Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Inappropriate secretion of antidiuretic hormone an overview of the syndrome Nasiruddin Khokhar To cite this article: Nasiruddin Khokhar (1977) Inappropriate secretion of antidiuretic hormone an overview of the syndrome, Postgraduate Medicine, 62:4, 73-79, DOI: 10.1080/00325481.1977.11714637 To link to this article: http://dx.doi.org/10.1080/00325481.1977.11714637
Published online: 07 Jul 2016.
Submit your article to this journal
View related articles
Citing articles: 4 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [Australian Catholic University]
Date: 19 August 2017, At: 11:45
Downloaded by [Australian Catholic University] at 11:45 19 August 2017
topics in primary care
• The syndrome of inappropriate secretion of antidiuretic hormone (ADH), first described in 1957,1 is being recognized with increasing frequency. The clinical features are due to water intoxication2 and include (1) hyponatremia with hypoosmolality of serum and extracellular fluid, (2) continued renal excretion of sodium, (3) absence of clinical evidence of volume depletion, ie, normal skin turgor and blood pressure, (4) greater osmolality of urine than is appropriate for the concomitant tonicity of plasma, ie, urine less than maximally dilute, (5) normal renal function, and (6) normal adrenal function.
inappropriate secretion of antidiuretic hormone an overview of the syndrome
Etiology
Nasiruddin Khokhar, MD
Inappropriate secretion of ADH has been reported to occur in a large number of disorders (table 1) and in association with many drugs (table 2). It is most commonly caused by bronchogenic carcinoma. High antidiuretic activity has been found in tumor extract3 8 •39 in such cases, and plasma levels of arginine vasopressin have been found to be markedly elevated. 6 •38 Antidiuretic substance has been demonstrated in lung tissue of patients with pulmonary tuberculosis, 13 and ADH-like material may be produced in the lungs of patients with pneumonia. 15
Veterans Administration Hospital and Wright State University School of Medicine Dayton, Ohio
lnappropriate secretion of antidiuretic hormone occurs in association with many disorders and circumstances. Hyponatremia is a cardinal feature of the resulting syndrome; treatment with fluid restriction is usually effective.
Clinical Features The symptoms of the syndrome of inappropriate secretion of ADH fluctuate from day to day according to serum sodium level. 40 They are nonspecific and may suggest sorne intracranial process. Thus, neurologie diagnostic procedures, such as pneumoencephalography and trephination, may be undertaken before the correct diagnosis is made. 2 •4 °Clinical manifestations of the syndrome may appear only after the serum sodium level falls to less than 120 mEq/liter. Progressive mental confusion, fatigue, headache, nausea, vomiting, and anorexia may occur. Later the patient may become hostile and violent. Coma or grand mal convulsions may ensue. If serum sodium concentration falls below 110 mEq/liter, severe neurologie signs appear (diminished or absent deep tendon reflexes, bilateral patellar and ankle clonus, bilateral Babinski sign, bulb ar or pseudobulbar pals y, muscle weakness, hyperventilation). 2 •40 •41 Brain damage can result from prolonged hypotonicity. 42 Aggravation of nocturnal an gina has been reported. 43 Without treatment, death may occur. 40 Recov-
Vol. 62 • No. 4 • October 1977 • POSTGRADUATE MEDICINE
73
Downloaded by [Australian Catholic University] at 11:45 19 August 2017
table 1. disorders in which inappropriate secretion of antidiuretic hormone is completely or partly responsible for clinical features Mallgnant Oat cell carcinoma of lung1·3 Adenocarcinome of lung4 Carcinoma of pancreas 5 Carcinoma of duodenums Thymoma6
Pulmonary Tuberculosis 12·13 Pneumonia14·15 Chronic lung infection1s Pulmonary aspergillosis with cavitation 17 Status asthmaticus 18
Central nervous system
Metabollc and endocrine Myxedema19·20 Porphyria21. 22 Addison disease2 Hypopituitarism2
Tuberculous meningitis2. 7 Herpes simplex encephalitis 8 Aneurysm 6 Abscess2. 6 Cerebrovascular disorders9 Subarachnoid hemorrhage2 Tumor2. 10 Trauma2. 10 Paroxysmal cerebral dysrhythmia11 Guillain-Barré syndrome4 Malformation4
Mlscellaneous
Postcommissurotomy dilutional syndrome 23 Postoperative states 2 Pulmonary complications requiring prolonged mechanical ventilation 24 ldlopathlc2 s
ery is rapid, however, if the dilutional state and its cause are recognized early and appropriate measures instituted. In spite ofwater retention, weight gain may be absent in sorne patients, eg, those with severe anorexia or conditions such as carcinoma in which body tissue is progressively lost. 2
Pathogenesis The pathogenesis of the syndrome of inappropriate secretion of ADH and of sorne of its features is still unclear, despite many clinical observations. ADH or an ADH-like material may be produced by diseased Jung tissue, eg, in oat cell tumor of the lung, 44 •45 pulmonary tuberculosis, 13 or pneumonia. 14 •15 A decrease in left atrial pressure causing release of ADH has been thought to be present in status asthmaticus, 18 pneumonia, 14 ·15 and the dilutional syndrome following commissurotomy. 23 Lesions of the median eminence and bilateral Joss of neurons of the supraoptic and paraventricular nuclei have been found in porphyria46; decreased blood volume associated with acute intermittent porphyria has also been reportedY
74
In patients receiving therapy with vincristine, neurotoxic effects on the hypothalamus, neurohypophyseal tract, or pituitary itself, involving sites of formation and storage of ADH, may be responsible for inappropriate secretion of ADH. 28 Among many other drugs associated with the syndrome (table 2), clofibrate may cause release of endogenous ADH34 and chlorpropamide may potentiate the activity of circulating ADH. 48 Hyponatremia has been attributed to dilution of serum because of water retention due to the activity of ADH.2.4 9 It may also result from loss of sodium in urine secondary to possible hypoaldosteronism and to an increase in the glomerular filtration rate due to overexpansion of plasma. 2•49 Reabsorption of sodium in the proximal renal tubule may b~ reduced due to a possible ''third factor.' ' 2 Intracellular shift of sodium has been proposed as a mechanism of hyponatremia in those patients who atypically excrete normal amounts of sodium in urine. 50 A diuretic agent may indirectly lead to hyponatremia by causing reduction in glomerular filtration rate with increased absorption of sodium and water in the proximal tubule, 51 potassium depletion leading to reduced extracellular volume and increased secretion of ADH, 30 or sodium depletion leading to release of angiotensin and subsequent antidiuresis. 52 Limitation of formation of "free" water in response to water loading, excessive proximal reabsorption of sodium and water, and greater-than-normal antidiuretic activity in plasma and urine have been found in congestive heart failure and cirrhosis of the Iiver. 2
Diagnosis The cardinal feature of the syndrome of inappropriate secretion of ADH is urine that is Jess than maximally dilute in the presence of plasma that is hypotonie. 2 Causes of hyponatremia other than the syndrome, eg, prolonged vomiting, diarrhea, or renal or adrenal
POSTGRADUATE MEDICINE • October 1977 • Vol. 62 • No. 4
Downloaded by [Australian Catholic University] at 11:45 19 August 2017
disease, must be ruled out. In pseudohyponatremia resulting from hyperlipemia and hyperlipoproteinemia, plasma osmolality is normal. In psychogenic polydipsia, urinary osmolality is low and the urine is nearly maximally dilute. Edema is characteristically absent in the syndrome of inappropriate secretion of ADH but may be present, 2 as it is in congestive heart failure and cirrhosis of the liver. Serum electrolyte determinations may be helpful in differentiating the syndrome from encephalitis or from other neurologie diseases. Diagnosis may be difficult in sorne patients with progressive water retention; they may achieve a new "steady state" in which sodium is nearly absent from urine if sodium intake is low. 2 Sodium administered to the se patients is rapidly excreted, and the forcing of fluid causes sodium loss in urine and hyponatremia.2
table 2. drugs associated with inappropriate secretion of antidiuretic hormone Hypoglycemie agents Chlorpropamide2s Tolbutamide27 Phenformin27 Metformin27 Antlneoplastlc agents Vincristine2s Cyclophosphamide29 Dluretlcs Chlorothiazide3o
Tranqulllzers
Amitriptyline2 7 Thioridazine2 7 Fluphenazine31 Thiothixene32 Carbamazepine33 Mlscell.,eous Clofibrate34 AcetaminophenJs lsoproterenoi36 Morphine37 Barbiturate37
Therapy for the syndrome of inappropriate secretion of ADH consists of ( 1) treatment of hyponatremia and (2) treatment of the underlying disease or disorder. Hyponatremia-Fluid restriction, to the extent that urinary and insensible lasses induce a negative water balance, will quickly restore normal body fluid volume, reduce urinary sodium excretion, and increase serum sodium level. 1 ' 3 Fluid intake can be limited to 500 to 700 ml/day. Infusion of hypertonie saline solution can be used to raise the osmolality of body fluids in patients with severe water intoxication who have convulsions or are comatose. This treatment is not oflong-term value, as most of the sodium load is promptly excreted in the urine. 2 A method recently described53 to correct hyponatremia rapidly consists of the intravenous administration of a patent diuretic, such as furosemide, in a dose of 1 mg for each kilo gram of body weight and houri y replacement of electrolytes lost in the urine. Serum
sodium levels can be normalized in six to eight hours. Lithium carbonate (300 mg by mouth every six to eight hours for up to seven days) has been used to treat hyponatremia because of its inhibitory effects on ADH activity .54 This agent probably interferes with the action of ADH in the distal tubule and collecting duct beyond the point of formation of cyclic adenosine-3'5'-monophosphate. 55 In patients with heart or liver disease, lithium carbonate may be used with special caution; toxicity may be a problem. Corticosteroid in large doses can cause sodium retention but does not affect the underlying problem. Because of the potentially serious side effects, use of steroid should be limited to replacement therapy in cases of adrenal or pituitary insufficiency. 2 Treatment of underlying conditionEffective treatment of pneumonia, meningitis, endocrine disorder, heart failure, or cirrhosis of the liver underlying the syndrome of inappropriate secretion of ADH is usually followed by disappearance of symptoms due to water intoxication. 2 In cases ofbronchogenic carcinoma, treatment in the form of surgery, irradiation, or chemotherapy may or may not bring about disappearance of these symptoms. 2 ~
Vol. 62 • No. 4 • October 1977 • POSTGRADUATE MEDICINE
75
Treatment
Downloaded by [Australian Catholic University] at 11:45 19 August 2017
Nasiruddin Khokhar
Dr Khokhar is a resident in internai medicine, Veterans Administration Hospital and Wright State University School of Medicine, Dayton, Ohio.
Summary The syndrome of inappropriate secretion of antidiuretic hormone is characterized by pro-
duction of less than maximally dilute urine in the presence of hypotonie plasma. lt may be secondary to malignant disease, central nervous system disorders, or pulmonary disease, among other conditions, or it may be idiopathie. Manifestations are those of water intoxication, eg, confusion, fatigue, nausea, headache, and neurologie signs. The pathogenesis is not completely understood. Restriction offluid intake to obtain a negative water balance is effective treatment. • Address reprint requests to Nasiruddin Khokhar, MD, Veterans Administration Center, 4100 W Third St, Dayton, OH 45428.
References 1. Schwartz WB, Bennet W, Curelop S: A syndrome ofrenal sodium Joss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med 23:529, 1957 2. Bartter FC, Schwartz WB: The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 42:790, 1967 3. Schwartz WB, Tasse! D, Bartter FC: Further observations on hyponatremia and renal sodium Joss probably resulting from inappropriate secretion of antidiuretic hormone. N Engl J Med 262:743, 1960 4. Goldberg M: Hyponatremia and the inappropriate secretion of antidiuretic hormone. Am J Med 35:293, 1963 5. Marks U, Berde B, Klein LA, et al: Inappropriate vasopressin secretion and carcinoma of the pancreas. Am J Med 45:967, 1968 6. Baumann G, Lopez-Amor E, Dingman JF: Plasma arginine vasopressin in the syndrome of inappropriate antidiuretic hormone secretion. Am J Med 52:19, 1972 7. Nyhan WL, Cook RE: Symptomatic hyponatremia in acute infections of the central nervous system. Pediatries 18:604, 1956 8. Rovit RL, Sigler MH: Hyponatremia with herpes simplex encephalitis: Possible relationship of limbic lesions and ADH secretion. Arch Neural 10:595, 1964 9. Jones NF, Barraclough MA, Forsling ML, et al: Inappropriate production of vasopressin, potassium deficiency and cerebrovascular disease. Am J Med 45:474, 1968 10. Carter NW, Rector FC Jr, Seldin DW: Hyponatremia in cerebral disease resulting from the inappropriate secretion of antidiuretic hormone. N Engl J Med 264:67, 1961 Il. Epstein FH, Levitin H, Glaser G, et al: Cerebral hyponatremia. N Engl J Med 265:513, !961 12. Weiss H, Katz S: Hyponatremia resulting from apparently inappropriate secretion of antidiuretic hormone in patients with pulmonary tuberculosis. Am Rev Respir Dis 92:609, 1965
78
13. VorherrH, Massry SG, FalletR, et al: Antidiuretic principie in tuberculous lung tissue of a patient with pulmonary tuberculosis and hyponatremia. Ann Intern Med 72:383, 1970 14. Rosenow EC 3d, Segar WE, Zehr JE: Inappropriate antidiuretic hormone secretion in pneumonia. Mayo Clin Proc 47:169, 1972 15. Mor J, Ben-Galim E, Abrahamov A: Inappropriate antidiuretic hormone secretion in an infant with severe pneumonia. Am J Dis Child 129:133, 1975 16. Spanos A, Spry CJ: Inappropriate secretion of antidiuretic hormone with chronic chest infections. Br Med J 3:785, 1974 17. Utz JP, German JL, Louria DB, etal: Pulmonary aspergillosis with cavitation. N Engl J Med 260:264, 1959 18. Baker JW, Yerger S, Segar WE: Elevated plasma antidiuretic hormone levels in status asthmaticus. Mayo Clin Proc 51:31, 1976 19. Chinitz A, Turner FL: The association of primary hypothyroidism and inappropriate secretion of antidiuretic hormone. Arch Intern Med 116:871, 1965 20. Pettinger W A, Talner L, Ferris TF: Inappropriate secretion of antidiuretic hormone due to myxedema. N Engl J Med 272:362, 1965 21. Hellman ES, Tschudy DP, Bartter FC: Abnormal electrolyte and water metabolism in acute intermittent porphyria: The transient inappropriate secretion of antidiuretic hormone. Am J Med 32:734, 1962 22. Lipschutz DE, Reiter JM: Acute intermittent porphyria with inappropriately elevated ADH secretion. JAMA 230:716,1974 23. Shu'ayb WA, Moran WH Jr, Zimmermann B: Studies of the mechanism of antidiuretic hormone secretion and the post-commissurotomy dilutional syndrome. Ann Surg 162:690; 1965 24. Sladen A, Laver MB, Pontoppidan H: Pulmonary complications and water retention in prolonged mechanical ven ti-
POSTGRAOUATE MEDICINE • October 1977 • Vol. 62 • No. 4
Downloaded by [Australian Catholic University] at 11:45 19 August 2017
lation. N Engl J Med 279:448, 1968 25. Grumer HA, Derryberry W, Dubin A, et al: Idiopathie, episodic, inappropriate secretion of antidiuretic hormone. Am J Med 32:954, 1962 26. Weissman PN, Shenkman L, Gregerman RI: Chlorpropamide hyponatremia: Drug-induced inappropriate antidiuretic-hormone activity. N Engl J Med 284:65, 1971 27. Moses AM, Miller M: Drug-induced dilutional hyponatremia. N Engl J Med 291:1234, 1974 28. Stuart MJ, Cuaso C, Miller M, et al: Syndrome of recurrent increased secretion of antidiuretic hormone following multiple doses of vincristine. Blood 45:315, 1975 29. DeFronzo RA, Braine H, Col vin M, et al: Water intoxication in man after cyclophosphamide therapy: Ti me course and relation to drug activation. Ann Intem Med 78:861, 1973 30. Fichman MP, Vorherr H, Kleeman CR, et al: Diureticinduced hyponatremia. Ann Intem Med 75:853, 1971 31. DeRivera JI: lnappropriate secretion of antidiuretic hormone from fluphenazine therapy. (Letter) Ann Intem Med 82:811, 1975 32. Ajlouni K, Kem MW, Tures JF, et al: Thiothixeneinduced hyponatremia. Arch Intem Med 134:1103, 1974 33. Rad6 JP: Water intoxication during carbamazepine trealment. Br Med J 3:479, 1973 34. Moses AM, Howanitz J, VanGemert M, et al: Clofibrateinduced antidiuresis. J Clin Invest 52:535, 1973 35. Nusynowitz ML, Forsham PH: The antidiuretic action of acetaminophen. Am J Med Sei 252:429, 1966 36. Schrier RW, Lieberman R, Ufferman RC: Mechanism of antidiuretic effect of beta adrenergic stimulation. J Clin ln vest 51 :97, 1972 37. Moses AM, Miller M: Drug-induced dilutional hyponatremia. (Letter) N Engl J Med 292:811, 1975 38. Bower BF, Mason DM, Forsham PH: Bronchogenic carcinoma with inappropriate antidiuretic activity in plasma and tumor. N Engl J Med 271:934, 1964 39. Amatruda TT Jr, Mulrow PJ, Gallagher JC, et al: Carcinoma of the lung with inappropriate antidiuresis: Demonstration of antidiuretic-hormone-like activity in tumor extract. N Engl J Med 269:544, 1963 40. Ivy HK: The syndrome of inappropriate secretion of antidiuretic hormone. Med Clin North Am 52:817, 1968 41. Swanson AG, Iseri OA: Acute encephalopathy due to
readySOUrCe AUDIOVISUALS
water intoxication. N Engl J Med 258:831, 1958 42. Lipsmeyer E, Ackerman GL: Irreversible brain damage after water intoxication. JAMA 196:286, 1966 43. Strauss CF: Chlorpropamide and angina pectoris. (Letter) Ann Intem Med 78:454, 1973 44. Lee J, Jones JJ, Barraclough MA: Inappropriate secretion of vasopressin. Lancet 2:792, 1964 45. Vorherr H, Massry SG, Utiger RD, et al: Antidiuretic principle in malignant tumor extracts from patients with inappropriate ADH syndrome. J Clin Endocrinol Metab 28:162, 1968 46. Perlroth MG, Tschudy OP, Marver HS, et al: Acute intermittent porphyria: New morphologie and biochemical findings. Am J Med 41:149, 1966 47. Stein JA, Curl FD, Valsamis M, et al: Abnormal iron and water metabolism in acute intermittent porphyria with new morphologie findings. Am J Med 53:784, 1972 48. Miller M, Moses AM: Mechanism of chlorpropamide action in diabetes insipidus. J Clin Endocrinol Metab 30:488, 1970 49. Clift GV, Schletter FE, Moses AM, et al: Syndrome of inappropriate vasopressin secretion: Studies on the mechanism of the hyponatremia in a patient. Arch Intem Med 118:453, 1966 50. Kaye M: An investigation into the cause of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 41:910, 1966 51. Earley LE, Orloff J: The mechanism of antidiuresis associated with the administration of hydrochlorothiazide to patients with vasopressin-resistant diabetes insipidus. J Clin lnvest 41:1988, 1962 52. Brown JJ, Chinn RH, Lever AF, et al: Renin and angiotensin as a mechanism of diuretic-induced antidiuresis in diabetes insipidus. Lancet 1:237, 1969 53. Hantman D, Rossier B, Zohlman R, et al: Rapid correction of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone: An alternative trealment to hypertonie saline. Ann Intem Med 78:870, 1973 54. White MG, Fetner CD: Treatment of the syndrome of inappropriate secretion of antidiuretic hormone with lithium carbonate. N Engl J Med 292:390, 1975 55. Forrest JN Jr, Cohen AD, Torretti J, et al: On the mechanism of lithium-induced diabetes insipidus in man and the rat. J Clin Invest 53:1115, 1974
WATER INTOXICATION
DO
Dlagnoals and Treatment of the Syndrome of Water Intoxication Burns 3:10-min tape, catalog no. 52 Source: Wisconsin Dial Access Tapes, 610 Walnut St, Madison, Wl 53706 Coat: $4, 1/4-in. audiotape; $10, Echomatic cartridge
Vol. 62 • No. 4 • October 19n • POSTGRADUATE MEDICINE
0
0
Fluld, Electrolyte, and Acld-Base Dlsordera Magee et al 60-min tape, catalog no. lM-23-14 Source: Audio-Digest Foundation, 1577 E Chevy Chase Dr, Glendale, CA 91206 Coat: $5.40, C-60 cassette or standard 5-in. reel For details on how to use ReadySource, sea page 143.
79
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Inappropriate secretion of antidiuretic hormone an overview of the syndrome Nasiruddin Khokhar To cite this article: Nasiruddin Khokhar (1977) Inappropriate secretion of antidiuretic hormone an overview of the syndrome, Postgraduate Medicine, 62:4, 73-79, DOI: 10.1080/00325481.1977.11714637 To link to this article: http://dx.doi.org/10.1080/00325481.1977.11714637
Published online: 07 Jul 2016.
Submit your article to this journal
View related articles
Citing articles: 4 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [Australian Catholic University]
Date: 19 August 2017, At: 11:45
Downloaded by [Australian Catholic University] at 11:45 19 August 2017
topics in primary care
• The syndrome of inappropriate secretion of antidiuretic hormone (ADH), first described in 1957,1 is being recognized with increasing frequency. The clinical features are due to water intoxication2 and include (1) hyponatremia with hypoosmolality of serum and extracellular fluid, (2) continued renal excretion of sodium, (3) absence of clinical evidence of volume depletion, ie, normal skin turgor and blood pressure, (4) greater osmolality of urine than is appropriate for the concomitant tonicity of plasma, ie, urine less than maximally dilute, (5) normal renal function, and (6) normal adrenal function.
inappropriate secretion of antidiuretic hormone an overview of the syndrome
Etiology
Nasiruddin Khokhar, MD
Inappropriate secretion of ADH has been reported to occur in a large number of disorders (table 1) and in association with many drugs (table 2). It is most commonly caused by bronchogenic carcinoma. High antidiuretic activity has been found in tumor extract3 8 •39 in such cases, and plasma levels of arginine vasopressin have been found to be markedly elevated. 6 •38 Antidiuretic substance has been demonstrated in lung tissue of patients with pulmonary tuberculosis, 13 and ADH-like material may be produced in the lungs of patients with pneumonia. 15
Veterans Administration Hospital and Wright State University School of Medicine Dayton, Ohio
lnappropriate secretion of antidiuretic hormone occurs in association with many disorders and circumstances. Hyponatremia is a cardinal feature of the resulting syndrome; treatment with fluid restriction is usually effective.
Clinical Features The symptoms of the syndrome of inappropriate secretion of ADH fluctuate from day to day according to serum sodium level. 40 They are nonspecific and may suggest sorne intracranial process. Thus, neurologie diagnostic procedures, such as pneumoencephalography and trephination, may be undertaken before the correct diagnosis is made. 2 •4 °Clinical manifestations of the syndrome may appear only after the serum sodium level falls to less than 120 mEq/liter. Progressive mental confusion, fatigue, headache, nausea, vomiting, and anorexia may occur. Later the patient may become hostile and violent. Coma or grand mal convulsions may ensue. If serum sodium concentration falls below 110 mEq/liter, severe neurologie signs appear (diminished or absent deep tendon reflexes, bilateral patellar and ankle clonus, bilateral Babinski sign, bulb ar or pseudobulbar pals y, muscle weakness, hyperventilation). 2 •40 •41 Brain damage can result from prolonged hypotonicity. 42 Aggravation of nocturnal an gina has been reported. 43 Without treatment, death may occur. 40 Recov-
Vol. 62 • No. 4 • October 1977 • POSTGRADUATE MEDICINE
73
Downloaded by [Australian Catholic University] at 11:45 19 August 2017
table 1. disorders in which inappropriate secretion of antidiuretic hormone is completely or partly responsible for clinical features Mallgnant Oat cell carcinoma of lung1·3 Adenocarcinome of lung4 Carcinoma of pancreas 5 Carcinoma of duodenums Thymoma6
Pulmonary Tuberculosis 12·13 Pneumonia14·15 Chronic lung infection1s Pulmonary aspergillosis with cavitation 17 Status asthmaticus 18
Central nervous system
Metabollc and endocrine Myxedema19·20 Porphyria21. 22 Addison disease2 Hypopituitarism2
Tuberculous meningitis2. 7 Herpes simplex encephalitis 8 Aneurysm 6 Abscess2. 6 Cerebrovascular disorders9 Subarachnoid hemorrhage2 Tumor2. 10 Trauma2. 10 Paroxysmal cerebral dysrhythmia11 Guillain-Barré syndrome4 Malformation4
Mlscellaneous
Postcommissurotomy dilutional syndrome 23 Postoperative states 2 Pulmonary complications requiring prolonged mechanical ventilation 24 ldlopathlc2 s
ery is rapid, however, if the dilutional state and its cause are recognized early and appropriate measures instituted. In spite ofwater retention, weight gain may be absent in sorne patients, eg, those with severe anorexia or conditions such as carcinoma in which body tissue is progressively lost. 2
Pathogenesis The pathogenesis of the syndrome of inappropriate secretion of ADH and of sorne of its features is still unclear, despite many clinical observations. ADH or an ADH-like material may be produced by diseased Jung tissue, eg, in oat cell tumor of the lung, 44 •45 pulmonary tuberculosis, 13 or pneumonia. 14 •15 A decrease in left atrial pressure causing release of ADH has been thought to be present in status asthmaticus, 18 pneumonia, 14 ·15 and the dilutional syndrome following commissurotomy. 23 Lesions of the median eminence and bilateral Joss of neurons of the supraoptic and paraventricular nuclei have been found in porphyria46; decreased blood volume associated with acute intermittent porphyria has also been reportedY
74
In patients receiving therapy with vincristine, neurotoxic effects on the hypothalamus, neurohypophyseal tract, or pituitary itself, involving sites of formation and storage of ADH, may be responsible for inappropriate secretion of ADH. 28 Among many other drugs associated with the syndrome (table 2), clofibrate may cause release of endogenous ADH34 and chlorpropamide may potentiate the activity of circulating ADH. 48 Hyponatremia has been attributed to dilution of serum because of water retention due to the activity of ADH.2.4 9 It may also result from loss of sodium in urine secondary to possible hypoaldosteronism and to an increase in the glomerular filtration rate due to overexpansion of plasma. 2•49 Reabsorption of sodium in the proximal renal tubule may b~ reduced due to a possible ''third factor.' ' 2 Intracellular shift of sodium has been proposed as a mechanism of hyponatremia in those patients who atypically excrete normal amounts of sodium in urine. 50 A diuretic agent may indirectly lead to hyponatremia by causing reduction in glomerular filtration rate with increased absorption of sodium and water in the proximal tubule, 51 potassium depletion leading to reduced extracellular volume and increased secretion of ADH, 30 or sodium depletion leading to release of angiotensin and subsequent antidiuresis. 52 Limitation of formation of "free" water in response to water loading, excessive proximal reabsorption of sodium and water, and greater-than-normal antidiuretic activity in plasma and urine have been found in congestive heart failure and cirrhosis of the Iiver. 2
Diagnosis The cardinal feature of the syndrome of inappropriate secretion of ADH is urine that is Jess than maximally dilute in the presence of plasma that is hypotonie. 2 Causes of hyponatremia other than the syndrome, eg, prolonged vomiting, diarrhea, or renal or adrenal
POSTGRADUATE MEDICINE • October 1977 • Vol. 62 • No. 4
Downloaded by [Australian Catholic University] at 11:45 19 August 2017
disease, must be ruled out. In pseudohyponatremia resulting from hyperlipemia and hyperlipoproteinemia, plasma osmolality is normal. In psychogenic polydipsia, urinary osmolality is low and the urine is nearly maximally dilute. Edema is characteristically absent in the syndrome of inappropriate secretion of ADH but may be present, 2 as it is in congestive heart failure and cirrhosis of the liver. Serum electrolyte determinations may be helpful in differentiating the syndrome from encephalitis or from other neurologie diseases. Diagnosis may be difficult in sorne patients with progressive water retention; they may achieve a new "steady state" in which sodium is nearly absent from urine if sodium intake is low. 2 Sodium administered to the se patients is rapidly excreted, and the forcing of fluid causes sodium loss in urine and hyponatremia.2
table 2. drugs associated with inappropriate secretion of antidiuretic hormone Hypoglycemie agents Chlorpropamide2s Tolbutamide27 Phenformin27 Metformin27 Antlneoplastlc agents Vincristine2s Cyclophosphamide29 Dluretlcs Chlorothiazide3o
Tranqulllzers
Amitriptyline2 7 Thioridazine2 7 Fluphenazine31 Thiothixene32 Carbamazepine33 Mlscell.,eous Clofibrate34 AcetaminophenJs lsoproterenoi36 Morphine37 Barbiturate37
Therapy for the syndrome of inappropriate secretion of ADH consists of ( 1) treatment of hyponatremia and (2) treatment of the underlying disease or disorder. Hyponatremia-Fluid restriction, to the extent that urinary and insensible lasses induce a negative water balance, will quickly restore normal body fluid volume, reduce urinary sodium excretion, and increase serum sodium level. 1 ' 3 Fluid intake can be limited to 500 to 700 ml/day. Infusion of hypertonie saline solution can be used to raise the osmolality of body fluids in patients with severe water intoxication who have convulsions or are comatose. This treatment is not oflong-term value, as most of the sodium load is promptly excreted in the urine. 2 A method recently described53 to correct hyponatremia rapidly consists of the intravenous administration of a patent diuretic, such as furosemide, in a dose of 1 mg for each kilo gram of body weight and houri y replacement of electrolytes lost in the urine. Serum
sodium levels can be normalized in six to eight hours. Lithium carbonate (300 mg by mouth every six to eight hours for up to seven days) has been used to treat hyponatremia because of its inhibitory effects on ADH activity .54 This agent probably interferes with the action of ADH in the distal tubule and collecting duct beyond the point of formation of cyclic adenosine-3'5'-monophosphate. 55 In patients with heart or liver disease, lithium carbonate may be used with special caution; toxicity may be a problem. Corticosteroid in large doses can cause sodium retention but does not affect the underlying problem. Because of the potentially serious side effects, use of steroid should be limited to replacement therapy in cases of adrenal or pituitary insufficiency. 2 Treatment of underlying conditionEffective treatment of pneumonia, meningitis, endocrine disorder, heart failure, or cirrhosis of the liver underlying the syndrome of inappropriate secretion of ADH is usually followed by disappearance of symptoms due to water intoxication. 2 In cases ofbronchogenic carcinoma, treatment in the form of surgery, irradiation, or chemotherapy may or may not bring about disappearance of these symptoms. 2 ~
Vol. 62 • No. 4 • October 1977 • POSTGRADUATE MEDICINE
75
Treatment
Downloaded by [Australian Catholic University] at 11:45 19 August 2017
Nasiruddin Khokhar
Dr Khokhar is a resident in internai medicine, Veterans Administration Hospital and Wright State University School of Medicine, Dayton, Ohio.
Summary The syndrome of inappropriate secretion of antidiuretic hormone is characterized by pro-
duction of less than maximally dilute urine in the presence of hypotonie plasma. lt may be secondary to malignant disease, central nervous system disorders, or pulmonary disease, among other conditions, or it may be idiopathie. Manifestations are those of water intoxication, eg, confusion, fatigue, nausea, headache, and neurologie signs. The pathogenesis is not completely understood. Restriction offluid intake to obtain a negative water balance is effective treatment. • Address reprint requests to Nasiruddin Khokhar, MD, Veterans Administration Center, 4100 W Third St, Dayton, OH 45428.
References 1. Schwartz WB, Bennet W, Curelop S: A syndrome ofrenal sodium Joss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med 23:529, 1957 2. Bartter FC, Schwartz WB: The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 42:790, 1967 3. Schwartz WB, Tasse! D, Bartter FC: Further observations on hyponatremia and renal sodium Joss probably resulting from inappropriate secretion of antidiuretic hormone. N Engl J Med 262:743, 1960 4. Goldberg M: Hyponatremia and the inappropriate secretion of antidiuretic hormone. Am J Med 35:293, 1963 5. Marks U, Berde B, Klein LA, et al: Inappropriate vasopressin secretion and carcinoma of the pancreas. Am J Med 45:967, 1968 6. Baumann G, Lopez-Amor E, Dingman JF: Plasma arginine vasopressin in the syndrome of inappropriate antidiuretic hormone secretion. Am J Med 52:19, 1972 7. Nyhan WL, Cook RE: Symptomatic hyponatremia in acute infections of the central nervous system. Pediatries 18:604, 1956 8. Rovit RL, Sigler MH: Hyponatremia with herpes simplex encephalitis: Possible relationship of limbic lesions and ADH secretion. Arch Neural 10:595, 1964 9. Jones NF, Barraclough MA, Forsling ML, et al: Inappropriate production of vasopressin, potassium deficiency and cerebrovascular disease. Am J Med 45:474, 1968 10. Carter NW, Rector FC Jr, Seldin DW: Hyponatremia in cerebral disease resulting from the inappropriate secretion of antidiuretic hormone. N Engl J Med 264:67, 1961 Il. Epstein FH, Levitin H, Glaser G, et al: Cerebral hyponatremia. N Engl J Med 265:513, !961 12. Weiss H, Katz S: Hyponatremia resulting from apparently inappropriate secretion of antidiuretic hormone in patients with pulmonary tuberculosis. Am Rev Respir Dis 92:609, 1965
78
13. VorherrH, Massry SG, FalletR, et al: Antidiuretic principie in tuberculous lung tissue of a patient with pulmonary tuberculosis and hyponatremia. Ann Intern Med 72:383, 1970 14. Rosenow EC 3d, Segar WE, Zehr JE: Inappropriate antidiuretic hormone secretion in pneumonia. Mayo Clin Proc 47:169, 1972 15. Mor J, Ben-Galim E, Abrahamov A: Inappropriate antidiuretic hormone secretion in an infant with severe pneumonia. Am J Dis Child 129:133, 1975 16. Spanos A, Spry CJ: Inappropriate secretion of antidiuretic hormone with chronic chest infections. Br Med J 3:785, 1974 17. Utz JP, German JL, Louria DB, etal: Pulmonary aspergillosis with cavitation. N Engl J Med 260:264, 1959 18. Baker JW, Yerger S, Segar WE: Elevated plasma antidiuretic hormone levels in status asthmaticus. Mayo Clin Proc 51:31, 1976 19. Chinitz A, Turner FL: The association of primary hypothyroidism and inappropriate secretion of antidiuretic hormone. Arch Intern Med 116:871, 1965 20. Pettinger W A, Talner L, Ferris TF: Inappropriate secretion of antidiuretic hormone due to myxedema. N Engl J Med 272:362, 1965 21. Hellman ES, Tschudy DP, Bartter FC: Abnormal electrolyte and water metabolism in acute intermittent porphyria: The transient inappropriate secretion of antidiuretic hormone. Am J Med 32:734, 1962 22. Lipschutz DE, Reiter JM: Acute intermittent porphyria with inappropriately elevated ADH secretion. JAMA 230:716,1974 23. Shu'ayb WA, Moran WH Jr, Zimmermann B: Studies of the mechanism of antidiuretic hormone secretion and the post-commissurotomy dilutional syndrome. Ann Surg 162:690; 1965 24. Sladen A, Laver MB, Pontoppidan H: Pulmonary complications and water retention in prolonged mechanical ven ti-
POSTGRAOUATE MEDICINE • October 1977 • Vol. 62 • No. 4
Downloaded by [Australian Catholic University] at 11:45 19 August 2017
lation. N Engl J Med 279:448, 1968 25. Grumer HA, Derryberry W, Dubin A, et al: Idiopathie, episodic, inappropriate secretion of antidiuretic hormone. Am J Med 32:954, 1962 26. Weissman PN, Shenkman L, Gregerman RI: Chlorpropamide hyponatremia: Drug-induced inappropriate antidiuretic-hormone activity. N Engl J Med 284:65, 1971 27. Moses AM, Miller M: Drug-induced dilutional hyponatremia. N Engl J Med 291:1234, 1974 28. Stuart MJ, Cuaso C, Miller M, et al: Syndrome of recurrent increased secretion of antidiuretic hormone following multiple doses of vincristine. Blood 45:315, 1975 29. DeFronzo RA, Braine H, Col vin M, et al: Water intoxication in man after cyclophosphamide therapy: Ti me course and relation to drug activation. Ann Intem Med 78:861, 1973 30. Fichman MP, Vorherr H, Kleeman CR, et al: Diureticinduced hyponatremia. Ann Intem Med 75:853, 1971 31. DeRivera JI: lnappropriate secretion of antidiuretic hormone from fluphenazine therapy. (Letter) Ann Intem Med 82:811, 1975 32. Ajlouni K, Kem MW, Tures JF, et al: Thiothixeneinduced hyponatremia. Arch Intem Med 134:1103, 1974 33. Rad6 JP: Water intoxication during carbamazepine trealment. Br Med J 3:479, 1973 34. Moses AM, Howanitz J, VanGemert M, et al: Clofibrateinduced antidiuresis. J Clin Invest 52:535, 1973 35. Nusynowitz ML, Forsham PH: The antidiuretic action of acetaminophen. Am J Med Sei 252:429, 1966 36. Schrier RW, Lieberman R, Ufferman RC: Mechanism of antidiuretic effect of beta adrenergic stimulation. J Clin ln vest 51 :97, 1972 37. Moses AM, Miller M: Drug-induced dilutional hyponatremia. (Letter) N Engl J Med 292:811, 1975 38. Bower BF, Mason DM, Forsham PH: Bronchogenic carcinoma with inappropriate antidiuretic activity in plasma and tumor. N Engl J Med 271:934, 1964 39. Amatruda TT Jr, Mulrow PJ, Gallagher JC, et al: Carcinoma of the lung with inappropriate antidiuresis: Demonstration of antidiuretic-hormone-like activity in tumor extract. N Engl J Med 269:544, 1963 40. Ivy HK: The syndrome of inappropriate secretion of antidiuretic hormone. Med Clin North Am 52:817, 1968 41. Swanson AG, Iseri OA: Acute encephalopathy due to
readySOUrCe AUDIOVISUALS
water intoxication. N Engl J Med 258:831, 1958 42. Lipsmeyer E, Ackerman GL: Irreversible brain damage after water intoxication. JAMA 196:286, 1966 43. Strauss CF: Chlorpropamide and angina pectoris. (Letter) Ann Intem Med 78:454, 1973 44. Lee J, Jones JJ, Barraclough MA: Inappropriate secretion of vasopressin. Lancet 2:792, 1964 45. Vorherr H, Massry SG, Utiger RD, et al: Antidiuretic principle in malignant tumor extracts from patients with inappropriate ADH syndrome. J Clin Endocrinol Metab 28:162, 1968 46. Perlroth MG, Tschudy OP, Marver HS, et al: Acute intermittent porphyria: New morphologie and biochemical findings. Am J Med 41:149, 1966 47. Stein JA, Curl FD, Valsamis M, et al: Abnormal iron and water metabolism in acute intermittent porphyria with new morphologie findings. Am J Med 53:784, 1972 48. Miller M, Moses AM: Mechanism of chlorpropamide action in diabetes insipidus. J Clin Endocrinol Metab 30:488, 1970 49. Clift GV, Schletter FE, Moses AM, et al: Syndrome of inappropriate vasopressin secretion: Studies on the mechanism of the hyponatremia in a patient. Arch Intem Med 118:453, 1966 50. Kaye M: An investigation into the cause of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 41:910, 1966 51. Earley LE, Orloff J: The mechanism of antidiuresis associated with the administration of hydrochlorothiazide to patients with vasopressin-resistant diabetes insipidus. J Clin lnvest 41:1988, 1962 52. Brown JJ, Chinn RH, Lever AF, et al: Renin and angiotensin as a mechanism of diuretic-induced antidiuresis in diabetes insipidus. Lancet 1:237, 1969 53. Hantman D, Rossier B, Zohlman R, et al: Rapid correction of hyponatremia in the syndrome of inappropriate secretion of antidiuretic hormone: An alternative trealment to hypertonie saline. Ann Intem Med 78:870, 1973 54. White MG, Fetner CD: Treatment of the syndrome of inappropriate secretion of antidiuretic hormone with lithium carbonate. N Engl J Med 292:390, 1975 55. Forrest JN Jr, Cohen AD, Torretti J, et al: On the mechanism of lithium-induced diabetes insipidus in man and the rat. J Clin Invest 53:1115, 1974
WATER INTOXICATION
DO
Dlagnoals and Treatment of the Syndrome of Water Intoxication Burns 3:10-min tape, catalog no. 52 Source: Wisconsin Dial Access Tapes, 610 Walnut St, Madison, Wl 53706 Coat: $4, 1/4-in. audiotape; $10, Echomatic cartridge
Vol. 62 • No. 4 • October 19n • POSTGRADUATE MEDICINE
0
0
Fluld, Electrolyte, and Acld-Base Dlsordera Magee et al 60-min tape, catalog no. lM-23-14 Source: Audio-Digest Foundation, 1577 E Chevy Chase Dr, Glendale, CA 91206 Coat: $5.40, C-60 cassette or standard 5-in. reel For details on how to use ReadySource, sea page 143.
79
