Venous thromboembolism in Cushing syndrome: results from an EuRRECa and Endo-ERN survey.

Background: Patients with Cushing syndrome (CS) are at increased risk of venous thromboembolism (VTE). Objective: The aim was to evaluate the current management of new cases of CS with a focus on VTE and thromboprophylaxis. Design and methods: A survey was conducted within those that report in the electronic reporting tool (e-REC) of the European Registries for Rare Endocrine Conditions (EuRRECa) and the involved main thematic groups (MTG's) of the European Reference Networks for Rare Endocrine Disorders (Endo-ERN) on new patients with CS from January 2021 to July 2022. Results: Of 222 patients (mean age 44 years, 165 females), 141 patients had Cushing disease (64%), 69 adrenal CS (31%), and 12 patients with ectopic CS (5.4%). The mean follow-up period post-CS diagnosis was 15 months (range 3-30). Cortisol-lowering medications were initiated in 38% of patients. One hundred fifty-four patients (69%) received thromboprophylaxis (including patients on chronic anticoagulant treatment), of which low-molecular-weight heparins were used in 96% of cases. VTE was reported in six patients (2.7%), of which one was fatal: two long before CS diagnosis, two between diagnosis and surgery, and two postoperatively. Three patients were using thromboprophylaxis at time of the VTE diagnosis. The incidence rate of VTE in patients after Cushing syndrome diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Conclusion: Thirty percent of patients with CS did not receive preoperative thromboprophylaxis during their active disease stage, and half of the VTE cases even occurred during this stage despite thromboprophylaxis. Prospective trials to establish the optimal thromboprophylaxis strategy in CS patients are highly needed. Significance statement: The incidence rate of venous thromboembolism in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Notably, this survey showed that there is great heterogeneity regarding time of initiation and duration of thromboprophylaxis in expert centers throughout Europe.

Establishing a valid cohort of patients with acromegaly by combining the National Patient Register with the Swedish Pituitary Register.

PURPOSE: The aim of this study was to establish a valid national cohort of patients diagnosed with acromegaly by combining data from the general National Patient Register (NPR) and the disease-specific Swedish Pituitary Register (SPR). METHODS: Patients ≥ 18 years of age at diagnosis of acromegaly reported from 1991 to 2018 who were registered in the NPR and/or SPR were included. The diagnosis of acromegaly was considered correct for patients identified in both registers or confirmed through chart review. Medical records were reviewed in two of Sweden´s six health care regions if the patient was reported only in the NPR. An algorithm for the NPR, with criteria requiring multiple diagnosis registrations and tumour and/or surgery codes, was constructed to reduce the number of patients to review in the remaining four regions. RESULTS: A total of 1866 patients were identified. Among these, 938 were reported in both registers. After application of the algorithm and chart review, the diagnosis was confirmed for 83 of the 906 patients found only in the NPR. Among 22 patients only registered in the SPR, a review of medical records confirmed acromegaly in 13. This resulted in a total of 1034 cases with acromegaly during the study period. The incidence rate of acromegaly in Sweden 1991-2018 was calculated to 4.0/million/year in the entire population and 5.1/million/year among subjects ≥ 18 years of age. CONCLUSION: The combination of the SPR and NPR established a valid cohort of patients diagnosed with acromegaly and increased the estimated incidence in Sweden.

Psychiatric and neurocognitive consequences of endogenous hypercortisolism.

Psychiatric and neurocognitive symptoms due to hypercortisolism were already described by Harvey Cushing in his original paper on patients with Cushing's syndrome (CS). Nowadays, it is well known that psychiatric and cognitive complaints are two of the most common, and most distressing, symptoms in patients with CS. Psychiatric symptoms are indeed a major clinical manifestation of CS. The most commonly observed psychiatric conditions are depression and anxiety, whilst mania and psychosis are less common. Several domains of cognitive function are impaired at diagnosis, including episodic and working memory, executive function and attention. Following treatment, one-fourth of the patients still experience depressed mood, and the cognitive impairments are only partially restored. Consequently, quality of life in patients with CS is severely and persistently affected. Neuroimaging studies have also illustrated the deleterious effects of hypercortisolism on the brain by demonstrating reduced grey matter volumes and cortical thickness, altered resting-state functional responses and during cognitive tasks, as well as widespread reduced white matter integrity, especially in structures important for cognitive function and emotional processing, both before and after successful abrogation of hypercortisolism. In this paper, we summarize the current knowledge on the psychiatric and neurocognitive consequences of hypercortisolism in patients with CS, both before, and after successful treatment. In addition, we review the structural and functional brain abnormalities associated with hypercortisolism and discuss the influence of these factors on quality of life.

Systematic review of surgery and outcomes in patients with primary aldosteronism.

BACKGROUND: Primary aldosteronism (PA) is the most common cause of secondary hypertension. The main aims of this paper were to review outcome after surgical versus medical treatment of PA and partial versus total adrenalectomy in patients with PA. METHODS: Relevant medical literature from PubMed, the Cochrane Library and Embase OvidSP from 1985 to June 2014 was reviewed. RESULTS: Of 2036 records, 43 articles were included in the final analysis. Twenty-one addressed surgical versus medical treatment of PA, four considered partial versus total adrenalectomy for unilateral PA, and 18 series reported on surgical outcomes. Owing to the heterogeneity of protocols and reported outcomes, only a qualitative analysis was performed. In six studies, surgical and medical treatment had comparable outcomes concerning blood pressure, whereas six showed better outcome after surgery. No differences were seen in cardiovascular complications, but surgery was associated with the use of fewer antihypertensive medications after surgery, improved quality of life, and (possibly) lower all-cause mortality compared with medical treatment. Randomized studies indicate a role for partial adrenalectomy in PA, but the high rate of multiple adenomas or adenoma combined with hyperplasia in localized disease is disconcerting. Surgery for unilateral dominant PA normalized BP in a mean of 42 (range 20-72) per cent and the biochemical profile in 96-100 per cent of patients. The mean complication rate in 1056 patients was 4·7 per cent. CONCLUSION: Recommendations for treatment of PA are hampered by the lack of randomized trials, but support surgical resection of unilateral disease. Partial adrenalectomy may be an option in selected patients.

Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency.

OBJECTIVE: The objective was to assess the long-term safety profile of dual-release hydrocortisone (DR-HC) in patients with adrenal insufficiency (AI). DESIGN: Randomised, open-label, crossover trial of DR-HC or thrice-daily hydrocortisone for 3 months each (stage 1) followed by two consecutive, prospective, open-label studies of DR-HC for 6 months (stage 2) and 18 months (stage 3) at five university clinics in Sweden. METHODS: Sixty-four adults with primary AI started stage 1, and an additional 16 entered stage 3. Patients received DR-HC 20-40 mg once daily and hydrocortisone 20-40 mg divided into three daily doses (stage 1 only). Main outcome measures were adverse events (AEs) and intercurrent illness (self-reported hydrocortisone use during illness). RESULTS: In stage 1, patients had a median 1.5 (range, 1-9) intercurrent illness events with DR-HC and 1.0 (1-8) with thrice-daily hydrocortisone. AEs during stage 1 were not related to the cortisol exposure-time profile. The percentage of patients with one or more AEs during stage 1 (73.4% with DR-HC; 65.6% with thrice-daily hydrocortisone) decreased during stage 2, when all patients received DR-HC (51% in the first 3 months; 54% in the second 3 months). In stages 1-3 combined, 19 patients experienced 27 serious AEs, equating to 18.6 serious AEs/100 patient-years of DR-HC exposure. CONCLUSIONS: This long-term prospective trial is the first to document the safety of DR-HC in patients with primary AI and demonstrates that such treatment is well tolerated during 24 consecutive months of therapy.

Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective randomized trial of a novel hydrocortisone dual-release formulation.

CONTEXT: Patients with treated adrenal insufficiency (AI) have increased morbidity and mortality rate. Our goal was to improve outcome by developing a once-daily (OD) oral hydrocortisone dual-release tablet with a more physiological exposure-time cortisol profile. OBJECTIVE: The aim was to compare pharmacokinetics and metabolic outcome between OD and the same daily dose of thrice-daily (TID) dose of conventional hydrocortisone tablets. DESIGN AND SETTING: We conducted an open, randomized, two-period, 12-wk crossover multicenter trial with a 24-wk extension at five university hospital centers. PATIENTS: The trial enrolled 64 adults with primary AI; 11 had concomitant diabetes mellitus (DM). INTERVENTION: The same daily dose of hydrocortisone was administered as OD dual-release or TID. MAIN OUTCOME MEASURE: We evaluated cortisol pharmacokinetics. RESULTS: Compared with conventional TID, OD provided a sustained serum cortisol profile 0-4 h after the morning intake and reduced the late afternoon and the 24-h cortisol exposure. The mean weight (difference = -0.7 kg, P = 0.005), systolic blood pressure (difference = -5.5 mm Hg, P = 0.0001) and diastolic blood pressure (difference: -2.3 mm Hg; P = 0.03), and glycated hemoglobin (absolute difference = -0.1%, P = 0.0006) were all reduced after OD compared with TID at 12 wk. Compared with TID, a reduction in glycated hemoglobin by 0.6% was observed in patients with concomitant DM during OD (P = 0.004). CONCLUSION: The OD dual-release tablet provided a more circadian-based serum cortisol profile. Reduced body weight, reduced blood pressure, and improved glucose metabolism were observed during OD treatment. In particular, glucose metabolism improved in patients with concomitant DM.

Risk of malignancy in an unselected cohort of Icelandic patients with systemic lupus erythematosus.

In the present literature there is still controversy as to whether patients with systemic lupus erythematosus (SLE) are at increased risk of developing malignant diseases. In recent years a number of epidemiological studies have been conducted and some have suggested an association between SLE and malignant diseases while other studies have not. The objective of this study was to investigate this relationship in an unselected cohort of Icelandic patients with SLE. All patients diagnosed with SLE registered in the Icelandic SLE database were compared to the Icelandic cancer registry. For completeness, hospital charts and outpatient notes were also reviewed. The study period was from 1957 to the end of 2001. The O/E (observed/expected ratio), CI and P-value were calculated for total number of malignancies as well as individual malignancy types. Of 238 patients diagnosed with SLE (213 women and 25 men) 39 malignancies were diagnosed in 36 patients; 32 women and four men. Of the 36 patients, 27 were diagnosed subsequently with SLE and malignant disease. The mean age at diagnosis of SLE was 43.2 years (range 10-81) and at time of diagnosis of malignancy 62.7 years (range 43-86). The O/R for the whole study population was 1.38 (CI 0.89-1.87, P = 0.063), 1.45 for the women (CI 0.91-1.99, P = 0.051) and 1.03 for the men (CI 0.22-2.66, P = 0.560). The O/R for the most frequent malignancies diagnosed subsequently to SLE was 6.43 for squamous cell skin cancer (CI 1.31-18.5, P = 0.012), 5.48 for lymphoma (CI 0.64-19.6, P = 0.052), 2.46 for uterine cancer (CI 0.29-8.78, P = 0.196), 2.0 for ovarian cancer (CI 0.23-7.14, P = 0.264), 1.72 for lung cancer (CI 0.36-4.95, P = 0.254) and 1.6 for breast cancer (CI 0.65-3.23, P = 0.154). The total number of patient-years at risk was 2774 years. The results from this study on an unselected cohort of Icelandic SLE patients do not suggest an overall association between SLE and malignancy. Squamous cell skin cancer was the only individual cancer type that was statistically increased in the population and the numbers for lymphoma were borderline statistically significant.

[Epidemiology and medical complications in patients with traumatic spinal cord injuries in Iceland.].

OBJECTIVE: To study the epidemiology of traumatic spinal cord injuries in Iceland, that have caused wheelchair-bound disability. To evaluate the frequency of medical complications in this group of patients both during the acute- and rehabilitation-stage as well as after discharge. To study the present condition and problems related to the urinary tract 1-23 years after the injury. MATERIAL AND METHODS: Medical records of all wheelchair-bound traumatic spinal cord injured individuals in Iceland in 1973-1996 were reviewed and the frequency of various medical complications recorded. Long-term complications were assessed by personal interviews. Urodynamic investigations were performed and the present kidney morphology and function studied by various radiological methods. RESULTS: The annual incidence of studied spinal cord injuries was 8:1,000,000. During the acute- and rehabilitation-stage the following complications were encountered; 14 patients (29%) got pressure sores, eight (17%) deep vein thrombosis, six (12%) pneumonia and five (10%) pulmonary embolism. In the follow-up after discharge and mean follow-up time of 14 years, 19 (54%) have had pressure sores, 16 (46%) have had one to four urinary tract infections each year, nine (26%) more than four. Nineteen patients (56%) complained of urinary incontinance and 18 (52%) had a history of urinary tract stones. One patient had lost a kidney due to reflux. Pathological findings were found in one third of patients who came for upper urinary tract image studies. Maximal detrusor pressure over 60 cmHbO was recorded in 12 (44%) patients and bladder capacity under 200 ml in seven (26%). Of those with injury above Th-6, 14 (58%) had experienced symptoms of autonomous dysreflexia, most commonly due to urinary tract infection or distended urinary bladder. Complications were more common among those who use reflex-voiding rather than intermittent catheterisation. One-third of the patients were either advised to change their way of bladder emptying or required pharmacological intervention according to results from urinary tract investigations. CONCLUSIONS: The incidence of traumatic spinal cord injuries in Iceland, which have caused wheelchair-bound disability, is low and has decreased over the past 25 years. Acute and long-term medical complications are, however, common in these patients. A more efficient follow-up program is needed to optimize bladder treatment and to reduce urinary tract and other medical complications in this patient population.