Original case by Óscar Aramburu-Bodas et al 

A 67-year-old woman was hospitalized with a 2-month history of asthenia without weight loss, neurologic, or respiratory symptoms. Her medical history included hypertension. Her medications at admission were enalapril and lorazepam. The physical examination revealed the patient to be alert, clinically euvolemic, and with a blood pressure of 147/90 mm Hg.
Laboratory tests showed a serum sodium (SNa) level of 112 mmol/L; low plasma osmolality (POSM), 250 mOsm/kg; high urine osmolality (UOSM), 562 mOsm/kg; and urine sodium (UNa) level of 88 mmol/L. Potassium was 4.9 mmol/L; urea, 12 mg/dL; creatinine, 0.4 mg/dL; and glucose, 95 mg/dL.
Q. What is your interpretation of these reports ?
Since the patient is euvolemic my differentials for the hyponatremia would be
2. Adrenal insufficiency
3. Hypothyroidism
Q. What are the criteria for SIADH ?

1. Serum osmolality <280 mom/kg
2. Urinary osmolality >100 mom/kg
3. Urinary sodium > 30 meq/l
4. Clinically euvolemic
5. Hypothyroidism and Adrenal insufficiency have been ruled out
Q. What would be your approach to treating hyponatremia in this case ?
This is based in European society of endocrinology protocol
1. 3% NaCl @75-100 ml/hr
2. Recheck Sodium after 4 hrs. If Serum sodium raise by 4 meq/l – I would go to next step else continue the 3% NaCl and recheck every 4 hours. Sodium should not raise by >10 meq/l in 24 hrs
3. Next I would search for the cause of SIADH
4. I would advice free fluid restriction additionally
5. Furosemide may be added if urine osmolality remains > 500 mom/kg

Upon admission, uric acid was 2.1 mg/dL; cortisol, 12.2 μg/dL; and thyroid-stimulating hormone, 2.28 mU/L. Tumor markers were within reference range. A computed tomography (CT) scan of the brain, chest, and abdomen revealed small nodes located in the mediastinum as the only finding.

Q. Can Adrenal insufficiency be ruled out with this baseline cortisol ?

Yes. Some guidelines suggest cortisol >10.8 ug/dl generally rules out adrenal insufficiency.

During hospitalization, enalapril was replaced with amlodipine, since angiotensin-converting enzyme (ACE) inhibitors are a potential cause of SIADH. The patient began with fluid restriction. Despite severe hyponatremia and a Furst formula of 1.09, there was only slight improvement in sodium level (from 112 to 126 mmol/L), but the symptoms disappeared. The patient was discharged with the recommendation to limit fluid intake and referred for outpatient follow-up.

Read : ACEI leading to SIADH (

Q. What is Furst formula ?
Furst formula gives the estimate of how much free fluid is lost and helps estimate the degree of free water restriction to be prescribed.
The formula is in a spot sample of urine – Urine Na + Urine K / Plasma Na
If the interpretation is as follows:
1. Value > 1.0- patient is not excreting any free water- advised 0 litre of free fluid
2. Value 0.5-1.0 – 500 ml of free fluid allowed
3. <0.5- good free fluid excretion- upto 1 litre of free fluid allowed
Q. What can explain the improvement in Sodium ?

Probably because of stopping of ACEI which can cause SIADH

Chest CT scan and laboratory tests were repeated 6 months later. CT revealed nonspecific mediastinal lymph nodes only (similar to the previous scan). New blood tests were within normal range, except for a SNa of 127 mmol/L and POSM of 250 mOsm/kg. Uric acid was 2.3 mg/dL. The patient remained asymptomatic. After a 2-year follow-up, she presented with marked weakness. Physical examination was normal. A chest X-ray was similar to the previous one. She was therefore prescribed tolvaptan 15 mg/day, and the dose was progressively increased to 60 mg daily. SNa rose to 136 mmol/L, with an excellent tolerance and clinical response. The evolution of laboratory variables is showed in Table 1.
One year after tolvaptan was initiated, she complained of progressive asthenia once more. SNa was 115 mmol/L despite receiving tolvaptan at the maximum recommended dose, and without changes in dietary habits, fluid intake, or medication. The patient was admitted to the hospital for further evaluation. The patient was euvolemic. Hypothyroidism and adrenal insufficiency were ruled out. Renal function, potassium, and tumor markers were normal. UNa was 109 mmol/L; urine potassium, 26 mmol/L; POSM, 249 mOsm/kg; and UOSM, 410 mOsm/kg. The diagnosis was made of SIADH of unknown origin resistant to tolvaptan treatment. A chest X-ray revealed that the mediastinum was slightly widened. A chest CT scan (Fig. 1) showed an anterosuperior mediastinal mass located in thymus gland. Plasma AVP concentration was determined, revealing extremely high levels (63.5 pg/mL; normal, <7.6 pg/mL).
The patient was treated with continuous 3% hypertonic saline (27 mL/hour) and the maximum dose of tolvaptan, which resulted in a marked improvement in SNa, although hyponatremia persisted throughout the hospitalization. She was discharged 10 days after admission, asymptomatic, with sodium levels of 130 mmol/L and was referred to thoracic surgery. Before surgery, she continued treatment with 60 mg of tolvaptan and sodium supplements daily (a salt diet with approximately 10 g of sodium). The patient underwent video thoracoscopy with total thymectomy.
Macroscopically, the tumor measured 7.2 × 6 × 4 cm. It was encapsulated, showing a heterogeneous cut surface with areas of necrosis, hemorrhage, and punctate calcifications. Microscopically, it consisted of a diffuse growth of small uniform cells with hyperchromatic nuclei, arranged in an eosinophilic fibrillar matrix consistent with a neuropil and vascular pattern. Immunohistochemical analysis was performed using the Ventana Benchmark System (Roche Laboratories, Basel, Switzerland) on formalin-fixed paraffin-embedded tissue sections cut to a thickness of 4 μm. The following antibodies were used: chromogranin A, synaptophysin, neuronal-specific enolase, CD56, S100 protein (prediluted, Roche Labs), and AVP (1:100, Merck-Millipore, Billerica, MA). AVP was positive in neuropil and cytoplasms of neuroblasts. Molecular analysis revealed no amplification of N-Myc and c-Myc.
SNa levels (140 mmol/L), blood osmolality, and plasma AVP concentration (<1.2 pg/mL) completely normalized 2 weeks after tumor removal. The treatment with tolvaptan was withdrawn

Q. What is the importance of measuring plasma AVP levels ?

Plasma AVP levels help determine etiology of SIADH. Very high AVP levels are generally seen in patients with cancer causing SIADH as in this case. Also in cancer patients it can be help to monitor response to therapy

Q. What is the side effect with chronic tolvaptan therapy ?
It can cause liver enzyme elevation and potential liver failure

Q. What are the two trials which have studied Tolvaptan use ?
1. EVEREST trial for heart failure
2. SALTWATER trial

Learning points from this case
1. Measurement of AVP may be useful to define etiology in patient with SIADH
2. Tolvaptan may be ineffective in patients with SIADH with very high AVP levels due to cancer.


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