Hyponatremia is the most common electrolyte disorder encountered in hospitals. Unfortunately, hyponatremia is often poorly evaluated, resulting in diagnostic and management errors that are associated with a poor outcome [1-14]. Despite a plethora of literature and guidelines concerning hyponatremia, still, less than 25-46% of patients receive adequate investigation [1,4-8]. Moreover, even if investigations are correctly performed, several issues challenge the establishment of a definitive diagnosis. First, clinical signs to differentiate a moderate volume depleted hyponatremic state from a dilutional hyponatremic condition are notoriously insensitive. Second, diagnostic laboratory assessment is complicated by overlapping laboratory criteria in distinct causes of hyponatremia [9-11,15,16]. Third, the applicability of flow charts and clinical diagnostic algorithms (CDAs) is limited because certain values are required before one can proceed in the algorithm. Last, less than half of hyponatremic cases presenting to the emergency department are due to a single cause [8,9,11,14]. As a result, in one survey only 10% of 46 physicians reached a correct diagnosis applying several CDAs for hyponatremia to four selected cases [9]. Here, we review shortcomings of regular clinical and physical examinations and the role of laboratory measurements in reaching a hyponatremia diagnosis. To circumvent these shortcomings, we developed a novel diagnostic application based on laboratory and clinical parameters and a 3-step approach framework to facilitate the appropriate evaluation of hyponatremia.

Plasma osmolality refers to the sum of the concentration of all osmotically active particles (electrolytes and nonelectrolytes) in the plasma and is normally between 285 and 295 mmol/L. A formula to calculate the plasma osmolality is [1,3,5,9,12,14]:

Calculated plasma osmomolality (mOsm/kg H₂O)= in mg/dL: 2 × plasma [Na⁺] (mmol/L) + 2 × plasma [K^+] (mmol/L) + blood urea nitrogen (BUN, in mg/dL)/2.8 + glucose (mg/dL)/18= in mmol/L: 2 × plasma [Na⁺] (mmol/L) + 2 × plasma [K⁺] (mmol/L) + BUN (mmol/L) + glucose (mmol/L).

All (cationic and anionic) electrolytes contribute to osmolality, the factor of two in the equation thus reflects a practical implementation of electroneutrality: the number of positive charges in a solution must equal the number of negative charges. Because of the low osmol contribution of 2x [K⁺] compared with 2x [Na⁺], potassium is usually omitted from this calculation for practical purposes.

Tonicity refers to osmotically active particles that cannot freely cross the cell membrane, i.e. the effective osmolality. Tonicity drives the intercompartmental water balance: if the extracellular tonicity changes, free water moves from the lower tonicity compartment to the higher tonicity compartment. Of the above mentioned components of plasma osmolality, only urea can move freely between the intracellular fluid (ICF) and extracellular fluid (ECF). Therefore, urea is not an effective plasma osmol as it is not restricted to a single fluid compartment and does not contribute to the tonicity [17], so BUN should be omitted from the formula to evaluate the tonicity:

Plasma effective osmolality (mOsm/kg H₂O), to calculate the tonicity: = in mg/dL: 2 × plasma [Na⁺] (mmol/L) + 2 × plasma [K^+] (mmol/L) + glucose (mg/dL)/18 = in mmol/L: 2 × plasma [Na⁺] (mmol/L) + 2 × plasma [K⁺] (mmol/L) + glucose (mmol/L).

Sodium balance, the dominant osmotically active electrolyte, is primarily regulated by the kidneys. Sodium excretion is regulated through the interaction of the renin-angiotensin-aldosterone system (RAAS), and the sympathetic nervous system. Water excretion is mainly controlled by antidiuretic hormone (ADH, also called arginine vasopressin, AVP) [1-10].

Hyponatremia in patients is usually due to reduced ADH suppression diminishing renal water excretion. The question, therefore, is why the kidneys are unable to reduce ADH to excrete the relative excess of free water. Under physiological states, the nervous system and the kidneys interact to maintain normal body homeostasis [18]. ADH is synthesized in the hypothalamus and is released to regulate volume status and plasma osmolality. Plasma ADH levels are low when the plasma osmolality is below 280 mOsmol/kg, thereby permitting the excretion of ingested water. ADH levels increase progressively as the plasma osmolality rises above 280 mOsmol/kg. The plasma volume status also plays a critical role in regulating ADH secretion [19-21]. Decrease in the extracellular fluid volume, which can be clinically inapparent, triggers ADH secretion. The water channels in the inner medulla of the kidneys will be opened by ADH, allowing water to move to the hyperosmotic renal medulla, be resorbed into the plasma, with decrease of the plasma osmolality. Urinary osmolality (Uosm) reflects ADH concentration and when ADH concentration rises from very low to a maximum plasma level, the Uosm rises from 50 mOsm/l to as high as 1200 mOsm/l (reflecting medullary osmolality), respectively. ADH has a short circulating half-life of about 16-24 minutes, allowing rapid changes in the ability to conserve or eliminate water [19-21].

Pregnancy related hyponatremia

The reference blood sodium concentration is 135–145 mmol/L in healthy persons. During pregnancy the plasma sodium decreases to about 130 mmol/L. This is considered normal physiology of pregnancy, likely caused by hormonal vasodilation, and changes in hypothalamic osmoreceptor sensitivity in relation to altered (placental) vasopressinase activity. Edema should not be present. When the blood sodium level decreases below 130 mmol/L, a serious problem may be present, most often during the peripartum period. [22,23]. Development of peripartum dilutional hyponatremia may be caused by low sodium fluid intake, but if the plasma sodium decreases below 125 mmol/L, obstetric and endocrine review should follow.

Increased water retention with edema

Patients with advanced renal insufficiency and fluid overload will usually have hypertension and edema with moderate hyponatremia. In other edematous states such as nephrotic syndrome, advanced liver cirrhosis, and severe heart failure a low effective circulating volume will lead to RAAS stimulation and ADH secretion leading to a low urine sodium (below 20 mmol/L) with a high urine osmolality. Laboratory and clinical clues include low plasma albumin in liver failure and nephrotic syndrome; ascites in liver or heart failure, high central venous pressure (heart failure), proteinuria (nephrotic syndrome). In most of these cases a diagnosis should be relatively easy to establish, and more details are beyond the scope of this paper [23,24].

Low solute intake

Sodium chloride (NaCl) and urea are the main solutes to conserve the renal interstitial hypertonicity to a value up to 1,200 mOsmol/kg H₂O. ADH opens the channels of the collecting duct to allow free water to be absorbed to the high osmol environment. The balance of sodium levels is based on the renal capability of excreting and retention of this so called “free water”. Free water retention is possible due to the osmotic gradient, but “free water excretion” is a misnomer because the kidneys need osmols to excrete water. Depending on the kidney’s urine diluting ability, about 50–100 mmol of solutes, mainly sodium, chloride, potassium and urea, are required to remove about 1 liter of fluid. Healthy kidneys have a huge capacity to excrete water (> 16 liter/day), but osmols are needed to excrete water. Therefore, in case of low solute intake, the number of available osmoles can be insufficient to remove the amount of the ingested water leading to hyponatremia. Examples of these conditions are “tea and toast”, or “beer potomania” related hyponatremia [1,2,8,9].

Impaired water excretion (inappropriately)

In most patients, hyponatremia developed after non-osmotic ADH secretion, causing increased reabsorption of renal water. Causes of non-osmotic ADH release include a low effective circulating volume, certain drugs and nonspecific stimuli such as anxiety, stress, pain, and nausea. Other less frequent hyponatremia inducing mechanisms include the ectopic production of ADH. The suppression of ADH secretion is essential for the excretion of any water load, and therefore the presence of high plasma concentrations of ADH is crucial for the development and maintenance of hyponatremia. Virtually all the causes of hyponatremia are therefore characterized by an excess of ADH, regardless a concomitant presence of hypotonicity. Exceptions are renal failure, primary polydipsia, and low dietary solute intake [1,20,21,25]. Primary polydipsia may be seen in psychotic patients who drink excessive quantities of fluid overwhelming the excretory capacity of the kidney.

A pathological, “inappropriate” secretion as in Syndrome of Inappropriate secretion of Antidiuretic Hormone (SIADH) occurs when ADH is secreted independently of circulating volume or plasma osmolality. This leads to a clinical undetectable excess of water of a few liters leading to substantial hyponatremia. SIADH is common in the elderly hospitalized patients with a hyponatremia below 125 mmol/L [12,20].

The major SIADH diagnostic criteria are according to the 2014 European guideline [12,20,24], in combination with the Japanese diagnostic criteria [17]:

1. No findings of ECF volume depletion
2. Plasma [Na⁺] <135 mmol/L
3. Plasma Osmolality <280 mOsm/kg H₂O
4. Despite hyponatremia and hypoosmolality, ADH concentration is not suppressed
5. Urine Osmolality >100 mOsm/kg H₂O (usually >300 mOsm/kg)
6. Urine [Na⁺] > 20-30 mmol/L with normal dietary protein, salt and water intake
7. Absence of adrenal, thyroid, pituitary or renal insuffi­ciency
8. No recent use of diuretic agents.

Supplemental criteria are according to the 2014 European guideline [12,20,24] :

1. a plasma uric acid below 0.24 mmol/L (<4 mg/dL),
2. BUN <1.8 mmol/L (<5 mg/dL),
3. failure to correct hyponatremia after 0.9% saline infusion,
4. fractional sodium excretion >0.5%,
5. fractional urea excretion >55%,
6. fractional uric acid excretion >12%,
7. correction of hyponatremia through ade­quate fluid restriction

Etiologies of SIADH include medications, cancer, pulmonary conditions, central nervous system disorders, or idiopathic. Some diseases that may be confused with SIADH are outlined in Table 2.

Timely diagnosis of a patient with hyponatremia is crucial to prevent treatment errors, but unfortunately, assessment remains problematic. Especially in the emergency setting with symptomatic hyponatremia, treatment should prevail time-consuming evaluation. The evaluation of hyponatremia starts with a meticulous history and physical examination to reveal the relevant differential diagnosis (Table 1) [1,2,4-9]. Major information that must be obtained include the cause of hyponatremia, the volume status, fluid and food intake, urine output, stool frequency and aspect. In addition, information should be acquired about experienced symptoms, medication use, known comorbidities such as heart, liver, kidney disease, and signs of chronic disease. The time frame leading to hyponatremia has a major impact on management. Acute hyponatremia is defined within 48 hour and chronic hyponatremia after 48 hours. Acute hyponatremia will cause water shifts into the brain and because the rigid skull limits expansion of the brain, severe neurological symptoms such as seizures and coma, require urgent therapy. People at risk of hyponatremic encephalopathy include children, women, patients with low BMI and patients with hypoxemia.

If the timeframe is unknown and the patient has no major neurologic symptoms, management is equal to a time after 48 hours [2-7].

Pitfalls in history and physical examination

Shortcomings in reliability of history

Unfortunately, history and physical examination are frequently not accurate to determine a patient’s volume status [1,7-9,15,26,27].

It may be difficult to obtain a reliable history because of errors in understanding a question, language barriers, memory, inaccurate definition of periods of time, complexity of past medical histories, cultural differences etc. [1,8,10,13,15,26].

Patient history can vary based on how and when questions are asked and even reversing their order can change responses [26]. Sensitive topics like alcohol or drug use may seem accusatory if asked too early or leave a negative impression if asked last. Miscommunication can also arise from rushed interactions or nonverbal cues. Repeated questioning by multiple providers may frustrate patients, and discrepancies in complaints or vital signs between ambulance and hospital can result from environmental changes or pre-hospital treatment [1,26].

Shortcomings in physical examination

Currently, most used non-invasive methods of volume depletion assessment include the assessment of skin turgor, dry skin mucosa, capillary refill time, tachycardia, and postural hypotension [1,15,26,27]. Poor skin turgor refers to the slow return of skin to its normal position after being pinched between the examiner's thumb and forefinger, but this is mainly influenced by the elasticity of the skin that declines with age. There may be also no correlation between degree of hypovolemia and dryness of mucous membranes [15]. The buccal moisture will dry rapidly if the patients breathe with open mouth.

It remains questionable if the theoretical accuracy of clinical tests is met in many cases in the acute care setting [15,26,28].

Postural hypotension, defined as a decrement in systolic blood pressure of more than 20 mm Hg after standing from the supine position, occurs in up to 10% of normovolemic individuals younger than 65 years and in 11% to 30% older than 65 years. Therefore, the symptom of mild or moderate postural dizziness is a poor predictor of postural hypotension [15,26]. In elderly patients with suspected hypovolemia, combinations of physical signs such as confusion, extremity weakness, nonfluent speech, dry mucous membranes, dry tongue, furrowed tongue, and sunken eyes may be an indication of dehydration, but none of these findings are very helpful when present in isolation [26,28].

In summary, volume status assessment is crucial for the diagnoses and management of patients in the acute care setting, but it remains a challenging clinical skill, with many limitations, challenges, and pitfalls. Fortunately, volume assessment may be improved by using Point of Care Ultrasound (POCUS) in emergency departments. POCUS is now widely available, relatively inexpensive and a helpful tool to complement clinical assessment [27].

Pitfalls in Laboratory/plasma measurements

Laboratory tests: Meticulous clinical evaluation of appropriate laboratory tests is essential for diagnosis and treatment. Urine samples should be taken simultaneously with blood samples. Most causes of hyponatremia can be established with clinical assessment and the following laboratory tests, blood/plasma: Hemoglobin, Hematocrit, sodium, potas­sium, albumin, osmol, blood urea nitrogen (BUN), creatinine, bicarbonate, chloride, glucose, and uric acid; and urine: dipstick (specific gravity, pH, bicarbonate, pro­tein), spot urine: dipstick, sodium, potassium, chloride, osmolal­ity, bicarbonate, creatinine and (calcium when thiazide use is involved). Sometimes one needs to evaluate mineralocorticoid deficiency or make use of arterial blood gases (Tables 1 and 3). Sediment microscopy is necessary when differentiation between prerenal failure or kidney injury due to glomerulone­phritis or interstitial nephritis is required [17,21,29-33].

Differentiating the etiology of hypotonic hyponatremia is usually challenging and important parameters are often not available initially. Consequently, treatment is frequently initiated before a proper diagnosis is established. Therefore, not surprisingly, a minimally required diag­nostic hyponatremia workup is often performed in less than 30% of patients [8,20], and adequate laboratory follow-up is omitted in up to 70% of cases [2,3,14]. As a result, up to 40% of hospital admitted patients may be still hyponatre­mic at discharge [1]. Inadequate monitoring may lead to a worse outcome, but adequate guidelines on the frequency of follow-up tests of blood electrolytes are limited [2,4,9,10]. Unfortunately, the usefulness of laboratory parame­ters is decreased after fluid therapy before testing, insufficient testing, inadequate use of tests, poor timing, inadequate follow up of investigations and overlapping laboratory criteria with somewhat arbitrary cutoff val­ues in different causes of hyponatremia [1-15].

Severe hypothyroidism is reported to cause hyponatremia, as decreased cardiac output increases ADH, causing water retention and hyponatremia. The association between very high TSH levels (above 50 mIU/mL) [34], and hyponatremia remains questionable because less than 1% of hyponatremia in subjects may be caused by hypothyroidism. Therefore, other causes of hyponatremia, such as Addison’s disease, should still be excluded in the presence of high TSH [34,35].

Pitfalls in plasma sodium value

Hyponatremia can occur in hyperosmotic, isosmotic, and hypoosmotic plasma. The measurement of plasma osmolality will differentiate between these three. Many hyponatremia assessment algorithms recommend an initial evaluation of the plasma osmolality. However, the clinician should not wait to proceed with the evaluation as the most common cause of hyponatremia will be hypoosmotic and other tests, such as glucose, may be available to bypass this step in the meantime [36,37].

Hyperosmolar hyponatremia: A high or normal plasma osmolality with a low plasma sodium, is mainly caused by hyperglycemia. One should calculate the decrease in plasma sodium in case of hyperglycemia. Increased blood sugars up to 400 mg/dL, require a correction factor of 1.6 and in glucose concentrations above 400 mg/dL, a correction factor of about 4.0 [7,38].

Hyponatremia is a common electrolyte disturbance in advanced chronic kidney disease. The nephron loss leads to a diminished ability to handle salt and water, but plasma sodium usually does not decrease to very low levels in severe chronic kidney disease. In case of advanced kidney disease and retention of water, hyponatremia may follow, but the measured plasma osmolality remains high due to high concentrations of blood plasma urea nitrogen [17,29].

In rare cases, medical interventions such as administration of mannitol, intravenous immunoglobulin or radio contrast may cause hyperosmotic hyponatremia. Other, hospital acquired, often -acute- dilutional hyponatremia is caused by large volumes of hypertonic solu­tions such as glycine and sorbitol used during hys­teroscopy, transurethral resection of the prostate, and polyethylene glycol-containing bowel cleansing preparations for colonoscopy [21,38,39].

Other rare causes of hyperosmolar hyponatremia may be heavy ethanol consumption with suspected alcoholic ketoacidosis. Ethanol is an ineffective osmol, thus hyponatremia is due to hypovolemia, pseudohyponatremia, or other [40]. An important clue in these cases may be an osmol gap of more than 10 mOsmol/kg between measured and calculated osmolality [41].

Pseudohyponatremia: Hyponatremia with a normal osmolality is a rare cause of hyponatremia but failure to recog­nize this artifact may result in unjustified and dangerous treatment. This rare laboratory artifact is observed with plasma sodium testing by automated analyzers using indirect ion selective electrodes that perform dilution, which are frequently employed in the central lab [42-47]. In the presence of extreme hyperlipidemia or hyperproteinemia, hyponatremia with normal osmolality may be present, because high levels of these solid components occupy a portion of the total plasma volume during the measurement. Important clues of very high levels of triglycerides or proteins are obstructive jaundice, milky (lipemic) plasma. Also, a much higher or normal sodium level will be noted in these cases by blood test with a point of care arterial blood gas that uses direct ion selective electrodes [1,46].

Seizure: A seizure may elevate the plasma sodium momentarily by an average of 13 mmol/L, concealing the original degree of hyponatremia. Skeletal muscle cells account for 50% of total body water and seizures generate new osmoles that cause water to shift from the extracellular fluid to the intracellular compartment. The plasma sodium should be tested a few minutes after the seizure to show the steady-state plasma sodium [48].

Pitfalls in urine measurements

Urine sodium: Numerous laboratory issues complicate proper evaluation and management of hyponatremia. Natriuresis is considered the cornerstone of the dif­ferential diagnosis of hyponatremia, most often by testing a spot urine sodium level. Urinary spot only gives information about a certain moment, and therefore it should pair with a blood sample. Because fluid intake or administration is not continuous, the urine spot sodium concentration can change rapidly. Urinary sodium concentrations also display large intra-individual variation due to volume status, solute intake, and disease [6,10,19,30,49]. The elderly are particularly predisposed to hyponatremia because of several factors, including a reduced sensitivity to thirst signals, low salt intake, a reduced percentage of total body water, a decreased ability to conserve sodium by the kidneys, a delayed or decreased capacity to excrete a water load, age-related reduction in glomerular filtration rate (GFR), often in combination with polypharmacy [10,11,50-52]. Urine dilution of sodium depends mainly on the tubular function of distal convoluted tubules and collecting ducts, but diuretics, kidney disease, heart failure and liver dis­ease also affects the urine sodium concentration [23,50-52]. In the ambulance or at the emergency ward, normal saline is frequently administered before plasma or urine chemistries are collected, further confounding interpre­tation [1-3].

Unexpected low urine sodium level: A high urine sodium is a hallmark of the syndrome of inappropriate antidiuresis (SIADH), but a urine sodium level below 30 mmol/l does not exclude SIADH if the salt intake is very low. A possible worst-case vicious circle scenario may be that hyponatremia lowers appetite, further reducing salt and protein intake. This low osmol intake reduces the ability to excrete free water, leading to a further decrease of plasma sodium after intake of only a few liters water [20,25,53].

In patients with “reset osmostat” there is a change in the set point of the osmoregulation, but the response to changes in osmolality remains intact. Decreased urine osmolality may follow when water intake reduces plasma osmolality below the new threshold for ADH release [12,14,54].

High or variable urine sodium level: The use of diuretics will increase renal sodium excretion until the effect wanes and the urine sodium level decreases. Occult use of diuretics or the use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors will increase renal sodium excretion [1]. Patients with chronic kidney disease may be less able to reabsorb sodium and advanced chronic kidney disease may impair water excretion [12,14,50,51]. Nevertheless, despite deteriorating kidney function, a significant capacity to regulate water balance may remain. The prevalence of hyponatre­mia in chronic kidney disease remains about 11%-12% in stages 3 to 5, because the kidneys adapt to widely varying sodium and water intake even in later stages of chronic renal failure. However, with declining renal function below 15-30 mL/min, the ability to excrete large volumes of dilute urine is limited [50,51]. In these cases, urine osmolality often remains between 200 to 300 mOsmol/kg, despite appropriate suppression of ADH. When the end stage renal disease is reached, the urine osmolality is gener­ally about 300 mOsmol/kg. Consequently, when solute ingestion is 600 mOsm/day, drinking much more than 2 L (600/300) water a day will cause hyponatremia [1,50,51].

In case of vomiting and metabolic alkalosis with hypovolemia, the urine sodium concentration may be higher than expected. Bicarbonate excretion accompanied by sodium may cause the false impression of a normal volume status. In these cases, the urine chloride will be low [41].

Urine osmolality: Measurement of urine osmolality is necessary to determine whether impaired renal free water excretion causes or contributes to hyponatremia [17,49,51]:

1. A low urine osmol (≤ 100 mOsm/kg H2O) implies that renal free water excretion is not impaired, because ADH is suppressed. In these cases, one should evaluate the possibility of polydipsia or low solute intake, such as in “tea and toast” syndrome or beer potomania [17,53].
2. A urine osmol of more than 100 mOsm/kg H₂O is usually due to impaired renal free water excretion. ADH secretion can be either inappropriate for osmotic stimuli, but appropriate for non-osmotic stimuli. The volume status may further differentiate these cases [17].

For assessing the free water clearance with the major solutes in urine and plasma that impact the tonicity one can use the formula that uses the main urine kations sodium (U_Na) and potassium (U_K) and the plasma sodium (P_Na) concentration [46,53]:

Electrolyte free water clearance = Urine_volume x [1 – U_Na + U_K)/P_Na]

The formula reflects the following water clearance:

1. Hypotonic urine (Uosm
2. Isotonic urine (Uosm = Posm): the free water clearance is zero.
3. Hypertonic urine (Uosm >Posm): the free water clearance is negative (i.e., water is retained).

Limitations of fractional excretion of solutes

Urinary electrolyte concentrations vary with urine volume, but creatinine production and excretion are relatively constant. About 1 gram (10 mmol) creatinine will be excreted daily in correlation with the urinary flow rate, in patients with normal renal function, without decreased lean body mass, or low meat intake. Then, the excretion of a “solute” can be related to the excretion of creatinine. This so-called fractional excretion is a better marker for assessing renal managing of electrolytes than spot urine electrolytes, because renal clearances of an electrolyte usually change proportionally with creatinine during the day [11,55-62]. The fractional excretion of a solute (FE_solute) is calculated by: (Urinary_solute x plasma_creatinine x 100%)/(urinary_creatinine x plasma_solute).

The fractional excretion of sodium (FE_Na) is often used in hospitals to differentiate prerenal azotemia from acute tubular necrosis. A FE_Na < 1% presumes prerenal azotemia as the kidney is conserving sodium to uphold an effective circulating volume. In case of acute kidney injury (AKI), a FE_Na > 1% implies tubular damage or acute tubular necrosis. Unfortunately, FE_Na has limited value when a low GFR causes a decreased daily sodium filtration [56-62]. A FE_Na below 1% can also be seen in glomerulonephritis, acute interstitial nephritis, rhabdomyolysis and early postrenal failure. A FE_Na above 1–2% may be present in diuretic use, adrenal insufficiency, bicarbonaturia, and chronic kidney disease. One should also recognize that the fractional excretion of sodium is based on a single test for creatinine and therefore does not reflect significant fluctuations in the glomerular filtration rate or individual creatinine excretion. Considering these limitations, the best utility of FE_Na, is an oliguric patient without diuretic therapy or chronic kidney disease [55-62].

Urea is reabsorbed largely in the proximal tubule. A fractional excretion of urea below 35% suggests a low effective circulating volume. Diuretics do not affect urea excretion, so if diuretics are used, a FE_Urea below 35% still suggests a low volume state. FE_Urea above 50-55% may be due to AKI or chronic renal failure [11,55-62]. FE_Urea may be less reliable when sodium-glucose cotransporter 2 (SGLT-2) inhibitors are used or in case of severe inflammation [55-63].

With diuretic therapy, a fractional urine excretion of uric acid above 11% may indicate SIADH as the underlying cause of hyponatremia [12,14,55-57].

Multiple causes of hyponatremia

Hyponatremia is multifactorial in a significant proportion of patients (Table 1). Coexistent diseases and therapies that predispose to hyponatremia include diabetes, chronic kidney disease, heart failure, and liver disease [23,29,64]. Also, more than 50 medications are associated with hyponatremia, such as psychofarmaca (antidepressants, antipsychotics) antiepileptics, anticancer drugs, antidiabetics, vasopressin analogues, proton pump inhibitors, NSAID’s, opiates, and amiodarone [1,6,10,12,64]. Loop diuretics may cause significant urine sodium loss, however, this usually does not result in hyponatremia because the resulting reduced osmolality in the renal medulla limits renal concentration capacity [12,14].

In elderly patients, multiple factors are often present in the development of hyponatremia [11,65].

Diagnostic errors in patients with adrenal insufficiency, SIADH, and cerebral salt wasting (CSW, or renal salt wasting: RSW)

Many physicians struggle with the differential diagnosis of SIADH, RSW, and adrenal insufficiency. This is the result of many overlapping features, and diagnostic errors are common [7,20,63,66-73]. SIADH causes water retention, but RSW and adrenal insufficiency are the result of sodium excretion and hypovolemic hyponatremia. Therefore, different therapeutic targets, such as water restriction versus saline infu­sion increases the risk of a poor outcome when the diagnosis is missed [9,11,14,18,42,66-73]. Physicians should, therefore, be vigilant to establish the diagnosis. The characteristics of these diseases are outlined in Table 2.

Primary adrenal insufficiency (Addison’s disease) is caused by dysfunction of the adrenal cortex. Secondary adrenal insufficiency develops in diseases of the hypothalamus and pituitary or suppression of the hypothalamic-pituitary axis [68-72].

Acute adrenal crisis occurs most commonly in patients with chronic adrenal insufficiency that did not receive extra steroids in stress situations. In rare cases patients with acute adrenal hemorrhage or pituitary apoplexy may also have this acute, possible life-threatening problem. Acute adrenal crisis often leads to hypotension, shock, fever, confusion, nausea, and vomiting. In case of acute adrenal hemorrhage, patients may have pain in abdomen, flank, or back. Severe headache and ophthalmoplegia are common in pituitary apoplexy [68-70].

Of note is that randomly measured cortisol levels may be of limited use. Plasma cortisol levels are highest in the early morning. A cortisol level below 100 nmol/l is strongly suggestive of adrenal insufficiency whereas a level above 500 nmol/l virtually excludes adrenal insufficiency. These cut-off values should be interpreted in the clinical context and are variable due to the use of different cortisol assays [68-72]. Critically ill patients present a special challenge concerning diagnosis and management of adrenal insufficiency, because of the unavailability of a reliable history, and the comorbidities that obscure a definitive diagnosis [72].

The main clinical difference between SIADH and RSW is the extracellular volume status. SIADH has an excess of volume that is hidden clinically and RSW is a hypovolemic status that also may be difficult to establish. Significant overlapping clinical findings are noted in Table 2. Both syndromes are associated with intracranial diseases, have normal adrenal function and similar laboratory tests such as hyponatremia, hypouricemia and concentrated urines, with high urine sodium and a high fractional excretion of urate. The volume stimulus of ADH is more potent than the osmolar stimulus. In RSW cases, the patient continues to secrete ADH despite becoming progressively hyponatremic while the patient continues to drink free water [21,25,42,66,67,73].

Maesaka et al., discovered a high prevalence of renal salt wasting related to haptoglobin-related protein without signal peptide, perhaps a RSW marker in the future [73].

If NaCL therapy is initiated before laboratory tests were done or before a proper diagnosis was made, one may use the effect of the therapy as an additional clue, because treatment response often reflects diagnosis. After NaCL 0.9%, a decrease in plasma sodium favors the diagnosis of SIADH, and an increase in the concentration supports other options such as dehydration, diuretic therapy or renal RSW. It remains imperative to exclude cortisol deficiency before diagnosing SIADH or RSW [20,25,63,66-70].

Hyponatremia caused by thiazide diuretics may resemble features similar to those in patients with the syndrome of ADH secretion (SIADH)

To distinguish SIADH and (occult) thiazide-induced hyponatremia may be challenging, because both may present with apparent euvolemia, low plasma uric acid and urea nitrogen concentrations [74-77]. In these cases, thiazide use may show a fractional excretion of potassium above 9% and urine calcium/creatinine ratio < 0.1, whereas SIADH is more likely with a calcium/creatinine ratio >0.1 [74,75]. The creatinine ratio depends on the rate of creatinine excretion, which is about 1 gram per day. However, creatine excretion is less than 1 gram in individuals with low muscle mass, and more than 1 gram in case of high muscle mass. Other parameters are outlined in Table 1. Discontinuation of thiazide results in rapid increase of plasma sodium when the thiazide effect wanes.

To complicate the differential diagnosis further, thiazide related hyponatremia may show either a volume depletion profile or signs consistent with a SIADH-like state. Thiazides use then have either a plasma uric level >4 mg/dl consistent with volume depletion, but also possible is a plasma uric level <4 mg/dl more consistent with fluid excess, such as in a SIADH profile [76].

Acid-base parameters and potassium

In hyponatremic patients in whom the diagnosis is not apparent, the evaluation of acid-base and potassium balance may be helpful. Diuretic use and vomiting may cause metabolic alkalosis and hypokalemia, and metabolic acidosis and hypokalemia suggest diarrhea and laxative abuse. Metabolic acidosis and hyperkalemia are considered the hallmark of primary adrenal insufficiency, but hyperkalemia is only present in one-third of these patients [41,69,78-80].

Plasma bicarbonate and potassium concentrations are typically normal in case of SIADH [20,63]. Patients with hypopituitarism may develop hyponatremia with many features of the SIADH, such as normal plasma potassium and low BUN and plasma uric acid, because they lack cortisol but not aldosterone. Plasma bicarbonate concentrations may be lower in hypopituitarism because plasma aldosterone levels may be lower in hypopituitarism [78] (Table 2).

Hospital acquired hyponatremia

It may be difficult to maintain an optimal sodium-water balance during hospitalization, because of illnesses, changes in water and food intake, fluid therapy, medi­cation use and medical interventions. The initial symptoms of hyponatremia are vague and may be confused with other medical conditions, delaying its identification especially when combined with insufficient laboratory monitoring. Hospital-acquired hyponatremia has a prevalence above 10 percent, and may be due to limited knowledge of physicians, inadequate management, medication use, inappropriate intravenous fluid prescribing practices, inadequate medical awareness, a lack of a hospital warning system, or inaccurate diagnostic and volume status assessment. Hyponatremia is an independent predictor and a direct cause of increased mortality. It also relates to an increased hospital length of stay, early hospital readmission, and increased hospital costs [3-6,81,82]. We need to improve diagnostic accuracy, clinical and biological monitoring, and knowledge to reduce management errors.

Methods & diagnostic application

Data source & interface development: Common diagnostic parameters (Table 1) extracted from the literature were used to construct the application [1-14,17-21]. The parameters were adapted from our recent comprehensive review of laboratory parameters (Table 1) [1]. We programmed several scripts containing parameters and diagnoses using the Python general-purpose programming language. In the application, the Python scripts compute the diagnoses based on the entered parameters and interact with a user interface developed in Vue using JavaScript [83,84]. To facilitate the use of the application, we implemented the interface of the web-based application on a public domain (http://hyponatremia.net; prior to publication restricted access through Username: hyponatremia_admin, Password: YTk2ZDJiYWEt). Clinicians may enter available clinical and laboratory chemistry data which will generate a differential diagnosis based on a comprehensive list of diagnostic parameters.

Diagnostic parameters: The preferred parameters include aspects of history and physical examination, in combination with laboratory tests, blood/plasma: Hemoglobin, Hematocrit, sodium, potassium, albumin, osmol, creatinine, blood urea nitrogen (BUN), bicarbonate, chloride, glucose, and uric acid; and in urine: dipstick (specific gravity, pH, bicarbonate, protein), spot urine: sodium, potassium, chloride, osmolality, bicarbonate, creatinine, and calcium (Table 1) [1]. For mineralocorticoid deficiency, cortisol should be tested and when pseudohyponatremia is suspected an arterial blood gas may be required.

Parameter processing: The scripts were designed in accordance with Table 1 of this manuscript where the returned diagnoses list is based on the total count of positive criteria [1-10]. A few modifications were implemented to facilitate the diagnostic process. Absence of vomiting, diarrhea, use of psychotropic medication, or methylenedioxymethamphetamine (MDMA, ‘ecstasy’) can be selected and will cause exclusion of these diagnoses. Selecting no use of diuretics will subtract one count, but as occult diuretics still can be an option, the diagnosis is not fully excluded. Similarly, low values for glucose (<10 mmol/L) and creatinine (<110 μmol/L) will exclude hyperglycemia and renal failure as diagnoses. Furthermore, laboratory chemistry results that conflict with diagnostic criteria of a diagnosis will assign a negative count of 0.5 (e.g. a high potassium >5.0 mmol/L where a low potassium <3.5 mmol/L is part of the diagnostic criteria). This was implemented to avoid direct (algorithmic-type) omission of diagnoses, whilst still maintaining a negative likelihood penalty for incongruous laboratory results. This is required to negate a criteria-count bias: certain diagnoses have a larger number of criteria and may therefore intrinsically have a higher prior likelihood of appearing in the diagnosis list. It is currently impossible to assign weight to criteria based on existing literature and applying standardization (percentage of diagnostic criteria fulfilled) would constitute a clinical selection bias. Recent hematocrit rise, proteinuria, and glycosuria were dichotomized to facilitate their use with limited information and simple binary dipstick urinalysis. Common unit conversions were added for creatinine, glucose, albumin, blood urea nitrogen (to urea), and urine osmolality (to specific gravity).

Although repeated measurements of these parameters would be required for optimal differential diagnosis, many of these are not available in clinical practice. While one cannot proceed in many flowcharts if crucial parameters such as the volume status are uncertain, the web-application evaluates parameters collectively, and can therefore still be used if certain clinical parameters are not available or uncertain. Moreover, it can be iteratively adjusted upon availability of new or changed parameters over time. Clinicians may consult Table 1 or the previous literature review [1] to select appropriate tests to support or oppose diagnoses of interest. The application will only use values inserted by the users.

Return of differential diagnosis: The web-based application or the supplementary file adapted from the related publication [1], will provide several diagnoses that may be present simultaneously, because multiple causes of hyponatremia are common. For further finetuning, or reassessment, a complete set of laboratory tests should be performed. If NaCl therapy is initiated before laboratory test were made or before a proper diagnosis was made, one may use the effect of the therapy as an additional clue because treatment response reflects diagnosis. A decrease in plasma sodium favors the diagnosis of syndrome of inappropriate antidiuretic hormone (SIADH), and an increase in the concentration supports other options such as dehydration, diuretic therapy or renal salt wasting (RSW). It remains worth noticing to exclude cortisol deficiency before diagnosing SIADH or RSW.

The application was tested using historical data from the author’s hospitals, medical journals, and public use on a small scale.

Step 1 concerns urgent management of severe symptomatic hyponatremia

Step 2 clinical evaluation with additional tests

Step 3 construct a differential diagnosis and if necessary, use the web based application

Adequate assessment of hyponatremia is a challenge and generally occurs in less than 50% of patients admitted to hospitals. The differential diagnosis is large and complex and there are limitations of current diagnostic tools. Also, important diagnostic laboratory tests are often omitted initially or at reassessment and errors in this evaluation lead to mistakes in diagnosis and therapy [1,2,4,5,8-10]. To facilitate the evaluation of hyponatremia we developed a Web-based application (http://hyponatremia.net; prior to publication restricted access through Username: hyponatremia_admin, Password: YTk2ZDJiYWEt). In this approach uncertain parameters such as the volume status can be bypassed by using a combination of known parameters to reach a differential diagnosis. This approach can also be used by inexperienced physicians because it facilitates the use of important, less-known, diagnostic parameters.

A possible limitation of this approach for the assessment of hyponatremia is that it is tested only in some cases from the author’s hospitals, some case reports in medical journals, and limited public use. However, as this approach combines current diagnostic flowcharts [1,2,4-14], the approach is, in fact, identical to other assessments. This diagnostic application is not intended to replace existing algorithms, but to provide an additional tool for the assessment of hyponatremia when there is uncertainty of certain clinical or when important laboratory parameters are unavailable. In addition, serial measurements of the blood and urine metabolic panel and reassessment after therapy remain required, as reconsideration of the cause of hyponatremia is often required in a significant proportion of patients [1-10].

Another computer-interpretable clinical guideline model for differential diagnosis of hyponatremia exists. However, this model was developed to be used for medical training and is limited to commonly used clinical parameters. A set of 65 hyponatremia patients were explored retrospectively, comparing the tool’s recommendation with a consensus diagnosis of two medical experts. The tool achieved a high ratio of agreement (61/65) with the experts. However, most cases had missing values (70.8%), and almost all cases (87.6 %) were either thiazide or SIADH related, limiting the validity of the gold standard endocrinologists as well as the tools’ generalizability and external validity [85].

An alternative option may be the use of artificial intelligence. We recently evaluated the performance of the free ChatGPT-3.5 for diagnosis and treatment suggestions in four challenging hyponatremia cases. We concluded that clinical implementation presently poses a risk of errors in diagno­sis and therapy in this respect [86].

Although the use of computer-based clinical decisions support methods is promising, we should not underestimate the risk of errors. Serious algorithm-related incidents have occurred due to a computer glitch in a heart risk tool where statins were wrongly given or denied [87].

In conclusion, this novel web-based screening tool is designed to be a useful aid to identify differential diagnosis in patients with hyponatremia. However, further validation of the tool is warranted to establish its true utility in routine clinical practice.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. MH is supported by the AZV grant, NW26J-06-00090.

Kenrick Berend wrote the manuscript, and Micah L.A. Heldeweg revised and reviewed the manuscript. Tomas T.R. Heldeweg created the web-based application. All authors have accepted responsibility for the entire con­tent of this manuscript and approved its submission.

Kenrick Berend http://orcid.org/0000-0003-0996-8539

Micah Liam Arthur Heldeweg http://orcid.org/0000-0001- 7420-8486