Abstract
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.
Keywords: Cushing’s disease, Pituitary tumour, Cortisol, Obesity, Pituitary surgery
Introduction
In our earlier report, the overall incidence of Cushing’s disease (CD) in Iceland from 1955 through 2009 was 1.5 cases per million per year which was similar to former reports from other countries. However, majority of patients (89%) were diagnosed during the second half of the study period (1982–2009) and the annual incidence peaked in the last 5 years at 2.6 per million cases per year. These results can possibly be explained by multiple factors such as, better registration and advances in diagnostic and treatment options. More awareness of possible CD in recent years is also a possible explanation for a higher incidence of CD in Iceland in modern times [1].
Collaboration of European countries on CD with the European Register on Cushing’s syndrome (ERCUSYN) project has led to more knowledge on the disease in recent years [2]. Iceland is a participant in ERCUSYN and has collected data on patients with CD in the country since 1955. Only few epidemiological studies have been published and in those, the estimated annual incidence of CD has been found to be between 1.2 and 2.4 cases per million [1, 3–6]. A recent Swedish study presenting the incidence to be 1.6 cases per million per year is in line with those studies [7]. In Iceland, the diagnostic process and surgical treatment of CD is exclusive to one tertiary care hospital, Landspitali University Hospital (LUH), in Reykjavik, which facilitates identification of patients with CD. We now present a follow-up study reporting the epidemiology of the disease in Iceland during a 10-year period from 2010 to 2019.
Methods
In this nationwide retrospective study, clinical information on patients diagnosed with CD during 2010–2019 was obtained from Landspitali’s electronic medical records. We searched the hospital’s database for ICD-10 diagnoses E24.0 (pituitary-dependent CD) and E24 (Cushing’s syndrome) plus D35.2 (benign pituitary adenoma) and validated the CD diagnosis by systematically reviewing documentation on clinical signs, investigations, diagnosis, and treatment. Consulting endocrinologists reviewed clinical information on patients with established diagnosis but information on patients with non-pituitary dependent Cushing’s syndrome were not specifically reviewed.
Biochemical and Hormonal Analysis
Serum cortisol (SeC) level was measured using Roche reagents with reference values between 135 and 540 nmol/L (from 6:00 to 10:00 a.m.) and 70–330 nmol/L (from 4:00 to 8:00 p.m.). 24-h urinary free cortisol was first determined by radioimmunoassay from Cisbo with reference values between 54 and 319 nmol/24 h but from January 2017 it was analysed by using liquid chromatography tandem mass spectrometry (LC-MS) with reference values between 12 and 165 nmol/24 h (men) and 8–119 nmol/24 h (women). Salivary cortisol (SaC) was first measured with Cortisol method using Roche reagents with reference values <19.1 nmol/L (from 8:00 to 10:00 a.m.) and <11.9 nmol/L (from 2:30 to 3:30 p.m.), but from September 2016 it was measured with Cortisol-II method using other reagents with reference values <24.1 nmol/L (from 6:00 to 10:00 a.m.), <9.65 nmol/L (from 4:00–8:00 p.m.), and <11.3 nmol/L (midnight hours). As no reference values for midnight measurements of salivary cortisol were outlined for the Cortisol method, it was decided to use values listed in leaflet published by Roche in 2008, Reference Ranges for Adults and Children, with references 3–43 nmol/L (morning hours) and <10 nmol/L (evening hours). Serum ACTH was determined by Siemens ACTH Immulite assay with reference values 0–46 ng/L. Overnight dexamethasone (dm) suppression test (ODST) was performed by giving 1 mg of dm orally at 11:00 p.m. and SeC analysed at 8:00 a.m. Low-dose dm suppression test (LDDST) was performed by giving 0.5 mg of dm every 6 h for 48 h, starting at 9:00 a.m. and ending at 3:00 a.m. with final levels of SeC measured at 8:00 a.m. High-dose dm suppression test (HDDST) was performed by giving 2 mg instead of 0.5 mg as described for the low-dose test. Post-corticotropin releasing hormone (CRH) test (Post-CRH) was performed by giving 0.1 mg of synthetic ovine CRH after an overnight fast with blood samples for cortisol collected at 15 min and 1 min before CRH administration and at 15, 30, 45, 60, 90, and 120 min after for measurements of cortisol and ACTH. Dm suppression CRH test (Dex-CRH) was performed in the same way as Post-CRH test but in continuation of a low-dose dm test.
Definition of remission at 3 years from diagnosis and at the end of the study period was defined as normal urinary free cortisol and/or normal LDDST (SeC <50 nmol/L) or signs of adrenal insufficiency. A positive histopathology of a ACTH producing adenoma in the pituitary after transsphenoidal surgery (TPS) was the criteria for a positive diagnosis of CD.
Data Analysis and Ethical Issues
In this retrospective, observational study we used descriptive statistics to describe outcomes from diagnosed patients with CD. Population numbers and registered cause of death was obtained from Hagstofan (Statistics Iceland). The study was approved by the National Bioethics Committee (licence No. 02-V2-S1) and Landspitali’s Chief Medical Officer and executed in compliance with ethical standards (i.e., Declaration of Helsinki).
Results
Seventeen patients were diagnosed with CD during the study period, 12 women (71%) and 5 men (29%) with age ranging from 13 to 85 years (mean 46 ± SD 19.7). One patient was diagnosed with CD at age 13 whereas other patients were adults. No patient had an adrenal tumour. Two patients died during the study period.
All 17 patients were registered with the ICD-10 diagnostic code E24.0 for pituitary-dependent CD and had available information on symptoms, signs, investigations, and treatment (see Table 1). Typical signs and symptoms for CD were recorded although not presented here. Biochemical analysis was documented for all patients (see Tables 1–3). Four patients were not evaluated with cortisol in serum or saliva at midnight, all of them had macroadenoma on imaging studies and other biochemical testing supporting CD and three of them had biopsy supporting the diagnosis of CD. The 1 patient not being operated on is described below. Twelve patients (71%) had visible pituitary adenoma on imaging studies, 11 on pituitary magnetic resonance imaging and one on computerized tomography (CT) scan. The 2 patients undergoing CT had implantable cardiac device not compatible with magnetic resonance imaging investigation. Seven patients (41%) performed inferior petrosal sinus sampling (IPSS) that was positive in all and histopathological diagnosis of ACTH secreting tumour was made for 14 patients (82%). Three patients missed histopathological diagnosis (see Table 1): (1) one was not operated as he was regarded as unfit for surgery due to multiple comorbidities, patient number 12 (Tables 1–3), (2) one with a large tumour suffered a severe bleeding during the operation and was therefore treated with bilateral adrenalectomy, patient number 5 (Tables 1–3), and (3) the last patient still had CD symptoms despite two operations and went for bilateral adrenalectomy later on, patient number 14 (Tables 1–3). In total, 16 patients (94%) were treated with transsphenoidal surgery of which three were re-operated for recurrence of pituitary adenomas. The same neurosurgeon was in charge of all operations. Four patients (24%) were treated with gamma knife radiosurgery post-operatively and 3 patients (18%) had bilateral adrenalectomy following unsuccessful pituitary surgery (one mentioned above already). Those having bilateral adrenalectomy had persistent hypercortisolism and increased ACTH levels despite extensive TPS: (1) in one no tumour was found although histopathology post TPS showed ACTH mixed adenoma and typical symptoms and signs of CD were recorded along with a positive IPSS, (2) one had severe intraoperative bleeding during TPS due to an arterial aneurysm, and (3) the last had persistent disease (large tumour not feasible for further operation) despite TPS and repeated gamma-knife surgery (see Table 1).
Table 1.
Patient clinical characteristics and year of diagnosis
| Patient | Biochemical analysis | Pituitary imaging | IPSS | TPS | Pathology | Gamma-knife radiosurgery | Bilateral adrenalectomy |
|---|---|---|---|---|---|---|---|
| 2010-1 | UFC, ODST, SeC, SaC, ACTH, LDDST | Microadenoma | No | Yes | ACTH adenoma | No | No |
| 1 | |||||||
| 2010-1 | UFC, ODST, SeC, HDDST | Not seen | Yes | Yes | Normal | No | No |
| 2 | |||||||
| 2012-1 | UFC, ODST, SeC, ACTH, LDDST, Dex-CRH | Microadenoma | No | Yes | ACTH adenoma | No | No |
| 3 | |||||||
| 2012-1 | UFC, ODST, SeC, ACTH, LDDST, Dex-CRH | Macroadenoma (extracellular invasion) | No | Yes | ACTH adenoma | Yes | Yes |
| 4 | |||||||
| 2012-1 | UFC, ODST, SeC, ACTH, LDDST, Dex-CRH | Not seen | Yes | Yes | No tissue | No | Yes |
| 5 | |||||||
| 2013-1 | UFC, ODST, SeC, SaC, ACTH, LDDST, Post-CRH | Not seen | Yes | Yes | ACTH adenoma | No | No |
| 6 | |||||||
| 2013-1 | UFC, ODST, SeC, ACTH | Macroadenoma (extracellular invasion) | No | Yes | ACTH adenoma | No | No |
| 7 | |||||||
| 2013-1 | UFC, ODST, SeC, ACTH, LDDST, Dex-CRH | Not seen | Yes | Yes | ACTH adenoma | Yes | No |
| 8 | |||||||
| 2014-2 | UFC, ODST, SeC | Macroadenoma (extracellular invasion) | No | Yes | ACTH adenoma | Yes | No |
| 9 | |||||||
| 2014-1 | UFC, ODST, SeC, SaC, ACTH, LDDST, Dex-CRH | Microadenoma | Yes | Yes | ACTH adenoma | No | No |
| 10 | |||||||
| 2014-2 | UFC, ODST, SeC, SaC, ACTH, LDDST | Microadenoma | No | Yes | ACTH mixed adenoma | No | No |
| 11 | |||||||
| 2015-2 | UFC, ODST, SeC, ACTH | Macroadenoma (extracellular invasion) (CT) | No | No | – | No | No |
| 12 | |||||||
| 2015-2 | UFC, ODST, SeC, SaC, ACTH, LDDST, Post-CRH | Not seen (CT) | Yes | Yes | ACTH mixed adenoma | No | No |
| 13 | |||||||
| 2016-1 | UFC, SeC, SaC, ACTH, ODST, LDDST | Microadenoma | Yes | Yes | ACTH mixed adenoma | No | Yes |
| 14 | |||||||
| 2016-1 | UFC, ODST, SeC, ACTH, LDDST | Microadenoma | No | Yes | ACTH adenoma | No | No |
| 15 | |||||||
| 2018-1 | UFC, ODST, SeC, ACTH, LDDST, Dex-CRH | Microadenoma | No | Yes | ACTH adenoma | Yes | No |
| 16 | |||||||
| 2019-2 | ODST, SeC, ACTH, LDDST | Macroadenoma (extracellular invasion) | No | Yes | ACTH adenoma | No | No |
| 17 |
First column includes: year of diagnosis, 1: female, 2: male and patient number.
IPSS, inferior petrosal sinus sampling; TPS, transsphenoidal surgery; UFC:24-h urinary free cortisol; ODST, overnight dexamethasone test; SeC, serum cortisol; SaC, salivary cortisol; LDDST, low-dose dexamethasone test; HDDST, high-dose dexamethasone test; Post-CRH, CRH stimulation test; Dex-CRH, CRH stimulation test in continuation of LDDST; ACTH adenoma, tissue with ACTH overproduction defined.
Table 3.
CRH stimulation test results
| Serial No. | Patient | Time from CRH injection (min) | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| −15 | 0 | 5 | 10 | 15 | 20 | 30 | 40 | 60 | 80 | 90 | 100 | 120 | |||
| 1 | 2010-1 | – | – | – | – | – | – | – | – | – | – | – | – | – | |
| 2 | 2010-1 | – | – | – | – | – | – | – | – | – | – | – | – | – | |
| 3 | 2012-1 | SeC, nmol/L | 218 | 194 | 192 | 233 | 399 | 555 | 751 | 705 | 604 | – | – | – | – |
| ACTH, ng/L | 22 | 21 | 39 | 45 | 52 | 43 | 43 | 50 | 39 | – | – | – | – | ||
| SeCΔ (%) | – | – | −12 | +7 | +83 | +155 | +244 | +223 | +177 | – | – | – | – | ||
| ACTHΔ (%) | – | – | +77 | +105 | +136 | +95 | +95 | +127 | +77 | – | – | – | – | ||
| 4 | 2012-1 | SeC, nmol/L | 174 | 135 | 138 | 175 | – | 324 | 298 | 251 | 242 | – | – | – | – |
| ACTH, ng/L | 48 | 42 | 66 | 79 | – | 75 | 71 | 73 | 58 | – | – | – | – | ||
| SeCΔ (%) | – | – | −21 | +1 | – | +86 | +71 | +44 | +39 | – | – | – | – | ||
| ACTHΔ (%) | – | – | +38 | +65 | – | +56 | +48 | +52 | +21 | – | – | – | – | ||
| 5 | 2012-1 | SeC, nmol/L | 650 | 660 | 679 | 804 | – | 889 | 937 | 946 | 936 | – | – | – | – |
| ACTH, ng/L | 74 | 71 | 118 | 133 | – | 156 | 150 | 145 | 145 | – | – | – | – | ||
| SeCΔ (%) | – | – | +4 | +24 | – | +37 | +44 | +46 | +44 | – | – | – | – | ||
| ACTHΔ (%) | – | – | +59 | +80 | – | +111 | +103 | +96 | +96 | – | – | – | – | ||
| 6 | 2013-1 | SeC, nmol/L | 674 | 755 | – | – | 853 | – | 947 | – | 751 | – | 604 | – | 779 |
| ACTH, ng/L | 80 | 98 | – | – | 184 | – | 144 | – | 56 | – | 40 | – | 83 | ||
| SeCΔ (%) | – | – | – | – | +27 | – | +41 | – | +11 | – | −10 | – | +16 | ||
| ACTHΔ (%) | – | – | – | – | +130 | – | +80 | – | –30 | – | –50 | – | +4 | ||
| 7 | 2013-1 | – | – | – | – | – | – | – | – | – | – | – | – | – | |
| 8 | 2013-1 | SeC, nmol/L | – | 100 | – | – | – | – | 374 | 624 | 750 | 977 | – | 975 | – |
| ACTH, ng/L | – | 18 | – | – | – | – | 26 | 58 | 132 | 104 | – | 70 | – | ||
| SeCΔ (%) | – | – | – | – | – | – | +274 | +524 | +650 | +877 | – | +875 | – | ||
| ACTHΔ (%) | – | – | – | – | – | – | +44 | +222 | +633 | +478 | – | +289 | – | ||
| 9 | 2014-2 | – | – | – | – | – | – | – | – | – | – | – | – | – | |
| 10 | 2014-1 | SeC, nmol/L | 54 | 57 | – | – | 67 | – | 71 | 60 | 56 | – | 97 | – | 74 |
| ACTH, ng/L | 11 | 13 | – | – | 18 | – | 13 | 11 | 16 | – | 18 | – | 16 | ||
| SeCΔ (%) | – | – | – | – | +24 | – | +31 | +11 | +4 | – | +80 | – | +37 | ||
| ACTHΔ (%) | – | – | – | – | +64 | – | +18 | 0 | +45 | – | +64 | – | +45 | ||
| 11 | 2014-2 | – | – | – | – | – | – | – | – | – | – | – | – | – | |
| 12 | 2015-2 | – | – | – | – | – | – | – | – | – | – | – | – | – | |
| 13 | 2015-2 | SeC, nmol/L | 645 | 605 | – | – | 550 | – | 506 | 498 | 482 | – | 608 | – | 711 |
| ACTH, ng/L | 58 | 51 | – | – | 45 | – | 48 | 44 | 49 | – | 68 | – | 67 | ||
| SeCΔ (%) | – | – | – | – | −15 | – | −22 | –23 | –25 | – | −6 | – | +10 | ||
| ACTHΔ (%) | – | – | – | – | −22 | – | −17 | –24 | –16 | – | +17 | – | +16 | ||
| 14 | 2016-1 | – | – | – | – | – | – | – | – | – | – | – | – | – | |
| 15 | 2016-1 | – | – | – | – | – | – | – | – | – | – | – | – | – | |
| 16 | 2018-1 | SeC, nmol/L | 637 | 609 | – | – | 587 | – | 618 | 638 | 638 | – | 706 | – | 711 |
| ACTH, ng/L | 63 | 57 | – | – | 53 | – | 61 | 65 | 68 | – | 74 | – | 76 | ||
| SeCΔ (%) | – | – | – | – | −8 | – | –3 | 0 | 0 | – | +11 | – | +12 | ||
| ACTHΔ (%) | – | – | – | – | −16 | – | –3 | +3 | +8 | – | +17 | – | +21 | ||
| 17 | 2019-2 | – | – | – | – | – | – | – | – | – | – | – | – | – | |
First column displays the patient number. Second column includes: year of diagnosis, 1: female, 2: male.
SeC, serum cortisol.
Outcome
After 3 years from diagnosis, 13 patients (76%) had no evidence of hypercortisolism. In the end of the study period, 15 patients (88%) had no evidence of disease recurrence. Two had died, patient number 7 (Tables 1–3) succumbed to postoperative respiratory failure following TPS and patient number 12 (Tables 1–3) who had unresectable pituitary tumour, multiple comorbidities and died from pneumonia and heart failure. Median time to follow-up was 99 months (IQR 71–118 months).
Discussion
During the 10-year study period, we found the overall incidence of CD to be 5.2 cases per million per year which is higher than the few other studies published including our former report (see Table 4). Previous studies, reporting annual incidence of 1.2–2.4 per million per year have spanned 10–54 years [1, 3–7]. An exception is a study from the USA by Broder et al. [8] which presented the annual incidence for 2009 and 2010 to be 6.2 and 7.6, respectively, per million, depending their results solely on diagnostic and procedure codes without routinely reviewing medical records. The importance of validating diagnoses as was done in our study, is presented clearly in the recent Swedish report by Ragnarsson et al. [7] where a correct diagnosis was verified in less than half of the patients with presumed CD by coding registry alone.
Table 4.
Incidence of CD in Iceland over 10 years
| Year | Patients, n | Icelandic population | Patients per million/year | Patients dead | Mortality in Icelandic population |
|---|---|---|---|---|---|
| 2010 | 2 | 317.630 | 6.3 | 0 | 2,020 |
| 2011 | 0 | 318.452 | 0 | 0 | 1,986 |
| 2012 | 3 | 319.575 | 9.4 | 0 | 1,955 |
| 2013 | 3 | 321.857 | 9.3 | 1 | 2,154 |
| 2014 | 3 | 325.671 | 9.2 | 0 | 2,049 |
| 2015 | 2 | 329.100 | 6.1 | 1 | 2,178 |
| 2016 | 2 | 332.529 | 6.0 | 0 | 2,309 |
| 2017 | 0 | 338.349 | 0 | 0 | 2,239 |
| 2018 | 1 | 348.450 | 2.9 | 0 | 2,254 |
| 2019 | 1 | 356.991 | 2.8 | 0 | 2,275 |
The outcome described in our study has to be considered very good as none of the living patients has had a relapse of CD until now. Only 5 of the tumours were found as macroadenomas on pituitary imaging possibly affecting the good outcome, and we are of course aware of the short follow-up period (99 months, IQR 71–118 months). The 3 patients missing a histopathological diagnosis of CD can of course be discussed. Patient number 2 did have a positive IPSS even though a tumour was not found. Nevertheless, the patient was cured of the hypercortisolism with increased ACTH after TPS. Thus, a diagnosis for CD seems to us to be the correct diagnosis. Patient number 5 were a tissue could not be received as the patient suffered a severe aneurysmal bleeding during TPS, had a positive IPSS indicating that CD was the right diagnosis. To clarify, none of our 17 patients had an adrenal tumour. Considering bilateral adrenalectomy as a cure for CD might be debated and seen as a weakness of our study. Nevertheless, the cure rate is good.
There are several factors that might explain the high incidence of CD found in our study. Advances in diagnostic and treatment options is probably the strongest cause of increased incidence in the later years but other factors such as genetics can also play a role. The Icelandic population is small consisting of only about 350,000 people and considerable changes in annual incidence of rare diseases such as CD are expected (see Table 2). Therefore, the incidence over a longer period of time is possibly more accurate. However, patients with suspected CD have possibly more chance of being diagnosed as there is only one tertiary care hospital in the country. As Iceland is an island, with a small nation, and the work up, treatment and follow-up on few hands, it might give a more complete result on diagnosis and cure rate and a favourable setting for work up of rare diseases.
Table 2.
Biochemical test results
| Serial No. | Patient | UFC, nmol/24 h | ODST – SeC, nmol/L | 24 h curve | 48 h DST – SeC, nmol/L | |||
|---|---|---|---|---|---|---|---|---|
| time | SeC, nmol/L | SaC, nmol/L | ACTH, ng/L | |||||
| 1 | 2010-1 | 253 | 215 | 8:00 p.m. | 621 | 39 | 13 | 229* |
| 12:00 a.m. | 763 | 45 | 43 | |||||
| 4:00 a.m. | 601 | 31 | 33 | |||||
| 8:00 a.m. | 466 | 39 | 6 | |||||
| 2 | 2010-–1 | 553 | 364 | 2:00 p.m. | 658 | – | – | 65** |
| 10:00 p.m. | 479 | – | – | |||||
| 2:00 a.m. | 463 | – | – | |||||
| 9:00 a.m. | 590 | – | 11 | |||||
| 3 | 2012-1 | 446 | 593 | 8:00 p.m. | 563 | – | 26 | 145* |
| 12:00 a.m. | 381 | – | 18 | |||||
| 4:00 a.m. | 193 | – | 14 | |||||
| 8:00 a.m. | 294 | – | 23 | |||||
| 4 | 2012-1 | 406 | 105 | 8:30 p.m. | 488 | – | 55 | 68* |
| 12:20 a.m. | 268 | – | 36 | |||||
| 4:00 a.m. | 279 | – | 45 | |||||
| 8:00 a.m. | 338 | – | 50 | |||||
| 5 | 2012-1 | 1,452 | 1,014 | 8:00 p.m. | 818 | – | 88 | 839* |
| 12:00 a.m. | 952 | – | 76 | |||||
| 4:00 a.m. | 868 | – | 96 | |||||
| 8:00 a.m. | 1,002 | – | 25 | |||||
| 6 | 2013-1 | 1,697 | 1,294 | 8:00 a.m. | 1,458 | 57 | – | 1,026* |
| 2:00 p.m. | 1,269 | 28 | – | |||||
| 8:00 p.m. | 1,064 | 19 | – | |||||
| 12:40 a.m. | 1,149 | 23 | 65 | |||||
| 8:00 a.m. | 1,261 | 26 | 77 | |||||
| 7 | 2013–-1 | 1,995 | 1,090 | 8:00 a.m. | 1,066 | – | 147 | – |
| 8 | 2013-1 | 525 | 596 | 8:00 p.m. | 852 | – | 24 | 220* |
| 12:00 a.m. | 572 | – | 16 | |||||
| 4:00 a.m. | 593 | – | 14 | |||||
| 8:00 a.m. | 650 | – | 14 | |||||
| 9 | 2014-2 | 810 | 255 | 8:00 a.m. | 510 | – | – | – |
| 10 | 2014-1 | 1,059 | 444 | 2:00 p.m. | 622 | 24 | – | 446* |
| 8:00 p.m. | 596 | 18 | – | |||||
| 1:00 a.m. | 670 | 24 | 56 | |||||
| 8:00 a.m. | 838 | 37 | 53 | |||||
| 11 | 2014-2 | 3,466 | 740 | 8:00 a.m. | 811 | 102 | – | 280* |
| 2:00 p.m. | 1,035 | 135 | – | |||||
| 8:00 p.m. | 657 | 33 | – | |||||
| 12:00 a.m. | 844 | 38 | 56 | |||||
| 12 | 2015-2 | 1,754 | 622 | 8:00 a.m. | 930 | – | 285 | – |
| 13 | 2015-2 | 1,065 | 558 | 8:00 a.m. | 752 | 18 | – | 81* |
| 2:00 p.m. | 868 | 21 | – | |||||
| 8:00 p.m. | 523 | 9 | – | |||||
| 12:00 a.m. | 642 | 14 | 60 | |||||
| 14 | 2016-1 | 571 | – | 9:00 a.m. | 135 | – | – | 12* |
| 2:00 p.m. | 450 | – | – | |||||
| 8:00 p.m. | 679 | – | – | |||||
| 12:00 a.m. | 216 | 5 | 27 | |||||
| 8:00 a.m. | 91 | – | 17 | |||||
| 15 | 2016-1 | 990 | 678 | 9:00 a.m. | 620 | – | – | 100* |
| 2:00 p.m. | 560 | 13 | – | |||||
| 8:00 p.m. | 459 | 7 | – | |||||
| 12:50 a.m. | 383 | 11 | 67 | |||||
| 8:00 a.m. | 452 | 8 | 82 | |||||
| 16 | 2018-1 | 1,654 | 660 | 12:00 p.m. | 760 | – | – | 637* |
| 4:00 p.m. | 450 | – | – | |||||
| 8:00 p.m. | 779 | – | 86 | |||||
| 12:00 a.m. | 704 | – | – | |||||
| 8:00 a.m. | 804 | – | 80 | |||||
| 17 | 2019-2 | – | 686 | 8:00 a.m. | 647 | – | 106 | 468* |
First column displays the patient number. Second column includes: year of diagnosis, 1: female, 2: male.
UFC, 24-h urinary free cortisol; ODST, overnight dexamethasone test; SeC, serum cortisol; SaC, salivary cortisol; 48 h DST, dexamethasone suppression test with *low-dose dexamethasone (0.5 mg) and **high-dose dexamethasone (2 mg).
Even so CD can easily be missed as the symptoms and signs often progress slowly during a long period of time. As the prevalence of obesity is increasing in western countries, it is of great importance to be aware of that the incidence of CD has been found to be up to 3% in patients with obesity and type 2 diabetes or resistant hypertension [9–12].
It is well known that although diagnostic tests are readily available, the definitive diagnosis of CD is always a challenge. Fifteen out of 17 patients in our study had biochemical results indicative of CD whereas 2 patients had a limited or contradictory biochemical analysis but in addition to typical Cushingoid features and a visible pituitary adenoma on imaging studies, histopathological examination confirmed ACTH secreting tumour in both of the patients. As IPSS is not available in Iceland, international co-operation is of great importance. All patients needing IPSS were sent to Sahlgrenska University Hospital in Gothenburg during this 10-year period (7 patients).
Two patients in our cohort developed thyroiditis after TPS, 1 patient 2 months after surgery and the other patient 6 months after surgery. Thyroid dysfunction has been described after transsphenoidal surgery speculating that a latent autoimmune process is suppressed by the endogenous hypercortisolism [13]. The paediatric case has previously been published as the first reported case of its kind in children [14]. It was noted that 2 male patients in our cohort had a prior diagnosis of Hodgkin’s lymphoma in early adulthood. This might merely be a coincidence, but endocrine dysfunction has been shown to be a late effect in cancer survivors although CD has not been reported as a late effect to our knowledge [15].
In summary, our study indicates that the annual incidence of CD might be substantially higher than previously reported in most studies or up to 5.2 cases per million per year. Even though the population in Iceland is relatively small compared to other reporting countries, all cases with CD are diagnosed and/or treated at the only university hospital in Iceland, making the annual incidence report very complete. The study emphasizes the importance of being alert for CD as the incidence appears to be higher than doctors have anticipated over the world and not to be forgotten in the increasing prevalence of obesity worldwide.
Statement of Ethics
The study was approved by the National Bioethics Committee (Vísindasiðanefnd, licence No. 02-V2-S1) and Landspitali’s Chief Medical Officer and executed in compliance with ethical standards (i.e., Declaration of Helsinki). The need for informed consent was waived by the National Bioethics Committee (licence No. 02-V2-S1) and Landspitali’s Chief Medical Officer, as no patient was contacted, all information was obtained from Landspitali’s electronic medical records and results presented without personally identifiable information.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was not supported by any sponsor or funder.
Author Contributions
All authors have read and approved submission of the manuscript. Þorgeir O. Harðarson and Anna Mjöll Matthíasdóttir have executed similar amount of work, gathering the data, working of results, and writing of the paper. They therefore should share the first name in the publication procedure. Steinunn Arnardóttir took part in gathering data, working on results, and writing of the paper as did Helga Ágústa Sigurjónsdóttir, the latter being in charge of the performance of the study and supervising the work throughout.
Funding Statement
This study was not supported by any sponsor or funder.
Data Availability Statement
All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.