Journal of Postgraduate Medicine Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India ISSN: 0022-3859 EISSN: 0972-2823 Vol. 49, Num. 1, 2003, pp. 69-71

Journal of Postgraduate Medicine, Vol. 49, No. 1, Jan-March, 2003, pp. 69-71

Case Report

Relative Adrenal Insufficiency in Post-transplant Lymphoproliferative Disorder

Cinclair RD, Rice JC, Agraharkar M

Nephrology Division, Department of Medicine, 4.200 John Sealy Annex, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas, 77555-0562, USA.
Address for Correspondence: Mahendra Agraharkar, MD, Nephrology Division, Department of Medicine, 4.200 John Sealy Annex, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas, 77555-0562, USA E-mail: mlagraha@utmb.edu

Code Number: jp03013

Abstract:

Post-transplant lymphoproliferative disorder is treated with rapid decrement of immunosuppressive therapy. This cannot be achieved with ease in patients on long-term glucocorticoid therapy, as chronically suppressed adrenal glands may not be capable of mounting adequate response to stress. A 52-year-old Caucasian male presented with fever, orthostatic hypotension, lymphadenopathy and hyponatraemia. Serum cortisol levels were within normal levels with a sub optimal response to stimulation by ACTH. Hyponatraemia and orthostasis responded poorly to fluid restriction, saline and salt repletion but corrected after increasing the steroid dose. The normal baseline cortisol levels represented a stimulated adrenal gland, however, the ACTH stimulation had inadequate response. This sub optimal stimulation and a good response to increased steroids suggest the presence of relative or occult adrenal insufficiency. Relative adrenal insufficiency must be considered in patients who have received prolonged glucococorticoid therapy and have symptoms such as hypotension and/or hyponatraemia. (J Postgrad Med 2003;49:69-71)

Key Words: Relative adrenal insufficiency, Post transplant lymphoproliferative disorder, Hyponatraemia, Orthostatic hypotension, Lymphoma, Occult adrenal insufficiency.

Post-transplant lymphoproliferative disorder (PTLD) is likely to be due to chronic immunosuppression after a transplant surgery. It is treated with rapid tapering and subsequent discontinuation of the immunosuppressive therapy. However, the management of patients who have received prolonged corticosteroid therapy as a part of immunosuppression can be tricky. In these patients, the adrenal glands suppressed due to exogenous steroids cannot resume synthesis of steroids after rapid withdrawal. Furthermore, PTLD can induce stress that may necessitate increment in the dose of steroid therapy. We would like to share our experience of managing such a patient, who had symptomatic relative adrenal insufficiency with orthostatic hypotension and hyponatremia.

Case History

A 52 year-old Caucasian male presented with complaints of light-headedness, dizziness, fatigue, orthopnea, fever with sweating episodes, and excessive thirst for 4 weeks. He had received cadaveric renal transplant 13 years ago for end-stage renal disease (ESRD) secondary to Alport's Syndrome. The post-transplant course was complicated by development of multiple skin cancers. He was being treated with cyclosporine 200 mg/d, prednisone 5 mg/d and multivitamins. Prior to presentation to our centre, he was started on Fludrocortisone in the dose of 0.1mg/d for hypotension and prednisolone was increased to 15 mg per day. Physical examination was significant for a temperature of 38.0°C. His supine blood pressure was 110/70 mm Hg that dropped to 86/58 mm Hg upon standing. The pulse rate was 70 beats per minute, which increased to 96/min on standing. There were multiple scars over the skin that were related to multiple biopsies and excision procedures that the patient had undergone. A non-tender left posterior cervical lymph node (diameter 1.5 cm) was palpable. A viable arterio-venous fistula was noted in the left forearm. Abdominal examination revealed a non-tender graft in the right lower quadrant.

Initial laboratory examination revealed a white count of 9600/ml, haemoglobin of 13.6 g/dl, and a platelet count of 219,000/ml. Serum chemistries revealed sodium of 127 mmol/L; potassium, 4.6 mmol/L; chloride, 91 mmol/L; bicarbonate, 27 mmol/L; blood urea nitrogen, 38 mg/dl; creatinine, 1.9 mg/dl and glucose of 97 mg/dl. His urinalysis was unremarkable. The serum osmolality was 272 mOsm/kg H₂O and the urine osmolality was 491 mOsm/kg H₂O, with urine sodium of 24 mEq/L. Serum thyroid-stimulating hormone (TSH) was 2.74 mU/L. He tested negative for HIV antibodies, hepatitis B antigen and cytomegalovirus (CMV). The test for Epstein-Barr virus (EBV) was positive and was quantitated by polymerase chain reaction (PCR) at 1.7 million copies/ml. Microbiological cultures for blood and urine were sterile. Fine needle aspirate as well as excision biopsy of the lymph node were indicative of lymphoproliferative disorder of B-cell phenotype.

The patient and medical team chose to discontinue cyclosporine, and taper the dose of prednisone to 5 mg per day. His intermittent fever spikes subsided over several days, however his main problem of hyponatremia and hypotension persisted.

Initially, because of the low serum osmolality and high urine osmolality, the hyponatremia was considered to be due to the syndrome of inappropriate anti-diuretic hormone secretion (SIADH). Therefore, the initial restriction of fluid intake to 1500 ml per day was further enhanced and patient was allowed an intake of only 750 ml per day. For the next several nights patient had fever despite negative blood and urine cultures. As the patient continued to demonstrate hyponatremia and worsening of orthostatic hypotension, he was treated with saline infusion and access to water was liberalized. Within 48 hours, the serum sodium levels improved, although, he continued to have orthostatic hypotension. Rapid adrenocorticotropin (ACTH) test revealed a baseline cortisol level of 19.6 mg/dl. Therefore the diagnosis of adrenal insufficiency was thought unlikely. However, the 30-minute and 60-minute post ACTH stimulation revealed serum cortisol levels of 21.3 mg/dl and 22.8 mg/dl, respectively. An ultrasound of the abdomen and CT scan of the chest, abdomen, and pelvis demonstrated normal adrenal glands. The patient was prescribed salt tablets, which resulted in increased natriuresis of 230 mg/dl. When the dose of prednisone was increased to 25 mg/d, the symptoms gradually resolved with an increment of serum sodium to 136 mEq/L and normalizing the blood pressure to 116/ 73 mm Hg supine and 114/72 mm Hg standing with no significant change in pulse rate of 72 beats per minute to 76 beats per minute.

Discussion

The use of immunosuppressive agents has facilitated solid organ transplantation. However, their use has also resulted in the development of post-transplant lymphoproliferative Disorder (PTLD). The disorder is most common in the first year following a transplant procedure and the frequency decreases thereafter. Late presentation PTLD is known to be associated with a more severe and aggressive form of the disease. Many risk factors such as EBV seronegative recipient mismatch, use of biologic agents, such as OKT3, anti-lymphocyte globulin and anti-thymocyte globulin and CMV mismatch or symptomatic disease increase the risk of development of PTLD 5-20 fold.¹ The use of cyclosporine has also been identified as a potential risk factor. However, the use of any particular immunosuppressive agent is not as important as the entire cumulative dose of immunosuppression.⁷ PTLD may present with mononucleosis-like illness in primary EBV infected individuals, and presents as extra nodal tumours in single or multiple organs. About half of affected patients have extra-nodal disease. CNS disease and allograft involvement are two other common presentations.² Reduction or withdrawal of immunosuppressive therapy is the mainstay of treatment. Surgical resection, radiation therapy, and use of antiviral agents may provide some benefit.^3-5 Although immunosuppression reduction is often effective, mortality rates may still be as high as 50-80%, especially in patients with late presentation of PTLD.³

The hypothalamic-pituitary-adrenal (HPA) axis can be activated by severe illness, trauma, anaesthesia, hypotension, and surgery.^6,7 The maintenance of homeostasis and the general adaptation to stress are controlled by the HPA axis. Activation of this axis can be illustrated by increased concentrations of both corticotrophin and cortisol. Primary adrenal insufficiency can be defined as destruction of the adrenal cortex itself while secondary adrenal insufficiency is a result of damage to either the hypothalamus or the pituitary. Symptoms of chronic adrenal insufficiency may include fatigue, weakness, listlessness, orthostatic dizziness, weight loss, anorexia, abdominal cramping, nausea, vomiting, and diarrhea.⁶ Although a baseline cortisol value of 20 may rule out the diagnosis of adrenal insufficiency in a healthy patient, values within the normal range do not rule out adrenal insufficiency in an acutely ill patient.^7,8 A normal response to rapid ACTH test has been variously defined as a baseline serum cortisol level above 18-20 micrograms/dl or a serum cortisol level that rises by 7 micrograms/dl or to over 20 micrograms/dl at 30 or 60 minutes following a rapid ACTH test.^9,10 Normal serum cortisol concentration does not necessarily indicate the ability of serum cortisol levels to rise to 50 micrograms/dl at 5 hours and therefore avoid the consequences of adrenal insufficiency in the face of severe illness, surgery, infectious, or neoplastic disease.^11,12 A baseline cortisol level below 10 micrograms/dl need not be representative of hypofunction nor does a baseline cortisol level of 20 micrograms/dl represent adequate adrenocortical function.^13,14 A condition such as this may be defined as relative adrenal insufficiency, in which levels that are otherwise considered normal are insufficient for a severely ill patient.

This case illustrates the importance of detecting relative adrenal insufficiency as a cause of hypotension in an acutely ill transplant patient. Post-transplant hyponatraemia and unexplained hypotension in a transplant patient should alert the clinician about the possibility of relative adrenal insufficiency, which is comparatively easy to treat with.

Acknowledgement

The authors thank Dr. Karen Szauter for her help and guidance in preparing the manuscript.

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