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group_5_presentation_1_-_glucocorticoid_hyperfunction_cushing_s_syndrome [2017/09/30 15:45] mohamesb [Epidemiology] |
group_5_presentation_1_-_glucocorticoid_hyperfunction_cushing_s_syndrome [2018/01/25 15:18] (current) |
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| + | ==== Adrenal Glucocorticoid Hyperfunction: Cushing's Syndrome PowerPoint ==== | ||
| + | |||
| + | {{:cushing_s_presentation.pptx|}} | ||
| ===== Introduction ===== | ===== Introduction ===== | ||
| - | <box 34% round left | > {{ :hpa_.jpg?nolink&400 |}} </box| Figure 1: The HPA (stress response) Axis > | + | <box 32% round right | > {{ ::screen_shot_2017-10-01_at_12.42.47_pm.png?345 |}} </box| Figure 1: The HPA (stress response) Axis > |
| - | Cushing’s syndrome results from excessive, long-term exposure to endogenous or exogenous forms of glucocorticoids (Orth, 1995). Glucocorticoids are a class of steroids, with cortisol being the most important. Glucocorticoids are particularly important in mediating the stress response of the body, and they are also involved in anti-inflammatory actions (Marshall, Bangert & Lapsley, 2012). Normally, the hypothalamic-pituitary-adrenal axis (HPA Axis) releases cortisol from the adrenal glands in response to a stressor (Figure 1). The hypothalamus releases corticotropin-releasing hormone (CRH), stimulating the pituitary gland to release adrenocorticotropic hormone (ACTH), which acts on the adrenal glands to release cortisol. | + | Cushing’s syndrome results from excessive, long-term exposure to endogenous or exogenous forms of glucocorticoids (Orth, 1995). Glucocorticoids are a class of steroids, with cortisol being the most important. Glucocorticoids are particularly important in mediating the stress response of the body, and they are also involved in anti-inflammatory actions (Marshall, Bangert & Lapsley, 2012). Normally, the hypothalamic-pituitary-adrenal axis (HPA Axis) releases cortisol from the adrenal glands in response to a stressor (Figure 1). Activation of the HPA axis initiates a cortisol cascade. Various stressors will result in the secretion of corticotropin-releasing hormone (CRH) from the hypothalamus, which then stimulates the pituitary gland to release adrenocorticotropic hormone (ACTH). Circulating ACTH acts on the adrenal cortex to release cortisol and exert negative feedback control to restore homeostasis. |
| - | However, in Cushing's Disease (the most prevalent endogenous subtype of this syndrome), a tumour in the pituitary causes excessive release of ACTH, therefore acting on the adrenal glands to produce abnormally high levels of cortisol(Orth, 1995). Other endogenous causes of Cushing’s syndrome include an adrenal adenoma over-secreting glucocorticoids, or an ectopic non-pituitary ACTH-producing tumour. Potential sources of an ectopic tumour include the lungs, pancreas, or thymus (Marshall, Bangert & Lapsley, 2012). | + | However, in Cushing's Disease (the most prevalent endogenous subtype of this syndrome), a tumour in the pituitary causes excessive release of ACTH, therefore acting on the adrenal cortex to produce abnormally high levels of cortisol (Orth, 1995). The excess release of glucocorticoids present life-threatening conditions and a host of clinical manifestations. Other endogenous causes of Cushing’s syndrome include a tumour of the adrenal cortex over-secreting cortisol, an ectopic non-pituitary ACTH-secreting tumour, or a tumour of the hypothalamus secreting excessive CRH leading to activation of the cortisol cascade. Potential sources of an ectopic tumour include the lungs, pancreas, or thymus (Marshall, Bangert & Lapsley, 2012). |
| Line 32: | Line 36: | ||
| Very little has been published on mortality rates of people with CS, but a retrospective meta-analysis was done in Stoke-on-Trent, UK, for CD’s mortality rates. The median age-range for diagnosis was 36-46 years old, and 85% of these patients were women (Clayton, Raskauskiene, Reulen, et al., 2011). The median follow-ups were 15 years after diagnosis, and 13 people died within that period - 9 of them due to cardiovascular problems (Clayton, Raskauskiene, Reulen, et al., 2011). Mortality rates reported of CD patients are nearly double that of the general population, but those in remission have mortality rates close to equal to the general population (Clayton, Raskauskiene, Reulen, et al., 2011). | Very little has been published on mortality rates of people with CS, but a retrospective meta-analysis was done in Stoke-on-Trent, UK, for CD’s mortality rates. The median age-range for diagnosis was 36-46 years old, and 85% of these patients were women (Clayton, Raskauskiene, Reulen, et al., 2011). The median follow-ups were 15 years after diagnosis, and 13 people died within that period - 9 of them due to cardiovascular problems (Clayton, Raskauskiene, Reulen, et al., 2011). Mortality rates reported of CD patients are nearly double that of the general population, but those in remission have mortality rates close to equal to the general population (Clayton, Raskauskiene, Reulen, et al., 2011). | ||
| - | The prevalence of Cushing’s Syndrome may be heavily underestimated as there are limited studies in its epidemiology. Also, CS’ cyclic nature, high variability of intensity, remission phases, and comorbid symptomology leaves many people misdiagnosed and treated just for symptoms like hypertension or diabetes. More research must be done in this field. | + | The prevalence of Cushing’s Syndrome may be heavily underestimated as there are limited studies in its epidemiology. Also, the cyclic nature of CS, the high variability of intensity, remission phases, and comorbid symptomology leaves many people misdiagnosed and treated just for symptoms like hypertension or diabetes. Evidently, more research must be done in this field. |
| - | ===== Signs and Symptoms ===== | + | ===== Signs and Symptoms of Cushing's ===== |
| + | A general diagnosis of Cushing’s Syndrome can be categorized into one of four classes: | ||
| - | A general diagnosis of Cushing’s Syndrome can be categorized into one of three classes: | + | * Primary (a tumour of the adrenal cortex) |
| + | * Secondary (a tumour of the pituitary) | ||
| + | * Tertiary (a tumour of the hypothalamus) | ||
| + | * Ectopic (a non-pituitary ACTH secreting tumour) | ||
| - | * Primary (damage to the adrenal cortex itself) | + | Regardless of the class of diagnosis, patients with Cushing’s exhibit a multitude of similar symptoms with some sex specific. |
| - | * Secondary (damage to the pituitary) | + | |
| - | * Tertiary (damage to the hypothalamus itself) | + | |
| - | + | ||
| - | Regardless of the class of diagnosis, patients with Cushing’s disease exhibit a multitude of similar symptoms with some sex specific. | + | |
| Most Common Symptoms: | Most Common Symptoms: | ||
| Line 63: | Line 67: | ||
| * Moon Face (Fat deposits around the face) | * Moon Face (Fat deposits around the face) | ||
| * Irregular Menstruation Cycle (Women) | * Irregular Menstruation Cycle (Women) | ||
| - | * Excessive Body Hair Growth (Women) | + | |
| Least Common Symptoms: | Least Common Symptoms: | ||
| Line 71: | Line 75: | ||
| * Edema of the Exteremities | * Edema of the Exteremities | ||
| * Erectile Dysfunction (Men) | * Erectile Dysfunction (Men) | ||
| + | * Excessive Body Hair Growth (Women) | ||
| + | ===== Hypothalamic-Pituitary Adrenal Axis ===== | ||
| - | ===== Diagnosis ===== | + | Several stimuli can perturb homeostatic mechanisms resulting in the secretion of glucocorticoids, mainly cortisol in humans, from the adrenal cortex. The most common stimulus, stress, is a potent activator of the HPA axis. Our body's stress system coordinates the adaptive responses of organisms to different types of stressors resulting in changes that improve our ability to adjust homeostasis and increase chances of survival (Tsigos & Chrousos, 2002). Cortisol is the end product of the activation of the hypothalamic-pituitary adrenal (HPA) axis. The HPA axis consists of excitatory signals and negative feedback loops to regulate its activity (Nicolaides, Kyratzi, Lamprokostopoulou, Chrousos, & Charmandari, 2015). |
| - | One of the goals of diagnosis is to distinguish Cushing’s disease from Cushing’s syndrome, as the disease is a variation of Cushing's syndrome. Secondary adrenal hyperfunction results from a pituitary tumour leading to excessive production of ACTH. Elevated ACTH stimulates the adrenal cortex to produce high levels of cortisol giving rise to the disease state. Testing for Cushing's is outlined below and random plasma cortisol levels is unacceptable due to the variations of cortisol levels throughout the day. | + | <box 30% round right | > {{ :hpa_cortisol.png?320 |}} </box| Figure 4: The excitatory signals and negative feedback loops of the hypothalamic-pituitary adrenal axis> |
| - | {{::screen_shot_2017-09-25_at_12.28.25_pm.png?650|}} | ||
| - | **Figure 2:** Suspected Cushing's syndrome algorithm to determine the origin of excess glucocorticoids in the blood (Marshall, Bangert & Lapsley, 2012) | + | ==== Physiology of Glucocorticoids: Cortisol ==== |
| + | In response to a stressor, the hypothalamus secretes corticotrophin releasing hormone (CRH) which acts on the anterior pituitary gland to secrete adrenocorticotrophin hormone (ACTH). Circulating ACTH is a key regulator of cortisol secretion from the adrenal cortex. The release of glucocorticoid hormones help regulate homeostatic imbalances and mediate the body's response to stress (Tsigos & Chrousos, 2002). | ||
| - | === 24-Hour Urinary Cortisol Excretion === | + | The most important glucocorticoid hormone is cortisol. Glucocorticoids inhibit the immune response, have anti-inflammatory and catabolic effects, maintain blood pressure by sensitizing the arterioles to norepinephrine and increase glucose levels in the blood (Marshall, Bangert & Lapsley, 2012). Figure 4 shows cortisol exerting negative feedback control on ACTH release through the inhibition of CRH as well as inhibiting CRH release itself (Marshall, Bangert & Lapsley, 2012). |
| - | Testing for Cushing’s involves screening for cortisol levels. The sample of interest in this screening process is almost always urine (although saliva can be an alternative), as urine cortisol levels are representative of blood cortisol. A 24-hour urine collection test is done to collect urine over a full daily cycle of the patient. 24-Urinary cortisol excretion have normal levels of under 300 nmol/24 hours. (Marshall, W. J., Bangert, S. K., Lapsley, M. (2012)). A positive result from this test indicates Cushing's Syndrome. | ||
| - | === Low-Dose Dexamethansone Suppression Test === | + | ==== Pathophysiology of Glucocorticoids: Excess Cortisol ==== |
| + | Regulation of the HPA axis is critical, otherwise disorders of the adrenal cortex can arise and present life-threatening conditions. In Cushing's Syndrome, there is overproduction of glucocorticoids. The various causes of Cushing's Syndrome, illustrated in figure 5 below, include a pituitary adenoma over-secreting ACTH, ectopic ACTH secretion, an adrenal adenoma over-secreting glucocorticoids, or an exogenous supply of glucocorticoids (Marshall, Bangert & Lapsley, 2012). The most common endogenous cause is a pituitary adenoma which accounts for 60-70% of diagnosis (Marshall, Bangert & Lapsley, 2012). | ||
| - | Dexmethasone is a synthetic glucocorticoid that binds to cortisol receptors in the pituitary and suppresses ACTH release which ultimately suppresses the secretion of cortisol by the adrenals in normal healthy individuals without Cushing’s. A 1mg dosage is given at night and blood is drawn for measurement of cortisol the next morning. In healthy individuals this level should be less than 50 nmol/L. (Marshall, W. J., Bangert, S. K., Lapsley, M. (2012)) Failure of suppression is characteristic of Cushing’s. | + | {{::screen_shot_2017-09-30_at_5.27.00_pm.png?600|}} |
| - | Once increased cortisol has been established, the measurement of plasma ACTH has is used to determine the cause of increased cortisol levels in the blood. Low levels of ACTH, a key regulator of glucocorticoid activity in the blood, suggests an adrenal tumour over-secreting cortisol. On the other hand, very high levels of ACTH suggest ectopic secretion of ACTH which could be from a pituitary tumour or an ectopic ACTH secreting tumor (Marshall, Bangert & Lapsley, 2012). In order to distinguish between the two, a high dose dexamethasone test is needed. | + | **Figure 5:** The possible causes of Cushing's Syndrome (Marshall, Bangert & Lapsley, 2012) |
| - | === High Dose Dexamethasone Suppression Test === | + | ==== Pathophysiology of Cushing's Disease ==== |
| - | A 2mg dosage is given to patients every 6 hours for a total of 48 hours. Plasma cortisol levels are then measured again at 9am the next morning. Patients with Cushing's Disease would have their cortisol concentration levels drop by at least 50% of pre-treatment value. This indicates that the high cortisol concentrations due to a pituitary tumour over-secreting ACTH is because of a failure in the negative feedback mechanisms that needed a higher dose to counteract. On the other hand, failure to suppress ACTH levels is suggestive of an ectopic ACTH secreting tumour that will continue to stimulate the adrenal cortex to release cortisol irregardless of the negative feedback loops. | + | <box 40% round right | > {{ :mri_cd.png?460 |}} </box| Figure 6: An MRI showing a pituitary tumour (“pituitary_adenoma_MRI.jpg (1259×682),” n.d.)> |
| - | === CRH Dynamic Testing === | + | Cushing’s disease, a subtype of Cushing’s syndrome, is a disease primarily due to excessive secretion of adrenocorticotropic hormone (ACTH) by a pituitary adenoma. The pituitary tumours are usually microadenomas, which are 10 mm or less in diameter. These tumours are often discovered by doing tests for other reasons, since these microadenomas do not have mass effects. (Kirk and Jones, 2000). Cushing’s disease accounts for about two thirds of the cases of endogenous Cushing’s syndrome. It mainly affects women of reproductive age, but can also affect males and females in general (Kirk and Jones, 2000). In Cushing’s disease, ACTH secretion from the pituitary is increased because the pituitary becomes less sensitive to glucocorticoid effects and negative feedback mechanisms become faulty. Consequently, excess cortisol will be required in order to suppress the release of ACTH from the pituitary through negative feedback. Therefore, as cortisol continues accumulating due to a failure in negative feedback mechanisms, it begins causing negative effects throughout the body (Marshall, Bangert & Lapsley, 2012). |
| - | Dynamic testing on patients is normally not performed unless absolutely necessary as it puts strain on the patient. In Cushing's dynamic testing is used to distinguish pituitary adenomas from ectopic ACTH secreting tumours or adrenal secreting tumours. Corticotropin Releasing Hormone (CRH) which is released by the hypothalamus in response to stress stimulates the entire cortisol release cascade. Providing CRH and measuring the ACTH levels helps to further diagnose the form of Cushing's. An exaggerated elevated response of excessive ACTH levels suggest a pituitary tumour (secondary class diagnosis) while no response after the administration of CRH indicates a primary class disorder. | + | ==== Presentation of clinical features ==== |
| - | {{::screen_shot_2017-09-25_at_12.47.42_pm.png?650|}} | + | The clinical features of Cushing's Syndrome are primarily due to excess production of glucocorticoids. Taking into account the actions of glucocorticoids, high levels in the bloodstream will lead to easy bruising, poor wound healing, glucose intolerance, truncal obesity and purple stretch marks among other features. Interestingly, glucocorticoids also have mineralcorticoid activity. This means that cortisol can also act as aldosterone, an important mineralcorticoid, and present some of the clinical features characteristic of a patient with high levels of aldosterone in their bloodstream. This explains why patients present with high blood pressure (hypertension) due to the sodium retention, and metabolic alkalosis due to potassium wasting. Metabolic alkalosis is an increase in serum bicarbonate concentrations due to loss of hydrogen ions in the body, or a gain in bicarbonate ions. Since glucocorticoids have mineralocorticoid effects, an excess amount of glucocorticoids will increase the retention of sodium, and also dump hydrogen ions into the renal tubules. This loss of hydrogen ions creates a state of metabolic alkalosis. |
| - | **Figure 3:** Typical results of Adrenal Hyperfunction tests in Cushing's syndrome (Marshall, Bangert & Lapsley, 2012) | + | <box 37% round left| > {{ :cushing_s.jpg?410 |}} </box| Figure 7: Some of the clinical features of excess glucocorticoid hormone (cortisol) in the bloodstream and some mineralcorticoid activity (Marshall, Bangert & Lapsley, 2012)> |
| - | + | ||
| - | + | ||
| - | === Screening for Tumours === | + | |
| - | + | ||
| - | CT (Computed Tomography) or an MRI (Magnetic Resonance Imaging)of the pituitary helps to visualize the regions of the brain where a ACTH-secreating tumour is suspected to be localized. These visualization tests are often ordered when the patient has failed the low-dose dexamethansone test and has exhibited an exaggerated response ACTH response. This test is done to confirm the existence of a ectopic tumour. | + | |
| ===== Lab Abnormalities ===== | ===== Lab Abnormalities ===== | ||
| Line 128: | Line 129: | ||
| * Eosinophils and Lymphocytes | * Eosinophils and Lymphocytes | ||
| - | - Eosinophils and lymphocytes are decreased because excess cortisol weakens the immune system. T-cells respond to cytokine molecules (called interleukins)via a signalling pathway. Cortisol blocks the proliferation of T-cells by preventing them from recognizing interleukin signals. | + | - Eosinophils and lymphocytes are decreased because excess cortisol weakens the immune system. T-cells respond to cytokine molecules (called interleukins)via a signalling pathway. Cortisol blocks the proliferation of T-cells by preventing them from recognizing interleukin signals. More specifically some individuals with Cushings' may also be needed to be treated for severe parasitic infections, since eosinophils are responsible for clearing parasitic infections, declined levels leave affected individuals more susceptible to parasites. |
| + | ===== Diagnosis of Adrenal Hyperfunction: Glucocorticoids ===== | ||
| + | One of the goals of diagnosis is to distinguish Cushing’s disease from Cushing’s syndrome, as the disease is a variation of Cushing's syndrome. Secondary adrenal hyperfunction results from a pituitary tumour leading to excessive production of ACTH. Elevated ACTH stimulates the adrenal cortex to produce high levels of cortisol giving rise to the disease state. Testing for Cushing's is outlined below and random plasma cortisol levels are unacceptable due to the variations of cortisol levels throughout the day. | ||
| + | {{::screen_shot_2017-09-30_at_5.03.43_pm.png?675}} | ||
| + | **Figure 2:** Suspected Cushing's syndrome algorithm to determine the origin of excess glucocorticoids in the blood (Marshall, Bangert & Lapsley, 2012) | ||
| - | ===== Hypothalamic-Pituitary Adrenal Axis ===== | + | === 24 Hour Urine Free Cortisol Excretion === |
| - | Several stimuli can perturb homeostatic mechanisms resulting in the secretion of glucocorticoids, mainly cortisol in humans, from the adrenal cortex. The most common stimulus, stress, is a potent activator of the HPA axis. Our body's stress system coordinates the adaptive responses of organisms to different types of stressors resulting in changes that improve our ability to adjust homeostasis and increase chances of survival (Tsigos & Chrousos, 2002). Cortisol is the end product of the activation of the hypothalamic-pituitary adrenal (HPA) axis. The HPA axis consists of excitatory signals and negative feedback loops to regulate its activity (Nicolaides, Kyratzi, Lamprokostopoulou, Chrousos, & Charmandari, 2015). | + | The best screening test for Cushing's is 24 hour urinary free cortisol, as urine cortisol levels are representative of blood cortisol levels. A 24 hour urine collection test is done to collect urine over a full daily cycle of the patient. 24 hour urinary cortisol excretion have normal levels of less than 300 nmol/24 hours (Marshall, Bangert & Lapsley, 2012). Values exceeding the normal range are characteristic of Cushing's. |
| - | <box 30% round right | > {{ :hpa_cortisol.png?320 |}} </box| Figure 4: The excitatory signals and negative feedback loops of the hypothalamic-pituitary adrenal axis> | + | === Low Dose Dexamethasone Suppression Test === |
| + | Dexamethasone is a synthetic glucocorticoid that binds to cortisol receptors in the pituitary and suppresses ACTH release. This ultimately suppresses the secretion of cortisol by the adrenal gland in normal, healthy individuals (Marshall, Bangert & Lapsley, 2012). A 1mg dosage is given at night and blood is drawn for measurement of cortisol the next morning. In healthy individuals this level should be less than 50 nmol/L. (Marshall, Bangert & Lapsley, 2012). Failure to suppress ACTH levels are suggestive of Cushing’s. | ||
| + | Once increased cortisol levels have been established, the measurement of plasma ACTH is used to determine the cause of increased cortisol levels in the blood. Low levels of ACTH, a key regulator of glucocorticoid activity in the blood, suggests an adrenal tumour over-secreting cortisol. On the other hand, very high levels of ACTH suggest excessive secretion of ACTH from a pituitary tumour or an ectopic non-pituitary ACTH secreting tumour (Marshall, Bangert & Lapsley, 2012). In order to distinguish between the two, a high dose dexamethasone test is needed. | ||
| + | === High Dose Dexamethasone Suppression Test === | ||
| - | ==== Physiology of Glucocorticoids: Cortisol ==== | + | A 2mg dosage is given to patients every 6 hours for a total of 48 hours. Plasma cortisol levels are then measured again at 9am the next morning. Patients with Cushing's Disease would have their cortisol concentration levels drop by at least 50% of pre-treatment value. This indicates that high cortisol concentrations due to a pituitary tumour over-secreting ACTH is because of faulty negative feedback mechanisms. As a result, a higher dose is required to counteract the faulty negative feedback mechanisms. On the other hand, failure to suppress ACTH levels is suggestive of an ectopic ACTH secreting tumour that will continue to stimulate the adrenal cortex to release cortisol irregardless of the negative feedback loops. |
| - | In response to a stressor, the hypothalamus secretes corticotrophin releasing hormone (CRH) which acts on the anterior pituitary gland to secrete adrenocorticotrophin hormone (ACTH). Circulating ACTH is a key regulator of cortisol secretion from the adrenal cortex. The release of glucocorticoid hormones help regulate homeostatic imbalances and mediate the body's response to stress (Tsigos & Chrousos, 2002). | + | |
| - | The most important glucocorticoid hormone is cortisol. Glucocorticoids inhibit the immune response, have anti-inflammatory and catabolic effects, maintain blood pressure by sensitizing the arterioles to norepinephrine and increase glucose levels in the blood (Marshall, Bangert & Lapsley, 2012). Figure x shows cortisol exerting its negative feedback control on ACTH release through the inhibition of CRH as well as inhibiting CRH release itself (Marshall, Bangert & Lapsley, 2012). | + | === CRH Dynamic Testing === |
| + | Dynamic testing on patients is normally not performed unless absolutely necessary as it puts strain on the patient. In Cushing's, dynamic testing is used to distinguish pituitary adenomas from ectopic ACTH secreting tumours or adrenal secreting tumours. Corticotropin Releasing Hormone (CRH), which is released by the hypothalamus in response to stress, stimulates the entire cortisol release cascade. Providing CRH and measuring the ACTH levels helps to further diagnose the type of Cushing's. An exaggerated elevated response of excessive ACTH levels suggest a pituitary tumour (secondary class diagnosis) while no response after the administration of CRH indicates a primary class disorder (i.e., an adrenal secreting tumour). | ||
| - | ==== Pathophysiology of Glucocorticoids: Excess Cortisol ==== | + | {{::screen_shot_2017-09-25_at_12.47.42_pm.png?650|}} |
| - | Regulation of the HPA axis is critical, otherwise disorders of the adrenal cortex can arise and present life-threatening conditions. In Cushing's Syndrome, there is overproduction of glucocorticoids. The various causes of Cushing's Syndrome include a pituitary adenoma over-secreting ACTH, ectopic ACTH secretion, an adrenal adenoma over-secreting glucocorticoids, or an exogenous supply of glucocorticoids (Marshall, Bangert & Lapsley, 2012). The most common cause is a pituitary adenoma which accounts for 60-70% of diagnosis (Marshall, Bangert & Lapsley, 2012). | + | |
| - | {{:causes.png?450|}} | + | **Figure 3:** Typical results of Adrenal Hyperfunction tests in Cushing's syndrome (Marshall, Bangert & Lapsley, 2012) |
| - | **Figure 5:** The possible causes of Cushing's Syndrome (Marshall, Bangert & Lapsley, 2012) | ||
| - | ==== Pathophysiology of Cushing's Disease ==== | + | === Screening for Tumours === |
| - | <box 40% round right | > {{ :mri_cd.png?460 |}} </box| Figure 6: An MRI showing a pituitary tumour (“pituitary_adenoma_MRI.jpg (1259×682),” n.d.)> | + | Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) of the pituitary helps to visualize the regions of the brain where an ACTH-secreting tumour is suspected to be localized. These visualization tests are often ordered when the patient has failed the low-dose dexamethasone test and has exhibited an exaggerated ACTH response. This test is done to confirm the existence of an ectopic tumour. |
| - | Cushing’s disease, a subtype of Cushing’s syndrome, is a disease caused due to the over secretion of adrenocorticotropic hormone (ACTH) by a pituitary adenoma. The pituitary tumors are usually microadenomas, which are 10 mm or less in diameter. These tumors are often discovered by doing tests for other reasons, since these microadenomas do not have mass effects. (Kirk and Jones, 2000). | ||
| - | Cushing’s disease accounts for about two thirds of the cases of endogenous Cushing’s syndrome. It mainly affects women of reproductive age, but can also affect males and females in general (Kirk and Jones, 2000). | ||
| - | In Cushing’s disease, ACTH secretion from the pituitary is increased because the pituitary becomes less sensitive to glucocorticoid effects. This means that excess cortisol will be required in order to suppress the release of ACTH from the pituitary though negative feedback. Therefore, as cortisol continues accumulating due to faulty negative feedback mechanisms, it begins causing negative effects throughout the body (Marshall, Bangert & Lapsley, 2012). | ||
| - | ==== Presentation of clinical features ==== | + | =====Treatment===== |
| - | The clinical features of Cushing's Syndrome are primarily due to excess production of glucocorticoids. Taking into account the actions of glucocorticoids, high levels in the bloodstream will lead to easy bruising, poor wound healing, glucose intolerance, truncal obesity and purple stretc hmarks among other features. Interestingly, glucocorticoids also have mineralcorticoid activity. This means that cortisol can also act as aldosterone, an important mineralcorticoid, and present some of the clinical features characteristic of a patient with high levels of aldosterone in their bloodstream. This explains why patients present with high blood pressure (hypertension) due to the sodium retention, and metabolic alkalosis due to potassium wasting. Metabolic alkalosis is an increase in serum bicarbonate concentrations due to loss of hydrogen ions in the body, or a gain in bicarbonate ions. Since glucocorticoids have mineralocorticoid effects, an excess amount of aldosterone will increase the retention of sodium, and also dump hydrogen ions into the renal tubules. This loss of hydrogen ions creates a state of metabolic alkalosis. | + | The mode of management or treatment selected for Cushing's syndrome depends on the type of Cushing's and its root cause. For those with iatrogenic Cushing's syndrome, the safest and least invasive way to treat the patient involves a gradual decrease in glucocorticoid medication intake, along with conscious efforts to treat the condition originally targeted by the medication (i.e. gradually weaning off of cortisone and incorporating a diet beneficial for arthritis). For Cushing's disease, the primary form of treatment is trans-sphenoidal hypophysectomy, which is the surgical removal of small pituitary adenomas (Marshall, Bangert & Lapsley, 2012). If the adenoma cannot be identified, then surgeons remove 50-90% of the pituitary gland. However, the problem with removing too much of the gland is that it reduces the effectiveness of the pituitary and causes problems with ovulation in women and sperm production in men. Cure rates for this approach range from 65-90% for microadenomas and much lower for macroadenomas (Fleseriu and Petersenn, 2012). |
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| - | <box 37% round left| > {{ :cushing_s.jpg?410 |}} </box| Figure 7: Some of the clinical features of excess glucocorticoid hormone (cortisol) in the bloodstream and some mineralcorticoid activity (Marshall, Bangert & Lapsley, 2012)> | + | |
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| - | =====Treatment===== | + | |
| - | The mode of management or treatment selected for Cushing's syndrome depends on the type of Cushing's and its root cause. For those with iatrogenic Cushing's syndrome, the safest and least invasive way to treat the patient involves a gradual decrease in glucocorticoid medication intake, along with conscious efforts to treat the condition originally targeted by the medication (i.e. gradually weaning off of cortisone and incorporating a diet beneficial for arthritis). For Cushing's disease, the primary form of treatment is trans-sphenoidal hypophysectomy, which is the surgical removal of small pituitary adenomas (Marshall, Bangert & Lapsley, 2012). If the adenoma cannot be identified, then surgeons remove 50-90% of the pituitary gland. However, the problem with removing too much of the gland is that it reduces the effectiveness of the pituitary and causes problems with ovulation in women and sperm production in men. Cure rates from this approach are from 65-90% for microadenomas and much lower for macroadenomas (Fleseriu and Petersenn, 2012). Another surgery that is performed occasionally is bilateral adrenalectomy, which is the surgical removal of the adrenal glands. This procedure stops cortisol production, but the pituitaries must still be dealt to not secrete too much ACTH which can lead to Nelson's syndrome (Marshall, Bangert & Lapsley, 2012). After both surgical procedures, respective steroid replacement therapy is necessary for the patient's lifetime (Marshall, Bangert & Lapsley, 2012). | + | Another surgery that is performed occasionally is bilateral adrenalectomy, which is the surgical removal of the adrenal glands. This procedure stops cortisol production, but the pituitaries must still be dealt with in order to not secrete too much ACTH which can lead to Nelson's syndrome (Marshall, Bangert & Lapsley, 2012). After both surgical procedures have been performed, respective steroid replacement therapy is necessary for the patient's lifetime (Marshall, Bangert & Lapsley, 2012). |
| <box 35% round left| > {{ :transsphenoidal_surgery.jpg?400 |}} </box| Figure 8. Performance of transsphenoidal surgery for the removal of a tumour on the pituitary gland> <box 38% round center| > {{ :pic_adrenalectomy.jpg?400 |}} </box| Figure 9. Bilateral adrenalectomy procedure> | <box 35% round left| > {{ :transsphenoidal_surgery.jpg?400 |}} </box| Figure 8. Performance of transsphenoidal surgery for the removal of a tumour on the pituitary gland> <box 38% round center| > {{ :pic_adrenalectomy.jpg?400 |}} </box| Figure 9. Bilateral adrenalectomy procedure> | ||
| ====Ketoconazole==== | ====Ketoconazole==== | ||
| - | <box 30% round right| > {{ :drugs.jpg?325 |}} </box| Figure 10. Various drugs for Cushing's disease and their area of effect (Fleseriu, 2014)> Ketoconazole is a drug that inhibits the process of steroidogenesis in the adrenal glands. This limits the production of steroids such as cholesterol. A study done with 200 patients with Cushing’s disease were treated with ketoconazole. At the last follow-up for the experiment, 49.3% of the patients showed normalized UFC levels and 25.6% had at least a 50% decrease. (Castinetti et al, 2014) However, this drug has shown to have some adverse side effects among patients that take the drug. Gastrointestinal issues seem to be common such as nausea and diarrhea. One major concern for the drug, although rare, is that it can increase liver enzyme levels and cause hepatotoxicity. (Fleseriu, 2014) | + | <box 30% round right| > {{ :drugs.jpg?325 |}} </box| Figure 10. Various drugs for Cushing's disease and their area of effect (Fleseriu, 2014)> |
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| + | Ketoconazole is a drug that inhibits the process of steroidogenesis in the adrenal glands. This limits the production of steroids such as cholesterol. A study done with 200 patients with Cushing’s disease were treated with ketoconazole. At the last follow-up for the experiment, 49.3% of the patients showed normalized urinary free cortisol (UFC) levels and 25.6% had at least a 50% decrease (Castinetti et al, 2014). However, this drug is shown to have some adverse side effects among patients that take it. Gastrointestinal issues, such as diarrhea and nausea, seem to be most common. One major concern for the drug, although rare, is that it can increase liver enzyme levels and cause hepatotoxicity(Fleseriu, 2014). | ||
| ====Pasireotide (Signifor)==== | ====Pasireotide (Signifor)==== | ||
| - | Pasireotide acts as an analog to somatostatin, which is known as a growth hormone-inhibiting hormone. The drug inhibits corticotropin secretion from the pituitary gland. Corticotrophin is what leads to the secretion of ACTH, and ACTH is what eventually leads to the secretion of cortisol (McKeage, 2013). | + | Pasireotide acts as an analog to somatostatin, which is known as a growth hormone-inhibiting hormone. The drug inhibits adrenocorticotropin (ACTH) secretion from the pituitary gland, a hormone that eventually leads to the secretion of cortisol (McKeage, 2013). |
| - | A study done by researchers looked at patients with Cushing’s disease and prescribed them with pasireotide for 6 months. At the end of the trials, 25% of all patients have normalized UFC levels and a significant decrease in the mean UFC levels of all patients. Patients that saw a reduction in their UFC levels also saw improvements in clinical symptoms as well such as blood pressure and body weight. The drug, however, has shown to cause hyperglycemia in patients and is still under further testing (McKeage, 2013). | + | A study done by researchers looked at patients with Cushing’s disease and prescribed them with pasireotide for 6 months. At the end of the trials, 25% of all patients have normalized UFC levels and a significant decrease in the mean UFC levels of all patients. Patients that saw a reduction in their UFC levels also saw improvements in clinical symptoms as well, such as blood pressure and body weight. The drug, however, has shown to cause hyperglycemia in patients and is still under further testing (McKeage, 2013). |
| ====Cabergoline==== | ====Cabergoline==== | ||
| - | Cabergoline is a dopamine receptor agonist and initially just used to inhibit the production of prolactin in patients that had hyperprolactinemia. However, studies have shown that Cabergoline might have some potential as a treatment for Cushing’s disease. A study looked at 30 patients with Cushing disease and treated them with Cabergoline at varying doses. Around 40% of the patients treated with a maximum dose of 6 mg/week achieved normalized UFC levels in little over 4 months. Around 30% of the patients that were prescribed long-term treatments at doses of 2.1 mg/week for 37 months achieved normalized UFC levels. (Godbout, 2010) | + | Cabergoline is a dopamine receptor agonist and initially just used to inhibit the production of prolactin in patients that had hyperprolactinemia. However, studies have shown that Cabergoline might have some potential as a treatment for Cushing’s disease. A study looked at 30 patients with Cushing's disease and treated them with Cabergoline at varying doses. Around 40% of the patients treated with a maximum dose of 6 mg/week achieved normalized UFC levels in little over 4 months. Around 30% of the patients that were prescribed long-term treatments at doses of 2.1 mg/week for 37 months achieved normalized UFC levels (Godbout, 2010). |
| ====Mitotane==== | ====Mitotane==== | ||
| - | Mitotane can be used to as a treatment of adrenocortical carcinoma, but it can also be used to limit cortisol production by inhibiting cholesterol side-chain cleavage and 11 β-hydroxylase, which is used in the final phase of cortisol synthesis as a catalyst. It has shown some prospect in managing hypercortisolemia, however, there are better options such as ketoconazole and metyrapone as they are easier on the body of patients. Some of the common side effects of this drug are diarrhea, nausea, and anorexia. (Trainer, 2013) | + | Mitotane can be used to as a treatment of adrenocortical carcinoma, but it can also be used to limit cortisol production by inhibiting cholesterol side-chain cleavage and 11 β-hydroxylase, which is used in the final phase of cortisol synthesis as a catalyst. It has shown some prospect in managing hypercortisolemia, however, there are better options such as ketoconazole and metyrapone as they are easier on the body of patients. Some of the common side effects of this drug are diarrhea, nausea, and anorexia (Trainer, 2013). |
| ====Metyrapone==== | ====Metyrapone==== | ||
| - | Metyrapone is an adrenal steroidogenesis inhibitor. Specifically, it inhibits the enzyme 11β-hydroxylase, which converts 11-deoxycortisol into cortisol. Metyrapone is used to treat adrenal insufficiencies, but also hypercortisolism in Cushing’s syndrome. Using this medication for the long-term results in side-effects, such as an increase in ACTH production, acne, hirsutism, hyperkalemia, and edema (Daniel, Aylwin, Mustafa, et al., 2015). Currently, it is used for short-term treatment before surgeries, but it shows some promise as a long-term treatment, especially when combined with other drugs (Daniel, Aylwin, Mustafa, et al., 2015). Metyrapone’s long-term use on its own is still in question as its depletion of cortisol levels does seem to affect memory formation and retrieval (Marin, Hupbach, Maheu, et al., 2011). Its long-term usage should not be ruled out but approached with caution. | + | Metyrapone is an adrenal steroidogenesis inhibitor. Specifically, it inhibits the enzyme 11β-hydroxylase, which converts 11-deoxycortisol into cortisol. Metyrapone is used to treat adrenal insufficiencies, but also hypercortisolism in Cushing’s syndrome. Using this medication for the long-term results in side-effects, such as an increase in ACTH production, acne, hirsutism, hyperkalemia, and edema (Daniel, Aylwin, Mustafa, et al., 2015). Currently, it is used for short-term treatment before surgeries, but it shows some promise as a long-term treatment, especially when combined with other drugs (Daniel, Aylwin, Mustafa, et al., 2015). Metyrapone’s long-term use on its own is still in question as its depletion of cortisol levels seem to affect memory formation and retrieval (Marin, Hupbach, Maheu, et al., 2011). Its long-term usage, however, should not be ruled out, rather it should be approached with caution. |
| ====Mifepristone==== | ====Mifepristone==== | ||
| - | Mifepristone is a progesterone receptor antagonist, but at higher doses, it also acts as a glucocorticoid receptor antagonist (Fleseriu, Biller, Findling, et al. 2012). It is most known for its use in abortions, but it is also used to treat Cushing’s disease. As a glucocorticoid receptor antagonist, mifepristone blocks cortisol’s mechanism of action. Studies do show benefits in its use for people with Cushing’s disease, especially for those with more fat and abnormal glucose metabolism, but there are still side effects worth examining. A few studies of mifepristone used for Cushing’s disease have exhibited symptoms such as increased blood pressure due to lowered HDL, low potassium, alkalosis, vaginal bleeding, and uterine contractions (Castinetti, Conte-Devolx, Brue, et al., 2010; Fleseriu, Biller, Findling, et al. 2012). Mifepristone has its benefits, but more research has to be done on its effects on blood pressure and deteriorative effects on the female reproductive system. | + | Mifepristone is a progesterone receptor antagonist, but at higher doses it also acts as a glucocorticoid receptor antagonist (Fleseriu, Biller, Findling, et al. 2012). It is most known for its use in abortions, but it is also used to treat Cushing’s disease. As a glucocorticoid receptor antagonist, mifepristone blocks cortisol’s mechanism of action. Studies do show benefits in its use for people with Cushing’s disease, especially for those with more fat and abnormal glucose metabolism, but there are still side effects worth examining. A few studies of mifepristone used for Cushing’s disease have exhibited symptoms such as increased blood pressure due to lowered high density lipoprotein (HDL), low potassium, alkalosis, vaginal bleeding, and uterine contractions (Castinetti, Conte-Devolx, Brue, et al., 2010; Fleseriu, Biller, Findling, et al. 2012). Mifepristone has its benefits, but more research has to be done on its effects on blood pressure and deteriorative effects on the female reproductive system. |
| ====Etomidate==== | ====Etomidate==== | ||
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| ====Future Research==== | ====Future Research==== | ||
| - | A study including 17 patients diagnosed with Cushing’s disease was given pasireotide as a treatment. After some time, five of those patients showed normalized UFC levels. The addition of cabergoline to the treatment normalized UFC levels in four further patients, furthermore the addition of ketoconazole normalized six more patients. At the end of the trials, only 2 out of 17 patients had elevated UFC levels. (Feelders and Hofland, 2013) | + | A study including 17 patients diagnosed with Cushing’s disease was given pasireotide as a treatment. After some time, five of those patients showed normalized UFC levels. The addition of cabergoline to the treatment normalized UFC levels in four further patients, and the addition of ketoconazole normalized six more patients. At the end of the trials, only 2 out of 17 patients had elevated UFC levels (Feelders and Hofland, 2013) |
| - | Another study looked at a combination of cabergoline and ketoconazole for treating Cushing’s disease. Initially, 12 patients were prescribed cabergoline for 6 months. Nine of these patients did not respond well to the treatment, however the addition of the ketoconazole to the treatment led to six of the nine patients having normalized UFC levels and the remaining patients showed a reduction in UFC levels of 44-52%. (Vilar et al, 2010) | + | Another study looked at a combination of cabergoline and ketoconazole for treating Cushing’s disease. Initially, 12 patients were prescribed cabergoline for 6 months. Nine of these patients did not respond well to the treatment, however the addition of the ketoconazole to the treatment led to six of the nine patients having normalized UFC levels and the remaining patients showed a reduction in UFC levels of 44-52% (Vilar et al, 2010) |
| Combination therapy is on the rise and has a lot of potential as it has shown to increase the effectiveness of different drugs while reducing their side effects. | Combination therapy is on the rise and has a lot of potential as it has shown to increase the effectiveness of different drugs while reducing their side effects. | ||
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| Vilar, L., Naves, L. A., Azevedo, M. F., Arruda, M. J., Arahata, C. M., Moura E Silva, L., … Canadas, V. (2010). Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing’s disease. Pituitary, 13(2), 123–129. https://doi.org/10.1007/s11102-009-0209-8 | Vilar, L., Naves, L. A., Azevedo, M. F., Arruda, M. J., Arahata, C. M., Moura E Silva, L., … Canadas, V. (2010). Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing’s disease. Pituitary, 13(2), 123–129. https://doi.org/10.1007/s11102-009-0209-8 | ||
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