Cushing Syndrome and Adrenocortical Carcinoma in a Patient With CD4+ Lymphocytopenia
Stephen F. Lewis, MD, MS, Bennett S. Vogelman, MD, and Frank M. Graziano, MD, PhD
In 1992, the Centers for Disease Control (CDC) defined idiopathic CD4+ lymphocytopenia as a syndrome of CD4+ cell counts less than 300/uL on more than one occasion in patients who are HIV- seronegative and have no known immunodeficiency state.1 Numerous cases of idiopathic CD4+ lym- phocytopenia have been reported and have been associated with a wide range of disease entities.2 We report here a case of idiopathic CD4+ lympho- cytopenia in a patient who was later found to have Cushing syndrome caused by adrenal carcinoma.
Case Report
A 50-year-old gay man complained after a recent trip to Australia of severe back pain and peripheral edema. The back pain had developed several weeks earlier and was not associated with neurologic com- promise or other systemic symptoms. The edema, which had developed gradually during the previous 12 months, was not associated with any other symptoms of renal, hepatic, cardiac, or thyroid dys- function.
His medical history was pertinent for hyperten- sion, geographic tongue, mild obesity, and sleep apnea requiring positive pressure ventilation.
One year before the onset of his symptoms, the patient’s partner died of acquired immunodefi- ciency syndrome (AIDS). Because the patient had engaged in unprotected sex with his partner before knowing his partner was infected with the human immunodeficiency virus (HIV), the patient was tested for HIV infection but was seronegative. His CD4+ cell count, however, was 270/uL (normal 500-1300/ML). An extensive evaluation for HIV infection, including enzyme immunoassays for
From the Department of Medicine, Section of General Internal Medicine (SFL), Section of Infectious Diseases (BSV), and Section of Rheumatology (FMG), University of Wisconsin School of Medicine, Madison. Address reprint requests to Frank M. Graziano, MD, PHD, University of Wisconsin Hospital and Clinics, Department of Medicine, H6/368 CSC, 600 Highland Ave., Madison, WI 53792.
HIV-1 and HIV-2, HIV-1 DNA by the polymerase chain reaction assay, HIV-1 peripheral blood lym- phocyte culture, and p-24 antigen testing, was neg- ative. These tests were repeated several months later and again were negative. The patient’s condi- tion was diagnosed as idiopathic CD4+ lymphocy- topenia. During the next 6 months, his absolute CD4+ cell count declined to 160/uL, and the pa- tient was started on trimethoprim-sulfamethox- azole prophylaxis for Pneumocystis cariniì infection.
When examined, the patient appeared cushin- goid but was in no acute distress. His body habitus was centrally obese with upper and lower extremity wasting. His blood pressure was 150/95 mm Hg. A cutaneous examination found multiple ecchymotic lesions on the upper extremities and lower abdo- men as well as a 1.5-cm nodule with a necrotic center on the lateral aspect of his right arm. A head and neck examination was pertinent for facial plethora and a white coating on the lateral surfaces of his tongue. Findings of an examination of the heart and lungs were unremarkable. His abdomen was protuberant, his umbilicus was inverted, and he had diffuse dullness to percussion. The lower ex- tremities showed moderate pitting edema to the knees bilaterally. A neurologic examination was non- focal, but the patient had to be frequently refocused on his current problem by the evaluating physician.
Pertinent laboratory studies are shown in Table 1. Important findings include hyperglycemia, an elevated cortisol level that did not respond to dexa- methasone, a markedly elevated urine free cortisol level, a low adrenocorticotrophin level, a low CD4+ cell count with an reversed CD4+ to CD8+ ratio, and low immunoglobulin levels.
Thoracic and lumbar spine films showed severe osteopenia and multiple compression fractures of the thoracic and lumbar spine. Computed tomo- graphs (CT) of the chest and abdomen showed a large adrenal mass and extensive lipomatosis. There were nodular lesions in the liver and right lower lobe of the lung. Biopsy of the lung lesion resulted in a diagnosis of metastatic adrenocortical
| Laboratory Tests and Measurements | At Admission | Normal Range |
|---|---|---|
| Hematocrit, % | 38.0 | 40.0-50.0 |
| White cell count, x103/ALL | 10.0 | 3.5-8.5 |
| Differential count, % | ||
| Neutrophils | 77 | |
| Lymphocytes | 8 | |
| Monocytes | 1 | |
| Metamyelocytes | 12 | |
| Myelocytes | 1 | |
| T cells, per uL | ||
| Absolute CD4+ count | 140 | 500-1300 |
| Absolute CD8+ count | 630 | 210-690 |
| CD4+ to CD8+ ratio | 0.2 | 1.2-3.0 |
| Immunoglobulin levels, mg/dL | ||
| IgA | 117 | 68-378 |
| IgG | 464 | 694-1618 |
| IgM | 45 | 60-263 |
| Sodium, mEq/L | 135 | 135-144 |
| Potassium, mEq/L | 4.0 | 3.6-4.8 |
| Chloride, mEq/L | 95 | 97-106 |
| Carbon dioxide, mEq/L | 25 | 22-32 |
| Glucose, mg/dL | 266 | 70-110 |
| Cortisol, ug/dL | ||
| Before dexamethasone | 51.7 | |
| After dexamethasone | 46.5 | |
| Corticotropin, midnight, pg/mL | <0.1 | 7-51 |
| Urinary free cortisol, ug/24 h | 1013 | 0-50 |
carcinoma. Biopsy of the skin nodule showed ple- omorphic fungal elements that were identified as Exophiala jeanselmei.
The patient underwent surgical debulking of the adrenal mass but died 5 months later as a result of complications of his metastatic disease. A postmor- tem examination was not performed.
Discussion
Marked reduction in the CD4+ lymphocyte count has been considered a marker of HIV infection. Since 1992, however, when the Centers for Disease Control and Prevention defined idiopathic CD4+ lymphocytopenia,1 it has become clear that many patients have low CD4+ counts without HIV in- fection. We report the first case of idiopathic CD4+ lymphocytopenia associated with adreno- cortical carcinoma and Cushing syndrome in a pa- tient who had clear risk factors for HIV infection but no laboratory evidence of the disease.
The epidemiologic and clinical aspects of idio- pathic CD4+ lymphocytopenia have now been ex-
tensively described. Epidemiologic investigation of patients with idiopathic CD4+ lymphocytopenia has failed to show clustering of cases, spread to close contacts, or any evidence of a transmissible agent.2 Immunologic studies indicate that the syn- drome differs from that seen with HIV infection in that all lymphocyte cell lines tend to decrease, and the lymphopenia is usually transient.3,4 In addition, immunoglobulin levels are normal or decreased in idiopathic CD4+ lymphocytopenia (as in our pa- tient) but are usually increased with HIV infection. From a clinical standpoint, 40% of patients with reported idiopathic CD4+ lymphocytopenia have developed AIDS-defining illnesses, including cryp- tococcal meningitis, histoplasmosis, and Mycobacte rium avium complex.2 The syndrome, however, has also been associated with many infectious entities not related to AIDS2 and with noninfectious dis- eases, such as autoimmune disorders,5 malnutri- tion,6 drugs,7 and skin disorders.8 Finally, a small subset of cases are asymptomatic, which raises the possibility that some persons are healthy but have had idiopathic CD4+ lymphocytopenia diagnosed through the recent increased screening for lympho- cyte subsets.2,9 In summary, idiopathic CD4+ lym- phocytopenia appears to represent a variety of dis- orders not related to HIV or any new transmissible agent but causing a generalized immunodeficiency state similar to that seen with HIV infection.
Approximately 20% of those patients with Cushing syndrome have adrenal tumors. Adreno- cortical carcinoma is a rare tumor; only about 150 new cases are diagnosed each year in the United States, which is less than one case per million pop- ulation and 0.02% of all invasive neoplasms. Adre- nocortical carcinoma can occur at any age, but most patients are 30 to 60 years old when the diagnosis is made. The incidence among men and women is about equal, and the cause is unknown. An in- creased incidence among those infected with HIV has not been reported. Cushing syndrome has been associated with a number of infectious entities, in- cluding Nocardia, Pneumocystis, and Aspergillus or- ganisms, and Cryptococcosis neoformans.1º Several cases of Alternaria infection, which is a pleomor- phic fungus similar to the Exophiala jeanselmei found in our patient, have been reported in Cush- ing syndrome.11,12 Our patient did not develop any infections other than the localized fungal infection of the skin.
Relatively little has been reported regarding the immunologic aspects of Cushing syndrome. Re- duction of total lymphocyte counts with the admin- istration of exogenous glucocorticoids has been known for years and is believed to be due to redis- tribution of these cells to other body compart- ments.13 In addition to the quantitative decrease in lymphocytes, qualitative abnormalities in lympho- cyte function have been reported.14 The effect of glucocorticoids on subtypes of T lymphocytes has not been well established,15 however, and the se- lective decrease in CD4+ lymphocytes, which we found in this patient, has not been reported.
This case of Cushing syndrome associated with idiopathic CD4+ lymphocytopenia was con- founded by several features. First, because the pa- tient was gay and his partner died of AIDS, the low CD4+ count was believed to be a marker for an immunodeficiency state related to the AIDS virus. In retrospect, our patient was developing the signs of Cushing syndrome about 1 year before he sought care for his symptoms. Our attention was drawn primarily to his immunologic status because of his personal history of exposure to HIV. Exten- sive testing (including DNA polymerase chain re- action and HIV culture) on two occasions ruled out HIV infection, however, and did not explain his CD4+ T cell lymphopenia. Second, Cushing syn- drome has many of the infectious disease sequelae found with AIDS, making the correct diagnosis more elusive. Furthermore, several reports16,17 suggest that Cushing syndrome and AIDS might be immunologically linked, because many patients with AIDS have increased levels of cortisol, inter- leukin-1, and other cytokines, which can alter the hypothalamic-pituitary-adrenal axis. It is likely that our patient’s low CD4+ count was due to the im- munosuppressive effect of high cortisol levels asso- ciated with Cushing syndrome. With the relatively intense monitoring of lymphocyte subsets now tak- ing place in many medical practices, it is important for the physician to know of idiopathic CD4+ lym- phocytopenia and the spectrum of causes for this process.
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