Trina Banerjee
Outline
Categories of Adrenal Insufficiency
Pathophysiology:
Hyponatremia in general
Glucocrticoid deficiency
Aldosterone deficiency
Diagnosis
Clinical Presentation
Treatment
Summary
Categories of Adrenal Insufficiency
Primary:
Affects the Adrenal Glands
Results in Deficiency of Glucocorticoids and Aldosterone
Secondary:
Affects the Hypothalamus or pituitary
Results in Deficiency of glucocorticoids
Pathophysiology: Water Reabsorption
Fluid volume must be delivered to the distal
Diluting segment of the nephron
NaCl must be reabsorbed in the water impermeable
thick ascending limb
Water must be permeable in the cortical and
medullary collecting ducts
Pathophysiology: ADH
ADH binds to the V2 receptor, which is coupled to a
guanine‐nucleotide‐binding protein Gs
Adenyl cyclase is activated, leading to increased
cAMP
Protein Kinase A is activated, which phosphorylates
the serine 256 residue at the C‐terminus of aquaporin 2
Aquaporin 2 is then translocated to the apical
membrane of the collecting duct
General Pathophysiology
Decrease in cardiac output and reduction in systemic
BP through unknown mechanisms , resulting in stimulus of ADH
Cortisol acts as a negative feedback mechanism on
both CRH and ADH.
ADH is cosecreted with CRF by the paraventricular nuclei.
If there is no cortisol the amount of ADH can continue to increase
Oelkers et al
Purpose: Are AVP levels increased in patients with
hypopituitarism?
Retrospective study looking at 5 women with
diagnosed hypopituitarism who were hospitalized with symptomatic hyponatremia
All patients were normovolemic and had
unsuccessfully received saline to reverse their hyponatremia
All patients had high ADH levels, which normalized
after cortisone
Kim et. al
Purpose: How do glucocorticoids affect AVP
transciption
1 kb upstream of the transcription site for the AVP
gene promoter are regulatory genes: GRE, CRE, and four binding sites for transcription factor activating
protein 2 (AP2)
Created different constructs of AVP: deleting GRE,
GRE and CRE, or GRE, CRE, and 2 AP2s
Deletion of GRE increased AVP
Concluded Glucocorticoids normally act on GRE to
inhibit AVP
Chen et. al
Purpose: Looked at the effect of glucocorticoid
deficiency on urinary concentrating ability
18 rats with bilateral adrenalectomies:
9 rats were given back aldosterone and dexamethasone (CTL)
9 rats only received aldosterone (GD)
Rats underwent a 36 hour water deprivation
AVP levels were the same for both control and GD
rats
Na/K/2Cl , AQP‐2 and UT‐A1 were decreased in the
GD rats compared to CTL
Wang et. al
Purpose: Looked at the effect of glucocortcoid
deficiency on urinary diluting ability
25 rats divided into 2 groups, 12 control animals and 13
glucocorticoid deficient
Observed for 12 days, then with water loading, then
following administration of a V2 antagonist
Wang et. al cont.
GD rats: impaired water excretion, higher urine
osmolarity and higher urine to plasma osmolarity ratio compared to controls
GD rats: increase in NHE3, Na/K/2Cl, AQP 2 and
AQP 3 compared to controls
Following water loading, the level of AQP was higher
in the GD rats than the control rats, this reversed with V2 antagonists
General Pathophysiology
Salt wasting and volume depletion result in
hypovolemia which stimulates the release of ADH via carotid baroreceptors
Ohara et. al
Purpose: Examine the effect of selective
mineralcorticoid deficiency in the rat on ion, urea, and aquaporin water channels
Three groups of rats were adrenalectomized:
Group 1 (CTL) in which both mineralcorticoid and glucocorticoids were replaced
Group 2 in which glucocorticoids were replaced and and rats were only drinking water (MDW)
Group 3 in which glucocorticoids were replaced and rats were only drinking saline (MDS).
Ohara et. Al cont
MDW rats had a downregulation of Na/K/2Cl and
Na/K ATPase and an upregulation of AQP 2 and 3 compared to MDS or CTL
Indicates that the changes seen in mineralcorticoid
depletion are mainly the result of sodium depletion
Diagnosis
Serum cortisol level:
Most patients with severe hyponatremia are in the ICU and the normal range of plasma cortisol in unstressed
healthy patients is a “yardstick of limited value”
Clinical Presentation
Diederich et. al:
Retrospective review of 28 patients with hyponatremia secondary to secondary adrenal insufficiency between
1981 and 2000
Serum sodium at admission ranged from 105‐127 mmol/L
Mean plasma osmolarity was 256+/‐16 mosm/kg
Urine osmolarity (n=14) was 399 +/‐
108
Urinary sodium (n=11) was 110+/‐
49
Treatment
Volume repletion to turn off ADH
Glucocoticoid
Deficiency:
V2 receptor antagonists
Physiologic Cortisol
Replacement with Hydrocortisone or Cortisone acetate
Aldosterone
Deficiency:
Replacement of aldosterone
Maintaining sodium balance
V2 receptor antagonists improve hyponatremia, but will not completely reverse it
Conclusion
Glucocorticoid
Deficiency:
Hyponatremia
results from elevated levels of ADH, as a result of decreased cardiac output and SVR, as well as
upregulation
of Na/K/2Cl, AQP2, and AQP 3
Aldosterone
Deficiency:
Hyponatremia
results from salt wasting, as well as upregulation
of aquaporin
2 and 3
Largely reversible by maintaining a normal sodium state