class: center, middle, inverse, title-slide .title[ # Posterior Pituitary Gland ] .author[ ### 盧子文醫師 <br>.lk[(<a href="tel:46-05211">GSM: 46-05211</a>)] ] .institute[ ### 高醫附設中和紀念醫院<br>.lk[<a href="mailto:highker@gap.kmu.edu.tw" class="email">highker@gap.kmu.edu.tw</a>] ] .date[ ### 2024/05/14 (updated: 2024-06-01) ] --- ## 學習目標 .e2[ - Anatomy - Posterior pituitary hormones - Arginine vasopressin(AVP) - Oxitocin - Diabetes insipidus(DI) - The Syndrome of Inappropriate Antidiuresis Hormones(SIADH) ] --- class: center, middle # Posterior pituity gland (Neurohypophysis) --- ### Posterior pituity gland .e4[ - Structure and Development: - The posterior pituitary is neural tissue and consists only of the distal axons of the hypothalamic magnocellular neurons that make up the neurohypophysis. - These neurons' cell bodies are located in the hypothalamus' paraventricular(PVN) and supraoptic nuclei(SON). - Neuroepithelial Cell Maturation: - During embryogenesis, neuroepithelial cells lining the third ventricle mature into magnocellular neurons. These cells migrate to form the supraoptic nuclei(SON) and the paraventricular nuclei(PVN). - Neurotransmitters and Neuronal Activity: - Glutamate is the major stimulatory neurotransmitter in the neurohypophysis. .red[Gamma-aminobutyric acid (GABA)] provides major inhibitory input. ] --- background-image: url(data:image/png;base64,#pit01.png) background-position: 95% 50% background-size: 50% .pull-left[ - Blood Supply - direct blood supply from the .red[inferior hypophyseal arteries], branches of the posterior communicating and internal carotid arteries. - Hormones Synthesized: - The main hormones produced by the posterior pituitary are .red[oxytocin and vasopressin]. Most magnocellular neurons are specific to one hormone, though a small number (~3%) can produce both. - Neuronal Distribution and Function: - The supraoptic nucleus mainly produces vasopressin, while the more complex paraventricular nucleus synthesizes other peptides like .ud[corticotropin-releasing hormone(CRH), thyrotropin-releasing hormone(TRH), somatostatin, and opioids]. ] --- ### Ectopic Posterior Pituitary .e3[ - MRI: - T1-weighted bright signal in the posterior pituitary - abnormal anatomy of the posterior pituitary when the “bright spot” was recognized in the base of the hypothalamus. - Cases with malformations are more likely to have diabetes insipidus or other osmotic dysfunction than simple ectopic posterior pituitary - Children with these pituitary abnormalities often present with growth retardation and deficiencies in the anterior pituitary rather than the posterior pituitary. - Deficiency of adrenocorticotropic hormone (ACTH) is common ] --- background-image: url(data:image/png;base64,#avp01.png) background-position: 50% 90% background-size: 50% ### Structures of AVP, Oxytocin, DDAVP --- ### AVP physiology .e4[ - The physiologic regulation of vasopressin synthesis and secretion involves two systems: osmotic and pressure/volume. - Functions of these two systems are so distinct that historically it was thought there were two hormones, .ud[an antidiuretic hormone and a vasopressor hormone.] Hence the two names that are used interchangeably for (8-arginine) .red[vasopressin] - `\(V_{1a}\)` receptors: on blood vessels; Glycogenolysis. - `\(V_2\)` receptors: - on renal collecting duct epithelia - stimulate factor VIII and von Willebrand factor production(vWF) - `\(V_{1b}\)` receptors: - stimulate ACTH secretion from the anterior pituitary - in numerous peripheral tissues and areas of the brain. ] --- .e3[ - The most important physiologic action of AVP is to reduce water excretion by promoting concentration of urine. - In the absence of AVP, these cells are impermeable to water and reabsorb little. - In this condition, the rate of urine output can be as high as 0.2 mL/kg per min and the specific gravity and osmolarity as low as ~1.000 and 50 mosmol/L - When AVP is secreted, it binds to V2 receptors on the basal surface of principal cells causing water channels composed of aquaporin-2(AQP2) to be inserted into the apical surface of the cell. ] --- .e3[ - The maximum anti-diuresis achievable in healthy humans occurs at plasma AVP levels in the range of 1 to 3 pg/mL and results in a urine osmolarity as high as 1200 mosmol/L and a rate of output as low as 0.35 mL/ min. - At high concentrations, AVP also causes contraction of smooth muscle in blood vessels in the skin and gastro-intestinal tract, induces glycogenolysis in the liver, and potentiates adreno-corticotropic hormone (ACTH) release by corticotropin-releasing factor(CRF). - via `\(V_{1a}\)` or `\(V_{1b}\)` receptors - 臨床上Low GI bleeding或angioplasia的病人會用DDAVP來止血(血管收縮+促進凝血因子釋放) - 半衰期 `\(t_{1/2}\)`： 10–30 min. - degradation in the liver and kidneys. ] --- background-image: url(data:image/png;base64,#avp02.png) background-position: 50% 50% background-size: 90% --- ### Volume and Pressure Regulation .e3[ - Location of Receptors - High-pressure arterial baroreceptors are located in the carotid sinus and aortic arch - Low-pressure volume receptors are located in the atria and pulmonary venous system. - Signal Transmission: - afferent signals from these receptors are transmitted to the brainstem through cranial nerves 9 and 10 - Baroreceptors and volume receptors normally inhibit magnocellular neurons, and decreases in this tonic inhibition result in the release of vasopressin. ] --- background-image: url(data:image/png;base64,#avp03.png) background-position: 70% 90% background-size: 45% .e4[ - Vasopressin action on `\(V_{1a}\)` receptors induces arterial and venous constriction, contracting vessels around the existing plasma volume to effectively increase plasma volume and reestablish inhibition of vasopressin secretion. - While vasopressin acts at the kidney to retain water and help replace volume, .red[the primary hormonal regulation of volume control is the .ud[Renin-Angiotensin-Aldosterone System (RAAS)]], which stimulates sodium reabsorption in the kidney. ] --- ### Thirst .e3[ - Thirst and fluid intake are regulated primarily by an osmostat that is situated in the anteromedial hypothalamus and is able to detect very small changes in the plasma concentration of sodium and its anions. - The thirst osmostat appears to be “set” about 3% higher than the AVP osmostat. - This arrangement ensures that thirst, polydipsia, and dilution of body fluids do not occur until plasma osmolarity/ sodium exceeds the defensive capacity of the antidiuretic mechanism. ] --- ### Oxitocin .e3[ - Oxytocin is also a nonapeptide that differs from AVP only at positions 3 and 8 - relatively little antidiuretic effect - act mainly on mammary ducts to facilitate milk - may help initiate or facilitate labor by stimulating contraction of uterine smooth muscle ] --- class: center, middle # Diabetes Insipidus --- ### Diabetes Insipidus .e4[ - Excretion of large volumes of urine (diabetes), hypotonic, dilute - The 24-h urine volume exceeds 40 mL/ kg body weight - The 24-h urine osmolarity is <280 mosm/L. - Tasteless (insipid). - Diabetes mellitus: hypertonic and sweet urine - clinical symptoms： increase in fluid intake (polydipsia) - Four abnormal pathophysiologic processes: 1. Primary polydipsia, caused by excess fluid intake 2. Hypothalamic or .red[central diabetes insipidus(CDI)], caused by diminished synthesis or secretion of vasopressin 3. Diabetes insipidus of pregnancy(gestational DI), caused by increased enzymatic metabolism of vasopressin 4. .red[Nephrogenic diabetes insipidus(NDI)], caused by renal resistance to vasopressin ] --- background-image: url(data:image/png;base64,#di01.png) background-position: 50% 50% background-size: contain --- ### Diabetes Insipidus Due to Excess Fluid Intake (Primary Polydipsia) .e3[ - Primary polydipsia is associated with a wide variety of organic structural brain lesions, including 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 - the disorder can be associated with psychiatric syndromes or be habitual throughout a lifetime. ] --- ###Central Diabetes Insipidus(CDI) .e4[ - Genes mutation - Autosomal dominant (AVP-neurophysin gene) - Autosomal recessive - Type A (AVP-neurophysin gene) - Type B (AVP-neurophysin gene) - Type C (Wolfram’s [4p-WFS1] gene) - X-linked recessive (Xq28) - Neurosurgical intervention with transsphenoidal or transcranial surgery causes CDI in as many as 50% to 60% of patients - Most of whom will recover, with only a small number having permanent diabetes insipidus. - Craniopharyngioma is particularly associated with CDI, particularly after extensive suprasellar surgery ] --- ### Nephrogenic diabetes insipidus(NDI) .e4[ - usually present in infancy, with vomiting, failure to thrive, and polyuria. - caused by a drug such as lithium, a disorder such as hypokalemia, or a genetic mutation - The most common genetic form is transmitted in a semirecessive X-linked manner and is due to mutations in the gene on chromosome Xq28 that encodes the V2 receptor. - caused by mutations of the gene on chromosome 20 that encodes the aquaporin-2 water channels ] --- ### Diabetes Insipidus of Pregnancy(Gestational DI) .e3[ - Caused by a deficiency of antidiuretic hormone (AVP) due to an increased rate of degradation by an N-terminal aminopeptidase produced in the placenta. - The signs and symptoms appear during pregnancy and usually remit several weeks after delivery. - Patients with Sheehan syndrome may exhibit asymptomatic partial diabetes insipidus but rarely develop overt diabetes insipidus. ] --- background-image: url(data:image/png;base64,#di08.png) background-position: 50% 50% background-size: 70% ####Pathophysiology of DI .footnote[ [Diabetes insipidus. Nat Rev Dis Primers 5, 54 (2019).](<https://doi.org/10.1038/s41572-019-0103-2>)] --- background-image: url(data:image/png;base64,#di02.png) background-position: 50% 90% background-size: 65% ### Approach to the Differential Diagnosis of Polyuric States --- .e3[ - polyuria(A 24-hour urine volume >50 mL/kg) - a random urine osmolality above 700 mOsm/kg excludes diabetes insipidus and makes the diagnosis of primary polydipsia certain. - Presenting serum sodium concentration is almost always normal in diabetes insipidus - → A 24-h urine on unrestricted fluid intake - → Check urine osmolarity - <280 mosm/L and the volume >50 mL/kg/day → the patient has DI → Water deprivation test ] --- background-image: url(data:image/png;base64,#di10.png) background-position: 50% 50% background-size: 90% #### **Modified algorithm for differential diagnosis of polyuria–polydipsia syndrome** .footnote[ [Diabetes insipidus. Nat Rev Dis Primers 5, 54 (2019).](<https://doi.org/10.1038/s41572-019-0103-2>) ] --- background-image: url(data:image/png;base64,#di03.png) background-position: 90% 50% background-size: 45% #### Water deprivation test .pull-left[ 1. The test should be started in the morning 2. Hourly measurements of body weight, plasma osmolality/Na concentration and urine volume and osmolality 3. The patient is maintained on a complete fluid restriction until urinary osmolality reach a plateau (an hourly increase of less than 30 mmol/kg for at least 3 successive hours) - DDAVP 0.03 ug/kg SC or IV → repeat the measurement of urine osmolality 1 to 2 h later 4. Urine didn't concentrate (osmolality > 300 mosmo/1g, specific gravity > 1.010) before body weight decrease by 5% or plasma sodium/osmolality exceed the upper limit of normal→primary polydispsia and a partial defect in AVP secretion or action are largely excluded] --- background-image: url(data:image/png;base64,#di032.png) background-position: 90% 50% background-size: 45% .pull-left[ 注意事項 1. 8am 前可以進食，8 am~4 pm (整個 test 當中) 需要禁食 + 禁水 2. 若病人排尿有困難，可以使用單導或是尿管。 3. 12 noon 紀錄完了之後，再打 DDAVP (2 μg) 0.5 ml sc (0.5 vial) 4. 嚴重尿崩症患者可能因過度限水而導致脫水，甚至因血液中滲透壓過 高而發生意識變化，尤其在體重下降達 3-5% 者，因此過程中需留意病 人體重變化及臨床症狀之有無，若有明顯意識變化或是血壓降低，請 立即停止 test 且給予點滴補充水分且通知總醫師。 5. 若限水前血液滲透壓已高達 300 mOsm/Kg 以上，則停止禁水，可直 接給予 DDAVP 測其反應。 6. 若病人體重下降 3%，orthostatic hypotension，則停止禁水，可直接 給予 DDVAP 測其反應 7. 實驗後應立即補充足夠液體以防止脫水。 ] --- ### Uosmo increase after vasopression <table> <thead> <tr> <th style="text-align:left;"> Type </th> <th style="text-align:left;"> ΔUosmo </th> </tr> </thead> <tbody> <tr> <td style="text-align:left;"> Normal </td> <td style="text-align:left;"> ＜9% </td> </tr> <tr> <td style="text-align:left;"> Complete CDI </td> <td style="text-align:left;"> &gt;50% </td> </tr> <tr> <td style="text-align:left;"> Partial CDI </td> <td style="text-align:left;"> 9%~50% </td> </tr> <tr> <td style="text-align:left;"> Primary polydispsia </td> <td style="text-align:left;"> &lt;9% </td> </tr> </tbody> </table> Water deprivation test can't differentiate primary polydipsia, partial CDI and partial NDI --- background-image: url(data:image/png;base64,#di07.png) background-position: 50% 50% background-size: 90% --- background-image: url(data:image/png;base64,#di06.jpg) background-position: 50% 50% background-size: 70% .footnote[REF: Ann Intern Med 7 February 2006;144 186-194 "Nephrogenic Diabetres Insipidus" ] --- background-image: url(data:image/png;base64,#di04.avif) background-position: 50% 50% background-size: contain .footnote[ ref:[myendoconsult.com](<https://myendoconsult.com/learn/water-deprivation-test/>) ] --- background-image: url(data:image/png;base64,#di05.jpg) background-position: 50% 50% background-size: contain .footnote[ [Gubbi S, Hannah-Shmouni F, Koch CA, et al. Diagnostic Testing for Diabetes Insipidus.](<https://www.ncbi.nlm.nih.gov/books/NBK537591/>) ] --- ### Treatment of Central DI .e3[ - DDAVP (Desamino-D-arginine-8 vasopressin) - Selectively at V2 receptor - More resistance to degrade than AVP→3-4 folds longer duration - Dose - IV/SC: 0.25 to 1 mcg every 12 to 24 hours - Nasal spray: Initial: 5 to 10 mcg once daily at bedtime; Usual maintenance dose: 5 to 20 mcg once or twice daily; suggested maximum dose: 40 mcg/day. - Oral: Initial: 0.05 to 0.2 mg once daily; Usual maintenance dose: 0.1 to 0.8 mg/day in 2 to 3 equally divided doses; suggested maximum dose: 1.2 mg/day ] --- ### Treatment of Central DI .e3[ - Chlorpropamide: - may involve potentiation of the effect of small amounts of AVP or direct activation of the V2 receptor - Antidiuretic effect can be enhanced by thiazide diuretic ] --- ### Treatment of Nephrogenic DI .e3[ - Nephrogenic diabetes insipidus does not respond to desmopressin therapy - occasionally partial defects have limited response to high doses of desmopressin - In congenital NDI, therapy aimed at reducing symptomatic polyuria is addressed primarily by inducing plasma volume contraction via .red[a low sodium diet and a thiazide diuretic]. - Drug-induced nephrogenic diabetes insipidus should be treated by stopping the offending agent if possible. ] --- ###Treatment of Primary polydipsia .e3[ - Treatment of primary polydipsia entails reduction of excessive fluid intakes, best done in a graded fashion to allow patients to slowly achieve a level of intake that reduced urine volume below polyuric levels (50 mL/kg BW). - Measures to reduce mouth dryness (e.g., ice chips, hard candy to stimulate salivary flow) are use- ful adjuncts to reduce thirst. - Pharmacologic therapies have been tried but without consistent evidence of success. ] --- ###Treatment of Diabetes Insipidus in Pregnancy .e3[ - Once diagnosis of gestational DI is confirmed, treatment with desmopressin is indicated, regardless of whether DI is permanent or transient - Desmopressin has 2% to 25% the oxytocic activity of lysine vasopressin or arginine vasopressin, and can be used with minimal stimulation of the oxytocin receptors in the uterus - Desmopressin is not destroyed by the cysteine aminopeptidase (oxytocinase) of pregnancy and is reported to be safe for both the mother and the child. ] --- class:center, middle # Syndrome of Inappropriate Antidiuresis (SIAD) --- ###Syndrome of Inappropriate Antidiuresis (SIAD) .e3[ - .y[the hallmark of SIAD is hypoosmolality] - Also called the syndrome of inappropriate antidiuretic hormone (SIADH) ] ### Clinical characteristics .e3[ - .red[hypo-osmolemic hyponatremia] and impaired urinary dilution in the absence of hypovolemia, hypotension, or other nonosmotic stimuli to AVP secretion. - Water intoxication: mild headache, confusion, anorexia, nausea, vomiting coma and convulsion ] --- ### Etiology .e4[ - The cause of SIAD is a failure to maximally dilute the urine and mount a water diuresis when total water intake exceeds urinary and insensible water loss. - In most cases, the defect in urinary dilution is due to an abnormality in AVP secretion and is commonly referred to as the syndrome of inappropriate antidiuretic hormone (SIADH). - Tumor: - 1st: bronchogenic carcinoma of the lung, small cell carcinoma of the lung - 2nd: Head and neck caners - Drugs: - Stimulated release of AVP (nicotine, phenothiazines, tricyclics) - Direct renal effects(DDAVP, oxytocin, prostaglandin synthesis inhibitors) - 3,4-methylenedioxymeth- amphetamine, “ecstasy”毒品 ] --- background-image: url(data:image/png;base64,#siad01.png) background-position: 50% 50% background-size: contain --- background-image: url(data:image/png;base64,#siad05.png) background-position: 50% 50% background-size: 90% .footnote[[ Endocrine Reviews, Volume 44, Issue 5, October 2023, Pages 819–861](<https://doi.org/10.1210/endrev/bnad010>)] --- ### Criteria for diagnosis of syndrome of inappropriate diuresis set forth by Schwartz and Bartter in 1967 .e4[ - Low serum osmolality: pOsm < 275 mOsmol/kgH2O) - Inappropriate urine concentration: urine osmolality > 100 mOsmol/kg H2O - Clinical euvolemia (absence of signs of hypovolemia or hypervolemia) - Elevated urinary sodium excretion > 30 mmol/L with normal salt and water intake - Absence of other potential causes of euvolemic hypo-osmolality (glucocorticoid insufficiency, severe hypothyroidism) - Normal renal functionc and absence of diuretic use (particularly thiazide diuretics) ] --- background-image: url(data:image/png;base64,#siad02.png) background-position: 50% 70% background-size: 95% ### Differential Diagnosis Start from .y[hypo-osmolemic hyponatremia] .footnote[[ Endocrine Reviews, Volume 44, Issue 5, October 2023, Pages 819–861](<https://doi.org/10.1210/endrev/bnad010>)] --- ### Differential Diagnosis .e3[ - SIAD must be differentiated from other types of hypo-osmolemic hyponatremia associated with impaired urinary dilution. - Hypervolemic hyponatremia (type I): generalized edema due to severe congestive heart failure or cirrhosis, .ud[elevated Plasma renin activity (PRA) and aldosterone]. - Hypovolemic hyponatremia (type II): loss of sodium and water due to severe vomiting, diarrhea, or primary adrenal insufficiency, with an elevation in PRA. - Euvolemic hyponatremia (type III) - Severe deficiency in cortisol or thyroxine - SIAD ] --- background-image: url(data:image/png;base64,#siad03.png) background-position: 50% 70% background-size: 95% --- ### Treatment of SIAD .e3[ - Correction of hyponatremia is associated with markedly improved neurologic outcomes in patients with severely symptomatic hyponatremia. - If the hyponatremia is mild and largely asymptomatic, restricting total water intake to ~30 mL/kg per day less than urine output for several days - If the hyponatremia is severe and symptomatic, the goal should be to partially correct it by intravenous infusion of hypertonic (3%) saline or administration of an AVP antagonist such as tolvaptan or conivaptan ] --- ### Treatment of SIAD .e4[ - For all therapies, careful attention should be paid to recommendations for goals and limits of correction of the serum [Na+] to reduce the risk of the osmotic demyelination syndrome (ODS). - Hypertonic Saline(3% NaCl ([Na+] = 513 mmol/L)) - Patient’s weight (kg) × desired correction rate (mEq/L/hr) = infusion rate of 3% NaCl (mL/hr) - usually Rate<0.05mL/kg/min - Serum sodium monitor every hour → stop when serum sodium by 12 mmol/L or to 130 mmol/L - If the hyponatremia has been corrected too rapidly → central pontine myelinolysis - Isotonic Saline([Na+] = 154 mmol/L) - clinical signs of hypovolemia or in whom a spot urine [Na+] < 20 to 30 mEq/L. - Fluid Restriction - fluids < 500 to 1000 mL/24 hours. ] --- background-image: url(data:image/png;base64,#siad07.png) background-position: 95% 50% background-size: 45% <br> <br> <br> <div id="htmlwidget-0cc90413be9c5532248f" style="width:50%;height:100%;" class="pixfigure html-widget"></div> <script type="application/json" data-for="htmlwidget-0cc90413be9c5532248f">{"x":{"path":["assets/8c2c3a584fc5e4649da02a31fc087621.png"],"caption":[],"h":"auto","w":"100%","fit":"cover","position":"center"},"evals":[],"jsHooks":[]}</script> --- ### Treatment of SIAD .e3[ - Arginine Vasopressin Receptor Antagonists - Tolvaptan: oral vasopressin V2 receptor antagonist → blocks AVP action in the kidney - Urea - Sodium-Glucose Cotransporter 2 Inhibitors(SGLT2i) - in the proximal renal tubule: 90% of renal glucose resorption and 65% of sodium resorption - Oral Sodium Chloride (Salt Tablets) - Loop Diuretics - Demeclocycline - Lithium - Apelin Analogues ] --- background-image: url(data:image/png;base64,#siad08.png) background-position: 50% 50% background-size: 95% .footnote[[ Endocrine Reviews, Volume 44, Issue 5, October 2023, Pages 819–861](<https://doi.org/10.1210/endrev/bnad010>)] --- background-image: url(data:image/png;base64,#siad09.png) background-position: 50% 50% background-size: 95% ### Management .footnote[[ Endocrine Reviews, Volume 44, Issue 5, October 2023, Pages 819–861](<https://doi.org/10.1210/endrev/bnad010>)] --- ## Take Home Messenge .e2[ - 臨床上SIADH比DI常見，但是DI考題比較多 - AVP的生理機轉與體液調控 - DI的分類與鑑別診斷 - .y[Water deprivation test] - SIAD的診斷與治療 - flowchart of hyponatremia ] --- # References .e3[ - Harrison's Principles of Internal Medicine, 21e - William's Endocrinology, 14e - Pocket Medicine, 8e - 臺大醫院代謝內分泌檢查工作手冊 - [Diabetes insipidus. Nat Rev Dis Primers 5, 54 (2019). ](<https://doi.org/10.1038/s41572-019-0103-2>) - [Syndrome of Inappropriate Antidiuresis: From Pathophysiology to Management, Endocrine Reviews, Volume 44, Issue 5, October 2023, Pages 819–861](<https://doi.org/10.1210/endrev/bnad010>) ] --- class: center, middle # Thanks for your attention! Slides created via the R package [**xaringan**](https://github.com/yihui/xaringan).