Background
The syndrome of inadequate secretion of antidiuretic hormone (ADH) is a common cause
of low sodium levels. There are three major aetiologies: 1. paraneoplastic
conditions with ectopic hormone production, 2. increased production of ADH in the
hypothalamus and secretion into the pituitary gland induced by systemic pathologies
like infections, trauma, medication, pulmonal disease or neurologic pathology and
3.
traumatic injury of the pituitary, e. g., due to neurosurgery. In the case
of the latter, SIADH is often transient and may be followed by a diabetes insipidus
due to the destruction of the posterior pituitary. It is important to exclude other
causes for hyponatremia before the diagnosis of SIADH is made [1 ].
Mechanistically, ADH, also named arginine vasopressin (AVP), is produced in the
hypothalamic nuclei supraopticus and paraventricularis and secreted into blood from
axonal endings in the posterior pituitary. Regulation is made by osmotic and
pressure-receptor. The AVP-receptors V1 and V2 are located in vessels and kidneys
and affects vasoconstriction and water restriction, and thereby, low sodium levels
[1 ]. Disorders of increased ADH
secretion lead to hyponatremia causing unspecific symptoms and neurologic failure.
After diagnosis, sodium level must adjusted carefully because of the risk for
osmotic demyelination syndrome [2 ].
Case-presentation
A 41-year-old male Caucasian presented with persistent abdominal pain since the
previous day at our emergency department of the University Medical Center,
Schleswig-Holstein. He reported some dizziness and an upset stomach. At that time,
the patient had a history of alcohol abuse. He resided in an assisted living
environment and had no history of any regular medication.
He had a medical history of hospitalization due to hyponatremia the month before the
current admission. Then sodium levels normalized after balancing fluid homeostasis.
Two months earlier, he had undergone surgery with colonic resection and ostomy after
colon perforation and peritonitis due to a para-rectal abscess. The procedure was
complicated by septic shock and ventilation therapy at intensive care unit (ICU) was
required.
Clinical examination at the current admission showed a patient with the reduced
general condition and post-surgery malnutrition (weight: 50.5 kg, height:
171 cm, BMI: 17.8 kg/m²). He reported light pressure
pain in the lower abdomen. The neurologic examination was clinically unremarkable.
There was no clinical evidence of infection or trauma at that time.
Investigation
Point of care laboratory testing showed a sodium of 110 mmol/l,
indicating biochemical severe hyponatremia while having clinically moderate
symptoms.
Vital signs were unremarkable (breathing rate: 16/min, temperature: 36.2
°C, heart rate: 64/min, oxygen-saturation: 99%, GCS: 15)
except for a blood-pressure of 160/100 mmHg. Electrocardiogram
showed no abnormalities.
A standard-laboratory workup for differential diagnoses of hyponatremia was done.
Essential criteria for SIADH had been fulfilled: plasma-osmolality was 253
mOsmol/kg indicating hypotonic hyponatremia. Hydration status was assessed
clinically and by ultrasound ruling out hypervolemia. Urine analyses showed
increased urine-sodium (110 mmol/l) and urine-osmolality (389
mOsmol/kg). There was no history of diuretics in medication. Renal function
testing was normal (creatinine: 50 µmol/l). Testing of
thyroid hormones showed a mild reduction of fT3 at the time of admission, most
likely in terms of a low-T3 syndrome (TSH: 3.36 mlU/l, fT3: 3.58
pmol/l, fT4: 14.9 pmol/l). Repeated testing of thyroid hormones
afterwards revealed concentrations within the normal range. Basal cortisol
concentrations were in the normal range with 141 nmol/l.
After the diagnosis of SIADH, a possible aetiology was investigated. There was no
evidence of tumour indicating ectopic production. No malignancies had been found in
computed tomography-scans of the thorax and abdomen. Ultrasound of the testis showed
no lesions or evidence of seminoma. AFP and beta-HCG were in the normal range. There
had been no signs of infection with normal CRP (2.62 mg/l), PCT
(<0.05 µg/l), clinical examination and pulmonary
X-ray.
For differential diagnoses of possible central neurological diseases as a cause of
SIADH, a brain magnetic resonance imaging (MRI) was performed. Of interest, while
common neurological causes of a SIADH could be excluded, a
3 mm×6 mm T2-hyperintense lesion in the posterior pituitary
was found. An experienced neuroradiologist classified this lesion as a micronodular
formulation. Despite this structure, no signal for the posterior pituitary gland was
recognizable ([Fig. 1a, b ]). Further
measurements of pituitary hormones revealed a mildly increased prolactin
(20.6 µg/l [ref.
4.0–15.2 µg/l]) and normal concentrations of insulin
-like growth factor-1 (132.0 µg/L [ref. 58–219]).
Total testosterone (8.3 µg/l [ref. 2.5–8.4]) was
also in the normal range but with increased levels for SHBG (144 nmol/l
[ref. 18.3–54.1]), thereby the free testosterone was calculated to be 203
pmol/l [ref. >243]. Luteinizing hormone (LH) and follicle
stimulating hormone (FSH) were in the normal range (LH: 4.9 U/l [ref.
1.7–8.6], FSH: 6.5 U/l [ref. 1.5–12.4]), thus indicating
mild normogonadotropic hypogonadism.
Fig. 1 Diagram with the timeline. Sodium level and Tolvaptan treatment
during the course of the disease.
Treatment
In ICU, the patient was stabilised by sodium chloride (NaCl) infusions and fluid
management. After slowly elevating sodium levels into the lower normal range, fluid
restriction was recommended for stabilisation of serum NaCl concentrations. However,
sodium levels tended to decrease very rapidly and therefore, Tolvaptan
7.5 mg per day was introduced under close control of electrolytes.
Fortunately, the targeted therapy with a final dose of 15 mg Tolvaptan
resulted in the stabilisation of sodium levels and complete clinical recovery. No
clinical signs of central osmotic demyelination syndrome occurred.
Outcome and follow-up
The patient was discharged from the hospital and scheduled to be followed-up in the
outpatient centre at the Division of Endocrinology, Diabetes and Clinical Nutrition.
Tolvaptan medication was increased to 15 mg per day. No clinical signs of a
transition to central diabetes insipidus (CDI) developed. One month after discharge
from the hospital and sustained sodium serum concentrations, an attempt was made to
reduce Tolvaptan treatment and switch to fluid restriction under regular control by
the primary care physician. However, some days later the patient was readmitted to
hospital with symptomatic hyponatremia (Na: 114 mmol/l) and Tolvaptan
medication was re-initiated followed by normalisation of sodium level.
Over the last two years, the patient showed very poor compliance regarding the
Tolvaptan medication and was admitted to our hospital several times with
hyponatremia following Tolvaptan termination. Each time Tolvaptan therapy was
re-started, sodium levels normalized ([Fig.
2 ]).
Fig. 2 Magnetic resonance imaging (MRI) imaging (10/2019). The MR
study was performed using a 3 T MRI (Phillips Healthcare). Brain MR
imaging shows a bright nodule in the posterior part of the hypophysis in
thin coronal T2-weighted sequences (a , magnification in c ). In
sagittal T1 post-gadolinium-enhanced sequences obtained directly after the
bolus injection, the formation can be identified as a relatively
non-enhancing lesion within an intensely enhancing pituitary gland
(b , magnification in d ).
The follow-up MRI of the pituitary gland showed constant findings ([Fig 1c, d ]).
Following the German guidelines for hormone-inactive microadenoma, the wait and watch
strategy was implemented. With stable disease and good response to therapy, no
neurosurgery was recommended; therefore, no histopathology was achieved. After
significantly improving the compliance by repetitive educational interventions of
the patient and his legal representative, the patient is now adherent and in good
condition.
Discussion
Here, we present a case of SIADH associated with a micronodular structure of the
posterior pituitary with relapsing hyponatremia responding to Tolvaptan therapy. The
workup of hyponatremia and SIADH as a common cause is a frequent clinical problem;
however, the present case suggests a rather uncommon cause giving insights into the
mechanism of SIADH.
There are two important possible mechanisms of SIADH: ectopic secretion vs.
stimulation of hypothalamic ADH-producing cells. In this case, imaging revealed no
malignancy, ruling out ectopic ADH production. An occult malignancy was highly
unlikely due to the long-term follow-up of more than 2 years now. Hence, there was
no sign of chronic (more than 2 years) systemic condition to cause SIADH.
Therefore, the micronodular structure of the posterior pituitary, as a remarkable
finding, might have led to ADH overproduction. There are only a few reports of
hormone-producing adenoma in the posterior pituitary, mostly ACTH-producing, but
none are known to produce ADH [3 ]. Cases
of SIADH due to a macroadenoma of the pituitary and cure after surgery have been
described [3 ]
[4 ]
[5 ]. In addition, a case of SIADH after pituitary apoplexy is also
reported [6 ]. In the absence of
histopathologic or laboratory evidence of hormone production, mechanical stimulus
leading to ADH production is suspected in these cases. The finding of hyponatremia
due to SIADH after hypothalamic surgery also suggests a mechanical stimulus. In the
present case with microadenoma and no compression of the pituitary stalk, a
different mechanism must be suggested. In vitro and in vivo secretion of AVP is
stimulated by different neurotransmitters. The precise pathways and their clinical
significance are not known yet. [7 ]
[8 ] In our patient, a stimulation by
neurotransmitters produced by the adenoma would be conclusive and explain the
clinical presentation. However, the exact mechanism is difficult to approach without
any invasive procedure.
Although being described as a marker for ADH production, we did no test for copeptin
in this clinical case because it is not recommended in clinical guidelines due to
its poor specificity in distinguishing SIADH from other causes of hyponatremia [9 ]
[10 ]
[11 ]. While measuring
copeptin repeatedly in a constant ambulance setting would be scientifically
interesting, we did not perform such testing due to the underlying compliance
problems.
Transition into central diabetes insipidus is often reported subsequent to SIADH in
case of traumatic injury, e. g., due to neurosurgical intervention. In this
case, no diabetes insipidus evolved, most likely due to the constant stimulation by
the microadenoma and the absence of cell destruction as described after surgery or
apoplexy [9 ].
At first admission to our hospital, the patient reported a history of alcohol abuse.
While acute ingestion is associated with ADH suppression, chronic alcohol
consumption can lead to an increase in ADH levels, mirroring SIADH. As a result,
hyponatremia may be present in approximately 17% of subjects with chronic
alcohol-use disorder [12 ]. While we
cannot rule out chronic alcohol abuse as a potentiating factor in the present case,
our patient did not show any withdrawal symptoms at any visit to our hospital and
did also not show other laboratory findings often associated with chronic alcohol
abuse, e. g. no hypertriglyceridemia (0.8 mmol/l [ref.
<2.31]), normal glutamate-oxalacetate transaminase (39.2 U/l [ref.
<50]), normal glutamate-pyruvate transaminase (26.1 U/l [ref.
<50]), normal gamma-glutamyltransferase (GGT) (53 U/l [ref.
<60). In addition, a drug screen was performed four times at the different
admissions during the last 2 years, whereby three times no alcohol was detectable;
only once, in May 2020, we measured 1.67 o/oo. These findings suggest acute
but not chronic alcohol abuse. We favoured GGT as an equal or slightly more
sensitive marker of alcohol abuse than the also described carbohydrate-deficient
transferrin (CDT) [13 ]
[14 ]
[15 ]. Furthermore, CDT is shown to be more specific in ruling out chronic
alcohol consumption, whereas GGT seems to have strength as an indicator for organ
damage, which was our main goal in the reported case [14 ].
Hence, while we do not have a histopathological examination as proof of ADH release
of the microadenoma, from our point of view, it is unlikely that chronic alcohol
abuse is the most likely cause of SIADH in the present case.
One also has to discuss our choice of therapy algorithm chosen: following German
guidelines, “wait and see” is recommended for microadenomas with no
proof of hormone production. Surgery as therapy for macroadenoma is accompanied by
a
risk of pituitary hypothyroidism, adrenal dysfunction and gonadal failure. In
addition, in this case surgery of the posterior pituitary gland most likely might
result in central diabetes insipidus, especially since no normal signal of the
posterior gland was detectable in the MRI. Since no morphological change could be
documented over a time period of 24 months, we therefore decided on a watch-and-wait
strategy and long-term Tolvaptan therapy in the present unique case.
In conclusion, we describe a case of SIADH associated with a micronodular structure
of the posterior pituitary gland suggesting new mechanistic insight into this rare
aetiology of ADH overproduction.
