Systemic diseases associated Systemic diseases associated with disorders of water with disorders of water

homeostasishomeostasisLisa L. Wong, MD, Endocrinol Metab Clin N Am, 2002Lisa L. Wong, MD, Endocrinol Metab Clin N Am, 2002

Reading by 林培哲 , 92-3-7

normal water homeostasis normal water homeostasis

Maintain within narrow limits (275 to 295 mOsMaintain within narrow limits (275 to 295 mOsm/kg H2O)m/kg H2O)

Osmoreceptor: anterior hypothalamusOsmoreceptor: anterior hypothalamus Thirst osmoreceptor: organum vasculosum of Thirst osmoreceptor: organum vasculosum of

the lamina terminalis and the anterior wall fo tthe lamina terminalis and the anterior wall fo the third ventriclehe third ventricle

Arginine vasopressin: synthesize: supraoptic Arginine vasopressin: synthesize: supraoptic (SON) and paraventricular nuclei (PVN)(SON) and paraventricular nuclei (PVN)

Secretion: only 1% to 2% leads to an increase iSecretion: only 1% to 2% leads to an increase in AVP of approximately 1 pg/mln AVP of approximately 1 pg/ml

Maximum antidiuresis: approximately 5 pg/mlMaximum antidiuresis: approximately 5 pg/ml

Osmotic threshold for thirst: 5 to 10 mOsm/kg Osmotic threshold for thirst: 5 to 10 mOsm/kg H2O above that for AVP release—only activateH2O above that for AVP release—only activated by larger and more threatening osmotic pertd by larger and more threatening osmotic perturbationurbation

Baroreceptors: located in the cardiac atria and Baroreceptors: located in the cardiac atria and large arteries, reduction in effective circulating large arteries, reduction in effective circulating volume (hypotension and volume depletion) 1volume (hypotension and volume depletion) 10 % to 20 % is required before a significant AV0 % to 20 % is required before a significant AVP response occursP response occurs

Nonosmotic stimuli: nausea, hypoxia, hypercaNonosmotic stimuli: nausea, hypoxia, hypercapnia, hypoglycemia, and various medicationspnia, hypoglycemia, and various medications

AVP V2 receptorAVP V2 receptor basolateral membrane of renal collecting duct basolateral membrane of renal collecting duct

cellscells family of G protein-coupled seven-transmembfamily of G protein-coupled seven-transmemb

rane domainrane domain linked to adenylyl cyclase signaling pathway; slinked to adenylyl cyclase signaling pathway; s

huttling aquaporin-2 (AQP2) water channels frhuttling aquaporin-2 (AQP2) water channels from intracellular vesicles into the apical plasmom intracellular vesicles into the apical plasma membrane of the renal collecting duct cellsa membrane of the renal collecting duct cells

Systemic disorders associated Systemic disorders associated with excess AVP secretion or with excess AVP secretion or

effectseffects SIADH: clinical criteria; SIADH: clinical criteria; true hypo-osmolality with a urine osmolality ttrue hypo-osmolality with a urine osmolality t

hat is greater than maximally dilute (i.e., >100 hat is greater than maximally dilute (i.e., >100 mOsm/kg H2O) and an elevatd utine Na+ exctemOsm/kg H2O) and an elevatd utine Na+ exctetio (i.e., >30 mmol/L). tio (i.e., >30 mmol/L).

clinical euvolemia also must be demonstratedclinical euvolemia also must be demonstrated absence of hypothyroidism, hypocortisolism, rabsence of hypothyroidism, hypocortisolism, r

enal insufficiency, and recent diuretic useenal insufficiency, and recent diuretic use

Systemic disorders associated Systemic disorders associated with excess AVP secretion or with excess AVP secretion or

effectseffects

SIAD: about 10 to 20 % meet above criterSIAD: about 10 to 20 % meet above criteria without lelvated AVP level: another ciria without lelvated AVP level: another circulating antidiuretic substance, or to incculating antidiuretic substance, or to increased AVP V2 receptor sensitivityreased AVP V2 receptor sensitivity

tumorstumors Pulmonary or mediastinalPulmonary or mediastinal

bronchogenic carcinomabronchogenic carcinoma MesotheliomaMesothelioma ThymomaThymoma Hodgkin’s lymphomaHodgkin’s lymphoma

Nonchest Nonchest Nasopharyngeal carcinomaNasopharyngeal carcinoma Duodenal carcinomaDuodenal carcinoma Pancreatic carcinomaPancreatic carcinoma Ureteral /prostatic carcinomaUreteral /prostatic carcinoma Uterine carcinomaUterine carcinoma leukemialeukemia

tumorstumors

Most commonMost common Small cell lung carcinoma (SCLC): Small cell lung carcinoma (SCLC): SIADH occur approximately 15 % SIADH occur approximately 15 % culture tumor tissue synthesize not only AVP bculture tumor tissue synthesize not only AVP b

ut also the entire AVP prohormoneut also the entire AVP prohormone only half possess AVP immunoreactivityonly half possess AVP immunoreactivity elevated mRNA for atrial natriuretic peptide (Aelevated mRNA for atrial natriuretic peptide (A

NP): contribute to hypo-osmolality in patients NP): contribute to hypo-osmolality in patients with low AVP levelwith low AVP level

Reset osmostatReset osmostat

TuberculosisTuberculosis MalnutritionMalnutrition Gastric carcinomaGastric carcinoma PneumoniaPneumonia encephalitisencephalitis

Reset osmostatReset osmostat

15 to 20 % regulates his plasma osmolality ap15 to 20 % regulates his plasma osmolality appropriately, but around a reduced set pointpropriately, but around a reduced set point

normal diluting capacity: defined as the ability normal diluting capacity: defined as the ability to excrete more than 80 % of a standard water to excrete more than 80 % of a standard water load within 4 hours and to decrease urine osmload within 4 hours and to decrease urine osmolality to less than 100 mOsm/kg H2O.olality to less than 100 mOsm/kg H2O.

chronic hyponatremia dose not appear to altechronic hyponatremia dose not appear to alter the osmotic threshold for AVP secretionr the osmotic threshold for AVP secretion

Reset osmostatReset osmostat

placental hormone relaxin causes a stimulation of AVP placental hormone relaxin causes a stimulation of AVP and oxytocin secretion that closely resembles the reseand oxytocin secretion that closely resembles the reset osmostat patternt osmostat pattern

some represent tumor-stimulated pituitary AVP secretsome represent tumor-stimulated pituitary AVP secretion rather than paraneoplastic AVP secretionion rather than paraneoplastic AVP secretion

hyponatremia only mild, asymptomatic, chronic, and fhyponatremia only mild, asymptomatic, chronic, and fairly stableairly stable

no specific therapy is required, otherwise, may overwno specific therapy is required, otherwise, may overwhelm urinary diluting capacity, resulting in lower and helm urinary diluting capacity, resulting in lower and more dangerous levels of hyponatremiamore dangerous levels of hyponatremia

CNS disorderCNS disorder

Mass lesionMass lesion Infectious/inflammatoryInfectious/inflammatory Demyelinative/degenerativeDemyelinative/degenerative

CNS disorderCNS disorder

No apparent common denominator No apparent common denominator linking themlinking them

Any diffuse CNS disorder potentially Any diffuse CNS disorder potentially can disrupt inhibit pathway from the can disrupt inhibit pathway from the brainstem to the hypothalamusbrainstem to the hypothalamus

Pulmonary disordersPulmonary disorders InfectionsInfections

TuberculosisTuberculosis AspergillosisAspergillosis PneumoniaPneumonia EmpyemaEmpyema

Mechanical/ventilatoryMechanical/ventilatory Acute respiratory failureAcute respiratory failure Chronic obstructive pulmonary diseaseChronic obstructive pulmonary disease Positive pressure ventilationPositive pressure ventilation

Pulmonary disordersPulmonary disorders

Hypoxia: induced antidiuresis mediated Hypoxia: induced antidiuresis mediated by way of baroreceptor-stimulated AVP rby way of baroreceptor-stimulated AVP release by a fall in PaO2 to less than 50 melease by a fall in PaO2 to less than 50 mmHgmHg

Hypercapnia: decreasing systemic resistHypercapnia: decreasing systemic resistance, and only secondarilyance, and only secondarily

Pulmonary disordersPulmonary disorders

Pneumonitis and advanced COPD, other than Pneumonitis and advanced COPD, other than TB, only in sporadic case reportsTB, only in sporadic case reports

Occur on the setting of respiratory failureOccur on the setting of respiratory failure Limited to the initial days, once clinical improvLimited to the initial days, once clinical improv

ement has begun, free water excretion generalement has begun, free water excretion generally spontaneously improvesly spontaneously improves

Mechanical ventilation: decreases pulmonary Mechanical ventilation: decreases pulmonary blood volume and left atrial pressure resulting blood volume and left atrial pressure resulting activation of carotid baroreceptorsactivation of carotid baroreceptors

Edema-forming statesEdema-forming states

Occur in advanced stageOccur in advanced stage Decrease intravascular volumeDecrease intravascular volume Decrease distal delivery of glomerular filtDecrease distal delivery of glomerular filt

rate and secondarily elevated AVP levelsrate and secondarily elevated AVP levels Activating renin-angiotensin-aldosterone Activating renin-angiotensin-aldosterone

system, the sympathetic nervous system system, the sympathetic nervous system and AVP secretionand AVP secretion

Systemic disorders associated with insufficient AVP secretion Systemic disorders associated with insufficient AVP secretion or effectsor effects

Central diabetes insipidusCentral diabetes insipidusGranulomatousGranulomatous

NeurosarcoidosisNeurosarcoidosisLangerhans cell histiocytosisLangerhans cell histiocytosis

TumorsTumorsGerminoma craniopharyngiomaGerminoma craniopharyngiomaMeningiomaMeningiomaLymphomaLymphoma

InfectionsInfectionsMeningitisMeningitisEncephalitisEncephalitis

IschemicIschemic Sheehan’s syndromeSheehan’s syndrome

Nephrogenic diabetes insipidusNephrogenic diabetes insipidusMetabolicMetabolic

HypercalcemiaHypercalcemiaHypokalemiaHypokalemia

InfiltrativeInfiltrativeAmyloidosisAmyloidosis

VascularVascularSickle cell diseaseSickle cell disease

GranulomatousGranulomatousSarcoidosisSarcoidosis

InfectiousInfectiousPyelonephritisPyelonephritis

ObstructionObstructionObstructive uropathyObstructive uropathy

Central diabetes insipidusCentral diabetes insipidus

90% fo magnocellular neurons lost before clini90% fo magnocellular neurons lost before clinically CDI developscally CDI develops

destruction of the posterior pituitary alone gedestruction of the posterior pituitary alone generally does not result in CDInerally does not result in CDI

transient CDI: following neurosurgery and reortransient CDI: following neurosurgery and reorganize their terminals from higher in the hypotganize their terminals from higher in the hypothalamus median eminencehalamus median eminence

Permanent CDI: injury in level og pituitary stalPermanent CDI: injury in level og pituitary stalk to cause retrograde neuronal degenerationk to cause retrograde neuronal degeneration

neurosarcoidosisneurosarcoidosis Noncaseating granulomata can involve tNoncaseating granulomata can involve t

he cranial nerves, the floor of the third vhe cranial nerves, the floor of the third ventricle and basal meninges, region of tentricle and basal meninges, region of the hypothalamus and optic chiasmhe hypothalamus and optic chiasm

Partial or total destruction of the pituitaPartial or total destruction of the pituitaryry

Extensive infiltration of the hypothalamExtensive infiltration of the hypothalamus by later autopsies—predominant site us by later autopsies—predominant site of functional disturbanceof functional disturbance

Less than one third of patients lacked suLess than one third of patients lacked sufficient AVP levelfficient AVP level

Destruction of magnocellularDestruction of magnocellular

Dipsogenic DIDipsogenic DI

Some patient reset thirst osmostat despSome patient reset thirst osmostat despite adequate AVP release in response to ite adequate AVP release in response to osmotic stimuliosmotic stimuli

Not respond to desmopressin therapy uNot respond to desmopressin therapy until Na concentration below the new thirntil Na concentration below the new thirst thresholdst threshold

No definitive diagnostic test specific for No definitive diagnostic test specific for NS—remain a diagnosis of exclusionNS—remain a diagnosis of exclusion

Tx: Corticosteroids Tx: Corticosteroids Pituitary hormone replacementPituitary hormone replacement

LCHLCH

CDI occurring in 5 to 50 %CDI occurring in 5 to 50 % Manifestation of CNS involvementManifestation of CNS involvement Water metqabolism similar to NSWater metqabolism similar to NS Aggressive chemotherapy may prevent tAggressive chemotherapy may prevent t

o CDIo CDI Radiotherapy—response to therapy? Or Radiotherapy—response to therapy? Or

spontaneous regressionspontaneous regression

Nephrogenic diabetes insipiduNephrogenic diabetes insipiduss

MetabolicMetabolicHypercalcemiaHypercalcemiaHypokalemiaHypokalemia

InfiltrativeInfiltrativeAmyloidosisAmyloidosis

VascularVascularSickle cell diseaseSickle cell disease

GranulomatousGranulomatousSarcoidosisSarcoidosis

InfectiousInfectiousPyelonephritisPyelonephritis

ObstructionObstructionObstructive uropathyObstructive uropathy

Nephrogenic diabetes insipiduNephrogenic diabetes insipiduss

Collecting duct permeability reflect to ACollecting duct permeability reflect to AVPVP

AVP regulates the transport of NaCl at thAVP regulates the transport of NaCl at thick ascending limb (TAL) of the loop of Hick ascending limb (TAL) of the loop of Henleenle

Decrease AQP2 expressionDecrease AQP2 expression

HypercalcemiaHypercalcemia Clinically apparent until calcium concenClinically apparent until calcium concen

tration >11 mg/dltration >11 mg/dl Inhibition of NaCl reabsorption in the TAInhibition of NaCl reabsorption in the TA

L—tubulointerstitial damage play the roL—tubulointerstitial damage play the rolele

Berl et al found the TAL impaired adenylBerl et al found the TAL impaired adenylyl cyclase activationyl cyclase activation

Decrease AQP2 expressionDecrease AQP2 expression

Activation of renal calcium-sensing receActivation of renal calcium-sensing receptors can impair concentrating ability of ptors can impair concentrating ability of loop of Henle and collecting tubulesloop of Henle and collecting tubules

Familial hypocalciuric hypercalcemia prFamilial hypocalciuric hypercalcemia preserve normal urinary concentrating abieserve normal urinary concentrating ability lity

Prostaglandin E2, angiotensin II may alsProstaglandin E2, angiotensin II may also inhibit TAL NaCl reabsorptiono inhibit TAL NaCl reabsorption

General is reversibleGeneral is reversible Hydration usually needed (Vicious cycle Hydration usually needed (Vicious cycle

of dehydration exacerbating hypercalceof dehydration exacerbating hypercalcemia and hypercalcemia worsening dehymia and hypercalcemia worsening dehydration continues)dration continues)

hypokalemiahypokalemia

Usually requires K deficit of greater than Usually requires K deficit of greater than 200 mEq and plasma <3 mEq/L200 mEq and plasma <3 mEq/L

Mechanism similar to hypercalcemia anMechanism similar to hypercalcemia and general less severed general less severe

Reversible once electrolyte imbalance cReversible once electrolyte imbalance correctionorrection

summarysummary

Disorder of AVP secretion and action sometimDisorder of AVP secretion and action sometimes present as the first manifestation of a varietes present as the first manifestation of a variety systemic diseasesy systemic diseases

Much of the pathophysiology is not understooMuch of the pathophysiology is not understood completelyd completely

Further investigation likely will allow physiciaFurther investigation likely will allow physicians to offer more effective treatment, such as thns to offer more effective treatment, such as the AVP V2 antagonist for SIADH and edema-fore AVP V2 antagonist for SIADH and edema-forming statesming states