Faculty Bibliography

Hypophosphatasia should be considered for any patient who presents with multiple metatarsal stress fractures and a low alkaline phosphatase.

The female athlete triad/ hypothalamic amenorrhea and polycystic ovarian syndrome (PCOS) are both common causes of irregular periods in young women. A 26-year-old woman presented with right hip pain after performing for 2 months in her first Broadway show. She was diagnosed with a left inferior (compression) femoral neck stress fracture by MRI scan. Because she had no history of fracture but had irregular periods, she was sent to endocrinology for evaluation. Her menarche was at 13-years-old. She had irregular periods throughout high school and she reported missing approximately 2-3 menstrual cycles a year. She took isotretinoin (Accutane) for acne in college and reported excess body hair, but was never worked up for PCOS. She denied weight changes and any eating disorder. Her food journal revealed an average intake of 1395 kcal per day with restriction of carbohydrates. Her food intake did not increase during periods of intense activity because of not taking time to plan ahead for meals and not wanting to eat before performing. Her weight was 98 pounds with a BMI of 19.83 kg/m². Her exam showed mild hirsutism (Ferriman-Gallwey score of 12) and cystic acne. Her blood work was unremarkable except her total testosterone was 40 ng/dL (nl: 9-55) and her dehydroepiandrosterone sulfate (DHEAS) was elevated at 428 ug/dL (nl: 65-380). Her bone density revealed an AP spine Z-score of-3.0, left femoral neck Z-score of-2.6, and right femoral neck Z-score of-2.9, all consistent with low bone mass for age. Her irregular periods provided a clue for underlying hormonal dysfunction and eating patterns that resulted in her low bone mass and fracture. While she did not have an overt eating disorder with anorexia or bulimia, long term exposure to restrictive eating patterns led to poor bone health and affected her accrual of peak bone mass. Her case also highlights that biochemical and physical evidence of elevated androgen levels often seen in PCOS may occur simultaneous with the female athlete triad and these symptoms may lead to challenges in the appropriate diagnosis

Background: In a young woman with bone pain and repeated stress fractures, the female athlete triad unmasked a rare genetic disorder, hypophosphatasia, which impairs bone mineralization and up until recently had no definitive therapy. Clinical case: A 20-year female division 1 cross-country runner was referred for evaluation of bone health in the setting of three metatarsal stress fractures over three months. She had normal developmental milestones and no premature loss of teeth. She noted painful shins after prolonged standing since age 9. Menarche was at age 13, followed by irregular cycles for which she started oral contraceptives at age 16. She joined the cross-country team in college and increased her running during her sophomore year, up to 60 miles per week. She also initiated a vegetarian diet at this time. On presentation, she had a left second metatarsal fracture and a right second and third metatarsal fracture with delayed healing. On exam, her BMI was 19.5 kg/m2. She was thin and had tenderness to palpation over her right third metatarsal joint. Laboratory evaluation was notable for an undetectable alkaline phosphatase <25 (normal: 39-117 U/L), calcium 9.5 (normal: 8.3-10.3 mg/dL), phosphorus 3.9 (normal: 2.5-4.5 mg/dL), and PTH 10 (normal: 15-75 pg/mL). Repeat labs showed an undetectable alkaline phosphatase with vitamin B6 of 195.9 (normal: 20-125 nmol/L). A bone density scan revealed a Z-score of -1.6 in the lumbar spine, 0.2 in the left femoral neck, and 1.0 in the right femoral neck. Based on this evaluation, there was high suspicion for hypophosphatasia. A TNSALP mutation analysis was sent and the gene analysis report showed an ALPL exon 4 heterozygous mutation. The patient met with a nutritionist to discuss energy intake and balance, and three months after her first visit gained weight and her BMI improved to 20.7 kg/m2. She initiated treatment with asfotase alpha and was able to complete her cross-country season. Conclusion: In this patient with bone pain, irregular menstruation and early bone loss, her initial symptoms were attributed to an energy imbalance in the setting of her intense exercise and vegetarian diet. It is likely that her new lifestyle unmasked her underlying metabolic bone disease. Adult hypophosphatasia is a rare, heterogeneous disease that may present with a variety of symptoms. While treatment was previously directed towards treating the symptoms of hypophosphatasia, enzyme replacement with asfotase alpha is a new therapy that may improve bone health and improve quality of life

AIM: To assess the performance of HbA1c and the 1-h plasma glucose (PG >/= 155 mg/dl; 8.6 mmol/l) in identifying dysglycemia based on the oral glucose tolerance test (OGTT) from a real-world clinical care setting. METHODS: This was a diagnostic test accuracy study. For this analysis, we tested the HbA1c diagnostic criteria advocated by the American Diabetes Association (ADA 5.7-6.4 %) and International Expert Committee (IEC 6.0-6.4 %) against conventional OGTT criteria. We also tested the utility of 1-h PG >/= mg/dl; 8.6 mmol/l. Prediabetes was defined according to ADA-OGTT guidelines. Spearman correlation tests were used to determine the relationships between HbA1c, 1-h PG with fasting, 2-h PG and indices of insulin sensitivity and beta-cell function. The levels of agreement between diagnostic methods were ascertained using Cohen's kappa coefficient (Kappa). Receiver operating characteristic (ROC) curve was used to analyze the performance of the HbA1c and 1-h PG test in identifying prediabetes considering OGTT as reference diagnostic criteria. The diagnostic properties of different HbA1c thresholds were contrasted by determining sensitivity, specificity and likelihood ratios (LR). RESULTS: Of the 212 high-risk individuals, 70 (33 %) were identified with prediabetes, and 1-h PG showed a stronger association with 2-h PG, insulin sensitivity index, and beta-cell function than HbA1c (P < 0.05). Furthermore, the level of agreement between 1-h PG >/= 155 mg/dl (8.6 mmol/l) and the OGTT (Kappa[95 % CI]: 0.40[0.28-0.53]) diagnostic test was stronger than that of ADA-HbA1c criteria 0.1[0.03-0.16] and IEC criteria (0.17[0.04-0.30]). The ROC (AUC[95 % CI]) for HbA1c and 1-h PG were 0.65[0.57-0.73] and 0.79[0.72-0.85], respectively. Importantly, 1-h PG >/= 155 mg/dl (8.6 mmol/l) showed good sensitivity (74.3 % [62.4-84.0]) and specificity 69.7 % [61.5-77.1]) with a LR of 2.45. The ability of 1-h PG to discriminate prediabetes was better than that of HbA1c (AUC: -0.14; Z value: 2.5683; P = 0.01022). CONCLUSION: In a real-world clinical practice setting, the 1-h PG >/= 155 mg/dl (8.6 mmol/l) is superior for detecting high-risk individuals compared with HbA1c. Furthermore, HbA1c is a less precise correlate of insulin sensitivity and beta-cell function than the 1-h PG and correlates poorly with the 2-h PG during the OGTT.

The public health outcry toward infectious entities appears to dwarf chronic diseases such as diabetes. This disparity is particularly astonishing given the considerable prevalence of diabetes and prediabetes. Diseases associated with short-term morbidity and mortality therefore seem to garner attention and demand an immediate public health response, whereas chronic illnesses, which can be considerably more devastating in the longer term, receive relatively less notoriety. It should not, however, be misconstrued that one disease entity is more important than the other-it is critical that both acute and chronic entities are given balanced attention in the public health, governmental, and scientific realms. The current perspective reflects on the disparate public health purviews toward acute and chronic illnesses, describes why prevention is so difficult and challenging, and addresses what can be done to reverse this trend. If there is any hope of conquering the spiraling prediabetes and diabetes epidemics, the medical community must grapple with the complex issues herein raised.

Osteoporosis and diabetes mellitus are chronic diseases with significant associated morbidity and mortality. Recent evidence suggests that both type 1 and type 2 diabetes are associated with an increased fracture risk. Fracture as a complication of diabetes must be considered when evaluating and treating patients with diabetes.

Hypoxia-induced endothelin (ET) and vascular endothelial growth or permeability factor (VEGF) play an important role in tumor biology by promoting angiogenesis. Angiogenesis alters hemostasis and promotes thromboembolic disease (TED). Therapeutic angiogenesis directed against ET and VEGF may reduce the incidence of TED in cancer patients.

The growth of anhydrous uric acid (UA) and uric acid dihydrate (UAD) crystals from supersaturated aqueous solutions containing methylene blue, a cationic organic dye, has been investigated. Low concentrations of dye molecules were found to be included in both types of crystal matrixes during the growth process. Incorporation of dye into UA crystals occurs with high specificity, affecting primarily [001] and [201] growth sectors, while UAD crystals grown from solutions of similar dye concentration show inclusion but little specificity. The orientation of the UA-trapped species was determined from polarization data obtained from visible light microspectrometry. To achieve charge neutrality, a second anionic species must also be included with the methylene blue into UA and UAD crystal matrices. Under high pH conditions, crystallization of 1:1 stoichiometric mixtures of methylene blue and urate yields methylene blue hexahydrate (MBU.6(H2O). The crystal structure of MBU.6(H2O) reveals continuous pi-pi stacks of planes of dye cations and urate anions mediated by water molecules. This structure provides an optimal geometry for methylene blue-urate pairs and additional support for the incorporation of these dimers in uric acid single-crystal matrices. The strikingly different inclusion patterns in UA and UAD demonstrate that subtle changes in the crystal surfaces and/or growth dynamics can greatly affect recognition events.