Plasma Agouti-Related Protein Levels in Acromegaly and Effects of Surgical or Pegvisomant Therapy.

CONTEXT: GH activates agouti-related protein (AgRP) neurons, leading to orexigenic responses in mice. The relationship between serum GH and plasma AgRP, which has been shown to reflect hypothalamic AgRP, has not been evaluated in humans. OBJECTIVE: To test the hypothesis that central stimulatory actions of GH on hypothalamic AgRP could be reflected in plasma AgRP in acromegaly. METHODS: We studied 23 patients with active acromegaly before and for ≤2 years after surgical (n = 13) or GH receptor antagonist therapy with pegvisomant (n = 10), and 100 healthy subjects with morning fasting blood samples for AgRP, leptin, GH, and IGF-1 and anthropometric measurements. RESULTS: The plasma AgRP levels were higher in those with active acromegaly than in the matched healthy subjects [median, 100 pg/mL; interquartile range (IQR), 78 to 139 pg/mL vs median, 63 pg/mL; IQR, 58 to 67 pg/mL; P < 0.0001]. Plasma AgRP decreased from before to after surgery (median, 102 pg/mL; IQR, 82 to 124 pg/mL vs median, 63 pg/mL; IQR, 55.6 to 83 pg/mL; P = 0.0024) and from before to during pegvisomant therapy (median, 97 pg/mL; IQR, 77 to 175 pg/mL vs median, 63; IQR, 61 to 109 pg/mL; P = 0.006). The plasma AgRP level correlated with GH (r = 0.319; P = 0.011) and IGF-1 (r = 0.292; P = 0.002). In repeated measure analysis, AgRP was significantly associated with IGF-1. CONCLUSIONS: Our data have provided evidence of a stimulatory effect of GH on plasma AgRP in humans. The levels were greater in active acromegaly and decreased in parallel with GH and IGF-1 decreases with acromegaly treatment. Data from mice suggest that AgRP may mediate some of the known effects of GH on energy metabolism. This warrants further study in patients with acromegaly and other populations.

Adipose Tissue Redistribution and Ectopic Lipid Deposition in Active Acromegaly and Effects of Surgical Treatment.

CONTEXT: GH and IGF-I have important roles in the maintenance of substrate metabolism and body composition. However, when in excess in acromegaly, the lipolytic and insulin antagonistic effects of GH may alter adipose tissue (AT) deposition. OBJECTIVES: The purpose of this study was to examine the effect of surgery for acromegaly on AT distribution and ectopic lipid deposition in liver and muscle. DESIGN: This was a prospective study before and up to 2 years after pituitary surgery. SETTING: The setting was an academic pituitary center. PATIENTS: Participants were 23 patients with newly diagnosed, untreated acromegaly. MAIN OUTCOME MEASURES: We determined visceral (VAT), subcutaneous (SAT), and intermuscular adipose tissue (IMAT), and skeletal muscle compartments by total-body magnetic resonance imaging, intrahepatic and intramyocellular lipid by proton magnetic resonance spectroscopy, and serum endocrine, metabolic, and cardiovascular risk markers. RESULTS: VAT and SAT masses were lower than predicted in active acromegaly, but increased after surgery in male and female subjects along with lowering of GH, IGF-I, and insulin resistance. VAT and SAT increased to a greater extent in men than in women. Skeletal muscle mass decreased in men. IMAT was higher in active acromegaly and decreased in women after surgery. Intrahepatic lipid increased, but intramyocellular lipid did not change after surgery. CONCLUSIONS: Acromegaly may present a unique type of lipodystrophy characterized by reduced storage of AT in central depots and a shift of excess lipid to IMAT. After surgery, this pattern partially reverses, but differentially in men and women. These findings have implications for understanding the role of GH in body composition and metabolic risk in acromegaly and other clinical settings of GH use.

Regional differences in recipient waitlist time and pre- and post-transplant mortality after the 2006 United Network for Organ Sharing policy changes in the donor heart allocation algorithm.

OBJECTIVES: This study examined the impact of the United Network for Organ Sharing (UNOS) policy changes for regional differences in waitlist time and mortality before and after heart transplantation. BACKGROUND: The 2006 UNOS thoracic organ allocation policy change was implemented to allow for greater regional sharing of organs for heart transplantation. METHODS: We analyzed 36,789 patients who were listed for heart transplantation from January 1999 through April 2012. These patients were separated into 2 eras centered on the July 12, 2006 UNOS policy change. Pre- and post-transplantation characteristics were compared by UNOS regions. RESULTS: Waitlist mortality decreased nationally (up to 180 days: 13.3% vs. 7.9% after the UNOS policy change, p < 0.001) and within each region. Similarly, 2-year post-transplant mortality decreased nationally (2-year mortality: 17.3% vs. 14.6%; p < 0.001) as well as regionally. Waitlist time for UNOS status 1A and 1B candidates increased nationally 17.8 days on average (p < 0.001) with variability between the regions. The greatest increases were in Region 9 (59.2-day increase, p < 0.001) and Region 4 (41.2-day increase, p < 0.001). Although the use of mechanical circulatory support increased nearly 2.3-fold nationally in Era 2, significant differences were present on a regional basis. In Regions 6, 7, and 10, nearly 40% of those transplanted required left ventricular assist device bridging, whereas only 19.6%, 22.3%, and 15.5% required a left ventricular assist device in regions 3, 4, and 5, respectively. CONCLUSIONS: The 2006 UNOS policy change has resulted in significant regional heterogeneity with respect to waitlist time and reliance on mechanical circulatory support as a bridge to transplantation, although overall both waitlist mortality and post-transplant survival are improved.

Prevention of fractures after solid organ transplantation: a meta-analysis.

CONTEXT: Bone loss and fracture are serious sequelae of organ transplantation, particularly in the first posttransplant year. Most interventional studies have been inadequately powered to detect effects on fracture. OBJECTIVE: The objective of the study was to determine whether treatment with bisphosphonates (BP) or active vitamin D analogs (vitD) during the first year after transplantation reduces fracture risk and estimate the effect of these interventions on bone loss. DATA SOURCES: Sources included PUBMED, MEDLINE, Cochrane Library, and abstracts from scientific meetings (presented 2003-2010). STUDY SELECTION: Randomized controlled clinical trials of BP or vitD in solid organ transplant recipients were included if treatment was initiated at the time of transplantation and fracture data were collected. DATA EXTRACTION: Two investigators independently extracted data and rated study quality. Fixed effect and random-effects models were used to obtain pooled estimates. DATA SYNTHESIS: Eleven studies of 780 transplant recipients (134 fractures) were included. Treatment with BP or vitD reduced the number of subjects with fracture [odds ratio (OR) 0.50 (0.29, 0.83)] and number of vertebral fractures, [OR 0.24 (0.07, 0.78)]. An increase in bone mineral density at the lumbar spine [2.98% (1.31, 4.64)] and femoral neck [3.05% (2.16, 3.93)] was found with treatment. When BP trials (nine studies, 625 subjects) were examined separately, there was a reduction in number of subjects with fractures [OR 0.53 (0.30, 0.91)] but no significant reduction in vertebral fractures [OR 0.34 (0.09, 1.24)]. CONCLUSIONS: Treatment with BP or vitD during the first year after solid organ transplant was associated with a reduction in the number of subjects with fractures and fewer vertebral fractures.