ABSTRACT

The diagnosis of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) relies on an adequate assessment of a hyponatremic state (that is a serum sodium level <136 mmol/l) and on the exclusion of other causative conditions leading to an appropriate secretion of antidiuretic hormone (ADH). The understanding of mechanisms involved in pathological ADH secretion is essential for diagnosis and therapy. Although some forms are due to dysregulation in central nervous system regulation, other forms are dependent on diseases in peripheral organs and structures including ADH-producing/secreting neuroendocrine tumors, while others are induced by drugs. ADH regulation is closely linked to other systems such as the sympathetic nervous system via and baroreflex regulation. Patients with hyponatremia should be assessed carefully whether or not neurological symptoms exist. Further, assessment of volume status is needed. Based on symptoms and volume status, the need for intensive-care monitoring is determined. In parallel, laboratory findings of blood and urine must be analyzed appropriately. It is important to demonstrate true hyponatremia, which is paralleled by a decrease in serum osmolality. Mandatory laboratory diagnostic steps comprise the determination of blood and urine electrolytes and serum and urine osmolality, analysis of thyroid, adrenocortical, and kidney function as well as uric acid. Different test results such as a high fractional uric acid excretion may hint to an existing SIADH. Assessment of urine osmolality and urine sodium concentration and intravascular volume level may allow for further discrimination and may be indicative for a specific underlying disorder, causing SIADH. Brain volume changes (“hydrocephalus ex vacuo”) may depend on age rendering the elderly more tolerant to acute or chronic serum sodium changes. The course of incident hyponatremia, if documented, may affect therapy. A serum sodium drop within less than 48 hours is considered acute hyponatremia. A rapid bolus of 100 to 150 ml of intravenous 3% hypertonic saline is appropriate to avoid catastrophic outcomes in severe cases of acute symptomatic hyponatremia. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

“Antidiuretic hormone” or “arginine vasopressin” (AVP) is physiologically released into the blood stream upon increases of plasma osmolality. AVP, a nine-amino-acid peptide, originates in the supraophthalmic nucleus (SON) of the hypothalamus and is directly regulated by plasma osmolality detected via a splice variant of the capsaicin receptor, the transient receptor potential vanilloid type-1 (Trpv1) receptor (1). AVP is axonally transported to the posterior pituitary and released into the blood upon respective stimulation. AVP regulation is, however, more complex than a mere response to changes of plasma osmolality. In fact, hypovolemia enhances AVP release upon increases of plasma osmolality. Conversely, hypervolemia attenuates AVP release for given increases of plasma osmolality.

In patients with “Syndrome of Inappropriate Antidiuretic Hormone Secretion” or SIADH, the cornerstone of diagnosis is hyponatremia (Na<136 mmol/l) (2) in a state of euvolemia, i.e. absence of either over- or dehydration. SIADH-related hyponatremia is caused by excess water reabsorption due to inappropriately high levels of AVP. Specifically, AVP binds to stimulatory G-protein-coupled vasopressin V₂-receptors of the basolateral membrane of collecting-duct cells, thereby increasing the intracellular cAMP level, which, in turn, activates Aquaporin-2 channels of the brush-border membrane or urine side of the collecting-duct principal cells. AVP action results in a reduced free-water clearance resulting in a more concentrated urine and total-body water (TBW) expansion. AVP-mediated TBW expansion mediates sympathoinhibition (Figure 1).

Figure 1.

Role of AVP in regulation of sympathetic tone. AVP translates into sympathoinhibition (Figure amended from (3) ).

In addition, AVP-induced TBW expansion translates into plasma-solute dilution leading to hyponatremia. Thereby, plasma osmolality (OSM) is decreased given the fact that sodium strongly determines OSM according to the following equation:

OSM (calculated) = 2 x Na (mmol/l) + Glucose (mmol/l) + Urea (mmol/l)

Besides AVP actions on OSM, AVP also enhances endothelial-cell synthesis and the release of von-Willebrand Factor, thereby affecting hemostasis (4). This AVP effect on hemostasis is therapeutically used in bleeding disorders involving Factor VIII or von-Willebrand factor deficiency (5, 6).

SIADH may be viewed as a primary central-nervous system dysregulation of OSM and/or thirst. The etiology still is incompletely understood. Alternatively, SIADH may relate to baroreceptor unloading due to clinically inapparent hypovolemia or, hypothetically, to carotid-artery atherosclerosis affecting baroreflex regulation (7). This alternative route of increased AVP release may ultimately translate into the clinical picture of SIADH. Generally, less wall distension of the carotid arterial walls and/or the aortic arch may lead to a decrease of arterial baroreceptor-related afferent autonomic nerve traffic to the rostral ventrolateral medulla and nucleus tractus solitarii (NTS) translating into less sympathoinhibition (sympathoexcitation) and to an increased release of AVP (8) (Figure 2).

Figure 2.

Baroreflex regulation and SIADH: arterial hypotension lowers baroreflex-mediated afferent nerve traffic to the nucleus tractus solitarii leading to an elevated efferent sympathetic nerve activity and increased AVP release.

Lastly, hypovolemia-related cardiopulmonary (CP) reflex deactivation mediated by less wall distension of the right atrial wall and pulmonary veins may increase plasma AVP leading to SIADH (9, 10). Conversely, CP reflex activation mediated by more right-atrial wall distension e.g. after body immersion in water is able to decrease plasma AVP (11).

The term “primary SIADH” is used for all above-mentioned causes involving a known or suspected dysregulation of OSM and/or circulating-blood volume. The term “secondary SIADH” is attributed to pituitary-independent causes of AVP increases, e.g., in hormone-active neoplasms such as small-cell lung cancer. In addition, a drug-induced type of SIADH is detailed here.

CLINICAL PRESENTATION OF SIADH

Both moderate and especially severe hyponatremia (Na < 125 mmol/l) found in newly admitted hospital patients is linked with a significantly elevated in-hospital mortality of 28% compared to 9% in-hospital mortality in normonatremic, matched control patients (12). Mortality, in fact, increases when serum Na levels are below 137 mmol/L (13). While (neurological) symptoms of hyponatremia such as gait disturbances, cognitive dysfunction and dizziness may lead to falls leading to subsequent injuries requiring medical care, either preceding symptom may be subtle and difficult to diagnose. Therefore, hyponatremia often is overseen or not given full attention. Furthermore, if hyponatremia is diagnosed, it is regularly classified to be asymptomatic. Diagnostic differentiation remains absent or incomplete. Thus, underlying reasons often remain obscure (14). However, cognitive and/or geriatric functional tests regularly reveal a significant impairment in states of hyponatremia.

Clearly, symptoms of hyponatremia depend on the time elapsed since the start of hyponatremia development. Hyponatremia developing in less than 48 hours may already present with severe symptoms which are mainly caused by cerebral edema and a high intracranial pressure. These include epileptic convulsions, a pronounced somnolence or coma, vomiting and/or a compromised respiratory regulation. Symptoms like headache or modest nausea generally reflect a rather moderate severity.

In patients with acute hyponatremia, a brief patient history and a physical examination should be performed (Table 1). In cases of a rather slowly developing or chronic hyponatremia, intracellular regulations such as decreased uptake of taurin aim to adapt to the decreased extracellular osmolality. Therefore, those patients may show very subtle or even no clinical alterations. Taurin is an endogenous amino acid that mediates cellular adaptation to hyperosmotic stress (15).

For the diagnosis of SIADH, the first diagnostic step, hyponatremia needs to be ascertained. False laboratory “measurements” of serum Na+ comprise primarily a hyperglycemic state. According to Hillier et al (16) an estimation of the true sodium concentration in serum can be drawn from the formula:

Corrected (Na+) = Measured (Na+) + 2.4 x (glucose (mg/dl) - 100 mg/dl)/100mg/dl

For example, a serum glucose level of 400 mg/dl with a measured serum sodium of 120 mmol/l corresponds to a true sodium value of 127 mmol/l (16).

Likewise, pseudohyponatremia may occur in patients with paraproteinemia, e.g. multiple-myeloma patients (17).

Another pitfall with serum sodium is the mode of its determination: the usual method involves ion-selective electrodes, not flame-photometric determination and may yield occasionally “diluted” Na⁺ levels (elevated triglyceride levels, paraproteinemia). Measured, not calculated serum osmolality may help discriminate true from pseudohyponatremia: true hyponatremia associates with a decreased serum osmolality.

True-hyponatremic patients are regularly identified at hospital admission, e.g., in the emergency room. However, a large number of hospitalized patients have or develop either mild (Na 131 – 136 mmol/l), moderate (Na 126 – 130 mmol/l) or severe (Na <125 mmol/l) hyponatremia after admission during the hospital stay. Although many hyponatremic patients will present with chronic hyponatremia, however, some patients present with a proven acute hyponatremia. Since acute hyponatremia means an incomplete adjustment of the difference in osmolality between plasma (extracellular space) and intracellular cell space of tissues and organs such as the brain, a 48-hours threshold to discern acute from chronic hyponatremia appears reasonable. However, in everyday practice, this discrimination might not be feasible due to a lack of documentation of serum sodium levels in newly hospitalized patients.

As an important step in the approach to the hyponatremic patient is to determine volume status. Accordingly, a state of overhydration characterized by the presence of peripheral edema needs to be ruled out. Hyponatremia accompanied by peripheral edema, anasarca, jugular vein distension in absence of a significant tricuspid-valve regurgitation, dyspnea, and/or signs of a lung fluid or pulmonary edema on the chest radiograph are not consistent with the diagnosis of SIADH. Here, underlying diseases such as chronic heart failure should be diagnosed and addressed. Likewise, hyponatremia in a state of hypovolemia needs to be excluded. In exsiccosis, e.g., due to diuretics, both water and solutes may be lost. Hypovolemia triggers sympathoactivation via CP and baroreflex leading to an appropriate ADH release.

In patients presenting with hyponatremia in a state of euvolemia, i.e., absence of overhydration or exsiccosis, the diagnosis of SIADH should be considered, after excluding conditions such as chronic heart failure. A known and medically treated chronic heart failure condition may present as a hypervolemic, euvolemic or – when vigorously treated – hypovolemic state. Both, chronic heart failure and liver cirrhosis are characterized by arterial underfilling and, hence, activation of both the renin-angiotensin-aldosterone system and antidiuretic hormone leading to both sodium chloride retention and water retention. The net effect may be hyponatremia, if AVP stimulation dominates. Thus, urine-sodium measurements in 24-hours urine collection may prove the presence of a sodium-sparing disorder, thereby rendering SIADH unlikely.

A useful algorithm to approach hyponatremia is depicted in Figure 3.

Figure 3.

Approach to the patient with hyponatremia (adapted and modified from (18), with permission).

In the clinical assessment, euvolemic patients suspected to have primary SIADH often show a slight weight gain by 5 – 10% of body weight and/or a worsened condition of arterial hypertension, and urine output is normal or slightly reduced. In secondary, neoplasm-associated SIADH, however, an unexplained weight loss and/or state of cachexia may prompt further diagnostics including chest radiograph and thoracic computed tomography scan, if deemed necessary.

It is crucial to assess and to treat infections effectively, since they may establish or worsen a tendency to hyponatremia.

To correctly evaluate laboratory results besides aspects of methodology, diuretics,

especially thiazides, should be discontinued, and nutritional sodium chloride intake should not exceed 5 – 6 g per day.

HYPONATREMIA IN EUVOLEMIA: ASSESSMENT FOR SIADH

The diagnostic, step-wise approach for evaluating hyponatremia in euvolemic patients is detailed below:

1^st Step

Here, a laboratory work-up (Table 2) is proposed to establish a preliminary diagnosis being consistent with SIADH.

Table 2.

Laboratory Work-Up for SIADH

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	Parameter	SIADH Diagnosis
Serum	Sodium Potassium Glucose Urea Creatinine Uric acid Thyroid hormones Cortisol Aldosterone Copeptin	<136 mmol/l Normal Normal Normal Normal Normal Normal Normal Normal Elevated
Urine	Osmolality Sodium Uric acid Creatinine Osmolality	>100 mosm/kg > 30 mmol/l Normal or Low Normal >12%

As a diagnostic cornerstone of SIADH diagnosis, determination of fractional uric-acid excretion has recently emerged (SIADH increased). Fenske et al. (19) confirmed earlier reports demonstrating fractional uric-acid excretion (cut-off greater than 12%) to rule out hyponatremic states with reduced extracellular fluid volume, e.g. due to diuretics (Figure 4).

Figure 4.

Calculation of fractional uric acid excretion.

There is sometimes debate on whether measurements of AVP in the plasma are helpful or not for diagnosis of SIADH or other hyponatremic circumstances. There are, however; multiple obstacles rendering AVP determination and interpretation difficult. Only a few laboratories provide tests with good sensitivity, since AVP is very unstable when isolated from plasma and binds to other structures. A potential alternative is the more stable copeptin, also called C-terminal proarginine vasopressin, which is generated by enzymatic cleavage of the vasopressin prohormone. Strikingly, SIADH patients were shown to have an elevated plasma copeptin (20). As an additional way to diagnose SIADH, correlation of plasma copeptin with changes in plasma osmolality (step 2, step 3) can be used (21). Furthermore, a hypertonic (3%) saline test has been proposed for SIADH (20). However, this test strategy still needs to be validated.

INTERPRETATION OF CLINICAL AND LABORATORY RESULTS

SIADH leads to an increase of free-water reabsorption, thereby increasing the circulating blood volume. By virtue of dilution mediated by AVP, both hematocrit and plasma sodium are decreased. Likewise, a decrease of urine output can be found.

In cases of a prolonged, subclinical hypovolemia, baroreflex- and/or CP-reflex unloading stimulates AVP secretion leading to the clinical picture of SIADH. There, discontinuation of diuretics and/or the empirical infusion of 500 ml saline (0.9%) as outlined above in step 2 may correct such a state of subclinical hypovolemia and lead to an improvement in hyponatremia driven by SIADH.

In assessing key laboratory results including plasma and urine sodium concentration and -osmolality, both the theoretical or calculated OSM should be compared to the actually measured OSM. That way, states of hyponatremia due to uremia or hyperglycemia can be ruled out. In such cases of hyponatremia, high plasma urea or high plasma glucose lead to a rise in OSM prompting a physiologic release of AVP, which, in turn, leads to a plasma-sodium dilution in order to maintain a normal OSM.

Urine sodium within normal range rules out a dietary sodium deficiency or states of increased tubular sodium reabsorption such as in chronic heart failure or liver cirrhosis.

After fulfilling the above-mentioned steps to diagnose SIADH, the following conditions should be separately considered as a possible differential diagnosis:

DIFFERENTIAL DIAGNOSIS OF HYPONATEMIA OTHER THAN SIADH

• Sodium chloride depletion, low dietary sodium intake regularly is accompanied by hypovolemia, low urine sodium, elevated serum uric acid and serum urea.
• Anterior-lobe pituitary gland insufficiency often is accompanied with signs and symptoms, and respective laboratory findings indicating hormone deficiencies such as hypothyroidism, hypocortisolism or hypogonadism. In addition, bitemporal hemianopsia and hyperprolactinemia are found in cases of anterior-lobe pituitary tumors as a cause of anterior-lobe pituitary gland insufficiency.
• Adrenal-gland insufficiency including iatrogenic mineralocorticoid-receptor antagonism (spironolactone/eplerenone) regularly is accompanied by hyperkalemia and hypovolemia.
• Thiazide diuretics can induce hyponatremia by an AVP-dependent mechanism and by a thiazide-induced increase of water permeability in the medullary collecting duct.
• Severe hypothyroidism regularly is accompanied by dilutional hyponatremia due to a reduced free-water clearance.
• Chronic kidney disease: In salt losing nephropathy, a condition that occurs in advanced kidney failure with a GFR below 15 ml/min, hyponatremia is paralleled by hypovolemia. This is a feature classically seen in interstitial kidney disease. On the other hand, many patients with near end-stage renal failure show increased Na excretion to balance body sodium content, but, due to (continuous) reduction in urine production, a diluted urine cannot be achieved, leading to hyponatremia.
• Acute kidney (transplant) failure without signs of uremia, a water-excretion dysfunction may lead to dilutional hyponatremia.
• Hyperglycemia or poor diabetes mellitus control may lead to a so-called translational hyponatremia due to intra- to extracellular water shift and consequent plasma sodium dilution (see above).
• Cerebral salt wasting is an important differential diagnosis to SIADH occurring in cases of aneurysmal subarachnoidal hemorrhage and in other intracranial pathologies. Cerebral salt wasting still is not completely characterized and most likely involves a putative central nervous system-derived factor and/or a sudden decrease of renal sympathetic nerve activity favoring a urinary loss of sodium chloride. Cerebral-salt wasting - associated urinary sodium-chloride loss improves after successful neurosurgical care of the initial intracranial disease condition and may require temporary high amounts of sodium chloride replacement.
• Overdose of antidiuretic-hormone analogs in cases of known central diabetes insipidus. If the primary physician is unaware of the underlying medical condition, SIADH may be suspected based on laboratory results described above. Patient history including the medication list clarifies the diagnosis.

THERAPY OF SIADH

If left untreated, SIADH may lead to a severe, life-threatening hyponatremia with or without clinically apparent overhydration. Acute complications of SIADH include cerebral edema and epileptic convulsions. SIADH therapy clearly depends on the specific etiology and the severity of symptoms.

Once therapy is initiated, repeat measurements of plasma sodium are mandatory to gauge the therapeutic response, and, most importantly, to ascertain a slow plasma-sodium normalization with a recommended maximum rate of 0.5 mmol/l/h plasma-sodium increase. Again, the delivery of higher concentrated sodium chloride solution is allowed strictly for symptomatic patients. A significant proportion of in-hospital mortality relating to hyponatremia likely is due to a too rapid sodium normalization in long-standing hyponatremia. The consequence of too rapid sodium normalization is the osmotic demyelination syndrome due to a rapid intra- to-extracellular water transfer and subsequent brain swelling that exceeds the percentage of cerebrospinal fluid volume capacity (usually around 8% but higher in elderly with a hydrocephalus ex vacuo).

Besides the therapeutic goal to avoid rapid changes in plasma osmolality, the underlying reason of hyponatremia in SIADH, excess total body water, should be addressed by balanced fluid-intake reduction. All therapeutic interventions discussed here target the consequences of exaggerated AVP secretion rather than sodium-chloride supplementation.

In primary SIADH, plasma-sodium dilution can be addressed by an ongoing fluid-intake restriction of 500-800 ml/day which many patients do not tolerate well.

However, subclinical hypovolemia and ensuing baroreflex and CP reflex suppression leading to AVP stimulation should be kept in mind. Addressing arterial hypotension and/or central-venous hypotension is effective in lowering AVP in plasma. At the same time, fluid-intake restriction may appear contradictory. Even though fluid-intake restriction appears to be a proven measure in terms of attenuation of AVP consequences, it is the clinician`s judgement to test both interventions and compare the best results in terms of a slow plasma-sodium increase.

In secondary SIADH, identification of the neoplasm is the goal. A thorough tumor search using positron-emission tomography and computed tomography is warranted to further determine the underlying pathology and, if applicable, consider all options of curative therapy. Chemotherapy, surgical and/or radiation therapy of malignancies with AVP activity represent definitive therapeutic approaches. On clinical grounds, neoplasm-associated, secondary SIADH often requires V2-receptor antagonism therapy until a specific oncologic care plan is employed. This might be especially true while performing cytostatic therapy cycles with increased intravenously administered fluid volumes. However, to date, no survival benefit has been demonstrated in favor of V2-receptor antagonism in oncologic care of patients with secondary, neoplasm-associated SIADH.

Besides malignancies, infections such as tuberculosis have been associated with occurrence of SIADH (24).

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