Hypophosphatasia: Canadian update on diagnosis and management.

Hypophosphatasia (HPP) is a rare inherited disorder of bone and mineral metabolism caused by loss of function mutations in the ALPL gene. The presentation in children and adults can be extremely variable and natural history is poorly understood particularly in adults. Careful patient evaluation is required with consideration of pharmacologic intervention in individuals meeting criteria for therapy. INTRODUCTION: The purposes of this review are to present current evidence regarding the diagnosis and management of hypophosphatasia in children and adults and provide evidence-based recommendations for management. METHOD: A MEDLINE, EMBASE, and Cochrane database search and literature review was completed. The following consensus recommendations were developed based on the highest level of evidence as well as expert opinion. RESULTS: Hypophosphatasia is a rare inherited disorder of bone and mineral metabolism due to loss of function mutations in the tissue non-specific alkaline phosphatase (ALPL) gene causing reductions in the activity of the tissue non-specific isoenzyme of alkaline phosphatase (TNSALP). Deficient levels of alkaline phosphatase result in elevation of inhibitors of mineralization of the skeleton and teeth, principally inorganic pyrophosphate. The impaired skeletal mineralization may result in elevations in serum calcium and phosphate. Clinical features include premature loss of teeth, metatarsal and subtrochanteric fractures as well as fragility fractures. Poor bone healing post fracture has been observed. Myalgias and muscle weakness may also be present. In infancy and childhood, respiratory and neurologic complications can occur. CONCLUSIONS: HPP is associated with significant morbidity and mortality. Pharmacologic intervention can result in significant clinical improvement. This Canadian position paper provides an overview of the musculoskeletal, renal, dental, respiratory, and neurologic manifestations of hypophosphatasia. The current state of the art in the diagnosis and management of hypophosphatasia is presented.

Correction to: Hypophosphatasia: Canadian update on diagnosis and management.

In the article mentioned above an author's name was misspelled.

Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus.

The purpose of this review is to assess the most recent evidence in the management of primary hyperparathyroidism (PHPT) and provide updated recommendations for its evaluation, diagnosis and treatment. A Medline search of "Hyperparathyroidism. Primary" was conducted and the literature with the highest levels of evidence were reviewed and used to formulate recommendations. PHPT is a common endocrine disorder usually discovered by routine biochemical screening. PHPT is defined as hypercalcemia with increased or inappropriately normal plasma parathyroid hormone (PTH). It is most commonly seen after the age of 50 years, with women predominating by three to fourfold. In countries with routine multichannel screening, PHPT is identified earlier and may be asymptomatic. Where biochemical testing is not routine, PHPT is more likely to present with skeletal complications, or nephrolithiasis. Parathyroidectomy (PTx) is indicated for those with symptomatic disease. For asymptomatic patients, recent guidelines have recommended criteria for surgery, however PTx can also be considered in those who do not meet criteria, and prefer surgery. Non-surgical therapies are available when surgery is not appropriate. This review presents the current state of the art in the diagnosis and management of PHPT and updates the Canadian Position paper on PHPT. An overview of the impact of PHPT on the skeleton and other target organs is presented with international consensus. Differences in the international presentation of this condition are also summarized.

Elevated content of cortisol in hair of patients with severe chronic pain: a novel biomarker for stress.

Hair analysis has been used to reflect long-term systemic exposure to exogenous drugs and toxins. Several studies have demonstrated the feasibility of measuring endogenous steroid hormones, e.g. cortisol, in hair. Recently, a study in macaques showed a significant increase in hair cortisol levels induced by stress. We explored whether hair cortisol levels may be used as a biomarker for long-term stress in humans. Patients with severe chronic pain, aged 18 years or older, receiving opioid treatment for at least one year were recruited. Controls were non-obese (body mass index, BMI < 30 mg/kg(2)) adults. The Perceived Stress Scale (PSS) questionnaire was used to assess perceived stress over the last 4 weeks. A hair sample was obtained from the vertex posterior. Cortisol was measured using an enzyme-linked immunosorbent assay. We included fifteen patients (nine females and six males) and 39 non-obese control subjects (20 females, 19 males). PSS scores (median and range) were significantly higher in chronic pain patients (24: 12-28) than in controls (12: 3-31)(P < 0.001). Hair cortisol contents (median and range) were significantly greater in chronic pain patients (83.1: 33.0-205 g/mg) than in controls (46.1: 27.2-200 pg/mg) (P < 0.01). We conclude that hair cortisol contents are increased in patients with major chronic stress. Measurement of cortisol levels in hair constitutes a novel biomarker of prolonged stress.

[No response to antihypertensive therapy: consider non-adherence]. / Geen reactie op antihypertensieve therapie: denk aan therapieontrouw.

In 3 patients, 2 men aged 62 and 43 years, respectively, and 1 woman aged 53 years, the medication prescribed to reduce blood pressure was insufficiently effective. Drug adherence was questioned. The first patient was afraid of the side effects mentioned in the medication information leaflet. The second patient had insufficient plasma levels of the medication but would not discuss the subject. The blood pressure of the third patient was uncontrolled despite treatment with three antihypertensive drugs. During a short hospital stay, her blood pressure responded favourably to treatment with only one of the three drugs. Subsequent repeated instruction did not improve her situation. Drug adherence is an important issue in daily clinical practice. In patients with asymptomatic conditions like hypertension, adherence is expected to be poor and worsen over time. Adherence is very difficult to measure. Risk factors for poor adherence include complex medication schedules, multiple dosing times, depression and real or suspected side effects. Measures to improve drug adherence include simplifying the medication schedule, discussing the schedule during check-ups, using automated blood pressure measuring devices at home, maintaining e-mail contact with the patient and involving a specialised nurse. Increased awareness of poor adherence is an important step toward improving hypertension treatment.

Regional Variation across Canadian Centers in Radioiodine Administration for Thyroid Remnant Ablation in Well-Differentiated Thyroid Cancer Diagnosed in 2000-2010.

Background. Use of radioactive iodine (RAI) ablation has been reported to vary significantly between studies. We explored variation in RAI ablation care patterns between seven thyroid cancer treatment centers in Canada. Methods. The Canadian Collaborative Network for Cancer of the Thyroid (CANNECT) is a collaborative registry to describe and analyze patterns of care for thyroid cancer. We analyzed data from seven participating centers on RAI ablation in patients diagnosed with well-differentiated (papillary and follicular) thyroid cancer between 2000 and 2010. We compared RAI ablation protocols including indications (based on TNM staging), preparation protocols, and administered dose. We excluded patients with known distant metastases at time of RAI ablation. Results. We included 3072 patients. There were no significant differences in TNM stage over time. RAI use increased in earlier years and then declined. The fraction of patients receiving RAI varied significantly between centers, ranging between 20-85% for T1, 44-100% for T2, 58-100% for T3, and 59-100% for T4. There were significant differences in the RAI doses between centers. Finally, there was major variation in the use of thyroid hormone withdrawal or rhTSH for preparation of RAI ablation. Conclusion. Our study identified significant variation in use of RAI for ablation in patients with well-differentiated thyroid cancer both between Canadian centers and over time.

Liquorice and hypertension.

Glycyrrhetinic acid, the active constituent of liquorice, inhibits renal IIbeta-hydroxysteroid dehydrogenase. This allows cortisol to stimulate mineralocorticoid receptors, which can result in hypertension and hypokalaemia. Treatment options are based on pathophysiological understanding.

Dehydroepiandrosterone administration in humans: evidence based?

Dehydroepiandrosterone (DHEA) and its ester dehydroepiandrosterone sulphate (DHEAS) are produced by the adrenal glands. These hormones are inactive precursors that are transformed into active sex steroids in peripheral target tissues. After a peak in early adulthood, there is a marked decrease in plasma concentrations throughout adult life. These hormones are thought to affect mood and well-being, have neurosteroid effects and may influence the immune system. Animal experiments suggest that DHEA has many other effects, including anticancer, immune-enhancing, neurotropic and general antiageing effects, but information based on studies in humans is limited. In female patients with adrenal insufficiency, treatment with DHEA replacement doses of 20 to 50 mg results in improvements in mood, quality of life and libido. These studies usually lasted only a few months, so the effect of chronic DHEA treatment or its effectiveness in male patients is not known. Some studies suggest a favourable effect of pharmacological doses of DHEA in the treatment of depression. DHEA may have a very limited effect on cognitive function in elderly people, and some studies suggest a beneficial immunomodulatory effect of DHEA in patients with autoimmune diseases, but further studies are warranted before introducing DHEA for these indications in clinical practice.

The role of 11 beta-hydroxysteroid dehydrogenase in the pathogenesis of hypertension.

The two 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) isozymes catalyze the interconversion of cortisol and cortisone. Type 1 11 beta-HSD (11 beta-HSD1) has bidirectional activity, while type 2 11 beta-HSD (11 beta-HSD2) mainly converts cortisol into cortisone. Of these two hormones only cortisol has affinity to mineralocorticoid receptors (MRs) and thus induces mineralocorticoid effects. A normal activity of 11 beta-HSD2 is crucial for prevention of mineralocorticoid activity of cortisol. Absent or decreased 11 beta-HSD2 activity results in cortisol-mediated hypermineralocorticoid hypertension. In several hypertensive syndromes a decreased 11 beta-HSD2 activity has been described as the pathogenetic mechanism of the increased blood pressure. In the apparent mineral corticoid excess (AME) syndrome type 1, absence of 11 beta-HSD2 activity is caused by mutations in the gene coding for 11 beta-HSD2. In licorice-induced hypertension glycyrrhetinic acid, the active substituent of licorice, inhibits 11 beta-HSD2 resulting in an acquired hypermineralocorticoid state. 11 beta-HSD2 activity is not decreased in glucocorticoid hypertension (Cushing's syndrome). In essential hypertension some evidence for decreased systemic and skin activity of 11 beta-HSD1 and/or 11 beta-HSD2 has been found, while renal activity of both isozymes appears to be normal. 11 beta-HSD2 activity is also present in cardiovascular myocytes of humans and dogs, and inhibition of 11 beta-HSD potentiates the vascular response to catecholamines. Although MRs in the central nervous system have been incriminated in the pathogenesis of mineralocorticoid hypertension, a pathophysiological role for 11 beta-HSD2 has not yet been described. Finally, in the placenta 11 beta-HSD2 reduces fetal exposure to maternal glucocorticoids and a decreased activity of this isozyme may result in low birth weight and increased risk of high blood pressure at adult age.

Exclusion of deep venous thrombosis with D-dimer testing--comparison of 13 D-dimer methods in 99 outpatients suspected of deep venous thrombosis using venography as reference standard.

In a direct assay comparison we evaluated the diagnostic performance of 10 novel D-Dimer assays for the exclusion of deep venous thrombosis (DVT). In addition, 3 conventional ELISA D-Dimer assays were included as reference tests. The study was performed in 99 consecutive outpatients referred to the emergency department for clinical suspicion of DVT. Venography was used as reference standard and demonstrated the presence of DVT in 50 patients (6 patients with isolated distal DVT and 44 patients with proximal DVT). The qualitative D-Dimer assays Minutex and SimpliRED and the quantitative BC DD showed overall sensitivities (for proximal and distal DVT) of only 80-83% with specificities that ranged from 87 to 94%. Overall sensitivity was 94% for the qualitative INSTANT I.A. and 98% for the quantitative Turbiquant at a cut-off level equal to the detection limit. Using different cut-off levels a sensitivity of 100% for proximal DVT and for proximal as well as distal DVT could be obtained for NycoCard, IL DD, Liatest, Tinaquant and VIDAS D-Dimer assays with specificities that ranged from 31% (NycoCard) to 71% (VIDAS) for proximal DVT and from 12% (NycoCard) to 47% (IL DD) for overall DVT. At a cut-off level equal to the upper limit of the reference range only Tinaquant and VIDAS showed a sensitivity of 100% for proximal as well as for distal DVT with a specificity of 39% and 41% respectively. The results of this study suggest that the VIDAS and Tinaquant D-Dimer assays have the highest sensitivity for the exclusion of DVT in outpatients. In outpatients that have a low or moderate pretest probability for DVT, these tests may be used in management studies where anticoagulation is withheld on the basis of D-Dimer testing alone.

Endurance run increases circulating IL-6 and IL-1ra but downregulates ex vivo TNF-alpha and IL-1 beta production.

We investigated whether a 6-h endurance run changes cytokine plasma concentrations and lipopolysaccharides (LPS) stimulated ex vivo production of cytokines in a whole blood culture of 19 well-trained athletes. The average distance covered was 65.1 +/- 8.64 (SD) km. At the end of the exercise, the mean plasma concentration of interleukin-1-receptor agonist (IL-1ra), which was 188 pg/ml 24 h before finish, increased to 886 pg/ml (P < 0.0005). The mean plasma interleukin-6 concentration increased from 18.5 +/- 4.2 to 71.5 +/- 33.3 pg/ml (P < 0.0001). The increase of neutrophils correlated with the increase of IL-1ra concentrations (r = 0.58, P < 0.005). We could not detect an effect of exercise on plasma concentrations of interleukin-1 beta (IL-1 beta) or tumor necrosis factor-alpha (TNF-alpha). The ex vivo LPS-stimulated production of IL-1 beta in athletes 24 h before the run was significantly higher than in sedentary controls. Exercise induced a decrease of LPS-stimulated production of IL-1 beta and TNF-alpha, whereas production of IL-1ra was unchanged. These results show that prolonged exercise elicits a selective downregulation of the proinflammatory cytokine production and upregulation of the cytokines IL-1ra and interleukin-6.

[Generalized histoplasmosis due to endogenous reactivation of a latent infection in an HIV-seronegative man]. / Gegeneraliseerde histoplasmose door endogene reactivering van een latente infectie bij een HIV-seronegatieve man.

A 63-year-old, Dutch, HIV-seronegative man presented with anal pain and itch of 6 months' duration, a perianal ulcer and a solitary colon ulcer. Crohn's disease was suspected; the patient was treated with corticosteroids, but later died. Autopsy revealed disseminated histoplasmosis, a fungal disease rare in the Netherlands. The patient had visited Honduras. This case report illustrates that disseminated histoplasmosis may mimic Crohn's disease leading to a delay in the diagnosis.

Measurement of cortisol and testosterone in hair of obese and non-obese human subjects.

OBJECTIVE: Hair analysis has been demonstrated to accurately reflect exposure to drug abuse, environmental toxins and exogenous hormones. We tested the feasibility of measuring cortisol and testosterone in hair of healthy and obese subjects. MEASUREMENTS: A modified immunoassay (ELISA) originally developed for saliva was used. Hair, urine and blood samples were collected from young non-obese and obese patients. Perceived stress (PSS) was measured using a validated questionnaire. RESULTS: There was no difference in PSS between non-obese and obese subjects. Hair cortisol levels were significantly correlated with weight (r = 0.27, p < 0.05) and systolic blood pressure (r = 0.28, p < 0.05), while the correlation with BMI did not reach statistical significance (p = 0.063). Hair cortisol levels did not correlate with age or urinary cortisol. There was a negative correlation between hair testosterone and age (r = -0.47, p < 0.05) and BMI (r = -0.40, p < 0.05). The correlation between hair testosterone and free androgen index (FAI) did not reach statistical significance (p = 0.098). The ratio of hair cortisol over hair testosterone (C/T) was higher in the obese group than in the young non-obese group. The C/T ratio correlated positively with age (r = 0.56, p < 0.01), waist circumference (r = 0.63, p < 0.01) and BMI (r = 0.62, p < 0.01), while the correlation between C/T ratio and FAI did not reach statistical significance. CONCLUSION: Hair cortisol levels increase, while hair testosterone levels decrease with obesity. The hair C/T ratio was significantly correlated with age, BMI and waist circumference better than hair cortisol or testosterone alone. As hair collection is non-invasive and is not influenced by moment-to-moment variations, the measurement of hormones in hair is a useful tool in research and possibly clinical practice.

Stress and reward: long term cortisol exposure predicts the strength of sexual preference.

Healthy individuals tend to consume available rewards like food and sex. This tendency is attenuated or amplified in most stress-related psychiatric conditions, so we asked if it depends on endogenous levels of the 'canonical stress hormone' cortisol. We unobtrusively quantified how hard healthy heterosexual men would work to consume erotic images of women versus men and also measured their exposure to endogenous cortisol in the prior two months. We used linear models to predict the strength of sexual preference from cortisol level, after accounting for other potential explanations. Heterosexual preference declines with self-reported anhedonia but increases with long term exposure to endogenous cortisol. These results suggest that cortisol may affect reward-related behavior in healthy adults.

An assessment of cortisol analysis in hair and its clinical applications.

Hair analyses for exogenous compounds, specifically drugs of abuse, have been a useful tool in detecting long-term drug exposure. More recently, studies have delved into the exposure of endogenous compounds in hair. Cortisol is synthesized in the adrenal cortex in response to stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis. While catecholamines generally indicate acute stress, cortisol can be used as an indicator for sub-acute and chronic stress. Studies on the effects of chronic stress are most often subjective in nature, relying on questionnaires asking the participant to recall on past stressors. This can lead to the issue of recall and reporting bias. A new objective measure of chronic stress is needed for a more accurate understanding of the effects of chronic stress on the body. This review uses emerging evidence to describe the usefulness of hair analysis for cortisol and discusses the current methods used.

Hair analysis provides a historical record of cortisol levels in Cushing's syndrome.

The severity of Cushing's Syndrome (CS) depends on the duration and extent of the exposure to excess glucocorticoids. Current measurements of cortisol in serum, saliva and urine reflect systemic cortisol levels at the time of sample collection, but cannot assess past cortisol levels. Hair cortisol levels may be increased in patients with CS, and, as hair grows about 1 cm/month, measurement of hair cortisol may provide historical information on the development of hypercortisolism. We attempted to measure cortisol in hair in relation to clinical course in six female patients with CS and in 32 healthy volunteers in 1 cm hair sections. Hair cortisol content was measured using a commercially available salivary cortisol immune assay with a protocol modified for use with hair. Hair cortisol levels were higher in patients with CS than in controls, the medians (ranges) were 679 (279-2500) and 116 (26-204) ng/g respectively (P<0.001). Segmental hair analysis provided information for up to 18 months before time of sampling. Hair cortisol concentrations appeared to vary in accordance with the clinical course. Based on these data, we suggest that hair cortisol measurement is a novel method for assessing dynamic systemic cortisol exposure and provides unique historical information on variation in cortisol, and that more research is required to fully understand the utility and limits of this technique.

Consensus recommendations for the diagnosis and management of well-differentiated gastroenterohepatic neuroendocrine tumours: a revised statement from a Canadian National Expert Group.

Well-differentiated neuroendocrine tumours (nets-previously called "carcinoid tumours") are relatively rare tumours originating from the diffuse neuroendocrine system; they are found most often in the bronchial or gastrointestinal systems. In Canada, gastroenterohepatic NETS represent less than 0.25% of oncology cases. Because of the relative rarity of these tumours, diagnostic and therapeutic approaches vary and are often based on individual physician experience. A number of European and North American groups have developed consensus guidelines for the diagnosis and management of well-differentiated gastroenterohepatic NETS, and in 2006, Canadian consensus guidelines were published by a Canadian expert group. The updated and expanded current Canadian guidelines are based on a consensus meeting held in Paris, France, in 2008 and are based on the most current literature.

Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women.

The effect of chronic oral opioids on hypothalamus-pituitary-gonadal axis in women, and on bone mineral density (BMD) in men and women is not known. The objective of this cross-sectional study was to determine the effect of long-term oral opioids on gonadal status and BMD in male and female patients with chronic non-cancer pain (CNCP). We included 26 community-dwelling CNCP patients, 12 men and 14 premenopausal women, treated with oral opioids for at least one year. We obtained Visual Analogue Scale for pain score, BMD and plasma LH and FSH in all patients; menstrual history and estradiol in women; free androgen index and total and free testosterone in men. Men were older then women (p<0.05) and had used opioids for a longer period (7.2+/-3.8 and 4.1+/-1.8 years, respectively; p<0.05), but there was no difference in opioid dose or pain score between sexes. The prevalence of hypogonadism was high in men (75%), while only 21% of the women reported oligo- or amenorrhea indicating hypogonadism (P<0.01, between sexes). Osteopenia was found in 50% of men and 21% of women (p=NS). We conclude that in CNCP patients receiving chronic opioid therapy there is a much higher prevalence of hypogonadism in men then in women. This needs to be considered clinical practice.

Solid-phase extraction of 18beta-glycyrrhetinic acid from plasma and subsequent analysis by high-performance liquid chromatography.

A new method is described for the solid-phase extraction of 18beta-glycyrrhetinic acid from plasma or serum, with subsequent analysis by HPLC. New aspects of the method include the use of commercially available 18alpha-glycyrrhetinic acid as the internal standard and the use of a Bond Elut C2 (ethyl) extraction column, to avoid the need to use large volumes of organic solvent to elute the isolates from the columns. Separation was achieved on a Shandon Hypersil BDS C18 analytical column, with a mobile phase consisting of acetonitrile-0.02 M phosphate buffer, pH 5.7 (55:45, v/v). The column effluent was monitored at 248 nm. Compared with previous methods, the procedure is much easier to carry out, whereas the sensitivity (limit of detection, 10 ng/ml, and limit of quantitation, 50 ng/ml), the precision (0.3-6.2%) and the accuracy (97.2-101.9%) are of the same order of magnitude.