Secondary adrenal insufficiency laboratory findings
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Iqra Qamar M.D.[2]
Overview
Laboratory findings consistent with the diagnosis of adrenal insufficiency may include eosinophilia,lymphocytosis,normocytic anemia,hyponatremia , mild hypercalcemia, and azotemia. Secondary adrenal insufficiency may be confirmed by dynamic tests such as insulin tolerance test and corticotropin stimulation test (standard and low dose). Adrenal function can be assessed by measuring basal ACTH secretion and ACTH reserve (via Metyrapone stimulation test).
Laboratory Findings
| Source of pathology | CRH | ACTH | DHEA | DHEA-S | cortisol | aldosterone | renin | Na | K | Causes5 |
| hypothalamus (tertiary)1 |
low | low | low | low | low3 | low | low | low | low | tumor of the hypothalamus (adenoma), antibodies, environment (i.e. toxins), head injury |
| pituitary (secondary) |
high2 | low | low | low | low3 | low | low | low | low | tumor of the pituitary (adenoma), antibodies, environment, head injury, surgical removal6, Sheehan's syndrome |
| adrenal glands (primary)7 |
high | high | high | high | low4 | low | high | low | high | tumor of the adrenal (adenoma), stress, antibodies, environment, Addison's Disease, trauma, surgical removal (resection), miliary tuberculosis of the adrenal |
| 1 | Automatically includes diagnosis of secondary (hypopituitarism) |
| 2 | Only if CRH production in the hypothalamus is intact |
| 3 | Value doubles or more in stimulation |
| 4 | Value less than doubles in stimulation |
| 5 | Most common, does not include all possible causes |
| 6 | Usually because of very large tumor (macroadenoma) |
| 7 | Includes Addison's disease |
Routine Investigations
- Complete blood count and differential count:
- Eosinophilia
- Lymphocytosis
- Normocytic anemia may be present.
- Serum ACTH levels - elevated in primary adrenal insufficiency and decreased in secondary form.
- Hypoglycemia[1][2][3]
- Serum electrolytes:
- Hyponatraemia - (low blood sodium levels)[4]
- Hyperkalemia- not present
- Mild hypercalcemia - in 20% patients
- Mild non–anion-gap metabolic acidosis
- Serum cortisol - decreased (<25mcg/dL)
- Urine and sweat sodium - elevated
- Azotemia- Elevated BUN and creatinine - when hypovolemia is the cause.
- Prolactin - mild elevation may be present.
| Hormone | Test | Procedure | Normal response |
|---|---|---|---|
| ACTH | Insulin tolerance | ||
| Corticotropin standard dose (250 μg) |
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| Corticotropin low dose (1 μg) |
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| ADH | Water deprivation test |
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Diabetes insipidus (DI): Plasma osmolality >295 mOsm/L with inappropriately hypotonic urine (urine osmolality/plasma osmolality ratio <2) during the fluid deprivation confirms DI (test is discontinued)
Partial/primary polydipsia: With partial DI or primary polydipsia, urine concentrates partially during the water deprivation test (300–800 mOsm/kg), and further investigation is required including a prolonged water deprivation test or DDAVP therapeutic trial |
1.Corticotropin:
(a) Basal ACTH secretion:
The normal range of serum cortisol is 5 to 25 mcg/dL (138 to 690 nmol/L). Serum cortisol levels are measured at 8 to 9 am and results are interpreted as follows:
| Serum cortisol | Basal adrenocorticotrophic hormone (ACTH) |
|---|---|
| Low: ≤3 mcg/dL (83 nmol/L) | Cortisol deficiency |
| High: ≥18 mcg/dL (497 nmol/L) | No cortisol deficiency even in times of stress |
| Intermediate: >3 mcg/dL (83 nmol/L)
but <18 mcg/dL (497 nmol/L) |
Needs evaluation for ACTH reserve |
(b) ACTH reserve:
- Patients with intermediate cortisol levels need to be tested for ACTH reserve. There are several tests to check the ACTH reserve. Metyrapone test is preferred over others as it is applicable to all adults with no age restriction and has good correlation with stress related cortisol response. The major disadvantage of the test is that it needs inpatient observation for blood pressure and pulse monitoring to prevent postural hypotension.
- Insulin-induced hypoglycemia test is not preferred as it needs continuous monitoring for hypoglycemic symptoms during the first hour of insulin administration in patients who are elderly and have cardiovascular or cerebrovascular issues or a seizure disorder. Hypoglycemia is treated with intravenous glucose. The standard or low dose cosynotropin stimulation test is not recommended as it can give falsely normal results.[5][6][7][8][9][10][11][12][13][14][15]
- The corticotropin-releasing hormone test indicates pituitary-adrenal function and is as reliable as insulin-induced hypoglycemia test but has a limitation that only a small number of patients can be evaluated and may cause transient nausea.
Metyrapone test:
Metyrapone blocks 11-beta-hydroxylase (CYP11B1), an enzyme that catalyzes the last step in cortisol production resulting in decreased cortisol and increased 11-deoxycortisol concentration. In this test 750 mg of Metyrapone is administered orally every 4 hours for 24 hours. Serum cortisol and 11-deoxycortisol concentration are checked at 8 am after 24 hours and the results are interpreted as follows:
| Subject | Cortisol level | 11-deoxycortisol level |
|---|---|---|
| Normal subjects | < 7 mcg/dL (172 nmol/L) | ≥10 mcg/dL (289 nmol/L) |
| Patients with decreased ACTH reserve | <7 mcg/dL (172 nmol/L) | <10 mcg/dL (289 nmol/L) |
References
- ↑ Burke CW (1985). "Adrenocortical insufficiency". Clin Endocrinol Metab. 14 (4): 947–76. PMID 3002680.
- ↑ Todd GR, Acerini CL, Ross-Russell R, Zahra S, Warner JT, McCance D (2002). "Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom". Arch. Dis. Child. 87 (6): 457–61. PMC 1755820. PMID 12456538.
- ↑ Stacpoole PW, Interlandi JW, Nicholson WE, Rabin D (1982). "Isolated ACTH deficiency: a heterogeneous disorder. Critical review and report of four new cases". Medicine (Baltimore). 61 (1): 13–24. PMID 6276646.
- ↑ Cuesta M, Garrahy A, Slattery D, Gupta S, Hannon AM, Forde H, McGurren K, Sherlock M, Tormey W, Thompson CJ (2016). "The contribution of undiagnosed adrenal insufficiency to euvolaemic hyponatraemia: results of a large prospective single-centre study". Clin. Endocrinol. (Oxf). 85 (6): 836–844. doi:10.1111/cen.13128. PMID 27271953.
- ↑ Spark RF (1971). "Simplified assessment of pituitary-adrenal reserve. Measurement of serum 11-deoxycortisol and cortisol after metyrapone". Ann. Intern. Med. 75 (5): 717–23. PMID 4330677.
- ↑ Jubiz W, Meikle AW, West CD, Tyler FH (1970). "Single-dose metyrapone test". Arch. Intern. Med. 125 (3): 472–4. PMID 4313728.
- ↑ Landon J, Greenwood FC, Stamp TC, Wynn V (1966). "The plasma sugar, free fatty acid, cortisol, and growth hormone response to insulin, and the comparison of this procedure with other tests of pituitary and adrenal function. II. In patients with hypothalamic or pituitary dysfunction or anorexia nervosa". J. Clin. Invest. 45 (4): 437–49. doi:10.1172/JCI105358. PMC 292718. PMID 5949228.
- ↑ Streeten DH, Anderson GH, Bonaventura MM (1996). "The potential for serious consequences from misinterpreting normal responses to the rapid adrenocorticotropin test". J. Clin. Endocrinol. Metab. 81 (1): 285–90. doi:10.1210/jcem.81.1.8550765. PMID 8550765.
- ↑ Soule SG, Fahie-Wilson M, Tomlinson S (1996). "Failure of the short ACTH test to unequivocally diagnose long-standing symptomatic secondary hypoadrenalism". Clin. Endocrinol. (Oxf). 44 (2): 137–40. PMID 8849565.
- ↑ Dickstein G, Shechner C, Nicholson WE, Rosner I, Shen-Orr Z, Adawi F, Lahav M (1991). "Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test". J. Clin. Endocrinol. Metab. 72 (4): 773–8. doi:10.1210/jcem-72-4-773. PMID 2005201.
- ↑ Mayenknecht J, Diederich S, Bähr V, Plöckinger U, Oelkers W (1998). "Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease". J. Clin. Endocrinol. Metab. 83 (5): 1558–62. doi:10.1210/jcem.83.5.4831. PMID 9589655.
- ↑ Soule S, Van Zyl Smit C, Parolis G, Attenborough S, Peter D, Kinvig S, Kinvig T, Coetzer E (2000). "The low dose ACTH stimulation test is less sensitive than the overnight metyrapone test for the diagnosis of secondary hypoadrenalism". Clin. Endocrinol. (Oxf). 53 (2): 221–7. PMID 10931104.
- ↑ Nye EJ, Grice JE, Hockings GI, Strakosch CR, Crosbie GV, Walters MM, Torpy DJ, Jackson RV (2001). "Adrenocorticotropin stimulation tests in patients with hypothalamic-pituitary disease: low dose, standard high dose and 8-h infusion tests". Clin. Endocrinol. (Oxf). 55 (5): 625–33. PMID 11894974.
- ↑ Suliman AM, Smith TP, Labib M, Fiad TM, McKenna TJ (2002). "The low-dose ACTH test does not provide a useful assessment of the hypothalamic-pituitary-adrenal axis in secondary adrenal insufficiency". Clin. Endocrinol. (Oxf). 56 (4): 533–9. PMID 11966747.
- ↑ Ospina NS, Al Nofal A, Bancos I, Javed A, Benkhadra K, Kapoor E, Lteif AN, Natt N, Murad MH (2016). "ACTH Stimulation Tests for the Diagnosis of Adrenal Insufficiency: Systematic Review and Meta-Analysis". J. Clin. Endocrinol. Metab. 101 (2): 427–34. doi:10.1210/jc.2015-1700. PMID 26649617.