Abnormal antidiuresis in bronchogenic carcinoma

Abnormal

Antidiuresis in

Bronchogenic

Carcinoma

M. L. GODLEY, M.D. AND WILLIAM LOCKE, M.D., New Orleans, Louisiana

From the Department of Internal Clinic, New Orleans, Louisiana.

Medicine,

ml. for several days, the serum sodium concentration rose to 128 mEq./L. At Ochsner Foundation Hospital the patient’s behavior was so bizarre and unpredictable that he was accommodated in the psychiatric unit. He continued to be preoccupied with his vision and from time to time experienced diplopia. Esotropia was demonstrated. Medical examination, which included bronchial biopsy, revealed an “oat cell” bronchogenic carcinoma of the left lung and hyponatremic, hypoosmolar serum. No evidence of extrathoracic metastases was found on physical and routine laboratory examinations, including determination of serum albumin and globulin concentrations, histologic examination of the left scalene lymph node, radiographic survey of bones, examination of the spinal fluid, electroencephalography, pneumoencephalography, bilateral carotid angiography, and isotopic brain scanning with mercury 203. On July 20, 1964, the left lung and perihilar lymph nodes were removed. The tumor was infected and partially necrotic. Neoplastic cells were found in only one of the eight lymph nodes examined. Postoperatively, neurologic and psychiatric. symptoms vanished. The patient returned to Panama, apparently well, but he soon became ill again and died on August 31, 1964. On postmortem examination metastases were found in the liver, spleen, and bone marrow; none was found in the pituitary, adrenal glands, or brain. * Immediately after its removal, the tumor, which weighed 35 gm., was frozen by dry ice and sent to Dr. A. V. Schally, Chief, Endocrine and Polypeptide Laboratory, Veterans Administration Hospital, New Orleans. One portion of the tumor was homogenized in ice cold O.lN acetic acid. The homogenate was centrifuged at 15,000 revolutions per minute and filtered at 6”~. The filtrate was assayed for vasopressor activity in rats pretreated with phenoxybenzamine. Vasopressin-like activity equivalent to

Ochsner

A

BNORMALANTIDIURRSIShas been noted in patients with bronchogenic carcinoma [l-6], tuberculous meningitis [7], cerebral diseases [8--101, porphyria [11], and myxedema [12]. Winkler and Crankshaw [I] first described this state in 1938 in a review of tuberculous meningitis in which they mentioned one patient with abnormal antidiuresis associated with bronchogenic carcinoma. Since then, about thirty cases of this association have been recorded. In the case to be reported herein, an untreated bronchial carcinoma which had been removed surgically was examined for vasopressin-like substances. This appears to have been the first such examination of an untreated bronchial carcinoma. In addition, the effects of waterloading, cortisone acetate, ethanol, atropine, and hypertonic saline solution on certain aspects of the patient’s salt and water metabolism were studied. CASEREPORT A forty-four year old man was admitted to the Neurologic Service of Ochsner Foundation Hospital on June 25, 1964. Ten days earlier he jumped out of bed during the night, telling his wife his “problem” was poor eyesight, whereupon he roamed around the house, trying on several pairs of glasses. Although previously an active, energetic person, during the following days he sat around the house staring into space, complaining about his vision, and crying. On June 16, 1964, he entered Gorgas Hospital, Panama Canal Zone. His mental acuity was impaired and his behavior decidedly odd. Mild disdiadochokinesia was present. Serum sodium and chloride concentrations were 120 and 73 mEq./L., respectively. After intravenous infusion of 1,000 ml. of a 5 per cent solution of sodium chloride and restriction of the daily allowance of water to 500 Vol.115,March

1968

* Autopsy findings kindly supplied by Dr. J. F. Lopez, Gorgas Hospital, Panama Canal Zone. 413

Godley and Locke

414

sJUNE 30’1

‘,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

5

IO

FY

20

2G

30’

AUG. 7

SO0 Strum MO0m.lh.g. -1

200

FIG. 1. Changes in certain aspects of patient’s salt and water metabolism. Between June 28 and July 14 and between July 25 and July 27, the diet provided 8 gm. of sodium chloride a day. On July 15 scalene node biopsy and transbronchial biopsy of the pulmonary tumor were performed. Between July 16 and July 24 the patient received varying amounts of cortisone acetate intramuscularly. On July 20 a neoplasm, part of which was necrotic and infected, was removed with the lung. Special tests were performed on the days indicated in Table I. of wet tissue was demonstrated. If this activity were due to arginine vasopressin, it would indicate that the entire 35 gm. of tumor contained about 700 mu. or 1.5 pg. of that hormone. The remainder of the tumor was desiccated and defatted with acetone for twenty-four hours. The tissue thus treated was dried in vacua and sent to Dr. Wilbur H. Sawyer, Columbia University College of Physicians and Surgeons, to be assayed for antidiuretic activity. A portion of the tissue was extracted in 0.05 M acetic acid at 100’~. for five minutes. The extract was tested for antidiuretic activity by intravenous injection into hydrated rats anesthetized with ethanol. The extract from 1 mg. of dry tumor had antidiuretic activity equivalent to that of about 100 wU. of arginine vasopressin. When this extract was tested for its ability to increase water permeability of the toad (Bufo marinus) bladder in vitro, it was found to have activity equivalent to that of 50 to 100 PU. of arginine vasopressin per milligram of dry tumor. These values were in agreement with the pressor activity previously determined on wet tissue. At least 90 per cent of the antidiuretic activity of the extract was destroyed by incubation in 0.01 M sodium thioglycolate at pH 7.6 for three hours. Investigative studies of the patient’s salt and water metabolism were necessarily limited since the patient was seriously ill and had entered the hospital 20 MU. per milligram

primarily for diagnosis and treatment. As in other similar cases, the patient’s psychosis imposed an additional restriction on preoperative investigation. Figure 1 records the results of pre- and postoperative measurement of serum osmolalities and sodium concentrations and of urinary volumes, Preosmolalities, and sodium concentrations. operatively, serum sodium concentrations and osmolalities were below normal levels. The osmolality of the urine always exceeded that of the serum and the daily urinary output of sodium was always more than 80 mEq., sometimes by a wide margin. By the fourth postoperative day, both serum sodium concentrations and osmolalities were at normal levels. Table I records the effects of intravenous waterloads and of intravenous waterloads plus selected agents on certain properties of serum and urine. The standard waterload was 750 ml. given intravenously during the first hour of the five hour test period, usually as a 5 per cent glucose solution. Voided specimens of urine were collected hourly for five hours. Blood was usually collected at the beginning, middle, and end of each test. Preoperatively, the agents selected for testing were 0.8 mg. of atropine sulfate, 75 mg. of cortisone acetate, 50 ml. of ethanol, and 22.5 gm. of sodium chloride (given as a 3 per cent saline solution). The urinary output per unit of time, osmolality, and occasionally American

Jownal

of Surgery

Bronchogenic Carcinoma ASPECTS OF PATIENT’S

415

TABLE IA SALT AND WATER METABOLISM: PREOPERATIVE

TESTS*

Urine Time

Volume (ml.)

Osmolality (m0sm.h.)

Serum Sodium (mEq./L.)

Osmolality (mOsm/kg.)

Sodium (mEq./L.)

Five Per cent Glucose in Water July 3 : 7:30 8:30 9: 30 10:30 11:30 12:30

A.M. A.M. A.M. A.M.

A.M. P.M.

127 52 70 62 52 28

738 780 774 798 862

102

255

122

112

256

124

Five Per cent Glucose in Water July 4: 8: 00 9:00 1O:OO 11:OO 12: 00 l:oo

124

A.M.

A.M. A.M. A.M. noon P.M.

60 133 37 69

598 630 653 668

74

241

241

Five Per cent Glucose in Water Plus Atropine July 6: 8:00

A.M. 9:soA.M. 10:mA.M. 10:soA.M. 11:30 A.M. 12:30 P.M. 1:OO P.M. 1:30 P.M.

121 28

580

48 45 20

584 600 609

79

623

239

230 123

Three Per cent Saline Solution July 7 : 8: 00 A.M. 9:OO A.M. 1O:OO A.M.

138 193

604 579

170

251

124

ll:OO A.M. 12:30 P.M. 1: 00 P.M.

160 195 183

562 563 594

194

251

121

115

Five Per cent Glucose in Water Plus Alcohol July 8 : 8: 30 A.M. 9:30 A.M.

122

10: 30 A.M.

28 67

693 701

168

255

119

11:30 A.M. 12:30 P.M. 1:30 P.M.

41 40 59

715 727 731

77

253

121

Continued on next page Vol.115,March 1968

Godley and Locke

416

TABLE IA (continued) ASPECTS OF PATIENT’S SALT AND WATER METABOLISM

: PREOPERATIVE

TESTS*

Urine Time

Volume

Serum

Osmolality (mOsm./kg.)

(ml.)

Sodium (mEq./L.)

Osmolality (mOsm/kg.)

Sodium (m&/L.

1

Five Per cent Glucose in Water Plus Cortisone July 9 :

8:oo

A.M. A.M. A.M. A.M. noon P.M.

9: 00 10: 00 11:OO 12: 00 1:OO

121 184 72 73 56 27

652 637 637 678 708

110

235

114

114

233

113

Five Per cent Glucose in Water July 10: 8: 60 9:oO 10: 60 11:Oo 12 : 00 I:00

sodium

A.M. A.M. A.M. A.M. noon P.M.

concentration

tively,

tests

sulfate

were

were

except

acetate

and

potassium,

most

sodium,

and

sera were

potassium,

tested

and

Failure

of expected

in all

except

tests

for osmolality

creatinine

concentra-

followed

the water-

when

sodium

the

before

waterload

chloride.

cretion

diuresis

both

and

after

Preoperatively,

of urine

operation,

contained

3 per

the

in the five hour

cent

average

ex-

during

the

period,

first hour of which 750 ml. of a 5 per cent solution glucose ml.

in water

The

infusion

only

comparable

was

given,

amounted

excretions

when

per cent saline

of

to 290

figure on the day of the saline

was 870 ml. Postoperatively, 5 per cent glucose solutions

were

the five hour in water

given

were

and

3

430 and

720 ml., respectively. None

of the treatments

ratio between

urinary

lality (uOsm./sOsm.). usually

ranged

osmolality

nitely

affected

treatments which

2 and The

to be lower

lality was normal. by

raised

postoperatively

them. as

clearances

that it

with effect

was

the hypo-

serum

uOsm./ osmo-

were not defi-

or by

any

hypertonic was

the

osmo-

uOsm./sOsm.

3 despite

postoperative

the operation This

affected serum

even though

Osmolar

except

and

Preoperatively,

between

of the serum.

sOsm. tended

conspicuously

osmolality

not

preoperatively.

103

231

114

periods

was urinary

osmo-

COMMENTS

concen-

tions. load

115

of

osmolal-

creatinine

231

lality less than serum osmolality.

atropine

tests. All specimens

94

none of the experimental

Postoperathe

urine were tested for volume,

ity, and sodium, trations,

592 543 530 539 633

measured.

repeated

and cortisone

postoperative

and

119 23 110 66 25 45

of the saline,

as striking During

The abnormal antidiuresis exhibited by certain patients with bronchogenic carcinoma could be brought about by (1) elaboration by the tumor of a substance which has a direct antidiuretic effect on the kidneys, (2) manufacture by the tumor of a substance which acts on the neurohypophyseal system to release vasopressin, oxytocin, or both, (3) a neural reflex originating in the thorax leading to release of vasopressin, oxytocin, or both, (4) production of adrenal or severe hepatic insufficiency by metastases, (5) some unsuspected mechanism or mechanisms, and (6) combinations of the foregoing possibilities. Our observations are consistent with the possibility that the tumor itself released a substance which acted directly on the kidneys to cause antidiuresis. The tumor extracts we examined possessed pharmacologic properties consistent with the presence of small amounts of arginine vasopressin. They contained vasopressor activity equivalent to that of about 20 PU. per milligram of wet weight, antidiuretic activity equivalent to about 100 pg. per milligram Amevican Sournal of Surgery

Bronchogenic of dry weight, and comparable activity on the isolated toad bladder. Antidiuretic activity was destroyed by sodium thioglycolate. Although the measured biologic properties of the tissue extracts could have been due to the presence of arginine vasopressin, this was not proved. Identification of the vasopressin-like substance found in some bronchogenic carcinomas will be possible only if it can be obtained in a sufficient amount to make more critical pharmacologic, chemical, and immunologic studies feasible. The highest concentration yet reported is about

Carcinoma

417

7 vasopressor mu. per milligram of dry weight P31. Although our data as well as those of others [3,13,14] provide strong evidence that certain bronchogenic carcinomas contain a vasopressinlike material, they do not exclude the possibility of their being a direct humoral or neural connection between the tumor and the neurohypophyseal system in some cases. We attempted to test the neural reflex postulate by giving our patient atropine; it had no observed effect. Data derived from canine experiments [15] published

TABLE IB ASPECTSOF PATIENT’S SALT AND WATER METABOLISM:POSTOPERATIVETESTS Urine Time

Volume (ml.)

Osmolality (m,“,“I/

Sodium (mEq./L.)

serum Potassium (mEq./L.)

Creatinine (mg. %)

Osmolality (m$I.j

‘Odium (mEq./L.)

Potassium (mEq./L.)

Creatinine (me. %)

297 289

141.5 137.0

4.2 4.1

1.0 1.0

288

137.0

4.0

0.9

Five Per cent Glucose in Water July 27, 1964: 8: 00 A.M. 9:00 A.M. 10: 00 A.M. 1t:OO A.M. 12 : 00 noon 1: 00 P.M.

54 106 55 120 95

605 590 559 568 560

99 98 93 94 96

47 45 43 45 44

75 67 65 67 68.5

Five Per cent Glucose in Water Plus Alcohol July 28, 9:30 10: 30 11:30 12:30 1:30 2:30

1964: A.M. A.M. A.M. P.M. P.M. P.M.

102 179 26 47 34

611 611 593 630 628

84 84 62 50 50

44 42 40 43.5 45

79 71.5 91.5 109 111

Three Per cent Sodium July 30, 1964: 8: 00 A.M. 9: 00 A.M. 1O:OO A.M. 10:30 A.M. 1l:OO A.M. 12 : 00 noon 1: 00 P.M.

302

140.0

1.0

310

136.0

3.3

0.9

290

138.0

4.0

1.0

295

138.5

4.5

1.0

307

146.0

4.5

1.0

309

145.5

4.7

0.9

Chloride

86 198

633 547

95 178

52 30

89 35

262 76 98

545 571 597

185.5 172.5 165

34.5 44.0 46

30 47 53

He was then given for about one hour an intra* Tests were started by having the patient empty the bladder. venous infusion of 750 ml. of 5 per cent glucose in water or 3 per cent saline solution. Voided specimens of urine were collected hourly. On July 6 he was given 0.8 mg. of atropine subcutaneously at the start of the test. On July 8 and July 28, 50 ml. of ethanol was added to the glucose solution. On July 9 he swallowed 75mg. cortisoneacetate two and a half hours before the infusion was started. Sodium and potassium concentrations were determined by Technicon flame photometry, creatinine concentrations by Technicon autoanalyser, and osmolalities by freezing point. Vol. 115, March 1968

418

Godley

after our study was completed suggest that anticholinergic agents are at most feeble inhibitors of the release of antidiuretic hormone which normally ensues upon stimulation of the central end of the vagus nerve, and that a more informative test of the neural reflex postulate would have been provided by the administration of an adrenergic blocking agent. Most of the antidiuretic tests we performed were waterloading tests. The observation that cortisone had no effect on disposal of the waterload (or serum osmolality) is strong evidence against an adrenocortical contribution to antidiuresis by our patient. Furthermore, at necropsy metastases were not observed in the adrenal or pituitary glands. The failure of ethanol to induce diuresis, which has also been noted by others [14,16 1, is susceptible to several interpretations. One is that the neurohypophyseal antidiuretic system was being activated by a stimulus not susceptible to inhibition by ethanol. Another and perhaps the most likely explanation is that the system was dormant as a result of uncontrolled secretion of antidiuretic material by the tumor. A curious observation in our study was the response to intravenous injection of 3 per cent saline solution. Instead of the antidiuresis which would normally ensue [17], a brisk urine flow occurred during the entire test period without appreciable change in urinary or serum osmolality. This may have been simple osmotic diuresis reflecting that the kidneys were concentrating urine to their maximal ability. Elaborate renal function studies, which we did not undertake, would, however, be necessary to obtain a clear understanding of the sequence of events leading to this diuresis. There has been a report of renal tubular dysfunction in a case of this kind [18]. A study in this direction might reveal some hitherto unsuspected abnormalities of renal function in patients with bronchogenic carcinoma. The persistence of antidiuresis postoperatively may have been due to the presence of metastases, the existence of which was proved by the course of clinical events, or conceivably the persistence of a renal defect induced by the bronchogenic carcinoma. The true incidence and cause or causes of abnormal antidiuresis in patients with bronchogenie carcinoma is obviously far from settled. However, the clinical importance of this association is already clearly evident. Patients with

and Locke bronchogenic carcinoma should be examined for abnormal antidiuresis; conversely, patients with abnormal antidiuresis should be examined for bronchogenic carcinoma. SUMMARY

A case of bronchogenic carcinoma with abnormal antidiuresis is reported. Treatment of the patient with 750 ml. of a 5 per cent solution of glucose in water intravenously, alone, and with ethanol, atropine sulfate, and cortisone acetate failed to produce diuresis; a 3 per cent saline solution, however, did so for unexplained reasons. Assay of the tumor revealed the presence of small amounts of arginine vasopressinlike activity. This appears to be the first report of assay of an untreated, surgically removed, bronchogenic carcinoma for vasopressin-like activity. Acknowledgment: We are indebted to Drs. Wilbur H. Sawyer and A. V. Schally for assays of the tumor extracts and for invaluable advice during preparation of the manuscript. REFERENCES

1. WINKLER, A. W. and CRANKSHAW, 0. F. Chloride depletion in conditions other than Addison’s disease. J. Clin. Invest., 17: 6, 1938. 2. Ross, E. J. Hyponatremic syndromes associated with carcinoma of the bronchus. Quart. J. Med., 32 : 297, 1963. 3. BOWER, B. F., MASON, D. M., and FORSHAM, P. H. Bronchogenic carcinoma with inappropriate antidiuretic activity in plasma and tumor. New England J. Med., 271: 934,1964. 4. GRANTHAM, J. J., BROWN, R. W., and SCHLOERB, P. R. Asymptomatic hyponatremia and bronchogenie carcinoma: the deleterious effects of diuretics. Am. J. M. Sci., 249: 273, 1965. 5. HBINEMANN,H. 0. and LARAGH, J. H. Inappropriate renal sodium loss reverted by vena cava obstruction. Ann. Int. Med., 65: 708, 1966. 6. CLIPT, G. V., SCHLETTER, F. E., MOSES, A. M., and STREETEN, D. H. P. Syndrome of inappropriate vasopressin secretion. Arch. Int. Med., 118: 453, 1966. 7. HARRISON, H. E., FINBERG, L., and FLEISHMAN, E. Disturbances of ionic equilibrium of intraand extracellular electrolytes in patients with tuberculous meningitis. J. C&z. Invest., 31: 300, 1952. 8. EPSTEIN, F. H. and LEVITIN, H. “Cerebral salt wasting”; an example of sustained inappropriate release of antidiuretic hormone. J. Clin. Invest., 38: 1001,1959. 9. CARTER, N. W., RECTOR, F. C., JR., and SELDIN, D. W. Hyponatremia in cerebral disease reAmerican Journal of Surgery

Bronchogenic Carcinoma suiting from the inappropriate secretion of antidiuretic hormone. New England J. Med., 264: 67, 1961. 10. HADEN, H. T. and KNOX, G. W. Cerebral hyponatremia with inappropriate antidiuretic hormone syndrome. Am. J. M. Sci., 249: 381, 1965. 11. NELSEN, B. and THORN, N. A. Transient excess urinary excretion of antidiuretic material in acute intermittent porphyria with hyponatremia and hypomagnesemia. Am. J. Med., 38: 345, 1965. 12. PETTINGER, W. A., TALNER, L., and FERRIS, T. F. Inappropriate secretion of antidiuretic hormone due to myxedema. New England J. Med., 272:

362,1965. 13. BBRDE, B. Les analogues synthetiques des hormones neurohypophysaires. Sont-ils une clef de l’etudes des troubles de l’hormonogenese de ce systeme? p. 33. Paris, 1965. Masson & Cie.

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14. AXATRUDA, T. T., MULROW, P. J., GALLAGHER, J. C., and SAWYER, W. H. Carcinoma of the iung with inappropriate antidiuresis. New

Eneland J. Med.. 269: 544.1963. 15. MILL& E. and WANG, S. C. Liberation of antidiuretic hormone: pharmacologic blockage of ascending pathways. Am. J. Physiol., 207: 1405, 1964. 16. THORN, W. A. and TRANSB~L, I. Hyponatremia and bronchogenic carcinoma associated with renal excretion of large amounts of antidiuretic material. Am. J. Med.. 35: 257. 1963. 17. HIC~~Y, R. C. and H.&E, K. The renal excretion of chloride and water in diabetes insipidus. J. Cl&z. Invest., 23: 768, 1944. 18. REES, J. R., ROSALKI, S. B., and MACLEAN, A. D. Hyponatremia and impaired renal tubular function with carcinoma of the bronchus. Lance& 2: 1005, 1960.