Adrenocorticotropic hormone-secreting phaeochromocytoma as a cause of treatment-resistant hypertension and recurrent pulmonary emboli.

We report an unusual case of a patient presenting with Cushing's syndrome caused by a phaeochromocytoma secreting adrenocorticotropic hormone (ACTH). The patient had a history of treatment-resistant hypertension, secondary amenorrhoea and tendency towards hypokalaemia. She had multiple signs of Cushing's syndrome, such as swelling, bruising, abdominal striae and proximal myopathy. Hypokalaemia is more common in patients with ectopic ACTH-secretion than other causes of Cushing's syndrome. Computed tomography, adrenal vein sampling and biochemistry could confirm an ACTH-secreting phaeochromocytoma. It is important to consider that hypersecretion of more than one hormone may exist in a unilateral adrenal adenoma. This patient also presented with recurrent pulmonary emboli, and there is an increased risk of venous thromboembolism in patients with ACTH-secreting phaeochromocytoma. Anticoagulation should be considered for as long as the disease is active. We demonstrate that unilateral adrenalectomy can be curative in patients with ACTH-secreting phaeochromocytoma.

Pituitary function before and after surgery for nonfunctioning pituitary adenomas-data from the Swedish Pituitary Register.

OBJECTIVE: Data on pre- and postoperative pituitary function in nonfunctioning pituitary adenomas (NFPA) are not consistent. We aimed to investigate pituitary function before and up to 5 years after transsphenoidal surgery with emphasis on the hypothalamic-pituitary-adrenal axis (HPA). DESIGN AND METHODS: Data from the Swedish Pituitary Register was used to analyze anterior pituitary function in 838 patients with NFPA diagnosed between 1991 and 2014. Patients who were reoperated or had received radiotherapy were excluded. RESULTS: Preoperative ACTH, TSH, LH/FSH, and GH deficiencies were reported in 31% (236/755), 39% (300/769), 51% (378/742), and 28% (170/604) of the patients, respectively. Preoperative median tumor volume was 5.0 (2.4-9.0) cm3. Among patients with preoperative, 1 year and 5 years postoperative data on the HPA axis (n = 428), 125 (29%) were ACTH-deficient preoperatively. One year postoperatively, 26% (32/125) of them had recovered ACTH function while 23% (70/303) patients had developed new ACTH deficiency. Thus, 1 year postoperatively, 163 (38%) patients were ACTH-deficient (P < .001 vs. preoperatively). No further increase was seen 5 years postoperatively (36%, P = .096). At 1 year postoperatively, recoveries in the TSH and LH/FSH axes were reported in 14% (33/241) and 15% (46/310), respectively, and new deficiencies in 22% (88/403) and 29% (83/288), respectively. CONCLUSIONS: Adrenocorticotrophic hormone deficiency increased significantly at 1 year postoperatively. Even though not significant, some patients recovered from or developed new deficiency between 1 and 5 years postoperatively. This pattern was seen in all axes. Our study emphasizes that continuous individual evaluations are needed during longer follow-up of patients operated for NFPA.

Long-term Follow-up of 84 Patients With Giant Prolactinomas-A Swedish Nationwide Study.

PURPOSE: To describe the clinical presentation and treatment outcomes in a nationwide cohort of patients with giant prolactinomas. METHODS: Register-based study of patients with giant prolactinomas [serum prolactin (PRL) > 1000 µg/L, tumor diameter ≥40 mm] identified in the Swedish Pituitary Register 1991-2018. RESULTS: Eighty-four patients [mean age 47 (SD ±16) years, 89% men] were included in the study. At diagnosis, the median PRL was 6305 µg/L (range 1450-253 000), the median tumor diameter was 47 mm (range 40-85), 84% of the patients had hypogonadotropic hypogonadism, and 71% visual field defects. All patients were treated with a dopamine agonist (DA) at some point. Twenty-three (27%) received 1 or more additional therapies, including surgery (n = 19), radiotherapy (n = 6), other medical treatments (n = 4), and chemotherapy (n = 2). Ki-67 was ≥10% in 4/14 tumors. At the last follow-up [median 9 years (interquartile range (IQR) 4-15)], the median PRL was 12 µg/L (IQR 4-126), and the median tumor diameter was 22 mm (IQR 3-40). Normalized PRL was achieved in 55%, significant tumor reduction in 69%, and combined response (normalized PRL and significant tumor reduction) in 43%. In the primary DA-treated patients (n = 79), the reduction in PRL or tumor size after the first year predicted the combined response at the last follow-up (P < .001 and P = .012, respectively). CONCLUSION: DAs effectively reduced PRL and tumor size, but approximately 1 patient out of 4 needed multimodal treatment. Our results suggest that the response to DA after 1 year is useful for identifying patients who need more careful monitoring and, in some cases, additional treatment.

Heterogeneity of beta-cell function in subjects with multiple islet autoantibodies in the TEDDY family prevention study - TEFA.

BACKGROUND: Individuals with multiple islet autoantibodies are at increased risk for clinical type 1 diabetes and may proceed gradually from stage to stage complicating the recruitment to secondary prevention studies. We evaluated multiple islet autoantibody positive subjects before randomisation for a clinical trial 1 month apart for beta-cell function, glucose metabolism and continuous glucose monitoring (CGM). We hypothesized that the number and type of islet autoantibodies in combination with different measures of glucose metabolism including fasting glucose, HbA1c, oral glucose tolerance test (OGTT), intra venous glucose tolerance test (IvGTT) and CGM allows for more precise staging of autoimmune type 1 diabetes than the number of islet autoantibodies alone. METHODS: Subjects (n = 57) at 2-50 years of age, positive for two or more islet autoantibodies were assessed by fasting plasma insulin, glucose, HbA1c as well as First Phase Insulin Response (FPIR) in IvGTT, followed 1 month later by OGTT, and 1 week of CGM (n = 24). RESULTS: Autoantibodies against GAD65 (GADA; n = 52), ZnT8 (ZnT8A; n = 40), IA-2 (IA-2A; n = 38) and insulin (IAA; n = 28) were present in 9 different combinations of 2-4 autoantibodies. Fasting glucose and HbA1c did not differ between the two visits. The estimate of the linear relationship between log2-transformed FPIR as the outcome and log2-transformed area under the OGTT glucose curve (AUC) as the predictor, adjusting for age and sex was - 1.88 (- 2.71, - 1.05) p = 3.49 × 10-5. The direction of the estimates for all glucose metabolism measures was positive except for FPIR, which was negative. FPIR was associated with higher blood glucose. Both the median and the spread of the CGM glucose data were significantly associated with higher glucose values based on OGTT, higher HbA1c, and lower FPIR. There was no association between glucose metabolism, autoantibody number and type except that there was an indication that the presence of at least one of ZnT8(Q/R/W) A was associated with a lower log2-transformed FPIR (- 0.80 (- 1.58, - 0.02), p = 0.046). CONCLUSIONS: The sole use of two or more islet autoantibodies as inclusion criterion for Stage 1 diabetes in prevention trials is unsatisfactory. Staging type 1 diabetes needs to take the heterogeneity in beta-cell function and glucose metabolism into account. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02605148 , November 16, 2015.

Natural history and surgical outcome of Rathke's cleft cysts-A study from the Swedish Pituitary Registry.

OBJECTIVE: Rathke's cleft cysts are benign, embryological remnants in the pituitary gland. The majority of them are small and asymptomatic but a few may become large, and cause mass effects, pituitary hormone deficiencies and visual impairment. Recommendations for the follow-up of Rathke's cleft cysts vary since data on the natural history are sparse. PATIENTS AND DESIGN: Data at diagnosis and at 1, 5 and 10 years for patients with a Rathke's cleft cyst (434 at diagnosis, 317 females) were retrieved from the Swedish Pituitary Registry. Cysts ≤3 mm in diameter were excluded from the study. MEASUREMENTS: Data included demographics, cyst size, pituitary function, visual defects and surgery. RESULTS: The mean age at diagnosis was 45 years. In patients with cysts <10 mm in diameter (n = 204) 2.9% had pituitary hormone deficiencies and 2% had visual field impairments. Cyst size did not progress during the 5 years. Cysts with a diameter of ≥10 mm that were not operated (n = 174) decreased in size over the years (p < .01). Pituitary hormone deficiencies and visual impairments were more frequent (18% and 5.7%, respectively) but were stable over time. Transphenoidal surgery was performed in 56 patients of whom 51 underwent surgery before the 1-year follow-up. The mean cyst diameter at diagnosis was 18 mm (range: 9─30 mm), 36% had pituitary hormone deficiency, 45% had visual field defects and 20% had impaired visual acuity. One year after surgery 60% had no cyst remnants, 50% had a pituitary deficiency, 26% had visual field defects and 12% had impaired visual acuity. No major changes were observed after 5 years. Twelve of the operated patients had a follow-up at 10 years, in eight the cyst remnants or recurrences increased in size over time (p < .05). CONCLUSIONS: Rathke's cleft cysts with a size less than 10 mm rarely grow and our results indicate that radiological follow-up can be restricted to 5 years. In contrast, progression of postoperative remnants or recurrent cysts is more likely and require long-term follow-up.

Beta cell function in participants with single or multiple islet autoantibodies at baseline in the TEDDY Family Prevention Study: TEFA.

Aim: The aim of the present study was to assess beta cell function based on an oral glucose tolerance test (OGTT) in participants with single islet autoantibody or an intravenous glucose tolerance test (IvGTT) in participants with multiple islet autoantibodies. Materials and methods: Healthy participants in Sweden and Finland, between 2 and 49.99 years of age previously identified as positive for a single (n = 30) autoantibody to either insulin, glutamic acid decarboxylase, islet antigen-2, zinc transporter 8 or islet cell antibodies or multiple autoantibodies (n = 46), were included. Participants positive for a single autoantibody underwent a 6-point OGTT while participants positive for multiple autoantibodies underwent an IvGTT. Glucose, insulin and C-peptide were measured from OGTT and IvGTT samples. Results: All participants positive for a single autoantibody had a normal glucose tolerance test with 120 minutes glucose below 7.70 mmol/L and HbA1c values within the normal range (<42 mmol/mol). Insulin responses to the glucose challenge on OGTT ranged between 13.0 and 143 mIU/L after 120 minutes with C-peptide values between 0.74 and 4.60 nmol/L. In Swedish participants, the first-phase insulin response (FPIR) on IvGTT was lower in those positive for three or more autoantibodies (n = 13; median 83.0 mIU/L; range 20.0-343) compared to those with two autoantibodies (n = 15; median 146 mIU/L; range 19.0-545; P = .0330). Conclusion: Participants positive for a single autoantibody appeared to have a normal beta cell function. Participants positive for three or more autoantibodies had a lower FPIR as compared to participants with two autoantibodies, supporting the view that their beta cell function had deteriorated.

Perioperative serum cortisol levels in ACTH sufficient and ACTH deficient patients during transsphenoidal surgery of pituitary adenoma.

PURPOSE: No previous study has analyzed serum cortisol levels during transsphenoidal endoscopic pituitary surgery in patients with and without hydrocortisone (HC) substitution. METHODS: A total of 15 patients undergoing surgery for a pituitary adenoma were studied. Those with normal ACTH function were either not given HC (n = 7) or received 50 mg intravenous HC at the start of surgery (n = 4). Patients with ACTH deficiency received intravenous HC of 100 mg in the morning before surgery (n = 4) with the additional 50 mg for an afternoon operation (n = 2). Propofol and remifentanil were used as anesthetics. Serum cortisol was measured at the start of and every 30 min during surgery. RESULTS: Among 7 patients with normal ACTH function without HC substitution, cortisol levels before surgery were 126-244 nmol/L, among the 4 patients undergoing surgery in the morning, whereas the 3 who underwent surgery in the afternoon had lower levels, 38-76 nmol/L. During nose/sinus surgery cortisol levels decreased to 79-139 and 24-54 nmol/L, respectively. At intrasellar manipulation a distinct rise was noted. Also, in the 4 ACTH sufficient patients receiving HC, cortisol levels decreased during nose/sinus surgery, but only with a slight increase during intrasellar surgery. In the 4 ACTH deficient patients cortisol peaked at 1914-2582 nmol/L. CONCLUSIONS: Patients with normal ACTH function without HC substitution had very low cortisol levels during the first part of surgery, likely suppressed by the anesthetics. After mechanical impact in the sella, a marked increase in cortisol was noted. Supraphysiological cortisol levels were achieved with our routine HC substitution, advising us to reduce the supplementation.

HLA-DQ genotypes in classic type 1 diabetes and in latent autoimmune diabetes of the adult.

In 1993-1996, islet autoantibodies, C-peptide, and HLA-DQ genotypes were evaluated in 345 insulin-treated diabetic patients of all ages from the Skaraborg Diabetes Registry 5-6 years after their diagnosis and in 216 control subjects from the Skaraborg County, Sweden, population. The aims of this study were to clarify the importance of age at diagnosis of diabetes for HLA-DQ associations in patients with classic type 1 diabetes and whether patients considered to have latent autoimmune diabetes of the adult differed in their human leukocyte antigen (HLA) associations. An abnormally low fasting C-peptide value was used as the definition of type 1 diabetes, found in 182 of 345 (53%) patients. No major associations between age at diagnosis and HLA susceptibility or protective genotypes were detected in type 1 diabetic patients. Among the 163 patients with preserved beta-cell function, the frequency of HLA protective genotypes was clearly decreased (5% vs. 42%) in the 46 of 163 with islet antibodies compared with the 117 of 163 antibody-negative patients. The authors conclude that there were no major effects of age at diagnosis on HLA-DQ associations in classic type 1 diabetic patients, whereas lack of HLA-DQ protective genotypes was a feature of patients with slow-progressing type 1 diabetes (latent autoimmune diabetes of the adult).

A 12-year prospective study of the relationship between islet antibodies and beta-cell function at and after the diagnosis in patients with adult-onset diabetes.

To clarify the relationships between islet antibodies (islet cell antibody [ICA], GAD antibody [GADA], and IA-2 antibody [IA-2A]) versus the progression of beta-cell dysfunction, we have followed a group of diabetic patients from their diagnosis at 21-73 years of age. Patients with ICA had high levels of GADA and/or IA-2A at diagnosis and a more severe beta-cell dysfunction 5 years after diagnosis than those with only GADA in low concentrations. The aim of the current 12-year follow-up study was to examine the further progression of beta-cell dysfunction in relation to islet antibodies at and after diagnosis. Among 107 patients, complete beta-cell failure 12 years after diagnosis was restricted to those with islet antibodies at diagnosis (16 of 21 [77%] with multiple antibodies and 4 of 5 [80%] with only GADA). In contrast, among antibody-negative patients, fasting P-C-peptide levels were unchanged. Most GADA-positive patients (22 of 27 [81%]) remained GADA positive after 12 years. Associated with decreasing fasting P-C-peptide levels (0.85 nmol/l [0.84] at diagnosis vs. 0.51 nmol/l [0.21] 12 years after diagnosis, P < 0.05), ICA developed after diagnosis in 6 of 105 originally antibody negative mostly overweight patients. In conclusion, multiple islet antibodies or GADA alone at diagnosis of diabetes predict future complete beta-cell failure. After diagnosis, GADA persisted in most patients, whereas ICA development in patients who were antibody negative at diagnosis indicated decreasing beta-cell function.