Improvement of hypertension control and left-ventricular function after cure of primary hyperparathyroidism.

Introduction: Cardiovascular mortality is significantly higher in patients with primary hyperparathyroidism (PHPT) compared to the general population. The role of the renin-angiotensin-aldosterone system (RAAS) as a mediator of cardiovascular pathology in PHPT is unclear, as is the question whether successful parathyroidectomy (PTX) mitigates hypertension (HT), and left-ventricular (LV) dysfunction. Methods: In 45 consecutive, hypercalcemic PHPT patients (91% female, 20 normotensive, mean age 54.6 ± 14.6), laboratory examinations, and 24 h ambulatory blood pressure monitoring (ABPM) were performed before, one and six months after successful PTX, while transthoracic echocardiography (TTE) pre- and six months post-PTX. Results: Both in patients with normotension (NT) and HT, lower calcemia and parathyroid hormone (PTH) as well as higher phosphatemia were observed on follow-up, while B-type natriuretic peptide, aldosterone, plasma renin activity, and aldosterone-to-renin ratios were comparable. Six months post-PTX, only in patients with HT, median 24-hour SBP/DBP decreased by 12/6 mmHg, daytime SBP by 10, and nighttime DBP by 5 mmHg. Improvement in BP was observed in approximately 78% of patients with HT. Six months post-PTX, TTE revealed: 1) decrease in median LV mass index (by 2 g/m2) and end-diastolic dimension (by 3 mm) among patients with HT; 2) normalization of global longitudinal strain in 22% of patients (comparable between those with NT and HT); 3) a mean 12.7% reduction in left-atrium volume index among patients with HT, which underlay normalization of indeterminate diastolic function in 3 out of 6 patients with HT, who exhibited it at baseline (dysfunction persisted in 2). Conclusions: PTX was shown to significantly reduce BP, LV hypertrophy and diastolic dysfunction parameters in PHPT patients with HT, and improve systolic function in all PHPT patients.

A study of acromegaly-associated headache with somatostatin analgesia.

The aim of this study is to characterise somatostatin analogue-responsive headache in acromegaly, hitherto not systematically documented in a significant cohort. Using the UK pituitary network, we have clinically characterised a cohort of 18 patients suffering from acromegaly-related headache with a clear response to somatostatin analogues. The majority of patients had chronic migraine (78%) as defined by the International Headache Society diagnostic criteria. Headache was present at the time of acromegaly presentation and clearly associated temporally with disease activity in all cases. Short-acting somatostatin analogues uniquely resolved pain within minutes and the mean duration of analgesia was 1-6 h. Patients on long-acting analogues required less short-acting injections (mean: 3.7 vs 10.4 injections per day, P = 0.005). 94% used somatostatin analogues to control ongoing headache pain. All patients presented with macroadenoma, most had incomplete resection (94%) and headache was ipsilateral to remnant tissue (94%). Although biochemical control was achieved in 78% of patients, headache remained in 71% of them. Patients selected for this study had ongoing headache post-treatment (mean duration: 16 years after diagnosis); only four patients reached headache remission 26 years (mean range: 14-33) after the diagnosis. Headache in acromegaly patients can be persistent, severe, unrelieved by surgery, long-lasting and uncoupled from biochemical control. We show here that long-acting analogues allow a decrease in the number of short-acting analogue injections for headache relief. Further studies are needed to understand the mechanisms, markers and tumour tissue characteristics of acromegaly-related headache. Until then, this publication serves to provide the clinical characteristics as a reference point for further study.

Oncogenic osteomalacia - detection of the tumour site upon physical examination.

Not required for Clinical Vignette.

Incidence of thyroid nodules in early stage autosomal polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. Defect in cilia-mediated signaling activity is a crucial factor leading to cyst formation. Hence, ADPKD is regarded as a systemic disorder with multiple extrarenal complications, including cysts in other organs, for instance, the liver, pancreas, spleen, or ovaries. Interestingly, loss-of-function of primary cilia has been recently found to contribute to a malignant transformation from degenerated thyroid follicles. However, the increased incidence of thyroid nodules in ADPKD patients has not yet been fully confirmed. OBJECTIVES: To determine the incidence of thyroid lesions in patients with ADPKD in comparison to previous population studies. Moreover, we aimed to investigate if the pace of the disease progression is associated with a higher prevalence of thyroid lesions. MATERIAL AND METHODS: In 49 early-stage ADPKD patients recruited from our center, we performed ultrasonography of the thyroid glands, and laboratory evaluation of thyroids function. We compared the results with population studies. RESULTS: Twenty-three individuals had solid, cystic-solid, or cystic lesions revealed in the ultrasonography and 2 patients had a positive past medical history for thyroidectomy due to nodular goiter. In 10 patients out of the 23, only minor cysts with no clinical significance were found and 13 out of the 23 patients had solid or cystic-solid lesions, which occurred to be benign based on three years of follow-up or the biopsy of the nodule. CONCLUSIONS: We found no increased incidence of thyroid gland lesions in early ADPKD patients in comparison to previous population studies. Plausibly, mechanisms other than defective cilia signaling are involved in the risk for focal thyroid lesions formation. Moreover, the rate of progression of kidney function decline seems to be not accompanied by the higher incidence of thyroid pathology.

Progress on Genetic Basis of Primary Aldosteronism.

Primary aldosteronism (PA) is a heterogeneous group of disorders caused by the autonomous overproduction of aldosterone with simultaneous suppression of plasma renin activity (PRA). It is considered to be the most common endocrine cause of secondary arterial hypertension (HT) and is associated with a high rate of cardiovascular complications. PA is most often caused by a bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenoma (APA); rarer causes of PA include genetic disorders of steroidogenesis (familial hyperaldosteronism (FA) type I, II, III and IV), aldosterone-producing adrenocortical carcinoma, and ectopic aldosterone-producing tumors. Over the last few years, significant progress has been made towards understanding the genetic basis of PA, classifying it as a channelopathy. Recently, a growing body of clinical evidence suggests that mutations in ion channels appear to be the major cause of aldosterone-producing adenomas, and several mutations within the ion channel encoding genes have been identified. Somatic mutations in four genes (KCNJ5, ATP1A1, ATP2B3 and CACNA1D) have been identified in nearly 60% of the sporadic APAs, while germline mutations in KCNJ5 and CACNA1H have been reported in different subtypes of familial hyperaldosteronism. These new insights into the molecular mechanisms underlying PA may be associated with potential implications for diagnosis and therapy.

The Role of Immunotherapy in the Treatment of Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) is a rare epithelial neoplasm, with a high tendency for local invasion and distant metastases, with limited treatment options. Surgical treatment is the method of choice. For decades, the mainstay of pharmacological treatment has been the adrenolytic drug mitotane, in combination with chemotherapy. Immunotherapy is the latest revolution in cancer therapy, however preliminary data with single immune checkpoint inhibitors showed a modest activity in ACC patients. The anti-neoplastic activity of immune checkpoint inhibitors such as anti-cytotoxic-T-lymphocyte-associated-antigen 4 (anti-CTLA-4), anti-programmed death-1 (anti-PD-1), and anti-PD-ligand-1 (PD-L1) antibodies in different solid tumors has aroused interest to explore the potential therapeutic effect in ACC as well. Multiple ongoing clinical trials are currently evaluating the role of immune checkpoint inhibitors in ACC (pembrolizumab, combination pembrolizumab and relacorilant, nivolumab, combination nivolumab and ipilimumab). The primary and acquired resistance to immunotherapy continue to counter treatment efficacy. Therefore, attempts are made to combine therapy: anti-PD-1 antibody and anti-CTLA-4 antibody, anti-PD-1 antibody and antagonist of the glucocorticoid receptor. The inhibitors of immune checkpoints would benefit patients with antitumor immunity activated by radiotherapy. Immunotherapy is well tolerated by patients; the most frequently observed side effects are mild. The most common adverse effects of immunotherapy are skin and gastrointestinal disorders. The most common endocrinopathy during anti-CTLA treatment is pituitary inflammation and thyroid disorders.

Nontoxic Goiter (NTG) and Radioiodine: What Do Patients Think About It? Quality of Life in Patients with NTG Before and After 131-I Therapy.

OBJECTIVE: Despite numerous publications regarding nontoxic goiter (NTG) treatment and an increasing interest in patients' quality of life, few studies present the outcome of 131-I treatment from the patients' perspective. Our study's main aim was to verify whether there is any improvement in life quality following 131-I treatment. MATERIALS AND METHODS: Thirty-five patients with NTG qualified to participate in the study. All patients completed a Thyroid-Related Health-Related Quality of Life (Thy-R-HRQoL) questionnaire created by us and the Medical Outcomes Study 36-item Short Form (SF-36), right before and 1 year after 131-I. RESULTS: We observed an improvement in six out of eight SF-36 and three out of seven Thy-R-HRQoL domains. In comparison with the control group, we observed worse results in two out of eight, prior to treatment, and one out of eight SF-36 afterward, as well as in all Thy-R-HRQoL domains. We did not find any correlation between improvement of Thy-R-HRQoL and SF-36 and goiter size reduction, except for Bodily Pain. There was also no correlation between improvement of SF-36 and Thy-R-HRQoL domains, and goiter size before treatment. The older the patient, the less noticeable improvement was observed in Physical and Social Functioning, and Vitality in SF-36, but age had no influence on the assessment by Thy-R-HRQoL. CONCLUSION: Radioiodine treatment improves life quality in patients with NTG. Use of the Health-Related Quality of Life questionnaire should be taken into consideration when evaluating life quality of patients with NTG. Relentless pursuit of maximal goiter size reduction in 131-I treatment is worth consideration. In our study, life quality improvement did not depend directly on the goiter size reduction. Life quality improvement after 131-I might not depend on initial goiter size, and for certain domains of SF-36 might be less clearly expressed in older patients.

Primary Ewing Sarcoma of the Thyroid-Eight Cases in a Decade: A Case Report and Literature Review.

Sarcomas represent less than 1% of all malignant tumors found in the thyroid. Of these, primary extraosseoussarcoma has been reported only a few times in the past decade. We present the case of a 34-year-old male who had a fast-growing hard mass in the lower left neck. FNA was inconclusive. Core needle biopsy revealed the diagnosis of an Ewing sarcoma/primitive neuroectodermal tumor. Mutation of EWSR1 was confirmed using the FISH method. Following treatment by neoadjuvant chemotherapy, we observed clinical, radiological, and finally histopathological remission. This was followed by a left-sided isthmolobectomy with unilateral cervical lymph node dissection by lateral lymphadenectomy, which revealed no residual disease. Posttreatment radiotherapy was administered but discontinued upon the patient's request. After 18 months of observation, the patient had no recurrence or metastasis and required l-thyroxine supplementation. We discuss our case using a comparative literature review to the few other known case reports.

A case report of Gitelman syndrome resulting from two novel mutations in SLC12A3 gene / El caso del síndrome de Gitelman causado por dos nuevas mutaciones en el gen SLC12A3

Introduction: Hypokalaemia is a common clinical problem. A potential but commonly overlooked cause of hypokalaemia is Gitelman syndrome. Material and methods: A 26-year-old man was admitted to the hospital due to syncope with general and muscular weakness and muscle cramps. The patient's history revealed previous recurrent syncope events associated to hypokalaemia with the lowest serum potassium value being 2.6mmol/l. At admission, blood pressure was normal and no changes were found at physical examination. Laboratory tests showed mild hypokalaemia (3.0mmol/l), hypomagnesaemia (1.36mg/dl), hypocalciuria (< 40mg/24h), and metabolic alkalosis (HCO3− 29.7mmol/l, BE 5.3mmol/l). Results: Further laboratory tests (FeK, TTKG) confirmed inappropriate kaliuresis. Conn's disease was excluded by hormonal and imaging assessments. Genetic testing was performed and two novel heterozygous mutations: c.35_36insA and c.1095+5G>A were found in transcriptNM_000339.2 in SLC12A3 gene. Conclusion: The patient was diagnosed with Gitelman syndrome and was treated with supplements of potassium and magnesium (AU)

Introducción: La hipopotasemia es un problema clínico común. El síndrome de Gitelman es una posible causa de hipopotasemia a veces no reconocida. Material y métodos: Un hombre de 26 años de edad ingresa en un hospital por causa de un síncope, debilidad generalizada y calambres musculares. La historia clínica del paciente reveló la incidencia del síncope con hipopotasemia recurrente con el valor más bajo de potasio en 2,6mmol/l. En el ingreso, el paciente presentaba una presión arterial normal y la exploración física no reveló ninguna enfermedad. La evaluación del laboratorio demostró una hipopotasemia leve (K+ 3,0mmol/l), hipomagnesemia (Mg 1,36mg/dl), hipocalciuria (<40mg/24h) y alcalosis metabólica (HCO3- 29,7mmol/l, exceso de base 5,3mmol/l). Resultados: Otras pruebas de laboratorio (FeK, TTKG) confirman una caliuresis inadecuada. La enfermedad de Conn fue excluida tras la evaluación hormonal y radiológica. Se realizaron las pruebas genéticas y 2 mutaciones heterocigóticas: c.35_36insA y c.1095+5G>A fueron encontradas en la transcripción NM_000339.2 del gen SLC12A3. Conclusión: El paciente fue diagnosticado con el síndrome de Gitelman y fue tratado con suplementos de potasio y magnesio (AU)

Large multinodular goiter--outpatient radioiodine treatment.

INTRODUCTION: 131-I treatment of nodular, especially nontoxic, goitre is still reserved mainly for elderly patients, whose numerous concomitant diseases disqualify them from surgery. Therapy often involves isolation and is available only in selected centres, which may be located far from some patients' places of residence, which is inconvenient for elderly people. The aim of the study was to assess the effectiveness of outpatient fractionated 131-I treatment of patients with large nodular goitres, as well as to evaluate complications and the factors affecting treatment results. MATERIAL AND METHODS: The study included 35 patients with a large nodular goitre. Thyroid volume and treatment results were evaluated using US and CT neck examination. RESULTS: Mean thyroid volume prior to treatment was 104.36 mL (range 36.23-301.09 mL). An average administered 131-I activity was 1806 MBq (range 800-4000). The average reduction of goitre volume was 43.18% (range -17.23-89.66%). Final treatment results correlated with the thyroid size reduction obtained three months after treatment (r = 0.74; p = 0.001). Symptoms of transient hyperthyroidism were observed in 8.57% of patients, in 5.4% Graves disease was induced (including severe Graves' orbitopathy in 2.7%), and in 2.86% TRAb increase without development of hyperthyroidism was observed. The treatment results were not influenced by initial thyroid volume (r = -0.01; p = 0.95). An increase in thyroid volume during the treatment was reported in 20% of patients, with a mean increase of 22.3% (range 0.63-55.03%). Post-treatment hypothyroidism was diagnosed in 42.9% of patients. One patient was diagnosed with salivary gland damage. CONCLUSIONS: Fractionated 131-I treatment of large nodular goitres is an effective method, the results of which are comparable to those obtained from the administration of one-time high doses of radioiodine.

US not bright but right method of thyroid volume estimation even in large and substernal extended goitres. Comparison of US and three methods of CT thyroid evaluation ­ prospective study.

BACKGROUND: Ultrasound is nowadays a method of choice for thyroid volume assessment. However, its disadvantage is some inaccuracy, which is said to be higher in huge, especially substernally extended goitres. AIMS: The aim of the study was to compare the US and CT thyroid volumetric measurements: multi-observers (CT MO) and one-observer (CT OO) to CT planimetry results (CT Pl) in patients with large goitres. MATERIALS & METHODS: The study material comprised 70 thyroid imaging examinations obtained from 35 patients with nontoxic goitres, scanned twice before and after radioiodine treatment. Mean thyroid volume was 88·97 ± 60·21 ml. Thirty-three thyroid scans revealed the extension below the jugular notch (mean of 2·46 cm). Thyroid volume in US, CT MO and CT OO was estimated using the ellipsoid formula. CT Pl was established a reference method. RESULTS: The mean thyroid volume in CT Pl was 88·97 ml (median 80·73, range 11·81 to 315·97). US underestimates thyroid volume by 7·55 ml (7·7%) with a sufficient correlation (R(2) = 0·89) and precision (20·37). CT OO is the closest and CT MO the most distant from CT Pl, with US between them in thyroid volume estimation. The percentage US bias is constant through all range of thyroid volume. There is no difference for percentage bias between US and CT Pl for goitres with (8·67%), and without (6·70%) substernal part. CONCLUSION: US examination is sufficient for epidemiological studies, radioiodine activity calculation and goitre size assessment in everyday medical practice. Neither initial size of the goitre nor its substernal extension affects US assessment precision.

[Oncogenic osteomalacia and its symptoms: hypophosphatemia, bone pain and pathological fractures]. / Onkogeniczna osteomalacja czyli hipofosfatemia, bóle kostne i zlamania patologiczne.

Oncogenic osteomalacia (OOM) is a rare paraneoplastic syndrome induced by tumor produced phosphaturic factors, i.e. phosphatonins. The disorder is characterized by renal tubular phosphate loss, secondary to this process hypophosphatemia and defective production of active form of vitamin D. The clinical course of oncogenic osteomalacia is characterized by bone pain, pathological fractures, muscle weakness and general fatigue. Osteomalacia-associated tumors are usually located in the upper and lower limbs, with half of the lesions primarily situated in the bones. Most of them are small, slow-growing tumors. Their insignificant size and various location coupled with rare occurrence of the disease and non-specificity of clinical symptoms lead to difficulties in reaching a diagnosis, which is often time-consuming and requires a number of additional tests. The average time between the appearance of the first symptoms and the establishment of an accurate diagnosis and the beginning of treatment is over 2.5 years. The aim of this study is to discuss the pathophysiology of disease symptoms, pathomorphology of tumors, diagnostic methods and treatment of oncogenic osteomalacia.

Oncogenic osteomalacia should be considered in hypophosphatemia, bone pain and pathological fractures.

The clinical manifestation of oncogenic osteomalacia includes bone pain, pathological fractures, general fatigue and muscle weakness. Such unspecific symptoms hinder the establishment of a proper diagnosis which very often requires long-lasting investigations with many diagnostic imaging methods. Here, we discuss difficulties in the diagnosis of oncogenic osteomalacia using the example of our own clinical case: a 56 year-old woman with a history of pain in the left hip and two years of walking difficulties. A plain radiograph and CT scan revealed pathological fractures. Multiple myeloma, primary hyperparathyroidism and bone metastatic disease were excluded. Routine laboratory tests showed elevated alkaline phosphatase and a mild degree of hypophosphatemia. CT and MR imaging confirmed the presence of a pathological mass in the thorax. Tumour excision and histopathological test results revealed the diagnosis of a phosphaturic mesenchymal tumour. Our case, showing the clinical course of the disease from the symptoms manifested at the beginning to the establishment of the diagnosis, can serve as a model illustration of the diagnostic struggle involved with oncogenic osteomalacia.

The estimation of selected endogenous anticoagulation system parameters in patients with subclinical Cushing's syndrome.

OBJECTIVE: An increased tendency towards thromboembolic events is observed in patients with Cushing's syndrome. There are much fewer publications available about thromboembolic complications in patients with subclinical Cushing's syndrome (SCS). Therefore, a question arises whether hemostatic disturbances appear in this particular disease phase. AIM OF STUDY: Estimation of protein C (PC), free protein S (FPS), antithrombin (AT) activity, thrombomodulin (TM) concentration and activated PC resistance (APCR) in patients with SCS. MATERIALS AND METHODS: We studied 35 patients with SCS. The control group consisted of 33 healthy volunteers. The activity of PC, AT, FPS, APCR and the concentration of TM was estimated in all representatives. RESULTS: The comparison of the examined coagulation parameters between the patients with SCS and the healthy individuals revealed significantly higher mean PC activity and mean FPS activity in the SCS group. Mean TM concentration was significantly lower in patients with SCS compared with the control group. The differences in APCR and AT activity were not significant. We did not prove any statistically significant correlations between the examined coagulation parameters and hormonal parameters. We did not find any correlation between the concentration of cortisol and basic coagulation parameters such as international normalized ratio, activated partial thromboplastin time or fibrinogen in the group with SCS either. CONCLUSIONS: The patients with SCS present disturbances in endogenous anticoagulation system defined as PC, FPS activity and TM concentration. This finding suggests an impact of mild autonomic cortisol overproduction on coagulation system.