A 67-year-old woman undergoes treatment for an autonomously functioning thyroid nodule. Around this time, she begins to feel increasingly unwell with new hypertension, palpitations and dizziness. She is rendered euthyroid, however presents 2 months following radioiodine ablation with left-sided chest pain, dyspnoea, fatigue, peripheral oedema and productive cough for green sputum. She has also developed progressive proximal myopathy and noticeably thin skin with worsening ecchymoses. Biochemistry reveals intermittent but spontaneous hypernatraemia and hypokalaemia. CT chest reveals cavitating left-sided pneumonia. Stenotrophomonas maltophilia and aspergillus fumigatum are isolated. Lung Biopsy is consistent with pneumonia without features to suggest malignancy. She is treated with directed antimicrobial therapy and is left to continue a course of voriconazole for presumed aspergilloma. A course of prednisolone therapy is also prescribed for possible allergic bronchopulmonary aspergillosis, although testing for this later returned negative.
2 weeks into the subsequent rehabilitation stay, she returns to hospital with severe epigastric pain. Investigation reveals a 7cm pancreatic pseudocyst secondary to presumed pancreatitis however with a normal serum lipase. For ongoing epigastric pain and anorexia with early satiety, therapeutic aspiration under endoscopic ultrasound is performed. Cytology is negative for malignancy. Prednisolone is inadvertently but fortunately withheld during this readmission and serum cortisol is performed to exclude hypothalamic-pituitary-adrenal axis suppression. It is > 1750 nmol/L and leads to endocrinology involvement for probable Cushing’s syndrome. Cushing’s syndrome is confirmed with elevated 24 hr urine free cortisol and 1mg dexamethasone suppression test (DST) that fails to suppress, serum cortisol 1036 nmol/L. Cyclic Cushing’s syndrome is demonstrated with four peaks and three troughs in cortisol production noted over a four-week period. Serum ACTH is elevated whilst hypercortisolaemic, confirming ACTH-dependent disease. 8mg DST fails to suppress the serum cortisol, 1088 nmol/L. Peripheral CRH stimulation test results in a 22% rise in serum cortisol with no rise in serum ACTH. Although the 8mg DST and CRH stimulation testing favour an ectopic source, MRI Pituitary however, reveals a 4.7mm pituitary microadenoma. Bilateral inferior petrosal sinus sampling achieved successful radiological catheterisation but fails to show an adequate prolactin gradient to verify pituitary venous effluent. Peak central-peripheral ACTH gradient measured 1.19 prior to administration of ACTH and only 1.25 following. The prolactin-normalised ACTH central-peripheral ratio was 1.23. Localisation studies are performed alongside the aforementioned investigations and are unable to reveal a source of potential ectopic ACTH. Investigation included but was not limited to DOTATATE PET/CT and FDG-PET imaging.
During the extensive work up, the patient experienced worsening features of Cushing’s syndrome. Pertinent challenges were that of progressive myopathy, and hypokalaemia despite the use of spironoIactone and oral potassium supplementation. In view of severe biochemical hypercortisolism, the rapidly advancing clinical phenotype and somewhat equivocal testing, ketoconazole was commenced with a view to bilateral adrenalectomy. Use of ketoconazole was met alternating adrenal insufficiency requiring glucocorticoid replacement and hypercortisolism due to extremely short peaks and troughs in cortisol production.
The patient has undergone bilateral adrenalectomy for definitive management of hypercortisolism. Surgery has been complicated by likely remnant adrenocortical tissue with biochemical evidence of endogenous cortisol secretion albeit less severe than previously. Clinical state remains preoccupied by a post-operative pancreatic leak requiring ongoing surgical intervention. Following a period of recovery, it is planned to recommence ketoconazole and consider the use of mitotane in further management of her Cushing’s syndrome.
Discussion:
Cushing’s Syndrome (CS) is associated with significantly increased mortality and morbidity. Majority of cases are ACTH-dependent with the bulk accounted for by Cushing’s Disease (CD). Ectopic ACTH secretion (EAS) is by comparison far less common. Distinguishing the two is essential as optimal outcomes are achieved only with directed management. Transphenoidal resection of an ACTH-secreting pituitary adenoma is the treatment of choice in CD. EAS is managed with excision of a culprit tumour, however medical therapy or bilateral adrenalectomy may need consideration in patients with occult disease which may occur in up to 17%.
Distinguishing EAS from CD can be challenging. High dose DST, CRH stimulation, Desmopressin, Combined CRH-Desmopressin are all dynamic tests that may discriminate between the two but none of these tests is infallible. Bilateral inferior petrosal sinus sampling (BIPSS) is considered the gold standard to distinguish EAS from CD, however false negatives have been described in CD usually relating to anomalous venous drainage or lack of expertise. False positives may be seen with cyclic and CRH-secreting EAS. Radiologically successful catheterisation is established by demonstrating retrograde flow of contrast into the contralateral cavernous sinus. Prolactin (PRL) levels have also been measured to improve diagnostic accuracy of BIPSS. Baseline central-peripheral PRL gradient > 1.8, is considered to represent successful sampling. Venous anomalies however may account for the absence of a prolactin gradient, and there is data that a prolactin-normalised ACTH central-peripheral ratio may be helpful in such cases. Ratios > 1.3 have been suggestive for CD, < 0.8 for EAS and those in between being indeterminate, however further prospective study is required.
Cyclic CS may account for false positives at BIPSS, when sampling is performed during a period of spontaneous remission of hypercortisolism. EAS has been reported to account for 26% of cyclic CS indicating a higher prevalence in cyclic CS than in all CS. Medical management of hypercortisolism in cyclic CS may encounter adrenal insufficiency during troughs in cortisol production, a challenging issue when cycle lengths are as short as in our case.
Bilateral adrenalectomy (BLA) is considered an effective and sometimes essential treatment option in selected patients with CS. It offers immediate control of hypercortisolism and is typically used in cases refractory to other medical options as it is not without significant risk. Median 30-day mortality has been reported as 3% with considerably higher rates in EAS than CD. Cardiovascular events and infection are leading causes of early death following BLA. Total mortality is also high with median mortality rate of 17% at 41 months follow up and again much higher rates are seen in EAS. Although laparoscopic approach is associated with improved morbidity, it has not demonstrated any mortality benefit. Despite the goal of serum cortisol levels falling to undetectable following BLA, persistent endogenous cortisol secretion is described in up to 34% of cases. Majority of these cases have adrenal remnants or ectopic adrenal tissue identifiable on imaging or further surgical exploration. Ectopic adrenal tissue has been described in retroperitoneal fat, gonads and mediastinum. Although persistent endogenous cortisol secretion may be encountered, few cases develop relapse of CS with clinical signs of hypercortisolism. Whilst BLA carries real risk, this must be weighed against the dismal prognosis of otherwise untreated CS.
CS poses significant diagnostic and management challenges. The rarity of the disease and particular aetiology such as EAS means that an individualised approach discussed in a multidisciplinary setting is essential to patient care. In some instances, definitive strategies for hypercortisolism will be required prior to extensive and sometimes time consuming investigation but the risks and benefits can only be considered on a case by case basis.
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