Understanding the Impacts of Cushing's Syndrome

Cushing syndrome SC is defined by a set of signs and symptoms that result from inappropriate prolonged exposure to circulating glucocorticoids. The most common cause is exposure to exogenous glucocorticoids. The incidence of endogenous CS may be underestimated since the disease is becoming milder.

Endogenous CS is more common in women than in men.

Cases whose cause depends on adrenocorticotrophic hormone (ACTH) represent around 80%. Of these, 80% are caused by a pituitary adenoma (called Cushing’s disease) and the rest, by the ectopic secretion of ACTH, mainly as a consequence of neuroendocrine tumors, particularly bronchial tumors.

Cushing’s disease is the cause of 90% of endogenous CS in women. ACTH-independent CS is caused by an adrenal adenoma in 60% of cases and by a carcinoma in 40%.

Adrenal causes exist but are very rare, mainly bilateral primary pigmented hypoplastic nodules (isolated or as part of the Carney complex), adrenal macronodular hyperplasia, ectopic actions of G protein-coupled receptors (e.g., gastric inhibitory peptide receptor ß-adrenergic), and McCunee-Albright syndrome. Somatic mutations in the catalytic subunit of protein kinase A, and in the USP8 deubiquitinase gene, cause about 40-50% of cases of adrenal and pituitary Cushing’s, respectively.

A recent meta-analysis found a duration of 34 months between the onset of symptoms and confirmation of the diagnosis. The signs that most reliably distinguish CS are: thin skin, easy bruising, and proximal myopathy. It is essential to exclude exogenous glucocorticoids as a cause of a “Cushingoid appearance.”

Which patients to study?

Before beginning investigations for CS, there must be a high index of clinical suspicion . In patients with unusual features for their age (e.g., osteoporosis and livid striae in young men; patients with multiple and progressive features, children with decreasing percentile height and weight gain, and patients with adrenal adenoma found incidentally on CT scans ( TC).

Diagnosing CS is a two-step process. It is essential to confirm the diagnosis before attempting to determine the cause. Intercurrent acute illnesses cause hypercortisolemia and false-positive results . For unknown reasons, some patients with CS exhibit cyclical cortisol secretion, which may fluctuate and remit spontaneously, sometimes over many years. This can cause considerable diagnostic difficulty, and periodic investigations may be necessary.

• Oral estrogens increase cortisol binding globulin and therefore a falsely elevated serum cortisol concentration occurs .
   
• Glucocorticoids should  be stopped for 6 weeks before investigation.

To establish the diagnosis, 3 tests are commonly used:

• Suppression test with low dose dexamethasone
• Nocturnal serum or nocturnal salivary cortisol
• Free cortisol in 24-hour urine.

At least 2 different concordant abnormal tests are needed to establish the diagnosis.

Low-dose dexamethasone suppression test : 2 tests are commonly used:

• Nocturnal suppression test with dexamethasone? 1 mg dexamethasone at 11:00 p.m. and measurement of serum cortisol at 9:00 a.m. the next day.
   
• 48-hour test?0.5 mg dexamethasone at 9:00 a.m., 3:00 p.m., 9:00 p.m., and 3:00 a.m., and measurement of serum cortisol at 9:00 a.m. at the beginning and end of the proof.

In healthy subjects, serum cortisol is 1.8 mcgr/dl) after either test. If patients are taking medications that increase the hepatic clearance of dexamethasone, including carbamazepine, phenytoin, phenobarbital, and rifampicin, both tests may give false-positive results.

5% of patients with Cushing’s disease show suppression of serum cortisol to <18 mcgr; Therefore, if the level of clinical suspicion is high, it is recommended to retest and resort to other tests.

Assessment of loss of circadian rhythm of salivary or serum cortisol : In CS, the normal circadian rhythm of cortisol secretion is lost. Nocturnal salivary cortisol is a useful and easily accessible screening test in the community. Liquid chromatography tandem mass spectrometry is recommended. Midnight serum cortisol concentration during sleep is also used for this purpose, but requires hospitalization, so it is recommended only in endocrine units and is not necessary in patients with a florid Cushing’s phenotype and other positive tests.

Free cortisol in 24-hour urine : at least 3 collections are required to avoid missing a mild disease. The amount excreted is reduced in renal failure.

After confirming CS, plasma ACTH is measured. To avoid falsely low results, samples should be centrifuged cold immediately after sampling, and flash frozen (-40 Cº) before storage for later study.

• Plasma ACTH <5 pg/ml indicates a primary adrenal cause of CS and the adrenal glands should be visualized by CT or magnetic resonance imaging (MRI).
• The. ACTH concentrations persistently >15 pg/ml can be reliably attributed to ACTH-dependent pathologies and require the following investigations.

ACTH-dependent Cushing’s syndrome : Nonpituitary ACTH-secreting neuroendocrine tumors (e.g., carcinoid tumors) can mimic many of the clinical features of Cushing’s (pituitary) disease, although patients with ectopic sources typically experience more severe disease. with a faster start. Rather than imaging, it is biochemical evaluation that best differentiates the pituitary origin of ACTH from a non-pituitary one, and it is strongly recommended that this be performed at a major referral center.

Plasma ACTH : Circulating plasma ACTH concentrations in Cushing’s disease and ectopic ACTH secretion overlap considerably and are not useful in discriminating between the two.

Plasma potassium : In Cushing’s disease, ectopic ACTH secretion is often associated with higher circulating cortisol concentrations. These concentrations exceed those of the enzyme 11ß-hydroxysteroid dehydrogenase type II, which allows cortisol to act as a mineralocorticoid in the kidney. Therefore, hypokalemia is more common in ectopic ACTH secretion, but is also present in 10% of patients with Cushing’s disease.

High-dose dexamethasone suppression test : 2 mg of dexamethasone is administered orally, strictly every 6 hours, and serum cortisol is measured at baseline and at 48 hours. Almost 80% of patients with Cushing’s disease show cortisol reduced to <50% of baseline concentration. However, this figure is lower than the pre-test probability of Cushing’s disease in women (90%). Therefore, this test is no longer recommended if it can be replaced by sampling through sinus access to the bilateral inferior petrosal sinus.

Corticotropin-releasing hormone (CRH) test : CRH stimulates the release of ACTH from the corticotrophs of the anterior pituitary. Patients with Cushing’s disease usually show an excessive increase in plasma cortisol when exogenous CRH is administered, whereas those with ectopic ACTH secretion usually do not.

Bilateral inferior petrosal sinus sampling : It is a highly specialized and invasive research method, but it is the most reliable test for the differentiation of pituitary and non-pituitary origin of ACTH. A basal central to peripheral ACTH gradient >2:1, or a CRH-stimulated gradient >3:1 is indicative of Cushing’s disease. However, it is not necessary if there is a clear pituitary macroadenoma.

Once ACTH-dependent CS is confirmed in a patient without an acute condition, images of the pituitary gland should be performed, in parallel with biochemical evaluations.

Pituitary : Most corticotroph adenomas are <1 cm in diameter and give a hypointense signal on MRI that does not improve with gadolinium. Using standard MRI protocols, 40% of corticotroph microadenomas are not visualized, while “incidentalomas” are found in 10% of the healthy population, highlighting the importance of biochemical evaluation.

Adrenal : CT provides the greatest spatial resolution for evaluation of adrenal anatomy.

Imaging in ectopic ACTH secretion : The most common sites of ectopic ACTH secretion are small cell lung cancers and bronchial carcinoid tumors, but tumors can arise in any tissue. High-definition multislice CT is requiredCarcinoid tumors can be visualized by radiolabeled octreotide scintigraphy.

> Surgery in Cushing’s syndrome

Transsphenoidal surgery : Selective removal of microadenomas by an experienced surgeon is the treatment of choice in most patients with Cushing’s disease. With this surgery, long-lasting remission is achieved, without other pituitary hormonal deficiencies in 50-60% of cases.

Adrenal surgery : in patients with isolated adrenal adenoma, the treatment of choice is laparoscopic unilateral adrenalectomy. The prognosis after removal of adrenocortical cortisol-secreting adenoma is good. In contrast, the prognosis is usually poor in patients with adrenocortical carcinoma. In ACTH-dependent CS of any cause, bilateral adrenalectomy may be necessary to control cortisol concentration.

Nelson syndrome (development of a locally aggressive pituitary tumor that secretes high concentrations of ACTH, causing pigmentation) is a major concern after bilateral adrenalectomy in patients with refractory Cushing’s disease. The tumor can be treated with further surgery and radiation therapy, but this rarely cures the disease.

Ectopic ACTH : Complete excision of an ACTH-secreting tumor generally results in durable remission.

> Other treatments

Preoperatively, cortisol can be reduced through medical therapy in cases of failed surgeries or if the patient is not a candidate for surgery. It is rarely a long-term solution and is mainly used as an adjuvant treatment alongside other modalities such as pituitary radiotherapy.

To inhibit the synthesis of serum cortisol (target 150-300 mmol/l, or to correct abnormally high urinary excretion of free cortisol), metyrapone is used , in doses escalated every 3-7 days until reaching 500-1,500 mg, 3- 4/day (maximum dose 6 g/day), and ketoconazole, increasing at intervals of 4-5 days, up to 200-400 mg, 3 times/day. For the absorption of ketoconazole, the presence of gastric acid is necessary, having been shown that proton pump inhibitors

reduce its absorption. Metyrapone causes an increase in androgenic corticosteroid precursors; Hirsutism is an adverse effect in women, which does not occur with ketoconazole. In the UK, mitotane is usually reserved for the treatment of adrenocortical carcinoma.

Pasireotide , a somatostatin analogue, reduces ACTH secretion and is effective in almost 25% of patients with Cushing’s disease, but hyperglycemia is a major adverse factor. Mifepristone (unlicensed in the UK), a glucocorticoid receptor antagonist, is also effective for treatment, but its use is very problematic as biochemical monitoring of the response is not possible .

Newer medications, such as osilodrostat and relacorilant , are still in development and may be used more frequently in the future.

Pituitary radiation therapy or gamma knife radiosurgery can be used to treat persistent hypercortisolemia after transsphenoidal surgery . The main adverse effect is progressive anterior pituitary deficiency; almost all patients. Ten years after treatment, almost all patients have growth hormone deficiency and gonadotropin deficiency. At 4 years after treatment, up to 80% of patients are in remission, with respect to circulating serum cortisol concentrations. Associated conditions such as hypertension and diabetes mellitus must also be treated.

Inadequately treated CS has a 5-fold higher mortality rate. This returns to normal with timely control of hypercortisolemia, although some cardiovascular risk persists. Depression often persists for years after healing, with a substantial impact on quality of life.