Adrenal Insufficiency - Case Study With Questions & Answers.

A 60-year-old man is hospitalized because of severe nausea, vomiting, and diarrhea of 4 days' duration. He admits to having experienced mild increasing fatigue and malaise for the last 6 months plus poor appetite, frequent abdominal cramps, and a 20-lb (9-kg) weight loss over the last 4 months. He feels dizzy in the morning and lightheaded after standing for more than an hour. He notes that he tends to take a nap in the late afternoon. Four days before presentation, abdominal cramps, vomiting, and diarrhea developed. He denies any skin changes and prolonged sun exposure. He admits to a decline in sexual desire. He has no history of hypertension, diabetes, asthma, or tuberculosis, and takes no medications.
Physical examination reveals a very tanned man, who appears acutely ill and some what dehydrated. He weighs 63 kg. His supine blood pressure (BP) is 106/68 mm Hg and his supine pulse is 90 beats per minute; his standing BP is 80/50 mm Hg and his standing pulse is 104 beats per minute.
His skin shows decreased turgor. His face, hands, extensor surfaces, chest, and back are notably tanned. The findings from the head, eyes, ear, nose, and throat examination are normal, except for the presence of hardened earlobes.
No heart abnormalities are noted and his lungs are clear.
Abdominal examination reveals the presence of diffuse tenderness, but no rebound or localized tenderness. The bowel sounds are hyperactive. There is decreased axillary hair. His testes are normal and central nervous system findings are unremarkable.

The following laboratory data are obtained:
hemoglobin (Hgb), 10.6 g, normochromic normocytic anemia;
white blood cell (WBC) count, 6,600 cells/mm3;
sodium, 128 mEq/L; potassium, 5.9 mEq/L; bicarbonate (HCO3-), 20 mEq/L; chloride, 96 mEq/L; 
creatinine, 2.0 mg/dL ; blood urea nitrogen (BUN), 39 mg/dL; and
calcium, 11.1 mg/dL.

The chest radiographic study findings are normal and the abdominal radiographic study show s a normal gas pattern, but bilateral adrenal calcification.
His electrocardiogram (ECG) is normal.

Seven months later, the patient becomes severely fatigued and weak and complains of cold intolerance, dry skin, somnolence, and constipation.
Physical examination at that time reveals a pale patient, with a supine BP of 110/60 mm Hg and supine pulse of 64 per minute. He weighs 72 kg. His skin is dry and warm and exhibits decreased turgor. Periorbital freckling and vitiligo are present, as well as mild, diffuse thyromegaly. Neurologic examination reveals generalized muscle weakness and decreased deep tendon reflexes symmetrically.

Laboratory data are as follows:
WBC, 6,900 cells/mm3 with normal differential;
serum sodium, 135 mEq/L; potassium, 4.7 mEq/L; chloride, 99 mEq/L; HCO3 -, 24.8 mEq/L; glucose, 78 mg/dL;
creatinine, 1.0 mg/dL; and BUN, 18 mg/dL.

Thyroid function tests reveal the following findings:
serum thyroxine (T4), 3.2 μg/dL (normal, 4 to 12 μg/dL);
triiodothyronine (T3) resin uptake, 20% (normal, 25% to 35%); and
TSH, 16 μU/mL (normal, 0.55.0 μU/mL).

The test result for antimicrosomal antibodies is positive, with a value of 1:50,000.

1. What is the most likely diagnosis in this patient?
2. What would be the first step in the diagnostic evaluation of this patient?
3. On the basis of the findings from the initial diagnostic evaluation, what is the diagnosis in this patient?
4. What would you recommend as an initial therapy?
5. How would you treat this patient's hypercalcemia?
6. What additional abnormalities may be seen in association with Addison's disease?
7. On the basis of the findings w hen the patient is seen 7 months later, what kind of thyroid disease does he have?
8. What is the most important advice to give this patient?

Answers And Discussion



1. What is the most likely diagnosis in this patient?
The most likely diagnosis in this patient is acute adrenal insufficiency resulting from either primary or secondary adrenal failure.
This patient illustrates the nonspecific nature of symptoms in the setting of chronic adrenal insufficiency, even though he exhibits the classic history and findings.
This patient's hyperpigmentation and electrolyte changes suggest primary adrenal failure. The hyperkalemia and hyponatremia are due to mineralocorticoid deficiency, often seen in the setting of primary adrenal failure. Because ACTH is not the predominant regulator of aldosterone secretion, electrolyte abnormalities are less common in patients with secondary adrenal failure.

Adrenal crisis occurs when a stressful situation brings about decompensation. The nature of the stress may range from mild (e.g., the flu) to severe (e.g., trauma or surgery). Adrenal decompensation is marked by dehydration, hypovolemia, profound hypotension, hyponatremia, hyperkalemia, hypoglycemia, and hypothermia.

Classic renal failure can mimic several aspects of chronic adrenal failure, including fatigue, malaise,
anorexia, hyponatremia, and hyperkalemia. In this patient, the BUN and creatinine abnormalities are more indicative of prerenal azotemia than of acute renal failure.

Decreased libido, which is common in patients with hypopituitarism, can also be seen in patients with Addison's disease and is due to the debilitating nature of the illness, the associated primary gonadal failure, and possibly the decreased adrenal androgens.

Calcification of the auricular and costal cartilage is uncommon in patients with Addison's disease, but can occur incidentally. A lack of axillary hair is actually a more common finding in female patients. The amount of pubic hair may also be diminished.

2. What would be the first step in the diagnostic evaluation of this patient?
The ACTH stimulation test should be performed initially to assess whether the adrenal glands can respond to exogenous ACTH by increasing the levels of cortisol and aldosterone. Simultaneously, the plasma ACTH level should be measured because patients with Addison's disease have very low cortisol levels but elevated ACTH levels. It is critical to have the laboratory process the samples correctly (check with your laboratory to determine the appropriate process for blood collection). Adrenal autoantibody testing is now available and has a 70% sensitivity.
In addition, because of the abdominal radiographic finding of adrenal calcification, a purified protein
derivative (PPD) skin test should be performed to assess for tuberculosis.

An ACTH stimulation test reveals a basal cortisol level of 2.8 μg/dL, which is then 2.8 μg/dL at 30 minutes and 3.0 μg/dL at 60 minutes.
The aldosterone level is 2.5 ng/mL at 0 minutes, 2.5 ng/mL at 30 minutes, and 3.1 ng/mL at 60 minutes
(normal values—cortisol, 9 to 25 μg/dL a.m. fasting, and 2 to 16 μg/dL p.m. fasting; aldosterone, normal salt upright: men, 6 to 22 ng/dL; women, 4 to 31 ng/dL).

The plasma ACTH level is found to be 779 pg/mL
(normal, <580 pg/mL at 8:00 a.m. upright; 526 pg/mL at 8:00 a.m. supine; and <517 pg/mL at 4:00 p.m. supine).

The PPD test result is negative.

3. On the basis of the findings from the initial diagnostic evaluation, what is the diagnosis in this patient?
The results of the ACTH stimulation test in this patient are clearly abnormal, showing subnormal responses to ACTH—indicative of adrenal failure. This is the classic situation in patients with primary adrenal failure, that is, the response of both cortisol and aldosterone to ACTH is absent; in secondary adrenal failure, the aldosterone response is preserved.
The plasma ACTH level is markedly elevated in this patient, and such extreme elevations may be seen in the context of severe stress, such as that caused by surgery, anesthesia, and hypoglycemia. Calcification of the adrenal glands can occur in the setting of tuberculosis, histoplasmosis, and
occasionally in autoimmune adrenal disease. Therefore, the cause of this patient's adrenal gland failure is primary adrenal failure, most likely secondary to the autoimmune destruction of the adrenals.
The negative PPD result supports a nontuberculous etiology of the primary adrenal failure.

4. What would you recommend as an initial therapy?
Because the clinical presentation suggests adrenal crisis, therapy should be instituted immediately because adrenal crisis is a life-threatening emergency and any delay in treatment could prove fatal. Such therapy includes

• the immediate IV administration of a soluble corticosteroid preparation, such as hydrocortisone (100 mg), 
• followed by rapid infusions of glucose and normal saline at a rate of 2 to 4 L per day. 
• For true crisis, large volumes (2 to 3 L) of 0.9% saline solution or 5% dextrose in 0.9% saline should be infused intravenously as quickly as possible.

The glucocorticoids and volume repletion cause the serum potassium levels to decrease. Definitive diagnostic testing should be carried out after the acute therapy has been instituted. Mineralocorticoid therapy should be deferred until the patient can take medication orally.

5. How would you treat this patient's hypercalcemia?
Because this patient's hypercalcemia is mild, no special treatment other than hydration with normal saline is required. Both hypercalcemia and hypocalcemia have been reported to occur during an adrenal crisis. This may stem from dehydration, but may also be a consequence of the increased
absorption of calcium from the gut, due to glucocorticoid deficiency. Occasionally, mild hypercalcemia and hyperparathyroidism may coexist with adrenal failure caused by a pituitary tumor that compromises the function of corticotrophs [multiple endocrine neoplasia type 1 (MEN 1)]. Hypocalcemia may occur in patients whose hypoadrenalism is a part of the autoimmune polyglandular syndrome type I (polyglandular failure).

6. What additional abnormalities may be seen in association with Addison's disease?
Other abnormalities that may arise in patients with Addison's disease include

• hypoglycemia, 
• hyperkalemia, 
• high ADH levels, 
• metabolic acidosis, 
• vitiligo, and 
• high levels of antithyroid antibodies. 

All of these can be a frequent component of the clinical picture in patients with adrenal insufficiency.

7. On the basis of the findings when the patient is seen 7 months later, what kind of thyroid disease does he have?
The findings are consistent w ith those of Hashimoto's thyroiditis.
Patients with idiopathic Addison's disease are prone to other autoimmune disorders, which may develop before or after adrenal failure is diagnosed.

These disorders include

• Graves' hyperthyroidism, 
• Hashimoto's thyroiditis,
• pernicious anemia, 
• diabetes, 
• hypoparathyroidism, 
• primary hypogonadism,
• vitiligo, and 
• moniliasis. 

Areas of vitiligo form in 4% to 6% of the patients with Addison's disease, especially in those whose disease has an autoimmune cause.

In this man who has a goiter, low T4 and high TSH levels, and strongly positive antithyroid antibody titers, levothyroxine therapy should be started, but only when adequate steroid replacement has been achieved and after the patient has been on steroid replacement therapy for at least 2 weeks. An
adrenal crisis could be precipitated if levothyroxine is given to a patient who is in a hypoadrenal state because of the resulting increased metabolic demands that levothyroxine imposes on the body.

8. What is the most important advice to give this patient?
In any patient with adrenal insufficiency, it is critical to emphasize the need for increasing the dosage of glucocorticoids during periods of stress or illness, such as colds, flu, diarrhea, infections, trauma, or surgery. Failure to do so might precipitate the rapid development of an acute adrenal crisis. In
addition, the patient must be instructed to w ear an identification bracelet or carry a card at all times indicating that he has the disease and needs supplemental steroids during stress. This is a crucial life-preserving measure and cannot be overemphasized.