Diabetes insipidus (DI), Polyuria, dilute urine, increased thirst, antidiuretic hormones, (ADH), Posterior pituitary, V2-receptors, Aquaporins, transmembrane G-protein, SIADH, ADH resistance

1. DIABETES INSIPIDUS
DR. OFONMBUK UMOH
REGISTRAR, CHEM. PATH
5TH MAY, 2021

2. OUTLINE
• Introduction
• Brief pathophysiology of DI
• Diagnostic work-ups for DI
• Management of DI
• Conclusion
• References
2

3. INTRODUCTION
• Whereas:
• Diabetes mellitus (DM) is a group of metabolic
diseases characterized by hyperglycemia resulting
from defects in insulin secretion, insulin action, or both.
•
• Diabetes insipidus (DI) is a disorder of water balance
characterized by large amounts of dilute urine and
increased thirst, due to defects in antidiuretic hormone
(ADH) secretion or its responsiveness.
3

4. The neurohypophysis
• Both ADH and Oxytocin are
nanopeptides which circulates as
free (unbound) hormones in
plasma, at physiologic pH.
• Oxytoin: Uterine contraction &
milk letdown reflexes.
4

5. Physiological actions of ADH
• V1a - smooth muscle of blood vessels, VEGF
(platelets aggregation, coagulation factor release)
• V1b - Anterior pituitary (ACTH release) & islet cells
(insulin release) in response to stress.
• In the kidneys, a transmembrane G-protein coupled
receptor for ADH, called V2 receptor, is located in the
collecting ducts of the renal tubules.
5

6. • ADH action at
the collecting
duct of renal
tubules:
6

7. • Normally, ADH is released in response to hypovolemia,
or an increase in plasma osmolality.
• Disorders of ADH involves excess hormone, as in
syndrome of inappropriate ADH secretion (SIADH), or
deficient states as in diabetes insipidus (DI).
• DI can result from ADH deficiency, ADH resistance or
renal tubular disease
7

8. • Normal plasma osmolality ranges from 275 – 295,
expressed either as mosm/kg or mmol/kg
• Plasma osmolality can be measured using an
osmometer, or calculated using the formula:
• 2[Na] + 2[K] + [Urea(mmol/L)] + [Glucose(mmol/L)]
• Normal urine osmolality varies widely from 250 – 750
mmol/kg
8

9. DIABETES INSIPIDUS (DI)
• DI is defined as a polyuric state (>3 L/24 hr)
characterized by low urine osmolality (< 300
mOsm/kg), high-normal plasma sodium & high-normal
plasma osmolality due to inadequate ADH activity.
• It is a pathologic diagnosis.
• Majorly, DI can be cranial or nephrogenic.
• Other forms are: gestational DI & primary polydipsia.
9

10. Causes of DI 10
CENTRAL D.I
Congenital Accquired
Familial DI
Midline malformations of the brain,
Pituitary malformations
DIDMOAD (Wolfram) syndrome
Brain tumours: craniopharyngioma, optic glioma, pituitary
adenoma, metastatic tumours
Head injury/trauma
Pituitary gland infarction, from: septic shock, Sheehan syndr,
hypoxic injury.
Infiltrative diseases: sarcoidosis, histiocytosis, leukemias
Brain cysts and cerebral aneurysms
Drugs: Opiates, alcohol, phenytoin etc
NEPHROGENIC D.I
Mutation of AVPR2 gene
Mutation of AQP2 gene
Lithium toxicity
Pyelonephritis
Ureteric obstruction: kidney stones, strictures  renal damage

11. • There could also be idiopathic cause of DI.
• The most common form is central DI after trauma or
surgery to the region of the pituitary and
hypothalamus, which could manifest either as transient
or permanent.
• NOTE other causes of polyuria: psychogenic (primary)
polydipsia, osmotic diuretics and diabetes mellitus.
11

12. • Neurogenic/central DI results from a lack of ADH;
occasionally it can present with decreased thirst as
regulation of thirst center and ADH production are in
close proximity in the hypothalamus.
• Nephrogenic DI results from lack of aquaporin
channels in the distal collecting duct (decreased
surface expression and transcription).
12

13. • The lack of ADH prevents water reabsorption and the
osmolarity of the blood increases.
• With increased osmolarity, the osmoreceptors in the
hypothalamus detect this change and stimulate thirst.
With increased thirst, the person now experiences a
polydipsia and polyuria cycle.
13

14. Clinical features of DI
• Thirst / polydipsia is a common
feature, in patients with an
intact nervous thirst
mechanism.
• … while dehydration,
hypernatremia and weight loss
and shock can occur in
helpless patients.
14

15. DIAGNOSTIC WORK-UP FOR DI
• If the clinical presentation suggests DI, laboratory tests
must be performed to confirm the diagnosis, as
follows:
• A 24-hour urine collection for determination of urine volume
• Serum electrolyte concentrations, including calcium and
glucose levels
• Urinary specific gravity
• Simultaneous plasma and urinary osmolality
• Plasma ADH level
15

16. • Additional studies that may be indicated include the
following:
• Water deprivation (Miller-Moses) test to ensure
adequate dehydration and maximal stimulation of ADH
for diagnosis;
• Hypertonic saline infusion test;
• Pituitary studies, including magnetic resonance
imaging (MRI) and measurement of circulating pituitary
hormones other than ADH.
16

17. 17

18. WATER DEPRIVATION TEST
• It is a dynamic, semiquantitative test tailored to ensure
adequate dehydration and maximal stimulation of ADH
for diagnosis, and is typically performed in patients with
chronic forms of DI.
• Water deprivation followed by the administration of 2 µg
i.m, of DDAVP; a synthetic analog of vasopressin may
help to differentiate central from nephrogenic DI.
• However, the result of this test must be interpreted with
caution, because patients with partial nephrogenic DI or
primary polydipsia may show similar response to that
seen in central DI.
18

19. • In healthy individuals, water deprivation
leads to a urinary osmolality that is 2-4
times greater than plasma osmolality.
• Additionally, in normal, healthy
subjects, administration of exogenous
ADH produces an increase of less than
10% in urinary osmolality.
• The duration of this test ranges from 4-
8 hours, as the time required to
achieve maximal urinary concentration
varies widely.
19

20. • Procedure:
• Patient should be in bed and closely observed.
• Patient not allowed food or water after 20.00 hr, on the night
before the test.
• Urinary osmolality and body weight are measured hourly.
• 08.00h: The bladder is emptied, blood and urine sample are
collected and their osmolalities are measured. If the plasma
osmolality is low-normal or low, water depletion is unlikely
and polyuria is probably due to an appropriate response to
a high intake.
20

21. • If the plasma osmolality is high-normal or high and the
urinary osmolality is more than 750 mmol/kg, the test
should be stopped.
• 09.00h… blood and urine are again collected and the
plasma and urinary osmolalities are measured hourly.
• If the urinary osmolality is more than 750 mmol/kg,
neither significant tubular disease nor DI is likely and
the test should be stopped.
21

22. • If the urinary osmolality is less than 750 mmol/kg and
plasma osmolality is normal, fluid restriction should be
continued and the estimations repeated at hourly
intervals. The test should be stopped as soon as the
urinary osmolality exceeds 750 mmol/kg.
• Failure of concentration of three (3) consecutive urine
specimens indicates either tubular disease or DI, from
which DDAVP should be administered henceforth.
22

23. • Remember:
• Urine osmolality below 300 mOsm/kg combined with
serum osmolality above 300 mOsm/kg (or with
hypernatremia) is diagnostic for diabetes insipidus.
• If urine osmolality is above 600 mOsm/kg and serum
osmolality is below 270 mOsm/kg, DI is unlikely.
23
Interpretation of the water deprivation test

24. 24

25. • In central and nephrogenic DI, urinary osmolality will be
less than 300 mOsm/kg after water deprivation. After the
administration of ADH, the osmolality will rise to more than
750 mOsm/kg in central DI but will not rise at all in
nephrogenic DI.
• In primary polydipsia, urinary osmolality will be above 750
mOsm/kg after water deprivation. A urinary osmolality that
is 300-750 mOsm/kg after water deprivation and remains
below 750 mOsm/kg after administration of ADH may be
seen in partial central DI, partial nephrogenic DI, and
primary polydipsia.
25

26. • Water deprivation test results may be misleading in
patient with chronic primary polydipsia, who may
experience partial washout of the medullary interstitial
gradient and downregulation of ADH release. This
would resemble nephrogenic DI, with an inability to
concentrate urine.
• The combination of a plasma ADH assay with water
deprivation test, can lead to greater accuracy in
differentiating the different forms of DI from each other,
and from primary polydipsia.
26

27. 27

28. HYPERTONIC SALINE INFUSION TEST
• Principles: the infusion of 5% hypertonic saline, by
raising plasma osmolality, would normally cause
maximal ADH secretion.
• The test overall lasts for about 3 hours and can be
initiated at 08:00 am. Medications that have diuretic or
anti-diuretic effects need to discontinued 24 hours prior
to testing.
• Results: patients with cranial DI have little or no rise in
ADH, but ADH is markedly released in nephrogenic DI.
28

29. • Procedures:
• The patient fasts from midnight till morning
• The patient lies in a supine position.
• Two intravenous cannulas are inserted, one for infusion and the
other for blood sampling.
• 5% saline is infused 0.04ml/kg per minute for 2hrs
• Blood samples are taken at baseline and 30 mins interval
• Plasma ADH is measured before & after the test along with urine
and plasma osmolality
• The patient must be closely monitored during the test.
Blood pressure and heart rate must be constantly
assessed, preferably on a monitor; and weight recorded.
29

30. • Other biochemical evaluation for DI could include a
morning plasma measurement of pituitary hormones
(growth hormone, prolactin, ACTH, TSH, FSH, and
LH).
• An MRI of the sella and suprasellar regions with
gadolinium may be obtained to evaluate for any
anatomical disruptions of the pituitary or hypothalamic
anatomy (macroadenomas, empty sella, infiltrative
diseases etc).
30

31. Management of DI
• Most patients with DI can drink enough fluid to replace their urine
losses. When oral intake is inadequate and hypernatremia is
present, provide fluid replacement as follows:
• Give dextrose and water or an intravenous fluid that is hypo-
osmolar with respect to the patient’s serum; do not administer
sterile water without dextrose IV.
• Administer fluids at a rate no greater than 500-750 mL/hr; aim at
reducing serum sodium by approximately 0.5 mmol/L (0.5
mEq/L) every hour
31

32. Pharmacologic therapeutic options include the following:
• Desmopressin (drug of choice for central DI)
• Synthetic vasopressin
• Thiazides
• Carbamazepine (rarely used; employed only when all
other measures prove unsatisfactory).
• Nonsteroidal anti-inflammatory drugs (NSAIDs), such as
indomethacin (may be used in nephrogenic DI, but only
when no better options exist).
32

33. CONCLUSION
• Making an accurate diagnosis of DI and ascertaining
its type and the underlying etiology poses a clinical
challenge, as there can be significant overlap in the
results among the various forms of polyuria-polydipsia
syndromes.
• However, specific testing protocols, such as the water
deprivation test in conjunction with DDAVP or the
hypertonic saline infusion test can assist with providing
a diagnosis with increased accuracy.
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34. REFERENCES
 Central Diabetes Insipidus. NORD (National
Organization for Rare Disorders). 2015. Archived from
the original on 21 February 2017.
 Tietz Textbook of Clinical Chemistry and Molecular
Diagnostics; fifth Ed., by Karl Burtis et al.
 Martin A. Crook; Clinical Chemistry and Metabolic
Medicine, 8th Edition.
 Clinical Chemistry; Principles, Techniques &
Correlations, 7th Ed., by Bishop et al.
 Harrison Principles of Internal Medicine, 18th Edition,
by Longo, Kasper, Fauci et al. McGraw-Hills Publishers,
2012.
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