Glucocorticoid remediable aldosteronism
Encyclopedia
Glucocorticoid remediable aldosteronism (GRA) is an autosomal dominant disorder in which the increase in aldosterone
secretion produced by ACTH is no longer transient.
It is a cause of primary hyperaldosteronism.
Aldosterone synthase
is a steroid
hydroxylase cytochrome P450 oxidase enzyme involved in the generation of aldosterone
. It is localized to the mitochondrial inner membrane. The enzyme has steroid 18-hydroxylase activity to synthesize aldosterone
and other steroids. Aldosterone synthase is found within the zona glomerulosa
at the outer edge of the adrenal cortex
. Aldosterone synthase normally is not ACTH sensitive, and only activated by angiotensin II.
Aldosterone causes the tubules of the kidneys to retain sodium
and water
. This increases the volume of fluid in the body, and drives up blood pressure
.
Steroid hormones are synthesized from cholesterol
within the adrenal cortex
. Aldosterone
and corticosterone
share the first part of their biosynthetic pathway. The last part is either mediated by the aldosterone synthase (for aldosterone) or by the 11β-hydroxylase (for corticosterone
).
encoding aldosterone synthase
and 11-hydroxylase are 95% identical and are close together on chromosome 8. In individuals with GRA, there is unequal crossing over so that the 5' regulatory region of the 11-hydroxylase gene is fused to the coding region of the aldosterone synthase.
The product of this hybrid gene is aldosterone synthase
that is ACTH-sensitive in the zona fasciculata
of the adrenal gland.
Although in normal subjects, ACTH accelerates the first step of aldosterone synthesis, ACTH normally has no effect on the activity of aldosterone synthase
. However, in subjects with glucocorticoid-remediable aldosteronism, ACTH increases the activity of existing aldosterone synthase
, resulting in an abnormally high rate of aldosterone synthesis and hyperaldosteronism
.
, but the following symptoms can be present
are remedied when ACTH secretion is suppressed by administering glucocorticoids.
Dexamethasone
, spironolactone
and eplerenone
have been used in treatment.
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
secretion produced by ACTH is no longer transient.
It is a cause of primary hyperaldosteronism.
Normal Physiology
Aldosterone synthase
Aldosterone synthase
Aldosterone synthase is a steroid hydroxylase cytochrome P450 oxidase enzyme involved in the generation of aldosterone....
is a steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
hydroxylase cytochrome P450 oxidase enzyme involved in the generation of aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
. It is localized to the mitochondrial inner membrane. The enzyme has steroid 18-hydroxylase activity to synthesize aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
and other steroids. Aldosterone synthase is found within the zona glomerulosa
Zona glomerulosa
The zona glomerulosa of the adrenal gland is the most superficial layer of the adrenal cortex, lying directly beneath the adrenal gland's capsule...
at the outer edge of the adrenal cortex
Adrenal cortex
Situated along the perimeter of the adrenal gland, the adrenal cortex mediates the stress response through the production of mineralocorticoids and glucocorticoids, including aldosterone and cortisol respectively. It is also a secondary site of androgen synthesis.-Layers:Notably, the reticularis in...
. Aldosterone synthase normally is not ACTH sensitive, and only activated by angiotensin II.
Aldosterone causes the tubules of the kidneys to retain sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
and water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
. This increases the volume of fluid in the body, and drives up blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
.
Steroid hormones are synthesized from cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
within the adrenal cortex
Adrenal cortex
Situated along the perimeter of the adrenal gland, the adrenal cortex mediates the stress response through the production of mineralocorticoids and glucocorticoids, including aldosterone and cortisol respectively. It is also a secondary site of androgen synthesis.-Layers:Notably, the reticularis in...
. Aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
and corticosterone
Corticosterone
Corticosterone is a 21-carbon steroid hormone of the corticosteroid type produced in the cortex of the adrenal glands.-Roles:In many species, including amphibians, reptiles, rodents and birds, corticosterone is a main glucocorticoid, involved in regulation of fuel, immune reactions, and stress...
share the first part of their biosynthetic pathway. The last part is either mediated by the aldosterone synthase (for aldosterone) or by the 11β-hydroxylase (for corticosterone
Corticosterone
Corticosterone is a 21-carbon steroid hormone of the corticosteroid type produced in the cortex of the adrenal glands.-Roles:In many species, including amphibians, reptiles, rodents and birds, corticosterone is a main glucocorticoid, involved in regulation of fuel, immune reactions, and stress...
).
- Aldosterone synthesis is stimulated by several factors:
- by increase in the plasma concentration of angiotensin III.
- by increased plasma angiotensin II, ACTH, or potassiumPotassiumPotassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
levels. - The ACTH stimulation testACTH stimulation testThe ACTH stimulation test is a medical test usually ordered and interpreted by endocrinologists to assess the functioning of the adrenal glands stress response by measuring the adrenal response to adrenocorticotropic hormone...
is sometimes used to stimulate the production of aldosterone along with cortisolCortisolCortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
to determine if primary or secondary adrenal insufficiencyAdrenal insufficiencyAdrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones , primarily cortisol, but may also include impaired aldosterone production which regulates sodium, potassium and water retention...
is present. - by plasma acidosisAcidosisAcidosis is an increased acidity in the blood and other body tissue . If not further qualified, it usually refers to acidity of the blood plasma....
. - by the stretch receptors located in the atriaAtriaAtria may refer to:*Atrium , an anatomical structure of the heart*Atrium , a large open space within a building*Atria or Alpha Trianguli Australis, a star in the constellation Triangulum Australe...
of the heartHeartThe heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
. - by adrenoglomerulotropin, a lipidLipidLipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
factor, obtained from pineal extracts. It selectively stimulates secretion of aldosterone. - The secretion of aldosterone has a diurnal rhythm.
- Control of aldosterone release from the adrenal cortex:
-
- The role of the renin-angiotensin systemRenin-angiotensin systemThe renin-angiotensin system or the renin-angiotensin-aldosterone system is a hormone system that regulates blood pressure and water balance....
:
- Angiotensin is involved in regulating aldosterone and is the core regulator. Angiotensin II acts synergistically with potassium.
- The role of sympatheticSympathetic nervous systemThe sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
nerves:
- Aldosterone production is also affected to one extent or another by nervous control which integrates the inverse of carotid arteryCarotid arteryCarotid artery can refer to:* Common carotid artery* External carotid artery* Internal carotid artery...
pressure, painPainPain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
, postureHuman positionHuman positions refers to the different positions that the human body can take.There are several synonyms that refer to the human position, often used interchangeably, but having specific flavors....
, and probably emotionEmotionEmotion is a complex psychophysiological experience of an individual's state of mind as interacting with biochemical and environmental influences. In humans, emotion fundamentally involves "physiological arousal, expressive behaviors, and conscious experience." Emotion is associated with mood,...
(anxietyAnxietyAnxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, fearFearFear is a distressing negative sensation induced by a perceived threat. It is a basic survival mechanism occurring in response to a specific stimulus, such as pain or the threat of danger...
, and hostilityHostilityHostility is a form of angry internal rejection or denial in psychology. It is a part of personal construct psychology, developed by George Kelly...
)(including surgical stress).
- The role of baroreceptors:
- Pressure in the carotid arteryCarotid arteryCarotid artery can refer to:* Common carotid artery* External carotid artery* Internal carotid artery...
decreases aldosterone
- The role of the juxtaglomerular apparatusJuxtaglomerular apparatusThe juxtaglomerular apparatus is a microscopic structure in the kidney, which regulates the function of each nephron. The juxtaglomerular apparatus is named for its proximity to the glomerulus: it is found between the vascular pole of the renal corpuscle and the returning distal convoluted tubule...
- The plasma concentration of potassiumPotassiumPotassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
:
- The amount of aldosterone secreted is a direct function of the serum potassium as probably determined by sensors in the carotid artery.
- The plasma concentration of sodiumSodiumSodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
:
- Aldosterone is a function of the inverseMultiplicative inverseIn mathematics, a multiplicative inverse or reciprocal for a number x, denoted by 1/x or x−1, is a number which when multiplied by x yields the multiplicative identity, 1. The multiplicative inverse of a fraction a/b is b/a. For the multiplicative inverse of a real number, divide 1 by the...
of the sodium intake as sensed via osmotic pressureOsmotic pressureOsmotic pressure is the pressure which needs to be applied to a solution to prevent the inward flow of water across a semipermeable membrane....
.
- Miscellaneous regulation:
- ACTH, a pituitary peptide, also has some stimulating effect on aldosterone probably by stimulating deoxycorticosteroneDeoxycorticosterone11-Deoxycorticosterone is a steroid hormone produced by the adrenal gland that possesses mineralocorticoid activity and acts as a precursor to aldosterone. As its names indicate, it can be understood as 21-hydroxy- variant of progesterone or a 11-deoxy- variant of corticosterone...
formation which is a precursorPrecursor (chemistry)In chemistry, a precursor is a compound that participates in the chemical reaction that produces another compound. In biochemistry, the term "precursor" is used more specifically to refer to a chemical compound preceding another in a metabolic pathway....
of aldosteroneAldosteroneAldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
. - Aldosterone is increased by blood loss, pregnancyPregnancyPregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
, and possibly by other circumstances such as physical exertion, endotoxin shock, and burnBurnA burn is an injury to flesh caused by heat, electricity, chemicals, light, radiation, or friction.Burn may also refer to:*Combustion*Burn , type of watercourses so named in Scotland and north-eastern England...
s.
- The role of the renin-angiotensin system
-
- Aldosterone feedbackFeedbackFeedback describes the situation when output from an event or phenomenon in the past will influence an occurrence or occurrences of the same Feedback describes the situation when output from (or information about the result of) an event or phenomenon in the past will influence an occurrence or...
:- Feedback by aldosterone concentration itself is of a non-morphological character (that is, other than changes in cell number or structure) and is relatively poor, so that electrolyte feedback predominates in the short term.
Pathophysiology
The genesGênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
encoding aldosterone synthase
Aldosterone synthase
Aldosterone synthase is a steroid hydroxylase cytochrome P450 oxidase enzyme involved in the generation of aldosterone....
and 11-hydroxylase are 95% identical and are close together on chromosome 8. In individuals with GRA, there is unequal crossing over so that the 5' regulatory region of the 11-hydroxylase gene is fused to the coding region of the aldosterone synthase.
The product of this hybrid gene is aldosterone synthase
Aldosterone synthase
Aldosterone synthase is a steroid hydroxylase cytochrome P450 oxidase enzyme involved in the generation of aldosterone....
that is ACTH-sensitive in the zona fasciculata
Zona fasciculata
The zona fasciculata constitutes the middle zone of the adrenal cortex, sitting directly beneath the zona glomerulosa. Constituent cells are organized into bundles or "fascicles"....
of the adrenal gland.
Although in normal subjects, ACTH accelerates the first step of aldosterone synthesis, ACTH normally has no effect on the activity of aldosterone synthase
Aldosterone synthase
Aldosterone synthase is a steroid hydroxylase cytochrome P450 oxidase enzyme involved in the generation of aldosterone....
. However, in subjects with glucocorticoid-remediable aldosteronism, ACTH increases the activity of existing aldosterone synthase
Aldosterone synthase
Aldosterone synthase is a steroid hydroxylase cytochrome P450 oxidase enzyme involved in the generation of aldosterone....
, resulting in an abnormally high rate of aldosterone synthesis and hyperaldosteronism
Hyperaldosteronism
Hyperaldosteronism, also aldosteronism, is a medical condition where too much aldosterone is produced by the adrenal glands, which can lead to lowered levels of potassium in the blood.-Types:...
.
Symptoms
Patients with GRA may be asymptomaticAsymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
, but the following symptoms can be present
- FatigueFatigue (physical)Fatigue is a state of awareness describing a range of afflictions, usually associated with physical and/or mental weakness, though varying from a general state of lethargy to a specific work-induced burning sensation within one's muscles...
- HeadacheHeadacheA headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
- High blood pressure
- HypokalemiaHypokalemiaHypokalemia or hypokalaemia , also hypopotassemia or hypopotassaemia , refers to the condition in which the concentration of potassium in the blood is low...
- Intermittent or temporary paralysisParalysisParalysis is loss of muscle function for one or more muscles. Paralysis can be accompanied by a loss of feeling in the affected area if there is sensory damage as well as motor. A study conducted by the Christopher & Dana Reeve Foundation, suggests that about 1 in 50 people have been diagnosed...
- Muscle spasms
- Muscle weaknessMuscle weaknessMuscle weakness or myasthenia is a lack of muscle strength. The causes are many and can be divided into conditions that have true or perceived muscle weakness...
- Numbness
- PolyuriaPolyuriaPolyuria is a condition usually defined as excessive or abnormally large production or passage of urine . Frequent urination is sometimes included by definition, but is nonetheless usually an accompanying symptom...
- PolydipsiaPolydipsiaPolydipsia is a medical symptom in which the patient displays excessive thirst. The word derives from the Greek πολυδιψία, which is derived from πολύς + δίψα...
- Tingling
- Hypernatraemia
- Metabolic alkalosisMetabolic alkalosisMetabolic alkalosis is a metabolic condition in which the pH of tissue is elevated beyond the normal range . This is the result of decreased hydrogen ion concentration, leading to increased bicarbonate, or alternatively a direct result of increased bicarbonate concentrations.-Terminology:*Alkalosis...
Treatment
In GRA, the hypersecretion of aldosterone and the accompanying hypertensionHypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
are remedied when ACTH secretion is suppressed by administering glucocorticoids.
Dexamethasone
Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
, spironolactone
Spironolactone
Spironolactone , commonly referred to as simply spiro, is a diuretic and is used as an antiandrogen.It is a synthetic 17-lactone drug that is a renal competitive aldosterone antagonist in a class of pharmaceuticals called...
and eplerenone
Eplerenone
Eplerenone is an aldosterone antagonist used as an adjunct in the management of chronic heart failure. It is similar to the diuretic spironolactone, though it may be more specific for the mineralocorticoid receptor and is specifically marketed for reducing cardiovascular risk in patients...
have been used in treatment.
See also
- HyperaldosteronismHyperaldosteronismHyperaldosteronism, also aldosteronism, is a medical condition where too much aldosterone is produced by the adrenal glands, which can lead to lowered levels of potassium in the blood.-Types:...
- AldosteroneAldosteroneAldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
- ACTH
- aldosterone synthaseAldosterone synthaseAldosterone synthase is a steroid hydroxylase cytochrome P450 oxidase enzyme involved in the generation of aldosterone....
- GlucocorticoidGlucocorticoidGlucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...