To the Editor,
Cushing’s syndrome can result from prolonged exposure to excessive glucocorticoids either from endogenous or exogenous sources. The causes are generally classified as ACTH-dependent and ACTH-independent . A rare, ACTH-dependent source includes small cell lung cancer (SCLC), which is a neuroendocrine tumor that can cause ectopic production of ACTH resulting in Cushing’s syndrome. This develops in 1%–5% of patients with SCLC , , and these patients tend to have a poor prognosis . Classic signs and symptoms consistent with hypercortisolemia include glucose intolerance, high blood pressure, supraclavicular fat accumulation, a cervical fat pad, facial plethora, thinned skin, wide purplish striae, hypokalemia, fatigue and proximal muscle weakness , , . Severe hypercortisolism can also result in uncontrolled diabetes, severe hypertension, severe infections, pulmonary embolism and psychosis . It is often difficult to distinguish ectopic ACTH secretion from Cushing’s disease, however, severe hypertension and hypokalemia are more common in patients with ectopic ACTH , , .
Per the 2015 Endocrine Society Clinical Practice Guidelines, primary treatment for metastatic ectopic ACTH secretion is steroidogenesis inhibitors. Treatment goals should be to normalize the action of cortisol at its receptors in order to eliminate the signs and symptoms of Cushing’s syndrome. Dose adjustments should be made as needed to avoid adrenal insufficiency . Ketoconazole is one of several treatment options as it impairs adrenal and gonadal steroidogenesis by inhibiting side-chain cleavage, 17,20-lyase, and 11-β hydroxylase enzymes , . It has also been shown to provide clinical improvements in diabetes, hypertension and hypokalemia. Despite treatment options, patients with ectopic Cushing’s syndrome due to SCLC have a grim prognosis, and typically live only 3–6 months , .
A 58-year-old White male with a history of tobacco use for 45 years, and recently diagnosed stage 4 metastatic SMLC with metastasis to sternum, liver, pelvis, femur, and spine presented to the emergency department at the VA Medical Center in Mather with progressive dyspnea, productive cough, lower extremity edema and profound weakness. Labs drawn 3 weeks prior to presentation revealed a plasma cortisol level>1656 nmol/L (reference range 240–618 nmol/L). On arrival, his serum potassium was 1.2 mmol/L, chloride 88 mmol/L, bicarbonate 44 mmol/L, and plasma glucose was 9.7 mmol/L. Blood pressure was 150/99 mmHg. CT abdomen revealed bilateral moderately enlarged adrenal glands consistent with hyperplasia. MRI of the brain including the pituitary gland was normal with no evidence of a pituitary mass. The physical exam revealed a dorso-cervical fat pad, otherwise no facial plethora or abdominal striae were noted. Further laboratory testing revealed elevated ACTH at 32.5 pmol/L (reference range, 1.6–13.9 pmol/L) and cortisol was again reported as >1656 nmol/L. Based on the hypokalemic alkalosis, hypertension and hyperglycemia with concomitant increase in both cortisol and ACTH, endocrinology was consulted for confirmation of diagnosis of ectopic ACTH syndrome as a para-neoplastic manifestation for further management. As the laboratory did not report cortisol levels >1656 nmol/L, the endocrinology consult service asked the laboratory to validate an extended reportable range to facilitate diagnosis and treatment, given a diagnosis of ectopic ACTH syndrome was entertained. The first precise cortisol level after validating the reportable range was markedly elevated at 3105 nmol/L. In Table 1 depicts the plasma cortisol and ACTH levels in our patient. As this was an acutely-ill patient, the classical work-up of Cushing’s syndrome was not undertaken. However, as we decided to commence therapy with ketoconazole, we performed the rapid overnight high dose dexamethasone suppression test (OHDDST) administering 8 mg PO at 11:00 p.m. and obtaining a plasma cortisol level at 08:00 a.m. the following day. Early morning cortisol level should suppress by >50% if due to pituitary lesions causing the excess ACTH and cortisol , . In our patient, the plasma cortisol only suppressed by 10.6% to 2782 nmol/L the following morning. Given our patient’s cortisol failed to suppress by >50%, ectopic ACTH secretion was confirmed based on the other clinical and biochemical features. The patient was started on ketoconazole 200 mg orally three times a day for cortisol suppression. ketoconazole can be administered in a dose range of 400–1200 mg/day and the major side effect is hepatotoxicity .
The patient was hypertensive throughout most of his admission, and he was treated with triamterene and losartan to improve both blood pressure and hypokalemia. He was also started on palliative chemotherapy with carboplatin and etoposide for his SCLC. After completing his first round of chemotherapy, he developed increased work of breathing and worsening hypoxemia for which he was transferred to the intensive care unit with septic shock secondary to pneumonia. He required intubation, pressors and broad spectrum antibiotics. He was continued on ketoconazole until cortisol levels decreased to 930 nmol/L, down from 3105 nmol/L 5 days earlier; a 70% reduction. He also developed hyperkalemia to 5.6 mmol/L, metabolic acidosis with bicarbonate 20.6 mmol/L, and his blood glucose decreased to low-normal levels with discontinuation of insulin. He also had acute renal failure (estimated GFR of 16.1 mL/min), leukopenia, thrombocytopenia with an increased D-Dimer and prothrombin time. At that time, there was concern for stress from septic shock and the need for steroid coverage. Hence, ketoconazole was discontinued and he was started on stress dose steroids. Repeat cortisol level the following day was elevated up to 2677 nmol/L, however, patient’s condition continued to deteriorate and he unfortunately expired.
The major message of this case report is to obtain an accurate plasma cortisol level when values exceed the laboratories reportable range in order to (1) accurately work-up Cushing’s syndrome and (2) monitor cortisol levels while providing treatment. When our patient’s cortisol level was initially obtained, it resulted as >1656 nmol/L. We had to personally call the laboratory director and request a dilution of cortisol to obtain an accurate number, as consistent with the vendors recommendation, the laboratory set the upper end of the reportable range as 1656 nmol/L. However in our patient, quantifiable cortisol levels were necessary in order to support the diagnosis of ectopic ACTH syndrome with our overnight high dose dexamethasone suppression test, and to monitor cortisol levels while the patient was treated with ketoconazole. Contacting the laboratory to validate an extended reportable range delayed our work-up and treatment, which is detrimental in a patient with very severe ectopic ACTH syndrome. Thus, it is vital that all laboratories have a protocol in place to dilute samples and report accurate levels if the value exceeds the reportable range. It is a plea to the vendors to extend the reportable range as all major vendors including Beckman, Abbott, Siemens-Centaur and Roche recommend a upper limit of 1656 or 2070 nmol/L for their plasma cortisol assays. Our laboratory used the Beckman assay which recommends an upper limit of 1656 nmol/L. Reflex dilution should be incorporated in all laboratories in order to avoid treatment delays in patients with extreme hypercortisolemia from ectopic ACTH syndrome or adrenal carcinoma. Whilst this might be the situation in major academic centers with astute medical directors it is incumbent on the vendors to provide leadership for all laboratories using their instrument and cortisol assay in the spirit of optimum patient care as many hospitals, especially in the USA, do not have a clinical chemist overseeing this area.
Accurate cortisol levels are also necessary to monitor the rate of decline in cortisol during treatment. Our patient’s cortisol level decreased from 3105 to 930 nmol/L in 5 days, during which time he developed septic shock, pancytopenia and acute renal failure. Although his cortisol level was still high, there was concern that he was unable to mount an appropriate response to his infection due to the significant decline in his cortisol level . He was therefore started on stress dose steroids. If we did not have accurate cortisol levels to monitor, we would not have been able to calculate the 70% decline in cortisol, and stress dose steroids may not have been initiated in a timely manner.
In conclusion, we report on a patient with ectopic ACTH Cushing’s syndrome whose cortisol levels exceeded the laboratory’s reportable range. Accurate cortisol levels were necessary to make the initial diagnosis and most importantly to monitor treatment. In order to avoid delays in diagnosis or treatment of patients with massively elevated cortisol levels, all vendors of cortisol assays should inform laboratories to reflexively perform a dilution in order to report accurate cortisol values to the physicians for optimum patient care.
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About the article
Published Online: 2017-06-23
Published in Print: 2017-11-27
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.