Syndrome of Inappropriate Secretion of ADH (SIADH): Symptoms, Causes, and Treatment

Overview

Antidiuretic hormone (ADH), also known as vasopressin, is normally produced in the hypothalamus and released by the posterior pituitary gland in response to increased blood osmolality or decreased blood volume. ADH acts on the kidneys to increase water reabsorption, concentrating the urine and conserving body water. In healthy individuals, ADH secretion is carefully regulated to maintain proper fluid and electrolyte balance.

In SIADH, ADH is released inappropriately, meaning it continues to be secreted even when blood osmolality is low and the body has adequate or excessive water. This results in continued water retention by the kidneys, leading to dilutional hyponatremia (low blood sodium concentration). The condition was first described by Schwartz and Bartter in 1967, and is sometimes referred to as Schwartz-Bartter syndrome.

SIADH affects approximately 1-2% of all hospitalized patients but may be present in up to 15-20% of patients with certain conditions such as lung cancers or central nervous system disorders. The prevalence increases with age, and the condition can range from asymptomatic mild hyponatremia to life-threatening severe hyponatremia with neurological symptoms.

The diagnosis of SIADH requires meeting specific criteria including hyponatremia, low plasma osmolality, inappropriately concentrated urine, normal kidney and adrenal function, and absence of volume depletion. Early recognition and appropriate treatment can prevent serious complications and significantly improve patient outcomes.

Types of SIADH

Classification by ADH Secretion Pattern

Type A: Unregulated ADH Secretion

Pattern: Autonomous, random ADH release
Response: No response to osmotic or volume changes
Cause: Often ectopic ADH production by tumors
Treatment: Usually requires vasopressin receptor antagonists

Type B: Osmotic Threshold Reset

Pattern: ADH responds to osmotic changes but at lower threshold
Response: Normal feedback but "reset" to lower osmolality
Cause: Central nervous system disorders
Treatment: Often responds to fluid restriction

Type C: ADH Leakage

Pattern: Baseline elevated ADH with normal osmotic response
Response: Can respond to osmotic suppression
Cause: Pituitary or hypothalamic dysfunction
Treatment: Variable response to different therapies

Classification by Underlying Cause

Malignancy-Related SIADH

Ectopic ADH production by tumors
Most commonly small cell lung cancer
Also pancreatic, duodenal, and other cancers
Often presents with rapid onset hyponatremia

Central Nervous System SIADH

Brain trauma, surgery, or infection
Stroke, hemorrhage, or tumor
Meningitis or encephalitis
Often has gradual onset

Pulmonary SIADH

Pneumonia, especially bacterial
Tuberculosis or fungal infections
Positive pressure ventilation
Usually resolves with treatment of underlying condition

Drug-Induced SIADH

Antidepressants (SSRIs, tricyclics)
Antipsychotics and mood stabilizers
Anticonvulsants and chemotherapy drugs
Usually reversible with drug discontinuation

Classification by Severity

Mild SIADH: Sodium 130-135 mEq/L, usually asymptomatic
Moderate SIADH: Sodium 125-129 mEq/L, mild symptoms
Severe SIADH: Sodium <125 mEq/L, significant neurological symptoms
Life-threatening SIADH: Sodium <120 mEq/L, seizures, coma

Symptoms

The symptoms of SIADH are primarily related to hyponatremia and its effects on cellular function, particularly in the brain. Symptoms typically correlate with the severity and rate of sodium decline, with rapid decreases causing more severe manifestations.

Early and Mild Symptoms

Nausea and loss of appetite
Fatigue and weakness
Mild confusion or difficulty concentrating
Headache
Dizziness and lightheadedness
Muscle cramps

Moderate Symptoms

Vomiting
Moderate confusion and disorientation
Increased weakness and fatigue
Unsteady gait and balance problems
Personality changes or irritability
Sleep disturbances

Severe Neurological Symptoms

Severe confusion and altered mental status
Agitation and combativeness
Seizures (focal or generalized)
Coma or decreased level of consciousness
Severe muscle weakness
Respiratory depression

Physical Symptoms

Feeling ill or general malaise
Decreased urine output despite adequate fluid intake
Weight gain without edema
Normal blood pressure (typically)
Absence of signs of dehydration

Neurological Examination Findings

Altered reflexes (hypoactive or hyperactive)
Muscle twitching or fasciculations
Pathological reflexes (Babinski sign)
Cross-eyed appearance or diplopia
Focal neurological deficits
Signs of increased intracranial pressure

Psychiatric Symptoms

Depression or anxiety
Psychosis or hallucinations
Paranoid thoughts
Mood swings
Cognitive impairment
Memory problems

Chronic SIADH Symptoms

Persistent mild fatigue
Subtle cognitive impairment
Increased fall risk in elderly
Reduced quality of life
Osteoporosis (long-term effect)
Attention and memory deficits

Age-Specific Presentations

Elderly Patients

Falls and gait instability
Delirium or acute confusion
Cognitive decline mimicking dementia
Increased risk of complications

Pediatric Patients

Irritability and behavioral changes
Poor feeding or appetite
Altered sleep patterns
Developmental regression

Causes

SIADH can result from various conditions that either increase ADH production from the hypothalamus-pituitary axis or cause ectopic ADH secretion from non-pituitary sources. Understanding the underlying cause is crucial for appropriate treatment.

Malignant Causes

Lung Cancers

Small cell lung cancer: Most common cause, 10-15% incidence
Non-small cell lung cancer: Less common but possible
Mesothelioma: Rare cause
Carcinoid tumors: Bronchial or pulmonary

Other Malignancies

Pancreatic cancer: Especially islet cell tumors
Duodenal carcinoma: Ectopic ADH production
Prostate cancer: Advanced stages
Lymphomas: Hodgkin's and non-Hodgkin's
Leukemia: Various types
Brain tumors: Primary or metastatic

Central Nervous System Causes

Traumatic Causes

Head trauma: Skull fractures, brain contusions
Neurosurgery: Especially pituitary or hypothalamic procedures
Subarachnoid hemorrhage: Aneurysm rupture
Subdural or epidural hematoma: Intracranial bleeding

Infectious Causes

Bacterial meningitis: Various organisms
Viral encephalitis: HSV, CMV, others
Fungal infections: Cryptococcus, histoplasmosis
Brain abscess: Bacterial or fungal
Tuberculosis: CNS involvement

Vascular Causes

Stroke: Ischemic or hemorrhagic
Cerebral thrombosis: Venous or arterial
Vasculitis: Affecting brain vessels
Anterior communicating artery aneurysm: Surgery or rupture

Pulmonary Causes

Infectious Pulmonary Conditions

Bacterial pneumonia: Especially severe cases
Tuberculosis: Pulmonary or miliary
Aspergillosis: Invasive forms
Legionella pneumonia: Particularly common cause

Other Pulmonary Conditions

Positive pressure ventilation: Mechanical ventilation
Acute respiratory failure: Various causes
Cystic fibrosis: With pulmonary complications

Drug-Induced Causes

Psychiatric Medications

Antidepressants: SSRIs, SNRIs, tricyclics, MAOIs
Antipsychotics: Typical and atypical
Mood stabilizers: Carbamazepine, valproic acid
Anxiolytics: Benzodiazepines (rare)

Other Medications

Chemotherapy agents: Cyclophosphamide, vincristine
Anticonvulsants: Carbamazepine, oxcarbazepine
Pain medications: Opioids, NSAIDs
Chlorpropamide: Sulfonylurea diabetes medication
Desmopressin: Synthetic ADH overdose

Endocrine and Metabolic Causes

Hypothyroidism: Severe cases
Adrenal insufficiency: Must be excluded for diagnosis
Acute intermittent porphyria: Rare metabolic disorder

Other Causes

HIV infection: Various mechanisms
Idiopathic SIADH: No identifiable cause
Hereditary SIADH: Rare genetic mutations
Stress: Physical or emotional stress
Exercise: Prolonged intense exercise

Risk Factors

Several factors can increase the likelihood of developing SIADH. Recognizing these risk factors helps healthcare providers maintain appropriate vigilance and implement preventive measures when possible.

Demographic Risk Factors

Advanced age: Increased risk in patients over 65
Hospitalization: Higher incidence in hospitalized patients
Male gender: Slightly higher risk, especially with lung cancers
Smoking history: Associated with lung cancer risk

Medical Conditions

Malignant Conditions

Lung cancer: Especially small cell type
Brain tumors: Primary or metastatic
Hematological malignancies: Lymphoma, leukemia
Other ectopic hormone-producing tumors: Various locations

Neurological Conditions

Previous head trauma: History of brain injury
Stroke history: Cerebrovascular disease
Neurosurgical procedures: Especially pituitary surgery
CNS infections: Meningitis, encephalitis

Pulmonary Conditions

Chronic lung disease: COPD, bronchiectasis
Recurrent pneumonia: Multiple episodes
Tuberculosis: Active or latent
Mechanical ventilation: Positive pressure support

Medication Risk Factors

High-Risk Medications

Selective serotonin reuptake inhibitors (SSRIs): All agents
Tricyclic antidepressants: Especially amitriptyline
Antipsychotics: Both typical and atypical
Carbamazepine: Anticonvulsant with high SIADH risk

Moderate-Risk Medications

Chemotherapy agents: Cyclophosphamide, vincristine
Opioid analgesics: Especially morphine
Proton pump inhibitors: Rare but reported
NSAIDs: Non-steroidal anti-inflammatory drugs

Surgical Risk Factors

Neurosurgery: Especially near hypothalamus or pituitary
Major surgery: Stress response and fluid management
Post-operative pain: Stress and opioid use
General anesthesia: Temporary ADH dysregulation

Environmental and Lifestyle Factors

Polydipsia: Excessive water intake
Endurance exercise: Marathon running, cycling
Heat exposure: Increased fluid intake behavior
Stress: Physical or psychological stress

Genetic Risk Factors

Family history: Rare familial SIADH cases
Cancer predisposition syndromes: Increased malignancy risk
Genetic polymorphisms: Affecting ADH receptor sensitivity

Institutional Risk Factors

ICU admission: Multiple risk factors convergence
Nursing home residents: Multiple medications, comorbidities
Psychiatric facilities: High psychotropic medication use
Oncology units: Cancer and chemotherapy exposure

Diagnosis

Diagnosing SIADH requires meeting specific clinical and laboratory criteria while excluding other causes of hyponatremia. The diagnosis is based on demonstration of inappropriate ADH activity in the setting of hyponatremia.

Diagnostic Criteria for SIADH

Essential Criteria

Hyponatremia: Serum sodium <135 mEq/L
Low plasma osmolality: <275 mOsm/kg H2O
Inappropriately concentrated urine: Urine osmolality >100 mOsm/kg H2O
Elevated urine sodium: >30 mEq/L with normal salt intake
Clinical euvolemia: No evidence of volume depletion or excess

Exclusion Criteria

Normal kidney function: No significant renal impairment
Normal adrenal function: Adequate cortisol response
Normal thyroid function: No severe hypothyroidism
No diuretic use: Within previous weeks
No recent vomiting or diarrhea: No volume loss

Laboratory Testing

Initial Laboratory Panel

Serum electrolytes: Sodium, potassium, chloride, CO2
Serum osmolality: Measured, not calculated
Urine osmolality: Spot or 24-hour collection
Urine sodium: Spot measurement
Blood urea nitrogen and creatinine: Kidney function
Glucose: Rule out hyperglycemia

Hormonal Assessment

Thyroid function tests: TSH, free T4
Cortisol levels: Random or stimulation test
ADH level: Usually not necessary for diagnosis
Plasma renin activity: If volume status unclear

Clinical Assessment

Volume Status Evaluation

Physical examination: Skin turgor, mucous membranes
Orthostatic vital signs: Blood pressure and heart rate changes
Edema assessment: Presence or absence
Weight monitoring: Daily weights if hospitalized

Neurological Assessment

Mental status examination: Cognitive function assessment
Neurological examination: Reflexes, coordination, strength
Glasgow Coma Scale: If altered consciousness
Seizure evaluation: EEG if indicated

Specialized Testing

Water Loading Test

Procedure: Administered water load after overnight fasting
Normal response: >80% water excretion in 4 hours
SIADH response: <40% excretion, concentrated urine
Contraindications: Severe hyponatremia, symptomatic patients

Fluid Restriction Test

Procedure: Restrict fluids to 800-1000 mL/day
Monitoring: Daily weights and electrolytes
Positive response: Gradual sodium normalization
Duration: Usually 3-5 days for response

Imaging Studies

Chest Imaging

Chest X-ray: Screen for lung pathology
CT chest: Detailed lung and mediastinal assessment
PET scan: If malignancy suspected

Brain Imaging

MRI brain: Hypothalamic and pituitary assessment
CT head: Rule out acute pathology
Pituitary MRI: Detailed pituitary evaluation

Differential Diagnosis

Other Causes of Hyponatremia

Volume depletion: Gastrointestinal losses, diuretics
Heart failure: Reduced effective arterial volume
Liver cirrhosis: Portal hypertension and ascites
Kidney disease: Advanced chronic kidney disease
Adrenal insufficiency: Primary or secondary
Hypothyroidism: Severe cases
Psychogenic polydipsia: Excessive water intake
Reset osmostat: Chronic mild hyponatremia

Monitoring During Diagnosis

Frequent electrolyte monitoring: Every 6-12 hours initially
Neurological checks: Regular assessment for deterioration
Fluid balance: Intake and output monitoring
Weight monitoring: Daily measurements
Symptom assessment: Regular evaluation of clinical status

Treatment Options

Treatment of SIADH depends on the severity of hyponatremia, the rate of development, the presence of symptoms, and the underlying cause. The goals are to safely correct the sodium level, treat the underlying condition, and prevent complications.

Emergency Treatment (Severe Symptomatic Hyponatremia)

Immediate Management

Hypertonic saline (3%): 100-150 mL boluses
Target rate: Increase sodium by 1-2 mEq/L per hour initially
Maximum correction: 8 mEq/L in first 24 hours
Monitoring: Electrolytes every 2-4 hours
Neurological assessment: Frequent evaluation

Seizure Management

Antiepileptic drugs: Lorazepam, phenytoin as needed
Airway protection: Consider intubation if altered consciousness
Rapid sodium correction: Target 4-6 mEq/L increase acutely
ICU monitoring: Intensive care setting

Conservative Management

Fluid Restriction

Restriction level: 800-1200 mL/day typically
Monitoring: Daily weights and electrolytes
Success rate: 50-70% of patients respond
Duration: May require weeks to months
Patient education: Importance of compliance

Dietary Modifications

Increased salt intake: 2-3 grams sodium daily
Protein increase: Enhance urea production
Avoid excessive free water: Limit hypotonic fluids

Pharmacological Treatment

Vasopressin Receptor Antagonists (Vaptans)

Tolvaptan (oral): 15-60 mg daily, first-line vaptan
Conivaptan (IV): Loading dose then continuous infusion
Mechanism: Block V2 receptors in kidney
Monitoring: Careful sodium monitoring, risk of overcorrection
Side effects: Thirst, polyuria, hypernatremia

Other Medications

Demeclocycline: 600-1200 mg daily, nephrotoxic
Furosemide with salt tablets: Alternative approach
Lithium: Rarely used due to toxicity
Urea: 30-60 grams daily, poorly tolerated

Treatment of Underlying Causes

Malignancy-Related SIADH

Chemotherapy: Treat underlying cancer
Radiation therapy: For localized tumors
Surgical resection: If feasible
Palliative care: For advanced disease

Drug-Induced SIADH

Medication discontinuation: If clinically appropriate
Dose reduction: Minimum effective dose
Alternative medications: Switch to non-SIADH causing drugs
Monitoring: Gradual improvement over days to weeks

CNS-Related SIADH

Treat underlying condition: Infection, inflammation
Neurosurgical intervention: If mass lesion present
Anti-inflammatory treatment: Corticosteroids if appropriate
Time for healing: May resolve with CNS recovery

Monitoring and Follow-up

Acute Phase Monitoring

Electrolyte checks: Every 4-6 hours initially
Neurological assessment: Hourly if severe
Fluid balance: Strict intake and output
Weight monitoring: Daily measurements

Chronic Management

Regular electrolyte monitoring: Weekly to monthly
Symptom assessment: Quality of life evaluation
Medication adherence: Compliance monitoring
Underlying disease monitoring: Cancer surveillance

Complications Prevention

Osmotic Demyelination Syndrome

Rate limits: Avoid correction >8 mEq/L per 24 hours
Risk factors: Chronic hyponatremia, malnutrition, alcoholism
Early recognition: New neurological symptoms
Treatment: Re-lowering sodium if overcorrection occurs

Other Complications

Dehydration: From overzealous fluid restriction
Hypernatremia: From aggressive treatment
Drug side effects: Monitor for medication toxicity
Fall prevention: Address confusion and weakness

Prevention

While many cases of SIADH cannot be prevented due to underlying medical conditions, several strategies can reduce the risk of developing the syndrome or minimize its severity when it does occur.

Primary Prevention

Medication Management

Careful prescribing: Consider SIADH risk when prescribing high-risk medications
Lowest effective dose: Use minimum necessary medication doses
Alternative selection: Choose medications with lower SIADH risk when possible
Patient education: Inform patients about SIADH symptoms

Cancer Prevention and Early Detection

Smoking cessation: Reduce lung cancer risk
Regular cancer screening: Early detection of high-risk cancers
Genetic counseling: For hereditary cancer syndromes
Healthy lifestyle: Diet, exercise, avoiding carcinogens

Secondary Prevention

High-Risk Patient Monitoring

Baseline electrolytes: Before starting high-risk medications
Regular monitoring: Periodic sodium levels
Symptom awareness: Educate patients and families
Dose optimization: Regular medication reviews

Hospitalized Patients

Admission electrolytes: Baseline laboratory studies
Medication reconciliation: Review all medications
Fluid management: Avoid excessive hypotonic fluids
Daily monitoring: Electrolytes for high-risk patients

Complication Prevention

Preventing Severe Hyponatremia

Early recognition: Prompt identification of mild symptoms
Regular monitoring: For patients with known risk factors
Patient education: When to seek medical attention
Healthcare provider awareness: Recognition of early signs

Fall Prevention in Elderly

Home safety assessment: Remove hazards
Medication review: Minimize CNS-active drugs
Balance training: Physical therapy if needed
Vision and hearing: Regular screening and correction

Institutional Prevention Strategies

Hospital Protocols

SIADH awareness programs: Staff education
Medication alerts: Electronic warnings for high-risk drugs
Laboratory protocols: Automatic reflexive testing
Quality improvement: Monitoring and feedback systems

Nursing Home Prevention

Medication management: Regular pharmacy reviews
Staff training: Recognition of symptoms
Routine monitoring: Periodic electrolyte screening
Communication systems: Prompt medical consultation

Patient and Family Education

Risk Recognition

Symptom awareness: Early warning signs
Medication effects: Understanding drug risks
When to call doctor: Clear guidelines
Medical alert identification: For high-risk patients

Lifestyle Modifications

Fluid intake awareness: Avoid excessive water consumption
Symptom monitoring: Regular self-assessment
Medical follow-up: Regular healthcare visits
Emergency planning: Action plans for symptoms

When to See a Doctor

Call 911 immediately for:

Seizures or convulsions
Loss of consciousness or coma
Severe confusion or inability to respond appropriately
Difficulty breathing or respiratory distress
Severe muscle weakness or paralysis
Persistent vomiting with inability to keep fluids down

Seek urgent medical evaluation for:

Significant confusion or disorientation
Severe headache with nausea and vomiting
Muscle cramps or twitching
Extreme fatigue or weakness
Balance problems or frequent falls
Personality changes or agitation
New onset cross-eyed vision or double vision

Contact healthcare provider promptly for:

Persistent nausea and loss of appetite
Dizziness or lightheadedness
Feeling ill without obvious cause
Muscle aches or cramps
Difficulty concentrating or memory problems
Sleep disturbances or excessive sleepiness
Changes in urination pattern (decreased output)

Schedule routine consultation for:

Starting high-risk medications (antidepressants, anticonvulsants)
Cancer diagnosis or treatment planning
Recent head injury or brain surgery
Lung infection or pneumonia recovery
Family history of SIADH or unexplained hyponatremia

Special Populations:

Elderly patients: Lower threshold for evaluation due to increased risk
Cancer patients: Regular monitoring during treatment
Psychiatric patients: Awareness of medication-related risks
Post-surgical patients: Monitoring in recovery period

Follow-up Care:

Regular monitoring if diagnosed with SIADH
Medication level checks if on chronic treatment
Electrolyte monitoring for high-risk patients
Symptom progression assessment

Related Conditions

Frequently Asked Questions

What is the difference between SIADH and diabetes insipidus?

SIADH involves excessive ADH activity leading to water retention and low sodium levels. Diabetes insipidus involves insufficient ADH activity, leading to excessive urination and potentially high sodium levels. They are essentially opposite conditions affecting the same hormone system.

Can SIADH be cured?

SIADH may be curable if the underlying cause can be eliminated, such as discontinuing a causative medication or successfully treating an underlying cancer. However, some cases may require long-term management, especially when the underlying cause cannot be corrected.

How quickly can SIADH develop?

SIADH can develop over hours to days, depending on the underlying cause. Drug-induced SIADH may develop within days of starting a medication, while malignancy-related SIADH may develop more gradually over weeks to months.

Is it safe to drink water if I have SIADH?

Patients with SIADH typically need fluid restriction as part of their treatment. The amount of safe fluid intake depends on individual circumstances and should be determined by your healthcare provider. Unrestricted water intake can worsen the condition.

Can SIADH cause permanent brain damage?

Severe, rapidly developing hyponatremia from SIADH can cause brain swelling and potentially permanent neurological damage. However, with prompt recognition and appropriate treatment, most patients recover completely. The risk is highest when sodium levels drop very rapidly or reach very low levels.

References

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.
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.
Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013;126(10 Suppl 1):S1-42.
Berl T. Impact of solute intake on urine flow and water excretion. J Am Soc Nephrol. 2008;19(6):1076-8.
Ghali JK, Koren MJ, Taylor JR, et al. Efficacy and safety of oral conivaptan: a V1A/V2 vasopressin receptor antagonist, assessed in a randomized, placebo-controlled trial in patients with euvolemic or hypervolemic hyponatremia. Am J Med Sci. 2006;331(4):182-8.