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CASE REPORT
Preventing a fatal outcome in Addison's disease
William C. Wilson, MMSc, PA-C
Mr. Wilson is a National Health Service Corps Scholar serving with Correctional
Care Associates, Chattanooga, Tenn. The author has indicated no relationships
to disclose relating to the content of this article.
Low serum sodium levels combined
with decreased extracellular volume are your key to recognizing this potentially
lethal but very treatable disease.
Case study
A 45-year-old man presented to his new family practice clinic for a complete
physical examination in September 2000, complaining of fatigue and weight loss.
The patient reported a history of GI bleeds, gastroesophageal reflux disease
(GERD), pneumothorax, hypothyroidism, and a blood transfusion 15 years previously.
His fatigue and weight loss—about 40 lb over 5 years—have been ongoing.
The fatigue, which was increasing, worsened later in the day. Previous episodes
of fatigue and weakness were attributed to hypothyroidism, necessitating an
increase in his levothyroxine dose because of elevated thyroid-stimulating hormone
(TSH) levels. The patient's current medications included daily oral levothyroxine
and lansoprazole. There was no family history of complications pertaining to
generalized fatigue or hypothyroidism. The patient had smoked four to five cigarettes
daily for the past 20 years.
Physical examination revealed a thin male weighing 123 lb and 69 in tall.
His temperature was 97.0°F; heart rate, 66 beats per minute (bpm); respiration,
20 breaths per minute; and sitting BP, 96/66 mm Hg. The patient appeared ill.
Examination of the skin revealed generalized hyperpigmentation of sun-exposed
areas on the extremities and posterior neck as well as multiple nevi, especially
on the anterior and posterior torso. Bowel sounds were positive, but there was
no abdominal tenderness. The patient had an enlarged left testicle without a
nodule, secondary to trauma. All other physical examination findings were normal.
Follow-up examination 2 months later revealed a sitting BP of 80/74 mm Hg,
a heart rate of 56 bpm, and the same skin hyperpigmentation. Weight was stable
at 123 lb. The ECG demonstrated sinus bradycardia. During the interview, the
patient indicated continued poor appetite and worsening fatigue despite the
increased levothyroxine dose. He denied feeling anxiety or depression but did
indicate increased frequency of headaches and night sweats.
Medical records from February 1999 revealed a sodium level of 127 mEq/L (normal
range, 136-142 mEq/L), chloride of 93 mEq/L (normal range, 96-106 mEq/L), and
TSH of 12.4 µIU/mL (normal range, 0.5-5.0 µIU/mL). The prior provider
had adjusted the levothyroxine level based upon the TSH results, but the low
serum sodium was not addressed. Other prior laboratory findings, including the
CBC, and iron and cyanocobalamin/folic acid levels, had been within normal limits.
The purified protein derivative (PPD) skin test and HIV test were negative,
although the morning cortisol level was low at 1.5 µg/dL (normal range
for AM cortisol, 6-24 µg/dL).
The clinician thought that this patient had adrenal insufficiency, and an
adrenocorticotropic hormone (ACTH) stimulation test was ordered. Results consistently
revealed cortisol levels less than 1 µg/dL with no response to ACTH, indicating
Addison's disease. The clinician prescribed oral hydrocortisone, 20 mg/d, and
referred the patient for an endocrinology consult. During his most recent follow-up,
1 month after starting the hydrocortisone, the patient's sitting BP had improved
to 92/62 mm Hg, and he reported feeling much better, stating, "I am able to
play football with my son for the first time in years." The patient also said
that his eating had improved and that he had gained 9 lb.
Pathophysiology of Addison's disease
Adrenocortical hormone deficiency can result from adrenal cortex dysfunction
or inadequate ACTH secretion. Addison's disease, also referred to as primary
adrenal insufficiency, results from pathologic dysfunction of the adrenal cortex.
All zones of the adrenal cortex are involved in Addison's disease, causing shortages
of glucocorticoids, mineralocorticoids, and androgens.1 More common
than primary adrenal insufficiency, secondary adrenal insufficiency is caused
by the partial or total absence of ACTH, resulting in inadequate adrenal stimulation.2
Corticotropin-releasing hormone (CRH) stimulates the pituitary release of ACTH,
leading the adrenal glands to release cortisol.
Secondary adrenal insufficiency, which disrupts the CRH-cortisol negative
feedback mechanism, results either from pituitary or hypothalamus malfunction
or from repression of the hypothalamic-pituitary axis, leading to inadequate
stimulation.3 Adrenal atrophy is caused by extended exposure to high
doses of exogenous glucocorticoids that lead to a decrease in ACTH secretion.
Adrenal crisis may occur if a patient's endogenous supplies of glucocorticoids
and mineralocorticoids are suddenly depleted. Such depletions may occur from
rapid removal of steroid treatment or from acute stressors such as trauma, surgery,
alcohol or narcotic withdrawal, or intense psychological distress.3
Patients being treated concurrently with glucocorticoids for other disorders
are afforded no protection against acute adrenal insufficiency and in fact have
an increased risk of Addison's disease. This is because acute adrenal insufficiency
is mostly associated with mineralocorticoid shortage, while the most commonly
prescribed corticosteroids have minimal mineralocorticoid activity.4
Addison's disease is considered an uncommon condition whose subtle onset can
cause an abrupt Addisonian crisis—a medical emergency that can be life-threatening
if left untreated (see "Complications: Addisonian crisis"). Addison's disease
will often go undetected until the patient is subjected to physiologic stress,
infection, illness, or overexertion.2 Symptoms of Addison's disease
usually do not appear until approximately 90% of the adrenocortical tissue has
been destroyed. This delay in symptom manifestation leads to delayed diagnosis
of the disease.2,5 The majority of Addison's patients initially present
to their primary care provider or to other specialists before seeing an endocrinologist—another
potential cause of late diagnosis.4 Once it has been diagnosed, Addison's
is easily treated.
Complications: Addisonian crisis
The signs and symptoms of adrenal crisis (Addisonian crisis) include
abrupt pain with onset in the lower back, legs, and abdomen, along with
severe vomiting and diarrhea, high fever, dehydration, hypotension, and
loss of consciousness. The laboratory findings for adrenal crisis are
similar to those for Addison's disease and include hyponatremia, hyperkalemia,
hypercalcemia, and fasting hypoglycemia coupled with aldosterone deficiency.
Serum cortisol levels provide the conclusive diagnosis.
Adrenal crisis can be fatal if left untreated because of a progression
of worsening symptoms: cardiac arrhythmia, cardiovascular breakdown, renal
failure, shock, and death. Electrolyte deviations and the increasing inability
to concentrate urine can cause severe dehydration, acidosis, depleted
circulatory volume, low BP, and finally circulatory failure.3
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Incidence and prevalence
Addison's disease affects an estimated 6 out of 1 million adults each year;
prevalence is 40 to 110 cases per 1 million adults.2 Primary adrenal
insufficiency occurs two to three times more often in women than in men.6
In the past, tuberculosis was the primary cause of Addison's; improved drug
therapy has changed this.1 Autoimmune reactions, in which progressive
unexplained wasting of the adrenal glands occurs, now constitute the most significant
cause of Addison's disease, responsible for 80% of current cases.3
Sixty to 70% of these autoimmune cases are caused by autoimmune adrenalitis.5
Infections, including cytomegalovirus, fungal infection, and tuberculosis, and
less common causes such as malignant neoplasms, coagulopathy with adrenal hemorrhage,
and bilateral adrenalectomy constitute the remaining 20% of cases.3
Addison's disease causes deficiency in the secretion of glucocorticoids, mineralocorticoids,
and androgens. These conditions are exacerbated by other concurrent autoimmune
diseases that may result in additional endocrine anomalies, including thyroid
disorders, diabetes mellitus, and candidiasis.2
Clinical manifestations
Deficiencies of cortisol, aldosterone, and androgens result in the typical
Addison's disease clinical presentation.1 Because of its subtle onset,
manifestations vary from patient to patient. A variety of stressors can be triggers.
Nonspecific symptoms include headache, weakness, and fatigue that worsen progressively
throughout the day. Numerous GI symptoms include anorexia, nonspecific abdominal
pain, and nausea. The patient may also exhibit weight loss, vomiting, and alternate
bouts of constipation and diarrhea. Decreased libido is another symptom associated
with chronic disease.3 Roughly 10% of patients with hypoadrenalism
present with abdominal pain; approximately 7% of that subset of patients have
severe pain and tenderness that can mimic peritonitis. This more severe symptom
is a precursor to Addison's disease.6 Another distinguishing feature
of Addison's is salt craving, which can be so intense that the patient has the
urge to eat salt directly from the shaker, sometimes accompanied by lemon or
pickle juice.
One of the most definitive signs of primary adrenal insufficiency is widespread
hyperpigmentation of the skin and buccal mucosa, leading to a tanned appearance
most prominent on the face, neck, elbows, knees, and palmar creases.2
Classic dermatologic manifestations may also include diffuse hyperpigmentation
of the gingiva and scars, including those from ear piercing.5 Failure
of the adrenals, with subsequent decreased cortisol secretion and increased
ACTH secretion, causes elevated melanocyte-stimulating hormone (MSH) levels.5
Increased pigmentation occurs because the higher levels of MSH cause increased
melanocyte activity.5 Patients with secondary adrenal insufficiency
do not exhibit hyperpigmentation because the ACTH level is not increased.2,3
In addition, female patients may have amenorrhea, diminished axillary hair,
and decreased libido due to low androgen secretion.2
Additional findings on physical examination may include resting tachycardia,
orthostatic hypotension, and dehydration.3 Addison's patients may
have normal BP in the supine position but have noticeable hypotension and tachycardia
for several minutes upon rising to an upright position. Thus, a patient may
go from 120/80 mm Hg supine down to 60/40 mm Hg upon standing, possibly while
exhibiting a rise in pulse rate from 80 to 140 bpm. An aldosterone shortage
causes increased sodium loss and intensified potassium reabsorption, resulting
in depletion of water and volume along with salt. The result is hypotension—which,
if severe, can cause shock as seen in acute adrenal insufficiency or Addisonian
crisis.1,2 Glucocorticoid deficiency may play a role in hypotension
and hyponatremia, but mineralocorticoid shortage is the key pathophysiologic
event leading to acute adrenal crisis.4 Signs and symptoms of adrenal
crisis often include sudden low back pain as well as abdominal and leg pain.
Patients may also have severe diarrhea and vomiting, high fever, dehydration,
hypotension, and loss of consciousness.3
Diagnostic testing
The following diagnostic tests should be ordered for any patient suspected
of having Addison's disease: serum electrolytes, BUN, creatinine, CBC, and short
ACTH stimulation test. Approximately 88% of patients with adrenal insufficiency
have hyponatremia (sodium levels less than 130 mEq/L), often accompanied by
hyperkalemia (potassium levels greater than 5 mEq/L). Abnormalities associated
with hyperkalemia are often found on ECG and include wide QRS complexes, prolonged
QT intervals, and peaked T waves.2 Dehydration often leads to elevated
BUN and hematocrit levels. Patients may present with anemia-associated eosinophilia.7
Plasma cortisol is decreased, while plasma ACTH is increased.1
Cortisol deficiency then leads to decreased gluconeogenesis, reduced liver glycogen,
and increased response of peripheral tissues to insulin.
Addison's patients also have low fasting blood glucose levels. The fasting
patient may become hypoglycemic because the combined changes in carbohydrate
metabolism result in decreased capacity to sustain normal blood glucose levels.1
Because patients with adrenal insufficiency have decreased glycogen storage,
they cannot go for long periods without food. This can be especially troublesome
in diabetic patients dependent on insulin who subsequently develop Addison's,
because insulin dosages that may have been adequate in the past may now lead
to hypoglycemia.1
Diagnosis of Addison's disease can generally be established with a short ACTH
stimulation test. This consists of obtaining a blood serum specimen for cortisol
measurements at baseline and at 30 and 60 minutes after IV or IM ACTH administration.
A response is considered normal when the maximum cortisol level is greater than
20 µg/dL. Maximum cortisol results of less than 20 µg/dL indicate
impaired adrenal function, and results less than 5 µg/dL point toward
adrenal insufficiency.7
Differential diagnosis
Because of the numerous nonspecific symptoms of chronic adrenal insufficiency,
the expanded differential diagnosis must include other incapacitating diseases
such as AIDS, disseminated tuberculosis, and metastatic cancer. Acute adrenal
crisis, however, is more often similar to septic or hypovolemic shock. While
most of the manifestations of adrenal insufficiency are very common, some are
specific enough to clearly indicate the proper diagnosis. Timely analysis with
an ACTH stimulation test should always be performed when a patient exhibits
symptoms of either chronic or acute adrenal insufficiency along with the existence
of skin hyperpigmentation, hyponatremia, hyperkalemia, or anemia with eosinophilia.7
Unrecognized chronic adrenal insufficiency might result in patients being treated
with glucocorticoids. The differential diagnosis should include adrenal crisis
if patients receiving glucocorticoid treatments develop acute disease.4
Treatment
Because worsening Addison's disease is life threatening, treatment must be
initiated as soon as pretreatment blood samples are obtained. Early treatment
is necessary to avoid progression to Addisonian crisis.6 Therapy
for Addison's disease must include replacement of mineralocorticoids and diurnal
cortisol.5 Treatment of these deficiencies is accomplished by prescribing
oral cortisol at 20 to 30 mg/d in divided doses (20 mg in the morning and 10
mg in the evening), along with the mineralocorticoid and aldosterone analog
fludrocortisone (Florinef), 0.05 to 0.2 mg/d. Patients may return to a normal
quality of life when these medications are used because the metabolic state
is reestablished.1 Fludrocortisone is administered if orthostatic
hypotension continues or if electrolyte abnormalities persist. Fludrocortisone
will also prevent sodium deficiency, hyperkalemia, and exhaustion of intravascular
volume.2,7 Because mineralocorticoid activity is spared in secondary
adrenal insufficiency, patients with this condition do not need mineralocorticoid
replacement.2
In Addisonian crisis, the most immediate treatment concerns are intravascular
volume and cortisol replacement.3 Hospitalization is essential. Therapy
for the crisis includes inverting the hypotension and electrolyte abnormalities,
along with administering IV hydrocortisone. Large volumes of 0.9% saline solution
and 5% dextrose in saline should be delivered IV as soon as possible. For at
least 48 to 72 hours, IV fluids and hydrocortisone should be continued, followed
by an oral glucocorticoid.2
In addition to drug therapy, another critical element in the management of
Addison's disease is good patient education directed at both the patient and
family. The patient must understand that glucocorticoid and mineralocorticoid
replacement is lifelong therapy for primary adrenal insufficiency. It is also
essential to educate the patient about dosage adjustment in order to adapt the
medication for surges in cortisol secretion that occur with stress, illness,
or surgery. In these cases, dosages must be doubled or tripled for approximately
2 to 3 days.
Other educational aspects include the following:
• Medication Patients need instruction on the self-administration
of IM hydrocortisone for those occasions when oral medications and fluids cannot
be tolerated because of nausea and vomiting.
• Diet Patients should avoid fasting and should continue progressive
salt intake (minimum, 150 mEq/d), especially during extreme temperatures. During
warm weather, the oral fludrocortisone dosage may have to be doubled to counteract
increased perspiration.
• Identification Patients should wear or carry a medical identification
bracelet or card at all times to identify their chronic illness state. This
is essential to help health care providers in an emergency situation when early
administration of steroids is possible.2
Conclusion
Although Addison's disease used to be fatal, today a patient can live an ordinary
life with a normal life expectancy, provided the condition is recognized and
treated promptly.1 A key tip-off to this disease for all health care
providers should be the low serum sodium levels combined with decreased extracellular
volume—a condition with a specific differential diagnosis. All clinicians
should be aware that an inability to recognize Addison's disease, or a failure
to provide appropriate therapy, can be fatal to the patient.6
KEY POINTS in this article
• Addison's disease will often go undetected until the patient
is subjected to physiologic stress, infection, illness, or overexertion.
Symptoms usually do not appear until approximately 90% of the adrenocortical
tissue has been destroyed.
• One distinguishing feature of Addison's is salt craving,
which can be so intense that the patient has the urge to eat salt directly
from the shaker.
• Diagnosis of Addison's disease can consistently be established
with a short ACTH stimulation test.
• Therapy for Addison's disease must include replacement
of mineralocorticoids and diurnal cortisol, along with extensive patient
education.
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REFERENCES
1. Price SA, Wilson LM, eds. Pathophysiology:
Clinical Concepts of Disease Processes. 5th ed. St Louis, Mo: Mosby-Year
Book; 1997.
2. Luken KK. Clinical manifestations and management
of Addison's disease. J Am Acad Nurse Pract. April 1999;11:151-154.
3. Sabol VK. Addisonian crisis. Am J Nurs.
July 2001;101:24AAA-24DDD.
4. Cronin CC, Callaghan N, Kearney PJ, et al. Addison
disease in patients treated with glucocorticoid therapy. Arch Intern Med.
1997;157:456-458.
5. Erickson QL, Faleski EJ, Koops MK, Elston DM.
Addison's disease: the potentially life-threatening tan. Cutis. July
2000;66:72-74.
6. Laws SA, Cook PR, Rees M. Adrenal insufficiency
masquerading as an acute abdomen. Hosp Med. February 2001;62:118,119.
7. McDermott MT, Georgitis WJ, Asp AA. Adrenal
crisis in active duty service members. Mil Med. 1996;161:624-626.
William Wilson. Preventing a fatal outcome in Addison's disease. JAAPA August 2004;17:35-38.
Copyright © 2004, Advanstar Medical Economics Healthcare Communications at Montvale, NJ 07645-1742. All rights reserved.
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