Evaluation of Hyponatremia – 3 Lab Approach to Diagnosis

Table of Contents

Table of Contents

Originally published May 2020.  Updated October 2021

Brandon Fainstad, MD¹
Yilin Zhang, MD²
Expert review – Pending

1 Assistant Professor, Department of Medicine, University of Colorado
2 Assistant Professor, Department of Medicine, Valley Medical Center


  1. Learn the “3 lab approach” to diagnosis of hyponatremia (this does not cover treatment!)
  2. Understand the role of ADH and aldosterone in hyponatremia

Teaching Instructions

Plan to spend at least 30 minutes preparing for this talk by using the Interactive Board for Learning/Preparing. After you feel comfortable with the content you can present this talk in one of two ways. 

  1. Project the Interactive Board (Presenter version) for Presentation OR
  2. Reproduce a drawing of the differential diagnosis figure and timeline on a whiteboard.   

Anticipated length of the talk is 20 min without cases and 30 min with cases. The learner version can be used for individual study. 

Introduction: Hyponatremia is a common finding in hospital admissions. Most of the time it occurs in the setting of an acute illness and improves with appropriate resuscitation and treatment of the presenting illness. So we usually don’t spend too much time thinking about it. But sometimes it is severe, unexplained or does not improve when we expect it would.

Many of us are taught to think of hyponatremia in terms of hyper/hypo/euvolemic states. Unfortunately, physicians are classically bad at determining volume status and this method does not sufficiently address the physiology.

Step 1: Is it real? (Serum Osm)

The first step in the evaluation of hyponatremia is determining “is it real?” True hyponatremia is hypoosmolar hyponatremia.

Hyponatremia associated with high

or normal serum osmolarity (Osm) is generally not considered “true hyponatremia.” Na represents a large portion of our serum osm. If Na is low we should expect the total serum osm to be low too. If the serum osm are normal or high (>290) we know there is something “extra” in the blood that is either usually absent or present in lower quantities. If the serum Osm is normal it is called pseudohyponatremia.  If the serum Osm is high, this is hyperosmolar hyponatremia. Click on each section to learn more.

  • Artifact/ Normal Osm (Pseudohyponatremia) – Most of our plasma is water plasma, but there is also a small percentage (~ 7%) of lipids and proteins. True hyponatremia occurs when the concentration of Na ([Na]) is low in water plasma.
    • Our standard plasma Na measures the [Na] in whole plasma. When there are a lot of lipids (i.e. hypertriglyceridemia) or lots of protein (i.e. multiple myeloma) this will dilute the whole plasma to give a falsely low [Na], even though the [Na] in the water plasma is still normal.  Send a ‘whole blood’ [Na] to confirm the true [Na].
  • Hyperosmolar hyponatremia – This is caused by something “extra”, or other osmotic molecules, in the blood. These osmotic compounds can either be active or inactive.
    • Active Osm  – Some compounds (most commonly glucose) do not freely cross the cell wall and osmotically pull water out of the cell, into the extracellular plasma in order to equilibrate the Osm gradient. This consequently dilutes the concentration of Na.

Step 2: Is ADH on or off? (Urine Osm) – ADH is secreted by the pituitary in response to low volume, high serum osm and acts on the kidneys to reclaim water. This results in the urine becoming more concentrated (or ↑ urine osm). Thus, when ADH is “on,” the urine osm is high.

  • The only causes of hyponatremia where ADH is off (urine osm <100) are if the patient is consuming large quantities of free water (i.e. psychogenic polydipsia) or if they are not consuming enough solute (i.e. tea and toast) for the kidney to filter.
  • Most cases of hypoosmolar hyponatremia result in high ADH state. The next differentiating question in these cases is what the trigger for ADH secretion and whether ADH secretion is appropriate or not.

Step 3: Are the kidneys seeing enough fluid?
 -Low volume or effective circulating volume (ECV) prompts ADH secretion from the pituitary and activates the RAAS (renin-angiotension-aldosterone system). RAAS activation leads the kidneys to reclaim Na from the urine resulting in a low urine Na (<25). Essentially, the urine Na helps differentiate if “the kidneys are seeing enough fluid”. 

  • High urine Na – This occurs in the absence of RAAS activation. If the kidneys are seeing enough fluid and ADH is on, there is likely inappropriate ADH secretion.
    • SIADH (syndrome of inappropriate ADH secretion) can occur with certain medications, surgery, pain, brain injury, lung disease, malignancies among many other causes. Common drug culprits are antidepressants, antiepileptics, and antipsychotics. These patients are euvolemic. 
    • Hypothyroidism and adrenal insufficiency can result in hypersecretion of ADH which is corrected by addressing underlying hormone deficiency.
    • Cerebral salt wasting is another potential cause of high ADH secretion in patients with CNS disease (particularly SAH) and is primarily differentiated from SIADH by volume status. Patients with cerebral salt wasting are hypovolemic. 
  • Low urine Na – This can occur in true hypovolemia or in cases where the total body volume is elevated but the ECV is low (heart failure and cirrhosis). Because the kidneys are seeing low volume, RAAS is activated to reclaim Na resulting  in a low urine Na. The only exception to this is in the presence of diuretic use. Diuretics cause salt wasting and typically result in an elevated urine Na even if patients are hypovolemic.


Interactive Boards

For Learning

For Self-Directed Learning and Preparing to Present

For Teaching

Use for Presenting – there is less text and fewer pop-ups

Take Home Points

  1. True hyponatremia is hypoosmolar hyponatremia (serum osm < 290). If the serum osm are normal or elevated, there is “something else in the blood” such as hyperlipidemia or hyperglycemia. 
  2. Hypoosmolar hyponatremia can be divided into high ADH states or low ADH states with a urine osm (which is low in low ADH states). Only primary polydipsia, beer potomania, and tea/toast diet are associated with low ADH states. 
  3. In hyponatremia with elevated ADH states (high urine osm > 100), the urine Na helps identify if the ADH ADH 



Comment on this article