Mne Lecture 30 - Diabetes Insipidus

Front 1

polyuria =

Back 1

excessive urine production

excessive urination will stimulate equivalently excessive fluid intake to match the fluid lost through the kidneys
excessive fluid intake will cause equivalently excessive urination to eliminate the ingested fluid

Front 2

polydipsia =

Back 2

excessive fluid intake

excessive urination will stimulate equivalently excessive fluid intake to match the fluid lost through the kidneys
excessive fluid intake will cause equivalently excessive urination to eliminate the ingested fluid

Front 3

Disorders causing polyurea

Back 3

1. diabetes mellitus
-->glucose in urine can cause osmotic diuresis of volumes of this nature BUT this patient had a normal fasting glucose eliminating that as a possibility

2. diabetes insipidus
-->if central, can be due to a deficiency of hypothalamic hormone VASOPRESSIN
-->if nephrogenic, due to a LACK of kidney RESPONSE to vasopressin 
-->if gestational, diabetes insipidus happens during pregnancy, can rule that out in this case

3. Primary polydpisia
-->simply drinking too much, no reason for this

4. Osmoreceptor dysfunction
-->can secrete ADH, and kidneys can respond to it, but the cells that control secretion aren’t working

Front 4

diabetes

Back 4

“passing water like a siphon” (Greek)

Front 5

mellitus

Back 5

“sweetened with honey”

-latin
-used to have medical students taste urine to make diagnosis

Front 6

insipidus

Back 6

“without taste”

-latin
-used to have medical students taste urine to make diagnosis

Front 7

Who first described the differentiation of diabetes insipidus from diabetes mellitus by tasting the urine for sweetness?
A. Sushruta (6th century B.C., India)
B. Hippocrates (460-377 B.C., Greece)
C. Araetus of Cappadocia (81-138 A.D., Turkey)
D. Sir Thomas Willis (1621-1675, England)

Back 7

D . He tasted the urine, figured out it was sweet, published about it
pioneer in clinical pathological analysis of diabetes
first to distinguish the form of diabetes known as diabetes mellitus


(C coined the term diabetes)

Front 8

Prevalence and Incidence of Diabetes mellitus v. inspidus

Back 8

diabetes mellitus
-1.6% ages 20-39 to 19.3% ages 75+
-15-20,000,000 cases worldwide

diabetes insipidus
-1 per 10-15,000 population (0.005-0.01%)
-15-20,000 cases
-not as prevalent

**the number of cases of DI is <0.1% of DM, and has not increased substantially for >50 years

Front 9

AVP is made by

Back 9

made by cells in supraoptic and paraventricular nuclei

AVP is synthesized in the cell bodies in the SON and PVN, then transported down the axons of the pituitary stalk and released from the neuron terminals in the posterior pituitary

Front 10

what stimulates AVP?

Back 10

Anything that signals the brain that there is a deficit of body fluids:
1. hyperosmolality
2. dehydration
3. hypovolemia
4. hormones that indicate hypovolemia, like angiotensin II
-->literally if you are viewed as having too little fluid in your body you secrete AVP in order to act at V2 receptors in kidney to conserve water so you don’t lose more water and become more fluid restricted
-->there are inhibitory stimuli, not talking about those today

AVP also acts on V1a receptors to cause vasoconstriction

Front 11

Back 11

Front 12

What happens when AVP is secreted?

Back 12

-when AVP is secreted because body detects you need to conserve water
-it activates AVP V2 receptor and the signal transduction cascade (cAMP --> PKA --> AQP2 inserted in membrane) inserting AQP2 (aquaporin 2) into the membrane.
-That’s like poking millions of holes in the membrane --> only diameter of water molecule so only water goes through.
-Water is reabsorbed back into the cell because osmotically the cell is more concentrated than urine so water flows back into the cell.
-Water in the cell flows out the back side via other aquaporins (AQP4) into the blood. That is ANTIDIEURESIS. 

Running on a hot day without waterbottle, this is the mechanism that keeps you from getting overly dehydrated.

If you don’t have enough AVP to secrete you cannot activate this mechanism and you constantly have increased urine excretion of water because you can’t activate the AVP V2 receptor that causes antidiuresis or conservation of urine by the kidney
**this v2 receptor and avp are crucial for water absorption to reoccur BUT there are many different steps, defect in any can have the same result

Front 13

What happens when you drink water and there is No avp secreted?

Back 13

where avp works is in the kideny
-specific cell in the distal part of kidney called the collecting duct
-the collecting duct epithelial cells (blue square)
-That cell is the single cell that sits in between urine in collecting duct which has come all the way down from the glomerolus the proximal __ on its way out of the kidney.
-Makes its way past this cell and goes out into the ureter into the bladder and out of the body.
-Sitting on the blood side of this cell is the AVP V2 receptor
-->blood supply is called the vasa recta of the kidney.

NO AVP in the plasma when you finish waterbottle, urine in collecting duct is relatively impermeable to water. Water shoots out into bladder have diuresis

Front 14

Neurogenic diabetes incipidis

Back 14

-aka central DI
-rare, prevalence <1:25,000

-hypothalamic lesion in ~40-50% (tumor, sarcoidosis, histiocytosis)
-->After head trauma or pituitary surgery in which case DI is created as a result
pituitary lesions are generally not sufficient to cause DI until

-postoperatively
-->In process of taking out tumor damage to posterior pituitary

-idiopathic in 20-30% (probable autoimmune process in most of these)

-genetic <5% (often delayed onset)

Front 15

What happens if you obliterate the pituitary?

Back 15

- Anterior pituitary hormones are made and synthesized in the anterior pituitary --> won’t get secretion
-Posterior pituitary hormones are made in the hypothalamus, all you would have destroyed is the release sites. You haven’t killed the cells that make the AVP. If these cells survive, they can reorganize to secrete AVP from higher up predominantly form the median eminence into the pituitary portal circulation

Front 16

Frequently see patients with very big tumors occupying the whole sella tursica, complete obliteration of anterior and posterior pituitary; have a deficiency of all anterior and posterior hormones

Do they necessarily have diabetes insipitus?

Back 16

they do NOT have diabetes insipitus because of this distinct difference in where the hormones are synthesized.

- Anterior pituitary hormones are made and synthesized in the anterior pituitary --> won’t get secretion
-Posterior pituitary hormones are made in the hypothalamus, all you would have destroyed is the release sites. You haven’t killed the cells that make the AVP. If these cells survive, they can reorganize to secrete AVP from higher up predominantly form the median eminence into the pituitary portal circulation

Front 17

Anterior hormones synthesized in the ____.

AVP and oxytocin synthesized in the ____.

Back 17

Anterior hormones synthesized in the anterior pituitary

AVP and oxytocin synthesized in the hypothalamus

Front 18

If you look at what causes DI without previous head trauma or surgery what do you find?

Back 18

-tumor in 25%

-genetic cause (familial diabetes insipitus) in 6%

-infiltrative disease typically langerhans’ cell histiocytosis (see this in kids-- rare disease involving clonal proliferation of Langerhans cells, abnormal cells deriving from bone marrow and capable of migrating from skin to lymph nodes; sarcodosis in humans?) in ~16%

-about 50% of cases IDIOPATHIC without tumor infiltration or obvious genetic cause

Front 19

What is causing these idiopathic cases?

Back 19

-autoimmune disease
-infiltration of lymphocytes into the neurohypophesis

-patient who presented here has:
a. thickening of pituitary stalk
-when cells are stained against T lymphocytes they’re positive
-just like other autoimmune and endocrine diseases, body can attack its own tissue, in this case the posterior pituitary, causing destruction, and this is called
LYMPHOCYTIC INFUNDIBULONEUROHYPOPHYSITIS
(neurohypophysis because this is what is inflamed and damaged includes the infundibulum because this is the cone shaped area that comes into the stalk before it becomes the posterior pituitary)

-MRI image of those patientssee pituitary stalk, which is normally very think stalk, as very swollen indicative of inflammation caused by lymphocytic infundibularneurohypophysitis
-not all pituitary stalk thickening is due to an autoimmune process

Front 20

see thickening in conjunction with DI think of infiltration of the pituitary stalk but don’t know exactly what’s causing it:

Back 20

a. could be autoimmune with T cells infiltrating
b. could be histiocytosis (abnormal increase in the number of langerhans’ cells) 
c. could be sarcoidosis (a disease in which abnormal collections of chronic inflammatory cells (granulomas) form as nodules in multiple organs)or a few other rare things.

Front 21

Nephrogenic (renal) DI

Back 21

Nephrogenic (renal) diabetes inspidus
-->patient can secrete AVP but kidney does not respond to it
-->even less common than neurogenic DI

-Familial forms:
--> X-linked recessive: AVP V2-receptor mutation on X chromosome
-->autosomal dominant: aquaporin-2 mutation
*females

-acquired: *majority of adult patients have more common acquired rather than rare familial
-->hypercalcemia (Ca++ > 13)
-->hypokalemia (K+ < 2.5)
-->drugs (lithium, demeclocycline)

Front 22

mutations in the AVP V2 receptor gene associated with hereditary nephrogenic DI

Back 22

-Black circles are all the mutations in the vasopressin V2 receptor sequence

-no one predominant mutation-can mutate receptor anywhere and get a loss of function mutation

-90% of kids who get this have loss of function of v2 receptor-no functional v2 receptor
-->cannot respond to AVP
-->continue to excrete dilute urine

Front 23

mutations in the aquaporin-2 gene associated with hereditary nephrogenic DI

Back 23

-~10% do NOT have a v2 mutation
--> have less common mutations in aquaporin 2 gene and these act the same 

-anywhere in pathway if you have a mutation the net effect is the same

-final common pathway: insertion of aquaporin 2 channels into the apical membrane, makes sense that if you had mutations in aquaporin 2 genes you’d get the same effect

-whether you don’t have a functional receptor or you can’t signal downstream of the receptor the net effect is the same: cannot reabsorb water and you’re secreting it --> diabetes inspidus

Front 24

primary polydipsia

Back 24

primary polydipsia
-most common cause of polyuria in western countries-drinking excessively
--> don’t retain water, you eliminate it 

-divided into 2 types:
1. dipsogenic DI:
-->Can get because of a reset thirst threshold
-->Some patients are too thirsty and drink too much because of :
a. mass lesions
b. granulomatous disease
c. idiopathic
d. aging

2. psychogenic DI:
-->increased fluid intake for reasons other than true thirst
-->see this pathologically in schizophrenia
schizophrenia: psychosis-intermittent hyponatremia-polydipsia (PIP) syndrome

- Among causes of increased fluid intake is belief that a lot of water is good for you
-Has no medical basis
-No need (physiologically) to drink any more than you need than when you’re thirsty; no health benefit from excess water (except for patients with kidney stones)

Front 25

It is important to differentiate from true diabetes insipidus because

Back 25

the TREATMENT is different

-->True diabetes insipidus need to treat excess water secretion
-->If you have primary polydipsia there’s nothing to treat in terms of excess water secretion; rather have to treat the cause of the increased drinking if it is of a pathological nature.

Front 26

DI: screening
How do you make the diagnosis:

Back 26

2 phases in medicine to recognizing diagnosis:
1. Screening phase
-use basic criteria to eliminate people who don’t have the disease you’re thinking of
-the patients who are left are those you need to make the diagnosis in

SCREENING:
show that the patient has hypotonic polyuria:
a. 24-h urine volume >50 ml/kg under conditions of ad lib intake
-->this is defined as polyuria under conditions of ad lib intake

b. urine S.G. <1.010, Uosm <300 mOsm/kg H2O
-->has to be hypotonic
-->cannot be glucosuria

c. absence of solute diuresis (urine dipstick negative for glucose)

fail to meet any of these criteria, you don’t work the patient up any further

Front 27

diabetes insipidus cannot be diagnosed until the patient is shown to excrete a __ urine in the presence of __ serum

Back 27

diabetes insipidus cannot be diagnosed until the patient is shown to excrete a hypotonic urine despite the presence of a hyperosmolar serum

Front 28

Most patients present with a normal serum sodium

why wasn’t it high?

Back 28

**plasma osmolality is usually normal in patients with all causes of polyuria**
Most people have normal plasma osmolality between 275 and 300
-because body maintains homeostasis of water and fluids, it has evolved to do that over thousands of years

-if you have 1’ polydipsia you simply have dilute urine and excrete it
-ability to excrete that urine maintains plasma osmolality in normal range
-if you have either form of diabetes insipitus you activate thirst and that thirst will increase your fluid intake which will match your excess water secretion allowing you to maintain osmolality 
-plasma osmolality is maintained in a state of homeostasis, regardless of whether you drink too much (secrete more urine) or you’re losing too much (drink more)
-only a small number of patients with 1’ polydipsia overdrink to the point that they develop a very low osmolality and lose the ability to excrete all the water that they’re drinking
-only a few patients with DI fail to drink enough to maintain their osmolality and subsequently present with a high osmolality

Front 29

When you can’t make a diagnosis based on base line characteristics from lab workup, what do you need to do?

Back 29

You need to CHALLENGE the patient!
-->Put the patient in a situation where you can either demonstrate inadequate or excess secretion so you can make the diagnosis

how can we put patient in situation where osmolality is increased to see if he can secrete avp and concentrate his urine?

challenge him with a water depravation test

Front 30

water deprivation tests

Back 30

1. outpatient --> overnight !
-withold all fluids after dinner until the next morning
-measure AM serum [Na+] and urine osmolality
-Uosm >800 eliminates DI, >600 effectively does in most cases as well

2. More formal (inpatient)
-withold all fluids until BW decreases by 3-5% OR shows he cannot concentrate urine any furhter -- urine osmolality plateaus X 2-3 successive measurements, or serum [Na+] >145 mmol/L
-administer AVP (5 U) or dDAVP (1 μg) sc and follow urine osmolality and volume for 2 more hours (dDAVP is AVP analogue)
-Uosm increase >50% following AVP/dDAVP indicates central DI, <10% indicates nephrogenic DI, intermediate responses (10-50%) are equivocal (if that’s the case, you have to look at other labs)

Front 31

water deprivation test: interpretation

Back 31

-this is the overall interpretation of this test and why we do it

-normal in purple, water deprive me for 6-10 hours, I would increase urine osmolality
WHERE? Somewhere between 800 and 1000 cc’s because that’s the normal kidney response

-patients who have complete central DI can’t do that because they lack AVP and when you give them AVP or dDAVP you have replaced what was deficient and they can concentrate their urine

-if this patient had nephrogenic DI, he would show the same initial response but when you gave him ADP he would have NO response
--> because nephrogenic DI is an absence of the ability of the kidney to respond to ADP

-sometimes patients don’t have complete ADP deficiency. This is true of all hormones that are on their way out (go through phase of insufficient but not completely gone). This is partial central DI. That patient might get up to 400-500 mOSM but not as far as a normal person would go. If they respond to AVP or dDAVP then you can make the central v. nephrogenic diagnosis

-what if they get to that level and they DON’T respond to the ADP?
THEN then have primary polydipsia

Front 32

chronic excess fluid administration does two things to the kidney:

Back 32

1. downregulates the aquaporin synthesis because you don’t need it, don’t have enough to maximally concentrate your urine

2. require that concentration gradient in the inner medulla of the kidney to conserve water and as you continually flush water through the body from excess drinking you wash out that medullary concentration so you cant wash out as much. People with primary polydypsia will NOT be able to maximally concentrate urine but it is NOT due to vasopressin insufficiency. Consequently you give them vasopressin and it doesn’t matter. This is the maximum the kidney can do.

Front 33

plasma AVP levels can differentiate CDI from other types of polyuria, if the plasma osmolality is

Back 33

>295 mOsm/kg

__

-can also test vasopressin deficiency directly
-grey area is the normal range of vasopressin-osmolality somewhere around 285 ish 
-someone with nephrogenic diabetes insipidus --> kidneys cannot respond but pituitary is normal they have high AVP levels. See DI and measure AVP levels as high that tells you it is nephrogenic diabetes inspidus 
-people with 1’ polydypsia have no problem with AVP secretion so if you measure the AVP (shown here by these open circles) it’s in the normal range.
-If your patient really has central DI they can’t make enough AVP, they have very low AVP levels when they should be high for an increased osmolality.

Front 34

if the posterior pituitary “bright spot” is seen, what is the likelihood of central DI?

Back 34

<5% likelihood of central DI

__
Posterior pituitary is bright, called a posterior pituitary “bright spot” which is characteristic in neuroradiology

Front 35

DI (central) Treatment

Back 35

Treatment:

1. Water
-could be just water
-he’s maintaining homeostasis through just water intake, but it’s inconvenient for him at work, at night (can’t get a full nights sleep)

2. treat with hormone that is deficient
-AVP

3. Antiduresis enhancing agents
-chlorpropamide
-cabamzepine
-indomethacin

Front 36

AVP half life in plasma?
Why might AVP have the half life it does?

Back 36

-->AVP has short half life in plasma : 15 minutes in the plasma 
--> need this because if you drank excess of a few liters of water and it took you several hours to excrete that would be bad because it would put you at risk of water toxification from normal amounts of water intake 
-->need to turn it on to save water in the kidney when you need it but also need to be able to turn it off quickly when you need to excrete water as well.
-now use DESMOPRESSIN (DDAVP) --> analogue of AVP with two changes

Front 37

AVP v. DDAVP

Back 37

-now use DESMOPRESSIN (DDAVP) --> analogue of AVP with two changes

-ddavp has a terminal elimination of the amino group on the amino terminal
-also substitution of d arginine for L arginine in the 8 position 
**those two key changes make it ideal for treating these patients because it has a LONGER DURATION than AVP

-urine output goes down briefly then comes back up
-treat with DDAVP goes down and stays down, much longer duration of action
-AND because these two changes make it selective for the V2 receptor it doesn’t interact with the V1a receptors that cause vasoconstriction
-->if you give AVP have to worry about vasoconstriction, don’t have to worry about that is ddavp
-->unlike AVP which has to be injected, dDAVP can be given intranasally or even orally which represents a major advantage for patients

Front 38

evolutionarily we evolved to not have to drink constantly because

Back 38

zebras have to drink but won’t go to the watering hole all the time because there are tigers lurking around there too 

evolutionarily we evolved to not have to drink constantly because it’s provided in a safety factor from predation

--> the more you have to go more frequently to get water the more you’re subject to potential predation by the predators who know you have to go there for water as well
-->zebras and other animals in the wild drink only once a day 
-->this thirst drive does make them eventually seek water from wherever they can find it
-->thirst is one of the key factors that has driven evolution

Front 39

the same osmoreceptors in the anterior part of the hypothalamus that control secretion of AVP from the SON (supraoptic nucleus) or PVN (paraventricular nucleus) also control

Back 39

THIRST!

-system is set up so that as soon as you respond with AVP you also stimulate thirst.
-if you reach a state of AVP secretion you’ve reached a state at which your body is sensing an insufficient amount of body water from body fluid. Yes you should want to save it in your kidney but you should also want to replace it-secrete AVP increase thirst

Front 40

OSMORECEPTOR dysfunction

what would happen if I had a lesion / patient had a lesion that obliterated the osmoreceptors?

Back 40

-This is more anterior in the hypothalamus than where the AVP receptors are.
-If you eliminate the AVP secreting neurons with infundibularneurohyopohysis you cannot secrete AVP so you get polyuria
-because osmoreceptors are intact you still get thirst, that’s why you have polyuria and polydypsia

Front 41

What if you have a lesion that eliminates the osmoreceptors without touching the neurons that secrete AVP? Will you have polyuria?

Back 41

YES
-cannot stimulate neurons even though they're there

Front 42

If you don’t have osmoreceptorswill you have polydypsia?

Back 42

NO. because you need the osmoreceptors for both thirst and avp secretion

Front 43

If you're dehydrated, what temperature fluids do you prefer?

Back 43

-If you’re dehydrated prefer cold fluids because cold fluids have a way of helping thirst better than warm
-if you aren’t dehydrated there is no strong preference
-if you see patient coming in w/ polydipsia with room temp bottle of water they probably have 1’ polydipsia
-if he sees patient with thermos bottle full of cold water because of physiologically driven thirst than a desire to drink more for whatever reason besides true thirst.