Syndrome of inappropriate antidiuretic hormone secretion in a patient with pituitary apoplexy

Abstract

Pituitary apoplexy (PA) is an endocrine emergency presenting with headache, visual and hormonal disturbances. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is rare after PA. A 64-year-old woman presented with acute frontal headache and nausea with normal neurological examination. Labs included normal sodium and creatinine. Echo showed new-onset congestive heart failure (CHF) and MRI of the brain revealed PA. She had normal cortisol levels and low thyroid stimulating hormone with normal thyroxine (T₄) levels. During her hospitalisation, patient developed hyponatraemia. Initially, this was attributed to CHF and she was treated with tolvaptan with normalisation of sodium. One week later, she was readmitted with diarrhoea and hyponatraemia. She was euvolaemic on examination indicating compensated CHF. Despite fluid challenge, patient had no improvement of sodium levels. The diagnosis of SIADH was made. Clinicians should suspect SIADH in patients with hyponatraemia in the setting of PA with normal T₄ and cortisol levels.

Background

Pituitary apoplexy (PA) is an endocrine emergency which usually presents with severe headache, visual and hormonal disturbances.¹ Although deficiency of one or more pituitary hormones can be found in PA, adrenocorticotropic hormone (ACTH) and thyroid stimulating hormone (TSH) are crucial for life. In a study with 11-year follow-up, long-term steroid and thyroid hormone replacement were necessary in 58% and 45% of cases, respectively.² Hyponatraemia which is another concerning finding in these patients can be due to hypocortisolism or hypothyroidism.^{3 4} However, syndrome of inappropriate antidiuretic hormone secretion (SIADH) is rarely reported as a result of PA causing hyponatraemia.^5–8

William Schwartz and Frederic Bartter established the clinical criteria for SIADH. Criteria includes serum sodium <135 mmol/L, serum osmolality <275 mmol/kg, urine sodium >40 mmol/L, urine osmolality >100 mmol/kg, the absence of clinical signs of volume depletion, the absence of other causes of hyponatraemia and successful correction of sodium levels with fluid restriction.

Case presentation

A 64-year-old woman with medical history of diabetes mellitus type 2, hypertension, coronary artery disease and no known pituitary adenoma presented with acute-onset frontal headache and nausea. On examination, she was hypertensive with a blood pressure of 166/90 mm Hg and heart rate of 72. She had bilateral crackles over bilateral lower lung fields, did not exhibit lower extremity oedema or abnormality on neurological examination, including intact visual fields.

Investigations

Labs were remarkable for sodium of 135 mmol/L, normal cortisol level, low TSH of 0.08 mcIU/ml with normal thyroxine (T₄) level and elevated brain natriuretic peptide (BNP) level of 856 pg/mL. Echo showed new-onset congestive heart failure (CHF) with ejection fraction (EF) of 35% and CT of the head did not show any evidence of acute intracranial abnormality.

Due to ongoing severe headache and new-onset blurry vision, MRI of the brain was performed. It revealed enlarged pituitary gland measuring 16 mm with evidence of recent haemorrhage (figure 1). Pituitary hormonal work up revealed normal T₄ and cortisol levels (table 1).

Figure 1.

MRI of the brain (figure 1) during hospitalisation demonstrating pituitary gland measuring 16.1 mm in craniocaudal dimension. Signal changes suggest the presence of recent haemorrhage.

Table 1.

This table shows hormone levels on sixth day of hospital admission and at 2-month follow-up. Parenthesis illustrates the normal range

	On day 6 of hospital admission	At 2-month follow-up
IGF-1	212 ng/mL		43–220 ng/mL
LH	1.1 mIU/mL*		(5.2–62.0) mIU/mL
FSH	7.0 mIU/mL*		(26.7–133.4) mIU/mL
Free T4	1.0 ng/dL	0.7 ng/dL	(0.7–1.5) ng/dL
TSH	0.08 mcIU/mL*	0.43 mcIU/mL	(0.40–4.50) mcIU/mL
Prolactin	0.7 ng/mL*		(2.0–20.0) ng/mL
Aldosterone	5.2 ng/dL		(<23.2) ng/dL
Renin	6.5 pg/mL		(3.1–57.1) pg/mL
ACTH	54 pg/mL†	13 pg/mL	(5–46) pg/mL
Cortisol	10.6 mcg/dL	9.3 mcg/dL	(3.7–19.4) mcg/dL
Cortrosyn stimulation test	Baseline: 9.3 At 30 min: 21.7 At 60 min: 26.1		Baseline: (2.9–19.4)

*Below normal range.

†Above normal range.

ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; IGF-1, insulin-like growth factor 1; LH, luteinising hormone; Free T₄, thyroxine; TSH, thyroid stimulating hormone.

During her hospitalisation, on day 5 of admission, patient developed hyponatraemia with a sodium level of 124 mmol/L. Serum osmolality was 275 mOsmol/kg (normal) and urine osmolality was 563 mOsmol/kg (high), with urine sodium <20 mmol/L (low, on spironolactone).

Treatment

On admission, patient was started on intravenous (IV) furosemide treatment. Two days later, diuresis was stopped due to resolved crackles on lung examination and increased creatinine levels. Initially, new-onset hyponatraemia on day 5 was thought to be result of ADH trigger secondary to CHF. Therefore, the patient was treated with one dose of tolvaptan and sodium levels improved. Later, patient was placed on fluid restriction with normalisation of sodium levels up to 135. On day 8 of admission, patient’s sodium level dropped again down to 130 mmol/L (low). Patient was euvolaemic on examination without crackles on lung examination and no lower extremity oedema. Urine osmolality was 739 mOsmol/kg (high) and urine sodium was 111 mmol/L (high, on spironolactone). BNP improved down to 297 pg/mL. Patient was treated with tolvaptan for SIADH and sodium levels normalised before discharge.

However, a week later, the patient was readmitted with diarrhoea and sodium level of 124 mmol/L. The patient was euvolaemic without any crackles on lung exam and no lower extremity oedema on exam. Blood osmolality was 271 mOsmol/kg (low) and urine osmolality was 437 mOsmol/kg (high) with urine sodium 60 mmol/L (high, on spironolactone). BNP was 678 pg/mL (high). Despite fluid challenge, stopping spironolactone and resolving diarrhoea on readmission, patient had no improvement of sodium levels. The diagnosis of SIADH was made and patient was started on salt tablets with furosemide showing improvement of sodium levels.

Outcome and follow-up

Patient followed up with endocrine, nephrology and cardiology on discharge. At 1-month follow-up with nephrology, patient did not have any signs or symptoms of hyponatraemia. She continued to take salt tablets for 3 days after hospital discharge and sodium level was normal at the office visit. Monthly sodium level checks and office visit in 4 months were planned. At 2-month follow-up with endocrine, she did not develop any signs or symptoms of hormonal deficiency, including fatigue and weight change. Thyroid and cortisol levels were normal (table 1). Repeat MRI of the brain showed decreased size of pituitary gland with residual haemorrhage. Residual blood in follow-up imaging limited the assessment of the underlying cause for haemorrhage (figure 2). At 4-month follow-up with cardiology, patient continued to have low EF of 30% on repeat echo and was a candidate for cardiac resynchronisation therapy (CRT-D).

Figure 2.

MRI of the brain (figure 2) at 2-month follow-up demonstrating decreased size of pituitary gland to 8 mm with residual chronic blood products in craniocaudal dimension.

Discussion

PA is defined as sudden haemorrhage into pituitary gland presenting with sudden onset headache, vomiting, altered consciousness, visual abnormalities or even haemodynamic instability.^{1 2 9} Although the risk factors for PA are not well established, male sex, tumour size and tumour type (functional vs non-functional tumour) found to be associated with increased risk for PA.^{10 11} Our patient was a woman who did not have any of the above-mentioned risk factors for PA. She presented with acute-onset headache and nausea. During her admission, ongoing severe headaches and new-onset blurry vision prompted us to get an MRI of the brain despite recent normal CT imaging results. Later, MRI of the brain revealed enlarged pituitary with recent haemorrhage. Since PA is usually sudden onset and has overlapping symptoms with other medical conditions, accurate diagnosis poses a challenge to prevent its life-threatening complications.

Pathophysiology of SIADH in PA is unclear. In a prior report, it was suggested local mechanical stress over pituitary stalk may cause exaggerated release of arginine vasopression (AVP) since the patient had high AVP levels and patient’s hyponatraemia resolved promptly after adenomectomy.⁷ Unfortunately, we do not have any AVP levels to compare with reported values and there were no signs of compression on pituitary stalk on MRI. Nevertheless, our patient developed blurry vision on the second day of admission, which might be a sign of mechanical compression and MRI report mentioned minimal deviation of pituitary stalk to the right. With decreasing size of pituitary gland on follow-up MRI, our patient’s blurry vision resolved by itself and sodium levels remained stable without further interventions. Another suggested mechanism of hyponatraemia in PA is similar to what happens after neurosurgery or brain trauma.⁸ Due to inappropriate release of ADH from posterior pituitary, patients after surgery might have hyponatraemia. Although pituitary surgery may elicit triphasic response with acute hypernatraemia, transient hyponatraemia and subsequent development of central diabetes insipidus, 5.2% of patients only developed transient hyponatraemia within 3–10 days after surgery.¹² Our patient developed hyponatraemia on day 5 of her admission. Although it is unclear when exactly she had PA, recent onset of headache and acute haemorrhage on MRI support similar timeline of hyponatraemia development as neurosurgery patients. Even though she did not presented with any polydipsia or polyuria during follow-up visits to suggest central diabetes insipidus, her repeated sodium levels were consistently at the high end of normal which was not the case prior to her PA (table 2).

Table 2.

This table shows concentration of selected blood and urine samples during hospital admission and at follow-up. Parenthesis illustrates the normal range

	On admission	On day 5	On day 8	On day 14 (readmission)	At 1 month	At 4 months
Serum Cr	0.93 mg/dL	0.91 mg/dL	0.93 mg/dL	0.80 mg/dL	1.01 mg/dL	1.11 mg/dL*	(0.50–1.10) mg/dL
BNP	856 pg/mL*		297 pg/mL*	678 pg/mL*			(0–100) pg/mL
Serum Na+	136 mmol/L	124 mmol/L†	130 mmol/L†	124 mmol/L†	145 mmol/L	144 mmol/L	(135–145) mmol/L
Serum osmolality		275 mOsmol/kg		271 mOsmol/kg†			(275–295) mOsmol/kg
Urine Na+		<20 mmol/L	111 mmol/L	65 mmol/L
Urine osmolality		563 mOsmol/kg	739 mOsmol/kg	437 mOsmol/kg			(50–1200) mOsmol/kg

*Above normal range.

†Below normal range.

BNP, brain natriuretic peptide; Cr, Creatinine; Na⁺, Sodium.

PA might cause visual field defects due to compression of optic chiasm and is found to complicate into meningitis in certain cases.^{13 14} However, in most cases, PA results in partial or complete hypopituitarism. Clinically, cortisol and thyroid hormone deficiencies are more evident at presentation, and are reported in 60% and 57% of patients with PA, respectively.¹⁵ Considering normal free T₄ levels with low TSH and mildly increased ACTH levels with normal morning cortisol and cortrosyn stimulation test, our patient did not have any thyroid or adrenal insufficiency. Additionally, another life-threatening consequence of PA is hyponatraemia. Hyponatraemia can be secondary to hypothyroidism or cortisol insufficiency. Yet, there are cases where SIADH was the aetiology of hyponatraemia in PA.^5–8 Moreover, our patient was found to have new onset heart failure with EF of 35%, further complicating the differential diagnosis of hyponatraemia.

Heart failure associated hyponatraemia is due to increasing AVP (also known as ADH) secretion as a compensatory response to decreasing effective blood volume.¹⁶ It is usually seen in advanced stage of heart failure indicating poor prognosis.¹⁶ Our patient had crackles on pulmonary examination, no lower extremity oedema, high BNP and new onset of low EF of 35% on echo on admission. After 2 days of IV lasix, her pulmonary crackles resolved. On day 5, she developed hyponatraemia in the setting of new onset of heart failure. When the volume status was evaluated, she did not have lower extremity oedema since the admission and she had resolved crackles on lung examination. Despite euvolaemic volume status and improved BNP value, her low urine sodium and borderline serum osmolality (almost hypotonic) lead us toward CHF-related hyponatraemia. Additionally, hyponatraemia improved after one dose of tolvaptan. However, during the subsequent episodes of hyponatraemia, patient was visibly euvolaemic on examination with improved levels of BNP compared with the admission values. Her labs were consistent with the criteria of SIADH (table 2). Moreover, during follow-up visit with cardiology, patient still had low EF requiring CRT-D placement but had resolution of hyponatraemia without further intervention. These findings make CHF-related hyponatraemia unlikely since she did not have obvious volume status change between these visits.

Besides CHF, our patient might have other aetiologies for hyponatraemia in the setting of recent acute-onset diarrhoea and diuretic treatment. There is no clear guidance of how to comment on urine sodium numbers for diagnosis of SIADH if patients are on diuretic treatment. Our patient was euvolaemic at both times with normal T₄ and cortisol levels. If there is a concern for hypovolaemia, it is usually recommended to do fluid challenge. If sodium is not correcting or worsening, it indicates SIADH rather than hypovolaemic hyponatraemia.¹⁷ Some studies recommend checking fractional excretion of uric acid (FE-UA) values and if FE-UA >10%–12%, it indicates SIADH rather than diuretic induced hyponatraemia.^{18 19} Moreover, spironolactone is reported to cause hyponatraemia in combination with other diuretics or at high doses.²⁰ Since her first episode of hyponatraemia, our patient has been only on low dose spironolactone without other diuretics. As noted earlier, she had normal T₄ and cortisol levels. In the view of euvolaemia on examination, no improvement of sodium level after fluid challenge and stopping spironolactone on readmission, it was more consistent with hyponatraemia due to SIADH. Since our patient did not have other possible aetiologies of SIADH, including any known carcinoma, CNS disease other than PA, drugs causing SIADH and recent surgery, it was presumed to be due to PA. Moreover, our patient responded to SIADH treatment appropriately at both times.

In conclusion, clinicians should also suspect SIADH in patients with hyponatraemia in the setting of PA along with more prevalent aetiologies, including central adrenal or thyroid insufficiencies.

Learning points.

• Pituitary apoplexy (PA) is an endocrine emergency which usually presents with severe headache and visual and hormonal disturbances.

• Ongoing severe headache might be the first sign of PA. It should be further investigated with serial neurological examinations and further imaging since patients might have unremarkable neurological examination and normal CT findings at the beginning.

• Multiple hormonal deficiencies or normal hormone levels might be seen with PA. Deficiency of cortisol and thyroid hormone can be life threatening and should be evaluated in every case.

• Although hyponatraemia in PA might be due to cortisol deficiency or hypothyroidism, syndrome of inappropriate antidiuretic hormone secretion should be kept in mind as a cause of hyponatraemia.