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The normal physiology of calcium metabolism is complex and depends on many factors such as renal function, diet, and age. When this normal metabolism is disrupted, it can acutely lead to hypercalcemia, which causes an increase in urinary calcium excretion through mediation of the calcium sensing receptor (CaSR) in the kidney. Hypercalciuria has been used as a diagnostic marker and indicator for parathyroidectomy in patients with primary hyperparathyroidism (PHPT). Urinary calcium excretion as a function of serum calcium was demonstrated more than 50 years ago.1 However, it is not clear if 24-hour urine calcium levels correlate with preoperative total serum or ionized calcium, parathyroid hormone (PTH), and vitamin D in patients with primary hyperparathyroidism. The 24-hour urinary sample, in addition to serologic studies, has historically been part of the standard diagnostic evaluation for patients suspected of PHPT. The use of 24-hour urine studies in PHPT has served two primary functions: elevated urinary calcium was thought to be a risk factor for nephrolithiasis, and 24-hour urine calcium studies have been used to distinguish asymptomatic PHPT from familial hypocalciuric hypercalcemia (FHH). However, guidelines published in the Journal of Clinical Endocrinology and Metabolism in 2009 no longer recommend hypercalciuria as a criterion for parathyroid surgery.2 The omission of urinary calcium in the updated guidelines for PHPT stems from new perspectives on the pathogenesis of nephrolithiasis. In the absence of nephrolithiasis, hypercalciuria alone is not considered to be an indication for surgery for PHPT; however, other surgeons still regard urinary calcium excretion of >400 mg an indication for surgery.2,3 The other role for urinary calcium studies in the workup of hypercalcemia is to rule out FHH, which is caused by a mutation that inactivates the CaSR, a G protein-coupled receptor expressed in the parathyroid gland and renal tubule. Patients with FHH typically present with hypercalcemia, normal to mildly elevated PTH, and hypocalciuria.4–6 If there is a strong suspicion for FHH, the presence of the mutation in the CaSR gene can be detected using readily available polymerase chain reaction techniques. FHH is an asymptomatic, benign disease; thus, it is important to make the distinction from PHPT, since parathyroidectomy is not indicated in this condition.7,8 For most patients presenting in our practice for evaluation of parathyroidectomy in the setting of primary hyperparathyroidism, a 24-hour urinary calcium level is obtained during the preoperative workup. Given the changing guidelines, with urinary calcium levels no longer a criterion for parathyroidectomy, we questioned the need for 24-hour calcium levels in patients with PHPT and wondered whether the urine calcium levels could be predicted from the elevated serum calcium levels. Therefore, we sought to determine if there was a correlation between 24-hour urinary calcium levels and serum and urinary laboratory markers relevant in this disease process.

Although type 2 diabetes mellitus (DM) appears to be associated with increased risk of many types of cancer, a notable exception is prostate cancer.1 Several studies have demonstrated a reduced risk of prostate cancer in men with DM. A 2012 meta-analysis of 45 studies of prostate cancer and diabetes published between 1970 and 2011 demonstrated a 14% reduction in the risk of prostate cancer in men with DM compared to non-diabetic men.2 The mechanism by which DM is associated with a reduced risk of prostate cancer is currently unknown, but it is thought to likely be related to testosterone levels. Evidence suggests that metabolic factors associated with DM impact on the hypothalamic-pituitary-testicular axis,3 and there is a clear inverse relationship between testosterone levels and DM.4–6 Since testosterone also plays an important role in the development and progression of prostate cancer, 7,8 lower levels of testosterone in diabetic patients may lessen the risk for prostate cancer.1 The problem, however, is that DM is a progressive disease associated with a number of physiological changes that start before its clinical onset (figure 1). DM-associated physiological changes and exposures with the potential to influence cancer risk evolve over time, and while studies have looked at risk post-DM onset, none have examined risk during the pre-diabetes phase. Of studies that have examined temporal relationships, it has usually been DM duration and risk, with the majority reporting an inverse relationship, whereby risk of prostate cancer is reduced with increased DM duration;3, 9–13 although there are discrepant reports.14–16 Data regarding the pre-diabetic state are lacking, and in the present study, we used an extensive electronic database to pinpoint the date of clinical DM onset to examine the temporal relationship between DM and prostate cancer in clearly delineated time periods pre- and post-DM onset. Figure 1 Progression of type 2 diabetes mellitus (DM). DM is a progressive disease in which several important physiological changes occur before and after the onset of overt clinical disease. Physiological changes and exposures thought to be related to increased ...

Although warfarin is the most commonly used drug for chronic prevention of thromboembolic events and stroke, it also ranks high among drugs that cause serious adverse events.1,2 The narrow therapeutic index coupled with substantial inter-individual variability in warfarin dose requirement puts patients at increased risk for hemorrhagic events, and the variability in dose requirements has been attributed to inter-individual differences in medical, personal, and genetic factors. Some factors known to contribute to this variability include valve replacement, diabetes, body surface area (BSA), age, and DNA variants in three enzymes whose activity impacts vitamin K-dependent synthesis of coagulation factors: CYP2C9, VKORC1, and CYP4F2.3–7 Regression models that incorporate these factors have been developed to predict stable dose in order to improve clinical management (eg, time in thereapeutic range) and reduce thrombotic and hemorrhagic events. However, because these algorithms collectively explain only 50% to 60% of dose variability in Caucasians,8,9 efforts are continuing to identify additional genetic and clinical factors that systematically impact warfarin dose requirements. Genetic influence on warfarin dose requirement has been linked to the direct metabolic effect on warfarin metabolism and vitamin K biological pathways. The enzyme CYP2C9 metabolizes warfarin, and patients encoding CYP2C9*2 and *3 genetic variants have reduced enzymatic activity of about 12% and 5%, respectively, as compared with the wild-type enzyme, leading to lower therapeutic warfarin dose requirements. The VKORC1 enzyme catalyzes the conversion of vitamin K 2,3 epoxide to vitamin K hydroquinone, which is an essential cofactor for the gamma carboxylase that catalyzes gamma carboxylation of pro-coagulation factors to cause the synthesis of active coagulation factors. Individuals homozygous T for the single nucleotide polymorphism (SNP) in intron 1 of the VKORC1 gene (rs9934438) have a daily warfarin dose that is nearly 45% lower (3.5mg/d) than that required by individuals who are homozygous C at this locus (6.2mg/d).10 Additional DNA variants in VKORC1 have been associated with warfarin resistance.11,12 Recently, metabolism of vitamin K by CYP4F2 was shown to measurably impact warfarin stable dose requirements.13,14 The DNA variant rs2108622 (Val433Met) results in decreased capacity for metabolism of vitamin K, resulting in an increased stable dose requirement of up to 24% among patients encoding the variant.7 To test the hypothesis that some patients who required high doses of warfarin had novel variants of CYP4F2, we sequenced the coding region of CYP4F2 in 16 patients whose actual dose requirement showed the highest divergence from the therapeutic warfarin dose predicted by our best regression model. Similarly, since VKORC1 is directly targeted by warfarin, genetic variability in the coding region of this enzyme could impact warfarin dosing requirements if enzymatic function or expression is affected. To test the hypothesis that some subjects in our population with warfarin resistance had missense variants of VKORC1, we sequenced the coding region of the VKORC1 gene in 10 subjects whose actual dose requirement showed the highest divergence from the dose predicted by our model.

Objectives: Warfarin is a commonly prescribed anticoagulant drug used to prevent thromboses that may arise as a consequence of orthopedic and vascular surgery or underlying cardiovascular disease. Warfarin is associated with a notoriously narrow therapeutic window where small variations in dosing may result in hemorrhagic or thrombotic complications. To ultimately improve dosing of warfarin, we evaluated models for stable maintenance dose that incorporated both clinical and genetic factors. Method: A model was constructed by evaluating the contribution to dosing variability of the following clinical factors: age, gender, body surface area, and presence or absence of prosthetic heart valves or diabetes. The model was then sequentially expanded by incorporating polymorphisms of cytochrome P450 (CYP) 2C9; vitamin K 2,3 epoxide reductase complex, subunit 1 (VKORC1); gamma carboxylase; factor VII; and apolipoprotein (Apo) E genes. Results: Of genetic factors evaluated in the model, CYP2C9 and VKORC1 each contributed substantially to dose variability, and together with clinical factors explained 56% of the individual variability in stable warfarin dose. In contrast, gamma carboxylase, factor VII and Apo E polymorphisms contributed little to dose variability. Conclusion: The importance of CYP2C9 and VKORC1 to patient-specific dose of warfarin has been confirmed, while polymorphisms of gamma carboxylase, factor VII and Apo E genes did not substantially contribute to predictive models for stable warfarin dose.

Objectives: To characterize the impact of several important clinical variables on the rate of anticoagulation during warfarin initiation (i.e., the first 30 days). Design: Retrospective study. Setting: An anticoagulation service of a large horizontally integrated, multispecialty group practice in central and northern Wisconsin. Participants: Patients with sufficient laboratory data obtained during the initiation phase of warfarin treatment. Methods: Patients were consented and genotyped for cytochrome P450 (CYP) 2C9 polymorphisms. Anticoagulation laboratory data were then electronically abstracted and fitted to a logistic growth model. Rate of anticoagulation was compared between groups. Results: During warfarin initiation, the mean slope for rise in International Normalized Ratio (INR) of prothrombin time was significantly associated with age (p=0.03, n=166). Because a relationship between diabetes and warfarin dosing has been suggested previously, we assessed the impact of this comorbidity in our model as well. Diabetes showed relatively little impact, but concomitant treatment with an anti-diabetic sulfonylurea medication was associated with an increase in slope (3-fold, p

OBJECTIVE Worldwide attention over iron deficiency anemia (IDA) in pregnancy has shifted recently from providing supplements during pregnancy to attempting to ensure that women, especially adolescents, have adequate iron stores prior to conception. We sought to determine whether adolescent and/or adult women still need supplements during pregnancy to avoid IDA, even if iron stores are adequate, and whether the IDA translates into maternal and/or infant morbidity and mortality. DESIGN Randomized, double-blind clinical trial with placebo control. SETTING Multicenter clinic setting in central Wisconsin. PARTICIPANTS Adolescent women 18 years or less in their first pregnancy, and adult women 19 years or older, who were found to be healthy and iron sufficient at their first prenatal visit. METHODS Participants were randomized to receive iron supplementation (60 mg/day elemental iron) or placebo. Serum ferritin of 12 ng/mL or less with simultaneous hemoglobin of 11 g/dL or less defined IDA. When IDA occurred at the second trimester, a therapeutic supplement of 180 mg of elemental iron per day was initiated. RESULTS Forty-seven percent of all placebo-supplemented and 16% of all iron-supplemented patients exhibited IDA (p