Introduction

Vasopressin or antidiuretic hormone (ADH) or arginine vasopressin (AVP) is a nonapeptide synthesized in the hypothalamus. Science has known it to play essential roles in the control of the body’s osmotic balance, blood pressure regulation, sodium homeostasis, and kidney functioning. Given its vital role in multiple functions, it is no surprise that ADH is of great clinical significance. ADH primarily affects the ability of the kidney to reabsorb water; when present, ADH induces expression of water transport proteins in the late distal tubule and collecting duct to increase water reabsorption. Several disease states arise when the body loses control of ADH secretion or responds to its presence.[1]

In states of hypovolemia or hypernatremia, ADH is released from the posterior pituitary gland and binds to the type-2 receptor in principal cells of the collecting duct. Binding to the receptor triggers an intracellular cyclic adenosine monophosphate (cAMP) pathway, which causes phosphorylation of the aquaporin-2 (AQP2). After achieving water homeostasis, the ADH levels decrease, and AQP2 is internalized from the plasma membrane, leaving the plasma membrane watertight again.[1]

Cellular Level

ADH synthesis occurs in the hypothalamus. Specifically, it is principally produced by neurons that have their cell bodies within the supraoptic nuclei of the hypothalamus. There is also production, albeit in smaller quantities, in neurons with cell bodies located in the paraventricular nuclei, the site primarily responsible for oxytocin, a homologous hormone mostly involved in uterine contraction and milk let down. These storage vesicles are transported down the neuron’s axon through the hypothalamic-hypophysial tract, where they are ultimately released in the posterior pituitary. The secreted hormones then enter nearby fenestrated capillaries where they enter the body’s systemic circulation.[1]

Development

ADH is a nonapeptide derived from the preprohormone called prepropressophysin, which contains a signal peptide, neurophysin II, and a glycoprotein. In the Golgi apparatus, the signal peptide portion is cleaved from prepropressophysin to produce a prohormone stored in secretory vesicles. In route to the posterior pituitary where ADH will be released, the prohormone is cleaved to produce ADH.

Organ Systems Involved

• Kidneys
• Posterior pituitary

Function

ADH is the primary hormone responsible for tonicity homeostasis. Hyperosmolar states most strongly trigger its release. ADH is stored in neurons within the hypothalamus. These neurons express osmoreceptors that are exquisitely responsive to blood osmolarity and respond to changes as little as two mOsm/L.[2] Therefore, slight elevations in osmolarity result in the secretion of ADH. ADH then acts primarily in the kidneys to increase water reabsorption, thus returning the osmolarity to baseline.

ADH secretion also occurs during states of hypovolemia or volume depletion. In these states, decreased baroreceptors sense arterial blood volume in the left atrium, carotid artery, and aortic arch. Information about low blood pressure sensed by these receptors is transmitted to the vagus nerve, which directly stimulates the release of ADH. ADH then promotes water reabsorption in the kidneys and, at high concentrations, will also cause vasoconstriction. These two mechanisms together serve to increase effective arterial blood volume and increase blood pressure to maintain tissue perfusion. It is also important to note that in states of hypovolemia, ADH will be secreted even in hypoosmotic states. Conversely, hypervolemia inhibits ADH secretion; therefore, in hyperosmotic hypervolemic states, ADH secretion will be reduced.[1]

Osmolarity and volume status are the two greatest factors that affect ADH secretion. However, a variety of other factors promote ADH secretion as well. These include angiotensin II, pain, nausea, hypoglycemia, nicotine, opiates, and certain medications. ADH secretion is also negatively affected by ethanol, alpha-adrenergic agonists, and atrial natriuretic peptide. Ethanol’s inhibitory effect helps to explain the increased diuresis experienced during intoxicated states as well as increased free water loss; without appropriate ADH secretion, the kidneys excrete more water.[3]

Mechanism

ADH principally exerts its effects by binding to the kidneys principal cells within the late distal tubule and collecting ducts. ADH binds to the V receptor on these cells and leads to the activation of adenylate cyclase, which causes a subsequent increase in the second messenger cyclic AMP (cAMP). cAMP activates protein kinase A (PKA), a phosphorylating enzyme that initiates an intracellular phosphorylation cascade. Ultimately, intracellular aquaporin-2 (AQP2) storage vesicles are phosphorylated, which promotes their movement and insertion into the apical membrane. AQP2 is a water channel that allows water to move passively into the cell guided by the osmotic gradient established by NaCl and urea, and thus promotes reabsorption of water in the kidney. This activity creates concentrated, or hyperosmotic, urine, and allows our body to conserve water in times of dehydration or loss of sufficient blood volume, as seen in hemorrhagic or edematous states.[1]

ADH also has a second action on vascular smooth muscle. ADH binds to V receptors on vascular smooth muscle and activates G protein. G activates phospholipase C (PLC), which results in the production of inositol triphosphate (IP-3) as well as diacylglycerol (DAG) from the cell membrane. IP-3 causes a release of intracellular calcium from the endoplasmic reticulum. DAG and calcium activate protein kinase C (PKC), which, like PKA, results in a signaling phosphorylation cascade. The net effect of this signaling cascade is a contraction of vascular smooth muscle leading to increases in total peripheral resistance and thus increases in blood pressure. This mechanism is synergistic with water reabsorption in that both mechanisms elevate blood pressure. This mechanism is crucial in periods where sufficient arterial blood volume is low to maintain tissue perfusion.[1]

Related Testing

The laboratory values commonly used to diagnose conditions associated with ADH abnormalities include serum osmolality, urine osmolality, urine electrolytes, thyroid function tests, cortisol levels, liver function tests, and serum uric acid.   

Pathophysiology

There are three pathologic states related to ADH. The first is the syndrome of inappropriate ADH (SIADH) and occurs when ADH is released in excessive unregulated quantities. SIADH results in excess water reabsorption and thus creates dilutional hyponatremia. Although water is retained in quantities greater than the body's needs, these patients typically remain euvolemic and do not exhibit features of the third spacing of fluid such as edema. The mechanism behind this is that, regardless of the excess ADH present, the kidneys maintain their ability to excrete salt. As ADH signals for increased water reabsorption, the body senses the increase in extracellular volume, and natriuretic mechanisms come into play that cause increased salt excretion via the kidneys. The increased salt in the urine will osmotically attract water to be excreted as well, thus keeping the body in a euvolemic state. This increase in salt excretion also contributes to the hyponatremia seen in SIADH. Settings in which SIADH arises include malignancies (most often by autonomous production of ADH by small cell lung cancer), central nervous system (CNS) disturbances (e.g., stroke, hemorrhage, infection, trauma, etc.), drugs (e.g., selective serotonin reuptake inhibitors, carbamazepine, and others), surgery (most likely secondary to pain), and more. Patients with SIADH may be asymptomatic or present with a spectrum of severity of complaints based on their level of hyponatremia. Nausea and malaise are typically the earliest presenting symptoms and present when the sodium acutely falls below 125 to 130 mEq/L. Lower levels of sodium are associated with headache, obtundation, seizure, and even coma and respiratory arrest.[4] These symptoms arise due to the increased movement of water into neurons as the extracellular osmolarity falls. The intracellular swelling causes neuronal dysfunction.[5]

Unlike the excess ADH seen in SIADH, the remaining two pathologic states related to ADH result from either decreased ADH or resistance to its effects. A failure of ADH secretion causes central diabetes insipidus. In this scenario, ADH levels are low; thus, the collecting tubules are impermeable to water, resulting in excess water excretion. In nephrogenic diabetes insipidus, ADH secretion is normal, but there is a defect in the V receptor or other signaling mediators that makes the kidneys unresponsive to ADH. In either disease, the net effect is increased excretion of water. The depletion of water causes the production of large volumes of dilute water and the concentration of body fluids leading to hypernatremia and hyperosmolarity. This status results in polyuria, polydipsia, and the effects of electrolyte imbalances that ensue.[6]

Central diabetes insipidus is the more common form and often seen after brain trauma or surgery that damages either the hypothalamus or posterior pituitary. Other cerebral infiltrative processes such as infection, autoimmune disease, or neoplastic disease may also cause central diabetes insipidus. Nephrogenic diabetes insipidus can be either inherited or acquired. The most common inherited form is attributed to mutations in the V receptor and often manifests in childhood. Acquired causes of nephrogenic diabetes insipidus are more often at play in adulthood expression of the disease. Most often, acquired nephrogenic diabetes insipidus is due to drugs, notably lithium and some antibiotics such as tetracyclines.[6]

Clinical Significance

ADH is an important hormone that is responsible for water, osmolar, and blood pressure homeostasis. Its function is vital in times of thirst, hemorrhage, the third spacing of fluid, and other scenarios where there is the diminution of effective arterial blood flow. Its efforts serve to maintain volume status as well as blood pressure to continue adequate tissue perfusion. Additionally, the pathologic states discussed above are important considerations when working up patients with electrolyte imbalances. SIADH is a common cause of hyponatremia and may be a sign of an underlying occult malignancy when no other risk factor is present. Clinically, SIADH is the diagnosis in a hyponatremic patient who has evidence of decreased plasma osmolarity (less than 275 mOsm/kg), inappropriately concentrated urine (urine osmolarity greater than 100 mOsm/kg), elevated urine sodium (greater than 20 mEq/L), and euvolemia.[5]

Diabetes insipidus is an important cause of hypernatremia. They are distinguished from each other and primary polydipsia, a disease of dysregulated thirst mechanism resulting in excess fluid intake and, therefore, polydipsia and polyuria, by a water deprivation challenge. In this test, a patient's urine and plasma osmolarity are measured at baseline and then repeatedly measured over a few hours while they are not allowed to drink water. If during this period of water deprivation, their urine osmolarity increases to above 750 mOsm/kg, then primary polydipsia is the diagnosis as this signals the body is adequately releasing ADH in response to a lack of fluid intake. If the urine osmolarity remains low, then this implies an issue with ADH is present, and diabetes insipidus is likely the culprit. To differentiate between nephrogenic and central forms of the disease, during the water deprivation challenge, one may administer desmopressin, an ADH analog. If after desmopressin administration urine osmolarity increases, then central diabetes insipidus is present as this scenario describes a working response ADH. If, however, desmopressin does not increase urine osmolarity, then we know the response to ADH is inappropriate, and it must be nephrogenic diabetes insipidus. This distinction is important to make as the treatment differs between nephrogenic and central diabetes insipidus. The treatment for the central form is to replace the inadequate ADH with desmopressin. In the nephrogenic form, the treatment of choice is thiazide diuretics. Thiazide diuretics act at the distal convoluted tubule to block sodium and chloride cotransport. The increased excretion of sodium chloride induces mild hypovolemia, which triggers increased sodium reabsorption in the proximal convoluted tubule. This increase in sodium reabsorption will promote the increase in passive water reabsorption in the same segment, resulting in a net decrease in water excretion, thus mitigating the polyuria seen in these patients.[6]

Aside from its role in homeostasis and its part in a variety of pathologies, ADH has also served as a medication to treat two important bleeding disorders: von Willebrand disease and hemophilia A. Von Willebrand disease is the most common inherited bleeding disorder in which mutations lead to disruption of the synthesis or function of von Willebrand factor (VWF), the factor that tethers platelets to endothelium by binding collagen on endothelial surface and GpIb on the platelet surface. VWF is a crucial factor in the development of primary hemostasis. Also, VWF plays a role in secondary hemostasis by binding to and stabilizing factor VIII. Desmopressin is used to treat von Willebrand disease as it leads to an increase in the secretion of VWF and factor VIII from endothelium.[7] Hemophilia A is a bleeding disorder owed to either an acquired or inherited lack of factor VIII. As stated, desmopressin also promotes the release of factor VIII from the endothelium, thus bridging the missing gap in hemophilia A's coagulopathy.[8]