Pathophysiology
Summary
The posterior pituitary releases two main hormones: antidiuretic hormone (ADH) and oxytocin. These hormones are synthesized in the hypothalamic nuclei, specifically the paraventricular and supraoptic nuclei. After synthesis, they are transported along axons for storage in nerve terminals within the posterior pituitary. This storage mechanism enables secretion even if the posterior pituitary sustains injury.
ADH is released when plasma osmolality > 300 mOsm/Kg (normal range of 275-295 mOsm/Kg). Elevated serum osmolality activates osmoreceptors in the hypothalamus, prompting the posterior pituitary to secrete ADH. Conditions such as hypovolemia, including dehydration, blood loss, cirrhosis, and heart failure, also stimulate ADH secretion. V1 receptors in vascular smooth muscle activate Gq proteins, resulting in vasoconstriction and increased blood pressure. Meanwhile, V2 receptors in the kidney activate Gs proteins, upregulating aquaporin channels in the collecting ducts for enhanced water reabsorption.
Diabetes insipidus (DI) can be central or nephrogenic in origin, and is is characterized by polyuria, hypernatremia, increased serum osmolality, and polydipsia.
Central DI is caused by reduced ADH production in the CNS, specifically the hypothalamus. While often idiopathic, triggers can include autoimmune diseases, hypothalamic brain tumors, and surgeries affecting the hypothalamic and pituitary regions. Treatment for is managed with exogenous ADH-analogs
Nephrogenic DI occurs despite normal ADH levels, as the kidneys are resistant to its effects, and occurs from hereditary mutations in genes encoding V2 receptors or aquaporins This resistance can stem from a lack of ADH receptors, dysfunctional aquaporins, or external factors such as lithium therapy or hypercalcemia. Nephrogenic DI is managed using a combination of medications like thiazide diuretics, amiloride, & NSAIDs, as well as dietary adjustments like low-salt & low-protein diets.
Water-deprivation testing can help distinguish between DI and primary polydipsia by assessing urine and serum osmolality under water deprivation. In DI, the test will reveal low urine osmolality (< 300 mOsm/kg) and elevated serum osmolality (>295 mOsm/kg). Desmopressin, an ADH analogue, is employed to differentiate between the central and nephrogenic DI, causing increased urine osmolality in central DI.
SIADH is characterized by excessive ADH secretion and consequent euvolemic hyponatremia. This is accompanied by concentrated urine and elevated urine sodium levels. In SIADH, initial water retention triggers the secretion of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) from the heart's atria and ventricles, leading to sodium excretion. Concurrently, volume expansion deactivates the renin-angiotensin-aldosterone system (RAAS), leading to reduced aldosterone levels and further sodium excretion.
SIADH can be induced by stroke, meningitis, head trauma, and cancer (e.g. small-cell lung cancer). Additional triggers include surgery and medications like carbamazepine, SSRIs, & cyclophosphamide. Mild cases of SIADH often respond to free water restriction, whereas severe cases may necessitate IV hypertonic saline or medications like V2 receptor blockers such as conivaptan, tolvaptan, and demeclocycline.
Lesson Outline
Don't stop here!
Get access to 155 more Pathophysiology lessons & 13 more medical school learning courses with one subscription!
FAQs
Antidiuretic hormone (ADH) plays a crucial role in maintaining plasma osmolality, which is primarily influenced by serum sodium levels. When plasma hyperosmolality is detected by osmoreceptors in the hypothalamus, it triggers the posterior pituitary gland to release ADH. This hormone acts on two main types of receptors: V1 and V2. V1 receptors are located in vascular smooth muscle and their stimulation leads to vasoconstriction, thereby increasing blood pressure. V2 receptors are found in the kidneys, specifically in the principal cells of the collecting tubules, where their activation upregulates aquaporin channels, leading to increased reabsorption of free water.
Diabetes insipidus (DI) commonly presents with symptoms such as polyuria, hypernatremia, and polydipsia, which result in elevated serum osmolality. Central DI is often idiopathic but can also be caused by autoimmune diseases, brain tumors affecting the hypothalamus, or surgeries involving the hypothalamic and pituitary regions. Nephrogenic DI can be triggered by factors like lithium therapy, hypercalcemia, or certain hereditary conditions that affect the kidneys' response to ADH.
A water-deprivation test is commonly used to distinguish between diabetes insipidus (DI) and primary polydipsia. In DI, this test will not result in an increase in urine osmolality, which remains low due to the inability to reabsorb free water. In contrast, in cases of primary polydipsia where ADH function is normal, the water-deprivation test will lead to increased urine osmolality due to enhanced free water reabsorption.
Syndrome of inappropriate ADH (SIADH) is characterized by excessive secretion of ADH, leading to euvolemic hyponatremia and elevated urine osmolality. This condition can be triggered by various factors such as stroke, meningitis, head trauma, small cell lung cancer, and certain medications like carbamazepine and cyclophosphamide. The excessive ADH leads to increased reabsorption of free water, resulting in dilutional hyponatremia.
For diabetes insipidus, the treatment varies depending on the type. Central DI is commonly treated with exogenous ADH-analogs, while nephrogenic DI may be managed with thiazide diuretics, amiloride, NSAIDs, and dietary modifications such as a low-salt, low-protein diet. In the case of syndrome of inappropriate ADH (SIADH), treatment options range from free water restriction for mild cases to IV hypertonic saline for severe cases. Other treatment options for severe SIADH include V2 receptor blockers like conivaptan and tolvaptan, or demeclocycline, which blocks ADH signaling at the collecting tubule.
MCAT® is a registered trademark of the Association of American Medical Colleges. The United States Medical Licensing Examination (USMLE®) is a joint program of the Federation of State Medical Boards (FSMB®) and National Board of Medical Examiners (NBME®). NAPLEX® is a registered trademark of the National Association of Boards of Pharmacy. PANCE© is a registered trademark of the National Commission on Certification of Physician Assistants. NCLEX® is a registered trademark and service mark of the National Council of State Boards of Nursing, Inc. None of the trademark holders are endorsed by nor affiliated with Sketchy or this website.
