Acromegaly management in the Nordic countries: A Delphi consensus survey.

OBJECTIVE: Acromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow-up exist. However, not all recommendations are strictly evidence-based. To evaluate consensus on the treatment and follow-up of patients with acromegaly in the Nordic countries. METHODS: A Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow-up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert-type scale (1-7). Consensus was defined as ≥80% of panelists rating their agreement as ≥5 or ≤3 on the Likert-type scale. RESULTS: Consensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first-generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first-generation SSA and pegvisomant as second- or third-line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists. CONCLUSION: This consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence-based data.

Incidence, Treatment, and Survival of Adrenocortical Carcinoma in Denmark 2003-2019.

Objectives: Adrenocortical carcinoma (ACC) is a malignant tumor originating from the adrenal cortex. The aim of the study was to report the incidence of ACC and survival of ACC in Denmark. The secondary objective was to describe the impact of treatment with mitotane on survival. Design: Retrospective population study of patients diagnosed with ACC between 2003 and 2019 in Denmark. Methods: Individuals at risk for ACC were identified in the national Danish Health registries, and diagnosis of ACC was confirmed by review of the health records. Data on demographics, presentation, treatment, recurrence, and death was evaluated. Results: 138 patients were included in the study with more females (59.4%) than males (40.6%). Incidence rate was 1.4 per million per year. The incidence rate ratio significantly increased only in females by 1.06 [95% confidence interval (CI): 1.02-1.12] per year. Overall median survival was 1.93 (95% CI: 1.24-3.00) years with no differences between males and females. The proportion of patients treated with mitotane (either as adjuvant treatment or as part of a chemotherapeutic regime) was 72.3%. Survival was significantly decreased in women not treated with mitotane compared to women treated with mitotane (either as adjuvant or as part of a chemotherapeutic regime) hazards ratio .30 (95% CI: .10-.89), adjusted for European Network for the Study of Adrenal Tumours score, age at diagnosis, and year of diagnosis, but survival was unaffected by mitotane treatment in men. Conclusion: Incidence of ACC in Denmark was 1.4 per million per year and increased in women but not in males during the study period 2003-2019.

Severe weight loss in a hypothyroid patient as an acute presentation of autoimmune polyglandular syndrome type II.

BACKGROUND: Autoimmune disease, including autoimmune thyroid disease, with uncharacteristic symptoms can be due to additional severe disease. We report a life-threatening debut of autoimmune polyglandular syndrome type II (APS II) defined as Addison's disease combined with autoimmune diabetes and/or thyroid disease. PATIENT FINDINGS: A 33-year-old male with newly diagnosed hypothyroidism was referred to a tertiary center due to fatigue and 20-kg rapid weight loss. Malignancy was excluded. After a gastroscopy, he developed Addison's crisis; he was admitted to our hospital and stabilized. Final diagnoses included Hashimoto's thyroiditis, Addison's disease, vitiligo, and pernicious anemia. Whole genome sequencing found no genetic variants associated with component diseases. Human leukocyte antigen typing revealed DR3/DR4 and DQ8/DQ2 heterozygosity associated with APS II. A patient with Hashimoto's thyroiditis and weight loss presented with Addison's crisis and was diagnosed with APS II. CONCLUSIONS: Awareness of potential polyautoimmunity in clinical evaluation of patients with thyroid disease improves diagnosis and can be lifesaving.

Concomitant familial hypocalciuric hypercalcemia and single parathyroid adenoma: a case report.

BACKGROUND: Primary hyperparathyroidism (PHPT) is a common endocrine disorder and the most frequent benign cause of hypercalcemia. PHPT is characterized by autonomous hypersecretion of parathyroid hormone (PTH), regardless of serum calcium levels. Familial hypocalciuric hypercalcemia (FHH) is a rare, benign syndrome only affecting the regulation of calcium metabolism. FHH is an autosomal-dominant genetic disease with high penetrance, caused by an inactivating variant in the CASR gene encoding the calcium-sensing receptor (CaSR). We present a unique case of concomitant PHPT and FHH without clinically actionable variants in MEN1. CASE PRESENTATION: A 47-year-old Caucasian man with severe hypercalcemia, genetic FHH, and initially normal parathyroid scintigraphy was referred for endocrine evaluation due to nonspecific symptoms. Biochemical evaluation showed elevated serum ionized calcium and PTH. The calcium-creatinine clearance ratio was low. All other biochemical measures were normal, including kidney function. Genetic evaluation was redone and confirmed FHH. A new parathyroid scintigraphy showed a significant single adenoma corresponding to the lower left gland. The patient underwent parathyroidectomy, and a parathyroid adenoma was removed. A reduced level of hypercalcemia persisted due to FHH. CONCLUSIONS: The correct diagnosis of the underlying cause of hypercalcemia is important to ensure the right treatment. Patients with FHH should avoid operative treatment, and PHPT should be differentiated from MEN1 to determine whether surgery should include parathyroidectomy with removal of one adenoma or 3.5 hyperplastic parathyroid glands.

[Pituitary apoplexy in a young woman].

Pituitary apoplexy occurs when a preexisting pituitary adenoma undergoes acute haemorrhage, infarct or both. The patho-genesis is not fully understood but macroadenomas and prolactinomas have been reported as being predisposed to apoplexy. Only a few cases are described in the paediatric population. We present a 17-year-old woman with secondary amenorrhoea, headache and blurred vision. An MRI showed a pituitary apoplexy in a preexisting macroadenoma. The majority of milder cases resolve spontaneously. Close monitoring of the pituitary function is important to detect pituitary insufficiency witch may need long-term hormone replacement therapy.

Peripheral markers of thyroid function: the effect of T4 monotherapy vs T4/T3 combination therapy in hypothyroid subjects in a randomized crossover study.

BACKGROUND: A recent randomized controlled trial suggests that hypothyroid subjects may find levothyroxine (l-T4) and levotriiodothyronine combination therapy to be superior to l-T4 monotherapy in terms of quality of life, suggesting that the brain registered increased T3 availability during the combination therapy. HYPOTHESIS: Peripheral tissue might also be stimulated during T4/T3 combination therapy compared with T4 monotherapy. METHODS: Serum levels of sex hormone-binding globulin (SHBG), pro-collagen-1-N-terminal peptide (PINP), and N-terminal pro-brain natriuretic peptide (NT-proBNP) (representing hepatocyte, osteoblast, and cardiomyocyte stimulation respectively) were measured in 26 hypothyroid subjects in a double-blind, randomized, crossover trial, which compared the replacement therapy with T4/T3 in combination (50 µg T4 was substituted with 20 µg T3) to T4 alone (once daily regimens). This was performed to obtain unaltered serum TSH levels during the trial and between the two treatment groups. Blood sampling was performed 24 h after the last intake of thyroid hormone medication. RESULTS: TSH remained unaltered between the groups ((median) 0.83 vs 1.18 mU/l in T4/T3 combination and T4 monotherapy respectively; P=0.534). SHBG increased from (median) 75 nmol/l at baseline to 83 nmol/l in the T4/T3 group (P=0.015) but remained unaltered in the T4 group (67 nmol/l); thus, it was higher in the T4/T3 vs T4 group (P=0.041). PINP levels were higher in the T4/T3 therapy (48 vs 40 µg/l (P<0.001)). NT-proBNP did not differ between the groups. CONCLUSIONS: T4/T3 combination therapy in hypothyroidism seems to have more metabolic effects than the T4 monotherapy.

Effect of combination therapy with thyroxine (T4) and 3,5,3'-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomised cross-over study.

BACKGROUND: Treatment of hypothyroidism with 3,5,3'-triiodothyronine (T(3)) is controversial. A recent meta-analysis concludes that no evidence is present in favour of using T(3). However, the analysis included a mixture of different patient groups and dose-regimens. OBJECTIVE: To compare the effect of combination therapy with thyroxine (T(4)) and T(3) versus T(4) monotherapy in patients with hypothyroidism on stable T(4) substitution. Study design Double-blind, randomised cross-over. Fifty micrograms of the usual T(4) dose was replaced with either 20 microg T(3) or 50 microg T(4) for 12 weeks, followed by cross-over for another 12 weeks. The T(4) dose was regulated if needed, intending unaltered serum TSH levels. Evaluation Tests for quality of life (QOL) and depression (SF-36, Beck Depression Inventory, and SCL-90-R) at baseline and after both treatment periods. Inclusion criteria Serum TSH between 0.1 and 5.0 mU/l on unaltered T(4) substitution for 6 months. RESULTS: A total of 59 patients (55 women); median age 46 years. When comparing scores of QOL and depression on T(4) monotherapy versus T(4)/T(3) combination therapy, significant differences were seen in 7 out of 11 scores, indicating a positive effect related to the combination therapy. Forty-nine percent preferred the combination and 15% monotherapy (P=0.002). Serum TSH remained unaltered between the groups as intended. CONCLUSION: In a study design, where morning TSH levels were unaltered between groups combination therapy, (treated with T(3) 20 microg once daily) was superior to monotherapy by evaluating several QOL, depression and anxiety rating scales as well as patients own preference.

N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) in different thyroid function states.

OBJECTIVE: N-terminal B-type natriuretic peptide (NT-pro-BNP) is secreted from the cardiac ventricles in response to volume expansion and pressure overload, and serum levels are elevated in systolic heart failure. The aim of this study was to evaluate the influence of thyroid function on NT-pro-BNP. DESIGN: Patients with overt or subclinical thyroid disease were evaluated before and after treatment for their dysthyroid state. PATIENTS: Seventeen overt and 21 subclinical hypothyroid patients together with six subclinical and 13 overt hyperthyroid patients without cardiac disease were included. Subclinical states had, by definition, free T4 and free T3 estimates within reference ranges. MEASUREMENTS: Serum levels of NT-pro-BNP and thyroid hormones were measured, and in 31 patients resting cardiac output was measured by impedance cardiography in the untreated state. RESULTS: NT-pro-BNP levels were more than four times higher in hyperthyroid than hypothyroid patients, with mean values of 30 and 7 pmol/l, respectively (P < 0.001). Serum NT-pro-BNP levels correlated to the thyroid function (vs. free T4 estimate: r = 0.52, P < 0.0001, n = 57). Treatment resulted in significant increases in NT-pro-BNP in both hypothyroid groups, and decreases in both hyperthyroid groups. A multiple linear regression analysis demonstrated that free T4 and free T3 (P < 0.001) estimates were independently associated with a high serum NT-pro-BNP, whereas cardiac output and resting pulse rate were not. CONCLUSIONS: Serum NT-pro-BNP levels are affected by thyroid function. This seems due to a direct stimulatory effect of thyroid hormones.