the period 1988–1993 when compared to 1994–2000 (11% vs. 9%; p = 0.002). The average percentage of adrenalectomies performed for benign neoplasm was significantly lower during 1988–1993 when compared to 1994–2000 (25% vs. 28%; p = 0.015). Adrenalectomy is being performed with increasing frequency. This is associated with an increase in the proportion of adrenalectomies performed for benign neoplasms. Assuming no significant change in disease prevalence during the study period, these data suggest that indications for adrenalectomy may have changed somewhat over that period.

Laparoscopic adrenalectomy for malignant disease

Malignant tumours of the adrenal gland are uncommon but are associated with substantial mortality. For most tumours resection is the only opportunity for cure. Advances in diagnostic and surgical techniques have improved the detection and treatment of these tumours. Further advances need new ways to make decisions about the use of laparoscopic resection for malignant, or potentially malignant, adrenal tumours. We review studies on the outcome of laparoscopic adrenalectomy for primary adrenal cancer as well as studies on metastatic disease to the adrenal glands. There are few prospective data because of the rarity of this condition. Careful individual judgment by the surgeon remains the cornerstone of safe and complete resection for adrenal malignant disease.

Sp1 Binds to the Rat Luteinizing Hormone β (LHβ) Gene Promoter and Mediates Gonadotropin-releasing Hormone-stimulated Expression of the LHβ Subunit Gene

The hypothalamic hormone gonadotropin-releasing hormone (GnRH) plays a critical role in reproductive function by regulating the biosynthesis and secretion of the pituitary gonadotropins. Although it is known that GnRH induces luteinizing hormone β (LHβ) gene transcription, the mechanisms by which this occurs remain to be elucidated. We have shown previously that GH3 cells transfected with the rat GnRH receptor cDNA (GGH3-1′ cells) support the expression of a cotransfected fusion gene composed of 797 base pairs of rat LHβ gene 5′-flanking sequence and the first 5 base pairs of the 5′-untranslated region fused to a luciferase reporter (−797/+5LHβLUC) and respond to a GnRH agonist with a 10-fold stimulation of activity. Furthermore, we have shown that DNA sequences at −490/−352 confer GnRH responsiveness to the rat LHβ gene. We have now identified two putative binding sites for Sp1, a three-zinc-finger transcription factor, within this region. Using electrophoretic mobility shift assay, DNase I footprinting, and methylation interference assays, we demonstrate that Sp1 can bind to these sites and that Sp1 is responsible for DNA-protein complexes formed using GGH3-1′ and αT3–1 nuclear extracts. Mutations of the Sp1 binding sites, which block binding of Sp1, blunt the stimulation of the LHβ gene promoter by GnRH. These data define GnRH-responsive elements in the LHβ 5′-flanking sequence and suggest that Sp1 plays an important role in conferring GnRH responsiveness to the LHβ subunit gene.

Lithium Therapy and Hyperparathyroidism: An Evidence-Based Assessment

BackgroundProlonged therapeutic exposure to lithium compounds can have adverse consequences on calcium homeostasis. A unique form of hyperparathyroidism appears to be causally linked to chronic lithium exposure. We provide a comprehensive review of relevant literature using a structured, evidence-based approach.MethodsPublished data were identified from systematic electronic literature searches. References are assigned a level of evidence according to a validated classification schema.ResultsLevel III and V evidence supports an etiologic link between sustained lithium therapy and both hypercalcemia and hyperparathormonemia (grade C recommendation). Level V evidence supports the use of preoperative parathyroid imaging if a focused exploration is planned (grade C recommendation). Level V evidence supports the use of intraoperative parathyroid hormone monitoring to guide appropriate surgical therapy (grade C recommendation). There is conflicting and equally weighted level V evidence supporting a routine preoperative plan of bilateral neck exploration versus selective unilateral exploration (no recommendation). There may be a role for calcimimetic drug therapy as an alternate, nonsurgical means of controlling lithium-associated hyperparathyroidism (grade C recommendation).ConclusionsEvidence-based recommendations support screening of patients on chronic lithium therapy for hypercalcemia. Appropriate surgical therapy may consist of either a bilateral or a unilateral approach when performed by an experienced endocrine surgeon. Focused approaches should be guided by preoperative imaging and intraoperative hormone monitoring. Calcimimetic therapy is a potential alternative to parathyroidectomy.

Identification and characterization of angiotensin II receptors in rat epididymal adipocyte membranes

To better understand the role of the mitogenic vasoactive peptide angiotensin II (AII) in growth and differentiation, we have investigated the existence of membrane receptors for this peptide in rat adipocytes. Following isolation of epididymal fat cells, membrane protein was removed and incubated with varying concentrations of 125I-AII with or without submicromolar concentrations of unlabeled AII. Binding of AII was highly specific, rapid, and reversible. Scatchard analysis indicated that adipocyte membranes contain a high-affinity AII receptor with a Kd of 0.90 nmol/L and a binding site concentration (Bmax) of 53.7 fmol/mg protein. Additional pharmacologic analyses resulted in a rank order potency for peptide agonists and antagonists similar to that reported for the vascular receptor. Determination of subtype specificity with selective organic compounds indicated that the epididymal adipocyte receptor was displaced at low concentrations of DuP753, a selective AT1 subtype antagonist. These studies have successfully identified and characterized a high-affinity membrane receptor for AII in fat cells, further establishing adipose tissue as a peripheral site containing regulatory components of the local renin-angiotensin system.

Transforming growth factor alpha and atrial natriuretic peptide in white adipose tissue depots in rats

Abstract. To detect the presence in adipose tissue of peptides known to affect tissue growth and to investigate potential regional differences, epididymal and perirenal adipose tissue depots from male Sprague‐Dawley rats were separated into adipocyte and stroma‐vascular fractions by collagenase digestion, sequential centrifugation and filtration. Identity and integrity of the fractions were demonstrated by light and electron microscopy, while dose‐response curves for angiotensin‐converting enzyme (ACE) were performed, revealing maintained functional capacity of the stroma‐vascular fraction. ACE, atrial natriuretic peptide (ANP), and transforming growth factor‐alpha (TGF‐alpha) concentrations were significantly greater in epididymal than perirenal stroma‐vascular tissue. Adipocyte fractions from both depots contained significant concentrations of ANP and TGF‐alpha. There was no detectable ACE in the adipocyte fractions, indicating that no contaminating stromal‐vascular cells were present in these fractions. These data show significant concentrations of peptides with effects on growth in subfractions of adipose tissue and demonstrate regional differences in concentrations between fat depots.

Identification of cis-Acting Deoxyribonucleic Acid Elements That Mediate Gonadotropin-Releasing Hormone Stimulation of the Rat Luteinizing Hormone β-Subunit Gene1

GnRH plays a critical role in reproductive development and function by regulating the biosynthesis and secretion of the pituitary gonadotropins, LH and FSH. Although it is known that GnRH induces gonadotropin subunit gene transcription, the mechanism by which this occurs has not been elucidated. Studies have been hindered by the lack of available cell lines that express the LH and FSH subunit genes and respond to GnRH. We have transfected the rat pituitary GH3 cell line with the rat GnRH receptor complementary DNA. These cells, when cotransfected with regulatory regions of the LH or FSH subunit genes fused to a luciferase reporter gene, respond to GnRH with an increase in promoter activity comparable to that seen in primary rat pituitary cells. In this study, we have used this cell model to identify cis-acting elements of the LHβ gene that mediate stimulation by GnRH. Analysis of a series of 5′-deletion and internal deletion constructs has revealed two regions of the rat LHβ gene promoter involved in medi...

Laparoscopic Partial Adrenalectomy for Bilateral Pheochromocytomas

BackgroundPatients with hereditary pheochromocytoma are at risk of the development of bilateral disease. Partial adrenalectomy can preserve adrenal function to avoid the morbidity associated with medical adrenal replacement. Here, we report a multimedia case study of synchronous bilateral partial adrenalectomy by the laparoscopic approach.MethodsA 13-year-old patient with von Hippel-Lindau disease was found to have high urinary metanephrines and normetanephrines. Computed tomography showed bilateral adrenal tumors (2.5 cm on the right side and 0.9 cm on the left). MIBG scan showed positive uptake in the right adrenal gland without extra-adrenal uptake. After adequate adrenergic blockade, the patient underwent laparoscopic partial adrenalectomy bilaterally.ResultsThe left side was approached first with the patient in the right decubitus position. Intraoperative ultrasound was performed to determine the line of tumor excision, which was carefully planned to preserve most of the normal-appearing gland. Both tumors were excised completely with good hemostasis. The main adrenal veins of both sides were precisely preserved. Operative time was 228 minutes. No clinically important hemodynamic fluctuations were noted. Pathologic examination confirmed bilateral entirely excised pheochromocytomas. The patient has not required exogenous corticosteroid replacement at follow-up.ConclusionLaparoscopic partial adrenalectomy for bilateral pheochromocytomas is safe and technically feasible. It should be considered the treatment of choice for hereditary pheochromocytoma.

Increased post‐operative complications with methylene blue versus lymphazurin in sentinel lymph node biopsies for skin cancers

Sentinel lymph node biopsy (SNLB) is the standard of care in staging of melanoma and other skin cancers. Early studies used lymphazurin (LZ) for SLNB. A national shortage of LZ promoted methylene blue (MB) as an alternate stain.

Familial hyperparathyroidism due to a germline mutation of the CDC73 gene: implications for management and age-appropriate testing of relatives at risk.

OBJECTIVE To discuss the implications of a young age at diagnosis in a family member with hyperparathyroidism-jaw tumor syndrome, the youngest published case to date, due to a mutation of the CDC73 gene (formerly known as HRPT2); to review this family with regard to modifications of guidelines for surveillance of hyperparathyroidism and other associated features in affected and at-risk relatives; and to discuss surgical recommendations in this syndrome. METHODS A review of English-language publications in PubMed and a review of GeneReviews were conducted pertaining to the subject of familial hyperparathyroidism. A case is described, and the family pedigree is discussed. RESULTS Review of the literature revealed that CDC73-related disorder has not previously been reported in patients younger than 10 years. This finding has been the basis for the recommendation for initiation of surveillance for disease manifestations at that age. Review of the family history of our current patient revealed a 7-year-old nephew with hypercalcemia attributable to primary hyperparathyroidism. CONCLUSION Surveillance of hyperparathyroidism in affected persons and genetic testing of relatives at risk are currently recommended to start at 10 years of age. We recommend that these be conducted at a younger age, preferably 5 to 10 years before the earliest diagnosis of hyperparathyroidism within the family, and potentially at birth in families with a known mutation of the CDC73 gene, in light of the malignant potential of the disease.