Symptoms and steroid dose adjustments following the Covid-19 vaccine in patients with adrenal insufficiency.

BACKGROUND: A proportion of patients with adrenal insufficiency (AI) require increases in their maintenance glucocorticoids following the Covid-19 vaccine as a result of vaccine-related symptoms or development of incipient or frank adrenal crisis. In a large cohort of AI patients, we aim to characterise symptoms, changes in glucocorticoid dosage, occurrence of adrenal crises and whether there are differences between the mRNA and adenovirus vector vaccines. PATIENTS AND METHODS: Patients with AI of any aetiology were invited to complete a short, structured questionnaire of their experience of the Covid-19 vaccination. RESULTS: 279 of the 290 patients enrolled to this study fully completed the questionnaires. 176, 100 and 3 received the Astra Zeneca (AZ), Pfizer-BioNTech (PB) and Moderna (MD) as initial vaccine respectively; and for the second vaccine, 170, 99 and 10 received AZ, PB and MD respectively. Moderate to severe symptoms occurred in 44.8 and 39.7% after the first and second vaccines respectively, were of early onset (6.0 h, IQR 2-12 &. 6.0 h, IQR 2-24 h) and short duration (24 h, IQR 12-72 h & 26 h, IQR 12-72 h). 34.4 and 29.7% increased their maintenance glucocorticoid dose. DISCUSSION: The Covid-19 vaccines appear well-tolerated in patients with AI, with similar frequency of symptoms to that reported in the background population. The AZ vaccine leads to slightly greater post-vaccination symptom burden and need to increase glucocorticoid dosage, but this does not translate to greater adverse outcomes.

Evaluation of cardiovascular risk factors in long-term survivors of adult- and childhood-onset brain tumours: a pilot study.

Background: Survivors of childhood brain tumours (SCBT) and teenage and young adult cancer survivors have an adverse cardiovascular risk profile, which translates into an increased vascular mortality. Data on cardiovascular risk profiles in SCBT are limited, and furthermore, there are no data in adult-onset (AO) brain tumours. Patients and: methods: Fasting lipids, glucose, insulin, 24-h blood pressure (BP), and body composition were measured in 36 brain tumour survivors (20 AO; 16 childhood-onset (CO)) and 36 age- and gender-matched controls. Results: Compared with controls, patients had elevated total cholesterol (5.3 ± 1.1 vs 4.6 ± 1.0 mmol/L, P = 0.007), LDL-C (3.1 ± 0.8 vs 2.7 ± 0.9 mmol/L, P = 0.011), insulin (13.4 ± 13.1 vs 7.6 ± 3.3 miu/L, P = 0.014), and increased insulin resistance (homeostatic model assessment for insulin resistance (HOMA-IR) 2.90 ± 2.84 vs 1.66 ± 0.73, P = 0.016). Patients showed adverse body composition, with increased total body fat mass (FM) (24.0 ± 12.2 vs 15.7 ± 6.6 kg, P < 0.001) and truncal FM (13.0 ± 6.7 vs 8.2 ± 3.7 kg, P < 0.001). After stratification by timing of onset, CO survivors showed significantly increased LDL-C, insulin, and HOMA-IR compared with controls. Body composition was characterized by the increased total body and truncal FM. Truncal fat mass was increased by 84.1% compared with controls. AO survivors showed similar adverse cardiovascular risk profiles, with increased total cholesterol and HOMA-IR. Truncal FM was increased by 41.0% compared with matched controls (P = 0.029). No difference in mean 24-h BP was noted between patients and controls irrespective of the timing of cancer diagnosis. Conclusion: The phenotype of both CO and AO brain tumour survivors is characterized by an adverse metabolic profile and body composition, putatively placing long-term survivors at increased risk of vascular morbidity and mortality.

Outcomes of 756 patients with differentiated thyroid cancer and excellent response to treatment: An evidence-based paradigm for long-term surveillance strategies.

BACKGROUND: The 2014 British Thyroid Association thyroid cancer guidelines recommend lifelong follow-up of all thyroid cancer patients. This is probably unnecessary, particularly for differentiated thyroid cancer (DTC) patients with an excellent response to treatment and places significant demand on health service resources. DESIGN: Single centre retrospective cohort analysis of patients diagnosed and treated at the Leeds Cancer Centre between 2001 and 2014. PATIENTS: A total of 756 patients were dynamically risk-stratified (DRS) as having 'excellent response to treatment' after total thyroidectomy and radioiodineremnant ablation (RRA) for DTC. RESULTS: Median follow-up was 11.2 (range: 6.5-18.5) years. Radiological recurrence occurred in 15/756 (2.0%) patients and was always preceded by a raised thyroglobulin or thyroglobulin antibody level. The vast majority of tumour recurrences (13/15, 85%) were identifiable within 5 years of diagnostic surgery. Patients classified as having high-risk disease as per American Thyroid Association (ATA) guidelines had an almost threefold higher recurrence rate (2/34 [5.9%] vs. 13/722 [1.8%]) than those with ATA low-risk or intermediate-risk disease. Tumour histology subtype was a significant contributing factor, with Hürthle cell cancer having a worse prognosis than papillary thyroid cancer (PTC) (5/68 [7.4%] vs. 9/582 [1.5%]; relative risk: 4.76 [95% confidence interval: 1.64-13.8]). CONCLUSIONS: The recurrence rate of DRS patients with excellent response to treatment is low. It is reasonable to consider discharge of ATA low-risk or intermediate-risk patients with PTC who remain disease-free after 5 years of secondary care follow-up. Lifelong follow-up, however, currently remains the standard for subgroups at greater risk.

Characterisation of the onset and severity of adrenal and thyroid dysfunction associated with CTLA4-related hypophysitis.

CONTEXT: The use of the CTLA4 inhibitor, ipilimumab, has proven efficacious in the treatment of melanoma, renal carcinoma and non-small cell lung cancer; however, it is associated with frequent immune-related adverse events (irAE). Ipilimumab-induced hypophysitis (IIH) is a well-recognised and not infrequent endocrine irAE. OBJECTIVE: To investigate the timing of onset and severity of adrenal and thyroid hormone dysfunction around the development of IIH in patients treated for melanoma. DESIGN: Aretrospective review of hormone levels in consecutive adult patients treated with ipilimumab (3 mg/kg) for advanced melanoma as monotherapy or in combination with a PD-1 inhibitor. RESULTS: Of 189 patients, 24 (13%; 13 males; 60.5 ± 12.2 years) presented with IIH at a median of 16.1 (range: 6.7-160) weeks after commencing treatment, occurring in 14 (58%) after the fourth infusion. At the presentation of IIH, corticotroph deficiency was characterised by an acute and severe decrease in cortisol levels to ≤83 nmol/L (≤3 µg/dL) in all patients, often only days after a previously recorded normal cortisol level. Free thyroxine (fT4) levels were observed to decline from 12 weeks prior to the onset of cortisol insufficiency, with the recovery of thyroid hormone levels by 12 weeks after the presentation of IIH. A median fall in fT4 level of 20% was observed at a median of 3 weeks (IQR: 1.5-6 weeks) prior to the diagnosis of IIH. CONCLUSION: IIH is characterised by an acute severe decline in cortisol levels to ≤83 nmol/L at presentation. A fall in fT4 can herald the development of ACTH deficiency and can be a valuable early indicator of IIH.

Interpretation of the endocrinology of hospital inpatients.

Blood tests to assess the endocrine system are commonly performed in patients admitted to hospital. This may be because an endocrinopathy is thought to be aetiological in the presenting disease or suspected as an incidental occurrence by the clinician. Many patients, in addition to the pathology leading to admission, frequently have one or more comorbidities, a change in nutritional status and polypharmacy. Added to this, presentation with acute illness is a major life stress. All of these are likely to impact on one or more endocrine axes, although often only transiently. Endocrine evaluation in the vast majority of cases can be safely deferred to the outpatient setting. This article considers the most common endocrine anomalies discovered in hospital, the confounders, and provides guidance on how to investigate these further.

The severity of obstructive sleep apnoea does not influence ambient IGF-I levels.

OBJECTIVE: Obstructive sleep apnoea (OSA) is reported to have effects on a number of hormone systems including the hypothalamo-pituitary axis. We aimed to determine the impact of OSA severity on insulin-like growth factor-I (IGF-I) levels. DESIGN AND METHODS: This is a prospective cohort study performed between November 2014 and May 2017. IGF-I was measured on serum samples, and data were collected on demographics, BMI and parameters of OSA. RESULTS: 611 participants were recruited (202 female, 53.5 ± 12.5 years; mean BMI 36.2 ± 8.0 kg/m2 ). 26.2% had mild OSA; 27.3%, moderate OSA; and 44.5%, severe OSA. 15.2% of IGF-I values were below the age-related reference range. Increasing BMI correlated with greater AHI (r = .28, p < .001), ODI (r = .30, p < .001), severity of OSA (r = .17, p < .001), duration with oxygen saturation (SaO2 ) <90% (r = .29, p = .001) and reduced median SaO2 levels (r = .19, p < .001). IGF-I levels correlated negatively with age (r = -.13, p = .001), BMI (r = -.16, p < .001), diabetes (r = -.108, p = .009), AHI (r = -0.10, p = .043) and severity of OSA (r = -.10, p = .013). No association of IGF-I was observed with ODI, median SaO2 levels or duration of SaO2  < 90%. Regression analyses were used to examine determinants of IGF-I, all of which contained the independent variables of age, gender and BMI. All models showed IGF-I to be predicted by age and BMI (p < .05); however, none of the parameters of OSA were significant within these models. CONCLUSION: Insulin-like growth factor-I levels in OSA are dependent on age and BMI; however, no additional effect of any OSA parameter was observed, supporting the hypothesis that OSA effects on IGF-I are indirect through concomitant body composition and metabolic parameters.

Management of persistent acromegaly following primary therapy: The current landscape in the UK.

Acromegaly is the clinical consequence of chronic exposure of the tissues to excess GH and IGF-I. It is almost exclusively the result of a GH-secreting pituitary adenoma. In addition to the somatic features, uncontrolled acromegaly is associated with a number of complications and excess mortality. Management is aimed at control of the tumour; normalization of GH and IGF-I secretion and relief of symptoms. Initial management of GH-secreting pituitary adenoma is widely accepted as endonasal trans-sphenoidal surgery, with second-line therapy where disease is uncontrolled in most cases being somatostatin analogue therapy. With the combination of surgery and somatostatin analogue therapy, control is achieved in around 75% of patients; however, this leaves a significant proportion of patients requiring multimodality therapy to achieve remission. Within the UK, the health system has finite resources, and decisions for management require consideration of efficacy and cost-effectiveness. To add to the complexity, subtle differences exist in availability of high-cost medications used in the treatment of patients with acromegaly across the devolved nations of the UK. In this article, we discuss options for the management of persistent acromegaly following initial surgery and somatostatin analogue therapy, and explore earlier use of dopaminergics and conservative management.

Current Management and Outcome of Pregnancies in Women With Adrenal Insufficiency: Experience from a Multicenter Survey.

CONTEXT: Appropriate management of adrenal insufficiency (AI) in pregnancy can be challenging due to the rarity of the disease and lack of evidence-based recommendations to guide glucocorticoid and mineralocorticoid dosage adjustment. OBJECTIVE: Multicenter survey on current clinical approaches in managing AI during pregnancy. DESIGN: Retrospective anonymized data collection from 19 international centers from 2013 to 2019. SETTING AND PATIENTS: 128 pregnancies in 113 women with different causes of AI: Addison disease (44%), secondary AI (25%), congenital adrenal hyperplasia (25%), and acquired AI due to bilateral adrenalectomy (6%). RESULTS: Hydrocortisone (HC) was the most commonly used glucocorticoid in 83% (97/117) of pregnancies. Glucocorticoid dosage was increased at any time during pregnancy in 73/128 (57%) of cases. In these cases, the difference in the daily dose of HC equivalent between baseline and the third trimester was 8.6 ± 5.4 (range 1-30) mg. Fludrocortisone dosage was increased in fewer cases (7/54 during the first trimester, 9/64 during the second trimester, and 9/62 cases during the third trimester). Overall, an adrenal crisis was reported in 9/128 (7%) pregnancies. Cesarean section was the most frequent mode of delivery at 58% (69/118). Fetal complications were reported in 3/120 (3%) and minor maternal complications in 15/120 (13%) pregnancies without fatal outcomes. CONCLUSIONS: This survey confirms good maternal and fetal outcome in women with AI managed in specialized endocrine centers. An emphasis on careful endocrine follow-up and repeated patient education is likely to have reduced the risk of adrenal crisis and resulted in positive outcomes.

Prothrombotic fibrin network characteristics in patients with acromegaly: a novel mechanism for vascular complications.

OBJECTIVE: There remains increased cardiovascular mortality in patients with acromegaly. This study aims to evaluate whether GH/IGF-1 excess increases vascular disease by adversely affecting fibrin network characteristics. DESIGN: Cross-sectional study in 40 patients with acromegaly (21 males, age 53 ± 13 years) and 40 age/gender-matched controls. METHODS: Clot structure was analysed using a validated turbidimetric assay and fibrin networks were visualised by laser scanning confocal microscopy (LSCM). Metabolic profile parameters, body composition, plasma fibrinogen and PAI-1 were also assessed. RESULTS: Twenty-two patients had active acromegaly and 18 were in remission. There was no difference in qualitative patient characteristics between the two groups. Both groups had less favourable body composition and cardiovascular risk profile compared with controls. Despite no difference in clot formation and lysis parameters between the two patient groups, active disease patients had higher fibrinogen and clot maximum absorbance compared with controls, after adjusting for BMI (3.8 ± 0.2 vs 2.6 ± 0.2 mg/mL, P < 0.001; and 0.39 ± 0.02 vs 0.33 ± 0.01 arbitrary units, P = 0.03, respectively). Patients in remission had higher fibrinogen compared with controls following adjustment for BMI (3.3 ± 0.2 vs 2.6 ± 0.2 mg/mL, P = 0.02) but not clot maximum absorbance (0.35 ± 0.03 vs 0.33 ± 0.02 arbitrary units, P = 0.6). LSCM showed increased fibrin network density only in active disease patients, consistent with turbidimetric analysis. In addition to active disease, BMI, fat mass and skinfold thickness were associated with higher clot density and longer lysis time. CONCLUSIONS: Patients with active acromegaly have more compact clots, thus conferring increased thrombosis risk. Prothrombotic fibrin networks may represent one mechanism for enhanced vascular risk in active acromegaly.

Outcomes of Patients with Nelson's Syndrome after Primary Treatment: A Multicenter Study from 13 UK Pituitary Centers.

CONTEXT: Long-term outcomes of patients with Nelson's syndrome (NS) have been poorly explored, especially in the modern era. OBJECTIVE: To elucidate tumor control rates, effectiveness of various treatments, and markers of prognostic relevance in patients with NS. PATIENTS, DESIGN, AND SETTING: Retrospective cohort study of 68 patients from 13 UK pituitary centers with median imaging follow-up of 13 years (range 1-45) since NS diagnosis. RESULTS: Management of Cushing's disease (CD) prior to NS diagnosis included surgery+adrenalectomy (n = 30; eight patients had 2 and one had 3 pituitary operations), surgery+radiotherapy+adrenalectomy (n = 17; two received >1 courses of irradiation, two had ≥2 pituitary surgeries), radiotherapy+adrenalectomy (n = 2), and adrenalectomy (n = 19). Primary management of NS mainly included surgery, radiotherapy, surgery+radiotherapy, and observation; 10-year tumor progression-free survival was 62% (surgery 80%, radiotherapy 52%, surgery+radiotherapy 81%, observation 51%). Sex, age at CD or NS diagnosis, size of adenoma (micro-/macroadenoma) at CD diagnosis, presence of pituitary tumor on imaging prior adrenalectomy, and mode of NS primary management were not predictors of tumor progression. Mode of management of CD before NS diagnosis was a significant factor predicting progression, with the group treated by surgery+radiotherapy+adrenalectomy for their CD showing the highest risk (hazard ratio 4.6; 95% confidence interval, 1.6-13.5). During follow-up, 3% of patients had malignant transformation with spinal metastases and 4% died of aggressively enlarging tumor. CONCLUSIONS: At 10 years follow-up, 38% of the patients diagnosed with NS showed progression of their corticotroph tumor. Complexity of treatments for the CD prior to NS diagnosis, possibly reflecting corticotroph adenoma aggressiveness, predicts long-term tumor prognosis.