Faculty Bibliography

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

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: Encapsulated non-invasive follicular variant papillary thyroid cancer (ENIFVPTC) has recently been re-termed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This designation specifically omits the word "cancer" to encourage conservative management since patients with NIFTP tumors have been shown to derive no benefit from completion thyroidectomy or adjuvant radioactive iodine (RAI) therapy. METHODS: IRB approved retrospective study of consecutive cases of tumors from 2007 to 2015 that met pathologic criteria for NIFTP. The Conservative Management (CM) group included patients managed with lobectomy alone or appropriately indicated total thyroidectomy. Those included in the Aggressive Management (AM) group received either completion thyroidectomy or radioactive iodine or both. RESULTS: From 100 consecutive cases of ENIFVPTC reviewed, 40 NIFTP were included for the final analysis. Of these, 10 (27%) patients treated with initial lobectomy received completion thyroidectomy and 6 of 37 (16%) also received post-surgical adjuvant RAI. The mean per-patient cost of care in the AM group was $17629+/-2865 nearly twice the $8637+/- 309 costs in the CM group, and was largely driven by the cost of completion thyroidectomy and RAI. CONCLUSIONS: The term NIFTP has been recently promulgated to identify a type of thyroid neoplasm, formerly identified as a low-grade cancer, for which initial surgery represents adequate treatment. We believe that since the new NIFTP nomenclature intentionally omits the word "cancer" the clinical indolence of these tumors will be better appreciated, and cost savings will result from a more conservative and appropriate clinical management.

Cholesterol reduction has markedly reduced major cardiovascular disease (CVD) events and shown regression of atherosclerosis in some studies. However, CVD has for decades also been associated with increased levels of circulating triglyceride (TG)-rich lipoproteins. Whether this is due to a direct toxic effect of these lipoproteins on arteries or whether this is merely an association is unresolved. More recent genetic analyses have linked genes that modulate TG metabolism with CVD. Moreover, analyses of subgroups of hypertriglyceridemic (HTG) subjects in clinical trials using fibric acid drugs have been interpreted as evidence that TG reduction reduces CVD events. This review will focus on how HTG might cause CVD, whether TG reduction makes a difference, what pathophysiological defects cause HTG, and what options are available for treatment.

Background Parathyromatosis, described as hyperfunctioning, benign parathyroid tissue scattered throughout the soft tissues of the neck, is a rare cause of recurrent hyperparathyroidism. Fewer than 40 cases have been described in the literature. We describe a case of a woman with recurrent hypercalcemia secondary to parathyromatosis; additionally this is the first reported case of a papillary pattern in parathyromatosis. Clinical Case A 45 year old woman with a history of a left parathyroid adenoma, status post focused parathyroidectomy 10 years ago, presented with constipation, polyuria and abdominal pain. Initial examination demonstrated a well healed cervical scar with no palpable neck masses. Admission laboratory findings were significant for a calcium level of 13.6 mg/dL (n 8-10.4 mg/dL) , ionized calcium 7.7 mg/dL (n 4.6-5.2 mg/dL), phosphorus 2.2 mg/dL (n 2.7-4.5 mg/dL), 25 OH-vitamin D 9.6 ng/mL (n 30-100 ng/mL), PTH 395 pg/mL (n 14-72 pg/mL), PTHrP <0.7 pmol/L (n <2.0 pmol/L) and urine calcium 484 mg/24 hr (n 50-250 mg/24hr). No obvious enlarged parathyroid was localized on neck ultrasound or sestamibi scan. Neck CT showed two 6 mm nodular lesions in the upper mediastinum. The patient had refractory hypercalcemia despite maximal medical therapy. She was taken to the operating room for reoperative neck exploration. She was noted to have diffuse exophytic fronds of tissue covering her left thyroid lobe, which prompted removal of the lobe. Intraoperative PTH decreased from 454 pg/mL to 39 pg/mL. Microsopic examination demonstrated multifocal hypercellular parathyroid nodules in skeletal muscle and perithyroid adipose tissue consistent with parathyromatosis. An unusual pathologic finding was its unique papillary configuration, raising consideration for a parathyroid carcinoma on frozen section. Final pathology confirmed parathyromatosis with no features of carcinoma (vascular invasion, fibrosis or high mitotic activity) with diffuse immunohistochemical reactivity for PTH and non-reactivity for Thyroid Transcription Factor-1. The patient's calcium level was normal post operatively (9.2 mg/dL) with resolution of symptoms. Conclusion Parathyromatosis is a rare disease that raises challenges in diagnosis and management. Preoperative localization of parathyromatosis is difficult, leading to a high surgical failure rate. Scarring and fibrosis from previous neck exploration leads to technical difficulty, since the most common cause for parathyromatosis is seeding of hypercellular parathyroid tissue during previous parathyroidectomy. Medical management is essential during the post-operative period to maintain a normocalcemic state. Our case presents with a pathologic finding of papillary pattern in parathyromatosis, which has not been previously described and can pose a diagnostic challenge in separation from papillary carcinoma on frozen section examination

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition. Emerging evidence suggests that vitamin D may play a role in the pathogenesis of NAFLD. AIM: To review systematically the association between vitamin D levels, measured as serum 25-hydroxy vitamin D [25(OH)D], and NAFLD. METHODS: We used PubMed and EMBASE databases to identify all studies that assessed the association between vitamin D and NAFLD up until 22 April 2013, without language restrictions. We included studies that compared vitamin D levels between NAFLD cases and controls and also those that compared the odds of vitamin D deficiency by NAFLD status. Pooled standardised differences and odds ratios were calculated using an inverse variance method. RESULTS: Seventeen cross-sectional and case-control studies have evaluated the association between vitamin D and NAFLD. NAFLD was diagnosed using biopsy (4 studies), ultrasound or CT (10 studies) and liver enzymes (3 studies). Nine studies provided data for a quantitative meta-analysis. Compared to controls, NAFLD patients had 0.36 ng/mL (95% CI: 0.32, 0.40 ng/mL) lower levels of 25(OH)D and were 1.26 times more likely to be vitamin D deficient (OR 1.26, 95% CI: 1.17, 1.35). CONCLUSIONS: NAFLD patients have decreased serum 25(OH)D concentrations, suggesting that vitamin D may play a role in the development of NAFLD. The directionality of this association cannot be determined from cross-sectional studies. Demonstration of a causal role of hypovitaminosis D in NAFLD development in future studies could have important therapeutic implications.