Two cases of Cushing's disease are presented. In both cases successful treatment was followed by the development of a steroid-responsive disease condition, a seronegative arthritis in the first case and retinal vasculitis in the second. It is likely that both these conditions were unmasked by the fall in the endogenous steroid levels following the successful treatment of the Cushing's disease by trans-sphenoidal hypophysectomy.
- Cushing's disease
- retinal vasculitis
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Cushing's disease was first described by Harvey W Cushing1 in 1932, as a syndrome that results from long-term exposure to glucocorticoids. The term ‘Cushing’s disease' is reserved for Cushing's syndrome caused by excessive secretion of corticotropin by pituitary corticotroph tumours. The tumours are usually microadenomas (<1 cm in diameter)2-3; macroadenamas are rare, and corticotroph hyperplasia and carcinomas4-5 are extremely rare. Hypersecretion of corticotropin from corticotroph adenomas causes bilateral adrenocortical hyperplasia and the resulting hypercortisolaemia suppresses both corticotropin-releasing hormone secretion and the secretion of corticotropin by normal corticotrophs. We describe two cases of Cushing's disease successfully treated by trans-sphenoidal hypophysectomy which were followed by the unmasking of coincidental seronegative arthritis in one and retinal vasculitis in the other due to a fall in endogenous steroid production.
A 60-year-old woman presented with right leg cellulitis and gave a history of muscle weakness, hirsutism, excessive sweating and easy bruising. Examination revealed her to be grossly cushingoid with a buffalo hump, hirsutism, pigmentation, moon-face, gross proximal weakness, peripheral oedema and bruising of her arms and legs with marked skin fragility. Blood pressure was 120/70 mmHg. Her medical history included hypertension, which was treated with a combination of amiloride hydrochloride 2.5 mg and cyclopenthiazide 250 μg, and nephritis 49 years previously.
Investigations revealed 09.00 h cortisol of 850 and 750 nmol/l (reference range 200–700) and a midnight cortisol of 735 nmol/l (50–185) showing a loss of diurnal variation. Repeated 24-h urinary free cortisol were 760–935 nmol/24 h (50–250). High dose dexamethasone suppression test at 2 mg 6-hourly orally for 48 h suppressed her plasma cortisol to 245 nmol/l, suggesting pituitary-driven Cushing's disease. She was subsequently started on metyrapone 250 mg 4-hourly which was subsequently increased to 500 mg five times daily which suppressed her 24-h urinary free cortisol measurements to <50 nmol/24 h.
Magnetic resonance imaging (MRI) of her pituitary showed bilateral microadenomas and she was treated with trans-sphenoidal hypophysectomy. Immunocytochemistry showed selective adrenocorticotropin (ACTH) and synactophysin immunostaining, and negative staining for prolactin, thyroid-stimulating hormone (TSH), luteinising hormone (LH), follicle-stimulating hormone (FSH) and growth hormone. Following surgery she was initially treated with replacement therapy of thyroxine 100 μg daily together with hydrocortisone 20 mg in the morning and 10 mg in the evening. Subsequent 24-h urinary free cortisol measurement off hydrocortisone was 52 nmol/24 h and an insulin stress test showed a normal cortisol response with a basal value of 305 nmol/l rising to 600 nmol/l at 60 minutes (normal response >550). Growth hormone response remained suboptimal with baseline at 5.2 mIU/l showing no rise with hypoglycaemia. FSH was >40 IU/l (postmenopausal >40), LH 27 IU/l (postmenopausal >50), testosterone <0.7 nmol/l (adult females 0–2.8). Her thyroid function tests were normal off thyroxine with a TSH of 1.7 (0.5–4.7) and a free thyroxine of 13 pmol/l (9–24). Her thyroxine and hydrocortisone were subsequently stopped and endocrinologically her Cushing's disease remains in remission.
However, one month after her trans-sphenoidal hypophysectomy she complained of pains in her elbows, knees and the small joints of her hands. An autoantibody screen was negative but erythrocyte sedimentation rate was elevated at 98 mm/h. X-Ray of her hands showed joint erosions of the fifth distal interphalangeal joints bilaterally and she was diagnosed as having a seronegative arthritis, which was treated with non-steroidal anti-inflammatory drugs. It was thought that her arthritis had been unmasked with the fall in her endogenous steroid production following the treatment of her Cushing's disease.
A 48-year-old non-insulin-dependent diabetic patient, on insulin treatment, presented with proximal muscle weakness. He was cushingoid with moon-facies, central obesity and had wasting and weakness of shoulder and pelvic girdle muscles. Fundoscopy showed bilateral background diabetic retinopathy and right-sided maculopathy. Electromyographic studies did not show any evidence of diabetic polyneuropathy.
24-Hour urinary free cortisol was markedly high at 515 nmol/24 h (50–250). Low dose dexamethasone suppression test failed to suppress cortisol levels and 09.00 h cortisol on the third day was 445 nmol/l. ACTH levels fell from 14 to less than 5 ng/l, after a high dose dexamethasone suppression test, indicating pituitary origin of the Cushing's disease. Venous petrosal sinus sampling was performed. Three samples taken from the left inferior petrosal vein demonstrated ACTH levels in excess of 800 in all three samples compared with levels of 25 and 380 obtained on two samples from the right inferior petrosal vein. MRI scan of the pituitary showed a small non-enhancing cystic lesion in the left side of the gland and a computed tomography (CT) scan of the abdomen showed enlarged adrenal glands bilaterally.
The patient was commenced on metyrapone awaiting trans-sphenoidal surgery. After the surgery his insulin requirements fell and he was commenced on hydrocortisone 20 mg in the morning and 10 mg in the evening. One month after the surgery, the patient presented to an ophthalmologist with central deterioration of vision in his right eye, inability to focus and blurring of vision. Fundoscopy showed papilloedema of the right optic disc and a diagnosis of retinal vasculitis was made. A repeat CT scan of the head did not reveal any intracranial lesion. An autoantibody screen was negative. The dose of steroids was increased but unfortunately the patient developed optic nerve atrophy.
In both of the cases presented, a steroid-responsive condition was unmasked as the patients endogenous steroid levels fell. The presence of joint erosions in our first patient indicate that her arthritis was long-standing but remained sub-clinical because of her high levels of endogenous steroids secondary to Cushing's disease and it became clinically apparent only after the successful treatment of her Cushing's disease with a resultant fall in endogenous steroid production. However, the arthritis did not manifest itself following metyrapone treatment, presumably because of the short time interval prior to surgery. She undoubtedly had both diseases at the same time, the arthritis becoming clinically apparent only after the fall in her endogenous steroid levels. Despite the well known anti-inflammatory properties of corticosteroids, their role in the management of inflammatory arthritides remains controversial, partly because of the relatively high doses needed and its antecedent side-effects. The results of the Arthritis and Rheumatism Council Low Dose Glucocorticoid Study Group6 clearly demonstrated that 7.5 mg of prednisolone daily in early rheumatoid arthritis halved the rate of onset and progress of erosions.
In our second case, the patient developed retinal vasculitis for the same reason, ie, a fall in endogenous steroid levels following successful treatment of Cushing's disease by trans-sphenoidal hypophysectomy. The development of optic nerve atrophy was thought to be due to the vasculitis affecting the blood supply of the optic nerve. It is difficult to determine whether the vasculitis was long standing, masked by the high endogenous steroid levels, or developed following a fall in the steroid levels after hypophysectomy. The aetiology of the vasculitis in our patient is also a matter of speculation, as it was not investigated thoroughly. The most common manifestations of retinal vasculitis are listed in the box.7 8 Less commonly, it presents with no associated systemic disease or concomitant ocular disease. The posterior segment findings in retinal vasculitis are vascular sheathing, retinal neovascularization, attenuated vessels, intraretinal haemorrhage, vascular occlusion and vitreous haemorrhage.9
Retinal vasculitis: common manifestations
systemic lupus erythematosus
Cushing's disease is uncommon but it may mask more common co-existing steroid-responsive conditions. Many patients with treated Cushing's disease complain of generalised ill health associated with a fall in endogenous steroid levels and it is important to investigate these complaints fully rather than assuming them to be due to steroid withdrawal.
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