Recognition and Treatment of Adrenal Insufficiency Secondary to Abiraterone: A Case Report and Literature Review.

OBJECTIVE: Abiraterone is a relatively noncytotoxic drug approved by the US Food and Drug Administration in 2011 for the treatment of metastatic prostate cancer (MPC). As an inhibitor of 17α-hydroxylase and C17,20-lyase (CYP17), abiraterone blocks androgen synthesis and glucocorticoid production. Decreased cortisol levels result in an increased ACTH release, which can lead to increased mineralocorticoid levels. While coadministration of abiraterone and glucocorticoids has been effective in reducing an apparent mineralocorticoid excess, adequate replacement of physiologic glucocorticoids, especially in times of acute stress, remains less well-defined. METHODS: A literature search was conducted using the PubMed and Google Scholar databases for abiraterone and adrenal insufficiency. Publications were selected based on the quality of the data and clinical relevance. We reviewed the landmark trials leading to FDA approval and establishment of the standard glucocorticoid replacement dosing. RESULTS: We present 2 patients with MPC on abiraterone therapy. These 2 patients required modification of the glucocorticoid therapy because of adverse effects. CONCLUSIONS: We found that a standard dose of prednisone of 5 mg/day as recommended previously may be inadequate to achieve physiologic glucocorticoid replacement in some patients with prostate cancer while on abiraterone treatment and as a result adrenal insufficiency due to inadequate dosing might be more common than initially thought. Additionally 10 mg of prednisone daily may cause adverse effects in some patients. Thus clinicians should be aware of the potential for development of adrenal insufficiency or symptoms of glucocorticoid excess in these patients receiving prednisone so that appropriate modifications in glucocorticoid dosing can be instituted without any delay. Prednisone dosing may need to be individualized in each patient receiving abiraterone therapy.

ASSOCIATIONS OF SERUM IONIZED CALCIUM, PHOSPHATE, AND PTH LEVELS WITH PARATHYROID SCAN IN PRIMARY HYPERPARATHYROIDISM.

OBJECTIVE: To evaluate the relationship between various biochemical parameters in patients with primary hyperparathyroidism (PHPT) with positive and negative technetium-99 sestamibi (Tc) parathyroid scans performed with single-photon emission computed tomography/computed tomography (SPECT/CT). METHODS: This retrospective analysis was used to develop a logistic probability model. It included 218 patients with PHPT. The main outcome measures were serum total calcium, ionized calcium, intact parathyroid hormone (PTH), albumin, alkaline phosphatase, phosphate, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D, 24-h urinary calcium levels, and parathyroid adenoma weight. RESULTS: Individually, using cut-off levels of 6.0 mg/dL for ionized calcium, 3.0 mg/dL for phosphate, and 90 pg/mL for intact PTH, we found that 91.3% ( P = .005), 70.7% ( P = .004) and 87.90% ( P = .023) of the patients had a positive Tc scan with their corresponding strengths of associations in the parentheses. Similar significant associations were sustained in multivariate setting for serum ionized calcium ( P = .015), phosphate ( P = .016), and intact PTH ( P = .028). A logistic probability model was designed to predict the probability of being positive for Tc scan given a set of covariates. CONCLUSION: There are significant associations between the levels of serum ionized calcium, phosphate, intact PTH, and Tc scan positivity. Further studies with larger patient populations are needed. ABBREVIATIONS: BMI = body mass index; CT = computed tomography; CV = coefficient variation; DXA = dual-energy x-ray absorptiometry; MRI = magnetic resonance imaging; PHPT = primary hyperparathyroidism; PPV = positive predictive value; PTH = parathyroid hormone; SPECT = single-photon emission computed tomography; Tc = technetium-99 sestamibi.

Coexistence of Cushing Disease With a Solitary Adrenocorticotrophic Hormone-Dependent Adrenal Adenoma.

OBJECTIVE: We report a 49-year-old woman who had minimal features of Cushing syndrome and an incidentally discovered adrenal adenoma. She was subsequently diagnosed with pituitary-dependent Cushing syndrome. METHODS: Laboratory and imaging studies including serum cortisol, plasma adrenocorticotrophic hormone (ACTH), high dose dexamethasone test, corticotropin-releasing hormone test, computed tomography (CT) scan, and magnetic resonance imaging were performed. RESULTS: A 49-year-old woman was admitted for urosepsis. An abdominal CT scan performed during the urosepsis workup showed a 2.7-cm right adrenal adenoma. She denied any abdominal striae or other symptoms. Physical examination showed normal vital signs, minimal facial fullness without central obesity, and striae. Laboratory results were as follows: 24-hour-urine cortisol 294 µg (reference 4.0-50.0), midnight serum cortisol 23.0 µg/dL (reference < 7.5), and plasma ACTH level 39 pg/mL (reference 5-27). A corticotropin-releasing hormone stimulation test showed >20% rise in serum cortisol and >35% rise in ACTH levels. A pituitary magnetic resonance image showed a 5 mm pituitary lesion. The patient underwent transsphenoidal pituitary surgery, which confirmed an ACTH-secreting lesion. Postoperatively, she required hydrocortisone replacement for the next 10 months. A follow-up adrenal CT performed 6 months later showed a decrease in the size of the adrenal adenoma (1.8 cm). CONCLUSION: This case highlights the importance of recognizing the coexistence of ACTH-dependent Cushing disease with an adrenal adenoma and partial ACTH dependency of the adrenal adenoma.

Multinodular goiter as the initial presentation of systemic sarcoidosis: limitation of fine-needle biopsy.

Sarcoidosis is a chronic systemic disease characterized by noncaseating granulomas. Thyroid involvement is rare, with a prevalence of 1-4% in large series of autopsied patients with systemic sarcoid. We report a case of a 65-year-old woman with a nontoxic multinodular goiter, dyspnea in the supine position, and rightward tracheal deviation as the initial presentation of systemic sarcoidosis. Fine-needle biopsy of the thyroid mass was consistent with benign adenomatoid goiter. A total thyroidectomy was performed because of compression symptoms. Histopathology revealed numerous diffuse noncaseating granulomata typical of thyroid sarcoidosis. Subsequent chest computed tomography showed extensive bulky mediastinal and hilar adenopathy and multiple small pulmonary nodules consistent with sarcoidosis. Transbronchial fine-needle biopsy also revealed noncaseating granulomas. The patient's supine dyspnea resolved quickly after total thyroidectomy. This case report illustrates that in patients with known sarcoidosis, careful thyroid examination is essential and supine dyspnea may be directly related to tracheal compression by a multinodular goiter rather than pulmonary sarcoidosis.

Bilateral Ovarian Leydig Cell Tumors in a Postmenopausal Woman Causing Hirsutism and Virilization.

OBJECTIVE: To evaluate a rare case of a postmenopausal woman with hirsutism and virilization due to Leydig cell tumors (LCTs) of both ovaries. METHODS: In this challenging case, the diagnostic studies included the detection of total/free testosterone, hemoglobin, and estradiol levels; adrenal computed tomography; and pelvic magnetic resonance imaging. RESULTS: A 61-year-old woman presented for the evaluation of hirsutism. Physical examination revealed normal vital signs and evidence of virilization. The baseline laboratory findings were hemoglobin level of 16.2 g/dL (reference, 12.0-15.5 g/dL), total testosterone level of 803 ng/dL (reference, 3-41 ng/dL), and free testosterone level of 20.2 pg/mL (reference, 0.0-4.2 pg/mL). Pelvic magnetic resonance imaging showed bilateral homogeneous ovarian enhancement. Based on the magnetic resonance imaging findings and clinical presentation, the patient was diagnosed with ovarian hyperthecosis and underwent laparoscopic bilateral oophorectomy. Pathology confirmed LCTs in both ovaries. Six months later, testosterone levels normalized, with significant improvement in hirsutism and virilization. CONCLUSION: Clinicians should be aware of androgen-secreting tumors, including rare bilateral LCTs in postmenopausal women presenting with progressing hirsutism and virilization. Marked hyperandrogenemia with total testosterone level of >150 ng/dL (5.2 nmol/L) or serum dehydroepiandrosterone sulfate level of >700 µg/dL (21.7 mmol/L) is typically found. It should be recognized that diffuse stromal Leydig cell hyperplasia and small LCTs may be missed on imaging, and in some cases only pathology can confirm the result.

Treatment of Severe Hypertriglyceridemia During Pregnancy With High Doses of Omega-3 Fatty Acid and Plasmapheresis.

OBJECTIVE: Severe hypertriglyceridemia carries increased health risks, including the development of pancreatitis. The objective of this study was to report on management of 2 cases with severe gestational hypertriglyceridemia. CASES: In case 1, a 33-year-old pregnant woman presented with serum triglyceride level of 14 000 mg/dL after discontinuing hypolipidemic medications. She was treated with Lovaza 12 g/day, and serum triglyceride remained near normal at level of less than 800 mg mg/dL until delivery. In case 2, a 28-year-old patient (29th week gestation) presented with acute pancreatitis and triglycerides >4000 mg/dL. She was treated with Gemfibrozil, Lovaza, insulin infusion, subcutaneous heparin, and escalated to plasmapheresis. She successfully delivered a baby at the week of 36th and her triglyceride level was 304 mg/dL after that. DISCUSSION: Case 1 was treated with high-dose Lovaza and case 2 was treated with plasmapheresis successfully. Triglyceride levels were reduced to less than 500 mg/dL until delivery of healthy babies in both cases. CONCLUSION: Omega-3 fatty acids and plasmapheresis may be effective and safe to treat pregnant women with severe hypertriglyceridemia and pancreatitis.

Comparative Effectiveness of Levothyroxine, Desiccated Thyroid Extract, and Levothyroxine+Liothyronine in Hypothyroidism.

INTRODUCTION: Studies comparing levothyroxine (LT4) therapy with LT4 + liothyronine (LT3) or desiccated thyroid extract (DTE) did not detect consistent superiority of either treatment. Here, we investigated these therapies, focusing on the whole group of LT4-treated hypothyroid patients, while also exploring the most symptomatic patients. METHODOLOGY: Prospective, randomized, double-blind, crossover study of 75 hypothyroid patients randomly allocated to 1 of 3 treatment arms, LT4, LT4 + LT3, and DTE, for 22 weeks. The primary outcomes were posttreatment scores on the 36-point thyroid symptom questionnaire (TSQ-36), 12-point quality of life general health questionnaire (GHQ-12), the Wechsler memory scale-version IV (VMS-IV), and the Beck Depression Inventory (BDI). Secondary endpoints included treatment preference, biochemical and metabolic parameters, etiology of hypothyroidism, and Thr92Ala-DIO2 gene polymorphism. Analyses were performed with a linear mixed model using subject as a random factor and group as a fixed effect. RESULTS: Serum TSH remained within reference range across all treatment arms. There were no differences for primary and secondary outcomes, except for a minor increase in heart rate caused by DTE. Treatment preference was not different and there were no interferences of the etiology of hypothyroidism or Thr92Ala-DIO2 gene polymorphism in the outcomes. Subgroup analyses of the 1/3 most symptomatic patients on LT4 revealed strong preference for treatment containing T3, which improved performance on TSQ-36, GHQ-12, BDI, and visual memory index (VMS-IV component). CONCLUSIONS: As a group, outcomes were similar among hypothyroid patients taking DTE vs LT4 + T3 vs LT4. However, those patients that were most symptomatic on LT4 preferred and responded positively to therapy with LT4 + LT3 or DTE.

Diarrhea as an Initial Presentation in Patients with Medullary Thyroid Cancer: Delaying the Diagnosis.

Tumoral secretion of various molecular factors, such as calcitonin (Ct), can cause diarrhea in patients with medullary thyroid cancer (MTC). We report 3 patients (age 26-38 years, serum Ct levels ranging from 2,890 to 52,894 ng/L) with chronic diarrhea, and the diagnosis of MTC was delayed. Diarrheal symptoms improved after thyroid surgery. Two patients with elevated Ct had no diarrhea. The link between tumor humoral secretion and diarrhea is not well established in patients with MTC. Diarrhea is more common in patients with metastatic disease and improves after resection of the tumor. Diarrhea may result from elevated circulating levels of Ct or other substances, such as prostaglandins or serotonin. Other proposed mechanisms include decreased absorption in the colon secondary to gastrointestinal motor disturbances. In conclusion, MTC should be considered when evaluating chronic diarrhea.

Benign-Appearing Glucagonoma Undergoing Malignant Transformation after a Prolonged Period.

Glucagonoma are rare neuroendocrine tumors arising in the Langerhans islets of the pancreas. We report a patient with glucagonoma differentiation into a malignant form after 13 years. A 63-year-old asymptomatic man was evaluated for an enhancing lesion at the distal pancreas. Physical examination was normal. Laboratory values were normal except for an elevated serum glucagon level (206 pg/mL, Ref. 50-150). Somatostatin and other tumor markers were normal. A PET scan confirmed abnormal uptake at the distal pancreas, correlating with a CT scan. The patient underwent laparoscopic distal pancreatectomy with resection of a 2.6-cm mass which predominantly expressed glucagon. Serum glucagon levels normalized immediately postoperatively. He remained asymptomatic for 13 years with normal blood glucose, glucagon, and chromogranin levels and normal surveillance MRI scans. Thirteen years following surgery, an elevated serum glucagon level (230 pg/mL) was observed. At this time he also remained asymptomatic. Abdominal MRI and a PET scan revealed hepatic lesions. Biopsy of the hepatic lesion confirmed metastatic glucagonoma. The patient was treated with lanreotide, which normalized the serum glucagon levels, and the tumor size remained stable for 12 months of follow-up. Complete remission without any treatment for more than 13 years confirmed the benign course of the glucagon-secreting tumor. The precipitating factors are unknown. This case highlights the importance of continuous monitoring of neuroendocrine tumors even beyond 10 years.

SUBCLINICAL ACROMEGALY DUE TO A PITUITARY CYSTIC SOMATOTROPH ADENOMA.

OBJECTIVE: Excess growth hormone (GH) secretion from a cystic sellar lesion is rare. Indeed, there have been few cases of hormone-secreting pituitary adenomas with a cystic component. METHODS: We report a rare case of subclinical acromegaly that presented as a cystic sellar lesion on magnetic resonance imaging (MRI). RESULTS: A 34-year-old Caucasian female presented with arthralgias, diaphoresis, paresthesias, cognitive slowing, headaches, presyncope, anxiety, and depression. She underwent evaluation by multiple providers without a diagnosis. Her physical examination was reportedly normal without evidence to suggest acromegaly. While she was undergoing workup for multiple sclerosis, a brain MRI scan revealed a cystic sellar lesion measuring approximately 1.6 × 0.9 cm approaching the optic chiasm. An insulin-like growth factor 1 level was incidentally screened months later and was elevated at 823 ng/mL (reference range is 69 to 227 ng/mL). A subsequent oral glucose tolerance test reported a growth hormone level of 7.5 ng/mL at its nadir (reference range is <1.0 ng/mL). Additional assessment of the pituitary axis reported normal levels of prolactin, luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, free thyroxine, cosyntropin stimulation test, and a normal 24-hour urinary free cortisol collection. The patient underwent transsphenoidal surgery and her pathology reported a somatroph tumor that stained positive for GH and alpha subunit. No postsurgical complications were noted and postoperative MRIs did not demonstrate evidence of tumor recurrence. CONCLUSION: Cystic pituitary adenomas can secret GH and may present with no classic clinical features of acromegaly. This case emphasizes the importance of a thorough hormonal evaluation in patients who present with a cystic pituitary incidentaloma.

Octreotide Use in a Patient with MEN-1 Syndrome and Multifocal Pancreatic Neuroendocrine Tumors: A Case Report and Review of the Literature.

We report a patient with multiple endocrine neoplasia type 1 with pancreatic polypeptide (PP) secreting subcentimeter pancreatic neuroendocrine tumors (pNETs) treated with octreotide and review the current literature that pertains to the management of these patients. Clinical data, laboratory results, and imaging were reviewed. A literature search was performed in PUBMED using combinations of the terms "multiple endocrine neoplasia type 1," "somatostatin," octreotide," "pancreatic polypeptide," and "pancreatic tumor." Relevant references were selected and reviewed. A 43-year-old male with a history of MEN1 and multiple subcentimeter neuroendocrine tumors with elevation of PP was treated with octreotide therapy leading to a reduction and normalization of PP levels. The patient tolerated octreotide therapy but self-discontinued octreotide after 24 months with a rise in PP levels off therapy. Tumors remained stable in size through 40 months of imaging follow-up. In patients with MEN1 and subcentimeter pNETs, octreotide therapy is well tolerated and can lead to a significant drop in PP levels with no change in lesion size. There is insufficient data to suggest long-term benefit with octreotide therapy but it may be considered versus standard conservative management.

R-CHOP-Associated Graves' Hyperthyroidism.

Radiation-induced thyroid dysfunction following oncologic treatment is not uncommon, however limited literature data has been found on patients that underwent chemotherapy only. A change in thyrometabolic autoimmune status is also a rare entity. We present a case of newly diagnosed Graves' thyrotoxicosis following a successful R-CHOP (Rituximab, Cyclophosphamide, Doxorubicine, Vincristine and Prednisone) treatment in a patient with concurrent abdominal and thyroid diffuse large B-cell lymphoma (DLBCL). Following chemotherapy, PET CT showed resolution of FDG-avid thyroid nodule as well as no evidence of the thyroid mass on repeat ultrasound. Her thyroid function also normalized. During her follow-up visit, patient reported significant unintentional weight loss and persistent fatigue over the past couple months. Repeat laboratory evaluation revealed TSH 0.005 mIU/mL, FT4 6.73 ng/dL and thyroid stimulating immunoglobulin (TSI) 535 (ref <140%). She was started on methimazole followed by radioactive iodine therapy. This unique case of Graves' disease following R-CHOP treatment in patients with known Hashimoto's and thyroid lymphoma is one of the first to be reported in the literature. The swing of pendulum from Hashimoto's to Graves' disease is very uncommon. As clinicians, we need to continue monitoring for clinical and biochemical thyroid dysfunction in this subset of population.

Palpation thyroiditis causing new-onset atrial fibrillation.

OBJECTIVE: Surgery-induced thyroiditis can pose a significant clinical problem that is underappreciated. We present a case of new-onset atrial fibrillation as a consequence of palpation thyroiditis in a 70-year-old man who underwent radical right neck dissection for malignant melanoma and review the limited literature on this topic. DESIGN: Biochemical parameters including thyrotropin, free thyroxine, triiodothyronine, erythrocyte sedimentation rate, C-reactive protein, thyroglobulin, thyroid stimulating immunoglobulins, thyroid binding inhibitory immunoglobulins, thyroid peroxidase, thyroglobulin antibodies, and 24-hour urine iodine were measured. Thyroid ultrasound and technetium-99m pertechnetate scintigraphy with radioactive iodine 131 uptake were employed for diagnostic purposes. MAIN OUTCOME: Following right neck exploratory dissection, the patient developed hyperthyroidism and atrial fibrillation. Imaging studies were compatible with right lobar thyroiditis. Other etiologies of thyroiditis were excluded. Despite normalization of thyroid function after 2 weeks, atrial fibrillation persisted and required cardioversion. CONCLUSIONS: Manipulation of the thyroid gland during neck exploratory surgery can result in hyperthyroidism with atrial fibrillation as a consequence. To avoid this complication, careful attention should be paid during surgical procedures or other clinical situations in which the thyroid gland is manipulated.

Modelling hyaluronan degradation by streptococcus pneumoniae hyaluronate lyase.

Hyaluronic acid (Hyaluronan) is a linear, high molecular weight polysaccharide that forms an important component of the extracellular matrix. It is an excellent biomaterial, and it is increasingly being used in biotechnology, biomedical applications, and drug delivery. Polymer chains of hyaluronan occur in many different lengths in nature, and can be as large as multiples of ten thousand. Since the biological function of a hyaluronan chain often depends on its molecular weight, it is of value for applications to develop reliable quantitative descriptions of the degradation processes of hyaluronan. In particular, the development of such models should assist with the rational design of production processes to create polymer chains in a given molecular weight category for a specific application. In this paper, we propose a new mathematical model for the degradation of hyaluronan by the enzyme streptococcus pneumoniae hyaluronate lyase. The model is based on a processive kinetic mechanism and consists of a coupled system of nonlinear ordinary differential equations for the species of interest. The model parameters are estimated using published experimental data, and good agreement between theory and experiment is found. Numerical experimentation and a Sobol global sensitivity analysis reveal that the key model parameters are the initial enzyme concentration and the rate constants for enzyme adsorption and catalysis.

Successful treatment of a patient with statin-induced myopathy and myotonic dystrophy type II with proprotein convertase subtilisin/kexin type 9 inhibitor, alirocumab (Praluent).

Presently there are limited treatment options for hypercholesterolemia in patients with statin intolerance and myotonic dystrophy. A 74 year-old male presented to endocrine clinic with hypercholesterolemia (serum LDL-C 210 mg/dL), hypogonadism, insulin-controlled type 2 diabetes mellitus, and minimally elevated serum creatine kinase (CK) levels (184 U/L, ref. range 38-174). Shortly after simvastatin treatment, patient developed severe myalgias in the proximal lower and upper extremities; and serum CK increased to 317 U/L. Subsequently patient was treated with various statins including rosuvastatin with similar outcomes. Patient was also treated with bile acid binding resin and ezetimibe without improvement. At this time, a diagnosis of myotonic dystrophy type 2 was confirmed. Patient was then treated with alirocumab, a PCSK9 inhibitor 75 mg subcutaneously every 2 weeks with significant improvement in LDL-C (90 mg/dL) and myalgias. In conclusion, PCSK9 inhibitors such as alirocumab may be an excellent lipid lowering agent in patients with statin intolerance and myotonic dystrophy.