Donald J. McMahon

The Use of Prostate Specific Antigen Density to Enhance the Predictive Value of Intermediate Levels of Serum Prostate Specific Antigen

Prostate specific antigen (PSA) is an extremely valuable tumor marker. However, its use in detection is limited by its low positive and negative predictive values. The ability of serum PSA to distinguish between benign and malignant prostatic conditions is particularly poor in the intermediate range of 4.1 and 10 ng./ml. by the Hybritech assay. We used transrectal ultrasound determined prostate volumes in a well characterized population of 533 men to form a serum PSA/prostate volume ratio called prostate specific antigen density (PSAD). The prevalence of cancer in the entire population was 18.4%. Discriminant analysis according to negative or positive outcome allowed for the construction of nomograms, which resulted in a PSAD defined cancer risk ranging from 3 to 100%. Predictive value nomograms created from PSAD may allow for a more individualized approach to evaluation of patients with intermediate levels of Hybritech serum PSA.

Characteristics of adult celiac disease in the USA: results of a national survey

OBJECTIVE:The clinical spectrum of adults with celiac disease in the United States, where the disease is considered rare, is not known. We sought this information by distributing a survey.METHODS:A questionnaire was distributed by way of a celiac newsletter, directly to celiac support groups, and through the Internet.RESULTS:Respondents (1612) were from all United States except one. Seventy-five percent (1138) were biopsy proven. Women predominated (2.9:1). The majority of respondents were diagnosed in their fourth to sixth decades. Symptoms were present a mean of 11 yr before diagnosis. Diarrhea was present in 85%. Diagnosis was considered prompt by only 52% and 31% had consulted two or more gastroenterologists. Improved quality of life after diagnosis was reported by 77%. Those diagnosed at age ≥60 yr also reported improved quality of life. Five respondents had small intestinal malignancies (carcinoma 2, lymphoma 3) accounting for a relative risk of 300 (60–876) for the development of lymphoma and 67 (7–240) for adenocarcinoma.CONCLUSIONS:Patients with celiac disease in the United States have a long duration of symptoms and consider their diagnosis delayed. Improved quality of life after diagnosis is common. An increased risk of developing small intestine malignancies is present.

The natural history of primary hyperparathyroidism with or without parathyroid surgery after 15 years.

CONTEXT Primary hyperparathyroidism (PHPT) often presents without classical symptoms such as overt skeletal disease or nephrolithiasis. We previously reported that calciotropic indices and bone mineral density (BMD) are stable in untreated patients for up to a decade, whereas after parathyroidectomy, normalization of biochemistries and increases in BMD ensue. OBJECTIVE The objective of the study was to provide additional insights in patients with and without surgery for up to 15 yr. DESIGN The study had an observational design. SETTING The setting was a referral center. PATIENTS Patients included 116 patients (25 men, 91 women); 99 (85%) were asymptomatic. INTERVENTION Fifty-nine patients (51%) underwent parathyroidectomy and 57 patients were followed up without surgery. MAIN OUTCOME MEASURE BMD was measured. RESULTS Lumbar spine BMD remained stable for 15 yr. However, BMD started to fall at cortical sites even before 10 yr, ultimately decreasing by 10 +/- 3% (mean +/- sem; P < 0.05) at the femoral neck, and 35 +/- 5%; P < 0.05 at the distal radius, in the few patients observed for 15 yr. Thirty-seven percent of asymptomatic patients showed disease progression (one or more new guidelines for surgery) at any time point over the 15 yr. Meeting surgical criteria at baseline did not predict who would have progressive disease. BMD increases in patients who underwent surgery were sustained for the entire 15 yr. CONCLUSIONS Parathyroidectomy led to normalization of biochemical indices and sustained increases in BMD. Without surgery, PHPT progressed in one third of individuals over 15 yr; meeting surgical criteria at the outset did not predict this progression. Cortical bone density decreased in the majority of subjects with additional observation time points and long-term follow-up. These results raise questions regarding how long patients with PHPT should be followed up without intervention.

Bone mass, vitamin D deficiency, and hyperparathyroidism in congestive heart failure.

PURPOSE In contrast to renal and hepatic failure, congestive heart failure (CHF) has not been associated with a defined metabolic bone disorder. However, low bone mass has been reported in patients with CHF who receive a cardiac transplant. Both the pathophysiology and therapy of CHF may influence bone and mineral homeostasis and evidence that calciotropic hormones may affect cardiovascular function is accumulating. Therefore, we evaluated patients with severe CHF to determine the prevalence of osteoporosis and to characterize relationships between mineral homeostasis, bone turnover, bone mass, and severity of CHF. PATIENTS AND METHODS One hundred one patients (79 men and 22 women, aged 25 to 70 years) with severe CHF (New York Heart Association functional class III or IV) referred for consideration for cardiac transplantation were evaluated with measurements of serum 25-hydroxyvitamin D (25-OHD), 1,25 dihydroxyvitamin D [1,25(OH)2D], intact parathyroid hormone (PTH), markers of bone turnover (serum osteocalcin, urinary hydroxyproline, and pyridinium crosslinks); bone mineral density (BMD) by dual energy x-ray absorptiometry was measured in 91 patients. Left ventricular ejection fraction (LVEF) and resting cardiac output (CO) were determined in 88 and maximal treadmill exercise testing and peak oxygen consumption were performed in 45 patients. RESULTS Osteoporosis (T score < or = -2.5) was present in 7% at the lumbar spine, 6% at the total hip, and 19% at the femoral neck. Osteopenia (T scores between -1.0 and -2.5) was present in 43% at the lumbar spine, 47% at the total hip, and 42% at the femoral neck. Women were more severely affected (P = 0.007). Frankly low serum 25-OHD (< or = 9 pg/mL) and 1,25(OH)2D (< or = 15 pg/mL) levels were found in 17% and 26% of the patients, respectively, and elevated serum PTH (> or = 65 pg/mL) in 30%. Both low serum 1,25(OH)2D and increased serum PTH were associated with prerenal azotemia. Low serum vitamin D metabolites were associated with biochemical evidence of increased bone turnover, but BMD did not differ by vitamin D or PTH status. Patients with more severe CHF had significantly lower vitamin D metabolites and higher bone turnover, whereas elevated PTH was associated with better LVEF (21 +/- 1 versus 18 +/- 1%; P = 0.05) and correlated positively with resting CO (R = 0.220; P = 0.04). CONCLUSIONS Osteopenia or osteoporosis were observed in approximately half of these patients with severe CHF. Abnormal calciotropic hormone concentrations, also common, were associated with evidence of increased bone resorption but were not related to BMD in this cross-sectional study. Abnormal concentrations of calciotropic hormones were related to the severity of cardiovascular compromise. Because both low BMD and low serum concentrations of 25-OHD in patients with CHF are associated with higher rates of bone loss and fracture after cardiac transplantation, patients should be evaluated for and receive appropriate therapy for these disorders.

Prospective Study of Gut Hormone and Metabolic Changes After Adjustable Gastric Banding and Roux-en-Y Gastric Bypass

Objective:The objective of this study was to quantify hormones that regulate energy and glucose homeostasis to establish possible mechanisms for the greater efficacy of Roux-en-Y gastric bypass (RYGB) compared with laparoscopic adjustable gastric banding (LAGB) in achieving weight loss and improved insulin sensitivity.Design:Longitudinal study of patients undergoing LAGB (n=15) and RYGB (n=28) who were studied before surgery and at 2, 12, 26 and 52 weeks afterwards.Measurements:Fasting blood samples were drawn at each visit. Postprandial blood samples were also obtained before surgery and at 26 and 52 weeks. Samples were assayed for peptide YY (PYY), ghrelin, glucagon-like peptide-1 (GLP-1), glucose, insulin, leptin, thyrotropic hormone, free T4 and free T3.Results:At 1 year there was greater weight loss in RYGB compared with LAGB patients (30 vs 15%), but final body mass index was similar (34 vs 33 kg m−2). At week 52, area under the curve (AUC) for PYY in RYGB subjects was greater than LAGB (P<0.01). GLP-1 levels at 30 min after meal were threefold greater after RYGB compared with LAGB (P<0.001). Conversely, ghrelin AUC increased after LAGB at week 52 (P<0.05) but tended to decrease after RYGB. Fasting glucose, insulin, and leptin and homeostasis model of assessment (HOMA-IR) decreased in both groups over time but were significantly lower at week 52 after RYGB compared with LAGB. The change in leptin correlated significantly with weight loss in LAGB (r=0.86) and RYGB (r=0.77), however, HOMA-IR correlated significantly with weight loss only in LAGB (r=0.78), and not RYGB (r=0.15). There was a significant decrease in free T3 (P<0.01) after RYGB.Conclusions:Differences in levels of gut hormones may play a role in promoting greater weight loss and insulin sensitivity after RYGB compared with LAGB, however, weight loss may be limited by decreases in free T3 and leptin.

Relationship between Moderate to Severe Kidney Disease and Hip Fracture in the United States

People with ESRD are at a high risk for hip fracture. However, the effect of moderate to severe chronic kidney disease (CKD) on hip fracture risk has not been well studied. As part of the Third National Health and Nutrition Examination Survey, information on both kidney function and history of hip fracture was obtained. This survey is a complex, multistage, probability sample of the US noninstitutionalized civilian population and was conducted between 1988 and 1994. A history of hip fracture was identified from the response to a questionnaire that was administered to all participants. There were 159 cases of hip fracture. There was a significantly increased likelihood of reporting a hip fracture in participants with estimated GFR <60 ml/min (odds ratio [OR] 2.12; 95% confidence interval [CI] 1.18 to 3.80). In younger participants (aged 50 to 74 yr), the prevalence of CKD was approximately three-fold higher in those with a history of hip fracture versus in those without a history of hip fracture (19.0 versus 6.2%, respectively; P = 0.04). In multivariate logistic regression analysis, only the presence of CKD (OR 2.32; 95% CI 1.13 to 4.74), a reported history of osteoporosis (OR 2.52; 95% CI 1.08 to 5.91), and low physical activity levels (OR 2.10; 95% CI 1.03 to 4.27) were associated with a history of hip fracture. There is a significant association between hip fracture and moderate to severe degrees of CKD, particularly in younger individuals, that is independent of traditional risk factors for hip fracture.

The decline in hip bone density after gastric bypass surgery is associated with extent of weight loss.

CONTEXT Bariatric surgery is common and may be associated with deleterious effects on the skeleton. OBJECTIVE Our objective was to assess bone metabolism and bone mineral density (BMD) after Roux-en-Y gastric bypass. DESIGN AND SETTING We conducted a 1-yr prospective longitudinal study at a university hospital bariatric surgery practice and metabolic bone disease unit. PARTICIPANTS Participants included 23 obese (mean body mass index 47 kg/m(2)) men and women, aged 20-64 yr. MAIN OUTCOME MEASURES Serum PTH, 25-hydroxyvitamin D, osteocalcin, and urinary N-telopeptide, and BMD were assessed. RESULTS Patients lost 45 +/- 2 kg 1 yr postoperatively (P < 0.01). PTH increased early (3 months, 43-50 pg/ml; P < 0.001) and urinary calcium dropped (161-92 mg/24 h; P < 0.01), despite doubling of calcium intake (1318-2488 mg/d; P < 0.001). Serum 25-hydroxyvitamin D concentrations were unchanged (23-26 ng/ml), although vitamin D intake increased by 260% (658 IU/d at baseline to 1698 IU/d at 12 months; P < 0.05). Markers of bone remodeling rose (P < 0.01 for both urinary N-telopeptide and osteocalcin), whereas BMD decreased at the femoral neck (9.2%, P < 0.005) and at the total hip (8.0%, P < 0.005). These declines were strongly associated with the extent of weight loss (femoral neck: r = 0.90, P < 0.0001; and total hip: r = 0.65, P = 0.02). Lumbar spine and distal radius sites did not change. CONCLUSIONS After Roux-en-Y gastric bypass, there was evidence of calcium and vitamin D malabsorption. Bone turnover increased, and hip bone density rapidly declined. The decline in hip BMD was strongly associated with weight loss itself. Vigilance for nutritional deficiencies and bone loss in patients both before and after bariatric surgery is crucial.

High-Resolution Peripheral Quantitative Computed Tomography Can Assess Microstructural and Mechanical Properties of Human Distal Tibial Bone

High‐resolution peripheral quantitative computed tomography (HR‐pQCT) is a newly developed in vivo clinical imaging modality. It can assess the 3D microstructure of cortical and trabecular bone at the distal radius and tibia and is suitable as an input for microstructural finite element (µFE) analysis to evaluate bones mechanical competence. In order for microstructural and image‐based µFE analyses to become standard clinical tools, validation with a current gold standard, namely, high‐resolution micro‐computed tomography (µCT), is required. Microstructural measurements of 19 human cadaveric distal tibiae were performed for the registered HR‐pQCT and µCT images, respectively. Next, whole bone stiffness, trabecular bone stiffness, and elastic moduli of cubic subvolumes of trabecular bone in both HR‐pQCT and µCT images were determined by µFE analysis. The standard HR‐pQCT patient protocol measurements, derived bone volume fraction (BV/TVd), trabecular number (Tb.N*), trabecular thickness (Tb.Th), trabecular spacing (Tb.Sp), and cortical thickness (Ct.Th), as well as the voxel‐based direct measurements, BV/TV, Tb.N*, Tb.Th*, Tb.Sp*, Ct.Th, bone surface‐to‐volume ratio (BS/BV), structure model index (SMI), and connectivity density (Conn.D), correlated well with their respective gold standards, and both contributed to µFE‐predicted mechanical properties in either single or multiple linear regressions. The mechanical measurements, although overestimated by HR‐pQCT, correlated highly with their gold standards. Moreover, elastic moduli of cubic subvolumes of trabecular bone predicted whole bone or trabecular bone stiffness in distal tibia. We conclude that microstructural measurements and mechanical parameters of distal tibia can be efficiently derived from HR‐pQCT images and provide additional information regarding bone fragility.

Very Low–Calorie Diet Mimics the Early Beneficial Effect of Roux-en-Y Gastric Bypass on Insulin Sensitivity and β-Cell Function in Type 2 Diabetic Patients

Marked improvement in glycemic control occurs in patients with type 2 diabetes mellitus shortly after Roux-en-Y gastric bypass surgery (RYGB) and before there is major weight loss. The objective of this study was to determine whether the magnitude of this change is primarily due to caloric restriction or is unique to the surgical procedure. We studied eleven subjects who underwent RYGB and fourteen subjects mean-matched for BMI, HbA1c, and diabetes duration who were admitted to our inpatient research unit and given a very low–calorie diet (VLCD) of 500 kcal/day with a macronutrient content similar to that consumed by patients after RYGB. Frequently sampled intravenous glucose tolerance tests were performed before and after interventions. Both groups lost an equivalent amount of weight over a mean study period of 21 days. Insulin sensitivity, acute insulin secretion after intravenous glucose administration, and β-cell function as determined by disposition index improved to a similar extent in both groups. Likewise, changes in fasting glucose and fructosamine levels were similar. Based on these data, VLCD improves insulin sensitivity and β-cell function just as well as RYGB in the short term.

Neuropsychometric Changes in Patients After Carotid Endarterectomy

BACKGROUND AND PURPOSE One hundred twelve patients undergoing elective carotid endarterectomy for symptomatic and asymptomatic carotid artery stenosis were enrolled in a prospective study to evaluate the incidence of change in postoperative cerebral function. METHODS Patients were evaluated preoperatively and postoperatively before hospital discharge and at follow-up 1 and 5 months later with a battery of neuropsychometric tests. The results were analyzed by both event-rate and group-rate analyses. For event-rate analysis, change was defined as either a decline or improvement in postoperative neuropsychometric performance by 25% or more compared with a preoperative baseline. RESULTS Approximately 80% of patients showed decline in one or more test scores, and 60% had one or more improved test scores at the first follow-up examination. The percentage of declined test scores decreased and the percentage of improved test scores increased with subsequent follow-up examinations. Group-rate analysis was similar for group performance on individual tests. However, a decline in performance was seen most commonly on verbal memory tests, and improved performance was seen most commonly on executive and motor tests. CONCLUSIONS Neuropsychometric evaluation of patients undergoing carotid endarterectomy for significant carotid artery stenosis demonstrates both declines and improvements in neuropsychometric performance. The test changes that showed decreased performance may be associated with ischemia from global hypoperfusion or embolic phenomena, and the improvement seen may be related to increased cerebral blood flow from removal of stenosis.