Plasma arginine vasopressin in the syndrome of antidiuretic hormone excess associated with bronchogenic carcinoma

Plasma Arginine Vasopressin in the Syndrome of Antidiuretic Hormone Excess Associated with Bronchogenic Carcinoma

PAUL L. PADFIELD, M.R.C.P. JAMES J. MORTON, Ph.D. JEHOIADA J. BROWN, F.R.C.P. ANTHONY

F. LEVER, F.R.C.P.

J. IAN S. ROBERTSON, MARTIN WOOD,

F.R.C.P.

M.R.C.P.

RUTH FOX, M.R.C.P. Glasgow, Scotland

From the M.R.C. Blood Pressure Unit, Western Infirmary,Glasgow, G116NT Scotland. Requests for reDrimsshould be addressedto Dr. Paul L. Padfield. Manuscript accepted March 3, 1976.

A study of plasma arginine vasopressin in 17 patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) associated with bronchogenic carcinoma, revealed that the arginlne vasopressin levels were distinctly elevated in most. In 14 patients with bronchogenic carcinoma, but without overt SIADH, plasma levels of arginine vasopressin were significantly higher than in normal subjects (p
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I

TABLE

IN SIADH-PADFIELD

ET AL

Patients with Overt SIADH

Age (vr) and Sex

CaseNo.

45.M 68.F 53,M 60.M 49,F 60,M 63.M 45,M 50,F 55.M 46.M 62,F 53,M 49.M 69.F 69.M 44.M

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

55 + 2

Mean + SEM

Serum Sodium (mmol/liter)

Plasma Osmolality (mosmol/kg)

123 118 106 121 118 120 123 117 118 121 137 134 118 123 120 126 120

262 242 218 236 263 248 268 250 248 258 297 304 250 264 247 270 252

121 f 1.6

Urine Osmolality (mosmollkg)

147 18 643 12 18 13 6.5 16.5 32 51 30 87 56 44 21 8 170

788 684 638 537 641 737 489 667 512 617 623 510 733 499 407 739

257 + 5

614?

Plasma Arginine Vasopressin (pg/ml)

28

Tumor Histology Oat cell Oat cell Oat cell Oat ceil Oat cell Unknown Unknown Oat cell Oat cell Unknown Squamous Anaplastic Oat cell Oat cell Oat cell Unknown Oat cell

cell

81 * 37

NOTE: Two patients (Cases 11 and 12) were studied while deprived of fluid; presenting serum sodium values were 128 and 118 mmol/ liter, respectively. Plasma vasopressin in Cases 9 and 10 was measured by the method of Beardwall [37].

had normal serum sodium concentrations (139 f 0.9 mmol/iiter) and were studied for comparison (Table II). Control measurements were made in a further 34 subjects (18 inpatients with psoriasis and 18 healthy volunteers). In six patients with bronchogenic carcinoma, histologic proof of the diagnosis was not obtained. Case 6. This patient presented with the Eaton Lambert (myasthenic) syndrome, and roentgenologic evidence of a right main stem bronchial lesion and lymphangitis carcinomatosis developed three months later. Case 7. This patient presented in extremis with finger clubbing, a grossly enlarged uneven liver and a large opacity in the right upper zone on chest film; he died after four days.

We report here the results obtained in patients with bronchogenic carcinoma studied under standardized conditions, using a recently developed radioimmunoassay for measuring plasma arginine vasopressin

[61. PATIENTS AND METHODS Thirty-one patients (24 male) with a diagnosis of bronchogenic carcinoma were studied; 17 of these were referred because of distinct hyponatremia of less than 125 mmoiliiter [ 12 1 f 1.8 mmol/liter; mean f standard error of the mean (SEM)]; each of these had plasma and urine osmolality relationships suggestive of SIADH (Table I). The remaining 14

TABLE

II

Patients Without

CaseNo. 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Mean + SEM

826

December

Age (yr) and Sex 62,M 56.M 61,M 69,M 54,F 58,M 39,M 80.M 57,M 61.M 65,F 64.M 70.M 77,M

Serum Sodium (mmol/liter) 137 140 141 137 135 141 138 137 139 141 145 141 137 139

62 t 3

1976

Overt SIADH

139 * 0.9

Plasma Osmolality (mosmol/kg)

Urine Osmolality (mosmol/kg)

290 279 294 279 277 285

409 845 787 596 678 416

278 288 288 276 296 284 285

565 579 721 652 908 796 867

285 * 2

678 f. 45

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Plasma Arginine Vasopressin (pg/ml) 5.7 8.6 4.0 5.0 7.0 10.0 7.0 7.5 11.4 8.5 12.5 15.0 10.5 9.0 8.7 f 0.8

Tumor Histology Unknown Anaplastic Anaplastic Oat cell Anaplastic Oat cell Anaplastic Anaplastic Squamous cell Squamous cell Oat cell Unknown Anaplastic Squamous cell

PLASMA

IN SIADH-PADFIELD

ET AL.

1,000 -

Case 10. This patient had a lesion on a chest film of the left main bronchus which, on bronchoscopy, looked malignant. Tissue damaged during fixation. Case 16. This patient had finger clubbing, a markedly enlarged liver with roentgenologic evidence of a lesion of the right main stem bronchus and osteolytic lesions in the ribs. Cases 16 and 29. Both of these patients had roentgenologic evidence of a bronchogenic neoplasm with bony secondaries. All patients and normal subjects were studied between 800 and 1000 hours, in the supine position, after food and fluid deprivation from 2200 the night before. Peripheral venous blood was obtained for measurement of plasma arginine vasopressin, osmolality, urea and electrolytes. All subjects passed urine 1 hour before and immediately after venepuncture; osmolality was measured in the second specimen (Advanced Osmometer). Nine patients (Cases 1-9, Table I) were studied again after a period of fluid restriction (12 f two days, range four to 24 days: 450 to 750 ml/24 hours). One patient (Case 2, Table I) was reinvestigated after a further nine days during which free access to fluid was allowed. In two patients (Cases 8 and 9, Table I) plasma volume [7] was measured before and after

ARGININE VASOPRESSIN

. 500PLASMAAVP Pq/mt

:

10 -

i q

5-

I

.. .

* =. .

L

I

I

NORMAL CONTROLS

fluid deprivation.

SlAbH

CONTROL Co BRONCHUS Ca BRONCHUS

Figure 1. Comparison of plasma arginine vasopressin (A VP) between groups. Means and standard errors indicated.

RESULTS In the 34 subjects without bronchogenic carcinoma, plasma osmolality was 295 f 0.9 mosmol/kg (range 287 to 306 mosmol/kg), urine osmolality 693 f 38 mosmol/kg (range 348 to 1,060 mosmol/kg) and plasma arginine vasopressin 6.1 f 0.3 pg/ml (range 3.5 to 11.9 pg/ml). In patients with SIADH, plasma osmolality was significantly lower (p
if300

-

r(Posu 218) 500PLASMAAVP w/ml

A

100A

50-

A A A A 10 -

A A

5-

1

L

235

245 255 265 275 285 PLASMAOSMOL.mormols/kq

295

305

Figure 2. Relationship between plasma arginine vasopressin (A VP) and plasma osmolality. A = bronchogenic carcinoma (S/ADHJ. A = bronchogenic carcinoma (SIADH) - fluid deprived when studied. i- = bronchogenic carciMNna (without overt SIADH). 0 = normal control subjects.

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change in one patient and a decrease in one other (Figure 3). Changes in plasma arginine vasopressin ranged from -25 per cent to i-400 per cent with an average increase of 86 per cent. There was a close positive correlation between the absolute changes in plasma arginine vasopressin and plasma osmolality (r = +0.8, p
PLASMA AVP

.A’

pq/m’ 100

COMMENTS

5 Basal

Dehydration

Rehydratlon

Figure 3. Plasma arginine vasopressin (A VP) in nine patients studied before and during fluid deprivation, with one patient studied again after rehydration.

vasopressin and plasma osmolality (r = -0.5, p
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Since the first demonstration of antidiuretic activity in the oat cell tumor of a patient with bronchogenic carcinoma and SIADH [8], some 50 patients have been described in whom measurements of ADH either in tumor cells, plasma or urine have been made (Table Ill). ADH-like activity is usually present in the tumors of patients with SIADH, although there are exceptions [9]. Plasma ADH levels are generally high (Table Ill). Arginine Vasopressin Levels in SIADH. Our data provide further evidence that most patients with SIADH associated with bronchogenic carcinoma do have markedly increased circulating levels of arginine vasopressin. The finding of normal, although inappropriately high, plasma or urinary ‘levels of arginine vasopressin in patients with distinct hyponatremia has also been described previously [lo-l 21 and suggests that these tumors may vary in their ability to secrete ADH. As reported here, significantly high plasma levels of arginine vasopressin also occur in patients with bronchogenic carcinoma without overt SIADH. This increase in arginine vasopressin might have been explained if the patients, by virtue of their illness, were more depleted of water than normal subjects. The observation of a significantly lower than normal plasma osmolality provides strong evidence against this possibility and therefore suggests that many of these patients also have SIADH, albeit subclinical. It is thus possible that many or all bronchogenic carcinomas might be capable of secreting arginine vasopressin, and the finding of a distinctly elevated plasma level associated with SIADH in a patient with a definite squamous cell lesion (Case 11, Table I) shows that the syndrome is not confined to patients with oat cell tumors. It has been shown that, in vitro, not only tumor cells from patients with SIADH but also tumor cells from patients without the syndrome are capable of forming antidiuretic material [ 131. This raises the possibility, therefore, that measurement of plasma arginine vasopressin may be helpful in the early diagnosis of bronchogenic carcinoma. It is not known for certain that ADH measured in patients with SIADH is the same as the naturally occurring hormone (arginine vasopressin), although there is evidence that it is either this or a chemically and biologically very similar compound [ 13-171. Our radioim-

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PLASMA ARGININE VASOPRESSIN

TABLE

III

Literature

Survey

of Antidiuretic

Activity

in SIADH

No. of Reference

Source

Amatruda et al. [81 Bower et al. [31 I

Lee et al. [321

De Sousa et al. I331 Utiger

1341

Barraclough

et al:

r351 Sawyer Cl71 Vorherr et al. [9]

Lipscomb et al.

[IS]

Marks et al. [361 Segar,

Moore

Beardwell

[231

[37]

George et al. [ 141 Baumann et al. [lOI Miller, Moses [l 11 Skowsky et al. [ 121 Present study NOTE: *For

Plasma Primary tumor Secondary tumor Plasma Urine Tumor Urine Tumor Tumor Plasma Tumor Tumor Tumor

Tumor Plasma Tumor (Pancreas) Tumor Plasma Plasma

Tumor Plasma Urine Plasma Plasma

BIO = bioassay. RIA

conversion

Assay

Cases

BIO BIO

1 1

BIO

1

BIO

2

RIA

1

BIO

6

BIO BIO RIA

5 10

BIO

1

BIO RIA

1

BIO RIA

1 4

RIA RIA RIA RIA RIA

1 4 5 6 I7

Associated

with

IN SIADH-PADFIELD

Bronchogenic

Amount of Antidiuretic Activity* 70-350 uU/mg dry weight 3.0-8.0 uU/ml 0.1-1.0 $J/mg dry weight 6.0-8.0 pU/mg dry weight 1.7 MU/ml 100 mu/24 hours 10 pU/mg dry weight 1.8 U/24 hours 7.0 mU/mg dry weight 142 pUlmg wet weight 2.6-16 pU/ml 4-75 pU/mg dry weight 20-150 @U/mg dry weight 130-763 uU/mg dry weight

0.2 mU/mg dry weight 80 pU/ml 0.29 f 0.03 U/mg.dry weight 0.38 U/mg dry weight 525 pU/mg dry weight 12.5 &U/ml 24-l 02 pg/ml

23.5 pU/mg wet weight 5.1-31 &/ml 1-316 mu/24 hours 11-242 uU/ml 6.5-643 pg/ml

ET AL.

Carcinoma Comments

Nil detected in other tissues No activity detected in plasma of normally hydrated controls Nil in normally hydrated controls; normal <15 mu/24 hours; tumor weight-143 g

Normal pituitary 8-l 1 Ulmg wet weight Nil in normally hydrated controls; nil detected in one necrotic tumor

. Activity detected in only 5 of 10 tumors; normal pituitary 85 + 15 mU/mg dry weight

Normal

subjects
Normal range l-4.3 pg/ml; uncorrected for recovery (46 f 8 per cent) Normal Normal Normal Normal

range range range range

2-12 pU/ml 12-108 mu/24 4-l 1.5 pU/ml 3.5-12 pglml

hours

= radioimmunoassay.

1 plJ of arginine vasopression

= 2.5 pg of standard

munologic results support this, although in the one patient whose plasma extract had a low cross reaction with the standard arginine vasopressin it is possible that there existed an antidiuretic substance chemically dissimilar from the usual human form of ADH. Reversed Relation of Plasma Arginine Vasopressin and Osmolality. In normal subjects, studied over a wide range of water intake, there is a significant positive correlation between plasma osmolality and arginine vasopressin concentration (r = i-0.67, p
[181Taking all patients with bronchogenic carcinoma together, however, the correlation reverses and becomes significantly negative (r = -0.5, p
arginine vasopressin.

of arginine vasopressin to concentrate urine and therefore, presumably, to retain water reaches a maximum at plasma levels below 15 pg/ml (Padfield, unpublished observations). This suggests that the linearity of the negative correlation between plasma osmolality and arginine vasopressin might not persist at higher concentrations of arginine vasopressin. An alternative explanation for the reversed relationship is that arginine vasopressin stimulates fluid intake and that this, together with increased urine concentration, produces the hypo-osmolar plasma. This seems unlikely as there is no good evidence of a direct dipsogenic effect of arginine vasopressin either in man [ 191 or in animals [20-221. A patient with SIADH and bronchogenic carcinoma has been described, however, who had inappropriate thirst [23]. None of the patients we describe in this paper complained to us of thirst at any stage in their illness. Control of Plasma Arginine Vasopressin in SIADH. There is good evidence that the bronchogenic carcinoma associated with StADH secretes ADH [ 13,141, and it is generally accepted that the secretion is autonomous [24]. However, in a study including four pa-

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tients with SIADH and bronchogenic carcinoma, plasma levels were found to be, at least in part, responsive to maneuvers which alter arginine vasopressin release in normal man [lo]. Only one subject had a distinctly elevated basal arginine vasopressin level (31 pU/ml) which rose markedly after the administration of nicotine (> 118 pU/ml). It cannot be concluded, however, that the arginine vasopressin was increased by the tumor rather than the pituitary gland. We have shown that in seven of nine patients studied, even initially very high plasma levels of arginine vasopressin can be increased still further by a period of fluid restriction involving a marked increase in plasma osmolality. This increase in arginine vasopressin is also generally accompanied by an increase in urine osmolality. The possibility that, during the period of dehydration, the underlying carcinoma enlarges and secretes more ADH is unlikely in view of the observation in one patient in whom arginine vasopressin levels fell again following free access to fluid. The decrease in plasma volume seen in two patients is not of sufficient magnitude to explain the increase in arginine vasopressin purely on the basis of hemoconcentration, although it may be partly responsible. It is, thus, possible that secretion of arginine vasopressin by tumors is not strictly autonomous but that it is, at least in part, responsive to physiologic maneuvers. However, it is known that the glomerular filtration rate is increased in patients with SIADH [25-281 and that this increase is corrected by fluid deprivation [26] _

As arginine vasopressin is removed from the circulation, mainly by the kidney [29,30], it is possible that, given a fixed rate of secretion of arginine vasopressin, a lowering of the glomerular filtration rate would raise the plasma level. Although the glomerular filtration rate was not measured in our patients, the striking increase in blood urea following fluid deprivation is probably a reflection of a decrease in the glomerular filtration rate. Without data on the metabolic clearance of arginine vasopressin, therefore, we are unable to be sure that an elevated plasma level reflects increased secretion. The appearance of overt SIADH in patients with bronchogenic carcinoma appears to herald a terminal stage in the illness, as in the 15 patients in whom details are available the mean survival time from the recognition of hyponatremia was only 16 weeks (range one to 40 weeks). In two patients the development of SIADH preceded the appearance of roentgenologic changes of the underlying bronchogenic carcinoma by three months. In conclusion, we have shown that, under conditions least likely to pick up a difference (mild dehydration), not only do patients with SIADH have excess circulating levels of arginine vasopressin but also that patients with bronchogenic carcinoma without overt SIADH tend to have relatively high levels. The possibility that such differences from normal would be accentuated by forced hydration is currently being investigated.

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Winkler AW, Crankshaw OF: Chloride depletion in conditions other than Addison’s disease. J Clin Invest 17: 1, 1938. Schwartz WB, Bennet W, Curelop S, Bartter FC: A syndrome of renal sodium loss and hyponatraemia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med 23: 529, 1957. Barber FC, Schwartz WB: The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 42: 790, 1967. Leaf A, Bartter FC, Santos RF, et al.: Evidence in man that urinary electrolyte loss induced by pitressin is a function of water retention. J Clin Invest 32: 868, 1953. Azzopardi JG. Freeman E, Poole G: Endocrine and metabolic disorders in bronchial carcinoma. Br Med J 4: 528, 1970. Morton JJ, Padfield PL, Forsling ML: A radioimmunoassay for plasma arginine vasopressin in man and dog. Application to physiological and pathological states. J Endocr 65: 411, 1975. Anderson SB: Simultaneous determination of plasma volume with 13’1labelled gamma-globulin, 13’1labelled albumin and T-1824. Clin Sci 23: 221. 1962. Amatruda TT, Mulrow PJ, Gallacher JC, et al.: Carcinoma of the lung with inappropriate antidiuresis. Demonstration of antidiuretic hormone-like activity in tumour extract. N Engl J Med 269: 544, 1963. Vorherr t-i, Massry SG, Utiger RD, et al.: Antidiuretic principle in malignant tumour extracts from patients with inappropriate ADH syndrome. J Clin Endocrinol 28: 162, 1968. Baumann G, Lopez-Amor E, Dingman JF: Plasma arginine

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vasopressin in the syndrome of inappropriate antidiuretic hormone secretion. Am J Med 52: 19, 1972. Miller M. Moses AM: Urinary antidiuretic hormone in polyuric disorders and in inappropriate ADH syndrome. Ann Intern Med 77: 715. 1972. Skowsky WR, Rosenbloom AA, Fisher DA: Radioimmunoassay measurement of arginine vasopressin in serum. Development and application. J Clin Endocrinol 38: 278, 1974. Vorherr H, Vorherr UF, McConnell TS, et al.: Localisation and origin of antidiuretic principle in para-sndocrine active malignant tumours. Oncology (Basel) 29: 201, 1974. George JM, Capen CC, Phillips AS: Biosynthesis of vasopressin in vtiro and ultrastructure of a bronchogenic carcinoma. J Clin Invest 51: 141, 1972. Hamilton BPM, Upton CV, Amatruda TT: Evidence for the presence of neurophysin in tumours producing the syndrome of inappropriate antidiuresis. J Clin Endocrinol 35: 764, 1972. Lipscomb HS, Wilson C, Retiene K, et al.: The syndrome of inappropriate antidiuretic hormone release. A case report and characteristics of the antidiuretic hormone- like material isolated from an oat cell carcinoma of the lung. Cancer Res 28: 378, 1968. Sawyer WH: Pharmacological characteristics of the antidiuretic principle in a bronchogenic carcinoma from a patient with hyponatraemia. J Clin Endocrinol 27: 1497, 1967. Verney EB: The antidiuretic hormone and the factors which determine its release. Proc Roy Sot 135: 25, 1947. Pasqualini RQ, Codevilla A: Thirst suppressing (“Antidipsetic”)

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