Disorders of Water Homeostasis: Hyponatremia and Hypernatremia

Question 1

Hypertonic Hyponatremia

Answer 1

Elevated serum glucose (or mannitol) increases plasma osmolality.
This draws water from the intracellular compartment diluting serum sodium.

Question 2

Types of hyponatremia

Answer 2

hypertonic
isotonic
hypotonic

Question 3

Etiology of hyponatremia

Answer 3

H2O intake > H2O excretion
Osmolality is normally maintained constant at 280-285 mOsm by matching rates of water excretion to rates of water intake. In the setting of hypotonicity, rates of water intake have exceeded rates of water excretion. Under normal circumstances, the
kidney has an enormous capacity to excrete water (up to ~18 L per day). If renal water handling is impaired for any reason, then only modest amounts of water intake can cause hypotonicity

Question 4

Pathophysiology of hyponatremia

Answer 4

The underlying pathophysiology for the development of hypotonic hyponatremia is either: (1) huge water intake with normal water excretion, or (2)
normal water intake with impaired renal water excretion

Question 5

What are the main mechanisms for impaired renal water excretion?

Answer 5

1. Increased ADH activity: It is the most common mechanism and it is most commonly caused by decrease EABV.
2. Decreased GFR
3. Decreased urinary solute excretion

Question 6

What are clinical manifestations of hyponatremia?

Answer 6

Depend on magnitude of the hyponatremia and rapidity of its development.
Acute (< 48 hrs): Symptoms at [Na+] of ≤ 125 mEq/L.
Seizures and coma at ≤ 115 mEq/L.
Chronic: often asymptomatic until [Na+] drops to ≤ 115 mEq/L; adaptation through loss of intracellular solutes (osmolytes)

Symptoms - mainly CNS

a. Early: nausea, malaise, headache, muscle twitching, lethargy
b. Late/Severe: obtundation, seizures, coma, respiratory arrest

Question 7

Evaluation of various causes of hyponatremia?

Answer 7

assess and classify patient’s ECF volume status

Question 8

Clinical manifestations of low-volume hyponatremia

Answer 8

Orthostasis, low jugular venous pressure, dry mucous membranes, poor
skin turgor, absent axillary sweat, etc.

Question 9

Etiology of low volume hyponatremia

Answer 9

Low ECF volume and low effective circulating blood volume with enhanced water intake.
i. Extrarenal - low ECFV and ECBV is caused by Na+ loss through GI tract, skin, third spacing (e.g., vomiting, diarrhea, blood loss, profuse sweating)
ii. Renal - low ECFV and ECBV is caused by Na+
loss via the kidneys (e.g., diuretics, osmotic diuresis). Diuretics, particularly thiazide diuretics, may result in a reduction in the ECF volume, leading to an increase in ADH release and in thirst.

Question 10

Physiology of low-volume hyponatremia

Answer 10

Low ECF volume along with effective circulating blood volume (ECBV) depletion causes the ADH release curve to shift to the left and have a steeper slope due to the low ECBV stimulus
Furthermore, thirst mechanisms may be activated as well at a lower plasma osmolality. The combined setting of increased thirst (increased water intake) and ADH release (decreased water excretion) will result in positive water balance and hyponatremia.
i. Low ECBV - significantly enhances proximal tubular fluid reabsorption => very limited delivery of fluid to distal nephron, which greatly limits the amount of water that could be potentially excreted by the kidneys, even if there were no ADH present
ii. High ADH - secondary to low ECBV (stimulates ADH release via baroreceptors in the carotid sinus and aortic arch)

Question 11

What are clinical manifestations of high volume hyponatremia?

Answer 11

Edema, jugular venous distention, relative hypotension ± pulmonary
edema; history of CHF, liver failure, or heavy proteinuria

Question 12

What is the etiology of high volume hyponatremia?

Answer 12

Although overall extracellular fluid volume is expanded, effective
circulating blood volume is also decreased in patients with severe heart failure or
liver cirrhosis, and a minority of patients with nephrotic syndrome, causing
125enhanced ADH release and thirst as outlined above. Why is ECBV decreased in
these patients?
i. Severe heart failure - poor pump function, so poor renal perfusion
ii. Cirrhosis – Pooling of blood in Splanchnic territory due to vasodilatation, so
poor renal perfusion
iii. Minority of patients with Nephrotic syndrome – Decreased oncotic pressure
Or, with severe acute kidney injury or chronic kidney disease, there is generally ECF
volume expansion with an inability to excrete water due to low GFR

Question 13

What is the physiology of high volume hyponatremia

Answer 13

cause of impaired water excretion:
i. Low ECBV => very limited delivery of fluid to distal nephron
ii. High ADH - secondary to secondary to low ECBV (stimulates ADH release
via baroreceptors in the carotid sinus and aortic arch)
iii. Renal failure

Question 14

describe clinical manifestations of normal-volume hyponatremia

Answer 14

: Patient is clinically euvolemic; i.e., not orthostatic and not edematous. Elements of the patient’s history, current medications, and/or laboratory findings are very helpful in establishing the diagnosis.

Question 15

What is the etiology and physiology of primary polydipsia

Answer 15

large water intake (>18L/day) with maximally dilute urine (<100 mOsm); usually easy to identify these patients. These occurs in patients with psychiatric disorders that predispose them to drink lots of water
(psychogenic polydipsia), in marathon runners (exercise-induced hyponatremia), water drinking contest in fraternities, and in ecstasy users
after rave parties

Question 16

What is the etiology and physiology of diuretic-induced normal volume hyponatremia?

Answer 16

Thiazide diuretics may cause hyponatremia even in the
absence of overt hypovolemia due to mild subclinical ECBV depletion with
enhanced ADH release, decreased distal fluid delivery, and enhanced
response to the effects of ADH (due to preservation of the strong gradient for
water reabsorption afforded by the lack of effect of thiazides on the
hypertonic medullary interstitium)

Question 17

What is the etiology and physiology of beer potomania?

Answer 17

• Beer drinkers drink beer all day and do not eat a significant amount of solute. Since urinary solute excretion is low then they will eliminate a limited volume of water retaining the extra water load. Beer is 90% water; if they drink a large volume of beer then hyponatremia will develop. A similar situation occurs in people who eat the so called “Tea and toast” diet.Carbohydrates provide no solute, only protein and salt do

Question 18

What is the etiology and physiology of glucocorticoid deficiency?

Answer 18

increased ADH; cortisol exerts negative feedback in ADH release. In patients with full-blown adrenal insufficiency where there is also low aldosterone levels then there will also be a high AHD due to
hypovolemia

Question 19

What is the etiology and physiology of hypothyroidism?

Answer 19

poor effective circulating volume due to poor pump function leads to increased ADH and diminished GFR and distal delivery of solute and water; direct renal tubular effects?

Question 20

what is the etiology and physiology of syndrome of inappropriate ADH secretion?

Answer 20

too much ADH due to
ectopic secretion (e.g., lung Ca.) or enhanced secretion from pituitary. This
diagnosis is based on exclusion of other potential causes of water retention.
The urine must not be maximally dilute in the presence of plasma
hypotonicity (i.e., ADH is being secreted). These patients are in sodium
balance, and urinary sodium output reflects input. As these patients are
126volume replete, they will respond to a volume (normal saline) challenge with a
natriuresis (enhanced urinary excretion of Na+
)

Question 21

What are causes of SIADH?

Answer 21

Tumors - esp. lung (e.g., small cell) Ca, other carcinomas, lymphoma,
leukemia
Pulmonary Disease - infectious (e.g., pneumonia, abscess, empyema, TB)
CNS Disorders - cerebral tumors, infections (e.g., abscess, meningitis,
encephalitis), bleeds
Drugs - e.g., carbamazepine, cyclophosphamide, clofibrate, SSRIs, phenothiazines, narcotics, nicotine

Question 22

therapy for increased ADH?

Answer 22

Correct underlying disorder if possible -

b. Restrict fluid intake
c. Increase solute intake (high-salt, high-protein diet)
d. Salt -
i. Hypertonic saline: when severe neurologic manifestations of hyponatremia are present
ii. Salt tablets - chronic therapy to increase daily solute load
e. Use drugs to block ADH effect
i. Demeclocycline - inhibits cellular effects of ADH in the collecting duct. It is not used commonly due to nephrotoxicity and side effects.
ii. Loop diuretics
iv. Treatment for SIADH initially consists of water restriction alone if [Na+] > 120 and symptoms are modest. For chronic therapy, increasing the solute load low-dose loop diuretics, and demeclocycline may all be helpful. It should be noted that administration of saline alone, without loop diuretics, may worsen the hypotonicity of SIADH, because the patient may excrete the solute in concentrated urine and retain the free water from the saline.

Question 23

What are the cellular adaptions to hyponatremia?

Answer 23

The brain and CNS are most notably affected in hyponatremia because any significant degree of hypotonic cell swelling causes neurologic signs and symptoms and a rise in intracranial pressure with risk of central herniation. Increased outflow of cerebrospinal fluid is an acute adaptation in response to rises in intracranial pressure. Within hours, acute cell volume regulatory responses involving the loss of intracellular K+ and anions
occur to reduce cell swelling. Chronic cell volume regulatory responses occur over several days whereby the net loss of organic osmolytes (amino acids such as glutamate and taurine, myo-inositol, and methylamines) gradually replaces the net loss of inorganic ions that occurs acutely. This chronic adaptation is more compatible with normal cellular
functioning

Question 24

What is hypernatremia and what does it tell us?

Answer 24

rates of water excretion > rates of water intake.
increased plasma osmolality –> ADH secretion and stimulate thirst. Thirst + ADH –> increase in water ingestion and decrease in renal water excretion. Hypernatremia cannot occur if the patient has access to water, patient is conscious, and thirst mechanism is intact

Question 25

Who are likely to develop hypernatremia?

Answer 25

hypothalamic lesion –> defect in thirst mechanism

elderly or infants without sufficient access to water (especially if they have excessive insensible water losses)

Question 26

What are consequences of hypernatremia

Answer 26

i. Cellular Dehydration
ii. Clinical Neurological Consequences. Brain cell dehydration causes neurological complications including fatigue, lethargy, muscular irritability,
and changes in mental status such as confusion and mental obtundation. Seizures, coma and even death can occur. The very young (infants) are particularly susceptible to neurological complications and long-term neurological sequelae because the fragility of their blood vessels makes
them prone to develop subdural hemorrhages and cerebral bleeding with hypertonic conditions.

Question 27

what is normal-volume hypernatremia - hypertonicity?

Answer 27

loss of electrolyte free water (loss of pure water).

Question 28

What are underlying causes of normal volume hypernatremia hypertonicity?

Answer 28

a. Renal losses*
- -central diabetes insipidus
- -nephrogenic diabetes insipidus
b. Unmatched extra renal (insensible) fluid losses*
- -fever
- -high ambient temperature w/ excessive sweating
- -hyperventilation

Question 29

what is the pathophysiology of normal volume hypernatremia?

Answer 29

Water deficits are shared by the various fluid
compartments according to the proportion of TBW in each compartment. Thus, in pure H2O loss only 1/12 of loss comes from plasma volume, 1/3 from
ECF and 2/3 from the ICF. This is why patients with pure water loss are usually clinically euvolemic (2 L of pure water loss only results in a ~167 mL (reduction in plasma volume).

Question 30

What are clinical findings in normal volume hypernatremia?

Answer 30

a. History
- -Presence of condition(s) that predispose(s) to electrolyte-free fluid loss
- -Lack of access to water or an appropriate sense of thirst
- -CNS symptoms
b. Physical Exam
- -Euvolemia
- -Normal to low blood pressure
- -No edema
c. Laboratory Findings
- -Hypernatremia
- -Urine
- large volume and dilute ( central or nephrogenic DI
- small volume and concentrated (>600 mOsm) => insensible losses

Question 31

Treatment of normal-volume hypernatremia

Answer 31

Replace water deficits with p.o. water or electrolyte-free i.v. fluids (D5W).
To prevent the development of cerebral edema, it is important to correct serum sodium no more than 10 mEq/L per day.

Question 32

when does central DI occur?

Answer 32

a. Central DI occurs when impairment in urinary concentration is due to reduced ADH secretion. This may be partial or complete and is usually
acquired. Etiologies include: idiopathic (?autoimmune), destruction of posterior pituitary by trauma, surgery, neoplasm, cyst, CNS sarcoidosis,
infection, vascular collapse, and bleed.

Question 33

When does nephrogenic DI occur?

Answer 33

b. Nephrogenic DI occurs when the failure to concentrate the urine results from inability of the collecting duct to respond to ADH. The congenital
defect (which is rare) is due to either defective or absent ADH receptors in the collecting duct (X-linked) or defects in the aquaporin 2 gene
(autosomal recessive). More common is the acquired type, commonly caused by chronic lithium treatment, tubulointerstitial or obstructive
disease (e.g., amyloidosis, myeloma, and sickle cell disease), hypercalcemia, or chronic severe hypokalemia.

Question 34

How do you distinguish central from nephrogenic DI?

Answer 34

The history and chronicity of the onset of polyuria can be very helpful, as CDI is often more acute. Administration of exogenous ADH (either
intranasally or subcutaneously) can serve as a diagnostic test. The disorder will correct with CDI, and urine volume will decrease and Uosm increase dramatically.

Question 35

What is chronic treatment for DI?

Answer 35

correcting the underlying cause is the most effective long-term strategy.
For central DI: establishment of a stable dose of a long acting ADH analog, such as dDAVP, that does not bind to vascular receptors.
For nephrogenic DI: thiazide diuretics are useful.

Proximal volume (Na+ and water) reabsorption will increase in response to mild volume depletion,
and the hypertonic medullary interstitium will be preserved to support any remaining ADH effect on distal water reabsorption, factors that will both
reduce polyuria.
- Limiting solute intake (low salt, low protein diet)
- NSAIDs will tend to enhance distal water reabsorption and thus are also sometimes
used to treat nephrogenic DI.
- amiloride may be especially beneficial in patients with lithium-induced nephrogenic DI who need to remain on chronic lithium therapy. In addition to the reasons that thiazide diuretics are helpful, amiloride has the advantage of limiting further lithium-induced damage to the collecting duct cells by inhibiting cellular lithium uptake through Na+ channels.

Question 36

What is high-volume hypernatremia hypertonicity

Answer 36

hypertonicity associated with a gain of solutes that

expands the ECF compartment and contracts the ICF compartment.

Question 37

What are the causes of high-volume hypernatremia?

Answer 37

solute administration (often iatrogenic)

a. NaHCO3 therapy
b. Hypertonic saline (
c. Salt poisoning in infants (e.g., incorrectly mixed formula)
d. Sea water ingestion
e. Soy sauce poisoning

Question 38

What is the clinical presentation of high-volume hypernatremia?

Answer 38

administration or ingestion of a hypertonic sodium fluid, CNS symptoms
Physical exam: evidence for increased ECBV (e.g., HTN, edema)
Laboratory findings: hypernatremia, Uosm >300 mOsm, elevated urine Na+

Question 39

What is the treatment of high-volume hypernatremia?

Answer 39

Because the ECF hypertonic Na+-containing solution increases ECF volume (excess Na+
is restricted to ECF), initial treatment is
designed to remove Na+ from the ECF compartment

a. diuretics (esp., loop diuretics) first removes Na+
and water
b. free water to replace water lost in urine from diuretic
c. dialysis may be necessary if patient has concomitant severe renal failure

Question 40

What is the treatment of low-volume hypernatremia - hypertonicity

Answer 40

hypertonicity associated with the loss of hypotonic
fluids This causes both ECF volume
depletion and a free water deficit (hypertonicity).

Question 41

What are causes of low-volume hypernatremia?

Answer 41

a. Renal losses of hypotonic fluid
- -Osmotic diuresis: This may be seen in patients who have high urea (BUN) secondary to high-protein enteral or parental feedings, patients who have received mannitol, or in diabetics with severe hyperglycemia and glucosuria. An osmotic diuresis leads to loss of sodium (hypovolemia) and water (hypertonicity), and both Na+ (and accompanying anions) and glucose contribute to the increase in plasma osmolality.
- -Diuretic therapy (esp. loop diuretics)
b. GI losses: diarrhea, vomiting, surgical drains or fistulas

Question 42

What are clinical consequences of low-volume hypernatremia?

Answer 42

History: CNS symptoms in association with: large urinary or GI fluid losses
Physical exam: evidence for hypovolemia (hypotension, orthostasis, no edema)
c. Laboratory findings:
-hypernatremia
-urine
–GI: low volume, high Uosm
–diuretics and glucosuria (DM): higher volume, Uosm ~300

Question 43

What is the treatment for low-volume hypernatremia?

Answer 43

Restore extracellular fluid volume deficit with saline or other isotonic fluids (e.g., blood products) first, then give free water only after ECF volume is re-expanded, since hypovolemia poses a greater
immediate risk to the patient than hypertonicity. Again, the free water deficit should be corrected slowly over a few days to prevent complications
associated with cerebral edema