Complications
This may occur following surgery. Pathological hypercortisolism can lead to suppression of the normal hypothalamic-pituitary-adrenal (HPA) axis. Following treatment, the normal function of the HPA axis often remains suppressed for several months. The resultant adrenal insufficiency necessitates treatment with glucocorticoid therapy until the HPA axis recovers normal function.
The major cause of mortality in patients with Cushing syndrome.[113] It is difficult to tell if the increase in cardiovascular mortality is due to the development of traditional risk factors such as hypertension, diabetes, and dyslipidaemia, or to hypercortisolism itself.[121] Risk factor modification and resolution of hypercortisolism are the keys to lowering cardiovascular mortality. Standard cardiovascular screening and treatment should be applied to patients with Cushing syndrome.
Adrenalectomy has a beneficial effect on cardiovascular risk factors in patients with subclinical Cushing syndrome overall and compared with conservative management.[110]
Occurs in 70% to 80% of patients.[122] Occurs equally in adrenocorticotrophic hormone-dependent and -independent Cushing syndrome. Generally mild to moderate but can be severe. Blood pressure usually normalises after successful therapy, but can persist secondary to vascular remodelling. No specific class of antihypertensive agent has been shown to have increased efficacy; standard agents for therapy of hypertension should be used.
Occurs in 20% to 60% of patients.[122] Glycaemic control can be very difficult in patients with hypercortisolism. No agent or combination of agents has been shown to be more effective in patients with Cushing syndrome than in other patients with diabetes. Insulin is often needed to adequately control blood sugars.
Alterations in haemostatic parameters and in vivo endothelial dysfunction lead to increased thrombotic events.[26][123]
Prophylactic anticoagulation should be considered for patients at risk for venous thromboembolism, including: history of embolism or abnormal coagulation testing; severe preoperative hypercortisolism; current use of oestrogen or oral contraceptives; poor mobility; extended preoperative or postoperative hospital stay; and high postoperative cortisol levels or cortisol over-replacement in patients with adrenal insufficiency.[26]
Premature osteoporosis and fracture are seen in around 50% of patients.[56] Excessive bone exposure to glucocorticoids causes decreased osteoblast activity, and also increases osteoclast activity. It may also interfere with calcium absorption in the gastrointestinal tract, further worsening bone disease. Patients should have periodic bone density assessments. Patients with persistent hypercortisolism and low or falling bone density should be treated with bisphosphonates.
Calcium renal stones occur in some patients.[23] The aetiology is related to altered calcium handling by the kidney in patients with cortisol excess. The most effective therapy is treatment of hypercortisolism. Therapies used for other patients with nephrolithiasis should also be employed.
Progression of a pituitary adenoma after bilateral adrenalectomy can result in intracranial mass effect from increased tumour size, and elevated adrenocorticotrophic hormone (ACTH) levels. The incidence of this complication varies depending on the exact definition used. Patients with Cushing's disease who undergo bilateral adrenalectomy should have plasma ACTH levels and pituitary MRI 6 to 12 months after surgery.
Therapy includes repeat surgery to debulk tumour, and radiotherapy.[126]
Transient postoperative adrenal insufficiency (defined as a morning serum cortisol of 55 nanomol/L [<2 micrograms/dL]) in patients treated with transsphenoidal surgery is an indicator of remission or cure. These patients generally have recovery of adrenal function within the first postoperative year. However, repeat pituitary surgery and occasional primary surgical therapy can result in permanent adrenal insufficiency.
Radiotherapy can cause adrenal insufficiency years after therapy, necessitating pituitary adrenal axis evaluation periodically after therapy.
Bilateral adrenalectomy also creates an absolute cortisol deficiency, and must be treated with replacement doses of hydrocortisone plus mineralocorticoid.
Long-term adrenal insufficiency secondary to pituitary adenomectomy occurs in 3% to 53% of patients.[67][124][125]
Steroidogenesis inhibitors can also sometimes cause adrenal insufficiency.
Therapy for Cushing's disease, either surgery or radiotherapy, can damage normal pituitary tissue. If hypopituitarism is the result of surgical therapy, deficits generally manifest immediately after surgery. Hypopituitarism after radiotherapy can occur many years after therapy. Individuals who have received radiotherapy should have periodic evaluation of pituitary function to monitor for development of recurrences.
Pituitary surgery may lead to deficiencies of hormones other than the adrenocorticotrophic hormone, requiring replacement with thyroid hormones, androgens or oestrogens, growth hormone, or desmopressin.[109]
Hyponatraemia is a known complication of pituitary surgery. Age, sex, tumour size, rate of decline of blood sodium, and Cushing syndrome are potential predictors of delayed symptomatic hyponatraemia.[127]
Occurs in between 3% and 48% of patients undergoing pituitary adenomectomy.[67][128][129][130][131] Pituitary surgery may lead to deficiencies of hormones other than the adrenocorticotrophic hormone, requiring replacement with thyroid hormones, androgens or oestrogens, growth hormone, or desmopressin.[109]
More than one quarter of patients who undergo surgery will develop vasopressin deficiency and rates are higher after the second surgery.[69][133][134]
Pituitary surgery may lead to deficiencies of hormones other than the adrenocorticotrophic hormone, requiring replacement with thyroid hormones, androgens or oestrogens, growth hormone, or desmopressin.[109]
Over 50% of patients with Cushing's disease treated with pasireotide develop hyperglycaemia that must be promptly managed.[92][97]
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