Diabetes Insipidus

Dr. Aniqa ShahidDr. Aniqa Shahid

PGR MU-1PGR MU-1

HistoryHistoryMy patient named “Razia Aslam” w/o My patient named “Razia Aslam” w/o Muhammad 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 with Presented on 4-12-11 in Medical OPD with the following complaints for last 4 months.the following complaints for last 4 months. Frequent large urine. Frequent large urine. Night wakening for urine.Night wakening for urine. Extreme thirst.Extreme thirst. Lethargy.Lethargy.

HOPIHOPIMy patient was in her usual state of health My patient was in her usual state of health four months back when for the first time four 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 to Ramadan she noticed that she was unable to keep her fast after mid day due to extreme keep her fast after mid day due to extreme feeling of thirst which was specifically for feeling of thirst which was specifically for water. water. Meanwhile she was frequently Meanwhile she was frequently passing large volume of colorless urine, So passing large volume of colorless urine, So by the end of fast she turned out to be very by the end 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 toilet water in a day with 7-8 times using toilet and about six to seven times during night and about six to seven times during night when she had to get up from sleep d/t thirst when she had to get up from sleep d/t thirst and to use toilet. She used to finish her and to use toilet. She used to finish her glass in one gulp rather than sipping it over glass in one gulp rather than sipping it over a period of time. She never collected the a period of time. She never collected the urine but gave H/O large volumes of urine urine but gave H/O large volumes of urine every time.every time.

HOPI (Contd.)HOPI (Contd.)

HOPI (Contd.)HOPI (Contd.)Her frequent wakening during night due Her frequent wakening during night due to thirst and passing of urine was making to 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 surgeryNo H/O dizziness, vertigo, palpitations or No H/O dizziness, vertigo, palpitations or heat intolerance.heat intolerance.No History of anxiety or other No History of anxiety or other psychiatric illness.psychiatric illness.

No history of any visual disturbance or No history of any visual disturbance or headache. 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 renal No history of diabetes, HTN or renal

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

daughters and one son. Eldest aged 12 daughters 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 drug No history of previous illness or any drug therapy, hospitalization or surgery.therapy, hospitalization or surgery.

Socio-Economic StatusSocio-Economic Status

Patient belongs to a middle class family. She Patient belongs to a middle class family. She is a house wife and her husband works in a is 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 bed A 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 dehydration No other signs of dehydration

Pallor -Pallor - Cyanosis -Cyanosis -

Jaundice -Jaundice - JVP not raisedJVP not raised

EdemaEdema Not PresentNot Present

Cervical, axillary or inguinal lymph nodes not Cervical, axillary or inguinal lymph nodes not palpable.palpable.

CNSCNS::Mental status examination:Mental status examination:

( Conscious ,alert , well oriented in time and ( Conscious ,alert , well oriented in time and space. MMSE normal )space. 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 no visible pulsationsApex beat normally localized .Ist and second heart sounds heard with no added sounds.

GIT:Normal shapeNon distended Non tenderNo visceromegalyBowel sounds audible

Lab InvestigationsLab Investigations CBC: CBC:

Urea Urea 18mg/dl18mg/dl S. Creatinine S. Creatinine 0.5mg/dl0.5mg/dl S. AlbuminS. Albumin 4.6mg/dl (3.8-5.1)4.6mg/dl (3.8-5.1) S. ProteinS. Protein 7.2mg/dl (6.2-8)7.2mg/dl (6.2-8) 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/l

Cl 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 0

RBCs 0RBCs 0 Casts -Casts -

Epith cells 0Epith cells 0

Specific gravity 1.006 (1.010- 1.025)Specific gravity 1.006 (1.010- 1.025) Sugar – NilSugar – Nil

ColorlessColorless PH 5PH 5

Turbidity -Turbidity - Blood -Blood -

Deposits -Deposits - Ketones -Ketones -

Albumin - NilAlbumin - Nil

Ultrasound of Abdomen Pelvis - NormalUltrasound of Abdomen Pelvis - NormalChest XRay normalChest XRay normalECG normalECG normal

DIABETES INSIPIDUSDIABETES INSIPIDUS

Brain MRI

D/DD/D PsychogenicPsychogenic CRFCRF MetabolicMetabolic

Hypercalcemia secondary to renal Hypercalcemia secondary to renal diseasedisease IatrogenicIatrogenic

IV fluid overloadIV fluid overload

DiureticsDiureticsNeoplasticNeoplastic

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

Hours Weight Urine Vol S.Osm Urine osm

0 51.0 kg - 293.0 101

1 50.5 kg 700

2 50.0 kg -

3 49.8 kg 600

4 49.6 kg - 299.4

5 49.4 kg 700

6 49.2 kg -

7 49.0 kg 500

8 48.8 kg - 307.0 119

Stage 2 :Stage 2 :Give Desmopressin 20ug through intranasal spray.Give Desmopressin 20ug through intranasal spray.

Measure urine Osmolality hourly for the next 4 hours.Measure urine Osmolality hourly for the next 4 hours.

CENTRAL DIABETES INSIPIDUS

IntroductionIntroduction

Central diabetes insipidus (CDI) results Central diabetes insipidus (CDI) results from any condition that impairs the from any condition that impairs the synthesis, transport, or release of synthesis, transport, or release of antidiuretic hormone (ADH), also known as antidiuretic hormone (ADH), also known as arginine 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.

IntroductionIntroduction ADH is produced in the hypothalamus and ADH is produced in the hypothalamus and

travels along nerve fibers to the posterior travels along nerve fibers to the posterior pituitary, where it is stored and released.pituitary, where it is stored and released.

ADH promotes reabsorption of water in the ADH promotes reabsorption of water in the collecting duct of nephrons.collecting duct of nephrons.

Increased plasma osmolality stimulates Increased plasma osmolality stimulates release of ADH in normal people.release of ADH in normal people.

Patients with CDI secrete lower than Patients with CDI secrete lower than normal levels of plasma ADH in response normal levels of plasma ADH in response to elevated plasma osmolality.to elevated plasma osmolality.

IntroductionIntroduction In patients with CDI, the degree of polyuria In patients with CDI, the degree of polyuria

is primarily determined by the degree of is primarily determined by the degree of ADH deficiency.ADH deficiency.

The urine output can range from 3 L/day in The urine output can range from 3 L/day in mild partial DI to over 15 L/day in patients mild partial DI to over 15 L/day in patients with severe disease.with severe disease.

CDI can be worsened or first diagnosed CDI can be worsened or first diagnosed during pregnancy, when ADH catabolism is during pregnancy, when ADH catabolism is increased by vasopressinases released increased by vasopressinases released from the placenta.from the placenta.

EtiologyEtiologyIdiopathic DI:Idiopathic DI:

Accounts for 30 to 50% of cases of Accounts for 30 to 50% of cases of CDI.CDI.

Autoimmune destruction of the ADH Autoimmune destruction of the ADH hormone-secreting cells in the hormone-secreting cells in the

hypothalamus.hypothalamus.Neurosurgery Neurosurgery Brain traumaBrain traumaPrimary or metastatic brain tumors Primary or metastatic brain tumors Infiltrative diseases (Langerhans cell Infiltrative 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 neurohypophyseal Also called familial neurohypophyseal

diabetesdiabetes insipidus (FNDI).insipidus (FNDI). Autosomal dominant Autosomal dominant Mutations in the ADH gene.Mutations in the ADH gene. Patients progressively develop ADH Patients 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 it Transient CDI has been associated with it

but no mechanism has been identified.but no mechanism has been identified. Wolfram syndrome (or DIDMOAD Wolfram 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-secreting CDI is due to loss of ADH-secreting

neurons in the hypothalamus and impaired neurons in the hypothalamus and impaired processing of ADH precursors.processing of ADH precursors.

SymptomsSymptoms The major symptoms of central DI are The major symptoms of central DI are

polyuria and polydipsia.polyuria and polydipsia. Polyuria is defined as a urine output of over 3 Polyuria is defined as a urine output of over 3

L/day in adults.L/day in adults. Polyuria must be differentiated from Polyuria must be differentiated from

frequency and nocturia, which are not frequency and nocturia, which are not associated with an increase in total urine associated with an increase in total urine output.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 and This is in contrast to nephrogenic DI and

primary polydipsia, in which onset of polyuria primary polydipsia, in which onset of polyuria is 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 most This 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 first As a result, nocturia is usually the first manifestation of a loss of concentrating manifestation of a loss of concentrating ability.ability.

Thus, a relatively dilute urine is excreted, Thus, a relatively dilute urine is excreted, with a urine osmolality of less than 200 with a urine osmolality of less than 200 mOsmol/kg.mOsmol/kg.

Dry skin and constipation are other Dry 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 only Most patients have a high-normal or only

mildly elevated plasma sodium mildly elevated plasma sodium concentration, usually greater than 142 concentration, usually greater than 142 mEq/L.mEq/L.

In addition, the plasma osmolality usually In addition, the plasma osmolality usually remains around values only slightly above remains around values only slightly above 290 mOsm/kg (normal is 280-295 290 mOsm/kg (normal is 280-295 mOsm/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 net thirst, which minimizes the degree of net water loss.water loss.

DiagnosisDiagnosis Stimulation of thirst does not occur, Stimulation of thirst does not occur,

however, when CDI is due to a central however, when CDI is due to a central lesion that impairs thirst causing lesion that impairs thirst causing hypodipsia or adipsia.hypodipsia or adipsia.

In such cases, the plasma sodium In such cases, the plasma sodium concentration can exceed 160 meq/L and concentration can exceed 160 meq/L and the plasma osmolality will rise significantly the plasma osmolality will rise significantly also.also.

This also occurs if a patient has no access This also occurs if a patient has no access to water.to water.

Withholding water in patients with CDI can Withholding water in patients with CDI can result in severe dehydration.result in severe dehydration.

Water Restriction TestWater Restriction Test In healthy individuals, water deprivation In healthy individuals, water deprivation

increases plasma osmolality, which increases plasma osmolality, which stimulates secretion of ADH by the stimulates secretion of ADH by the posterior pituitary.posterior pituitary.

This then acts on the kidney to increase This then acts on the kidney to increase urine osmolality to 1000 to 1200 urine osmolality to 1000 to 1200 mOmol/kg and to restore plasma mOmol/kg and to restore plasma osmolality to normal levels.osmolality to normal levels.

Giving exogenous ADH does not increase Giving exogenous ADH does not increase urine osmolality further because it is urine osmolality further because it is already maximal in response to an already maximal in response to an individual’s endogenous release of ADH.individual’s endogenous release of ADH.

Water Restriction TestWater Restriction Test The test should be continued until one of the The test should be continued until one of the

following occurs:following occurs:• The urine osmolality reaches a normal The urine osmolality reaches a normal

value, which is above 600 mOsm/kg, value, which is above 600 mOsm/kg, indicating that both ADH release and effect indicating that both ADH release and effect are intact. are intact.

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

• The plasma osmolality exceeds 295 to 300 The 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 Osms Urine osms are greater than plasma Osms

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

exogenous ADH.exogenous ADH.• Central Diabetes Insipidus:Central Diabetes Insipidus:

Urine osms remain less than plasma Urine osms remain less than plasma osms after water restriction.osms after water restriction.

After ADH is given, urine osms increase After ADH is given, urine osms increase 100% in complete CDI and over 50% in 100% in complete CDI and over 50% in partial 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 than After ADH, urine osms increase by less than

50%.50%.

TreatmentTreatment

There are several medications available There are several medications available for the treatment of CDI, of which for the treatment of CDI, of which desmopressin is the most common.desmopressin is the most common.

DesmopressinDesmopressin

Desmopressin is a two-amino acid Desmopressin is a two-amino acid substitute of ADH that has potent substitute of ADH that has potent antidiuretic activity but no vasopressor antidiuretic activity but no vasopressor activity.activity.

It is also known as dDAVP, which stands for It is also known as dDAVP, which stands for 1-deamino-8-D-arginine vasopressin.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 the It is safe during pregnancy for both the mother and the fetus.mother and the fetus.

DesmopressinDesmopressin The initial aim of therapy is to reduce The initial aim of therapy is to reduce

nocturia, in order to provide adequate nocturia, in order to provide adequate sleep. sleep.

Thus, the first dose is usually given in the Thus, the first dose is usually given in the late evening to control nocturia.late evening to control nocturia.

After that is achieved, control of daily After that is achieved, control of daily diuresis is the goal.diuresis is the goal.

The size of and necessity for a daytime The 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.

DesmopressinDesmopressin

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

This dose is titrated up in 5 microgram This dose is titrated up in 5 microgram increments as needed depending on the increments as needed depending on the response of the nocturia.response of the nocturia.

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

DesmopressinDesmopressin An oral tablet preparation is also available.An oral tablet preparation is also available. Absorption of the oral form is decreased Absorption 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 the The oral form has about 1/10 to 1/20 the

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

It is recommended to start with the nasal It is recommended to start with the nasal form before attempting a trial of oral form before attempting a trial of oral therapy.therapy.

Risks of DesmopressinRisks of Desmopressin

Potential risks of desmopressin include Potential risks of desmopressin include water retention and the development of water retention and the development of hyponatremia.hyponatremia.

This may occur because once dDAVP is This may occur because once dDAVP is given, the patient has nonsuppressible given, the patient has nonsuppressible ADH activity and may be unable to excrete ADH activity and may be unable to excrete ingested water normally.ingested water normally.

This can be avoided by giving the This can be avoided by giving the minimum daily dose required to control minimum daily dose required to control the polyuria.the polyuria.

Other DrugsOther Drugs

The other agents available are less The other agents available are less effective and associated with more effective and associated with more adverse effects than desmopressin.adverse effects than desmopressin.

Chlorpropamide, carbamazepine, and Chlorpropamide, carbamazepine, and clofibrate can be used in cases of partial clofibrate can be used in cases of partial CDI and can lower the urine output by as CDI and can lower the urine output by as much as 50%.much as 50%.


Chlorpropamide:Chlorpropamide:• An oral hypoglycemic agent.An oral hypoglycemic agent.• Acts by promoting the renal response to Acts by promoting the renal response to

ADH or dDAVP.ADH or dDAVP.• The usual dose is 125 to 250 mg, once The usual dose is 125 to 250 mg, once

or twice a day.or twice a day.• Higher doses may produce a somewhat Higher doses may produce a somewhat

greater response but also increase the greater response but also increase the risk of hypoglycemia.risk of hypoglycemia.


Carbamazepine:Carbamazepine:• An anticonvulsant.An anticonvulsant.• Enhances ADH release and raises the Enhances 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 typical 100 to 300 mg twice daily is the typical

dose. dose.


Clofibrate:Clofibrate:• A lipid lowering agent.A lipid lowering agent.• Stimulates residual ADH production in Stimulates residual ADH production in

the hypothalamus, therefore increasing the hypothalamus, therefore increasing ADH release from the posterior pituitary. ADH release from the posterior pituitary.

• 500 mg every six hours is the usual 500 mg every six hours is the usual dose.dose.

THANK YOU

ReferencesReferences Bichet, Daniel G. Diagnosis of polyuria and Bichet, Daniel G. Diagnosis of polyuria and

diabetes 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 a Diabetes 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. Nephrogenic Sands, 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