區別cushing syndrome和cushing disease
Cushing syndrome, named after the famous neurosurgeon, Harvey Cushing who first described it, is an endocrine disorder with elevated cortisol levels in the blood.
Insome cases, Cushing syndrome results from a pituitary adenoma making excessACTH, and in those situations it's called Cushing disease.
CRH→ACTH→cortisol
Normally, the hypothalamus, which is located at the base of the brain, secretes corticotropin-releasing hormone, known as CRH, which stimulates the pituitary gland to secrete adrenocorticotropic hormone, known as ACTH. ACTH, then,travels to the pair of adrenal glands, on top of each kidney, where itspecifically targets cells in the adrenal cortex.
腎上腺皮質分層
The adrenal cortexis the outer part of the adrenal gland and is subdivided into three layers:
the zona glomerulosa 球狀帶,
the zona fasciculata 束狀帶,
and the zona reticularis 網狀帶.Zonafasciculata is the middle zone and also the widest zone and it takes up the majority of the volume of the whole adrenal gland.
可的松的化學性質,代謝途徑
The ACTH specifically stimulates cells in this zone to secrete cortisol, which belongs to a class of steroids, or lipid-soluble hormones, called glucocorticoids.
Glucocorticoids are not soluble in water, so most cortisol in the blood is bound to a special carrier protein, called cortisol-binding globulin, and only about 5% is unbound or free. In fact, only this small fraction of free cortisolis biologically active, and its levels are carefully controlled. Excess free cortisol is filtered in kidneys and dumped into the urine.
可的松的作用
Free cortisol in the blood is involved in a number of things and it’s part of the circadian rhythm. Cortisol levels peak in the morning, when the body knows we need to 「get up andgo」 and then drop in the evening, when we’re preparing for sleep.
In times of stress,the body needs to have plenty of energy substrates around, so cortisol
increases gluconeogenesis 糖異生, which is the synthesis of new glucose molecules,proteolysis 蛋白質水解, which is the breakdown of protein and lipolysis 脂類分解, which is the breakdown of fat.Cortisol also helps to maintain the blood pressure by increasing the sensitivity of peripheralblood vessels to catecholamines- epinephrine and norepinephrine, and this narrows the blood vessel lumen. Cortisol helps to dampen the inflammatory andimmune response by reducing the production and release of inflammatorymediators, like prostaglandins and interleukins, as well as inhibiting the proliferation of T-lymphocytes. Finally, cortisol receptors are present in the brain, where their full effect is still actually unclear but might influence things like mood and memory.
負反饋調節
For all this to work properly, though, the levels of free cortisol have to stay within the normal range. To do that, the body uses negative feedback, which means that high levels of cortisol tell the hypothalamus and pituitary gland to decrease their secretion of CRH and ACTH, respectively. Less CRH also tells the pituitary to make less ACTH, so the pituitary ends up having two reasons not to make ACTH.With less ACTH floating around, the zona fasciculata gets less stimulation tomake cortisol, and eventually, cortisol levels go back down to the normal range again.
In Cushing syndrome,cortisol levels are constantly higher than normal, so its effects are exaggerated.
1 Excess cortisol leads to severe muscle, bone and skin breakdown which are the major protein stores of the body.
2 It also leads to elevated blood glucose levels,
3 and that leads to high insulin levels. Insulin, among its many actions, preferentially targets adipocytes or fat cells in the center of the body - around the waist and buttocks. In those cells, the insulin activates lipoprotein lipase, which is an enzyme that helps those adipocytes accumulatemore fat molecules. The result is central obesity.
In addition, to thisthe high cortisol levels cause hypertension for two reasons.
First, they amplify the effect of catecholamines on blood vessels. Second, cortisol startscross-reacting with mineralocorticoid receptors, which normally only binds arelated steroid hormone - mineralocorticoids which are secreted from the zonaglomerulosa layer of the adrenal cortex. In other words because the cortisol isstructurally similar to mineralocorticoid it can bind to that receptor and itcan trigger the mineralocorticoid effect - which is mainly to increase bloodpressure by retaining fluid.High levels of cortisol also inhibit the secretion of gonadotropin 促性腺激素- releasing hormone from the hypothalamus, which messes up normal ovarian and testicular function. Excess cortisol also dampens the inflammatory and immune response, making individuals more susceptible to infections. Finally, high levels of cortisol seem to impair normal brain function but the exact mechanism of that is unclear.
庫興症候群病因
Cushing syndrome can happen because of exogenous cortisol meaning that it comes from 「outside」usually in the form of medications, or because of endogenous cortisol - meaning that the excess cortisol is made by the body.
1 外源性可的松
The majority of cases of Cushing syndrome occur in individuals using exogenous steroid medications over a long period oftime - often to treat autoimmune and inflammatory disorders, like asthma orrheumatoid arthritis. That’s because the molecular structure of exogenous steroid medications is so similar to cortisol that they mimic its actions onvarious tissues. In fact, exogenous steroid medications can also cause negative feedback on the hypothalamus and the pituitary gland. This causes a decrease in CRH and ACTH, which in turn, shuts down cortisol production from the zonafasciculata.
Over time, this lack of stimulation can cause zona fasciculata to physically shrink or become atrophic. Since that's the widest part of the adrenal cortex, it can have a measurable effect on the overall size of the adrenal gland. Even though this results in less endogenous cortisol production it still doesn’t quite compensate for the huge levels of exogenous cortisol, and that causes Cushing syndrome to develop.
2 內源性可的松
In addition to taking exogenous steroid medications, Cushing syndrome can also result from increased levels of endogenous cortisol. The most common reason for that is excess ACTH. The leading cause of that is a pituitary adenoma, which is a benign tumor of the pituitary gland - and this specific condition is called Cushing disease. The exact reason for the development of this sort of benign tumor isn’t known - but unlike a malignant tumor - the cells don’t invade neighboring tissues or spread to other parts of the body. Instead, the pituitary adenoma simply grows in size and secretes too much ACTH. The excess ACTH overstimulates zona fasciculata of both adrenal glands, which grow larger and secrete excess cortisol.
Apart from pituitary adenomas, there are ectopic sources of ACTH like small cell lung cancer, and in these cases the excess ACTH is coming from somewhere other than the pituitary.
An other common cause of endogenous Cushing syndrome is tumors of the adrenal glands that make excess cortisol - like adrenal adenomas, which are benign tumors, and adrenal carcinomas, which are malignant tumors. In both adrenal adenomas and carcinomas, the cells of the zona fasciculata within the adrenal cortex startdividing abnormally and secrete excess cortisol. As before, the excess cortisol provides negative feedback to the hypothalamus and pituitary gland, suppressing CRH and ACTH production.
Although this doesn’t have any effect on zona fasciculata of the involved adrenal gland,since the neoplastic cells are autonomous, meaning that they have grown independent from any stimulatory signals, the zona fasciculata of the uninvolved, normal adrenal gland shrinks and produces less than the standardamount of cortisol. The net result, though, is still abnormally high levels ofcortisol, and that causes Cushing syndrome to develop.
症狀
Regardless of the cause, the symptoms of Cushing syndrome are directly related to the effects of excess cortisol on its various target tissues. Resulting from the increased breakdown of most types of tissue, the individual presents with muscle wasting and thin extremities, skin thinning, easy bruising and abdominal striae orlines, as well as fractures due to osteoporosis or brittle bones.
At the same time,there’s fat redistribution, so classic findings include a round, full moonshaped face, a buffalo hump - which is a fatty hump on the upper back, andtruncal obesity - where fat gathers around the abdomen and trunk rather than inthe limbs. Finally, excess cortisol causes hyperglycemia or high blood sugarlevels that can progress to diabetes mellitus, hypertension or increased bloodpressure along with a high risk for cardiovascular disease, as well asincreased vulnerability to infections, poor wound healing, amenorrhea or absentmenstrual bleeding and psychiatric- mental disturbances.
診斷
Diagnosis of Cushing syndrome is initially based on measuring the free, or unbound cortisol in a24-hour urine sample, in order to assess the total amount of cortisol excretedin the urine over a 24-hour period.
Alternatively, blood or saliva tests late at night can help check if there’s a normal daily rise and fall of cortisollevels.
Another option is also the dexamethasone suppression test, which is when a person is given a low dose of dexamethasone, which is an exogenous steroid that suppresses ACTH production in the pituitary gland. Normally thatshould cause a decrease in serum cortisol levels, but if Cushing syndrome is caused by endogenous cortisol production, then the serum cortisol levels shouldremain unchanged. If that test is positive, the next step is to determine the exact cause of endogenous cortisol production, and ACTH plasma levels can bechecked.
Low ACTH levels can be seen in adrenal adenomas and carcinomas, whereas high ACTH levels can beseen in Cushing disease and ectopic ACTH production. If the ACTH level is high,the next step is to give an injection of a high dose of dexamethasone. Unlike pituitaryadenomas, ectopic sites of ACTH productions typically don’t respond even tohigh doses of dexamethasone, and the serum cortisol remains high.
After all that,imaging can be used. An MRI of the pituitary gland, in the case of Cushing disease, a CT of the adrenals, when adrenal pathology is suspected, or a CT ofthe chest, abdomen, or pelvis, if there seems to be an ectopic site of ACTH production.
治療Treatment of Cushing syndrome depends on the underlying cause.
If it’s due to exogenous medications, then the offending drug is gradually decreased and eventually stopped if possible. It’s important to avoid sudden steroid withdrawal, though, because that can cause an adrenal crisis which is life threatening. That’s because the adrenal glands may be atrophied and may need months to recover fully, and during that time, the body needs the exogenous steroids to function normally.
If Cushing syndrome is due to a pituitary adenoma - like in Cushing disease - then surgical excision of the adenoma may be needed.
Alternatively, medications such as adrenal steroid inhibitors, like ketoconazole and metyrapone can be helpful -especially for cases of ectopic ACTH production or adrenal carcinomas that have already spread.
Summary
Cushing syndrome is any condition or situation that causes increased levels of cortisol. It can be exogenous, meaning drug-related, or endogenous,meaning that it’s from an adrenal tumor or excess ACTH from a pituitary adenomas,in which case it’s called Cushing disease, or from an ectopic site like smallcell lung cancer.