Faculty Bibliography

Objective: Long-term Proton pump inhibitors (PPIs) used has been associated with hypocalcaemia, but few cases have been reported in literature. The risk only appears to exist with PPI use of over 1 year. We report a case of severe hypocalcemia after 4 days of PPI use. Case Presentation: A 58 year-old female with prior history of thyroidectomy due to papillary thyroid carcinoma, with post-surgical hypoparathyroidism presented to the hospital. She was on vitamin D treatment. Due to history of calcium kidney stones she was not on calcium supplement. Patient started PPI due to reflux symptoms. After 4 days of treatment with PPI, she experienced numbness and tingling of all extremities, leading to presentation in the emergency department. Her exam was remarkable for carpopedal spasm. Laboratories were notable for calcium 5.9 mg/dL, magnesium 1.4 mg/dL, phosphorus 6.5 mg/ dL, albumin 3.6 g/dL, vitamin D 25(OH) 16 ng/mL, and iPTH 5 pg/mL. ECG showed prolonged QTc 484 msec. She was treated with intravenous calcium gluconate. Next day spontaneous spasms resolved but had a positive trousseau's sign, also magnesium levels normalized to 2.0 mg/dL and serum calcium increased to 7.0 mg/dL. She was discharged on calcitrol, calcium citrate, and PPI stopped. Discussion: Bioavailability of the calcium source (digestibility and solubilization) plays an important role in patients with increased risk of hypocalcemia, as hypoparathyroidism. Solubility is mainly determined by the pH of the gastrointestinal tract. When pH increases, calcium solubility decreases. The low pH of the stomach dissolves calcium salts into Ca2+ ions. The pH is acidic in the duodenum, being the site with the maximum solubility. The pH rises to alkaline levels in the lower half of the small intestine. As a result of this change in pH, less calcium is solubilized. PPIs cause an increase in the pH. O'Connell et al. (2005) using a radiolabeled calcium isotope, reported that 7 days of omeprazole 20 mg daily reduced calcium absorption in elderly women under fasting conditions compared with the placebo group. Although conflicting evidence exists. Hansen et al. (2010) assessed calcium absorption using radioactive tracers and did not find evidence for a decrease in absorption under short-term PPI treatment. Calcium carbonate is the most widely used calcium salt, but it is the least water-soluble salt at a neutral pH. For this reason, less-soluble calcium salts, or almost insoluble as calcium carbonate, is a relatively poor source of calcium, and in patients using PPIs, is absorbed poorly. Conclusion: We recommend in patients with increased risk of hypocalcemia using a more soluble calcium salts, instead of calcium carbonate, when the use of PPIs is needed

INTRODUCTION recent clinical trials have shown immunotherapeutic agents to be effective against metastatic melanoma. These agents include anti-CTLA-4 and anti-PD1 monoclonal antibodies that enhance T-cell activation to increase tumor cell destruction. Autoimmune diabetes, also known as type 1 diebetes (T1DM), has been related to the use of anti-PD1 agents. We present a case of autoimmune diabetes manifesting with severe hyperglycemia in a patient taking nivolumab for melanoma. CASE PRESENTATION A 75 year-old male with prior history of hypothyroidism, and metastatic melanoma who received 3 cycles of ipilimumab and nivolumab presented to the hospital. One week after his latest cycle of treatment, he developed polyuria, fatigue, blurry vision and 12- pound unintentional weight loss. He denied personal or family history of diabetes or autoimmune disease. Due to severe fatigue, he presented to the emergency department. There, his exam showed a thin patient in mild distress with dry mucous membranes. Blood work revealed glucose of 678 mg/dL, large degree of ketonuria, anion gap 19 mmol/L, pH 7.39 and calculated serum osmolality of 315 mOsm/kg. Patient received intravenous fluids and insulin resulting in normalization of laboratory values and symptoms. Further investigation revealed c-peptide 0.3 ng/mL, anti-glutamic acid decarboxylase (GAD65) >250IU/mL, negative anti-islet cell antibody (ICA) and insulin antibody (IAA), hemoglobin A1C 7.6%, normal cortisol, ACTH and thyroid hormone levels. DISCUSSION Autoimmune diabetes is characterized by the development of an adaptive immune response that includes the presence of certain autoantibodies, such as IAA, ICA and GAD65, which cause destruction of insulin-producing beta-cells in the pancreas. Normally, PD-1 suppresses T cell activation and helps to prevent autoimmune disease. During anti-PD-1 therapy, there can be inappropriate T cell activation and infiltration in different organs including pancreas. Diabetes related to anti-PD-1 therapy appears to develop and progress rapidly, and usually manifests with acute onset of symptomatic hyperglycemia with ketosis, and the absence of ICA. Notably, hemoglobin A1C may be normal or mildly elevated in contrast to the significant elevation often seen with similar acute, symptomatic presentations of conventional T1DM. In summary, we add to the developing case literature with this report on a man on immunotherapy for metastatic melanoma who develops fulminant autoimmune diabetes and presents with ketosis, hyperosmolarity, severe hyperglycemia, and absence of ICA

Diabetes insipidus (DI) during pregnancy and the perinatal period is an uncommon medical problem characterized by polyuria and excessive thirst. Diagnosis of DI may be overlooked in the setting of pregnancy, a time when increased water intake and urine output are commonly reported. We report two cases: one of transient DI in a young woman during her third trimester of twin pregnancy in association with acute fatty liver and hypertension and one of postpartum DI secondary to Sheehan syndrome from rupture of a splenic artery aneurysm. These cases illustrate the spectrum with which DI related to pregnancy and delivery can present and highlight the difficulty in making the diagnosis since the symptoms are often initially overlooked.

Pituitary adenomas are benign intracranial neoplasms that are frequently well-controlled with standard treatments that include surgical resection, radiotherapy, and agents that modulate hormonal excess. Unfortunately, a subset of patients remains uncontrolled or develops complications from these interventions. For these patients, chemotherapy is an additional treatment option that could improve outcomes. Temozolomide is an oral chemotherapy with a favorable side-effect profile that has shown activity against pituitary adenomas. Its non-overlapping toxicity and ability to induce rapid tumor regression renders it a potentially important adjunctive treatment. In patients with tumors that cannot be optimally addressed with standard treatments, there may be a role for early initiation of temozolomide.

Osteopenia and osteoporosis are major complications of anorexia nervosa (AN). Since bone is a tissue requiring large amounts of energy, we examined the disproportionate increase in resting energy expenditure (REE) that occurs with refeeding of AN patients to determine if it was related to bone accretion. Thirty-seven AN patients aged 23.4 ± 4.8 years underwent a behavioral weight-gain protocol lasting a median of 66 days; 27 remained amenorrheic, and 10 regained menses. Sixteen controls aged 25.1 ± 4.7 years were age- and % IBW matched with patients. REE was measured using a respiratory chamber-indirect calorimeter. Significant correlations were found between REE and changes in spine (r = 0.48, P < 0.02) and leg (r = 0.43, P < 0.05) BMDs in AN patients. Further subgroup analysis of the amenorrheics revealed significant correlation between REE and change in spine BMD (r = 0.59, P < 0.02) and higher IGF-1 after weight gain compared to controls. Amenorrheics also had lower BMDs. These findings were absent in the regained menses group. The increase in REE seen in women with AN during nutritional rehabilitation may be related to active bone formation, which is not as prominent when menses have returned.

The purpose of this study was to compare the hormonal/clinical profiles and markers of bone health of women with hypothalamic amenorrhea (HA) to women with suspected HA and underlying polycystic ovary syndrome (PCOS). The results indicate that compared to women with HA, women with HA and underlying PCOS exhibit higher body mass index (BMI), bone mineral densities, and incidence of hyperandrogenism, that they may exhibit increased hyperandrogenism and irregular menses with weight gain, and that they remain at similar risk for osteopenia and osteoporosis.