SURPRISINGLY FEW WOMEN WITH SEVERE OSTEOPOROSIS BY BONE DENSITOMETRY UNDERGO WORKUP FOR SECONDARY CAUSES - A RETROSPECTIVE EVALUATION.

We describe clinical features of women with extremely low bone density, and investigate secondary causes of osteoporosis. Our hypothesis was that this population would be enriched in identifiable causes of osteoporosis. We performed a retrospective review of medical records of all women seen at our university over 4 years with T-score on bone densitometry at/below -4 at any site. Historical and fracture details were abstracted. We considered a thorough work up to include Vitamin D, PTH, CBC, chemistry panel, cortisol, transglutaminase, myeloma screen, tryptase and 24-hour urine calcium. Results: 137 women were identified with T-score at/below -4. Percent identified as Asian was 26% (higher than local prevalence of 8%). Average BMI was 21.6 kg/m2. Clearly identifiable causes of osteoporosis were noted in 57% (inflammatory disorder, glucocorticoid or antacid exposure, prolonged immobilization and alcoholism were most prevalent). Of the remainder, full work up was performed only in 8%. Endocrine consultation and white race predicted thoroughness of secondary work-up. Conclusion: Fragility fractures, leanness and Asian race were common in women with very low T-score. However, few new causes were identified. Underlying etiology was either immediately evident or inadequately studied, especially in minorities.

Circulating ghrelin concentrations are lowered by intravenous glucose or hyperinsulinemic euglycemic conditions in rodents.

Ghrelin is a peptide secreted mainly by gastric parietal cells that may play a role in appetite regulation. Circulating ghrelin is abruptly lowered by food intake, but factors involved in ghrelin regulation remain unclear. The aim of this study was to determine whether intravenous glucose infusion lowers ghrelin, and to determine whether glucose, insulin or some measure of insulin action best predicts the effect of feeding on ghrelin. Rats were infused over 3 h with either A. saline (controls); B. dextrose to steady state blood glucose approximately 16.7 mM, or C. insulin 7.5 mU/kg x min, plus dextrose as needed to clamp to euglycemic basal concentrations. During 3 h of infusion, group B had significantly greater (P<0.01) glucose, 17.4+/-0.3 mM, than groups A (6.6+/-0.3) or C (6.1+/- 0.2). Groups B and C had hyperinsulinemia at the end of the 3 h infusion (894+/-246, 804+/-156 pM) compared with saline-infused (222+/-24 pM, P<0.01). Ghrelin concentrations were reduced (P<0.01) in both hyperinsulinemic groups (B=85+/-2; C=103+/-0.6 pM) versus controls (163+/-9). Ghrelin was strongly correlated with insulin (r=-0.68), glucose infusion rate (r=-0.75) and free fatty acids (r=0.67), when all 3 groups were combined, although only the 2 latter variables were independent predictors of ghrelin. In conclusion, neither a rise in blood glucose nor presence of nutrient in the stomach is required for the effect of feeding on ghrelin. The data suggest that whole body insulin responsiveness plays either a direct or indirect role in meal-related ghrelin inhibition.

Endotoxin-induced inhibition of growth hormone receptor signaling in rat liver in vivo.

The bacterial lipopolysaccharide endotoxin induces a catabolic response characterized by resistance to multiple anabolic hormones. The objective of this study was to determine the effects of endotoxin on the GH signaling pathway in rat liver in vivo. After the iv injection of Escherichia coli endotoxin (1 mg/kg), there was a progressive decrease in liver STAT5 (signal transducer and activator of transcription-5) tyrosine phosphorylation in response to GH (40% decrease 6 h after endotoxin), which occurred in the absence of a change in abundance of the STAT5 protein. Endotoxin resulted in a rapid 40-fold increase in liver Janus family kinase-2 (JAK2) messenger RNA, followed by a 2-fold increase in JAK2 protein abundance. This was associated with a 50% decrease in phosphorylated/total JAK2 after GH stimulation. GH receptor abundance was unchanged, suggesting a postreceptor site of endotoxin-induced GH resistance. Rat complementary DNAs for three members of the suppressor of cytokine signaling gene family were cloned [cytokine-inducible sequence (CIS), suppressor of cytokine signaling-2 (SOCS-2), and SOCS-3] and, using these probes, messenger RNAs for SOCS-3 and CIS were shown to be increased 10- and 4-fold above control values, respectively, 2 h after endotoxin infusion. The finding of endotoxin inhibition of in vivo STAT5 tyrosine phosphorylation in response to a supramaximal dose of GH in the absence of a change in GH receptor abundance or total GH-stimulated JAK2 tyrosine phosphorylation provides the first demonstration of acquired postreceptor GH resistance. We hypothesize that this may occur through a specificity-spillover mechanism involving the induction of SOCS genes by cytokines released in response to endotoxin and subsequent SOCS inhibition of GH signaling.

Gangliocytoma masquerading as a prolactinoma. Case report.

The authors describe the case of a 36-year-old man who presented with bitemporal hemianopsia and a serum prolactin concentration of 1440 ng/ml. Magnetic resonance imaging of the pituitary revealed a presumed macroadenoma with suprasellar and temporal lobe extension. Although the patient's prolactin level was lowered to 55 ng/ml by bromocriptine therapy, no tumor shrinkage occurred. Fourteen months later, progression of visual field defects necessitated transsphenoidal resection, which was incomplete. Immunocytochemical analysis of the biopsy tissue was positive for prolactin and, in view of the clinical picture, more detailed analysis was not performed. External-beam radiotherapy was given 2 years later because of enlargement of residual tumor. Subsequently, despite a fall in the serum prolactin concentration to less than 20 ng/ml in response to the course of bromocriptine, the mass displayed further extension into the temporal lobe. Nine years after the patient's initial presentation, he underwent transfrontal craniotomy for sudden deterioration in visual acuity caused by hemorrhage into the mass. No adenohypophyseal tissue was identified in the resected tissue. The mass was composed of dysplastic neurons that were strongly immunoreactive for synaptophysin and neurofilament (indicating neural differentiation) and prolactin. Review of the original biopsy specimen indicated that the prolactin-positive cells had striking neuronal morphological characteristics. The final diagnosis in this case is prolactin-secreting gangliocytoma. Although exceedingly rare, this disease must be added to the differential diagnosis in cases of "prolactinoma" when bromocriptine therapy is followed by a marked decline in serum prolactin that is not accompanied by significant tumor shrinkage. Furthermore, in such instances, consideration should be given to "obtaining a biopsy sample prior to electing for radiotherapy.

Incidence, prognosis, and etiology of end-stage liver disease in patients receiving home total parenteral nutrition.

BACKGROUND: Elevations in liver function tests have been reported in patients receiving total parenteral nutrition (TPN). The clinical aspects of end-stage liver disease (ESLD) associated with the prolonged use of home TPN have not been fully clarified. In previous series patients with duodenocolostomies appeared to be at higher risk than persons with some jejunum or ileum remaining in situ. METHODS: The records of 42 patients treated with home TPN for more than 1 year were examined. This constituted 283 person-years of home TPN. Patients with duodenocolostomies were examined as a separate group on the basis of the literature experience. RESULTS: Six of 42 patients who received chronic home TPN had ESLD with 100% subsequent mortality, at an average of 10.8 +/- 7.1 months after the initial bilirubin elevation. Thirteen of 42 patients had superior mesenteric artery or vein thrombosis (SMT) leading to duodenocolostomy. In 8 of these 13 patients with SMT and underlying inflammatory or malignant disorder, 2 had ESLD. The remaining 5 SMT patients who had only minimal liver enzyme elevation over 13.6 +/- 6.7 (range 3 to 19) years of home TPN were significantly younger (36 +/- 7 years vs 64 +/- 13 years) and did not have underlying inflammation either by clinical diagnosis or as reflected in the high normal serum albumin level (> or = 4.0 g/dL). Despite their extreme short bowel syndrome and long exposure to home TPN, ESLD did not develop. CONCLUSIONS: Approximately 15% of patients who receive prolonged TPN have ESLD with a high rate of morbidity and mortality. The combination of chronic inflammation and the short bowel syndrome appears to be necessary for the development of ESLD with prolonged home TPN.

In vivo insulin signaling in the myocardium of streptozotocin-diabetic rats: opposite effects of diabetes on insulin stimulation of glycogen synthase and c-Fos.

Diabetes induced by streptozotocin (STZ) in laboratory rats leads to impaired glucose metabolism in the heart and changes in myocardial contractile protein isoform expression and cardiac function. The purpose of this study was to investigate in vivo insulin signaling responses in the myocardium of STZ-diabetic rats. Insulin rapidly stimulated tyrosine phosphorylation of the insulin receptor, insulin receptor substrate-1 (IRS-1) and, to a lesser extent, IRS-2 in normal and diabetic myocardium. In diabetic rats, there was 2-fold higher insulin receptor content and insulin-stimulated receptor tyrosine phosphorylation in comparison with control rats. IRS-1 tyrosine phosphorylation also increased in STZ diabetes in spite of a decrease in IRS-1 content, resulting in a 4-fold higher ratio of phosphorylated to total IRS-1. This was associated with 2-fold higher IRS-1 precipitable phosphatidylinositide 3-kinase activity in diabetic animals. Insulin stimulation of glycogen synthase activity was significantly diminished in STZ diabetes, consistent with resistance to insulin in a step downstream from phosphatidylinositide 3-kinase activation. Under the same experimental conditions, there was a marked increase in insulin stimulation of myocardial c-fos messenger RNA content in diabetic animals in comparison with controls. These data demonstrate altered early steps in insulin signaling in STZ-diabetic rat myocardium. Consequent oppositely directed disturbances in growth regulatory and glucose regulatory responses to insulin may contribute to the development of myocardial functional abnormalities in this model of diabetes.

Obesity and its comorbid conditions.

Obese patients are at an increased risk for developing many medical problems, including insulin resistance and type 2 diabetes mellitus, hypertension, dyslipidemia, cardiovascular disease, stroke, sleep apnea, gallbladder disease, hyperuricemia and gout, and osteoarthritis. Certain cancers are also associated with obesity, including colorectal and prostate cancer in men and endometrial, breast, and gallbladder cancer in women (1-6). Excess body weight is also associated with substantial increases in mortality from all causes, in particular, cardiovascular disease. More than 5% of the national health expenditure in the United States is directed at medical costs associated with obesity (7). In addition, certain psychologic problems, including binge-eating disorder and depression, are more common among obese persons than they are in the general population (8.9). Finally, obese individuals may suffer from social stigmatization and discrimination, and severely obese people may experience greater risk of impaired psychosocial and physical functioning, causing a negative impact on their quality of life (10).