United States

Prenatal exposure to bisphenol-A (BPA), an ubiquitously present endocrine-disrupting chemicals, induces peripheral insulin resistance as well as lipotoxicity and oxidative stress in the liver and muscle along with tissue-specific transcriptional changes in female sheep. To gain a mechanistic understanding of contributors to these liver and muscle-specific transcriptional changes, we hypothesized that prenatal BPA exposure impacts non-coding RNA (ncRNA), regulators of transcriptional and post-transcriptional control of coding RNAs. We sequenced ncRNA (including lncRNA, microRNA, snoRNA, and snRNA) in the liver and muscle obtained during the late follicular phase from 21-month-old control and prenatal BPA-treated (0.5mg/kg/day from days 30 to 90 of gestation; Term: 147days) female sheep (n=4 control and 4 prenatal BPA treated). The sequence data were subjected to differential expression analysis and multivariate modeling to identify specific ncRNA signatures. In the liver, 77 lncRNA (49 down, 28 up), 14 microRNAs (6 down, 8 up), 127 snoRNAs (63 down, 64 up) and 55 snRNAs (15 down, 40 up) were dysregulated (FDR&lt;0.1, absolute log2FC&gt;0.5) with BPA exposure. In the muscle 6 lncRNA were upregulated and 65 snoRNAs (47 down, 18 up) were dysregulated (FDR&lt;0.1, absolute log2FC&gt;0.5). Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) plots identified microRNAs MIR200B, MIR409, MIR30B, and MIR154A in the liver and miRNAs MIR26B, MIR29A, MIR125B, and MIR127 in muscle and several uncharacterized ncRNAs as signatures of prenatal BPA exposure. Multiple ncRNA signatures correlated with coding genes including LCORL, MED17, and ZNF41 in the liver, but none were correlated in the muscle. Among the coding genes which correlated with ncRNA, LCORL is reported to be related to steatosis of the liver in geese, a feature also observed in livers from prenatal BPA-treated female sheep. Since lipid accumulation in the liver may result from increased fatty acid biosynthesis, MED17 which is involved in transcriptional activation of lipogenic genes that correlated with multiple ncRNA in the liver may be a contributor to the steatosis observed in this model. In addition, MIR200B and MIR30B in the liver and MIR26B and MIR29A in the muscle are linked to lipid dysfunction, endoplasmic reticulum stress, and fibrosis. These findings provide mechanistic clues into the role of ncRNA in the prenatal BPA-induced lipid accumulation and oxidative stress in the liver and muscle, contributors to metabolic dysfunction observed in this female sheep model of gestational BPA exposure. In addition, findings from this precocial model of human translational relevance is a step towards gaining mechanistic insights in the programming of metabolic dysfunctions from environmental exposure to BPA, an endocrine disruptor of public health relevance.

ENDO 2022

Non-coding RNA Signatures of Prenatal BPA Exposure in Liver and Muscle of Female Sheep

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ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

Prenatal exposure to bisphenol-A (BPA), an ubiquitously present endocrine-disrupting chemicals, induces peripheral insulin resistance as well as lipotoxicity and oxidative stress in the liver and muscle along with tissue-specific transcriptional changes in female sheep. To gain a mechanistic understanding of contributors to these liver and muscle-specific transcriptional changes, we hypothesized that prenatal BPA exposure impacts non-coding RNA (ncRNA), regulators of transcriptional and post-transcriptional control of coding RNAs. We sequenced ncRNA (including lncRNA, microRNA, snoRNA, and snRNA) in the liver and muscle obtained during the late follicular phase from 21-month-old control and prenatal BPA-treated (0.5mg/kg/day from days 30 to 90 of gestation; Term: 147days) female sheep (n=4 control and 4 prenatal BPA treated). The sequence data were subjected to differential expression analysis and multivariate modeling to identify specific ncRNA signatures. In the liver, 77 lncRNA (49 down, 28 up), 14 microRNAs (6 down, 8 up), 127 snoRNAs (63 down, 64 up) and 55 snRNAs (15 down, 40 up) were dysregulated (FDR<0.1, absolute log2FC>0.5) with BPA exposure. In the muscle 6 lncRNA were upregulated and 65 snoRNAs (47 down, 18 up) were dysregulated (FDR<0.1, absolute log2FC>0.5). Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) plots identified microRNAs MIR200B, MIR409, MIR30B, and MIR154A in the liver and miRNAs MIR26B, MIR29A, MIR125B, and MIR127 in muscle and several uncharacterized ncRNAs as signatures of prenatal BPA exposure. Multiple ncRNA signatures correlated with coding genes including LCORL, MED17, and ZNF41 in the liver, but none were correlated in the muscle. Among the coding genes which correlated with ncRNA, LCORL is reported to be related to steatosis of the liver in geese, a feature also observed in livers from prenatal BPA-treated female sheep. Since lipid accumulation in the liver may result from increased fatty acid biosynthesis, MED17 which is involved in transcriptional activation of lipogenic genes that correlated with multiple ncRNA in the liver may be a contributor to the steatosis observed in this model. In addition, MIR200B and MIR30B in the liver and MIR26B and MIR29A in the muscle are linked to lipid dysfunction, endoplasmic reticulum stress, and fibrosis. These findings provide mechanistic clues into the role of ncRNA in the prenatal BPA-induced lipid accumulation and oxidative stress in the liver and muscle, contributors to metabolic dysfunction observed in this female sheep model of gestational BPA exposure. In addition, findings from this precocial model of human translational relevance is a step towards gaining mechanistic insights in the programming of metabolic dysfunctions from environmental exposure to BPA, an endocrine disruptor of public health relevance.

technical paper

Introduction: Many patients in the US with hypothyroidism receive suboptimal treatment with thyroid hormone. Sustained off-target TSH levels have been shown to cause serious harm to patients, including increased risk of cardiovascular disease and excess mortality over time. Suboptimal treatment may also impact hospital outcomes. The primary objective of the study was to identify differences in hospital outcomes between patients with and without hypothyroidism.Methods: This is a retrospective cohort study that utilized the propensity score-based fine stratification method to balance covariates. Patient data was extracted from a large, US-based, IBM MarketScan® Commercial Claims and Encounters Database from January 1, 2008 to December 31, 2015. Participants included patients 64 years and younger who had commercial insurance and a thyrotropin (TSH) level collected prior to a medical or surgical hospital admission. Covariates included age, sex, US region, type of admission (medical vs surgical), year of admission, and co-morbidities. The primary exposure was defined as clinical hypothyroidism, which was divided into 4 subgroups based on pre-hospitalization TSH level: low (TSH <0.40 mIU/L), normal (TSH 0.40 – 4.50 mIU/L), intermediate (TSH 4.51 – 10.00 mIU/L), and high (TSH >10.00 mIU/L). Non-hypothyroidism was the non-exposure (control). The primary outcomes were length of stay (LOS), in-hospital mortality, and readmission outcomes following medical and surgical admission.Results: A total of 46,235 patients were included in the final study population, of whom 9,394 had a diagnosis of hypothyroidism. Those with a high pre-hospitalization TSH level had a LOS that was 1.2 days longer (95% CI [1.1 – 1.3]; p = 0.001), a 41% higher risk of 30-day readmission (RR 1.41, 95% CI [1.13 – 1.75]; p = 0.002), and 33% higher rate of 90-day readmission (RR 1.33, 95% CI [1.13 – 1.56]; p <0.001) compared to balanced controls. Patients with intermediate TSH levels exhibited increased likelihood of 30-day readmission (RR 1.20, 95% CI [1.01 – 1.43]; p = 0.04). Conversely, those with a normal pre-hospitalization TSH level had a decreased risk of in-hospital mortality (RR 0.55, 95% CI [0.34 – 0.89]; p = 0.02) and 90-day readmission (RR 0.91, 95% CI [0.85 – 0.99]; p = 0.02).Conclusions: Suboptimal treatment of hypothyroidism appears to be associated with worse hospital outcomes, including longer LOS and higher rate of readmission. Public health strategies designed to deliver appropriate, consistent outpatient treatment of hypothyroidism are needed to improve hospital outcomes in those patients with off-target TSH levels.

Suboptimal Thyroid Hormone Replacement is Associated with Worse Hospital Outcomes

Levothyroxine (LT4) is the recommended treatment for hypothyroidism and the second most prescribed medication in the US. Several formulations are available, however most patients take LT4 tablets. Evidence suggests that absorption of levothyroxine tablets is decreased when taken with food, especially those rich in soy, iodine, and fiber. In order to avoid erratic absorption of LT4, it is recommended that oral formulations are taken on an empty stomach, 30-60 minutes before breakfast. However, compliance with this recommendation is often difficult for patients with busy schedules or on multiple medications, yet important in patients with conditions that are sensitive to changes in TSH levels such as pregnancy and thyroid cancer.There is evidence that oral liquid LT4 formulations that bypass the gastric dissolution phase of absorption may mitigate this food effect. ThyquidityTM (levothyroxine sodium) oral solution has demonstrated bioequivalence to Synthroid® under fasting conditions and allows individualized dosing flexibility. A bioavailability study was conducted to assess the rate and extent of absorption of the oral LT4 solution (100 mcg /5 mL) administered either 10 or 30 minutes before a standardized high-calorie, high-fat breakfast in an open-label, randomized, single-dose, 2-period, 2-sequence, crossover study. A single 600 μg oral dose of LT4 solution (ThyquidityTM, 30 mL) was administered to healthy adults either 10 or 30 minutes before consuming a 950 kcal, high fat (56%) breakfast in each study period and blood was collected for total (bound and free) T4 for 48 hours after drug administration. Treatment periods were separated by a 40-day wash-out period.The ratios of geometric LS means with corresponding 90% confidence intervals were calculated from the exponential of the difference between the LT4 solution administration 10 and 30 minutes prior to the meal for AUC0-48 and Cmax. An absence of food effect (bioequivalence) would be concluded if the baseline corrected 90% confidence intervals of this ratio fell within 80.00% to 125.00% for Ln-transformed AUC0-48 and Cmax.Forty healthy volunteers participated in the trial, 38 were included in the data analysis. There were no serious adverse events or discontinuations due to AEs. The geometric LS mean ratios of AUC0-48 and Cmax for baseline-adjusted LT4 were 88.74% (84.71-92.95%) and 85.07% (81.1-89.33%) respectively. The corresponding 90% CIs were included within the acceptable range for bioequivalence, indicating the absence of a meaningful difference in LT4 absorption when administering at 10 or 30 minutes before a meal.Based on these results, it may be possible to decrease the interval between the administration of Thyquidity (levothyroxine sodium) oral solution to 10 minutes before breakfast, thus offering patients further dosing flexibility.

Comparable Bioavailability of a Novel Levothyroxine Solution taken 10 or 30 minutes prior to a High-Fat, High-Calorie Breakfast

Introduction:Thyroid storm is a life-threatening condition with a high morbidity and mortality rate. It can lead to severe end organ damage including liver injury, which can preclude the use of thionamides. Therapeutic plasma exchange can be a lifesaving option for treatment of thyroid storm in such cases. Multiorgan failure can also necessitate the use of extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT).Case Presentation:A 34-year-old woman with a history of Graves' disease, untreated for several years, presented to the emergency department with fatigue, palpitations, dyspnea, and edema which developed over 1 month. Labs showed suppressed thyroid stimulating hormone (TSH) with significantly elevated free T4 of 10.8 ng/dL (normal 0.89-1.76 ng/dL). She had evidence of atrial fibrillation and heart failure. She was started on treatment with propylthiouracil, propranolol, and hydrocortisone and then Lugol's iodine was added. However, she quickly deteriorated with worsening mentation, dyspnea, and hypotension. She progressed to multiorgan failure including significant liver injury likely due to ischemic hepatitis. Thus, thianomides could not be used any further. She was started on cholestyramine; hydrocortisone and Lugol's iodine were continued.An echocardiogram revealed global hypokinesis with a left ventricular ejection fraction of 20%. Beta blockers were discontinued due to hypotension. The cardiogenic shock worsened despite aggressive medical therapy requiring initiation of veno-arterial (V-A) ECMO. She also required CRRT due to renal failure.Plasmapheresis was initiated for treatment of thyroid storm and she received 4 treatments with normalization of free T4: 1.48 ng/dL and T3 levels: 3.4 ng/dL (normal 2.3-4.2 ng/dL). Her condition subsequently improved and she was decannulated from the ECMO device after 5 days. She was then able to receive definitive treatment with thyroidectomy 11 days following admission. The patient was discharged in improved condition after a 10-week hospital course.Discussion:Thyroid storm is a rare complication of thyrotoxicosis with a mortality rate of 10-30%. Treatment classically involves inhibiting the synthesis, release, and peripheral conversion of thyroid hormone as well as supportive management. Major causes of mortality in thyroid storm, present in our patient, include cardiogenic shock, arrhythmia, and multiorgan failure. Cardiac and hepatic failure can preclude the use of beta blockers and thionamides, which may necessitate the use of extracorporeal treatments, such as plasmapheresis for clearance of high burden of circulating thyroid hormone; V-A ECMO and CRRT for end organ damage. These therapeutic measures were used in our patient and led to a favorable outcome. This case highlights the successful use of these extracorporeal treatments as a bridge to thyroidectomy when standard medical treatment is contraindicated or unsuccessful.

Plasmapheresis and Extracorporeal Membrane Oxygenation (ECMO) for Treatment of Thyroid Storm with Multiorgan Failure

The relationship between obesity and thyroid function tests (TFT) has been studied in the past decades with increasing interest, however, studies have been inconsistent . The objectives of this study were to examine the effect of weight loss induced by laparoscopic sleeve gastrectomy(LSG) on TFT in obese euthyroid subjects and to correlate that with the changes in serum leptin, adiponectin, and insulin resistance.55 euthyroid obese subjects(BMI > 30) and 52 non-obese (BMI < 30), age-matched controls were recruited at baseline. We measured body weight, BMI, body composition, thyroid-stimulating hormone (TSH), Free T4 (FT4), Free T3(FT3), fasting leptin, adiponectin. Insulin resistance was quantified by HOMA-IR. Data are presented as mean ± SEM. The same parameters were repeated at 3- and 6-months in the obese group. Obese subjects had significantly higher TSH compared to non-obese subjects, 2.7 ±0.18 V.s 1.7±0.13 ( normal range 0.27-4.2 mIU/L . Mean FT3 was 3.9± 0.1pmol/L ( normal 3.1-6.8) in obese subjects compared to 5.0 ± 0.1 pmol/L in the non-obese controls, respectively, P value 0.001, however, FT4 (Normal 12-22 pmol/L) was similar in the two groups.Repeated measures ANOVA showed significant reduction in body weight from 140±26.5 kg at baseline to 115.8 ± 22.3 kg at 3 months, P < 001, and 104.2 ± 21.1 kg at 6 months, P<0.001, respectively. Serum TSH (N=48) reduced from 2.6 ±0.86 at baseline, to 2.0 ± 0.85 at 3 months, P = 0.06, and was 2.2± 0.78, at 6 months , P=0.23, in comparison with baseline, N=47). Free T3 reduced from 3.7.0 ± 0.41 pmol/L at baseline to 3.2 ±0.4 at 3 months (P < 0.9) and increased to 3.9± 0.53 at 6 months, P < 0.33. Changes in FT4 were not significant at 3 and 6 months, respectively. HOMA-IR reduced within 6 months and correlated with baseline FT3 .Serum leptin (N=38) significantly reduced from 25.9 ng/ml at baseline to 17.5 ng/ml at 3 months( p=0.037) to 15.2 ng/ml at 6 months, respectively, P < 0.011 compared to baseline. On the other hand , serum adiponectin (N=22) significantly increased from the baseline value of 9.2 ng/ml to 12.4 ng/ml at 3 months (p=0.001) and 16.6 ng/ml at 6 months( p<0.001 from baseline). TSH and Free T3 tend to decrease within 6 months following weight loss with LSG in obese subjects . Serum leptin significantly decreased and serum adiponectin significantly increased following LSG, however, there were no correlations between the changes in these adipose tissue markers and TFTs . We speculate that the changes in TSH and FT3 in obese euthyroid subjects may be due to the influence of the obesity and are unlikely to be causative, since they tend to reverse after weight loss, however, further studies on larger numbers of patients are needed to further explore the relationship between obesity and TFTs.

The Relationship Between Thyroid Function and Body Mass Index, Leptin, Adiponectin, and Insulin Resistance in Euthyroid Subjects Before and After Laproscopic Sleeve Gastrectomy

Interpretation of abnormal thyroid function tests (TFTs) is routine in endocrine practice. However, when there is a discrepancy between biochemical parameters and the clinical picture, sleuthing is necessary to provide appropriate care.A 34-year-old woman was evaluated by an outside endocrine clinic for abnormal TFTs in the setting of worsening anxiety, night sweats, and menstrual irregularities. These showed elevated free thyroxine (FT4) levels (7.3; ref: 0.9-1.7 ng/dL), free triiodothyronine (FT3) levels (13.9; ref: 2.3-4.1 pg/mL) and total triiodothyronine (T3) (186; ref: 94-170 ng/dL) with normal TSH (0.65; ref: 0.27-4.20 mIU/L), negative microsomal and thyroid receptor antibodies. She denied use of contraceptives, biotin, lithium, glucocorticoids, prior radiation, or recent intravenous contrast. Mother and maternal aunt had unspecified thyroid disease. No physical signs of overt hyperthyroidism/hypothyroidism were noted. Our workup also showed elevated FT4 (1.8 ng/dL), FT3 (13.3 pg/mL), total thyroxine (T4) (24.8; ref: 5.5-10.2 µg/dL), T3 (>651; ref: 79-165 ng/dL), normal TSH (0.71; ref: 0.4-5.5 mIU/L), and normal gonadotropin alpha subunit; ultrasound showed no nodules nor evidence of thyroiditis. FT4 by equilibrium dialysis and liquid chromatography-mass spectrometry was normal (1.3; ref: 0.8-2.0 ng/dL). Human anti-mouse antibodies (HAMA) treated TSH was within normal limits (1.4; ref: 0.4-4.5 mIU/L; Siemens). Leading differential diagnosis was initially thyroid hormone resistance; however subsequent labs, done by PCP for non-specific symptoms, revealed a suppressed parathyroid hormone (PTH) (<6; ref 15-65 pg/mL) with normal serum calcium levels. Given no clinical correlate, lab interference was considered. All the testing, with the exception of the FT4 by mass spectrometry and HAMA TSH, were analyzed utilizing Roche Diagnostics (electrochemiluminescent immunoassays). To evaluate vendor-specific interferences, labs were analyzed utilizing Siemens (chemiluminescent immunoassay) which showed normal T4, T3, FT3, and PTH levels. Unlike the Siemens assays, Roche depends on the formation of a biotin-streptavidin complex during measurement and a ruthenium complex to produce a signal. HAMA and polyethylene glycol treatment also returned differing results from untreated samples possibly indicating the interference was a heterophilic antibody to an unknown target. An investigation by Roche Diagnostics showed evidence of streptavidin antibodies. Streptavidin is a common reagent in endocrine assays. The endogenous streptavidin antibody produces an unintended competition between streptavidin-biotin and streptavidin-antibody in the assay; resulting in falsely-low results for sandwich assays (e.g. PTH) and falsely-high results for competitive assays (e.g. FT3 and T4). The impact to the individual analyte is variable due to assay formulation (e.g. TSH).Interference from anti-streptavidin antibodies is a rare phenomenon and may cause unnecessary diagnostics or treatment. Analytical interference should be considered when clinically suspicious of results, and lab consultation is recommended. The patient was advised to obtain a Medic-Alert bracelet. She was also provided a letter detailing the findings so that providers may consult the laboratory prior to testing.

The Curious Case of Abnormal Thyroid Function Tests: Think Streptavidin Interference

Levothyroxine (LT4) is the treatment of choice for hypothyroidism and the second most prescribed medication in the United States. Despite its established efficacy and widespread availability, approximately 40% of patients treated with LT4 fail to achieve thyroid stimulating hormone (TSH) levels within the normal range. Current LT4 product guidelines recommend administration in the fasting state 30-60 minutes before breakfast to avoid a food interaction leading to reduced intestinal absorption of LT4. This recommendation may impact compliance, as over 50% of adult Americans drink coffee every day, 65% of which is consumed during breakfast.While the majority of patients receive LT4 tablets, there is evidence that liquid formulations that bypass the gastric dissolution phase may mitigate the interference with coffee. ThyquidityTM (levothyroxine sodium) oral solution has demonstrated bioequivalence to Synthroid® under fasting conditions and allows individualized dosing flexibility in a variety of clinical scenarios. A bioavailability study was conducted to assess the rate and extent of absorption of the oral LT4 solution (100 mcg /5 mL) administered with coffee compared to administration under fasting conditions in an open label, randomized, two-period, two-treatment, two-sequence, crossover, single dose bioavailability study in 40 healthy adults. A single 600 μg oral dose of LT4 solution (ThyquidityTM, 30 mL) was administered 5 minutes before drinking 8 ounces of American coffee (without milk or sweeteners) or under fasting conditions in each study period. Blood samples were collected for total (bound and free) T4 for 48 hours after drug administration. Treatment periods were separated by a 40-day wash-out period.The ratios of geometric LS means with corresponding 90% confidence intervals (CI) were calculated from the exponential of the difference between the LT4 solution administration 5 minutes prior to coffee and administration under fasting condition for AUC0-48 and Cmax. An absence of a food effect would be concluded if the baseline corrected 90% CIs of this ratio fell within 80.00% to 125.00% for Ln-transformed AUC0-48 and Cmax.Forty healthy adults participated in the trial. There were no serious adverse events (AE) or discontinuations due to AEs. The geometric LS mean ratio of AUC0-48 and Cmax for baseline-adjusted LT4 were 93.98% (90.06-98.07%) and 95.99% (92.64- 99.45%) respectively. The corresponding 90% CIs were included within the acceptance range for bioequivalence.This study demonstrated comparable bioavailability of a single oral 600 μg dose of Thyquidity oral solution administered, 5 minutes prior to coffee or under fasting conditions. These results are consistent with earlier evidence that liquid LT4 overcomes the interference from coffee seen with LT4 tablets and may offer additional flexibility for patients.

Comparable Bioavailability of a Novel Levothyroxine Solution when Administered with Coffee

Background: Thyrotoxic Periodic Paralysis (TPP) is a rare complication of thyrotoxicosis mostly reported in Eastern Asian countries with relatively few known cases among non-Asian diaspora in the West.Case: A 28-year-old African American male with no documented medical history reported to the ED with concern for mechanical fall secondary to progressively worsening muscle weakness. Symptoms began the prior evening with proximal lower extremity and bilateral shoulder weakness which then became severe generalized weakness in all four extremities by morning prompting a fall due to unstable gait and inability to maintain stable seated position. A 60 lb weight loss over the prior year was also noted. Vital signs were notable for blood pressure 154/67 mmHg, tachycardia 109 beats per minute, and tachypnea 20 breaths per minute. Initial labs were significant for hypokalemia 2.2 mEq/L (3.5 – 5.5 mEq/L), hs-troponin 59 ng/L (n < 20 ng/L), CK 444 U/L (38 – 174 U/L), ALP 186 U/L (35 – 110 U/L), TSH < 0.01 uIU/mL (0.35 – 5.5 uIu/mL), free T4 4.13 ng/dL (0.61 – 1.12 ng/dL), free T3 15.10 pg/mL (2.5 – 3.9 pg/mL) and total T3 404 ng/dL (87 – 178 ng/dL). EKG revealed sinus tachycardia with prolonged PR-interval to 236 ms and prominent precordial U-waves. The patient was given potassium chloride 40 meq IV and PO supplementation, started on propranolol 10mg PO QID and methimazole 30mg PO daily, and admitted to telemetry. Endocrinology recommended increasing the methimazole dose to 20mg PO TID. Thyroid ultrasound revealed a heterogeneous hyper-vascular gland. Follow up labs included: thyroid stimulating immunoglobulin 4.97 IU/L (n < 0.10 IU/L), thyroid peroxidase antibody 19 IU/L (n < 9 IU/mL), gamma glutamyl transpeptidase 22 (9 – 65 U/L). Findings were consistent with Graves' disease. Repeat metabolic panel showed appropriate potassium response to supplementation trending between 3.9 meq/L to 4.2 meq/L at six-hour intervals. Hs-troponin peaked at 108 ng/L likely due to demand ischemia in the setting of persistent tachycardia. Follow-up 2D echocardiogram was remarkable for borderline LVH with 60% EF. Patient displayed rapid improvement in muscle strength as potassium normalized; creatine kinase trended down to 49 U/L with resolving myopathy. Patient was discharged on methimazole 20mg PO TID and propranolol 10mg PO QID and told to increase PO intake of potassium rich foods. He was advised to avoid strenuous activity for at least 2 weeks.His potassium was 4.5 meq/L on follow-up endocrinology appointment one week after discharge. He did not endorse residual symptoms and remained compliant with medications.Conclusion: This is a case of TPP amidst undiagnosed Graves' disease that resolved with timely potassium repletion. Documented TPP cases in non-Asians, especially African Americans, are rare and should be investigated further.

Thyrotoxic Periodic Paralysis: An Uncommon Complication Presenting From an Unsuspected Demographic

Background: SH2B adaptor protein 1 (SH2B1) binds to Janus kinase 2 and enhances leptin signaling through the central melanocortin-4 receptor (MC4R) pathway, a key regulator of energy balance. Variants in SH2B1 or a 220–kilobase pair distal deletion of chromosome 16p11.2, including SH2B1, are associated with hyperphagia (pathologic insatiable hunger), severe early-onset obesity, reduced final height, and insulin resistance. Setmelanotide, an MC4R agonist, produced significant weight and hunger reduction after 3 months in patients with SH2B1 heterozygous variants or 16p11.2 deletion in a Phase 2 study. This analysis is the first to assess the continued efficacy of ~1 year of setmelanotide treatment in patients with SH2B1 genetic obesity.
Methods: Patients aged ≥6 years with SH2B1 heterozygous variants or 16p11.2 deletion encompassing SH2B1 were eligible for this long-term extension (LTE) trial (NCT03651765) if they completed a prior (index) trial in which they received setmelanotide and demonstrated clinical benefit based on weight and hunger results, and acceptable safety as determined by the investigator. Patients received a minimum of 4 months of setmelanotide treatment as part of the index trial and began the LTE immediately following the completion of the index trial. Study visits occurred approximately every 3 months. Study objectives included evaluating changes in body weight measures and assessing tolerability. The current analysis reports outcomes after ~1 year of setmelanotide treatment across the index and LTE trials relative to index trial baseline.
Results: As of October 29, 2021, 35 patients with obesity and SH2B1 heterozygous variants or 16p11.2 deletion had enrolled in the index trial. Of patients entering the LTE, 19, 15, and 14 had received at least 6, 9, and 12 months of treatment, respectively. At index trial baseline, mean (standard deviation [SD]) body mass index (BMI) for all patients was 47.2 (12.8) kg/m2, body weight in patients aged ≥18 years (n=22) was 139.7 (35.4) kg, and BMI Z-score in patients aged <18 years (n=13) was 3.56 (0.60). Mean (SD) percent change in BMI was −3.4% (8.1%; n=19), −5.9% (10.0%; n=15), and −9.7% (8.0%; n=14) after 6, 9, and 12 months of treatment. Mean (SD) percent change in body weight in patients aged ≥18 years was −4.4% (5.0%; n=9), −6.8% (5.0%; n=7), and −7.7% (10.0%; n=8) after 6, 9, and 12 months, respectively. Mean (SD) change in BMI Z-score was −0.55 (0.17; n=6) after 12 months. No patients discontinued due to adverse events during the LTE . No new safety concerns emerged during long-term treatment.
Conclusions: Setmelanotide treatment provided clinically meaningful reductions in weight-related measures in patients with SH2B1 heterozygous variants or 16p11.2 deletion up to ~1 year. These data support the continued investigation of setmelanotide in this population, which is underway in the planned Phase 3 EMANATE trial (NCT05093634).

Body Mass Index and Weight Reduction in Patients With SH2B1 Genetic Variant Obesity After One Year of Setmelanotide

Background: Lipodystrophy syndromes are associated with inadequate adipocyte capacity that results in an earlier threshold for ectopic deposition and metabolic dysfunction. We have previously reported that patients with familial partial lipodystrophy (FPLD) present with metabolic severity equivalent to what is observed at 8-12 BMI points higher in a population with common obesity. Currently, there is no strong evidence that any specific diet is the preferred treatment, but bariatric surgery has been reported to improve metabolic outcomes in a few patients. Here, we report the effect of an aggressive calorie-restricted diet in a patient with FPLD who showed remarkable benefit after 16 weeks of the intervention. Clinical Case: This is a 38-year-old female diagnosed with FPLD type 2, with LMNA p. R482Q mutation who had a history of recurrent pancreatitis, NAFLD, impaired ovulation, and diabetes mellitus. She had a short-term goal of improving her metabolic state rapidly to achieve pregnancy by IVF. Upon presentation, body weight was 81.6kg, BMI 23.2kg/m2, HbA1c 7.7% and triglycerides 215mg/dL. She was started on very-low calorie diet (VLCD) (800 kcal/day) employing a formula total liquid diet meal replacement:  160 kcal per shake (18g total carbohydrates, 15g net carbohydrates, 3.5g fat, and 16g protein) with the goal to reduce body weight by 15% as has been described for patients in the University of Michigan Weight Management Program. After 1 week on diet, she discontinued glucose and lipid lowering therapies. After 12-weeks of VLCD followed by 4 weeks of transition to low-calorie diet (incorporating 3 meal replacements, one meal, and ad libitum non-starchy vegetables), we observed 12.3kg of body weight and a 1.4% decrease in HbA1c. Insulin resistance was reduced by 66.7 and 61.5% (HOMA-IR and ADIPO-IR, respectively). Fasting insulinemia was reduced by 64.2%. We also performed an OGTT with 75g of glucose for 180 min and observed a decrease in the area under the curve of insulin (-33.2%), triglycerides (-40.7%), and free fatty acids (-34%). DEXA scan showed a reduction in total body fat of 16%. Liver fat via the chemical shift MRI method was reduced from 10±2% to 2±1%. She did not experience any adverse events during the intervention. More importantly, her egg retrieval rate and egg quality during IVF were far superior to past attempts. Conclusion: This case illustrates the strong effect and safety of a VLCD intervention in a patient with lipodystrophy. We observed rapid reduction in body weight, and in insulin resistance leading to the remission of diabetes mellitus, hypertriglyceridemia and fatty liver disease. Moreover, there was improved response to ovulation induction. Our data encourage the use of this medical approach for other patients with similar metabolic and reproductive abnormalities due to adipose tissue distribution abnormalities.

A Very-Low Calorie Diet Can Reduce Insulin Resistance and Cause Remission of Diabetes Mellitus and Hypertriglyceridemia in a Patient With Familial Partial Lipodystrophy Type 2

Background: The prevalence of sarcopenic obesity (SO) is increasing worldwide, posing important challenges to public health and national health care system, especially during the COVID pandemic. In subjects with SO, it is essential to reduce body weight preserving lean mass, in order to avoid a worsening of muscle function. Lifestyle modification with adequate nutrition and proper physical activity is essential to counteract SO progression. In accordance with the Position Statement of the Italian Society of Endocrinology, Very Low Calorie Ketogenic Diet (VLCKD), a well established nutritional intervention in the context of obesity, has been promoted also for the treatment of SO (1). To date, the effects of physical training during VLCKD have not been studied. Aim: This pilot study aims to determine the efficacy of VLCKD combined with interval training, compared to a VLCKD alone, on weight-loss, body composition and physical performance in patient with SO. Materials and methods: Twenty-six patients with SO, aged between 50 and 70 years, who met the inclusion criteria, accepted to adhere to a VLCKD nutritional program (< 800 Kcal/die) and gave informed consent, were enrolled in the study. Thirteen patients followed a structured VLCKD protocol (VLCKD group) and thirteen patients followed a structured VLCKD protocol combined with interval training (IT), two times a week (VLCKD+IT group). Data were collected at baseline (T0) and after 45 days (T45). Anthropometric indexes, body composition analysis by Bioelectrical Impedance Analysis (BIA), muscle strength measurement by Chair Stand Test and physical performance analysis by Short Physical Performance Battery were assessed at baseline and at the end of treatment. Results: At the end of the study, Body Mass Index, body weight and waist circumference were significantly reduced both in the VLCKD group and in the VLCKD+IT group. Moreover, significant improvement of muscle strength and physical performance was found in all groups. A significant reduction in hip circumference was observed only in the VLCKD+IT group. A multiple comparison of delta variations in the measured parameters between groups was performed. No differences were observed for the majority of parameters, with the exception of FFM and FM: interestingly, the individuals fed with VLCKD combined with IT preserved their FFM (p <0.0001) and reduced their FM (p = 0.0006) to a greater extent than in the VLCKD group. Conclusions: Our pilot study showed that VLCKD was effective in terms of body weight reduction, particularly of FM; moreover, we conclude that the combination of VLCKD and interval training determines a better preservation of FFM. References: 1. Caprio, M. et al. Very-low-calorie ketogenic diet (VLCKD) in the management of metabolic diseases: systematic review and consensus statement from the Italian Society of Endocrinology (SIE). J Endocrinol Invest 2019, 42, 1365-1386, doi: 10.1007/s40618-019-01061-2.

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