Antidiuretic Hormone (ADH): Physiology, Pathophysiology, Diagnostic Evaluation, and Clinical Implications
AntiDiuretic Hormone (ADH) is a neuropeptide secreted from the hypothalamus in response to hypovolemia and elevated plasma osmolality.
ADH, also known as vasopressin or arginine vasopressin, plays a critical role in regulating water balance, blood pressure, and vascular resistance. It is essential for maintaining homeostasis and is involved in various pathophysiological conditions, including cardiovascular diseases and diabetes insipidus. Understanding the function of vasopressin is vital for developing therapeutic strategies targeting these conditions.
ADH, also known as vasopressin or arginine vasopressin, plays a critical role in regulating water balance, blood pressure, and vascular resistance. It is essential for maintaining homeostasis and is involved in various pathophysiological conditions, including cardiovascular diseases and diabetes insipidus. Understanding the function of vasopressin is vital for developing therapeutic strategies targeting these conditions.
Neurohypophisars: ADH/Vasopressin
ADH is a peptide hormone pivotal in maintaining fluid, electrolyte, and blood pressure homeostasis. ADH is synthesized by the supraoptic and paraventricular nuclei in the hypothalamus and transported to the posterior pituitary gland (is stored in the pituitary gland). ADH release: the neurohypophysis release ADH, in response to changes in blood osmolality and blood volume. Hence, it is secreted by the posterior pituitary in response to hyperosmolarity and hypovolemia, ADH promoting therefore water reabsorption in the kidneys and causing vasoconstriction. ADH acts on the kidneys to increase water reabsorption, reducing urine output and helping to maintain fluid balance and blood pressure. ADH's major action is on the distal or collecting tubules of the kidney where it promotes reabsorption of solute free water. Its tightly regulated mechanism ensures the preservation of effective arterial blood volume and osmotic equilibrium. ADH secretion is stimulated by an increase in plasma osmolality via osmoreceptors and by a decrease in plasma volume via volume receptors. The hormone's action is primarily mediated through the V2 receptors in renal principal cells, facilitating aquaporin-2 insertion and passive water transport, and through V1 receptors in vascular smooth muscle that increase peripheral resistance. Clinically, disorders of ADH secretion or response manifest in three primary conditions: syndrome of inappropriate ADH secretion (SIADH), central diabetes insipidus (CDI), and nephrogenic diabetes insipidus. Diagnostic evaluation involves serum and urine osmolality, electrolyte panels, water deprivation testing, and response to desmopressin. Understanding the physiological and pathological aspects of ADH is essential for diagnosing and managing a wide spectrum of endocrine, renal, and hematologic conditions.
Antidiuretic Hormone (ADH) Test, Plasma
Mixed forms of diabetes insipidus (DI) can exist, and both central and peripheral DI may be incomplete, complicating the interpretation of results.
Diabetes insipidus (DI) is a rare disorder of water homeostasis characterized by the excretion of abnormally large volumes of hypotonic urine due to the inability to appropriately concentrate urine in response to volume and osmolar stimuli. The primary causes of DI are decreased ADH production (central DI) or decreased renal response to ADH (nephrogenic DI); both of which lead to hypotonic polyuria which is usually accompanied by polydipsia. Along with these etiologies, the differential diagnosis of hypotonic polyuria includes primary polydipsia. In primary polydipsia, there is no initial compromise in ADH secretion or renal action and instead, excessive fluid intake leads to a drop in plasma osmolality and a suppression of ADH synthesis. Primary polydipsia can be caused by an abnormality in the thirst center (dipsogenic polydipsia) or, more commonly, as the result of one of a number of psychiatric disorders (psychogenic polydipsia).
The two major clinical syndromes of antidiuretic hormone secretion are neurogenic diabetes insipidus (DI), an ADH deficiency disorder, and the syndrome of inappropriate ADH secretion (SIADH), a disorder of excess ADH synthesis. The tests used for the differential diagnosis of DI and SIADH, are: serum sodium, plasma osmolality, urine osmolality, U/P osmol ratio, urine output.
Laboratory tests and examinations (DI versus SIADH)
DI is the chronic excretion of very high volumes of hypo-osmotic urine due to ADH deficiency. Polyuria triggers the thirst mechanism resulting in increased polydipsia. If water intake is inadequate, dehydration occurs. DI can be categorized as neurogenic and nephrogenic. In neurogenic DI, ADH secretion by the pituitary or hypothalamus is decreased. ADH deficiency can be partial or complete, depending on the degree of disturbance to the hypothalamus or pituitary. In nephrogenic DI, ADH production and secretion are adequate and appropriate, but the kidneys do not respond to the hormone because of damage to the renal tubules.
Plasma osmolality, urine osmolality and serum sodium are the principal laboratory tests used to diagnose ADH abnormalities. Polyuria increases plasma osmolality to >295 mmol/L and serum sodium to >145 meq/L. Urine osmolality is <300 mmol/L. In partial neurogenic DI, urine osmolality may range between 300 and 800 mmol/L.
Diabetes insipidus can be confirmed with an overnight water deprivation test. This test should be done if a baseline serum osmolality is <295 mosmol. Fluid intake is restricted for 12 to 18 hours and the body weight, urine osmolality, volume and plasma osmolality are measured every 1-2 hours. The test should be discontinued if body weight falls by more than 3%. The objective is to obtain consecutive urine osmolality's which do not differ by more than 30 mosmol.
One can also measure antidiuretic hormone levels at maximum dehydration, which helps differentiate neurogenic from nephrogenic DI. In neurogenic DI, ADH levels decrease as plasma osmolality increases. Conversely, in nephrogenic DI, ADH levels increase with increasing plasma osmolality.
SIADH is the clinical condition that results from inappropriate continued secretion of ADH in the presence of low serum osmolality. The low serum osmolality is due to the retention of water by the kidney in response to ADH. The low serum sodium concentration is due to the dilutional effect of water retention and to the loss of sodium in the urine. Initial symptoms include anorexia, nausea, vomiting, and headache. Cerebral symptoms begin to appear when serum sodium is less than 125 meq/L. Severe hyponatremia (sodium <110 meq/L) or rapidly developing hyponatremia can cause cerebral edema, which is expressed as irritability, confusion, disorientation, convulsions, hemiparesis, and coma.
The major causes of SIADH include neoplasia, pulmonary disorders, neurological disorders and certain drugs.
Laboratory test results that favor a diagnosis of SIADH include: serum sodium <120 meq/L, serum osmolality <280 mOsm, decreased BUN, decreased serum uric acid, urine osmolality >100 mOsm, and urine sodium >20 meq/L. Other diagnostic criteria include the absence of dehydration, edema, adrenal insufficiency, hypothyroidism or renal failure.
The Neurohypophysis: Endocrinology of Vasopressin and Oxytocin
The neurohypophysis consists of three parts: the supraoptic and paravetricular nuclei of the hypothalamus; the supraoptico-hypophyseal tract; and the posterior pituitary. The neurohypophysis is one component of a complex neurohumoral system coordinating physiological responses to changes in both the internal and external environment.
Two hormones made by the hypothalamus and posterior pituitary are vassopressin (AVP) and oxytocin (OT). These hormones have key roles in water balance and reproductive function.
The neurohypophysis is the structural foundation of a neuro-humoral system coordinating fluid balance and reproductive function through the action of the two peptide hormones, vasopressin and oxytocin. Vasopressin is the principle endocrine regulator of renal water excretion, facilitating adaptive physiological responses to maintain plasma volume and plasma osmolality.
Oxytocin is important in parturition and lactation. Data support a wider role for both peptides in the neuro-regulation of complex behaviour. Clinically, deficits in the production or action of vasopressin manifest as diabetes insipidus. An understanding of the physiology and pathophysiology of vasopressin is also critical in approaching the diagnosis and management of hyponatremia, the most common electrolyte disturbance in clinical practice.
Vasopressin receptors
- V1b: pituitary corticotroph;
- V2: basolateral membrane of distal nephron.
Physiological effects of receptor subtypes:
- V1a: smooth muscle contraction, stimulation of glycogenolysis, enhanced platelet adhesion, neurotransmitter & neuromodulatory function;
- V1b: enhanced ACTH release;
- V2: increased synthesis & assembly of aquaporin-2.
Vasopressin and renal water handling
Although AVP has multiple actions, its principle physiological effect is in the regulation of water resorption in the distal nephron, the structure and transport processes of which allow the kidney to both concentrate and dilute urine in response to the prevailing circulating AVP concentration. Active transport of solute out of the thick ascending loop of Henle generates an osmolar gradient in the renal interstitium, which increases from renal cortex to inner medulla, a gradient through which distal parts of the nephron pass end route to the collecting system. AVP stimulates the expression of a specific water channel protein (aquaporin) on the luminal surface of the interstitial cells lining the collecting duct.
The presence of aquaporin (AQP) in the wall of the distal nephron allows resorption of water from the duct lumen along an osmotic gradient, and excretion of concentrated urine; 13 different AQPs are important in humans, seven of which (AQP1-4, AQP6-8) are found in the kidney. AQPs act as passive pores for small substrates and are divided into 2 families: the water only channels; and the aquaglyceroporins that can conduct other small molecules such as glycerol and urea. Most substrates are neutral. However, this is not always the case. For example, AQP6 is a gated ion channel. AQPs are involved in a variety of cell processes: small molecule permeation; gas conduction and cell-cell interaction.
Maximum diuresis occurs at plasma AVP concentrations of 0.5 pmol/l or less. As AVP levels rise, there is a sigmoid relationship between plasma AVP concentration and urine osmolality, with maximum urine concentration achieved at plasma AVP concentrations of 3-4 pmol/L. Following persistent AVP secretion, antidiuresis may diminish. Down-regulation of both V2-R function and AQP2 expression may be responsible for this escape phenomenon.
Figure (on the left side) representing the relationship of plasma AVP concentration to urine osmolality. Shaded area represents range of normal; single line indicates representative individual. AVP has additional effects at other sites in the nephron: decreasing medullary blood flow; stimulating active urea transport in the distal collecting duct; and stimulating active sodium transport into the renal interstitium. As a final outcome, there is generation and maintenance of a hypertonic medullary interstitium, and augment AVP-dependent water resorption.
Regulation of vasopressin release
Osmoregulation of Vasopressin
Plasma osmolality is the most important determinant of AVP secretion. The osmoregulatory systems for thirst and AVP secretion, and in turn the actions of AVP on renal water excretion, maintain plasma osmolality within narrow limits of 284 to 295 mOsmol/kg. The relationship between plasma osmolality and plasma AVP concentration has 3 characteristics.
- The osmotic threshold or 'set point' for AVP release
- The shape of the line describing changes in plasma AVP concentration with changing plasma osmolality
- The sensitivity of the osmoregulatory mechanism coupling plasma osmolality and AVP release.
There are situations where the normal relationship between plasma osmolality and AVP concentration breaks down:
- Rapid changes of plasma osmolality: rapid increases in plasma osmolality result in exaggerated AVP release;
- During the act of drinking: drinking rapidly suppresses AVP release, through afferent pathways originating in the oropharynx;
- Pregnancy: the osmotic threshold for AVP release is lowered in pregnancy.
Additional Mechanisms Regulating Vasopressin Release
A number of other stimuli influence AVP release independent of osmotic and hemodynamic status:
- Nausea and emesis
- Unspecific stress
- Pain
- Manipulation of abdominal contents
- Immune-response mediators and inflammatory triggers
These stimuli contribute to high plasma AVP values observed in acute illness and after surgery.
Additional effects of vasopressin
Thirst
As with AVP release, there are also specific physiological situations in which the relationship between plasma osmolality and thirst breaks down.
- The act of drinking: reduces osmotically stimulated thirst.
- Extracellular volume depletion: this stimulates thirst through volume-sensitive cardiac afferents and the generation of circulating and intra-cerebral A-II, a powerful dipsogen.
- Pregnancy, the luteal phase of the menstrual cycle and super ovulation syndrome: these states reduce the osmolar threshold for thirst.
- Aging: both thirst appreciation and fluid intake can be blunted in the elderly.
The act of drinking reduces thirst perception before any change in plasma osmolality.
This effect is produced through three mechanisms: oropharyngeal sensory afferents; gastro-intestinal stretch-sensitive afferents; and peripheral osmoreceptors in the hepatic portal vein. As with AVP release, hypovolemia resets the relationship between plasma osmolality and thirst. A-II is one of the key mediators of this physiological response. Peripheral A-II generation can act on central osmoreceptors, to increase both thirst and AVP release. An independent, intra-cerebral A-II system is activated in parallel. A-II is a powerful central dipsogen.
Clinical problems secondary to defects in the hypothalamo-posterior pituitary axis
Defects in the production or action of AVP manifest as clinical problems in maintaining plasma sodium concentration and fluid balance, reflecting the key role of the hormone in these processes. A further group of related clinical conditions reflect primary defects in thirst. In some cases, the two may coincide, reflecting the close anatomical and functional relationship of both processes.
Diabetes Insipidus
Classification
Diabetes insipidus (DI) is characterized by production of dilute urine in excess of >50 ml/kg/24 hours in adults. DI arises through one of four mechanisms:
- Deficiency of AVP: central diabetes insipidus (CDI), also called Arginine Vasopressin Deficiency
- Inappropriate, excessive water drinking: primary polydipsia
- Renal resistance to the antidiuretic action of AVP: nephrogenic diabetes insipidus (NDI), also called Arginine Vasopressin Resistance
- Increased vasopressinase expression in pregnancy: gestational diabetes insipidus
Figure showing different forms of hypotonic polyurea
Central Diabetes Insipidus (CDI) (Arginine Vasopressin Deficiency)
CDI (also known as neurogenic or cranial DI) is the result of partial or complete lack of osmoregulated AVP secretion. Plasma AVP concentrations are inappropriately low with respect to prevailing plasma osmolalities. Presentation with CDI implies destruction or loss of function of more than 80% of vasopresinergic magnocellular neurons. Though persistent polyuria can lead to dehydration, most patients can maintain water balance through appropriate polydipsia if given free access to water.
Hypothalamic tumors (e.g., craniopharyngioma) or pituitary metastases (e.g., breast or bronchus) can present with CDI. However, primary pituitary tumors rarely cause CDI. In childhood, craniopharyngioma and germinoma/teratoma are a relatively common cause.
When obvious causes are not present, most cases of CDI will be "idiopathic". However, the possibility of an autoimmune process should be considered, as many idiopathic cases are considered to be autoimmune in origin. A well-recognized cause of autoimmune CDI is lymphocytic infundibulohypophysitis.
Primary Polydipsia (PP)
PP is a polyuric syndrome secondary to excess fluid intake. PP can be associated with organic structural brain lesions, e.g. sarcoidosis of the hypothalamus and craniopharyngioma. It can also be produced by drugs that cause a dry mouth or by any peripheral disorder causing an elevation of renin and/or angiotensin. However, mostly there is no identifiable pathologic etiology; in this circumstance the disorder is often associated with psychiatric syndromes. It also seems to be increasingly prevalent in health conscious people who voluntarily change their drinking habits with the aim to improve their well-being, in which case it is often called habitual polydipsia.
Nephrogenic Diabetes Insipidus (NDI)
NDI is due to renal resistance to the antidiuretic effects of AVP. Genetic variants of NDI usually present in infancy. In these forms, NDI can occur as a result of mutations in the V2 receptor and mutations of the aquaporin 2 water channels.
The development of NDI in an adult is less likely to reflect a genetic cause. Among causes of acquired NDI are hypokalemia, hypercalcemia, and release of bilateral urinary tract obstruction associated with downregulation of aquaporin 2 and decreased function of vasopressin. NDI secondary to lithium is characterized by dysregulated AQP2 expression and trafficking along the whole collecting duct as well as dysregulated expression of the amiloride-sensitive epithelial sodium channel (ENaC) in the cortical collecting duct.
Gestational Diabetes Insipidus
In normal pregnancy, physiologic adaptations include expansion of blood volume and decreased plasma osmolality and serum sodium. Thirst and increased fluid intake are commonly reported in pregnancy, but in some patients the increased thirst is driven by marked polyuria, which may point to the presence of diabetes insipidus. Two types of transient diabetes insipidus must be differentiated in pregnancy, both caused by the placental enzyme cysteine aminopeptidase, named oxytocinase, which enzymatically degrades oxytocin. Because of the close structural homology between AVP and oxytocin, this enzyme also metabolizes AVP. In the first type of pregnancy-associated DI, the activity of oxytocinase is abnormally elevated. This syndrome has been referred to as vasopressin resistant diabetes insipidus of pregnancy and has been reported to be associated with preeclampsia, acute fatty liver, and coagulopathies.
Figure showing the algorithm for the differential diagnosis for the diabetes insipidus.
In establishing the underlying mechanisms of central DI, once the diagnosis is confirmed, imaging of the hypothalamus, pituitary and surrounding structures with MRI is essential. If no mass lesion is identified, imaging should be repeated after 6-12 months so that slow growing germ cell tumors are not missed. Idiopathic and familial central DI are often associated with loss of the normal hyper-intense signal of the posterior pituitary on T1-weighted images. Signal intensity is correlated strongly with AVP content of the gland.
Evidence of anterior pituitary dysfunction should be looked for in central DI, though it is relatively uncommon in the adult population. Interestingly, evidence of organ-specific autoimmune disease is relatively common in adult patients with isolated central DI, consistent with an autoimmune basis for the condition.
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