bluuebunny/crossref_metadata_2025 huggingface dataset:
Refractory Postsurgical Hypothyroidism in Nephrotic Syndrome
Authors: Rendon Casey
Published: May 2021

62-year-old female with a history of thyroid cancer of unknown type s/p thyroidectomy 30 years prior to presentation, who had 2 months of worsening generalized edema and increasing need of dose escalation of her oral thyroid replacement by her PCP. Despite increasing her thyroxine dose multiple times and adding Armour thyroid based on increasing TSH and decreasing FT4 on outpatient labs, her edema continued to get worse. She presented to the Emergency Department. She takes no other medications. Symptoms include malaise, cold intolerance, weight gain, hair loss, bloating without constipation,“feeling foggy” and that her memory seemed a bit “off”, and she felt her mood was more “sensitive”, and she had atypical non-exertional chest discomfort. On exam she was was bradycardic to 56 and hypertensive to 175 systolic, had faint bibasilar crackles were present bilaterally, had significant pitting edema of the bilateral lower extremities, 3+ up to the level of her abdomen, as well as pitting edema of her bilateral upper extremities, and no periorbital edema was seen. Her neurologic exam was non-focal. Outpatient labs included TSH 178, free T4 0.35, albumin 1.2, and BNP level of 57. Her liver and kidney function tests were normal. Hospital labs included a normal CBC, chemistry with an albumin of 2.2 and normal range liver and kidney function. Thyroid function tests included a very high TSH level of 141, low free T4 level of 0.37, and a free T3 toward the lower end of normal. Lipid panel showed severe hypercholesterolemia. Urine studies showed microhematuria as well as the equivalent of proteinuria to the level of 10 grams per day. HIV was negative and complement levels were within normal limits. CXR, renal US, transvaginal US, and CT chest/abdomen/pelvis were performed to investigate the proteinuria and potential secondary causes of the proteinuria, all of which were unremarkable for acute or pertinent findings. Pathology results from a kidney biopsy showed membranous nephropathy. The patient initially received IV steroids and IV thyroxine as well as an albumin infusion. She was quickly transitioned to oral thyroxine due to her stability on presentation. She was given a statin and ACE inhibitor as well as IV Lasix. And she was discharged on thyroxine, with Armour thyroid being discontinued. She had severe hypothyroidism in a patient dependent on exogenous thyroid hormone which was exacerbated by severe proteinuria due to a new-onset nephrotic syndrome. Her hospital course uneventful. She responded well to intravenous diuretics. After her diagnosis of membranous nephropathy, Nephrology recommended continued conservative treatment due to her normal renal function and improving edema with outpatient follow up. She only received a single dose of IV thyroxine and remained stable after switching to oral thyroxine.
The Diagnostic Accuracy of Dehydroepiandrosterone Sulfate in Diagnosing Adrenal Insufficiency
Authors: Suresh Malavika , Gruber Lucinda , Bancos Irina
Published: May 2021

Background: Evaluation for adrenal insufficiency (AI) includes dynamic testing that is cumbersome, expensive, and may not always be accessible. Our objective was to evaluate the diagnostic accuracy of dehydroepiandrosterone sulfate (DHEAS) in diagnosing AI.

Methods: This is a single-center retrospective study of patients evaluated for AI between July 10th, 2012 to January 7th, 2020 who underwent Cosyntropin stimulation testing (CST) or Insulin tolerance test (ITT), and had baseline measurement of DHEAS. Diagnosis of adrenal insufficiency was based on peak cortisol of <18 ug/dL during either CST or ITT.

Results: We identified 491 patients (379 [77.2%] women, median age 42 years [range 18–84]) who met inclusion criteria. Primary adrenal insufficiency (PAI) was diagnosed in 16 (3%) patients, secondary adrenal insufficiency (SAI) was diagnosed in 211 (43%) patients, and AI was excluded in 264 (54%) patients. CST was performed in 478 (97%) patients, ITT was done in 45 (9%) patients, with 32 patients having both CST and ITT performed. Using a peak cortisol of <18 mcg/dl during CST to diagnose AI, ROC analysis of DHEAS demonstrated an area under the curve of 0.79, p<0.0001. A DHEAS cutoff of 100 mcg/dL excluded AI with a sensitivity of 93%, specificity of 41%, and a false negative rate of 3%. A DHEAS cut-off of 25 mcg/dl diagnosed AI with a false positive rate of 9% (Sensitivity 57% and specificity 85%). Notably, of 32 patients who had both CST and ITT performed, the diagnosis of AI was concordant in only 5 patients, while additional 27 patients had discordant results (26 were diagnosed with SAI based on ITT, but with a normal CST, and 1 patient was diagnosed with AI on CST but not on ITT). When excluding the 27 patients with discordant results, the overall performance of DHEAS in diagnosis of AI based on CST has not changed.

Conclusion: DHEAS is a valuable baseline diagnostic test for AI. DHEAS >100 mcg/dl predicts a normal response during CST with a false negative rate of 3%, while DHEAS <25 mcg/dl is reflective of underlying adrenal insufficiency and predicts an abnormal CST with a false positive rate of 9%. In these situations, CST can be avoided.
Subacute Thyroiditis After SARS-CoV-2 Infection Presenting With Pyrexia of Unknown Origin
Authors: Singh Santosh
Published: May 2021

Subacute thyroiditis(SAT) is associated with viral(destructive) or post-viral(inflammatory) origin.[1]The most common clinical characteristics of SAT are female sex preponderance, anterior neck pain and fever.[2,3] Heart rhythm disorders and silent cervical forms have been described in SAT associated with SARS-CoV-2 infection,which occurs 16 to 36 days after resolution of COVID-19.[1,3] Symptomatic improvement occurs in a few days after initiation of therapy with sterods or NSAID.[3] Pyrexia of Unknown Origin (PUO) is a very rare presentation of SAT.[2] Hereby, a case of SAT, presenting with painful neck swelling and persistent fever (5weeks duration), two weeks after resolution of COVID-19, is being discussed. The index patient was a 50-year old obese,normotensive, diabetic (10 years duration, HbA1c-6.6% on SU, metformin, sitagliptin and dapagliflozin) male. TSH was suppressed (0.02 mIU/L), FT4 (3.06 ng/dl, upper limit of normal-1.48ng/dl) and FT3 (3.9 pg/ml, upper limit of normal-3.71 pg/ml) were elevated. Total T4 and T3 were normal. HS-CRP was markedly elevated. IL-6 and TBG were not estimated. Cervical USG revealed diffuse hypoechogenecity of thyroid gland and thyromegaly. There was reduced uptake in thyroid scan (technetium). The patient became afebrile after 4 days of initiation of 30 mg prednisolone (tapered by 10 mg every 5 days). The initial tachycardia reverted to sinus rhythm with marked reduction of neck tenderness. This case highlights certain considerations for SAT associated with SARS-CoV-2 infection. Firstly, it can present with PUO (first case report). Secondly, it may be associated with normal total T4 and T3 which can happen due to reduced TBG consequent upon increased IL-6.[4] References: 1. Caron Philippe: Thyroid disorders and SARS-CoV-2 infection: From pathophysiological mechanism to patient management. Ann Endocrinol (Paris), 2020, Sept. 2. Fever of Unknown Origin as a Sole Presentation of Subacute Throiditis in an Elderly Patient. A Case Report with Literature Review. Raj R, Yada S, Jacob A et al: Hindawi Case Reports in Endocrinology, 2018, Article ID 5041724 3. Brancatella A, Ricci D, Latrofa F et al: Is subacute thyroidits an underestimated manifestation of SARS-CoV-2 infection? Insights from a case serie. J Clin Endocrinol Metab, 2020, Aug 11, dgaa537. 4. Bartaleno L, Brogioni S, Grasso L and Martino E: Increased serum interleukin-6 concentration in patients with subacute thyroiditis:relationship with concomitant changes in serum T4-binding globulin concentration. Journal of Endocrinological Investigation, 1993, 16, 213-218.
Tuberculous Thyroiditis Post COVID-19 Infection
Authors: Win Kyaw Zin , Hamidi Afshin , Sattar Alamgir , Karunakaran Abhijana
Published: May 2021

Thyroid tuberculosis (TT) is a rare disease and can be a diagnostic challenge. Here we highlight a case of TT following COVID-19 infection. A 38-year Myanmar immigrant female presented with nocturnal fever, fatigue, nausea, sore throat, appetite and weight loss for 1 week with dysphagia, neck swelling, dyspnea, and watery diarrhea. Medical history included renal transplant due to ESRD from IgA nephropathy, DM and treated latent TB with no prior or family history of thyroid disease. She had COVID 7 months ago, complicated by allograft rejection. She was tachycardic, febrile but not in acute distress. Neck exam revealed diffuse thyromegaly with tenderness on right lobe without bruit, palpable cervical lymphadenopathy nor tremors. Labs showed WBC 12.8x109/L (4.8-10), and ESR 50 ml/hr (20-40). On admission, she developed AKI and immunosuppressant meds were discontinued. She was started on broad-spectrum antibiotic. CT chest reported moderate loculated right pleural effusion with mid and lower lobe consolidation. Blood and urine culture, pleural fluid, sputum culture for acid-fast bacilli (AFB) and QuantiFERON-TB were negative. Upon persistent fever, RIPE therapy (rifampin, isoniazid, pyrazinamide, ethambutol) was started and stopped after 10 days due to transaminitis and negative TB PCR. Further labs showed TSH 0.04 mIU/ml (0.27-4.2), FT4 2.81 ng/dl (0.93-1.7), TT3 127 ng/dl (80-200), negative TPO and TSI. Endocrinology was consulted for thyroiditis. Ibuprofen and Propranolol were initiated with continuation of prednisone. Repeat thyroid labs normalized in 4 days. US thyroid noted diffuse, heterogenous thyromegaly without hypervascularity or abscess. CT neck showed diffuse thyromegaly 4.2x7.2x7.5 cm in size; right thyroid lobe extended to posterior clavicle with enhanced capsule, without discrete lymph node or vascularity changes, suggestive of thyroiditis. Fine needle aspiration (FNA) of left thyroid lobe drained 3 ml purulent fluid and AFB were seen on direct smear. She was diagnosed as TT, but unable to restart RIPE therapy due to worsening liver function. She expired after cardiac arrest due to intracranial bleeding and brain abscess. Thyroid tuberculosis is a rarely reported clinical entity. This is the first reported case of secondary TB (TT) in post-COVID infected patient from reactivation of latent TB. In our case, follicular destruction caused initial hyperthyroidism with later recovery. It can be difficult to distinguish subacute from suppurative thyroiditis due to TB. Imaging may not always show clear abscess formation. FNA is crucial for diagnosis, and drainage of any abscess. Anti-TB meds can be given, surgery is rarely required. TT should be considered in any immunocompromised patient with fever and neck pain. Imaging should also include evaluation for any CNS spread of TB. Early detection and treatment will help reduce significant morbidity and mortality.
Two Cases of Graves’ Hyperthyroidism Treated With Homeopathic Remedies Containing Herbal Extracts from Lycopus spp. and Melissa officinalis
Authors: Kaplan Daniel , Dosiou Chrysoula
Published: May 2021

Background: Plant extracts from species of Lycopus (bugleweed) and Melissa officinalis (lemon balm) have long been used as folk remedies in the treatment of hyperthyroidism1. In vitro studies have shown that extracts from bugleweed and lemon balm inhibit stimulation of thyroid hormone production by both TSH and Graves’ antibodies1. An in vivo study in rats showed that oral bugleweed extract alters extra-thyroidal T4 conversion2.

Case 1: A 64 year-old woman presented for routine examination and was found to have a TSH of 0.01 mIU/L on 6/6/2016. Labs the next month showed FT4 1.4ng/dL (0.8-1.8) and FT3 4.7pg/mL (2.3-4.2). TSI was elevated to 275% (Normal<140%), consistent with Graves’. She did not have symptoms of hyperthyroidism. The patient’s cat had been treated for hyperthyroidism with Thyrosoothe (TS), a formulation containing extracts from bugleweed and lemon balm. After being diagnosed with hyperthyroidism, the patient began taking TS. On 9/12/16 the patient’s labs were improved with TSH 0.02mIU/L, FT4 0.88 ng/dL (0.8-1.8) and Total T3 86 (76-181). Three months later, the patient’s TSH was 1.89 with normal FT4, Total T3 and TSI. She took TS for 9 months. Her thyroid function tests have remained normal since starting TS, without the need for any other anti-thyroid medications.

Case 2: A 46 year-old female presented with periorbital edema in July 2018 and was referred to an ophthalmologist, who diagnosed her with thyroid eye disease. She was also complaining of palpitations and “jitteriness”. She was found to be hyperthyroid on labs and was treated with methimazole (MMI) between August 2018 and February 2019, requiring doses of up to 10mg BID. In March 2019 she stopped MMI due to transaminitis and began taking a thyroid tincture containing bugleweed and lemon balm extract. She has remained euthyroid on the herbal tincture, her transaminitis has resolved, and she has not required any further anti-thyroid medication. Her TSI, which was 0.84 IU/L (Normal<0.55) in May 2019, normalized to 0.36 IU/L in June 2020, after 15 months on this tincture, which she is still taking.

Conclusion: In vitro and rat studies of bugleweed and lemon balm extract have demonstrated anti-thyroidal effects. This is the first report of the use of these plant extracts in the treatment of two patients with Graves’ disease, in whom it led to restoration of euthyroidism and normalization of TSI titers. Further study of the anti-thyroidal effects of bugleweed and lemon balm in humans is warranted to evaluate its potential role as an adjunctive therapy in Graves’ disease.References: 1. Auf’Mkolk, M., et al. “Extracts and Auto-Oxidized Constituents of Certain Plants Inhibit the Receptor-Binding and the Biological Activity of Graves’ Igs*.” Endocrinology, vol. 116, no. 5, May 1985, pp. 1687–93. 2. Winterhoff, H., et al. “Endocrine Effects of Lycopus Europaeus L. Following Oral Application.” Arzneim. Forsch., vol. I, no. 44, 1944.
Altered Intracellular Trafficking of Mutant Thyroid Hormone Receptors in Resistance to Thyroid Hormone Syndrome
Authors: Tofil Hannah P , Allison Lizabeth Ann
Published: May 2021

Resistance to Thyroid Hormone α (RTHα), a reduced sensitivity to thyroid hormone (T3) in peripheral tissues, is caused by mutations in thyroid hormone receptor α (TRα), a nuclear receptor that mediates T3-responsive gene expression. All mutations characterized in RTHα, to date, are in the ligand binding domain (LBD), resulting in reduced affinity for T3. In addition, some mutations result in truncated proteins lacking all or part of helix 12. Previously, we have used fluorescence recovery after photobleaching (FRAP) to examine the effects of select RTHα mutations on the intracellular trafficking of TRα. After transfecting HeLa cells with expression plasmids for green fluorescent protein (GFP)-tagged wild-type TRα and each of the mutants, we first assessed their intracellular distribution and initial intranuclear mobility. Although wild-type TRα is known to shuttle between the nucleus and cytoplasm, it is primarily localized to the nucleus at a steady state. We showed that TR-E403X, Ala382ProfsX7, and F397fs406X are also primarily localized to the nucleus, and FRAP revealed that wild-type TRα and the RTHα mutants are highly dynamic within the nucleus, indicating that the receptors rapidly dissociate and reassociate with DNA binding sites and/or other nuclear binding sites, independent of T3 (1). Some studies have shown that Nuclear Receptor Corepressor 1 (NCoR1), which interacts with the hinge region of TRα (the region between the DNA-binding domain and LBD) has a higher affinity for RTHα mutants compared to wild-type TRα, supporting the hypothesis that helix 12 of the LBD also functions to disassociate NCoR1 from TRα when it is bound to T3 (2). We proposed that this increased affinity for NCoR1 alters the mobility of TRα in the nucleus, impacting its function. Here, we show that NCoR1 has slower FRAP recovery kinetics compared with TRα, and we evaluate the intranuclear dynamics of RTH TRα1 mutants ΤR-E403X, Ala382ProfsX7, and F397fs406X in response to increased levels of NCoR1. Investigation of the effects of overexpression of NCoR1 will provide further insight into the impact of altered binding affinity for NCoR1 on the intranuclear dynamics of RTHα mutants. References: (1) Femia et al., Journal of Cellular Biochemistry, 2020 2020 Apr; 121(4), 2909-2926.(2) Bochukova et al., New England Journal of Medicine, 2012 Jan. 19; 366(3), 243–249.
Nuclear Receptor Corepressors NCoR1 and SMRT Plays Unique Roles in Central Nervous System
Authors: Amano Izuki , Ninomiya Ayane , Ritter Megan , Vella Kristen R , Hollenberg Anthony Neil , Koibuchi Noriyuki
Published: May 2021

The nuclear corepressor 1 (NCoR1) and the silencing mediator of retinoid and thyroid hormone receptors (SMRT) are critical coregulators of the thyroid hormone receptor (TR), mediating transcriptional repression via histone deacetylation. Thyroid hormone (TH) plays an essential role in many physiological processes via the TR. How the corepressors regulate TR signaling is not fully understood, especially in central nervous system (CNS). To determine the role of NCoR1 and SMRT in the CNS, we used mice with conditional NCoR1 (NCoR1lox/lox) and SMRT (SMRTlox/lox) alleles in combination with mice that express Cre recombinase in a neuronal specific fashion (Snap25-Cre). Global deletion of NCoR1 or SMRT during embryogenesis results in lethality. We also showed that NCoR1/SMRT double knock-out mice die within two weeks after induction of Cre activity in adult mice. Now, we found that neuronal specific NCoR1 or SMRT KO mice survive without obvious impairment of neuronal development. However, NCoR1/SMRT double knock-out mice die within postnatal 1-2 weeks and have impaired body growth. Thus, both NCoR1 and SMRT have important roles in maintaining normal neuronal function. Recently, cased of mutations in NCoR1 and SMRT in humans have been reported. These cases report phenotypes including Autism Spectrum Disorder (ASD) and intellectual disability. The cerebellum has been thought to contribute to motor control and learning. Surprisingly, it has also been shown to be a key brain structure involved in social cognition and its dysfunction may play a role in ASD. The Purkinje cell is the main neuron in the cerebellum. Thus, we generated cerebellar Purkinje cell specific NCoR1/SMRT knock-out mice using L7/Pcp2-Cre mice. In contrast to neuronal specific KO mice, both NCoR1 or SMRT single or double knock-out mice survive until adulthood. SMRT Purkinje cell knock-out mice showed abnormalities in 3ch social interaction test indicating impaired social functioning, similar to some ASD symptoms. Electrophysiological testing showed current injection evoked more action potentials in SMRT KO mice. These results suggest Purkinje cell dysfunction caused by SMRT deletion may result in social disability. Our data demonstrate for the first time that NCoR1 and SMRT have separate functions in different areas of the brain but also have some redundant function when knocked out together in all neurons.
T3-Dependent Transcriptional Programming by TRβ in Thyroid Cells Requires SWI/SNF Chromatin Remodelers
Authors: Gillis Noelle , Tomczak Jennifer , Frietze Seth , Carr Frances E
Published: May 2021

Transcriptional regulation in response to thyroid hormone (T3) is a dynamic and cell-type specific process that maintains cellular homeostasis and identity. A bimodal switch model, where T3 binding alters the co-regulator profile of a constitutively DNA-bound thyroid hormone receptor (TR) to affect downstream gene expression, is widely used to describe the interaction between TRβ and chromatin. To test this model on a genome-wide scale, we used an integrated genomics approach to profile and characterize the cistrome of TRβ by CUT&RUN, map changes in chromatin accessibility by ATAC-seq, and capture the transcriptomic changes in response to T3 by RNA-seq in the normal thyroid cell line, Nthy-ORI. Our CUT&RUN data demonstrated that T3 binding causes significant shifts in TRβ genomic occupancy; these shifts are associated with differential chromatin accessibility. Most of the T3-induced differentially expressed genes have a TRβ binding site associated with the proximal protomer region within one kilobase of the transcriptional start site, suggesting that these are direct TRβ regulatory target genes. Remarkably, the majority of TRβ binding sites were found in transgenic regions and distal regulatory elements. In order to identify the co-regulatory proteins that are required for execution of a T3-dependent transcriptional program in our thyroid cells, we used a TRβ-miniTurboID fusion construct to perform a proximity ligation assay followed by mass spectrometry. We identified 1,138 nuclear proteins that interact with TRβ. Of these proteins, 75 interact preferentially in the presence of T3 and 68 in the absence of T3. All of the core SWI/SNF complex subunits from both of the major subtypes (BAF and PBAF) were identified as TRβ. Interestingly, we found that the PBAF-specific subunit, PBRM1, was significantly enriched in the presence of T3. BAF complex-specific subunits, such as ARID1A, were also present in our dataset. To test whether TRβ could differentially recruit BAF and PBAF complexes to its binding sites, we performed CUT&RUN targeting BRG1, PBRM, and ARID1A to determine the degree of co-occupancy with TRβ. Based on our comprehensive genomic and proteomic analyses, we propose a new model for selective recruitment of BAF and PBAF SWI/SNF complexes to TRβ binding sites for differential functions in regulating chromatin accessibility.
ERa-Dependent Lethal Hyperactivation of the Anticipatory Unfolded Protein Response Induces Complete Regression Without Recurrence of Advanced Breast Cancer
Authors: Duraki Darjan , Boudreau Matthew , Wang Lawrence , Mao Chengjian , Tang Bingtao , Ma Liqian , Roy Edward , Fan Timothy , Park Ben Ho , Nelson Erik Russell , Hergenrother Paul , Shapiro David J
Published: May 2021

Metastatic estrogen receptor α (ERα) positive breast cancer is presently incurable and most patients die within 7 years. From a medicinal chemistry program, we identified a novel small molecule that acts through ERα to kill breast cancer cells and often induces complete regression without recurrence of large, therapy-resistant primary breast tumors and of lung, bone, and liver metastases. We exploited our finding that estrogen-ERα activates an extranuclear tumor-protective, signaling pathway, the anticipatory unfolded protein response (UPR). We repurposed this tumor protective pathway by targeting it with the small molecule, ErSO. ErSO kills cancer cells by acting non-competitively through ERα to induce lethal hyperactivation of the anticipatory UPR (a-UPR), triggering rapid necrotic cell death. Using luciferase to image primary tumors and metastases containing lethal ERαD538G and ERαY537S mutations seen in metastatic breast cancer, oral and injected ErSO exhibited unprecedented antitumor activity. In mouse xenografts bearing large breast tumors, oral and injected ErSO induced complete regression (>115,000 fold mean regression) in about 45% of mice (18/39). Although durable response without treatment for 4-6 months was common, tumors that did recur remained fully sensitive to ErSO re-treatment. Consistent with the essential nature of the a-UPR pathway targeted by ErSO, in more than 100 tumor-bearing mice, we have never seen an ErSO-resistant tumor. In just 7 days, oral ErSO induced complete regression of most lung, bone, and liver metastases. ErSO is well-tolerated in mice and blood-brain-barrier penetrant. Injected ErSO induced profound regression of challenging brain tumors. On average, ErSO-treated tumors were >180-fold smaller than vehicle-treated tumors. Moreover, use of ErSO is not limited to breast cancer. With its unique mechanism of action through the a-UPR, ErSO eradicated orthotoptic ERα positive ovarian tumors that do not require estrogen for growth. These xenograft studies used human cancer cells in immune compromised mice and therefore did not exploit the known ability of inducers of necrotic cell death to activate immune cells and induce immunogenic cell death. Notably, medium from breast cancer cells killed by ErSO contained high levels of the established immune cell activators, HMGB1 and ATP, robustly activated mouse and human macrophages and increased macrophage migration. ErSO’s potent activity against advanced primary and metastatic ERα-positive breast cancers represents a paradigm shift in leveraging ERα for anticancer efficacy.
Pro-Tumorigenic Role of Neutrophil Elastase in Lymphangioleiomyomatosis (LAM)
Authors: Gibbons Erin , Taya Manisha , Minor Briaunna , Seger Christina , Hammes Stephen R
Published: May 2021

Lymphangioleiomyomatosis (LAM) is an estrogen-sensitive lung disease found almost exclusively in women. LAM is characterized by the hyperproliferation of smooth muscle cells creating small tumors throughout the lungs, resulting in the formation of large cysts that replace normal alveolar space. Growth of these tumors and progression of the cyst development leads to loss of pulmonary function, and sometimes subsequent lung transplantation. LAM tumor cells contain mutations in one of the tuberous sclerosis genes (TSC1 or TSC2), leading to activation of the mTORC1 pathway. In fact, mTOR inhibitors are commonly used to treat LAM; however, these drugs are not always effective and have significant side effects, suggesting the need for new therapeutic targets. Additionally, tumors recur even after lung transplantation and LAM cells are found in circulating body fluids, suggesting a metastatic nature of LAM, and a question of the origin of the LAM cell. Due to LAM’s estrogen sensitivity, female specificity, and metastatic nature, we previously proposed that LAM cells originate from the uterine myometrium. We therefore designed a uterine-specific TSC2-null mouse model where all the mice generate uterine tumors characteristic of LAM and half develop lung metastases. Using RNASeq analysis of uterine tissue from this mouse model, when focusing on genes regulated by estrogen and TSC2, we discovered significant upregulation of inflammatory proteases such as Neutrophil Elastase (NE). NE is secreted by myeloid cells such as polymorphonuclear cells (PMNs) and has been reported to promote invasion, migration, and proliferation in various cancers. We found this to be true in LAM as well, as depleting myeloid cells with an antibody directed against PMNs, or inhibiting NE with the NE inhibitor, sivelestat, markedly decreased TSC2-null uterine tumor growth. NE is released when PMNs undergo Neutrophil Extracellular Trap release, or NETosis. NETosis has been shown to have a pro-tumorigenic role in various cancers and we are investigating the effects of NETosis in LAM. We have also generated a novel uterine-specific TSC2-null mouse in the background of no NE to determine whether uterine tumor burden and lung metastases are reduced in NE-null mice and if these mice have PMNs capable of undergoing NETosis in the absence of NE. Overall, our results suggest that NE release from PMNs is critical for LAM tumor development and may be a novel target for its treatment.
A Rare Case of Adult Nesidioblastosis Causing Persistent Hypoglycemia in Patient With Atrial Fibrillation and Chronic Kidney Disease
Authors: Zarghamravanbakhsh Paria , Murthi Swetha , Liao Emilia Pauline
Published: May 2021

Nesidioblastosis is a very rare adult disorder in the absence of gastrointestinal surgery. Nesidioblastosis is a disorder of the endocrine pancreas causing hyperinsulinemic hypoglycemia. We describe a case of 83 year-old Caucasian male, with a 3-year history of severe refractory hypoglycemia with glucose level below 2.1 mmol/L. Confusion and sleepiness were reported as his neuroglycopenic symptoms. According to his family, his symptoms improved within 30 minutes of drinking orange juice. Hypoglycemia episodes mostly occurred while fasting and post exercise (after playing golf). His work up included low venous plasma glucose levels, high insulin and C-peptide levels that were consistent with an insulinoma. His history is remarkable for chronic kidney disease stage 3, penicillin allergy and atrial fibrillation with loop recorder for cardiac rhythm monitoring, which precluded him from undergoing CT with IV contrast or MRI studies. Abdominal computed tomography with oral contrast did not reveal any lesion. In an attempt to localize the suspected Insulinoma, he had celiac angiogram and portal vein sampling, which were inconclusive. He had a PET scan with dotatate that showed increased amount activity in the uncinate process of the pancreas. He was diagnosed with insulinoma and placed on monthly lanreotide injections, however continued to have severe hypoglycemia episodes. Due to persistent refractory hypoglycemia, patient underwent distal pancreatectomy and splenectomy and the histological findings were consistent with nesidioblastosis. Patient developed hyperglycemia in the post-operative course which was controlled with a carb consistent diet. This case demonstrates that differentiation between insulinoma and nesidioblastosis is very challenging, and in most cases, the diagnosis is made post operatively based on histologic findings.
A Unique Presentation of a Paraganglioma and Its Consequences
Authors: Shah Kunal , Mimms Remy , Anolik Jonathan Robert
Published: May 2021

Introduction: Paragangliomas (PGL) are extremely rare tumors arising from extra-adrenal neural crest cells with an incidence of 0.8 per 100,000 person-years. Sympathetic chain PGLs usually arise in the abdomen, with about 75% of them arising intra-abdominally [2]. On CT or MRI, PGLs are usually have homogenous enhancement or central areas of low attenuation. The consequences of PGLs are many, and one complication that is rarely noted is glycemic disturbances with catecholamine excess. Here, we present a case of a radiographically unique appearing PGL that resulted in dramatic improvement of diabetes after resection.

Case: 41 year old male with a past medical history of diabetes, CKD and developmental delay presented with hyperglycemia. Patient’s home regimen of Glargine 15 units qHS and Humalog 5 units TID AC had run out a few days prior. Patient had Hemoglobin A1c of 11.8% mg/dL and a C-peptide of 0.4 ng/ml. Endocrine was initially consulted for glucose management. Hospital course was complicated by abdominal pain and CT imaging showed low attenuation splenic masses, retroperitoneal lymphadenopathy and a large, necrotic appearing mesenteric mass consistent with lymphoma. MRI reaffirmed mass with peripheral enhancement and central necrosis consistent with neoplasm.

Patient underwent biopsy of lymphadenopathy, which came back benign and then went for biopsy of mass. As the needle entered the mass, the patient became acutely hypertensive and tachycardic. He received phentolamine with good response and labs were drawn for catecholamine producing tumor. Plasma norepinephrine level was 6048 pg/ml and a chromogranin level of 4788 ng/ml. An MIBG scan revealed focal uptake at the lesion without evidence of metastasis. In the subsequent weeks, he was alpha- and then beta-blocked and underwent resection of mass that was complicated by transient hypotension and hypoglycemia. Eventually, patient’s blood pressure was controlled and insulin requirements dropped precipitously to just requiring 4 units of glargine by discharge.

Discussion: This patient had a mass on CT scan that appeared to be consistent with lymphoma as opposed to PGL that led to biopsy and subsequent catecholamine crisis. Fortunately, this was controlled and subsequent resection led to improvement in the patient’s glycemic control. It has been thought that glucose intolerance in PGL patients is due to impaired insulin release through desensitization of the beta-adrenergic receptor. Furthermore, Catecholamines, as counter-regulatory hormones, have been well documented to raise blood sugar on this basis as well. Fortunately for our patient, he survived an initial biopsy and post-operatively, was able to actually have an improvement in his glycemic control. It also is a reminder to always do a screen for PGL before doing a needle biopsy of a compatible abdominal mass.
An Atypical Presentation of a Patient With Postprandial Hypoglycemic Induced Seizures
Authors: Harmson Jeremy S , Sosa-Pagan Max
Published: May 2021

Background: Insulinomas are exceptionally uncommon pancreatic islet cell neuroendocrine tumors. Typically, insulinoma induced hypoglycemia occurs exclusively in the fasting state in 73 percent, reported in a retrospective analysis of 237 patients, whereas 6 percent reported only postprandial symptoms.

Clinical Case: A 53-year-old female with a history of rheumatoid arthritis, obesity, and prediabetes initially admitted for new onset seizures and recurrent spontaneous hypoglycemic episodes. She experienced recurrent, symptomatic, post-prandial, hypoglycemia daily for the past 8 years. Each episode was closely associated with a high carbohydrate meal, inducing a post-prandial hypoglycemia more consistently and more profoundly than intermittent fasting. Symptoms of lightheadedness, shakiness, and seizure were exacerbated by each carbohydrate meal. Initial labs revealed serum glucose of 35 mg/dl. After recovery with dextrose infusion, a brief fasting trial less than 24 hours was performed with no recurrence of hypoglycemia. However, a mixed meal study utilizing watermelon resulted in a postprandial serum hypoglycemia of 28 mg/dl, provoking a seizure within 30 minutes. During her hospitalization, recurrent hypoglycemia was found during the postprandial period rather than intermittent fasting periods requiring dextrose infusion and octreotide. A Hypoglycemia panel sent during the initial episode was consistent with endogenous hyperinsulinism (Serum glucose=35, Insulin level=24, Proinsulin=166, C-peptide=0.9, BHB=undetectable, Sulfonurea=negative). A subsequent CT of the abdomen/pelvis revealed a mass associated with the pancreatic tail, measuring 4.1 x 4.4 x 5.2 cm concerning for pancreatic malignancy. A fine needle aspiration followed by a distal pancreatectomy and splenectomy with histopathological and immuno-histochemical evaluation confirming a well differentiated (grade 1), 5.0 x 4.5 x 3.0 cm, neuroendocrine tumor (insulinoma). Her recovery, post-operatively, was complicated by an intraabdominal abscess, left pleural effusion, necessitating insulin therapy for hyperglycemia believed to be secondary to morbid obesity, weight gain, and insulin resistance. Hypoglycemic symptoms resolved, blood glucose normalized, and insulin therapy was weaned over the following 3 months and she remains on metformin to date with no evidence of recurrence.

Conclusion: Although rare, an insulinoma should be considered in the differential diagnosis of any individual with recurrent episodes of frequent symptomatic hypoglycemia. The classical clinical manifestation of an insulinoma is a fasting hypoglycemia, with distinct episodes of autonomic symptoms. However, postprandial symptoms have been reported with increasing frequency. Here we present a case of surgically confirmed insulinoma with predominantly post-prandial hypoglycemia.
Atypical Carcinoid Tumor of the Mediastinum Presenting as Ectopic Cushing’s Syndrome
Authors: Medina Mora Luis Augusto , Siddiqui Raheel Sufian , Landry Ian , Cheng Kwan , Reich David Michael
Published: May 2021

Introduction: Ectopic Cushing’s syndrome (ECS) refers to Cushing’s syndrome (CS) that results from extra-pituitary secretion of adrenocorticotropic hormone (ACTH). Neuroendocrine tumors (NETs) are a rare cause of ECS, and their presence in the anterior mediastinum only represents 2-4% of all cases. We report a rare case of ECS in a patient with an atypical mediastinal carcinoid tumor.

Case Presentation: A 38-year-old male with a history of depression presented with generalized weakness, fatigue, and myalgia for one month. A one-week history of nausea and slight shortness of breath was reported. Physical exam and vital signs were unremarkable. Labs revealed hyperglycemia, hypokalemia, and metabolic alkalosis. A random serum cortisol was 47.7 mcg/dL (normal: 3-21 mcg/dL) and a 24-hour urine free cortisol was 7405 mcg/24 hours (normal: 3.5-45 mcg/24 hours). The morning serum cortisol after 8 mg dexamethasone at midnight, was 58.7 mcg/dL. Serum aldosterone and plasma renin activity were both undetectable. CT of the chest showed an anterior mediastinal mass measuring 9.0 x 10.3 x 6.1 cm accompanied by two large mediastinal lymph nodes. A PET CT confirmed the anterior mediastinal mass, which showed mild heterogeneous uptake and no evidence of metastatic disease. Core biopsy of mediastinal mass showed grade II neuroendocrine tumor/atypical carcinoid. Potassium, Spironolactone, Ketoconazole, and Metyrapone were used to control hypokalemia and hypercortisolemia. Trimethoprim-sulfamethoxazole (TMP-SMX) was started for Pneumocystis pneumonia prophylaxis. The patient underwent complete resection of the anterior mediastinal mass, thymectomy, and mediastinal lymph nodes dissection. Histopathology confirmed an atypical carcinoid in the mediastinal mass with negative margins. The rest of the thymus tissue and lymph nodes were negative for malignancy. ACTH and cortisol levels dropped significantly after surgery and the patient was discharged on oral hydrocortisone and TMP-SMX. At 4 weeks follow-up in the clinic, the patient was feeling much better and reported complete resolution of symptoms.

Discussion: ECS caused by an atypical carcinoid tumor is an extremely rare finding. Mediastinal NETs tend to have a poor prognosis due to their metastatic tendency and recurrence rates. Due to limited evidence in the medical literature, there’s much uncertainty and controversy regarding the best treatment of NETs. Standardized guidelines for the management of these atypical tumors are not well established. The primary mode of treatment is surgical resection of the ACTH-secreting tumor. However, in cases of advanced and metastatic tumors, surgical resection might not be sufficient and medical therapy with adrenal enzyme synthesis inhibitors may be needed. The use of neoadjuvant chemotherapy and/or radiotherapy remains unclear.
Carney Complex With Endocrine Involvement Isolated to the Thyroid Gland
Authors: Williams Vanessa , Jabri Hadoun , Jakoby Michael G
Published: May 2021

Introduction: Carney complex is a rare autosomal dominant disorder characterized by pigmented lesions of skin and mucosae, endocrine neoplasms or overactivity, and myxomas of the heart, skin, and other organs. Most patients have at least two affected endocrine organs at time of diagnosis. We present a case of Carney complex with endocrine involvement limited to the thyroid gland. Case: A 48-year-old female was referred for evaluation of thyroid nodules incidentally discovered on imaging for submandibular salivary gland swelling. Ultrasound evaluation of the thyroid revealed numerous, bilateral nodules that were mostly cystic or spongiform, though some had irregular borders and microcalcifications. A brother with Carney complex had been diagnosed with papillary carcinoma, and the patient decided to undergo thyroidectomy. Fortunately, no thyroid carcinoma was found on postsurgical histopathology. Initial biochemical evaluation showed no evidence of hypercortisolemia (8 AM cortisol 1.7 mcg/dL on 1 mg dexamethasone suppression test; 24-h urine cortisol 26.1 mcg [reference: 4-50]), growth hormone excess (IGF-1 190 ng/mL [reference: 52-328]), or hyperprolactinemia (prolactin 10 ng/mL [reference: 2.74-26.72]). Imaging showed no pituitary or adrenal masses. The patient underwent total hysterectomy with bilateral salpingo-oophorectomy for endometrial cancer prior to referral. She was diagnosed with Carney complex at age 19 years, and her manifestations included atrial and ventricular myxomas, intraductal adenoma of the breast, multiple skin lesions (lentigines, blue nevi, and cutaneous myxomas), and myxomas of the external auditory canals. She is in a Carney complex kindred that includes her mother, two brothers, and a niece. Discussion: Carney complex is usually caused by inactivating mutations or large deletions in the protein kinase A type I alpha regulatory subunit (PRKAR1A) gene located on chromosome 17q22-24. Most mutations are inherited in an autosomal dominant manner, though approximately 30% of cases are due to de novo mutations. In a review of 365 cases, the median age at diagnosis was 20 years. Growth hormone adenomas or somatomammotroph hyperplasia occurs in approximately 75% of patients, and most have at least one additional endocrine abnormality including multinodular goiter, primary pigmented nodular adrenocortical hyperplasia, and testicular or ovarian masses. There is an approximately 10% chance of developing well differentiated thyroid carcinoma. Treatment for Carney complex is individualized depending on the patient’s presentation and includes excision or surgical removal of myxomas, neoplasms, and skin lesions, as well as regular evaluation for cardiac myxomas and endocrine overactivity. This case of Carney complex is unusual because the only endocrinopathy is multinodular goiter.
Cerebral Venous Sinus Thrombosis as a First Presentation of Glucagonoma
Authors: Alamri Bader Nasser , Rivera Juan Andres
Published: May 2021

Background: Glucagonoma is a very rare type of pancreatic neuroendocrine tumor (pNET) which represent about 2% of all pNETs (Yao et al.). Although glucagonoma can occur in multiple endocrine tumor syndromes (e.g., MEN-1), most cases are non-hereditary (John & Schwartz). The typical 4Ds presentation are diabetes (DM), depression, dermatosis, & deep vein thrombosis (DVT) (Cunha-Silva et al.). About 50% of glucagonoma patients have DVT during their disease course (Feingold et al.). Most reported DVT cases in glucagonoma are either lower limb DVT or pulmonary embolism (Teixeira, Nico & Ghideti; Castro et al.). To our knowledge, there is no report of a cerebral venous sinus thrombosis (CVST) as the first presentation for glucagonoma.

Clinical Case: A 67-year-old male with a history of psoriasis & benign prostatic hyperplasia presented to the emergency department with a diffuse headache. He was sent home with conservative management. Four days later, he developed acute left-sided weakness with numbness & facial droop. CT head with contrast revealed a superior sagittal sinus thrombosis extending into the right transverse & right sigmoid sinuses. Heparin infusion was initiated. Due to the extensive sinus vein thrombosis & lack predisposing conditions, a pan CT was done for possible malignancy. The scan showed a solid, well-defined, markedly enhancing lesion in the pancreatic tail, suggestive of a NET. At the same time, a new diagnosis of type 2 DM was made based on HbA1C of 11.8%. The patient denied any diarrhea, fever, abdominal pain or episodes suggestive of hypoglycemia. However, he endorsed night sweats with weight loss. His family history was significant for a brother who had a pNET that was resected. Endocrinology was consulted, & a workup for pNET was ordered. Chromogranin A (CgA) was elevated at 439.9 ng/ml (<=82), while on PPI. 24-hour urine cortisol was normal. PTH, serum calcium, & the pituitary hormonal panel were all normal. hCG & CEA were normal. Given the new onset DM & DVT plasma glucagon was requested & came back elevated at 202 pg/ml (reference range 80 pg/ml). MRI showed an hypervascular T2 isointense lesion at the pancreas’ tail measuring 10 x 11 x 10 mm. A Ga68-DOTATATE PET scan was ordered. With this constellation of findings, we initiated somatostatin analog therapy while surgical resection was planned. We referred the patient to medical genetics.

Conclusion: DVT is a common presentation in glucagonoma & a major cause of mortality. The possible mechanism appears to be related to increased secretion of factor X by pancreatic alpha cells (Lobo et al.). Although DVT is not unusual, an extensive CVST as the first presentation in glucagonoma has not been reported. In this case, & in addition to unexplained DVT, the new diagnosis of DM in an elderly patient raised the suspicion of secondary causes. Such a presentation should encourage clinicians to broaden the differential diagnoses, including pNET.
Composite Pheochromocytoma With Ganglioneuroblastoma: A Case Report
Authors: Pastor Paola M Lockhart , Wong Beatrice Y , Stefan Simona
Published: May 2021

Introduction: A composite pheochromocytoma (PC) is an adrenal tumor that is often diagnosed post-operatively on histopathology. PCs are unique in that it is a combination of typicalpheochromocytoma and neural crest derived tumors. The incidence is reported to be less than 3%of adrenal neoplasms. The most common co-existing tumor within a PC is a ganglioneuroma. Wepresent a rare case of PC containing ganglioneuroblastoma (PC-GNBL) in a woman withoutsignificant biochemical manifestation of excess catecholamine production. Case Report: A 63-year-old woman with a prolonged history of uncontrolled hypertension on 4 oral anti-hypertensive medications (Amilodipine 10mg daily, Valsartan/HCTZ 320/25mg daily andClonidine 0.1mg/24h patch) and uncontrolled type 2 diabetes on insulin was diagnosed with a1.5x1.8x1.5cm right adrenal incidentaloma 2 years prior on CT imaging for abdominal pain. Hormonal evaluation was notable for plasma free metanephrine of 66 (<57pg/ml),normetanephrine 229 (<148pg/ml), and total metanephrines of 295 (205 pg/ml). However, 24-hour urine metanephrine evaluation was normal on two occasions: metanephrine 121 and 168mcg/24h (90-315), norepinephrine 237 and 336 mcg/24h (122-676) and total metanephrines 358and 504mcg/24 h (224-832). Hyperaldosteronism and hypercortisolism were ruled out. Follow-up CT scan 14 months later demonstrated growth of the right adrenal nodule to 1.7x2x2cm with49% washout. She underwent laparoscopic right adrenalectomy without perioperativecomplications. Pathology was consistent with a PC-GNBL. The PASS score was 7, consistentwith malignant pheochromocytoma. Within weeks of surgery, she had marked clinicalimprovement. Blood pressure was controlled on one anti-hypertensive and Hgb A1c decreased to7.1% from 11% without requiring insulin. CT abdomen/pelvis 6 months post-operatively did notshow evidence of metastasis. She was referred for genetic testing. Conclusion: This case highlights an unusual presentations of pheochmocytoma. It’s important to recognizethat resistant hypertension can present without episodic headaches, diaphoresis, palpitations, andwithout biochemical evidence of catecholamine excess. Composite PCs are indistinguishableclinically or radiologically from ordinary pheochmocytomas. These exceedingly rare mixedtumors are only diagnosed via surgical pathology. To date, there are only a few cases reported inthe medical literature of co-existing PC-GNBL tumors. Due to the scarcity of composite PCscases, important information regarding its presentation and prognosis are unknown. It remains tobe seen whether the GNBL part of the tumor changes the prognosis of the tumor. However, inour case, the clinical status of our patient improved.