Diabetes Insipidus

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Central Diabetes InsipidusCentral Diabetes Insipidus

Dr. Aniqa ShahidDr. Aniqa Shahid

PGRY-1 MU-1PGRY-1 MU-1



HistoryHistory

My patient named “Razia Aslam” W/OMy patient named “Razia Aslam” W/OMuhammad Aslam.Muhammad Aslam.

32 Years old female.32 Years old female.

Resident of Gulberg Faisalabad.Resident of Gulberg Faisalabad.Presented on 4-12-11 in Medical OPD withPresented on 4-12-11 in Medical OPD with

the following complaints for last 4 months.the following complaints for last 4 months.

Frequent large urineFrequent large urine

Night awakenings for urineNight awakenings for urine

Extreme thirst.Extreme thirst.

Lethargy.Lethargy.



HOPIHOPI

My patient was in her usual state of healthMy patient was in her usual state of healthfour months back when for the first timefour months back when for the first time

while observing fasts during the month of while observing fasts during the month of

Ramadan she noticed that she was unable toRamadan she noticed that she was unable to

keep her fast after mid day due to extremekeep her fast after mid day due to extremefeeling of thirst which was specifically forfeeling of thirst which was specifically for

water.water. Meanwhile she was frequently passingMeanwhile she was frequently passing

large volume of colorless urine, So by thelarge volume of colorless urine, So by the

end of fast she turned out to be veryend of fast she turned out to be very

lethargic & thirsty.lethargic & thirsty.



She used to drink more than fifteen glass of She used to drink more than fifteen glass of water in a day with 7-8 times using toiletwater in a day with 7-8 times using toilet

and about six to seven times during nightand about six to seven times during night

when she had to get up from sleep d/t thirstwhen she had to get up from sleep d/t thirst

and to use toilet. She used to finish herand to use toilet. She used to finish her

glass in one gulp rather than sipping it overglass in one gulp rather than sipping it over

a period of time. She never collected thea period of time. She never collected the

urine but gave H/O large volumes of urineurine but gave H/O large volumes of urineevery time.every time.

HOPI (Contd.)HOPI (Contd.)



HOPI (Contd.)HOPI (Contd.)

Her frequent wakening during night dueHer frequent wakening during night dueto thirst and passing of urine was makingto thirst and passing of urine was making

her anxious.her anxious.

History of good appetite.History of good appetite.No history of head injury or surgeryNo history of head injury or surgery

No H/O dizziness, vertigo, palpitationsNo H/O dizziness, vertigo, palpitations

or heat intolerance.or heat intolerance.No History of anxiety or otherNo History of anxiety or other

psychiatric illness.psychiatric illness.



No history of any visual disturbance orNo history of any visual disturbance orheadache.headache.

No H/O diabetes mellitus.No H/O diabetes mellitus.

History of regular menstrual cycle.History of regular menstrual cycle.

No history of galactorrhoea.No history of galactorrhoea.

No history of any change in bowel habitsNo history of any change in bowel habits

No H/O joint painsNo H/O joint pains

No H/O any respiratory problem.No H/O any respiratory problem.

No H/O cardiovascular illness.No H/O cardiovascular illness.



Family HistoryFamily History

No family history of similar complaints.No family history of similar complaints.

No history of diabetes, HTN or renalNo history of diabetes, HTN or renal

problems.problems. Married with three live issues. TwoMarried with three live issues. Two

daughters and one son. Eldest aged 12daughters and one son. Eldest aged 12

years and youngest aged 6 years.years and youngest aged 6 years.



Drug/Medical HistoryDrug/Medical History

No history of previous illness or any drugNo history of previous illness or any drug

therapy, hospitalisation or surgery.therapy, hospitalisation or surgery.

Socio-Economic StatusSocio-Economic Status

Patient belongs to a middle class family. ShePatient belongs to a middle class family. Sheis a house wife and her husband works in ais a house wife and her husband works in a

factory. They are living in their own home.factory. They are living in their own home.



GPEGPE

A young lady sitting comfortably in the bedA young lady sitting comfortably in the bed

with following vitals.with following vitals.

BPBP 110/70110/70

P/RP/R 84/min84/min

R/RR/R 16/min16/min

Dry oral MucosaDry oral Mucosa

No other signs of dehydrationNo other signs of dehydration

Pallor -Pallor - Cyanosis -Cyanosis -

Jaundice -Jaundice -JVP not raisedJVP not raised



EdemaEdema Not PresentNot Present

All accessible lymph nodes not palpable.All accessible lymph nodes not palpable.

CNSCNS::

Mental status examination:Mental status examination:( Conscious ,alert , well oriented in time and( Conscious ,alert , well oriented in time and

space. GCS 15/15, MMSE normal )space. GCS 15/15, MMSE normal )

Motor and sensory system intact.Motor and sensory system intact.Cerebellum : IntactCerebellum : Intact

Cranial nerves : IntactCranial nerves : Intact



RESPIRATORY SYSTEM :Inspection:

Palpation:Percussion:Auscultation :All normal

CARDIOVASCULAR SYSTEM :Precordium shape was normal with novisible pulsationsApex beat normally localized .Ist and second heart sounds heard withno added sounds.



GIT:Normal shapeNon distendedNon tender

No visceromegalyBowel sounds audible



Lab InvestigationsLab Investigations

CBC:CBC:

Urea 18mg/dlUrea 18mg/dl

S.Creatinine 0.5mg/dlS.Creatinine 0.5mg/dl S. AlbuminS. Albumin

S. ProteinS. Protein

Blood Glucose Random 85mg/ dlBlood Glucose Random 85mg/ dl

HbHb 13.2g/dl13.2g/dl

ESRESR 1212

WBCsWBCs 5900/cmm5900/cmm

PltPlt 3,15,0003,15,000



ElectrolytesElectrolytes

Na 146 mmol/lNa 146 mmol/lCl 102 mmol/lCl 102 mmol/l

K 3.7 mmol/lK 3.7 mmol/l

HCO3 23mmol/lHCO3 23mmol/l S. Calcium 9.7g/dlS. Calcium 9.7g/dl

S. Phosphorus 4.2g/dlS. Phosphorus 4.2g/dl



Urine complete Examination :Urine complete Examination :

Pus cells 0Pus cells 0 Crystals 0Crystals 0RBCs 0RBCs 0 Casts -Casts -

Epith cells 0Epith cells 0

Specific gravity 1.006 (1.010-Specific gravity 1.006 (1.010-1.025)1.025)

Sugar – NilSugar – Nil

ColourlessColourless PH 5PH 5

Turbidity -Turbidity - Blood -Blood -

Deposits -Deposits - Ketones -Ketones -

Albumin - NilAlbumin - Nil



Ultrasound of Abdomen Pelvis - NormalUltrasound of Abdomen Pelvis - Normal

Chest XRay normalChest XRay normal

ECG normalECG normal



Brain MRI



D/DD/D

PsychogenicPsychogenic CRFCRF

MetabolicMetabolic

Hypercalcemia secondary to renalHypercalcemia secondary to renaldiseasedisease IatrogenicIatrogenic

IV fluid overloadIV fluid overloadDiureticsDiuretics

NeoplasticNeoplastic

Pituitary AdenomaPituitary Adenoma



D/DD/D

ToxicToxic

AminoglycosidesAminoglycosides

NSAIDSNSAIDS

Vascular(Hypovolemia)Vascular(Hypovolemia) Inflammatory / infectiousInflammatory / infectious

PyelonephritisPyelonephritis

Immune complex glomerulonephritisImmune complex glomerulonephritis



Water deprivation testWater deprivation testFree fluids until 7:30 amFree fluids until 7:30 am

Light breakfast at 6:30 amLight breakfast at 6:30 am

No tea, no coffee, no smokingNo tea, no coffee, no smoking



Stage 2 :Stage 2 :

Give Desmopressin 20ug throughGive Desmopressin 20ug throughintranasal spray.intranasal spray.

Measure urine Osmolality hourly forMeasure urine Osmolality hourly for

the next 4 hours.the next 4 hours.



IntroductionIntroduction

Central diabetes insipidus (CDI) resultsCentral diabetes insipidus (CDI) results

from any condition that impairs thefrom any condition that impairs the

synthesis, transport, or release of synthesis, transport, or release of

antidiuretic hormone (ADH), also know asantidiuretic hormone (ADH), also know asarginine vasopressin (AVP).arginine vasopressin (AVP).

It occurs equally in both sexes.It occurs equally in both sexes.

It effects all ages.It effects all ages.

The complete form is less common thanThe complete form is less common than

the partial form.the partial form.




ADH is produced in the hypothalamus andADH is produced in the hypothalamus andtravels along nerve fibers to the posteriortravels along nerve fibers to the posteriorpituitary, where it is stored and released.pituitary, where it is stored and released.

ADH promotes reabsorption of water in theADH promotes reabsorption of water in the

collecting duct of nephrons.collecting duct of nephrons. Increased plasma osmolality stimulatesIncreased plasma osmolality stimulates

release of ADH in normal people.release of ADH in normal people. Patients with CDI secrete lower thanPatients with CDI secrete lower than

normal levels of plasma ADH in responsenormal levels of plasma ADH in responseto elevated plasma osmolality.to elevated plasma osmolality.




In patients with CDI, the degree of In patients with CDI, the degree of polyuria is primarily determined by thepolyuria is primarily determined by thedegree of ADH deficiency.degree of ADH deficiency.

The urine output can range from 3 L/dayThe urine output can range from 3 L/day

in mild partial DI to over 15 L/day inin mild partial DI to over 15 L/day inpatients with severe disease.patients with severe disease.

CDI can be worsened or first diagnosedCDI can be worsened or first diagnosedduring pregnancy, when ADH catabolism isduring pregnancy, when ADH catabolism is

increased by vasopressinases releasedincreased by vasopressinases releasedfrom the placenta.from the placenta.



EtiologyEtiology

Idiopathic DI:Idiopathic DI:

Accounts for 30 to 50% of casesAccounts for 30 to 50% of cases

of of CDI.CDI.

Autoimmune destruction of theAutoimmune destruction of theADHADH hormone-secreting cells inhormone-secreting cells in

thethe hypothalamus.hypothalamus.

NeurosurgeryNeurosurgeryBrain traumaBrain traumaPrimary or metastatic brain tumorsPrimary or metastatic brain tumorsInfiltrative diseases (Langerhans cellInfiltrative diseases (Langerhans cell

histiocytosis,Wegener’s granulomatosis)histiocytosis,Wegener’s granulomatosis)



EtiologyEtiology

RadiationRadiation to the brainto the brain Infection such as meningitis or encephalitisInfection such as meningitis or encephalitis Cerebral edemaCerebral edema Intracranial hemorrhageIntracranial hemorrhage

Familial DI:Familial DI: Also called familial neurohypophysealAlso called familial neurohypophyseal

diabetesdiabetes insipidus (FNDI).insipidus (FNDI). Autosomal dominantAutosomal dominant

Mutations in the ADH gene.Mutations in the ADH gene. Patients progressively develop ADHPatients progressively develop ADH

deficiency.deficiency.



EtiologyEtiology

Hypoxic or ischemic encephalopathyHypoxic or ischemic encephalopathy Acute fatty liver of pregnancy:Acute fatty liver of pregnancy: Transient CDI has been associated with itTransient CDI has been associated with it

but no mechanism has been identified.but no mechanism has been identified. Wolfram syndrome (or DIDMOADWolfram syndrome (or DIDMOAD

syndrome):syndrome): Autosomal recessiveAutosomal recessive CDI, DM, optic atrophy, and deafness.CDI, DM, optic atrophy, and deafness. CDI is due to loss of ADH-secretingCDI is due to loss of ADH-secreting

neurons in the hypothalamus and impairedneurons in the hypothalamus and impairedprocessing of ADH precursors.processing of ADH precursors.



SymptomsSymptoms

The major symptoms of central DI areThe major symptoms of central DI arepolyuria and polydipsia.polyuria and polydipsia. Polyuria is defined as a urine output of over 3Polyuria is defined as a urine output of over 3

L/day in adults.L/day in adults.

Polyuria must be differentiated fromPolyuria must be differentiated fromfrequency and nocturia, which are notfrequency and nocturia, which are notassociated with an increase in total urineassociated with an increase in total urineoutput.output.

The onset of polyuria is usually abrupt in CDI.The onset of polyuria is usually abrupt in CDI. This is in contrast to nephrogenic DI andThis is in contrast to nephrogenic DI and

primary polydipsia, in which onset of polyuriaprimary polydipsia, in which onset of polyuriais almost always gradual.is almost always gradual.



SymptomsSymptoms

Nocturia is often the first sign of CDI.Nocturia is often the first sign of CDI. This is because urine is usually mostThis is because urine is usually most

concentrated in the morning due to lack of concentrated in the morning due to lack of fluid ingestion overnight.fluid ingestion overnight.

As a result, nocturia is usually the firstAs a result, nocturia is usually the firstmanifestation of a loss of concentratingmanifestation of a loss of concentratingability.ability.

Thus, a relatively dilute urine is excreted,Thus, a relatively dilute urine is excreted,

with a urine osmolality of less than 200with a urine osmolality of less than 200mOsmol/kg.mOsmol/kg. Dry skin and constipation are otherDry skin and constipation are other

symptoms that may occur in CDI.symptoms that may occur in CDI.



DiagnosisDiagnosis

Most patients have a high-normal or onlyMost patients have a high-normal or onlymildly elevated plasma sodiummildly elevated plasma sodiumconcentration, usually greater than 142concentration, usually greater than 142mEq/L.mEq/L.

In addition, the plasma osmolality usuallyIn addition, the plasma osmolality usuallyremains around values only slightly aboveremains around values only slightly above290 mOsm/kg (normal is 280-295290 mOsm/kg (normal is 280-295mOsm/kg).mOsm/kg).

This occurs because the initial loss of This occurs because the initial loss of water results in concurrent stimulation of water results in concurrent stimulation of thirst, which minimizes the degree of netthirst, which minimizes the degree of netwater loss.water loss.



DiagnosisDiagnosis

Stimulation of thirst does not occur,Stimulation of thirst does not occur,however, when CDI is due to a centralhowever, when CDI is due to a centrallesion that impairs thirst causinglesion that impairs thirst causinghypodipsia or adipsia.hypodipsia or adipsia.

In such cases, the plasma sodiumIn such cases, the plasma sodiumconcentration can exceed 160 meq/L andconcentration can exceed 160 meq/L andthe plasma osmolality will rise significantlythe plasma osmolality will rise significantlyalso.also.

This also occurs if a patient has no accessThis also occurs if a patient has no accessto water.to water. Withholding water in patients with CDI canWithholding water in patients with CDI can

result in severe dehydration.result in severe dehydration.



Water Restriction TestWater Restriction Test

In healthy individuals, water deprivationIn healthy individuals, water deprivationincreases plasma osmolality, whichincreases plasma osmolality, whichstimulates secretion of ADH by thestimulates secretion of ADH by theposterior pituitary.posterior pituitary.

This then acts on the kidney to increaseThis then acts on the kidney to increaseurine osmolality to 1000 to 1200urine osmolality to 1000 to 1200mOmol/kg and to restore plasmamOmol/kg and to restore plasmaosmolality to normal levels.osmolality to normal levels.

Giving exogenous ADH does not increaseGiving exogenous ADH does not increaseurine osmolality further because it isurine osmolality further because it isalready maximal in response to analready maximal in response to anindividual’s endogenous release of ADH.individual’s endogenous release of ADH.



Water Restriction TestWater Restriction Test

The test should be continued until one of theThe test should be continued until one of thefollowing occurs:following occurs:

• The urine osmolality reaches a normalThe urine osmolality reaches a normalvalue, which is above 600 mOsm/kg,value, which is above 600 mOsm/kg,

indicating that both ADH release and effectindicating that both ADH release and effectare intact.are intact.

• The urine osmolality is stable on 2 or 3The urine osmolality is stable on 2 or 3successive measurements despite a risingsuccessive measurements despite a rising

plasma osmolality.plasma osmolality.• The plasma osmolality exceeds 295 to 300The plasma osmolality exceeds 295 to 300

mOsm/kg.mOsm/kg.



Water Restriction TestsWater Restriction Tests Interpretation:Interpretation:

• Normal subjects and primary polydipsia:Normal subjects and primary polydipsia:Urine osms are greater than plasma OsmsUrine osms are greater than plasma Osms

after water restriction.after water restriction.Urine osms increase minimally (<10%) afterUrine osms increase minimally (<10%) after

exogenous ADH.exogenous ADH.

• Central Diabetes Insipidus:Central Diabetes Insipidus:Urine osms remain less than plasmaUrine osms remain less than plasma

osms after water restriction.osms after water restriction.After ADH is given, urine osms increaseAfter ADH is given, urine osms increase

100% in complete CDI and over 50% in100% in complete CDI and over 50% inpartial CDI.partial CDI.• Nephrogenic Diabetes Insipidus:Nephrogenic Diabetes Insipidus:

Urine osms remain less than plasma osms.Urine osms remain less than plasma osms.After ADH, urine osms increase by less thanAfter ADH, urine osms increase by less than

50%.50%.



TreatmentTreatment

There are several medications available forThere are several medications available forthe treatment of CDI, of whichthe treatment of CDI, of which

desmopressin is the most common.desmopressin is the most common.



DesmopressinDesmopressin

Desmopressin is a two-amino acidDesmopressin is a two-amino acidsubstitute of ADH that has potentsubstitute of ADH that has potentantidiuretic activity but no vasopressorantidiuretic activity but no vasopressoractivity.activity.

It is also known as dDAVP, which standsIt is also known as dDAVP, which standsfor 1-deamino-8-D-arginine vasopressin.for 1-deamino-8-D-arginine vasopressin.

It is currently the drug of choice for long-It is currently the drug of choice for long-

term therapy of CDI to control polyuria.term therapy of CDI to control polyuria. It is safe during pregnancy for both theIt is safe during pregnancy for both themother and the fetus.mother and the fetus.




The initial aim of therapy is to reduceThe initial aim of therapy is to reducenocturia, in order to provide adequatenocturia, in order to provide adequatesleep.sleep.

Thus, the first dose is usually given in theThus, the first dose is usually given in the

late evening to control nocturia.late evening to control nocturia. After that is achieved, control of dailyAfter that is achieved, control of daily

diuresis is the goal.diuresis is the goal. The size of and necessity for a daytimeThe size of and necessity for a daytime

dose is determined by the effectiveness of dose is determined by the effectiveness of the evening dose and any recurrence of the evening dose and any recurrence of polyuria during the day.polyuria during the day.




A initial dose of 10 micrograms of theA initial dose of 10 micrograms of theintranasal form is given at bedtime.intranasal form is given at bedtime.

This dose is titrated up in 5 microgramThis dose is titrated up in 5 microgram

increments as needed depending on theincrements as needed depending on theresponse of the nocturia.response of the nocturia.

The typical daily maintenance dose is 10The typical daily maintenance dose is 10to 20 micrograms once or twice daily.to 20 micrograms once or twice daily.




An oral tablet preparation is also available.An oral tablet preparation is also available. Absorption of the oral form is decreasedAbsorption of the oral form is decreased

40-50% when taken with meals.40-50% when taken with meals. The oral form has about 1/10 to 1/20 theThe oral form has about 1/10 to 1/20 the

potency of the nasal form because onlypotency of the nasal form because onlyabout 5% is absorbed from the gut.about 5% is absorbed from the gut.

It is recommended to start with the nasalIt is recommended to start with the nasalform before attempting a trial of oralform before attempting a trial of oral

therapy.therapy.



Risks of DesmopressinRisks of Desmopressin

Potential risks of desmopressin includePotential risks of desmopressin includewater retention and the development of water retention and the development of hyponatremia.hyponatremia.

This may occur because once dDAVP isThis may occur because once dDAVP isgiven, the patient has nonsuppressiblegiven, the patient has nonsuppressibleADH activity and may be unable to excreteADH activity and may be unable to excreteingested water normally.ingested water normally.

This can be avoided by giving theThis can be avoided by giving theminimum daily dose required to controlminimum daily dose required to controlthe polyuria.the polyuria.



Other DrugsOther Drugs

The other agents available are lessThe other agents available are lesseffective and associated with moreeffective and associated with moreadverse effects than desmopressin.adverse effects than desmopressin.

Chlorpropamide, carbamazepine, andChlorpropamide, carbamazepine, andclofibrate can be used in cases of partialclofibrate can be used in cases of partialCDI and can lower the urine output by asCDI and can lower the urine output by asmuch as 50%.much as 50%.




Chlorpropamide:Chlorpropamide:

• An oral hypoglycemic agent.An oral hypoglycemic agent.

• Acts by promoting the renal response toActs by promoting the renal response to

ADH or dDAVP.ADH or dDAVP.

• The usual dose is 125 to 250 mg, onceThe usual dose is 125 to 250 mg, once

or twice a day.or twice a day.

• Higher doses may produce a somewhatHigher doses may produce a somewhatgreater response but also increase thegreater response but also increase the

risk of hypoglycemia.risk of hypoglycemia.




Carbamazepine:Carbamazepine:

• An anticonvulsant.An anticonvulsant.

• Enhances ADH release and raises theEnhances ADH release and raises the

sensitivity of the collecting duct to it.sensitivity of the collecting duct to it.

• 100 to 300 mg twice daily is the typical100 to 300 mg twice daily is the typical

dose.dose.




Clofibrate:Clofibrate:

• A lipid lowering agent.A lipid lowering agent.

• Stimulates residual ADH production inStimulates residual ADH production in

the hypothalamus, therefore increasingthe hypothalamus, therefore increasingADH release from the posterior pituitary.ADH release from the posterior pituitary.

• 500 mg every six hours is the usual500 mg every six hours is the usual

dose.dose.



THANK YOU



ReferencesReferences

Bichet, Daniel G. Diagnosis of polyuria andBichet, Daniel G. Diagnosis of polyuria anddiabetes insipidus. UpToDate. 2007.diabetes insipidus. UpToDate. 2007.

Makaryus, Amgad N.; McFarlane, Samy I.Makaryus, Amgad N.; McFarlane, Samy I.Diabetes insipidus: Diagnosis and treatment of aDiabetes insipidus: Diagnosis and treatment of a

complex disease. Cleveland Clinic Journal of complex disease. Cleveland Clinic Journal of Medicine. Volume 73, Number 1, January 2006.Medicine. Volume 73, Number 1, January 2006. Rose, Burton D; Bichet, Daniel G. Treatment of Rose, Burton D; Bichet, Daniel G. Treatment of

central diabetes insipidus. UpToDate. 2007.central diabetes insipidus. UpToDate. 2007. Sands, Jeff M., Bichet, Daniel G. NephrogenicSands, Jeff M., Bichet, Daniel G. Nephrogenic

Diabetes Insipidus. Ann Intern Med. 2006;Diabetes Insipidus. Ann Intern Med. 2006;144:186-194.144:186-194.

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Diabetes Insipidus