hyponatremia and its diagnosis

8/12/2019 Hyponatremia and its diagnosis

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water

50% of body weight in women and 60% in men

Total body water is distributed in two major compartments

55

75% is intracellular [intracellular fluid (ICF)], and 25

45% isextracellular [extracellular fluid (ECF)].

ECF is subdivided into intravascular (plasma water) and

extravascular (interstitial) spaces in a ratio of 1:3.


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Certain solutes, particularly urea, do not contribute to water shifts

across most membranes and are thus known asineffective

osmoles.


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Vasopressin secretion, water ingestion, and renal water transport

collaborate to maintain human body fluid osmolality between 280 and

295 mosmol/kg.

Vasopressin (AVP) is synthesized in magnocellular neurons within the

hypothalamus.

A network of central osmoreceptor neurons that includes the AVP-

expressing magnocellular neurons themselves sense circulating

osmolality via nonselective, stretch-activated cation channels.

\ These osmoreceptor neurons are activated or inhibited by modest

increases and decreases in circulating osmolality, respectively;

activation leads to AVP release and thirst.


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AVP secretion is stimulated as systemic osmolality increases

above a threshold level of 285 mosmol/kg, above which there is

a linear relationship between osmolality and circulating AVP

Thirst and thus water ingestion also are activated at 285

mosmol/kg, beyond which there is an equivalent linear increase in

the perceived intensity of thirst as a function of circulating

osmolality


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ECF volume strongly modulates the relationship between

circulating osmolality and AVP release so thathypovolemia

reduces the osmotic threshold and increases the slope of the

response curve to osmolality

hypervolemiahas the opposite effect, increasing the osmotic

threshold and reducing the slope of the response curve


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AVP has a half-life in the circulation of only 1020 min; thus,

changes in extracellular fluid volume and/or circulating osmolality

can affect water homeostasis rapidly.

In addition to volume status, a number of nonosmotic stimuli have

potent activating effects on osmosensitive neurons and AVP

release, including nausea, intracerebral angiotensin II, serotonin,

and multiple drugs.


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Plasma osmolality graph

AVP acts on renal V2-type receptors in the thick ascending limb

of Henle and principal cells of the collecting duct (CD), increasing

cyclic adenosine monophosphate (AMP) and activating protein

kinase A (PKA)

dependent phosphorylation of multiple transport

proteins.

The AVP- and PKA-dependent activation of Na+-Cland K+

transport by the thick ascending limb of the loop of Henle (TALH)

is a key participant in the countercurrent mechanism.


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Water transport across apical and basolateral aquaporin-1 water

channels in the descending thin limb of the loop of Henle is thus

involved, as is passive absorption of Na+-Clby the thin

ascending limb, via apical and basolateral CLC-K1 chloride

channels and paracellular Na+transport.

Renal urea transport in turn plays important roles in the

generation of the medullary osmotic gradient and the ability to

excrete solute-free water


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AVP-induced, PKA-dependent phosphorylation of the aquaporin-

2 water channel in principal cells stimulates the insertion of active

water channels into the lumen of the collecting duct, resulting in

transepithelial water absorption down the medullary osmoticgradient

In the absence of circulating AVP, insertion of aquaporin-2

channels and water absorption across the collecting duct are

essentially abolished, resulting in secretion of a hypotonic, dilute

urine (osmolality as low as 3050 mosmol/kg).


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Arterial perfusion and circulatory integrity are, in turn, determined

by renal Na+retention or excretion, in addition to the modulation

of systemic arterial resistance.

Within the kidney, Na+is filtered by the glomeruli and then

sequentially reabsorbed by the renal tubules.

The Na+cation typically is reabsorbed with the chloride anion (Cl

); thus, chloride homeostasis also affects the ECFV


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On a quantitative level, at a glomerular filtration rate (GFR) of

180 L/d and serum Na+of 140 mM, the kidney filters some

25,200 mmol/d of Na+.

This is equivalent to 1.5 kg of salt, which would occupy roughly

10 times the extracellular space; 99.6% of filtered Na+-Clmust

be reabsorbed to excrete 100 mMper day.

Minute changes in renal Na

+

-Cl

excretion will thus havesignificant effects on the ECFV, leading to edema syndromes or

hypovolemia.


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Approximately two-thirds of filtered Na+-Clis reabsorbed by the

renal proximal tubule via both paracellular and transcellular

mechanisms.

The TALH subsequently reabsorbs another 25

30% of filtered Na+-

Clvia the apical, furosemide-sensitive Na+-K+-2Clcotransporter.

The adjacent aldosterone-sensitive distal nephron, which encompasses

the distal convoluted tubule (DCT), connecting tubule (CNT), and

collecting duct, accomplishes the "fine-tuning" of renal Na+-Cl

excretion


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Decreased body sodium, increased urine sodium

Renal loses

Diuretic excess

Mineralo corticoid deficiency

Salt losing deficiency

Bicarbanoturia with RTA and metbalic alkalosis

Ketonuria

Osmotic diuresis

Cerebral salt wasting syndrome


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Hypovolemia

True volume depletion, or hypovolemia,

generally refers to a state of combined salt

and water loss that leads to contraction of the

ECFV.

The loss of salt and water may be renal or

nonrenal in origin.


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Renal Causes

Excessive urinary Na+-Cland water loss is a feature of several conditions.

A high filtered load of endogenous solutes, such as glucose and urea,

can impair tubular reabsorption of Na+-Cland water, leading to an osmotic

diuresis.

Exogenous mannitol, which often is used to decrease intracerebral pressure,is filtered by glomeruli but not reabsorbed by the proximal tubule, thus causing

an osmotic diuresis.

Pharmacologic diuretics selectively impair Na+-Clreabsorption at specific

sites along the nephron, leading to increased urinary Na+-Clexcretion.

Other drugs can induce natriuresis as a side effect. For example,

acetazolamide can inhibit proximal tubular Na+-Clabsorption through its

inhibition of carbonic anhydrase;


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other drugs, such as the antibiotics trimethroprim and pentamidine,

inhibit distal tubular Na+

reabsorption through the amiloride-sensitiveENaC channel, leading to urinary Na+-Clloss.

Hereditary defects in renal transport proteins also are associated with

reduced reabsorption of filtered Na+-Cland/or water.

Alternatively, mineralocorticoid deficiency, mineralocorticoid resistance,

or inhibition of the mineralocorticoid receptor (MLR) can reduce Na+-

Clreabsorption by the aldosterone-sensitive distal nephron.

Finally, tubulointerstitial injury, as occurs in interstitial nephritis, acutetubular injury, or obstructive uropathy, can reduce distal tubular Na+-

Cland/or water absorption.


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Extrarenal Causes

Nonrenal causes of hypovolemia include fluid loss from the

gastrointestinal tract, skin, and respiratory system.

Accumulations of fluid within specific tissue compartments

typically the interstitium, peritoneum, or gastrointestinal tract

also can cause hypovolemia.


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Approximately 9 L of fluid enters the gastrointestinal tract daily, 2 L

by ingestion and 7 L by secretion

Almost 98% of this volume is absorbed so that daily fecal fluid loss is

only 100

200 mL.

Impaired gastrointestinal reabsorption or enhanced secretion of fluid

can cause hypovolemia.

Since gastric secretions have a low pH (high H+concentration),

whereas biliary, pancreatic, and intestinal secretions are alkaline (high

HCO3concentration), vomiting and diarrhea often are accompanied by

metabolic alkalosis and acidosis, respectively.


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Hyperventilation also can increase insensible losses via the

respiratory tract, particularly in ventilated patients; the humidity of

inspired air is another determining factor.

Profuse sweating without adequate repletion of water and Na+-

Clthus can lead to both hypovolemia and hypertonicity.

Alternatively, replacement of these insensible losses with a surfeit

of free water without adequate replacement of electrolytes may

lead to hypovolemic hyponatremia.


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Excessive fluid accumulation in interstitial and/or peritoneal spaces

also can cause intravascular hypovolemia.

Increases in vascular permeability and/or a reduction in oncotic

pressure (hypoalbuminemia) alter Starling forces, resulting in

excessive "third spacing" of the ECFV.

This occurs in sepsis syndrome, burns, pancreatitis, nutritional

hypoalbuminemia, and peritonitis.


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Alternatively, distributive hypovolemia can result from accumulation

of fluid within specific compartments, for example, within the

bowel lumen in gastrointestinal obstruction or ileus.


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Diagnostic Evaluation

A careful history usually determines the etiologic cause of

hypovolemia.

Symptoms of hypovolemia are nonspecific and

include fatigue, weakness, thirst, and postural

dizziness; more severe symptoms and signs

include oliguria, cyanosis, abdominal and

chest pain, and confusion or obtundation.


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Associated electrolyte disorders may cause additionalsymptoms, for example, muscle weakness in patients withhypokalemia. On examination, diminished skin turgor anddry oral mucous membranes are less than ideal markers ofa decreased ECFV in adult patients; reliable signs of

hypovolemia include a decreased jugular venous pressure(JVP), orthostatic tachycardia (an increase of >1520 beatsper minute upon standing), and orthostatic hypotension (a>1020-mmHg drop in blood pressure on standing). Moresevere fluid loss leads to hypovolemic shock, with

hypotension, tachycardia, peripheral vasoconstriction, andperipheral hypoperfusion; these patients may exhibitperipheral cyanosis, cold extremities, oliguria, and alteredmental status.


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Routine chemistries may reveal an increase in blood ureanitrogen (BUN) and creatinine, reflecting a decrease in GFR.

Creatinine is the more dependable measure of GFR, sinceBUN levels may be influenced by an increase in tubularreabsorption (prerenal azotemia), an increase in ureageneration in catabolic states, hyperalimentation, orgastrointestinal bleeding and/or a decreased ureageneration in decreased protein intake.

In hypovolemic shock, liver function tests and cardiacbiomarkers may show evidence of hepatic and cardiacischemia, respectively.


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Mild hypovolemia usually can be treated withoral hydration and resumption of a normalmaintenance diet. More severe hypovolemia

requires intravenous hydration Isotonic, "normal" saline (0.9% NaCl, 154 mM

Na+) is the most appropriate resuscitation fluidfor normonatremic or hyponatremic patients

with severe hypovolemia; colloid solutions suchas intravenous albumin are not demonstrablysuperior for this purpose.


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Sodium Disorders

caused by abnormalities in water homeostasis

that lead to changes in the relative ratio of Na+

to body water.

Water intake and circulating AVP constitute

the two key effectors in the defense of serum

osmolality; defects in one or both of these

defense mechanisms cause most cases ofhyponatremia and hypernatremia


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volume status also modulates the release of AVP

by the posterior pituitary so that hypovolemia is

associated with higher circulating levels of the

hormone at each level of serum osmolality. Similarly, in hypervolemic causes of arterial

underfilling, e.g., heart failure and cirrhosis, the

associated neurohumoral activation is associatedwith an increase in circulating AVP, leading to

water retention and hyponatremia


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Hyponatremia

plasma Na+concentration


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Hypovolemic Hyponatremia

Nonrenal causes of hypovolemic hyponatremia includegastrointestinal (GI) loss (vomiting, diarrhea, tube drainage,etc.) and insensible loss (sweating, burns) of Na+-Clandwater in the absence of adequate oral replacement; urineNa+concentration is typically


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The renalcauses of hypovolemic hyponatremia sharean inappropriate loss of Na+-Clin the urine, leading tovolume depletion and an increase in circulating AVP;urine Na+concentration is typically >20 mM

A deficiency in circulating aldosterone and/or its renaleffects can lead to hyponatremia in primary adrenalinsufficiency and other causes of hypoaldosteronism;hyperkalemia and hyponatremia in a hypotensive

and/or hypovolemic patient with high urine Na+concentration (much >20 mM) should strongly suggestthis diagnosis


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Salt-losing nephropathies may lead to

hyponatremia when sodium intake is reduced

due to impaired renal tubular function; typical

causes include reflux nephropathy, interstitialnephropathies, post-obstructive uropathy,

medullary cystic disease, and the recovery

phase of acute tubular necrosis.


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Thiazide diuretics cause hyponatremia via a

number of mechanisms, including polydipsia

and diuretic-induced volume depletion.

Notably, thiazides do not inhibit the renalconcentrating mechanism so that circulating

AVP has a maximal effect on renal water

retention.


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Finally, the syndrome of "cerebral saltwasting" is a rare cause of hypovolemichyponatremia, encompassing hyponatremia

with clinical hypovolemia and inappropriatenatriuresis in association with intracranialdisease; associated disorders include

subarachnoid hemorrhage, traumatic brain

injury, craniotomy, encephalitis, andmeningitis


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Hypervolemic Hyponatremia

an increase in total body Na+-Clthat is accompaniedby a proportionately greaterincrease in total bodywater, leading to a reduced plasma Na+concentration.

The pathophysiology of hyponatremia in the sodium-

avid edematous disorders [congestive heart failure(CHF), cirrhosis, and nephrotic syndrome] is similar tothat in hypovolemic hyponatremia except that arterialfilling and circulatory integrity are decreased due to thespecific etiologic factors, e.g., cardiac dysfunction in

CHF and peripheral vasodilation in cirrhosis. Urine Na+concentration is typically very low, i.e.,


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Euvolemic Hyponatremia

in moderate to severe hypothyroidism, withcorrection after the achievement of a euthyroidstate.

Severe hyponatremia also can be a consequence

of secondary adrenal insufficiency due topituitary disease

whereas the deficit in circulating aldosterone inprimary adrenal insufficiency causes hypovolemic

hyponatremia, the predominant glucocorticoiddeficiency in secondary adrenal failure isassociated with euvolemichyponatremia.


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The syndrome of inappropriate antidiuresis is

the most common cause of euvolemic

hyponatremia

The generation of hyponatremia in SIAD

requires an intake of free water, with

persistent intake at serum osmolalities that

are lower than the usual threshold for thirst


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Four distinct patterns of AVP secretion have beenrecognized in patients with SIAD, independent for the mostpart of the underlying cause.

Unregulated, erratic AVP secretion is seen in about a thirdof patients, with no obvious correlation between serumosmolality and circulating AVP levels.

Other patients fail to suppress AVP secretion at lowerserum osmolalities, with a normal response curve tohyperosmolar conditions

others have a reset osmostat, with a lower thresholdosmolality and a left-shifted osmotic response curve.

The fourth subset consists of patients who have essentially

no detectable circulating AVP, suggesting either a gain infunction in renal water reabsorption or a circulatingantidiuretic substance that is distinct from AVP


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note Strictly speaking, patients with SIAD are not euvolemic

but are subclinically volume expanded due to AVP-induced water and Na+-Clretention

vasopressin escape mechanisms invoked by sustainedincreases in AVP serve to limit distal renal tubulartransport, preserving a modestly hypervolemic steadystate.

Serum uric acid is often low (


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Low Solute Intake and Hyponatremia

this occurs in alcoholics whose sole nutrient is

beer, hence the diagnostic label "beer

potomania"; beer is very low in protein and

salt content, containing only1

2 millimole perliter of Na+. The syndrome also has been

described in nonalcoholic patients with highly

restricted solute intake due to nutrient-restricted diets, e.g., extreme vegetarian diets.


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hyponatremia and its diagnosis

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