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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 11 5255-5257
Copyright © 2003 by The Endocrine Society

Low Plasma Bicarbonate Level in Hyponatremia Related to Adrenocorticotropin Deficiency

G. Decaux, W. Musch, R. Penninckx and A. Soupart

Research Unit for the Study of Hydromineral Metabolism, Department of General Internal Medicine, University Hospital Erasme, 1070 Brussels, Belgium

Address all correspondence and requests for reprints to Guy Decaux, M.D., Ph.D., Research Unit for the Study of Hydromineral Metabolism, Department of General Internal Medicine, University Hospital Erasme, 808 Route de Lennik, 1070 Brussels, Belgium. E-mail: guy.decaux{at}skynet.be.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Patients with hyponatremia related to adrenocorticotropic deficiency are not easily distinguished by routine laboratory studies from patients with nonendocrine inappropriate secretion of antidiuretic hormone (SIADH). We wanted to investigate whether, in the routine biological analysis of such patients, some parameters could help to better identify this subgroup of hyponatremic patients. The biochemical profiles of 13 consecutive patients with hyponatremia related to ACTH deficiency were analyzed and compared with 30 consecutive patients with classical SIADH. Patients with adrenocorticotropic deficiency presented low uric acid and urea levels as in nonendocrine SIADH, but their total carbon dioxide was significantly lower (total CO2, 20.5 ± 3 vs. 25.5 ± 2.4 mmol/liter; P < 0.001). Nine of the 13 patients presented a value lower than 22 mmol/liter, although this was not observed in the nonendocrine SIADH patients (P < 0.001). Arterial blood gas analysis was available in eight patients and showed a compensated respiratory alkalosis in most of them (pH 7.42 ± 0.02; PCO2, 30 ± 5 mm Hg; HCO3-, 20 ± 2 mmol/liter; base excess, -3.4 ± 1.8 mmol/liter). Aldosterone levels were much lower in ACTH deficiency patients during the hyponatremic state (33 ± 40 pg/ml) when compared with the nonendocrine SIADH (120 ± 60 pg/ml; P < 0.01). Correction of hyponatremia by cortisone therapy normalized total CO2 and aldosterone levels. Low carbon dioxide level is a frequent observation in hyponatremia related to ACTH deficiency and could help to differentiate it from classical SIADH.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
ENDOCRINE DISORDERS, PARTICULARLY hypopituitarism (HP) must be excluded in patients presenting with hyponatremia related to inappropriate secretion of antidiuretic hormone (SIADH) (1, 2).

In SIADH, despite dilution, the plasma bicarbonate level remains typically normal (1). Otherwise, urea and uric acid levels decrease more than expected for the dilution due to higher renal clearance (3, 4). In rats with acute severe (3 h) or chronic hypotonic dilution (>24 h), the bicarbonate level stays normal (5). In dogs (6) and rats (5) with experimental chronic SIADH, it has been shown that the normal bicarbonate level is related to the development of hyperaldosteronism induced by hyponatremia. The pituitary gland is implicated in the development of this hyperaldosteronism by regulating cortisone levels (7). In humans with hyponatremia due to experimentally induced (8) or spontaneous (9, 10, 11) SIADH, aldosterone remains usually normal despite low renin levels, contributing to the avoidance of excessive urinary salt losses (9).

In a previous small series of patients presenting with hyponatremia related to ACTH deficiency (AD) we noted a decrease in total carbon dioxide (TCO2) levels associated with low urea and uric acid levels as observed in SIADH (12). However, in these cases, blood acid-base equilibrium and renin-aldosterone levels were not available.

The present study describes a larger series of patients with hyponatremia related to ACTH deficiency and confirms a decrease in TCO2 levels related to respiratory alkalosis and to relative hypoaldosteronism.

This observation could be helpful as a diagnostic tool for patients with adrenocorticotropic deficiency presenting with hyponatremia.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
We analyzed the clinical laboratory data of 13 consecutive patients with hyponatremia related to adrenocorticotropic deficiency (five males and eight females; mean age, 64 ± 18 yr) observed over a 10-yr period and compared their biochemical data with those of 30 consecutive patients of similar sex and age with nonendocrine SIADH. ACTH deficiency was secondary to pituitary tumors in seven patients, secondary to Sheehan’s syndrome in two, and of undetermined causes in four. In four patients, AD was isolated (two related to tumor and two idiopathic), and in five, mild hypothyroidism was associated. Nine patients also presented sexual hormone deficiency. SIADH was due to oat cell carcinoma in 10 patients, to organic brain disease in 10, to carbamazepine in three, to pneumonia in one, and to larynx carcinoma in one and was idiopathic in five. Routine biochemical parameters were available in AD before and after serum Na (SNa) correction by steroid therapy (cortisone, 37.5 mg/d).

All the patients were asymptomatic during the hyponatremic state.

Spot urine was also available for calculation of fractional Na excretion. All serum and chemical measurements were performed in the hospital clinical laboratory (automatic clinical analyzer). Uric acid was measured by the uricase method. To minimize laboratory variations, for each patient the mean value of two determinations for electrolytes and TCO2 was used. In eight patients with AD, arterial blood gas analysis was also available before and after correction of SNa. All the patients presented a SNa value lower than 130 mmol/liter. Most patients presented morning cortisol levels lower than 50 pg/ml (to convert to nanomoles per liter, multiply by 2.76) and ACTH levels lower than 10 pg/ml (to convert to micromoles per liter, multiply by 0.2202). Five patients presented a cortisol level between 50 and 70 pg/ml and an ACTH level between 10 and 20 pg/ml. In nine patients a rapid ACTH test using 0.25 mg ACTH-(1–24) (Synacthen, Ciba, Basel, Switzerland) was performed between 0800 and 1000 h and was abnormal. This test was done in the five patients with cortisol levels between 50 and 70 pg/ml. All hormones were measured by routine RIA. Statistical analysis was performed by one-way ANOVA followed by Fisher’s least-significant differences test when the former indicated that a significant difference (P < 0.05) existed. Results are presented as mean ± SD.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Blood pressure and pulse rate were similar in patients with AD and SIADH. Uric acid and urea levels were similar in the SIADH and the AD group. No patients presented hypoglycemia. TCO2 was clearly lower in the AD group (20.5 ± 2.5 mmol/liter and 25.5 ± 2 mmol/liter; P < 0.001) (Table 1Go). Nine patients with AD presented a TCO2 level lower than 22 mmol/liter, whereas, in the SIADH group, all presented a value higher or equal to 22 mmol/liter (P < 0.001) (Fig 1Go). Arterial blood values were available in eight of the 13 patients with adrenocortical insufficiency and in 12 of the nonendocrine SIADH patients (Table 1Go). The patients with AD presented a compensated respiratory alkalosis. In the four hyponatremic patients with AD and normal TCO2, no obvious difference in hormone deficiency was noted.


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  		TABLE 1. Some serum biochemical data in patients with hyponatremia related to AD (n = 13) and nonendocrine SIADH (n = 30) before and after correction of SNa (by cortisone in the AD group)

 


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  		FIG. 1. Evolution of TCO2 concentration in 13 patients with hyponatremia related to adrenocorticotropic deficiency (HP) before and after normalization of SNa by cortisone therapy. The right part of the figure shows the normal TCO2 value of 30 patients with similar levels of hyponatremia secondary to classical SIADH. The shaded area represents the normal range for TCO2.

 
Despite mild volume expansion, as attended by the low protein concentration (13) in both groups, patients with SIADH presented normal aldosterone levels, whereas the AD group presented much lower aldosterone levels (P < 0.01). In four patients with ACTH deficiency, the TCO2 normalized in a few days after normalization of SNa by urea therapy or water restriction before cortisone administration. This suggests that the respiratory alkalosis was induced by the hyponatremic state itself. In all the patients, once cortisone was administered, the SNa and the TCO2 normalized in 2 or 3 d. When mild hypothyroidism was present, thyroxine was administered after SNa was normalized. In some patients, supine aldosterone was available before and after cortisone therapy, and we observed a normalization of the aldosterone value (33 ± 40 pg/ml and 114 ± 32 pg/ml; P < 0.01) (Table 1Go).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
It is well known that an endocrine origin must always be excluded in a patient with SIADH (1, 2). Similarly, it has been shown that the presence of a low uric acid level (usually lower than 4 mg/dl) associated with hyponatremia is highly suggestive of SIADH (14), and this was also observed in our AD patients (12). Our data identified a new routine biochemical measurement (TCO2) allowing recognition of many patients with hyponatremia related to ACTH deficiency.

It is interesting to note that in four patients treated by water restriction or urea alone (15) before hypoadrenalism was diagnosed, we observed a normalization of the TCO2 and of the arterial blood values [aldosterone was measured in only one of them who normalized it (180 pg/ml)], suggesting that hyponatremia induced the respiratory alkalosis. In the SIADH group, mean aldosterone levels were normal, despite mild volume expansion as attested by the low plasma renin activity (PRA) and low protein concentration (8, 13). This relative hyperaldosteronism has been well documented in animals (5, 6) (in dogs it can even be associated with hypokalemia) and in experimentally induced SIADH in humans (8). In isolated perfused canine adrenal glands, low sodium concentration stimulates aldosterone secretion (16). In rats, acute hyponatremia (3 h) is associated with normal bicarbonate and blood acid-base equilibrium, whereas during chronic hyponatremia (>24 h) bicarbonate is still normal but blood acid-base equilibrium shows a mixed respiratory and metabolic alkalosis (5). We have shown that cortisone plays a critical role in the development of this hypotonic-related hyperaldosteronism, which induces the metabolic alkalosis (7). The origin of the respiratory alkalosis observed during chronic hyponatremia remains to be determined, but it could reflect some subclinical brain edema (5). In hyponatremia related to SIADH, the relative hyperaldosteronism induces a metabolic alkalosis that could decrease the respiratory alkalosis. In the AD patients with hyponatremia, the low aldosterone concentration explains why a metabolic alkalosis doesn’t develop, and a compensated respiratory alkalosis is observed, which explains their lower serum bicarbonate levels.

In our AD group, aldosterone levels were particularly low during the hyponatremic state, and the concomitant low PRA and low ACTH levels both probably contribute to the development of this hypoaldosteronism. Serum K+ remained normal in these patients despite the hypoaldosteronism; this is probably due to the euvolemic state. It is likely that in these hyponatremic patients, the lack of cortisol was the main factor for the hypoaldosteronism (7), but the low TCO2 was also due to respiratory alkalosis (7). Similarly, it has been shown that PRA and aldosterone are normal in nonhyponatremic HP patients (reflecting euvolemia) but that cortisol plays a permissive role on glomerulosa response to a potassium load. Under potassium chloride stimulus the aldosterone response in hypopituitary patients was observed only when cortisol was given (17).

When cortisone was added to the treatment, the SNa normalized, but aldosterone also increased. The mean arterial pH of the AD patients being 7.42 suggested respiratory alkalosis. However, some patients presented lower pH values (7.36 and 7.38) and in those patients, the metabolic acidosis related to the hypoaldosteronism probably contributes to the respiratory alkalosis (simple dilution acidosis is an unlikely explanation for the low TCO2) (5).

It must be noted that four of the 13 AD patients have a TCO2 value comparable to those with SIADH so that using this criterion alone, the diagnoses of ACTH deficiency would be missed. In all patients with hyponatremia of undetermined origin, an ACTH stimulation test should be performed.


   Acknowledgments
 
We thank Drs. J. Unger, B. Namias, L. Crenier, and B. Renneboog, who participated in the care of the patients.


   Footnotes
 
This work was supported by a grant from the Fonds National de la Recherche Scientifique (1.5.141.00F and N°3.4574.01).

Abbreviations: AD, ACTH deficiency; HP, hypopituitarism; PRA, plasma renin activity; SIADH, inappropriate secretion of antidiuretic hormone; SNa, serum Na; TCO2, total CO2.

Received March 6, 2003.

Accepted July 31, 2003.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Bartter FC, Schwartz WB 1967 The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 42:790–806[CrossRef][Medline]
  2. Oelkers W 1989 Hyponatremia and inappropriate secretion of vasopressin (antidiuretic hormone) in patients with hypopituitarism. N Engl J Med 321:492–496[Abstract]
  3. Dorhout Mees EJ, Blom van Assendelf TP, Nieuwenhuis MG 1971 Elevation of uric acid clearance caused by inappropriate antidiuretic hormone secretion. Acta Med Scand 189:69–72[Medline]
  4. Decaux G, Genette F, Mockel J 1980 Hypouremia in the syndrome of inappropriate secretion of antidiuretic hormone. Ann Intern Med 93:716–717
  5. Decaux G, Crenier L, Namias B, Gervy C, Soupart A 1994 Normal acid-base equilibrium in acute hyponatremia and mixed alkalosis in chronic hyponatremia induced by arginine vasopressin or 1-deamino-8D-arginine vasopressin in rats. J Lab Clin Med 123:892–898[Medline]
  6. Cohen JJ, Hulter HN, Smithline N, Melby JC, Schwartz WB 1976 The critical role of the adrenal gland in the renal regulation of acid-base equilibrium during chronic hypotonic expansion. J Clin Invest 58:1201–1208
  7. Decaux G, Crenier L, Namias B, Gervy C, Soupart A 1994 Restoration by corticosteroids of the hyperaldosteronism in hyponatremic rats with panhypopituitarism. Clin Sci 87:435–439[Medline]
  8. Boer WH, Koomans HA, Dorhout Mees EJ 1987 Lithium clearance during the paradoxical natriuresis of hypotonic expansion in man. Kidney Int 32:376–381[Medline]
  9. Fichman MP, Michelakis AM, Horton R 1974 Regulation of aldosterone in the syndrome of inappropriate hormone secretion (SIADH). J Clin Endocrinol Metab 39:136–144[Abstract/Free Full Text]
  10. Mc Kenna TJ, Sequeira SJ, Hefferman A, Chambers J, Cunninghams S 1991 Diagnosis under random conditions of all disorders of the renin-angiotensin-aldosterone axis, including primary hyperaldosteronism. J Clin Endocrinol Metab 73:952–957[Abstract/Free Full Text]
  11. Decaux G 2001 Difference in solute excretion during correction of hyponatremia in patients with cirrhosis or SIADH by oral vasopressin V2 receptor antagonist VPA-985. J Lab Clin Med 138:18–21[CrossRef][Medline]
  12. Decaux G, Schlesser M, Coffernils M, Prospert F, Namias B, Brimioulle S, Soupart A 1994 Uric acid, anion gap and urea concentration in the diagnostic approach to hyponatremia. Clin Nephrol 42:102–108[Medline]
  13. Namias B, Soupart A, Kornreich A, Decaux G 1996 In human patients, vascular water retention during AVP-related hyponatremia occurs mainly in the plasma volume and not in the erythrocyte. J Lab Clin Med 128:612–617[CrossRef][Medline]
  14. Beck LH 1979 Hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med 301:528–530[Medline]
  15. Decaux G 2001 Long-term treatment of patients with inappropriate secretion of antidiuretic hormone by the vasopressin receptor antagonist conivaptan, urea or furosemide. Am J Med 110:582–584[CrossRef][Medline]
  16. Schneider EG, Taylor RE, Radke KJ, Davis PH 1984 Effect of sodium concentration on aldosterone secretion by isolated perfused canine adrenal glands. Endocrinology 115:2195–2204[Abstract/Free Full Text]
  17. Lopez JM, Rodriguez JA, Marusie ET 1980 Plasma aldosterone response to angiotensin II and potassium chloride infusions in hypopituitary patients. Clin Endocrinol (Oxf) 4:331–337



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