Julio Libman and Astrid M. Libman

Cushing's syndrome is the set of metabolic and clinical manifestations resulting from excess endogenous or exogenous glucocorticoids.

Pathophysiology

In humans, the main glucocorticoid is cortisol or hydrocortisone, produced by the fascicular and reticular areas of the adrenal cortex, through a series of stages from cholesterol. Each of these steps is regulated by enzymes (see Fig. 64-1). Cortisol synthesis is stimulated by ACTH, a 39 amino acid polypeptide produced by the anterior pituitary in response to the hypothalamic ACTH-releasing hormone. In ACTH secretion, and consequently in cortisol, a circadian rhythm is observed, producing a peak in the morning, followed by an irregular decrease during the day until reaching minimum values ​​at bedtime. The other determining factor of ACTH secretion is constituted by plasma cortisol concentrations,

A normal adult produces between 20 and 30 mg of cortisol daily. Once secreted, 90% of cortisol is reversibly bound to a specific  globulin, trascortin. This fraction bound to proteins is biologically inactive, constituting a kind of circulating reservoir, while the free fraction is the one that exerts metabolic actions. The most abundant metabolic derivative of cortisol is tetrahydrocortisol, conjugated in the liver with glucuronic acid and subsequently excreted in the urine.

Once hydrolyzed, the metabolites are determined as 17-hydroxycorticosteroids, representing the most important urinary derivatives of cortisol. A fraction of the cortisol is excreted as urinary free cortisol.

Glucocorticoids have broad physiological actions. In one way or another, practically all cells in the body are affected by cortisol, which regulates the levels of enzyme activity in many tissues. It is characterized by important effects on the metabolism of carbohydrates, proteins, fats, minerals and water. The clinical manifestations of hypercortisolism are proteiform, and their common pathogenetic mechanism is the catabolic action on proteins, the hyperglycemic effect due to increased hepatic gluconeogenesis and peripheral resistance to the action of insulin, the effect of sodium retention and excretion of potassium at the kidney level, and the immunosuppressive action of glucocorticoids. From a laboratory point of view,

There are four root causes of Cushing syndrome.

Cushing's disease. It is characterized by excessive production of ACTH by the anterohypophysis, which produces a bilateral hyperplasia of the adrenal cortex. It constitutes 70% of the cases of spontaneous Cushing syndrome. In 90% of patients, a pituitary microadenoma can be found, defined as an adenoma less than 10 mm in diameter. Given its small size, it is not possible to expect, from a clinical point of view, the existence of the so-called pituitary tumor syndrome, consisting of headaches and visual field alterations.

Adrenal adenoma and carcinoma. They produce cortisol autonomously and independently of the pituitary ACTH, which they inhibit, with the consequent atrophy of the rest of the adrenal parenchyma. The evolution of both injuries is, of course, absolutely different. They constitute 15% of spontaneous Cushing cases. A rare form of Cushing's syndrome is bilateral nodular hyperplasia, which may present with varying degrees of functional autonomy or dependence on pituitary ACTH.

Ectopic ACTH production syndrome. Due to extra-pituitary tumors, it leads to bilateral adrenal hyperplasia with hypercortisolism and inhibition of pituitary ACTH. Although multiple tumors capable of producing ACTH have been described, the most common are bronchial adenocarcinomas of oat cells, pancreatic, thymus, and medullary thyroid. Some tumors, such as bronchial carcinoid, can produce a peptide similar or identical to hypothalamic ACTH-releasing hormone, which stimulates pituitary production of this hormone. The clinical picture of this variety of Cushing's syndrome, which constitutes about 15% of the spontaneous Cushings seen clinically, differs, as will be seen later, from the classic syndrome.

Iatrogenic Cushing syndrome. It is due to the excessive use, in dose and time, of corticosteroids or ACTH for the treatment of various non-endocrine diseases. In these cases, and even when the patients usually present a florid Cushing clinical picture, there is an inhibition of ACTH secretion induced by exogenous corticosteroids, with the consequent inhibition and adrenal atrophy. This fact is of enormous clinical importance since patients are carriers of latent adrenal insufficiency, which implies the need to discontinue exogenous corticosteroids slowly and gradually; They should be considered as high-risk patients under various stressful circumstances for a period of 9 to 12 months, a period that takes to recover the functional integrity of the hypothalamic-pituitary-adrenal axis. This constitutes,

Signs and symptoms

The patient with Cushing's syndrome may present with one or more of the manifestations described below.

Predominant centripetal obesity is characteristic at the level of the face and trunk, with accumulations of adipose tissue in the supraclavicular fossae and in the cervicodorsal region, constituting the so-called buffalo hump. This particular fat distribution is attributable to the predominance in the trunk of the lipogenic action of insulin over the lipolytic action of glucocorticoids, in contrast to what occurs in the extremities, whose striking thinness also contributes to generalized muscular atrophy. The facies is round with fatty accumulations above and below the zygomatic arches; the lips, thin, have a characteristic concavity downwards, constituting the so-called fish mouth.

The skin is thin, with visible wide wine-red streaks on the trunk and proximal extremities, produced by the rupture of the elastic fibers of the dermis. It has a ruddy tint, determined by the greater thinness that allows visualization of the underlying capillary network, and the concomitant polyglobulia, due to the stimulating action that corticosteroids exert on erythropoiesis. The increased capillary fragility makes subcutaneous bruising easily. Healing of skin wounds is slow, with frequent infections, determined by the fact that these patients are immunosuppressed.

Muscle atrophy contributes to lean limbs and a prominent abdomen with flattening of the gluteal area. Alterations in protein and carbohydrate metabolism, as well as electrolytes, manifested by a K deficiency, are factors that contribute to asthenia and functional impotence, which can be manifested by the inability to stand up while squatting .

The catabolic action on proteins has its maximum expression in the lack of growth of children with Cushing's syndrome, to which the inhibition of the synthesis of somatomedins also contributes as an expression of the same mechanism. The observation of a tall stature in an obese child practically excludes the existence of Cushing's syndrome.

Diffuse bone pain and pathological fractures occur with some frequency, and in this sense dorsolumbar pain due to vertebral compression fractures may be one of the initial symptoms. Bone alterations are attributable to a combined picture of osteoporosis and osteomalacia, due to inhibition of osteoblastic activity, catabolic action on the proteins of the bone matrix, inhibition of intestinal calcium absorption and increased renal excretion. The negative balance of calcium is due to alterations in the metabolism of vitamin D, since corticosteroids inhibit the 1-hydroxylation of this vitamin at the renal level with the consequent decrease in its active metabolite, 1,25 - (OH) 2 cholecalciferol. .

Hypertension is a common finding, probably as a direct consequence of glucocorticoid excess. Occasionally, patients may present with hypokalemia and edema, perhaps due to the concomitant excessive production of mineralocorticoids.

The presence, in female patients, of hirsutism, acne and amenorrhea or oligohypomenorrhea, a manifestation of excessive androgen production, is commonly observed.

The alteration in carbohydrate metabolism can be manifested by clinical diabetes or an altered glucose tolerance curve. Conduct disorders sometimes configure a manifest psychosis.

Patients with the syndrome of ectopic ACTH production present different manifestations. Due to the severity of the underlying disease, they show marked weight loss, asthenia disproportionate to the evolutionary stage of the neoplasia, and hyperpigmentation. Asthenia is due in part to marked hypokalemia, determined by excessive urinary loss of K, induced by excess corticosteroids. Pigmentation is caused by high production of ACTH and related peptides.

Study methodology

The investigation of a patient who presents all or some of the clinical manifestations that suggest the existence of Cushing's syndrome, once the administration of exogenous corticosteroids has been ruled out by the questioning, goes through two stages: first, the diagnosis must be established. existence of hypercorticalism; Once this has been confirmed, the second step is to determine the cause of the syndrome.

Evidence for Cushing's syndrome

Short suppression test with dexamethasone. Dexamethasone 1 mg is administered orally at 23 hours. Under normal conditions, plasma cortisol at 8 o'clock the next day is below 1.8 ug%.

Urinary free cortisol. It is the best urinary parameter for the diagnosis of Cushing's syndrome. The upper limit of normality is 100 ug in 24 hours, depending on the procedure used for its quantification.

Urinary 17-hydroxycorticoids. They basically represent the metabolic product of glucocorticoids. Normal values ​​range from 2.5 to 10 mg in 24 hours, or less than 7 mg per gram of creatinine excreted.

Plasma cortisol (circadian rhythm). Normal values ​​are around 20 ug% in the morning and 10 ug% in the afternoon.

Low-dose dexamethasone suppression test. 24-hour urine is collected for the determination of 17-hydroxycorticoids, free cortisol, and creatinine before and on the second day after the administration of 0.5 mg of dexamethasone every 6 hours. Normally 17-hydroxycorticoids decrease to less than 2 mg per day and urinary free cortisol to less than 10 ug in 24 hours.

Tests to determine the etiology of Cushing's syndrome

High-dose dexamethasone suppression test.This test is very useful to differentiate hypothalamic-pituitary Cushing (where a certain degree of functionality of the negative feedback mechanism is maintained), from Cushing caused by adrenal tumors (where ACTH is already suppressed) or by ectopic ACTH production . The protocol to be followed is similar to that of the suppression tests with low doses of dexamethasone, administering 2 mg instead of 0.5 mg of dexamethasone every 6 hours. Suppression of urinary 17-hydroxycorticoids and free cortisol by 40% or more of baseline values ​​suggests Cushing's disease. Adrenal adenomas and carcinomas do not suppress it. This also does not occur in Cushings due to ectopic ACTH production and in 80% of nodular adrenal hyperplasias.

Methopyrone test. It is useful in differentiating Cushing's disease from adrenal tumors. This substance blocks the production of cortisol by inhibiting 11-alpha-hydroxylase, an enzyme that converts 11-deoxycortisol into cortisol. In normal individuals or in patients with Cushing's disease who partially preserve the functionality of the negative feedback system, the decrease in cortisol leads to an increase in ACTH, with the consequent increase in plasma 11-deoxycortisol and urinary 17OH-corticosteroids, which they represent the precursors of cortisol. With the administration of 750 mg every 4 hours for 24 hours, an increase of at least 100% in urinary 17OH-corticosteroids is considered normal. No response is seen in autonomous adrenal tumors.

Plasma ACTH. Normal baseline concentrations in the morning hours are below 100 pg / ml, while in the afternoon they do not exceed 30 ug / ml. Plasma concentrations are very low in autonomous adrenal tumors, "normal" (high relative to concurrent elevated plasma cortisol levels), or slightly above normal in Cushing's cases of hypothalamic-pituitary cause, and very high in cases of ectopic ACTH production.

Other methods to determine the etiology of Cushing include the CRH (ACTH-releasing hypothalamic hormone) test and catheterization of the inferior petrosal sinuses with ACTH measurement before and following CRH administration.

Localization procedures include MRI of the hypothalamic pituitary region and CT of the abdomen. In this sense, it is important to remember that between 5 and 8% of normal individuals may present incidentalomas of the pituitary or adrenal.

When the clinical picture and laboratory data suggest the presence of an ectopic Cushing, studies such as chest radiographs that can detect up to 50% of the lesions, or a chest CT scan are necessary.