ACTA ENDOCRINOLOGICA
88
Charing
(1978)
285-290
Department of Physiology, Hospital Medical School,
Cross
London
INCREASED VASOPRESSIN EXCRETION IN PATIENTS WITH HYPOTHYROIDISM
By A. K. Waters
ABSTRACT
Twenty-four h urinary vasopressin excretion 15 patients with untreated hypothyroidism
was
and
by bioassay in compared with plasma
measured
sodium concentration. Four patients had raised excretion of an antidiuretic substance and in 3 of these patients excretion was reduced after thyroid replacement therapy. The criteria applied supported the view that the antidiuretic substance was arginine vasopressin. Plasma sodium concentration was normal in all these 4 patients. A further 4 patients had hyponatraemia without raised arginine vasopressin excretion. The results suggest that: (1) excess arginine vasopressin secretion is not the cause of the hyponatraemia of hypothyroidism and (2) an increased secretion of arginine vasopressin does occur in some cases of normonatraemic hypothyroidism, the cause requiring further clucidation.
Hyponatraemia has often been reported in patients with severe myxoedema and may be of prognostic significance (Royce 1971) although the incidence in unselected series of hypothyroid patients is unclear. Excess vasopressin secre¬ tion with water retention has been postulated as the mechanism for such hypo¬ natraemia (Senior et al. 1971; Goldberg 8c Reivich 1962; Pettinger et al. 1965; Liechty et al. 1970) though reduced renal function has also been implicated (Derubertis et al. 1971). However, vasopressin levels have never been measured in an unselected group of hypothyroid patients but only in occasional isolated ') Present address: Dr. A. K. Waters,
Leeds,
Department
England. 285
of Medicine, The General
Infirmary,
case
of
reports (Bayard
et
This paper reports the results (AVP) output in a series of 15 unselected untreated hypothyroidism of non-pituitary
al. 1972; Gharib
urinary arginine vasopressin patients with newly-diagnosed origin.
1968).
PATIENTS AND METHODS Fifteen patients (12 post-menopausal females, 1 pre-menopausal female and 2 males) of age range 34 to 72 years (mean 60 years) gave informed consent for the investigation. Normal levels of AVP excretion were assessed in 9 apparently healthy normal subjects of age range 29 to 93 years (mean 41 years). Twenty-four h urine collections were carried out in hospital with trained nursing staff supervision during the second 24 h of a 48 h period of bed rest. Arginine vasopressin (AVP) was extracted from a 100 ml aliquot of each collection by zinc ferrocyanide precipitation with ammoniated-ethanol elution (Noble et al. 1939). Collection and extraction procedures were as detailed by Penn (1967). The extract was assayed against 3rd International Standard for Oxytocic. Vasopressor and Antidiuretic Substances (1957) by the ethanol-anaesthetised rat method °f Jeffers et al. (1942) with minor modifications (Forsling et al. 1968). 95% confidence limits for this assay are ± 20% (Fabian 1970). At least 3 assays in at least 2 assay preparations were performed on each extract. A recovery experiment using iOO mU standard AVP was conducted simultaneously with each sample extraction and the results of assays adjusted accordingly. A series of experiments using between 500 /(U and 100 mU standard AVP added has shown the percentage recovery to remain con¬ stant (unpublished observation). The antidiuretic substance present was characterised as AVP by characteristic response, parallelism of log-dose response curves of 4-point assays and by thioglycollate inactivation (Ames Se Van Dyke 1951; Lee et al. 1964). Hypothyroidism was confirmed by routine laboratory measurements of thyroxine, triiodothyronine and (calculated) free thyroxine. Raised serum thyrotrophin and normal response of plasma cortisol to 250 /eg Synacthen were taken to indicate a non-pituitary origin of the hypothyroid state. Plasma osmolality was recorded on an Advanced 30 Osmometer. Blood volume was measured by standard radio-isotope dilution methods using [1251]albumin and ''chromium-tagged red blood cells.
RESULTS
Plasma sodium, plasma osmolality, 24 h urine AVP output before (15 patients) and after treatment (3 patients) are recorded in Table 1. Under the conditions of the study normal urine output of AVP in the con¬ trol subjects was 6.6 mU/24 h (sd ± 2.1) with a 95 °/o confidence level for the assay of ± 20%. Normal laboratory range of plasma sodium is 137-143 mmol/1. Hyponatraemia was defined as a plasma sodium below 135 mmol/1. Mean blood volume change was -6.2 °/o (sd ± 16%) compared with that predicted from sex, age and weight. Plasma creatinine in all patients was below 124 ^mol/1 and urea below 7.8 mmol/1. Renal function, assessed as creatinine clearance, was reduced (mean 286
o. •*
>
(M
88
Charing
(1978)
285-290
Department of Physiology, Hospital Medical School,
Cross
London
INCREASED VASOPRESSIN EXCRETION IN PATIENTS WITH HYPOTHYROIDISM
By A. K. Waters
ABSTRACT
Twenty-four h urinary vasopressin excretion 15 patients with untreated hypothyroidism
was
and
by bioassay in compared with plasma
measured
sodium concentration. Four patients had raised excretion of an antidiuretic substance and in 3 of these patients excretion was reduced after thyroid replacement therapy. The criteria applied supported the view that the antidiuretic substance was arginine vasopressin. Plasma sodium concentration was normal in all these 4 patients. A further 4 patients had hyponatraemia without raised arginine vasopressin excretion. The results suggest that: (1) excess arginine vasopressin secretion is not the cause of the hyponatraemia of hypothyroidism and (2) an increased secretion of arginine vasopressin does occur in some cases of normonatraemic hypothyroidism, the cause requiring further clucidation.
Hyponatraemia has often been reported in patients with severe myxoedema and may be of prognostic significance (Royce 1971) although the incidence in unselected series of hypothyroid patients is unclear. Excess vasopressin secre¬ tion with water retention has been postulated as the mechanism for such hypo¬ natraemia (Senior et al. 1971; Goldberg 8c Reivich 1962; Pettinger et al. 1965; Liechty et al. 1970) though reduced renal function has also been implicated (Derubertis et al. 1971). However, vasopressin levels have never been measured in an unselected group of hypothyroid patients but only in occasional isolated ') Present address: Dr. A. K. Waters,
Leeds,
Department
England. 285
of Medicine, The General
Infirmary,
case
of
reports (Bayard
et
This paper reports the results (AVP) output in a series of 15 unselected untreated hypothyroidism of non-pituitary
al. 1972; Gharib
urinary arginine vasopressin patients with newly-diagnosed origin.
1968).
PATIENTS AND METHODS Fifteen patients (12 post-menopausal females, 1 pre-menopausal female and 2 males) of age range 34 to 72 years (mean 60 years) gave informed consent for the investigation. Normal levels of AVP excretion were assessed in 9 apparently healthy normal subjects of age range 29 to 93 years (mean 41 years). Twenty-four h urine collections were carried out in hospital with trained nursing staff supervision during the second 24 h of a 48 h period of bed rest. Arginine vasopressin (AVP) was extracted from a 100 ml aliquot of each collection by zinc ferrocyanide precipitation with ammoniated-ethanol elution (Noble et al. 1939). Collection and extraction procedures were as detailed by Penn (1967). The extract was assayed against 3rd International Standard for Oxytocic. Vasopressor and Antidiuretic Substances (1957) by the ethanol-anaesthetised rat method °f Jeffers et al. (1942) with minor modifications (Forsling et al. 1968). 95% confidence limits for this assay are ± 20% (Fabian 1970). At least 3 assays in at least 2 assay preparations were performed on each extract. A recovery experiment using iOO mU standard AVP was conducted simultaneously with each sample extraction and the results of assays adjusted accordingly. A series of experiments using between 500 /(U and 100 mU standard AVP added has shown the percentage recovery to remain con¬ stant (unpublished observation). The antidiuretic substance present was characterised as AVP by characteristic response, parallelism of log-dose response curves of 4-point assays and by thioglycollate inactivation (Ames Se Van Dyke 1951; Lee et al. 1964). Hypothyroidism was confirmed by routine laboratory measurements of thyroxine, triiodothyronine and (calculated) free thyroxine. Raised serum thyrotrophin and normal response of plasma cortisol to 250 /eg Synacthen were taken to indicate a non-pituitary origin of the hypothyroid state. Plasma osmolality was recorded on an Advanced 30 Osmometer. Blood volume was measured by standard radio-isotope dilution methods using [1251]albumin and ''chromium-tagged red blood cells.
RESULTS
Plasma sodium, plasma osmolality, 24 h urine AVP output before (15 patients) and after treatment (3 patients) are recorded in Table 1. Under the conditions of the study normal urine output of AVP in the con¬ trol subjects was 6.6 mU/24 h (sd ± 2.1) with a 95 °/o confidence level for the assay of ± 20%. Normal laboratory range of plasma sodium is 137-143 mmol/1. Hyponatraemia was defined as a plasma sodium below 135 mmol/1. Mean blood volume change was -6.2 °/o (sd ± 16%) compared with that predicted from sex, age and weight. Plasma creatinine in all patients was below 124 ^mol/1 and urea below 7.8 mmol/1. Renal function, assessed as creatinine clearance, was reduced (mean 286
o. •*
>
(M
