SIADH …

General Neurology

Updated 11.27.2022
Released 08.03.1994
Expires For CME 11.27.2025

SIADH

Authors: J Dedrick Jordan MD PhD, Caitlin Clark MD

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Editor: Matthew Lorincz MD PhD

SIADH

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Introduction

Overview

Hyponatremia is the most common electrolyte disorder in hospitalized patients (01) and is associated with increased morbidity and mortality (34; 07). Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a leading cause of euvolemic hyponatremia in hospitalized patients (30). It occurs with an independent release of arginine vasopressin (also known as ADH) not in response to baroreceptor or osmole sensing receptor changes. Clinically, it is distinguished from other hyponatremic states by apparent euvolemia, as opposed to hypovolemic or fluid overload states. By labs, the urine appears inappropriately concentrated compared to the fluid status of the patient. SIADH is typically the clinical manifestation of another underlying disease state, most commonly malignancy, pulmonary disease, or central nervous system disease. Treatment of SIADH requires treatment of the underlying etiology for definitive management. Hyponatremia may be acutely corrected for symptom management while other diagnostic studies or treatments are underway.

Key points

	• SIADH can only be diagnosed after excluding other forms of hyponatremia, adrenal insufficiency, and hypothyroidism.
	• Most common etiologies of SIADH include malignancy, medications, CNS disorders, and pulmonary disorders.
	• Hyponatremia is associated with increased morbidity and mortality.
	• Urgency of sodium correction depends on acuity of hyponatremia and presence of symptoms.
	• Some genetic mutations have been identified that lead to a syndrome of antidiuresis.
	• Vasopressin antagonists can be considered for treatment, but controversy exists regarding dosing and strength of recommendation.
	• Overcorrection of chronic hyponatremia may lead to osmotic demyelination.

Historical note and terminology

Hyponatremia has been described in association with pulmonary and central nervous system disease states since the 1930s. In 1957, Bartter and Schwartz published a description of 2 patients with bronchogenic carcinoma and hyponatremia in the setting of inappropriately high urine sodium content and euvolemia. In their study of these patients they identified that correction of serum sodium was achieved with fluid restriction (26). They posited an inappropriate secretion of antidiuretic factor as the etiology of hyponatremia, and a decade later this became known as syndrome of inappropriate antidiuretic hormone and clinical criteria were described (03).

Science has now come to recognize that the etiologies of hyponatremia related to the vasopressin system go beyond abnormal secretion of the hormone and may include genetic mutations of receptors which respond to ADH. A broader term to include these etiologies is syndrome of inappropriate antidiuresis or SIAD. In this article, the terminology SIADH will be used.

Differential diagnosis

When considering the diagnosis of SIADH, it is important to rule out other etiologies of hyponatremia.

Hypovolemic hyponatremia is the most important differential to recognize as it is readily reversible, and absence of recognition can lead to life threatening complications including multi-system organ failure. Hyponatremia of this type occurs when the overall intravascular solute is depleted, such as with vomiting or diarrhea, and the concentration mechanism of the urine is maximized as stimulated by the baroreceptive responses.

Pseudohyponatremia (also known as hyperosmotic hyponatremia) is a laboratory artifact that occurs when high levels of lipids or proteins are present in serum, such as patients with triglyceridemia or paraproteinemia. A confirmation test for true hyponatremia would be to check the serum osmolality in this scenario. Another form of artificial hyponatremia is that of hyperosmotic hyponatremia including hyperglycemic states and iatrogenic hyperosmolar states such as with the use of mannitol. This occurs when the increased osmolarity of the serum drives free water into the extracellular space, thereby reducing the concentration of sodium. This is often incorrectly referred to as pseudohyponatremia.

Hypervolemic hyponatremia is typically seen in disease states in which the effective hemodynamic volume and pressure is low, thus activating the anterior hypothalamus to release ADH, such as in heart failure and cirrhosis. Due to low cardiac output and decreased perfusion pressures, the patient may be clinically volume overloaded, but the physiologic mechanisms to contract and retain water are activated.

This is distinguished from excess free water states such as primary polydipsia or beer potomania in which not enough solute and excess water is consumed. Other iatrogenic forms of hyponatremia include diuretic use (thiazides and loop diuretics).

Another less common, though important disease to consider as an etiology for hyponatremia, is adrenal insufficiency. In this setting, deficiency in cortisol or aldosterone can lead to ADH secretion. Hypothyroidism is also noted as a potential cause for hyponatremia; however, the evidence for causality is weak and hyponatremia is typically only noted in severe cases of hypothyroidism, such as seen in myxedema coma (18).

For patients with neurologic disease, an important differential to consider is cerebral salt wasting. This is often difficult to distinguish from SIADH as patients with neurologic injury can have either or both. Most commonly associated with subarachnoid hemorrhage, cerebral salt wasting is the loss of sodium via renal loss. It can clinically be distinguished by hypovolemic state, as free water will be excreted with sodium. The urine concentration in this setting is often normal. Unlike the management of SIADH, which often entails fluid restriction, cerebral salt wasting requires restoration of intravascular volume (23; 20).

Diagnostic workup

The diagnostic criteria are largely unchanged from that initially described by Schwartz and Bartterer. It requires decreased effective osmolality less than 275 mOsm/kg of H20, urine osmolality greater than 100 mOsm/kg of H20, clinical euvolemia, urinary sodium greater than 40 mmol/L, normal thyroid and adrenal function, and no recent diuretic use (03). Despite these criteria, the diagnosis can be difficult to establish and clinical determinations of euvolemia uncertain. Low blood urea nitrogen, low serum uric acid, and high urine sodium may be suggestive of SIADH (10). Fractional excretion of uric acid may be useful in distinguishing SIADH from that of diuretic use, with FEua greater than 12% having the highest sensitivity and specificity (12). Copeptin, which is a cleaved byproduct of ADH, has generated interest as a means to distinguishing forms of hyponatremia, but data have been mixed and may be most useful in distinguishing primary polydipsia and hypovolemic hyponatremia (05; 19).

It is important to remember that SIADH requires exclusion of the differential diagnoses for hyponatremia as listed in the previous section. When the diagnosis of SIADH is established, it is also likely a symptom of an underlying disorder and workup should involve evaluations for the etiology.

An initial thorough review of medications is indicated. The most common implicated medications include antidepressants (SSRI, MAOI, and TCA), phenothiazine antipsychotics, and antiepileptics (most commonly, lamotrigine, oxcarbazepine, carbamazepine, and valproic acid). Other medications that have been implicated include chemotherapeutic drugs (vinca alkaloids, platinum compounds, methotrexate, ifosfamide, and cyclophosphamide) and illicit drugs such as MDMA and levamisole (11).

Even targeted therapies, such as anti-VEGFR drugs and immune checkpoint inhibitors (which have become very popular treatments of certain oncologic malignancies) have been associated with hyponatremia and SIADH. The exact mechanism of hyponatremia in the antiangiogenic drugs is unknown. However, in the immune checkpoint inhibitors, hyponatremia is related to hypophysitis associated with immune-related side effects of the drugs (15).

Central nervous systems pathologies that might result in SIADH are vast and may include tumors, stroke, hemorrhage, traumatic injury, or infection. Rarely would hyponatremia lead to the diagnosis of CNS disease without any other presenting neurologic symptoms. Another related neurologic etiology of SIADH is the transient hyponatremia that occurs following pituitary resection as part of the well-described “triple-phase response.” This may occur following sellar mass resections, which is where there is initial suppression of ADH presenting as diabetes insipidus, followed by release of ADH with clinical hyponatremia before a longer standing impairment of ADH production ensues (14).

Perhaps more importantly, a work-up for malignancy is indicated, particularly if hyponatremia is present with other concerning symptoms such as weight loss. Small cell lung cancer is the most common association and is known to be an ectopic source of ADH secretion (17). There have been reports of lymphoma, GI malignancy, and oropharyngeal malignancy also leading to SIADH. Though lung malignancy is the most commonly recognized pulmonary pathology, it can also be seen in cystic fibrosis and in infectious pulmonary disease with bacterial pneumonia, tuberculosis, fungal infections, etc.

Hereditary forms of inappropriate diuresis have been identified. Although not all of these directly cause an excess of ADH, they do cause alterations in normal functioning of the system as described previously. Mutations leading to a loss of the TRVP4 receptor leads to insensitivity of the osmole receptors, thereby blunting suppression of ADH in the setting of low serum osmolality (29). Mutations in the V2 receptor can result in gain of function leading inappropriate resorption of water, similar to the effect of ADH (13).

Management

Traditionally, fluid restriction was the therapy of choice for management of SIADH if symptoms were clinically mild or absent. Based on an analysis of a hyponatremia registry, fluid restriction alone only generates modest increases in sodium (median 1 ml/dL per day), and only half of patients treated with fluid restriction alone will successfully correct greater than 5 mmol/L (33).

For moderate to severe symptoms of hyponatremia (ie, with neurologic symptoms), correction with hypertonic saline is recommended by both European and United States guidelines. Though they vary in dosage, both recommend a small bolus 100 to 150 ml of 3% hypertonic saline to increase the serum sodium between 4 to 6 mmol/L to prevent life threatening cerebral edema (32; 28).

An alternative osmotic agent in raising serum sodium is enteral urea. European guidelines recommend this as an alternative therapy at 0.25 to 0.5 g/kg daily. There are also data to suggest safety for use in patients with critical neurologic injury with SIADH (22; 02). A commercial formulation of enteral urea has become available in the United States and may be considered for sodium correction in the inpatient setting (24). Caution is advised in patients with cirrhosis.

Vasopressin antagonists, tolvaptan and conivaptan, have been FDA approved in the United States for the treatment of hyponatremia secondary to SIADH. They work by disrupting the binding of ADH to vasopressin receptors, thereby preventing the insertion of water channels into the membrane of the collecting duct (04). Randomized controlled trials demonstrate conivaptan intravenous at 40 mg per day, increased plasma sodium by 6.3 mmol/L (35), and tolvaptan (oral) by 3.6 mmol/L over 4 days (25). Post marketing analysis has suggested that in clinical use, the rate of correction may be more rapid with 1 study reporting up to 25% of patients with SIADH correcting greater than 12 mEq/L per day, with the highest risk being in patients with low serum sodium (less than or equal to 121 mEq/L) and low serum urea nitrogen (less than or equal to 10mg/dL) with tolvaptan (16). It is important to note that in the above-mentioned randomized trials, patients with serum sodium less than 120 mEq/dL were excluded, as were patients with symptomatic neurologic deficits. This is especially important when considering its use in neurologic patients, as normal thirst response may help protect patients from overcorrection, which may be lacking in the neurologic population. Therefore, it is recommended to discontinue fluid restriction and hypertonic therapies when treating with vasopressin receptor antagonists (32; 04). Medications that have fallen out of favor in the treatment of hyponatremia include lithium and demeclocycline. These medications are not recommended due to their variable efficacy and adverse side effect profiles (28).

The rate of appropriate correction in chronically hyponatremic patients is debated and grows more conservative with emerging evidence. Although previous correction of no greater than 12 mmol/L within the first 24 hours was considered safe, more recent case reports of post-therapy neurologic complications at these rates have led to changes in recommendations. Currently, the European guidelines recommend no greater than 10mmol/L within the first day, and no greater than 8 mmol/L during the second day. The United States guidelines take an even more conservative approach recommending 4 to 8 mmol/L per day, and if the patient is at high risk for osmotic demyelination (cirrhosis, hypokalemia, alcoholism), then 4 to 6 mmol/lL per day is recommended.

Outcomes

Scientific evidence that correction of serum sodium reduces morbidity and mortality has been variable despite the support of evidence that hyponatremia leads to worse outcomes in hospitalized patients and leads to chronic comorbidities such as falls and bone fractures. The most feared complication of sodium correction is osmotic demyelination in a patient who is chronically hyponatremic and corrected too rapidly. In patients who are chronically hyponatremic (greater than 24 hours), there is a reduction in organic osmolytes intracellularly. With correction of sodium, there is efflux of free water extracellularly and cell shrinkage. Progressive neurologic symptoms occur over days. Neurologic symptoms such as quadriparesis can be permanent. It has been long recognized that this can occur in extrapontine sites. Patients at increased risk include patients with liver disease, liver transplant, alcoholism, and malnutrition (27).

References

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02: Annoni F, Fontana V, Brimioulle S, Creteur J, Vincent JL, Taccone FS. Early effects of enteral urea on intracranial pressure in patients with acute brain injury and hyponatremia. J Neurosurg Anesthesiol 2017;29(4):400-5. PMID 27438797
03: Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 1967;42(5):790-806. PMID 5337379
04: Berl T. Vasopressin antagonists. N Engl J Med 2015;372(23):2207-16.** PMID 26039601
05: Christ-Crain M, Fenske W. Copeptin in the diagnosis of vasopressin-dependent disorders of fluid homeostasis. Nat Rev Endocrinol 2016;12(3):168-76. PMID 26794439
06: Corona G, Giuliani C, Parenti G, et al. Moderate hyponatremia is associated with increased risk of mortality: evidence from a meta-analysis. PLoS One 2013;8(12):e80451. PMID 24367479
07: Corona G, Giuliani C, Verbalis JG, Forti G, Maggi M, Peri A. Hyponatremia improvement is associated with a reduced risk of mortality: evidence from a meta-analysis. PLoS One 2015;10(4):e0124105. PMID 25905459
08: Corona G, Norello D, Parenti G, Sforza A, Maggi M, Peri A. Hyponatremia, falls and bone fractures: A systematic review and meta-analysis. Clin Endocrinol (Oxf) 2018;89(4):505-13. PMID 29920727
09: Cui H, He G, Yang S, et al. Inappropriate antidiuretic hormone secretion and cerebral salt-wasting syndromes in neurological patients. Front Neurosci 2019;13:1170. PMID 31780881
10: Decaux G, Musch W. Clinical laboratory evaluation of the syndrome of inappropriate secretion of antidiuretic hormone. Clin J Am Soc Nephrol 2008;3(4):1175-84.** PMID 18434618
11: Ellison DH, Berl T. The syndrome of inappropriate antidiuresis. N Engl J Med 2007;356(20):2064-72.** PMID 17507705
12: Fenske W, Stork S, Koschker AC, et al. Value of fractional uric acid excretion in differential diagnosis of hyponatremic patients on diuretics. J Clin Endocrinol Metab 2008;93(8):2991-7. PMID 18477658
13: Hague J, Casey R, Bruty J, et al. Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD). Endocrinol Diabetes Metab Case Rep 2018;2018. PMID 29472987
14: Lindsay RS, Seckl JR, Padfield PL. The triple-phase response--problems of water balance after pituitary surgery. Postgrad Med J 1995;71(837):439-41. PMID 7567742
15: Mentrasti G, Scortichini L, Torniai M, et al. Syndrome of inappropriate antidiuretic hormone secretion (SIADH): optimal management. Ther Clin Risk Manag 2020;16:663-72. PMID 32801723
16: Morris JH, Bohm NM, Nemecek BD, et al. Rapidity of correction of hyponatremia due to syndrome of inappropriate secretion of antidiuretic hormone following tolvaptan. Am J Kidney Dis 2018;71(6):772-82. PMID 29478867
17: Moses AM, Scheinman SJ. Ectopic secretion of neurohypophyseal peptides in patients with malignancy. Endocrinol Metab Clin North Am 1991;20(3):489-506. PMID 1935917
18: Nagata T, Nakajima S, Fujiya A, Sobajima H, Yamaguchi M. Prevalence of hypothyroidism in patients with hyponatremia: a retrospective cross-sectional study. PLoS One 2018;13(10):e0205687. PMID 30308047
19: Nigro N, Winzeler B, Suter-Widmer I, et al. Evaluation of copeptin and commonly used laboratory parameters for the differential diagnosis of profound hyponatraemia in hospitalized patients: 'The Co-MED Study'. Clin Endocrinol (Oxf) 2017;86(3):456-62. PMID 27658031
20: Oh JY, Shin JI. Syndrome of inappropriate antidiuretic hormone secretion and cerebral/renal salt wasting syndrome: similarities and differences. Front Pediatr 2014;2:146. PMID 25657991
21: Pazhayattil GS, Rastegar A, Brewster UC. Approach to the diagnosis and treatment of hyponatremia in pregnancy. Am J Kidney Dis 2015;65(4):623-7. PMID 25542410
22: Pierrakos C, Taccone FS, Decaux G, Vincent JL, Brimioulle S. Urea for treatment of acute SIADH in patients with subarachnoid hemorrhage: a single-center experience. Ann Intensive Care 2012;2(1):13. PMID 22647340
23: Rabinstein AA, Bruder N. Management of hyponatremia and volume contraction. Neurocrit Care 2011;15(2):354-60. PMID 21748503
24: Rondon-Berrios H, Tandukar S, Mor MK, et al. Urea for the treatment of hyponatremia. Clin J Am Soc Nephrol 2018;13(11):1627-32. PMID 30181129
25: Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006;355(20):2099-112. PMID 17105757
26: Schwartz WB, Bennett W, Curelop S, Bartter FC. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med 1957;23(4):529-42. PMID 11729259
27: Singh TD, Fugate JE, Rabinstein AA. Central pontine and extrapontine myelinolysis: a systematic review. Eur J Neurol 2014;21(12):1443-50. PMID 25220878
28: Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrol Dial Transplant 2014;29 Suppl 2:i1-i39. PMID 24569496
29: Tian W, Fu Y, Garcia-Elias A, et al. A loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia. Proc Natl Acad Sci U S A 2009;106(33):14034-9. PMID 19666518
30: Upadhyay A, Jaber BL, Madias NE. Epidemiology of hyponatremia. Semin Nephrol. 2009;29(3):227-38. PMID 19523571
31: Verbalis JG. How does the brain sense osmolality? J Am Soc Nephrol 2007;18(12):3056-9.** PMID 18003769
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34: Waikar SS, Mount DB, Curhan GC. Mortality after hospitalization with mild, moderate, and severe hyponatremia. Am J Med 2009;122(9):857-65. PMID 19699382
35: Zeltser D, Rosansky S, van Rensburg H, Verbalis JG, Smith N, Conivaptan Study G. Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia. Am J Nephrol 2007;27(5):447-57. PMID 17664863

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

J Dedrick Jordan MD PhD

Dr. Jordan of LSU Health Shreveport has no relevant financial relationships to disclose.
See Profile
Caitlin Clark MD

Dr. Clark of Duke University has no relevant financial relationships to disclose.
See Profile

Editor

Matthew Lorincz MD PhD

Dr. Lorincz of the University of Michigan has no relevant financial relationships to disclose.
See Profile

Former Authors

Michael Brines MD PhD, Silvio Inzucchi MD (original authors), Andrew P Rose-Innes MD, Sarika Shirsat MD, and Winnie Lau MD

Patient Profile

Age range of presentation: 1 month to 65+ years
Sex preponderance: male=female
Heredity: X-linked
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: SIADH: 253.6
ICD-10: Hypo-osmolality and hyponatremia: E87.1

Syndrome of inappropriate secretion of antidiuretic hormone: E22.2

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SIADH

Associated Disorders

Acute asthmatic exacerbation
Acute intermittent porphyria
Adenocarcinoma of pancreas, duodenum, prostate
Adult respiratory distress syndrome
Brain abscesses
- Brain tumors
- Cerebral trauma
- Cystic fibrosis
- Diabetic insipidus
- Ewing sarcoma
- Guillain-Barre syndrome
- Hyponatremia
- Hypoosmolality
- Intracranial hemorrhage
- Lymphoma
- Meningitis
- Mesothelioma
- Pneumonitides
- Pneumothorax
- Postoperative state
- Pseudohyponatremia
- Psychogenic polydipsia
- Pulmonary abscess
- Small cell lung carcinoma
- Thymoma
- Tuberculosis

Differential Diagnosis

hypertriglyceridemia
severe paraproteinemias
cardiac failure
nephrotic syndrome
cirrhosis
- hypofunction of adrenal glands
- hypofunction of thyroid glands
- psychogenic polydipsia
- pseudohyponatremia
- hypocortisolism
- subarachnoid hemorrhage
- tuberculous meningitis
- complications of intracranial surgery
- primary renal salt wasting
- hypovolemia
- cerebral salt wasting syndrome
- hyponatremia
- intrafetal shunting
- conditions of volume depletion and significant fluid overload
- hypothyroidism
- reset osmotat

SIADH …

SIADH

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Differential diagnosis

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Brain death/death by neurologic criteria

Hepatic encephalopathy

Bowel dysfunction in neurologic disorders

Coma due to primary brainstem and diencephalic lesions

Transient visual loss

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Sports activities: neurologic complications

Neurotechnology: brain-computer and brain-machine interfaces

SIADH

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Differential diagnosis

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Brain death/death by neurologic criteria

Hepatic encephalopathy

Bowel dysfunction in neurologic disorders

Coma due to primary brainstem and diencephalic lesions

Transient visual loss

Neuroimaging in acute stroke

Sports activities: neurologic complications

Neurotechnology: brain-computer and brain-machine interfaces

This is an article preview.
Start a Free Account
to access the full version.