Faculty Bibliography

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

Parathyromatosis is a rare but recognized cause of recurrent primary hyperparathyroidism. Initially described in 1975 by Palmer et al.(1), about 40 cases have been described in the literature. Most patients are middle-aged females. A small majority of the cases arise in the context of secondary hyperplasia due to end-stage renal disease.(2) The nature of parathyromatosis is unknown. It may be a low-grade carcinoma, seeding of a prior adenoma, or overgrowths of embryologic rests. Several oncogenes of interest have been identified in parathyroid neoplasms (PRAD1, MEN1, HRPT2, CaSR). (3) A biallelic CDC73/HRPT2 inactivating mutation is known to be present in about 75% of sporadic parathyroid carcinomas and absent in most adenomas. (4) Their possible relationship to parathyromatosis has not been studied. As such, differentiating parathyromatosis from other parathyroid neoplasms is challenging.(5-10) This article is protected by copyright. All rights reserved.

Purpose Abnormalities of water and sodium balance, including diabetes insipidus (DI) and the syndrome of inappropriate anti-diuretic hormone (SIADH) are common complications of transsphenoidal surgery. Postoperative practice patterns vary among clinicians and no consensus guidelines exist to direct their monitoring and management. We aimed to identify and compare practice patterns regarding the evaluation and management to these postoperative complications. Methods. A questionnaire was utilized to capture demographic data and practice habits in the postoperative setting. Respondents were members of the Pituitary Society, an international organization comprised of clinicians and researchers dedicated to the study of pituitary disease. Results. Eighty-six respondents completed at least part of the survey. The geographic distribution of respondents was roughly even between American and non-American practitioners. The majority of respondents practiced at academic institutions (67.4%), worked in multidisciplinary teams (88.4%), and possessed significant greater than 10 years of clinical experience (71%). Compared to non-American practitioners, American practitioners describe a shorter length of stay post-operatively (p<0.001) and prescribe more restrictive volume recommendations for post-operative SIADH (p=0.0035). Early career clinicians (less than 10 years in practice) checked first post-operative sodium level earlier than later career clinicians (p=0.010). Conclusion. Water and sodium dysregulation are common following transsphenoidal surgery, but their management is not well-standardized in clinical practice. We created a questionnaire to define and compare practice patterns. Most respondents practice in academic settings in multidisciplinary teams. The length of clinical experience did not significantly impact practice habits. Practice location influenced length of stay postoperatively and fluid-restriction in SIADH.

Objective/UNASSIGNED:To describe an unusual presentation of a follicle-stimulating hormone-secreting pituitary adenoma leading to ovarian hyperstimulation syndrome. We also discuss the pathophysiology and subsequent management of these tumors. Methods/UNASSIGNED:This is a case report and review of the literature. A 37-year-old female with menorrhagia was found to have bilateral multilocular adnexal cysts with concern for ovarian hyperstimulation syndrome. Results/UNASSIGNED:Labs revealed elevated follicle-stimulating hormone, and an eminent estradiol level. Pituitary magnetic resonance imaging revealed a macroadenoma with cavernous sinus invasion. The patient went on to have a successful transsphenoidal resection with normalization of hormones and subsequent resumption of menstrual cycles. Conclusion/UNASSIGNED:With the help of this case report, we illustrate the pathogenesis of functioning gonadotroph adenomas as well as the management challenges associated with these tumors. Our case is unique in its presentation with severe hyperestrogenemia and cavernous sinus invasion pointing towards a clinically aggressive adenoma. It is important to increase awareness of these tumors to ensure timely and effective management of their complications.

OBJECTIVES/OBJECTIVE:Biotin is a component of the vitamin B complex used in standard immunoassays to detect serum levels of various hormones and non-hormones, including thyrotropin (TSH) and thyroxine. These assays involve a strong bond between streptavidin and biotin, which serves as an anchor for measured analytes. Large doses of exogenous biotin for the treatment of certain medical conditions have resulted in assay interference, causing TSH to be spuriously lowered. Smaller doses of biotin found in dietary supplements also have caused assay interference. METHODS:We describe four cases in which over-the-counter (OTC) biotin caused erroneous thyroid diagnosis and clinical confusion in patients with preexisting thyroid disease. Serum TSH and thyroxine were measured by the Vitros 5600 assay. CONCLUSIONS:Although the biotin-streptavidin interaction is sensitive for detecting serum levels of TSH, it is subject to interference by exogenous biotin at levels found in OTC products. The widespread use of OTC biotin for cosmetic purposes can adversely affect the diagnosis of the entire spectrum of functional thyroid disorders. Physicians must carefully and routinely question for the use of biotin before thyroid function testing.

A middle-aged woman with obesity, hyperlipidaemia and diet-controlled diabetes was referred for resistant hypertension. Her blood pressure (BP) was uncontrolled on five medications, including a diuretic. Physical exam revealed a systolic ejection murmur, and ECHO demonstrated moderate hypertrophy. Laboratory examination revealed elevated aldosterone level (20.7 ng/dL) and elevated aldosterone:renin ratio (41.4 (ng/dL)/(ng/mL/h)), meeting criteria for primary aldosteronism (PA), and confirmed by saline infusion testing. CT scan of the adrenals was non-localising. Adrenal venous sampling confirmed bilateral idiopathic adrenal hyperplasia. Concurrent primary hyperparathyroidism was demonstrated by elevated calcium and parathyroid hormone levels and localised by sestamibi scan. Idiopathic adrenal hyperplasia was treated medically with spironolactone. Her BP remained elevated until postparathyroidectomy. Evidence shows that a hyperfunctioning parathyroid gland may contribute to maintaining hyperaldosteronism in PA making this bidirectional link unique. The significance of this case is in the potential for further understanding of the pathophysiology of common causes of secondary hypertension.

Growth hormone (GH) and insulin like growth factor-1 (IGF-1) are anabolic hormones that facilitate somatic and skeletal growth, and regulate metabolism via endocrine and autocrine/paracrine mechanisms. We hypothesized that excess tissue production of GH will protect skeletal growth and integrity in states of reductions in serum IGF-1 levels. To test our hypothesis we used the bovine GH (bGH) transgenic mice as a model of GH hypersecretion and ablated the liver-derived acid labile subunit (ALS), which stabilizes IGF-1 complexes with IGF-binding protein-3 (IGFBP-3) and -5 in circulation. We used a genetic approach to create bGH/ALSKO mice, and siRNA gene silencing approach to reduce als or igf-1 gene expression. We found that in both models, decreased IGF-1 levels in serum associated with decreased body and skeletal size of the bGH mice. Excess GH produced more robust bones, but compromised mechanical properties in male mice. Excess GH production in tissues did not protect from trabecular bone loss in response to reductions in serum IGF-1 (in bGH/ALSKO or bGH mice treated with siRNAs). Reduced serum IGF-1 levels in the bGH mice did not alleviate the hyperinsulinemia, and did not resolve liver or kidney pathologies that resulted from GH hypersecretion. We conclude that reduced serum IGF-1 levels decrease somatic and skeletal growth even in states of excess GH.

Biotin is a small B vitamin that is used in standard immunoassays to detect serum levels of various hormones, including TSH (1). Recent reports have demonstrated that large doses of exogenous biotin can interfere with the immunoassay, causing euthyroid patients to appear biochemically hyperthyroid (2). In the fall of 2016 one Endocrinology practice encountered four consultations in which over-the-counter (OTC) biotin caused erroneous TSH measurement, leading to clinical confusion and the potential for improper management. (1) Sub-acute thyroiditis (SAT) masquerading as thyrotoxicosis. A 78 year-old woman with a remote history of SAT was referred because depressed TSH 0.2 mIU/L (0.5-5.0 mIU/L) suggested disease recurrence. She was asymptomatic and clinically euthyroid; she revealed she was taking a biotin supplement. TSH rose to 2.8 mUI/L (0.5-5.0 mIU/L) 72 hours after biotin was stopped. (2) Non-toxic goiter confused for toxic nodular goiter (TNG). A 69 year-old woman was diagnosed with TNG as her TSH was low 0.167 mUI/L (0.5-5.0 mIU/L). She was referred for treatment with radioactive iodine (I-131). She reported using an OTC biotin supplement containing 300 mcg for "thinning hair." Repeat TSH days after stopping biotin was 0.937 mUI/L (0.5-5.0 mIU/L). (3) Sub-clinical hypothyroidism mistaken for Graves' disease. An 84 year-old woman reported excess fatigue and depression. However, TSH was low 0.13 mIU/L (0.5-5.0 mIU/L), FT4 was normal, and the serum was positive for anti-thyroglobulin antibody and negative for anti-TPO antibody. I-131 therapy was entertained for presumed Graves' disease. The patient admitted to using over-the-counter biotin for "nail breakage." After biotin was stopped, TSH rose to 5.5 mIU/L (0.5-5.0 mIU/L). Given her symptoms, positive antibodies, and elevated TSH off of biotin, the patient was diagnosed with sub-clinical hypothyroidism due to Hashimoto's thyroiditis and prescribed levothyroxine. (4) Stable Hashimoto's thyroiditis mistaken for progression to Graves' disease. A 66 year-old woman with a past diagnosis of Hashimoto's thyroiditis had been taking OTC biotin intermittently. Recent thyroid tests revealed low TSH 0.193 mIU/l (0.5-5.0 mIU/L) with normal T3 and Free T4. There was concern for progression to Graves' disease. Repeat TSH testing off biotin was normal. In conclusion, while the biotin-streptavidin immunoassay is sensitive for detecting serum levels of TSH (1), it is subject to interference by exogenous biotin at levels found in OTC supplements 1000 times smaller than previously reported (2). Our case series shows that the widespread use of OTC biotin for cosmetic purposes can adversely affect the diagnosis and management of the entire spectrum of functional thyroid disorders. Physicians must carefully and routinely question for the use of this supplement to ensure that patients with thyroid disorders are correctly diagnosed and managed

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