Syndrome of inappropriate antidiuretic hormone associated with eosinophilic granulomatosis and polyangiitis

Abstract

A 62-year-old man presented with classic signs and symptoms of eosinophilic granulomatosis and polyangiitis (EGPA, also known as Churg-Strauss syndrome)—mononeuritis multiplex, palpable purpura, hypereosinophilia, positive P-ANCA (perinuclear anti-neutrophil cytoplasmic antibodies) developed diffuse alveolar haemorrhage. The patient had longstanding mild hyponatraemia, but developed moderate and symptomatic hyponatraemia characteristic of the syndrome of inappropriate antidiuretic hormone. The patient’s serum sodium returned to his baseline- mildly hyponatraemic, after initiation of treatment targeted towards EGPA.

Background

This case demonstrates how syndrome of inappropriate antidiuretic hormone (SIADH) is not just a disease itself, but can be a heralding sign of a serious pathology. The reason the patient presented to the hospital was not because of the typical eosinophilic granulomatosis and polyangiitis (EGPA) symptoms, but because a serum sodium of 120 meq/L. This was fortuitous as the patient required intubation 6 days later for sudden development of massive haemoptysis with diffuse alveolar haemorrhage. This case is also important because it shows that SIADH can be associated with EGPA.

Case presentation

A 62-year-old man with a medical history of asthma, chronic sinusitis, a rash which would worsen every winter, and mild to moderate hyponatraemia (sodium nadir of 127 meq/L) presented to the emergency department at the behest of his primary care doctor for an abnormal serum sodium level of 120 meq/L. The patient reported generalised weakness as well as in specific body parts. The weakness began in his right lower extremity, resolved, then began in his left lower extremity, and eventually started in both of his upper extremities. It had been worsening since onset. Furthermore, he felt numbness and tingling in both of his feet, more so in to his left foot.

Review of systems was positive for arthralgias and myalgias. Physical examination revealed 3–4 mm papules with haemorrhagic crusts over the torso and upper extremities. There were also a few raised, pink papules on the shins bilaterally. The papules were not lower-extremity predominant; however, they would not blanche on pressure.

Medical history was significant for hypertension, allergic rhinitis and sinusitis his whole life (to cats, dogs, pollen, dust mites, mould, weed and grass, which were treated with 3 years of immunotherapy in the patient’s teens), asthma for 15 years, and a rash which would worsen every winter for 15 years, similar to the current one. Family history was significant for kidney disease and hypertension in the father. Social history was significant for two servings of alcohol daily (cut down from four to five drinks daily 3 months prior) and occasional marijuana use. No cocaine or other drug use. Current medications were montelukast 10 mg once daily, topical triamcinolone 0.1% topically twice daily, olmesartan 40 mg once daily, amlodipine 5 mg once daily, inhaled mometasone furoate-formoterol 100–5 mg two actuations twice daily and inhaled albuterol 108 μg actuations as needed. The patient was not using any diuretics, neither as prescriptions nor occultly, and denied taking any other medications or supplements.

On the sixth day of hospitalisation, the patient developed dyspnea, haemoptysis and hypoxia with diffuse opacities on radiographic imaging. Bronchoscopy visualised diffuse bleeding.

Investigations

At presentation:

• Eosinophils: 8.5×10⁹/L.

• Erythrocyte sedimentation rate 45 mm/h (reference 0–15).

• Urinalysis: small ketones, small blood.

• Urine drug screen: cannabinoids.

• Microscopic urinalysis: 3–5 red blood cells.

• Serum sodium: 123 meq/L.

• Serum osmolality: 259 mOsm/kg H2O (reference 280–295).

• Urine sodium: 18 meq/L at 02:00.

• Urine osmolality: 189 mOsm/kg H2O (reference 250–1,200) at 13:00.

• Serum creatinine, blood urea nitrogen and thyroid function were unremarkable.

The patient was presumed to be hypovolaemic and was hydrated with 0.9% sodium chloride. The serum sodium initially improved to 128, but then started to worsen again to 126. With further 0.9% saline, the serum sodium worsened again to 123. Studies were repeated.

Three days after presentation:

• Serum sodium: 123 meq/L.

• Urine sodium: 98 meq/L.

• Urine osmolality: 513 mOsm/kg H2O.

The patient is started on fluid restriction and urea.

Seventeen days after presentation:

• Serum sodium: 133.

• Urine sodium: 162.

• Urine osmolality: 773.

Treatment

The patient received nebulised tranexamic acid through the endotracheal tube, plasmapheresis every other day for 14 days, and steroids. Subsequently, the patient was continued on steroids and administered rituximab. All told, the patient was intubated for 9 days. He was transfused of two units of packed red blood cells.

Outcome and follow-up

The patient’s condition improved markedly. The clinical course was complicated by mediastinal emphysema from barotrauma, however it did not require any operative treatment.

After 22 days, the patient was discharged to inpatient rehabilitation because of significant remaining weakness. Twenty-five days after admission, the patient’s serum sodium returned to his usual baseline mild hyponatraemia of 133 meq/L.

Discussion

The patient had mild hyponatraemia not requiring any treatment for a few years (it may have been related to being on olmesartan, an angiotensin receptor blocker, as these medicines often affect serum sodium by modulating the renin-angiotensin-aldosterone system) but then his serum sodium inexplicably decreased to 120 meq/L (with proven hypoosmolarity ruling out pseudohyponatraemia) along with constitutional symptoms. After the patient was ensured to be volume repleted, he continued to be hyponatraemic despite isotonic 0.9% saline and in fact the serum sodium decreased. This is characteristic of syndrome of inappropriate diuretic hormone.

This patient received enteral urea for treatment. Urea has been tested in both long-term SIADH lasting greater than a year¹ as well as acute SIADH.² High doses such as 30 g/day can even allow treatment of SIADH without fluid restriction.³ However, the patient’s condition, along with hyponatraemia, most significantly improved with corticosteroids and especially after plasmapheresis/rituximab targeted towards the EGPA.

SIADH can be associated with a large number of underlying pathologies, with central nervous system disturbances, malignancies and drugs being the most common etiologies.⁴ However, we were able to find only three cases of SIADH documented occurring in association with EGPA, all in Japan.^5–7 Our patient was Caucasian.

Learning points.

• This case is interesting because the syndrome of inappropriate antidiuretic hormone (SIADH) was associated with eosinophilic granulomatosis and polyangiitis (EGPA). SIADH is characterised by hypotonic hyponatraemia (with corresponding hypoosmolality) in the euvolemic setting, renal excretion of sodium inappropriately elevated (usually above 20 meq/L) and a urine osmolality of above 100 (the urine is less than maximally dilute). There should be absence of clinical evidence of volume depletion as well as absence of other causes of hyponatraemia such as adrenal insufficiency (mineralocorticoid deficiency, glucocorticoid deficiency), hypothyroidism, pituitary insufficiency, renal disease with salt wastage, or drugs that impair renal water excretion.

• SIADH is a diagnosis of exclusion (impaired renal and endocrine function must both be excluded prior to diagnosis)

• The mainstay of treatment of SIADH with chronic (>48 hours) hyponatraemia is fluid restriction. A next tier of treatment is the addition of salt tablets and loop diuretics (note that thiazide diuretics typically lower serum sodium, while loop diuretics typically raise serum sodium). A further tier of treatment is a vasopressin receptor antagonist such as a vaptan, demeclocycline (a tetracycline antibiotic), or lithium (not much in use in clinical practice). There is emerging data on oral urea in the treatment of SIADH. Vaptans are not used as first-line treatments because they are very expensive and can have adverse effects, such as liver toxicity.

• SIADH often occurs secondary to central nervous system disturbances, malignancies (particularly small cell lung cancer, 10% of which causes SIADH), and a variety of drugs. However, it can also occur associated with other pathologies, such as demonstrated in this case. It is not known how SIADH could be caused by EGPA, but it may have to do with inflammation affecting the hypothalamus.