bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survival Benefit of Corticosteroid Replacement in Critically Ill Patients: One Treatment Effect or Two?
Authors: Laies Slavita M , Qualls Clifford R , Dorin Richard I 
Published: May 2021

Abstract
Survival benefit of corticosteroid replacement in critically ill patients: one treatment effect or two?
Background: In the comparison of placebo versus corticosteroid replacement therapy (CRT) among ill patients, the treatment effect (difference in 28-day mortality rate between placebo and CRT) tends to vary according to mortality in the placebo group. In this context, we treat 28-day mortality in the placebo group as a surrogate for severity of illness [1]. Hypothesis: In the present era of physiologic CRT, critical illness related corticosteroid insufficiency (CIRCI) may be defined operationally by the difference in clinical outcomes, such as 28-day mortality, between placebo and CRT treatment groups. In this simulation analysis, we examined the hypothesis that treatment effects of CRT observed in various randomized, placebo-controlled clinical trials may be explained by heterogeneous population consisting of two strata, S1 and S2, having discrete conditional probabilities of mortality when treated with CRT vs. placebo. Methods: Using published Randomized Controlled Trial (RCT) data, the relationship between treatment effect and severity of illness was analyzed using a least squares solution weighted by sample sizes. A probability model included likelihoods for outcomes (28-day mortality with placebo vs. CRT) in two population strata: (i) a minority stratum (S1) having treatment effect &gt; 0 and (ii) a majority stratum (S2) having a treatment effect ≤ 0. In a simple simulation scenario we varied the treatment effect in S1 as function of the placebo group mortality in S2 in order to fit the relationship obtained from published RCT data. The potential impact of sensitivity and specificity on diagnostic tests to identify S1 was also addressed. Results: A hyperbolic function (y = [Mx/(K+x)] - A) provided a good fit for published RCT trials of physiologic CRT (treatment effect [y] vs. placebo group mortality rate [x]). Pooling results for S1 and S2 having population frequencies of 0.2 and 0.8, respectively, approximated the observed
hyperbolic function of treatment effects and severity of illness. A significant treatment effect was maintained when S1 was identified by diagnostic tests having 75% sensitivity-specificity. Conclusions: Population heterogeneity has not been excluded as an explanation for the relatively modest treatment effect of CRT in critically ill patients. Given the possibility of harm of CRT in the majority population (S2), our model further suggests that clinical or laboratory measures that would distinguish S1 and S2 with reasonable accuracy would significantly improve clinical outcomes and reduce numbers needed to treat. Our findings also support the more general hypothesis that the treatment effects of CRT vary according to severity of illness (1).
References: 1.Briegel, J., V. Huge, and P. Mohnle, Hydrocortisone in septic shock: all the questions answered? J. Thorac. Dis, 2018. 10(Suppl 17): p. S1962-S1965.
Lenvatinib-Induced Destructive Thyroiditis in a Patient With Hepatocellular Carcinoma
Authors: Pandya Anjani , Shakil Jawairia 
Published: May 2021

Abstract
Lenvatinib is an antineoplastic oral agent that acts as a multi-kinase inhibitor against vascular endothelial growth factor (VEGF). This drug is commonly known for its use against radioiodine-refractory differentiated thyroid cancer, but it is also approved for unresectable hepatocellular carcinoma (HCC). Side effects such as fatigue, hypertension, palmar-plantar erythrodysesthesia, diarrhea, decreased appetite, and hypothyroidism are frequently reported adverse effects. However, the incidence of hyperthyroidism is a less known phenomenon. This case describes a patient with HCC on lenvatinib therapy who develops destructive thyroiditis. A 69-year-old man with hepatitis c cirrhosis complicated by progressive hepatocellular carcinoma (Child-Pugh class A6) presented with generalized weakness, unintentional weight loss, heat intolerance, palpitations, and tremors. He had been started on chemotherapy with lenvatinib 12 mg/day four weeks prior to presentation. Endocrinology was consulted due to abnormal thyroid function tests (TFTs). He had no previous history of thyroid function abnormalities or family history of thyroid disease. Laboratory tests revealed a hyperthyroid state [total thyroxine (T4), 14.3 µg/dL (normal range 4.5-11.7); free thyroxine (FT4), 1.9 ng/dL (normal range 0.9-1.7); thyroid-stimulating hormone (TSH), 0.07 µIU/mL (normal range 0.27-4.20), and negativity for antibodies [anti-thyroid peroxidase antibody (TPO Ab), 0.8 IU/mL (normal range 0.0-9.0); thyroglobulin antibody (Tg Ab), &lt; 0.9 IU/mL (normal range 0.0-4.0); thyroid stimulating immunoglobulin (TSI), 90% (normal range &lt; 122)]. Ultrasonography revealed a mildly prominent thyroid gland, a homogenous echo texture, and no suspicious thyroid nodules. In addition, a 99m-technetium (99mTc) scintigraphy demonstrated reduced radioactive uptake that was consistent with thyroiditis. Therefore, this patient was diagnosed with lenvatinib-induced destructive thyroiditis. Palpitations improved with a beta-blocker and the patient was resumed on a lower dose of lenvatinib, 8 mg/day, one week later. About six weeks after the initial dose of lenvatinib, his TFT results normalized. Lenvatinib disrupts cell proliferation which can affect many organs, including the thyroid gland. Although several theories have been proposed, the exact underlying mechanism by which this occurs remains unknown. It is important to note that in addition to hypothyroidism, lenvatinib may also cause hyperthyroidism in the form of a transient destructive thyroiditis. This emphasizes the need to routinely check TFTs prior to the initiation of lenvatinib and throughout the course of therapy.
Non-MAS Non-APS Rare Case: Co-Occurrence of Graves’ Disease (GD), Latent Autoimmune Diabetes in Adult (LADA), Systemic Lupus Erythematosus (SLE), and Ulcerative Colitis (UC)
Authors: Harris Laura , Tahapary Dicky L , Wisnu Wismandari , Purnamasari Dyah , Yunir Em , Waspadji Sarwono 
Published: May 2021

Abstract
Background: Advancement in medical technology has allowed us to diagnose complicated autoimmune diseases. There is a growing report of multiple autoimmunity co-occurence. Multiple Autoimmune Syndrome (MAS) is a combination of at least three autoimmune diseases, whereas Autoimmune Polyendocrine Syndromes (APS) comprise autoimmunity that involves multiple endocrine gland. Case Illustration: A 47-year old female came with chief complaint of palpitation. She had a history of systemic lupus erythematosus in the last three years, after suffering from malar rash, alopecia, and polyarthritis. Her 24-hour urine protein was 1575 mg. She routinely consumes methylprednisolone, hydroxychloroquine, and mycophenolic acid. She also experienced hematochezia and the biopsy from colonoscopy revealed chronic colitis with crypt destruction. She was diagnosed with ulcerative colitis and was treated with mesalazine. Since last year, her blood glucose was consistently high, accompanied with polydipsia and polyuria. She was treated with metformin, despite persistent increase in her A1C, as well as fasting and random blood glucose. We performed GAD65 test which came back positive, hence we diagnosed her with latent autoimmune diabetes in adult. In the past three months, she experienced palpitations, tremor, diarrhea, diaphoresis, and unexplainable weight loss. No exophthalmos was found, but she complained of an enlargement around her neck. We run thyroid hormone test, her TSHs was &lt;0.003 (0.35-4.94 μIU/mL) and FT4 was 4.17 (0.70-1.48 ng/mL). Her ultrasound revealed diffuse enlargement of both thyroid with increased vascularization. We diagnosed her with Graves’ disease and treated her with methimazole and propranolol. Discussion: This case highlighted the rare co-occurrence of four autoimmune diseases. The underlying genetic predisposition of individual with autoimmune disease, will make them prone to develop multiple defect in their self-tolerance mechanism. However, the strict criteria of APS or MAS constrained us from putting all her autoimmunities into one big umbrella. Based on epidemiological data, hyperthyroidism in female productive age, with diffuse thyroid enlargement, is commonly due to Graves’ disease. However, this diagnosis needs to be further evaluated with thyroid scintigraphy and confirmed with TSH-receptor antibody test. Conclusion: Improvement in medical diagnostic tools as well as better understanding of the underlying pathophysiology will make it inevitable to find more autoimmunity co-occurrence in the future. In order to keep up with this progress, the traditional classification of APS or MAS should be reviewed to allow clinician to see the case in one big entity. Keywords: GD, LADA, SLE, UC
Overt Hypothyroidism Induced by Prolonged Therapy With Imatinib
Authors: Wang Ally W , Nosova Emily V 
Published: May 2021

Abstract
Background: Imatinib, a tyrosine kinase inhibitor (TKI), is commonly used to treat chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors. TKI-induced thyroid dysfunction is recognized as an adverse class effect with most cases occurring between six to twelve months after treatment initiation.
Clinical Case: 76-year-old man with hypertension and CML on Imatinib that had been started twenty months prior was admitted for confusion. The patient also reported constipation, cold intolerance, and weight gain despite no change in diet, appetite, or physical activity. On evaluation, his responses to questioning were noticeably delayed, however he was not lethargic. His vital signs were normal and he was otherwise euthyroid on physical exam. He had no known history of thyroid dysfunction. Labs showed a TSH of 94.7 (0.4 - 4.2 uIU/mL), Free T4 0.4 (0.8 - 1.5 ng/dL), and Total T3 30 (87 - 178 ng/dL). Thyroglobulin antibody was 1016 (0.0 - 4.1 U/mL) and TPO antibody was &gt;2000 (0.0 - 5.6 IU/mL). A TSH checked two months before admission was 1.1. Antibody levels had not been checked previously. Thyroid ultrasound demonstrated a hyperemic and heterogeneous thyroid, consistent with thyroiditis. Levothyroxine at a dose of 50 mcg daily was advised, due to patient’s advanced age as well as history of arrhythmia. The patient’s confusion resolved on hospital day three. Repeat thyroid function tests will be checked four to six weeks after Levothyroxine initiation.
Discussion: As a class, tyrosine kinase inhibitors are known to cause thyroid dysfunction with the most common medication being Sunitinib. Data related to the effects of thyroid function during Imatinib treatment are limited. Previous cases of Imatinib-induced thyroid dysfunction report only hypothyroidism in thyroidectomized patients and no clinically significant change in thyroid function among patients who were euthyroid prior to therapy initiation. Our case reports a patient with no prior thyroidectomy who developed overt hypothyroidism while on Imatinib for nearly two years. The mechanism for TKI-induced thyroid dysfunction has not been elucidated. Due to relatively acute onset and markedly positive TPO and thyroglobulin antibodies, we suspect that TKI may alter HLA recognition on thyroid follicular cells, thereby inducing autoimmunity. Our case showcases the need to maintain awareness and continuous surveillance for thyroid dysfunction when patients are on long term TKI as overt hypothyroidism may be induced by prolonged treatment.
Rapidly Progressive Cognitive Decline and Varicella Zoster Blisters Associated With Teprotumumab in 2 Patients With Graves’ Orbitopathy
Authors: Hoang Thanh Duc , Chou Eva , Nguyen Nguyen T , Shakir Mohamed K M 
Published: May 2021

Abstract
Introduction: Teprotumumab, an IGF-1R antagonist, was approved for treatment of Graves’ orbitopathy (GO) in 2020. Common side effects include nausea, diarrhea, muscle spasms, hearing impairment, dysgeusia, headache, dry skin, infusion reactions, and hyperglycemia. We report here 2 cases of unexpected adverse effects. Patient #1 is a 76-year-old man with Graves’ disease diagnosed in 2018, treated with methimazole 2.5mg every other day. His GO manifestations included diplopia, proptosis, and exposure keratopathy. Past history was significant for hypertension, hyperlipidemia, and prostate hyperplasia. He lived independently and walked several miles daily. Teprotumumab was initiated. Between the 4th and 5th doses, his family noted 6-weeks of rapidly progressive cognitive decline characterized by behavioral changes, confabulation, memory deficit, delirium/delusions/mania. He was admitted to neurology service and subsequent doses held. Lumbar puncture was unremarkable. TFT was normal before, during and after stopping teprotumumab. Thyroid antibodies were notable for elevated TSI but normal thyrotropin receptor Ab and TPO/TgAb. Other labs: IL2, IL6, ESR, CRP, heavy metals, IgG, IgM, SARS-CoV-2 IgM/IgGs, vitamins B1, B6, and B12 were all normal. His most recent repeat TPO Ab was 14 IU/mL (increased from &lt;6), TgAb 18.4 IU/mL (increased from &lt;1.0). EEG showed no epileptiform activity. Head MRI/MRA showed cerebral amyloid angiopathy without stenosis or aneurysms in the intracranial arterial vasculature. Symptoms progressed with IV glucocorticoids and IV Ig therapy. He subsequently underwent plasmapheresis with resolution of symptoms. Patient #2 is a 48-year-old man with Graves’ disease and GO diagnosed in 2018, initially treated with methimazole and subsequently underwent total thyroidectomy in 2019. Patient is euthyroid on levothyroxine. Ophthalmic signs and symptoms included significant proptosis and retrobulbar pain. He was started on teprotumumab infusions. After his 4th dose, he noted painful vesicles in a dermatomal distribution on his right posterior thigh. Direct fluorescent antibody stain was positive for varicella zoster, and rashes resolved with valacyclovir therapy. Discussion: Paraneoplastic/autoimmune encephalitis syndromes can be associated with antibodies to neuronal cell surfaces/synaptic proteins and may occur in the presence or absence of cancer. The incidence of varicella-zoster virus infection is associated with the immune status of the patient, disease-related immunocompromised, or iatrogenic immunosuppression, with age being the major risk factor for 90% of adult cases. This could be incidental, or related to other disorders, or perhaps teprotumumab may have activated auto-immunity. The exact mechanisms for rapidly progressive cognitive decline and shingles remains unclear.
Severe Rhabdomyolysis and Acute Renal Failure Due to Noncompliance to Levothyroxine Therapy
Authors: Raj Rishi , Ghayur Ayesha , Elahi Qurrat , Patel Chinmaya 
Published: May 2021

Abstract
Background: Noncompliance to levothyroxine (LT4) is common however only rarely it leads to severe side effects. We report a case of rhabdomyolysis leading to acute kidney injury (AKI) requiring hemodialysis (HD) due to noncompliance to LT4 therapy for one month. Clinical Case: A 68-year-old Caucasian male presented with a 2-week history of worsening fatigue and generalized weakness, accompanied by pain in bilateral lower extremities. Medical history included coronary artery disease, heart failure with reduced ejection fraction, hypertension, dyslipidemia, hypothyroidism, type 2 diabetes mellitus, CKD. Home medications included LT4 200 mcg daily, metoprolol 25 mg daily, doxazosin 2 mg daily, amlodipine 5 mg daily, fluocinonide 40 mg daily, fosinopril 40 mg twice daily, metformin 500 mg twice daily and rosuvastatin 40 mg daily. Further history revealed the patient to be not taking LT4 as “he ran out of it for a month” and only resumed taking it 3 to 4 days before coming to the hospital. On examination, he had proximal muscle weakness with power 3/5 in bilateral lower extremities and mild tenderness on thigh muscles. Labs revealed creatinine 13.1 mg/dL (0.60-1.10 mg/dL), BUN 101 mg/dL (0-30 ng/dL), eGFR 4.0 ml/min/1.73m2, CK 69,500 U/L (22-198 U/L), TSH 55.8 uIU/ml (0.45-4.5 uIU/ml), and FT4 0.61 ug/dL (0.8-1.8 ug/dL). ABG showed metabolic acidosis. Routine labs three months prior revealed normal thyroid function tests (TSH 1.6 uIU/ml and FT4 1.3 ug/dL) on LT4 200 mcg and baseline CKD stage 3b (EGFR 51 ml/min/1.73m2 with baseline creatinine 1.4 mg/dL). The patient was diagnosed with severe rhabdomyolysis secondary to noncompliance with LT4 therapy in presence of concurrent statin use, leading to AKI. Rosuvastatin was stopped and he was treated with aggressive intravenous hydration, sodium bicarbonate, and LT4 200 mcg daily. Despite two days of aggressive treatment, CK remains elevated and hence HD was initiated. The patient underwent three sessions of HD during the course of his hospitalization. Due to lack of renal recovery, outpatient HD was arranged. At 4 weeks of outpatient follow-up, the patient was oliguric and HD dependent. At 8 weeks outpatient follow up, CK, TSH, and FT4 was normal on LT4 200 mcg daily and became dialysis independent. Conclusion: Noncompliance to LT4 therapy along with concomitant use of statin can result in severe rhabdomyolysis induced AKI in patients with CKD.
Severe Thyrotoxicosis Following Topical Iodine Application
Authors: Coyne Kasey , Papagiannis Ioannis G 
Published: May 2021

Abstract
Background: Exposure to iodine can lead to iodine-induced hyperthyroidism in patients with underlying thyroid disease. Clinical Case: A 67 year-old woman with a history of nontoxic multinodular goiter and atrial fibrillation presented with fatigue, palpitations, weight loss, and tremor. Laboratory evaluation demonstrated new-onset profound biochemical hyperthyroidism (FT4 &gt; 7.77 ng/dL, n 0.8 – 1.8 ng/dL; FT3 &gt;27.0 pg/mL, n 2.0-4.4 pg/mL). She was treated with beta-blocker, high doses of methimazole, and cholestyramine while further evaluation was pursued. She declined SSKI due to reported iodine allergy and steroids due to concerns about impact on wound healing following recent hip arthroplasty. TSI and TRAb were negative, and thyroid ultrasound showed stable nodules at 1.7cm. Pelvic ultrasound and MRI were obtained due to concern for non-thyroidal etiology, and revealed a 3.7cm septated cystic ovarian lesion, raising suspicion for struma ovarii. Whole body scan to localize site of thyroid hormone production could not be obtained due to high risk of clinical deterioration off methimazole, as she had persistent clinical and biochemical thyrotoxicosis on high doses (up to 90mg/day). She ultimately required 3 sessions of plasma exchange to lower her thyroid hormone levels, and then underwent bilateral salpingo-oophorectomy. Final pathology revealed mucinous cystadenoma without ectopic thyroid tissue. Post-operatively, her thyroid hormone levels were persistently elevated but improved compared to pre-operative levels, allowing for brief cessation of methimazole and completion of whole body scan. Imaging demonstrated a single focus of radioactive iodine uptake in the lower right thyroid lobe, correlating with the dominant 1.7 cm nodule on prior ultrasound, consistent with a toxic adenoma. Additionally, she was found to have an elevated urine iodine level (1200 mcg/24 hours, n 75 – 851 mcg/24 hours). Patient endorsed low iodine diet due to allergy history, and denied recent contrasted imaging study, dietary supplements, or amiodarone use. Upon further inquiry, she recalled using povidone-iodine solution to care for her surgical site post-arthroplasty, approximately a week before the onset of her initial symptoms. Her clinical presentation was ultimately attributed to toxic adenoma, with severe thyrotoxicosis exacerbated by iodine load. She underwent total thyroidectomy and is doing well on levothyroxine post-operatively. Conclusions: Topical iodine administration can contribute to iodine-induced hyperthyroidism in patients with underlying thyroid disease, and its use should be carefully considered in these patients. When evaluating a patient with new thyrotoxicosis, a detailed history of oral, IV, and topical iodine use should be obtained.
Stress Cardiomyopathy Due to Exogenous Thyrotoxicosis From T3 Supplementation
Authors: Shaw Kirsten E , Jamrozy Anya 
Published: May 2021

Abstract
Background: Wilson’s Temperature Syndrome (WTS) refers to a constellation of nonspecific symptoms, some of which include a low-normal body temperature, headaches, and fatigue. WTS was rejected by the American Thyroid Association as a valid medical diagnosis in 2005. Originally proposed in 1990 by Dr. E Denis Wilson, the etiology was theorized to be an impaired ability to convert T4 to T3, although this was not corroborated in thyroid lab abnormalities. Despite being publicly rebuffed as a true medical diagnosis, WTS has continued to gain traction amongst certain alternative medical groups and is treated with T3 supplementation. The development of a stress cardiomyopathy due to T3 supplementation is rare. Extrapolating from endogenous thyroid mediated stress cardiomyopathy and T4 supplementation induced stress cardiomyopathy, the pathophysiologic mechanism is likely excessive sympathetic activation.
Clinical Case: A 58-year old female with no prior cardiac history presented to the emergency department with chest pain. Physical exam revealed a euvolemic appearing women, with intact and symmetric distal pulses, and a normal cardiac exam without murmurs or other abnormal heart sounds. There were no abnormal lung sounds. Her O2 sats were normal on room air. EKG and CXR were unremarkable. Her troponin was elevated (3.7 ng/mL, n&lt; 0.034 ng/mL) and her BNP was elevated (4,568 pg/mL, n&lt; 150 pg/mL). The patient was given aspirin and started on therapeutic heparin given concern for NSTEMI. Echocardiogram revealed an ejection fraction of 30% with hypokinesis of the entire apex and mid ventricle, raising concern for a stress cardiomyopathy.
Coronary angiogram was performed which demonstrated no coronary artery disease. The patient underwent a cardiac MRI which confirmed a stress cardiomyopathy. Meanwhile, her laboratory workup was completed which revealed an undetectable TSH, a low T4 (0.53 ng/dL, n 0.7-1.8 ng/dL), and an elevated T3 (6.37 pg/mL, n 1.71-3.71 pg/mL). Patient endorsed taking oral liothyronine (T3) at doses of 5-40 mcg BID over the past 6 weeks per her alternative medicine provider for treatment of WTS. Her stress cardiomyopathy was presumed to be due to her exogenous thyrotoxicosis from T3 supplementation. She was counseled on the importance of cessation of T3 supplementation, and was started on heart failure medications. On hospital day 3, her T3 normalized to 2.73 pg/mL, and T4 remained low (0.4 pg/mL). Follow-up echocardiogram four months later demonstrated an ejection fraction that had improved to 45%.
Conclusion: This case highlights the importance of physician awareness of alternative medicine diagnoses and treatment regimens that affect thyroid hormones and may cause harm to patients. This case is an important reminder of the effect thyroid hormones have on coronary vasculature, myocytes and myocardial function.