SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION
SIADH is the most common cause of euvolemic hypoosmolality. It is also the single most prevalent cause of hypoosmolality of all etiologies encountered in clinical practice, with prevalence rates ranging from 20% to 40% among all hypoosmolar patients.
12,
41,
93,
94 The clinical criteria necessary to diagnose SIADH remain basically as set forth by Bartter and Schwartz in 1967.
2 A modified summary of these criteria is presented in
Table 70.3 along with several other clinical
findings that support this diagnosis. Several points about each of these criteria deserve emphasis and/or qualification:
1. True hypoosmolality must be present and hyponatremia secondary to pseudohyponatremia or hyperglycemia alone must be excluded.
2. Urinary concentration (osmolality) must be inappropriate for plasma hypoosmolality. This does not mean that urine osmolality must be greater than plasma osmolality (a common misinterpretation of this criterion), but simply that the urine must be less than maximally dilute (i.e., urine osmolality >100 mOsm per kg H
2O). It also should be remembered that urine osmolality need not be elevated inappropriately at all levels of plasma osmolality, because in the reset osmostat variant of SIADH, AVP secretion can be suppressed with resultant maximal urinary dilution and free water excretion if plasma osmolality is decreased to sufficiently low levels.
95,
96 Hence, to satisfy the classical criteria for the diagnosis of SIADH, it is necessary only that urine osmolality be inadequately suppressed at some level of plasma osmolality less than 275 mOsm per kg H
2O.
3. Clinical euvolemia must be present to establish a diagnosis of SIADH, because both hypovolemia and hypervolemia strongly suggest different causes of hypoosmolality. This does not mean that patients with SIADH cannot become hypovolemic or hypervolemic for other reasons, but in such cases it is impossible to diagnose the underlying inappropriate antidiuresis until the patient is rendered euvolemic and found to have persistent hypoosmolality.
4. The criterion of renal “salt-wasting” has probably caused the most confusion regarding diagnosis of SIADH. This criterion is included because of its utility in differentiating between hypoosmolality caused by a decreased EABV, in which case renal Na+ conservation occurs, and distal dilution-induced disorders, in which urinary Na+ excretion is normal or increased secondary to ECF volume expansion. However, two important qualifications limit the utility of urine [Na+] measurement in the hypoosmolar patient: urine [Na+] also is high when solute depletion is of renal origin, as seen with diuretic use or Addison disease, and patients with SIADH can have low urine Na+ excretion if they subsequently become hypovolemic or solute depleted, conditions that sometimes follow severe sodium and water restriction. Consequently, although a high urine Na+ excretion is the rule in most patients with SIADH, its presence does not guarantee this diagnosis, and, conversely, its absence does not rule out the diagnosis.
5. The final criterion emphasizes that SIADH remains a diagnosis of exclusion. Thus, the presence of other potential causes of euvolemic hypoosmolality must always be excluded. This includes not only thyroid and adrenal dysfunction, but also diuretic use, because this can also sometimes present as euvolemic hypoosmolality.
Table 70.3 also lists several other criteria that support, but are not essential for a diagnosis of SIADH. The first of these, the water load test, is of value when there is uncertainty regarding the etiology of modest degrees of hypoosmolality in euvolemic patients, but it does not add useful information if the plasma osmolality is <275 mOsm per kg H
2O. Inability to excrete a standard water load normally (with normal excretion defined as a cumulative urine output of at least 90% of the administered water load within 4 hours, and suppression of urine osmolality to <100 mOsm per kg H
2O
97) confirms the presence of an underlying defect in free water excretion. Unfortunately, water loading is abnormal in almost all disorders that cause hypoosmolality, whether dilutional or depletion-induced with secondary impairments in free water excretion. Two exceptions are primary polydipsia, in which hypoosmolality can rarely be secondary to excessive water intake alone, and the reset osmostat variant of SIADH, in which normal excretion of a water load can occur once plasma osmolality falls below the new set point for AVP secretion. The water load test may also be used
to assess water excretion after treatment of an underlying disorder thought to be causing SIADH. For example, after discontinuation of a drug associated with SIADH in a patient who has already achieved a normal plasma osmolality by fluid restriction, a normal water load test can confirm the absence of persistent inappropriate antidiuresis much more quickly than can simple monitoring of the serum [Na
+] during a period of ad libitum fluid intake. Despite these limitations as a diagnostic clinical test, the water load test remains an extremely useful tool in clinical research for quantitating changes in free water excretion in response to physiologic or pharmacologic manipulations.
The second supportive criterion for a diagnosis of SIADH is an inappropriately elevated plasma AVP level in relation to plasma osmolality. At the time that SIADH was originally described, inappropriately elevated plasma levels of AVP were merely postulated because the measurement of plasma levels of AVP was limited to relatively insensitive bioassays. With the development of sensitive AVP radioimmunoassays capable of detecting the small physiologic concentrations of this peptide that circulate in plasma,
98 there was hope that measurement of plasma AVP levels might supplant the classic criteria and become the definitive test for diagnosing SIADH, as is the case for many syndromes of hormone hypersecretion. This has not occurred for several reasons. First, although plasma AVP levels are elevated in most patients with this syndrome, the elevations generally remain within the normal physiologic range and are abnormal only in relation to plasma osmolality (
Fig. 70.3). Therefore, AVP levels can be interpreted only in conjunction with a simultaneous plasma osmolality and knowledge of the relation between AVP levels and plasma osmolality in normal subjects (see
Chapter 4). Second, 10% to 20% of patients with SIADH do not have measurably elevated plasma AVP levels; as shown in
Figure 70.3, many such patients have AVP levels that are at, or even below, the limits of detection by radioimmunoassay. Whether these cases are true examples of inappropriate antidiuresis in the absence of circulating AVP, or whether they simply represent inappropriate AVP levels that fall below the limits of detection by radioimmunoassay, is not clear. For this reason, Zerbe et al. have proposed using the term SIAD (syndrome of inappropriate antidiuresis) rather than SIADH to describe this entire group of disorders.
99 Studies of hyponatremic children have discovered two genetic mutations of the vasopressin V2 receptor (V2R) that were responsible for constitutive activation of antidiuresis in the absence of AVP-V2R ligand binding.
100 The true incidence of these, and similar V2R mutations, as well as how often they are responsible for patients with SIADH but low or unmeasurable plasma AVP levels, remains to be determined. Third, just as water loading fails to distinguish among various causes of hypoosmolality, so do plasma AVP levels. Many disorders causing solute and volume depletion are associated with elevations of plasma AVP levels secondary to hemodynamic stimuli. For similar reasons, patients with disorders that cause decreased EABV, such as congestive heart failure and cirrhosis, also have elevated AVP levels (see
Chapters 67 and
68). Even glucocorticoid insufficiency has been associated with inappropriately elevated AVP levels, as is discussed in the following section.
101 Therefore, multiple different disorders cause stimulation of AVP secretion via nonosmotic mechanisms, rendering this measurement of relatively limited differential diagnostic value. Recent studies using a newly developed assay for copeptin, the glycopeptide C-terminal fragment of the AVP prohormone, have confirmed AVP secretion in most cases of dilutional hyponatremia except for primary polydipsia, where this measurement may prove to be of use diagnostically.
102
Finally, an improvement in plasma osmolality with fluid restriction but not with volume expansion can sometimes be helpful in differentiating between disorders causing solute depletion and those associated with dilution-induced hypoosmolality. Infusion of isotonic NaCl in patients with SIADH provokes a natriuresis with little correction of osmolality, whereas fluid restriction allows such patients to achieve solute and water balance gradually through insensible free water losses.
1 In contrast, isotonic saline is the treatment of choice in disorders of solute depletion, because once volume deficits are corrected the stimulus to continued AVP secretion and free water retention is eliminated. The diagnostic value of this therapeutic response is limited somewhat by the fact that patients with proximal types of dilution-induced disorders may show a response similar to that found in patients with SIADH. However, the major drawback is that this represents a retrospective test in a situation in which
it would be preferable to establish a diagnosis before making a decision regarding treatment options. Nonetheless, in difficult cases of euvolemic hypoosmolality, an appropriate therapeutic response can sometimes be helpful in confirming a diagnosis of SIADH.
Etiology
Although the list of disorders associated with SIADH is long, they can be divided into four major etiologic groups (
Table 70.4).
Tumors
One of the most common associations of SIADH remains with tumors. Although many different types of tumors have been associated with SIADH (
Table 70.4), bronchogenic carcinoma of the lung has been uniquely associated with SIADH since the first description of this disorder in 1957.
1 In virtually all cases, the bronchogenic carcinomas causing this syndrome have been of the small cell variety; a few squamous cell types have been described, but these are rare. Incidences of hyponatremia as high as 11% of all patients with smallcell carcinoma,
103 or 33% of cases with more extensive disease,
104 have been reported. The unusually high incidence of small cell carcinoma of the lung in patients with SIADH, together with the relatively favorable therapeutic response of this type of tumor, makes it imperative that all patients presenting with an otherwise unexplained SIADH be investigated thoroughly and aggressively for a possible tumor. The evaluation should include a computed tomography (CT) or magnetic resonance imaging (MRI) scan of the thorax. In cases with a high degree of suspicion (e.g., hyponatremia in a young smoker) bronchoscopy with cytologic analysis of bronchial washings should be considered even if the results of routine chest radiography are normal, since several studies have reported hypoosmolality that predated any radiographically evident abnormality in patients who then were found to harbor bronchogenic carcinomas 3 to 12 months later.
105,
106 Head and neck cancers account for another group of malignancies associated with relatively higher incidences of SIADH,
107 and some of these tumors have clearly been shown to be capable of synthesizing AVP ectopically.
108 A report from a large cancer hospital showed an incidence of hyponatremia for all malignancies combined of 3.7%, with approximately one third of these due to SIADH.
20
Central Nervous System Disorders
The second major etiologic group of disorders causing SIADH has its origins in the central nervous system (CNS). Despite the large number of different CNS disorders associated with SIADH, there is no obvious common denominator linking them. However, this is actually not surprising when one considers the neuroanatomy of neurohypophysial innervation. The magnocellular AVP neurons receive excitatory inputs from osmoreceptor cells located in the anterior hypothalamus, but also have a major innervation from brainstem cardiovascular
regulatory and emetic centers (
Fig. 70.4). Although various components of these pathways have yet to be fully elucidated, many of them appear to have inhibitory as well as excitatory components.
109 Consequently, any diffuse CNS disorder can potentially cause AVP hypersecretion either by nonspecifically exciting these pathways via irritative foci, or alternatively by disrupting them and thereby decreasing the level of inhibition impinging upon the AVP neurons in the neurohypophysis. The wide variety of diverse CNS processes that can potentially cause SIADH stands in contrast to CNS causes of diabetes insipidus, which are for the most part limited to lesions localized to the hypothalamus and/or posterior pituitary that destroy the magnocellular vasopressin neurons (see
Chapter 71).
Pulmonary Disorders
Pulmonary disorders represent a relatively common but frequently misunderstood cause of SIADH. A variety of pulmonary disorders have been associated with this syndrome, but other than tuberculosis,
128 acute pneumonia,
129,
130,
131 and advanced chronic obstructive lung disease,
132 the occurrence of hypoosmolality has been noted mainly in sporadic case reports. Some bacterial infections appear to be associated with a higher incidence of hyponatremia, particularly
Legionella pneumoniae.
133 Although one case of pulmonary tuberculosis has been reported that suggested the possibility that tuberculous lung tissue might synthesize AVP ectopically,
134 several other studies have reported that advanced pulmonary tuberculosis is associated with the reset osmostat form of SIADH,
96,
128 presumably from nonosmotic stimulation of posterior pituitary AVP secretion. Most cases of pulmonary SIADH not associated with either tuberculosis or pneumonitis have occurred in the setting of respiratory failure. Although hypoxia has clearly been shown to stimulate AVP secretion in animals,
135,
136 it appears to be less effective as a stimulus in humans,
137 in whom the stimulus to abnormal water retention appears to be hypercarbia more so than hypoxia.
138,
139 When such patients were evaluated serially, the inappropriate AVP secretion was found to be limited to the initial days of hospitalization, when respiratory failure was most marked.
140 Even cases of tubercular SIADH generally have occurred in patients with far advanced, active, pulmonary tuberculosis, although interestingly hyponatremia was also found in 74% of a series of patients with miliary tuberculosis.
141 Therefore, SIADH in non-tumor-related pulmonary disease generally conforms to the following characteristics: (1) the pulmonary disease will always be obvious as a result of severe dyspnea or extensive radiographically evident infiltrates, and (2) the inappropriate antidiuresis will usually be limited to the period of respiratory failure— once clinical improvement has begun, free water excretion generally improves rapidly. Mechanical ventilation can cause inappropriate AVP secretion, or it can worsen any SIADH caused by other factors. This phenomenon has been associated most often with continuous positive pressure ventilation,
142 but it can also occur to a lesser degree with the use of positive end expiratory pressure.
Other Causes
One of the most recently described causes of hypoosmolality is the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC), in patients with human immunodeficiency virus (HIV) infection, with incidences of hyponatremia reported as high as 30% to 38% in adults
143,
144,
145 and children.
146 Although there are many potential etiologies for hyponatremia in patients with AIDS/ARC, including dehydration, adrenal insufficiency, and pneumonitis, from 12% to 68% of AIDS patients who develop hyponatremia appear to meet criteria for a diagnosis of SIADH.
143,
144,
145 Not unexpectedly, reports have implicated some of the medications used to treat these patients as the cause of the hyponatremia, either via direct renal tubular toxicity or SIADH.
147,
148
A recent series of reports have documented a surprisingly high incidence of hyponatremia during endurance exercise events such as marathon
149 and ultramarathon
150 foot races, triathlons,
151 forced marching,
152 and hiking.
153 Occasionally, this has caused fatal outcomes associated with hyponatremic encephalopathy from acute brain edema.
154,
155 Most studies support excess drinking during the exercise as the major cause of the induced hyponatremia,
156,
157 but it now appears that water retention under such conditions is also contributed to by SIADH as a result of multiple potential nonosmotic stimuli (e.g., volume depletion, nausea, increased cytokine levels).
158,
159
Unexplained or idiopathic causes account for a relatively small proportion of all cases of SIADH. Although the etiology of the syndrome may not be diagnosed initially in many cases, the numbers of patients in whom an apparent cause cannot be established after consistent follow-up over time are relatively few. However, an exception to this appears to be elderly patients who sometimes develop SIADH without any apparent underlying etiology.
160,
161,
162 Coupled with the significantly increased incidence of hyponatremia in geriatric patients,
7,
13,
14,
93,
163,
164 this suggests that the normal aging process may be accompanied by abnormalities of regulation of AVP secretion that predispose to SIADH. Such an effect could potentially account for the fact that virtually all causes of drug-induced hyponatremia occur much more frequently in elderly patients.
82,
165,
166 In several series of elderly patients meeting criteria for SIADH, 40% to 60% remained idiopathic despite rigorous evaluation,
167,
168,
169 leading some to conclude that extensive diagnostic procedures were not warranted in such elderly patients if routine history, physical examination, and laboratory evaluation failed to suggest a diagnosis.
167
Some well-known stimuli of AVP secretion are notable primarily because of their exclusion from
Table 70.4. Despite unequivocal stimulation of AVP secretion by nicotine,
170 cigarette smoking has only rarely been associated with SIADH,
and primarily in psychiatric patients who have several other potential causes of inappropriate AVP secretion.
39,
171,
172 This is in part because of chronic adaptation to the effects of nicotine, but also because the short half-life of AVP in plasma (approximately 15 min in humans
173) limits the duration of antidiuresis produced by relatively short-lived stimuli such as smoking. Although nausea remains the most potent stimulus to AVP secretion known in man,
174 chronic nausea is rarely associated with hypoosmolality unless accompanied by vomiting with subsequent ECF solute depletion followed by ingestion of hypotonic fluids.
175 Similar to smoking, this is probably attributable to the short half-life of AVP, but also to the fact that most such patients are not inclined to drink fluids under such circumstances. However, hyponatremia can occur when such patients are infused with high volumes of hypotonic fluids. This is likely a factor contributing to the hyponatremia that often occurs in cancer patients who are receiving chemotherapy.
103 Finally, a causal relation between stress and SIADH has often been suggested, but never conclusively established. This underscores the fact that stress, independent of associated nausea, dehydration, or hypotension, is not a major stimulus causing sustained elevations of AVP levels in humans.
176