The characterization of adrenal insufficiency and identification of its risk factors in patients with plasma cell dyscrasias
Authors: Douglas Tremblay, Nadim choudhury, Aarti Ravikumar, Alice C. Levine, Ajai Chari
Journal: American Journal of Hematology (2015)

To the Editor: Multiple myeloma (MM) is becoming more of a chronic disease with an overall survival that has doubled in the past decade 1. This has been achieved by the advent of new combination therapies, most of which utilize corticosteroids. However, prolonged steroids use has numerous long-term complications, including secondary adrenal insufficiency (AI) 2. Although corticosteroid use in MM has decreased, the impact of weekly dexamethasone, which is frequent enough to suppress endogenous adrenal function yet infrequent enough to prevent secondary AI, is unknown. AI is characterized by malaise, anorexia, headache, nausea, fever, hypotension, and diarrhea 3. The nonspecific symptoms that accompany secondary AI, especially in the context of chemotherapy, could result in delayed or missed AI diagnoses, potentially leading to increased morbidity and mortality due to adrenal crisis and shock during infection. Patients with PCDs are also at risk for primary AI. In particular, primary (AL) amyloidosis is associated with primary AI due to the replacement of adrenal tissue with amyloid fibrils 4. Decreased adrenal function can lead to impairment of cortisol-regulated processes such as gluconeogenesis, nutrient metabolism, and of particular importance in MM, immune function, given that infections are the most common cause of morbidity and mortality 5, 6. The link between cancer patients and AI has not been well studied. Children with acute lymphoblastic leukemia (ALL) undergoing high dose chemotherapy are the only at-risk patient population that has been analyzed for AI 3. To date, there have been no published studies characterizing AI in patients with plasma cell dyscrasias (PCDs). Our aims were to characterize the presentation, risk factors, and outcomes of AI in patients with PCDs. We retrospectively identified 17 patients who had PCDs and were diagnosed with AI. Diagnosis of AI was made based on AI symptoms concordant with a low serum cortisol level (normal 6.7–22.6 mcg/dL), an inadequate cortisol response on an ACTH stimulation test, or patients with a fulminant clinical presentation who demonstrated a rapid clinical improvement upon initiation of corticosteroid replacement therapy. We excluded patients who had serum cortisol levels checked in the setting of recent administration of corticosteroids or had an adequate cortisol response with an ACTH stimulation test. To characterize AI in these patients, the charts were reviewed with attention to the time of AI diagnosis relative to the disease diagnosis, the presence of AL amyloid, and the amount of corticosteroid exposure in dexamethasone equivalents. To calculate cumulative steroids taken, for those patients where exact dosages could not be obtained, an estimate based on a typical dose and schedule was used. This study was approved by our Institutional Review Board. Twenty patients with suspected AI were initially screened in this analysis and three patients were excluded based on the criteria stated above. The baseline characteristics of the 17 selected patients are summarized in Table 1. The median overall age at PCD diagnosis was 58 (range 44–73), and six out of the 17 patients were male. The patients were distributed across all International Staging System (ISS) and Durie-Salmon (DS) stages. Four of the 17 patients (24%) had AL amyloidosis: patient 1 had primary AL amyloidosis, patient 2 and 3 had AL amyloidosis with concurrent asymptomatic and symptomatic MM respectively, and patient 4 had MM and was subsequently found to have AL amyloid nearly 4 years later. The median age of patients at the time of AI diagnosis was 63 (Range: 44–76). The median time from initial treatment to AI diagnosis was 30 months (Range 0.5–129 months). The symptoms and signs of AI at the time of diagnosis include fatigue (88%), hypotension (59%), diarrhea (53%), orthostasis (41%) and weight loss (35%). Two patients also presented with septic shock. The median number of steroid cycles taken before AI diagnosis was 10 (Range: 4–50) over a median of 30 months (Range: 3–129), resulting in a cumulative median dose equivalent of 960 mg dexamethasone (Range: 480–10931 mg). The median amount of corticosteroids administered in the 6 months prior to AI diagnosis was 20 mg of dexamethasone per week (Range: 9–36 mg/week). The median serum cortisol was 3.8 mcg/dL (Range: 0.5–5.4 mcg/dL, except patient 3 who had level 21, which was inappropriately low in the setting of septic shock). To treat AI, patients received a total of 15–20 mg of hydrocortisone divided into two doses on days when not receiving PCD treatment doses of steroids. Given the inherent limitations of retrospective studies in determining the time to resolution of subjective complaints, we focused more on the objective findings of hypotension and weight loss. For the 16 patients evaluable for response, normalization of hypotension and weight required a median of 9 days (Range 2–43 days) and 2 months (Range 0.3–20 months) respectively to return to their pre-AI levels. Orthostasis resolved after a median of 33 days (Range: 22–72 days), however, this must be interpreted with caution, as orthostatics were not checked at each clinic visit. The typical patient in our case series was approximately 63 years old and was diagnosed with AI 30 months after starting therapy. Interestingly, the two patients with AL amyloid without MM were younger and presented with AI sooner. One also had an elevated ACTH level, raising the possibility of amyloid infiltration into the adrenal glands, resulting in primary AI. Clearly, AI is not the sole reason for nonspecific symptoms such as diarrhea or hypotension in chemotherapy patients. In addition, other populations may be at risk at developing AI, including elderly oncology patients receiving chronic intermittent steroids as anti-emetics. The diagnosis of AI can also be challenging, since corticosteroid exposure can lead to temporary endogenous adrenal suppression and associated low cortisol levels for up to seven days depending on the half-life of the corticosteroid. Fortunately, cortisol can be added on to a serum specimen that may have been obtained before corticosteroid/chemotherapy administration. It is important for hematologists and oncologists to be attentive to the nonspecific presentation of AI and initiate diagnostic and therapeutic interventions in a timely fashion to minimize the morbidity and mortality of this condition. Douglas Tremblay1, Nadim Choudhury1, Aarti Ravikumar2, Alice C. Levine2, and Ajai Chari1* 1Department Of Medicine, Division Of Hematology And Medical Oncology, Icahn School Of Medicine At Mount Sinai, New York, New York, 2Division Of Endocrinology, Diabetes And Bone Diseases, Icahn School Of Medicine At Mount Sinai, New York, New York