#411 Adrenal Insufficiency with Dr. Atil Kargi

October 9, 2023 | By Elena Gibson

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Feel confident diagnosing adrenal insufficiency. Learn how to accurately interpret a stimulation test, differentiate primary from secondary adrenal insufficiency, and teach patients about preventing an adrenal crisis with Dr. Atil Kargi (UNC School of Medicine) 

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• Intro
• Case 1
• Case 2
• Topic
• Outro

Adrenal Insufficiency Pearls

1. The hypothalamic-pituitary-adrenal (HPA) axis is responsible for regulation and production of cortisol
2. The most common etiology of primary adrenal insufficiency (PAI) in western societies is autoimmune adrenalitis.
3. After a diagnosis of PAI is made, the 21-hydroxylase antibody should be checked for autoimmune adrenalitis. 
4. Typically in PAI, cortisol will be low and ACTH will be elevated. 
5. For secondary adrenal insufficiency, cortisol will be low and ACTH will typically be low or normal. 
6. Cortisol levels should be checked around the time a patient usually wakes up, typically from 7 to 9 am. 
7. When ACTH >300, the adrenal glands are maximally stimulated, and no change in cortisol levels would be expected with a stimulation test. Therefore a stimulation test may be unnecessary when basal A TH levels are above 300 pg/mL.
8. Since cortisol is protein bound, low total cortisol with normal free cortisol can be seen with low albumin/protein states including chronic liver disease and sepsis.
9. Oral estrogen replacement can lead to total serum cortisol levels 50-70% higher than normal with normal free cortisol. 
10. Ensure patients with adrenal insufficiency have a medic alert bracelet and an emergency hydrocortisone injection  kit to avoid or treat adrenal crisis. 

Adrenal Insufficiency Notes

When to Consider Adrenal Insufficiency

Adrenal insufficiency should be on the differential for patients with unexplained anorexia, weight loss and other GI symptoms including nausea/vomiting and diarrhea. Patients at increased risk of developing adrenal insufficiency include individuals with a history of other autoimmune conditions, prior steroid use, or a history of pituitary or brain directed radiation or surgery. 

Hypothalamic-Pituitary-Adrenal (HPA) Axis 

The hypothalamic-pituitary-adrenal (HPA) axis is responsible for regulation and production of cortisol. The adrenal gland has a medulla and a cortex, and cortisol is produced in the cortex. The pituitary gland stimulates the cortex to produce cortisol via adrenocorticotropic hormone (ACTH), and the hypothalamus stimulates the pituitary to produce ACTH via corticotropin-releasing hormone (CRH). Once produced, circulating cortisol exerts negative feedback on the HPA axis to avoid overproduction (Husebye 2021). 

Primary vs. Secondary Adrenal Insufficiency 

Uniform with Endocrine terminology, primary, secondary and tertiary forms of adrenal insufficiency exist based on the location of pathology. In practice, secondary adrenal insufficiency is used to describe both secondary and tertiary adrenal insufficiency as it is difficult to distinguish the two forms on a clinical basis as the hypothalamus and pituitary typically work together as a unit and there is not a simple way to measure CRH. Addison’s disease refers to Primary Adrenal Insufficiency.

1. Primary Adrenal Insufficiency: adrenal cortex unable to make cortisol
   • Cortisol: Low
   • ACTH: Elevated 
2. Secondary Adrenal Insufficiency: Pathology at level of Pituitary or Hypothalamus
   • Cortisol: Low
   • ACTH: Low or inappropriately normal 

Primary Adrenal Insufficiency

Primary Adrenal Insufficiency (PAI) is a rare disease with an incidence of 4 per 1 million per year  (Bornstein 2016). Addison’s disease=PAI and patients with PAI can present with hyperpigmentation of their skin particularly in the palmar creases, knuckles, gums, and areola. In addition to cortisol deficiency, patients with PAI will have mineralocorticoid or aldosterone deficiency as the adrenal gland is not producing all hormones. Clues for mineralocorticoid deficiency include salt craving, hyperkalemia and hyponatremia. 

The most common causes of PAI are autoimmune in the developed world (Bornstein 2016). At least 50% of patients with PAI disease have another autoimmune disease, most commonly hypothyroidism. Additional etiologies include infiltrative diseases such as tuberculosis or fungal infections, malignancy, and bilateral adrenal hemorrhage.

Following a diagnosis of PAI the evaluation for the etiology includes (Husebye 2021,Bornstein 2016) : 

1. 21 hydroxylase antibody testing : positive in ~80% of patients with autoimmune adrenalitis. The further from diagnosis more people seroconvert to negative 
2. If antibody is negative: Image the Adrenal glands to evaluate for evidence of malignancy, infiltrative disease and rarely bilateral adrenal hemorrhage for the etiology
3. Above negative and young man: check very long chain fatty acids for Adrenal Leukodystrophy

Secondary Adrenal Insufficiency

Pathology occurs at the level of the pituitary or hypothalamus. Secondary/Tertiary AI is far more common than primary. Secondary AI occurs when there is an inability to mount an elevation in ACTH response to a low serum cortisol. The most common cause of secondary AI is (abrupt discontinuation of) chronic steroid treatment for another disease (Gruber 2021). 

Adrenal Insufficiency Diagnostic Testing 

Cortisol 

The diagnosis of Adrenal Insufficiency starts with recognition of a low serum cortisol level.  One challenge with the diagnosis is the natural fluctuation in serum cortisol levels based on the body’s circadian rhythm. Cortisol levels should be checked at 8-9am when they peak around the time an individual wakes up (ie. be mindful of checking at different times in individuals with differences in their circadian rhythm due to shift work for example).

<3-5mcg/dL: very low consistent with adrenal insufficiency

5-15mcg/dL: indeterminate 

>15mcg/dL: normal rules out adrenal insufficiency 

Remember cortisol is lipophilic and bound to cortisol binding globulin, so total cortisol levels can be falsely low in patients with low protein/albumin states such as liver disease or sepsis. You can measure free cortisol levels, but this is typically a send-off test that takes ~1 week to return. There are protocols for using albumin as a surrogate marker. One suggests if albumin <2 a cortisol level of >12 instead of >18 should be used for the cosyntropin stimulation test. Conversely, oral estrogen replacement (oral contraceptive pills or hormone replacement) increases CBG levels and will lead to high serum cortisol levels with a 50-70% increase from normal (Qureshi 2007). 

ACTH

In patients with an indeterminate or low cortisol level, checking the ACTH should be the next step to diagnose adrenal insufficiency. ACTH is necessary to differentiate primary (high ACTH) and secondary AI (low to normal).  When ACTH >300, the adrenal glands are maximally stimulated, and no change in cortisol levels would be expected with a stimulation test making a cosyntropin test unnecessary in such situations. When the suspicion for AI is high, it is reasonable to check ACTH along with the initial cortisol, but if suspicion is low/ moderate check the cortisol first to avoid unnecessary testing (expert opinion).

Stimulation Testing

The common protocol for the cosyntropin stimulation test is 1) measure a baseline cortisol level 2) Give 250mcg of cosyntropin and 3) check cortisol level at 30 minutes and 60 minutes. Dr. Karti recommends the following simplified testing protocol for ease of use in primary care clinics

1) Measure a baseline cortisol level 

2) Administer 250mcg of cosyntropin IM (doesn’t need to be IV) 

3) Measure cortisol one time 30-60 minutes later 

4) If >19mcg/dL adrenal insufficiency is effectively ruled out 

The low dose cosyntropin test uses 1mcg of cosyntropin for the stimulation which is difficult because 250mcg is the full vial and dilution to 1mg is difficult. Dr. Kargi describes how there is ongoing debate about the incremental benefit of the low dose testing, but it can be helpful in the diagnosis of secondary adrenal insufficiency when the test may have higher sensitivity. High  dose stimulation testing is very good at diagnosing PAI where pathology occurs at the level of the adrenal gland. With secondary AI, high dose stimulation testing can result in more false negatives. Due to a chronic lack of stimulation, the adrenal glands may respond to a high dose of ACTH, but they won’t have a robust response to low dose stimulation. 

Testing On Steroids

For patients on hydrocortisone test before the patient takes their AM dose and ensure the patient has not taken hydrocortisone for 12-16 hours. 

Adrenal Insufficiency Treatment

The backbone of AI treatment is steroids. Patients with PAI should receive treatment for glucocorticoid and mineralocorticoid deficiency with hydrocortisone and fludrocortisone, respectively. Patients with secondary AI do not need fludrocortisone as their mineralocorticoid production is adequate (Bornstein 2016). 

Glucocorticoid replacement

Hydrocortisone is the preferred glucocorticoid because it is the most physiologic way to replace cortisol with 8-10 hours of effect. Most patients require twice daily dosing of hydrocortisone at a total dose of 8-10mg/m2/day (usual dose is between 15- 30 mg per day with ⅔ of dose given upon arising in the morning and a second smaller dose in the mid to late afternoon) with a larger dose in the morning to mimic physiological rhythms of cortisol production. It is important to monitor for signs of glucocorticoid excess including elevated blood pressure, easy bruising, and elevated blood sugar. 

Mineralocorticoid replacement

Fludocrotisone is used to replace aldosterone and is typically dosed starting at 0.1mg but the dose ranges from .05-0.2mg. Excess replacement can lead to hypertension, edema, and hypokalemia. Inadequate replacement can be identified by salt craving, hypotension, hyperkalemia and hyponatremia. Mineralocorticoid replacement can be monitored with the plasma renin activity level. 

Avoiding Adrenal Crisis

As a reminder we cover Adrenal Crisis management on Episode #372 Endocrine Emergencies. Dr. Kargi stresses the importance of stress dose education for patients and recommends the National Adrenal Diseases Foundation Website as a resource for patients. There is limited evidence for the various situations that can require stress dose changes, so most of the recommendations are expert opinion. For febrile illness, Dr. Kargi typically recommends patients double their daily dose of hydrocortisone for 2-3 days or until their fever subsides. Similarly dose adjustments should be considered for high stress activities such as working in the heat or running a marathon as well as procedures or surgeries. It is recommended that patients with AI obtain a medical alert bracelet and keep a home hydrocortisone emergency kit (Rushworth 2019) . 

Links

1. Episode #372 Endocrine Emergencies
2. National Adrenal Diseases Foundation Website
3. Core IM Adrenal Insufficiency Episode

Goal

Listeners will develop an approach to the initial diagnosis and management of adrenal insufficiency.

Learning objectives

After listening to this episode listeners will…  

1. Define primary, secondary and tertiary adrenal insufficiency
2. Identify common etiologies of primary and secondary adrenal insufficiency 
3. Review the diagnostic algorithm for adrenal insufficiency 
4. Recognize the initial treatment options for adrenal insufficiency 

Disclosures

Dr. Kargi reports prior consulting fee with Nordisk, Xeris and Recordati Rare Disease (relationships ended).  The Curbsiders report no relevant financial disclosures. 

Citation

Gibson EG, Kargi A, Williams PN, Watto MF. “### Adrenal Insufficiency”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast Final publishing date Month Day, 202X.