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ODESA NATIONAL MEDICAL UNIVERSITYDepartment of Internal Medicine № 1 with the course of cardiovascular diseasesMETHODIC RECOMMENDATIONS FOR PRACTICAL CLASSESEducational discipline "Internal Medicine, including endocrinology"Topic "Diseases of the adrenal glands. Chronic insufficiency of the adrenal cortex. Etiology, pathogenesis, symptoms, diagnostics, prevention and treatment. Hormon-producing tumors of the adrenal glands "Course IV Faculty: internationalSpecialty : 222 -"Medicine"The lecture was discussed on the methodical meeting of the department___________________ Protocol № Head of the department Prof, Yu.I. Karpenko OdesaActuality of the topic.Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones (chemicals produced by the body that regulate organ function), primarily cortisol, but may also include impaired aldosterone production (a mineralcorticoid) which regulates sodium, potassium and water retention. Craving for salt or salty foods due to the urinary losses of sodium is common.II. The purpose of the lecture:To acquaint students with the functional anatomy and physiology of adrenal glands.To acquaint students with etiology, pathogenesis, clinical presentation, diagnosis, prevention and treatment of Chronic Insufficiency of Adrenal Cortex glands (Addison’s disease) and Acute Adrenal Insufficiency.To acquaint students with classification of Tumors of Adrenal Glands.To acquaint students with clinical presentation, diagnosis, treatment of Cushing’s syndrome.To acquaint students with clinical presentation, diagnosis, treatment ofConn’ssyndrome.To acquaint students with etiology, pathogenesis, clinical features, diagnosis and treatment of Pheochromocytoma.To acquaint students with clinical forms, diagnosis and treatment of Congenital Adrenal Hyperplasia.This discipline needs basic knowledge:Peculiarities of anatomy and physiology of endocrine systemAnamnesis of endocrine patientsObjective investigationMethods of instrumental and laboratory diagnosisDifferential diagnosis of chronic insufficiency of adrenal cortexTreatment of chronic insufficiency of adrenal cortexIII. A task for the self-preparation of a student for a lessonInformation for raising the level of basic knowledge can be found in the following textbooks:Training: 1. Davidson’s “Principles of Practice of Medicine” 22th edition, 2014.2. Harrison’s “Principles of internal medicine”, 19th edition, 2015Additional:American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas ? 2009An Endocrine Society Clinical Practice Guideline:The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment (2016)Diagnosis and Treatment of Primary Adrenal Insufficiency (2015)Treatment of Cushing’s Syndrome (2015)Diagnosis and Treatment of Pheochromocytoma and Paraganglioma (2014)Congenital Adrenal Hyperplasia Due to Steroid 21-hydroxylase Deficiency (2010)Diagnosis of Cushing's Syndrome (2008). Questions:Spread among population in Ukraine and other countriesEtiology and pathogenesis of chronic insufficiency of adrenal cortexClinical manifestations of chronic insufficiency of adrenal cortexLaboratory methods of diagnostics in patients with chronic insufficiency of adrenal cortex Methods of treatment of chronic insufficiency of adrenal cortexV. Plan of self-study:#Consequence of actionsIndications1Diagnosis of chronic insufficiency of adrenal cortexPlan of patient examination2Basic clinical and instrumental laboratory data of chronic insufficiency of adrenal cortexCriterions of chronic insufficiency of adrenal cortex diagnosis, tests3Practical actions in clinicsClinical diagnosis, prescribe medicineTask for self-study: References, tables, schemes of treatmentVI.The content of the topic:The normal adrenal glands weigh 6–11 g each. They are located above the kidneys and have their own blood supply. Arterial blood flows initially to the subcapsular region and then meanders from the outer cortical zona glomerulosa through the intermediate zonafasciculata to the inner zona reticularis and eventually to the adrenal medulla. The right suprarenal vein drains directly into the vena cava while the left suprarenal vein drains into the left renal vein. During early embryonic development, the adrenals originate from the urogenital ridge and then separate from gonads and kidneys about the 6th week of gestation. Concordant with the time of sexual differentiation (seventh to ninth week of gestation), the adrenal cortex starts to produce cortisol and the adrenal sex steroid precursor DHEA. The orphan nuclear receptors SF1 (steroidogenic factor 1) and DAX1 (dosage-sensitive sex reversal gene 1), among others, play a crucial role during this period of development, as they regulate a multitude of adrenal genes involved in steroidogenesis.Histologically, the cortex is divided into three zones, but these function as two units (zona glomerulosa and zonaefasciculata/reticularis) which produce corticosteroids in response to humoral stimuli. The adrenal cortex produces several hormones. The most important are aldosterone (a mineralocorticoid), cortisol (a glucocorticoid), and androgen and estrogen (sex hormones). These hormones manage metabolism and body characteristics, such as hair growth and body shape. The adrenal cortex secretes 3 types of hormones: (1) mineralocorticoids (the most important of which is aldosterone), which are secreted by the zona glomerulosa; (2) glucocorticoids (predominantly cortisol), which are secreted by the zonafasciculata and, to a lesser extent, the zona reticularis; and (3) adrenal androgen (mainly dehydroepiandrosterone [DHEA]), which is predominantly secreted by the zona reticularis, with small quantities released from the zonafasciculata. All adrenocortical hormones are steroid compounds derived from cholesterol. Cortisol binds to proteins in the blood, mainly cortisol-binding globulin or transcortin. More than 90% of cortisol is transported in the blood in this bound form. In contrast, only 50% of aldosterone is bound to protein in the blood. All adrenocortical steroids are degraded in the liver and predominantly conjugated to glucuronides, with lesser amounts of sulfates formed. About 75% of these degradation products are excreted in the urine, and the rest is excreted in the stool by means of the bile.MineralocorticoidsAldosterone accounts for 90% of mineralocorticoid activity, with some activity contributed by deoxycorticosterone, corticosterone, and cortisol. The normal concentration of aldosterone in the blood ranges from 2–16 ng/dL supine and 5–41 ng/dL upright, although the concentration exhibits diurnal variation, and the secretory rate is generally 150–250 mcg/d.Aldosterone promotes sodium reabsorption and potassium excretion by the renal tubular epithelial cells of the collecting and distal tubules. As sodium is reabsorbed, water follows passively, leading to an increase in the extracellular fluid volume with little change in the plasma sodium concentration. Persistently elevated extracellular fluid volumes cause hypertension. This helps minimize further increases in extracellular fluid volume by causing a pressure diuresis in the kidney, a phenomenon known as aldosterone escape. Without aldosterone, the kidney loses excessive amounts of sodium and, consequently, water, leading to severe dehydration.As sodium is actively reabsorbed, potassium is excreted. Imbalances in aldosterone thus lead to hypokalemia and muscle weakness if levels are increased and to hyperkalemia with cardiac toxicity if levels are decreased. In addition to sodium being exchanged for potassium at the renal tubules, hydrogen is also exchanged, although to a much lesser extent. Therefore, with aldosterone excess, mild metabolic alkalosis may develop. In addition to the effects of aldosterone on the renal tubules, a smaller but similar effect is noted on the sweat glands and salivary glands. Aldosterone stimulates sodium chloride reabsorption and potassium secretion in the excretory ducts, which helps prevent excessive salivation and conserve body salt in hot climates. Aldosterone also affects sodium absorption in the intestine, especially the colon. Deficiency may cause a watery diarrhea from the unabsorbed sodium and water. Many factors affect aldosterone secretion, the most important of which involve the renin-angiotensin system and changes in the plasma potassium concentration.Activation of the renin-angiotensin system: The juxtaglomerular apparatus senses decreased blood flow to the kidney secondary to hypovolemia, hypotension, or renal artery stenosis and releases renin in response. Renin is an enzyme that activates angiotensinogen to release angiotensin I. In the lung, ACE converts angiotensin I to angiotensin II, a potent vasoconstrictor and stimulator of aldosterone release by the adrenal gland.Concentration of potassium in the extracellular fluid: Increases in the plasma potassium concentration stimulate the release of aldosterone to encourage potassium excretion by the kidney.Concentration of sodium in the extracellular fluid: Decreases in sodium concentration also stimulate aldosterone release.Adrenocorticotropic hormone (ACTH) secretion: ACTH secreted by the anterior pituitary primarily affects release of glucocorticoids by the adrenal but, to a lesser extent, also stimulates aldosterone release.GlucocorticoidsApproximately 95% of glucocorticoid activity comes from cortisol, with corticosterone, a glucocorticoid less potent than cortisol, making up the rest. The normal cortisol concentration in the blood averages 12 mcg/dL, with a secretory rate averaging 15–20 mg/d. Cortisol release is almost entirely controlled by the secretion of ACTH by the anterior pituitary gland, which is controlled by corticotropin-releasing hormone (CRH) secreted by the hypothalamus. In normal situations, CRH, ACTH, and cortisol secretory rates demonstrate a circadian rhythm, with a zenith in the early morning and a nadir in the evening. Various stresses also stimulate increased ACTH and, thus, cortisol secretion. A negative feedback effect of cortisol on the anterior pituitary and the hypothalamus help control these increases and regulate plasma cortisol concentrations.Cortisol has many effects on the body.Cortisol stimulates gluconeogenesis in the liver by stimulating the involved enzymes and mobilizing necessary substrates, specifically amino acids from muscle and free fatty acids from adipose tissue. It simultaneously decreases glucose use by extrahepatic cells in the body. The overall result is an increase in serum glucose (ie, adrenal diabetes) and increased glycogen stores in the liver.Cortisol decreases protein stores in the body, except in the liver, by inhibiting protein synthesis and stimulating catabolism of muscle protein.Cortisol has clinically significant anti-inflammatory effects, blocking the early stages of inflammation by stabilizing lysosomal membranes, preventing excessive release of proteolytic enzymes, decreasing capillary permeability and, consequently, edema, and decreasing chemotaxis of leukocytes. In addition, it induces rapid resolution of inflammation that is already in progress.Immunity is adversely affected. Eosinophil and lymphocyte counts in the blood decrease with atrophy of lymphoid tissue.Adrenal androgensThe adrenal cortex continually secretes several male sex hormones, including DHEA, DHEA sulfate (DHEAS), androstenedione, and 11-hydro-xyandrostenedione, with small quantities of the female sex hormones progesterone and estrogen. Most of the effects result from extra-adrenal conversion of the androgens to testosterone. All have weak effects, but they likely play a role in early development of the male sex organs in childhood, and they have an important role in women during pubarche. ACTH has a definite stimulatory effect on androgen release by the adrenal. Therefore, secretion of these hormones parallels that of cortisol.Adrenal Medulla. The adrenal medulla is a completely different entity.Epinephrine (80%) and norepinephrine (20%), with minimal amounts of dopamine, are secreted into the bloodstream due to direct stimulation by acetylcholine release from sympathetic nerves. Preganglionic sympathetic nerve fibers pass from the intermediolateral horn cells of the spinal cord through the sympathetic chains and splanchnic nerves, without synapsing, into the adrenal medulla. These hormones are responsible for an increase in cardiac output and vascular resistance and for all the physiologic characteristics of the stress response.Addison’s Disease (Chronic Insufficiency of Adrenal Cortex glands)Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones (chemicals produced by the body that regulate organ function), primarily cortisol, but may also include impaired aldosterone production (a mineralcorticoid) which regulates sodium, potassium and water retention. Craving for salt or salty foods due to the urinary losses of sodium is common.Addison's disease is the worst degree of adrenal insufficiency, which if not treated, results in severe abdominal pains, diarrhea, vomiting, profound muscle weakness and fatigue, depression, extremely low blood pressure, weight loss, kidney failure, changes in mood and personality and shock may occur (adrenal crisis). An adrenal crisis often occurs if the body is subjected to stress, such as an accident, injury, surgery, or severe infection; death may quickly follow.Adrenal insufficiency can also occur when the hypothalamus or the pituitary gland, both located at the base of the skull, doesn't make adequate amounts of the hormones that assist in regulating adrenal function. This is called secondary adrenal insufficiency and is caused by lack of production of ACTH in the pituitary or lack of CRH in the hypothalamus.TypesThere are two major types of adrenal insufficiency.Primary adrenal insufficiency is due to impairment of the adrenal glands. - The most common subtype is called idiopathic or unknown cause of adrenal insufficiency. - Some are due to an autoimmune disease called Addison's disease or autoimmune adrenalitis. - Other cases are due to congenital adrenal hyperplasia or an adenoma (tumor) of the adrenal gland. Secondary adrenal insufficiency is caused by impairment of the pituitary gland or hypothalamus. These can be due to a form of cancer: a pituitary microadenoma, or a hypothalamic tumor; Sheehan's syndrome, which is associated with impairment of only the pituitary gland; or a past head injury. "Tertiary adrenal insufficiency" is due to hypothalamic disease and decrease in corticotropin releasing factor (CRF).Causes- Autoimmune (may be part of Type 2 autoimmune polyglandular syndrome, which can include type I Diabetes Mellitus), hyperthyroidism, autoimmune thyroid disease (also known as autoimmune thyroiditis, Hashimoto's thyroiditis and Hashimoto's disease). Hypogonadism and pernicious anemia may also present with this syndrome. - Adrenoleukodystrophy- Discontinuing corticosteroid therapy without tapering the dosage (severe adrenal suppression with ACTH suppression) - Illness or any other forms of stress (this is termed critical illness–related corticosteroid insufficiency) - kidney injury - environmental- toxic (eg. mercury poisoning) - genetics- Head injury - Radiation - Surgery - infections (eg, miliary tuberculosis affecting the adrenal glands, meningitis, histoplasmosis) - congenital hypopituitarism - congentialhypoadrenalismSymptomsThe person may show symptoms of hypoglycemia, dehydration, weight loss and disorientation. They may experience weakness, tiredness, dizziness, low blood pressure that falls further when standing (orthostatic hypotension), muscle aches, nausea, vomiting, and diarrhea. These problems may develop gradually and insidiously. Addison's can present with tanning of the skin which may be patchy or even all over the body. In some cases a person with normally light skin may be mistaken for another race with darker pigmentation. Characteristic sites of tanning are skin creases (e.g. of the hands) and the inside of the cheek (buccal mucosa). Goitre and vitiligo may also be present.DiagnosisIf the person is in adrenal crisis, the ACTH stimulation test may be given. If not in crisis, cortisol, ACTH, aldosterone, renin, potassium and sodium are tested from a blood sample before the decision is made if the ACTH stimulation test needs to be performed. X-rays or CT of the adrenals may also be done. The best test for adrenal insufficiency of autoimmune origin, representing more than 90% of all cases in a Western population, is measurement of 21-hydroxylase autoantibodies.TreatmentAdrenal crisis - Intravenous fluids- Intravenous steroid (Solu-Cortef or Solumedrol), later hydrocortisone, prednisone or methylpredisolone tablets - Rest Cortisol deficiency (primary and secondary) - Adrenal cortical extract (usually in the form of a supplement, non prescription in the United States) - Hydrocortisone (Cortef) (between 20 and 35 mg)- Prednisone (Deltasone) (7? mg) - Prednisolone (Delta-Cortef) (7? mg) - Methylprednisolone (Medrol) (6 mg) - Dexamethasone (Decadron) (1/4 mg, some doctors rescribe 1/2 to 1 mg, but those doses tend to cause side effects resembling Cushing's disease) ACUTE ADRENAL INSUFFICIENCYAcute adrenal insufficiency usually occurs after a prolonged period of nonspecific complaints and is more frequently observed in patients with primary adrenal insufficiency, due to the loss of both glucocorticoid and mineralocorticoid secretion. Postural hypotension may progress to hypovolemic shock. Adrenal insufficiency may mimic features of acute abdomen with abdominal tenderness, nausea, vomiting, and fever. In some cases, the primary presentation may resemble neurologic disease, with decreased responsiveness, progressing to stupor and coma. An adrenal crisis can be triggered by an intercurrent illness, surgical or other stress, or increased glucocorticoid inactivation (e.g., hyperthyroidism).1.The Waterhouse-Friderichsen SyndromeThe bacterial infection leads to massive hemorrhage into one or (usually) both adrenal glands. It is characterized by overwhelming bacterial infection meningococcemia leading to massive blood invasion, organ failure, coma, low blood pressure and shock, disseminated intravascular coagulation with widespread purpura, rapidly developing adrenocortical insufficiency and death. Multiple species of bacteria can be associated with the condition: Meningococcus is another term for the bacterial species Neisseria meningitidis; blood infection with said species usually underlies WFS. While many infectious agents can infect the adrenals, an acute, selective infection is usually Meningococcus. Pseudomonas aeruginosa can also cause WFS. WFS can also be caused by Streptococcus pneumoniae infections, a common bacterial pathogen typically associated with meningitis in the adult and elderly population. Mycobacterium tuberculosis could also cause WFS. Tubercular invasion of the adrenal glands could cause hemorrhagic destruction of the glands and cause mineralocorticoid deficiency. Staphylococcus aureus has recently also been implicated in pediatric WFS. It can also be associated with Haemophilusinfluenzae. Cytomegalovirus can cause adrenal insufficiency, especially in the immunocompromised. Signs and symptoms. WFS is the most severe form of meningococcal septicemia. The onset of the illness is nonspecific with fever, rigors, vomiting, and headache. Soon a rash appears; first macular, not much different from the rose spots of typhoid, and rapidly becoming petechial and purpuric with a dusky gray color. Low blood pressure (hypotension) is the rule and rapidly leads to septic shock. The cyanosis of extremities can be impressive and the patient is very prostrated or comatose. In this form of meningococcal disease, meningitis generally does not occur. There is hypoglycemia with hyponatremia and hyperkalemia, and the ACTH stimulation test demonstrates the acute adrenal failure. Leukocytosis need not to be extreme and in fact leukopenia may be seen and it is a very poor prognostic sign. C-reactive protein levels can be elevated or almost normal. Thrombocytopenia is sometimes extreme, with alteration in prothrombin time (PT) and partial thromboplastin time (PTT) suggestive of diffuse intravascular coagulation (DIC). Acidosis and acute renal failure can be seen as in any severe sepsis. Meningococci can be readily cultured from blood or CSF, and can sometimes be seen in smears of cutaneous lesions. Dysphagia, atrophy of the tongue, and cracks at the corners of the mouth are also characteristic features.2.Addisonian crisisIn an emergency, anyone with Addison’s disease can experience symptoms of extreme weakness, a serious drop in blood pressure and mental confusion. This means they need extra steroid medication immediately, and may need an emergency injection. As a general rule, an Addisonian should give themselves an emergency injection of 100 mg hydrocortisone sodium (Efcortesol or Solu-Cortef) if they vomit more than once. The causes of an Addisonian crisis: severe physical shock, e.g. a car accident; severe infection, e.g. flu with a high temperature; severe dehydration, e.g. stomach bug with vomiting The symptoms of an Addisonian crisis: extreme weakness, mental confusion, extreme drowsiness, in advanced cases slipping towards a coma, pronounced dizziness, nausea and/or vomiting, severe headache, abnormal heart rate – either too fast or too slow, abnormally low blood pressure, feeling extremely cold, possibly a fever, possibly abdominal tenderness.Unilateral adrenalectomy in Cushing's syndrome or glucocorticosteromaCongenitalAdrenalaplasiaMetastasistoAdrenalglandsDysfunction of adrenal cortex in stress conditionsWithdrawal symptoms in patients with long-term corticosteroid therapyDiseases of the hypothalamic-pituitary with deficiency of adreno-corticotropic hormoneCNS disease: brain tumor, meningitis, encephalitis, optic nerve glioma10. Adrenogenital syndromeAcute adrenal insufficiency (AAI) is a rare but severe condition caused by a sudden defective production of adrenal steroids (cortisol and aldosterone). It represents an emergency, thus the rapid recognition and prompt therapy are critical for survival even before the diagnosis is made. The disease may occur at any age. The onset is often sudden. The initial presentation may be limited to abdominal pain, nausea, vomiting and fever. Hypoglycemic seizures or symptoms of dehydration are common manifestations seen in children. If untreated, shock and bilateral adrenal hemorrhage can rapidly lead to death.The clinical signs are nonspecific but the diagnosis of AAI is suspected if a patient presents with hypotonia or shock that responds poorly to catecholamines. Laboratory exams show signs of adrenal insufficiency (hypoglycemia, hyponatremia and elevated natriuresis, hyperkaliemia, hemoconcentration, hypochloremic metabolic acidosis and functional renal failure) confirmed by hypocortisolemia, increased ACTH, and an insufficient response to rapid ACTH stimulation testing that leads to the diagnosis of absolute and peripheral AAI. The mineralocorticoid insufficiency, when present, can be confirmed by low aldosterone levels and high plasma renin activity (PRA). The etiological diagnosis is based on various imaging exams (CT-scan, ultrasound, or MRI). In case of anterior pituitary insufficiency, ACTH is low. Secondary adrenal insufficiency needs to be eliminated. Peritonitis is often a differential diagnosis as well as other causes of adrenal destruction such as bilateral adrenalectomy, Waterhouse-Friderichsen syndrome, autoimmune adrenalitis, infectious adrenalitis and tumour infiltration.Acute adrenal insufficiency requires immediate initiation of rehydration, usually carried out by saline infusion at initial rates of 1 L/h with continuous cardiac monitoring. Glucocorticoid replacement should be initiated by bolus injection of 100 mg hydrocortisone, followed by the administration of 100– 200 mg hydrocortisone over 24 h, either by continuous infusion or provided by several IV or IM injections. Mineralocorticoid replacement can be initiated once the daily hydrocortisone dose has been reduced to <50 mg because at higher doses hydrocortisone provides sufficient stimulation of mineralocorticoid receptors. Prognosis varies depending on the etiologies, but is generally correlated with the rapidity of diagnosis and medical assistance. Death is rare when the patients receive appropriate medical assistance.Cushing's syndromeCushing's syndrome (also called hyperadrenocorticism or hypercorticism) is a hormone (endocrine) disorder caused by high levels of cortisol (hypercortisolism) in the blood. This can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or adrenocorticotropic hormone (ACTH). Cushing's disease refers to one specific cause, a tumor (adenoma) in the pituitary gland that produces large amounts of ACTH, which in turn elevates cortisol. It can usually be cured by surgery. It was described by Harvey Cushing in 1932.Cushing's syndrome is not confined to humans and is also a relatively common condition in domestic dogs and horses.Signs and symptomsSymptoms include rapid weight gain, particularly of the trunk and face with sparing of the limbs (central obesity). A common sign is the growth of fat pads along the collar bone and on the back of the neck (buffalo hump) and a round face often referred to as a "moon face". Other symptoms include hyperhidrosis (excess sweating), telangiectasia (dilation of capillaries), thinning of the skin (which causes easy bruising and dryness, particularly the hands) and other mucous membranes, purple or red striae (the weight gain in Cushing's syndrome stretches the skin, which is thin and weakened, causing it to hemorrhage) on the trunk, buttocks, arms, legs or breasts, proximal muscle weakness (hips, shoulders), and hirsutism (facial male-pattern hair growth), baldness and/or cause hair to become extremely dry and brittle. In rare cases, Cushing's can cause hypercalcemia, which can lead to skin necrosis. The excess cortisol may also affect other endocrine systems and cause, for example, insomnia, inhibited aromatase, reduced libido, impotence, amenorrhoea/oligomenorrhea and infertility due to elevations in androgens. Patients frequently suffer various psychological disturbances, ranging from euphoria to psychosis. Depression and anxiety are also common.Other striking and distressing skin changes that may appear in Cushing's syndrome include facial acne, susceptibility to superficial dermatophyte and malassezia infections, and the characteristic purplish, atrophic striae on the abdomen.Other signs include polyuria (and accompanying polydipsia), persistent hypertension (due to cortisol's enhancement of epinephrine's vasoconstrictive effect) and insulin resistance (especially common in ectopic ACTH production), leading to hyperglycemia (high blood sugar) which can lead to diabetes mellitus. Untreated Cushing's syndrome can lead to heart disease and increased mortality. Cushing's syndrome due to excess ACTH may also result in hyperpigmentation, such as acanthosisnigricans in the axilla. This is due to Melanocyte-Stimulating Hormone production as a byproduct of ACTH synthesis from Pro-opiomelanocortin (POMC). Cortisol can also exhibit mineralcorticoid activity in high concentrations, worsening the hypertension and leading to hypokalemia (common in ectopic ACTH secretion). Furthermore, gastrointestinal disturbances, opportunistic infections and impaired wound healing (cortisol is a stress hormone, so it depresses the immune and inflammatory responses). Osteoporosis is also an issue in Cushing's syndrome since, as mentioned before, cortisol evokes a stress-like response. Consequently, the body's maintenance of bone (and other tissues) becomes secondary to maintenance of the false stress response. Additionally, Cushing's may cause sore and aching joints, particularly in the hip, shoulders, and lower back.CauseThere are several possible causes of Cushing's syndrome.Exogenous vs. endogenousHormones that come from outside the body are called exogenous; hormones that come from within the body are called endogenous.The most common is exogenous administration of glucocorticoids prescribed by a health care practitioner to treat other diseases (called iatrogenic Cushing's syndrome). This can be an effect of steroid treatment of a variety of disorders such as asthma and rheumatoid arthritis, or in immunosuppression after an organ transplant. Administration of synthetic ACTH is also possible, but ACTH is less often prescribed due to cost and lesser utility.Endogenous Cushing's syndrome results from some derangement of the body's own system of secreting cortisol. Normally, ACTH is released from the pituitary gland when necessary to stimulate the release of cortisol from the adrenal glands.In pituitary Cushing's, a benign pituitary adenoma secretes ACTH. This is also known as Cushing's disease and is responsible for 65% of endogenous Cushing's syndrome. In adrenal Cushing's, excess cortisol is produced by adrenal gland tumors, hyperplastic adrenal glands, or adrenal glands with nodular adrenal hyperplasia. Finally, tumors outside the normal pituitary-adrenal system can produce ACTH that affects the adrenal glands. This final etiology is called ectopic or paraneoplastic Cushing's syndrome and is seen in diseases like small cell lung cancer. PathophysiologyThe hypothalamus is in the brain and the pituitary gland sits just below it. The paraventricular nucleus (PVN) of the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release adrenocorticotropin (ACTH). ACTH travels via the blood to the adrenal gland, where it stimulates the release of cortisol. Cortisol is secreted by the cortex of the adrenal gland from a region called the zonafasciculata in response to ACTH. Elevated levels of cortisol exert negative feedback on the pituitary, which decreases the amount of ACTH released from the pituitary gland. Strictly, Cushing's syndrome refers to excess cortisol of any etiology. One of the causes of Cushing's syndrome is a cortisol secreting adenoma in the cortex of the adrenal gland. The adenoma causes cortisol levels in the blood to be very high, and negative feedback on the pituitary from the high cortisol levels causes ACTH levels to be very low. Cushing's disease refers only to hypercortisolism secondary to excess production of ACTH from a corticotrophic pituitary adenoma. This causes the blood ACTH levels to be elevated along with cortisol from the adrenal gland. The ACTH levels remain high because a tumor causes the pituitary to be unresponsive to negative feedback from high cortisol levels.Cushing's Syndrome was also the first autoimmune disease identified in humans.DiagnosisWhen Cushing's syndrome is suspected, either a dexamethasone suppression test (administration of dexamethasone and frequent determination of cortisol and ACTH level), or a 24-hour urinary measurement for cortisol offer equal detection rates. Dexamethasone is a glucocorticoid and simulates the effects of cortisol, including negative feedback on the pituitary gland. When dexamethasone is administered and a blood sample is tested, high cortisol would be indicative of Cushing's syndrome because there is an ectopic source of cortisol or ACTH (e.g.: adrenal adenoma) that is not inhibited by the dexamethasone. A novel approach, recently cleared by the US FDA, is sampling cortisol in saliva over 24 hours, which may be equally sensitive, as late night levels of salivary cortisol are high in Cushingoid patients. Other pituitary hormone levels may need to be ascertained. Performing a physical examination to determine any visual field defect may be necessary if a pituitary lesion is suspected, which may compress the optic chiasm causing typical bitemporal hemianopia.When any of these tests are positive, CT scanning of the adrenal gland and MRI of the pituitary gland are performed to detect the presence of any adrenal or pituitary adenomas or incidentalomas (the incidental discovery of harmless lesions). Scintigraphy of the adrenal gland with iodocholesterol scan is occasionally necessary. Very rarely, determining the cortisol levels in various veins in the body by venous catheterization, working towards the pituitary (petrosal sinus sampling) is necessary.MnemonicC - Central obesity, Cervical fat pads, Collagen fibre weakness, Comedones (acne)U - Urinary free cortisol and glucose increaseS - Striae, Suppressed immunityH - Hypercortisolism, Hypertension, Hyperglycaemia, HirsutismI - Iatrogenic (Increased administration of corticosteroids)N - Noniatrogenic (Neoplasms)G - Glucose intolerance, Growth retardationTreatmentMost Cushing's syndrome cases are caused by steroid medications (iatrogenic). Consequently, most patients are effectively treated by carefully tapering off (and eventually stopping) the medication that causes the symptoms.If an adrenal adenoma is identified it may be removed by surgery. An ACTH-secreting corticotrophic pituitary adenoma should be removed after diagnosis. Regardless of the adenoma's location, most patients will require steroid replacement postoperatively at least in the interim as long-term suppression of pituitary ACTH and normal adrenal tissue does not recover immediately. Clearly, if both adrenals are removed, replacement with hydrocortisone or prednisolone is imperative.In those patients not suitable for or unwilling to undergo surgery, several drugs have been found to inhibit cortisol synthesis (e.g. ketoconazole, metyrapone) but they are of limited efficacy.Removal of the adrenals in the absence of a known tumor is occasionally performed to eliminate the production of excess cortisol. In some occasions, this removes negative feedback from a previously occult pituitary adenoma, which starts growing rapidly and produces extreme levels of ACTH, leading to hyperpigmentation. This clinical situation is known as Nelson's syndrome.Primary aldosteronismPrimary aldosteronism, also known as primary hyperaldosteronism, is characterized by the overproduction of the mineralocorticoid hormonealdosterone by the adrenal glands, when not a result of excessive renin secretion. Aldosterone causes increase in sodium and water retention and potassium excretion in the kidneys, leading to arterial hypertension (high blood pressure). An increase in the production of mineralocorticoid from the adrenal gland is evident. It is the most common cause of secondary hypertension.Primary hyperaldosteronism has many causes, including adrenal hyperplasia and adrenal carcinoma. When it occurs due to a solitary aldosterone-secreting adrenal adenoma(a type of benign tumor), it is known as Conn's syndrome. In practice, however, the two terms are often used interchangeably, regardless of the underlying physiology.CausesThe syndrome is due to:- bilateral idiopathic adrenal hyperplasia 70?% - unilateral idiopathic adrenal hyperplasia 20?% - aldosterone-secreting adrenal adenoma (benign tumor, < 5%) - rare forms, including disorders of the renin-angiotensin system Signs, symptoms and findingsAldosterone enhances exchange of sodium for potassium in the kidney so increased aldosteronism will lead to hypernatremia and hypokalemia. Once the potassium has been significantly reduced by aldosterone, a sodium/hydrogen pump in the nephron becomes more active leading to increased excretion of hydrogen ions and further exacerbating the hypernatremia. The hydrogen ions that are exchanged for sodium are generated by carbonic anhydrase in the renal tubule epithelium causing increased production of bicarbonate. The increased bicarbonate and the excreted hydrogen combine to generate a metabolic alkalosis. The high pH of the blood makes calcium less available to the tissues and causes symptoms of hypocalcemia (low calcium levels).The sodium retention leads to plasma volume expansion and elevated blood pressure. The increased blood pressure will lead to increased glomerular filtration rate and cause a decrease in renin release from the peritubular capillary epithelium in the kidney. If there is a primary hyperaldosteronism the decreased renin (and subsequent decreased angiotensin II) will not lead to a decrease in aldosterone levels (a very helpful clinical tool in diagnosis of primary hyperaldosteronism).Aside from high blood pressure manifestations of muscle cramps (due to hyperexcitability of neurons secondary to hypocalcemia), muscle weakness (due to hypoexcitability of skeletal muscles secondary to hypokalemia), and headaches (due to hypokalemia or high blood pressure) may be seen.Secondary hyperaldosteronism is often related to decreased cardiac output which is associated with elevated renin levels.DiagnosisMeasuring aldosterone alone is not considered adequate to diagnose primary hyperaldosteronism. Rather, both renin and aldosterone are measured, and the ratio is diagnostic.Usually, renin levels are suppressed, leading to a very low renin-aldosterone ratio (<0.0005). This test is confounded by antihypertensive drugs, which have to be stopped up to 6 weeks.If plasma levels of renin and aldosterone suggest hyperaldosteronism, CT scanning can confirm the presence of an adrenal adenoma. If the clinical presentation primarily involves hypertension and elevated levels of catecholamines, CT or MRI scanning can confirm a tumor on the adrenal medulla, typically a pheochromocytoma.Hyperaldosteronism can be mimicked by Liddle syndrome, and by ingestion of licorice and other foods containing glycyrrhizin. In one case report, hypertension and quadriparesis resulted from intoxication with a non-alcoholic pastis (an anise-flavored aperitif containing glycyrrhizinic acid).TherapyThe treatment for hyperaldosteronism depends on the underlying cause. In patients with a single benign tumor (adenoma), surgical removal (adrenalectomy) is curative. This is usually performed laparoscopically, through several very small incisions. For patients with hyperplasia of both glands, successful treatment is often achieved with spironolactone or eplerenone, drugs that block the effect of aldosterone. In males, one common side effect of spironolactone drug therapy sometimes seen is gynecomastia. Gynecomastia usually does not occur with eplerenone drug therapy.In the absence of proper treatment, individuals with hyperaldosteronism often suffer from poorly controlled high blood pressure, which may be associated with increased rates of stroke, heart disease, and kidney failure. With appropriate treatment, the prognosis is excellent.Congenital adrenal hyperplasiaCongenital adrenal hyperplasia (CAH) refers to any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands (steroidogenesis).Most of these conditions involve excessive or deficient production of sex steroids and can alter development of primary or secondary sex characteristics in some affected infants, children, or adults. Only a small minority of people with CAH can be said to have an intersex condition, but this attracted American public attention in the late 1990s and many accounts of varying accuracy have appeared in the popular media. Approximately 95% of cases of CAH are due to 21-hydroxylase deficiency.Associated conditionsThe symptoms of CAH vary depending upon the form of CAH and the gender of the patient. Symptoms can include:Due to inadequate mineralocorticoids:- vomiting due to salt-wasting leading to dehydration and death Due to excess mineralocorticoids:- hypertension (11beta[OH] deficiency) Due to excess androgens:ambiguous genitalia, in some females, such that it can be initially difficult to determine sex - early pubic hair and rapid growth in childhood - precocious puberty or failure of puberty to occur (sexual infantilism: absent or delayed puberty) - excessive facial hair, virilization, and/or menstrual irregularity in adolescence - infertility due to anovulation ClassificationCortisol is an adrenal steroid hormone that is required for normal endocrine function. Production begins in the second month of fetal life. Poor cortisol production is a hallmark of most forms of CAH. Inefficient cortisol production results in rising levels of ACTH, which in turn induces overgrowth (hyperplasia) and overactivity of the steroid-producing cells of the adrenal cortex. The defects causing adrenal hyperplasia are congenital (i.e., present at birth).TreatmentTreatment of all forms of CAH may include any of:- supplying enough glucocorticoid to reduce hyperplasia and overproduction of androgens or mineralocorticoids - providing replacement mineralocorticoid and extra salt if the person is deficient - providing replacement testosterone or estrogen at puberty if the person is deficient - additional treatments to optimize growth by delaying puberty or delaying bone maturation - genital reconstructive surgery to correct problems produced by abnormal genital structure All of these management issues are discussed in more detail in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.PheochromocytomaPheochromocytoma, is a neuroendocrine tumor of the medulla of the adrenal glands (originating in the chromaffin cells), or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually adrenaline (epinephrine) if in the adrenal gland and not extra-adrenal, and noradrenaline (norepinephrine). Extra-adrenal paragangliomas (often described as extra-adrenal pheochromocytomas) are closely related, though less common, tumors that originate in the ganglia of the sympathetic nervous system and are named based upon the primary anatomical site of origin.About 17% of adrenal cases are bilateral (suggesting hereditary disease) About 18.4% of adrenal cases occur in children (also suggesting hereditary disease) About 15% are extra-adrenal (located in any orthosympathetic tissue): of these 9% are in the abdomen and 1% are located elsewhere. Some extra-adrenal phaeochromocytomas are probably actually paragangliomas, but the distinction is only possible after surgical resection. About 11.1% of adrenal cases are malignant, but this rises to 30% for extra-adrenal cases About 26% are hereditary (earlier opinion had 10%) About 3% recur after being resected About 14% of affected individuals do not have arterial hypertension (Campbell's Urology) Signs and SymptomsThe signs and symptoms of a pheochromocytoma are those of sympathetic nervous system hyperactivity, including:- Skin Sensations - Flank Pain - Elevated heart rate - Elevated blood pressure, including paroxysmal (sporadic, episodic) high blood pressure, which sometimes can be more difficult to detect; another clue to the presence of pheochromocytoma is orthostatic hypotension (a fall in systolic blood pressure greater than 20 mmHg or a fall in diastolic blood pressure greater than 10 mmHg on making the patient stand) - Palpitations - Anxiety often resembling that of a panic attack - Diaphoresis- Headaches - Pallor- Weight loss- Localized amyloid deposits found microscopically - Elevated blood glucose level (due primarily to catecholamine stimulation of lipolysis (breakdown of stored fat) leading to high levels of free fatty acids and the subsequent inhibition of glucose uptake by muscle cells. Further, stimulation of beta-adrenergic receptors leads to glycogenolysis and gluconeogenesis and thus elevation of blood glucose levels). A pheochromocytoma can also cause resistant arterial hypertension. A pheochromocytoma can be fatal if it causes malignant hypertension, or severely high blood pressure. This hypertension is not well controlled with standard blood pressure medications.Not all patients experience all of the signs and symptoms listed. The most common presentation is headache, excessive sweating, and increased heart rate, with the attack subsiding in less than one hour.Tumors may grow very large, but most are smaller than 10?cm.CauseUp to 25% of pheochromocytomas may be familial. Mutations of the genes VHL, RET, NF1, SDHB and SDHD are all known to cause familial pheochromocytoma/extra-adrenal paraganglioma.Pheochromocytoma is a tumor of the multiple endocrine neoplasia syndrome, type IIA and type IIB (also known as MEN IIA and MEN IIB, respectively). The other component neoplasms of that syndrome include parathyroid adenomas, and medullary thyroid cancer. Mutations in the autosomal RET proto-oncogene drives these malignancies. Common mutations in the RET oncogene may also account for medullary sponge kidney as well. Pheochromocytoma linked to MEN II can be caused by RET oncogene mutations. Both syndromes are characterized by pheochromocytoma as well as thyroid cancer (thyroid medullary carcinoma). MEN IIA also presents with hyperparathyroidism, while MEN IIB also presents with mucosal neuroma. It is now postulated that Lincoln suffered from MEN IIB, rather than Marfan's syndrome as previously thought, though this is uncertain.Pheochromocytoma is also associated with neurofibromatosis.DiagnosisThe diagnosis can be established by measuring catecholamines and metanephrines in plasma or through a 24-hour urine collection. Care should be taken to rule out other causes of adrenergic (adrenalin-like) excess like hypoglycemia, stress, exercise, and drugs affecting the catecholamines like stimulants, methyldopa, dopamine agonists, or ganglion blocking antihypertensives. Various foodstuffs (e.g. vanilla ice cream) can also affect the levels of urinary metanephrine and VMA (vanillylmandelic acid). Imaging by computed tomography or a T2 weighted MRI of the head, neck, and chest, and abdomen can help localize the tumor. Tumors can also be located using Iodine-123 meta-iodobenzylguanidine (I123 MIBG) imaging.One diagnostic test used in the past for a pheochromocytoma is to administer clonidine, a centrally-acting alpha-2 agonist used to treat high blood pressure. Clonidine mimics catecholamines in the brain, causing it to reduce the activity of the sympathetic nerves controlling the adrenal medulla. A healthy adrenal medulla will respond to the clonidine suppression test by reducing catecholamine production; the lack of a response is evidence of pheochromocytoma.Another test is for the clinician to press gently on the adrenal gland. A pheochromocytoma will often release a burst of catecholamines, with the associated signs and symptoms quickly following. This method is NOT recommended because of possible complications arising from a potentially massive release of catecholamines.Pheochromocytomas occur most often during young-adult to mid-adult life. Less than 10% of pheochromocytomas are malignant (cancerous), bilateral or pediatric.These tumors can form a pattern with other endocrine gland cancers which is labeled multiple endocrine neoplasia (MEN). Pheochromocytoma may occur in patients with MEN 2 and MEN 3 (MEN 2B). Von Hippel Lindau patients may also develop these tumors.Patients experiencing symptoms associated with pheochromocytoma should be aware that it is rare. However, it often goes undiagnosed until autopsy; therefore patients might wisely choose to take steps to provide a physician with important clues, such as recording whether blood pressure changes significantly during episodes of apparent anxiety.Tumor LocationIn adults, approximately 80% of pheochromocytomas are unilateral and solitary, 10% are bilateral, and 10% are extra-adrenal. In children, a fourth of tumors are bilateral, and an additional fourth are extra-adrenal. Solitary lesions inexplicably favor the right side. Although pheochromocytomas may grow to large size (>3kg), most weigh <100g and are <10cm in diameter. Pheochromocytomas are highly vascular.The tumors are made up of large, polyhedral, pleomorphic chromaffin cells. Fewer than 10% of these are malignant. As with several other endocrine tumors, malignancy cannot be determined from the histologic appearance; tumors that contain large number of aneuploid or tetraploid cells, as determined by flow cytometry, are more likely to recur. Local invasion of surrounding tissues or distant metastases indicate malignancy.Extra-adrenal Pheochromocytomas: Extra-adrenal pheochromocytomas usually weigh 20 to 40g and are <5cm in diameter. Most are located within the abdomen in association with the celiac, superior mesenteric, inferior mesenteric ganglia and Organ of Zuckerkandl. Approximately 10% are in the thorax, 1% are within the urinary bladder, and <3% are in the neck, usually in association with the sympathetic ganglia or the extracranial branches of the ninth cranial nerves.TreatmentSurgical resection of the tumor is the treatment of first choice, either by open laparotomy or else laparoscopy. Given the complexity of perioperative management, and the potential for catastrophic intra and postoperative complications, such surgery should be performed only at centers experienced in the management of this disorder. In addition to the surgical expertise that such centers can provide, they will also have the necessary endocrine and anesthesia resources. It may also be necessary to carry out adrenalectomy, a complete surgical removal of the affected adrenal gland(s).Either surgical option requires prior treatment with the non-specific and irreversible alpha adrenoceptor blocker Phenoxybenzamine. Doing so permits the surgery to proceed while minimizing the likelihood of severe intraoperative hypertension (as might occur when the tumor is manipulated). Some authorities would recommend that a combined alpha/beta blocker such as labetalol also be given in order to slow the heart rate. Regardless, a "pure" beta blocker such as atenolol must never be used in the presence of a pheochromocytoma due to the risk of such treatment leading to unopposed alpha agonism and, thus, severe and potentially refractory hypertension.The patient with pheochromocytoma is invariably volume depleted. In other words, the chronically elevated adrenergic state characteristic of an untreated pheochromocytoma leads to near-total inhibition of renin-angiotensin activity, resulting in excessive fluid loss in the urine and thus reduced blood volume. Hence, once the pheochromocytoma has been resected, thereby removing the major source of circulating catecholamines, a situation arises where there is both very low sympathetic activity and volume depletion. This can result in profound hypotension. Therefore, it is usually advised to "salt load" pheochromocytoma patients before their surgery. This may consist of simple interventions such as consumption of high salt food pre-operatively, direct salt replacement or through the administration of intravenous saline solution.Methodical recommendations is prepared by assistant of department O.G. Kozlova, docent O.I. Perstnev ................
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