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* From the Division of Pulmonary, Critical Care and Sleep Medicine, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH.
Correspondence to: Moayyed Moallem, MD, Bell-Greve, 2500 MetroHealth Dr, Cleveland, OH 44109; e-mail: mmoallem{at}metrohealth.org
A 22-year-old, white woman presented with fever, sore throat, and left jaw pain for 4 days. Dental caries of her left lower third molar were diagnosed 3 days prior to presentation; she was started on oral penicillin and metronidazole, and was scheduled for tooth extraction. She continued to have fevers, decreased oral intake, and swelling in the left jaw developed. The patient was otherwise healthy, with no previous medical or surgical problems. She denied tobacco, ethanol, or drug abuse. Occupational and family histories were unremarkable.
Physical Examination
The patient appeared dehydrated and in mild distress. Vital signs were as follows: temperature, 39.1°C; heart rate, 123 beats/min; BP, 85/57 mm Hg; respiratory rate, 28 breaths/min; and oxygen saturation, 99% on room air. The skin was bronze in appearance, with areas of dark brown pigmentation on the fingers and over the knees. The oropharynx was erythematous, and there were caries in the left second and third molars with mucosal induration and trismus. The rest of her examination was unremarkable.
Laboratory Findings
WBC count was 7.2 x 103/µL with a normal differential count. A basic metabolic panel showed mild hyponatremia (134 mmol/L) and hypokalemia (3.4 mmol/L), with normal BUN and creatinine levels.
Hospital Course
The patient was resuscitated with IV fluids (5 L of normal saline solution) and received IV antibiotics (ampicillin/sulbactam) for a presumed tooth abscess. Following resuscitation, BP was 100/60 mm Hg. The next day, she underwent a left molar extraction and neck-jaw CT scan, which did not reveal any focal abscess. Later on the same day, the patient was noted to be lethargic, with a drop in systolic BP to 60 mm Hg. She subsequently went into pulseless electrical activity arrest. Resuscitation was unsuccessful.
What is the diagnosis?
Diagnosis: Addisonian crisis due to primary adrenal insufficiency
Adrenal insufficiency was first described by Thomas Addison in 1855, although the first case of acute adrenal insufficiency was not recognized until 1961 in a surgical patient who was receiving long-term glucocorticoid therapy. Adrenal insufficiency is categorized into three types: primary adrenal insufficiency or Addison disease, caused by destruction of the adrenal cortex; secondary adrenal insufficiency, caused by deficient secretion of adrenocorticotropic hormone from the pituitary; and tertiary adrenal insufficiency, caused by deficient secretion of corticotrophin-releasing hormone from the hypothalamus. Although primary adrenal insufficiency is rare, with an incidence of six cases per million adults per year, it is potentially fatal if not recognized and treated promptly.
Autoimmune adrenalitis is the most common cause of primary adrenal insufficiency in western countries. The remaining causes are infectious diseases, metastatic cancer, adrenal hemorrhage, sarcoidosis, amyloidosis, and medication induced. Tuberculosis is still one of the most common causes worldwide because of its high prevalence; however, it results less commonly in adrenal insufficiency compared to malignancy because tuberculosis less frequently involves the adrenal cortex. Autoimmune adrenalitis, previously termed idiopathic primary adrenal insufficiency, can be either isolated or combined with other autoimmune endocrine disorders such as polyglandular autoimmune syndromes type I and II. Both humoral and cell-mediated immune systems are involved in the destruction of the adrenal cortex. Antibodies can be directed against all three zones of the adrenal cortex. The serum concentration of specific antiadrenal antibodies correlates with the degree of adrenal insufficiency. As the disease progresses, the adrenal gland becomes smaller, with thickening of the capsule and destruction of the cortex, although the medulla is spared. Autoimmune adrenal insufficiency can be familial, and it has been shown to be associated with human leukocyte antigen DR3 and human leukocyte antigen DR4 alleles.
Clinical signs and symptoms do not appear until at least 90% of cortex has been destroyed. This explains the insidious onset of the disease and why it may not be detected until a stress or illness precipitates adrenal crisis. While mineralcorticoid deficiency is the major factor driving the course of an adrenal crisis, glucocorticoid deficiency may contribute to the hypotension.
The clinical features of chronic primary adrenal insufficiency are nonspecific, with most patients complaining of generalized weakness, fatigue, anorexia, and weight loss. GI symptoms are common, especially nausea, vomiting, and abdominal pain. The patient may present with dizziness secondary to postural hypotension and, uncommonly, with salt craving. Electrolytes abnormalities are frequently seen, and include hyponatremia, hyperkalemia and, on occasion, hypercalcemia. Our patient’s hypokalemia was likely secondary to vomiting. Hyperpigmentation is one of the characteristic physical findings in primary adrenal insufficiency, although it is absent in secondary and tertiary adrenal insufficiency. The hyperpigmentation is usually generalized and most pronounced in the palmer creases, areola, and areas exposed to long-term friction or light, as demonstrated in our patient. Patchy mucosal pigmentation may also occur on the inner surface of the lips and on the buccal mucosa.
In primary adrenal insufficiency, adrenal crisis usually presents as shock associated with a major physiologic stress or infection in an undiagnosed patient or in a patient known to have primary adrenal insufficiency but not receiving adequate glucocorticoid replacement. In addition to shock, patients often have other nonspecific symptoms such as nausea, vomiting, abdominal pain, weakness, fever, and coma. The fever and abdominal pain may mimic an acute surgical abdomen. Caution should be exercised because surgical exploration may lead to severe shock and death.
Bilateral adrenal hemorrhage or infarction can also precipitate adrenal crisis. This usually occurs in patients receiving anticoagulants, and in rare cases secondary to meningiococemia or pseudomonas bacteremia. Acute adrenal insufficiency should be considered in any patient with known adrenal insufficiency during major stress or infection, and in patients with predisposing risk factors (AIDS, tuberculosis, anticoagulation, and metastatic cancer) who present with shock unresponsive to vasopressors and volume resuscitation.
Treatment should be immediate, with IV infusion of large volumes of isotonic saline solution, and stress dose corticosteroids, typically 100 mg hydrocortisone q6h. Treating the underlying cause of the stress is crucial. Once the patient’s condition is stable, parenteral corticosteroid therapy can be tapered and converted to an oral maintenance dose. Mineralcorticoid therapy should be started prior to discontinuation of the saline solution infusion. Evaluation for the cause of the adrenal insufficiency should be pursued once the patient’s condition is stable.
Clinical Course
Our patient’s status deteriorated quickly, and the shock was refractory to aggressive volume resuscitation, multiple doses of epinephrine, and norepinehrine infusion. She was pronounced dead after 40 min of cardiopulmonary resuscitation. Gross postmortem examination demonstrated inconspicuous adrenal glands; microscopically, the adrenal glands showed marked inflammation, fibrosis, and cortical atrophy. The autopsy also revealed lymphocytic infiltrates in the stomach, thyroid, liver and salivary glands, suggestive of a systemic autoimmune process associated with autoimmune adrenalitis. Based on these findings, we concluded that the underlying cause of the shock was Addisonian crisis. Postmortem analysis of blood collected prior to the patient’s death showed a serum cortisol level < 0.5 µg/dL (normal range, 2.0 to 15.0 µg/dL) and a serum adrenocorticotropic hormone level of 344 pg/mL (normal range, 6 to 58 pg/mL). No other cause of the shock was found at autopsy; postmortem cultures of blood, spleen, and lung were negative. According to the patient’s family, her skin had been gradually darkening in the 2 years prior to presentation. Since autoimmune adrenalitis can be a familial disorder, we advised the family to seek medical counseling for the patient’s siblings.
Clinical Pearls
Footnotes
This work was performed at MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH.
The authors have no financial or other potential conflicts of interest to report.
Received for publication December 27, 2006. Accepted for publication January 27, 2007.
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