Mohan, Sneha

Abstract Disclosure: S. Mohan: None. M.T. Sheehan: None. P.J. Tebben: None. R.A. Wermers: None. Introduction: Elevated 1,25-dihydroxyvitamin D (1,25(OH)2D) is a rare cause of non-parathyroid hormone (PTH) mediated hypercalcemia. An increase in the activating enzyme 1-alpha hydroxylase is seen in granulomatous diseases and lymphoma, while mutations in the CYP24A1 gene leads to reduced catabolism of 1,25(OH)2D. Cinacalcet has been shown to successfully treat 1,25(OH)2D-mediated hypercalcemia of malignancy. Extrapolating this, we report 3 patients with non-malignant 1,25(OH)2D-mediated hypercalcemia treated with cinacalcet. Case Series: The patients (2 male and 1 female) were 55-71 years old. At presentation to our clinic, all had hypercalcemia with serum calcium concentrations between 10.6-11.5 mg/dL (normal, 8.8-10.2 mg/dL). PTH ranged between 16-35 pg/ml (normal 15-65 pg/ml), PTH-related peptide was normal in all patients, 25-hydroxyvitamin D was 32-51 ng/ml, and 1,25(OH)2D was inappropriately normal between 31-77 pg/ml (normal 18-78 pg/mL) in the setting of hypercalcemia and chronic kidney disease in 2 patients with estimated glomerular filtration rates 35-42 ml/min. Other causes of hypercalcemia including sarcoidosis, tuberculosis and malignancy were ruled out. The female patient had hypercalciuria (288 mg/24 hours) without nephrolithiasis and both male patients had severe hypercalciuria (400-660 mg/24 hours) with recurrent nephrolithiasis. One male patient had biallelic variants in the CYP24A1 gene, while the other male patient was suspected to have similar mutations, but not identified on genetic testing. The female patient with a PTH of 35 pg/mL on our initial measurement had documented 1,25(OH)2D level of 82 pg/mL with PTH <20 pg/mL while previously hypercalcemic. Upon cinacalcet initiation all patients demonstrated normalization of calcium levels (8.6-9.5 mg/dl) with doses between 30-90 mg daily. The patient with CYP24A1 gene mutations experienced symptomatic hypocalcemia with calcium of 8.1 mg/dL requiring dose reduction and eventual discontinuation of cinacalcet due to limited clinical benefit. There were no consistent changes in 24-hour urine calcium or fractional excretion of calcium. Levels of 1,25(OH)2D increased and PTH decreased on cinacalcet while serum calcium levels were maintained within normal range, including 2 subjects with continued normocalcemia after 2 years of therapy. Conclusion: Cinacalcet may be a therapeutic option in non-malignant 1,25(OH)2D-mediated hypercalcemia. Further evaluation is needed to confirm efficacy, understand risks and benefits, and elucidate potential mechanisms of action. Mild decrease in PTH may lead to reduced skeletal calcium efflux while the maintenance of normocalcemia despite rising 1,25(OH)2D, which was also seen in our reported patients with malignant 1,25(OH)2D-mediated hypercalcemia, suggests cinacalcet may decrease intestinal calcium absorption. Presentation: Saturday, June 17, 2023

Diabetic ketoacidosis (DKA) is an obstetrical emergency that is associated with an elevated risk of adverse pregnancy outcomes. This includes pregnancy loss in up to 1 in 3 cases. Due to the normal metabolic changes that occur during pregnancy, females who are pregnant are more vulnerable to DKA, and it can occur at lesser than expected degrees of hyperglycaemia. Presenting symptoms can be non-specific and include nausea and vomiting, fatigue, polydipsia, and polyuria. DKA may be the first presentation of previously undiagnosed diabetes. Therefore, high index of suspicion, along with prompt diagnosis and management, is essential. The cornerstones of management include intravenous insulin, intravenous fluids, and electrolyte replacement. Treatment generally follows the principles for DKA management outside of pregnancy, with some additional considerations. Close maternal and fetal monitoring is essential, and intensive care unit admission is typically required to adequately achieve this goal. In all situations, a thorough investigation should occur to address the underlying cause of the DKA and prevent further episodes. This review article outlines the potential etiopathogenesis, clinical presentation, and management of DKA in pregnancy.

Abstract Context Diabetic ketoacidosis (DKA) in pregnancy is an obstetric emergency with risk of maternofetal death. Objective This work aimed to evaluate DKA events in pregnant women admitted to our inpatient obstetric service, and to examine associated clinical risk factors, presentation, and pregnancy outcomes. Methods A retrospective cohort study was conducted at the Mayo Clinic, Rochester, Minnesota, USA, and included women aged 17 to 45 years who were treated for DKA during pregnancy between January 1, 2004 and December 31, 2021. Main outcome measures included maternal and fetal death along with a broad spectrum of maternal and fetal pregnancy outcomes. Results A total of 71 DKA events were identified in 58 pregnancies among 51 women, 48 (82.8%) of whom had type 1 diabetes. There were no maternal deaths, but fetal demise occurred in 10 (17.2%) pregnancies (6 miscarriages and 4 stillbirths). Maternal social stressors were frequently present (n = 30, 51.0%), and glycemic control was suboptimal (median first trimester glycated hemoglobin A1c = 9.0%). Preeclampsia was diagnosed in 17 (29.3%) pregnancies. Infants born to women with DKA were large for gestational age (n = 16, 33.3%), suffered from neonatal hypoglycemia (n = 29, 60.4%) and required intensive care unit admission (n = 25, 52.1%). Conclusion DKA is associated with a high rate of maternofetal morbidity and fetal loss. Prenatal education strategies for women with diabetes mellitus should include a strong focus on DKA prevention, and clinicians and patients should have a high index of suspicion for DKA in all pregnant women who present with symptoms that could be attributed to this condition.

Abstract Introduction: Optimal initial antithyroid drugs (ATD) dosing may achieve rapid improvement in thyroid hormone levels while minimizing risk of adverse events. As ATD have become the most common first line therapy for the treatment of Graves’ disease (GD), we examined trends over time in initial ATD dosing, and the association between guideline-based ATD dosing with time to normalization of FT4 and frequency of adverse events. Methods: This is a single cohort retrospective study in Mayo Clinic, Rochester, MN. We identified adults (≥18 years old) diagnosed with new onset GD between January 1, 2002-December 31, 2019 treated with at least 14 days of ATD and with available initial follow up data within 3 months prior to a dose change. Propylthiouracil (PTU) doses were converted to Methimazole (MMI) equivalents at 10:1 ratio. Guideline concordant care was defined as initial ATD dosed based on 2016 American Thyroid Association guidelines (i.e. 5-10 mg for presenting FT4 between >1.7-2.55 ng/dL, 10-20 mg for 2.56-3.40 ng/dL, and 30-40 mg for 3.41 ng/dL and above). Based on the first follow up FT4 values, patients were grouped into categories of: normal range (FT4 0.9-1.7 ng/dL) and under treated (FT4 >1.7 ng/dL). Results: 398 patients were included; mean (SD) age was 49 years (16.6), and 75% were women. Mean initial (SD) Free T4 value was 3.9 ng/dL (2.8), with patients treated with ATD at mean (SD) starting dose of 21.9 mg (13.3) MMI equivalent. Over time there was a decrease in the starting ATD dose from 30 mg MMI equivalent in 2002-2004 to 20 mg in 2017-2019, despite steady presenting FT4 values (2.7 ng/dL in 2002-2005 and 3.1 ng/dL in 2017-2019). In the subset of 340 patients with overt hyperthyroidism, 181 (53%) received guideline concordant (GC) dosing. Patients receiving GC care had a higher initial FT4 (4.9 vs. 3.6 ng/dL, p=0.002), larger goiters (40 vs. 30 g, p<0.001) and higher initial ATD mean dose (SD) 25 mg (15.7) vs. 21.3 mg (9.9), p= 0.05. However at follow up (median 32 days vs 35 days respectively), both groups had similar proportion of patients with normal FT4 values (43% vs. 42%, p=0.79); undertreated patients (45% vs. 45%, p=0.99) and frequency of adverse events (4% vs. 6%, p=0.40). Conclusion: The initial dose of ATD for the treatment of GD has decreased over the past 2 decades. Most clinicians initiate ATD at a dose concordant to guidelines. Despite this, a significant proportion of patients have persistent hyperthyroidism on initial follow up. In light of evidence of risks associated with duration of hyperthyroidism, strategies to improve optimization of initial dosing are needed. Pending further subgroup analysis by presenting FT4 severity, these preliminary results suggest and approach factoring other variables apart from guideline based initial ATD dose is needed to optimize response. Our data will be utilized to pilot an individualized, patient specific predictive model to guide initial dosing to this end.

Abstract Introduction: Anti-thyroid Drugs (ATD) have become the most frequently used treatment for Graves’ disease (GD) in the United States. However, the response to this therapy is variable. Factors that predict biochemically responsive vs. biochemically persistent disease remain unknown. Identifying predictors of disease poorly responsive to ATD can help guide treatment decision making, follow up planning and prognosis. Methods: From a database of patients with GD treated with ATD and receiving care at an academic medical center between 2009–2019, we selected adults with incident GD treated with ≥14 days of ATD. Results: 172 patients (from a database of 730 patients with GD on ATD) were sampled for the purpose of this pilot and 97 of these met inclusion criteria. Patients had a median age of 50 (18–90); female, 70.1%; never smokers, 64.9%; median goiter size of 40 g (15–100); and median TRAb on presentation of 8.1 mIU/L (1.0- 60). Graves’ orbitopathy (GO) was present in 13.4% at baseline. Patients (100%) were started on methimazole at a median dose of 20 mg (2.5–60). The median time from presentation until biochemical improvement (defined as the first instance of FT4 ≤1.7 ng/dL) was 120.9 days (18–1525), and to biochemical euthyroidism (normal TSH & FT4) was 251 days (41–1259) including a median of 3 (0–17) dose adjustments. In a univariate analysis, response to ATD was divided into two groups; biochemically responsive and biochemically persistent disease (based on reaching biochemical improvement in ≤6 months, or >6 months respectively). Biochemically persistent disease was more common in those with GO at presentation (38.5% vs.11.1%) (p .024). There was a trend towards greater prevalence of biochemically persistent disease in those with TRAb ≥ 8.0 mIU/L (46.2% vs. 27.8%) (p .204), and goiter estimated 30 grams or above by physical examination (30.8% vs. 19.4%) (p .460). Biochemically responsive disease was associated with higher frequency of hypothyroidism during treatment (p .047). Conclusion: Our preliminary results illustrate the spectrum of response to ATD and predictors of biochemically persistent disease. We aim to expand this analysis utilizing a large database. As use of ATD increases, clinicians and patients can apply this data to estimate response to therapy, and identify patients that may require more aggressive therapy, thereby tailoring management plans.

Abstract Background: Vitamin D deficiency is common in patients presenting with low energy hip fractures. The relationship between Vitamin D levels at the time of a fracture with long term functional outcomes has not been studied. Identifying a benefit to recovery with adequate vitamin D would support supplementation in elderly patients at risk for hip fracture. Methods: A retrospective cohort of patients >/= 50 years, who were treated surgically for low energy hip fracture between July 1 2016 and June 30 2018 were identified. The correlation between Vitamin D levels and functional recovery, assessed using the time up and go (TUG) test, survival at 3 months and 1 year, and readmission within 3 months was examined. The Charlson comorbidity index (CCI) at baseline was also assessed. Results: A total of 216 patients were treated for a hip fracture of which 174 were included with measured baseline Vitamin D levels. A majority were female (112, 64.4%), mean age 79.6 years (+/-11.9), mean Vitamin D level 28.2 ng/ml (+/- 12.4) and mean CCI 5.9 (+/- 2.5). Vitamin D <20 ng/ml was seen in 39 (22.4%) patients and all received appropriate supplementation. 39 (22.4%) individuals died within a year of surgery, among whom 17 (43.6% of 39) passed away within 3 months. 36 (20.7%) were readmitted within 3 months of surgery and 14 (8%) sustained a second fracture within a year. The correlation of Vitamin D levels, taken as a continuous variable, to outcomes, was analyzed using logistic regression. Although not significant, higher Vitamin D was found to be protective against death within 3 months (OR=0.995, p=0.8), but actually increased the odds of death within 1 year (OR=1.008, p=0.62), readmission within 3 months (OR=1.001, p=0.96), second fracture within 1 year (OR=1.017, p=0.33) and failure to recover (OR=1.002, 0.86). After adjusting for age, gender and CCI, Vitamin D levels were non-significantly inversely associated with both TUG 1 and TUG2, with every 1 unit higher Vitamin D associated with a TUG lowered by 0.15 seconds, p=0.42 and 0.44. Vitamin D was poorly correlated to CCI with correlation coefficient of 0.02, p = 0.71. Conclusions: Our results indicate that Vitamin D levels at the time of a hip fracture do not correlate with patients’ functional outcomes. It is possible that replacing vitamin D eliminated the possible negative impact on functional recovery.