A 67-Year-Old Woman With Orthostatic Hypotension and Edema

Catherine Anastasopoulou, MD, PhD; Kimberly Lessard, DO

Disclosures

March 08, 2018

Adrenal hemorrhage has been associated with infectious etiologies. One such condition, Waterhouse-Friderichsen syndrome, involves adrenal hemorrhage secondary to meningococcemia and has hallmark features of fever and petechiae (50%-60%). Additional bacterial causes of sepsis involving bilateral adrenal hemorrhage include Haemophilus influenzae, Escherichia coli, Mycoplasma pneumoniae, Streptococcus pneumoniae, and Staphylococcus aureus. Adrenal hemorrhage/infarction has also been associated with Rocky Mountain spotted fever, murine and epidemic typhus, and viral infections, including cytomegalovirus, parvovirus B19, and Epstein-Barr virus.

Because adrenal crisis and insufficiency can be difficult to discern from other conditions in such patients, the diagnosis should be considered when any such risk factor is present. Without appropriate treatment, hypotension often progresses to shock with very high mortality. Furthermore, adrenal function rarely returns to normal in such patients and often requires permanent hormone replacement therapy.

In this patient, secondary adrenal insufficiency was less likely given the suspicion for adrenal hemorrhage. Secondary adrenal insufficiency involves adrenocorticotropic hormone (ACTH) deficiency due to pituitary causes or, less often, hypothalamic causes, including suppression from exogenous corticosteroid. In secondary adrenal insufficiency, mineralocorticoid function is typically spared. As a result, secondary adrenal insufficiency generally does not result in hypotension, hyponatremia, hyperkalemia, or hyperpigmentation. Differentiating primary adrenal insufficiency from secondary adrenal insufficiency typically involves measuring ACTH. In the setting of low morning cortisol levels, inappropriately low ACTH levels are diagnostic of secondary adrenal insufficiency. Conversely, ACTH levels are elevated in primary adrenal insufficiency in response to absent cortisol. Secondary adrenal insufficiency often coexists with hypothyroidism and/or growth-hormone deficiency; neither were present in this patient.

Tertiary adrenal insufficiency at the level of the hypothalamus was also considered in the differential diagnosis. In tertiary adrenal insufficiency, classic findings include low cortisol levels, low-normal ACTH levels, and reduced corticotropin-releasing hormone levels. Once again, a normal thyroid function makes dysfunction at the level of the hypothalamus less likely.

SIADH, although also part of the differential diagnoses for hyponatremia, was less likely in this patient and requires the exclusion of adrenal insufficiency and hypothyroidism. The patient in this case appeared to be hypovolemic and required IV fluid resuscitation for clinical stabilization. The correction of sodium to normal values following administration of IV fluids makes SIADH, which is typically treated with fluid restriction, less likely. Additionally, the patient has several clinical features not explained by SIADH alone, including hypotension, hyperkalemia, and peripheral edema. The sodium level in this patient was also not low enough to explain her neurologic symptoms.

Although the patient was noted to have grade 1 diastolic dysfunction as well as peripheral edema, decompensated heart failure was less likely given the patient's relatively normal echocardiography and lack of clinical findings (no jugular venous distention or pulmonary edema) with only slightly elevated brain natriuretic peptide. Although patients with congestive heart failure and/or renal insufficiency do not usually have peripheral edema, they may have difficulty getting rid of fluids due to reduction in free water clearance.

Autonomic dysfunction should be considered as a cause of hypotension in the elderly, particularly following trauma, but was unlikely to account for the electrolytic abnormalities in this patient. The patient is noted to be anemic, which is likely multifactorial in origin, with a hemoglobin below the standard threshold for symptom development (approximately 12 g/dL). However, her history of chronic anemia and lack of acute drop in hemoglobin made this less likely to be the cause of her symptoms. Also, it also would not account for her metabolic abnormalities. However, in the context of therapeutic anticoagulation and recent adrenal hemorrhage, hemoglobin should be closely monitored in patients like the one in this case.

A morning serum cortisol level <3 µg/dL alone is diagnostic of adrenal insufficiency. Based on clinical presentation and etiology related to adrenal hemorrhage, primary adrenal insufficiency can be presumed. Thus, further testing is not indicated to differentiate between primary, secondary, or tertiary causes of adrenal insufficiency.

A morning ACTH level can be used, albeit less commonly, in differentiating between primary, secondary, and tertiary adrenal insufficiency. ACTH is a hormone secreted by the anterior pituitary with the principle effect of promoting cortisol production at the level of the adrenal cortex. In the setting of a decreased morning cortisol level, an appropriately elevated ACTH level is suggestive of dysfunction at the level of the adrenal gland and thus primary adrenal insufficiency. Conversely, an inappropriately low level of ACTH in the setting of decreased cortisol is suggestive of dysfunction at the level of the pituitary (secondary adrenal insufficiency) or potentially at the level of the hypothalamus (tertiary adrenal insufficiency). ACTH measurement was not indicated in this patient due to sufficient evidence of primary adrenal insufficiency.

A cosyntropin stimulation test is used to confirm the presence of adrenal insufficiency by evaluating the adrenal response to ACTH. This is done by injection of cosyntropin (synthetic ACTH) and measurement of baseline and subsequent cortisol levels 30 minutes, 60 minutes, and 90 minutes later. The primary use of a cosyntropin stimulation test is to rule out adrenal insufficiency when cortisol levels are intermediate or inconclusive (ie, 3-15 µg/dL). Interpretation of this test may also aid in differentiating between primary and secondary adrenal insufficiency. In healthy individuals with a normal baseline morning cortisol level (20-30 µg/dL), the cortisol level is expected to rise by 200% (ie, double) within 60 minutes of cosyntropin administration. In primary adrenal insufficiency, the baseline cortisol is generally <10 µg/dL and has no more than a 25% increase in response to cosyntropin administration. Secondary adrenal insufficiency can result in variable response to cosyntropin. In general, a failure for cortisol level to rise >18 µg/dL is considered confirmation of adrenal insufficiency. The insulin tolerance test is considered the criterion standard test for diagnosing adrenal insufficiency. However, due to risks and side effects of the insulin tolerance test, the cosyntropin stimulation test is more commonly used. The cosyntropin stimulation test is 97% sensitive (at 95% specificity) for diagnosing primary adrenal insufficiency and is only 57%-61% sensitive for diagnosing secondary adrenal insufficiency. The patient in this case was found to have a significantly reduced morning cortisol level, well below 3 µg/dL. For this reason, no further testing was needed to confirm the presence of adrenal insufficiency.

Although aldosterone levels are expected to be low in patients with primary adrenal insufficiency, levels can be normal in secondary and tertiary adrenal insufficiency. Although these levels can be adjunctive to low morning cortisol in confirming mineralocorticoid deficits in primary adrenal insufficiency, they are not routinely measured and are not needed for diagnosis in patients like the one described here. Furthermore, if primary adrenal insufficiency is suspected, treatment with both mineralocorticoid and glucocorticoid replacement should be empirically started and should not be withheld while awaiting serum aldosterone levels.

The measurement of 24-hour urine cortisol is used to confirm the presence of hypercortisolism in Cushing disease. Although basal urinary cortisol levels may be low in patients with severe adrenal insufficiency, they may be low-normal in a patient with partial adrenal insufficiency. Thus, urine cortisol is not indicated for assessment of adrenal insufficiency. PM salivary cortisol testing is used to assess for hypercortisolism in Cushing disease and takes into consideration the diurnal release of cortisol. This test has no role in the evaluation of adrenal insufficiency.

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