Hospital Medicine

Addison's disease (primary adrenocortical insufficiency)

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I. What every physician needs to know.

Addison's disease, or primary adrenocortical insufficiency, is characterized by a deficiency in endogenous cortisol production secondary to destruction or dysfunction of the adrenal cortices. In the United States (US), Addison's disease is most commonly caused by autoimmune destruction (80% of spontaneous cases), but also has infectious, vascular, metastatic, deposition, drug-induced, and genetic etiologies.

Clinical manifestations of Addison's disease typically declare themselves after chronic destruction of the adrenal cortices and not until at least 90% of the adrenal cortical tissue is lost. Additionally, depending on the etiology of Addison's disease, varying degrees of mineralocorticoid deficiency and androgen deficiency may be present, complicating the presentation and treatment.

In the early stages of Addison's disease, cortical destruction begins to limit the reserve function of the adrenal gland. While the basal steroid secretion of the adrenal cortex remains normal, the adrenal gland is unable to respond to stress or illness, potentially precipitating acute adrenal insufficiency (adrenal crisis). With continued destruction, the adrenal cortex eventually is unable to maintain a normal basal secretion of endogenous steroids, resulting in the clinical manifestations of Addison's disease and possible acute adrenal insufficiency in the setting of even minor stress or illness.

Low plasma cortisol results in increased production of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland, due to the lack of feedback inhibition. The precursor to ACTH, pro-opiomelanocortin (POMC), also contains melanocyte-stimulating hormone (MSH), which is released with the production of ACTH. The subsequent deposition of MSH in the skin is responsible for the well-recognized hyperpigmentation of Addison's patients.

While primary adrenal insufficiency typically manifests chronically, acutely inadequate glucocorticoid activity in the setting of severe illness and increased stress has been studied, most notably in sepsis and septic shock. This form of adrenal insufficiency is termed adrenal insufficiency in critical illness (AICI).

The mechanism of adrenal insufficiency in sepsis remains unclear. The release of cytokines, such as tumor necrosis factor-α, is thought to compete with corticotropin releasing hormone (CRH) for glucocorticoid regulation and may also induce tissue resistance to glucocorticoids. The interplay between neuropeptides, neurotransmitters, oxidative stress and adrenal activity continues to be studied in sepsis and other critical illnesses such as acute respiratory distress syndrome (ARDS) and acute liver failure. Since the exact mechanism of adrenal insufficiency in sepsis is not fully elucidated, current recommendations continue to be debated and revised.

A. History Part I: Pattern Recognition:

Addison's disease often manifests insidiously and may go undetected until an illness or stress induces acute adrenal insufficiency. The manifestations of Addison's disease are dependent on the extent of cortical destruction and concomitant mineralocorticoid insufficiency.

Acute adrenal insufficiency

Also known as adrenal crisis, acute adrenal insufficiency is a medical emergency, which can result in death and requires swift recognition of symptoms and signs to expedite treatment. When there is underlying loss of adrenal function, acute adrenal insufficiency may be precipitated by a serious infection or acute stress (i.e., from trauma or surgery). Normal adrenal glands can undergo bilateral hemorrhage or infarction (i.e., from sepsis or coagulopathy). The resulting shock is a result of both glucocorticoid and mineralocorticoid deficiency. This is in contrast to secondary/tertiary adrenal insufficiency, which has intact aldosterone secretion and less commonly presents as adrenal crisis.

The primary clinical manifestation is severe hypotensive crisis or shock.

Other non-specific symptoms that may accompany hypotension are:

  • Fever

  • Confusion, altered mental status or coma

  • Weakness and fatigability

  • Anorexia

  • Nausea

  • Vomiting

Hypoglycemia is common in children presenting with adrenal crisis, as well as in patients with secondary/tertiary adrenal insufficiency, but is rare in adults with primary adrenal insufficiency.

Chronic Addison's disease

Typically, chronic primary adrenal insufficiency has an insidious onset and presents with many non-specific symptoms and signs:

- Weakness and fatigability (99%), anorexia (99%), nausea/vomiting, abdominal pain, myalgias/arthralgias.

- Orthostatic hypotension (90%)

- Electrolyte abnormalities: hyponatremia (88%), hyperkalemia (64%), hypercalcemia (6%)

- Hyperpigmented skin and mucosa

- Sparse axillary hair (more common in women), amenorrhea, decreased libido (both men and women) if concomitant androgen deficiency

- Associated autoimmune manifestations - autoimmune thyroid disease, vitiligo, primary gonadal failure, atrophic gastritis, type I diabetes mellitus

- Neutropenia, eosinophilia, relative leukocytosis, anemia

Adrenal insufficiency in critical illness

AICI should be suspected in any critically ill patient (i.e., sepsis, acute lung injury or ARDS, acute liver failure, etc.) who demonstrates hypotension, or is unresponsive to fluids or catecholamine infusions.

These may be associated with:

  • Abdominal or flank pain

  • Fever with negative cultures and unresponsive to antibiotic therapy

  • Unexplained mental changes (i.e., apathy, depression)

  • Electrolyte abnormalities (hyponatremia, hyperkalemia, hypoglycemia)

  • Neutropenia, eosinophilia

B. History Part 2: Prevalence:

In the US, the most common etiology of Addison's disease is autoimmune adrenal destruction (approximately 80% of cases). However, around the world (and in the US prior to 1920) tuberculosis is the most common cause of Addison's disease.

AUTOIMMUNE ADDISON'S DISEASE

Autoimmune Addison's disease may present alone or in association with other diseases. Approximately 50% of patients with autoimmune adrenal insufficiency have one or more other autoimmune endocrine disorders. Autoimmune thyroid disease is most commonly associated with primary adrenal insufficiency. Other associated manifestations, which are less common, include vitiligo, primary gonadal failure, type I diabetes mellitus and atrophic gastritis.

Additionally, the prevalence of sub-clinical primary adrenal insufficiency in the setting of previously diagnosed autoimmune disease is higher than traditionally thought; therefore, adrenal dysfunction should be considered in any patient with autoimmune disease.

The combination of autoimmune adrenal insufficiency with other autoimmune endocrine disorders is referred to as the polyglandular autoimmune (PGA) syndrome, of which there are two types:

  • PGA, type I, is an autosomal recessive inherited defect in T-cell immunity, which typically presents in childhood. It manifests as adrenal insufficiency associated with mucocutaneous candidiasis and hypoparathyroidism. In adulthood, PGA-1 can present with a wide spectrum of disease, including hypothyroidism, hypogonadism, alopecia, pernicious anemia, and vitiligo.

  • PGA, type II (Schmidt's disease), is an autosomal dominant disease, which typically presents in adulthood, usually in the 3rd-5th decade of life and has a 3:1 female predominance. PGA-2 typically presents with autoimmune adrenal insufficiency, type I diabetes mellitus, and autoimmune thyroid disease.

ACQUIRED ADDISON'S DISEASE

Acquired Addison's disease may occur in the setting of infection, vascular abnormalities, metastatic disease, deposition diseases, and drug-induced etiologies.

Infectious etiologies

- Tuberculosis is the leading cause of Addison's disease worldwide; rare cause in the US.

- Cytomegalovirus (CMV) is more common in immunocompromised patients, particularly human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS).

- Mycobacterium avium complex is more common in immunocompromised patients, particularly HIV/AIDS.

- Disseminated histoplasmosis and coccidioidomycosis can disseminate and cause primary adrenal insufficiency, which is more common in immunocompromised patients.

- Gummatous syphilis typically occurs 1-45 years after initial infection; manifested by soft, tumor-like inflammatory nodules disseminating in skin, bone, liver and adrenal cortex.

Vascular etiologies

  • Hemorrhagic/infarction

- Sepsis in the setting of disseminated intravascular coagulopathy (DIC), microvascular thrombosis and bleeding lead to bilateral adrenal hemorrhage.

- Anticoagulation predisposes patients to adrenal hemorrhages, particularly in the setting of trauma or stress.

- Antiphospholipid antibody syndrome is a pro-thrombotic disorder, which can lead to adrenal vein thrombosis and subsequent adrenal hemorrhage.

- Waterhouse-Friderichsen syndrome (WFS) refers to bilateral adrenal hemorrhage traditionally caused by Neisseria meningitidis bacteremia. WFS is characterized by overwhelming bacteremia leading to septic shock and DIC causing bilateral adrenal hemorrhage and subsequent rapid-onset adrenal insufficiency. Other pathogens, such as Staphylococcus aureus (possibly methicillin-resistant) and Streptococcus pneumonia have been linked to WFS.

- Heparin-induced thrombocytopenia may lead to adrenal vein thrombosis and subsequent adrenal hemorrhage, causing primary adrenal insufficiency.

  • Trauma

Metastatic disease

Lymphomas and Carcinomas (especially lung) can lead to adrenal insufficiency when roughly 90% of tissue is destroyed.

Deposition diseases

- Hemochromatosis is a recessive disorder resulting in iron overload and deposition in tissues, including the adrenal cortex.

- Amyloidosis results in the accumulation of insoluble fibrillar protein. Adrenal insufficiency is caused by deposition beta-amyloid and by-products of peptide hormones in the adrenal cortex.

- Sarcoidosis is a chronic inflammatory disease with granulomatous deposition in multiple organs, including the adrenal cortex.

- Scleroderma is a chronic autoimmune disease characterized by fibrosis, which can affect the adrenal cortex.

Drug-induced etiologies

  • Hemorrhage

- Anticoagulants (heparin, warfarin)

- Sunitinib - a tyrosine kinase inhibitor, used to treat gastrointestinal stromal tumors (GIST)

  • Drugs that inhibit cortisol biosynthesis

- Ketoconazole, fluconazole - anti-mycotic drug

- Etomidate – sedative

- Aminoglutethiamide - an anti-epileptic drug

  • Drugs that accelerate metabolism of endogenous cortisol and synthetic glucocorticoids

- Phenytoin - anti-epileptic drug

- Phenobarbital- sedative/anti-epileptic drug

- Rifampin – antibiotic

ADRENAL INSUFFICIENCY IN CRITICAL ILLNESS

The incidence of AICI has been found to be higher than traditionally thought. The exact incidence of AICI largely depends on the population studied and the diagnostic criteria used. Reported incidences of AICI range from 15-75% of critically ill patients.

GENETIC ETIOLOGIES

While rare relative to other etiologies, genetic disorders account for a small percentage of Addison's disease cases. The following are some of the more prevalent genetic disorders causing primary adrenal insufficiency.

- Congenital adrenal hyperplasia

- Adrenoleukodystrophy

- Smith-Lemli-Opitz syndrome

- Kearns-Sayre

- Wolman Disease

- Sitosterolemia

- Familial glucocorticoid deficiency

- Triple A syndrome (achalasia-addisonianism-alacrima or Allgrove syndrome

C. History Part 3: Competing diagnoses that can mimic Addison's disease.

Primary adrenal insufficiency should be considered in any case of unexplained hypotension; however, it should be emphasized that Addison's disease is rare relative to other etiologies of shock (septic, hypovolemic, cardiogenic).

Non-specific symptoms and signs, such as weight loss, anorexia, nausea/vomiting, and abdominal pain may be the early presentation of chronic primary adrenal insufficiency, but may also mimic an occult malignancy or intrinsic gastrointestinal disease.

D. Physical Examination Findings.

- Hypotension, especially orthostatic hypotension

- Hyperpigmentation, on un-exposed skin e.g.,

  • Mucous membranes

  • Skin folds - joints of hand, feet, arms, and legs; palmar creases, nape of the neck

  • Nail beds - develop longitudinal pigmented bands

  • Nipples and areola

  • Pressure areas - buttocks, waist-line, bra-line

  • Scars

- Manifestation of other autoimmune diseases, particularly vitiligo in 10% of cases

- Scant axillary and pubic hair

- Confusion

- Neuropsychiatric symptoms - with adult-onset adrenoleukodystrophy

E. What diagnostic tests should be performed?

See laboratory and imaging studies below.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Suspected adrenal insufficiency

- Basic metabolic panel (BMP or chemistry [Chem-7]) - hyponatremia, hyperkalemia, hypochloremia, acidosis and possibly hypoglycemia will support the diagnosis of adrenal insufficiency.

- Complete blood count (CBC) with differential - neutropenia, eosinophilia, and relative lymphocytosis may be seen with primary adrenal insufficiency.

Diagnosis confirmation

- Early morning serum cortisol level (4:00 am-8:00 am) - less than 3 mcg/dL is strongly suggestive of adrenal insufficiency and greater than 18 mcg/dL effectively rules out adrenal insufficiency, except in the setting of sepsis (discussed below in Adrenal Insufficiency in Critical Illness). In the hospital setting where many patients are experiencing physiologic stress, it is reasonable to start with a stimulation test.

- Low albumin levels (<2.5 mg/dL) can lead to falsely low cortisol levels. If appropriate, free cortisol levels may be measured.

Adrenocorticotropic hormone (cosyntropin) stimulation tests

- Standard – 250 mcg of ACTH (cosyntropin) is given intravenously, followed by measurement of serum cortisol levels at baseline, 30 and 60 minutes. While baseline cortisol level is not necessarily needed, in practice it is often drawn to help interpret the rise in post-stimulation cortisol levels. The test can be performed any time of day. A serum cortisol of greater than 18 mcg/dL at either time point is considered a normal response.

Because 250 mcg is a supra-physiologic dose of ACTH, this test is not sensitive for diagnosing early secondary adrenal insufficiency.

- Low-Dose ACTH test:– 1 mcg of ACTH (cosyntropin) is given intravenously and serum cortisol levels are measured at 0, 10, 15, 20, 25, 30, 35, 40, and 45 minutes. The test is theoretically more sensitive than the standard test, because 1 mcg of ACTH is similar to physiologic levels. A value greater than 18 mcg/dL at any time is consistent with normal adrenal function. The test should be performed at 2:00 pm, when ACTH levels are the lowest physiologically. Superiority over the standard 250 mcg dose is controversial. The practical challenge of diluting a 250 mcg vial of cosyntropin to a 1 mcg sample limits the use of this test.

Adrenal insufficiency in critical illness

Any critically ill patient with refractory shock should be treated empirically for adrenal insufficiency. Recommendations are that treatment should not rely upon random, or stimulated cortisol levels, which are not reliable in this setting.

Corticotropin releasing hormone test

This tests the ability of the pituitary to produce ACTH and the adrenal's cortisol response; it is used to differentiate between secondary and tertiary adrenal insufficiency.

This test is not appropriate in the acute setting.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Radiographic studies are not necessary to diagnose Addison's disease; however some supporting evidence of Addison's disease and its etiology can be obtained by certain imaging.

Chest radiograph

This is useful to determine a cause for primary adrenal insufficiency, such as tuberculosis, fungal infections, sarcoidosis, and adenocarcinoma of the lung.

Magnetic resonance imaging and computed tomography scan of the adrenals

- Autoimmune Addison's disease - small, non-calcified adrenal glands are the hallmark of autoimmune mediated disease.

- Tuberculosis-mediated - calcification is noted in approximately 50% of cases; however, similar findings can be seen in hemorrhage and disseminated fungal infections.

Enlarged adrenal glands on magnetic resonance imaging (MRI) and computed tomography (CT) scan may indicate hemorrhage, metastatic disease, deposition-mediated or infectious causes; however, normal appearance of the adrenal glands does not rule out Addison's disease (Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6).

Figure 1.

Normal adrenal glands on MRI

Figure 2.

Normal adrenal glands on CT scan

Figure 3.

Adrenal hemorrhage of CT Scan

Figure 4.

Adrenal CT - hemorrhage versus tuberculosis

Figure 5.

Adrenal lymphoma CT scan

Figure 6.

Lung cancer metastases to the adrenal glands - CT scan

MRI is superior to CT scan in differentiating adrenal masses; however, even MRI is unable to distinguish a malignancy from an inflammatory process.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

- Extended ACTH stimulation tests. Eight-hour and 2-day ACTH stimulation tests are costly, inefficient and should not be used as initial testing.

- Metyrapone test. This tests the ability of the pituitary to produce ACTH and the adrenal's ability to produce steroid precursors. Metyrapone inhibits 11-hydroxylase, which is an enzyme in cortisol synthesis, stimulating ACTH release. Serum cortisol, ACTH, 11-deoxycortisol and urinary 17-hydroxycorticosteroid levels are measured. Limited availability of Metyrapone, coupled with adverse outcomes linked to its administration, has sharply limited its use.

Insulin Tolerance Test (ITT). This remains the “gold standard” test. Hypoglycemia target levels of 35 mg/dL stimulates counter-regulatory hormones, namely cortisol.

There is a risk of hypoglycemic seizure, and even death. This test should only be performed under close cardio-pulmonary monitoring and with the supervision of an endocrinologist.

Basal cortisol levels are not required in stimulation tests. There is no longer any incremental increase (or ‘delta’) needed to interpret a normal response to stimulation. The time of day and physiologic stress experienced precludes any meaningful interpretation of basal levels. However, baseline cortisol levels are still commonly drawn.

III. Default Management.

Acute adrenal insufficiency

  • Volume resuscitation with isotonic crystalloid fluid (e.g., normal saline)

  • Administer glucocorticoids and mineralocorticoids

  • Evaluate for reversible cause (e.g., glucocorticoid withdrawal, sepsis)

Chronic adrenal insufficiency

  • Chronic replacement of glucocorticoids and mineralocorticoids

  • Treat underlying etiology if applicable

Adrenal insufficiency in critical illness

  • Replace glucocorticoids and mineralocorticoids

  • Treat underlying cause

A. Immediate management.

Acute adrenal insufficiency

As with any medical emergency, circulation, airway and breathing should be assessed. Intravenous (IV) access with two large bore peripheral catheters is appropriate for volume resuscitation. Central venous catheter may be necessary if peripheral IV access is unattainable.

Initial management is aimed at treating hypotensive crisis, with a focus on volume resuscitation, electrolyte correction and replacement of endogenous steroid.

- Volume resuscitation with isotonic crystalloid solution (e.g., normal saline); bolus administration

- Hydrocortisone 50-100mg IV every 6-8 hours is the drug of choice for glucocorticoid and mineralocorticoid replacement

If ACTH stimulation testing will be performed, hydrocortisone can be substituted with:

Dexamethasone 2-4mg IV every 6 hours and fludrocortisone 50mcg per os (PO) daily as this regimen does not interfere with serum and urinary steroid measurements during ACTH stimulation testing. After testing is complete, may transition to hydrocortisone IV.

- Once initial treatment is complete and the patient is hemodynamically stable, the cause of the acute adrenal insufficiency should be evaluated.

- Parenteral steroids can be tapered over 3-4 days and converted to a PO maintenance therapy.

Further evaluations for patients with acute adrenal insufficiency

- Continuous blood pressure monitoring; in the setting of sepsis or other severe illnesses, arterial catheter monitoring may be appropriate. Goals are situation based: in critically ill patients mean arterial pressures (MAPs) should be maintained above 65mmHg, otherwise blood pressure goals can be titrated based on symptomatology.

- BMP, CBC with differential, serum cortisol and ACTH.

- Other appropriate laboratory tests can be measured at this time, i.e., blood cultures, liver function tests, lactic acid level, etc.

- ACTH stimulation tests can be measured, however this should NOT delay management in the setting of acute adrenal insufficiency.

Adrenal insufficiency of critical illness

Based on available evidence and current recommendations of consensus statements hydrocortisone IV should be given in the setting of septic shock if the patient is unresponsive to IV fluids and vasopressors:

- Hydrocortisone 50mg IV every 6 hours or 100mg IV every hour (200-300mg per day).

The duration of treatment is still under debate. Current level 2 recommendations suggest treatment should continue for at least 7 days and then be tapered, not stopped abruptly.

Current evidence and recommendations do not recommend other steroid replacement in the setting of sepsis (i.e., mineralocorticoid or androgen replacement).

The level 2 recommendation is reasonably justifiable based on available scientific evidence and strongly supported by expert opinion.

B. Physical Examination Tips to Guide Management.

Blood pressure and hemodynamic stability.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Basic metabolic profile - monitor daily as necessary to evaluate for electrolyte abnormalities and appropriate correction as therapy is initiated.

Blood glucose - monitor daily as appropriate for hypoglycemia to ensure correction as therapy is initiated.

D. Long-term management.

Patients with primary adrenal insufficiency require life-long glucocorticoid and mineralocorticoid replacement.

Patient and family education is the most important aspect of chronic management of Addison's disease. Patients should be aware of the life-long need for steroid replacement and how to dose their regimen in the setting of minor or major stress and emergencies. Patients should be encouraged to purchase a medical alert bracelet.

Glucocorticoid replacement

- Hydrocortisone 20-30 mg PO daily (2/3 dose in the morning, 1/3 in the afternoon) is the drug of choice because it is a natural and short-acting glucocorticoid, which leads to less side effects.

- Prednisone 5-7.5 mg PO daily can also be used; long-acting steroid, which is more likely to produce loss of lean body mass and bone density and gain of visceral fat.

Dosing in special circumstances

Minor stress/physiologic stress (febrile illness, vomiting, dental procedures):

  • Glucocorticoid can be increased up to three times the maintenance dose, typically for 3 days. This management is titrated to the specific stress as needed. Severe stress (surgery, trauma, severe illness or repeated emesis):

  • Glucocorticoid may need to be increased up to ten times the maintenance dose to prevent acute adrenal insufficiency; use IV steroids if appropriate. If surgery is the severe stress, the stress dose may be decreased by 50% on postoperative day two and normal maintenance dose can be resumed on postoperative day three.

Mineralocorticoid replacement

Fludrocortisone 0.05-0.1 mg PO every morning is the drug of choice. The dose may be titrated based on individual symptoms, namely the patient's weight and blood pressure. Patients on prednisone or dexamethasone may require higher doses, whereas patients on hydrocortisone may require a lower dose because of its mineralocorticoid activity.

Androgen replacement

DHEA 50 mg PO daily is the drug of choice. The value of DHEA in treating Addison's disease remains controversial; however DHEA replacement has been shown to increase muscle mass and reverse bone loss at the femoral neck in female patients.

Emergency therapy

All patients should wear a medical alert bracelet, stating 'Adrenal insufficiency - takes hydrocortisone (or prednisone, etc)'. Additionally, patients should carry a detailed list of their medications including dosage and frequency. A 'back-up' dexamethasone 4 mg IM pre-filled syringe should be given to the patient for emergency situations.

IV. Management with Co-Morbidities

NA

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in standard management.

E. Diabetes or other Endocrine issues

No change in standard management.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

No change in standard management.

J. Hematologic or Coagulation Issues

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment

No change in standard management.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

A diagnosis of Addison's disease or adrenal insufficiency should be made clear to the providers assuming care of the patient. Providers should anticipate being called with reports of hypotension, with fluid resuscitation and steroid replacement goals established. Lab schedules for BMP and goals for electrolyte replacement should be well defined. Relay the differential or confirmed diagnosis regarding the etiology of adrenal insufficiency, so the assuming providers can anticipate confounding factors to management.

B. Anticipated Length of Stay.

Addison's disease and acute adrenal insufficiency alone should warrant inpatient management as long as there is hemodynamic instability. Once the patient is stable, discharge is appropriate with close outpatient follow-up with the primary care provider and/or endocrinologist.

Confounding diagnoses and etiologies (i.e., sepsis, coagulopathy, malignancy, etc.) may necessitate longer hospitalization.

C. When is the Patient Ready for Discharge.

A patient with primary adrenal insufficiency may be discharged from the inpatient unit when:

  • Hemodynamic stability is maintained on PO maintenance dose steroids.

  • Patient education is complete, i.e., disease education and medication education, including stress dosing.

  • Maintenance and emergency steroids are provided to the patient.

  • Adequate follow-up is arranged with a primary care provider and/or endocrinologist.

D. Arranging for Clinic Follow-up

A primary care provider should be capable of managing a patient with primary adrenal insufficiency; however, the patient should establish care with an endocrinologist, especially in the setting of other endocrinopathies, i.e., polyglandular autoimmune syndrome.

After a diagnosis of acute adrenal insufficiency, the patient should follow-up with a primary care provider within 1-2 weeks after discharge, or sooner if they have any problems or concerns regarding their medications.

The patient should be seen by endocrinology at least annually, however this can be arranged as per the endocrinologist's preference and the patient's well-being.

1. When should clinic follow up be arranged and with whom.

NA

2. What tests should be conducted prior to discharge to enable best clinic first visit.

While inpatient it may be prudent to perform some studies that require close observation and measurement, e.g., CRH stimulation testing. Contacting the patient's endocrinologist may be helpful to formulate a diagnostic and management plan that suits both providers and benefits the patient.

Further, if any imaging were necessary and available as an inpatient, it would provide added information to the outpatient provider, especially if the first appointment is soon after discharge.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

With good control and management, no routine studies are necessary.

Following a hospitalization for acute adrenal insufficiency, it would be prudent to have a basic metabolic profile, including electrolytes and renal function, measured on the day of the first clinic appointment. This is particularly important if electrolyte abnormalities were present during the admission, as trending these values is helpful in further management.

Otherwise, laboratory studies particular to the patient may be necessary depending on the etiology of their adrenal insufficiency.

E. Placement Considerations.

Placement is patient-specific. The outpatient management of Addison's disease is optimized on PO medications and does not necessitate skilled nursing. If a patient's particular comorbidities necessitate higher-acuity of care after discharge, the arrangements should be made as soon as possible.

F. Prognosis and Patient Counseling.

The overall prognosis for Addison's is favorable, with a normal life expectancy. Patient counseling should be centered on disease education and medication compliance to ensure minimal morbidity and no increased mortality rates.

Mortality

Patients with autoimmune Addison's disease have a normal life expectancy, assuming the patients are knowledgeable about their disease and they have proper medication compliance. Any increase in mortality rates may be related to comorbidity of associated autoimmune diseases.

Patients with Addison's disease from another etiology may have an increase in all-cause mortality secondary to the associated underlying condition (i.e., infection, malignancy, genetics, etc.). The mortality rates in these cases mimic the confounding diseases.

The impact of AICI on mortality remains unclear. Several large, multi-center, randomized, double-blind, placebo-controlled trials demonstrated that steroid replacement (namely hydrocortisone) helped to reverse septic shock, despite offering no significant mortality benefit. The mortality benefits of steroid replacement in AICI related to septic shock and other critical illnesses are still under investigation.

Morbidity

Patients may have increased hospitalizations and potentially increased mortality rates with poor compliance to outpatient regimens. Adrenal crisis may occur in patients who stop their medications or who do not increase their steroid replacement in times of stress or illness.

The most common complaints among Addison's patients are chronic fatigue and general malaise. These complaints are thought to be secondary to the inadequacy of steroid replacement to mimic the body's inherent cortisol circadian rhythms.

Fatigue may also be an indicator of under-dosed steroids, an electrolyte imbalance or concurrent disease, such diabetes mellitus or hypothyroidism.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

NA

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Prevention of readmission for Addison's disease or acute adrenal insufficiency hinges on patient education. The patient, and family if applicable, should be aware of the absolute necessity for life-long steroid replacement. Ideally, they should have a thorough understanding of their disease and its management, i.e., dosage of steroids in settings of stress and illness.

In conjunction with a primary care provider, an endocrinologist can assist with patient education and outpatient management to prevent readmission and morbidity from Addison's disease.

Additionally, to ensure questions and concerns are addressed in a timely manner in the outpatient setting, the patient should be provided with contact information of providers responsible for outpatient management and local resources (if available, i.e., support groups, list-serves, etc.).

VII. What's the evidence?

Chakera, AJ. "Addison disease in adults: diagnosis and management". Am J Med. vol. 123. 2010. pp. 409-13.

Neufeld, M, Maclaren, NK, Blizzard, RM. "Two types of autoimmune Addison's disease associated with different polyglandular autoimmune (PGA) syndromes". Medicine. vol. 60. 1981. pp. 355-62.

Bornstein, SR. "Predisposing Factors for Adrenal Insufficiency". N Engl J Med. vol. 360. 2009. pp. 2328-2339.

Arlt, W. "The approach to the adult with newly diagnosed adrenal insufficiency". J Clin Endocrinol Metab. vol. 944. 2009. pp. 1059-67.

Neary, N. "Adrenal insufficiency: etiology, diagnosis and treatment". Curr Opin Endocrinol Diabetes Obes. vol. 17. Jun 2010. pp. 217-23.

Ten, S, New, M, Maclauren, N. "Addison’s Disease 2001". J Clin Endocrinol Metab. vol. 86. 2001. pp. 2909-2922.

Dellinger, RP, Levy, MM, Rhodes, A. "Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2012". Crit Care Med. vol. 41. 2013. pp. 580-637.

Hamrihan, A. "Measurements of serum free cortisol in critically ill patients". N Eng J Med.. vol. 350. 2004. pp. 1629-38.

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