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.

Cushing's Disease May Have Higher Incidence than Previously Thought: A Nationwide Study in Iceland 2010-2019.

INTRODUCTION: In 2011, we reported the overall incidence of Cushing's disease (CD) in Iceland from 1955 through 2009 to be 1.5 cases per million per year with highest incidence in the last decade of the study, a higher incidence then earlier reported. We now present a follow-up study reporting the epidemiology of the disease in Iceland during the 10-year period from 2010 to 2019. METHODS: In this nationwide retrospective study, clinical information on patients diagnosed with CD was obtained from electronic medical records, reviewed by consulting endocrinologists. RESULTS: Seventeen patients were diagnosed with CD, 12 women (71%) and 5 men (29%) giving an overall incidence of 5.2 cases per million per year. The mean age at diagnosis was 46 years (range 13-85 years). Biochemical analysis was recorded for all patients and 12 patients (71%) had visible pituitary adenoma on imaging studies. Sixteen patients (94%) were treated with transsphenoidal surgery of which 4 patients (24%) had gamma knife radiosurgery and three (18%) bilateral adrenalectomy after pituitary surgery. Two patients died during the study period. CONCLUSION: The overall incidence of CD of 5.2 cases per million per year is higher than previously reported, indicating the importance of awareness of CD. As all patients with CD are diagnosed and/or treated at the only University Hospital in Iceland, housing the only department of endocrinology as well as neurosurgery, we are confident that all cases diagnosed during the study period were included in the study.

[Licorice consumption can be life-threatening].

A 71-year-old man came to the emergency department (ED) at Landspitali University Hospital after collapsing at his home. He had a severely decreased serum potassium concentration of 2.1 mmol/L (ref. 3,5-4,8 mmol/L), along with an influenza A infection and thigh muscle weakness. Further investigations revealed atrial fibrillation, new-onset hypertension and increased urinary excretion of potassium. Serum values of aldosterone and renin were under the limit of detection. The patient had consumed a significant amount of liquorice with marzipan, over 250g per day, in the days preceding his visit to the ED. He was subsequently diagnosed with liquorice-induced hypertension and syndome of apparent mineralocordicoid excess (pseudohyperaldosteronism). This case emphasizes the need for clinicians to be aware of the dangers of liquorice consumption.

[Resistant hypertension - pheochromocytoma].

We report a case of a man with a 30-year history of treatment-resistant hypertension, hydropoiesis, tachycardic spells and dysgeusia. Despite repeated visits to the emergency department and work-up in an out-patient clinic, the diagnosis was unknown. Three years prior to remittance to an endocrinologist, the hypertension worsened, and he developed diabetes type-II. Further work-up revealed a 3 cm extra-adrenal pheochromocytoma, a paraganglioma. After surgical removal of the tumor, he is without medication and symptom free. Pheochromocytoma and paraganglioma are rare causes of hypertension, estimated to explain 0.1-0.6% of all cases, but nonetheless an important diagnosis to make, due to serious side effects.

Are We Only Detecting the Tip of the Iceberg? A Nationwide Study on Primary Aldosteronism with up to 8-Year Follow-up.

BACKGROUND: Long-term follow-up studies on primary aldosteronism (PA) are lacking. OBJECTIVE: We aim to review results of diagnostic procedures and histopathology for patients diagnosed during 2012-2016 in Iceland, compare unilateral (UD) and bilateral disease (BD) and assess treatment response. METHODS: Thirty-two patients aged 28-88 were diagnosed and treated according to guidelines. RESULTS: The majority had BD. Everyone needed potassium supplementation at case detection. We saw a reduction in systolic blood pressure (p < .001, both groups), antihypertensive agents (p = .002 UD and p = .04 BD) and potassium supplementation (p < .001, both groups). CONCLUSION: Similar treatment response was seen in both subgroups. Ratio of hypokalemia and number of cases indicates severe PA underdiagnosis in Iceland.

[Obesity isn't always obesity: Cushing's disease - case report]. / Offita er ekki alltaf offita: Cushing-sjúkdómur, sjúkratilfelli

Woman in her thirties presented to the emergency room with a two-week history of worsening headache and diplopia. For eight years she had suffered from progressive weight gain, diabetes and hypertension that didn't improve with lifestyle modification. A lumbar puncture demonstrated increased intracranial pressure and MRI a pituitary adenoma. Physical examination was consistent with Cushing's syndrome and endocrine workup confirmed Cushing's disease. Treatment was complex, including unsuccessful pituitary surgery and gamma knife radiosurgery, and eventually bilateral adrenalectomy with subsequent development of Nelsons syndrome. This case illustrates the diagnostic delay that many patients with CD suffer from.

Antiepileptic drugs are associated with central hypothyroidism.

OBJECTIVE: Studies in children have shown an increased frequency of central hypothyroidism (CH) with long-term use of antiepileptic drugs (AEDs). The aim of this study was to search for CH in adults treated with AEDs and find whether the type of AEDs used matters. MATERIALS AND METHODS: Adult epileptic patients treated at the neurology outpatient clinic at Landspitali University Hospital (LSH) from 1998 to 2011 were included. Patients were invited for a blood test if serum levels for TSH (s-TSH) or free-T4 (s-fT4 ) had not already been obtained. CH was defined as s-fT4 below the reference range (12-22 pmol/L) and normal s-TSH levels (0.30-4.20 mIU/L). Data were analyzed using logistic regression and Mann-Whitney test. RESULTS: We identified 165 patients (92 women), mean age 45.6 (±15.5, range: 20-92) years. The mean s-fT4 -level in our group was 14.2 (±2.9, range: 8.1-24.4) pmol/L compared with 16.9 (±6.1) pmol/L in a sample of 13248 measurements at LSH during one year (LSH-group) (P < 0.001). The difference in s-fT4 -level between men and the LSH-group was significant and also for women (P < 0.001 and P < 0.001, respectively). Thirty-five patients (21%) had CH. A significant association with the use of carbamazepine or oxcarbazepine was found, odds ratio for women 15.0 (95% CI: 4.6-49.5) and 1.8 (95% CI: 0.4-8.3) for men. CONCLUSION: 21% of patients treated with AEDs had CH, more often patients taking carbamazepine or oxacarbazepine, and more often women. The s-fT4 -level was lower among patients treated with AEDs.

Hypopituitarism 3 and 12 months after traumatic brain injury and subarachnoid haemorrhage.

OBJECTIVE: High prevalence of hypopituitarism (HP) has been reported after traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH). The aim of the study was to prospectively evaluate the prevalence and progression of HP in patients after TBI and SAH in Icelandic population. DESIGN: A 12 month prospective single-centre study. METHODS AND PROCEDURES: A total of 27 patients were included, 15 patients with TBI and 12 patients with SAH. Pituitary function was evaluated with baseline hormone measurements and diagnostic tests. An insulin tolerance test was used unless contraindicated, then the GHRH-arginine test and Synachten test were used. RESULTS: At three months, 16.7% (2/12) of the patients had HP after TBI and 33.3% (4/12) after SAH. At 12 months, 21.4% (3/14) of patients had HP after TBI and 9.1% (1/11) after SAH. Gonadotropin deficiency was the most common deficiency at 3 months and GH and gonadotropin deficiency at 12 months. CONCLUSIONS: There is a considerable risk of HP after TBI and reason to study pituitary function further in patients with SAH. We believe that neuroendocrine evaluation is important in these patients. Since recovery commonly occurs 12 months after the event, evaluation should be performed after that time if not clinically indicated earlier.

INCREASING PREVALENCE OF ADDISON DISEASE: RESULTS FROM A NATIONWIDE STUDY.

OBJECTIVE: Primary adrenal insufficiency is a life-threatening endocrine disease unless properly treated. However, few studies on the prevalence, concomitances of the disease, and prescribing of drugs have been published. The goal of the study was to establish the prevalence of primary adrenal insufficiency in Iceland and additionally, to study the most common concomitant diseases in patients with primary adrenal insufficiency, as well as the mode of glucocorticoid replacement therapies. METHODS: To achieve this, the medical records of all patients in Iceland who had received the International Classification of Diseases and Related Health Problems, 10th Revision, diagnosis code E27, were evaluated for true primary adrenal insufficiency. Additionally, these records were evaluated for concomitant diseases, as well as the mode of glucocorticoid replacement therapy. The study covered the whole population of Iceland over 18 years of age. It was thus a nationwide study. The records were retrieved from large hospitals and clinics and every practicing specialist in endocrinology. RESULTS: Primary adrenal insufficiency was found in 53 individuals, 26 women and 27 men, yielding a prevalence of 22.1 per 100,000 population. Hypothyroidism was by far the most common concomitant disease. Most patients had their glucocorticoid deficiency replaced with short-acting glucocorticoids. CONCLUSION: The prevalence of primary adrenal insufficiency in Iceland is higher than in earlier reports, with comorbidities being in line with recent studies. Treatment is according to the latest protocols.

The incidence and prevalence of acromegaly, a nationwide study from 1955 through 2013.

CONTEXT: Acromegaly is a rare disease with complications and increased mortality. The incidence and prevalence of acromegaly worldwide is not well known. OBJECTIVE: To gather information on patients diagnosed with acromegly in Iceland over 59 years. DESIGN: Information was retrospectively gathered about patients diagnosed with acromegaly from 1955 through 2013. Incidence was calculated from the total Icelandic population. SETTING/PATIENTS: Information was gathered from medical records at Landspitali National University Hospital, Iceland, housing the only endocrine department in the country, at the largest hospital outside of Reykjavik (Sjúkrahúsið á Akureyri, Akureyri Hospital) and the largest private outpatient clinic in Reykjavik, where some of the patients received follow-up care. Further, information on patients were sought from all endocrinologists treating adult patients in Iceland. All patients diagnosed with acromegaly during the study period were included. RESULTS: Fifty-two patients (32 men) were diagnosed during the study period. The average age at diagnosis was 44.5 years. Nine patients had died. Symptoms had been present for more than 3 years in most cases. Twenty-five patients had hypertension (48 %). Follow up information was available for 48 patients, 63 % were considered cured after treatment. CONCLUSIONS: The incidence of acromegaly in Iceland during the study period was much higher than earlier reports have indicated. During the last 9 years of the study 7.7 patients were diagnosed per million per year. At diagnosis, 38 % had developed hypertension and 10 % were diagnosed during follow up. This indicates the importance of endocrine disorders in the aetiology of hypertension.

Pituitary dysfunction following mild traumatic brain injury in female athletes.

Objective: Pituitary dysfunction following mild traumatic brain injury can have serious physical and psychological consequences, making correct diagnosis and treatment essential. To the best of our knowledge, this study is the first to study the prevalence of pituitary dysfunction following mild traumatic brain injury in an all-female population following detailed endocrinological work-up after screening for pituitary dysfunction in female athletes. Design: This is a retrospective cohort study. Methods: Hormone screening blood tests, including serum blood values for thyroid-stimulating hormone, free thyroxin, insulin-like growth factor 1, prolactin, cortisol, follicle-stimulating hormone, luteinizing hormone, estrogen and progesterone, were taken in 133 female athletes. Results were repeatedly outside the reference value in 88 women necessitating further endocrinological evaluation. Two of those were lost to follow-up, and further endocrinological evaluation was performed in 86 participants. Results: Six women (4.6%, n = 131) were diagnosed with hypopituitarism, four (3.1%) with central hypothyroidism and two with growth hormone deficiency (1.5%). Ten women (7.6%) had hyperprolactinemia, and four (3.1%) of them had prolactinoma. Medical treatment was initiated in 13 (9.9%) women. Significant prognostic factors were not found. Conclusions: As 12.2% of female athletes with a history of mild traumatic brain injury had pituitary dysfunction (hypopituitarism 4.6%, hyperprolactinemia 7.6%), we conclude that pituitary dysfunction is an important consideration in post-concussion care. Hyperprolactinemia in the absence of prolactinoma may represent pituitary or hypothalamic injury following mild traumatic brain injury. Significance statement: Mild traumatic brain injury (mTBI) has become a growing public health concern as 50 million people worldwide sustain a traumatic brain injury annually, with mTBI being the most common (70-90%). As studies on mTBI have focused on mostly male populations this study aims to explore pituitary dysfunction (PD) in female athletes following mTBI. To the best of our knowledge, it is the first all-female study on PD following mTBI. The study found that 12.2% of the participating women had PD after mTBI. Six (4.6%) had hypopituitarism and ten (7.6%) had hyperprolactinemia. These findings suggest that PD following mTBI is an important consideration that endocrinologists and other medical staff working with athletes need to be aware of.

Screening for possible hypopituitarism following mild traumatic brain injury: The first all-female study. Who do we need to evaluate further?

BACKGROUND: Studies on hypopituitarism (HP) following mild traumatic brain injury (mTBI) have focused on male populations although women may be more susceptible to the sequelae of mTBI. This is, to the best of our knowledge, the first all-female study screening for HP following mTBI. OBJECTIVE: Screening for possible HP in female athletes reporting a history of one or more mTBI. METHODS: Pituitary hormone screening blood tests (SBT) were performed in 133 of the 151 female athletes included. Repeated results outside the reference value (O-RV) were considered abnormal necessitating further endocrinological evaluation. RESULTS: Repeated SBT were O-RV in 88 women (66.2%). Decreased levels of serum insulin growth factor 1 (S-IGF1) were found in 55.6% of participants and elevated levels of serum prolactin (S-prolactin) in 22.6%. Serum cortisol levels were below the RV in 6.0% and thyroid hormonal levels in 11.3%. Lower age and increased number of mTBI symptoms correlated significantly with the risk of hormonal results O-RV. CONCLUSION: The majority of the study population had SBT O-RV, warranting further workup of possible HP. Decreased levels of S-IGF1 were most commonly observed followed by elevated S-prolactin possibly indicating hypothalamic-pituitary impairment. Lower age and increased number of symptoms of mTBI may indicate the need to screen for HP.

Unilateral adrenal hyperplasia is a usual cause of primary hyperaldosteronism. Results from a Swedish screening study.

BACKGROUND: The existence of unilateral adrenal hyperplasia (AH) has been considered a rare cause of primary hyperaldosteronism (PA). METHODS: In a prospective study we screened for PA in a non-selected (NSP) and selected hypertensive population (SP), to define the cause of PA. We included 353 consecutive patients with hypertension; age 20 to 88 years, 165 women and 188 men, from a university-based Hypertension and Nephrology Outpatient clinics (123 SP) and two primary care centres, (230 NSP) from the same catch-up area. Serum aldosterone and plasma renin activity (PRA) were measured and the ARR calculated. Verifying diagnostic procedure was performed in patients with both elevated aldosterone and ARR. Patients diagnosed with PA were invited for adrenal venous sampling (AVS) and offered laparoscopic adrenalectomy when AVS found the disease to be unilateral. RESULTS: After screening, 46 patients, 13% of the whole population (22.8% SP and 7.8% NSP) had aldosterone and ARR above the locally defined cut-off limits (0.43 nmol/l and 1.28 respectively). After diagnostic verification, 20 patients (6%) had PA, (14.5% SP and 1.4% NSP). Imaging diagnostic procedures with CT-scans and scintigraphy were inconclusive. AVS, performed in 15 patients verified bilateral disease in 4 and unilateral in 10 patients. One AVS failed. After laparoscopic adrenalectomy, 4 patients were found to have adenoma and 5 unilateral AH. One patient denied operation. CONCLUSION: The prevalence of PA was in agreement with previous studies. The study finds unilateral PA common and unilateral AH as half of those cases. As may be suspected PA is found in much higher frequency in specialised hypertensive units compared to primary care centers. AVS was mandatory in diagnosis of unilateral PA.

[Severely increased serum lipid levels in diabetic ketoacidosis - case report].

Severe hypertriglyceridemia is a known, but uncommon complication of diabetic ketoacidosis. We discuss the case of a 23-year-old, previously healthy, woman who initially presented to the emergency department with abdominal pain. Grossly lipemic serum due to extremely high triglyceride (38.6 mmol/L) and cholesterol (23.2 mmol/L) levels were observed with a high blood glucose (23 mmol/L) and a low pH of 7.06 on a venous blood gas. She was treated successfully with fluids and insulin and had no sequale of pancreatitis or cerebral edema. Her triglycerides and cholesterol was normalized in three days and she was discharged home on insulin therapy after five days. Further history revealed a recent change in diet with no meat, fish or poultry consumption in the last 12 months and concomitantly an increase in carbohydrate intake which might have contributed to her extremely high serum lipid levels. This case demonstrates that clinicians should be mindful of the different presentations of diabetic ketoacidosis. Key words: diabetic ketoacidosis, hypertriglyceridemia, hyperlipidemia, vegan diet, carbohydrate diet. Correspondence: Hrafnkell Stefansson, hrafnkell.stefans@gmail.com.

Primary aldosteronism: from case detection to histopathology with up to 6 years of follow-up.

The authors aimed to investigate the clinical characteristics, accuracy of diagnostic tests, and long-term outcomes after interventions in patients diagnosed with primary aldosteronism (PA) in Iceland throughout 5 years. A retrospective chart review was performed for all patients diagnosed with PA during the years 2007-2011 at Landspitali Hospital in Iceland, a referral center for the whole country. Workup after detection included salt loading test, positional test, computed tomography, and adrenal vein sampling. Patients with unilateral disease were offered treatment with adrenalectomy. A total of 33 patients were diagnosed with PA during the study period: 17 patients with bilateral disease and 16 with unilateral disease. Results from salt loading test were positive in 90% of patients. In patients with adenoma, 36% were responsive on their positional test and computed tomography scan showed a nodule in 73%. All patients with unilateral disease had a lateralization index ≥3. After surgery, patients had lower systolic blood pressure (P<.001) and number of hypertensive medications (P<.01).