Glucocorticoid Therapy and Cushing Syndrome Follow-up
- Author: George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London); Chief Editor: Stephen Kemp, MD, PhD more...
Further Outpatient Care
Regular follow-up care is required for patients with Cushing syndrome (CS) who are receiving adrenal steroid replacement. Obtain a history of the number of illnesses, frequency with which stress doses are administered, and symptoms of adrenal insufficiency at 3-month assessments. Measure height (growth velocity should normalize unless another pathology is present), weight, and blood pressure and look for signs of overtreatment. Encourage patients to adhere to a diet that is rich in calcium (at least 1-1.5 g/d during teenage years) and vitamin D. Patients should also participate in regular exercise to improve muscle tone, to lose weight, and to strengthen bones.
Perform Cortrosyn stimulation testing at 6-month intervals to determine when HPA axis recovery occurs. Once a 30-minute cortisol exceeds 18 mcg/dL, hydrocortisone can be weaned and stopped.
Patients who have had bilateral adrenalectomy require similar follow-up care, with the exception of the Cortrosyn testing. Plasma renin activity (PRA) should be measured to ensure adequacy of Florinef (fludrocortisone acetate) replacement. These patients may also require saline tablets in warm humid weather. If Florinef requirements appear excessive, glucocorticoid doses should be reviewed because high requirements may occur with inadequate glucocorticoid replacement.
Patients with ectopic corticotropin (ACTH) production should be seen every 3 months to ensure that they have no signs of toxicity from their ketoconazole (including checking liver function tests) or other steroid synthesis inhibitor. Patients should undergo reassessment at 6-month intervals to look for the origin of the tumor.
Inpatient & Outpatient Medications
In patients with endogenous Cushing syndrome, the same medications are used in inpatient and outpatient care, with the exception of etomidate, which is intravenously administered in very sick inpatients.
Transfer
Age of transfer to adult care varies between institutions, ranging from 16-21 years. Patients who have had adrenalectomy require lifelong care by an endocrinologist. Patients who have achieved full height can switch to a longer-acting steroid, such as dexamethasone, which has the advantage of only 1 daily dose. Fludrocortisone dosing must also be continued.
Deterrence/Prevention
Prevention of complications related to long-term glucocorticoid treatment requires constant attention to ensure that the drug being used is appropriate for the condition, that systemic absorption of glucocorticoid is minimized, that the duration of treatment is as short as possible, and that the dose is the lowest required to control disease activity.
When glucocorticoid treatment cannot be stopped, ensuring that intake of vitamin D and calcium is adequate and that a regular exercise routine is maintained is essential. Actively screen for potential complications to ensure that prompt treatment is instituted as needed.
Complications
Complications of glucocorticoid excess are summarized in Table 2.
Complications may arise from the invasive testing that some patients with Cushing syndrome require. Adrenal vein sampling can be associated with hemorrhage into the adrenal gland, which, if it occurs in the unaffected side, may render the patient permanently adrenally insufficient, following excision of their adenoma. Inferior petrosal sinus sampling can rarely cause bleeding or thrombosis of petrosal sinuses with neurologic sequelae. Therefore, reserve these procedures for occasions when findings from prior investigations are either contradictory or inconclusive.
Surgical management may be associated with the following complications:
Pituitary adenoma
One of the most common complications is invasion of the walls of the cavernous sinuses or other surgically inaccessible places, which may occur with failure of surgical cure.
Complications of transsphenoidal surgery include bleeding due to injury to the carotid arteries, paresis, fracture of the orbit with optic nerve entrapment, or trapping of orbital muscles. Hypopituitarism, infection, and damage to the optic nerves or their blood supply may also occur. Frequency of these complications depends on the extent of the tumor and the skill of the surgeon. Diabetes insipidus (DI) occurs transiently in approximately 25% of cases and is more common with repeat surgery and with tumors near the posterior lobe. In about 25% of cases, DI is permanent. Again, this tends to occur with large tumors and repeat surgeries.
Less frequently, transiently excessive secretion of vasopressin may occur (syndrome of inappropriate secretion of antidiuretic hormone [SIADH]), which requires careful management of fluid intake. Nelson syndrome used to occur in 10-30% of patients with incurable pituitary adenoma treated with adrenalectomy. With advances in radiotherapy techniques and surgical techniques, this condition is likely to be avoided.
Surgical approach
Morbidity associated with adrenal surgery is reduced considerably if an anterior abdominal approach is avoided, unless carcinoma is suspected and staging of the liver and lymph nodes must be performed. Where possible, employ a laparoscopic approach. Risk of bleeding is always present and may require converting to open procedures in a percentage of cases.
Prognosis
Hypothalamic-pituitary-adrenal (HPA) axis recovery
More than 90-95% of patients have recovery of their HPA axis by 12 months after stopping treatment, with more than 50% of the remainder recovering in the following 6-12 months. Permanent adrenal insufficiency has been described, although it is rare. Early recognition and prompt treatment of the early signs of adrenal insufficiency is essential because this may be life threatening if not managed appropriately.
Growth
Growth velocity usually normalizes and weight loss occurs in children once pharmacologic doses of glucocorticoids have been reduced to physiologic levels. However, catch-up growth is frequently disappointing, with a tendency not to achieve predicted final height.
Bone density
Patients with significant osteoporosis experience some recovery in bone density, provided they have adequate calcium and vitamin D replacement and regular exercise. Bisphosphonate treatment may be needed in severe cases. Residual deficits in bone density are more likely if treatment was prolonged and occurred at a time of peak bone mass accrual. The role of prophylactic treatment with bisphosphonates is still being studied.
Metabolic disorders
Diabetes and insulin resistance resolve with cessation of therapy, although patients who become frankly diabetic when on glucocorticoids are likely to have significant preexisting insulin resistance and are at risk of developing type 2 diabetes in later life. Dyslipidemia should also improve as insulin resistance resolves, although this also depends upon premorbid lipid status.
Cushing disease
With transsphenoidal pituitary surgery, the cure rate for uncomplicated cases is approximately 95% and the recurrence rate is about 5%. If evidence of cavernous sinus invasion is noted or if repeat surgery is required, the cure rate falls significantly and the complication rate also rises.
Adrenal neoplasms
For nonmalignant adrenal neoplasms, the cure rate remains excellent. For malignant tumors, surgery offers the best chance of cure or prolongation of survival, with excision of isolated metastases in the lung or lymph nodes being primary treatment. Results of chemotherapy and radiation therapy have been disappointing, and, although disease control has been achieved, cure with these methods is uncommon so they have a more palliative role.
Patient Education
Educate patients and parents to recognize situations where an increase in glucocorticoid dosage is required. Unfortunately, the medical profession often also needs education on this issue because physicians sometimes do not appreciate the urgency of treatment in the patient who is developing signs of adrenal insufficiency.
Ensure that parents and patients understand the importance of proper technique for administering their glucocorticoid treatments (eg, the need for a spacer device with asthma, the importance of using potent steroid creams sparingly).
Children with Cushing syndrome are commonly diligent workers. Warn the family that their school performance and concentration may suffer after successful treatment and that the child may also develop psychiatric symptoms, including anxiety and depression, possibly requiring psychiatric treatment.[10]
Siblings in the same household should not receive attenuated live-virus vaccines because of the risk of causing infection in the child who is affected by Cushing syndrome.
All patients receiving glucocorticoid therapy for longer than 1-2 months should be provided a medic-alert bracelet identifying them as dependent on steroids.
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| Type | Drug | Dose | Relative Glucocorticoid Potency | Relative Mineralocorticoid Potency | Plasma Half-Life (mg) | Biologic Half-Life (h) |
| Short-acting | Cortisol | 20 | 1.0 | 2 | 90 | 8-12 |
| Hydrocortisone‡ | 25 | 0.8 | 2 | 80-118 | 8-12 | |
| Intermediate-acting | Prednisone | 5 | 4 | 1 | 60 | 18-36 |
| Prednisolone | 5 | 4 | 1 | 115-200 | 18-36 | |
| Triamcinolone | 4 | 5 | 0 | 30 | 18-36 | |
| Methylprednisolone | 4 | 5 | 0 | 180 | 18-36 | |
| Long-acting | Dexamethasone | 0.5 | 25-50 | 0 | 200 | 36-54 |
| Betamethasone | 0.6 | 25-50 | 0 | 300 | 36-54 | |
| Mineralocorticoid | Aldosterone | 0.3 | 0 | 300 | 15-20 | 8-12 |
| Fludrocortisone | 2 | 15 | 150 | 200 | 18-36 | |
| Desoxycorticosterone acetate | 0 | 0 | 20 | 70 | … |
| System | Effects |
| Endocrine and metabolic | Suppression of hypothalamic-pituitary-adrenal (HPA) axis (adrenal suppression) Growth failure in children Hyperinsulinemia/insulin resistance Abnormal glucose tolerance test result/diabetes mellitus |
| GI | Gastric irritation, peptic ulcer Acute pancreatitis (rare, secondary to insulin resistance and hypertriglyceridemia) Fatty infiltration of liver (hepatomegaly, rare) |
| Hemopoietic | Leukocytosis Neutrophilia - Increased recruitment from bone marrow, demargination, and decreased migration from blood vessels Lymphopenia - Migration from blood vessels to lymphoid tissue Eosinopenia Monocytopenia |
| Immune | Suppression of delayed (type IV) hypersensitivity (important with Mantoux testing for tuberculosis) Inhibition of leukocyte and tissue macrophage migration Inhibition of cytokine secretion/action Suppression of the primary antigen response |
| Musculoskeletal | Osteoporosis, spontaneous fractures Avascular necrosis of femoral and humoral heads and other bones Myopathy (particularly of the proximal muscles [eg, unable to comb hair or climb stairs]) |
| Ophthalmic | Posterior subcapsular cataracts (more common in children) Elevated intraocular pressure/glaucoma |
| CNS (neuropsychiatric disorders) | Sleep disturbances, insomnia (particularly with long-acting glucocorticoids and nocturnal dosing) Euphoria, depression, mania, psychosis (more commonly observed in adults) Obsessive behaviors (children with hypercortisolism are often more studious) Pseudotumor cerebri (benign increase of intracranial pressure) |
| Cardiovascular[4] | Hypertension[5] Congestive heart failure in predisposed patients |
| Other cushingoid features | Moon facies (broad cheeks with temporal muscle wasting) facial plethora Generalized and truncal obesity (more marked in adults) Supraclavicular fat collection Posterior cervical fat deposition (dorsocervical hump) Glucocorticoid-induced acne Thin and fragile skin, violaceous striae (more common in adults) Impotence, menstrual irregularity Decreased thyroid-stimulating hormone and triiodothyronine Hypokalemia (with very high cortisol levels or in the presence of potassium-wasting diuretics), metabolic alkalosis |
| Cause | Features | Genetics |
| MEN1 | Associated with pancreatic tumors producing gastrin, insulin, and/or ACTH that may metastasize to the liver; multigland hyperparathyroidism, pituitary tumors, lipomas, and angiofibromas | 11p13 (MIM 131100) |
| McCune-Albright syndrome | Mosaic constitutively activating postzygotic GS alpha mutation that can lead to polyostotic fibrous dysplasia, pigmented skin lesions, gonadotropin-releasing hormone–independent precocious puberty, hyperthyroidism, renal phosphate wasting, and other endocrine and nonendocrine manifestations | 20q13.2 (MIM 174800) |
| Beckwith-Wiedemann syndrome (Risk of adrenal malignancy) | Macroglossia; visceromegaly; hyperinsulinemia; omphalocele; and risk of adrenal carcinoma, nephroblastoma, hepatoblastoma, rhabdomyosarcoma, and thoracic neuroblastoma requiring biannual sonograms | 11p13 (MIM 130650) |
| Hemihypertrophy (Risk of adrenal malignancy) | Adrenal tumors in association unilateral tissue overgrowth on ipsilateral or contralateral side Compare upper and lower limbs and look for facial asymmetry | (MIM 235000)[6] |
| Li-Fraumeni syndrome (Risk of adrenal malignancy) | Adrenal neoplasm Personal or family history of multiple tumors (eg, lung, breast, nasopharynx, CNS, melanoma, pancreas, gonads, prostate) | 17p13.1 -TP53 gene 22q12.1 (MIM 191170; 151623) |
| Carney complex | Primary pigmented nodular adrenal disease (PPNAD); lentigines; myxomas of the heart, skin, and breast; melanotic schwannoma; growth hormone– and prolactin-secreting pituitary adenomas; Sertoli cell tumors of the testis; multiple small hypoechoic thyroid lesions; thyroid carcinoma | 2p16 and 17q22-24 (MIM 605244; 160980) |
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